2- Vinyl Indoles, Pyrido and Azepino Indole Derivatives, 2-Alkynyl Indoles, 2- Alkynyl Benzo[Z»|furans, Their Precursors and Novel Processes for the Preparation Thereof

Cross-reference to Related Application

This application claims priority from U.S. Provisional Application Serial No. 60/802,801, filed May 24, 2006.

1. Field of the Invention

The present invention relates to novel processes for the preparation of indole compounds, in particular to 2-vinyl indoles, pyrido and azepino derivatives, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-vinyl indoles from ortho-gem- dibromovinylaniline compounds and alkene reagents using a palladium pre- catalyst, a base, and, in some instances, a ligand or additive. The present invention also relates to the preparation of pyrido and azepino derivatives via a palladium-catalyzed tandem intramolecular Buchwald-Hartwig amination and Heck coupling reaction of appropriately functionalized ortho-gem- dibromovinylanilines. The invention also relates to processes for the production of or/Aø-gem-dibromovinylanilines which are useful as starting materials in the production of 2-vinyl indoles, pyrido and azepino derivatives, and novel compounds prepared by these processes.

The present invention also relates to novel processes for the preparation of indole compounds, in particular to 2-alkynyl indoles, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-alkynyl indoles from ortho-gem- dibromovinylaniline compounds, which can be synthesized using above

mentioned processes, and alkyne reagents using a palladium pre-catalyst, a copper pre-catalyst, a base, and a ligand.

The present invention also relates to novel processes for the preparation of benzo[6]furan compounds, in particular to 2-alkynyl benzo[ό]furans, which may be optionally substituted at other positions on benzo[ό]furan ring, compounds prepared by such processes, and their synthetic precursors. More particularly, the present invention relates to the preparation of 2-alkynyl benzo[ό]furans from ørtλø-gem-dibromovinylphenol compounds and alkyne reagents using a palladium pre-catalyst, a copper pre-catalyst, a base, and a ligand. The invention also relates to processes for the production of ortho-gem -dibromovinylphenols which are useful as starting materials in the production of 2-alkynyl benzo[5]furans, and novel compounds prepared by these processes.

2. Brief Description of the Related Art.

Numerous processes have been developed for the synthesis of 2-vinyl indoles and derivatives thereof, several of which are shown below with the reported yields for the preparation of various 2-vinyl indoles.

To date, many of the prior art processes are reported to have numerous drawbacks such as being inefficient, requiring multiple steps, requiring commercially unavailable or expensive starting materials, requiring the use of harsh reaction conditions, and/or are challenging to adapt to an industrial scale. Moreover, direct methodologies to synthesize 2-vinyl indoles are rare; usually pre-functionalized indoles are required. A general description of several prior art processes is set out below in Schemes 1-14, additional details of which are set out in the references as indicated.

2-vinyl indoles have been prepared using Wittig related olefination reactions (Scheme 1) on 2-formyl- or 2-ketoindoles (Eitel, M.; Pindur, U. Synthesis 1989, 364; Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Conzalez-Perez, P.; Perez-Castells, J. Synthesis 2002, 1810) and by treatment of indol-2-

ylmethyltriphenylphosphorane or diethylphosphonates with carbonyl compounds (Nagarathnam, D. Synthesis 1992, 743 and references cited therein).

Scheme 1

R = PPh ₃ Br ^" R = PO(OR) ₂

Direct formation of 2-vinyl indoles also occurring via a Wittig reaction (shown in Scheme 2) has been reported to have occurred intramolecularly (Eitel, M.; Pindur, U. Synthesis 1989, 364 and references cited therein).

Scheme 2

Hetero-Cope rearrangement has been shown to provide short and stereoselective syntheses of 2-vinyl indoles by a tandem process involving a N- phenylhydroxylamine, aldehyde and electron deficient allene (Wilkens, J.; Kuhling, A.; Blechert, S. Tetrahedron 1987, 43, 3237; Blechert, S. Synthesis 1989, 71; Scheme 3).

Scheme 3

36-77%

A synthesis of N-hydroxy 2-vinylindoles (Scheme 4) has been realized via the cyclization of allyl nitroaryl acetonitriles (Wrobel, Z., Makosza, M. Synlett 1993, 597).

Scheme 4

A two step synthesis of 2-vinyl indoles has also been described. Reaction of the anions of methyl indole carboxylates with ketone or aldehyde derivatives leads directly to 2-vinyl indoles as shown in Scheme 5 (Macor, J. E., Newman, M. E.; Ryan, K. Tetrahedron Lett. 1989, 30, 2509).

Scheme 5

33-99%

A palladium-catalyzed intermolecular alkenylation of indoles is shown in Scheme 6. The regioselectivity of the reaction is dependant on the choice of solvent (Grimster, N. P.; Gauntlett, C; Godfrey, C. R. A.; Gaunt, MJ. Angew. Chem. Int. Ed. 2005, 44, 3125; see also: Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854; Lu, W.; Jia, C; Kitamura, T.; Fujiwara, Y. Org. Lett. 2000, 2, 2927; Itahara, T.; Ikeda, M.; Sakakibara, T. J. Chem. Soc. Perkin Trans. / 1983, 1361).

Scheme 6

62-91 % 51 -57%

Another way to produce 2-vinyl indoles is via a Stille cross-coupling reaction between 2-halo indole and vinyl stannane (Scheme 7) (Somei, M.; Sayama, S.; Naka, K.; Yamada, F. Heterocycles 1988, 27, 1988; Beccalli, E. M.; Marchesini, A. Tetrahedron 1995, 51, 2353) or between 2-stannyl indole and vinyl halide (Hudkins, R. L.; Dielbold, J. L.; Marsh, F. D. J. Org. Chem. 1995, 60, 6218).

Scheme 7

X, Y = halogen or SnR ₃

A radical cyclization of 2-alkenylphenyl isocyanide (Scheme 8) provides access to 2-stannyl indoles as intermediates which can be readily converted to 2-vinyl indoles by a palladium-mediated cross-coupling reaction in a one-pot procedure (Tokuyama, H.; Kaburagi, Y.; Chen, X., Fukuyama, T. Synthesis 2000, 429; Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127).

Scheme 8

Also reported by Fukuyama, T. and coworkers is a similar type of cyclization using a Heck cross-coupling reaction or Stille cross-coupling reaction in one pot or by isolating the 2-iodo indole intermediate. (Scheme 9, Tokuyama, H.; Kaburagi, Y.; Chen, X., Fukuyama, T. Synthesis 2000, 429).

Scheme 9

Annulation of 2-alkynylanilines catalyzed by gold (III) (Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 610) or palladium (II) (Cacchi, S.; Carcicelli, V.; Marinelli, F. J. Organomet. Chem. 1994, 475, 289) affords 2-vinyl indoles (Scheme 10).

Scheme 10

Having regard to the synthesis of pyrido indoles, one group has reported a synthesis from 2-iodoindole by an intramolecular Heck reaction, as shown in Scheme 11, (Germain, A. L.; Gilchrist, T. L.; Kemmitt, P. D. Heterocycles 1994, 37, 697; Gilchrist, T. L.; Kemmitt, P.D. Tetrahedron 1997, 53, 4447).

Scheme 11

Pyrido and azepino indoles have also been prepared by Ring Closing Metathesis of conveniently functionalized substrates catalyzed by Grubb's ruthenium catalyst (Scheme 12) (Conzalez-Perez, P.; Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Perez-Castells, J. Tetrahedron Lett. 2002, 43, Al 61).

Scheme 12

A Dieckmann approach (Scheme 13) was used to prepare pyrido and azepino indoles in two steps from 2-carboxylate indoles (Bit, R. A.; Davis, P. D.; Hill, C.H.; Keech, E.; Vesey, D. R. Tetrahedron 1991, 47, 4645).

Scheme 13

A intramolecular combination of a [Cp ₂ TiMe ₂ ]-catalyzed hydroamination of alkynes with Pd-catalyzed N-arylation of an imine results in synthesis of pyrido indoles (Scheme 14, Siebeneicher, H.; Bytschkov, L; Doye, S. Angew. Chem. Int. Ed. 2003, 42, 3042).

Scheme 14

In view of the above, there remains a need for novel and versatile processes for synthesizing 2-vinyl indole compounds, pyrido-indoles, azepino-indoles and derivatives. The development and implementation of such processes could simplify the preparation of commercially important indole compounds.

One such commercially important indole containing a 2-vinyl substitution is the lipid metabolism regulator fluvastatin (sold as Lescol ^® ), the structure of which is shown below in its sodium salt form:

Fluvastatin is currently sold as a racemate of two erthryo enantiomers of which one exerts the pharmacological activity. Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form (Compendium of Pharmaceuticals and Specialities (CPS), 2005, 40 ^th Edition, Canadian Pharmacists Association). Synthetic methods exist for the synthesis of the racemic version of the drug (Repic, O.; Prasad, K.; and Lee, G. T. Organic Process Research & Development 2001, 5, 519-527), however, processes for making the enantiopure drug are highly desired.

Another important indole containing a 2-vinyl substitution is the following potent and selective inhibitor of the osteoclatic Vacuolar H+-ATPase named SB-242782 (Farina, C; Gagliardi, S.; Nadler, G. M. PTC Int. Appl. WO 9801113 Al 19980115, Smithkline Beecham, 1998; Nadler, G.; Morvan, M.; Delimoge, L; Pietro, B.; Zocchetti, A.; James, L; Zembryki, D. Bioorganic & Medicinal Chemistry Letters 1998, 8, 3621; Visentin, L.; Dodds, R. A.; valente, M.; Misiano, P.; Bradbeer, J. N.; Oneta, S.; Liang, X.; Gowen, M.; Farina, C. Journal of Clinical Investigation 2000, 106, 309; Price, P.A.; June, H. H.; Buckley, J. R.; Williamson, M. K. Circulation Reasearch 2002, 91, 547; Whyteside, G.; Meek, P.J.; Ball, S. K.; Dixon, N.; Finbow, M. E.; Kee, T. P.; Findlay, J.B.C.; Harrison, M. A. Biochemistry 2005, 44, 15024):

Methods for synthesizing SB-242782 are known in the art and provide the desired compound (Conde, J. J.; .McGuire, M.; Wallace, M. Tetrahedron Lett. 2003, 44, 3081; Yu, M.S.; Lopez de Leon, L.; McGuire, M.A.; Botha, G. Tetrahedron Lett. 1998, 39, 9347). The presently published synthesis suffers from linearity and the synthesis is relatively long; with the new methodology of the present invention, it is envisioned that SB-242782 can be obtained in fewer steps with a convergent synthesis.

2-vinylindoles have proven to be versatile dienes in Diels- Alder reactions aiming at regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest, both in inter- and intramolecular reactions (for reviews, see: Pindur, U. Heterocycles 1998, 27, 1253; Pindur, U. In Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; Cycloaddition Reaction of Indoles Derivatives; JAI Press: Greenwich, 1995; Vol. 1 , p 121 ; Sundberg, R.In Best Synthetic Methods, Sub-series Key Systems and Functional Group; Meth-Cohen, O., Ed. Indoles; Academic Press: London, 1996; p 159). The carbazole ring is the core of a wide range of alkaloids, and therefore is a very important building block in the synthesis of pharmacologically active compounds.

Numerous processes have been developed for the synthesis of 2-alkynyl indoles and derivatives thereof, several of which are shown below with the reported yields for the preparation of various 2-alkynyl indoles.

To date, many of the prior art processes are reported to have numerous drawbacks such as being inefficient, requiring multiple steps, requiring commercially unavailable or expensive starting materials, requiring toxic reagents, requiring the use of harsh reaction conditions, and/or are challenging to adapt to an industrial scale. Moreover, direct methodologies to synthesize 2-alkynyl indoles are rare;

usually pre-functionalized indoles are required. A general description of several prior art processes is set out below in Schemes 15-21, additional details of which are set out in the references as indicated.

Sonogashira coupling reaction of 2-haloindoles with terminal alkynes have been reported to synthesize 2-alkynyl indoles. (Zhang, H.; Larock, R. C J Org. Chem., 2002, 67, 7048; Scheme 15)

Scheme 15

Sonogashira coupling reaction with (2-trifluoromethanesulfonyloxy)indoles and terminal alkynes has also been reported. (Elisabetta, R.; Giorgio, A.; Valentina, C; Giuseppe, C; Elsa, M. Synthesis., 2006, 2, 299; Scheme 16)

Scheme 16

2-Alkynyl indoles have been prepared using Stille coupling reaction (Scheme 17) with 2-bromoindoles (Eitel, M.; Pindur, U. J. Heterocyclic Chemistry 2006, 43, 701; Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Conzalez-Perez, P.; Perez-Castells, J. Synthesis 2002, 1810) and by treatment of 1-bromo-l -alkynes with 2-stannylindoles (Nagarathnam, D. Synlett 1993, 771 and references cited therein).

Scheme 17

A five-step transformation from a 2-methoxycarbonyl indole to a 2-alkynyl indole has also been reported. In this case, a 2-dibromovinylindole was prepared from the corresponding ester derivative in three steps. Then the 2-dibromovinylindole was converted to the 2-ethynylindole using first potassium tert-amylate and then dimethyl phosphate as shown in Scheme 18 (Thottathil, J. K., Li, W. S. US patent 5298625, 1994).

Scheme 18

A direct formation of 2-vinyl indoles using low-valent titanium has been reported (Furstner, A.; Ernst, A.; Krause, H.; Ptock, A. Tetrahedron 1996, 52 7329; Scheme 19).

Scheme 19

A 2-alkynylindole is used as a pivotal intermediate during the synthesis of SB- 242782 (referenced above). It was achieved by a cross-coupling process via an organotin intermediate as well as by a reduction-isomerization sequence (Conde, J. J.; McGuire, M.; Wallace, M. Tetrahedron Lett. 2003, 44, 3081; Scheme 20).

Scheme 20

2-alkynyl indoles have also played important roles as key intermediates for the synthesis of natural products. Fukuyama, T. and coworkers achieved the total synthesis of (-)-Aspidophytine using an 2-alkynylindole as a key intermediate. This intermediate is obtained by a Sonogashira coupling between a terminal alkyne and an 2-iodoindole which was prepared from vanillin in 11 steps (Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59, 8571; Scheme 21).

Scheme 21

In view of the above, there remains a need for novel and versatile processes for synthesizing 2-alkynyl indole compounds and derivatives. The development and implementation of such processes could simplify the preparation of pharmaceutically important indole containing compounds and provide rapid access to a new class of indoles exhibiting broad pharmacological properties.

One such important indole containing a 2-alkynyl substitution is the lipid metabolism regulator SQ-33600, the structure of which is shown below in its sodium salt form (Karanewsky, D. S.; Badia, M. C; Adams, B. C; Michael, G. E.; Joseph, S. M.; DE 3817298 Al 19881201, Bristol-Myers Squibb, 1988; Karanewsky, D. S.; Badia, M. C; Ciosek, C. P. Jr; Robl, J. A.; Sofia, M. J.; Simpkins, L. M.; DeLange, B.; Harrity, T. W.; Biller, S. A.; Gordon, E. M. J. Med. Chem. 1990, 33, 2952; Jagoda, E.; Stouffer, B.; Ogan, M.; Tsay, H. M.; Turabi, N.; Mantha, S.; Yost, F.; Tu, J. I. Therapeutic Drug Monitoring 1993, 15, 213);

Methods for synthesizing SQ-33600 are known in the art and provide the desired compound (Karanewsky, D. S.; Badia, M. C; Ciosek, C. P. Jr; Robl, J. A.; Sofia,

M. J.; Simpkins, L. M.; DeLange, B.; Harrity, T. W.; Biller, S. A.; Gordon, E. M.

J. Med. Chem. 1990, 33, 2952). The presently published synthesis suffers from

linearity and the synthesis is relatively long; with the new methodology of the present invention, it is envisioned that SQ-33600 can be obtained in fewer steps with a convergent synthesis.

Regarding 2-alkynyl benzo[&]furans and derivatives, there have not been many reports on the processes for the synthesis of such compounds. Some representative examples of these are shown below in Schemes 22-26 with the reported yields for the preparation of various 2-vinyl benzo[6]furans. Additional details are set out in the references as indicated.

In addition, some of the prior art processes have been reported to have numerous drawbacks, such as a narrow scope, being inefficient, requiring multiple steps, requiring commercially unavailable or expensive starting materials, requiring the use of harsh reaction conditions, and/or are challenging to adapt to an industrial scale. Moreover, direct methodologies to synthesize 2-alkynyl benzo[Z>]furans are rare; usually pre-functionalized benzo[6]furans are required.

Sonogashira coupling reaction of 2-halobenzo[6]furans with terminal alkynes has been reported to synthesize 2-alkynyl benzo[6]furans. (Bach, T.; Bartels, M. Synlett, 2001, 8, 1284; Scheme 22)

Scheme 22

2-Ethynylbenzo[ό]furan has been prepared by a coupling of 2-iodobenzo[ό]furan with ethynylzinc bromide. (Negishi, E.; Xu, C; Kotora, M.. Heterocycles, 1997, 46, 209; Scheme 23)

Scheme 23

72%

Generation of an 2-iodobenzo[&]furan has been reported using intermolecular anionic cyclization of ø-cinnamyloxybenzylideneamines even though in low yield. (Tsuge, O.; Ueno, K.; Oe, K. Chem. Lett., 1981, 135; Scheme 24)

Scheme 24

The two-step synthesis of a benzo[ό]furandiyne has been conducted from 1,2- diformylbenzo[ό]furan. (Sahu, B.; Namboothiri, I. N. N.; Persky, R. Tetrahedron. Lett., 2005, 46, 2593; Scheme 25)

Scheme 25

The reaction of 2-lithiobenzo[&]furan with phenylethynyl- IH-1, 2,3 -benzotriazole derived from benzoyl chloride in three steps has been reported to give 2- phenylethynylbenzo[6]furan. (Sahu, B.; Namboothiri, I. N. N.; Persky, R. Tetrahedron. Lett., 2005, 46, 2593; Scheme 26)

Scheme 26

In view of the above, there remains a need for novel and versatile processes for synthesizing 2-alkynyl benzo[ό]furan compounds and derivatives. The development and implementation of such processes could simplify the preparation

of pharmaceutically important benzo[Z>]furan containing compounds and provide rapid access to a new class of indoles exhibiting broad pharmacological properties.

Summary of the Invention

The present invention provides novel and versatile processes for synthesizing 2- vinyl indole compounds, pyrido-indoles, azepino-indoles and derivatives. As aforementioned, it is envisioned that these processes may be used in the preparation of commercially important indole compounds.

Included in the scope of the invention is a process for the preparation of 2-vinyl indole compounds, hi particular, in one aspect, the invention provides a process for the preparation of a compound of Formula (I):

(I)

wherein

each Ri is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , -C(0)NR ^* ₂ , - NR ^* C0-R ^* , -NR ^* COO-R ^* , -NR ^* C0NR ^* wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R _a , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R ^* are unsubstituted or substituted;

R ₂ is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;

the process comprising reacting an ort/zo-gem-dibromovinylaniline compound of Formula (II)

wherein Rj and R ₂ are as defined above,

with an alkene Heck acceptor of the Formula (III)

(III)

wherein R ₃ is selected from the group comprising alkyl; lower alkyl-hydroxy; lower alkyl-O-R _b wherein R _b is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R ^** , - C(O)OR ^** , -C(O)NR ^** ₂ , -SO ₂ R ^** , -SO ₂ MT ₂ , lower alkyl-CO-R ^** , lower alkyl-CO- OR ^** , lower alkyl-C(O)NR ^** ₂ , lower alkyl-NR ^** CO-R ^* \ lower alkyl-NR ^** COO-R ^** wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl, and where R ₃ is -C(0)NR ^** ₂ both R ^** groups may form a heterocyclic ring with the nitrogen atom; and each of R ₃ and R" are unsubstituted or substituted;

in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (I).

In another aspect, the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:

It is expected that the 2-vinyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest.

In another aspect, the invention provides an improved process for the preparation of a compound of the following Formula (II)

(II)

wherein

each Ri is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , - C(O)NR ^* ₂ , -NR ^* C0-R ^* , -NR ^* C00-R ^* , and -NR ^* C0NR ^* , wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R _a , wherein R ₃ is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the phenyl ring; wherein n ¹ is a whole integer from 1 to 4; and each of Ri and R ^* are unsubstituted or substituted;

and R ₂ is H;

comprising reaction of a compound of Formula (VI)

(Vl)

with CBr ₄ and P(OR) ₃ , wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, to form a compound of Formula (VII)

isolating the compound of Formula (VII), and reducing the compound of Formula (VII) to obtain the compound of Formula (II).

In another aspect, the invention provides novel σrt/jo-gem-dibromovinylaniline compounds or salts thereof selected from the group consisting of:

These derivatives are useful in the preparation of the desired 2-vinyl indole compounds.

In yet another aspect, the invention provides a process for the preparation of a c -o i:mpound of Formula (IV) and/or Formula (IV)'

wherein

each R ₄ is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , -C(0)NR ^* ₂ , -

NR ^* C0-R ^* , -NR ^* C00-R ^* , -NR ^* CONR ^* wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR ₂ , wherein

R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of R» and R ^* are unsubstituted or substituted;

the process comprising reacting an ørt/zo-ge/M-dibromovinylaniline compound of Formula (V):

wherein R ₄ is as defined above, n is 0 to 3,

and R ₅ is selected from the group comprising H, lower alkyl; lower alkyl- hydroxy; lower alkyl-O-R _b wherein R _b is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; - C(O)R ^** , -C(O)OR ^** , -C(0)NR ^** ₂ , -SO ₂ R ^** , -SO ₂ NR ^** ₂ , lower alkyl-CO-R ^** , lower alkyl-CO-OR ^** , lower alkyl-C(O)NR ^** ₂ , lower alkyl-NR ^** CO-R", lower alkyl- NR ^** COO-R ^** wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R ₅ and R" are unsubstituted or substituted;

in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (IV) and/or Formula (IV)'.

In yet another aspect, the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:

These compounds are useful in the preparation of the compounds of Formulas (IV) and (IV)'.

The present invention also provides novel and versatile processes for synthesizing 2-alkynyl indole compounds. As aforementioned, it is envisioned that these processes may be used in the preparation of pharmaceutically important indole compounds.

Included in the scope of the invention is also a process for the preparation of a compound of Formula (VIII):

wherein

each R] is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , - C(0)NR ^* ₂ , -NR ^* C0-R ^* , -NR ^* C00-R ^* , and -NR ^* C0NR ^* , wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R _a , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R ^* are unsubstituted or substituted;

R ₂ is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;

the process comprising reacting an ortho-gem-dibromovinylaniline compound of Formula (II)

wherein Rj and R ₂ are as defined above,

with an alkyne of the Formula (IX)

(IX)

wherein Rg is selected from the group comprising -SiR ¹ R ¹¹ R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O- R _b wherein R _b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R ^** , lower alkyl-CO-OR' ^* , lower alkyl-C(O)NR" ₂ , lower alkyl-NR"CO-R'\ lower alkyl-NR ^** COO-R ^** wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R" are unsubstituted or substituted;

in the presence of a base, a palladium metal pre-catalyst, a copper metal pre- catalyst and a ligand to form the compound of Formula (VIII).

In another aspect, the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:

It is expected that the 2-alkynyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [ό]annulated indole derivatives of pharmacological interest.

The present invention also provides novel and versatile processes for synthesizing 2-alkynyl benzo[ό]furan compounds. As aforementioned, it is envisioned that these processes may be used in the preparation of pharmaceutically important benzo[&]furan compounds.

Included in the scope of the invention is also a process for the preparation of 2- alkynyl benzo[ό]furan compounds, hi particular, in one aspect, the invention provides a process for the preparation of a compound Formula (X):

(X)

wherein

each R ₆ is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , - C(0)NR ^* ₂ , -NR ^* C0-R ^* , -NR ^* C00-R ^* , and -NR ^* CONR ^* , wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR ₃ , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of Re and R ^* are unsubstituted or substituted;

and R ₉ is H or lower alkyl;

the process comprising reacting an ortho-gem-dibromovinylphenol compound of Formula (XI)

wherein R ₆ and R ₉ are as defined above,

with an alkyne of the Formula (IX)

= — 1 (IX)

Rs is selected from the group comprising -SiR ¹ R ¹¹ R'" wherein R ¹ , R", and R ¹ " are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl -hydroxy; lower alkyl-O-R _b wherein R _b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R", lower alkyl- CO-OR ^** , lower alkyl-C(O)NR ^** ₂ , lower alkyl-NR ^** CO-R ^* \ lower alkyl- NR ^** COO-R ^** wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R ^** are unsubstituted or substituted;

in the presence of a base, a palladium metal pre-catalyst, a copper metal pre- catalyst and a ligand to form the compound of Formula (X).

In another aspect, the invention provides novel 2-substituted benzo[&]furans or salts thereof selected from the group consisting of:

It is expected that the 2-alkynyl benzo[6]furan compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of benzo[ό]furan derivatives of pharmacological interest.

In another aspect, the invention provides an improved process for the preparation of a compound of the following Formula (XI)

wherein

each R ₆ is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , - C(0)NR ^* ₂ , -NR ^* C0-R ^* , -NR ^* C00-R ^* , and -NR ^* C0NR ^* , wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR ₃ , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of R ₆ and R are unsubstituted or substituted;

comprising reaction of a compound of Formula (XII)

wherein R ₇ is selected from the group consisting of H, or a suitable protective group,

with CBr ₄ and P(OR) ₃ , wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, under reaction conditions effective to form a compound of Formula (XIII)

(XIII)

isolating the compound of Formula (XIII), and deprotection, if needed, of the protective group under conditions effective to yield the compound of Formula (XI).

In another aspect, the invention provides novel ort/20-ge/w-dibromovinylphenol compounds or salts thereof selected from the group consisting of:

These derivatives are useful in the preparation of the desired 2-alkynyl benzo[&]furan compounds.

Detailed Description

Chemical terms used herein are to be given meanings in keeping with what is understood by those of skill in the art.

The term "suitable substituent" as used in the context of the present invention is meant to include independently H; hydroxyl; protected hydroxyl groups such as - O-THP (tetrahydropyranyl) and -O-TBDPS (t-butyldiphenylsilyl); cyano; alkyl, such as lower alkyl, such as methyl, ethyl, propyl, n-butyl, t-butyl, hexyl and the like; alkoxy, such as lower alkoxy such as methoxy, ethoxy, and the like; aryloxy,

such as phenoxy and the like; vinyl; alkenyl, such as hexenyl and the like; alkynyl; formyl; haloalkyl, such as lower haloalkyl which includes CF ₃ , CCl ₃ and the like; halide; aryl, such as phenyl and naphthyl; heteroaryl, such as thienyl and furanyl and the like; amide such as C(O)N(CH ₃ ) ₂ and the like; acyl, such as C(O)- C ₆ H ₅ , and the like; ester such as -C(O)OCH ₃ the like; ethers and thioethers, such as O-Bn and the like; amino; thioalkoxy; phosphino and the like. It is to be understood that a suitable substituent as used in the context of the present invention is meant to denote a substituent that does not interfere with the formation of the desired product by the claimed processes of the present invention.

As used in the context of the present invention, the term "lower alkyl" as used herein either alone or in combination with another substituent means acyclic, straight or branched chain alkyl substituent containing from one to six carbons and includes for example, methyl, ethyl, 1 -methylethyl, 1-methylpropyl, 2- methylpropyl, and the like. A similar use of the term is to be understood for "lower alkoxy", "lower thioalkyl", "lower alkenyl" and the like in respect of the number of carbon atoms. For example, "lower alkoxy" as used herein includes methoxy, ethoxy, t-butoxy.

The term "alkyl" encompasses lower alkyl, and also includes alkyl groups having more than six carbon atoms, such as, for example, acyclic, straight or branched chain alkyl substituents having seven to ten carbon atoms.

