Applications of N-Chlorosuccinimide in Organic Synthesis€¦ · of Industrial Organic Chem-istry in Warsaw. Since 2001 he has been carrying out graduate research under su-pervision

REVIEW 3599

Applications of N-Chlorosuccinimide in Organic SynthesisN-Chlorosuccinimide in Organic SynthesisW. Marek Gołębiewski,* Mirosław GucmaInstitute of Industrial Organic Chemistry, 6 Annopol St., 03-236 Warsaw, PolandFax +48(22)8110799; E-mail: [email protected] 2 May 2007; revised 16 August 2007

SYNTHESIS 2007, No. 23, pp 3599–3619xx.xx.2007Advanced online publication: 31.10.2007DOI: 10.1055/s-2007-990871; Art ID: E18407SS© Georg Thieme Verlag Stuttgart · New York

Abstract: N-Chlorosuccinimide (NCS) is a versatile reagent and itssignificance is not limited to chlorination and oxidation. It mediatesor catalyzes many chemical reactions, including halocyclizations,formation of heterocyclic systems, formation of new carbon–carbonbonds, rearrangements, and functional group transformations.

1 Introduction2 Chlorinations3 Replacement of Other Groups by Chlorine4 Halocyclizations5 Rearrangements and Functional Group Transformations6 Formation of New Carbon–Carbon Bonds7 Formation of Heterocyclic Systems8 Oxidations9 Deprotections10 Transformations of NCS11 Miscellaneous Reactions12 Biological Activity of NCS13 Conclusions

Key words: N-halosuccinimides, N-chlorosuccinimide, chlorina-tion, oxidation, deprotection, rearrangement

1 Introduction

N-Chlorosuccinimide (1) (1-chloropyrrolidine-2,5-dione;NCS) was first synthesized in 1886 by the chlorination ofsuccinimide (2) with chlorinated lime.1 In newer methods,potassium hypochlorite,2 tert-butylhypochlorite(Scheme 1)3 and chlorine in aqueous sodium hydroxide4

have been applied for this transformation.

Scheme 1

From the very beginning, NCS was used in chlorinationand oxidation reactions. In the last 20 years, however,there has been an upsurge of interest in NCS, arising fromthe observation that it is a versatile reagent capable of me-diating a plethora of different chemical transformations.In modern synthetic organic chemistry, the search contin-ues for new methods excelling in selectivity, mildness,and efficiency.

NCS, with a molecular mass of 133.53 a.m.u.(C4H4ClNO2), is a colorless solid that melts with decom-position at 150 °C. NCS is slowly hydrolyzed by water(pK 5.82) with formation of hypochlorous acid which is asource of bactericidal activity. Its reaction with a hydro-halic acid affords succinimide and the halogen. The oxi-dation of halides to halogens is used in the test withiodide-starch paper to indicate the presence of NCS in areaction mixture. NCS is soluble in CCl4 at room temper-ature, whereas its conjugate product, succinimide, is not;this facilitates the separation of the reaction mixture. Justlike the other N-chloroamines, NCS is, to some extent,thermally unstable and there have been reports of violentreactions with alcohols and benzylamine.5 NCS is one ofseveral commercially available N-chloramines: chlor-amine-T (3), 1,3-dichloro-5,5-dimethylhydantoin (4)(NDDH), trichloroisocyanuric acid (5) (TCCA) (Figure 1).

Figure 1

Some properties of the three chloroimides NCS, NDDHand TCCA were recently compared in a review concern-ing TCCA.6All three reagents are easy to handle and all ofthe halogen is consumed, not half as in the case of elemen-tal halogens. Although NCS has the lowest content of ac-tive chlorine and the lowest oxidizing ability of thesethree reagents, NCS is the least toxic, and as described lat-er in this review, is the most selective reagent from thisgroup. As opposed to NCS, TCCA chlorinates esters andcyclic ethers (THF, dioxane), and aliphatic ethers are ox-idized to esters, and this imposes limits on the use of sev-eral common solvents.7

Because of the large volume of work encompassing NCS,this review focuses on the most representative and recentapplications of the reagent published until the end of2006. The chemistry and applications of N-bromosuccin-imide (NBS) have been amply reviewed,8–12 but a compar-ison of the reactivity of NCS with that of other N-halosuccinimides is presented herein.

t-BuOClO ON

Cl

O ON

12H

ClNSO2Me

Na

Me

Me

Cl

O

Cl

O

Cl

O

Cl

O

Cl

O

N N

N

4 53

+–

3600 W. M. Gołębiewski, M. Gucma REVIEW

Synthesis 2007, No. 23, 3599–3619 © Thieme Stuttgart · New York

2 Chlorination

2.1 Chlorination of Benzene Derivatives

Aromatic chlorination reactions are usually carried outwith elemental chlorine, sulfuryl chloride, chlorine(I) ox-ide, or hypochlorites.13 In the search for new and safer re-agents, NCS has been examined.

