Author Topic: Microwave alpha-halogenation of carbonyl compounds  (Read 1653 times)

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Microwave alpha-halogenation of carbonyl compounds
« on: March 02, 2004, 10:24:00 PM »
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


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A 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.13

In 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 MgX2 (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 (SiO2, 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.


This work was supported by a grant from the Korea Research Foundation (KRF-2002-015-CP0217).

References and Notes

1. 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!


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More articles on alpha-halogenation
« Reply #1 on: October 15, 2004, 03:51:00 PM »
Here are some papers metioned in the "References" section of the above post.

Reference #5

Efficient alpha-Halogenation of Carbonyl Compounds by N-Bromosuccinimide and N-Chlorosuccinimde
Jong Chan Lee, Yong Hun Bae, and Suk-Kyu Chang
Bull. Korean Chem. Soc. 2003, 24 (4), 407-408

_______ _____ ___ _

Reference #11

Mercury(II) Chloride-Iodine: A Useful Reagent for the Direct and Regiospecific Synthesis of alpha-Iodocarbonyl Compounds
Jose Barluenga, Jose M. Martinez-Gallo, Carmen Najera, Miguel Yus
Synthesis 1986, 8, 678-680

Abstract - alpha-Iodoaldehydes and alpha-iodoketones are obtained by direct iodination of the corresponding carbonyl compounds with mercury(II) chloride-iodine in a regiospeciffic manner.

_______ _____ ___ __

Reference #16

Efficient alpha-Iodination of Carbonyl Compounds Under Solvent-Free Conditions Using Microwave Irradiation
Jong Chan Lee, Yong Hun Bae
Synlett 2003, 4, 507-508

Abstract - Direct conversion of carbonyl compounds into alpha-iodocarbonyl compounds has been successfully achieved under
solvent-free microwave irradiation conditions using N-iodosuccinimide
and p-toluenesulfonic acid.


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Reference #11
« Reply #2 on: October 16, 2004, 04:28:00 AM »
I've carried out this reaction before.

The yields were not as great as the article claims but the method is easy and very simple to perform.  The intermediate a-iodo carbonyl compound can, if so desired, be reacted further with an amine in much the same way that, for the most part, a-bromo carbonyl compounds do.  The most interesting observation to this synthesis, based on one experiment, is that a-iodo carbonyl compounds appear to be completely lacking all of the lacrymatory properties of their a-chloro and a-bromo counterparts.  Very interesting indeed.

Reference #5 could likely use N-chloro or N-bromosaccharin instead of the N-chloro or N-bromo succinimide:

Post 531553

(psychokitty: "N-Halosaccharin for halogenations?", Chemistry Discourse)