The term "aryl" as used herein, either alone or in combination with another substituent, means an aromatic monocyclic system containing 6 carbon atoms or a polycyclic aromatic system, such as an aromatic bicyclic system containing 10 carbon atoms. For example, the term "aryl" includes a phenyl or a naphthyl ring.

The term "heteroaryl" as used herein, either alone or in combination with another substituent means a 5, 6, or 7-membered unsaturated heterocycle containing from one to 4 heteroatoms selected from nitrogen, oxygen, and sulphur and which form an aromatic system.

The term "cycloalkyl" as used herein, either alone or in combination with another substituent, means a cycloalkyl substituent that includes for example, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "cycloalkyl-alkyl-" as used herein means an alkyl radical to which a cycloalkyl radical is directly linked; and includes, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl,

2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl and 2-cyclohexyl ethyl.

A similar use of the "alkyl" term is to be understood for aryl-alkyl-, heteroaryl- alkyl-, and the like as used herein. For example, the term "aryl-alkyl-" means an alkyl radical, to which an aryl is bonded. Examples of aryl-alkyl- include, but are not limited to, benzyl (phenylmethyl), 1 -phenyl ethyl, 2-phenylethyl and phenylpropyl.

As used herein, the term "heterocycle", either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a three- to seven-membered saturated or unsaturated (including aromatic) heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur. Examples of such heterocycles include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, hydantoin, diazepine, imidazole, isoxazole, thiazole, tetrazole, piperidine, piperazine, homopiperidine, homopiperazine, 1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide or pyrimidine, and the like.

The term "alkenyl", as used herein, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a double bond. Examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl.

The term "alkynyl", as used herein is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a triple bond. Examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

The term "alkoxy" as used herein, either alone or in combination with another radical, means the radical -O-(Ci _-n )alkyl wherein alkyl is as defined above containing 1 or more carbon atoms and includes for example methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. Where n is 1 to 6, the term "lower alkoxy" applies, as noted above, whereas the term "alkoxy" encompasses "lower alkoxy" as well as alkoxy groups where n is greater than 6 (for example, n = 7 to 10). The term "aryloxy" as used herein alone or in combination with another radical means -O-aryl, wherein aryl is defined as noted above.

As used herein the term "heteroatom" means O, S or N.

The term "suitable protective group" is to be understood to denote a protective group for a functionality, such as a hydroxyl group, that does not interfere with the formation of the desired product by the claimed processes of the present invention. Suitable protective groups are known to those of skill in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981, the details of which are incorporated herein by reference.

The present invention provides novel processes for the preparation of indole compounds, in particular to 2-vinyl indoles, pyrido and azepino derivatives, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors.

In one embodiment, the invention provides a process for the preparation of a compound of Formula (I):

(I)

wherein

each R ₁ is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy;

lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , -C(0)NR ^* ₂ , - NR ^* C0-R ^* , -NR ^* C00-R ^* , -NR ^* C0NR ^* wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R _a , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R are unsubstituted or substituted;

R ₂ is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;

the process comprising reacting an ortAo-ge/«-dibromovinylaniline compound of Formula (II)

wherein Ri and R ₂ are as defined above,

with an alkene Heck acceptor of the Formula (III)

(III)

wherein R ₃ is selected from the group comprising alkyl; lower alkyl-hydroxy; lower alkyl-O-R _b wherein R _b is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R", -

C(O)OR ^** , -C(0)NR ^** ₂ , -SO ₂ R ^** , -SO ₂ NR ^** ₂ , lower alkyl-CO-R ^** , lower alkyl-CO- OR", lower alkyl-C(O)NR" ₂ , lower alkyl-NR"CO-R", lower alkyl-NR"COO-R" wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl, and where R ₃ is -C(O)NR ₂ both R groups may

form a heterocyclic ring with the nitrogen atom; and each OfR ₃ and R ^** are unsubstituted or substituted;

in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (I). In one embodiment, R ₃ is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR ¹ R ¹¹ R'", where R ¹ , R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R ¹ , R", and R" ¹ is H; and R _b is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl ₃ CCO, Troc, HCO, Bn, PMB, MOM, MEM, Me, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.

In another embodiment, the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:

As aforementioned, 2-vinylindoles have proven to be versatile dienes in Diels- Alder reactions aiming at regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [b]annelated indole derivatives of pharmological interest, both in inter- and intramolecular reactions (Pindur, U. Heterocycles 1998, 27, 1253; Pindur, U. hi Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; Cycloaddition Reaction of Indoles Derivatives; JAI Press: Greenwich, 1995; Vol. 1, p 121; Sundberg, R. in Best Synthetic Methods, Sub- series Key Systems and Functional Group; Meth-Cohen, O., Ed. Indoles; Academic Press: London, 1996; p 159). The carbazole ring is a very important building block in the synthesis of pharmacologically active compounds, as it is the core of a wide range of alkaloids. It is expected that the 2-vinyl indole compounds of the present invention will be useful precursors in regioselective and stereoselective syntheses of indole alkaloids, carbazoles and non-natural [bjannelated indole derivatives of pharmological interest.

In another embodiment, the invention provides an improved process for the preparation of a compound of the following Formula (II)

(II)

wherein

each R] is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , - C(O)NR ^* ₂ , -NR ^* C0-R ^* , -NR ^* C00-R ^* , and -NR ^* CONR ^* , wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; 0R _a , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the phenyl ring; wherein n' is a whole integer from 1 to 4; and each of Ri and R ^* are unsubstituted or substituted;

and R ₂ is H;

comprising reaction of a compound of Formula (VI)

(Vl)

with CBr ₄ and P(OR) ₃ , wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, to form a compound of Formula (VII)

isolating the compound of Formula (VII), and reducing the compound of Formula (VII) to obtain the compound of Formula (II). In one embodiment, R _a is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR ¹ R ¹¹ R'", where R ¹ , R", and R" ¹ are independently selected from H, lower alkyl and aryl, with the proviso that only one of R ¹ , R", and R ¹ " is H.

In another embodiment, R is isopropyl. In yet another embodiment, the compound of Formula (VII) is isolated via recrystallization. In still another embodiment, the compound of Formula (VII) is isolated via addition of HOAc/HCl followed by a basic workup procedure.

In another embodiment, the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:

These derivatives are useful in the preparation of the desired 2-vinyl indole compounds.

In yet another embodiment, the invention provides a process for the preparation of a compound of Formula (IV) and/or Formula (IV)'

wherein

each R ₄ is independently selected from the group comprising H; fluoro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , -C(0)NR ^* ₂ , - NR ^* C0-R ^* , -NR ^* C00-R ^* , -NR ^* CONR ^* wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR ₃ , wherein R ₃ is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n' is a whole integer from 1 to 4; and each of R ₄ and R are unsubstituted or substituted;

the process comprising reacting an ort/zo-gerø-dibromovinylanihne compound of Formula (V):

wherein R ₄ is as defined above, n is 0 to 3,

and R ₅ is selected from the group comprising H, lower alkyl; lower alkyl- hydroxy; lower alkyl-O-R _b wherein Rb is a suitable protective group; lower alkenyl; lower haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -

C(O)R ^** , -C(O)OR", -C(O)NR ^** ₂ , -SO ₂ R ^** , -SO ₂ NR ^** ₂ , lower alkyl-CO-R ^** , lower alkyl-CO-OR ^* ', lower alkyl-C(O)NR ^** ₂ , lower alkyl-NR ^** CO-R ^** , lower alkyl-

NR ^** COO-R ^** wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R ₅ and R ^** are unsubstituted or substituted;

in the presence of a base and a palladium metal pre-catalyst to form the compound of Formula (IV) and/or Formula (IV)'. In one embodiment, R _a is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR ¹ R ¹¹ R'", where R ¹ , R", and R ¹ " are independently selected from H, lower alkyl and aryl with the proviso that only one of R', R", and R'" is H; and R _b is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl ₃ CCO, Troc, HCO, Bn, PMB, MOM, MEM, Me, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.

In another embodiment, the invention provides novel ortho-gem- dibromovinylaniline compounds or salts thereof selected from the group consisting of:

These compounds are useful in the preparation of the compounds of Formulas (IV) and (IV)'.

In one embodiment, the palladium pre-catalyst used in the processes of the present invention for preparing 2-substituted indoles, and pyrido and azepino derivatives thereof, is Pd(OAc) ₂ , Pd(PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd(CH ₃ CN) ₂ Cl ₂ , PdCl ₂ , K ₂ PdCl ₄ , Pd/C or Pd ₂ (dba) ₃ -HCCl ₃ . Palladium pre-catalysts are commercially available, and methods for preparing such palladium pre-catalysts are known to those skilled in the art. A description of general synthetic techniques used for preparing such pre- catalysts found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. Palladacycles are also possible (J. Dupont, Consorti, C. S., Spencer, J. Chem. Rev. 2005, 105, 2527), such as for example trans-di(μ-acetato)bis[o-(di-o- tolylphosphino)benzyl] dipalladium (II) :

The quantity of pre-catalyst which can be used can be any quantity which allows for the formation of the desired product. In one embodiment, the pre-catalyst is present in an amount of about 1.5 mole percent to about 6 mole percent relative to the ortAo-gem-dihalovinylaniline compound used in the reaction.

Ligands for use in the present processes for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof, comprise a phosphorous-

containing ligand or a nitrogen-containing carbenoid ligand, such as S-Phos, X- Phos, P(o-tol) ₃ , PPh ₃ , P(O-CF ₃ -Ph) ₃ , P(JBu) ₃ , BINAP, tol- BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh ₃ , DavePhos, HP(tBu) ₃ BF ₄ , and

Mes^ \^ Mes

+ cr , and the like, hi one embodiment, the ligand is S-Phos. In another embodiment, the ligand is P(o-tol) ₃ . Methods for preparing such ligands are well known to those skilled in the art. A description of general synthetic techniques used for preparing such ligands as found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. In other embodiments, no additional ligand is necessary in order for the desired reaction to occur.

The quantity of ligand which can be used can be any quantity which allows for the formation of the 2-substituted indoles, and pyrido and azepino derivatives thereof. In one embodiment, the ligand is present in amount of about 3 mole % to about 12 mole % relative to the ortAo-gem-dihalovinylaniline compound used in the reaction.

In another embodiment of the processes of the present invention for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof, the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof. In one embodiment, the base comprises K ₃ PO ₄ -H ₂ O, K ₃ PO ₄ , NEt ₃ , iPr ₂ NH or Cy ₂ NMe. hi one embodiment, the base comprises NEt ₃ /K ₃ PO ₄ .H ₂ O. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 3 the details of which as relating to the bases is hereby incorporated herein by reference.

Additives for use in the processes of the present invention for the formation of 2- substituted indoles, and pyrido and azepino derivatives thereof are of the type R ₄ NX (R = lower alkyl and X = halogen, OAc) and include nBu ₄ NCl, 11Bu ₄ NOAc, and Me ₄ NCl. The additive has multiple roles according the literature; details are provided in: Jeffery, T. Tetrahedron 1996, 52, 10113.

Any solvent may be used in the processes of the present invention for the formation of 2-substituted indoles, and pyrido and azepino derivatives thereof, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable. A suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, and the like.

In general, the reagents may be mixed together or added together in any order for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.

The process conditions for the preparation of 2-substituted indoles, and pyrido and azepino derivatives thereof can be any operable conditions which yield the desired indole product. A preferred temperature for the processes for the production of the indoles of the present invention is about 120 ⁰ C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 80 and 14O ⁰ C). Typical reaction times are between 3 and 48 hours, although longer or shorter times may be used if necessary.

The 2-substituted indoles, and pyrido and azepino derivatives thereof can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the indole product will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used. Typically, the desired indoles are provided in a yield greater than 40 %, preferably in a yield of greater than 65 %, more preferably in a yield greater than 75 %.

In another embodiment of the present invention, when R ₂ is benzyl, or a substituted benzyl in the final 2-substituted indole, and pyrido and azepino derivatives thereof, prepared by the processes of the present invention, the process may also include an additional step of cleavage of the optionally substituted N- benzyl group to afford a 2-vinyl indole wherein R ₂ is H. Methods and reaction conditions for the cleavage of benzyl groups are known to those skilled in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981, the details of which are incorporated herein by reference.

The present invention also provides novel processes for the preparation of indole compounds, in particular to 2-alkynyl indoles, which may be optionally substituted at other positions on the indole ring, compounds prepared by such processes, and their synthetic precursors.

In one embodiment, the invention provides a process for the preparation of a compound of Formula (VIII):

wherein

each R ₁ is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , - C(0)NR ^* ₂ , -NR ^* C0-R ^* , -NR ^* C00-R ^* , and -NR ^* CONR ^* , wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR ₂ , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the indole ring; wherein n ¹ is a whole integer from 1 to 4; and each of Ri and R are unsubstituted or substituted;

R ₂ is selected from the group comprising H, lower alkyl, cycloalkyl, aryl, heteroaryl, aryl-loweralkyl-, or heteroaryl-loweralkyl-, each of which are unsubstituted or substituted;

the process comprising reacting an ortho-gem-dibromovinylaniline compound of Formula (II)

wherein Ri and R ₂ are as defined above,

with an alkyne of the Formula (IX)

(IX)

wherein Rs is selected from the group comprising -SiR ¹ R ¹¹ R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O- R _b wherein R _b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R ^** , lower alkyl-CO-OR ^** , lower alkyl-C(O)NR ^** ₂ , lower alkyl-NR"CO-R", lower alkyl-NR ^** COO-R" wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R ^** are unsubstituted or substituted;

in the presence of a base, a palladium metal pre-catalyst, a copper metal pre- catalyst and a Ii gand to form the compound of Formula (VIII). In one embodiment, R _a is selected from MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR ¹ R ¹¹ R'", where R ¹ , R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R ¹ , R", and R ¹ " is H; and R _b is selected from the group comprising TBS,

TBDPS, TES, TMS, Ac, Bz, Piv, Cl ₃ CCO, Troc, HCO, Bn, PMB, MOM, MEM, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr .

In another embodiment, the invention provides novel 2-substituted indoles or salts thereof selected from the group consisting of:

In one embodiment, the palladium pre-catalyst used in the processes of the present invention for preparing 2-alkynyl indoles is Pd(OAc) ₂ , Pd(PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd(CH ₃ CN) ₂ Cl ₂ , Pd(PhCN) ₂ Cl ₂ , PdCl ₂ , Pd(acac), K ₂ PdCl ₄ , Na ₂ PdCl ₄ , Pd/C, Pd(OH) ₂ /C (Pearlman's catalyst), Pd-Al ₂ O ₃ , Pd-BaSO ₄ , Pd-CaCO ₃ , [Pd(allyl)Cl] ₂ , or Pd ₂ (dba) ₃ HCCl ₃ but is not limited to these pre-catalysts. Palladium pre- catalysts are commercially available, and methods for preparing such palladium

pre-catalysts are known to those skilled in the art. A description of general synthetic techniques used for preparing such pre-catalysts found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. Palladacycles are also possible (J. Dupont, Consorti, C. S., Spencer, J. Chem. Rev. 2005, 105, 2527), such as for example trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipall adium (II):

The quantity of palladium pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynylindole product, hi one embodiment, the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ortλo-gew-dihalovinylaniline compound used in the reaction. In another embodiment, the palladium pre-catalyst is Pearlman's catalyst, such as 10% Pd/C Pearlman (50% wetted powder) from Strem (product # 46-1706). Palladium on carbon is an ideal palladium source for industrial processes due to its lower cost, easy recovery, and low level of palladium contamination in the product.

In one embodiment, the copper pre-catalyst used in the processes of the present invention for preparing 2-alkynyl indoles is CuI, Cu(OAc), CuCl, CuBr, or Cu(OTf), but is not limited to these pre-catalysts. Copper pre-catalysts are commercially available, hi one embodiment, the copper pre-catalyst is CuI.

The quantity of copper pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynylindole product. In one embodiment, the pre-catalyst is present in an amount of about 1 mole percent to about 10 mole percent relative to the ort/jo-gem-dihalovinylaniline compound used in the reaction.

Ligands for use in the present processes for the preparation of 2-alkynyl indoles, comprise a phosphorous-containing ligand, a diamine ligand, a diketone ligand, a phenol containing ligand, an alcohol-containing ligand or a nitrogen-containing

carbenoid ligand, such as S-Phos, X-Phos, P(o-tol) ₃ , P(σ-tol-p-OMe) ₃ , P(o- MeOPh) ₃ , P(p-MeOPh) ₃ , PPh ₃ , P(O-CF ₃ -Ph) ₃ , P(tBu) ₃ , BINAP, tol-BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh ₃ , DavePhos, HP(tBu) ₃ BF _4, 1,10-phenanthroline, neocuproine, trans- 1,2-cyclohexyldiamine, cis-\,2- cyclohexyldiamine, ethylenediamine, N-methylethylenediamine, N,N- dimethylethylenediamine, dipivaloylmethane, 2-acetylcyclohexanone, 2- propionylcyclohexanone, 2-isobutyrylcyclohexanone, iV,./V-dimethylsalicylamides, ethylene glycol, ethanolamine,

and

Mes ^S V^ Mes

+ cr , and the like. Methods for preparing such ligands are well known to those skilled in the art. A description of general synthetic techniques used for preparing such ligands as found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. Pn one embodiment, the ligand is P(/?-MeOPh) ₃ . In another embodiment, the ligand is PPh ₃ .

The quantity of ligand which can be used can be any quantity which allows for the formation of the 2-alkynyl indoles. In one embodiment, the ligand is present in amount of about 4 mole % to about 10 mole % relative to the ortho-gem- dihalovinylaniline compound used in the reaction.

In another embodiment of the processes of the present invention for the preparation of 2-alkynyl indoles, the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof. Pn one embodiment, the base comprises K ₂ CO ₃ , K ₃ PO ₄ , NEt ₃ , iPr ₂ NH, iPr ₂ NEt, DABCO or Cy ₂ NMe. In another embodiment, the base is iPr ₂ NH. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S. Brase, A. de Meijere in Metal-Catalysed Cross

Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 3 the details of which as relating to the bases is hereby incorporated herein by reference.

Any solvent may be used in the processes of the present invention for the formation of 2-alkynyl indoles, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable. A suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, H ₂ O and the like.

In general, the reagents may be mixed together or added together in any order for the preparation of 2-alkynyl indoles. Air can be removed from the reaction vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.

The process conditions for the preparation of 2-alkynyl indoles can be any operable conditions which yield the desired indole product. A preferred temperature for the processes for the production of the 2-alkynyl indoles of the present invention is about 100 ⁰ C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 20 and 140°C). Typical reaction times are between 1 and 48 hours, although longer or shorter times may be used if necessary.

The 2-alkynyl indoles can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the indole product will vary depending upon the specific pre-catalyst, ligand, base, starting materials and process conditions used. Typically, the desired indoles are provided in a yield greater than 40 %, preferably in a yield of greater than 65 %, more preferably in a yield greater than 75 %.

In another embodiment of the present invention, when R ₂ is benzyl, or a substituted benzyl in the final 2-alkynyl indole prepared by the processes of the present invention, the process may also include an additional step of cleavage of the optionally substituted N-benzyl group to afford a 2-alkynyl indole wherein R ₂ is H. Methods and reaction conditions for the cleavage of benzyl groups are

known to those skilled in the art, for example, such as those disclosed in Theodora W. Greene, Protective Groups in Organic Synthesis, Wiley Interscience Publications, John Wiley & Sons, New York, copyright 1981), the details of which are incorporated herein by reference.

The present invention also provides novel processes for the preparation of benzo[ό]furan compounds, in particular to 2-alkynyl benzo[Z>]furan, which may be optionally substituted at other positions on the benzo[ό]furan ring, compounds prepared by such processes, and their synthetic precursors.

In one embodiment, the invention provides a process for the preparation of a compound Formula (X) :

(X)

wherein

each R^ is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , - C(0)NR ^* ₂ , -NR ^* C0-R ^* , -NR ^* C00-R ^* , and -NR ^* C0NR ^* , wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR ₃ , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of R _O and R are unsubstituted or substituted;

and R ₉ is H or lower alkyl;

the process comprising reacting an ortho-gem-dibromovinylphenol compound of

Formula (XI)

wherein R$ and R ₉ are as defined above,

with an alkyne of the Formula (IX)

≡^R ₈ (IX)

Rg is selected from the group comprising -SiR ¹ R ¹¹ R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R"' is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-R _b wherein R _b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-nitrile; lower alkyl-CO-R ^** , lower alkyl- CO-OR ^** , lower alkyl-C(O)NR ^** ₂ , lower alkyl-NR ^** CO-R ^** , lower alkyl- NR ^** COO-R ^** wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R ^** are unsubstituted or substituted;

in the presence of a base, a palladium metal pre-catalyst, a copper metal pre- catalyst and a ligand to form the compound of Formula (X). In one embodiment, R _a is selected from the group comprising MOM, MEM, THP, MTM, BOM, POM, trichloroethoxymethoxy, SEM, Tr, and SiR ¹ R ¹¹ R'", where R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; and R _b is selected from the group comprising TBS, TBDPS, TES, TMS, Ac, Bz, Piv, Cl ₃ CCO, Troc, HCO, Bn, PMB, MOM, MEM, MTM, BOM, POM, trichloroethoxymethoxy, SEM, THP and Tr.

In another embodiment, the invention provides novel 2-substituted benzo[ό]furan or salts thereof selected from the group consisting of:

In one embodiment, the palladium pre-catalyst used in the processes of the present invention for preparing 2-alkynyl benzo[fr]furans is Pd(OAc) ₂ , Pd(PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd(CH ₃ CN) ₂ Cl ₂ , Pd(PhCN) ₂ Cl ₂ , PdCl ₂ , Pd(acac), K ₂ PdCl ₄ , Na ₂ PdCl ₄ , Pd/C, Pd(OH) ₂ /C (Pearlman's catalyst), Pd-Al ₂ O ₃ , Pd-BaSO ₄ , Pd-CaCO ₃ , [Pd(allyl)Cl] ₂ , or Pd ₂ (dba) ₃ HCCl ₃ but is not limited to these pre-catalysts. Palladium pre-catalysts are commercially available, and methods for preparing such palladium pre-catalysts are known to those skilled in the art. A description of general synthetic techniques used for preparing such pre-catalysts found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. Palladacycles are also possible (J. Dupont, Consorti, C. S., Spencer, J. Chem. Rev. 2005, 105, 2527), such as for example trans-di(μ-acetato)bis[o-(di-σ-tolylphosphino)benzyl]dipal ladium (II):

The quantity of palladium pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynyl benzo[ό]furan product. In one embodiment, the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ort/zo-gem-dihalovinylphenol compound used in the reaction. In one embodiment, the palladium pre-catalyst is Pearlman's catalyst.

In one embodiment, the copper pre-catalyst used in the processes of the present invention for preparing 2-alkynyl benzo[&]furans is Cu(OAc), CuCl, CuBr, CuI, or Cu(OTf), but is not limited to these pre-catalysts. Copper pre-catalysts are commercially available. In one embodiment, the copper pre-catalyst is CuI.

The quantity of copper pre-catalyst which can be used can be any quantity which allows for the formation of the desired 2-alkynyl benzo[Z?]furan product. In one embodiment, the pre-catalyst is present in an amount of about 0.1 mole percent to about 10 mole percent relative to the ort/?o-ge/rø-dihalovinylphenol compound used in the reaction.

Ligands for use in the present processes for the preparation of 2-alkynyl benzo[6]furans, comprise a phosphorous-containing ligand, a diamine ligand, a diketone ligand, a phenol containing ligand, alcohol containing ligand or a nitrogen-containing carbenoid ligand, such as S-Phos, X-Phos, P(O-U)I) ₃ , P(o-tol- P-OMQ) ₃ , P(O-MeOPh) ₃ , P(^-MeOPh) ₃ , PPh ₃ , P(O-CF ₃ -Ph) ₃ , P(JBu) ₃ , BINAP, tol- BINAP, dppm, dppe, dppp, dppb, dppf, Xanphos, BIPHEP, AsPh ₃ , DavePhos, HP(tBu) ₃ BF _4, 1,10-phenanthroline, neocuproine, trans- 1,2-cyclohexyldiamine, cώ-l,2-cyclohexyldiamine, ethyl enediamine, N-methylethylenediamine, N,N- dimethylethylenediamine, dipivaloylmethane, 2-acetylcyclohexanone, 2- propionylcyclohexanone, 2-isobutyrylcyclohexanone, N,iV-dimethylsalicylamides, ethylene glycol, ethanolamine,

and

Mes - ^N \^ Mes cr , and the like. In one embodiment, the ligand is P(P-MeOPh) ₃ .

Methods for preparing such ligands are well known to those skilled in the art. A description of general synthetic techniques used for preparing such ligands as found in Jiro Tsuji, Palladium Reagents and Catalysts, John Wiley & Sons Ltd., 2004, is hereby incorporated herein by reference. .

The quantity of ligand which can be used can be any quantity which allows for the formation of the 2-alkynyl benzo[ό]furans. hi one embodiment, the ligand is present in amount of about 2 mole % to about 10 mole % relative to the ortho- gem-dihalovinylphenol compound used in the reaction.

In another embodiment of the processes of the present invention for the preparation of 2-alkynyl benzo[Z?]furans, the base comprises an organic base or an inorganic base, such as a metal carbonate, a metal hydroxide, a metal phosphonate or a trialkylamine, and the like, or combinations thereof. In one embodiment, the base comprises K ₂ CO ₃ , iPr ₂ NEt, DABCO, K ₃ PO ₄ H ₂ O, K ₃ PO ₄ , NEt ₃ , iPr ₂ NH or Cy ₂ NMe. In one embodiment, the base is iPr ₂ NEt. Additional bases for use with the present processes are known to those skilled in the art, for example, such as those disclosed in the publication of S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 3 the details of which as relating to the bases is hereby incorporated herein by reference.

Any solvent may be used in the processes of the present invention for the formation of 2-alkynyl benzo[ό]furans, provided that it does not interfere with the formation of the desired product. Both protic and aprotic and combinations thereof are acceptable. A suitable solvent includes but is not limited to toluene, dioxane, benzene, THF, H ₂ O and the like. In one embodiment, toluene is the solvent, hi another embodiment, a mixture of toluene and water is used.

In general, the reagents may be mixed together or added together in any order for the preparation of 2-alkynyl benzo[Z?]furans. Air can be removed from the reaction

vessel during the course of the reaction and the solvent and reaction mixtures can be sparged with a non-reactive gas.

The process conditions for the preparation of 2-alkynyl benzo[6]furan can be any operable conditions which yield the desired benzo[6]furan product. A preferred temperature for the processes for the production of the indoles of the present invention is about 100 ⁰ C, although this temperature can be higher or lower depending upon the reagents, reaction conditions and the solvent used (between 20 and 140 ⁰ C). Typical reaction times are between 1 and 48 hours, although longer or shorter times may be used if necessary.

The 2-alkynyl benzo[ό]furan can be recovered by conventional methods known to those skilled in the art, for example crystallization and silica gel chromatography. The yield of the benzo[&]furan product will vary depending upon the specific pre- catalyst, ligand, base, starting materials and process conditions used. Typically, the desired benzo[b]furan are provided in a yield greater than 50 %, preferably in a yield of greater than 75 %, more preferably in a yield greater than 90 %.

