Sulfur-Mediated Decarboxylative Coupling of 2-Nitrobenzyl Alcohols and Arylacetic Acids

In memory of Assoc. Prof. Dr. Quan Thanh Pham

Abstract

We report a new method for the synthesis of substituted quinazolines by the condensation of 2-nitrobenzyl alcohols with arylacetic acids. The transformation requires the use of urea as a nitrogen source, elemental sulfur as a promoter, DABCO as a base, and DMSO as a solvent. Functionalities such as chloro, fluoro, trifluoromethyl, thienyl, and indolyl groups were all compatible with the reaction conditions. Because our method uses stable simple substrates to obtain the N,N-heterocycles in the absence of transition metals, it offers a potential pathway for preparing complex structures under mild conditions.

Key words

quinazolines - nitrobenzyl alcohols - arylacetic acids - cyclocondensation - decarboxylation

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• 11 6,7-Dimethoxy-2-phenylquinazoline (3da); Typical Procedure A 4-mL screw-cap vial was charged with 4,5-dimethoxy-2-nitrobenzyl alcohol (21 mg, 0.1 mmol), phenylacetic acid (2a; 34 mg, 0.25 mmol), DABCO (28 mg, 0.25 mmol), elemental sulfur (8 mg, 0.25 mmol, 32 g/mol), urea (18 mg, 0.3 mmol), and DMSO (0.3 mL). The tube was tightly capped and the mixture was stirred at 140 °C for 2 h until the reaction was complete. The mixture was then cooled to r.t. and diluted with EtOAc (5 mL) and 10% aq NaHCO₃ (5 mL). The mixture was extracted with 10% aq NaHCO₃ (2 × 3 mL), and the organic layers were combined, dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude product was purified by column chromatography [silica gel, hexanes–EtOAc (10:1)] to give a light-yellow solid; yield: 17.8 mg (67%); mp 125–126 °C; R_f = 0.45 (hexanes–EtOAc, 5:1). ¹H NMR (500 MHz, CDCl₃): δ = 9.16 (s, 1 H), 8.48 (d, J = 7.1 Hz, 2 H), 7.46–7.41 (m, 3 H), 7.33 (s, 1 H), 7.05 (s, 1 H), 4.02 (s, 3 H), 3.97 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 159.8, 157.0, 156.4, 150.5, 148.6, 138.2, 130.2, 128.6, 128.2, 119.4, 106.8, 104.0, 56.5, 56.3. HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₆H₁₅N₂O₂: 267.1128; found: 267.1131.
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