[128-09-6]  · C4H4ClNO2  · N-Chlorosuccinimide  · (MW 133.53)

(electrophilic a-chlorination of sulfides, sulfoxides, and ketones; preparation of N-chloroamines)

Alternate Name: 1-chloro-2,5-pyrrolidinedione; NCS.

Physical Data: mp 144-146 °C.

Solubility: sol H2O; sl sol CCl4, benzene, toluene, AcOH; insol ether.

Form Supplied in: white powder or crystals having a weak odor of chlorine when pure; widely available.

Purification: the commercial reagent acquires a light yellow color and a rather strong odor of chlorine after long storage but is easily recrystallized from acetic acid: rapidly dissolve 200 g of impure sample in 1 L preheated glacial AcOH at 65-70 °C (3-5 min); cool to 15-20 °C to effect crystallization; filter through a Buchner funnel and wash the white crystals once with glacial AcOH and twice with hexane; dry in vacuo (>85% recovery).

Analysis of Reagent Purity: the standard iodide-thiosulfate titration method is suitable.

Handling, Storage, and Precautions: store under refrigeration and protect from moisture; acutely irritating solid, with toxic effects similar to those of the free halogens; avoid inhalation; use an efficient fume hood; perform all operations as rapidly as possible to avoid extensive decomposition of the reagent.

N-Chlorosuccinimide is a convenient reagent for the electrophilic substitution and addition of chlorine to organic compounds. Other chlorinating agents of use include Chlorine, Sulfuryl Chloride, Chloramine-T, t-Butyl Hypochlorite, and Trichloroisocyanuric Acid. The primary advantages of using NCS include the ease in handling, the mild conditions under which chlorination proceeds, and the ease of removal of the inoffensive byproduct succinimide.

a-Chlorination of Carbonyl Derivatives.

Carbonyl compounds can be chlorinated in the a-position by addition of NCS directly to the lithium enolates, enoxyborinates, or more commonly to the silyl enol ether derivatives.1 In combination with methods for the regiospecific generation of enolates and silyl enol ethers, a-chloroketones of desired structure can be produced. For example, b-ionone can be chlorinated selectively in the a-position by addition of NCS to the kinetic enolate (eq 1).2 With the appropriate chiral auxiliary, NCS chlorinates silyl ketene acetals with high levels of diastereoselectivity (eq 2).3 a-Chloro ketones, a-chloro esters, and a-chloro sulfones may also be prepared by reaction of NCS with the b-keto derivatives and in situ deacylation in the presence of base (eq 3).4 NCS is also an effective reagent for the a-chlorination of acid chlorides.5

Chlorination of Sulfides and Sulfoxides.6

The reaction of alkyl sulfides with NCS has been used extensively for the preparation of a-chloro sulfides, and NCS is generally regarded as the reagent of choice for the preparation of these useful synthetic intermediates (see also Trichloroisocyanuric Acid). Since the mechanism of chlorination involves initial formation of an S-chlorosulfonium salt followed by a Pummerer-like rearrangement, monochlorination proceeds smoothly in CCl4 or benzene in the absence of added acid or base.7 The most straightforward procedure involves the addition of NCS to a solution of the sulfide in CCl4 at rt or reflux, followed by removal of insoluble succinimide by filtration. The resulting a-chloro sulfides are easily hydrolyzed and, as this is usually undesirable, a-chloro sulfides must be prepared under strictly anhydrous conditions and are often used without further purification. A method has been developed for the conversion of benzylic halides to aromatic aldehydes (eq 4);8 however, this transformation is more conveniently effected in one operation with other reagents (see Hexamethylenetetramine). Many advantages have led to the preferred use of NCS in the Ramberg-Bäcklund rearrangement sequence (eq 5), which has been recently reviewed.9