Scheme 2

The treatment of reactive aromatic compounds, such as N-alkylanilines, with NCS in hot benzene gave a mixture ofo- and p-chloroanilines in a ratio exceeding 2:1(Scheme 2). The results were interpreted as arising from arearrangement of intermediate N-chloro isomers.14,15 Dif-ficulties in obtaining monochlorinated products with ac-ceptable yields in the reaction of deactivated anilines wereobviated by the use of a dipolar aprotic solvent such asacetonitrile.16

Ring chlorination of aromatic compounds with NCS pro-ceeds by electrophilic substitution and involves a positivehalonium species, the formation of which is facilitated bypolar solvents and the presence of acidic catalysts. The re-quired amount of the catalyst depends on the character ofthe substituents. Chlorination of polyalkylbenzenes re-quired the use of catalysts such as p-toluenesulfonic acid

or strong mineral acids. A good yield of 2-chloro-1,3,5-trimethylbenzene (7) was obtained from 6 by treatmentwith an equimolar amount of NCS and catalytic amount ofp-toluenesulfonic acid in methanol at reflux temperature.A comparable result was obtained in a reaction performedat room temperature overnight with two equivalents of thecatalyst (Scheme 3).17

Scheme 3

Electrophilic chlorination and bromination of activatedaromatics was carried out efficiently in a biphasic solid–liquid system (NXS–hexane or NXS–CCl4) using catalyt-ic amounts of 70% perchloric acid. Both 1,3-dimethoxy-benzene and 2,3-dimethylanisole (8; Scheme 4) werehalogenated regiospecifically at the 4-position at roomtemperature.18

Scheme 4

RHN

NCS Cl

RHN

Cl

RHN

o/p >2:1

+

W. Marek Gołębiewskiwas born at Grądy (Poland)in 1945. He studied chemis-try at the University of War-saw and received his PhD in1973 under direction ofProf. J. T. Wróbel achievingthe first total synthesis ofLythraceae alkaloid deca-line. After graduation he as-sumed the position of aresearch associate at the

same university. He per-formed postdoctoral re-search at McMasterUniversity (Ontario, Cana-da) with Prof. I. D. Spenserand at Purdue University(Indiana, USA) with Prof.M. S. Cushman. He ob-tained his Habilitation at theUniversity of Warsaw in1986. In 1994, he moved tothe Institute of Industrial

Organic Chemistry, wherehe was promoted to the po-sition of Associate Profes-sor in 1996. His currentresearch interests are thestereoselective synthesis ofbiologically active com-pounds and the structureelucidation of natural prod-ucts.

Mirosław Gucma was bornin Żary (Poland) in 1972. Hereceived his diploma fromthe Department of Chemis-try at the Technical Univer-sity of Warsaw. In 1999 hestarted work at the Institute

of Industrial Organic Chem-istry in Warsaw. Since 2001he has been carrying outgraduate research under su-pervision of Prof. W. M.Gołębiewski, where he is in-vestigating the application

of cycloaddition reaction inthe synthesis of new plant-protection agents. His re-search interests include newsynthetic methods andstructure–activity relation-ships.

Biographical Sketches

NCS

TsOH

Me

MeMeCl

Me

MeMe

81%

6 7

Me

OMe

MeNXS

HClO4

X

Me

OMe

Me

9a, X = Cl, 94%9b, X = Br, 90%

8

REVIEW Applications of N-Chlorosuccinimide in Organic Synthesis 3601


The chlorination of 9-bromoanthracene (10) with NCSand a catalytic amount of hydrochloric acid produced both9,10-dichloroanthracene (11) (65% yield) and 9-bromo-10-chloroanthracene (12) (35% yeild) as shown inScheme 5. This result was explained by the better leaving-group ability of bromide compared to chloride.19 Recrys-tallized NCS did not react with dibenzo[a,c]anthracenewithout the presence of HCl, underlining the need forchlorine generation to initiate the reaction.

Scheme 5

The treatment of 9-methylanthracene (13) with NCS andhydrochloric acid affords a nuclear chlorination product,9-chloro-10-methylanthracene (14) (65% yield), and abenzylic radical chlorination product, 9-chloromethylan-thracene (15) (35% yield) as shown in Scheme 6.

Scheme 6

The participation of Lewis acids as catalysts in the chlori-nation of a wide range of substituted benzenes by NCS inacetonitrile was recently described.20 In the case of elec-tron-donating substituents, catalytic amounts of iron(III)chloride were sufficient; for unsubstituted benzene, or inthe case of electron-withdrawing substituents, an equimo-lar loading of iron(III) chloride was required. For stronglydeactivated systems, such as nitrobenzene, increased tem-peratures (150 °C) and/or solvent-free conditions were in-dispensable. Various activated aromatic compounds wereefficiently and selectively halogenated in dichlo-romethane with NCS, NBS and NIS in the presence of cat-alytic amounts of zirconium(IV) chloride.21

To circumvent the harsh reaction conditions required fordeactivated aromatics, new superacidic catalysts were in-troduced. Boron trifluoride monohydrate was found to bean effective and inexpensive catalyst for several reactions,including halogenations with NXS (X = Cl, Br, I).22 Thereaction temperatures and times were adjusted dependingon the degree of substrate deactivation. For nitrobenzene,the reaction mixture was heated to 110 °C for 18 hours ina closed pressure tube. Reactions with hypochlorites andsodium chlorate–trimethylsilane complex were extremelysluggish. Quantum chemical density functional theorycalculations suggested that the reaction of benzene chlori-

nation proceeds via Cl+ transfer from the triply protonateddestabilized NCS (16) to an aromatic substrate(Scheme 7). A driving force for the reaction is probablyan electrostatic relief which accompanies the transfer ofthe positively charged chlorine cation to yield chloroben-zene (17).

