Process for preparing substituted biphenyls

Abstract

The present invention relates to a process for preparing substituted biphenyls via Suzuki coupling using specific phosphorus ligands and a solvent mixture containing water, a non-polar organic solvent and a polar aprotic co-solvent.

Claims

1. A process for preparing substituted biphenyls of the formula I ##STR00028## in which the substituents are each defined as follows: R.sup.1 is nitro, amino, C.sub.1-C.sub.4-alkylamino, N(H)PG, NHCOR, NCRR or a moiety of the formula Q.sup.1, Q.sup.2 or Q.sup.3 ##STR00029## with PG being a protective group; R and R being independently of each other and independently of each occurrence C.sub.1-C.sub.4-alkyl or phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; R.sup.4 being methyl, optionally substituted by 1, 2 or 3 fluorine atoms; and # being the attachment point to the remainder of the molecule; R.sup.2 is selected from the group consisting of cyano, nitro, halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.3-C.sub.10-cycloalkyl which may carry 1, 2, 3 or 4 C.sub.1-C.sub.4-alkyl substituents; C.sub.3-C.sub.10-halocycloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylcarbonyl; C.sub.1-C.sub.6-haloalkylcarbonyl; C.sub.1-C.sub.6-alkoxycarbonyl; C.sub.1-C.sub.6-haloalkoxycarbonyl; aryl; aryl-C.sub.1-C.sub.4-alkyl; arylcarbonyl; aryl-C.sub.1-C.sub.4-alkylcarbonyl; aryloxycarbonyl; aryl-C.sub.1-C.sub.4-alkoxycarbonyl, wherein aryl in the six last-mentioned radicals may carry 1, 2, 3 or 4 substituents selected from halogen, cyano, nitro, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; aminocarbonyl, C.sub.1-C.sub.4-alkylaminocarbonyl, and di-(C.sub.1-C.sub.4-alkyl)-aminocarbonyl; n is 0, 1, 2 or 3, where, in case that n=2 or 3, the R.sup.2 radicals may have identical or different definitions; and R.sup.3 is hydrogen, cyano, halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl or C.sub.1-C.sub.4-alkoxy; which comprises reacting a compound of the formula II ##STR00030## in which Hal is chlorine or bromine and R.sup.1 and R.sup.3 are each as defined above, in the presence of a base and of a palladium catalyst which comprises a palladium source and a phosphorus ligand of the formula III ##STR00031## in which R.sup.5 is C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.6-C.sub.10-aryl or 5- to 10-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N and O as ring members; R.sup.6, R.sup.7, R.sup.8 are each independently selected from the group consisting of hydrogen, trifluoromethyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, 5- to 11-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO.sub.2 as ring members, C.sub.6-C.sub.10-aryl and NR.sup.16R.sup.17, wherein the above C.sub.3-C.sub.10-cycloalkyl, 5- to 11-membered heterocyclyl and C.sub.6-C.sub.10-aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and trifluoromethyl; or R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8, together with the carbon atoms they are bound to, form a 5- or 6-membered partially unsaturated or maximally unsaturated carbocyclic or heterocyclic ring, where the heterocyclic ring contains 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, NO and SO.sub.2 as ring members; where the carbocyclic or heterocyclic ring may carry one or more substituents selected from the group consisting of trifluoromethyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, 5- to 11-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, NO and SO.sub.2 as ring members, C.sub.6-C.sub.10-aryl and NR.sup.16R.sup.17, wherein the above C.sub.3-C.sub.10-cycloalkyl, 5- to 11-membered heterocyclyl and C.sub.6-C.sub.10-aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and trifluoromethyl; R.sup.9, R.sup.10 are each independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, 