NOONAN, Gary (65 Younger Gardens, St. AndrewsFife, Scotland Fife KYI68AB, KYI68AB, GB)
DR. REDDY'S LABORATORIES, INC. (200 Somerset Corporate Boulevard, 7th FloorBridgewater, New Jersey, 08807, US)
COBLEY, Christopher James (43 Park Avenue, Histon Cambridgeshire CB24 9JU, 9JU, GB)
NOONAN, Gary (65 Younger Gardens, St. AndrewsFife, Scotland Fife KYI68AB, KYI68AB, GB)
| CLAIMS: 1. A compound of the formula 4: 4 wherein n and m are each independently an integer from 1 to 3; Ar1 are both independently C6-Ci4aryl or Ci -Cgheteroaryl, which can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, Ci-C6haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (C C6alkyl)amino-, di(Ci-C6alkyl)amino-, HO2C-, (Ci-C6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(C C6alkyl)amido-, H2NC(0)-, (Ci-C6alkyl)amido-, or 02N-; and -Ai^-Ar2- is a bi(C6-Ci4aryl), bi(Ci -Cgheteroaryl), or -(C6-Ci4aryl)-(C Cgheteroaryl)- diradical, which can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, d-C6haloalkyl-, hydroxyl, hydroxyl(C C6alkyl)-, H2N-, (C C6alkyl)amino-, di(C C6alkyl)amino-, H02C-, (d- C6alkoxy)carbonyl-, (CrC6alkyl)carboxyl-, di(C C6alkyl)amido-, H2NC(O)-, (Ci- C6alkyl)amido-, or O2N-. 2. The compound of claim 1 , wherein -Ai^-Ar2- is a bi(C6-Ci4aryl) diradical, which can be unsubstituted or substituted with one or more of the following groups: C C6alkyl-, halogen, CrC6haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (C C6alkyl)amino-, di(Ci-C6alkyl)amino-, H02C-, (CrC6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(CrC6alkyl)amido-, H2NC(0)-, (CrC6alkyl)amido-, or 02N-. 3. The compound of claim 2, wherein -Ai^-Ar2- is a biphenyl diradical, which can be unsubstituted or substituted with one or more of the following groups: C C6alkyl-, halogen, C C6haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (Ci- C6alkyl)amino-, di(CrC6alkyl)amino-, H02C-, (C-i-C6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(CrC6alkyl)amidc~, H2NC(0)-, (Ci-C6alkyl)amido-, or 02N-. 4. The compound of claim 3, wherein -At^-Ar2- is a 2,2'-biphenyl diradical, which can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, C-i-C6haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (d- C6alkyl)amino-, di(C C6alkyl)amino-, HO2C-, (CrC6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(C C6alkyl)amido-, H2NC(0)-, (CrC6alkyl)amido-, or 02N-. 5. The compound of claim 4, wherein -Ar^-Ar2- is a 2,2'-biphenyl diradical, substituted with one or more CrC6alkyl- groups. 6. The compound of any one of claims 1 to 5, wherein Ar1 are both independently C6-Ci aryl. 7. The compound of any one of claims 1 to 6, wherein Ar1 are both phenyl. 8. The compound of any one of claims 1 to 7, wherein n and m are both 1. 9. The compound of any one of claims 1 to 8, which is of the formulae 1, 2a, 2b, 3a, or 3b: 1 -27- 1 1. A process for the synthesis of the ligands of formula 4 of claim 1 comprising: 4 wherein X is a leaving group. 12. A process for the asymmetric hydroformyiation of prochiral olefins in the presence of Rh catalysts derived from ligands of formula 4, of claim 1. 13. The process of claim 12, wherein the prochiral terminal olefin is RCH2CH=CH2, wherein R is C6-Caryl, d-Cgheteroaryl, or Ci-C-6alkyl, and any C6- Caryl, d-Cgheteroaryl, or CrC6alkyl radical, is optionally substituted by one or more with one or more of the following groups: halogen, H2N-, (CrC6alkyl)amino-, di(Ci-C6alkyl)amino-, (Ci-C6alkyl)C(0)N(Ci-C3alkyl)-, (Ci-C6alkyl)carboxyamido-, HC(0)NH-, H2NC(0)-, (CrC6alkyl)NHC(0)-, di(Ci-C6alkyl)NC(0)-, NC-, hydroxyl, CrC6alkoxy-, Ci-C6alkyl-, H02C-, (C C6alkoxy)carbonyl-, (C C6alkyl)C(O)-, C6- Ci4aryl-, CrCgheteroaryl-, C3-C8cycloalkyl-, CrC6haloalkyl-, amino(Ci-C6alkyl)-, (Ci-C6alkyl)carboxyl-, Ci-C6carboxyamidoalkyl-, or 02N-. 14. The process of claim 12, wherein the prochiral olefin is styrene and the hydroformyiation uses Syn gas in the presence of Rh catalysts derived from ligands of formul 15. The process of claim 12, wherein the prochiral olefin is allyl cyanide and the hydroformylation uses Syn gas in the presence of Rh catalysts derived from ligands of formula 4, the process comprising: 16. The process of claim 12, wherein the prochiral olefin is vinyl acetate and hydroformylation uses Syn gas in the presence of Rh catalysts derived from ligands of formula 4 the process comprising: 17. The process of claim 13, wherein the regioselectivity of the hydroformylation in favor of the linear aldehyde product is reversed towards the branched aldehyde product. |
INTRODUCTION
The invention relates to phosphine-phosphite ligands with a chiral phospholane (S,S)-diphenylphospholane and chiral or achiral biaryl phenols linked by a hydroxym ethyl bridge. In one aspect, the invention provides compounds of the formula 4:
4
wherein the constituent variables are defined below.