Scheme 7 Chlorination of benzene in superacidic media

2.2 Heterocyclic Systems

The chlorination of heterocyclic systems with two het-eroatoms and substituted at the 3- and 5-positions yieldsselectively ring-chlorinated products. The chlorination of3,5-diarylisoxazoles 18 with NCS in refluxing acetic acidafforded the 4-chloro derivatives 19 (Scheme 8).23 In thecases of electron-withdrawing substituents or a methylgroup on the Ar group, the addition of a catalytic amountof sulfuric acid was required for an efficient chlorination.

Scheme 8

The chlorination of the bis(oxazole)indole 20 using NCSgave the dichloride 21 (86% yield) and the trichloride 22(5% yield), where chloride was installed at both position4 of the isoxazole and position 2 of the indole system(Scheme 9). The partial synthesis of the oxazole naturalproduct diazonamide was thus completed.24

NCS

Cl

Cl

Cl

Br

+

65% 35%

10 11 12

Br

Me

NCS

HCl

Cl

Me CH2Cl

+

65% 35%13 14 15

HOH

Cl HO N

HOH

HO N

H

Clδ+

δ+

H

HOH

O N

H

Clδ+

Cl

16

17

+ +

+

+ +

+ + +

Ph

Ar ON

NXS

AcOH

X Ph

Ar ON

X = Cl, Br, I

18 1952–97%

Scheme 9

Me Me

BocHN

HN

OO

N

NH

NCS

CCl4

+ R Cl

N

Cl Cl

O

NCl

NH

Cl

O

N

5%

20

2221

86%

R

= R



The treatment of 3,5-dimethylpyrazoles 23 (N1-unsubsti-tuted or N1-substituted with methyl or aryl groups) withNXS in ethyl acetate or acetone afforded 4-haloderivatives 24 in good yields and short times under ultra-sound irradiation and in the absence of any catalysts(Scheme 10).25

Scheme 10

The chlorination of heterocyclic systems that have justone heteroatom takes place mainly at the a-position.Treatment of 1-methylpyrrole (25) with NCS in chloro-form yielded a mixture of 2-chloro-1-methylpyrrole (26,X = Cl) and 1-methyl-2-succinimidopyrrole (27)(Scheme 11). The yield of 2-chloropyrrole depended onthe solvent (was high in benzene, CCl4, THF), and on thepresence of a base (NaHCO3), which suppressed the acid-catalyzed a-chlorination. Similar treatment of 1-methyl-pyrrole with NBS or NIS yielded only the 2-halo-1-meth-ylpyrroles 26. 2H NMR spectroscopic studies showed thatthe imide-substituted pyrrole was formed by an addition–elimination process. Unsubstituted pyrrole gave only 2-chloropyrrole, as did pyrroles with extremely large N-sub-stituents.26–28

Scheme 11

The chlorination of (1¢-methyl-1¢H-pyrrol-2¢-yl)-2,2-di-methylpropan-1-one (28) furnished the 5¢-chloro deriva-tive 29 (Scheme 12).29

Scheme 12

Acid-sensitive substrates are effectively chlorinated byNCS in the presence of mildly acidic ammonium nitrate;in the specific case of thiophene (Scheme 13), a mixture

of 2-chlorothiophene (31) (59% yield) and 2,5-dichlo-rothiophene (32) (10% yield) was obtained.20 In anotherapproach, the halogenation took place in a two-phase sys-tem – solid NXS (1 equiv) in hexane or CCl4 – with cata-lytic amounts of 70% perchloric acid and afforded 2-chloro- or 2-bromothiophene. When two equivalents ofNXS were used, 2,5-dihalothiophenes were obtained inhigh yield. 2-Methylthiophene and halo derivativesshowed similar reactivity.

Scheme 13

The chlorination of disubstituted aziridines 33 with NCSin the presence of trifluoromethylcarbinols as chiral sol-vating agents gave the optically active N-chloroaziridines34 in very good chemical yield (Scheme 14). The chlori-nation of 2-phenylaziridine under kinetic resolution con-ditions yielded optically active (E)- and (Z)-1-chloro-2-phenylaziridines along with unreacted optically activesubstrate.30

Scheme 14

The treatment of 2-methylsulfanyl-3H-pyrimidin-4-one(35a) and its 6-methyl derivative 35b with NCS affordedproducts 36 corresponding to chlorination at position 5 ofthe ring (Scheme 15). A similar result was obtained in thechlorination of 2,4(1H,3H)-pyrimidine-2,4-dione.31

Scheme 15

The reaction of NCS and imidazo[1,2-a]pyridines 37,substituted at the 3-position with electron-withdrawinggroups such as formyl, nitro or bromide, led to the ipso re-action products 38 with chlorine installed at position 3 ofthe imidazole ring (Scheme 16). On the other hand, treat-ment of imidazo[1,2-a]pyridines substituted at the 3-posi-tion by an ester or chlorine group resulted in chlorinationat the 5-methyl group to afford compounds 39. The inter-mediacy of 3-halogenoimidazo[1,2-a]pyridinium com-pounds was proposed in order to explain the results.32

R

Me

Me NN

NXS

R

X Me

Me NNEtOAc

)))

