Method for the preparation of a compound of the general formula R'-R ¹ and/or R'-R ² using homo and hetero coupling reactions

The present application relates to a method for the preparation of a compound of the general formula R ¹ -R ¹ and/or R ¹ -R ² using homo and hetero coupling reactions in the presence of an organic oxidant.

Coupling reactions belong to the most powerful tools for forming C-C bonds in modern organic chemistry. ¹ ' ² For most types of cross-couplings, transition metals are required as mediators or catalysts. ³ Usually at least 0.5 equivalents of Cu(I) salts ⁴ for Ullmann-type ⁵ coupling reactions, 1.5 equivalents of TiCl ₄ ⁶ or the addition of catalytic amounts of other

7 7 H transition metals are needed. ' The importance for finding new catalytic systems and using atmospheric oxygen ⁹ or its derivatives ¹⁰ for the performance of oxidation reactions is well recognized. However, this oxidation chemistry is often unselective, since it is governed by the chemistry of high-energy zwitterions, (di)radicals, or electron-transfer reactions without stereochemical control.

It is an object of the present invention to provide a method which allows for the selective preparation of homo and hetero coupling products at mild conditions.

This object is achieved by the features of the independent claims. Preferred embodiments are set forth in the dependent claims.

A new concept which allows for the performance of coupling reactions using not only transition but also main-group metal derivatives is postulated by the inventors. The inventors envisioned that the reaction of the metal center with an oxidant being readily reduced would function as an electron-shuttle and would allow a reductive coupling to take place. Thus, the presence of an organic oxidant (Ox) converts the intermediate A to the key intermediate B which can undergo an oxido-reduction process leading to a C-C bond formation (oxidative coupling) and simultaneously to the reduction of Ox which by accepting two electrons is leading to the reduced compound (Red). It is important to notice that the metal keeps its oxidation stage during the entire process. A schematic view of the reaction process is given in Scheme 1 below. Without being bound to theory it is believed that the oxidant binds to the metal complex A to form the compound B. In this compound, the target compound R '-R ² is

formed by a reduction of the oxidant to Red, while the metal is removed from compound B. The reduced oxidant Red can be recovered and recycled to the oxidant with oxygen or air. This oxidant can then be used again.

R ¹ x

R ² A

Scheme 1: Tentatively supposed mechanism for the coupling reaction using organic oxidants.

An aspect of the present invention provides a method for the preparation of a compound of the general formula

R'-R ² (I) and/or R'-R ¹ (II) comprising providing a compound of the general formula R ¹ ^ ₁ M ¹ A _1n -ZM ⁴ Z _n (III) or R ¹ R ² M ¹ R^A ₁₁₁ -XM ⁴ Z _n (IV) or R ¹ M ¹ R ² R ³ ^ ² A _1n -XM ⁴ Z _n (V) or R ¹ M ³ R ² M ¹ ^xM ⁴ Z _n (VI) and reacting this compound IH-VI with a quinone to produce a compound of the general formula I or II or a mixture of compounds I and II, wherein

M ¹ , M ² and M ⁴ are independently selected from Li, Na, K, Cs, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Co, Ni, Ag, Au, Zn, Cd, Hg, B, Al, Tl, Ga, In, Si, Ge, Sn, Pb, As, Sb, Bi, Se, Te, La, Ce, Nd, Sm, Tm, Pr, Eu, Gd, Tb, Dy, Lu, Yb, Ho; or alloys thereof; and M can be additionally be selected from the cation of a phase-transfer catalyst; M is selected from Cu and Fe;

R , R and R are independently selected from substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms; linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, silyl or derivatives thereof; or R ¹ and R ² together can be part of a cyclic or polymeric structure; an alcoholate of the general formula OR ^X ; a thiolate of the general formula SR ^X ; and an amide of the general formula NR ^X ₂ wherein R is a substituted or unsubstituted aryl or heteroaryl containing one or more heteroatoms; linear, branched or cyclic, substituted or unsubstituted alkyl, alkenyl, alkynyl, silyl or derivatives thereof; or H;

in the case of NR ₂ the two residues R can be the same or different, or the residue

R ₂ can be part of a cyclic structure; under the proviso that for the compound of formula VI, R ¹ and R ² are different; A and Z are independently selected from the group consisting of F; Cl; Br; I; CN; SCN; NCO; HaIO _n , wherein n = 3 or 4 and Hal is selected from Cl, Br and I; BF ₄ ; PF ₆ ; H; a carboxylate of the general formula R ^X CO ₂ ; an alcoholate of the general formula OR ^X ; a thiolate of the general formula SR ^X ; R ^X P(O)O ₂ ; SCOR ^X ; SCSR ^X ; O _n SR ^x , wherein n = 2 or 3; or NO _n , wherein n = 2 or 3; an amide of the general formula NR ^X ₂ ; a phosphine of the general formula PR ₃ , and derivative thereof; wherein R is defined as above; z > 0; x > 0; d is I ₅ 2, 3 or 4; k is O, 1 or 2; m is 0, 1, 2 or 3; and n is 1, 2, 3 or 4.