Olefin hydroformylation has been practiced industrially for decades for the production of commodity aldehyde intermediates. Since linear regioisomers are desired often, a major industrial focus has been the development of highly linear- selective ligands for rhodium-catalyzed hydroformylation. Several phosphorous- based ligands have been developed which exhibit sufficiently high regioselectivity for linear aldehydes for this methodology to be industrially applicable. Linear regioisomers are desired most often in the commodity chemicals sector. However, in organic synthesis of the more complex molecules used in the fine chemicals and pharmaceutical sector, there are demands for both linear and branched aldehyde regioisomers. In the latter case, the branched regioisomers of the aldehydes are also frequently preferred in optically active form; thus such products can be prepared by regioselective and enantioselective hydroformylation of olefins. The current state-of-the-art catalysts for enantioselective hydroformylation only deliver the branched aldehyde regioisomer for a select number of carefully chosen olefinic substrates. In the case of terminal olefins, these take the form R-CH=CH 2 where Ar = aryl, heteroaryl or heteroatom, and XCH 2 CH=CH 2 where X = heteroatom or CN. These catalysts deliver very poor regioselectivity in favor of the branched aldehydes for the hydroformylation of alkenes of type RCH 2 CH=CH 2 , where R refers to an aryl, heteroaryl or alkyl group or functionalized derivative as defined herein. In addition, There is also an unmet need to attain extremely high regioselectivity (>99%) in the cases of olefins where the state of the art catalysts only provide moderate regioselectivity for the branched isomer. The invention described here addressed these unmet needs.
Significant advances in chiral ligand design have been made recently which have led to increased enantioselectivity in hydroformylation. Three such advances are Ph-BPE [Klosin et al, Angew. Chem. Int. Ed. 2005, 44, 5834], Kelliphite [Whiteker et al, J. Org. Chem., 2004, 6, 3277], and Binaphos [Takaya et al, J. Am. Chem. Soc, 1997, 1 19, 4413]. The structures of these three ligands are shown below in Figure 1 .
CR,S)-BINAPHOS Figure 1
Ph-BPE has shown high activity and enantioselectivity for the asymmetric hydroformylation of selected olefins. Kelliphite, a bisphosphite ligand was discovered to be effective for enantioselective hydroformylation after a comprehensive screen of novel ligands of this class. Binaphos, an atropisomeric biaryl-based phosphine-phosphite has proven to be a prominent ligand for enantioselective hydroformylation with arguably the widest applicability demonstrated to date with high enantioselectivies observed with a range of terminal olefins bearing aryl, heteroaryl, alkenyl, heteroatom substituted groups, and a range of internal olefins. High enantioselectivity is a common feature in these reactions, with olefinic substrates chosen for their tendency to preferentially form the desired branched isomer giving regioselectivities of between 75% and in exceptional cases 99%. However, it has also been demonstrated that, in common with other types of hydroformylation catalyst, hydroformylation of an olefin of type RCH 2 CH=CH 2 does not deliver the branched aldehyde selectively; in fact only around 25% of the aldehydes formed from a typical substrate, hex-1 -ene are the desired branched regioisomer as demonstrated in "Asymmetric hydroformylation catalyzed by an Rh(l)-(R,S)-BINAPHOS complex: substituent effects on the regioselectivity", J. Organomet. Chem. 1997, 527, 103. Research described in "Substituent Effect in Asymmetric Hydroformylation of Olefins Catalysed by Rhodium(l) Complexes of (fi,Sj-BINAPHOS Derivatives: A protocol for improvement of regio- and enantio-selectivities", Adv. Synth. Catal. 2001 , 343, 61 ; seeks to improve this situation, but only results in a poor 29.8% selectivity for enantioselective hydroformylation of hex-1 -ene. It is therefore widely known that Rh catalysts derived from phosphine-phosphites, up to now, give similar regioselectivity in the hydroformylation of olefins to simple achiral ligands such as triphenylphosphine or 1 ,2-bis-(diphenylphosphino)ethane. Despite many catalysts having been investigated for this transformation, this problem remained unsolved and is reflected in quotes from two authorative reviews; "the preferred formation of the branched aldehyde in particular for simple alkyl substituted alkenes is an unsolved problem" quoted from "Recent Advances in Chemo-, Regio- and Stereoselective Hydroformylation", Synthesis, 2001 , 1 , and similar conclusions in "Branched Selective Hydroformylation", Curr. Org. Chem. 2005, 9, 701 . There is a strong industrial demand for such branched aldehydes or products obtained directly from them as evidenced by less direct protocols described by "Hydrogenation Processes in the Synthesis of Perfumery Ingredients", Acc. Chem. Res. 2007, 40, 1312 and " The Synthesis of the High Potency Sweetener NC- 00637 Part 1 : The Synthesis of (S)-2-Methyl Hexanoic Acid", Org. Proc. Res. Dev. 2003, 7, 369.
Phosphine-phosphites have been reported lacking the diphenylphospholane moiety. The closest example is from Landis using a 1 ,2- benzene backbone and the diazaphospholane moiety for the phosphine, the best result for these ligands is 90% e. e. with b/l = 20 for styrene as referred to in "Highly Enantioselective Hydroformylation of Aryl Alkenes with Diazaphospholane Ligands", Organic Letters, 2008), 10(20), 4553;. Further examples of phosphine- phosphites that do not contain a phospholane moiety include "Asymmetric Hydroformylation Using Taddol-Based Chiral Phosphine-Phosphite Ligands", Organometallics 2010, 29(2), 478; "Asymmetric Hydroformylation of Olefins with Rh Catalysts Modified with Chiral Phosphine-Phosphite Ligands", Organometallics 2007, 26(25), 6428; "Synthesis of a chiral phosphite-phosphine ligand, its coordination behavior with rhodium(l) cation and the application in catalytic reaction", Zhongshan Daxue Xuebao, Ziran Kexueban, 2006, 45(4), 58; "Tuning of the structures of chiral phosphane-phosphites: application to the highly enantioselective synthesis of a-acyloxy phosphonates by catalytic hydrogenation", Chemistry-A European Journal 2007, 13(6), 1821 .