X = Cl, Br, I; R = H, Me, aryl

23 24

Me

N

O

O

N

Me

ClN

O

O

N

Me

N

– HCl

X = Cl

X

Me

NOO NX

Me

N

NXS

27

2625

X = Cl, Br, I

–

+

Me

MeMe

OMe

N

NCS

Cl Me

MeMe

OMe

N

28 29

S

NCS

NH4NO3 ClS Cl ClS+

59% 10%30 31 32

R2

R1

NH

CF3

OH

H

R

NCSClR2

R1

N

R1, R2 = Ph, Me, H; R = aryl, cyclohexyl

33 34*

R SMeN

NH

NCS

AcOH

52–64%

Cl

R SMeN

NH

35a R = H35b R = Me

36a R = H36b R = Me

OO



Scheme 16

The chlorination of b-carbolines 40 with NCS (and N-chlorobenzotriazole) in solution and in the solid state wasdescribed (Scheme 17).33 Electrophilic aromatic substitu-tion resulted in formation of the monochloro derivatives41 and 42 (R1 = H, Me; R2 = H). More reactive deriva-tives with oxygen-containing R2 substituents afforded, inaddition, substantial amounts of 6,8-dichloro compounds.Reactions in the solid state showed lower conversion ratesand regioselectivity, but oxidation reactions leading to thepolymeric products did not take place. Semi-empiricalAM1 and PM3 calculations have been done to predict thereactivity based on frontier orbital energies and differen-ces in the charge densities of b-carbolines and chloro-b-carbolines.

Scheme 17

Syntheses of the 2-substituted imidazo[1,2-b]pyridazines43 and 45, as well as their electrophilic substitution reac-tions, were described (Scheme 18).34 Chlorination withNCS occurred at C-3 of the imidazole and/or on the het-eroaryl (aryl) substituent at C-2. The structures of theproducts 44 and 46 were established using 1H NMR and13C NMR spectroscopic methods.

Electrophilic halogenation of 2H-cyclopenta[d]pyrid-azines 47 with NCS in dichloromethane readily affordedthe 5- and 7-derivatives 48 and 49 as well as 6-chlorocompounds in a much slower reaction (Scheme 19). Onthe other hand, reaction of the 5,6,7-trichloro derivative of47a in refluxing carbon tetrachloride with one equivalentof NCS under a nitrogen atmosphere furnished the prod-uct of radical substitution at the methyl group (64%).35

Scheme 19

The reaction of the 1-methylpyridazino[3,4-b]quinoxa-line-4,4-dicarboxylates 50 with NCS or NBS in aceticacid afforded the 3-halogeno-1-methylpyridazino[3,4-b]quinoxaline-4,4-dicarboxylates 51.36 The reaction ofthese dicarboxylate compounds with hydrazine hydrateresulted in hydrolysis and decarboxylation to provide themonocarboxylates 52; treatment of the latter compoundswith nitrous acid effected oxidation to furnish the respec-tive 3-halogeno-4-hydroxy-1-methylpyridazino[3,4-b]quinoxaline-4-carboxylates 53. Further reaction ofthese products with hydrazine hydrate afforded the 3-ha-logeno-1-methylpyridazino[3,4-b]quinoxalin-4-ols 54,and subsequent oxidation with NCS or NBS in water oraqueous acetic acid provided the 3-halogeno-1-methylpy-ridazino[3,4-b]quinoxalin-4(1H)-ones 55 (Scheme 20).These final products demonstrated in vitro antifungal ac-tivity.

