Next Article in Journal
Synthesis and Antitumor Evaluation of Novel Derivatives of 6-Amino-2-phenylbenzothiazoles
Previous Article in Journal
Solvent Effects in Electrocoagulation of Selected Plant Pigments and Tannin
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 11
Issue 5
10.3390/11050318
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

A Handy and Solventless Direct Route to Primary 3-[3-Aryl)-1,2,4-oxadiazol-5-yl]propionamides Using Microwave Irradiation

by
Ricardo A.W. Neves, Filho
and
Rajendra M. Srivastava
*
Departamento de Química Fundamental, Universidade Federal de Pernambuco, 50.740-540 Recife, PE, Brazil
*
Author to whom correspondence should be addressed.
Molecules 2006, 11(5), 318-324; https://doi.org/10.3390/11050318
Submission received: 15 December 2005 / Revised: 24 March 2006 / Accepted: 5 May 2006 / Published: 9 May 2006
Browse Figures
Versions Notes

Abstract

:
A one-step, simple and straightforward synthesis of the title amides from the corresponding carboxylic acids, urea and imidazole under microwave irradiation is described.

Introduction

1,2,4 Oxadiazoles are well known compounds which exhibit diversified biological activities [1,2,3,4]. The work from our laboratory also cites other pharmacological properties previously reported by other researchers [5,6]. The analgesic and antiinflammatory effects of 5-methyl-3-phenyl-1,2,4-oxadiazole were discovered as early as in 1972 [7]. Incorporation of a carboxyl function into the C-5 side-chain of 1,2,4-oxadiazoles improves both analgesic and antiinflammatory properties [8]. Similar pharmacological properties have been displayed by carboxylic acid amides as well [9,10] and incorporation of a carboxylic acid derivative, like an amide, might result in different biological activity. For example, while lysergic acid is inactive, its N,N-diethylamide derivative (LSD) thoroughly changes the human behavior and causes psychic alterations and hallucinations at doses as low as 1mg/kg body weight [11]. Although the preparation of amides using conventional procedures is well documented [12,13], clean, fast and less cumbersome methods are less common. A literature search did reveal some reports of the preparation of amides using microwave radiation [14a-d-18], but mostly dealing with secondary and tertiary amides. Two reports describe preparation of primary amides, one employing carboxylic acid, imidazole and urea [19] and the other using carboxylic acid, urea and pyridine [20]. On the other hand 1,2,4-oxadiazoles containing a primary amide function in their C-5 side-chain have drawn practically no attention. Two companies market 3-[3-phenyl-1,2,4-oxadiazol-5-yl]propionamide (4a, [21a,b], but no experimental details are available. Because of the great significance of the amide functionality, we wished to develop a speedy, eco-friendly and solvent-free technique to obtain such compounds. Herein, we report the synthesis of six 3-[3-(aryl)-1,2,4-oxadiazol-5-yl]propionamides 4a-f under solvent-free conditions employing an unmodified domestic microwave oven [22] (Scheme 1). The reactions are clean, the work-up is simple and the yields are relatively high (Table 1).
Molecules 11 00318 g001 550
Scheme 1. Preparation of 4a-f from 1a-f and 2.
Scheme 1. Preparation of 4a-f from 1a-f and 2.
Molecules 11 00318 g001
Table
Table 1. Observed experimental results for the synthesis of 4a-f.
Table 1. Observed experimental results for the synthesis of 4a-f.
CompoundReactionTemp.(°C) aYield (%) bRf values cM.p (° C) d
4a130730.22175-176
4b110830.28124-125
4c117850.26122-123
4d115870.26168-169
4e110840.19174-175
4f120870.24161-162
a Temperature recorded by a Minipa model 350 infrared thermometer.
b Chromatographically pure material.
c Solvent system: 5.0:4.5:0.5 benzene-ethyl acetate-methanol.
d Crystallized from chloroform containing a little ethyl acetate.