The chlorination of trimethylsilylmethyl sulfides with NCS and trifluoroacetic acid affords the product of chlorodesilation in high yield.10 The degradation of carboxylic acids to ketones can be achieved by a-sulfenation followed by reaction with NCS in the presence of NaHCO3 (eq 6).11 The S-chlorosulfonium ion intermediate undergoes a decarboxylative Pummerer-like rearrangement to afford the ketone upon hydrolysis. a-Phenylthio esters and amides can be successfully a-chlorinated using NCS in CCl4 at 0 °C (eq 7).12 1,3-Dithianes are deprotected to afford ketones by reaction with NCS alone or in combination with Silver(I) Nitrate in aqueous acetonitrile (see also N-Bromosuccinimide, Mercury(II) Chloride, 1,3-Diiodo-5,5-dimethylhydantoin).13

Sulfides can be oxidized to sulfoxides by reaction with NCS in methanol (0 °C, 1 h).14 Similarly, selenides couple with amines when activated by NCS to form selenimide species. These have been generated from allylic selenides in order to prepare allylic amines and chiral secondary allylic carbamates by [2,3]-sigmatropic rearrangement (eq 8).15

The a-chlorination of sulfoxides is generally performed in dichloromethane in the presence of a base (either K2CO3 or pyridine) and proceeds more slowly than the reactions with sulfides.16 a-Chloro sulfoxides bearing high optical purity at sulfur are especially useful in asymmetric synthesis, but unfortunately the chlorination of optically active sulfoxides is generally accompanied by significant racemization at sulfur. Alternate procedures are available for achieving chlorination with predominant retention or inversion.17 Using NCS and Potassium Carbonate the degree of racemization is minimized and chloromethyl p-tolyl sulfoxide can be prepared in 87% ee and 91% chemical yield (eq 9).18

Reaction with Vinylic and Acetylenic Derivatives.

NCS is a suitable source of chlorine for the conversion of vinylcopper and other organometallic derivatives to the corresponding vinyl chlorides.19 (E)-(1-Chloro-1-alkenyl)silanes are available from the appropriate 1-trimethylsilylalkynes by hydroalumination with Diisobutylaluminum Hydride followed by direct treatment of the vinylaluminum intermediate with NCS in ether at -20 °C (eq 10) (the corresponding (Z)-isomer is obtained by NBS-catalyzed isomerization of the (E)-isomer).20 1-Chloroalkynes can be prepared by reaction of the corresponding lithium acetylides with NCS in THF.21

Chlorination of Aromatic Compounds.

NCS has also been used for the chlorination of pyrroles and indoles; however, the reaction is less straightforward than when NBS and N-Iodosuccinimide are used.22 In the chlorination of 1-methylpyrrole, it has been demonstrated that basic conditions (NaHCO3, CHCl3) lead to the formation of 1-methyl-2-succinimidylpyrrole (eq 11).23 In the presence of catalytic amounts of perchloric acid, thiophenes and other electron-rich aromatic compounds have been chlorinated with NCS.24 (N-Chlorosuccinimide-Dimethyl Sulfide is used for the selective o-substitution of phenols.)

Synthesis of N-Chloroamines.

The conversion of secondary amines to N-chloroamines by reaction with NCS in ether or dichloromethane has many advantages over the use of aqueous hypochlorite, including ease of isolation. This method has been used repeatedly in the preparation of N-chloroamines for alkene amination (eqs 12 and 13)25 and other reactions.26

Other Oxidation and Chlorination Reactions.27

gem-Chloronitro compounds are prepared by treating nitronate anions with NCS in aqueous dioxane, or alternatively by reaction of ketoximes with NCS (eq 14).28 Oxidative decarboxylation of carboxylic acids with Lead(IV) Acetate and NCS has been used effectively for the synthesis of tertiary alkyl chlorides (eq 15).29

NCS is also regularly used for the direct oxidation of alcohols to ketones. The presence of Triethylamine serves to activate the reagent for rapid quantitative oxidation of catechols and hydroquinones to o- and p-quinones, respectively, and for the oxidation of benzophenone hydrazone to diphenyldiazomethane.30 N-Chlorosuccinimide-Dimethyl Sulfide is also used in the mild oxidation of alcohols, as well as in the conversion of allylic alcohols to allylic chlorides.

