Patent Application
20050154205
The present invention relates to complexes of N-heterocyclic carbenes, to the use thereof and to the precursors of such complexes.
Polyaryl compounds, especially substituted biphenyls, are of great importance as fine chemicals and intermediates for producing medicaments and agrochemicals.
Polyaryl compounds can be synthesized for example by the coupling, with transition metal catalysis, of activated bromo- or iodoaromatic compounds with aryl-grignard, aryl zinc, trialkylaryl compounds or arylboronic acids, where appropriate in the presence of a base (see, for example, Suzuki, A. J., J. Organomet. Chem., 576, 1999, 329-340). The disadvantage of the synthesis, described in the reference, using arylboronic acids is, however, the use of the costly bromo- and iodoaromatic compounds, and the reaction conditions which are in some cases very drastic.
There have already been tests, as catalysts for preparing polyaryl compounds from the lower-cost chloroaromatic compounds, of transition metal complexes of N-heterocyclic carbenes. Zhang and Trudell for example developed (Tetrahedron Letters, 41, 2000, pp. 595-598) a process in which bisimidazol-2-ylidene palladium complexes are employed as catalysts and are generated in situ from palladium acetate and bisimidazolium salts. However, the preparation of such bisimidazolium salts is very elaborate and the process is therefore unsuitable for industrial use.
A similar process of Nolan (J. Org. Chem., 1999, 64, 3804-3805) is based on catalysis by systems, generated in situ, of palladium dibenzylidene acetone [Pd2(dba)3] and the monoimidazolium salt 1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride. However, the reactivity of these systems depends very greatly on the choice of the base employed and is, as was shown by Böhm et al. (J. Organomet. Chem., 595, 2000, pp. 186-190), not applicable to other monoimidazolium salts. Thus, for example, the system palladium dibenzylidene acetone [Pd2(dba)3] and 1,3-bis(tert-butyl)imidazolium tetrafluoroborate completely lacks catalytic activity.
The same authors therefore also employed as catalysts defined palladium-imidazol-2-ylidene complexes of the type [Pd(imidazol-2-ylidene)2], which can be isolated. The isolated complexes which were used showed, however, only moderate conversion rates at 80° C. No reaction was observed at 40° C.
There was thus a need to develop catalysts which are advantageously suitable for a process for preparing polyaryl compounds, in particular starting from aryl chlorides, under mild reaction conditions.
A process for preparing polyaryl compounds has now been found and is characterized in that
Examples of preferred reactive aryl compounds are trialkyltinaryl compounds, arylboronic acids, arylzinc and arylmagnesium compounds.
In the process according to the invention for preparing polyaryl compounds there is preferably use of aryl halides or aryl sulphonates of the general formula (m) and aryl compounds of the general formulae (IVa, b, c and d), of which aryl compounds of the formula (IVa) are further preferred.
In the formulae
Ar1—Y (III)
Ar2—B(OH)2 (IVa)
Ar2—Sn(C1-C6-alkyl)3 (IVb)
Ar2—ZnX (IVc)
Ar2—MgX (IVd)
Examples of sulphonates are trifluoromethanesulphonate, pentafluoroethanesulphonate or nonafluorobutanesulphonate.
Y is particularly preferably chlorine or bromine and very particularly preferably chlorine.
Substituted or unsubstituted aromatic radicals are preferably carbocyclic aromatic radicals having 6 to 24 carbon atoms in the framework, such as, for example, phenyl, naphthyl, biphenyl, binaphthyl or anthracenyl, which may furthermore be substituted by up to five identical or different substituents on each ring.
Substituted or unsubstituted heteroaromatic radicals are preferably heteroaromatic radicals having 5 to 24 carbon atoms in the framework, in which zero, one, two or three carbon atoms in the framework of each ring, but at least one carbon atom in the whole framework of the molecule, may be replaced by heteroatoms selected from the group of nitrogen, sulphur or oxygen, such as, for example, pyrrolyl, pyrazolyl, pyrimidinyl, pyridinyl, oxazolyl, thiophen-yl, furanyl, indolyl, triazolyl, thiazolyl, dibenzofuranyl, dibenzothiophenyl or quinolinyl and which may furthermore be substituted by up to five identical or different substituents on each ring.