3- to 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO.sub.2 as ring members, C.sub.6-C.sub.10-aryl and Si(R.sup.16).sub.3, wherein the above C.sub.3-C.sub.6-cycloalkyl, 3- to 6-membered heterocyclyl and C.sub.6-C.sub.10-aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and trifluoromethyl; R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, 5- to 11-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO.sub.2 as ring members, C.sub.6-C.sub.10-aryl, NR.sup.16R.sup.17, Si(R.sup.16).sub.3 and SR.sup.16, wherein the above C.sub.3-C.sub.10-cycloalkyl, 5- to 11-membered heterocyclyl and C.sub.6-C.sub.10-aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and trifluoromethyl; or any two adjacent instances of R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, together with the carbon atoms to which they are bound, form a five- or six-membered partially unsaturated or maximally unsaturated carbocyclic or heterocyclic ring, where the heterocyclic ring contains 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from N, O, NO and SO.sub.2 as ring members; where the carbocyclic or heterocyclic ring may carry one or more substituents selected from the group consisting of trifluoromethyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.10-aryl, 5- to 11-membered saturated, partially unsaturated or maximally unsaturated heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO.sub.2 as ring members, and NR.sup.16R.sup.17, wherein the above C.sub.3-C.sub.10-cycloalkyl, 5- to 11-membered heterocyclyl and C.sub.6-C.sub.10-aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and trifluoromethyl; R.sup.16, R.sup.17 are each independently selected from the group consisting of hydrogen, trifluoromethyl, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, saturated, partially unsaturated or maximally unsaturated 5- to 11-membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, NO and SO.sub.2 as ring members, C.sub.6-C.sub.10-aryl, wherein the above C.sub.3-C.sub.10-cycloalkyl, 5- to 11-membered heterocyclyl and C.sub.6-C.sub.10-aryl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and trifluoromethyl; in a solvent mixture of water, a non-polar organic solvent and a polar aprotic co-solvent, with an organoboron compound of the formula IV ##STR00032## wherein R.sup.2 and n are as defined above and the compound of formula IV is selected from the group consisting of (i) boronic acids with o=0, m=2; p=1 and Z=hydroxy, or their trimers; (ii) boronic acid derivates with o=0, m=2; p=1 and Z=halogen; C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.6-C.sub.10-aryl or C.sub.6-C.sub.10-aryloxy; (iii) borinic acids or borinic acid derivatives with o=0, m=1; p=2 and Z=hydroxy, halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.6-C.sub.10-aryl or C.sub.6-C.sub.10-aryloxy; (iv) mixed borinic acids or borinic acid derivatives with o=1, m=1; p=1, A=C.sub.1-C.sub.4-alkyl and Z=hydroxy, halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.6-C.sub.10-aryl or C.sub.6-C.sub.10-aryloxy; (v) cyclic boronic esters with o=0, m=2 and p=1, wherein the two Z groups form together a bridging group O(CH.sub.2).sub.qO, wherein q is 2 or 3, so that the two Z groups, together with the boron atom to which they are attached, form a 5- or 6-membered ring, where each CH.sub.2 group is independently optionally substituted by one or two C.sub.1-C.sub.4-alkyl groups; (vi) boronates with o=0, m=3, p=1 and Z=hydroxy, halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.6-C.sub.10-aryl or C.sub.6-C.sub.10-aryloxy, and accompanied by a cation which compensates the negative charge of the boronate anion; (vii) triarylboranes with o=0, m=0 and p=3; (viii) tetraarylborates with o=0, m=0 and p=4, and accompanied by a cation which compensates the negative charge of the borate anion.