In another embodiment, the invention provides an improved process for the preparation of a compound of the following Formula (XI)

wherein

each R ₆ is independently selected from the group comprising H; fluoro; chloro; lower alkyl; cycloalkyl; lower alkenyl; lower alkynyl; lower alkoxy; aryloxy; benzyloxy; lower haloalkyl; aryl; heteroaryl; -OH; -OCO-R ^* , -C(O)O-R ^* , - C(O)NR ^* ₂ , -NR ^* C0-R ^* , -NR ^* COO-R ^* , and -NR ^* C0NR ^* , wherein R ^* is independently selected from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl; OR _a , wherein R _a is a suitable protective group; and an alkenyl group bonded so to as to form a 4- to 20-membered fused monocycle or polycyclic ring

with the benzo[b]furan ring; wherein n' is a whole integer from 1 to 4; and each of R _ό and R ^* are unsubstituted or substituted;

comprising reaction of a compound of Formula (XII)

(XII)

wherein R ₇ is selected from the group consisting of H, or a suitable protective group,

with CBr ₄ and P(OR) ₃ , wherein R is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl, under reaction conditions effective to form a compound of Formula (XIII)

isolating the compound of Formula (XIII), and deprotection, if needed, of the protective group under conditions effective to yield the compound of Formula (XI). In one embodiment, the protective group is selected from the group comprising a silyl protective group, an ester protective group, and an ether protective group. In another embodiment, the silyl protective group is selected from the group comprising TMS, TBS, TBDPS and TES. In another embodiment, the ester protective group is selected from the group comprising Ac, Piv, and Bz. In yet another embodiment, the ether protective group is selected from the group comprising MOM, Tr and MEM.

In another embodiment, the invention provides novel ortλø-gem-dibromovinylphenol compounds or salts thereof selected from the group consisting of:

These derivatives are useful in the preparation of the desired 2-alkynyl benzo[ό]furan compounds.

Presentation of the reaction. We report a highly efficient and modular synthesis of 2- vinyl indoles of Formula (I) from readily available starting material ortho-gem- dibromovinylanilines of Formula (II) via a Pd-catalyzed tandem C-N/C-C coupling with alkenes of Formula (III):

Scheme 27

(H) (D

Optimization of the reaction conditions. The reaction conditions have been optimized using two substrates as shown below by screening different Pd sources, ligands, organic and inorganic bases, additives, reaction time and reaction temperature. Three conditions giving good yields have been found depending on the type of the R ₂ group (for Heck conditions with quaternary ammonium salt, see: T. Jeffery, Tetrahedron 1996, 52, 10113; T. Jeffery, Tetrahedron 1994, 35, 3051). Procedure A needs longer reaction times but

yields, depending on the substrate, are generally better than those obtained with Procedure B. Procedure C is recommended when there is an aryl group on the aniline nitrogen; otherwise, with Procedures A and B, undesired by-products are observed, although the desired reaction products are still obtained. Procedures A and B work if R ₂ = phenyl (Procedure A, 48% yield with R ₂ = Ph; Procedure B, 50% yield with R ₂ = Ph), and Procedure C yields the desired product in 55 % yield when R ₂ = Bn.

Scheme 28

R ₂ = Bn or Ph

Procedure A: Pd(OAc) ₂ (4%), Me ₄ NCl (1 equiv.), NEt ₃ /K ₃ PO ₄ .H ₂ O (2 equiv. each), toluene (0.1 M), 120 ⁰ C, 4Oh, 79% (R ₂ = Bn)

Procedure B: Pd(OAc) ₂ (4%), P-(o-tolyl) ₃ (8%), NEt ₃ /K ₃ PO ₄ .H ₂ O (2 equiv. each) toluene (0.1 M), 120 ⁰ C, 15h, 71% (R ₂ = Bn)

Procedure C: Pd ₂ dba ₃ (3%), S-Phos (12%), NEt ₃ /K ₃ PO ₄ .H ₂ O (2 equiv. each), toluene (0.1 M), 12O ⁰ C, 15h, 78% (R ₂ = Ph)

Proposed mechanism. Without being bound by theory, we propose the following stepwise cyclization catalytic cycle to explain the formation of the product (Scheme 29). It is believed to involve an alkyne formation (for alkyne formation from gem- dibromoalkenes and higher reactivity of trans C-Br bond, see: Zapata, A. J., Ruiz, J. J. Organomet. Chem. 1994, 479 ; Shen, W. ; Wang, L. J. Org. Chem. 1999, 64, 8873 ; Shen, W. Synlett 2000, 737 ; W. Shen, S. Thomas Org. Lett. 2000, 2, 2857) and occurs via an Buchwald-Hartwig animation following by a Heck cross-coupling reaction:

Scheme 29

Scope of the reaction. The following Tables 1, 2 and 3 present representative examples illustrating the scope of the new processes of the present invention.

The results of various tandem C-N and C-C bond formation reactions to afford 2-vinyl indoles in good yield using various alkenes of different electronic and steric character and benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine are shown in Table 1 (entries 1-11). The reaction conditions can tolerate a wide variety of alkene reagents, such as vinyl esters, sulfones, nitriles, primary and secondary amides, vinyl ketones, aryl alkenes with neutral, electron-rich or electron-poor substituents, allylic and vinylic alcohols.

Table 1

Procedure A: Pd(OAc) ₂ (4 mol%), Me ₄ NCI, NEt ₃ /K ₃ PO ₄ .H ₂ O, toluene, 12O ⁰ C Procedure B: Pd(OAc) ₂ (4 mol%), P(o-tolyl) ₃ (8 mol%), NEt ₃ /K ₃ PO ₄ .H ₂ O, toluene, 12O ⁰ C

Alkene Heck acceptors commonly known in the literature may be used in the processes of the present invention. Examples of these are given in the following reviews, the contents of which are herein incorporated by reference in this regard: N J. Whitcombe, 5 K.K. Hii, S. E. Gibson, Tetrahedron 2001, 57, 7449; I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009; S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 3. Thus, R ₃ may be selected from the group including but not limited to alkyl; lower alkyl-hydroxy; lower alkyl-O-R- _b wherein R _b is a suitable protective group; lower alkenyl; lower

10 haloalkyl; aryl; heteroaryl; cycloalkyl; nitrile; lower alkyl-nitrile; -C(O)R ^** , -C(O)OR ^** , - C(O)NR ^** ₂ , -SO ₂ R", -SO ₂ NR ^** ₂ , lower alkyl-CO-R ^** , lower alkyl-CO-OR ^** , lower alkyl- C(O)NR ^** ₂ , lower alkyl-NR ^* 'CO-R", lower alkyl-NR ^** COO-R ^** wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, and lower alkenyl, and where R ₃ is -C(O)NR ^** ₂ both R ^** groups may form a heterocyclic ring with the nitrogen

15 atom; and each Of R ₃ and R ^** are unsubstituted or substituted.

The effect of substitution on the aniline nitrogen of the ort/zo-gem-dihalovinylaniline starting materials is shown in Table 2 (entry 1-8). The tandem coupling reaction proceeded smoothly to afford the desired product in good to excellent yield with different substitution. Use of the N-benzyl secondary amine (R ₂ = benzyl) as starting material yielded similar results as the phenyl-substituted amine (R ₂ = phenyl), and a variety of different substituents on the phenyl group were tolerated (electron-withdrawing and electron-rich groups). Alkyl substitution on the nitrogen atom, whether sterically hindered or not, was also tolerated. The use of the non-protected aniline as starting materials yielded the desired product, but yields were lower under the optimized 0 conditions. The use of electron- withdrawing and activating acetyl protecting groups on the nitrogen group gave no result under optimized conditions.

Table 2

Procedure A: Pd(OAc) ₂ (4 mol%), Me ₄ NCI, NEt ₃ /K ₃ PO ₄ .H ₂ O, toluene, 120 ⁰ C Procedure B: Pd(OAc) ₂ (4 mol%), P(o-tolyl) ₃ (8 mol%), NEt ₃ /K ₃ PO ₄ .H ₂ O, toluene, 120 ⁰ C Procedure C: Pd ₂ dba ₂ (3 mol%), S-Phos (12 mol%), NEt ₃ /K ₃ PO ₄ .H ₂ O, toluene, 120 ⁰ C

(5.0 mol%) and P(o-tolyl) ₃ (10.0 mol%).

In Table 3 (entry 1-8), various substituted ort/zø-gem-dibromovinylanilines were reacted with tert-buty\ acrylate under the reaction conditions noted below. This methodology

5 proved to be a very general and efficient method to prepare several functionalized

indoles. In general, electronic factors had little effect on yield. This method is compatible with a broad spectrum of electron-donating and electron-withdrawing functionalities. In terms of limitations, yields tend to be poor for 3-substituted indoles.

Table 3

Procedure A: Pd(OAc) ₂ (4 mol%), Me ₄ NCI, NEt ₃ /K ₃ PO ₄ .H ₂ O, toluene, 12O ⁰ C Procedure B: Pd(OAc) ₂ (4 mol%), P(o-tolyl) ₃ (8 mol%), NEt ₃ /K ₃ PO ₄ .H ₂ O, toluene, 12O ⁰ C

For the above-mentioned processes, it should also be noted that yields are poor when any of Ri, R ₂ , and R ₃ are iodo-substituted aryl or alkene groups.

5 To summarize, the following novel 2-vinyl indole compounds have been prepared by this new methodology:

The novel and versatile processes of the present invention may be used to synthesize commercially important indole compounds, such as, for example, Fluvastatin, and the

potent and selective inhibitor of the osteoclatic Vacuolar H+-ATPase named SB-242782 (Farina, C; Gagliardi, S.; Nadler, G. M. PTC Int. Appl. WO 9801113 Al 19980115, Smithkline Beecham, 1998; Nadler, G.; Morvan, M.; Delimoge, I.; Pietro, B.; Zocchetti, A.; James, I.; Zembryki, D. Bioorganic & Medicinal Chemistry Letters 1998, 8, 3621; Visentin, L.; Dodds, R. A.; valente, M.; Misiano, P.; Bradbeer, J. N.; Oneta, S.; Liang, X.; Gowen, M.; Farina, C. Journal of Clinical Investigation 2000, 106, 309; Price, P.A.; June, H. H.; Buckley, J. R.; Williamson, M. K. Circulation Reasearch 2002, 91, 547; Whyteside, G.; Meek, P.J.; Ball, S. K.; Dixon, N.; Finbow, M. E.; Kee, T. P.; Findlay, J.B.C.; Harrison, M. A. Biochemistry 2005, 44, 15024):

It is envisioned that the active compound SB-242782 should be obtained easily in few steps using this new methodology. The major step of this synthesis is as proposed in Scheme 30:

Scheme 30

Description of the Synthesis of ørt/tø-ge/M-dibromovinylanilines

Methods of preparing ortAo-gem-dihalovinylanilines are known to those skilled in the art. For example, see Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45, 907-910 and Topolski, M. J. Org. Chem. 1995, 60, 5588-5594. Additional

methods for the preparation of ortho-gem-dibmmovinyl compounds are disclosed in Eymery, F.; Iorga, B, Synthesis, 2000, 185-213.

Another method of preparing orrto-gem-dibromovinylanilines is described in PCT Application Publication Number WO/2006/047888 (International Application No. PCT/CA2005/001703, filed November 4, 2005, published May 11, 2006) to Mark Lautens and Yuanqing Fang entitled "2-Substituted Indoles, their Precursors and Novel Processes for the Preparation Thereof", the contents of which are hereby incorporated by reference in this regard. This method is shown in Scheme 31. Using this method, the ørt/zø-ge/n-dibromovinylaniline is obtained from the olefination of 2-nitrobenzaldehyde by treatment with CBr ₄ /PPh ₃ (92%) followed by SnCl ₂ -2H ₂ O, or Fe, HOAc, or Fe, FeCl ₃ , HOAc or H ₂ , V-doped Pt/C. However, in the process, at least two equivalents of solid triphenylphosphine are generated as a byproduct. Isolation of the desired product can sometimes be problematic.

Scheme 31

85% 2 steps one pot

The new improved process of the present invention comprises reaction of 2- nitrobenzaldehydes using trialkyl- or triphenylphosphite, which is more readily available and less expensive. Additionally, the product ortλo-gem-dibromovinylnitrobenzenes can be easily isolated from liquid trialkyl- or triphenylphosphate byproduct.

Among various phosphites tested (Table 4), triisopropyl phosphite was found to be optimal, giving 92% isolated yield. The product or/Ao-gem-dibromovinylnitrobenzene (Compound "A" in the reaction scheme shown in Table 4) can be isolated from the reaction mixture either by recrystallization from hexanes or treatment of HOAc/HCl to hydrolyze trialkyl- or triphenylphosphate byproducts into phosphoric acid and

isopropanol, which can be easily removed under basic workup procedure (Scheme 32). No chromatographic purification is needed.

Table 4

(3 eq.)

Scheme 32

(VII) (VII)

Reduction of or^o-gem-dibromovinylnitrobenzene using SnCl ₂ -2H ₂ O; or Fe, HOAc; or Fe, FeCl ₃ , HOAc; or H ₂ , V-doped Pt/C will result in the desired ortho-gem- dibromovinylaniline.

Several new ort/jø-gem-dibromovinylanilines presenting a substituent on the nitrogen of the aniline have been prepared according following schemes. The alkylation step of different or^o-gem-dibromovinylanilines has been accomplished by reductive amination with different aldehydes or by alkylation with benzyl bromide.

Scheme 33

1c 42%

Scheme 34

1f 40%

Scheme 35

1b

Scheme 36

To summarize, the following novel orώo-gem-dibromovinylanilines have been prepared as described above and in the Examples:

An intramolecular version: introduction. An intramolecular version of the processes of the invention has also been developed to provide pyrido and azepino indole structures of Formula (IV)/(IV)'. These processes involve a Pd-catalyzed tandem intramolecular Buchwald-Hartwig amination and Heck coupling reaction from readily accessible and appropriately functionalized ortAo-gew-dibromovinylanilines of Formula (V).

In the above-referenced formulas (IV)/(IV)' and (V), n can be between 0 and 3 to make five to eight membered rings. Intramolecular Heck reactions are described in S. Brase, A. de Meijere in Metal-Catalysed Cross Coupling Reactions (Eds: F. Diederich, P. J. Stang), Wiley, Weinheim, 1998, Chap. 6.

Optimization. The substrate 3a shown below has been used to optimize the reaction conditions by screening different Pd sources, ligands, organic and inorganic bases, additives, reaction times and reaction temperatures. It appears that the optimal conditions

are Pd ₂ dba ₃ (4 mol%), «Bu ₄ NCl (1 equiv.), NEt ₃ /K ₃ PO ₄ .H ₂ O (2 equiv. of each), toluene, 120 ⁰ C, 15h The pyrido indole 4 is obtained as an easily separable mixture of 4a and 4a' with 76% (4a/4a': 3/1; Scheme 38).

Scheme 38

Scope of the reaction. The versatility of the reaction is illustrated by the results shown in Table 5 (entry 1-5). Substituents on the aromatic ring having different electronic properties have been used with success (entries 1-3) and the reaction also proceeds with a non-activated alkene (entry 4). Moreover, seven membered rings fused with the indole 10 moiety have been produced easily using this new methodology (entry 5).

Table 5

To summarize, the following novel pyrido and azepino indoles have been prepared as described above and in the Examples:

Preparation of starting materials for pyrido and azepino indoles synthesis. The starting materials needed for the above-mentioned reactions were prepared in one step from ort/zo-gem-dibromovinylaniline and aldehydes containing the alkene unit (easily prepared in two or three steps (S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A.D. Smith Org.& Bio. Chem. 2005, 3, 1284) or commercially available) by a reductive amination procedure (Richard C. Larock, in Comprehensive Organic Transformation, Wiley VCH, New York, copyright 1999; Reddy, TJ. et al. Synlett 2005, 583; Abdel-Magid, A. F. et al J. Org. Chem. 1996, 61, 3849; Bomann, M.D. et al. J. Org. Chem. 1995, 60, 5995). Table 6 presents the details of the synthesis of these precursors.

Table 6

To summarize, the following compounds have been prepared using the procedures described above and in the Examples:

Presentation of the reaction. We also report a highly efficient and modular synthesis of 2-alkynyl indoles of Formula (VIII) from readily available starting material ortho-gem- dibromovinylanilines of Formula (II) via a Pd-catalyzed tandem C-N/C-C coupling with alkynes of Formula (IX):

Scheme 39

Optimization of the reaction conditions. The reaction conditions have been optimized using [2-(2,2-dibromovinyl)phenyl]-amine and oct-1-yne as shown below by screening different Pd sources, different copper sources, ligands, organic and inorganic bases, solvents, reaction time and reaction temperature. In general, it was found that monodentate triarylphosphines were more effective than electron-rich and sterically hindered phosphines such as S-Phos, P(^Bu) ₃ , or bidentate ligands such as dppf. It was revealed that subjecting the two substrates to the reaction conditions using Pearlman's catalyst, CuI, P(MeOPh) ₃ and iPr ₂ NH in toluene at 100 ⁰ C. (Procedure A) or using Pd-C, CuI, PPh ₃ and iPr ₂ NH in toluene at 100 ⁰ C . gave good yields of the product (Procedure B). It was also found that adding water as the co-solvent under Procedure A could reduce the Pd-catalyst loading down to 0.1 mol %, even though a longer reaction time was needed (Procedure C).

Scheme 40

base .

Procedure A: Pearlman's catalyst (2 mol%), CuI (4 mol%), P(MeOPh) ₃ (8 mol%), iPr ₂ NH (2.5 equiv.), toluene (0.17 M), 100 ⁰ C, 1.5h, 83% Procedure B: Pd-C (5 mol%), CuI (5 mol%), PPh ₃ (11 mol%), iPr ₂ NH (2.5 equiv.), toluene (0.17 M), 100 ⁰ C, Ih, 92%

Procedure C: Pd-C (0.1 mol%), CuI (2 mol%), P(MeOPh) ₃ (4 mol%), iPr ₂ NH (2.5 equiv.), toluene-H ₂ O (2:1, 0.17 M), 100 ⁰ C, 36h, 82%

Proposed mechanism. We propose the following catalytic cycle to explain the formation of the product (Scheme 41). It is believed to involve an initial indole formation followed by typical Sonogashira coupling between the resulting 2-bromoindole and an alkyne:

Scheme 41

This reaction mechanism is supported by the following experiments. When the tandem C- N/Sonogashira reaction was performed in the presence of a catalytic amount of CuI(PPh ₃ ) ₂ in the absence of Pd-C using HNzPr ₂ as the base, no desired product was observed. However, a significant amount of 2-bromoindole was observed, presumably formed via an intramolecular Ullman reaction (Ullmann, F. Chem. Ber. 1903, 36, 2382). When the reaction was performed in the presence of Pd/C and PPh ₃ without CuI, only the starting material was recovered.

Scope of the reaction. The following Tables 7, 8 and 9 present representative examples illustrating the scope of the new processes of the present invention.

10 The results of various tandem C-N and C-C bond formation reactions to afford 2-alkynyl indoles in good yield using various alkenes of different electronic and steric character and [2-(2,2-dibromovinyl)phenyl] -amine are shown in Table 7 (entries 1-9). A wide variety of alkyne reagents, such as alcohol containing alkynes, chloro containing alkynes, nitrile containg alkynes, pyridine containing alkynes can tolerate the reaction conditions.

15 Table 7

Procedure A: Pearlman's catalyst (2 mol%), CuI (4 mol%), P(MeOPh) ₃ (8 mol%), iPr ₂ NH (2.5 equiv.), toluene (0.17 M), 100 ⁰ C

Procedure B: Pd-C (5 mol%), CuI (5 mol%), PPh ₃ (1 1 mol%), iPr ₂ NH (2.5 equiv.), 20 toluene (0.17 M), 100 ⁰ C

Alkyne units in the Sonogashira coupling reaction commonly known in the literature may be used in the processes of the present invention. Examples of these are given in the following reviews, the contents of which are herein incorporated by reference in this regard: K. Sonogashira, S. Takahashi, Yuki Gosei Kagaku Kyokaishi 1993, 51, 1053; K. Sonogashira. Handbook of Organopalladium Chemistry for Organic Synthesis (Ed: E. Negishi), Wiley, Hoboken, 2002, Chap. 1, 493-529. Thus, R ₈ maybe selected from the group including but not limited to, -SiR ¹ R ¹¹ R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-R _b wherein R _b is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl-

nitrile; lower alkyl-CO-R ^** , lower alkyl-CO-OR", lower alkyl-C(O)NR ^** ₂ , lower alkyl- NR ^** CO-R ^** , lower alkyl-NR ^** COO-R" wherein R" is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of Rs and R ^** are unsubstituted or substituted.

The effect of substitution on the aniline nitrogen of the or/λo-gem-dihalovinylaniline starting materials is shown in Table 8 (entry 1-4). The tandem coupling reaction proceeded smoothly to afford the desired product in good yield with different substitution. Use of the N-substituted secondary amine as starting material yielded poorer

10 results as compared with non-substituted aniline under the optimized conditions and higher catalyst loadings both of palladium and copper sources were required to complete the conversion of starting materials.

Table 8

Procedure A

15 Procedure A: Pearlman's catalyst, CuI, P(MeOPh) ₃ , iPr ₂ NH (2.5 equiv.), toluene (0.17 M), 100°C for 24h

In Table 9 (entry 1-4), various substituted ortho-gem -dibromovinylanilines were reacted with oct-1-yne under the reaction conditions noted below. This methodology proved to be a very general and efficient method to prepare several functionalized indoles. In general, substrates with electron-withdrawing substituents tend to show low reactivities to the tandem coupling reactions and higher catalyst loadings are required to obtain higher yields of the products. However, this method is still compatible with a broad spectrum of electron-donating and electron-withdrawing functionalities. In terms of limitations, the optimized conditions fail to give 3 -substituted indoles.

Table 9

F

Procedure A: Pearlman's catalyst, CuI, P(MeOPh) ₃ , iPr ₂ NH (2.5 equiv.), toluene (0.17 M), 100 ⁰ C for 12h

To summarize, the following novel 2-alkynyl indole compounds have been prepared by this new methodology:

Presentation of the reaction. We also report a highly efficient and modular synthesis of 2-alkynyl benzo[6]furan of Formula (X) from readily available starting material ortho- gem-dibromovinylphenols of Formula (XI) via a Pd-catalyzed tandem C-N/C-C coupling with alkynes of Formula (IX):

Scheme 42

Optimization of the reaction conditions. The reaction conditions have been optimized using 2-(2,2-dibromovinyl)-phenol and oct-1-yne or ethynylbenzene as shown below by

screening different Pd sources, different copper sources, ligands, organic and inorganic bases, solvents, reaction time and reaction temperature. Two conditions giving good yields have been found depending on the type of the R ₈ group. Procedure A generally gives better yields of the products than those obtained with Procedure B. However when using the aryl substituted acetylenes or trimethylsilylacetylene as the terminal alkynes, Procedure B gives the products in much better yield. It is thought that the positive effect of water may be due to its ability to remove bromide from the organic phase. A control experiment, in which an external source of bromide (Bu ₄ NBr) was found to inhibit the reaction progress, lends support to this proposal.

Scheme 43

Procedure A: Pearlman's catalyst (1 mol%), CuI (2 mol%), P(MeOPh) ₃ (4 mol%), iPr ₂ NH (2.5 equiv.), toluene-H ₂ O (2:1, 0.17 M), 100 ⁰ C, 12h, 80%

Procedure B: Pearlman's catalyst (1 mol%), CuI (2 mol%), P(MeOPh) ₃ (4 mol%), iPr ₂ NH (2.5 equiv.), toluene (0.17 M), 100 ⁰ C, 12h, 71%

Proposed mechanism. We propose the following catalytic cycle to explain the formation of the product the same as the 2-alkynyl indole cases (Scheme 44). It is believed to involve an initial benzo[6]furan formation followed by typical Sonogashira coupling between the resulting 2-bromobenzo[6]furan and an alkyne:

Scheme 44

(X)

Scope of the reaction. The following Tables 10 and 11 present representative examples illustrating the scope of the new processes of the present invention. The results of various tandem C-O and C-C bond formation reactions to afford 2-alkynyl benzo[ό]furans in good yields using various alkenes of different electronic and steric character and 2-(2,2-

dibromovinyl)-phenol are shown in Table 10 (entries 1-9). A wide variety of alkyne reagents, such as alcohol containing alkynes, phenol containing alkynes, chloro containing alkynes, nitrile containing alkynes, pyridine containing alkynes can tolerate the reaction conditions.

Table 10

Procedure A: Pearlman's catalyst (1 mol%), CuI (2 mol%), P(MeOPh) ₃ (4 mol%), iPr ₂ NH (2.5 equiv.), toluene-H ₂ O (2:1, 0.17 M), 100 ⁰ C, 12h

10 Procedure B: Pearlman's catalyst (1 mol%), CuI (2 mol%), P(MeOPh) ₃ (4 mol%), iPr ₂ NH (2.5 equiv.), toluene (0.17 M), 100 ⁰ C, 12h

Alkyne units in the Sonogashira coupling reaction commonly known in the literature may be used in the processes of the present invention. Examples of these are given in the following reviews, the contents of which are herein incorporated by reference in this regard: K. Sonogashira, S. Takahashi, Yuki Gosei Kagaku Kyokaishi 1993, 51, 1053; K. Sonogashira. Handbook of Organopalladium Chemistry for Organic Synthesis (Ed: E. Negishi), Wiley, Hoboken, 2002, Chap. 1, 493-529. Thus, R ₈ is selected from the group including, but not limited to, -SiR ¹ R ¹¹ R'" wherein R', R", and R'" are independently selected from H, lower alkyl and aryl, with the proviso that only one of R', R", and R'" is H; lower alkyl; lower alkyl-hydroxy; lower alkyl-O-R _b wherein Rb is a suitable protective group; lower alkenyl; steroid; lower haloalkyl; aryl; heteroaryl; cycloalkyl; lower alkyl- nitrile; lower alkyl-CO-R ^** , lower alkyl-CO-OR", lower alkyl-C(O)NR ^** ₂ , lower alkyl- NR ^** CO-R", lower alkyl-NR"COO-R ^** wherein R ^** is selected independently from H, lower alkyl, cycloalkyl, aryl, heteroaryl, lower alkenyl; and each of R ₈ and R" are unsubstituted or substituted.

The effect of substitution on the phenyl ring of the ort/zo-gem-dihalovinylphenol starting materials is shown in Table 11 (entry 1-4). The tandem coupling reaction using oct-1-yne proceeded smoothly to afford the desired product in good to excellent yields. This methodology proved to be a very general and efficient method to prepare several functionalized benzo[ό]furans. In general, electronic factors had little effect on yields. This method is compatible with a broad spectrum of electron-donating and electron-

withdrawing functionalities. However, in the case of the substrate with the ortho methoxy group, a higher catalyst loading and a longer reaction time are required for the complete conversion, probably due to the coordination of 6-methoxy group to the copper which deactivate the catalytic system.

Table 11

Procedure A: Pearlman's catalyst, CuI, P(MeOPh) ₃ , 1Pr ₂ NH (2.5 equiv.), toluene-H ₂ O (2:1, 0.17 M), 100 ⁰ C, 12h

reaction time was 64 h.

To summarize, the following novel 2-alkynyl benzo[6]furan compounds have been prepared by this new methodology:

Description of the starting material synthesis used for the 2-alkynyl benzo[b]furans synthesis.

A typical method of preparing ort/zø-gem-dibromovinylphenols used in the processes of 10 invention is shown in Scheme 45. The ort/zo-gem-dibromophenol is obtained from

silylation of 2-hydroxybenzaldehyde by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate and 2,6-lutidine followed by olefination of the aldehyde functionality using CBr ₄ ZPPh ₃ and subsequent removal of TBS group with TBAF.

Scheme 45

Several new ort/zo-gem-dibromovinylphenol possessing a substituent on the phenyl ring have been prepared according following schemes.

Scheme 46

Scheme 47

7b

Scheme 48

Scheme 49

7d

To summarize, the following novel ortho-gem-dibromovinylphenols have been prepared as describe above and in the Examples:

Examples

General Procedures: All reactions were carried out under N ₂ . Solvents and solutions were added with a syringe, unless otherwise noted. Analytical TLC was performed using EM separations precoated silica gel 0.2 mm layer UV fluorescent sheets. Column chromatography was carried out as "flash chromatography" as reported by Still using Merck 60 (230-400 mesh) silica gel (Still, W. C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-5). Unless otherwise specified, extracts were dried over MgSO ₄ and solvents were removed with a rotary evaporator at aspirator pressure.