Recently, the inventors found that mono- and diorganomagnesium reagents complexed with lithium chloride' ' can be efficiently coupled by treatment with readily available 3,3', 5, 5'- tetra-/-butyldiphenoquinone (1), which acts as two-electron acceptor (Scheme 2 and Table 1).

2 R-MgCI LiCI or R ₂ Mg LiCI

Scheme 2: Coupling of organomagnesium reagents with 3,3',5,5'-tetra-/-butyldipheno- quinone (1).

Different mono and diorganozinc compounds can be coupled as well using the more active oxidizing reagent chloranil (Scheme 3). Organozinc compounds could be prepared by direct insertion of Zn, I/Zn-exchange reaction, B/Zn-exchange reaction or by transmetallation of organolithium or Grignard reagents. Thus, the reaction of 2,5-dibromothiophene with /-PrMgCl LiCl (25 ⁰ C, 1 h) followed by the addition of ZnCl ₂ produces a zinc reagent. This

zinc reagent affords in a reaction with chloranil (1.03 equiv, -60 ⁰ C to -10 ⁰ C, 12 h) the expected dimer in 90% yield.

2 R-ZnHaI or R ₂ Zn

THF, - 60 ⁰ C to 25°C

B

Scheme 3: Coupling of organozinc reagents with chloranil.

In the case of using the mixture of two different organometallic reagents, or a diorganometallic reagents with two different radicals R ¹ and R ² , product C corresponding to the heterocoupling reaction can be obtained (Scheme 4). The ratio between products in heterocoupling reactions, i.e. the two homo coupling products R '-R ¹ and R ² -R ² and the hetero coupling product R -R , depends on ratio of the organometallic reagents, the nature of the radicals R ¹ and R ² , and on the way of preparing the mixed diorganometallic reagent. In most cases, a ratio close to the statistical distribution of coupling products was obtained.

quinone or

M ¹ A, + R ² -M ² A| diphenoquinone or ^ ^► R ¹ -R ¹ + R ¹ -R ² + F R ² -R ²

R ¹ M ¹ R 2 THF, - 20 ⁰ C to 25 ⁰ C C

PhMgCI + ToIMgCI or

PhLi + ToIMgCI 1 or chloranil or Ph-Ph + Ph-ToI + ToI-ToI

PhZnCI + ToIMgCI _" "1 / ~2 / -1 or > 90 % yield PhLi + ToIZnCI or

PhCu + ToIZnCI

Scheme 4: Heterocoupling reactions (ToI = tolyl, Ph = phenyl).

However, the inventors were able to perform selective heterocoupling reaction between lithium amides and organocopper reagents. The reaction has a broad scope, and a wide variety of functional groups can be tolerated. In this case, only small amounts of homocoupling products from the organocopper reagent and no homocoupling products from lithium amides are obtained. This approach allows for the preparation of different primary, secondary and tertiary amines (Scheme 5).

PhCu + LiN(SiMe ₃ ) ₂ ^chloranil í p _hN (SiMe ₃ ) ₂ -^ PhNH ₂

- 60 ⁰ C

65 % chloranil

PhCu + LiNHPh - PhNHPh

- 60 ⁰ C 72 % chloranil

PhCu + LiNPh ₂ - Ph ₃ N

- 60 °C 94 % chloranil PhCu + LiN(Z-Pr) ₂ PhN(Z-Pr) ₂

- 60 ⁰ C 80 %

Scheme 5: Synthesis of amines (Me = methyl; Ph = phenyl; /-Pr = /so-propyl).