Scheme 20

RMe

N

N

ClMe

N

N

NCS

RMe

N

N

RCH2Cl

N

N

NCS

THF

THF

37 39

R = CHO, NO2, Br

R = Cl, CO2Et

37 38

Cl

R2 NH

NCS6

8R2 NH

+

Cl

R2 NH

R1 = H, Me; R2 = H, OMe, OH, OAc

40 41

42

N

R1

N

R1

N

R1

Scheme 18

S

NCS

CHCl3 RS

O

NCS

CHCl3 R2O

4344 R = Cl, H

4546

R1, R2 = Cl, H

NN

N

ClCl

NN

N

Cl

NN

N

Cl NN

N

ClR1

RN

N

NCS

CH2Cl2

Cl

RN

N

ClR

N

N

+

47a R = Me47b R = Ph47c R = H

48a 9%48b 20%

49a 40%49b 41%49c 88%

Me

CO2EtEtO2C

R N

N

X

Me

CO2EtEtO2C

R N

N

NXS

CO2Et

X

Me

R N

N

N2H4

X

Me

CO2EtHO

R N

N

NaNO2

OH

X

Me

R N

N

N2H4

O

X

Me

R N

N

NXS

R = Cl, H; X = Cl, Br

50 51

52 53

54 55



2.3 Oximes

Base-induced dehydrohalogenation of hydroximoyl chlo-rides 57 generates nitrile oxides 58, which are versatile in-termediates in heterocyclic chemistry (Scheme 21). Thehydroximoyl chlorides can be obtained by a plethora ofmethods. Originally the most popular, though not safe,methods for its synthesis were chlorination of oximes 56with chlorine gas37 or nitrosyl chloride.38 In newer meth-ods, tert-butyl hypochlorite,39 sodium hypochlorite,40 ahydrogen chloride–Oxone system,41 benzyltrimethyl-ammonium tetrachloroiodate42 and N-tert-butyl-N-chlorocyanamide43 are used. The most convenient andmost frequently used method of selective hydroximoylchloride preparation, without accompanying ring chlori-nation, utilizes NCS with N,N-dimethylformamide as sol-vent.44 As the only exception to this rule, the authorsdescribed that the reaction of strongly activated 2,4-dimethoxybenzaldehyde oxime yielded a 2:1 mixture ofring-chlorinated product and hydroximoyl chloride.French chemists reported a clean synthesis of 4-N,N-di-methylphenylhydroximoyl chloride by chlorination of 4-N,N-dimethylbenzaldehyde oxime in chloroform in thepresence of pyridine.45 However, in our hands, the repeat-ed reaction still afforded a mixture of products.46

Scheme 21

2.4 Amines, Imines, Enamines

N-Halogenation of amines have been performed with so-dium hypochlorite or hypobromite.47 NCS chlorination ofvolatile aliphatic amines using vacuum gas/solid reactionwas shown to give primary and secondary N-chloraminesand N,N-dichloroamines efficiently (Scheme 22).48 Theprocess was carried out at room temperature with solidNCS. In the case of primary amines, adipic acid was usedas a co-reagent to trap small amounts of unreacted amine.The same technique, when applied to imines, resulted inN-chloroaldimines.49

The chlorination of secondary amines of 7-azabenzonor-bornadienes like 64 with NCS at low temperatures afford-ed mainly the anti-N-chloro products 65 (Scheme 23).Kinetic control of the reaction was governed by electronicfactors.50 The contribution of syn-derivatives 66 increasedalong with enhancement of the electronegativity of thearomatic substituents.

The reaction of benzylamine with NCS was found to in-volve addition of the amine to electrophilic Cl to yield N-chlorobenzylamine, rather than hydride abstraction fromthe amine a-C by the oxidant, as was previously proposedin the literature.51

Alk-4-enylamines 67 were shown to undergo N-chlorina-tion with NCS in benzene. Heating of the obtained w-chloroalkenes 68 with tributyltin hydride and 2,2¢-azo-bis(isobutyronitrile) (AIBN) under reflux afforded thetrans-2,5-disubstituted pyrrolidines 69 stereospecifically,in yields of up to 63% (Scheme 24).52

The chlorination of enamines with NCS afforded a-halo-genated derivatives. The course of the reaction was foundto depend on the basicity of the enamines. While dimethylenamine 70 was directly chlorinated to derivative 71, themore basic pyrrolidine enamine 72 required an indirectapproach with participation of succinimidosulfoniumchloride (Corey–Kim reagent), formed from NCS anddimethyl sulfide (Scheme 25).53

An ingenious one-step synthesis of a,a-dihalogenated ali-phatic aldehydes 77 was elaborated (Scheme 26). The keystep was halogenation with two equivalents of NCS (orNBS) of imines 75 formed in the reaction of aldehydeswith tert-butylamine. The dihalo Schiff base 76 was sub-sequently hydrolyzed to the aldehyde in hydrochloric acidat room temperature.54

Regioselective a,a-dichlorination of 2,3,4,5-tetrahydro-pyridines 78 with 2.5 equivalents of NCS followed by

R

HNOHC

NCS RCl

NOHCbase

ONCR

56 57 58

+ –

Scheme 22

H

HNR1 NCS

0.1 Torr

(HO2C-CH2CH2)2

85–88% Cl

HNR1

Cl

ClNR1

80–88%

R2

HNR1

97–99% R2

ClNR1

59

60

61

62 63

alumina

NCS, 0.1 Torr

Scheme 23

F F

F

FNH Cl

F F

F

FN

Cl

F F

F

FN

NCS

–50 °C

+

80%25 °C

anti syn 20%

anti syn

20% 80%

64 65 66

Scheme 24

R4R2

R3

R1 N

BuSnHNCS

C6H6 AIBN

R1, R2 = H, alkyl, Ph

67 68 69NH

R1

R2

R3

R4

N

R1

R2

R3

R4

Cl



double dehydrochlorination of the dichloroimines 79 withmethanolic sodium methoxide afforded a new, efficientsynthesis of pyridines 80 (Scheme 27).55a 1-Pyrrolineswere similarly converted into 3-chloropyrroles.55b

Scheme 27 Aromatization via imine dichlorination and double de-hydrochlorination

A new regio-, stereo-, and chemoselective method hasbeen elaborated for the synthesis of 2-dichloromethylimi-dazoline derivatives 83 by the reaction of enones 81 withp-toluenesulfonamide and NCS as nitrogen and chlorinesources, respectively (Scheme 28).56 A proposed mecha-nism for this electrophilic reaction involves the formationof aziridinium intermediates 82 from interaction of TsN-HCl with olefins and a new [2+3] cycloaddition via aziri-dinium ring opening. In this reaction, it was not possibleto replace NCS by NBS. Acidic hydrolysis of the productimidazolines afforded vicinal diamines, important inter-mediates in the synthesis of pharmaceutically valuablecompounds.