The research described in "Rhodium(l), Palladium(ll), and Platinum(ll) Complexes Containing New Mixed Phosphane-Phoshite Ligands - Effect of the Catalytic System stability on the Enantioselective Hydroformylation of Styrene", Eur. J. Inorg. Chem., 2002, 71 1 ; shows that chiral phosphine-phosphites containing a CH 2 O backbone but lacking a phospholane moiety are precedented, but do not give any notable enantioselectivity.
Despite the widespread nature of phosphine-phosphites, it is clear that there are no examples containing phospholane groups (as opposed to diazaphospholane groups) as the phosphine part of the ligand. Secondly, since there are no obvious leads to solve the problem of control of regioselectivity in hydroformylation of olefins of type RCH 2 CH=CH 2 , the examination of this distinct ligand class was examined, leading to the invention described herein. The hydroxymethyl bridge was selected as an initial starting backbone due to ease of synthesis. Thus, this family of ligands uses the diphenylphospholane moiety as the phosphine donor and CH 2 0 as the backbone. As a result they are easier to make than those phosphine-phosphites previously reported. More importantly, the results obtained using these ligands show that they have unique performance in producing the branched aldehyde in hydroformylation of olefins of type RCH 2 CH=CH2, and, in addition provide amongst the highest combination of regioselectivities and enantioselectivities observed in the hydroformylation of other olefin substrates. These ligands offer ease of synthesis, higher enantioselectivities, and higher regioselectivities.
SUMMARY
In one aspect, the invention provides compounds of the formula 4:
4
wherein the constituent variables are defined below.
DETAILED DESCRIPTION In one aspect, the invention provides compounds of the formula 4:
wherein n and m are each independently an integer from 1 to 3;
Ar are both independently C-6-Ci 4 aryl or Ci-Cgheteroaryl, which can be unsubstituted or substituted with one or more of the following groups: CrC 6 alkyl-, halogen, CrCehaloalkyl-, hydroxyl, hydroxyl(CrC 6 alkyl)-, H 2 N-, (C C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, HO2C-, (CrC 6 alkoxy)carbonyl-, (d- C 6 alkyl)carboxyl-, di(CrC 6 alkyl)amido-, H 2 NC(0)-, (CrC 6 alkyl)amido-, or 0 2 N-; -Ar^-Ar 2 - is a bi(C 6 -Ci 4 aryl), bi(Ci-C 9 heteroaryl), or -(C 6 -Ci 4 aryl)-(Ci- Cgheteroaryl)- diradical, which can be unsubstituted or substituted with one or more of the following groups: CrC 6 alkyl-, halogen, d-Cehaloalkyl-, hydroxyl, hydroxyl(CrC 6 alkyl)-, H 2 N-, (C C 6 alkyl)amino-, di(C C 6 alkyl)amino-, H0 2 C-, (C C 6 alkoxy)carbonyl-, (C C 6 alkyl)carboxyl-, di(Ci-C 6 alkyl)amido-, H 2 NC(0)-, (C C 6 alkyl)amido-, or O 2 N-.
In one aspect, the invention provides compound 3b (Fig. 3 crystal structure and Fig.4).
Fig. 3 Crystal structure of diphenyl-phospholane-phosphite ligand 3b In one aspect, the invention provides compounds of the formulae 1 , 2a, 2b, and 3b.
4
In one aspect the invention provides a synthesis of 2-phenylpropanal from styrene and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
In one aspect the invention provides a synthesis of 3-methyl-4- oxobutanenitrile from allyl cyanide and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
In one aspect the invention provides a synthesis of 1 -oxopropan-2-yl acetate from vinyl acetate and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
These results using in-situ formation Rh complexes of 3b are summarized
in Table 1 branched linear
In Table 1 are shown the results for the above hydroformylation of styrene using catalysts derived from ligands of type 4, which identified ligand 3b as the most enantioselective ligand. Table 1 ; Rh catalyzed hydroformylation of styrene
3 T= 30 °C, S:G= 250:1 , Catalyst formed from 0.4 % [Rh(acac)(CO) 2 ]
and Iigand1-3b (0.5%) , 1 mmol styrene, 3.5 ml_ toluene.
b calculated by GC of crude reaction mixture on a Beta Dex 225 chiral column.
c Initial Pressure = 10 bar
In one aspect the invention provides a regioselective synthesis of 2-methyl- 3-phenylpropan-1 -al from allyl benzene and Syngas in the presence of an Rh catalyst derived from ligands of type 4, under conditions where ligands outside the phospholane-phosphite class give no selectivity as shown in Table 2.
Table 2. Hydroformylation of allyl benzene, using a range of hydroformylation cataly
(L)
[a] Catalysts preformed from 0.4 % [Rh(acac)(CO) 2 ] and 0.5 % bidentate ligand
or 1.2% monodentate ligand by stirring at 5 bar Syngas at 50 "C for 40 minutes
in toluene (3 ml), prior to running reactions at room temperature at 5 bar
initial syngas pressure for 3 days. Dppe = l,2-bis-(diphenylphosphino)ethane
[b] % Product determined by Ή NMR using tetraefhylsilane as internal standard.
[c] Determined by HPLC analysis of the alcohol formed after reduction with NaBH 4 (Chiracel OD-H) [d] 53 % isolated yield of the corresponding alcohol over 2 steps.
[e] Reaction time of 4 hours at 30 °C. In one aspect the invention provides a method by which the natural regioselectivity of the Rh catalyzed hydroformylation towards linear aldehydes from olefins of type RCH 2 CH=CH 2 as previously defined is reversed towards the branched regioisomer by the use of phospholane-phosphites as ligands for the catalyst.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. BH 3 DMS is borane dimethyl sulfide complex ((CH 3 ) 2 S BH 3 ), DABCO is 1 ,4-diazabicyclo[2.2.2]octane, r. t. is room temperature, TMS-I is iodotrimethylsilane. The term "% e. e." means the enantiomeric excess of a substance, which is defined as the absolute difference between the mole fraction of each enantiomer.