According to a preferred embodiment of the present invention, the quinone used is an orhto- or /røra-benzoquinone, a quinodimethane, or a diphenoquinone, or a naphthoquinone, or an anthraquinone, or a phenanthrenedione, or a cyclic 1,2- or 1 ,4-diketone, or indigo derivatives, preferably selected from the group consisting of 3,3 ,5,5 -tetra-t-butyl diphenoquinone, 1,4- benzoquinone and 2,3,5,6-tetrachloro-p-benzoquinone (chloranil), 2,3,5,6-tetramethyl-p- benzoquinone (duroquinone), 2,6-dimethyl-l ,4-benzoquinone, 2,5-dimethyl-l,4-benzo- quinone, tetracyanoquinodimethane (TCNQ).

In another preferred embodiment of the present invention, the reaction is performed in the presence of a complexing agent M ⁴ Z _n , preferably wherein the complexing agent is selected from LiZ, ZnZ ₂ , AlZ ₃ or MgZ ₂ . The compounds of the formulae HI-VI can optionally be complexed with cyclic, linear or branched mono or polyethers, thioethers, amines, phosphines, and derivatives thereof containing one or more additional heteroatoms selected from O, N, S and P, preferably dimethyl sulfide, diethylether, THF, triethylamine or pyridine. This latter complexing agent can be used additionally or alternatively to the complexing agent M ⁴ Z _n . The complexing agent M ⁴ Z _n may not be present in the formulae IV-VI, i.e. x may be 0.

In contrast thereto, in formula III, the complexing agent M ⁴ Z _n is always present, i.e. z may not be 0.

In all aspects of the invention, z and/or x is preferably in the range from 0.01 - 5, more preferably from 0.5 - 3, even more preferably from 0.8 - 2 and most preferred about 1, i.e. in the range of 0.9 to 1.1.

In the complexing agent M Z _n , n may be 2 in a preferred embodyment of the invention. In this case, Z ₂ may be a divalent anion, selected from the group consisting of diamines, dialkoxides and dithiols. The diamine may have the general formula R'NH-R-NHR', the dialkoxide may have the general formula HO-R-OH and/or the dithiol may have the general formula HS-R- SH, wherein R' und R are independently selected from the same group as R ^x , wherein R is a divalent radical, preferably the divalent radical of CH ₃ NHCH ₂ CH ₂ NHCH ₃ , HOCH ₂ CH ₂ OH, binol or 1,2-diamino cyclohexane.

To prepare compounds of the general formula R -R , a mixture of the two different compounds of the general formula III, wherein the compounds of formula III differ at least at R , can be used in the reaction with a quinone according to a preferred embodiment of the present invention. Thus, one compound has a general formula R ¹ _J M ¹ A _m -ZM ⁴ Z _n , (III) whereas the other compound has a general formula R ² _d Mα _m -zM ⁴ Z _n (HIa). The variables M ¹ , A, M ⁴ , Z, d, m, n are defined as above and may be the same or different. A reaction of these compounds provides a heterocoupling product R'-R ² .

When a compound R ¹ -R ² is prepared by any of the above methods, in a preferred embodiment R ¹ or R ² may contain a hetero atom selected from O, S, Se and N as the coupling atom, as mentioned above. In the case R or R contain a hetero atom for coupling, the other residue R ² or R ¹ is coupled via a carbon atom, i.e. the coupling forms a C-O, C-S, C-Se or C-N bond, and not a hetero atom-hetero atom bond. The formation of hetero couplings with nitrogen, i.e. the formation of C-N bonds, may advantageously be performed using compounds of formula VI, and in a further preferred embodiment under addition of a ligand as described below.

In a preferred embodiment of the invention, M ¹ , M ² and M ⁴ are independently selected from Li, Cs, Mg, Ti, Zr, V, Cr, Mo, W, Mn, Fe, Co, Ni, Zn, B, Al, In, Si, La, Ce, Nd, Sm, Tm, Pr, Eu, Gd, Tb, Dy, Lu, Yb, Ho; or alloys thereof.

In a further preferred embodiment, M ¹ is selected from Mg, Ca, Zr, Ti, Mn, Zn, B and Al and/or M ² is selected from Li, Cs, Mg and Zn and/or M ⁴ is selected from Li, Cs, R ^X ₄ N ⁺ , wherein R ^x is defined as above.

The compounds of formulae III to VI may be produced in situ before carrying out the method described above. This may include the formation of a Grignard reagent and/or a transmetallation reaction. When compounds of formula VI are used, these compounds can be prepared by transmetallation reaction from e.g. Grignard or Li organic reagents. In this case, the Cu or Fe may be added in a catalytic amount, i.e. sub-stoichiometrically. In a preferred embodiment, the Cu or Fe may be added in an amount of 1 mol.-% to 50 mol.-%, preferably 10 mol.-% to 30 mol.-%, based on the compound to be converted to the compound VI.

