Ruthenium-Catalyzed, Microwave-Mediated [2+2+2] Cycloaddition: A Useful Combination for the Synthesis of 2-Aminopyridines

Abstract

A ruthenium-catalyzed [2+2+2] cycloaddition between α,ω-diynes and cyanamides is reported under microwave irradiation to access 2-aminopyridines. In contrast to the classical thermal conditions, this atom-economical sustainable protocol allows access to diverse functionalized 2-aminopyridine derivatives with high yields and excellent regioselectivities in MeTHF with short reaction times.

Key words

ruthenium - cycloaddition - microwave - aminopyridines - diynes - cyanamides

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Diynes 1a, 1b, and 1h were prepared according to:
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Diyne 1d and 1e were prepared according to:
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Diyne 1f was prepared according to:
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Diyne 1g was prepared according to the procedure reported by:
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• 40 General Procedure for the Ru-Catalyzed [2+2+2] Cycloaddition of Diynes and Cyanamides In a microwave tube equipped with [Cp*Ru(CH₃CN)₃]PF₆ (2 mol%) and diyne 1 (0.2–0.5 mmol, 1.0 equiv), a solution of cyanamide 2 (0.3–0.6 mmol) in MeTHF (1 mL) was added under an argon atmosphere. The reaction mixture was then stirred at 50 °C, with 50 W irradiation for 15 min in a microwave reactor (fixed power mode). The crude mixture was concentrated under reduced pressure. The dark oil was then filtered through a silica pad, washing with MeTHF, or purified by flash chromatography on silica gel. In some cases,the excess cyanamide was removed by bulb-to-bulb distillation.
• 41 Although the cycloadduct 3c was obtained in moderate yield under thermal conditions, a side product was observed^38e in 27% yield. The microwave irradiation minimizes the formation of side or degradation products.