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Synthesis 2007(16): 2495-2502  
DOI: 10.1055/s-2007-983811
PAPER
© Georg Thieme Verlag Stuttgart · New York

Unprecedented One-Pot Stereoselective Synthesis of Knoevenagel-Type Derivatives­ via in situ Condensation of N-Methyleniminium Salts of Ethylenethiourea­ and Ethyleneurea with Active Methylene Reagents

Angelo Ranise*a, Sara Cesarinia, Andrea Spallarossaa, Fernando Sancassanb, Francesco Bondavallia, Olga Brunoa, Silvia Schenonea, Giulia Menozzia, Paola Fossaa, Luisa Mostia
a Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, 16132 Genoa, Italy
b Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, 16146 Genoa, Italy
Fax: +39(010)3538358; e-Mail: ranise@unige.it;
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Publication History

Received 3 April 2007
Publication Date:
09 August 2007 (online)

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Abstract

A facile stereoselective synthesis of Knoevenagel-type compounds 8 and 9 was accomplished through a one-pot two-step procedure. The reaction of ethylenethiourea (1) and ethyleneurea (2) with benzoyl chloride-N,N-dimethylformamide complex in N,N-dimethylformamide gave the corresponding isolable ternary N-methyleniminium chlorides 3 and 4, along with benzoic acid (5) as a byproduct. Hydrolysis of salts 3 and 4 yielded the N-formyl derivatives 6 and 7, thus confirming the N-methyleniminium structure. Salts 3 and 4 condensed in situ at 120 °C with a variety of acyclic active methylene reagents Y-CH2-Z (Y = or ≠ Z), in the presence of 5 (Procedure A) or of 5 and triethylamine (1.5 equiv) (Procedure B), afforded α,β-unsaturated compounds 8 and 9. The overall yields ranged from poor to good. Mechanistic hypotheses concerning the formation of 3 and 4 and the origin of the stereoselectivity are also discussed.

Key words

ternary iminium salts - active methylene reagents - stereoselective synthesis - Knoevenagel reaction

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