Toluene was distilled under N ₂ from Na/benzophenone, dichloromethane was distilled from automatic distillation (SPS system) and 1,2-dichloroethane was distilled from CaH ₂ immediately prior to use. EtOH and DMF were purchased from Aldrich and were used

without further distillation. S-Phos was purchased from Strem Chemical Company, and other pre-catalysts or reagents were obtained from commercial sources without further purification. 10% Pd-C Pearlman's catalyst was purchased from Strem (Palladium, 10% on activated carbon, Pearlman (50% wetted powder), Strem # 46-1706), which was originally produced by Degussa (Degussa E4, lot No. 20058613).

Melting points were taken on a Fisher- Johns melting point apparatus without correction. IR spectra were obtained using Nicolet DX FT IR spectrometer as a chloroform solution with NaCl cellule. High-resolution mass spectra were obtained from a VG 70-250S (double focusing) mass spectrometer at 70 eV. ¹ H, ¹³ C, and ¹⁹ F NMR spectra were obtained using Varian Mercury 400 or Mercury 300 spectrometers. Splitting patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; quint., quintuplet; sext, sextuplet; sept., septuplet; m, multiplet and br, broad peak. ¹ H spectra were referenced to tetramethylsilane (TMS, 0 ppm) using CDCl ₃ as solvent; ¹³ C spectra were referenced to solvent carbons (77.0 ppm for CDCl ₃ ).

In the examples which follow, PCT Application Publication Number WO/2006/047888 is referenced for the preparation of certain compounds (International Application No. PCT/CA2005/001703, filed November 4, 2005, published May 11, 2006, to Mark Lautens and Yuanqing Fang entitled "2-Substituted Indoles, their Precursors and Novel Processes for the Preparation Thereof), the contents of which are hereby incorporated by reference in this regard.

Preparation of ort/to-gg/«-dibromovinylaniline compounds of Formula (II)

General optimization process for the preparation of ortho-gem- dibromovinylnitrobenzenes :

To a solution of o-nitrobenzaldehyde (0.151 g, 1 mmol) and CBr ₄ (0.49 g, 1.5 mmol) in DCM (4 mL) was added dropwise a solution of corresponding phosphine or phosphite (3.0 mmol) in DCM (1 mL) at 0 ⁰ C. After 30 min, the reaction was warmed to rt, quenched with NaHCO ₃ , extracted with Et ₂ O, dried over MgSO ₄ . The product was

isolated using column chromatography and yields are shown in Table 4 above. The ¹ H NMR spectrum of the product was identical to the authentic sample.

Example A: Synthesis of l-(2,2-dibromo-vinyl)-2-nitro-benzene with non- chromatographic purification:

To a solution of o-nitrobenzaldehyde (2.0 g, 13.2 mmol) and CBr ₄ (6.6 g, 19.9 mmol) in dichloromethane (DCM) (50 mL) was added dropwise a solution of corresponding triisopropylphosphite (7.2 mL, 29 mmol) in DCM (10 mL) at 0 ⁰ C. After 30 min, the reaction was warmed to rt, quenched with NaHCO ₃ , extracted with Et ₂ O. After removal of solvent, the mixture was taken into concentrated HCl (12 N, 15 mL) and HOAc (15 mL) and refluxed overnight. The mixture was cooled to rt, diluted with H ₂ O (50 mL), neutralized by Na ₂ CO ₃ , extracted with Et ₂ O. After dried over MgSO ₄ , the solvent was removed in vacuum to give an off-white solid (3.51 g, 87%). The ¹ H NMR showed the product was analytically pure and identical to the authentic sample.

Example Ia: Preparation of Butyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine

2-(2,2-dibromo-vinyl)phenylamine (600.0 mg, 2.166 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and butyraldehyde (195.0 μL, 2.166 mmol) were mixed in 1 ,2-dichloroethane (8.0 mL, 0.28

M) and then treated with sodium triacetoxyborohydride (640.0 mg, 3.031 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 h. The reaction mixture was then quenched by addition of aqueous saturated NaHCO ₃ , and the product was extract with EtOAc. The organic phase was dried (Na ₂ SO ₄ ) and the solvent was evaporated to give the crude product. The mixture was purified by flash chromatography (30/l:hexanes/EtOAc) to afford a yellow solid (0.66 g, 92 %). mp 34-36 ⁰ C; IR (CHCl ₃ ) v 3423, 2960, 2932, 1602, 1578, 1506, 1456, 1319 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.26-7.20 (m, 3H), 6.69 (t, J= 7.5 Hz, IH), 6.63 (d, J= 8.3 Hz, IH), 3.52 (br, IH), 3.12 (t, J= 7.1 Hz, 2H), 1.63 (quint., J= 7.4 Hz, 2H), 1.43 (sext, J= 7.4 Hz, 2H), 0.96 (t, J= 7.3Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 145.2, 134.1, 129.8, 129.1, 121.3, 116.4, 110.6, 92.9, 43.5, 31.5, 20.3, 13.9; MS (EI) m/z 330.8 [ ⁷⁹ Br ⁷⁹ BrM] ⁺ , 332.8 [ ⁷⁹ Br ⁸¹ BrM] ⁺ , 334.8 [ ⁸¹ Br ⁸¹ BrM] ⁺ , 251.9 [ ⁷⁹ Br ⁸¹ BrM- ⁸¹ Br] ⁺ ; HRMS (EI) m/z calcd. for: [ ⁷⁹ Br ⁷⁹ BrM] ⁺ 330.9571, m/z found: 330.9577.

Example Ib: Preparation of [2-(2,2-Dibromo-vinyl)-phenyl]-isopropyl-amine

1b

To a solution of 2-(2,2-dibromo-vinyl)phenylamine (0.554 g, 2.0 mmol) in DCE (6.0 mL) was sequentially added vinyl methyl ether (287.0 μL, 2.0 mmol), acetic acid (114.0 μL) and NaBH(O AC)3 (0.636 g) in one portion. The mixture was stirred at room temperature for 20 h. The mixture was quenched by pouring into NaHCO ₃ solution, extract with DCM and dried over Na ₂ SO ₄ . The mixture was purified by flash chromatography (5 % EtOAc in hexanes). Yield: 100 %, white solid, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.19 (m, 3H), 6.71-6.42 (m, 2H), 3.65 (m, IH), 3.38 (br, IH), 1.23 (d, 6H).

Example Ic: Preparation of (2-Bromo-benzyl)-[2-(2,2-dibromo-vinyl)-phenyl]-amine

Following the same procedure as for Ia with 2-(2,2-dibromo-vinyl)phenylamine (see

PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2-bromobenzaldehyde. Yield: 42 %, yellow solid, mp 144-146 ⁰ C; IR (CHCl ₃ ) v 3443, 1603, 1458, 1321 cm ^'1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59-7.48 (m,

IH), 7.35 (m, 2H), 7.28-7.23 (m, 2H), 7.18-7.15 (m, 2H), 6.75 (t, J= 7.4 Hz, IH), 6.53 (d,

J= 8.2 Hz, IH), 4.45 (s, 2H), 4.18 (br, IH); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.4, 137.6,

134.0, 132.8, 129.8, 129.2, 128.9, 128.7, 127.6, 123.2, 121.9, 117.4, 111.3, 93.7, 48.3;

MS (EI) m/z 442.9 [M] ⁺ , 444.9 [M] ⁺ , 446.9 [M] ⁺ , 448.9 [M] ⁺ , 365.9 [M- ⁸¹ Br] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 442.8510, m/z found: 442.8519.

Example Id: Preparation of 3-BenzyIamino-4-(2,2-dibromo-vinyl)-benzoic acid methyl ester

1d

Following the same procedure as for Ia with 3-amino-4-(2,2-dibromo-vinyl)-benzoic acid methyl ester (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzaldehyde. Yield: 66 %, yellow oil; IR (CHCl ₃ ) v 3441, 2952, 2846, 1717, 1571, 1438, 1299, 1265, 1201 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36-7.25 (m, 9H), 4.77 (s, 2H), 4.00 (br, IH), 3.83 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.0, 144.8, 138.3, 133.2, 131.2, 129.2, 128.7 (2C), 127.6 (2C), 127.5, 125.8, 118.3, 111.8, 94.7, 52.1, 48.0; MS (EI) m/z 425.0 [ ⁷⁹ Br ⁸¹ BrM] ⁺ ; HRMS (EI) m/z calcd. for: [ ⁷⁹ Br ⁷⁹ BrM] ⁺ 422.9469, m/z found: 422.9469.

Example Ie: Preparation of Benzyl-[2-(2,2-dibromo-vinyl)-5-fluoro-phenyl]-amine

1e

Following the same procedure as for Ia with 2-(2,2-dibromo-vinyl)-5-fluoro- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzaldehyde. Yield: 43 %, white solid, mp 94-95 ⁰ C; IR (CHCl ₃ ) v 3440, 3035, 3011, 1613, 1590, 1514, 1202 cm ^'1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.28 (m, 4H), 7.22-6.27 (m, 3H), 6.40 (td, J= 8.3, 2.4 Hz, IH), 6.29 (dd, J = 11.5, 2.4 Hz, IH), 4.32 (d, J= 5.5 Hz, 2H), 4.12 (br, IH); ¹³ C NMR (400 MHz, CDCl ₃ ) δ 164.1 (J _CF = 245.7 Hz), 146.6 {J _CF = 11.1 Hz), 138.1, 133.1, 130.6 (J _C F= 10.4 HZ), 128.8 (2C), 127.5, 127.3 (2C), 117.4 (J _CF = 2.7 Hz), 103.7 (J _CF = 22.2 Hz), 98.3 (J _Cf = 26.5 Hz), 93.9, 48.0; MS (EI) m/z 385.0 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 382.9320, m/z found: 382.9322.

Example If: Preparation of BenzyI-[4-benzyloxy-2-(2,2-dibromo-vinyl)-phenyl]- amine

1f

Following the same procedure as for Ia with 2-(2,2-dibromo-vinyl)-4-phenoxy- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzaldehyde. Yield: 40 %, orange oil; ¹ H NMR (300

MHz, CDCl ₃ ) δ 7.42-7.35 (m, 6H), 7.31-7.24 (m, 5H), 7.00 (d, J= 2.9 Hz, IH), 6.87 (ddJ

= 2.9, 8.9 Hz, IH), 6.58 (d, J= 8.9 Hz, IH), 4.99 (s, 2H), 4.32 (s, 2H), 3.72 (br, IH); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 150.6, 139.5, 139.1, 137.3, 133.7, 128.6 (2C), 128.5 (2C), 127.8, 127.4 (2C), 127.3 (2C), 127.2, 122.6, 117.0,, 116.0, 112.6, 93.1, 70.9, 48.8; MS (EI) m/z 473.1 [ ⁷⁹ Br ⁸¹ BrM] ⁺ ; HRMS (EI) m/z calcd. for: [ ⁷⁹ Br ⁷⁹ BrM] ⁺ 470.9822, m/z found: 470.9833.

Example Ig: Benzyl-[3-benzyloxy-2-(2,2-dibromo-vinyl)-4-methoxy-phenyl]- amine

ig

Following the same procedure as for Ii with 2-(2,2-dibromo-vinyl)-4-methoxy-3- phenoxy-phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzyl bromide. Yield: 77 %, brown oil; IR (CHCl ₃ ) v 3443, 3044, 1580, 1439 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.24 (m, 11 H), 7.13 (s, IH), 6.83 (d, J= 8.8 z, IH), 6.31 (d, J= 8.8 Hz, IH), 4.99 (s, 2H), 4.33 (s, 2H), 3.79 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 145.8, 144.7, 139.6, 139.4, 137.6, 132.5, 128.6 (2C), 128.4 (2C), 128.3 (2C), 127.9, 127.2 (2C), 127.1, 117.6, 114.8, 106.3, 95.2, 75.0, 56.7, 48.7; MS (EI) m/z 500.7 [ ⁷⁹ Br ⁷⁹ BrM] ⁺ , 502.7 [ ⁷⁹ Br ⁸¹ BrM] ⁺ , 504.7 [ ⁸¹ Br ⁸¹ BrM] ⁺ ; HRMS (EI) m/z calcd. for: [ ⁷⁹ Br ⁷⁹ BrM] ⁺ 500.9939, m/z found: 500.9924.

Example Ih: Preparation of Benzyl-[2-(2,2-dibromo-vinyl)-3-methyl-phenyl]-amine

Following the same procedure as for Ii with 2-(2,2-dibromo-vinyl)-3-methyl- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and benzyl bromide. Yield: 71 %, white solid, mp 44-46

⁰ C; IR (CHCl ₃ ) v 3444, 3065, 3004, 2921, 1582, 1496, 1471, 1452, 1322 cm ^"1 ; ¹ H NMR

(400 MHz, CDCl ₃ ) δ 7.34-7.26 (m, 6H), 7.07 (t, J= 7.8 Hz, IH), 6.57 (d, J= 7.5 Hz, IH), 6.43 (d, J= 8.2 Hz, IH), 4.37 (s, 2H), 4.14 (br, IH), 2.20 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.5, 139.2, 136.4, 134.8, 129.2, 128.6 (2C), 127.1, 127.0 (2C), 121.4, 118.8, 108.3, 95.3, 48.0, 20.0; MS (EI) m/z 379.1 [ ⁷⁹ Br ⁷⁹ BrM] ⁺ , 381.1 [ ⁷⁹ Br ⁸¹ BrM] ⁺ , 383.1 [ ⁸¹ Br ⁸¹ BrM] ⁺ , 300.0 [M- ⁸¹ Br] ⁺ ; HRMS (ESI) m/z calcd. for: [ ⁷⁹ Br ⁷⁹ BrM+H] ⁺ 379.9643, m/z found: 379.9640.

Example Ii: Preparation of Benzyl-[2-(2,2-dibromo-vinyl)-naphthalen-l-yl]-amine

To a suspension of the 2-(2,2-dibromo-vinyl)-naphthalen-l-ylamine (200.0 mg, 0.615 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and K ₂ CO ₃ (102.0 mg, 0.738 mmol) in DMF (2.0 ml) was added benzyl bromide (90.0 μL, 0.738 mmol). The mixture was stirred at room temperature for 48 h under nitrogen. Then mixture was diluted with Et ₂ O, washed with

H ₂ O, brine. The mixture was purified by flash chromatography (2 % EtOAc in hexanes) to afford an orange oil (151.0 mg, 59 %). IR (CHCl ₃ ) v 3445, 3064, 3002, 1567, 1511,

1453, 1391 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J= 8.3 Hz, IH), 7.78 (d, J= 9.3

Hz, IH), 7.55-7.41 (m, 5H), 7.34-7.28 (m, 5H), 4.34 (s, 2H); ¹³ C NMR (100 MHz,

CDCl ₃ ) δ 142.9, 139.9, 136.1, 134.4, 128.7 (2C), 128.6, 127.9 (2C), 127.7, 127.6, 126.6,

126.5, 125.9, 123.8, 122.2, 122.0, 91.4, 54.9; MS (EI) m/z 414.8 [ ⁷⁹ Br ⁷⁹ BrM] ⁺ , 416.8 [ ⁷⁹ Br ⁸¹ BrM] ⁺ , 418.8 [ ⁸¹ Br ⁸¹ BrM] ⁺ ; HRMS (EI) m/z calcd. for: [ ⁷⁹ Br ⁷⁹ BrM] ⁺ 414.9571, m/z found: 141.9587.

Example Ij: Preparation of 2-(2,2-Dibromo-vinyl)-6-methoxy-phenylamine

To a solution of the 3-methoxy-2-nitrobenzaldehyde (1.087 g, 6.0 mmol) and carbon tetrabromide (2.985 g, 9.0 mmol) in CH ₂ Cl ₂ (30.0 niL) at 0 ⁰ C was added dropwise a solution of triphenylphosphine (4.721 g, 18.0 mmol) in CH ₂ Cl ₂ (20.0 mL). After the addition was complete, the reaction was stirred at 0 ⁰ C for 0.5 h then warmed to rt and stirred for another hour. The solvent was removed in vacuo and the crude material purified using chromatography eluting with 20% EtOAc/hexane to give a yellow solid (1.866 g, 5.5 mmol). Yield: 92 %, yellow solid, mp 98-99 ⁰ C; IR (neat) v 1602, 1514, 1289, 1069 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ .46 (IH, t, J 8.1), 7.39 (IH, s), 7.22 (IH, d, J 7.9), 7.06 (IH, d, J 8.6), 3.93 (3H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 151.3, 131.3, 130.7, 129.9, 121.4, 113.0, 96.2, 56.8; HRMS (EI) m/z calcd. for: [M] ⁺ 334.8793, m/z found: 334.8792. The substrate (1.80 g, 5.3 mmol) and acetic acid (1.6 mL) in EtOH (16.0 mL) were warmed to 40 ⁰ C, then Fe (2.07 g, 37.1 mmol) and FeCl ₃ -OH ₂ O (143.0 mg, 0.53 mmol) added to it. After 3.5 h, tic showed incomplete reaction, therefore another 0.10 mL of acetic acid was added to the reaction. After an additional 0.5 h the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The solvent was removed in vacuo to yield the pure product as an off-white solid (1.524 g, 4.9 mmol). Yield: 93 %, white solid, mp ⁰ C; IR (CHCl ₃ ) v 3333, 2942, 1619, 1463, 1241 cm ^" '; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (IH, s), 6.99-6.94 (IH, m), 6.82-6.71 (2H, m), 3.91 (2H, br s), 3.87 (3H, s); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 147.5, 134.1 (2C), 121.8, 121.1, 117.7, 110.2, 92.8, 55.8; HRMS (EI) m/z calcd. for: [M] ⁺ 304.9051, m/z found: 304.9051.

Preparation of 2-vinyl indoles of Formula (D

The results of the preparation of various 2-substituted indoles of Tables 1, 2 and 3 above are shown in Examples 2a-2aa below.

General Procedures A, B and C for intermolecular palladium-catalyzed tandem reactions using an alkene reagent

A tube (24x150 mm) of Carousel reaction station was charged with ortho-gem- dibromovinylaniline (1.0 equiv.), powdered K ₃ PO ₄ -H ₂ O (2.0 equiv.) and Procedure A: Pd(OAc) ₂ (4.0 mol %), Me ₄ NCl (1.0 equiv.) or Procedure B: Pd(OAc) ₂ (4.0 mol %), P(σ-tolyl) ₃ (8.0 mol %) or Procedure C: Pd ₂ dba ₃ (3.0 mol %), S-Phos (12.0 mol %) and the mixture was purged with argon and vacuum three times. Triethylamine (2.0 equiv.), alkene (2.0 equiv.) and toluene (0.1M) were added and the reaction stirred at 120 ⁰ C until all the starting material had been consumed (typically 15-96 h). The reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with EtOAc, the organic phase was dried (Na ₂ SO ₄ ) and the solvent was evaporated. The crude product was purified by flash chromatography (typically 2% EtOAc in hexanes) to afford the indole 2.

Example 2a: Preparation of 3-(l-Benzyl-lH-indol-2-yl)-acrylic acid tert-butyl ester

2a

Following General Procedure A. A tube (24><150 mm) of carousel reaction station was charged with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) (200.0 g, 0.545 mmol), powdered K ₃ PO ₄ -H ₂ O (250.0 mg, 1.089 mmol), Pd(OAc) ₂ (4.9 mg, 0.022 mmol, 4.0 mol %), Me ₄ NCl (60.0 mg, 0.545 mmol) and the mixture was purged with argon and vacuum three times. Triethylamine (151.0 μL, 1.089 mmol), tertbutyϊ acrylate (160.0 μL, 1.089 mmol) and toluene (5.5 mL, 0.1M) were added and the reaction stirred at 120 ⁰ C until all the starting material had been consumed (15 h). The reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with EtOAc, the organic phase was dried (Na ₂ SO ₄ ) and the solvent was evaporated. The crude product was purified by flash chromatography (2 % EtOAc in hexanes) to afford 2a. Yield: 79 %, yellow solid, mp 84-86 ⁰ C; IR (CHCl ₃ ) v 3015, 2981, 1698, 1629, 1453, 1347, 1369, 1314, 1288, 1147 cm ^'1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ

7.65 (d, J= 15.7 Hz, IH), 7.64 (d, J= 7.8 Hz, IH), 7.29-7.25 (m, 5H), 7.23 (t, J= 6.8 Hz, IH), 7.13 (t, J= 6.8 Hz, IH), 7.05-7.02 (m, 2H), 6.41 (d, J= 15.7 Hz, IH), 5.46 (s, 2H), 1.48 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.1, 138.7, 137.2, 135.1, 131.5, 128.8 (2C), 127.7, 127.5, 126.0 (2C), 123.6, 121.3, 120.7, 120.6, 110.0, 103.6, 80.5, 46.7, 28.2 (3C); MS (EI) m/z 333.2 [M] ⁺ , 232.1 [M-CO ₂ ^Bu] ⁺ ; HRMS (EI) m/z calcd.for: [M] ⁺ 333.1728, m/z found: 333.1731.

Example 2b: Preparation of l-Benzyl-2-styryl-lH-indole

2b

Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and styrene. Yield: 65 %, yellow solid, mp 98-101 ⁰ C; IR (CHCl ₃ ) v 3061,

3006, 2976, 1597, 1496, 1453, 1348, 1319 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d,

J= 6.8 Hz, IH), 7.36 (m, 2H), 7.29-7.15 (m, 8H), 7.11-7.00 (m, 5H), 6.85 (s, IH), 5.39 (s,

2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.3, 137.9, 137.7, 137.0, 131.1, 128.8 (2C), 128.7 (2C), 128.0, 127.8, 127.4, 126.4 (2C), 126.0 (2C), 122.0, 120.5, 120.2, 116.9, 109.5, 99.6,

46.7; MS (EI) m/z 309.2 [M] ⁺ , 91.0 [Bn] ⁺ ; HRMS (EI) m/z calcd.for: [M] ⁺ 309.1517, m/z found: 309.1521.

Example 2c: Preparation of l-Benzyl-2-[2-(4-chloro-phenyl)-vinyl]-lH-indole

Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and l-chloro-4-vinyl -benzene. Yield: 71 %, yellow solid, mp 132-135 ⁰ C; IR (CHCl ₃ ) v 3030, 3023, 3006, 1490, 1453, 1348, 1319 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J= 6.6 Hz, IH), 7.33-7.23 (m, 8H), 7.18-7.11 (m, 2H), 7.08-6.99 (m, 4H), 6.88

(s, IH), 5.44 (s, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.0, 137.9, 137.7, 135.5, 133.3, 129.7 (4C), 128.8, 128.1, 127.5 (2C), 127.4, 126.0 (2C), 122.2, 120.6, 120.3, 117.5, 109.5, 99.9, 46.8; MS (EI) m/z 343.1 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 343.1127, m/z found: 343.1126.

Example 2d: Preparation of l-Benzyl-2-[2-(4-methoxy-phenyl)-vinyl]-lH-indole

Following General Procedure B with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and l-methoxy-4-vinyl-benzene. Yield: 73 %, yellow solid, mp 151-155 ⁰ C; IR (CHCl ₃ ) v 3061, 3006, 2936, 1605, 1509, 1453, 1250, 1175 cm ^"1 ; ¹ U NMR (400 MHz, CDCl ₃ ) δ 7.61 (m, IH), 7.33 (d, J= 8.6 Hz, 2H), 7.27-7.20 (m, 4H), 7.14-7.05 (m, 5H), 6.92 (s, IH), 6.88-6.83 (m, 3H), 5.41 (s, 2H), 3.78 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.4, 138.7, 137.8 (2C), 130.9, 129.8, 128.8 (2C), 128.2, 127.7 (2C), 127.3, 126.0 (2C), 121.7, 120.3, 120.1, 114.8, 114.1 (2C), 109.4, 98.9, 55.3, 46.7; MS (EI) m/z 339.3 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 339.1623, m/z found: 339.1622.

Example 2e: Preparation of 3-(l-Benzyl-lH-indol-2-yl)-acrylonitrile

Following General Procedure B with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and acrylonitrile. Yield: 70 % (conversion 80 %), yellow white solid, mp 121-124 ⁰ C; IR (CHCl ₃ ) v 3023, 2216, 1616, 1521, 1454, 1348, 1324, 1234, 1215, 1201 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (dt, J= 8.0, 0.9 Hz, IH), 7.33 (d, J= 16.3 Hz, IH), 7.31-7.24 (m, 5H), 7.15 (t, J= 8.0 Hz, IH), 7.02 (s, IH), 6.98-6.96 (m, 2H), 5.80 (d,

J= 16.3 Hz, IH), 5.40 (s, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 139.1, 138.2, 136.6, 133.7, 129.0 (2C), 127.8, 127.3, 125.7 (2C), 124.7, 121.7, 121.1, 118.3, 110.0, 104.6, 95.7, 46.8; MS (EI) m/z 258.2 [M] ⁺ , 91.0 [Bn] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 258.1156, m/z found: 258.1159.

Example 2f: Preparation of 2-(2-Benzenesulfonyl-vinyl)-l-benzyl-lH-indole

Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and ethenesulfonyl-benzene. Yield: 40 %, brown solid, mp 133-137 ⁰ C; IR (CHCl ₃ ) v 3024, 3009, 1606, 1521, 1447, 1347, 1324, 1147, 1085 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (m, 3H), 7.69 (d, J= 15.2 Hz, IH), 7.62 (d, J= 8.0 Hz, IH), 7.58 (m, IH), 7.48 (m, IH), 7.32-7.23 (m, 6H), 7.14 (t, J= 7.9 Hz, IH), 7.00-6.97 (m, 2H), 6.77 (d, J= 15.2 Hz, IH), 5.47 (s, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 140.7, 139.2, 136.9, 133.2, 132.3, 130.8, 129.2 (2C), 128.9 (2C), 127.7, 127.5 (2C), 127.4, 126.6, 126.0 (2C), 124.6, 121.7, 121.0, 110.0, 105.9, 46.9; MS (ESI) m/z 374.1 [M+H] ⁺ , 396.1 [M+Na] ⁺ ; HRMS (ESI) m/z calcd. for: [M+H] ⁺ 374.1209, m/z found: 374.1215.

Example 2g: Preparation of l-(l-BenzyI-lH-indol-2-yl)-pent-l-en-3-one

Following General Procedure B with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and pent- l-en-3 -one. Yield: 38 %, orange solid, mp 122-125 ⁰ C; IR (CHCl ₃ ) v 3025, 3007, 1657, 1598, 1454, 1349, 1322 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, J= 8.0 Hz, IH), 7.57 (d, J= 15.8 Hz, IH), 7.25-7.16 (m, 5H), 7.09 (m, IH), 7.03 (s, IH),

6.97 (m, 2H), 6.74 (d, J= 15.8 Hz, IH), 5.42 (s, 2H), 2.54 (q, J= 7.3 Hz, 2H), 1.07 (t, J= 7.3 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 200.0, 139.1, 137.2, 135.0, 129.8, 128.9 (2C), 127.9, 127.6, 125.9 (2C), 125.8, 123.9, 121.5, 120.8, 110.0, 104.3, 46.8, 34.7, 8.2; MS (EI) m/z 289.2 [M] ⁺ , 232.2 [M-C ₃ H ₅ O] ⁺ , 91.0 [Bn] ⁺ ; HRMS (EI) m/z calcd.for: [M] ⁺ 289.1466, m/z found: 289.1465.

