Synthesis of 1-benzoyl-3-alkylthioureas by transamidation under microwave in dry media

Article abstract of DOI:10.1016/S0040-4039(00)00047-2

1-Benzoyl-3,3-diethylthiourea was transamidated with several amines to the corresponding 1-benzoyl-3-alkylthioureas in open vessels under microwave irradiation using a domestic oven. The syntheses were performed in solvent- free conditions on potassium fluoride impregnated alumina. Yields were dramatically improved in comparison with classical heating under the same conditions. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00047-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1753–1756
Synthesis of 1-benzoyl-3-alkylthioureas by transamidation under
microwave in dry media†
Heiddy Márquez,a Eduardo R. Pérez,a Ana M. Plutín,a Margarita Morales a and
André Loupy b,∗
aLaboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, 10400, La Habana, Cuba
bLaboratoire des Réactions Sélectives sur Supports, ICMO, UMR 8615, Bât. 410, Université Paris-Sud, 91405 Orsay Cédex,
France
Received 19 November 1999; accepted 24 December 1999
Abstract
1-Benzoyl-3,3-diethylthiourea was transamidated with several amines to the corresponding 1-benzoyl-3-
alkylthioureas in open vessels under microwave irradiation using a domestic oven. The syntheses were performed
in solvent-free conditions on potassium fluoride impregnated alumina. Yields were dramatically improved in
comparison with classical heating under the same conditions. © 2000 Published by Elsevier Science Ltd. All
rights reserved.
The chemistry of organic sulfur compounds such as thioureas, has been developed with increasing
interest due to their important biological activities.1,2 Classical methods to obtain thiourea-like com-
pounds show several difficulties involving very toxic isothiocyanates and some undesirable effects of the
solvents. Also these reactions are classically carried out under refluxing conditions for long durations
frequently with some decomposition of the reagents or products.
During the last years, ‘non-classical’ methods have been developed in organic synthesis in order
to improve both yields, selectivity and experimental conditions.3 Especially the use of microwave
technology in conjunction with the use of solvent-free conditions allows expeditious and efficient
procedures in organic synthesis.4–7 The salient features of these high yield protocols lie in enhanced
reaction rates, higher purity of products and very simplified ease of manipulation and work-up. They
clearly constitute an eco-friendly ‘green’ approach.8
In the present work, we report the synthesis of 1-benzoyl-3-alkylthioureas 2 by a transamidation pro-
cedure under microwave irradiation in dry media using several inorganic solid supports as a convenient
and efficient way to prepare these classes of organic compounds (Scheme 1).
∗
†
Corresponding author. Fax: 33-1-69-15-46-79; e-mail: aloupy@icmo.u-psud.fr (A. Loupy)
This paper is dedicated to the memory of Professor Yolanda Rodríguez Esteva (Universidad de La Habana).
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00047-2
tetl 16327

1754
Scheme 1.
Microwave experiments were carried out testing several inorganic supports in order to achieve
the best yields avoiding decomposition of both reagents and products. The support/substrate relative
amounts were previously optimized. Experiments were replicated in order to ensure reproducibility.
Final temperatures were measured immediately after the reaction using a glass thermometer. In order
to check the possible intervention of specific (non-purely thermal) microwave effects, the reactions were
also carried out using a thermostated oil bath at 95–100°C with the same reaction medium and conditions
as under microwave.
Table 1 shows the most significant results obtained in the synthesis of 2a (R1=H, R2=CH2C6H5) under
microwave irradiation using several supports in dry media. The best yield (81% in isolated product) was
reached using potassium fluoride impregnated on alumina as support.9 Experiments performed at higher
output power and for longer exposure times were unsuccessful (no higher yields were observed and more
decomposition products were detected by TLC analysis of the reaction mixtures). Yields were determined
from isolated products.10
Table 1
Synthesis of 2a under microwaves (power 560 W) using several inorganic supports (1 g), by reacting
equivalent amounts of 1 and benzylamine (2 mmol)
Experiments performed in a thermostated oil bath lead to low yields as shown in Table 2, with the
starting materials and decomposition products as the complements.
The results shown in Table 2 allow us to propose the microwave–dry media coupled method with
potassium fluoride impregnated alumina as an efficient and selective technique to prepare the 1-benzoyl-
3-alkyl thioureas 2a–f by the transamidation reaction. A strong specific non-thermal microwave effect
was evidenced as yields were incremented from 4–35% to 69–90%.

1755
Table 2
Comparison between microwave and oil bath (95–100°C) for synthesis of 2a–f
We could suggest two explanations for the improvement achieved with this method both on product
yields and reaction selectivity:
(i) The more polar charged intermediates could have a strong microwave absorption with a conse-
quent rise of temperature which accelerates the formation of very polar and volatile diethylamine
(bp=55°C) and also avoids the reversibility of the process.
(ii) The second effect could be the strong basicity of KF-alumina. Whereas benzoylthiourea 1 is more
acidic (generating thus the polydentate anion 3), its ionization does not lead to any reaction. On the
other hand, ionization of the amines (or at least weakening of N–H bond due to hydrogen bonding)
can take place and then induce activation of amine nucleophilicity9,13 (Scheme 2).
Scheme 2.
In short, we have described an alternative efficient method to obtain 1-benzoyl-3-alkyl
thioureas which does not present the selectivity problems associated with direct alkylations of the
benzoylthioureas.14

1756
References
1. Ramadas, K.; Suresh, G.; Janarthanan, N. Pestic. Sci. 1998, 52, 145.
2. Liu, S.Q.; Tang, C.; Ho, B. J. Med. Chem. 1998, 41, 4693.
3. Chemistry under extreme or non-classical conditions; Van Eldik, R.; Hubbard, C. D., Eds.; J. Wiley & Sons: New York,
1996.
4. Bram, G.; Loupy, A.; Villemin, D. In Solid Supports and Catalysts in Organic Synthesis; Smith, K., Ed.; Ellis Horwood,
PTR Prentice Hall: Chichester, 1992, 302.
5. Pérez, E. R.; Marrero, A. L.; Pérez, R.; Autié, M. A. Tetrahedron Lett. 1995, 36, 1779.
6. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathé, D. Synthesis 1998, 1213.
7. Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A.; Tetrahedron 1999, 55, 10851.
8. Varma, R. S. Green Chemistry 1999, 1, 43.
9. Clark, J. M. Chem. Rev. 1980, 80, 429.
10. Typical procedure: 1-benzoyl-3,3-diethylthiourea 1 (2 mmol) was dissolved in acetone. An equimolar amount of the
indicated amines were then added and the mixture then smoothly mixed with 1 g of KF-alumina. The solvent was removed
under reduced pressure. The resulting mixture was placed into a Pyrex-glass open vessel and irradiated in a microwave
domestic oven at 560 W for the times and final temperatures as indicated in Tables 1 and 2. The products were extracted
from the support with acetone and precipitated with ice water.
11. Plutín, A. M. M.Sc. Thesis Estudio de la alquilación de un sistema polidentado: 1-aciltioureas — 3,3-disustituidas;
University of Havana, Cuba, 1997.
12. Elmore, D. T.; Ogle, J. R. J. Chem. Soc. 1958, 1141.
13. Villemin, D.; Ricard, M. Tetrahedron Lett. 1984, 25, 1059.
14. Rodríguez, Y.; Cardeñas, M.C.; Plutín, A. M.; Macías, A.; Del Bosque, J. R. An. Quím. 1995, 91, 696.