Synthesis of b-hydroxyacetamides from unactivated ethyl acetates under base-free conditions and microwave irradiation Eugenio Hernández-Fernández a,⇑ , Pedro Pablo Sánchez-Lara a , Mario Ordóñez b,⇑ , Oscar Abelardo Ramírez-Marroquín b , Francisco G. Avalos-Alanís a , Susana López-Cortina a , Víctor M. Jiménez-Pérez a , Tannya Rocio Ibarra-Rivera c a Universidad Autónoma de Nuevo León, Facultad de Ciencias Químicas, Pedro de Alba s/n, Ciudad Universitaria, 66400 San Nicolás de los Garza, Nuevo León, Mexico b Universidad Autónoma del Estado de Morelos, Centro de Investigaciones Químicas, Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico c Universidad Autónoma de Nuevo León, Facultad de Medicina, Fco. I. Madero s/n, Mitras Centro, 64460 Monterrey, Nuevo León, Mexico article info Article history: Received 18 November 2014 Accepted 24 November 2014 abstract The amidation of unactivated ethyl esters with achiral and chiral 1,2-amino alcohols under microwave irradiation and base-free conditions is described. This procedure provides a convenient method for the synthesis of b-hydroxyacetamides bearing pyrazole, imidazole, and benzimidazole groups in high yields and without racemization. The protocol described herein is environmentally friendly and allows for the preparation of a wide variety of b-hydroxyacetamides, which are key intermediates in the synthesis of oxazolines and other derivatives of biological interest. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction Amide bond formation is a general and versatile reaction widely used to prepare peptides, polymers, and other complex molecules. The mildest conditions require activation of the carboxylic acid derivatives using stoichiometric quantities of activating or con- densing agents. 1 Amides bearing chiral 1,2-amino alcohols, which have been used as building blocks in the synthesis of more complex molecules, 2 and as chiral ligands, 3 are usually prepared by the reaction of activated carboxylic acids with chiral 1,2-amino alcohols. Other amides bearing chiral amino alcohols have been obtained by reactions between mildly activated esters and 1,2-amino alcohols without the need of coupling reagents, 4 or in a single-step carbene-catalyzed reaction of esters with chiral 1,2- amino alcohols, 5 catalyzed by 2-tert-butylimino-2-diethylamino- 1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), 6 and using K 3 PO 4 as the catalyst. 7 However, these methods suffer from one or more disadvantages such as the use of specialized handling techniques and tedious work-up, long reaction times, vigorous reaction conditions, the requirement of an excess of reagents, the use of solvent, which leads to unsatisfactory yields, and a lack of generality. On the other hand, Microwave-Assisted Organic Synthesis (MAOS) has been successfully applied in the synthesis of amide from non-activated acids, and optically active compounds are com- patible with these methods. 8 However, the preparation of amides bearing chiral 1,2-amino alcohols under microwave irradiation has not been reported. Therefore, in connection with our previous studies concerning the synthesis of amides bearing chiral 1,2-amino alcohols, 9 we herein report an operationally simple, and expeditious base-free synthesis of several b-hydroxyamides from unactivated esters under microwave irradiation. The versatil- ity of this method was exploited to obtain b-hydroxyamides, with moderate to excellent yields in very short reaction times, which can be used as key intermediates in the synthesis of more complex molecules and as ligands. 2. Results and discussion For the synthesis of target compound 1, we envisaged two syn- thetic procedures: (a) reaction of easily obtained N-chloroacetamido alcohols 2, with several cyclic amines, and (b) the reaction of ethyl acetate derivative 3 with chiral 1,2-amino alcohols (Scheme 1). Initially we developed a general procedure to prepare the novel b-hydroxyacetamides 1a–f following route A. In this context, using a recently described procedure the N-chloroacetamido alcohol 2 was readily obtained, 9,10 which was then reacted with different het- erocyclic amines such as pyrrolidine, piperidine, and morpholine in the presence of K 2 CO 3 in CH 3 CN at room temperature, obtaining the http://dx.doi.org/10.1016/j.tetasy.2014.11.015 0957-4166/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. Tel./fax: +52 818329 40 00x6293 (E.H.-F.); tel./fax: +52 7773297997 (M.O.). E-mail addresses: eugenio.hernandezfr@uanl.edu.mx (E. Hernández-Fernández), palacios@uaem.mx (M. Ordóñez). Tetrahedron: Asymmetry 26 (2015) 73–78 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy