Addition of α-Lithiated Nitriles to Azaheterocycles

Abstract

The addition of α-deprotonated nitriles to azahetero­cycles followed by rearomatization is described. A simple two-step, one-pot procedure for the sequence is also presented.

Key words

quinazoline - oxidation - nitrile - dehydrogenation - ­pyrimidine

• References and Notes

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• 16 General Procedure: 1-(Quinazolin-4-yl)-cyclohexanecarbonitrile (Table 3 Entry 1) To a solution of cyclohexanecarbonitrile (146 μL, 1.2 mmol, 1.2 equiv) in THF (5 mL) at –78 °C was added LiHMDS (1.2 mL of 1 M in THF, 1.2 mmol, 1.2 equiv) dropwise and stirred at –78 °C for 5 min. Quinazoline (130 mg, 1.0 mmol, 1.0 equiv) was added, the cooling bath was removed, and the reaction mixture was stirred for 1 h. Solid KMnO₄ (316 mg, 2 mmol, 2 equiv) and MeCN (1 mL) were added, and the reaction mixture was stirred at r.t. until the reaction was complete (as judged by LC–MS analysis, in this case 4.5 h). The reaction mixture was poured into sat. aq NaHCO₃ and extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried (Na₂SO₄), filtered, and evaporated to dryness. The crude residue was purified by silica gel flash chromatography (12 g silica, 0–40% EtOAc in hexanes) to yield 1-(quinazolin-4-yl)cyclohexane-carbonitrile as a white solid (222 mg, 94% yield). ¹H NMR (400 MHz, CDCl₃): δ = 9.29 (s, 1 H), 8.70 (d, J = 8.6 Hz, 1 H), 8.13 (d, J = 8.2 Hz, 1 H), 7.94 (ddd, J = 8.4, 6.9, 1.3 Hz, 1 H), 7.72 (ddd, J = 8.4, 6.9, 1.3 Hz, 1 H), 2.52 (d, J = 12.3 Hz, 2 H), 2.17–2.08 (m, 2 H), 2.02–1.95 (m, 4 H), 1.93–1.87 (m, 1 H), 1.40–1.28 (m, 1 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 166.61, 153.75, 151.05, 133.79, 130.02, 127.89, 124.73, 122.31, 121.92, 44.40, 35.58, 25.06, 22.97 ppm.
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• 18 We speculate that the ease of enolate formation may be why dehydrogenation was not observed under these conditions (Scheme 3). Alternatively, as pointed out by a reviewer, the ester intermediate can adopt a six-membered transition state that could facilitate the reverse process (Scheme 4).