Process for preparing 4-substituted 2-alkylbiphenyls and...

Details Process for preparing 4-substituted 2-alkylbiphenyls and... Process for preparing 4-substituted 2-alkylbiphenyls and...

2002-02-11

2003-05-20

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitriles

C570S182000

Reexamination Certificate

active

06566546

ABSTRACT:

The invention relates to a process for preparing 4-substituted 2-alkybiphenyls and 2-alkoxybiphenyls.
Such 4-substituted biphenyls are versatile building blocks in organic synthesis and important intermediates in the synthesis of active compounds for the agrochemical and pharmaceutical industries.
Despite the existing high level of economic interest in these compounds, few preparative routes to compounds of this type having a specific substitution pattern have been described in the literature, and these routes are then, if they are available at all, expensive and complicated.
For example, no syntheses of the compounds 4-iodo-2-methylbiphenyl, 4-bromo-2-methylbiphenyl, 4-chloro-, 4-bromo- and 4-iodo-2-methoxybiphenyl have hitherto been documented in the chemical literature.
Various syntheses have been described for 4-chloro-2-methylbiphenyl, but these are all associated with serious disadvantages:
Thus, for example, irradiation of 3-chloro-2-methylbiphenyl, which is in itself difficult to prepare, in cyclohexane (J. Chem. Soc. Perkin Trans. 2, 1983, 859-862) gives the product as a mixture of isomers together with dehalogenation products.
Also known is the coupling of 4-chloro-1-iodo-2-methylbenzene and iodobenzene by means of copper at 270° C. (de la Mare, J. Chem. Soc. 1962, 3784-3796). The disadvantages are, in particular, the poor selectivities and thus low yields and the complicated preparation of the raw material chloroiodomethylbenzene, as well as the fact that the products obtained in this way have to be subjected to elaborate purification to meet the quality requirements for pharmaceutical applications.
A further known process is the diazotization of 4-amino-2-methylbiphenyl and heating with benzene (Huntress, J. Am. Chem. Soc. 1939, 816, 820). Here too, the preparation of the raw material aminomethylbiphenyl is very complicated; a further disadvantage is the use of carcinogenic benzene. In addition, the yields obtained are also unsatisfactory.
There is therefore a need for a process for preparing compounds of the formula (I) which starts out from commercially readily available and inexpensive starting compounds and makes it possible to obtain the target products in good yields and high purities.
The present invention achieves this object and provides a process for preparing 4-substituted 2-alkylbiphenyls and 2-alkoxybiphenyls of the formula (I),
where the substituents X, R and R
1′
to R
5′
have the following meanings:
X is NH
2
, NHAc, NH(C═O)R
1
, where R
1
=straight-chain or branched C
1
-C
8
-alkyl, in particular C
1
-C
4
-alkyl, fluorine, chlorine, bromine, iodine, N
2
H
3
or cyanide,
R is straight-chain or branched C
1
-C
8
-alkyl, in particular C
1
-C
4
-alkyl, or C
1
-C
5
-alkoxy, preferably C
1
-C
3
-alkoxy, and
R
1′
to R
5′
are each, independently of one another, H, CH
3
, straight-chain or branched C
1
-C
8
-alkyl, in particular C
1
-C
4
-alkyl, F, Cl, CN, NO
2
, CHO, COOH, CH
2
OH, C(═O)CH
3
, C
1
-C
5
-alkoxy, in particular C
1
-C
3
-alkoxy,
by reaction of phenylboronic acids of the formula (II) with 4-bromo- or 4-iodo-alkyl- or -alkoxy-anilines or -anilides of the formula (III) to form compounds of the formula (IV),
 if desired, subsequent deacylation to form (V) and subsequent diazotization to form compounds of the formula (VI) and reaction with a nucleophile (X) or a reducing agent to give 4-substituted 2-alkylbiphenyls and 2-alkoxybiphenyls of the formula (I)
The process of the invention opens up an efficient, short route to the respective 4-substituted 2-alkylbiphenyl or 2-alkoxybiphenyl (I) which gives high yields in each step.
In the above formulae (III) and (IV), R
2
can be hydrogen, formyl or acyl having n=1 to 5 carbon atoms (C(═O)—C
n
H
2n+1
).