Results and Discussion

Based upon previous suggestions concerning the reaction of a carboxylic acid and imidazole [14,23], Khalafi-Nezhad et al. [19] proposed the formation of an imidazolium carboxylate salt, which absorbs microwave energy. The energy increase then causes the decomposition of urea followed by proton exchange with the imidazolium ion and subsequent formation of a ammonium carboxylate salt which furnishes an amide. Aside from this, the mechanism of primary amide formation from an acid, imidazole and urea has not been discussed. To us, the decomposition of the ammonium carboxylate salt at a relatively low temperature and in such a short time seems difficult. In order to know whether an ammonium salt of a carboxylic acid is responsible for the amide formation, we took readily available ammonium benzoate and subjected it to microwave irradiation under conditions similar to those described earlier. Ammonium benzoate remained unchanged as verified by TLC and the melting point of the crystals. This indicates that ammonium salts is not responsible for primary amide formation in such a reaction. Therefore, we postulate a different mechanism, in which the highly reactive iminoketene 9, formed through reaction of urea with imidazolium ion, is the main agent in the transformation of the carboxylate into an amide: nucleophilic attack of the carboxylate on the iminoketene, followed by proton exchange with imidazolium ion results in 11 which, through a SNi reaction similar to the formation of acyl halides with SOCl2, gives the amide. This mechanism is more logical and is being proposed here for the first time (Scheme 2).
Molecules 11 00318 g002 550
Scheme 2. Mechanism of formation of primary amides 4a-f from 3a-f in the presence of imidazole and urea under microwave irradiation.
Scheme 2. Mechanism of formation of primary amides 4a-f from 3a-f in the presence of imidazole and urea under microwave irradiation.
Molecules 11 00318 g002

Conclusions

In summary, we have synthesized six primary amides 4a-f in six minutes using microwave energy. A new mechanism of formation of these amides from an acid, imidazole and urea is being proposed for the first time.

Experimental Section

General

Melting points were determined on an Electrothermal (Mel-Temp) apparatus (Model No. 1002D) and are uncorrected. All reactions were monitored by TLC analysis (TLC plates GF254 Merck). IR spectra were measured with a IFS66 Bruker spectrometer employing KBr disks. 1H-NMR spectra were recorded with a Varian Unity Plus 300 MHz spectrometer using SiMe4 as an internal standard. All reactions were conduced in a Sanyo domestic microwave oven model EM-300B (220v/650W/2450 MHz).

General Synthetic Procedure

An appropriate arylamidoxime 1a-f (1.0 mmol) was allowed to react with succinic anhydride (2, 1.1 mmol) in a domestic microwave oven following the procedure reported earlier to afford 3a-f [22]. A mixture of an appropiate acid 3a-f (1.0 mmol), imidazole (1.5 mmol) and urea (3.0 mmol) were well triturated and placed in a small glass test tube followed by irradiation for 6.0 min. in an unmodified domestic microwave oven (50% power) and then cooled. The solid was treated with ethyl acetate and filtered to remove the insoluble material. TLC analysis (elution with 5.0:4.5:0.5 benzene-ethyl acetate-methanol, followed by visualization under ultraviolet light) showed spots with Rf values ranging from 0.19-0.28. The product dissolved in ethyl acetate was applied to a thick-layer chromatographic plate and developed with the above-mentioned solvent mixture. Work-up furnished chromatographically pure primary amides 4a-f. The main experimental details for each case are compiled in Table 1.