Substituents for carbocyclic aromatic or heteroaromatic radicals may be selected, for example, from the group of OH, iodine, bromine, chlorine, fluorine, nitro, cyano, free or protected formyl, C1-C12-alkyl, C2-C12-alkenyl, C6-C12-aryl, C7-C13-arylalkyl, C1-C8-hydroxyalkyl, C1-C8-hydroxyalkoxy, C1-C8-hydroxyalkylamino, —PO—[(C1-C8)-alkyl]2, —PO—[(C6-C12)-aryl]2, tri(C1-C6-alkyl)siloxyl or radicals of the general formula (V)
A-B-D-E (V)
in which, independently of one another,
M may also be hydrogen. However, in this case, the acidic groups are then present in the reaction medium in the form of the salts of the base employed.
Alkyl or alkylene means in all contexts of the invention, in each case independently, a straight-chain, cyclic, branched or unbranched alkyl or alkylene radical which may optionally be further substituted by alkoxy groups. The same applies to the alkyl moiety of an arylalkyl radical.
The general term aryl as substituent means in all contexts of the invention not only carbocyclic radicals but also heteroaromatic radicals in which zero, one, two or three carbon atoms in the framework of each ring, but at least one carbon atom in the whole framework of the radical, is replaced by heteroatoms selected from the group of nitrogen, sulphur or oxygen.
Alkoxy means in all contexts of the invention, in each case independently, a straight-chain, cyclic or branched or unbranched alkoxy radical.
Haloalkyl and haloalkoxy mean in all contexts of the invention, in each case independently, straight-chain, cyclic, branched or unbranched alkyl radicals and alkoxy radicals which may be substituted by one, more than one or completely by fluorine or chlorine atoms. It is furthermore possible for these radicals to be substituted further by alkoxy radicals.
Ar1 and Ar2 are particularly preferably, in each case independently of one another, the carbocyclic aryl radicals phenyl, naphthyl, biphenyl, binaphthyl or anthracenyl, or heteroaryl radicals selected from the group of pyrrolyl, pyrimidinyl, pyridinyl, oxazolyl, thiophen-yl, furanyl, indolyl or quinolinyl, each of which may be further substituted by zero, one, two or three substituents selected from the group of OH, iodine, bromine, chlorine, fluorine, nitro, cyano, free or protected formyl, C1-C4-alkyl, benzyl, C1-C4-hydroxyalkyl, —PO—[(C1-C8)-alkyl]2, —PO—[(C6-C12-aryl]2, or radicals of the general formula (V) in which, independently of one another,
A has the meaning indicated above, and X is ONa or OK.
Ar1 and Ar2 are particularly preferably, in each case independently of one another, phenyl, pyrrolyl, pyrimidinyl, pyridinyl radicals which are further substituted by zero, one or two substituents selected from the group of fluorine, nitro, cyano, formyl, methyl, ethyl, methoxy, trifluoromethyl, amino, dimethylamino, aminoacetyl, acetyl, COONa or SO3Na.
The compounds of the general formula (III) which are very particularly preferably employed for the process according to the invention are 4-chlorotoluene, 2-chlorotoluene, 1-chloro-4-trifluoromethylbenzene, 1-chloro-4-methoxybenzene and 1-chloro-4-acetylbenzene.
Compounds of the general formula (IVa) are very particularly preferably employed for the process according to the invention, particularly preferably phenylboronic acid, 2-methylphenylboronic acid and 3-methoxyphenylboronic acid.
The aryl halides or aryl sulphonates which can be employed in the reaction, and the reactive aryl compounds are either commercially available or can be prepared by literature methods or in analogy thereto.