In a further preferred embodiment when using compounds of formula VI, a ligand may be added to the reaction mixture. Without being bound to this theory, it is assumed that this ligand can form a complex with the Cu- or Fe-containing compound and can thus increase the yield when performing the reaction.

The ligand may be selected from any ligand capable of coordinating a Cu or Fe. In a preferred embodiment, this ligand is selected from unsaturated organic compounds, preferably from substituted or unsubstituted alkynes and dienes. In a more preferred embodiment, the ligand is selected from substituted alkynes, substituted 1,3 -butadienes and substituted or unsubstituted cyclopentadienes. In another preferred embodiment, the ligand is selected from tertiary saturated or unsatured amines or saturated or unsaturated nitriles. In a specifically preferred embodiment, the ligand is selected from diphenylacetylene; phenylacetylene; 1 -phenyl- 1- propyne; 1 -phenyl- 1-butyne; styrene; 4-octyne; όz5-(4-methoxy-phenyl)-acetylene; 4,4'- ethynediyl-di-benzonitrile; 1 ,2-(p-cyano-p'-methoxydiphenyl)ethyne; 2,4,6-trimethyl- diphenyl-acetylene; phenyl-o-tolyl-acetylene; phenyl-p-tolyl-acetylene; 1 ,3-butadiene; 1,4- diphenylbutadiene; Z>zs-(2-cyanoethyl)-ether; bz ^' s[2-(N,N,dimethylamino)ethyl]ether; 1,4-bis- (dimethylamino)-butan; l,4-6«-(dimethylamino)-hexan; ethylene diamine, l,4-diazabicyclo[2.2.2]octane. Most preferably, the ligand is selected from dipheynlacetylene, phenylacetylene, b/5'[2-(λ ^r ,7V-dimethylamino)ethyl]ether and N,NJψ,W- tetramethyl ethylene diamine.

When a ligand, like an unsaturated organic compound, is used, the amount of ligand is preferably in the same amount as Cu or Fe in the solution. If the Cu or Fe is used stoichiometrically, the ligand is added in approximately the same amount. The same applies to cases where Cu or Fe are used catalytically. However, it is obvious to a person skilled in the art that the ligand can be used in any amount, i.e. in excess or less than the amount of metal.

In a preferred embodiment of the present invention, the solvent is selected from cyclic, linear or branched mono or polyethers, thioethers, amines, phosphines, and derivatives thereof containing one or more additional heteroatoms selected from O, N, S and P, preferably tetrahydrofuran (THF), 2-methyltetrahydrofuran, dibutyl ether, diethyl ether, tert-butylmethyl ether, dimethoxy ethane, dioxanes, preferably 1,4-dioxane, triethylamine, ethyldiisopropylamine, dimethyl sulfide, dibutylsulfide; cyclic or linear amides, preferably N- methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), N,N-Dimethylformamid (DMF), N,N-Dimethylacetamid (DMAC); cyclic, linear or branched alkanes and/or alkenes wherein one or more hydrogens are replaced by a halogen, preferably dichloromethane, 1 ,2-dichloroethane, CCl ₄ ; urea derivatives, preferably N,N'-dimethyl- propyleneurea (DMPU); aromatic, heteroaromatic or aliphatic hydrocarbons, preferably benzene, toluene, xylene, pyridine, pentane, cyclohexane, hexane, heptane; hexamethylphosphorus triamide (HMPA), CS ₂ ; H ₂ O; alcohols preferably ethanol, methanol, ter/-butanol; nitriles, preferably acetonitrile; esters, preferably ethylacetate; nitrocompounds, preferably nitromethane; pyridine derivatives, preferably pyridine; acids, preferably acetic acid; ionic liquids or combinations thereof.

The reaction can also be carried out without any solvent in another embodiment of the invention. Further, microwaves may be applied to the reaction mixture in an embodiment of the invention.

In all compounds HI to VI, the variables d, k, 1 and n are selected to result neutral compounds. A person skilled in the art will anticipate that in compound III; d and 1 will sum up to the oxidation state of M ¹ , in compound IV, k and 1 will sum up to the oxidation state of M ¹ minus 2, and in compound V, k and 1 will sum up to the sum of the oxidation state of M ¹ and the oxidation state of M minus 2. Similarly, in compound VI, the sum of the oxidation state of the metals M ¹ and M ³ must be 2.

