Efficient microwave induced direct alpha-halogenation of carbonyl compounds Jong Chan Lee,* Jin Young Park, So Young Yoon, Yong Hun Bae and Seung Jun Lee Department of Chemistry, Chung-Ang University, Seoul 156-756, South Korea
Tetrahedron Letters 45 (2004) 191–193
DOI:
10.1016/j.tetlet.2003.10.133
Full-text PDF:
AbstractA novel and direct method for the synthesis of
alpha-halocarbonyl compounds using sequential treatment of carbonyl compounds with [hydroxy(tosyloxy)iodo]benzene followed by magnesium halides under solvent-free microwave irradiation conditions is described.
Keywords: carbonyl compounds; halogenation ; hypervalent iodine sulfonates ; magnesium halides ; solvent- free microwave heating.
alpha-Haloketones are among the most versatile intermediates in organic synthesis and their high reactivity makes them prone to react with large number of nucleophiles to provide a variety of useful compounds.
1 Direct conversion of carbonyl compounds into
alpha-halocarbonyl compounds is a very important synthetic transformation that has been received considerable attention. Generally the direct conversion to
alpha-chloroketones from ketones can be accomplished by using chlorination agents such as copper(II) chloride,
2 sulfuryl chloride,
3 p-toluenesulfonyl chloride,
4 N-chlorosuccinimide,
5 and tetraethylammonium trichloride.
6 alpha-Bromination of ketones can be achieved using various reagents which include bromine,
7 copper(II) bromide,
8 N-bromosuccinimide,
5 and tetrabutylammonium tribromide.
9 In addition,
alpha-iodination of ketones is commonly achieved using iodine–cerium(IV) ammonium nitrate,
10 iodine–mercury( II) chloride,
11 and iodine–selenium dioxide.
12 However, these methods suffer from drawbacks such as long reaction times, use of hazardous chemicals, and cumbersome workup procedures. Furthermore, most of these methods generally employed strongly acidic or basic conditions, which accompanied by undesirable formation of
alpha, alpha-dihalogenated products in signi?cant amount. Recently a lot of effort has been made to the development of new effcient reaction conditions on the
alpha-halogenation reactions of 1,3-dicarbonyl compounds. For example, combination of magnesium perchlorate with N-halosuccinimide has been recently demonstrated to be as effective for
alpha-halogenation of 1,3-dicarbonyl compounds.
13In the last decade, microwave promoted reactions under solvent-free conditions have received considerable attention as a powerful technique to effect various organic transformations.
14 Very recently, microwave induced
alpha-bromination of ketones achieved under solvent-free conditions by use of dioxane–dibromide in combination with silica gel.
15 In addition, we recently reported the use of N-iodosuccinimide and p-toluenesulfonic acid for facile microwave induced
alpha-iodination of ketones.
16 However, to the best of our knowledge, method for
alpha-chlorination of carbonyl compounds under solvent-free microwave irradiation conditions has been unprecedented to date.
Hypervalent iodine compounds received continuous attention in organic synthesis and amongst these, [hydroxy(tosyloxy)iodo]benzene (Koser's reagent, HTIB) has been most commonly employed in numerous organic transformations.
17 In continuation of our research on application of hypervalent iodine(III) sulfonates to microwave promoted solvent-free reactions, we now wish to report the ?rst method that can be generally applicable to
alpha-chlorination as well as
alpha-bromination and
alpha-iodination of carbonyl compounds under solventfree microwave irradiation conditions, which involves sequential reaction of the carbonyl compounds with HTIB and followed by MgX
2 (X = Br, Cl, and I). The reactions were carried out by treating neat ketones with 1.2 equiv of HTIB under microwave irradiation and subsequent microwave irradiated reaction of preformed
alpha-tosyloxyketone intermediates with 2.0 equiv of magnesium halides (Scheme 1). When the reactions were performed using sodium, potassium, and zinc halides in place of magnesium halides, the yields of reactions were signi?cantly reduced with increased impurities. Presumably this result can be explained by superior coordinating ability of magnesium toward both carbonyl oxygen and sulfonate oxygen. A variety of arylmethylketones, arylmethyleneketones, and cyclic ketones were reacted well under the present reaction conditions to give the corresponding
alpha-halogenated ketones in good to excellent yields. The results of our studies are shown in Table 1. All of the reactions studied were completed in less than 4 min. Both
alpha-chlorination and
alpha-bromination reactions were accomplished equally well along with somewhat reduced yields in cases of
alpha-iodination as demonstrated in Table 1. We next explored the scope of the present method by treating 1,3-dicarbonyl compounds at present reaction conditions. As shown in Table 1 (entries 9–12), the reactions were highly successful to give
alpha-halogenated 1,3-dicarbonyl compounds with high yields in short reaction times. Therefore, we have developed the ?rst method for the microwave promoted efficient preparation of
alpha-chlorocarbonyl compounds under solvent- free conditions. In addition, the yields of
alpha-brominated and
alpha-iodinated compounds obtained in this study are superior or comparable to those obtained from the other previously reported microwave induced
alpha-bromination and
alpha-iodination methods.
