Beckmann Rearrangement of Oximes under Very Mild Conditions Lidia De Luca, Giampaolo Giacomelli,* and Andrea Porcheddu Dipartimento di Chimica, Universita ` degli Studi di Sassari, Via Vienna 2, I-07100 Sassari, Italy ggp@uniss.it Received May 23, 2002 Abstract: A variety of ketoximes, easily prepared from the corresponding ketones, undergo the Beckmann rearrange- ment upon treatment with 2,4,6-trichloro[1,3,5]triazine in N,N-dimethylformamide at room temperature in excellent yields. This procedure can be applied to aldoximes for obtaining the corresponding nitriles. The rearrangement of ketoximes to the corresponding amide, known as the Beckmann reaction, is a common method in organic chemistry 1 and is a topic of current interest. It accomplishes in one stroke both the cleavage of a carbon-carbon bond and the formation of a carbon- nitrogen bond. It represents a powerful method particu- larly for manufacturing ǫ-caprolactam in the chemical industry. The reaction generally requires high reaction temperatures and strongly acidic and dehydrating me- dia. 1 Thus, the reaction can lead to large amounts of byproducts and preclude its application to sensitive substrates. On these bases milder conditions were tried and several interesting variants developed. 2,3 Recently the Beckmann rearrangement was reported to occur in ionic liquids at room temperature. 4 Nevertheless until now the occurrence of mild conditions was related to the use of rather toxic solvents and expensive reagents or solvents. As part of an ongoing program directed to the develop- ment of efficient reagents for use under mild conditions and following our latest interest in the use of [1,3,5]- triazine derivatives in organic synthesis, 5 we report a very mild and selective procedure for the quantitative conversion of ketoximes into the corresponding amides. The procedure is based on the reaction of a complex formed by 2,4,6-trichloro[1,3,5]triazine (cyanuric chloride, TCT), a very inexpensive reagent, and DMF, 6 with a DMF solution of 1 mol equiv of the ketoxime (Scheme 1). 7 The complex is easily prepared by dissolving the TCT in the least volume of commercial DMF at room temper- ature, 8 followed by the addition of the oxime 9 in DMF, after disappearance of free TCT (TLC monitoring). The mixture is stirred at room temperature for the required time and then quenched with water. The triazine byprod- ucts are then removed by aqueous workup. The corre- sponding amides can be recovered chemically pure in high yields (Table 1) without any purification. The reaction is reasonably fast (less than 4 h) only with acetophenone and cyclohexanone oximes and requires almost 24 h for completion in most of the cases. However, this method can be successfully applied on a large scale. Moreover no deoximation of the oximes to carbonyl compounds occurs. On examination of Table 1 some observations can be made. In all cases only one of the two possible amides were recovered. Contrary to what was observed in most of the conventional Beckmann rearrangement, 1 electron- donating groups on the aromatic ring seem to reduce the reaction rate, in particular when the substituent is on the ortho-para positions (runs 2, 3, and 4). Generally, migration of an aryl group predominates over that of an alkyl group. However, in the case of both tert-butyl phenyl ketone oxime and the oxime of 3,3-dimethylbutan- 2-one (runs 8 and 9) the rearrangement gives rise to migration of the tert-butyl group. Moreover the results obtained suggest that the stereochemistry of the oximes has very little effect on the reaction as in other Beckmann rearrangements. 10 The results obtained with the oximes of cyclic ketones are noteworthy and indicate a simple and mild approach to lactams 11 which are particularly important molecules as synthetic intermediates for biologically important compounds. 12 The conversion of the cyclohexanone oxime (1) Gawly, R. E. Org. React. 1988, 35, 1 and references therein. Smith, M. B.; March, J. In Advanced Organic Chemistry, 5th ed.; John Wiley & Sons: New York, 2001; p 1415 and references therein. (2) Arisawa, M.; Yamaguchi, M. Org. Lett. 2001, 3, 311. Kikugawa, Y.; Tsuji, C.; Miyazawa, E.; Sakamoto, T. Tetrahedron Lett. 2001, 42, 2337. Anilkumar, R.; Chandrasekhar, S. Tetrahedron Lett. 2000, 41, 5427. Sato, H.; Yoshioka, H.; Izumi, Y J. Mol. Catal. A: Chemical 1999, 149, 25. Laurent, A.; Jacquault, P.; Di Martino, J. L.; Hamelin, J. J. Chem. Soc., Chem. Commun. 1995, 1101. (3) Thakur, A. J.; Boruah, A.; Prajapati, D.; Sandhu, J. S. Synth. Commun. 2000, 30, 2105. (4) Peng, J.; Deng, Y. Tetrahedron. Lett. 2001, 42, 403. Ren, R. X.; Zueva, L. D.; Ou, W. Tetrahedron. Lett. 2001, 42, 8441. (5) (a) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett. 1999, 40, 4395. (b) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J. Org. Chem. 1999, 64, 8962. (c) Falchi, A.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Synlett 2000, 275. (d) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66, 2534. (e) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 1519. (f) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041. (g) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2001, 66, 7907. (h) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553. (i) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, in press. (6) (a) Gold, H. Angew. Chem. 1960, 72, 956. (b) Gupton, J. T.; Colon, C.; Harrison, C. R.; Lizzi, M. J.; Polk, D. E. J. Org. Chem. 1980, 45, 4522. (7) No reaction was observed operating with solvents different from DMF, such as dichloromethane or THF. Furthermore, the reaction rate decrease noticeably operating with a reduced amount of TCT with respect to the oxime. (8) No gas evolution (CO 2) was noted. (9) The oximes were either obtained from commercial sources or prepared by standard procedures. No separation of the E:Z isomer was made. (10) Probably the E- and Z-oximes interconvert under the reaction conditions (see also ref 13). (11) Evans, P. A.; Modi, D. P. J. Org. Chem. 1995, 60, 6662. SCHEME 1 6272 J. Org. Chem. 2002, 67, 6272-6274 10.1021/jo025960d CCC: $22.00 © 2002 American Chemical Society Published on Web 07/25/2002