In general, the number of carbon atoms present in a given group is designated "C x -C y ", where x and y are the lower and upper limits, respectively. For example, a group designated as "Ο-ι-Οβ" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycabonyl" refers to the group (C 6 -Ci 4 aryl)-(Ci-C 6 alkyl)-O- C(O)-. It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
"(Alkoxy)carbonyl" refers to the group alkyl-O-C(O)-. Exemplary (Cr C 6 alkoxy)carbonyl groups include but are not limited to methoxy, ethoxy, n- propoxy, 1 -propoxy, n-butoxy, and t-butoxy. An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, -NH 2 , (C C 6 alkyl)N-, (Ci-C 6 alkyl)(Ci-C 6 alkyl)N-, -N(C C 3 alkyl)C(0)(Ci- Cealkyl), -NHC(0)(Ci-C 6 alkyl), -NHC(0)H, -C(0)NH 2 , -C(0)NH(CrC 6 alkyl), - C(0)N(Ci-C 6 alkyl)(Ci-C 6 alkyl), -CN, C C 6 alkoxy, -C(0)OH, -C(0)0(C C 6 alkyl), - C(O)(d-C 6 alkyl), C 6 -C 14 aryl, C C 9 heteroaryl, C 3 -C 8 cycloalkyl, Ci-C 6 haloalkyl-, C C 6 aminoalkyl-, -OC(0)(CrC 6 alkyl), Ci-C 6 carboxyamidoalkyl-, or -N0 2 .
"Alkyl-" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C-|-Ci 0 alkyl- group may have from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of C C 6 alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (Ci-C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, (C C- 6 alkyl)C(0)N(Cr C 3 alkyl)-, (C C 6 alkyl)carboxyamido-, HC(0)NH-, H 2 NC(O)-, (Ci-C 6 alkyl)NHC(0)-, di(Ci-C 6 alkyl)NC(O)-, NC-, hydroxyl, CrC 6 alkoxy-, CrC 6 alkyl-, HO 2 C-, (C C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(0)-, C 6 -C aryl-, C-i-Cgheteroaryl-, C 3 - Cscycloalkyl-, CrC 6 haloalkyl-, amino(Ci-C 6 alkyl)-, (CrC 6 alkyl)carboxyl-, C C 6 carboxyamidoalkyl-, or 0 2 N-.
"(Alkyl)amido-" refers to a -C(0)NH- group in which the nitrogen atom of said group is attached to an alkyl group, as defined above. Representative examples of a (CrC 6 alkyl)amido group include, but are not limited to, - C(O)NHCH 3 , -C(0)NHCH 2 CH 3 , -C(0)NHCH 2 CH 2 CH 3 , -C(0)NHCH 2 CH 2 CH 2 CH 3l - C(0)NHCH 2 CH 2 CH 2 CH 2 CH 3 , -C(O)NHCH(CH 3 ) 2 , -C(0)NHCH 2 CH(CH 3 ) 2l - C(0)NHCH(CH 3 )CH 2 CH 3 , -C(O)NH-C(CH 3 ) 3 and -C(0)NHCH 2 C(CH 3 ) 3 .
"(Alkyl)amino-" refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above. Representative examples of an (Ci-C 6 alkyl)amino- group include, but are not limited to CH 3 NH-, CH 3 CH 2 NH-, CH 3 CH 2 CH 2 NH-, CH 3 CH 2 CH 2 CH 2 NH-, (CH 3 ) 2 CHNH-, (CH 3 ) 2 CHCH 2 NH-, CH 3 CH 2 CH(CH 3 )NH- and (CH 3 ) 3 CNH-. An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, Η 2 Ν-, (CrC 6 alkyl)amino-, di(CrC 6 alkyl)amino-, (Ci-C 6 alkyl)C(0)N(CrC 3 alkyl)-, (CrC 6 alkyl)carboxyamido-, HC(0)NH-, H 2 NC(0)-, (d-C 6 alkyl)NHC(0)-, di(C C 6 alkyl)NC(0)-, NC-, hydroxyl, C C 6 alkoxy-, C C 6 alkyl-, H0 2 C-, (C C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(0)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, C 3 - Cscycloalkyl-, CrC 6 haloalkyl-, amino(CrC 6 alkyl)-, (CrC 6 alkyl)carboxyl-, C C 6 carboxyamidoalkyl-, or 0 2 N-.
"Alkylcarboxy" refers to an alkyl group, defined above, attached to the parent structure through the oxygen atom of a carboxyl (C(O)-O-) functionality. Examples of (CrC 6 alkyl)carboxy include acetoxy, ethylcarboxy, propylcarboxy, and isopentylcarboxy.
"Aryl-" refers to an aromatic hydrocarbon group. Examples of an C 6 - Ci 4 aryl- group include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, 3- biphen-1 -yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. An aryl group can be unsubstituted or substituted with one or more of the following groups: CrC 6 alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(CrC 6 alkyl)-, H 2 N-, amino(C C 6 alkyl)-, di(CrC 6 alkyl)amino-, H0 2 C-, (Ci- C 6 alkoxy)carbonyl-, (C C 6 alkyl)carboxyl-, di(Ci-C 6 alkyl)amido-, H 2 NC(0)-, (C C 6 alkyl)amido-, or 0 2 N-.
"Di(alkyl)amido-" refers to a -NC(O)- group in which the nitrogen atom of said group is attached to two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of a di(C C 6 alkyl)amido- group include, but are not limited to, -C(O)N(CH 3 ) 2 , - C(O)N(CH 2 CH 3 ) 2 , -C(O)N(CH 3 )CH 2 CH 3) -C(0)N(CH 2 CH 2 CH 2 CH 3 ) 2 , -C(0)N(CH 2 CH 3 )CH 2 CH 2 CH 3 , -C(0)N(CH 3 )CH(CH 3 ) 2l -C(O)N(CH 2 CH 3 )CH 2 CH(CH 3 ) 2 , - C(0)N(CH(CH 3 )CH 2 CH 3 ) 2> -C(O)N(CH 2 CH 3 )C(CH 3 ) 3 and -C(O)N(CH 2 CH 3 )CH 2 C(CH 3 ) 3 .