Example 2h: Preparation of Acetic acid 3-(l-benzyl-lH-indol-2-yl)-allyl ester

Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and acetic acid allyl ester. Yield: 36 %, yellow solid, mp 83-85 ⁰ C; IR (CHCl ₃ ) v 3031, 3009, 1735, 1454, 1235, 1219 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, J= 7.5 Hz, IH), 7.27-7.22 (m, 4H), 7.16-7.10 (m, 2H), 7.01 (m, 2H), 6.76 (s, IH), 6.62 (d, J= 15.8 Hz, IH), 6.35 (t, J= 6.4 Hz, IH), 6.31 (t, J= 6.4 Hz, IH), 5.38 (s, 2H), 4.67 (dd, J= 6.4, 1.2 Hz, IH), 2.06 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.7, 137.7, 137.6, 136.7, 128.8 (2C), 127.9, 127.4, 125.9 (2C), 125.8, 122.7, 122.2, 120.6, 120.2, 109.6, 100.3, 64.8, 46.7, 20.9; MS (EI) m/z 305.1 [M] ⁺ , 262.1 [M-Ac] ⁺ , 246.1 [M-OAc] ⁺ , 91.0 [Bn] ⁺ ; HRMS (EI) m/z calcd.for: [M] ⁺ 305.14154, m/z found: 305.1414.

Example 2i and 2i': Preparation of l-(l-Benzyl-lH-indol-2-yl)-decan-3-one and 1- (l-Benzyl-lH-indol-2-yl)-dec-l-en-3-ol

Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this

compound) and cec-l-en-3-ol. Yield: 82 % (2i/2i': 3/1). 2i: yellow solid, 49-51 ⁰ C; IR

(CHCl ₃ ) v 3006, 2929, 2857, 1711, 1496, 1463, 1453, 1409, 1355 cm ^"1 ; ¹ H NMR (400

MHz, CDCl ₃ ) δ 7.55 (m, IH), 7.23-7.20 (m, 4H), 7.13-7.05 (m, 2H), 6.97-9.94 (m, 2H),

6.29 (d, J=Hz, IH), 5.34 (s, 2H), 2.96 (m, 2H), 2.77 (m, 2H), 2.36 (t, J= 7.5 Hz, 2H), 1.53 (m, 2H), 1.25 (m, 8H), 0.87 (t, J= 7.0 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ

209.6, 139.8, 137.7, 137.2, 128.7 (2C), 127.9, 127.2, 125.9 (2C), 121.1, 119.8, 119.6,

109.3, 99.2, 46.3, 42.9, 41.1, 31.6, 29.1, 29.0, 23.8, 22.6, 20.5, 14.0; MS (EI) m/z 361.1

[M] ⁺ , 234.0 [M-C ₈ Hi ₅ O] ⁺ , 91.0 [Bn] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 361.2405, m/z found: 361.2390. 2i': white solid, mp 45-48 ⁰ C; IR (CHCl ₃ ) v 3602, 3008, 2929, 2857, 1496, 1453, 1354, 1318, 1199 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (dd, J= 6.9, 1.3 Hz, IH), 7.27-7.20 (m, 4H), 7.14-7.06 (m, 2H), 7.00 (m, 2H), 6.71 (s, IH), 6.55 (d, J= 15.7 Hz, IH), 6.27 (dd, J= 15.7, 6.4 Hz, IH), 5.37 (s, 2H), 4.21 (m, IH), 1.54 (m, 4H), 1.25 (m, 8H), 0.87 (t, J= 6.9 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 137.7, 137.6, 137.5, 135.7, 128.7 (2C), 128.0, 127.3, 126.0 (2C), 121.9, 120.4, 120.0, 118.8, 109.5, 99.5, 72.8, 46.7, 37.3, 31.8, 29.5, 29.2, 25.3, 22.6, 14.1; MS (EI) m/z 361.1 [M] ⁺ , 234.0 [M-C ₈ H ₁₅ O] ⁺ , 91.0 [Bn] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 361.2405, m/z found: 361.2411.

Example 2j : Preparation of 3-(l-Benzyl-lH-indol-2-yl)-N-tert-butyl-acrylamide

Following General Procedure A with benzyl- [2-(2,2-dibromo-vinyl)-phenyl] -amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and N-tert-butyl-acrylamide. Yield: 45 %, white solid, mp 215-217 ⁰ C; IR (CHCl ₃ ) v 3434, 3005, 1664, 1621, 1507, 1453, 1348, 1320 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J= 15.2 Hz, IH), 7.61(d, J= 7.8 Hz, IH), 7.25-7.17 (m, 6H), 7.11 (t, J= 6.9 Hz, IH), 6.99 (m, 2H), 6.92 (s, IH), 6.37 (d, J= 15.2 Hz, IH), 5.44 (s, 2H), 1.40 (s,

9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.7, 138.4, 137.3, 135.6, 128.8 (2C), 128.4, 127.7, 127.4, 125.9 (2C), 123.2, 122.9, 121.0, 120.5, 110.0, 102.3, 51.5, 46.6, 28.8 (3C); MS (EI) m/z 332.3 [M] ⁺ , 91.0 [Bn] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 332.1888, m/z found: 332.1885.

Example 2k: Preparation of 3-(l-Benzyl-lH-indol-2-yl)-l-morpholin-4-yl- propenone

Following General Procedure C with benzyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and l-morpholin-4-yl-propenone. Yield: 63 %, yellow solid, mp 155-157 ⁰ C; IR (CHCl ₃ ) v 3019, 2925, 2861, 1641, 1597, 1454, 1434, 1347, 1221, 1209 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J= 15.2 Hz, IH), 7.63 (d, J= 7.9 Hz, IH), 7.29-7.20 (m, 6H), 7.13 (t, J= 7.7 Hz, IH), 7.02 (m, 2H), 6.98 (s, IH), 6.82 (d, J= 15.2 Hz, IH), 5.47 (s, 2H), 3.68 (m, 5H), 3.50 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.1, 138.8, 137.4, 135.7, 131.4, 128.8 (2C), 127.6, 127.5, 125.9 (2C), 123.6, 121.2, 120.6, 117.0, 109.9, 103.5, 66.7, 46.9; MS (EI) m/z 346.1 [M] ⁺ , 232.1 [M-C ₅ H ₈ NO ₂ ] ⁺ , 91.0 [Bn] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 346.1681, m/z found: 346.1676.

Example 21: Preparation of 3-(lH-Indol-2-yl)-acrylic acid tert-butyl ester

Following General Procedure B with with 2-(2,2-dibromo-vinyl)-phenyl]-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tertbutylacrylate. Pd(OAc) ₂ (6.0 % mol) and P(o-tolyl) ₃ (12.0 % mol)

were used and were added a second time after 24 h of reflux. Yield: 50 %, yellow-orange solid, mp 131-134 ⁰ C; IR (CHCl ₃ ) v 3471, 3012, 2982, 1696, 1615, 1631, 1615, 1369, 1297, 1153 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (br, IH), 7.58 (d, J= 16.0 Hz, IH), 7.57 (m, IH), 7.34 (m, IH), 7.24 (t, J= 7.5 Hz, IH), 7.10 (t, J= 7.4 Hz, IH), 6.77 (s, IH), 6.25 (d, J= 16.0 Hz, IH), 1.56 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.5, 137.8, 133.6, 133.5, 128.4, 124.3, 121.4, 120.4, 117.6, 111.1, 108.4, 80.8, 28.2 (3C); MS (ESI) m/z 266.1 [M+Na] ⁺ ; HRMS (ESI) m/z calcd. for: [M+Na] ⁺ 266.1151, m/z found: 266.1169 (Grimster, N. P.; Gauntlett, C; Godfrey, CR. A.; Gaunt, M.J. Angew. Chem. Int. Ed. 2005, 44, 3125).

Example 2m: Preparation of 3-(l-Butyl-lH-indol-2-yl)-acrylic acid tert-butyl ester

Following General Procedure A with butyl-[2-(2,2-dibromo-vinyl)-phenyl]-amine Ia and tertbutylacrylate. Yield: 69 %, yellow solid, mp 50-52 ⁰ C; IR (CHCl ₃ ) v 3060, 2963, 2875, 1699, 1630, 1521, 1456, 1406, 1368, 1314, 1145 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (d, J= 15.7 Hz, IH), 7.59 (d, J= 7.6 Hz, IH), 7.31 (m, IH), 7.22 (t, J= 7.6 Hz, IH), 7.09 (t, J= 7.4 Hz, IH), 6.92 (s, IH), 6.43 (d, J= 15.7 Hz, IH), 4.21 (t, J= 7.3 Hz, 2H), 1.75 (quint., J= 7.5 Hz, 2H), 1.55 (s, 9H), 1.35 (sext, J= 7.4 Hz, 2H), 0.94 (t, J= 7.4 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.4, 138.2, 134.6, 131.6, 127.5, 123.1, 121.3, 120.2 (2C), 109.7, 102.8, 80.6, 43.1, 32.7, 28.2 (3C), 20.2, 13.7; MS (EI) m/z 299.3 [M] ⁺ , 243.2 [M-C ₄ Hg] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 299.1885, m/z found: 299.1884.

Example 2n: Preparation of 3-(l-Isopropyl-lH-indol-2-yl)-acrylic acid tert-butyl ester

Following General Procedure A with [2-(2,2-Dibromo-vinyl)-phenyl]-isopropyl-amine Ib and rerfbutylacrylate. Yield: 67 %, yellow solid, mp 75-76 ⁰ C; IR (CHCl ₃ ) v 2981, 2935, 1697, 1626, 1369, 1314, 1279, 1149 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J= 15.4 Hz, IH), 7.59 (d, J= 7.7 Hz, IH), 7.47 (d, J= 7.6 Hz, IH), 7.19 (t, J= 7.8 Hz, IH), 7.06 (t, J= 7.8 Hz, IH), 6.88 (s, IH), 6.39 (d, J= 15.5 Hz, IH), 4.86 (sept, J= 7.0 Hz, IH), 1.64 (d, J= 7.0 Hz, 6H), 1.55 (s, 9H) ; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.4, 137.0, 134.7, 132.6, 128.2, 122.7, 121.4, 120.6, 119.9, 111.5, 103.3, 80.6, 47.2, 28.2 (3C), 22.0 (2C); MS (ESI) m/z 286.2 [M+H] ⁺ , 308.2 [M+Na] ⁺ ; HRMS (ESI) m/z calcd. for: 286.1801 [M+H] ⁺ , m/z found: 286.1790.

Example 2o: Preparation of 3-[l-(2-Bromo-benzyl)-lH-indol-2-yl]-acrylic acid tert- butyl ester

Following General Procedure A with (2-Bromo-benzyl)-[2-(2,2-dibromo-vinyl)-phenyl]- amine Ic and tertbutylacrylate. Yield: 62 %, yellow solid, mp 110-115 ⁰ C; IR (CHCl ₃ ) v 3005, 2981, 1699, 1629, 1456, 1444, 1407, 1369, 1314, 1291, 1148 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J= 7.7 Hz, IH), 7.60 (d, J= 7.7 Hz, IH), 7.52 (d, J= 15.7 Hz, IH), 7.18-7.04 (m, 6H), 6.40 (d, J= 15.7 Hz, IH), 6.27 (d, J= 7.4 Hz, IH), 5.47 (s, 2H), 1.50 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.1, 138.6, 136.1, 135.1, 132.7, 131.1, 129.0, 127.9, 127.7, 127.0, 123.8, 121.5, 121.4, 121.0, 120.9, 109.9, 103.9, 80.7, 47.1, 28.2 (3C); MS (EI) m/z 411.2 [ ⁷⁹ BrM] ⁺ , 413.2 [ ⁸² BrM] ⁺ ; HRMS (EI) m/z calcd. for: [ ⁷⁹ Br M] ⁺ 411.0833, m/z found: 411.0825.

Example 2p: Preparation of 3-(l-Phenyl-lH-indol-2-yl)-acrylic acid tert-butyl ester

Following General Procedure C with [2-(2,2-dibromo-vinyl)-phenyl]-phenyl-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tertbutylacrylate. Yield: 78 %, yellow oil; IR (CHCl ₃ ) v 3019, 1699, 1629, 1501, 1392, 1343, 1230, 1154, 1142 cm ^'1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65 (m, IH), 7.57-7.44 (m, 4H), 7.38-7.32 (m, 2H), 7.17-7.12 (m, 3H), 7.07 (s, IH), 6.26 (d, J= 15.9 Hz, IH), 1.47 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.2, 139.6, 136.9, 135.5, 132.4, 129.7 (2C), 128.3 (2C), 128.3, 127.6, 123.8, 121.2, 121.0, 120.1, 110.7, 104.4, 80.4, 28.1 (3C); MS (EI) m/z 319.0 [M] ⁺ , 218.0 [M-CO ₂ ^Bu] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 319.1572, m/z found: 319.1575.

Example 2q: Preparation of 3-[l-(4-Trifluoromethyl-phenyl)-lH-indol-2-yl]-acrylic acid tert-butyl ester

Following General Procedure C with [2-(2,2-dibromo-vinyl)-phenyl]-(4-trifluoromethyl- phenyl)-amine (see PCT Application Publication Number WO/2006/047888, supra, for

preparation of this compound) and tør/butylacrylate. Yield: 68 %, yellow oil; IR (CHCI ₃ ) v 3005, 2981, 2933, 1701, 1629, 1522, 1450, 1393, 1369, 1325, 1107 cm ^'1 ; ¹ H NMR (W MHz, CDCl ₃ ) δ 7.82 (d, J= 8.3 Hz, 2H), 7.65 (m, IH), 7.47 (d, J= 8.2 Hz, 2H), 7.37 (d, J- 15.8 Hz, IH), 7.21-7.13 (m, 3H), 7.10 (s, IH), 6.32 (d, J= 15.8 Hz, IH), 1.49 (s, 9H); MS (EI) m/z 387.1 [M] ⁺ .

Example 2r: Preparation of 3-[l-(4-Fluoro-phenyl)-lH-indol-2-yl]-acrylic acid tert- butyl ester

Following General Procedure C with [2-(2,2-dibromo-vinyl)-phenyl]-(4-fluoro-phenyl)- amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tørtbutylacrylate and use Pd(OAc) ₂ (5.0 % mol), P(o- tolyl) ₃ (10.0 % mol). Yield: 60 %, yellow solid, mp 95-100 ⁰ C; IR (CHCl ₃ ) v 3004, 2981, 2933, 1699, 1629, 1512, 1451, 1393, 1369, 1343, 1312, 1142 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (m, IH), 7.37 (d, J= 15.9 Hz, IH), 7.30-7.13 (m, 6H), 7.07-7.04 (m, 2H), 6.24 (d, J= 15.9 Hz, IH), 1.48 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.1, 162.1 (J _CF = 248.7 Hz), 139.7 (J _CF =3.2 Hz), 135.5, 132.8, 132.0, 130.0, 129.9, 127.5, 123.9, 121.1 (Jc _F = 6.2 Hz, 2C), 120.3, 116.7 (J _CF = 22.8 Hz, 2C), 110.5, 104.5, 80.5, 28.1 (3C); MS (EI) m/z 337.0 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 337.1478, m/z found: 337.1472.

Example 2s: Preparation of 3-[l-(3,4-Dimethoxy-phenyl)-lH-indol-2-yl]-acrylic acid tert-butyl ester

Following General Procedure B with [2-(2,2-Dibromo-vinyl)-phenyl]-(3,4-dimethoxy- phenyl)-amine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and tertbutylacrylate. Yield: 60 %, white solid, mp 136- 140 ⁰ C; IR (CHCl ₃ ) v 3006, 2981, 2937, 1698, 1628, 1516, 1456, 1346, 1310, 1255, 1141 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J=7.7 Hz, IH), 7.42 (d, J= 15.9 Hz, IH), 7.19-7.10 (m, 3H), 7.04 (s, IH), 7.00 (m, IH), 6.91 (m, IH), 6.83 (d, J=2.2 Hz, IH), 6.25 (d, J= 15.9 Hz, IH), 3.97 (s, 3H), 3.86 (s, 3H), 1.48 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.3, 149.6, 149.1, 140.0, 135.7, 132.5, 129.6, 127.4, 123.8, 121.2, 120.9, 120.7, 119.9, 111.6, 111.4, 110.8, 104.1, 80.4, 56.1 (2C), 28.1 (3C); MS (EI) m/z 379.1 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 379.1783, m/z found: 379.1785.

Example 2t: Preparation of l-Benzyl-2-(2-tert-butoxycarbonyl-vinyl)-lH-indole-6- carboxylic acid methyl ester

Following General Procedure A with 3-benzylamino-4-(2,2-dibromo-vinyl)-benzoic acid methyl ester Id and tertbutylacrylate. Yield: 71 %, yellow solid, 120-123 ⁰ C; IR (CHCl ₃ ) v 3017, 2981, 1701, 1633, 1610, 1454, 1436, 1368, 1354, 1313, 1277, 1242, 1150 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, IH), 7.80 (dd, J= 8.4, 1.3 Hz, IH), 7.64 (d, J= 8.4 Hz, IH), 7.60 (d, J= 15.7 Hz, IH), 7.29-7.22 (m, 3H), 7.01-7-6.99 (m, 3H), 6.45 (d, J= 15.7 Hz, IH), 5.50 (s, 2H), 3.90 (s, 3H), 1.50 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 167.7, 165.7, 138.1, 137.9, 136.8, 131.0, 130.8, 128.9 (2C), 127.7, 125.9

(2C), 124.9, 122.7, 121.5, 120.9, 112.2, 103.2, 80.8, 52.0, 46.8, 28.1 (3C); MS (EI) m/z 391.2 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 391.1783, m/z found: 391.1777.

Example 2u: Preparation of 3-(l-Benzyl-6-fluoro-lH-iudol-2-yl)-acrylic acid tert- butyl ester

Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-5-fluoro-phenyl]- amine Ie and tertbutylacrylate. Yield: 70 %, yellow solid, mp 105-107 ⁰ C; DR. (CHCl ₃ ) v 3005, 2979, 1698, 1628, 1491, 1361, 1315, 1248, 1146, 1146, 1098 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J= 15.7 Hz, IH), 7.54 (m, IH), 7.28-7.25 (m, 3H), 7.00 (m, 2H), 6.93 (s, IH), 6.91-6.86 (m, 2H), 6.36 (d, J= 15.7 Hz, IH), 5.37 (s, 2H), 1.50 (s, 9H); ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -111.2; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.1, 160.7 (J _CF = 240.7 Hz), 138.8 (J _CF = 11.6 Hz), 136.7, 135.7 (J _CF = 4.0 Hz), 131.1, 128.9, 127.7 (2C), 125.9 (2C), 124.2, 122.3 (J _CF = 10.0 Hz), 120.5, 109.7 (J _CF = 25.2 Hz), 103.7, 96.3 (J _CF = 26.2 Hz), 80.6, 47.0, 28.2 (3C); MS (EI) m/z 351.3 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 351.1634, m/z found: 351.1628.

Example 2v: Preparation of 3-(l-Benzyl-6-benzyloxy-lH-indol-2-yl)-acryIic acid tert-butyl ester

Following General Procedure A with benzyl-[4-benzyloxy-2-(2,2-dibromo-vinyl)- phenyl]-amine If and /ertbutylacrylate. Yield: 64 %, yellow solid, mp 126-128 ⁰ C; IR (CHCl ₃ ) v 3007, 2978, 1697, 1617, 1453, 1369, 1314, 1298, 1185, 1151 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, J= 15.7 Hz, IH), 7.47-7.13 (m, 10H), 7.00-6.90 (m, 4H), 6.36 (d, J= 15.7 Hz, IH), 5.39 (s, 2H), 5.08 (s, 2H), 1.50 (s, 9H); ¹³ C NMR (100 MHz,

CDCl ₃ ) δ 166.2, 153.9, 137.4, 137.3, 135.4, 134.3, 131.4, 128.8 (2C), 128.5 (2C), 127.9, 127.8, 127.5 (2C), 125.9 (2C), 120.4, 115.2, 110.9, 103.5, 103.1, 80.5, 70.6, 46.8, 28.3 (3C); MS (EI) m/z 439.4 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 439.2147, m/z found: 439.2153.

Example 2w: Preparation of 3-(l-Benzyl-4-benzyloxy-5-methoxy-lH-indol-2-yl)- acrylic acid tert-butyl ester

Following General Procedure A with benzyl-[3-benzyloxy-2 ^' -(2,2-dibromo-vinyl)-4- methoxy-phenyl] -amine Ig and te/tbutylacrylate. Yield: 39 %, orange solid, mp 104-107 ⁰ C; IR (CHCl ₃ ) v 3005, 2978, 1697, 1629, 1496, 1369, 1341, 1296, 1252, 1149 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J= 15.7 Hz, IH), 7.55-7.52 (m, 2H), 7.41-7.23 (m, 7H), 7.01-6.99 (m, 2H), 6.95 (d, J= 8.8 Hz, IH), 6.90 (d, J= 8.8 Hz, IH), 6.37 (d, J= 15.7 Hz, IH), 5.37 (s, 2H), 5.25 (s, 2H), 3.88 (s, 3H), 1.49 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.1, 145.4, 141.0, 138.1, 137.2, 136.0, 135.3, 131.3, 128.8 (2C), 128.3 (2C), 128.0 (2C), 127.8 127.5, 126.0 (2C), 123.2, 120.8, 113.9, 105.2, 100.7, 80.5, 75.0, 58.3, 46.9, 28.2 (3C); MS (EI) m/z 469.0 [M] ⁺ , 378.0 [M-Bn] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 469.2279, m/z found: 469.2269.

Example 2x: Preparation of 3-(l-Benzyl-4-methyl-lH-indol-2-yl)-acrylic acid tert- butyl ester

Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-3-methyl-phenyl]- amine Ih and tør/butylacrylate. Yield: 38 %, yellow solid, mp 55-58 ⁰ C; IR (CHCl ₃ ) v 3005, 2980, 2932, 1699, 1628, 1496, 1455, 1369, 1350, 1314, 1145 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J= 15.7 Hz, IH), 7.28-7.23 (m, 3H), 7.11-7.09 (m, 2H), 7.04- 7.00 (m, 3H), 6.92 (m, IH), 6.41 (d, J= 15.7 Hz, IH), 5.43 (s, 2H), 2.56 (s, 3H), 1.50 (s, 9H); ¹³ C NMR (IOO MHZ, CDCl ₃ ) δ 166.2, 138.5, 137.3, 134.5, 131.5, 130.9, 128.8 (2C), 127.7, 127.5, 126.0 (2C), 123.8, 120.7, 120.4, 107.6, 102.2, 80.5, 46.9, 28.2 (3C), 18.6; MS (EI) m/z 347.2 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 347.1885, m/z found: 347.1882.

Example 2y: Preparation of 3-(l-Benzyl-lH-benzo[g]indol-2-yl)-acrylic acid tert- butyl ester

Following General Procedure A with benzyl-[2-(2,2-dibromo-vinyl)-naphthalen-l-yl]- amine Ii and førtbutylacrylate. 4.0 mol % of Pd(OAc) ₂ and 8.0 mol % P(o-tolyl) ₃ was added after 48 h of reflux. Yield: 43 %, yellow solid, mp 123-125 ⁰ C; IR (CHCl ₃ ) v 3008, 2977, 1696, 1622, 1388, 1368, 1290, 1147 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J= 8.1 Hz, IH), 7.89 (m, IH), 7.69 (d, J= 8.6 Hz, IH), 7.66 (d, J= 15.6 Hz, IH), 7.51 (d, J= 8.6 Hz, IH), 7.38-7.25 (m, 6H), 7.18-7.12 (m, 2H), 6.42 (d, J= 15.6 Hz, IH), 5.89 (s, 2H), 1.50 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.4, 137.1, 135.0, 132.8, 132.4, 131.3, 129.4, 129.1 (2C), 127.6, 125.7 (2C), 125.2, 124.2, 122.6, 122.3, 121.2, 120.7, 119.9, 105.2, 80.5, 49.5, 28.2 (3C); MS (EI) m/z 383.3 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 383.1885, m/z found: 383.1885.

Example 2z: Preparation of 3-(7-Methoxy-lH-indol-2-yl)-acrylic acid tert-butyl ester

Following General Procedure B with 2-(2,2-Dibromo-vinyl)-6-methoxy-phenylamine Ij and tertbutylacrylate. Yield: 53 %, yellow solid, mp 163-166 ⁰ C; IR (CHCl ₃ ) v 3470, 3005, 2979, 1698, 1634, 1369, 1330, 1307, 1256, 1152 cm ^"1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (br, IH), 7.57 (d, J= 16.0 Hz, IH), 7.20 (d, J= 7.9 Hz, IH), 7.01 (t, J= 7.9 Hz, IH), 6.74 (d, J= 2.3 Hz, IH), 6.67 (d, J= 7.9 Hz, IH), 6.18 (d, J= 16.0 Hz, IH), 3.95 (s, 3H), 1.53 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.1, 145.9, 133.3, 133.2, 129.6, 128.4, 120.9, 117.6, 113.9, 108.5, 103.7, 80.5, 55.4, 28.2 (3C); MS (EI) m/z 273.1 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 273.1364, m/z found: 273.1360.

Example 2aa: Preparation of 3-[3-(4-Fluoro-phenyl)-lH-indol-2-yl]-acrylic acid tert- butyl ester

Following General Procedure B with 2-[2,2-Dibromo-l-(4-fluoro-phenyl)-vinyl]- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and fertbutylacrylate. Yield: 16 % (conversion 76 %), yellow-white, mp 230-232 ⁰ C; IR (CHCl ₃ ) v 3470, 3023, 1696, 1626, 1613, 1502, 1229 1153 cm- ¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.30 (br, IH), 7.62 (d, J= 16.0 Hz, IH), 7.60 (d, J= 7.9 Hz, IH), 7.45-7.41 (m, 2H), 7.32 (m, IH), 7.28 (t, J= 8.0 Hz, IH), 7.16-7.10 (m, 3H), 6.15 (d, J= 16.0 Hz, IH), 1.49 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.3, 162.2 (JcF= 245.6 Hz), 137.0, 132.1, 131.6 (J _CF = 8.0 Hz, 2C), 130.0, 129.4 (J _CF = 3.4 Hz), 127.7, 125.2, 122.6, 120.8, 120.3, 117.6, 115.7 (J _CF = 21.4 Hz, 2C), 111.1, 80.8, 28.2

(3C); MS (EI) m/z 337. 1 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 337.1478, m/z found: 337.1480.

Preparation of ortλo-ggm-dibromovinylaniline containing an alkene of Formula (V)

The results of the preparation of various cyclization precursors of the compounds shown in Table 5, above are shown in Examples 3a-3e below and in Table 6 above.

General Procedure D for reductive amination. Example 3a : Preparation of 6- [2- (2,2-Dibromo-vinyl)-phenylamino]-hex-2-enoic acid tert-butyl ester

2-(2,2-dibromo-vinyl)phenylamine (900.0 mg, 3.26 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2- hexenenoic acid-6-oxo-tbutyl ester (600.0 mg, 3.26 mmol; for a preparation see: S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A.D. Smith Org.& Bio. Chem. 2005, 3, 1284) were mixed in 1,2-dichloroethane (15.0 mL, 0.22 M) and then treated with sodium triacetoxyborohydride (900.0 mg, 4.24 mmol) and glacial acetic acid (186.0 μL, 3.26 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 20 h. The reaction mixture was then quenched by addition of aqueous saturated NaHCO ₃ , and the product was extract with EtOAc. The organic phase was dried (Na ₂ SO ₄ ) and the solvent was evaporated to give the crude product. The mixture was purified by flash chromatography (3/l:hexanes/CH ₂ Cl ₂ ) to afford a pink solid (0.88 g, 60 %). mp 33-35 ⁰ C; IR (CHCl ₃ ) v 3438, 3006, 2980, 2936, 1705, 1653, 1602, 1507, 1457, 1368, 1318, 1259, 1154 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.24 (m, 3H), 6.87 (dt, , J= 15.6, 6.8 Hz IH), 6.71 (t, J= 7.4 Hz, IH), 6.62 (d, J= 8.1 Hz, IH), 5.79 (d, J= 15.6, 7.4 Hz, IH), 3.56 (br, IH), 3.17 (t, J= 6.9 Hz, 2H), 2.29 (q, J= 7.1 Hz, 2H), 1.80 (quint., J= 7.1 Hz, 2H), 1.48 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.7, 146.5, 144.8, 134.0, 129.8, 129.2, 123.6, 121.5, 116.8, 110.6, 93.1, 80.1, 43.1, 29.4, 28.1 (3C),

27.8; MS (EI) m/z 444.9 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 443.0095, m/z found: 443.0092.

Example 3b: Preparation of 6-[4-Benzyloxy-2-(2,2-dibromo-vinyl)-phenylamino]- hex-2-enoic acid tert-butyl ester

Following General Procedure D as for 3a with 4-Benzyloxy-2-(2,2-dibromo-vinyl)- phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2-hexenenoic acid-6-oxo-Autyl ester (for a preparation see: S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A.D. Smith Org.& Bio. Chem. 2005, 3, 1284). Yield: 54 %, brown liquid; IR (CHCl ₃ ) v 3435, 3005, 2980, 2936, 1705, 1505, 1653, 1454, 1369, 1292, 1155 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43-7.25 (m, 6H), 6.99-6.85 (m, 3H), 6.59 (d, J= 8.8 Hz, IH), 5.78 (dt, J= 15.6, 1.5 Hz, IH), 5.00 (s, 2H), 3.25 (br, IH), 3.13 (t, J= 7.1 Hz, 2H), 2.29 (m, 2H), 1.79 (quint, J= 7.3 Hz, 2H), 1.48 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.8, 150.5, 146.6, 139.5, 137.3, 133.7, 128.4 (2C), 127.7, 127.4 (2C), 123.6, 122.6, 117.1, 115.9, 112.3, 92.9, 80.1, 70.9, 43.9, 29.5, 28.1 (3C), 27.9; MS (EI) m/z 551.0 [M] ⁺ , 460 [M-CH ₂ Ph] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 549.0515, m/z found: 549.0514.

Example 3c: Preparation of 3-(5-tert-Butoxycarbonyl-pent-4-enylamino)-4-(2,2- dibromo-vinyl)-benzoic acid methyl ester

Following General Procedure D as for 3a with 3-amino-4-(2,2-dibromo-vinyl)-benzoic acid methyl ester (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2-hexenenoic acid-6-oxo-/butyl ester (for a preparation see: S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P.

D. Price, A.D. Smith Org.ά. Bio. Chem. 2005, 3, 1284). Yield: 65 %, orange oil; IR

(CHCl ₃ ) v 3009, 2981, 1710, 1572, 1439, 1299, 1254, 1155 cm ^"1 ; ¹ K NMR (300 MHz,

CDCl ₃ ) δ 7.38-7.25 (m, 4H), 6.87 (dt, J= 15.6, 6.8 Hz, IH), 5.80 (dt, J= 15.6, 1.5 Hz,

IH), 3.90 (s, 3H), 3.67 (br, IH), 3.24 (t, J= 7.0 Hz, 2H), 2.31 (m, 2H), 1.85 (quint., J= 7.2 Hz, 2H), 1.48 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.1, 165.8, 146.4, 144.8, 133.2,

131.2, 129.2, 125.7, 123.7, 118.0, 111.4, 94.6, 80.2, 52.1, 43.1, 29.4, 28.1 (3C), 27.8; MS

(EI) m/z 502.9 [M] ⁺ , 445.8 [M-^Bu] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 501.0150, m/z found: 501.0156.

Example 3d: Preparation of [2-(2,2-Dibromo-vinyl)-phenyl]-pent-4-enyl-amine

Following General Procedure D as for 3a with 2-(2,2-dibromo-vinyl)phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 4-pentenal (commercially available at Alfa-Aesar). Yield: 91 %, incolor oil; IR (CHCl ₃ ) v 3421, 3078, 3005, 2935, 2860, 1640, 1602, 1578, 1506, 1457, 1319, 1261 cm ^"1 ; ¹ U NMR (300 MHz, CDCl ₃ ) δ 7.26-7.21 (m, 3H), 6.71 (td, J= 7.4, 1.0 Hz, IH), 6.64 (d, J= 8.3 Hz, IH), 5.85 (m, IH), 5.08 (m, IH), 5.02 (m, IH), 3.58 (br, IH), 3.17 (t, J= 7.1 Hz, 2H), 2.18 (m, 2H), 1.76 (quint, J= 7.3 Hz, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 145.1, 137.9, 134.1, 129.8; 129.2, 121.4, 116.6, 115.3, 110.6, 93.0, 43.3, 31.3,

28.4; MS (EI) m/z 342.9 [ ⁷⁹ Br ⁷⁹ BrM] ⁺ , 344.9 [ ⁷⁹ Br ⁸¹ BrM] ⁺ , 346.9 [ ⁸¹ Br ⁸¹ BrM] ⁺ ; HRMS (EI) m/z calcd.for: [ ⁷⁹ Br ⁷⁹ BrM] ⁺ 342.9571, m/z found: 342.9585.

Example 3e: Preparation of 7-[2-(2,2-Dibromo-vinyl)-phenylamino]-hept-2-enoic acid tert-butyl ester

Following General Procedure D as for 3a with 2-(2,2-dibromo-vinyl)phenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound) and 2-heptenoic acid-7-oxo-tbutyl ester (for a preparation see: S. G. Davies, D. Diez, S.H. Dominguez, N. M. Garrido, D. Kruchinin, P. D. Price, A.D. Smith Org.& Bio. Chem. 2005, 3, 1284). Yield: 61 %, brown-white solid, mp 45-47 ⁰ C; IR (CHCl ₃ ) v 3420, 3006, 2980, 2936, 2862, 1704, 1652, 1602, 1578, 1507, 1457, 1368, 1317, 1154 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.26-7.21 (m, 3H), 6.85 (dt, J = 15.6, 6.9 Hz, IH), 6.71 (t, J= 7.5 Hz, IH), 6.63 (d, J= 8.4 Hz, IH), 5.76 (dt, J= 15.6, 1.5 Hz, IH), 3.5 (br, IH), 3.1 (t, J= 6.8 Hz, 2H), 2.24 (m, 2H), 1.69 (m, 2H), 1.56 (m, 2H), 1.48 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.9, 147.1, 145.0, 134.0, 129.8, 129.2, 123.4, 121.4, 116.6, 110.6, 93.0, 80.0, 43.5, 31.6, 28.9, 28.1, 25.6 (3C); MS (EI) m/z 458.8 [M] ⁺ , 401.7 [M- ^Bu] ⁺ ; HRMS (EI) m/z calcd.for: [M] ⁺ 457.0252, m/z found: 457.0239.

Preparation of pyrido- and azepino-indoles of Formula (IVV(IV)'

The results of the preparation of various tricyclic indole derivatives of Table 5, above are shown in Examples 4a, 4a'-4e, 4e' below.

General Procedure E for intramolecular palladium-catalyzed tandem reactions.

A tube (24x150 mm) of carousel reaction station was charged with 3 (1.0 equiv.), powdered K ₃ PO ₄ -H ₂ O (2.0 equiv.) and Pd ₂ dba ₃ (4.0 mol %), Bu ₄ NCl (1.0 equiv.) and the mixture was purged with argon and vacuum three times. Triethylamine (2.0 equiv.) and toluene (0.1 M) were added and the reaction stirred at 120 ⁰ C until all the starting material had been consumed (typically 15-22 h). The reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with EtOAc, the organic phase was dried (Na ₂ SO ₄ ) and the solvent was evaporated to give the crude product. The residue was purified by flash chromatography (typically 2 % EtOAc in hexanes) to afford the tricyclic indole adducts 4 and 4'.

Example 4a and 4a': Preparation of (6,7-Dihydro-pyrido[l,2-a]indol-9-yl)-acetic acid tert-butyl ester and (7,8-Dihydro-6H-pyrido[l,2-a]indol-9-ylidene)-acetic acid tert-butyl ester

Following General Procedure E. A tube (24x150 mm) of carousel reaction station was charged with 3a (138.0 mg, 0.331 mmol), powdered K ₃ PO ₄ -H ₂ O (135.0 mg, 0.623 mmol), Pd ₂ dba ₃ (10.7 mg, 0.012 mmol, 4 mol %), Bu ₄ NCl (81.0 mg, 0.331 mmol) and the mixture was purged with argon and vacuum three times. Triethylamine (82.0 μL,

0.623 mmol) and toluene (3.0 mL, 0.1 M) were added and the reaction stirred at 120 ⁰ C until all the starting material had been consumed (15 h). The reaction mixture was cooled to room temperature and diluted with EtOAc. After aqueous workup and extraction with

EtOAc, the organic phase was dried (Na ₂ SO ₄ ) and the solvent was evaporated to give the crude product. The residue was purified by flash chromatography (2 % EtOAc in hexanes) to afford the tricyclic adducts 4a and 4a'. Yield: 76 % (4a/4a': 3/1). 4a: yellow solid, mp 78-82 ⁰ C; IR (CHCl ₃ ) v 3026, 3010, 2979, 1727, 1456, 1369, 1339, 1220, 1200, 1148 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (d, J= 7.8 Hz, IH), 7.25 (m, IH), 7.18 (t,

J= 7.7 Hz, IH), 7.05 (t, J= 7.7 Hz, IH), 6.44 (s, IH), 5.89 (t, J= 4.5 Hz, IH), 4.09 (t, J=

7.0 Hz, 2H), 3.34 (s, 2H), 2.66 (m, 2H), 1.45 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.6, 137.0, 135.7, 128.3, 125.8, 123.1, 121.9, 120.7, 119.5, 108.7, 98.0, 80.9, 39.8, 39.4, 28.0 (3C), 24.3; MS (EI) m/z 283.1 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 283.1572, m/z found: 283.1566. 4a': yellow solid, mp 100-105 ⁰ C; IR (CHCl ₃ ) v 3007, 2979, 1692, 1618, 1476, 1368, 1249, 1141 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60 (d, J= 8.0 Hz, IH), 7.31-7.20 (m, 2H), 7.10 (t, J= 7.9Hz, IH), 6.93 (s, IH), 6.41 (s, IH), 4.12 (t, J= 5.9 Hz, 2H), 3.27 (t, J= 7.2 Hz, 2H), 2.13 (quint., J= 6.1 Hz, 2H), 1.53 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.5, 145.4, 137.2, 134.9, 127.4, 122.7, 121.2, 120.4, 113.7, 109.2, 98.9, 79.9, 41.7, 28.3, 25.0, 22.8 (3C); MS (EI) m/z 283.1 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 283.1572, m/z found: 283.1573.

Example 4b and 4b': Preparation of (2-Benzyloxy-6,7-dihydro-pyrido[l,2-a]indol-9- yl)-acetic acid tert-butyl ester and (2-Benzyloxy-7,8-dihydro-6H-pyrido[l,2-a]indol- 9-yIidene)-acetic acid tert-butyl ester

Following General Procedure E with 3b as starting material. Yield: 58 % (4b/4b': 3/1).

4b: brown oil; IR (CHCl ₃ ) v 3006, 2979, 1726, 1480, 1369, 1336, 1281, 1182, 1148 cm - ^" 1 ¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48-7.45 (m, 2H), 7.40-7.30 (m, 3H), 7.13 (d, J= 8.8 Hz, IH), 7.11 (d, J= 2.3 Hz, IH), 6.92 (dd, J= 8.8, 2.3 Hz, IH), 6.35 (s, IH), 5.86 (t, J= 4.5 Hz, IH), 5.09 (s, 2H), 4.03 (t, J= 7.0 Hz, 2H), 3.31 (d, J= 1.1 Hz, 2H), 2.64 (m, 2H), 1.45 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.6, 153.2, 137.7, 136.4, 132.6, 128.6, 128.4 (2C), 127.7, 127.5 (2C), 125.7, 122.8, 112.9, 109.3, 104.4, 97.7, 80.8, 70.9, 39.7, 39.6, 28.0 (3C), 24.3; MS (EI) m/z 389.0 [M] ⁺ , 298.0 [M-Bn] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 389.1990, m/z found: 389.1989. 4b': yellow solid, mp 115-120 ⁰ C; IR (CHCl ₃ ) v 3027, 3018, 1691, 1610, 1521, 1368, 1201, 1145 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48-7.31 (m, 5H), 7.19 (d, J= 8.9 Hz, IH), 7.09 (d, J= 2.3 Hz, IH), 6.97 (dd, J= 8.9, 2.4 Hz, IH), 6.83 (s, IH), 6.36 (t, J= 1.9 Hz, IH), 5.13 (s, 2H), 4.08 (t, J= 5.8 Hz, 2H), 3.24

(m, 2H), 2.10 (quint., J= 6.1 Hz, 2H), 1.53 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.5, 153.8, 145.3, 137.5, 135.3, 133.0, 128.5 (2C), 127.8, 127.7, 127.5 (2C), 114.5, 113.4, 110.0, 103.5, 98.5, 79.9, 70.7, 41.8, 28.3 (3C), 24.8, 22.8; MS (EI) m/z 389.0 [M] ⁺ , 298.0 [M-Bn] ⁺ ; HRMS (EI) m/z calcd.for: [M] ⁺ 389.1990, m/z found: 389.1994.

Example 4c and 4c': Preparation of 9-tert-Butoxycarbonylmethyl-6,7-dihydro- pyrido[l,2-a]indole-3-carboxylic acid methyl ester and 9-tert- Butoxycarbonylmethylene-θ^S^-tetrahydro-pyridofljl-aJindole O-carboxylic acid methyl ester

Following General Procedure E with 3c as starting material. Yield: 67 % (4c/4c': 7/1). 4c: brown oil; IR (CHCl ₃ ) v 3006, 2981, 2952, 1708, 1456, 1436, 1369, 1338, 1267, 1245, 1148 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (s, IH), 7.58 (dd, J= 8.3, 1.4 Hz, IH), 7.56 (d, J= 8.3 Hz, IH), 6.46 (s, IH), 5.99 (t, J= 4.5 Hz, IH), 4.16 (t, J= 7.1 Hz, 2H), 3.93 (s, 3H), 3.35 (d, J= Hz, 2H), 2.69 (m, 2H), 1.45 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.3, 168.1, 138.7, 136.3, 132.0, 125.5, 125.0, 123.3, 120.7, 120.1, 111.0, 98.2, 81.1, 51.8, 39.6, 39.4, 28.0 (3C), 24.2; MS (EI) m/z 341.0 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 341.1627, m/z found: 341.1632. 4c': orange solid, mp 137-140 ⁰ C; IR (CHCl ₃ ) v 3026, 3014, 2953, 1697, 1607, 1436, 1367, 1241, 1201, 1146 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (s, IH), 7.78 (dd, J= 8.4, 1.4 Hz, IH), 7.60 (d, J= 8.4 Hz, IH), 6.93 (s, IH), 6.45 (t, J= 1.9 Hz, IH), 4.20 (t, J= 6.0 Hz, 2H), 3.94 (s, 3H), 3.28 (m, 2H), 2.16 (quint., J= 6.0 Hz, 2H), 1.53 (s, 9H); MS (EI) m/z 341.0 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 341.1627, m/z found: 341.1628.

Example 4d: Preparation of 9-Methyl-6,7-dihydro-pyrido[l,2-a]indoIe

Following General Procedure E with 3d as starting material but 4 mol % Pd(OAc) ₂ and

8 mol % P(o-tolyl) ₃ was used instead of Pd ₂ dba ₃ (4 mol %) and Bu ₄ NCl. Yield: 72 %, white solid, mp 74-75 ⁰ C; IR (CHCl ₃ ) v 3026, 3007, 1473, 1456, 1416, 1361, 1314 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.56 (d, J= 7.8 Hz, IH), 7.25-7.14 (m, 2H), 7.04 (t, J= 6.7

Hz, IH), 6.42 (s, IH), 5.72 (m, IH), 4.04 (t, J= 7.08 Hz, 2H), 2.57 (m, 2H), 2.09 (q, J=

1.7 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 137.3, 136.9, 128.4, 127.5, 121.7, 120.6,

120.2, 119.4, 108.7, 97.4, 39.6, 24.2, 18.3; MS (EI) m/z 183.2 [M] ⁺ , 168.2 [M-Me] ⁺ ;

HRMS (EI) m/z calcd. for: [M] ⁺ 183.1048, m/z found: 183.1043 (Gilchrist, T. L., Kemmitt, P.D. Tetrahedron 1997, 53, 4447).

Example 4e and 4e': Preparation of 8-Dihydro-6H-azepino[l,2-a]indoI-10-yl)-acetic acid tert-butyl ester and (6,7,8,9-Tetrahydro-azepino[l,2-a]indol-10-ylidene)-acetic acid tert-butyl ester

Following General Procedure E with 3e as starting material. Yield: 70 % (4e/4e': 2/3). 4e: white solid, 117-119 ⁰ C; IR (CHCl ₃ ) v 3020, 3009, 2979, 1724, 1464, 1393, 1368, 1324, 1220, 1148 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55 (d, J= 7.8 Hz, IH), 7.28 (m, IH), 7.17 (t, J= 6.9 Hz, IH), 7.04 (t, J= 6.9 Hz, IH), 6.50 (s, IH), 5.87 (t, J= 5.4 Hz, IH), 4.25 (m, 2H), 3.39 (d, J= 0.9 Hz, 2H), 2.48 (m, 2H), 2.13 (m, 2H), 1.38 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.4, 139.0, 137.3, 130.1, 127.6, 126.1, 121.7, 120.6, 119.2, 108.8, 101.5, 80.7, 44.7, 44.2, 29.4, 28.0 (3C), 27.9; MS (EI) m/z 297.3 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 297.1728, m/z found: 297.1726. 4e': white solid, 95-97 ⁰ C; IR (CHCl ₃ ) v 3027, 3018, 2979, 2935, 1696, 1624, 1455, 1393, 1368, 1226, 1144 cm ^"1 ; ¹ H NMR (300

MHz, CDCl ₃ ) δ 7.58 (d, J= 7.9 Hz, IH), 7.29 (m, IH), 7.21 (t, J= 6.9 Hz, IH), 7.08 (t, J= 7.9 Hz, IH), 6.60 (d, J= 0.7 Hz, IH), 6.17 (s, IH), 4.17 (m, 2H), 3.12 (m, 2H), 2.00 (m, 2H), 1.89 (m, 2H), 1.53 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.9, 150.7, 143.2, 138.3, 127.4, 122.2, 121.0, 119.7; 119.7, 109.2, 101.4, 80.2, 44.1, 29.4, 28.3 (3C), 27.8, 25.8; MS (EI) m/z 297.2 [M] ⁺ ; HRMS (EI) m/z calcd. for: [M] ⁺ 297.1728, m/z found: 297.1729.

Preparation of 2-alkynyl indoles of Formula (VIII)

The results of the preparation of various 2-substituted indoles of Tables 7, 8 and 9 above are shown in Examples 5a-5q below.

Example 5a: Preparation of 2-Oct-l-ynyl-lH-indole

To a tube (24x150 mm) of Carousel reaction station was charged with ortho-gem- dibromovinylaniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.010 mmol, 2 mol%), P(p-MeOPh) ₃ (14.1 mg, 0.040 mmol, 8 mol%), and CuI (3.8 mg, 0.020 mmol, 4 mol%), and the tube was evacuated and purged with argon three times followed by addition of toluene (3 mL, degassed), /Pr ₂ NH (175 μL, 1.25 mmol), and 1- octyne (110 μL, 0.75 mmol). The reaction mixture was heated to 100 ⁰ C for 1.5 h. H ₂ O (10 mL) was added, and the mixture was extracted with EtOAc (2 x 15 mL), and dried over MgSO ₄ . The crude material after removal of solvent was purified by flash chromatography using 3% EtOAc in hexane to afford the titled compound as a pale yellow oil (93.5 mg, 83%). IR (neat, cm ^"1 ) 3410, 2931, 2858, 2231, 1453, 1349, 1296, 1145. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (IH, br), 7.55 (IH, d, J= 7.9 Hz), 7.26 (IH, d, J= 8.0 Hz), 7.19 (IH, J= 7.6, 7.6, 0.9 Hz), 7.09 (IH, ddd, J= 7.4, 7.4, 1.2 Hz), 6.65 (IH, m), 2.44 (2H, t, J = 7.1 Hz), 1.66-1.56 (2H, m), 1.49-1.41 (2H, m), 1.34-1.28 (4H, m), 0.91 (3H, t, J = 6.8 Hz) ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 135.9, 128.0, 123.1, 120.7, 120.4, 119.8, 110.7, 107.6, 94.1, 73.2, 31.6, 28.8, 28.7, 22.7, 19.8, 14.3. HRMS (ESI) calc'd for Ci ₆ H ₁₉ N ([M] ⁺ ): 225.1518. Found: 225.1517.

Example 5b: Preparation of 2-Phenylethynyl-lH-indole

To a 10 niL round-bottomed flask was charged with 10% Pd-C (26.6 mg, 0.025 mmol) and PPh ₃ (14.4 mg, 0.055 mmol), and the flask was purged with argon for at least 10 min. To the second separate flask was charged with ørt/20-gewz-dibromovinylaniline (0.139 g, 0.5 mmol), CuI (4.8 mg, 0.025 mmol), and the flask was purged with argon for 10 min, followed by addition of toluene (5 mL), phenylacetylene (82 μL, 0.75 mmol), and /Pr ₂ NH (174 μL, 1.25 mmol). After the mixture in the second flask became homogenous, it was cannulated into the first flask, and the resulting mixture was heated at 100 ⁰ C for 1 h. The mixture was diluted with Et ₂ O (30 mL), washed with H ₂ O (20 mL), brine (15 mL), and dried over MgSO ₄ . The crude material after removal of solvent was purified by flash chromatography using 5 -»10% EtOAc in hexane to give the title compound as a pale yellow solid (0.088 g, 85%). mp 161-162 ⁰ C. IR (neat, cm ^"1 ): 3384, 3052, 2213, 1596, 1482, 1442, 1398, 1353, 1308, 1235, 1104. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (IH, br), 7.60 (IH, d, J - 7.9 Hz), 7.56-7.52 (2H, m), 7.37-7.32 (4H, m), 7.24 (IH, ddd, J = 7.6, 7.6, 1.0 Hz), 7.13 (IH, ddd, J= 7.5, 7.5, 0.9 Hz), 6.84 (IH, d, J= 1.6 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 136.4, 131.7, 128.8, 128.0, 123.8, 122.8, 121.1, 120.7, 119.0, 110.9, 109.1, 92.8, 82.0.

Example 5c: Preparation of 5-(lH-Indol-2-yl)-pent-4-yn-l-ol

To a 10 mL round-bottomed flask was charged with 10% Pd-C (26.6 mg, 0.025 mmol) and PPh ₃ (14.4 mg, 0.055 mmol), and the flask was purged with argon for at least 10 min. To the second separate flask was charged with ørt/20-gem-dibromovinylaniline (0.139 g, 0.5 mmol), CuI (4.8 mg, 0.025 mmol), and the flask was purged with argon for 10 min, followed by addition of toluene (5 mL), pent-4-yn-l-ol (69 μL, 0.75 mmol), and /Pr ₂ NH

(174 μL, 1.25 mmol). After the mixture in the second flask became homogenous, it was cannulated into the first flask, and the resulting mixture was heated at 100 °C for 1 h. The mixture was diluted with Et ₂ O (30 mL), washed with H ₂ O (20 mL), brine (15 mL), and dried over MgSO ₄ . The crude material was purified by flash chromatography using 3.5->5% EtOAc in hexane to afford the product as a pale yellow oil (0.065 g, 65%). IR (neat, cm ^"1 ): 3541, 3396, 2948, 2233, 1451, 1350, 1296, 1046. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (IH, br), 7.55 (IH, d, J= 7.9 Hz), 7.25 (IH, d, J= 8.1 Hz), 7.18 (IH, J = 7.6, 7.6, 1.1 Hz), 7.09 (IH, ddd, J= 7.5, 7.5, 0.9 Hz), 6.65 (IH, d, J= 1.5 Hz), 3.80 (2H, t, J= 5.3 Hz), 2.56 (2H, t, J= 7.0 Hz), 1.97 (IH, br), 1.85 (2H, quintet, J = 6.5 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 136.0, 127.9, 123.2, 120.8, 120.4, 119.4, 110.9, 107.7, 92.9, 73.8, 61.8, 31.3, 16.3. HRMS (EI) calc'd for Ci ₃ Hi ₃ NO ([M] ⁺ ): 199.0997. Found: 199.0995.

Example 5d: Preparation of 2-[5-(Tetrahydropyran-2-yloxy)-pent-l-ynyl]-lH- indole

To a 10 mL round-bottomed flask was charged with 10% Pd-C (26.6 mg, 0.025 mmol) and PPh ₃ (14.4 mg, 0.055 mmol), and the flask was purged with argon for at least 10 min. To the second separate flask was charged with ort/zo-gem-dibromovinylaniline (0.139 g, 0.5 mmol), CuI (4.8 mg, 0.025 mmol), and the flask was purged with argon for 10 min, followed by addition of toluene (5 mL), 2-pent-4-ynyloxytetrahydropyran (0.115 g, 0.676 mmol), and /Pr ₂ NH (174 μL, 1.25 mmol). After the mixture in the second flask became homogenous, it was cannulated into the first flask, and the resulting mixture was heated at 100 ⁰ C for 1 h. The crude material was purified by flash chromatography using 15→20% EtOAc in hexanes to afford the product as a slightly yellow oil (0.105 g, 71%). IR (neat, cm ^"1 ): 3406, 3283, 2944, 2870, 2244, 1452, 1350, 1296, 1137, 1119, 1033. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.27 (IH, br), 7.55 (IH, d, J = 7.8 Hz), 7.28 (IH, d, J = 8.1 Hz), 7.19 (IH, J = 7.5, 7.5, 0.9 Hz), 7.09 (IH, t, J = 7.6 Hz), 6.64 (IH, d, J = 1.8 Hz),

4.65 (IH, t, J = 3.4 Hz), 3.95-3.88 (2H, m), 3.59-3.50 (2H, m), 2.58 (2H, t, J= 7.1 Hz), 1.96-1.70 (4H, m), 1.63-1.54 (4H, m); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 135.9, 127.9, 123.1, 120.8, 120.4, 119.6, 110.8, 107.6, 99.1, 93.2, 73.6, 66.1, 62.5, 30.9, 28.9, 25.7, 19.7, 16.7. HRMS (EI) calc'd for Ci ₈ H ₂ iNO ₂ ([M] ⁺ ): 283.1572. Found: 283.1572.

Example 5e: Preparation of 3-(l//-Indol-2-yl)prop-2-yn-l-ol

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-Dibromovinyl)aniline (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (9.2 mg, 0.0087 mmol, 2 mol%), P(P-MeOPh) ₃ (12.0 mg, 0.034 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (157 μL, 1.12 mmol) and propargyl alcohol (0.30 ml, 5.2 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 50→ 60% EtOAc in hexane to afford the titled compound as a pale brown solid (29.6 mg, 40%). m.p.:49-51°C; IR (CHCl ₃ ) v 3398, 2923, 2228, 1450, 1403, 1350, 1299, 1229, 1038, 1012 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.19 (IH, s), 7.58 (IH, d, J= 7.6 Hz), 7.19-7.19 (2H, m), 7.12 (IH, t, J= 7.3 Hz), 6.76 (IH, br s), 4.54 (2H, s), 1.82 (IH, br s); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 127.7, 123.9, 121.1, 120.7, 111.0, 109.3, 90.8, 51.8; HRMS (EI) m/z calcd.for: [M] ⁺ 171.0684, m/z found: 171.0682.