The treatment of tricyclic enaminones 84 with one equiv-alent of NCS in dichloromethane at room temperaturegave a-chloroenaminones 85 in an efficient manner.When the reaction was repeated with two equivalents ofNCS, the a,g-dichloro compound 86 was obtained(Scheme 29). These results were rationalized in terms ofan initial reaction at nitrogen atom. The isolated C8–C9double bond turned out to be completely inert under thesehalogenation conditions.57

2.5 Alkynes and Alkenes

1-Chloroalkynes 88 are prepared in good yields by reac-tion of lithium acetylides 87 with NCS (Scheme 30) as analternative to chlorination with chlorine gas or hypochlo-

ric acid. Tetrahydrofuran turned out to be the best solventfor this transformation which is equilibrium-controlled.58

Scheme 30

Reaction of NCS (or NBS) with olefins can proceed via anionic or radical pathway, depending on the electron densi-ty of the double bond. Electron-poor olefins tend to under-go the radical chain reaction. Halogenation of electron-rich olefins, such as enol ethers or tetraalkylolefins 89,can follow an ionic mechanism with formation of haloni-um ions 90 (Scheme 31).59 When an active allylic protonis available, it can be abstracted by the succinimide baseto furnish the allylic halides 91 with a shifted olefinicbond. If the double bond shift cannot occur, the base canabstract a homoallylic proton (as in intermediate 92) to af-ford the homoallylic halides 94 via intermediate a-halocy-clopropanes 93.

Although the majority of direct allylic halogenations ofolefins are usually free-radical reactions, selenium com-pounds have been shown to catalyze a non-radical pro-cess.60 Arylselenyl chlorides and aryl diselenides

Scheme 25

Me

N

Cl

N

Me

N

NCS

Me

N

NCS⋅SMe2

70 71 72 73

NMeMe

NMe Me

Me

N

N

Cl

Scheme 26

R

Ot-BuNH2

R

Nt-Bu2 NXS

CCl4 X

X

R

Nt-BuH+

X

X

R

O

74 75 76 77X = Cl, Br

R

N

81–84%

NCSCCl4

R

N

R

NbaseMeOH

91–95%

78 79 80

R = aryl, alkyl

ClCl

Scheme 28

COR2

R1

TsNHCl+ MeCN

R1 COR2

TsH

NNC

Me

Ts

H

COR2R1

Me

NN

Ts

COR2R1

Me

NN

– HCl

NCS

H

ClTs

COR2R1

CH2

NNCl

Ts

COR2R1

NN

Cl

Ts

COR2R1

CH2Cl

NNTs

COR2R1

CHCl2

NNNCS

R1, R2 = aryl, alkyl

81

82

83

+ +

–

+

Scheme 29

NR1R2

O

X

NR1R2

O

NXS1 equiv

1 equiv NYSX

NR1R2

O

2 equiv NXS

X = Cl, Br, I; Y = Cl, Br

84 85

86

X(Y)

LiCCR +

Cl

OO N

THFClCCR +

Li

OO N87 88



catalyzed the chlorination of olefins with NCS. Reactionof mono-, di- and trialkyl olefins yielded rearranged allyl-ic chlorides as the major products, with vinyl chlorides asthe minor components. The selectivity of the reaction wasimproved when electron-withdrawing groups werepresent, as in alkene 95; here, the reaction resulted in pre-ferred elimination of the selenium compound leading to-wards the conjugated products 96 (Scheme 32).61

Similarly, a steric bias favors formation of allylic chlo-rides, since in syn-elimination, the conformation of the Hand Se moiety that would lead to the vinyl chloride is dis-favored.

Scheme 32

On the other hand, NCS serves as a source of chlorine rad-icals when initiators are present. Allylic chlorination of(+)-3-carene (97) with NCS in the presence of either a,a¢-azobisisobutyronitrile (AIBN), UV light, or silica gel re-sulted in a rearranged allylic chloride 98 as the majorproduct, in addition to the non-rearranged allylic chloride99 and 3,4-dichlorocarane (100) which was a result of for-mal addition of chlorine to the original double bond(Scheme 33).62 Since the reaction catalyzed by a typicalfree-radical initiator (in this case, AIBN) required a muchlonger time than the reaction catalyzed by a mildly acidicsilica gel, it is likely that the latter chlorination is not afree-radical process. Reaction of (+)-2-carene with NCSunder the same conditions as above afforded mainly aro-matic products formed by cleavage of the cyclopropanering.

Scheme 33

Treatment of 1-substituted 1-alkoxy-1,3-dienes 101 withNCS or NBS, followed by selective electrophilic attack onthe terminal olefinic bond, afforded the g-halogenatedcarbonyl compounds 102 or the a,b-unsaturated acetals103, according to the chosen experimental conditions(Scheme 34).63

Scheme 34

Halofluorination of different aliphatic, alicyclic and aro-matic alkenes was performed in a highly regio-, stereo-,and chemoselective way with halogen fluorides or with acombination of fluoride reagents and some halogensources, such as N-haloamides or N-haloimides.64 Newer,more versatile, sources of fluoride include silicon tetra-fluoride as well as ammonium and phosphonium com-pounds (Scheme 35).64 Yields decreased from NISthrough NBS to NCS. The Markovnikov rule of selectivi-ty was followed in all the reactions.

