Microwave-assisted Michaelis-Arbuzov reaction

IGNACIO S. LUPPI BERLANGA; LILIANA R. ORELLI

Itapema

Congreso; 12th Brazilian Meeting on Organic Synthesis; 2007

Sociedad Química de Brasil

Microwave-assisted Michaelis-Arbuzov reactionIgnacio S. Luppi Berlanga and Liliana R. Orelli*Departamento de Química Orgánica. Facultad de Farmacia y Bioquímica. Universidad de Buenos Aires. Junín 956 (1113) Buenos Aires. Argentina*Corresponding author. Tel.: +11 49648250; fax: +11 49648250; e-mail: lorelli@ffyb.uba.arKeywords: microwaves, Michaelis-Arbuzov reaction and phosphonoacetamides. INTRODUCTIONPhosphonoacetamides 1 are the starting materials of choice for the preparation of ,-unsaturated amides via Horner-Wadsworth-Emmons olefination of carbonyl compounds. Compounds 1 are generally prepared employing the Michaelis-Arbuzov1 or Michaelis-Becker reactions.2 They can alternatively be synthesized by aminolysis of phosphonate esters, by reaction between an -phosphonyl carbanion and an isocyanate or a carbamate or by condensation of an amide enolate with diethylchlorophosphate.3 The Michaelis-Arbuzov reaction, however, is the most general method, although it requires an excess of the reagent and prolonged reaction times (from hours to days).4 Reactions performed under microwave irradiation proceed in general faster, more cleanly, and with better yields than under conventional heating.5 This prompted us to investigate the use of microwave irradiation to enhance the Michaelis-Arbuzov reaction for the synthesis of compounds 1.RESULTS AND DISCUSSIONOn the basis of previous work we employed a domestic microwave oven (Sanyo EM-D2013) adapted for reflux heating, with pulsed irradiation. Reactions were thus conducted under atmospheric pressure. We examined first the reaction of N-(4-chlorophenyl)chloroacetamide and equimolar amounts of triethyl phosphite under different experimental conditions, including: solvents (neat, DME, THF, acetonitrile, DMF), irradiation time and power. We also investigated the use of NaI or KI as catalysts and neutral Alumina as a solid support or additive. The results were compared to those obtained employing conventional heating. In solventless conditions, the use of microwaves notably accelerated the reaction. The solvent of choice was DMF, probably due to its higher dielectric constant and boiling point. Catalytic amounts of NaI improved the reaction yield. Addition of neutral Alumina enhanced the reaction rate, but its reproducibility was poor and violent boiling of the reaction mixture was observed even with the lowest irradiation power available.Employing the optimized reaction conditions (solvent: DMF, catalyst: NaI, irradiation power: 700 Watt, irradiation time: 5 min or less) we synthesized a series of N-mono and N,N-disubstituted aryl and/or alkyl phosphonoacetamides 1 with good to high yields.Scheme 1a-c: R1=H, R2=phenyl, 4-chlorophenyl, 4-methylphenyl; 1d,e: R1= H, R2= benzyl, tert-butyl; 1f: R1= Me, R2= phenyl; 1g: R1, R2= phenyl; 1h: R1= ethyl, R2= benzylCONCLUSIONWe have developed an efficient microwave based protocol for the Michaelis-Arbuzov reaction, that can be conducted in a domestic microwave oven without specialized equipment. The method is general for secondary and tertiary alkyl or aryl phosphonoacetamides 1. Its main advantages are the remarkably short reaction times, improvement in product yields and the use of equimolar amounts of the reagent. ACKNOWLEDGMENTSWe thank Ms. Romina A. Torres for her valuable collaboration.1.B. A. Arbuzov, Phys. Chem. Soc., 1906,38:6872.J. I. G. Cadogan, Organophosphorus Reagents in Organic Synthesis. Academic Press. London, 1979 3.M.K. Tay et. Al., Tetrahedron, 1989, 45 (14) :4415-44304.Phophorus, Sulfur and Silicon, 2002, 177:137-1495. (a) Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Discovery 2006, 5, 55; (b) Shipe, W. D.; Wolkenberg, S. E.; Lindsley, C.W. Drug Discovery Today: Tech. 2005, 2, 155; (c) Leadbeater, N. E. Chem. Commun. 2005, 2881; (d) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250; (e) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225; (f) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199