Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates

Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C–C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C–H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.

Micellar Catalysis of Organic Reactions. XXXI. A Study of the Effects of Micelles of Cetyltrimethylammonium Bromide on Some SNAr Reactions in Aqueous Binary Mixtures

The effect of micelles of cetyltrimethylammonium bromide ( ctab ) on the SNAr reactions of 1-fluoro-2,4-dinitrobenzene (1), 2-fluoro-5-nitrobenzoate (2) and 4-fluoro-3-nitrobenzoate (3) with sodium hydroxide in aqueous binary mixtures with several alcohols has been studied. Two products were detected in all of these reactions: the phenol from reaction with hydroxide ions, and an aryl alkyl ether from reaction with the alkoxide ions. Micelles of ctab increased the percentage yield of the ether product at the expense of the phenol for compounds (1) and (2) in most of the binary mixtures used. For compound (3), however, micelles of ctab had little effect on the product distribution. These differences were attributed to differences in the orientation of substrates (2) and (3) when solubilized by micelles of ctab . Very high yields of the ether were obtained for the reaction of compound (1) with hydroxide ions in trifluoroethanol /water mixtures, and this was attributed to the considerable ionization of trifluoroethanol which was the most acidic alcohol used in this work. The lowest yield of the ether product was obtained in reactions of compound (1) with hydroxide ions in propan-2-ol/water mixtures since propan-2-ol was the least acidic alcohol used. These results are compared with those previously reported for the reaction of compound (1) in the presence of hydroxy-functionalized micelles and β- cyclodextrin. In the presence of micelles of ctab the aryl alkyl ethers derived from compounds (1) and (2) underwent a subsequent SNAr reaction with hydroxide ions during which the alkoxide ion was displaced. For compound (3) no subsequent reaction of the ether was detected in the presence of micelles of ctab . This was also attributed to the orientation of this product within the micelle. The reaction centre was buried in the micellar interior, and hence was shielded from a subsequent reaction. The rates of this subsequent reaction for compound (1), and of the decomposition of micellar aryl ethers and of cyclodextrin aryl ethers derived from compound (1), are also compared. The increase in the yield of the ether product in the presence of micelles was attributed to the increased ionization of alcohols in the presence of cationic micelles.