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Synthesis 2006(22): 3859-3864  
DOI: 10.1055/s-2006-950320
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Convenient and Efficient Synthesis of the First (Nitroimidazolyl)succinic Esters and their Diacids

Jesús Pacheco-Torresb, Elena Pérez-Mayorala, Elena Sorianob, Pilar López-Larrubiab, Olivier Ouaria, Araceli González-Cortésc, Sebastián Cerdánb, Paloma Ballesteros*a
a Laboratorio de Síntesis Orgánica e Imagen Molecular por Resonancia Magnética, Instituto Universitario de Investigación, UNED, Paseo Senda del Rey 9, 28040 Madrid, Spain
Fax: +34(91)3986697; e-Mail: pballesteros@ccia.uned.es;
b Laboratorio de Resonancia Magnética, Instituto de Investigaciones Biomédicas CSIC, c/ Arturo Duperier 4, 28029 Madrid, Spain
c Departamento de Química Analítica, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain
Further Information

Publication History

Received 10 July 2006
Publication Date:
12 October 2006 (online)

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Abstract

We report an easy and efficient synthetic approach to the first series of (nitroimidazolyl)succinic esters and diacids involving the Michael-type addition of the nitroimidazole to the α,β-unsaturated ester. Voltammetric measurements revealed similar redox potentials to those of previous nitroimidazoles used in hypoxia detection. Theoretical calculations were implemented to understand the mechanism of the addition.

Key words

nucleophilic addition - heterocycles - succinic acid derivatives - imidazoles - tumor hypoxia

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Reaction in absence of solvent using domestic microwave oven (Panasonic, 200 to 600 W).

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Gaussian 03, Revision B.03, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.; Gaussian, Inc., Pittsburgh PA, 2003.

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Michael addition of imidazole to dimethyl acetylenedicarboxylate was also carried out to give the corresponding Z/E-isomers 4c and 5c. Notably, results were the opposite when a mixture of 4c and 5c was refluxed in MeCN with of PTSA as catalyst, yielding the E-isomer 5c as the major reaction product.

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Diesters 6a,b were solubilized using small amounts of MeOH as co-solvent.