One-Pot Suzuki-Hydrogenolysis Protocol for the Modular Synthesis of 2,5-Diaryltetrazoles

Abstract

2,5-Diaryltetrazoles are a diverse range of compounds of considerable interest within the field of photochemistry as a valuable precursor of the nitrile imine 1,3-dipole. Current literature approaches toward this heterocycle remain unsuitable for the practical synthesis of a library of these derivatives. Herein, we disclose the development of a modular approach toward 2,5-diaryltetrazoles compatible with an array-type protocol, facilitated by a tandem Suzuki-hydrogenolysis approach.

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

“…The crude mixture was purified by flash chromatography (50% EtOAc/hexanes (300 mL), then 75% EtOAc/ hexanes (300 mL)) to separate the two tetrazole isomers. Tetrazole 16 (93.0 mg, 0.380 mmol, 76% yield) was isolated as a pale-yellow oil: R f 0.52 (75% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 ) δ 7.49 (d, J = 3.9 Hz, 1H), 6.90 (d, J = 3.9 Hz, 1H), 4.75 (t, J = 6.9 Hz, 2H), 3.69 (t, J = 5.7 Hz, 2H), 3.02 (br s, 1H), 2.23 (qn, J = 6.4 Hz, 2H); 13 8-(5-(5-Chlorothiophene-2-yl)-2H-tetrazol-2-yl)octan-1-ol (17). The title compound was prepared according to general procedure A using 5-(4-bromophenyl)-1H-tetrazole (113 mg, 0.500 mmol, 1.00 equiv), 8-amino-1-octanol (189 mg, 1.25 mmol, 2.50 equiv), and 1,3-(2,2-dimethyl)propanedinitrite (0.093 mL, 0.800 mmol, 1.60 equiv) in EtOAc (4 mL).…”

“…Numerous methods, mostly based on 1,3-dipolar cycloadditions with an azide reagent, are available to synthesize a large variety of 1,5-Tz derivatives. − Conversely, condensation reactions to synthesize 2,5-Tz compounds are limited. − Typically, 2,5-Tz are prepared from 1 H -Tz via substitution at the nitrogen. − While a variety of substituted 2,5-Tz have been reported to be prepared in high yields and selectivities, these methods were not suitable for the preparation of 2,5-Tz products containing nucleophilic groups, such as alcohols or amines. As a result, despite recent advances, there remains a need for synthetic methods to afford diversely substituted 2,5-Tz.…”

Light-Triggered Click Chemistry

“…However, this method employs hazardous reagents and suffers from laborious purification steps. Alternatively, the transition metal-catalyzed N 2 -arylation of 5-substituted tetrazoles with diverse arylating reagents such diaryliodonium salts and aryl boronic acids have been developed. − Among these approaches, the Cu-catalyzed regioselective arylation of 5-substituted tetrazoles provides rapid access to 2,5-disubstituted tetrazoles under mild conditions (Scheme c) …”

Understanding the regioselectivity of 5-substituted 1H-tetrazoles alkylation

“…In contrast to 1,5-disubstituted tetrazoles (1,5-Tz), for which many methods are available to produce the desired compounds in high yields, 6 it remains a challenge to synthesize 2,5-Tz via a cycloaddition process. 7 Not only are these condensation reactions limited in the synthesis of N -aryl substituted 2,5-Tz, but functional groups such as amines or alcohols are also not compatible. As a result, for most cases, the method of choice for the synthesis of 2,5-Tz is the nucleophilic substitution from 1 H -5-monosubstituted tetrazoles (1 H -Tz).…”