Simple preparation of new N-aryl-N-(3-indolmethyl) acetamides and their spectroscopic analysis

Universitas Scientiarum, 2009, Vol. 14 N° 2-3: 216-224 Universitas. SCIENTIARUM Disponible en línea en: www.javeriana.edu.co/universitas_scientiarum Facultad de Ciencias 2009, Vol. 14 N° 2-3: 216-224 SICI: 2027-1352 (200905/12) 14:2-3 <216: SPONNAATSA> 2.0. TS; 2-2 Original paper Simple preparation of new N-aryl-N-(3-indolmethyl) acetamides and their spectroscopic analysis Josué S. Bello,a Diego F. Amado,a José A. Henao, b Reinaldo Atencio c and Vladímir V. Kouznetsov*a a Laboratorio de Química Orgánica y Biomolecular, bGrupo de Investigación en Química Estructural, CIBIMOL, Escuela de Química, Universidad Industrial de Santander, A.A. 678, Bucaramanga, Colombia. c Laboratorio de Síntesis y Caracterización de Nuevos Materiales, Centro de Química, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela. *; Received: 05-11-2009; Accepted: 30-12-2009 Abstract Objectives. To prepare new indolic molecules and characterize them by spectroscopic methods. Materials and methods: All reagents were purchased from Aldrich, commercial grade. The purity of the products and the composition of the reaction mixtures were monitored by thin layer chromatography over Silufol UV254 0.25 mm-thick chromatoplates. Product isolation and purification were performed by column chromatography (SiO2), using ethyl acetate-petroleum ether mixtures as eluents. Results. The synthesis of new N-aryl-N-(3indolmethyl) acetamides based on first step iminization reaction of indol-3-carbaldehyde is accomplished. The structures of the C-3 substituted indoles were confirmed by 1H-NMR and 13C-NMR studies supported by inverse-detected 2D NMR experiments and also through monocrystal X-ray diffraction. Conclusions. An efficient, economic, and fast synthetic route was designed to the construction of the N-aryl-N-(3-indolmethyl) acetamides, structural analogues of some alkaloids. Key words: indole, acetamides, iminization Resumen Preparación sencilla de nuevas N-aril-N-(3-indolmetil) acetamidas y su análisis espectroscópico. Objetivos: Preparar nuevas moléculas indólicas y caracterizarlas por los métodos espectroscópicos. Materiales y métodos. Todos los reactivos fueron adquiridos de Aldrich, de grado comercial. La pureza de los productos y composición de las mezclas de reacción fueron monitoreadas por la cromatografía en capa delgada, Silufol UV254 0.25 mm-grosor de cromatoplacas. El aislamiento y purificación de los productos fueron realizados por la cromatografía en columna (SiO2), usando mezclas de acetato de etilo y éter de petróleo como eluentes. Resultados. Se ha realizado la síntesis de nuevas N-aril-N-(3-indolmetil) acetamidas, basada en la reacción de iminización del indol-3-carbaldehído. Las estructuras de los indoles C-3 sustituidos fueron confirmadas por estudios de 1H, 13C -RMN, experimentos de 2D RMN y también por difracción monocristal de Rayos X. Conclusiones. Se ha diseñado una nueva ruta de síntesis eficiente, económica y rápida para la construcción de las N-aril-N(3-indolmetil) acetamidas, análogos estructurales de diversos alcaloides. Palabras clave: indol, acetamidas, iminización 216 Bello et al Simple preparation of new N-aryl-N-(3-indolmethyl) acetamides and their spectroscopic analysis Resumo Preparação simples de novas N-aril-N-(3-indolmetil)acetamidas e sua análise espectroscópica. Objetivos. Preparar novas moléculas indólicas e caracterizar-las através de métodos espectroscópicos. Materiais e métodos. Todos os reagentes foram obtidos de Aldrich, de tipo comercial. A pureza dos produtos e a composição das misturas de reação foram monitoradas por cromatografia em camada fina, Silufol UV254 0,25 mm de espessura das cromatoplacas. O isolamento e a purificação dos produtos foram feitos através de cromatografia em coluna (SiO2), utilizando misturas de acetato de etila e éter de petróleo como eluente. Resultados. Realizou-se a síntese de novas N-arilN-(3-indolmetil)acetamidas, baseada na reação de iminización do indol-3-carbaldeído. As estruturas dos indóis C-3 substituídos foram confirmadas por estudos de 1H, 13C -RMN, experimentos de 2D RMN e também por difração monocristal dos Rayos X. Conclusões. Desenhou-se una nova rota de síntese eficiente, econômica e rápida para a construção das N-aril-N-(3-indolmetil) acetamidas, análogos estruturais de vários alcalóides. Palavras-chave: indol, acetamidas, iminização Introduction The research of the indol chemistry has been and still is one of the most active areas of heterocyclic chemistry. In recent years, much interest has been attracted to the preparation of substituted indoles due to their numerous biologically significant activities.1 The 3-indolylmethanamine derivatives 1 were the important intermediates of the natural and natural-like products, such as hydro-γcarboline and pyrido[4,3-b]indole derivatives.2,3 This 3indolyl methanamine motif is also embedded in numerous indole alkaloids from simple alkaloid gramine 2 to complex aspidospermine alkaloid 34,5 (Figure 1). delivery. We were particularly interested in 3-indolylmethanamine derivatives molecules that could serve as useful precursors to many drug-like indolic compounds in our quest for compounds with antiparasitic properties.12-14 To the best of our knowledge, a simple preparation of new (3indolmethyl) acetamide and (1-acetylindolmethyl-3) acetamide regulating only a solvent nature has not been described. The results of our investigation on preparation, spectral and structural characterization of new two acetamides based on 3-indolyl methanamine motif are reported in this work. Materials and methods Figure 1. Relevant natural alkaloids derived from the 3indolylmethanamine system. As a result of their biological and synthetic importance, a variety of methods have been reported for the preparation of 3-substituted indoles, using indol or 3-indolcarboxyaldehyde as starting materials. Generally, the Mannich reaction6,7 and the catalyzed Friedel-Crafts alkylation reactions of indoles8-11 are considered as a powerful carboncarbon bond process to afford the 3-indolylmethanamine derivatives 1. However, another synthetic route to these compounds by using 3-indolcarboxyaldehyde via its imino derivatives formation is valid. This route has been employed by our laboratory, which recently started an own medicinal program directed to small molecules for drug All reagents were purchased from Aldrich, commercial grade. The purity of the products and the composition of the reaction mixtures were monitored by thin layer chromatography over Silufol UV 254 0.25 mm-thick chromatoplates. Product isolation and purification were performed by column chromatography over silica gel, using ethyl acetate-petroleum ether mixtures as eluents. The IR spectra were measured with a Lumex infralum FT-02 spectrophotometer in KBr. The 1H-NMR spectra were acquired Bruker Advance AM-400 spectrometers using CDCl3 as a solvent and TMS as internal reference. The mass spectra were obtained on an (...truncated)