"Di(alkyl)amino-" refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of an di(CrC 6 alkyl)amino- group include, but are not limited to, - N(CH 3 ) 2 , -N(CH 2 CH 3 )(CH 3 ), -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , N(CH 2 CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 ) 2 ) 2 , -N(CH(CH 3 ) 2 )(CH 3 ), -N(CH 2 CH(CH 3 ) 2 ) 2 , - NH(CH(CH 3 )CH 2 CH 3 ) 2 , -N(C(CH 3 ) 3 ) 2, -N(C(CH 3 ) 3 )(CH 3 ), and -N(CH 3 )(CH 2 CH 3 ). The two alkyl groups on the nitrogen atom, when taken together with the nitrogen to which they are attached, can form a 3- to 7- membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with -N(H)-, -N(CrC 6 alkyl)-, -N(C 3 -C 8 cycloalkyl)-, -N(C 6 -C 4 aryl)-, -N(d- Cgheteroaryl)-, -N(amino(Ci-C 6 alkyl))-, -N(C 6 -Ci 4 arylamino)-, -O-, -S-, -S(O)-, or - S(0) 2 -.
"Halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.
"Haloalkyl-" refers to an alkyl group, as defined above, wherein one or more of the Ci-C 6 alkyl group's hydrogen atoms has been replaced with -F, -CI, - Br, or -I. Each substitution can be independently selected from -F, -CI, -Br, or -I. Representative examples of an Ci-C 6 haloalkyl- group include, but are not limited to, -CH 2 F, -CCI 3 , -CF 3 , CH 2 CF 3 , -CH 2 CI, -CH 2 CH 2 Br, -CH 2 CH 2 I, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CH 2 CI, -CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, -CH CH 2 CH 2 CH 2 CH 2 Br, - CH 2 CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH(Br)CH 3 , -CH 2 CH(CI)CH 2 CH 3 , -CH(F)CH 2 CH 3 and - C(CH 3 ) 2 (CH 2 CI).
"Heteroaryl-" refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur, and nitrogen. Examples of monocyclic Ci -Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyi, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl. Examples of bicyclic C Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl. The contemplated heteroaryl- rings or ring systems have a minimum of 5 members. Therefore, for example, Ci heteroaryl- radicals would include but are not limited to tetrazolyl, C 2 heteroaryl- radicals include but are not limited to triazolyl, thiadiazoyi, and tetrazinyl, Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl. A heteroaryl group can be unsubstituted or substituted with one or more of the following groups: C-i-C 6 alkyl-, halogen, CrC 6 haloalkyl-, hydroxyl, Ci-C 6 hydroxylalkyl-, H 2 N-, amino(Ci-C 6 alkyl), di(Ci-C 6 alkyl)amino-, -COOH, (CrC 6 alkoxy)carbonyl-, (CrC 6 alkyl)carboxyl-, di(CrC 6 alkyl)ainnido-, H 2 NC(0)-, (Ci-C 6 alkyl)amido-, or 0 2 N-.
"Hydroxylalkyl-" refers to an alkyl group, as defined above, wherein one or more of the C-i-Cealkyl group's hydrogen atoms have been replaced with hydroxyl groups. Examples of hydroxyl (C Cealkyl)- moieties include, for example, - CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 OH, -CH 2 CH(OH)CH 3 , - CH(CH 3 )CH 2 OH and higher homologs.
"Leaving group" refers to an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. For example, in the heterolytic solvolysis of benzyl bromide in acetic acid: the leaving group is bromide. In the reaction of N,N,N-trimethyl-1 -phenylmethanaminium ion with methanethiolate, the leaving group is trimethylamine. In the electrophilic nitration of benzene, it is H + . The term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates {i.e. CH 3 COO ~ , CF 3 C0 2 " , or (CH 3 ) 2 CH 2 COO ~ ), F ~ water, CI " , ΒΓ, Γ, N 3 ~ SCNT, trichloroacetimidate, thiopyridyl, tertiary amines (i.e. trimethylamine), phenoxides (i.e. o- nitrophenoxide), and sulfonates (/ ' . e. tosylate, mesylate, or triflate).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention. EXAMPLES
iylphospholane-CH 2 O moiety:
air stable a j r stable crystalline solid crystalline solid
Bisphosphite moiety:
1: R= H. Biphenyl
2a:R=H. ( -Binaphthyl
2b:R=H. (S Binaphthyl
3a: R= t Bu. (i?)-BIPHEN
3b: R= ¾u. (S)-BIPHEN
Ligand formation:
ive than chloridite Preparation of ligand (3b)
To a Schlenk flask containing (S)-3,3 ' -di-teri-butyl-5,5 ' ,6,6 ' -tetramethyl-[1 ,Γ- biphenyl]-2,2 ' -diol] ((S)-BIPHEN) (2.00 g, 5.64 mmol) and triethylamine (1.65 mL, 1.20 g, 11.84 mmol, 2.1 eq.) was added phosphorus trichloride (517 μί, 814 mg, 5.92 mmol, 1.05 eq.) and the reaction stirred at room temperature overnight. The crude reaction mixture was then filtered under nitrogen atmosphere, toluene (3 x 5 mL portions) added to the residue, and removed under reduced pressure, to remove any residual phosphorus trichloride leaving a colorless solid. The crude 31 P NMR (121.4 MHz, C 6 D 6 ) spectrum showed a single peak at δ Ρ = 178.8 ppm, corresponding to (S)-BIPHEN chlorophosphite. In a glove box under a nitrogen atmosphere (S)-BIPHEN chlorophosphite (1.0 g, 2.39 mmol) from above was dissolved in toluene, excess trimethylsilyl iodide (1.5 mL, 2.11 g, 10.53 mmol) added and the reaction mixture allowed to stir for 2 hours at room temperature. The excess trimethylsilyl iodide was then removed under reduced pressure and toluene (3 x 5 mL portions) added to the residue and removed under reduced pressure, to remove any residual trimethylsilyl iodide. The crude 31 P NMR (121.4 MHz, C 6 D 6 ) spectrum showed two peaks, one at δρ = 178.8 ppm and another at δ Ρ = 222.1 ppm indicating only partial conversion to the desired iodo-phosphite (3). This mixture was used in the coupling step below to form ligand (3b), without further purification. Step 2:
All procedures reactions were carried out in a glove box under a nitrogen atmosphere. To a Schlenk flask containing a solution of phospholane (707 mg, 2.39 mmol, 1 eq.) and a mixture of chloro- and iodo-phosphite (2.39 mmol) in toluene (10 ml_), was added 1 ,4-diazabicyclo-[2,2,2]-octane (DABCO, 1 .34 g, 1 1 .95 mmol, 5 eq.) and the solution allowed to stir at room temperature overnight. The product was isolated after filtration through silica as a pale yellow oil, which solidified to pale yellow crystals on standing. Yield: 547 mg, 0.84 mmol, (35%). etc 25 = +387.1 ° (c = 0.41 , toluene); 31 P NMR (121 .4 MHz, C 6 D 6 ) δ Ρ = 139.3 (P1 ), 22.5 (P4); 1 H NMR (400 MHz, C 6 D 6 ) δ Η = 7.00-7.30 (m, 12H, ArCH), 4.09-4.21 (m, 1 H, C3H), 3.24-3.49 (m, 3H, C3H', C5H and C8H), 2.12-2.26 (m, 1 H, C6H or C7H), 2.09 (s, 3H, CH 3 ), 2.08 (s, 3H, CH 3 ), 1.83-1 .95 (m, 2H, C6H2 or C7H2), 1 .78 (s, 3H, CH 3 ), .62 (s, 3H, CH 3 ), 1 .50-1 .60 (m, H, C6H or C7H), 1 .50 (s, 9H, C(CH 3 ) 3 ), 1 .38 (s, 9H, C(CH 3 ) 3 ); 13 C NMR (75.5 MHz, C 6 D 6 ) 6 C = 146.73, 146.68, 146.05, 146.03, 144.59, 44.40, 138.52, 138.50, 138.48, 138.45, 137.30, 135.32, 134.59, 132.66, 132.24, 132.19, 131 .62, 131 .27, 131 .24 (ArCquat.), 128.71 , 128.69, 128.62, 128.34, 128.25, 128.00, 127.96, 126.14, 126.12, 126.04, 126.02 (ArCH), 62.40 (dd, 1 JC-P = 29.0, 3.7 Hz, C3), 46.20 (d, 1 JC-P = 15.9 Hz, C5 or C8), 45.45 (d, 1 -P = 14.9 Hz, C5 or C8), 36.42 (C6 or C7), 32.67 (d, 2JC-P = 3.1 Hz, C6 or C7), 31 .76 (d, J = 5.0 Hz, C(CH 3 ) 3 ), 31 .29 (C(CH 3 ) 3 ), 20.4 (CH 3 ), 20.37 (CH 3 ), 16.74 (CH 3 ), 16.45 (CH 3 ).
EXAMPLE 2 Regioselective and enantioselective hydroformylation of allyl benzene.. [Rh(acac)(CO) 2 ] (1 mg, 0.004 mmol, 0.4 mol%) was added into a vial, a stirring bar was added and the vial was sealed with a crimp cap a put under inert atmosphere (N 2 ). Two needles were pierced into the vial and this was introduced into the autoclave. The autoclave was then purged with three vacuum/N 2 cycles. A solution of the ligand (Ligand 3a, 3.3 mg, 0.005 mmol, 0.5 mol%) in toluene (1 mL) from a stock solution was added using a syringe. The autoclave was then purged three times with syngas (50/50, CO/H 2 ), pressurized to 5 bar, immersed into an oil bath preheated at 50 °C and stirred at 900 r.p.m for 40 minutes. After this time, the autoclave was cooled down to room temperature by partial immersion in cold water and the pressure released. A solution of alkene (allylbenzene, 118 mg, 133 μΙ, 1 mmol) and internal standard (tetraethylsilane, 30 μΙ) in toluene (1 mL) was added using a syringe. The autoclave was then pressurized back to the desired pressure (5 bar) and stirred at room temperature at 900 r.p.m. After the desired reaction time, (75 hours), the pressure was slowly released and the autoclave was opened. A small sample was taken and analyzed by 1 H NMR (CDCI3) to calculate conversion (64%) and branched to linear ratio of the resulting aldehydes (4.00: 1). To determine enantioselectivity (e.e, = 90% for the branched aldehyde), the products were converted into the corresponding alcohols by NaBH 4 reduction with the alcohol produce being obtained after work up (dichloromethane (5 mL), quenched with HCI aqueous (5 mL, 1 M), followed by 3 further extractions with dichloromethane (3x10 mL). The combined organic layers were dried over anhydrous MgS0 and the solvent was removed with a rotary evaporator to give the crude mixture which was purified by chromatography on using hexane/EtOAc 4:1 as eluent to give the branched and linear alcohols as a colorless oil (79 mg, 53%). [a] D rt = -12.2 (c 0.5, CHCI 3 ) (for the branched alcohol).
NMR data for branched and linear alcohols.
2-methyl-3-phenylpropan-1-ol: 1 H NMR (300 MHz, CDCI 3 ): 6= 0.90 (3H, d, J = 6.8 Hz), 1.43 (1 H, br s), 1.87-1.99 (1 H, m), 2.41 (1 H, dd, J = 13.4, 8.1 Hz), 2.74 (1 H, dd, J = 13.4, 6.3 Hz), 3.46 (1 H, dd, J = 10.6, 6.0 Hz), 3.52 (1 H, dd, J = 10.6, 5.9 Hz), 7.14-7.28 (5H, m); MS (ES+): 173.1 ([MNa] + , 100%). 4-phenylbutan-1-ol: 1 H NMR (300 MHz, CDCI 3 ): δ= 1.38 (1 H, br s), 1.55- 1.72 (4H, m), 2.62 (2H, t, J = 7.5 Hz), 3.64 (2H, t, J = 6.4 Hz), 7.15-7.28 (5H, m); MS (ES+): 173.1 ([MNa] + , 100%). The enantiomeric excess of the branched alcohol was determined by HPLC on a Chiralcel™ OD-H column, 250 x 4.6 mm, 95:5 n-hexane: 2-propanol, 0.5 ml/min, 210 nm, fR[(-)-(S), major] = 18.6 min, fo[(+)-(ft). minor] = 22.8 min, i R [linear] = 30.2 min.