Spectral and Analytical Data of Compounds 4a-f

3-[3-Phenyl-1,2,4-oxadiazol-5-yl]propionamide (4a): IR: ν 3500 (N-H, asymm.), 3250 (N-H, symm.), 1693 (C=O) cm-1; 1H-NMR (CDCl3): δ 2.86 (t, 2H, J = 7.2 Hz, CH2-7), 3.31(t, 2H, J = 7.2 Hz, CH2-6), 5.45 and 5.66 (2bs, 2H, NH2), 7.40–7.54 (m, 3H, arom.), 7.80-8.08 (m, 2H, arom.); Anal. calcd. for C11H11O2N3: C, 60.82, H, 5.10, N, 19.34. Found: C, 61.05, H, 5.51, N, 19.42.
3-[3-(o-Tolyl)-1,2,4-oxadiazol-5-yl]propionamide (4b): IR: ν 3436 (N-H, asymm.), 3250 (N-H, Symm), 1695 (C=O) cm-1; 1H-NMR (CDCl3): δ 2.61 (s, 3H, CH3), 2.86 (t, 2H, J = 7.2Hz, CH2-7), 3.31 (t, 2H, J = 7.2 Hz, CH2-6), 5.55 and 5.70 (2bs, 2H, NH2), 7.29-7.41 (m, 3H, arom.), 7.94 (d, 1H, J= 9.3Hz, arom.); Anal. calcd. for C12H13O2N3: C, 62.33, H, 5.67, N, 18.17. Found: C, 62.22, H, 5.93, N, 18.56.
3-[3-(m-Tolyl)-1,2,4-oxadiazol-5-yl]propionamide (4c): IR: ν 3347 (N-H, asymm.), 3250 (N-H, symm.), 1694 (C=O) cm-1; 1H-NMR (CDCl3): δ 2.42 (s, 3H, CH3), 2.85 (t, 2H, J = 7.2 Hz, CH2-7), 3.30 (t, 2H, J = 7.2 Hz, CH2-6), 5,71 and 5,78 (2bs, 2H, NH2), 7.26 -7.39 (m, 2H, arom.), 7.80-8.00 (m, 2H, arom.); Anal. calcd. for C12H13O2N3: C, 62.33, H, 5.67, N, 18.17. Found: C, 62.40, H, 5.71, N, 17.98.
3-[3-(p-Tolyl)-1,2,4-oxadiazol-5-y]propionamide (4d): IR: ν 3323 (N-H, asymm.), 3250 (N-H, symm.), 1693 (C=O) cm-1; 1H-NMR (CDCl3): δ 2.41 (s, 3H, CH3 ), 2.85 (t, 2H, J = 7.2 Hz, CH2-7), 3.29 (t, 2H, J = 7.2 Hz, CH2-6), 5.46 and 5.70 (2bs, 2H, NH2), 7.28 (d, 2H, J = 7.2 Hz, H-3' & H-5'), 7.93 (d, 2H, J = 7.2 Hz, H-2' & H-6'); Anal. calcd. for C12H13O2N3: C, 62.33, H, 5.67, N, 18.17. Found: C, 62.36, H, 5.69, N, 18.20.
3-[3-(4-Anisyl)-1,2,4-oxadiazol-5-yl]propionamide (4e): IR: ν 3339 (N-H, asymm.), 3250 (N-H, symm.), 1693 (C=O) cm-1; 1H-NMR (CDCl3): δ 2.85 (t, 2H, J = 7.2 Hz, CH2-7), 3.29 (t, 2H, J = 7.2 Hz, CH2-6), 3.87 (s, 3H, CH3O-), 5.39 and 5.69 (2bs, 2H, NH2), 6.78 (d, 2H, J = 9.0 Hz, H-3' & H-5', arom.), 7.99 (d, 2H, J = 9.0 Hz, H-2' & H-6', arom.); Anal. calcd for C12H13O3N3: C, 58.29, H, 5.30, N, 16.99. Found: C, 58.61, H, 5.41, N, 17.01.
3-[3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl]propionamide (4f): IR: ν 3350 (N-H, asymm.), 3250 (N-H, symm.), 1669 (C=O) cm-1; 1H-NMR (DMSO-d6): δ 2.68 (t, 2H, J = 7.2 Hz, CH2-7), 3.16 (t, 2H, J = 7.2 Hz, CH2-6), 6.85 and 7.49 (2bs, 2H, NH2), 7.77 (d, 2H, J = 8.4 Hz, H-3' & H-5', arom.), 7.92 (d, 2H, J = 8.4 Hz, H-2' & H-6', arom.); Anal. calcd. for C11H10O2N3Br: C, 44.62, H, 3.40, N, 14.19. Found: C, 44.81, H, 3.68, N, 14.00.

Acknowledgments

The authors express their gratitude to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for financial assistance; one of us (R.A.W.N.F.) extends his thanks to CNPq for an undergraduate fellowship (August 2004 to present).