The reaction for the preparation of R'-R ¹ and/or R'-R ² is preferrably performed at a temperature in the range of -100 ⁰ C to 160 ⁰ C, more preferably in the range of -80 ⁰ C to 8O ⁰ C. The reaction may further be carried out under an inert gas atmosphere, preferably in an atmosphere of N ₂ or Ar gas.

When carrying out the invention, the compound(s) according to the formulae IH-VI is(are) used with or without a solvent. When used in combination with a solvent, the solution of the compound(s) is as concentrated as possible according to a preferred embodiment. A concentration as high as possible may be limited by the solubility of the compound(s), especially at reduced temperatures like up to -100 ⁰ C. Additionally, a person skilled in the art will select a concentration low enough to avoid concentration effects during carrying out the invention. If the concentration is too high, undesired effect may arise, and the object of the present invention may not be achieve, i.e. the preparation of compounds I and/or II at high yields. According to a preferred embodiment of the invention, the concentration of the compound(s) according to formulae HI-VI is in the range of 0.01 M to 5 M, more preferably in the range of 0.05 M to 3 M, and most preferably in the range of 0.1 M to 2 M.

After the starting material(s) is(are) dissolved in a solvent, or used as they are, they are brought to a desired reaction temperature. Then, the formation of the metal organic agent according to formulae III-VI may be performed. The formation of the metal organic agent may be achieved according to standard procedures well known to a person skilled in the art and may include formation of Grignard reagents, direct metallation reactions or transmetallation reactions.

Subsequently, the compound(s) are brought to the desired reaction temperature for performing the reaction according to the invention. This may include cooling or heating of the reaction mixture. When having reached the desired reaction temperature, the oxidising agent, i.e. the quinone, is slowly added. In a preferred embodiment, the addition of the quinone is effected over a period of 1 min to 24 hours, preferably over a period of 10 min to 6 hours, more preferably over a period of 20 min to 3 hours.

After the addition of the quinone is completed, the reaction mixture may be stirred for an additional period of time at the same or a different temperature in order to achieve a complete

or almost complete conversion. This may include stirring over a period of up to 48 hours, preferably up to 24 hours, more preferably up to 12 hours. The conversion of the reaction may be controlled by standard means, e.g. by gas chromatography (GC).

When the reaction has come to a completion, the desired product I and/or II may be isolated by methods known in the art. A person skilled in the art will be able to select an appropriate method.

In another preferred embodiment of the present invention, the reaction results a hydroquinolate and/or a biphenol. This hydroquinolate and/or biphenol is the reduced product of the quinole, the organic oxidant, used in the reaction according to the invention. The hydroquinolate or biphenol may be separated from the reaction mixture and may then be recovered. The recovered hydroquinolate or biphenol may be recycled to the corresponding quinone or diphenoquinone by oxidation, preferably by oxidation with oxygen or air.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications and other references mentioned herein are incorporated by reference in their entirety.

As used herein, the terms "alkyl", "alkenyl" and "alkynyl" refer to linear, cyclic and branched, substituted and unsubstitued C|-C ₂ o compounds. Preferred ranges for these compounds are Ci-Cio for alkyl, and C ₂ -C]O, for alkenyl and alkynyl. The term "cycloalkyl" generally refers to linear and branched, substituted and unsubstitued C ₃ -C ₂₀ cycloalkanes. Here, preferred ranges are C ₃ -C] ₅ , more preferably C ₃ -C ₈ .

Whenever any of the residues R , R , R and/or R are substituted by a substituent, the substituent may be selected by a person skilled in the art from any known substituent. A person skilled in the art will select a possible substituent according to his knowledge and will be able to select a substituent which will not interfere with other substituents present in the molecule and which will not interfere or disturb possible reactions, especially the reactions described within this application. Possible substituents include without limitation halogenes, preferably fluorine, chlorine, bromine and iodine;

aliphatic, alicyclic, aromatic or heteroaromatic hydrocarbons, especially alkanes, alkylenes, arylenes, alkylidenes, arylidenes, heteroarylenes and heteroarylidenes; carbonxylic acids including the salts thereof; carboxylic acid halides; aliphatic, alicyclic, aromatic or heteroaromatic carboxylilc acid esters; aldehydes; aliphatic, alicyclic, aromatic or heteroaromatic ketones; alcohols and alcoholates, including a hydroxyl group; phenoles and phenolates; aliphatic, alicyclic, aromatic or heteroaromatic ethers; aliphatic, alicyclic, aromatic or heteroaromatic peroxides; hydroperoxides; aliphatic, alicyclic, aromatic or heteroaromatic amides or amidines; nitriles; aliphatic, alicyclic, aromatic or heteroaromatic amines; aliphatic, alicyclic, aromatic or heteroaromatic imines; aliphatic, alicyclic, aromatic or heteroaromatic sulfides including a thiol group; sulfonic acids including the salts thereof; thioles and thiolates; phosphonic acids including the salts thereof; phosphinic acids including the salts thereof; phosphorous acids including the salts thereof; phosphinous acids including the salts thereof.