Scheme 35

Scheme 31

RR

RR

+ YCl

R

R

R

RCl

Y

H

R

R

R

RCl

Y

HY +

R

R

R

R

Cl

H R'

RR

RCl

Y

HY +

R

R'

R

RCl

ClR'R

R R

89 90 91

92 93 94

+

+ +

––

–

Cl

CO2HEt

PhSeCl

SePh

Cl

CO2HEt

SePh

Cl

CO2HEt

NCS

fast

NCS

slow

Cl

CO2HEt

CO2HEt

83%

95

96

MeMe

Me

NCSCl

MeMe

CH2

+

MeMe

CH2Cl

Cl

MeMe

+

97 98 99 100

Me Cl

NXS

THF

H2O

MeOH

O

R

X

OMe

OMeR

XR = alkyl, TMS, X = Cl, Br

101

102

103

OEt

R

R3

R2

R1

H

Bu4P+HF2–

NXSX

R3

R2

R1

F

H

X = Cl, Br, I

104 105



Chlorination of silyl enol ether 106 with NCS in acetoni-trile gave the adduct of chlorosiloxycarbinyl cation withsuccinimide. In the presence of an azide nucleophile anda quaternary ammonium chloride, the chlorosiloxycarbi-nyl cations 107 underwent a Schmidt-type rearrangementto anilide derivatives 109 via chloroazides 108 when heat-ed in boiling decalin (Scheme 36).65

Scheme 36

NCS also served as an electrophile in the electrophilic ad-dition of various alcohols to the enol ethers 110. The reac-tions occurred readily in non-polar solvents, such asbenzene. Polar solvents slowed the reaction down dramat-ically and lowered the yield of ethers 111 and 112(Scheme 37).66

Scheme 37

The haloamidation of olefins was carried out by reactionwith N-haloimides (X = Cl, Br) or bromoamides with ni-triles in the presence of Lewis acids.67 It was presumedthat the reaction involves nucleophilic attack of nitrile onthe halonium ion 113 followed by hydrolysis to afford ha-loamides 114 (Scheme 38).

Scheme 38

2.6 Aralkyl and Alkylheterocyclic Systems

The chlorination of aralkyl and heteroaralkyl systems isgenerally a free-radical process, particularly in the pres-ence of free-radical initiators as well as in nonpolar sol-vents, and products of benzylic chlorination are formed.The chlorination of 6-methylphenanthridine furnishes 6-chloromethylphenanthridine.68 Similarly, chlorination of

1-methylnaphthalene results in 1-chloromethylnaphtha-lene.69

In some alkyl heterocyclic compounds, an ionic mecha-nism is plausible. Chlorination of 2-aryl-4,5-dimethyl-1,3-oxazoles 115 with NCS in acetonitrile provided 4-chloromethyl derivatives 116 as the major products and 5-chloromethyl derivatives 117 as the minor components(Scheme 39). A proposed mechanism invokes addition tothe C4–C5 double bond of the oxazole ring and regiose-lective opening of the halonium intermediate. No ‘benzyl-ic’ chlorination was observed in the case of the reaction inrefluxing acetic acid with NCS of 3,5-diarylisoxazoleswith a p-methyl substituent on 5-phenyl ring.70 Similarly,2-aryl-4,5-dimethyl-1,3-thiazoles undergo highly regiose-lective halogenation at the C4-methyl group.71

Scheme 39

2.7 Carbonyl and Carboxylic Compounds

Halogenation of methylene groups activated by carbonyland carboxyl functions requires the presence of appropri-ate catalysts. An efficient a-halogenation of b-ketoestersand a-halogenation of cyclic ketones with NCS and acidicAmberlyst-15 was described.72 The reaction occurred atroom temperature in ethyl acetate with high yields. Alter-natively, methyl ketones were monochlorinated via theirlithium enolates.73

The other catalyst that has been used for a-monochlorina-tion of ketones and b-ketoesters is phenylselenyl chlo-ride.61 The regioselectivity of the mesityl oxide (118)reaction was solvent-dependent (Scheme 40). In acetoni-trile, a vinyl halogenation took place, whereas in methanolonly methyl halogenation was observed and furnished120.

Scheme 40

Enantioselective halogenation of b-keto esters with N-ha-losuccinimides catalyzed by Lewis acids has been elabo-rated. With 5 mol% of titanium–TADDOL complexes atroom temperature, enantioselectivities of up to 88% eecould be obtained for the chlorination reaction. Under

H

RTBDMSO

Ar

NCSR

Cl

HTBDMSO

Ar

N3–

N3 R

Cl

HTBDMSO

Ar

∆

Cl

R

O

N

106 107

108 109 R = alkyl, H

+

H

Ar

ROH

NXS+

X = Cl, Br, I110 111 112

O

OMe

O

OMe

ORXO

OMe

ORX

BF3⋅OEt2NXS

MeCNX

MeCN

COMeN

X

H2O

NHCOMe

X

114

+

113

Me

Me

Ar O

N

Me

CH2X

Ar O

N+

CH2X

Me

Ar O

NNXS

major minorX = Cl, Br

115 116 117

MeCN

Me

O

MeMe

NCS, PhSeCl

MeCNCl

Me

O

MeMe

Cl

O

MeMe

MeOH118

119

120



comparable conditions, the bromination reactions withNBS are slower and less stereoselective.74