References and Notes

  1. Clapp, L.B. “Advances in Heterocyclic Chemistry”; Katritzky, A.R., Ed.; Academic Press: New York, 1976; Volume 20, pp. 65–116. [Google Scholar]
  2. Clapp, L.B. “Comprehensive Heterocyclic Chemistry”; Katritzky, A.R., Rees, C.W., Eds.; Pergamon Press: Oxford, 1984; Volume 6, pp. 365–391. [Google Scholar]
  3. Jochims, J.C. “Comprehensive Heterocyclic Chemistry II”; Katritzky, A.R., Rees, C.W., Scriven, E.F.D., Eds.; Elsevier Science: Oxford, 1996; Volume 4, pp. 179–228. [Google Scholar]
  4. Hemming, K. Recent developments in the synthesis, chemistry and applications of the fully unsaturated 1,2,4- oxadiazoles. J. Chem. Res. 2001, 216, 209–216. [Google Scholar] [CrossRef]
  5. Antunes, R.; Batista, H.; Srivastava, R.M.; Thomas, G.; Araújo, C.C.; Longo, R.L.; Magalhães, H.; Leão, M.B.C.; Pavão, A.C. Synthesis, characterization and interaction mechanism of new oxadiazolo-phthalimides as peripheral analgesics. IV. J. Mol. Struct. 2003, 600, 1–13. [Google Scholar] [CrossRef]
  6. Srivastava, R.M.; Morais, L.P.F.; Catanho, M.T.J.A.; Souza, G.M.L.; Seabra, G.M.; Simas, A.M.; Rodriguez, M.A.L. Synthesis and antiinflammatory activity of 3-aryl-5-isopropyl-1,2,4-oxadiazoles. Heterocycl. Commun. 2000, 6, 41–48. [Google Scholar]
  7. Dahlgren, S.E.; Dalhamn, T. Antiinflammatory action of phenyl-methyl-oxadiazole (pmo) - experimental study on guinea-pig trachea. Acta Pharmacol. Toxicol. 1972, 31, 193–202. [Google Scholar] [CrossRef]
  8. Afiatpour, P.; Srivastava, R.M.; de Oliveira, M.L.; Barreiro, E.J. Analgesic and antiinflammatory effects of 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid. Braz. J. Med. Biol. Res. 1994, 27, 1403–1406. [Google Scholar] [PubMed]
  9. Glushkov, V.A.; Anikina, L.V.; Vikharev, Y.B.; Stryapunina, O.G.; Shklyaev, Y.V.; Tolstikov, A.G. Synthesis and antiinflammatory activity of N-[2-(p-hydroxyphenyl)-1,1-dialkylethyl]-α-dialkylamino acetamides. Pharm. Chem. J. 2004, 38, 86–89. [Google Scholar] [CrossRef]
  10. Sladowska, H.; Sieklucka-Dziuba, M.; Rajtar, G.; Sodowski, M.; Kleinrok, Z. Investigations on the synthesis and pharmacological properties of amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]-pyrimidine-5-carboxylic acid. Il Farmaco 1999, 54, 773–779. [Google Scholar]
  11. Sanders-Bush, E.; Mayer, S.E. “Goodman & Gilman’s” The Pharmacological Basis of Therapeutics, 10th International Edition; Hardman, J.G., Linbird, L.E., Eds.; McGraw-Hill: New York, 2001; pp. 284–285. [Google Scholar]
  12. Benz, G. Comprehensive Organic Synthesis; Trost, B.M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Volume 6, pp. 381–418. [Google Scholar]
  13. Smith, M.B.; March, J. March’s Advanced Organic Chemistry. Reactions, Mechanisms and Structure, Fifth Edition; John Wiley & Sons: New York, 2001; pp. 506–513. [Google Scholar]
  14. Baldwin, B.W.; Hirose, T.; Wang, Z.-H. Improved microwave oven synthesis of amides and imides promoted by imidazole; convenient transport agent preparation. Chem. Commun. 1996, 2669–2670. [Google Scholar] Vasquez-Tato, M.P. Microwave-mediated synthesis of amides. Synlett 1993, 506. [Google Scholar] Gelens, E.; Smeets, L.; Sliedregt, L.A.J.M.; van Steen, B.J.; Kruse, C.G.; Leurs, R.; Orru, R.V.A. An atom efficient and solvent-free synthesis of structurally diverse amides using microwaves. Tetrahedron Lett. 2005, 45, 3751–3754. [Google Scholar] Gorelski, C.; Krlej, A.; Steffens, C.; Ritter, H. Microwave-assisted single-step synthesis of various (meth)acrylamides and poly(meth)acrylamides directly from (meth)acrylic acid and amines. Macromol. Rapid Commun. 2004, 25, 513–516. [Google Scholar]
  15. Varma, R.S.; Naicker, K.P. Solvent-free synthesis of amides from non-enolizable esters and amines using microwave irradiation. Tetrahedron Lett. 1999, 40, 6177–6180. [Google Scholar] [CrossRef]
  16. Chen, J.J.; Deshpande, S.V. Rapid synthesis of alpha-ketoamides using microwave irradiation-simultaneous cooling method. Tetrahedron Lett. 2003, 44, 8873–8876. [Google Scholar] [CrossRef]
  17. Perreux, L.; Loupy, A.; Volatron, F. Solvent-free preparation of amides from acids and primary amines under microwave irradiation. Tetrahedron 2002, 58, 2155–2162, and references cited therein. [Google Scholar]
  18. Sauer, D.R.; Kalvin, D.; Phelan, K.M. Microwave-assisted synthesis utilizing supported reagents: a rapid and efficient acylation procedure. Org. Lett. 2003, 5, 4721–4724. [Google Scholar] [CrossRef] [PubMed]
  19. Khalafi-Nezhad, A.; Mokhtari, B.; Rad, M.N.S. Direct preparation of primary amides from carboxylic acids and urea using imidazole under microwave irradiation. Tetrahedron Lett. 2003, 44, 7325–7328. [Google Scholar]
  20. Pasha, M.A.; Jayashankara, V.P. Synthesis of amides from carboxylic acids and urea in the presence of pyridine under microwave irradiation. J. Ind. Chem. Soc. 2005, 82, 675–676. [Google Scholar]
  21. a) InterBioScreen Ltd., P.O. Box 218, Moscow, Russia, publication date: Mar. 15, 2005; b) ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego, CA, 92127, U.S.A. ChemBridge Screening Library, publication date: Jan. 12, 2005.
  22. We have taken precautions to ensure that the results are reproducible. We first determined the region inside the microwave oven where the heating was the maximum using water samples and recording the temperatures with an infrared thermometer. After doing this, we repeated the reaction and got the same results. In our opinion, the reactions can be repeated easily without any problem by any chemist
  23. Rault, P.; Pilard, J.; Touaux, B.; Texier-Boullet, F.; Hamelin, J. Rapid generation of amines by microwave irradiation of ureas dispersed on clay. Synlett 1994, 935–936. [Google Scholar]
  24. Srivastava, R.M.; Seabra, G.M. Preparation and reactions of 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propionic acids. J. Braz. Chem. Soc. 1997, 8, 397–405. [Google Scholar]
  • Sample availability: Please contact the authors.

