Biaryls by Aryl Coupling

We consider here the syntheses of 2-cyano-4 -methylbiphenyl and of 4-chloro-2 -nitrobiphenyl as the best known examples. The former product is an important intermediate to Valsartan (Clariant) and analogous sartan compounds used to control blood pressure by inhibiting angiotensin, while 4-chloro-2 -nitrobiphenyl is an intermediate to the fungicide Boscalid (BASF-Novartis). 

Examples from patents [S. Haber and N. Egger, US Patent 6 140 265 (2000), to Clariant S. Haber and H.-J. Kleiner, US Patent 5 756 804 (1998), to Hoechst-Clariant] describe the synthesis of 2-cyano-4 -methylbiphenyl by reaction of 2-chlorobenzonitrile and p-tolueneboronic acid, in the presence of Na2C03, PdCl2, and triphenylphosphinetrisulfonic acid (4 mol) in a water-toluene system, with a co-solvent miscible with water such as DMSO or 

This process has the advantage of giving the product in only one step in place of the five previously needed. 

PdCl2-dppp. The yield is 95%. Magnesium and manganese salts are discarded after the work up and incorporated in building materials. This is an ecological strategy that may be generally useful for industrial effluents. 

Boscalid was shown to be an effective fungicide and its industrial production is expected to begin soon. The biphenyl intermediate, 4 -chloro-2-nitrobiphe-nyl, is prepared by palladium-catalyzed coupling of 2-nitrochlorobenzene with 4-chloroboronic acid according to Equation 19. Other details are not available. Boscalid is the 2-chloronicotinic acid amide derivative of the amine obtained by reduction of the nitrobiphenyl product. 

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