Tetrahedron Letters Tetrahedron Letters 46 (2005) 4103–4106 An efficient route to regioselective opening of N-tosylaziridines with zinc(II) halides Manas K. Ghorai,* Kalpataru Das, Amit Kumar and Koena Ghosh Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India Received 22 December 2004; revised 31March 2005; accepted 4 April 2005 Available online 22 April 2005 Dedicated to Dr. Ganesh Pandey on the occasion of his 50th birthday Abstract—An efficient route for the regio- and stereoselective ring opening of N-tosylaziridines with zinc dihalides (ZnX2, X = Cl, Br, I) is described. Depending on the solvent and Zn(II) halide, b-halo amines or imidazolines are obtained selectively in good to excellent yields. Ó 2005 Elsevier Ltd. All rights reserved. Aziridines are attractive as well as versatile building Zn(II) halides to give b-halo amines in good to excellent blocks, widely used for the syntheses of various natural yields. products and bioactive molecules.1 Regio- and stereo- selective ring opening reactions of aziridines with vari- To test our methodology, we synthesized N-tosylazir- ous nucleophiles have been exploited by several groups idines (1a–c, Scheme 1) following known literature for chemical transformations of contemporary interest.2 methods.14 As shown in Scheme 1, N-tosylaziridine 1 Although, several methods are known for the cleavage when subjected to our reaction conditions,15 gave ring of aziridines with a range of heteroatom3 and carbon opened 2 as the major product in very good yield. The nucleophiles,4 only a limited number of methods for results of the ring opening studies with various N-tosyl- regioselective nucleophilic ring opening by halide aziridines and ZnX2 (X = Cl, Br and I) are listed in Table 1. anions have been reported. These methods include using In the case of N-tosyl-2-phenylaziridine 1a (entries 1, HCl,5 metal halides,6 Amberlyst-15/LiCl,7 cerium(III) 5 and 9) only one regioisomer 2a was formed16 where 8 9 chloride, indium trihalides, BF3ÆOEt2 as a fluorine the halide ion attacked at the benzylic position and for- source,10 tetrabutylammonium halides in the presence mation of the other regioisomer 3 (Scheme 1) was not of b-cyclodextrin11 and an activated DMF complex.12 observed. In the case of N-tosylcyclohexene aziridine Most of these methodologies suffer from disadvantages 1b (entries 2, 6 and 10), the corresponding trans-halo such as long reaction times, formation of other insepar- amine 2b was formed in excellent yield. The trans stereo- able regioisomers, high temperature and pH dependence, chemistry of the product from 1b was established from etc. Hence, it is desirable to develop a mild and efficient the coupling constants of the ring protons. All the N- method for the regiospecific opening of substituted azir- tosylaziridines shown in Table 1 underwent nucleophilic idines to afford b-halo amines. Such halo amines are precursors for the syntheses of various biologically active molecules and also exhibit several biological Ts 13 X NHTs TsHN X activities. Herein, we describe a highly regioselective N ZnX2 ( X = Cl, Br, I ) + opening of activated aziridines by readily available 1 2 1 2 1 2 R R CH2Cl2, reflux R R R R 1 2 3 up to 88% 1 2 1 2 Keywords: Aziridine; Zinc(II) halide; b-Halo amine; [3+2] a : R = Ph, R = H; b : R , R = -(CH2)4- 1 2 1 2 Cycloaddition. c : R = Ph, R = CH2OTBDMS; d : R = CH2Ph, R = H * Corresponding author. Tel.: +91 512 2597518; fax: +91 512 2597436; e-mail: [email protected] Scheme 1. Reaction of N-tosylaziridines with zinc dihalides. 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.04.006 4104 M. K. Ghorai et al. / Tetrahedron Letters 46 (2005) 4103–4106 Table 1. Regioselective opening of various N-tosylaziridines with Zn(II) halides a b Entry Aziridine 1 ZnX2 Product 2 Time (h) Yield (%) Ratio 2:3 1 Ts Ph Cl N ZnCl2 186 >99:1 Ph H NHTs Cl 2 N Ts ZnCl2 5 82 >99:1 NHTs Ts Ph Cl N c 3 ZnCl2 3 65 (58:42) 86:14 Ph TBDMSO OTBDMS NHTs Ts Cl Ph d 4 N ZnCl2 128728:72 Ph H NHTs Ts Ph Br N 5 ZnBr2 183 >99:1 Ph H NHTs Br 6 N Ts ZnBr2 5 78 >99:1 NHTs Ts Ph Br N c 7 ZnBr2 2 52 (55:45) 82:18 Ph TBDMSO OTBDMS NHTs Ts NHTs Ph d 8 N ZnBr2 127318:82 Ph H Br Ts Ph I N 9 ZnI2 188 >99:1 Ph H NHTs I 10 N Ts ZnI2 186 >99:1 NHTs Ts Ph I N c 11 ZnI2 1 56 (81:19) >99:1 Ph TBDMSO OTBDMS NHTs a Isolated yield after column chromatographic purification. b The ratio was determined by 1H NMR analysis of the crude reaction mixture. c Isolated yield of 2 as a diastereomeric