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

Abstract

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.

Fig. 1.. Important heterobiaryl-containing drugs and synthetic strategies.

(A) Heterobiaryls in drugs. (B) Heterobiaryls via metal-catalyzed cross-coupling reactions. R denotes a general organic group; Hal, halogen substituent. (C) Test system for heterobiaryl synthesis via phosphorus ligand coupling reactions. Ph, phenyl; Me, methyl; Et, ethyl; Tf, trifluoromethylsulfonyl; DBU, 1,8-diazabicyclo[5.4.0] undec-7-ene; rt, room temperature.

Fig. 2.. Computational and experimental investigation of phosphorus ligand coupling.

(A) Biaryl-coupling activation barriers [coupled cluster/density functional theory SMD-DLPNO-CCSD(T)/cc-pV(DT)Z//ωB97XD/6–31+G(d), kcal/mol] decrease upon protonation and consistently favor heterobiaryl formation. Py, pyridine. (B) Computed bond orders show a single (apical) P−C(py) bond breaking along the reaction coordinate, with little involvement of oxygen lone pairs. LP_Ox, number of electrons in each oxygen lone pair. (C) Optimized structures for [Int-III·2H]²⁺, [TS-I·2H]²⁺, and [Int-IV·2H]²⁺ show stepwise apical-equatorial ligand coupling. (D) A kinetic study indicates that alcohol addition is rate-limiting. TfOH was used in place of HCl because of poor solubility of aryl derivatives. Yields after complete consumption of the phosphonium salts were approximately the same in each case (89 to 94%). (E) Room-temperature coupling using ethoxide as a nucleophile.

Fig. 3.. Azaarene scope and guidelines for phosphonium salt formation.

Yields of isolated products after each stage are shown. n-Bu, normal butyl group; n-Pr, normal propyl group. Reaction guidelines are shown for phosphonium salt formation involving ortho and non-ortho substituted pyridines as partners. Further details of challenges and limitations are highlighted in fig. S25.

Fig. 4.. Heterobiaryl synthesis in complex molecules.

Yields of isolated products after each stage are shown. Further examples of advanced stage couplings are shown in fig. S26.