2. The process of claim 1, wherein R.sup.1 is nitro.

3. The process of claim 1, wherein R.sup.2 is fluorine or chlorine, and n is 1, 2 or 3.

4. The process of claim 1, wherein R.sup.3 is hydrogen or fluorine.

5. The process of claim 1, wherein R.sup.1 and R.sup.3 are in para positions to one another.

6. The process of claim 1, wherein the biphenyl I is 4-chloro-2-nitro-biphenyl, 3,4-dichloro-2-nitro-biphenyl, 3,4-difluoro-2-nitro-biphenyl, 3,4,5-trifluoro-2-nitro-biphenyl, 3-chloro-4,5-difluoro-2-nitro-biphenyl, 3,4-dichloro-5-fluoro-2-nitro-biphenyl, 3,5-dichloro-4-fluoro-2-nitro-biphenyl, 4-chloro-biphenyl-2-ylamine, 3,4-dichloro-biphenyl-2-ylamine, 3,4-difluoro-biphenyl-2-ylamine, 3,4,5-trifluoro-biphenyl-2-ylamine, 3-chloro-4,5-difluoro-biphenyl-2-ylamine, 3,4-dichloro-5-fluoro-biphenyl-2-ylamine or 3,5-dichloro-4-fluoro-biphenyl-2-ylamine.

7. The process of claim 1, wherein the phosphorus ligand III is a compound of formula IIIa ##STR00033##

8. The process of claim 1, wherein the palladium source is a palladium(II) salt or a palladium(0) complex.

9. The process of claim 1, wherein the palladium source, calculated on the basis of the Pd content, is used in an amount of from 0.0001 mol % to 0.5 mol %, relative to 1 mol of compound II or compound IV, if these are used in equimolar amounts, or, if compounds II and IV are not used in equimolar amounts, relative to 1 mol of that compound II or IV which is not used in excess.

10. The process of claim 9, wherein the palladium source, calculated on the basis of the Pd content, is used in an amount of from 0.0001 mol % to 0.01 mol %, relative to 1 mol of compound II or of compound IV, if these are used in equimolar amounts, or, if compounds II and IV are not used in equimolar amounts, relative to 1 mol of that compound II or IV which is not used in excess.

11. The process of claim 1, wherein the organoboron compound IV is a phenylboronic acid IVa or a diphenylborinic acid Ivc ##STR00034## or a mixture of IVa and IVc, in which R.sup.2 and n are each as defined in claim 1.

12. The process of claim 1, wherein the reaction is performed at a temperature of from 50 to 140 C.

13. The process of claim 1, wherein the non-polar organic solvent is selected from the group consisting of aliphatic hydrocarbons, cycloaliphatic hydrocarbons, chlorinated aliphatic hydrocarbons, aromatic hydrocarbons, open-chained ethers and mixtures thereof; and the polar aprotic co-solvent is selected from the group consisting of amides, sulfoxides, lactams, cyclic ethers, ketones, nitriles, lactones, nitro compounds, ureas, sulfones, carbonic acid esters and mixtures thereof.

14. The process of claim 13, wherein the non-polar organic solvent is an aromatic hydrocarbon.

15. The process of claim 13, wherein the polar aprotic co-solvent is a cyclic ether.

16. The process of claim 1, where in the solvent mixture water, the non-polar organic solvent and the polar aprotic co-solvent are contained in following amounts: water: 0.5 to 20% by weight, based on the total weight of the solvent mixture; non-polar organic solvent: 20 to 99% by weight, based on the total weight of the solvent mixture; and polar aprotic co-solvent: 1 to 60% by weight, based on the total weight of the solvent mixture; where the amounts of water, non-polar organic solvent and polar aprotic co-solvent add to 100% by weight.

17. The process of claim 16, wherein the solvent mixture water, the non-polar organic solvent and the polar aprotic co-solvent are contained in following amounts: water: 1 to 15% by weight, based on the total weight of the solvent mixture; non-polar organic solvent: 60 to 96% by weight, based on the total weight of the solvent mixture; and polar aprotic co-solvent: 3 to 25% by weight, based on the total weight of the solvent mixture; wherein the amounts of water, non-polar organic solvent and polar aprotic co-solvent add to 100% by weight.