mixture and the diastereomeric ratio is given in parentheses. d Combined yield of isolated 2 and 3. ring opening with halide ions smoothly except for N-tos- We also studied the reaction in DCM, THF, CHCl3 and yl-2-benzylaziridine (entries 4 and 8), derived from CH3CN. Excellent yields of the product, with high reg- chiral L-phenylalanine, which reacted slowly and gave ioselectivity were found in DCM as the solvent. Interest- a low yield of 2. This can be attributed to the reduced ingly, the reaction of N-tosyl-2-phenylaziridine 1a with electrophilic nature at the homobenzylic position. In ZnX2 was very sensitive to solvent. In acetonitrile, the case of N-tosyl-2-phenylaziridine, the more stable b-chloro- or iodo- amines were isolated as the only carbocation type intermediate facilitates attack by the products when ZnCl2 or ZnI2 was used. Surprisingly, nucleophile at the benzylic position. In 1b ring strain substituted imidazoline 4 was obtained (Scheme 2, Table may be the driving force for the easy attack by the nucleo- 2) in good yield by a [3+2] cycloaddition reaction when 17 phile. When ZnI2 was used as the halogen source using ZnBr2 at reflux in acetonitrile. Similar cyloaddi- (entries 9–11), ring opening took place at room temper- tions of aziridines with nitriles but using boron com- ature within 1h. plexes have been reported earlier.18 The b-halo amines M. K. Ghorai et al. / Tetrahedron Letters 46 (2005) 4103–4106 4105 Ts R In conclusion, we believe that the described methodol- ogy using Zn(II) halides represents an important as well N ZnBr2 N N Ts R-CN as a convenient approach for the regiospecific opening Ph 80 oC, 1 h of N-tosylaziridines to give b-halo amines under extre- Ph 1a 4 mely mild reaction conditions. We have also demon- R = CH3, Ph 61-73% strated that ZnBr2 is a selective reagent for [3+2] cycloaddition of N-tosylaziridines with nitriles. Further Scheme 2. ZnBr2 promoted [3+2] cycloaddition of N-tosyl-2-phenyl- aziridine with nitriles. applications of our methodology are under active investigation. Table 2. ZnBr2 promoted [3+2] cycloaddition of N-tosyl-2-phenylaz- Acknowledgements iridine with nitriles Entry RCN ZnX2 Product Time (h) Yield (%) M.K.G. is grateful to IIT-Kanpur and DST, India, for CH financial support. K.D. thanks IIT–Kanpur, A.K. and 3 K.G. thank CSIR for their research fellowships. Ts 1CH 3CN ZnBr2 N N 161 Ph Supplementary data Ph Supplementary data associated with this article can be Ts 2 PhCN ZnBr2 N N 173 found, in the online version, at doi:10.1016/j.tetlet.2005. 04.006. Ph References and notes and cycloaddition products were characterized by 1H 13 NMR, C NMR and mass spectral data. Our strategy 1. (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599– is significant, compared to earlier reports, as we can con- 619; (b) McCoull, W.; Davis, F. A. Synthesis 2000, 1347– trol the direction taken by the reaction to produce either 1365. b-halo amines or substituted imidazolines simply by 2. Hu, X. E. Tetrahedron 2004, 60, 2701–2743, and references selecting a particular Zn(II) halide and solvent. cited therein. 3. (a) Chandrasekhar, S.; Narsihmulu, C.; Sultana, S. S. The mechanism for formation of the cycloaddition Tetrahedron Lett. 2002, 43, 7361–7363; (b) Prasad, B. A. product is rationalized in Scheme 3, where the aziridine B.; Sekar, G.; Singh, V. K. Tetrahedron Lett. 2000, 41, 4677–4679; (c) Bisai, A.; Pandey, G.; Pandey, M. K.; nitrogen is coordinated to ZnBr2 generating a highly Singh, V. K. Tetrahedron Lett. 2003, 44, 5839–5841; (d) reactive intermediate 5, which would then undergo a Furuta, Y.; Kumamoto, T.; Ishikawa, T. Synlett 2004, [3+2] cycloaddition reaction with nitriles to provide 362–364; (e) Petra, D. G. I.; Kamer, P. C. J.; Spek, A. L.; the substituted imidazoline 4. To support the mecha- Schoemaker, H. E.; van Leeuwen, P. W. N. M. J. Org. nism, we carried out the ring opening reaction of a chiral Chem. 2000, 65, 3010–3017; (f) Chakraborty, T. K.; aziridine, R-(À)-2-phenyl-1-(toluene-4-sulfonyl)aziri- Ghosh, A.; Raju, T. V. Chem. Lett. 2003, 32, 82–83; (g) dine. When it was treated with ZnX2 (X = Cl, Br and Duran, F.; Leman, L.; Ghini, A.; Burton, G.; Dauban, P.; I) in DCM, nonracemic b-halo amines were formed. Dodd, R. Org. Lett. 2002, 4, 2481–2483. 4. (a) Vicario, J. L.; Badia, D.; Carrillo, L. J. Org. Chem. Similarly, the same reaction in CH3CN as solvent in the presence of ZnBr also produced a nonracemic imi- 2001, 66, 5801–5807; (b) Nenajdenko, V.