The arylboronic acids can be used as free boronic acids (R″=H), as boronic anhydrides or as esters of straight-chain or branched, monohydric or polyhydric alcohols (R″=C
1
-C
8
-alkyl, in particular C
1
-C
4
-alkyl-, or B(OR″)
2
is a boronic anhydride radical). Preference is given to using the free boronic acids, the anhydrides or the esters with methanol, ethanol or glycol as starting compound.
The reason for the circuitous route via acylated anilines and subsequent deacylation is that, owing to the lability of the NH
2
group in coupling reactions, only moderate yields are observed in the coupling reaction in some cases. It has surprisingly been able to be shown that in these cases the abovementioned circuitous route is more economical despite the greater number of steps because of higher yields and product purities.
As stated above, X in the above formula can be NH
2
, NHAc, NH(C═O)R
1
where R
1
=straight-chain or branched C
1
-C
8
-alkyl, fluorine, chlorine, bromine, iodine, N
2
H
3
or cyanide, and the corresponding reactants for preparing these compounds from the diazonium salt are then as described in the prior art, for example CuBr for X=Br, alkali metal iodides for X=I, CuCN for X=CN, or appropriate reducing agents such as sulfites or disulfites or ZnCl
2
for X=N
2
H
3
, to name only a few.
The aniline derivatives of the formula (V) are reacted by the Sandmeyer reaction via the corresponding diazo compounds of the formula (VI) with appropriate chloride, bromide, iodide or cyanide compounds to form 2-alkyl-or 2-alkoxy-4-chloro-, -bromo-, -iodo- or -cyano-biphenyls of the formula (I).
Hydrazino compounds of the formula (I) (X=N
2
H
3
) are preferably prepared by reacting the diazonium salts of the formula (VI) with a reducing agent, in particular a sulfite, hydrogensulfite, disulfite or tin chloride.
The raw materials for the synthesis of the invention are either commercially available or can be prepared simply and in good yields. 4-bromo- or 4-iodo-3-alkyl- or alkoxy-anilines or -anilides of the formula (III), for example, can all be procured commercially at an acceptable price, even in large amounts. The phenylboronic acids (II) to be used for the Suzuki couplings are likewise commercially available, but can in many cases be prepared more cheaply in good yields by reaction of the corresponding Grignard compounds with boron compounds using methods known to those skilled in the art.
The Suzuki couplings of boronic acids of the formula (II) with anilines of the formula (III) to form aminobiphenyls of the formula (IV) can be achieved by means of Pd-catalyzed coupling reactions which can be carried out by methods based on those of the prior art (“Metal-catalyzed Cross-coupling Reactions”, Diederich/Stang, Wiley-VCH, Weinheim 1998). Suitable solvents for the coupling reaction are, for example, alcohols, DMSO, NMP, DMF, DMAc, ethers or hydrocarbons; preference is given to carrying out the coupling reaction in alcoholic solvents such as methanol, ethanol or glycol. The reaction is carried out in the presence of noble metal catalysts, in particular palladium-containing catalysts. In a preferred embodiment, use is made of palladium or nickel catalysts selected from the following group: NiCl
2
, PdCl
2
, PdCl
2
(dppf), PdCl
2
(PPh
3
)
2
, PdCl
2
(dppe), PdCl
2
(dppp), PdCl
2
(dppb), Pdl
2
, PdBr
2
or Pd(OAc)
2
, to name only a few (in these formulae, dppe=1,2-bis(diphenylphosphino)ethane, dppp=1,2-bis(diphenylphosphino)propane, dppb=1,2-bis(diphenylphosphino) butane and dppf=1,2-bis(diphenylphosphino)ferrocene, Ph=phenyl). In general, the catalyst is initially charged in the appropriate solvent and the boronic acid of the formula (II) and the aniline and anilide of the formula (III) are slowly added dropwise. During the addition, the temperature of the reaction solution is kept in the range from 0 to 150° C., in particular from 70 to 135° C. After addition of the reactants is complete, it may be useful to add a further 0.001-1 mol % of catalyst, based on the compound of the formula (II), to the reaction solution in order to achieve the highest possible conversion. The solution is subsequently refluxed for from 1 to 24 ho

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