The substituents may be bound to the residues R ¹ , R ² , R ³ and/or R ^x via a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom, or a phosphorus atom. The hetero atoms in any structure containing hetero atoms, as e.g. heteroarylenes or heteroaromatics, may preferably be N, O, S and P.

In the following, examples are given to illustrate the present invention. However, these examples are given for illustrative purposes only and are not supposed to limit the scope of the invention which is determined by the claims below.

The reaction of phenylmagnesium bromide with 0.5 equivalents of phenoquinone 1 at -2O ⁰ C leads to the formation of biphenyl 3b with quantitative yield. The reaction proceeds well with electron-rich (4a) or electron-poor (5a) arylmagnesium chlorides affording the corresponding biaryls 4b and 5b in high yields. At low reaction temperature, functionalized organomagnesium compounds bearing a nitrile (6a) or an ester (7a) can be coupled in excellent yields (leading to 6b and 7b). Functional groups in ortho position do not disturb the reaction, and the corresponding ortho,ortho' disubstituted biaryls 8b and 9b were formed in 85-88% yield. Even the sterically hindered ortho-tert-buty\- (10a) and mesitylmagnesium (l la) derivatives give biaryls 10b and lib in 83-88% yields. 1-Naphthylmagnesium reagents 12a and 13a are also suitable substrates and afford the corresponding binaphthyls 12b and 13b in good yields. Heterocyclic organomagnesium reagents can also be coupled by diphenoquinone 1. Thus, 5-bromopyridin-3-ylmagnesium chloride leads to the corresponding dipyridine 14b in 80 % yield. The organomagnesium reagent 15a, which was generated from l,l '-oxybis(2-iodobenzene), undergoes selective intramolecular coupling with quantitative formation of dibenzofuran (15b).

While coupling of ortλo-iodophenyl Grignard reagent 16a leads only to a moderate yield of biaryl 16b, 80 % of 16b was obtained when diorganomagnesium reagent 16c was used (Scheme 6). Coupling of the allyloxy-substituted organomagnesium reagent 17a, which was prepared by selective Br/Mg-exchange from dibromide 17b and /-PrMgCl LiCl ¹³ gave rise to biaryl 17c. We did not observe any ring closure products arising from radical cyclization. The diester 18a can be selectively deprotonated with the mixed Mg/Li base 19 ¹⁴ and coupled with the formation of the highly substituted biaryl 18b. This example shows that the presence of an NH-group (2,2,6, 6-tetramethylpiperidine) is tolerated.

Scheme 6: Formation of biaryls (Et = ethyl; z-Pr = /so-propyl, rt = room temperature).

The coupling of sp-organomagnesium compounds that are easily available by deprotonation of corresponding acetylenes with /-PrMgCl LiCl was also examined. Although Glaser couplings, ¹⁵ Eglinton procedures ¹⁶ and modifications thereof ¹⁷ are well known, all of them require the addition of transition metals, usually Cu(I), that requires their recycling or disposal. Reactions of alkynylmagnesium reagents with diphenoquinone 1 proceed cleanly with the formation of only desired diacetylenes. Thus, phenyl- (20a), «-hexyl- (20b), trimethylsilyl- (20c) and cyclohexenyl- (2Od) ethynyl-magnesium chlorides react with diphenoquinone 1 to give the corresponding diacetylenes 21a-d within 12 h at 25°C in 80- 90% yield (Scheme 7).

/-PrMgCI LiCI 1

R- R HZ MgCI LiCI -» ^► R- -≡ — ≡— R

O ⁰ C, 10 min 25-C, 12 h 20a-d 21a-d

, 88 %

Scheme 7: Formation of diacetylenes.