15;16 General experimental procedure is as follows: A carbonyl compound (1.0 mmol) and HTIB (0.470 g, 1.2 mmol) were mixed and placed in a 50mL of glass tube. The reaction mixture was inserted in an alumina bath inside household microwave oven
and irradiated at the power of 700W three times for a period of 30 s with 20 s intervals. After cooled down the reaction mixture to room temperature, a magnesium halide (2.0 mmol) was added and additionally irradiated for two times for a period of 60 s with 20 s interval. The reaction mixture was extracted with dichloromethane (2 x 25mL) and washed with water (40 mL). The dichloromethane layer was separated and dried over MgSO4. After evaporation of the solvent, the residue was puri?ed by ?ash column chromatography (SiO
2, methylene chloride) to give pure
alpha-halocarbonyl compound.
In conclusion, we have developed a new and effcient method for the
alpha-halogenation of carbonyl compounds using commercially available reagents under solvent-free microwave irradiation conditions. The advantages of the present method in terms of ease of manipulation, fast reaction rates, and formation of cleaner products under neutral reaction conditions should make this protocol as a valuable alternative to the existing methods.
AcknowledgementsThis work was supported by a grant from the Korea Research Foundation (KRF-2002-015-CP0217).
References and Notes1. De Kimpe, N.;Verheé, R. In
The Chemistry of alpha- Haloketones, alpha-Haloaldehydes and alpha-Haloimines ;Patai,S., Rappoport, Z., Eds.; John Wiley: Chichester, UK, 1988 ; pp 1–119.
2. Kosower, E. M. ; Cole, W. J. ; Wu, G.-S. ; Cardy, D. E. ; Meisters, G.
J. Org. Chem. (1963) 28, 630.
3. Warnhoff, E. W. ; Martin, D. G. ; Johnson, W. S.
Org. Synth. Coll. IV (1963) 162.
4. Brummond, K. M. ; Gesenberg, K. D.
Tetrahedron Lett. (1999) 40, 2231.
5. Lee, J. C. ; Bae, Y. H. ; Chang, S.-K.
Bull. Korean Chem. Soc. (2003) 24, 407.
6. Schlama, T. ; Gabriel, K. ; Gouverneur, V. ; Mioskowski, C.
Angew. Chem., Int. Ed. Engl. (1997) 36, 2342.
7. Pearson, D. I.;Poper, H. W.;Hargrove, W. E.
Org. Synth. (1973) V, 117.
8. King, L. C. ; Ostrum, G. K.
J. Org. Chem. (1964) 29, 3459.
9. Kajigaeshi, S.; Kakinami, T. ; Okamoto, T. ; Fujisaki, S.
Bull. Chem. Soc. Jpn. (1987) 60, 1159.
10. Horiuchi, C. A. ; Kiji, S.
Chem. Lett. (1988) 31.
11. Barluenga, J. ; Martinez-Gallo, J. M. ; Najera, C. ; Yus, M.
Synthesis (1986) 678.
12. Bekaert, A. ; Barberan, O. ; Gervais, M. ; Brion, J.-D.
Tetrahedron Lett. (2000) 41, 2903.
13. Yang, D. ; Yan, Y.-L. ; Lui, B.
J. Org. Chem. (2002) 67, 7429.
14. (a) Loupy, A. ; Petit, A. ; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.;Mathé, D.
Synthesis (1998) 1213;
(b) Varma, R. S.
Green Chem. (1999) 1, 43;
(c) Lidstrom, P. ; Tierney, J. ; Wathey, B. ; Westman, J.
Tetrahedron (2001) 57, 9225.
15. Paul, S. ; Gupta, V. ; Gupta, R. ; Loupy, A.
Tetrahedron Lett. (2003) 44, 439.
16. Lee, J. C. ; Bae, Y. H.
Synlett (2003) 507.
17. (a) Koser, G. F. ; Relenyi, A. G. ; Kalos, A. N. ; Rebrovic, L. ; Wettach, R. H.
J. Org. Chem. (1982) 47, 2487;
(b) Koser, G. F.
Aldrichim. Acta (2001) 34, 89;
(c) Nicolaou, K. C. ; Montagnon, T. ; Ulven, T. ; Baran, P. S. ; Zhong, Y.-L. ; Sarabia, F.
J. Am. Chem. Soc. (2002) 124, 5718.
EDIT: Oops, I forgot to add the table. Has been done now. Also, on second thought, I think it was maybe not really on its place in the Novel Discourse, I should have posted in the Chemistry Discourse or in a thread on cathinones synthesis. My apologies.
The upload thingie is a very good idea, it makes posting much faster now. Thanks!