18. The process of claim 1, wherein the base is selected from inorganic bases.

19. The process claim 18, wherein the base is potassium carbonate.

20. The process of claim 1, wherein the substituted biphenyls obtained, wherein R.sup.1 nitro, amino, N(H)PG, NHCOR or NCRR, are subsequently converted to carboxamides of the formula V ##STR00035## where Q is Q.sup.1, Q.sup.2 or Q.sup.3, where Q.sup.1, Q.sup.2 and Q.sup.3 are as defined in claim 1, and R.sup.2, R.sup.3 and n are as defined in any of claim 1, by following reaction: in case that R.sup.1 is an amino group: subjecting the compound (I) wherein R.sup.1 is an amino group to an N-acylation with an acyl precursor of one of the radicals Q.sup.1, Q.sup.2 or Q.sup.3 to obtain a compound of formula (V); in case that R.sup.1 is a nitro group: reducing the compound (I) wherein R.sup.1 is a nitro group to a compound (I) wherein R.sup.1 is an amino group; and subjecting the compound (I) wherein R.sup.1 is an amino group to an N-acylation with an acyl precursor of one of the radicals Q.sup.1, Q.sup.2 or Q.sup.3 to obtain a compound of formula (V); in case that R.sup.1 is a N(H)PG, NHCOR or NCRR group: subjecting the compound (I) wherein R.sup.1 is a N(H)PG, NHCOR or NCRR group to a deprotection reaction to a compound (I) wherein R.sup.1 is an amino group; and subjecting the com-pound (I) wherein R.sup.1 is an amino group to an N-acylation with an acyl precursor of one of the radicals Q.sup.1, Q.sup.2 or Q.sup.3 to obtain a compound of formula (V); where the acyl precursor of one of the radicals Q.sup.1, Q.sup.2 or Q.sup.3 is a compound Q.sup.11, Q.sup.22 or Q.sup.33 ##STR00036## wherein R.sup.4 is as defined in claim 1 and W is OH, a halide, OR.sup.A, or OC(O)R.sup.B, where the compound Q.sup.11, Q.sup.22 or Q.sup.33 wherein W is OR.sup.A is an ester of a C.sub.1-C.sub.4-alkanol R.sup.AOH in which R.sup.A is C.sub.1-C.sub.4-alkyl, of a C.sub.2-C.sub.6-polyol, of p-nitrophenol, N-hydroxybenzotriazole, N-hydroxysuccinimide or pentafluorophenol; and the compound Q.sup.11, Q.sup.22 or Q.sup.33 wherein W is OC(O)R.sup.B is a symmetric anhydride or is an asymmetric anhydride with chloroformic acid or chloroacetic acid.

Description

EXAMPLES

Example 1: Synthesis of 3,4,5-trifluoro-2-nitrobiphenyl

(1) ##STR00027##

(2) 88.8 g (99 wt %, 0.50 mol, 1.0 eq) of solid (3,4,5-trifluorophenyl)boronic acid were placed in a reactor together with 441 g of toluene, 44.8 of water, 77 g of THF and 138.0 g (1.00 mol, 2.0 eq) of potassium carbonate. Finally 151.0 g of ortho-chloro-nitrobenzene (o-CNB; 50% in toluene, 0.48 mol, 0.96 eq) were added and 3 bar of nitrogen pressure was applied as a pressure test of the vessel. After releasing the pressure, 6.0 mg (0.027 mmol, 0.0054 mol %, relative to the boronic acid) of palladium acetate and 10.0 mg (0.027 mmol, 0.0054 mol %, relative to the boronic acid) AntPhos (phosphorus ligand of formula IIIa) were added. The reactor was evacuated twice to 200 mbar and each time refilled with nitrogen. Finally, the reactor was evacuated again to 200 mbar and the temperature was raised to 110 C. jacket temperature in 30 minutes. The temperature was kept at 110 C. for 6 h. The reactor was cooled to 25 C., the pressure released, 540 g of water were added and the phases were separated. The organic phase (736 g) was assayed for the desired biphenyl by quantitative HPLC. The organic phase contained 16.4 wt % of the title compound (120.7 g, 0.477 mol, 95.4%; yield percentage based on o-CNB).