Alkenylmagnesium reagents also can be coupled according to the invention. Bis-α-styryl magnesium (22a) reacts with diphenoquinone 1 affording 2,3-diphenylbutadiene (22b) in 87% yield. Stereoselective couplings of terminal alkenes are of great interest since the resulting isomerically pure 1,3-dienes cannot be prepared by conventional Witttig reaction. ¹⁸ This methodology allows to perform the coupling of E- (23a, 25a) or Z- (24a, 26a) alkenylmagnesium reagents with complete retention of the double bond stereochemistry affording isomerically pure EE- (23b, 25b) and ZZ- (24b, 26b) dienes, respectively (Scheme 8).

22b: 87 %

1

MgCI LiCI - 2O ⁰ C, 10 min 23a, E:Z = 99:1 23b, 86 %, EEzEZ = >99:1

24a, EZ = 1 :99 24b, 88 %, EE:ZZ = 1 :>99

1

TBDMS. TBDMS

O' ^" ^{^} MgCI LiCI - 2O ⁰ C, 10 min (T ^ ⁵ " ^ ^ ^" TBDMS 25a, EZ = 100:0 25b, 90 %, EE-EZ = 100:0

TBDMSs

26a, E:Z = 7:93 26b, 82 %, EZ-ZZ = 6:94

Scheme 8: Stereoselective coupling of alkenylmagnesium reagents (TBDMS = tert- butyldimethylsilyl, secBu = sec-butyl).

In conclusion, we have shown that the use of 3,3',5,5'-tetra-?-butyldiphenoquinone (1) as electron acceptor allows a simple, high yield preparation of a broad range of functionalized biaryls, diynes and dienes via coupling reaction of readily available organomagnesium reagents. Coupling of alkenylmagnesium reagents proceeds with high stereoselectivity. All reactions take place within a convenient range of temperatures (-2O ⁰ C - room temperature), and can be easily extended to large scale preparations. We have performed for the first time an effective coupling of a broad range of organomagnesium reagents without the addition of any transition metals using a conceptually new process (Scheme 1). Extensions of this work to other organometallics as Zn-reagents have already been demonstrated. Moreover, with our new methodology on hands we were also able for the first time to perform heterocoupling reactions by using mixed organocopper reagents and chloranil.

It is also possible to perform coupling reaction for the organomanganese and organoaluminium compounds. Thus, diphenyl manganese reagent 27a was smoothly coupled with 1 yielding biphenyl 28 in 85%. Triphenylaluminium reacts 27b with chloranil at -60 ⁰ C affording biphenyl 28 in 67% yield..

27b 28: 67 %

Scheme 9: Coupling of alkenylmaganese and organoaluminium reagents.

The inventors of the present application found that a ligand can be used to increase the yield of the coupling reaction when Cu or Fe are involved as metals. Especially, the yield of hetero atom coupling reactions can be increased. An additional finding was that Cu or Fe can be used catalytially. A typical example of the use of a ligand, i.e. diphenyl acetylene, is given in Scheme 10 below.

1 )CuCI-2LιCI (1.05 equtv.)

98 % GC-yield 89 % isolated

Scheme 10: Coupling of pyridine copper compound with amid.

Experimental Section:

Typical procedure.

Preparation of diethyl biphenyl-4,4'-dicarboxylate (4e):

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with ethyl 4-iodobenzoate (552 mg, 2.0 mmol) in THF (2 mL). The reaction mixture was cooled to -20°C and /-PrMgCl LiCl (2 mL, 1.05 M in THF, 2.1 mmol) was added dropwise. After 20 min at -20 ⁰ C the I/Mg-exchange was complete (checked by GC analysis of reaction aliquots) and a solution of the diphenoquinone (1, 449 mg, 1.1 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred for 2 h at 0°C. After usual workup the crude residue was purified by flash chromatography (pentane:CH ₂ Cl ₂ ) yielding the diethyl biphenyl-4,4'-dicarboxylate (4e, 184 mg, 93%) as white crystals.

The products listed in table 1 below can be produced according to the preparation of diethyl biphenyl-4,4'-dicarboxylate (4e).

Table 1. Formation of biaryls.