The molar ratio of aryl halide or aryl sulphonate to reactive aryl compound employed can be, for example, 0.01:1 to 100:1, and a molar ratio of 0.5:1 to 5:1 is preferred, particularly preferably 0.8:1 to 1:1.5.
In a preferred embodiment of the process according to the invention, arylboronic acids are employed as reactive aryl compounds, and bases are employed, such as, for example:
The bicarbonates, carbonates, (2 base equivalents) methanolates, ethanolates, isopropoxides, tert-butanolates and acetates of lithium, sodium, potassium and caesium, and caesium fluoride, are preferably employed.
Caesium fluoride and carbonate are particularly preferred.
Caesium fluoride is very particularly preferred.
The molar ratio of base equivalents to reactable aryl halide or aryl sulphonate can be, for example, 0.5:1 to 100:1, and a molar ratio of 1:1 to 5:1 is preferred, particularly preferably 1:1 to 1.5:1.
Reactable means in this connection that proportion of aryl halide or aryl sulphonate for which one equivalent of arylboronic acid is employed in the reaction.
The process according to the invention is, where appropriate, carried out in the presence of one or more aprotic solvents. These are preferably:
1,4-Dioxane is particularly preferred.
The amount of aprotic solvent employed where appropriate can be, for example, 50 ml to 5.000 ml, preferably 500 to 3.000 ml, per mole of the aryl halide or aryl sulphonate employed.
Preferred N-heterocyclic carbenes are those of the general formula (I) in which
Particularly preferred N-heterocyclic carbenes of the general formula (I) are those in which Z is a 1,2-ethenediyl radical and the two radicals R1 and R2 are identical and are radicals of the general formula (II), and in which CR5R6R7
Examples of possible substituents on the adamantyl radical are:
Very particularly preferred N-heterocyclic carbenes of the general formula (I) are 1,3-di-(1R,2S,5R-(−)menthylimidazolin-2-ylidene, 1,3-di-(1S,2R,5S—)-(+)methylimidazolin-2-ylidene and 1,3-diadamantylimidazolin-2-ylidene.
The most preferred N-heterocyclic carbene ligand of the general formula (I) is 1,3-diadamantylimidazolin-2-ylidene.
The catalysts preferably employed for the process according to the invention are nickel or palladium complexes in the formal oxidation state of zero, which comprise per metal atom at least one N-heterocyclic carbene of the general formula (I) in which Z, R1, R2, R3 and R4 each have the stated meaning, independently of further N-heterocyclic carbenes of the general formula (I) which are present where appropriate.
Particularly preferred catalysts are palladium complexes in the formal oxidation state of zero, which comprise per metal atom at least one N-heterocyclic carbene of the general formula (I) in which Z, R1, R2, R3 and R4 each have the stated meaning, independently of further N-heterocyclic carbenes of the general formula (I) which are present where appropriate.
Very particularly preferred complexes are palladium complexes of the general formula (VIII)
[Pd(L)2] (VIII)
in which the two ligands L are each, independently of one another, N-heterocyclic carbenes of the general formula (I) in which Z, R1, R2, R3 and R4 each, independently of one another, have the meaning mentioned there.
The two ligands L in formula (II) are preferably identical.
The most preferably employed catalysts are the complexes [bis(1,3-diadamantyl-imidazol-2-ylidene)palladium], [bis(1,3-di-(−)-menthylimidazol-2-ylidene)palladium] and [bis(1,3-di-(−)-menthylimidazol-2-ylidene)palladium], of which [bis(1,3-diadamantylimidazol-2-ylidene)palladium] is even more preferred.
It may be pointed out at this juncture that the invention encompasses any combinations of all the preferred ranges.
The complexes employed as catalysts can be prepared, for example, by ligand substitution reactions on a suitable precursor complex.