EXAMPLE 3 Regioselective and enantioselective hydroformylation of hex-1-ene. [Rh(acac)(CO) 2 ] (1 mg, 0.004 mmol, 0.4 mol%) was added into a vial, a stirring bar was added and the vial was sealed with a crimp cap and put under an inert atmosphere (N 2 ). Two needles were pierced into the vial and this was introduced into the autoclave. The autoclave was then purged with three vacuum/N 2 cycles. A solution of the ligand (Ligand 3a, 3.3 mg, 0.005 mmol, 0.5 mol%) in toluene (1 ml) from a stock solution was added using a syringe. The autoclave was then purged three times with syngas (50/50, CO/H 2 ), pressurized to 5 bar, immersed into an oil bath preheated at 50 °C and stirred at 900 r.p.m for 40 min. After this time, the autoclave was cooled down to room temperature by partial immersion in cold water and the pressure released. A solution of alkene (1 - hexene, 84 mg, 124 μΙ, 1 mmol) and internal standard (tetraethylsilane, 30 μΙ) in toluene (1 ml) was added using a syringe. The autoclave was then pressurized back to the desired pressure (5 bar) and stirred at room temperature at 900 r.p.m. After the desired reaction time (46 h), the pressure was slowly realized and the autoclave was opened. A small sample was taken and analyzed by 1 H NMR (CDCI 3 ) to calculate conversion (70%) and branched to linear ratio of the resulting aldehydes (2.98: 1 ). To determine enantioselectivity (e. e. = 93% for the branched aldehyde), the products were converted into the Cbz-esters of the corresponding alcohols by reduction using NaBH 4 and protection in the standard way. NMR data for branched and linear alcohols. [a] D 20 -1 1.6 (c 1.4, CHCI 3 , e. e. 93%)
2-methylhexan-1-ol: 1 H NMR (300 MHz, CDCI 3 ): δ= 0.89 (3H, t, J = 6.9 Hz), 0.91 (3H, d, J = 6.7 Hz), 1.05-1.67 (8H, m), 3.40 (1 H, dd, J = 10.5, 6.5 Hz), 3.50 (1 H, dd, J = 10.5, 5.8 Hz); MS (ES+): 139.1 ([MNa] + , 100%). heptan-1-ol: H NMR (300 MHz, CDCI 3 ): δ= 0.88 (3H, t, J = 6.4 Hz), 1.28- 1 .60 (1 1 H, m), 3.63 (2H, t, J = 6.6 Hz); MS (ES+): 139.1 ([MNa] + , 100%). The enantiomeric excess of the branched Cbz-derived alcohol was determined by HPLC on a tandem of Chiralpak™ AD-H, 250 x 4.6 mm, and Chiralcel™ OD-H, 250 x 4.6 mm, 99:1 n-hexane: 2-propanol, 0.5 ml/min, 210 nm, fR[(-)-(S), major] = 20.5 min, fR[(+)-(fl). minor] = 25.2 min, f R [linear] = 24.2 min.
EXAMPLE 4 Regioselective and enantioselective hydroformylation of pentafluoro-allyl benzene. Using a similar procedure as described in examples 2 and 3, but using pentafluoro-allylbenzene as substrate and a reaction temperature of 40 °C the branched aldehyde was again formed. After the desired reaction time (4 h), the pressure was slowly released and the autoclave was opened. A small sample was taken and analyzed by H NMR (CDCI 3 ) to calculate conversion (90%) and branched to linear ratio of the resulting aldehydes (5.3: 1 ). To determine enantioselectivity (e. e.= 88% for the branched aldehyde), the aldehyde was reduced using NaBH 4 in the standard way, with standard purification by chromatography on silica gel using hexane/EtOAc 4:1 as eluent to give the branched and linear alcohols as colorless oil (150 mg, 63%). [a] D 20 = - 8.7 (c 2.75, CHCI 3 , e. e. 88%);
(-)-2-methyl-3-(perfluorophenyl)propan-1 -ol. 1 H NMR (400 MHz, CDCI 3 ): δ Η = 0.92 (d, J = 6.8 Hz, 3H), 1 .77 (s, 1 H), 1 .89-2.01 (m, 1 H), 2.55 (ddt, J = 13.6, 8.4, 1 .7 Hz, 1 H), 2.85 (ddt, J = 13.6, 5.8, 1 .7 Hz, 1 H), 3.50 (dd, J = 8.9, 4.2 Hz, 1 H), 3.54 (dd, J = 8.9, 4.0 Hz, 1 H); 19 F NMR (376 MHz, CDCI 3 ): 5 F = -163.6- -163.4 (m, 2F), -158.2 (t, J = 20.8 Hz, 1 F), -143.7—143.6 (m, 2F); 13 C NMR (75 MHz, CDCI3): 5c = 16.0, 25.9, 36.2, 67.3, 1 13.7-1 14.0 (m), 136.1 -146.4 8 (m); MS (Cl + ): 239.0 ([M-2H+H] + , 100%), 240 ([MH] + , 13), 250.0 ([M+NH 4 ] + , 8); HRMS (CI+): m/z = 258.0914 [M+NH 4 ] + , Ci 0 H 13 ONF 5 requires 258.0912.