Share and Cite

MDPI and ACS Style

Neves, R.A.W., Filho; Srivastava, R.M. A Handy and Solventless Direct Route to Primary 3-[3-Aryl)-1,2,4-oxadiazol-5-yl]propionamides Using Microwave Irradiation. Molecules 2006, 11, 318-324. https://doi.org/10.3390/11050318

AMA Style

Neves RAW Filho, Srivastava RM. A Handy and Solventless Direct Route to Primary 3-[3-Aryl)-1,2,4-oxadiazol-5-yl]propionamides Using Microwave Irradiation. Molecules. 2006; 11(5):318-324. https://doi.org/10.3390/11050318

Chicago/Turabian Style

Neves, Ricardo A.W., Filho, and Rajendra M. Srivastava. 2006. "A Handy and Solventless Direct Route to Primary 3-[3-Aryl)-1,2,4-oxadiazol-5-yl]propionamides Using Microwave Irradiation" Molecules 11, no. 5: 318-324. https://doi.org/10.3390/11050318

APA Style

Neves, R. A. W., Filho, & Srivastava, R. M. (2006). A Handy and Solventless Direct Route to Primary 3-[3-Aryl)-1,2,4-oxadiazol-5-yl]propionamides Using Microwave Irradiation. Molecules, 11(5), 318-324. https://doi.org/10.3390/11050318

Article Metrics

Back to TopTop