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.

Incomplete Electrocyclization of a Sterically Hindered 1,4‐Diphosphabutadiene

“…Copper‐mediated intramolecular homocoupling reaction of 3 and butyllithium provided the desired product 4 , which was isolated as an air‐ and moisture‐tolerant crystalline compound after SiO 2 column chromatography (Scheme ). The related compound, 3,4‐bis(phosphanylidene)‐1,2,5‐oxadisilolane 6 was also synthesized by using phosphine‐mediated homocoupling of the precursor 5 (Scheme ).…”

“…The organic layer was extracted with hexane, and the solvent was removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane) to afford 4 as a yellow solid (212 mg, 26 %); 1 H NMR (300 MHz, CDCl 3 ) δ 7.36 (s, 2H, arom), 7.28 (s, 2H, arom), 1.76 (s,, 1.50 (s,18H,, 1.32 (s,18H,, 0.68 (t, 3 J HH = 9.8 Hz, 2H, CHH), 0.60 (t, 3 J HH = 9.8 Hz, 2H, CHH), À 0.40 (s, 6H, SiMe), À 0.66 (s, 6H, SiMe); 13 34.9, 34.4 (pt, ( 4 J PC + 7 J PC )/2 = 6.0 Hz), 33.1 (pt, ( 4 J PC + 7 J PC )/2 = 4.5 Hz), 31.3, 9.8, À 2.6 (d, 3 J PC = 6.0 Hz); 31…”

Transition‐Metal‐Free Aryl–Aryl Cross‐Coupling: C−H Arylation of 2‐Naphthols with Diaryliodonium Salts

“…Several approaches for achieving the transition metal‐free formation of aryl–aryl bonds exist, often exploiting the reactivities of p‐block elements, such as phosphorus, sulfur, or iodine . These cross‐couplings include a number of reactions proceeding via the direct functionalization of C−H bonds, which is the most desirable variant from green chemistry and atom economy viewpoints –…”

Metal‐Free Aryl Cross‐Coupling Directed by Traceless Linkers

“…Most known metal‐free approaches, however, suffer from disadvantages such as narrow scope and low selectivity because of the harsh conditions required . Recent approaches to transition‐metal‐free biaryl syntheses involve, for example, Grignard reagents, oxidative coupling of electron‐rich arenes, base‐mediated coupling of aryl halides, and phosphorus ligand coupling . Furthermore, photolytic reactions have been employed to generate radicals or aryl radical cations, which set the stage for C−C bond formation.…”