Yield

Entry Grignard reagent Biaryl (9)

(%) ^[a]

3a: FG = H, X =Br 3b: FG = H 96

2 4a: FG = MeO, X = Br 4b: FG = MeO 94 3 5a: FG - CF ₃ , X = Cl 5b: FG = CF ₃ 92 4 6a: FG = CN, X = Cl 6b: FG = CN 96

5 7a: FG = CO ₂ Et, X = Cl 7b: FG = CO ₂ Et 93

8a: FG = CN 8b: FG = CN 85 9a: FG = CO ₂ Et 9b: FG = CO ₂ Et 88 10a: FG = t-Bu 10b: FG = t-Bu 83

12a: FG = H 12b: FG = H 99

1 1 13a: FG = OMe 13b: FG = Ome 90

14a 14b 80

15a 15b 96 ^w Isolated yield of analytically pure product;

Typical procedure:

Procedure for the preparation of 5-bromo-λyV-diphenylpyridin-3-amine (32)

1) CuCl 2LiCl(O 3 eqiv ),

Scheme 11: Preparation of 5-bromo-N,iV-diphenylpyridin-3-amine (32)

A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirrer and a septum, was charged with /PrMgCl LiCl (1.22 M in THF; 0.86 mL, 1.05 mmol) and cooled to O ⁰ C. 3,5- dibromopyridine (237 mg, 1.0 mmol) was added and the mixture was stirred at 0 ⁰ C for 30 min and 30 min at room temperature to afford the Grignard reagent 31. The Br/Mg-exchange was completed after 1 h as determined by the GC analysis of a reaction aliquot. The mixture was diluted with 0.3 ml of dry THF and then cooled to -60 ⁰ C. Meanwhile CuCl 2LiCl (1.0 M in THF; 0.3 mL, 0.3 equiv.) was added to a mixture of diphenylacetylene (178 mg, 1.0 mmol) in 1 ml of dry THF and was stirred at room temperature for 10 min. The resulting copper complex was added dropwise to the cooled solution of the Grignard reagent 31. The mixture was stirred for 30 min at -60 ⁰ C. To the resulting aryl cuprate, TV-lithium diphenylanilide (1.5 mmol; prepared by adding «BuLi (1.5 mmol) to a 1.0 M solution (254 mg, 1.5 mmol) of diphenylaniline in THF at -4O ⁰ C and stirring for 5 min, followed by further stirring for 30 min at O ⁰ C) was added dropwise and the mixture was stirred for 60 min at -60 ⁰ C. The reaction mixture was cooled to -78 ⁰ C, then chloranil (270 mg, 1.1 mmol) in dry THF (7 mL), was added slowly over a period of 45 min. The reaction mixture was warmed up to -50 ⁰ C and stirred for 12 h. Diethyl ether (10 mL) was added to the crude reaction mixture and it was filtered through Celite, washed with diethyl ether thoroughly, and the filtrate was washed with 2 x 10 mL portions OfNH ₄ OH (aq., 2.0 M). The organic extract was dried over MgSO ₄ , filtered and concentrated under reduced pressure. Purification by flash column chromatography (pentane/CH ₂ Cl ₂ ; 1 :1 -> 1 :2) afforded the title amine 32 (256 mg, 79%) as a brown solid.

According to the above given procedure for the preparation of 5-bromo-7V,7V-diphenylpyridin- 3 -amine (32), the compound 32 was prepared using different ligands replacing diphenylacetylene in the above given procedure

Table 2. Preparation of 5-bromo-N,λ/-diphenylpyridin-3-amine (32) using different ligands

Entry ligand GC yield (%) Isolated yield (%)

Me ₂ N ^' NMe ₂ 61

( ^/ X -Me 83

According to the above given typical procedure for the preparation of 32, different amounts of copper and different amounts of different ligand were used. A scheme of the reaction is given in Scheme 12. The amount of copper in the general procedure is 0.3 equiv, corresponding to 30 mol.-%. Accordingly, an amount of 10 mol.-% corresponds to 0.1 equiv. Similarly, the amount of ligand in the above given typical procedure is 1.0 mmol, corresponding to 100 mol.-%. An amount of 30 mol.-% thus corresponds to 0.3 mmol. The amount of Cu and ligand is based on the amount of dibromopyridine. It is obvious from the results shown in table 3 that Cu can be used in a catalytical amount. The preferred amount is about 30 mol.-%, based on the amount of starting material. The influence of the amount of ligand in view of the amount of copper is not very strong, as can be seen from a comparison of entries 1-3 of table 3. Preferably, the amount of ligand is therefore in the same magnitude as the amount of copper.

M MagCuI-LLiiCUI

-78 ⁰ C, 3 h.

Scheme 12: Reaction scheme for the reaction to evaluate catalytic actvity. * : Chloranil was added dropwise over a period of 3 hours.

Table 3. Catalytic activity of Cu using different ligands and different amounts of ligand and Cu

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