Example 5f: Preparation of 2-TrimethylsilanylethynyI-l//-indole

A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.01 mmol, 2 mol%), P(P-OMePh) ₃ (14.2 mg, 0.040 mmol, 8 mol%), and CuI (3.8 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (175 μL, 1.25 mmol) and trimethylsilylacetylene (0.71 ml, 5.0 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 10% EtOAc in hexane to afford the titled compound as a pale brown solid (61.0 mg, 57%). m.p.: 91-92°C; IR (CHCl ₃ ) v 3402, 2961, 2157, 1398, 1343, 1249 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.16 (IH, br s), 7.57 (IH, d, J = 7.9 Hz), 7.29 (IH, dd, J = 7.9, 1.2 Hz), 7.22 (IH, td, J = 7.9, 1.2 Hz), 7.11 (2H, td, J = 7.9, 1.2 Hz), 6.77 (IH, d, J = 1.2 Hz), 0.27 (9H, s); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 135.8, 127.4, 123.6, 120.9, 120.4, 118.5, 110.6, 109.2, 98.3, 96.8, -0.20; HRMS (EI) m/z calcd. for: [M] ⁺ 213.0974, m/z found: 213.0974.

Example 5g: Preparation of 6-(l//-Indol-2-yl)hex-5-ynenitrile

A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.0087 mmol, 2 mol%), PO-OMePh) ₃ (14.1 mg, 0.040 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (180 μL, 1.28 mmol) and 5-hexynenitrile (80 μL, 0.75 mmol), and then heated to 100 ⁰ C with stirring for 24 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash

chromatography eluting with 25% EtOAc in hexane to afford the titled compound as a pale brown oil (52.3 mg, 50%). IR (CHCl ₃ ) v 3390, 2358, 1995, 1350, 1295 cm ^"1 ; ¹ H- NMR (CDCl ₃ ) δ: 8.23 (IH, s), 7.56 (IH, d, J= 7.9 Hz), 7.33-7.07 (3H, m), 6.68 (IH, br s), 2.65 (2H, t, J = 6.7 Hz), 2.56 (2H, t, J = 7.0 Hz), 2.03-1.92 (2H, m); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 136.0, 127.8, 123.5, 120.9, 120.6, 119.4, 118.8, 110.9, 108.2, 90.6, 75.2, 24.5, 19.0, 16.5; HRMS (EI) m/z calcd.for: [M] ⁺ 208.1000, m/z found: 208.0996.

Example 5h: Preparation of 2-(6-Chlorohex-l-ynyl)-l//-indole

A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.0087 mmol, 2 mol%), P(p-MeOPh) ₃ (12.0 mg, 0.034 mmol, 8 mol%), and CuI (3.9 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 rnL, degassed), Z-Pr ₂ NH (175 μL, 1.25 mmol) and 6-chloro-l-hexyne (80 μL, 0.75 mmol), and then heated to 100 ⁰ C with stirring for 48 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc in hexane to afford the titled compound as a pale yellow oil (81.3 mg, 70%). IR (CHCl ₃ ) v 3405, 2950, 1615, 1538, 1451, 1349, 1295 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.08 (IH, s), 7.55 (IH, d, J= 7.9 Hz), 7.33-7.05 (3H, m), 6.66

(IH, d, J= 1.5 Hz), 3.60 (2H, t, J= 6.4 Hz), 2.50 (2H, t, J= 6.9 Hz), 2.02-1.71 (4H, m);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 135.9, 127.9, 123.3, 120.8, 120.5, 119.4, 110.8, 107.9,

93.0, 73.8, 44.7, 31.9, 25.9, 19.1; HRMS (ESI) m/z calcd. for: [M+H] ⁺ 232.0890, m/z found: 232.0887.

Example 5i: Preparation of 2-Pyridin-3-ylethynyl-lH-indole

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)aniline (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.010 mmol, 2 mol%), P(P-MeOPh) ₃ (14.1 mg, 0.040 mmol, 8 mol%), and CuI (3.8 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), zPr ₂ NH (175 μL, 1.25 mmol) and 3-ethynylpyridine (80.0 mg, 0.77 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 40% EtOAc in hexane to afford the titled compound as a colorless solid (88.0 mg, 81%). m.p.: 209-211 ⁰ C; IR (CHCl ₃ ) v 3403, 2157, 1652, 1558, 1539, 1506, 1457, 1249 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.83 (IH, s), 8.60 (IH, s), 7.83 (IH, dt, J= 8.1, 1.8 Hz), 7.63 (IH, d, J= 8.1 Hz), 7.41-7.22 (4H, m), 7.19-7.10 (IH, m), 6.89 (IH, dd, J = 2.1, 0.9 Hz); ¹³ C NMR (75 MHz, OMSO-d ₆ ) δ 152.0, 149.7, 139.0, 137.2, 127.7, 124.4, 123.9, 121.2, 120.6, 119.8, 118.1, 112.0, 109.0, 89.2, 86.5; HRMS (EI) m/z calcd.for: [M] ⁺ 218.0844, m/z found: 218.0846.

Example 5j: Preparation of l-Methyl-2-oct-l-ynyl-l.H-indole

To a solution of [2-(2,2-dibromovinyl)phenyl]amine (1.15 g, 4.15 mmol), formaldehyde (37 wt. % solution in H ₂ O, 400 mg), acetic acid (0.5 mL) in dichloroethane (3 mL) and MeOH (3 mL) was added sodium triacetoxyborohydride (1.10 g, 5.19 mmol) at 0 ⁰ C, and the mixture was stirred for 24 h at rt. The solvent was removed in vacuo and the resultant

crude material was dissolved with EtOAc (50 mL) and sat. NaHCO ₃ (20 rnL). The mixture was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and then concentrated in vacuo. The resulting material was purified by flash chromatography eluting with 3%→ 5% EtOAc in hexane to yield [2-(2,2-dibromovinyl)phenyl]methylamine as a pale yellow oil (495 mg, 41%). IR (CHCl ₃ ) v 3418, 2913, 2815, 1602, 1520, 1316, 1259, 1166cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.31-7.23 (3 H, m), 6.73 (IH, dt, J = 7.6, 0.9 Hz), 6.64 (IH, d, J = 8.5 Hz), 3.65 (IH, br s), 2.87 (3H, s); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 146.2, 134.3, 130.1, 129.3, 121.7, 116.9, 110.3, 93.2, 30.8; HRMS (EI) m/z calcd. for: [M] ⁺ 288.9102, m/z found: 288.9103

A carousel reaction tube (24x150 mm) was charged with [2-(2,2- dibromovinyl)phenyl]methylamine (130 mg, 0.45 mmol), Pearlman's catalyst (Degussa E4) (14.2 mg, 0.013 mmol, 3 mol%), P(^-MeOPh) ₃ (6.3 mg, , 0.018 mmol, 4 mol%), and CuI (1.7 mg, 0.0089 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (190 μL, 1.34 mmol) and 1-octynye (100 μL, 0.67 mmol), and then heated to 100 ⁰ C with stirring for 24 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 1%→ 3% EtOAc in hexane to afford the titled compound as a pale yellow oil (65.1 mg, 61%). IR (CHCl ₃ ) v 2928, 2856, 1462, 1385, 1340, 1313, 1237 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.54 (IH, dt, J = 7.9, 1.0 Hz), 7.27- 7.18 (2H, m), 7.12-7.05 (IH, m), 6.65 (IH, s), 3.77 (3H, s), 2.50 (2H, t, J= 7.0 Hz), 1.71- 1.59 (2H, m), 1.55-1.26 (6H, m), 0.91 (3H, t, J= 7.0 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 136.8, 127.2, 122.9, 122.4, 120.6, 119.8, 109.2, 106.0, 96.6, 72.2, 31.3, 30.4, 28.6(2C), 22.5, 19.6, 14.0; HRMS (EI) m/z calcd. for: [M] ⁺ 239.1674, m/z found: 239.1678.

Example 5k: Preparation of l-Isopropyl-2-oct-l-ynyl-lH-indole

A carousel reaction tube (24x150 mm) was charged with [2-(2,2-dibromovinyl)- phenyljisopropylamine (160 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (26.5 mg, 0.025 mmol, 5 mol%), P(p-MeOPh) ₃ (14.1 mg, , 0.040 mmol, 8 mol%), and CuI (6.0 mg, 0.020 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (210 μL, 1.49 mmol) and 1- octynye (110 μL, 0.75 mmol), and then heated to 100 ⁰ C with stirring for 24 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting 2.5% EtOAc in hexane to afford the titled compound as a pale yellow oil (80.0 mg, 60%). IR (CHCl ₃ ) v 2929, 2856, 2361, 2340, 1454, 1408, 1352, 1313, 1192 cm ^'1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.54 (IH, d, J = 7.9 Hz), 7.42 (IH, d, J = 8.5 Hz), 7.21-7.13 (IH, m), 7.10-7.02 (IH, m), 6.65 (IH, s), 5.04-4.88 (IH, m), 2.49 (2H, t, J= 7.0 Hz), 1.70-1.28 (8H, m), 1.64 (6H, d, J= 7.0 Hz), 0.91 (3H, t, J = 6.9 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 135.2, 128.1, 122.1, 121.7, 121.0, 119.6, 110.8, 107.5, 96.9, 73.3, 48.3, 31.5, 28.8, 28.7, 22.8, 21.8, 19.9, 14.2; HRMS (EI) m/z calcd. for: [M] ⁺ 267.1987, m/z found: 267.1987.

Example 51: Preparation of l-Benzyl-2-oct-l-ynyl-l//-indole

A carousel reaction tube (24x150 mm) was charged with Benzyl[2-(2,2- dibromovinyl)phenyl]amine (120 mg, 0.33 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst

(Degussa E4) (23.7 mg, 0.022 mmol, 7 mol%), P(^-MeOPh) ₃ (11.2 mg, , 0.033 mmol, 10 mol%), and CuI (6.0 mg, 0.033 mmol, 10 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (115 μL, 0.82 mmol) and 1-octynye (72 μL, 0.49 mmol), and then heated to 100 ⁰ C with stirring for 24 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 2.5% EtOAc in hexane to afford the titled compound as a pale yellow solid (52.6 mg, 51%). m.p.: 43-44°C; IR (CHCl ₃ ) v 3029, 2927, 2855, 1454, 1391, 1345, 1312, 1161 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.58-7.54 (IH, m), 7.34-7.04 (8H, m), 6.73 (IH, s), 5.41 (2H, s), 2.44 (2H, t, J= 7.0 Hz), 1.62-1.23 (8H, m), 0.87 (3H, t, J= 6.5 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 138.1, 136.5, 128.8, 127.8, 127.5, 126.9, 122.8, 120.9, 120.3, 122.8, 120.9, 120.3, 110.1, 106.8, 97.1, 72.5, 48.0, 31.5, 28.8, 28.7, 22.7, 19.9, 14.2; HRMS (EI) m/z calcd. for: [M] ⁺ 315.1987,

Example 5m: Preparation of 2-Oct-l-ynyl-l-phenyl-lH-indole

A carousel reaction tube (24x150 mm) was charged with [2-(2,2- dibromovinyl)phenyl]phenylamine (130 mg, 0.37 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (3.9 mg, 0.0037 mmol, 1 mol%), P(/?-MeOPh) ₃ (5.2 mg, , 0.015 mmol, 4 mol%), and CuI (1.4 mg, 0.0074 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (134 μL, 0.97 mmol) and 1-octynye (81 μL, 0.55 mmol), and then heated to 100 ⁰ C with stirring for 24 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were

washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 2% EtOAc in hexane to afford the titled compound as a colorless oil (72.1 mg, 65%). IR (CHCl ₃ ) v 3057, 2928, 2854, 1596, 1499, 1449, 1377, 1360, 1330, 1314, 1241, 1201, 1144 cm ^"1 ; ¹ H- NMR (CDCl ₃ ) δ: 7.63-7.37 (6H, m), 7.24-7.09 (3 H, m), 6.82 (IH, s), 2.32 (2H, t, J= 7.0 Hz), 1.39-1.39 (2H, m), 1.15-1.14 (6H, m), 0.87 (3H, t, J= 6.9 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 138.0, 137.3, 129.3, 129.1, 127.8, 127.6, 127.5, 123.2, 122.9, 120.8, 110.6, 108.4, 96.9, 72.8, 31.5, 28.6, 28.4, 22.7, 19.7, 14.3; HRMS (EI) m/z calcd. for: [M] ⁺ 301.1831, m/z found: 301.1834.

Example 5n: Preparation of 2-Oct-l-ynyl-l//-benzo[i*]indole

A carousel reaction tube (24x150 mm) was charged with 2-(2,2- dibromovinyl)naphthalen-l-ylamine (110 mg, 0.34 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (7.1 mg, 0.0066 mmol, 2 mol%), P(p-MeOPh) ₃ (4.6 mg, 0.013 mmol, 4 mol%), and CuI (2.8 mg, 0.0066 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (120 μL, 0.84 mmol) and 1-octynye (80 μL, 0.54 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc in hexane to afford the titled compound as a pale brown solid (51.0 mg, 55%). m.p.: 90- 91 ⁰ C; IR (CHCl ₃ ) v 3414, 2930, 1519, 1393 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.83 (IH, s), 7.85-7.85 (2H, m), 7.61 (IH, d, J= 8.8 Hz), 7.54-7.37 (3H, m), 6.78 (IH, d, J= 2.1 Hz), 2.48 (2H, t, J= 7.0 Hz), 1.72-1.23 (8H, m), 0.92 (3H, t, J= 6.7 Hz); ¹³ C NMR (75 MHz,

CDCl ₃ ) δ 131.0, 130.6, 129.1, 125.8, 124.4, 124.0, 121.5, 121.4, 120.6, 119.7, 118.0, 109.2, 93.9, 73.2, 31.6, 28.9, 28.8, 22.8, 19.8, 14.3; HRMS (EI) m/z calcd. for: [M] ⁺ 275.1674, m/z found: 275.1679.

Example 5o: Preparation of 4-Benzyloxy-5-methoxy-2-oct-l-ynyl-lH-indole

A carousel reaction tube (24 ^χ 150 mm) was charged with 3-benzyloxy-2-(2,2- dibromovinyl)-4-methoxyphenylamine (136 mg, 0.33 mmol; see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound), Pearlman's catalyst (Degussa E4) (7.0 mg, 0.0066 mmol, 2 mol%), P(^-MeOPh) ₃ (4.6 mg, 0.013 mmol, 4 mol%), and CuI (1.3 mg, 0.0063 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (140 μL, 1.0 mmol) and 1-octynye (118 μL, 0.85 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 5% EtOAc in hexane to afford the titled compound as a colorless oil (96.0 mg, 81%). IR (CHCl ₃ ) v 3334, 3031, 2930, 2857, 1583, 1504, 1463, 1454, 1428, 1331, 1282, 1245, 1174, 1093 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.98 (IH, s), 7.55-7.48 (2H, m), 7.41-7.27 (3H, m), 6.94 (2H, t, J= 9.4 Hz), 6.69 (IH, d, J= 2.1 Hz), 5.21 (2H, s), 3.87 (3H, s), 2.43 (2H, t, J= 7.0 Hz), 1.67-1.24 (8H, m), 0.91 (3H, t, J = 6.9 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 145.5, 140.8, 138.4, 133.0, 128.5, 128.2, 127.9, 123.4, 120.1, 113.3, 105.9, 105.1, 94.1, 75.2, 73.0, 58.6, 31.5, 28.8, 28.7, 22.7, 19.7, 14.2; HRMS (EI) m/z calcd. for: [M] ⁺ 361.2042, m/z found: 361.2046.

Example 5p: Preparation of 4-Fluoro-2-oct-l-ynyl-lH-indole

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)-3- fluorophenylamine (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound; 150 mg, 0.51 mmol), Pearlman's catalyst (Degussa E4)) (10.6 mg, 0.010 mmol, 2 mol%), P(^-MeOPh) ₃ (7.1 mg, 0.020 mmol, 4 mol%), and CuI (2.0 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), *Pr ₂ NH (180 μL, 1.25 mmol) and 1-octynye (110 μL, 0.75 mmol), and then heated to 100 ⁰ C with stirring for 24 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 5% EtOAc in hexane to afford the titled compound as a pale yellow oil (88.0 mg, 72%). IR (CHCl ₃ ) v 3412, 2925, 2856, 1582, 1534, 1507, 1351, 1237, 1168, 1036 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.15 (IH, s), 7.15-7.02 (2H, m), 6.80-6.69 (2H, m), 2.44 (2H, t, J= 7.0 Hz), 1.68-1.24 (8H, m), 0.91 (3H, t, J = 6.9 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 156.1 (J _CF = 246.0 Hz), 138.1 (J _CF = 10.5 Hz), 123.6 (J _CF = 7.5 Hz), 119.9, 117.2, 106.8 (J _CF = 3.8 Hz), 105.1 (J _CF = 18.8 Hz), 103.5, 94.5, 72.6, 31.5, 28.8, 28.6, 22.7, 19.7, 14.2; HRMS (ESI) m/z calcd. for: [M+H] ⁺ 244.1495, m/z found: 244.1496.

Example 5q: Preparation of l-Oct-l-ynyl-lH-indole-S-carboxylic acid methyl ester

A carousel reaction tube (24x 150 mm) was charged with 4-amino-3-(2,2- dibromovinyl)benzoic acid methyl ester (see PCT Application Publication Number WO/2006/047888, supra, for preparation of this compound; 110 mg, 0.33 mmol),

Pearlman's catalyst (Degussa E4) (17.5 mg, 0.017 mmol, 5 mol%), P(/?-MeOPh) ₃ (9.2 mg, 0.026 mmol, 8 mol%), and CuI (2.7 mg, 0.014 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (140 μL, 1.00 mmol) and 1-octynye (80 μL, 0.54 mmol), and then heated to 100 ⁰ C with stirring for 24 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 10% EtOAc in hexane to afford the titled compound as a pale brown solid (78.1 mg, 84%). m.p.:87- 88 ⁰ C; IR (CHCl ₃ ) v 3317, 2931, 2857, 1694, 1615, 1538, 1435, 1347, 1315, 1259, 1156 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.42-8.30 (2H, m), 7.90 (IH, dd, J= 8.6, 1.8 Hz), 7.29 (IH, d, J = 8.6 Hz), 6.72 (IH, s), 3.92 (3H, s), 2.44 (2H, t, J= 7.0 Hz), 1.22-1.22 (8H, m), 0.91 (3H, t, J = 6.9 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 168.2, 138.4, 127.6, 124.5, 123.7, 122.6, 121.3, 110.4, 108.6, 95.1, 72.5, 52.0, 31.5, 28.8, 28.6, 22.7, 19.7, 14.2; HRMS (EI) m/z ceded, for: [M] ⁺ 283.1572, m/z found: 283.1577.

Preparation of 2-alkvnyl benzofblfurans of Formula (X)

The results of the preparation of various 2-substituted indoles of Tables 9 and 10 above are shown in Examples 6a-6n below.

Example 6a: Preparation of 2-Oct-l-ynylbenzofuran

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (115 mg, 0.41 mmol), Pearlman's catalyst (Degussa E4) (4.4 mg, 0.0041 mmol, 1 mol%), P(^-MeOPh) ₃ (5.8 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0083 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (145 μL, 1.03 mmol) and 3-ethynylpyridine

(83 μL, 0.75 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with

EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ CI and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 2% EtOAc in hexane to afford the titled compound as a colorless solid (74.5 mg, 80%). IR (CHCl ₃ ) v 2927, 2855, 2230, 1567, 1448, 1349,

1304, 1253, 1196, 1156, 1141, 1107, 1009 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.55-7.49 (IH, m),

7.45-7.40 (IH, m), 7.33-7.18 (2H, m), 6.81 (IH, s), 2.48 (2H, t, J = 7.0 Hz), 1.71-1.24

(8H, m), 0.91 (3H, t, J= 6.9 Hz); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 139.5, 125.2, 123.2, 121.1, 111.2, 110.2, 97.3, 71.4, 31.5, 28.8, 28.4, 22.7, 19.8, 14.2; HRMS (EI) m/z calcd. for: [M] ⁺ 226.1358, m/z found: 226.1356.

Example 6b: Preparation of (2-Phenylethynyl)benzofuran

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.;

Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (5.3 mg, 0.0043 mmol, 1 mol%), P(^-MeOPh) ₃

(7.1 mg, 0.020 mmol, 4 mol%), and CuI (2.0 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (176 μL, 1.25 mmol) and phenylacetylene (83 μL, 0.75 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 1% EtOAc in hexane to afford the titled compound as a colorless solid (77.7 mg, 71%). m.p.: 71-72°C; IR (CHCl ₃ ) v 2926, 2857, 1595, 1499, 1450, 1377, 1313 cm ⁴ ;

¹ H-NMR (CDCl ₃ ) δ: 7.62-7.55 (3H, m), 7.48 (IH, d, J= 7.9 Hz), 7.42-7.23 (5H, m), 7.02 (IH, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 154.9, 138.7, 131.6, 129.1, 128.5, 127.7, 125.6, 123.3, 121.8, 121.2, 111.6, 111.2, 95.0, 79.6; HRMS (EI) m/z calcd. for: [M] ⁺ 218.0732, m/z found: 218.0732.

Example 6c: Preparation of (4-Benzofuran-2-yl)but-3-yn-l-ol

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P(p-MeOPh) ₃ (6.0 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (157 μL, 1.12 mmol) and 3-butyn-l-ol (50 μL, 0.65 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 20%→ 30% EtOAc in hexane to afford the titled compound as a pale yellow oil (50.6 mg, 63%). IR (CHCl ₃ ) v 3376, 2886, 2234, 1566, 1471, 1448, 1350, 1304, 1253, 1190, 1158, 1141, 1108, 1043, 1010 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.54 (IH, d, J= 8.4 Hz), 7.43 (IH, d, J= 8.4 Hz), 7.35-7.19 (2H, m), 6.87 (IH, s), 3.87 (2H, q, J = 6.3 Hz), 2.78 (2H, t, J = 6.3 Hz), 1.80 (IH, t, J = 6.3 Hz); ¹³ C NMR (75 MHz, DMSO-rf ₆ ) δ 154.7, 138.8, 127.8, 125.6, 123.4, 121.3, 111.3, 111.0, 93.4, 73.2, 60.9, 24.2; HRMS (EI) m/z calcd. for: [M] ⁺ 186.0685, m/z found: 186.0681.

Example 6d: Preparation of (3-Benzofuran-2-yl)prop-2-yn-l-ol

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P(p-MeOPh) ₃ (6.0 mg, 0.017 mmol, 4 mol%), and CuI (1.6 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (157 μL, 1.12 mmol) and propargyl alcohol (0.10 ml, 1.30 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 33% EtOAc in hexane to afford the titled compound as a colorless oil (36.0 mg, 49%). IR (CHCl ₃ ) v 3350, 2224, 1566, 1448, 1349, 1306, 1265, 1189, 1157, 1141, 1108, 1027 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) O: 7.55 (IH, d, J= 7.6 Hz),

7.45 (IH, d, J = 7.3 Hz), 7.38-7.20 (2H, m), 6.95 (IH, s), 4.56 (2H, d, J = 6.0 Hz), 1.80

(IH, t, J = 6.0 Hz); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 155.0, 137.9, 127.6, 125.9, 123.5,

121.5, 112.2, 111.5, 93.5, 76.5, 51.7; HRMS (EI) m/z calcd. for: [M] ⁺ 172.0532, m/z found: 172.0524.

Example 6e: Preparation of [(3-Benzofuran-2-yl)prop-2-ynyloxy]-tert- butyldiphenylsilane

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol

[prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (140 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (5.3 mg, 0.0050 mmol, 1 mol%), P(^-MeOPh) ₃

(7.1 mg, 0.020 mmol, 4 mol%), and CuI (1.9 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (175 μL, 1.25 mmol) and tert- butyldiphenylprop-2-ynyloxysilane (221 mg, 0.75 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 4% EtOAc in hexane to afford the titled compound as a colorless oil (165 mg, 80%). IR (CHCl ₃ ) v 3071, 2931, 2857, 1589, 1568, 1471, 1463, 1450, 1428, 1372, 1255, 1191, 1113 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.78-7.72 (4H, m), 7.57-7.20 (1OH, m), 6.86 (IH, d, J= 0.6 Hz), 4.58 (2H, s), 1.09 (9H, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 154.7, 138.3, 135.6, 132.8, 129.9, 127.8, 127.5, 125.5, 123.2, 121.1, 111.7, 111.2, 93.7, 75.5, 53.0, 26.7, 19.2; HRMS (EI) m/z calcd.for: [M] ⁺ 410.1702, m/z found: 410.1704.

Example 6f : Preparation of Benzofuran-2-ylethynyltrimethylsilane

A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (140 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.01 mmol, 1 mol%), P(^-OMePh) ₃ (7.1 mg, 0.02 mmol, 4 mol%), and CuI (1.9 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (180 μL, 1.28 mmol) and trimethylsilylacetylene (0.71 ml, 5.0 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography

eluting with 0.2% EtOAc in hexane to afford the titled compound as a colorless oil (50.0 mg, 47%). IR (CHCl ₃ ) v 2960, 2900, 2160, 1557, 1448, 1413, 1352, 1307, 1252, 1181, 1108, 1010 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.25 (IH, d, J= 7.6 Hz), 7.14 (IH, d, J= 8.5 Hz), 7.07-6.90 (2H, m), 6.65 (IH, s), 0.03 (9H, t, J = 11.7 Hz); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 155.0, 138.8, 127.7, 126.1, 123.6, 121.6, 123.6, 121.6, 112.3, 111.6, 102.2, 94.6, 0.0; HRMS (EI) m/z calcd.for: [M] ⁺ 214.0814, m/z found: 214.0820.

Example 6g: Preparation of (6-Benzofuran-2-yl)hex-5-ynenitrile

A carousel reaction tube (24x 150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (120 mg, 0.43 mmol), Pearlman's catalyst (Degussa E4) (4.6 mg, 0.0043 mmol, 1 mol%), P(^-MeOPh) ₃ (6.1 mg, 0.017 mmol, 4 mol%), and CuI (1.7 mg, 0.0086 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (160 μL, 1.18 mmol) and 5-hexynenitrile (70 μL, 0.65 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc in hexane to afford the titled compound as a colorless oil (68.5 mg, 76%). IR (CHCl ₃ ) v 3061, 2945, 2246, 1732, 1568, 1450, 1428, 1351, 1306, 1253, 1199, 1158, 1142, 1109, 1010 cm ^'1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.54 (IH, d, J = 7.6 Hz), 7.44 (IH, d, J= 8.2 Hz), 7.37-7.20 (2H, m), 6.87 (IH, s), 2.70 (2H, t, J= 6.9 Hz), 2.58 (2H, t, J= 6.9 Hz), 2.03 (2H, q, J= 6.9 Hz); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 154.8, 138.6, 127.7, 125.7, 123.4, 121.3, 119.1, 111.3, 111.2, 93.6, 73.3, 24.4, 18.9, 16.5; HRMS (EI) m/z calcd.for: [M] ⁺ 209.0841, m/z found: 209.0839.

Example 6h: Preparation of 3-Benzofuran-2-ylethynyl-pyridine

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (139 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (5.3 mg, 0.0043 mmol, 1 mol%), P(p-OMePh) ₃ (7.1 mg, 0.020 mmol, 4 mol%), and CuI (2.0 mg, 0.010 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (3 mL, degassed), /Pr ₂ NH (180 μL, 1.28 mmol) and 3-ethynylpyridine (77.8 mg, 0.75 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 25%→ 30% EtOAc in hexane to afford the titled compound as a colorless solid (67.3 mg, 61%). m.p.: 75-76°C; IR (CHCl ₃ ) v 2357, 1558, 1506, 1472, 1447, 1407, 1257, 1169, 947 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.83 (IH, s), 8.60 (IH, s), 7.86 (IH, dt, J = 7.9, 1.8 Hz), 7.60 (IH, d, J = 7.6 Hz), 7.49 (IH, d, J = 8.2 Hz), 7.40-7.23 (3H, m), 7.07 (IH, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 155.2, 152.4, 149.5, 138.6, 127.7, 126.2, 123.6, 123.3, 121.6, 112.7, 111.5, 91.8, 83.1; HRMS (EI) m/z calcd. for: [M] ⁺ 219.0684, m/z found: 219.0683.