Palladium complexes of the general formula (VIII) can be prepared directly, for example in analogy to Cloke (J. Organomet. Chem., 2001, 617-618, 635-639), by reacting the N-heterocyclic carbenes of the general formula (I) with allylpalladium chloridedimer and sodium dimethyl malonate.
It is furthermore possible for example for palladium complexes of the general formula (VIII) also to be prepared in an advantageous way by reacting palladium complexes of the general formula (IX)
[Pd(P)2] (IX)
in which P is a monodentate phosphane ligand, with the N-heterocyclic carbenes of the general formula (I) in the presence of solvent. [Bis(tri-tert-butylphosphane)-palladium] is preferably employed as palladium complex of the general formula (IX) in this case.
Examples of solvents suitable for the reaction are ethers such as, for example, tetrahydrofuran, aliphatic or aromatic hydrocarbons such as, for example, pentene, n-hexane, cyclohexane, toluene.
Hexane is particularly preferably employed as solvent in this case.
The temperature can be, for example, between −20° C. and 80° C., and 10 to 50° C. are preferred, and room temperature is particularly preferred.
It is possible by the described process, which is likewise encompassed by the invention, to obtain palladium complexes of the general formula (VIII) in high yields.
If N-heterocyclic carbenes of the general formula (I) are required for syntheses of complexes according to the invention, these can take place in the manner known per se by deprotonation from the analogous salts of the general formula (X)
in which Z, R1, R2, R3 and R4 have the meanings mentioned for formula (I), and in which An is the anion of an acid.
Formula (X) represents the possible tautomeric compounds which are likewise encompassed by the scope of the invention.
An is preferably an anion of an acid which has a pKa of 3 or less. An is particularly preferably hydrogen sulphate, chloride, bromide, iodide, tetrafluoroborate, hexafluorophosphate or a half equivalent of sulphate.
An is very particularly preferably chloride.
The deprotonation is moreover preferably effected by alkali metal hydrides such as, for example, sodium hydride in a mixture of an ether such as, for example, THF and liquid ammonia at temperatures between −35 and −80° C.
The salts according to the invention of the general formula (X) can be prepared for example by stepwise alkylation of compounds of the general formula (XI)
in which
If the radicals R1 and R2 in the salts of the general formula (X) are identical, and if Z is a 1,2-ethenediyl radical, the preparation preferably takes place by reacting amines of the general formula (XII)
H2N—R1 (XII)
The salts of the general formula (X) likewise form part of the invention and can be employed either directly, for example by the method of Cloke (loc.cit.), or after previous deprotonation for preparing the catalysts and complexes according to the invention.
The compounds of the general formula (X) in which Z is a 1,2-ethanediyl radical can be prepared for example as described by or in analogy to J. F. Hartwig, Org. Lett. 2000, 2, 10, p. 1423.
The individual stages which may lead to the preparation of the catalysts according to the invention may be represented diagrammatically by the example of [bis(1,3-diadamantylimidazol-2-ylidene)palladium]:
The process according to the invention for preparing polyaryl compounds can be carried out for example at a reaction temperature of 0 to 100° C., preferably 20 to 80° C. Room temperature is very particularly preferred.
The reaction may take, for example, 5 minutes to 168 h, preferably 20 min to 25 h.
The reaction can, for example, be carried out under 0.2 to 100 bar, preferably atmospheric pressure.
The reaction is preferably carried out under protective gas and with substantial exclusion of oxygen and moisture. Examples of suitable protective gases are nitrogen and noble gases such as, for example, argon or mixtures thereof.
In a preferred embodiment, the arylboronic acid of the general formula (IVa), the complex of the general formula (VIII) and the base are introduced where appropriate into a solvent under a protective gas atmosphere, and then the aryl halide or the aryl sulphonate is added, where appropriate dissolved in a solvent, and the mixture is stirred at a temperature between 20 and 80° C. After the reaction is complete (detection for example by GC/MS), water is added to the reaction mixture, and the precipitated palladium black is removed by filtration or centrifugation and can subsequently be recycled. The product can be obtained in a manner known per se, for example by evaporation of solvent, and further purified where appropriate furthermore for example by distillation, sublimation, recrystallization or reprecipitation.
