C–H Arylation of Heterocyclic N-Oxides Through in Situ Diazotisation Of Anilines without Added Promoters: A Green And Selective Coupling Process

Abstract

A green and selective method for the generation of biaryl compounds through C−H arylation of heterocyclic N-oxides, in which the addition of ascorbic acid as a promoter is not required for either the generation of an aryldiazonium species or the subsequent arylation, is presented. Reaction conditions were optimized through multivariate data analysis, including orthogonal projections to latent structures (OPLS) and design of experiments (DoE) methodologies, resulting in further sustainability improvements, and were then applied to a range of substrates to establish the scope and limitations of the process. The reaction was studied using in situ infrared spectroscopy and a mechanism is presented that accounts for the available data from this and previous studies. The reaction was also performed on a multigram scale, with calorimetry studies to support further scale-up of this promoter-free transformation.

Radical Arylation of Triphenyl Phosphite Catalyzed by Salicylic Acid: Mechanistic Investigations and Synthetic Applications

“…(60.8 mg, 0.19 mmol, 63%). The spectral data matched that reported: 15 TLC (hexane/EtOAc 80:20) R f 0.28: 1 H NMR (300 MHz, CDCl 3 ) δ 8.08 (ddd, J = 15.2, 7.7, 1.3 Hz, 1H), 7.51 -7.44 (m, 1H), 7.35 -7.09 (m, 13H), 2.76 (d, J = 1.8 Hz, 3H) ppm; 13 C NMR { 1 H} (75 MHz, CDCl 3 ) δ 150.5 (d, 2 J C-P = 7.8 Hz, 2xC 1' ), 142.2 (d, 2 J C-P = 10.6 Hz, C 2 -Me), 134.5 (d, 2 J C-P = 11.1 Hz, C 6 -H), 133.4 (d, 4 J C-P = 3.1 Hz, C 4 -H), 131.6 (d, 3 J C-P = 15.8 Hz, C 3 -H), 129.8 (4xC 3' -H), 125.79 (d, 3 J C-P = 15.8 Hz, C 5 -H), 125.73 (d, J C-P = 188.6 Hz, C-P), 125.1 (d, 5 J C-P = 1.2Hz, 2xC 4' -H), 120.5 (d, 3 J C-P = 4.6 Hz, 4xC 2' -H), 21.6 (d, 3 J C-P = 3.6 Hz, CH 3 ) ppm; LRMS (EI) m/z (%) 324 (M + , 100), 288 (18), 231(25), 212(30), 77 (54).Diphenyl[1,1'-biphenyl]-2-ylphosphonate (2s). Following the general procedure, compound 2s was obtained after FC (from 95:5 to 80:20 hexane/EtOAc) and further purified by recrystallization from i-PrOH as an orange crystalline solid (67.2 mg, 0.174 mmol, 58%): TLC (hexane/EtOAc 80:20) R f 0.30; mp (i-PrOH) 93-95 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.36 -8.27 (m, 1H), 7.65 (tt, J = 7.6, 1.6 Hz, 1H), 7.54 (dtd, J = 7.6, 3.8, 1.4 Hz, 1H), 7.51 -7.46 (m, 2H), 7.45 -7.38 (m, 4H), 7.25 -7.17 (m, 4H), 7.13 -7.05 (m, 2H), 6.93 -6.86 (m, 4H); C NMR { 1 H} (75 MHz, CDCl 3 ) δ 150.5 (d, 2 J C-P = 8.4 Hz, 2xC 1' ), 146.6 (d, 2 J C-P = 10.0 Hz, C 2 ), 141.2 (d, 3 J C-P = 4.2 Hz, C 7 ), 134.6 (d, 2 J = 10.8 Hz, C 6 -H), 133.0 (d, 4 J C-P = 3.1 Hz, C 4 -H), 131.9 (d, 3 J C-P = 14.9 Hz, C 5 -H), 129.7 (2xC 9 -H), 129.6 (4xC 3' -H), 127.8 (C 10 -H), 127.8 (2xC 8 -H), 127.2 (d, 3 J C-P = 15.6 Hz, C 3 -H), 125.…”

Anion Induced Dediazotization of In Situ Generated Aniline Diazonium Compounds in Direct C–H Arylation of Heteroarenes: An Experimental and Computational Study

“…The formation of triazene in the diazonium based reaction is suggested by Horan and co-workers in their recent work. [17] The triazene disintegrates in the subsequent step into aryl radical and amine radical. The calculations show that formation of the triazene by the reaction of 6 and 4-nitroaniline is exoergic by 10.9 kcal/mol.…”

Recent Progress in Non‐Catalytic C–H Functionalization of Heterocyclic N‐Oxides

“…The Gomberg-Bachmann reaction is performed on pyridine N-oxides in the regioselective variant under mild conditions with in situ generations of aryldiazonium salts (Scheme 62). [99] Scheme 62. Synthesis of 2-(4-nitrophenyl)pyridine N-oxide via Gomberg-Bachmann reaction.…”