1. (a) Hambly, G. F.; Chan, T. H. TL 1986, 27, 2563. (b) Hooz, J.; Bridson, J. N. CJC 1972, 50, 2387. (c) Ohkata, K.; Mase, M.; Akiba, K. CC 1987, 1727.
2. Vaz, A. D. N.; Schoellmann, G. JOC 1984, 49, 1286.
3. Oppolzer, W.; Dudfield, P. TL 1985, 26, 5037.
4. Mignani, G.; Morel, D.; Grass, F. TL 1987, 28, 5505.
5. Harpp, D. N.; Bao, L. Q.; Black, C. J.; Gleason, J. G.; Smith, R. A. JOC 1975, 40, 3420.
6. Dilworth, B. M.; McKervey, M. A. T 1986, 42, 3731.
7. Tuleen, D. L.; Stephens, T. B. JOC 1969, 34, 31.
8. Paquette, L. A.; Klobucar, W. D.; Snow, R. A. SC 1976, 6, 575.
9. Paquette, L. A. OR 1977, 25, 1.
10. Ishibashi, H.; Nakatani, H.; Maruyama, K.; Minami, K.; Ikeda, M. CC 1987, 1443.
11. (a) Trost, B. M.; Tamaru, Y. JACS 1977, 99, 3101. (b) Trost, B. M.; Crimmin, M. J.; Butler, D. JOC 1978, 43, 4549.
12. Ishibashi, H.; Uemura, N.; Nakatani, H.; Okazaki, M.; Sato, T.; Nakamura, N.; Ikeda, M. JOC 1993, 58, 2360.
13. Corey, E. J.; Erickson, B. W. JOC 1971, 36, 3553.
14. Harville, R.; Reed, S. F., Jr. JOC 1968, 33, 3976.
15. (a) Fitzner, J. N.; Shea, R. G.; Fankhauser, J. E.; Hopkins, P. B. JOC 1985, 50, 418. (b) Spaltenstein, A.; Carpino, P. A.; Hopkins, P. B. TL 1986, 27, 147.
16. (a) Tsuchihashi, G.; Ogura, K. BCJ 1971, 44, 1726. (b) Ogura, K.; Imaizumi, J.; Iida, H.; Tsuchihashi, G. CL 1980, 1587.
17. Calzavara, P.; Cinquini, M.; Colonna, S.; Fornasier, R.; Montanari, F. JACS 1973, 95, 7431.
18. (a) Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. TL 1988, 29, 313. (b) Drabowicz, J. S 1986, 831.
19. Levy, A. B.; Talley, P.; Dunford, J. A. TL 1977, 3545.
20. Zweifel, G.; Lewis, W. JOC 1978, 43, 2739.
21. (a) Murray, R. E. SC 1980, 10, 345. (b) Verboom, W.; Westmijze, H.; De Noten, L. J.; Vermeer, P.; Bos, H. J. T. S 1979, 296.
22. (a) Gilow, H. M.; Burton, D. E. JOC 1981, 46, 2221. (b) Powers, J. C. JOC 1966, 31, 2627.
23. De Rosa, M.; Nieto, G. C. TL 1988, 29, 2405.
24. Goldberg, Y.; Alper, H. JOC 1993, 58, 3072.
25. (a) Kametani, T.; Suzuki, Y.; Ban, C.; Honda, T. H 1987, 26, 1491. (b) Honda, T.; Yamamoto, A.; Cui, Y.; Tsubuki, M. JCS(P1) 1992, 531.
26. (a) Wolff, M. E. CRV 1963, 63, 55. (b) Stella, L. AG(E) 1983, 22, 337.
27. Filler, R. CRV 1963, 63, 21.
28. (a) Amrollah-Madjdabadi, A.; Beugelmans, R.; Lechevallier, A. S 1986, 828. (b) Amrollah-Madjdabadi, A.; Beugelmans, R.; Lechevallier, A. S 1986, 826. (c) Corey, E. J.; Estreicher, H. TL 1980, 21, 1117.
29. Becker, K. B.; Geisel, M.; Grob, C. A.; Kuhnen, F. S 1973, 493.
30. Durst, H. D.; Mack, M. P.; Wudl, F. JOC 1975, 40, 268.

Scott C. Virgil

Massachusetts Institute of Technology, Cambridge, MA, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.