In a further preferred embodiment, the aryl halide or the aryl sulphonate of the general formula (III), the arylboronic acid of the general formula (IVa), the complex of the general formula (VIII) and the base are mixed under a protective gas atmosphere, then solvent is added, and the mixture is stirred at a temperature between 20 and 80° C. until the conversion exceeds 95%.
Polyaryl compounds of the general formula (XV)
Ar1—Ar2 (XV)
in which Ar1 and Ar2 have the meanings mentioned for the general formulae (III) and (IVa to d) are obtained in an advantageous manner in a process according to the invention.
The polyaryl compounds prepared in the manner according to the invention are particularly suitable for preparing medicaments, agrochemicals and polymers, especially conducting polymers.
The particular advantage of the present invention is that the provision of novel salts and the N-heterocyclic carbenes derived therefrom and complexes thereof makes novel catalysts available, which make it possible in a superior manner to carry out Suzuki coupling in particular of aryl chlorides with reactive aryl compounds even at room temperature with very good yields and previously unachieved activities.
Bis-tri-tert.-butylphosphane)palladium(0) (1000 mg, 1.81 mmol) was dissolved in 30 mL of n-hexane. A solution of 1,3-diadamantylimidazol-2-ylidene (1400 mg, 4.16 mmol) in 30 mL of n-hexane was added. The mixture was stirred at room temperature for 24 to 48 h, during which a yellow solid precipitated. Filtration and drying in vacuo resulted in a pale yellow solid. The X-ray structural analysis was carried out after recrystallization from diethyl ether.
Yield: 1 177 mg, 1.51 mmol, 83% of theory.
1,3-Diadamantylimidazol-2-ylidene (222.1 mg, 0.66 mmol) allylpalladium (II) chloride dimer (60.4 mg, 0.165 mmol) and sodium dimethyl malonate (50.9 mg, 0.33 mmol) are dissolved in 20 mL of toluene under a nitrogen atmosphere. The mixture is heated in a Schlenk tube at 90° C. for 16 h. Then small amounts of palladium black and produced NaCl are removed by filtration, the filtrate is concentrated to half the volume, and the product is precipitated at −78° C. Yield: 102 mg, 0.13 mmol, 40% of theory.
Melting point >285° C. (decomposition); 1H NMR (400 MHz, d8-toluene, 25° C.): δ=1.64 (m, 24H, CH2C10H15), 180 (m, 12H, CHC10H15), 2.11 (m, 24H, CH2C10H15), 6.69 (s, 4H, NCHCHN); 13C{1H} NMR (100.5 MHz, d8-toluene, 25° C.); δ=31.0, 36.8, 44.0 (C10H15), 57.2 (iso-C C10H15), 112.7 (NCHCHN), 191.8 (NCN); Cl-MS; m/z (%): 778 (3) [M+] 336 (100) [NHC+], 281 (33), 207-(27), 203 (40); C46H64N4Pd (779.50): calculated C 70.88, H 8.22, N 7.19; found C 70.80, H 8.24, N 7.22.
Bis(1,3-diadamantyl-2-ylidene)palladium(0) (23.4 mg, 0.03 mmol), CsF (303.8 mg, 2 mmol), the arylboronic acid (1.5 mmol) and the aryl chloride (1 mmol) were introduced under a nitrogen atmosphere into a Schlenk tube. After addition of 3 mL of 1,4-dioxane, the mixture was stirred at room temperature. The reaction was stopped after the stated time by adding a few drops of water, and the palladium black was removed by filtration. The yield was determined by GC/MS analysis with diethylene glycol di-n-butyl ether as internal standard.
The results of the catalyses are shown in Table 1.
Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10152989.9 | Oct 2001 | DE | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10279895 | Oct 2002 | US |
| Child | 11076757 | Mar 2005 | US |
