Pd(ii)-catalyzed, controllable C–H mono-/diarylation of aryl tetrazoles: concise synthesis of Losartan

Abstract

A palladium(II)-catalyzed C-H arylation directed by tetrazole, a metabolically stable surrogate for the carboxylic acid group in drug design, has been developed. Excellent mono-/di-selectivity was achieved through adjustment of the protecting site on the tetrazole ring. The synthetic utility of this new transformation was demonstrated in the concise total synthesis of Losartan.

Alkylation of 5-Substituted 1H-Tetrazoles via the Diazotization of Aliphatic Amines

“…Tetrazole 2 (36.8 mg, 0.117 mmol, 23% yield) was isolated as a white solid. Spectral data matched those reported in the literature: R f 0.28 (20% EtOAc/hexanes); mp 92–94 °C; 1 H NMR (300 MHz, CDCl 3 ) δ 87.64 (d, J = 9 Hz, 2H), 7.45 (d, J = 9 Hz, 2H), 7.37–7.34 (m, 3H), 7.17–7.12 (m, 2H), 5.61 (s, 2H); 13 C­{1H} NMR (75 MHz, CDCl 3 ) δ154.0, 133.8, 132.7, 130.4, 129.4, 129.1, 127.2, 126.3, 122.8, 51.6. The title compounds were also prepared according to general procedure B1 using 4-bromobenzonitrile (91.0 mg, 0.500 mmol, 1.00 equiv), dibutyltin oxide (18.7 mg, 0.075 mmol, 0.150 equiv), azidotrimethylsilane (0.986 mL, 0.750 mmol, 1.50 equiv), benzylamine (0.137 mL, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)­propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in toluene (4 mL, 1.5 mL for the first step + 2.5 mL for the second step) leading to tetrazole 1 (102 mg, 0.324 mmol, 65% yield) as a white solid and tetrazole 2 (37.8 mg, 0.120 mmol, 24% yield) as a white solid.…”

Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

“…In 2015, Li, Wang and co-workers described another concise synthesis of losartan (64). 49 As depicted in Scheme 17, the first step of this synthesis involved the tetrazole-directed phosphine-free ortho-arylation of 1-benzyl-5-phenyl-1H-tetrazole (77) with a large molar excess of 4-iodotoluene (78) in TFA at 150 °C for 24 hours in the presence of 5 mol% Pd(OAc) 2 and 4.0 equiv of AgOAc, which produced compound 79 in 73% yield. The subsequent reaction of 79 with 0.75 equiv of 1,3-dibromo-5,5-dimethylhydantoin (80) and 5 mol% BPO in CCl 4 under reflux, followed by treatment of the resulting crude benzyl bromide with 2-butyl-4chloro-1H-imidazole-5-carbaldehyde 81…”

Ruthenium(II) biscarboxylate-Catalyzed C(sp2)-H and C(sp3)-H Functionalizations by Chelation Assistance

“…Importantly, our robust reaction conditions employed a single-component catalyst and toluene as the solvent to guarantee robust C-H functionalizations with remarkable selectivity. [78] Thus, a carboxylic acid derived ruthenium (II) catalyst enabled syntheses of biaryl tetrazoles, key structural motifs in various angiotensin II receptor blockers. [79] This paved the way for a more appealing catalytic system in the Ackermann group recently.…”