4-(perfluorophenyl)butan-1 -ol. H NMR (400 MHz, CDCI 3 ): δ Η = 1 .46 (br s, 1 H), 1 .57-1 .72 (m, 4H), 2.72-2.75 (m, 2H), 3.67 (t, J = 6.2 Hz, 2H); 19 F NMR (376 MHz, CDCIs): δ Ρ = -163.5- -163.4 (m, 2F), -158.5 (t, J = 20.9 Hz, 1 F), - 144.9- -144.8 (m, 2F); 13 C NMR (100 MHz, CDCI 3 ): 5 C = 22.0, 25.5, 32.0, 62.3, 1 14.7-1 15.0 (m), 136.1 -146.3 (m). The enantiomeric excess of the branched alcohol was determined by HPLC on a tandem series of Chiralpak™ AS-H, 250 x 4.6 mm, and Chiralpak AD-H columns, 250 x 4.6 mm, 99:1 n-hexane: 2-propanol, 0.5 mL/min, 210 nm, fR[(-), major] = 69.1 minutes, fo[(+), minor] = 74.0 minutes, f F near] = 97.2 minutes.
EXAMPLE 5 Regioselective and enantioselective hydroformylation of W-methyl-W-phenylbut-3-enamide. Using a similar procedure as described in examples 2 and 3, but using A/-methyl-/V-phenylbut-3-enamide as substrate and a reaction temperature of 15 °C, the branched aldehyde was again formed. After the desired reaction time (29 h), the pressure was slowly released and the autoclave was opened. A small sample was taken and analyzed by 1 H NMR (CDCI 3 ) to calculate conversion (71 %) and branched to linear ratio of the resulting aldehydes (4.5:1 ). To determine enantioselectivity (e. e.= 92% for the branched aldehyde), the aldehyde was reduced using NaBH 4 in the standard way, with standard purification by chromatography on SiO 2 using EtOAc as eluent to give the branched and linear alcohols as a colorless oil (1 13 mg, 55%). [a] D 20 -7.7 (c 0.85,
(-)-4-hydroxy- V,3-dimethyl-A/-phenylbutanamide. Purified by chromatography on silica gel using EtOAc as eluent to give the branched and linear alcohols as a colorless oil (1 13 mg, 55%). [α]ο 20 -7.7 (c 0.85, CHCI 3 , e. e. 92%); 1 H NMR (300 MHz, CDCI 3 ): δ = 0.79 (d, J = 6.3 Hz, 3H), 2.00-2.21 (m, 3H), 3.24 (s, 3H), 3.29-3.34 (m, 2H), 3.50 (dd, J = 10.3, 3.4 Hz, 1 H), 7.14-7.18 (m, 2H), 7.30-7.43 (m, 3H); 13 C NMR (75 MHz, CDCI3): δ = 17.2, 33.1 , 37.4, 38.9, 68.1 , 127.2, 127.8, 129.8, 143.9, 173.2; MS (ES + ): 230.0 ([MNa] + , 100%); HRMS (ES + ): m/z = 230.1 161 [MNa]\ Ci 2 H 17 NO 2 Na requires 230.1 157.
5-hydroxy-A/-methyl-A -phenylpentanamide. H NMR (300 MHz, CDCI 3 ): δ Η = 1 .42-1 .51 (m, 2H), 1 .61 -1 .70 (m, 2H), 2.09 (t, J = 7.0 Hz, 2H), 2.24 (br s, 1 H), 3.25 (s, 3H), 3.54 (t, J = 6.3 Hz, 2H), 7.15-7.18 (m, 2H), 7.31 -7.44 (m, 3H); 13 C NMR (75 MHz, CDCI 3 ): 5 C = 21 .2, 32.2, 33.6, 37.4, 62.0, 127.3, 127.9, 129.8, 144.1 , 173.3; MS (ES + ): 230.0 ([MNa] + , 100%). The enantiomeric excess of the branched alcohol was determined by HPLC on a Chiralpak™ AD-H column, 250 x 4.6 mm, 93:7 n-hexane: 2-propanol, 0.5 mL/min, 254 nm, fo[(-), major] = 33.8 minutes, fFt[(+), minor] = 36.2 minutes, ^[linear] = 41 .2 minutes.
EXAMPLE 6: Regioselective and enantioselective hydroformylation of Vinyl acetate. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO) 2 ] and ligand 3a were prepared as 1 mg per ml_ solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes. The pressure was then vented and the apparatus cooled to room temperature. The require substrate (vinyl acetate 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 ml_ volume. The apparatus was then purged three times with Syngas, placed at 2.5 bar pressure and heated to 60 °C at constant pressure for 4 hours, after which time no further Syngas uptake was used up (>99% conversion). The AE was then cooled and the reaction mixture analyzed by GC in the standard protocol using a beta- Dex 225 chiral column. This along with NMR revealed that the only product present was the branched aldehyde (B / L >99:1 ) and with an e. e.. of 83 %.
EXAMPLE 7: Regioselective and enantioselective hydroformylation of styrene. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO) 2 ] and ligand 3a were prepared as 1 mg per mL solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes. The pressure was then vented and the apparatus cooled to room temperature. The require substrate (styrene 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 mL volume. The apparatus was then purged three times with Syngas, placed at 10 bar pressure and heated to 60 °C at constant pressure for 6 hours, after which time no further Syngas uptake was used up (>99% conversion). The AE was then cooled and the reaction mixture analyzed by GC in the standard protocol using a beta-Dex 225 chiral column. This revealed >99% conversion to aldehydes, (B / L = 79.3:1 ) and with an e. e.. of 92 %.
EXAMPLE 8: Regioselective and enantioselective hydroformylation of allyl cyanide. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO)2] and ligand 3a were prepared as 1 mg per ml_ solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes. The pressure was then vented and the apparatus cooled to room temperature. The require substrate (allyl cyanide, 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 mL volume. The apparatus was then purged three times with Syngas, placed at 10 bar pressure and heated to 30 °C at constant pressure for 14 hours, after which time no further Syngas uptake was used up (>99% conversion). The AE was then cooled and the reaction mixture analyzed by 1 H NMR spectroscopy utilizing enantiopure (fl)-1 -phenylpropan-1 -amine as a chiral derivatizing agent to facilitate calculation of enantiomeric excess, with the branched selectivity and conversion also measured using NMR. In some cases conversion, and branched to linear were also checked using chiral CG using an alpha-Dex 225 column. This revealed >99% conversion, a B : L = 10.0:1 and an e. e.. of 81 %.
Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
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