Example 6i: Preparation of (8^,95,135,145,17S)-17-Benzofuran-2-ylethynyl-13- methyl-7,8,9,ll,12,13,14,15,16,17-decahydro-6H-cyclopenta[fl ]phenanthrene-3,17- diol

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)phenol [prepared from salicylaldehyde according to the procedure by Bisseret (Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 907)] (100 mg, 0.36 mmol), Pearlman's catalyst (Degussa E4) (3.8 mg, 0.0036 mmol, 1 mol%), P(p-OMePh) ₃ (5.1 mg, 0.014 mmol, 4 mol%), and CuI (1.4 mg, 0.0072 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (180 μL, 1.28 mmol) and 17-α- ethynylestradiol (148 mg, 0.54 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 35%→ 40% EtOAc in hexane to afford the titled compound as a colorless solid (102.0 mg, 69%). m.p.: 208-210 ⁰ C; IR (CHCl ₃ ) v 3378, 3017, 2913, 2398, 1578, 1493, 1436, 1358, 1216, 1134, 1108, 1059, 1006 cm- ¹ ; ¹ H- NMR (DMSO-J ₆ ) δ: 8.98 (IH, s), 7.61 (IH, d, J = 7.0 Hz), 7.55 (IH, d, J = 8.5 Hz), 7.39- 7.19 (3H, m), 7.05 (IH, d, J= 8.5 Hz), 6.50 (IH, dd, J= 8.4, 2.4 Hz), 6.42 (IH, d, J= 2.4 Hz), 5.74 (IH, s), 2.70 (2H, s), 2.38-2.18 (2H, m), 2.15-1.90 (2H, m), 1.86-1.56 (5H, m), 1.48-1.16 (4H, m), 0.92 (3H, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 155.6, 154.7, 138.6, 137.8, 130.8, 127.9, 126.8, 126.4, 124.1, 122.0, 115.6, 113.4, 111.9, 111.7, 101.9, 79.5, 75.5, 50.2, 48.0, 43.9, 33.6, 29.8, 27.6, 26.8, 23.3, 13.5.

Example 6j: Preparation of 2-Oct-l-ynylnaphtho[2,l-Z>]furan

A carousel reaction tube (24x150 mm) was charged with l-(2,2- dibromovinyl)naphthalen-2-ol 7a (135 mg, 0.41 mmol), Pearlman's catalyst (Degussa E4) (4.4 mg, 0.0041 mmol, 1 mol%), P(^-MeOPh) ₃ (5.8 mg, 0.016 mmol, 4 mol%), and CuI (1.7 mg, 0.0082 mmol, 2 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (145 μL, 1.03 mmol) and 1-octyne (100 μL, 0.66 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 0.8% EtOAc in hexane to afford the titled compound as a colorless oil (112.0 mg, 98%). IR (CHCl ₃ ) v 3056, 2930, 2857, 2233, 1629, 1556, 1524, 1455, 1386, 1344, 1326, 1292, 1236, 1218, 1158, 1135, 1079 cm ¹ ; ¹ H-NMR (CDCl ₃ ) δ: 8.06 (IH, d, J = 8.2 Hz), 7.90 (IH, d, J= 8.2 Hz), 7.71 (IH, d, J = 9.1 Hz), 7.61-7.43 (3H, m), 7.30 (IH, s), 2.51 (2H, t, J = 7.0 Hz), 1.72-1.23 (8H, m), 0.91 (3H, t, J= 6.3 Hz); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 152.3, 138.9, 130.6, 128.9, 127.5, 126.7, 126.3, 124.9, 123.6, 123.3, 112.3, 109.3, 97.3, 71.6, 31.5, 28.8, 28.5, 22.7, 19.9, 14.3; HRMS (EI) m/z calcd.for: [M] ⁺ 276.1505, m/z found: 276.1514.

Example 6k: Preparation of 7-Methoxy-2-oct-l-ynylbenzofuran

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)-6- methoxyphenol 7c (120 mg, 0.39 mmol), Pearlman's catalyst (Degussa E4) (29.0 mg, 0.027 mmol, 7 mol%), P(^-MeOPh) ₃ (13.7 mg, 0.039 mmol, 10 mol%), and CuI (3.7 mg, 0.020 mmol, 5 mol%), and was evacuated and purged with argon three times. To this

mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (164 μL,

1.17 mmol) and 1-octyne (86 μL, 0.58 mmol), and then heated to 100 ⁰ C with stirring for

64 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 2% EtOAc in hexane to afford the titled compound as a pale yellow oil (80.0 mg, 80%). IR (CHCl ₃ ) v 2934,

2857, 2234, 1621, 1615, 1593, 1494, 1489, 1455, 1435, 1359, 1318, 1270, 1210, 1183,

1159, 1098, 1061 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.17-7.08 (2H, m), 6.84-6.74 (2H, m), 4.00 (3H, s), 2.46 (2H, t, J = 7.0 Hz), 1.68-1.23 (8H, m), 0.90 (3H, t, J = 6.9 Hz). ¹³ C NMR

(75 MHz, OMSO-d ₆ ) δ 145.3, 144.0, 139.7, 129.6, 123.9, 113.4, 110.3, 107.3, 97.1, 71.2,

56.3, 31.5, 28.8, 28.4, 22.7, 19.7, 14.2; HRMS (EI) m/z calcd. for: [M] ⁺ 256.1468, m/z found: 256.1463.

Example 61: Preparation of l-Oct-l-ynyl-benzofuran-S-carboxylic acid methyl ester

A carousel reaction tube (24x150 mm) was charged with 3-(2,2-dibromovinyl)-4- hydroxybenzoic acid methyl ester 7b (105 mg, 0.31 mmol), Pearlman's catalyst (Degussa E4) (6.6 mg, 0.0062 mmol, 2 mol%), P(^-OMePh) ₃ (8.8 mg, 0.025 mmol, 8 mol%), and CuI (2.4 mg, 0.013 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (123 μL, 0.875 mmol) and 1-octyne (70 μL, 0.47 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 3% EtOAc in hexane to afford the titled compound as a colorless oil (82.4 mg, 93%). IR (CHCl ₃ ) v

2920, 2234, 1732, 1615, 1574, 1435, 1348, 1311, 1197, 1148, 1116, 1087 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.26 (IH, d, J= 1.5 Hz), 8.02 (IH, dd, J = 8.8, 1.8 Hz), 7.44 (IH, d, J = 8.5 Hz), 6.86 (IH, s), 3.93 (3H, s), 2.49 (2H, t, J= 7.2 Hz), 1.71-1.24 (8H, m), 0.91 (3H, t, J = 6.9 Hz); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 167.3, 157.1, 140.9, 128.1, 126.9, 125.7, 123.6, 111.1, 110.4, 98.2, 70.9, 52.3, 31.5, 28.8, 28.3, 22.7, 19.8, 14.2; HRMS (EI) m/z calcd.for: [M] ⁺ 284.1416, m/z found: 284.1412.

Example 6m: Preparation of 3-Methyl-2-oct-l-ynyl-benzofuran

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-Dibromo-l- methylvinyl)phenol [prepared from 2-hydroxyacetophenone according to the procedure by Topolski (Topolski, M. J. Org. Chem. 1995, 60, 5588)] (145 mg, 0.50 mmol), Pearlman's catalyst (Degussa E4) (10.6 mg, 0.010 mmol, 2 mol%), P(p-MeOPh) ₃ (13.9 mg, 0.040 mmol, 8 mol%), and CuI (4.0 mg, 0.022 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (210 μL, 1.49 mmol) and 1-octyne (100 μL, 0.66 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent was removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 0.5%→ 1.0% EtOAc in hexane to afford the titled compound as a colorless oil (98.4 mg, 82%). IR (CHCl ₃ ) v 2927, 2857, 2228, 1995, 1586, 1451, 1360, 1348, 1256, 1197, 1115, 1094 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.48-7.43 (IH, m), 7.40-7.35 (IH, m), 7.29 (IH, dt, J= 7.3, 1.5 Hz), 7.21 (IH, dt, J= 7.3, 1.2 Hz), 2.52 (2H, t, J= 7.2 Hz), 2.28 (3H, s), 1.72-1.59 (2H, m), 1.55-1.21 (6H, m), 0.91 (3H, t, J = 6.9 Hz); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 154.2, 136.6, 129.2, 125.2, 122.7, 119.6 (2C), 111.2, 99.4, 70.8, 31.5, 28.8, 28.6, 22.7, 19.9, 14.2, 8.9; HRMS (EI) m/z calcd. for: [M] ⁺ 240.1514, m/z found: 240.1508.

Example 6n: Preparation of (4,6-Dimethoxybenzofuran-2-ylethynyl)trimethylsilane

A carousel reaction tube (24x150 mm) was charged with 2-(2,2-dibromovinyl)-3,5- dimethoxyphenol 7d (120 mg, 0.355 mmol), Pearlman's catalyst (Degussa E4) (18.8 mg, 0.017 mmol, 5 mol%), P(p-OMePh) ₃ (5.1 mg, 0.014 mmol, 4 mol%), and CuI (2.8 mg, 0.014 mmol, 4 mol%), and was evacuated and purged with argon three times. To this mixture were added toluene (2 mL, degassed), H ₂ O (1 mL, degassed), /Pr ₂ NH (180 μL,

1.28 mmol) and trimethylsilylacetylene (0.5 mL, 3.6 mmol), and then heated to 100 ⁰ C with stirring for 12 h. The reaction mixture was then cooled to rt and H ₂ O (10 mL) added. The mixture was extracted with EtOAc (2 x 15 mL), and combined extracts were washed with sat. NH ₄ Cl and brine, then dried and solvent removed in vacuo. The resulting crude material was purified by flash chromatography eluting with 7% EtOAc in hexane to afford the titled compound as a pale yellow solid (36.0 mg, 37%). m.p.: 58-60 ⁰ C; IR (CHCl ₃ ) v 2958, 2837, 2153,1615, 1501, 1455, 1372, 1320, 1293, 1251, 1217, 1157, 1134, 1105, 1042 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 6.95 (IH, d, J= 0.9 Hz), 6.59-6.54 (IH, m),

6.29 (IH, d, J = 2.1 Hz), 3.88 (3H, s), 3.83 (3H, s), 0.28 (9H, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 160.5, 156.5, 153.5, 136.2, 111.5, 109.7, 101.1, 94.6, 87.8, 55.7, 55.6, -0.3 (3C); HRMS (EI) m/z calcd.for: [M ] ⁺ 274.1025, m/z found: 274.1018.

Preparation of ortho-gem-dibromovinylphenol compounds of Formula (XI) Example 7a: Preparation of l-(2,2-Dibromovinyl)naphthaIen-2-ol

To a solution of 2-hydroxy-l-naphthaldehyde (3.0 g, 17.4 mmol) and Et ₃ N (4.9 ml, 35 mmol) in CH ₂ Cl ₂ (50 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate

(5.2 mL, 22.6 mmol) at O ⁰ C, and the mixture was stirred for 3 h at rt. Sat. NaHCO ₃ (30 mL) was added, and the resulting mixture was extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined extracts were washed with brine, dried (MgSO ₄ ) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 10% EtOAc in hexane to afford 2-(tert-butyldimethylsilyloxy)naphthalene-l-carbaldehyde as a colorless oil (4.6 g, 93%). IR (CHCl ₃ ) v 2928, 1673, 1632, 1592, 1507, 1463, 1435, 1314, 1245, 1155, 1012 m ¹ ; ¹ H-NMR (CDCl ₃ ) δ: 10.87 (IH, s), 9.28 (IH, d, J = 8.8 Hz), 7.95 (IH, d, J = 9.1 Hz), 7.76 (IH, d, J= 7.3 Hz), 7.65-7.57 (IH, m), 7.46-7.39 (IH, m), 7.06 (IH, d, J = 8.8 Hz), 1.05 (9H, s), 0.32 (6H, t, J = 3.2 Hz); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 196.4, 165.6, 141.1, 135.8, 133.6, 133.0, 132.2, 129.0 (2C), 124.7, 123.2, 29.7, 22.5, 0.0; HRMS (EI) m/z calcd.for: [M] ⁺ 287.1467, m/z found: 287.1465.

To a solution of 2-(te/t-butyldimethylsilyloxy)naphthalene-l-carbaldehyde (3.2 g, 11.2 mmol) in CH ₂ Cl ₂ (50 mL) was added carbon tetrabromide (5.56 g, 16.8 mmol) and triphenylphosphine (8.78 g, 33.5 mmol) at 0 ⁰ C, and the mixture was stirred for 12 h at rt. IM Na ₂ S ₂ O ₃ (30 mL) was added, and the resulting mixture was extracted with CH ₂ Cl ₂ (2 x 120 mL). The combined extracts were washed with sat. NaHCO ₃ , H ₂ O and brine, then dried (MgSO ₄ ) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 2% EtOAc in hexane to afford ter/-butyl-[l-(2,2- dibromovinyl)naphthalen-2-yloxy]dimethylsilane as a colorless oil (4.05 g, 82%). IR (CHCl ₃ ) v 3062, 2955, 2928, 2857, 1592, 1505, 1471, 1463, 1429, 1377, 1338, 1282, 1250, 1143, 1075 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.56-7.48 (3H, m), 7.37 (IH, s), 7.25 (IH, t, J= 6.7 Hz), 7.11 (IH, t, J= 8.2 Hz), 6.83 (IH, d, J= 8.8 Hz), 0.82 (9H, s), 0.00 (6H, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 154.4, 138.1, 135.5, 134.0, 133.2 (2C), 130.7, 128.5, 128.0, 125.8, 124.9, 98.4, 81.5, 81.0, 80.6, 29.8, 22.2, 0.0; HRMS (EI) m/z calcd. for: [M] ⁺ 439.9823, m/z found: 439.9807.

To a solution of tert-butyl-[l-(2,2-dibromovinyl)naphthalen-2-yloxy]dimethyls ilane (3.7 g, 8.3 mmol) in THF (45 mL) was added TBAF (11.7 mL, 11.7 mmol) at 0 ⁰ C, and the mixture was stirred for 2 h at rt. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 100 mL). The combined extracts were washed with sat. NH ₄ Cl

and brine, then dried (MgSO ₄ ) and solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 20%→ 25% EtOAc in hexane to afford the titled compound as a colorless solid (2.60 g, 95%). m.p.: 74-75 ⁰ C; IR (CHCl ₃ ) v 3534, 1620, 1596, 1514, 1466, 1432, 1387, 1346, 1264, 1201, 1141 cm ^"1 ; ¹ H- NMR (CDCl ₃ ) δ: 7.80 (2H, d, J = 8.5 Hz), 7.68 (IH, d, J = 9.1 Hz), 7.66 (IH, s), 7.51 (IH, dt, J= 7.9, 1.2 Hz), 7.42-7.34 (IH, m), 7.17 (IH, d, J = 9.1 Hz), 5.23 (IH, s); ¹³ C NMR (75 MHz, DMSO-4) δ 150.0, 132.3, 131.6, 131.0, 129.0, 128.6, 127.3, 124.2, 123.7, 118.0, 115.7, 97.2; HRMS (EI) m/z calcd. for: [M] ⁺ 325.8940, m/z found: 325.8942.

Example 7b: Preparation of 3-(2,2-Dibromovinyl)-4-hydroxybenzoic acid methyl ester

To a solution of 3-formyl-4-hydroxybenzoic acid (1.00 g, 5.9 mmol) in toluene-MeOH (2:1, 30 mL) was added (trirnethylsilyl)diazomethane (2.0 M solution in hexane, 16 mL, 32 mmol) at 0 ⁰ C, and the mixture was stirred for 1 h at rt. After evaporating the solvent, the resulting residue was filtrated through a plug of silica gel eluting with 15% EtOAc in hexane to afford 3-formyl-4-hydroxybenzoate as a colorless solid (1.06 g, 99%). To a solution of methyl 3-formyl-4-hydroxybenzoate (900 mg, 5.0 mmol) and 2,6-lutidine (0.93 ml, 8.0 mmol) in CH ₂ Cl ₂ (11 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (1.5 mL, 6.5 mmol) at 0 °C, and the mixture was stirred for 3 h at rt. Sat. NaHCO ₃ (10 mL) was added, and the resulting mixture was extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined extracts were washed with brine, dried (MgSO ₄ ) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 10%→ 15% EtOAc in hexane to afford methyl A-tert- butyldimethylsilyloxy-3-formylbenzoate as a colorless solid (1.18 g, 81%). m.p.: 52- 53 ⁰ C; IR (CHCl ₃ ) v 2952, 1725, 1692, 1607, 1491, 1272, 1118 cm ^'1 ; ¹ H-NMR (CDCl ₃ )

5: 10.46 (IH, s), 8.50 (IH, d, J= 2.3 Hz), 8.14 (IH, dd, J= 8.8, 2.3 Hz), 6.93 (IH, d, J = 8.8 Hz), 3.91 (3H, s), 1.03 (9H, s), 0.32 (6H, s); ¹³ C NMR (75 MHz, DMSO-^) δ 193.5, 170.2, 166.5, 140.9, 134.9, 131.0, 127.8, 124.3, 56.4, 29.9 (3C), 22.6, 0.0 (2C); HRMS (EI) m/z calcd.for: [M-ZBu] ⁺ 237.0583, m/z found: 237.0581.

To a solution of methyl 4-fert-butyldimethylsilyloxy-3-formylbenzoate (500 mg, 1.70 mmol) in CH ₂ Cl ₂ (50 mL) was added carbon tetrabromide (5.56 g, 16.8 mmol) and triphenylphosphine (8.78 g, 33.5 mmol) at 0 ⁰ C, and the mixture was stirred for 15 h at rt. IM Na ₂ S ₂ O ₃ (30 mL) was added, and the resulting mixture was extracted with CH ₂ Cl ₂ (2 x 120 mL). The combined extracts were washed with sat. NaHCO ₃ , H ₂ O and brine, then dried (MgSO ₄ ) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 5% EtOAc in hexane to afford A-(tert- Butyldimethylsilyloxy)-3-(2,2-dibromovinyl)benzoic acid methyl ester as a colorless oil (660 mg, 86%). IR (CHCl ₃ ) v 2953, 2858, 1732, 1605, 1488, 1286, 1116, 998 cm ^"1 ; ¹ H- NMR (CDCl ₃ ) δ: 8.36-8.33 (IH, m), 7.91 (IH, dd, J = 8.5, 2.1 Hz), 7.56 (IH, s), 6.81 (IH, d, J= 8.5 Hz), 3.89 (3H, s), 1.02 (9H, s), 0.24 (6H, s); ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 170.8, 161.4, 137.4, 135.7, 135.6, 131.7, 127.4, 123.4, 95.6, 56.4, 30.0, 29.9, 22.5, 0.0; HRMS (EI) m/z calcd.for: [M] ⁺ 448.9792, m/z found: 448.9777.

To a solution of 4-(tert-Butyldimethylsilyloxy)-3-(2,2-dibromovinyl)benzoic acid methyl ester (600 mg, 1.32 mmol) in THF (45 mL) was added TBAF (2.0 mL, 2.0 mmol) at 0 ⁰ C, and the mixture was stirred for 3 h at rt. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 100 mL). The combined extracts were washed with sat. NH ₄ Cl and brine, then dried (MgSO ₄ ) and solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 10%→ 30% EtOAc in hexane to afford the titled compound as a colorless solid (365 mg, 82%). m.p.:199-200°C; IR (CHCl ₃ ) v 3411, 1770, 1683, 1652, 1270 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 8.40 (IH, d, J= 2.1 Hz), 8.10 (IH, dd, J= 8.4, 2.1 Hz), 7.68 (IH, s), 7.03 (IH, d, J= 8.4 Hz), 5.61 (IH, s), 4.06 (3H, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 166.3, 159.8, 133.0, 132.0, 130.9, 122.9, 120.7, 116.2, 91.1, 52.5; HRMS (EI) m/z calcd. for: [M] ⁺ 334.8929, m/z found: 334.8912.

Example 7c: Preparation of 2-(2,2-Dibromovinyl)-6-methoxyphenol

To a solution of o-vanillin (6.0 g, 39.4 mmol) and 2,6-lutidine (7.34 ml, 63.0 mmol) in CH ₂ Cl ₂ (SO niL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (12.7 mL, 55.0 mmol) at 0 ⁰ C, and the mixture was stirred for 3 h at rt. Sat. NaHCO ₃ (20 mL) was added, and the resulting mixture was extracted with CH ₂ Cl ₂ (2 x 50 mL). The combined extracts were washed with brine, dried (MgSO ₄ ) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 5%→ 8% EtOAc in hexane to afford 2-hydroxy-3-methoxy-benzaldehyde as a colorless oil (8.50 g, 81%). To a solution of 2-hydroxy-3-methoxy-benzaldehyde (5.0 g, 18.7 mmol) in CH ₂ Cl ₂ (250 mL) was added carbon tetrabromide (9.35 g, 28.2 mmol) and triphenylphosphine (14.7 g, 56.1 mmol) at 0 ⁰ C, and the mixture was stirred for 24 h at rt. IM Na ₂ S ₂ O ₃ (40 mL) was added, and the resulting mixture was extracted with CH ₂ Cl ₂ (2 x 60 mL). The combined extracts were washed with H ₂ O and brine, then dried (MgSO ₄ ) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 5% EtOAc in hexane to afford tert-butyl[2-(2,2-dibromovinyl)-6- methoxyphenoxyjdimethylsilane as a colorless oil (7.50 g, 95%). IR (CHCl ₃ ) v 2927, 2854, 1576, 1476, 1256, 1229, 1076 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.59 (IH, s), 7.24-7.19 (IH, m), 6.89 (IH, d, J = 8.0 Hz), 6.84 (IH, dd, J= 8.0, 1.8 Hz), 3.79 (3H, s), 1.02 (9H, s), 0.17 (6H, s); ¹³ C NMR (75 MHz, DMSO-^ ₆ ) δ 150.4, 142.6, 134.3, 127.9, 120.8 (2C), 111.8, 90.0, 55.1, 25.9, 18.7, -4.2; HRMS (EI) m/z calcd. for: [M-ZBu] ⁺ 362.9052, m/z found: 362.9047.

To a solution of fert-butyl[2-(2,2-dibromovinyl)-6-methoxyphenoxy]dimethylsil ane (7.5 g, 17.7 mmol) in THF (80 mL) was added TBAF (26 mL, 26.0 mmol) at 0 ⁰ C, and the mixture was stirred for 3 h at rt. This mixture was then concentrated on a rotary evaporator to approximately 40 ml. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 60 mL). The combined extracts were washed with sat.

NH ₄ Cl and brine, then dried (MgSO ₄ ) and solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 20% EtOAc in hexane to afford the titled compound as a colorless solid (4.42 g, 81%). m.p.: 43-44°C; IR (CHCl ₃ ) v 3504, 2935, 2837, 1613, 1473, 1359, 1258, 1068 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.65 (IH, s), 7.38-7.30 (IH, m), 6.89-6.82 (2H, m), 5.85 (IH, s), 3.90 (3H, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 146.6, 143.5, 132.1, 122.0, 120.9, 119.4, 110.8, 90.3, 56.3; HRMS (EI) m/z calcd.for: [M] ⁺ 305.8891, m/z found: 305.8898.

Example 7d: Preparation of 2-(2,2-Dibromovinyl)-3,5-dimethoxyphenol

To a solution of methyl 4,6-dimethoxysalicylaldehyde (commercially available from Aldrich) (1.0 g, 5.5 mmol) and 2,6-lutidine (1.64 ml, 7.1 mmol) in CH ₂ Cl ₂ (I l mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (1.6 mL, 7.1 mmol) at 0 ⁰ C, and the mixture was stirred for 3 h at rt. Sat. NaHCO ₃ (10 mL) was added, and the resulting mixture was extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined extracts were washed with brine, dried (MgSO ₄ ) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 10%→ 15% EtOAc in hexane to afford 2- (fert-butyldimethylsilanyloxy)-4,6-dimethoxybenzaldehyde as a colorless oil (1.50 g, 92%). IR (CHCl ₃ ) v 2930, 2857, 1682, 1605, 1470, 1455, 1410, 1347, 1303, 1255, 1209, 1158, 1120, 1052, 1004 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 10.34 (IH, s), 6.10 (IH, d, J = 2.2 Hz), 5.98 (IH, d, J = 2.2 Hz), 3.87 (3H, s), 3.83 (3H, s), 1.01 (9H, s), 0.26 (6H, s); ¹³ C NMR (75 MHz, DMSO-J ₆ ) δ 188.0, 165.6, 163.1, 161.7, 111.5, 97.7, 91.8, 56.0, 55.4, 25.7 (3C), 18.4, -4.3 (2C); HRMS (EI) m/z calcd. for: [M-fBuSiMe ₂ +H] ⁺ 182.0579, m/z found: 182.0580.

To a solution of 2-(tert-butyldimethylsilanyloxy)-4,6-dimethoxybenzaldehyde (940 mg, 3.17 mmol) in CH ₂ Cl ₂ (OO mL) was added carbon tetrabromide (1.65 g, 4.98 mmol) and triphenylphosphine (2.49 g, 9.5 mmol) at 0 ⁰ C, and the mixture was stirred for 24 h at rt.

IM Na ₂ S ₂ O ₃ (10 mL) was added, and the resulting mixture was extracted with CH ₂ Cl ₂ (2 x 60 mL). The combined extracts were washed with H ₂ O and brine, then dried (MgSO ₄ ) and solvent removed under reduced pressure. The residue was purified by flash chromatography eluting with 5% EtOAc in hexane to afford tert-butyl-[2-(2,2- dibromovinyl)-3,5-dimethoxyphenoxy]-dimethylsilane as a colorless oil (600 mg, 42%). IR (CHCl ₃ ) v 2930, 2856, 1601, 1574, 1463, 1417, 1361, 1254, 1221, 1202, 1153, 1117, 1055, 1003 cm ^'1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.15 (IH, s), 6.12 (IH, d, J= 2.3 Hz), 6.02 (IH, d, J = 2.3 Hz), 3.79 (3H, s), 3.77 (3H, s), 1.01 (9H, s), 0.20 (6H, s); ¹³ C NMR (75 MHz, DMSO-έfc) δ 161.1, 158.1, 154.2, 131.9, 110.3, 97.7, 93.1, 91.8, 55.6, 55.3, 25.6 (3C), 18.1, -4.4 (2C); HRMS (EI) m/z calcd.for: [M] ⁺ 449.9857, m/z found: 449.9861.

To a solution of ierf-butyl-[2-(2,2-dibromovinyl)-3,5-dimethoxyphenoxy]-dimet hylsilane (600 mg, 1.32 mmol) in THF (10 mL) was added TBAF (2.0 mL, 2.0 mmol) at 0 ⁰ C, and the mixture was stirred for 3 h at rt. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 50 mL). The combined extracts were washed with sat. NH ₄ Cl and brine, then dried (MgSO ₄ ) and solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 15% EtOAc in hexane to afford the titled compound as a colorless oil (320 mg, 72%). IR (CHCl ₃ ) v 3417, 2935, 1621, 1615, 1505, 1456, 1343, 1203, 1150, 1099, 1049 cm ^"1 ; ¹ H-NMR (CDCl ₃ ) δ: 6.12 (IH, d, J = 2.3 Hz), 6.06 (IH, d, J = 2.3 Hz), 5.14 (IH, s), 3.78 (6H, s); ¹³ C NMR (75 MHz, DMSO-(Z ₆ ) δ 162.1, 158.4, 153.8, 131.2, 105.3, 94.2, 93.5, 91.6, 55.9, 55.6; HRMS (ESI) m/z calcd.for: [M+H] ⁺ 336.9069, m/z found: 336.9064.

Every reference cited herein is hereby incorporated by reference in its entirety.