(3) HPLC Method:

(4) Zorbax XDB-C18 1.8 m; 504.6 mm; mobile phase: A: water+0.1% phosphoric acid; B: acetonitrile (MeCN)+0.1% phosphoric acid; gradient: 30% to 50% B in 5.0 minutes; 50% to 100% B in 1.0 min; 100% B 2.0 min; flow: 1.5 mL/min, pressure 240 bar, temperature 30 C.

(5) Retention time of 3,4,5-trifluoro-2-nitrobiphenyl: 6.4 min

(6) The examples in table 1 were carried out analogously, however with the amounts of ortho-chloronitrobenzene (o-CNB; amount given in mol equivalents, relative to 1 mol of the boronic acid), potassium carbonate (amount given in mol equivalents, relative to 1 mol of the boronic acid) and solvents and the reaction temperature as shown in each line of table 1, respectively.

(7) TABLE-US-00001 TABLE 1 o-CNB K.sub.2CO.sub.3 Toluene Water THF T Yield Example eq. eq. [g] [g] [g] [ C.] [%]* Comp-1 0.96 2 981 19 130 36.5 Comp-2 0.96 2 900 99 130 37.5 Comp-3 0.96 2 981 130 16.7 1 0.96 2 931.9 18.6 96 130 92.3 2 0.96 2 594 42 74 130 95.8 3 0.96 2 441 44.8 77 110 99.4 4 0.96 2 404.5 48.5 80.9 110 99.7 5 0.98 2 503 45.3 75.5 110 100.3** 6 0.98 1 503 45.3 75.5 110 101.9** 7 1 1.2 604 54.3 90.6 130 98.7.sup.# *based on o-CNB **yield over 100% due to analytic fluctuation .sup.#4 h reaction time

(8) As the comparative examples Comp-1, Comp-2 and Comp-3 show, omitting water or THF or both results in a significantly lowered yield.

Example 2: Efficiency of the Ligand of Formula III

(9) In order to show the importance of the ligand used according to the invention, (3,4,5-trifluorophenyl)boronic acid and ortho-chloro-nitrobenzene were reacted in a mixture of toluene, water and THF in the presence of potassium carbonate and a Pd catalyst under analogous conditions, using however different ligands for the Pd catalyst.

(10) TABLE-US-00002 TABLE 2 Conversion Yield Example Ligand [%] [%] 11 AntPhos (compound IIIa) 100 97.2 Comp-4 triphenylphosphine 22.5 0.3 Comp-5 dppe 23.9 0.5 Comp-6 dppf 23.1 0.7 Comp-7 Pepstar 23.6 1.3 Comp-8 tricyclohexylphosphine 26.7 2.4 Comp-9 Xantphos 26.9 0.7 Comp-13 cBRIDP 26.7 0.5 Comp-19 RockPhos 27.1 0.5 Comp-21 PhenCar-Phos 35.8 8.8 Comp-23 Unnicore CX21.sup.# 55.5 14.3 Comp-24 Unnicore CX31.sup.# 53.7 6.3 .sup.#Pd complex used dppe: 1,2-Bis(diphenylphosphino)ethane dppf: 1,1-Bis(diphenylphosphino)ferrocene Pepstar: 2,2-Dimethyl-1,3-bis(diphenylphosphinopropane) Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene cBRIDP: Di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine, Mo-Phos RockPhos: [(2-Di-tert-butylphosphino-3-methoxy-6-methyl-2,4,6-triisopropyl-1,1-biphenyl)-2-(2-aminobiphenyl)]palladium (II) methanesulfonate PhenCar-Phos: 9-[2-(Di-i-propylphosphino)phenyl]-9H-carbazole Umicore CX21: Allylchloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium (II) Umicore CX31: Chlorophenylallyl[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium (II)