The a-fluoro- and a-chloro-b-keto esters 122 and 123were prepared by electrophilic reaction of b-keto esters121 with NCS or 1-chloromethyl-4-fluoro-1,4-diazonia-bicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA) inthe presence of titanium chlorides such as titanium tetra-chloride, (h5-cyclopentadienyl)titanium trichloride, or thetitanium–TADDOL complexes (Scheme 41).75 CpTiCl3

was the most effective catalyst used for the preparation ofa-fluoro- or a-chloro-b-keto esters from b-keto esters; inmost cases the ratio of mono- to difluorinated b-keto es-ters was greater than 9:1. Titanium–TADDOL complexeswere shown to be effective catalysts for the one-pot enan-tioselective heterodihalogenation of b-ketoesters with F-TEDA and NCS, affording a-chloro-a-fluoro-b-keto-esters in moderate to good yields. Either enantiomer of a-chloro-a-fluoro-b-ketoester 124 or 125 could be prepared,simply by reversing the order of reagent addition in thehalogenation step.

An imidazolidine-type diamine with C2-symmetry servedas the organocatalyst in an asymmetrical a-chlorinationreaction of simple ketones. Optically active a-chloro ke-tones were formed with excellent enantioselectivities us-ing NCS as the chlorine source.76 These products havebroad synthetic utility, in particular for pharmaceuticalapplications.

NCS was used as an acid scavenger in the chlorination ofa,b-unsaturated ketones and esters by chlorine in meth-anol. Mixtures of Markovnikov and anti-Markovnikovmethoxychlorides and dichlorides were obtained.77 NCSdid not react in this process with hydrochloric acid to gen-erate chlorine as was the case with NBS, but was pre-sumed to chlorinate directly an intermediate methoxy enolto afford the anti-Markovnikov product.

Alternatively, the a-monohalogenation of 1,3-diketones,b-keto esters, and cyclic ketones has been conducted atroom temperature in ionic liquids with N-halosuccinim-ides in excellent yields in the absence of a catalyst.78

These recovered green recyclable reaction media were re-used up to six times with consistent activity.

Enantioselective a-chlorination of aldehydes by NCS cat-alyzed by L-proline amide and (2R,5R)-diphenylpyrroli-dine was achieved (Scheme 42).79 The aldehydes wereisolated with excellent yield (up to 99%) and optical puri-

ty (up to 95%). The proposed mechanism involves N-chlorination of initially formed enamine followed by a1,3-sigmatropic shift of the chlorine atom and then hy-drolysis. This mechanistic hypothesis was supported bystudies of reaction kinetics, isotope effects and densityfunctional theory calculations.80

Scheme 42

An efficient and chemoselective a-chlorination of acylchlorides was accomplished with NCS in thionyl chlorideas a solvent in the presence of catalytic amounts of hydro-chloric acid (Scheme 43).81,82 This ionic reaction wasslowed down considerably when a-substituents werepresent. NBS reacted faster than NCS, while a-iodinationwas achieved with molecular iodine. This method is supe-rior to the Hell–Volhard–Zelinsky reaction that used chlo-rine and that lacked the selectivity observed with NCS.

Scheme 43

The halogenation of N-benzoyl- and N-Boc-protectedazetidinones 128 with NXS in acetonitrile in the presenceof sodium bicarbonate afforded the 3-halo azetidinones asa mixture of two diastereoisomers, 129 and 130, with thetrans isomer prevailing under kinetic control(Scheme 44).83

Scheme 44

Scheme 41

OR2

OO

R1

F-TEDA

Ti cat. (5 mol%)

NCS

F

OR2

OO

R1

Cl FOR2

OO

R1

Cl

OR2

OO

R1

NCS

F ClOR2

OO

R1

F-TEDA121

122

123

124

125

R1 = alkyl, aryl; R2 = alkyl, Bn, aryl, aralkyl

OR

organocatalyst

NCS O

Cl

R

R = alkyl, allyl, Bn

HH

H

COClCl

COCl

NCS

SOCl2

126 127

R

O

SO2Ph

O

Ph

N

X

R

O

SO2Ph

O

Ph

NX

R

O

SO2Ph

O

Ph

NNXS+

R = Ph, t-BuO; X = Cl, Br, I

128 129 130



The kinetics of chlorine transfer reactions between NCSand four conjugated bases – phenyldinitromethane, Mel-drum’s acid, phenylmalononitrile and phenylnitro-methane – in water were examined.84 A straight-linerelation of log k for the SN2 reactions and the pKa of thefirst three conjugated acids of the nucleophiles was ob-served. The deviation of phenylnitromethane was ex-plained by proton-transfer reactions.

2.8 Chalcogen Compounds

The most widely used chemicals for chlorination of sul-fides are sulfuryl chloride and NCS. NCS is particularlyconvenient because the extent of chlorination can be eas-ily controlled and this reagent can be used with acid-sen-sitive substrates, in contrast to sulfuryl chloride, where aside product is hydrochloric acid. The sulfide chlorinationreaction follows an ionic mechanism that involves a trans-fer of chlorine from sulfur to carbon. The treatment of di-alkyl sulfides and alkyl aryl sulfides with NCS gave a-chlorosulfides which were hydrolyzed without isolationto aldehydes (Scheme 45). On the other hand, the treat-ment of diaryl or alkyl aryl selenides and diaryl or dialkyltellurides with NCS followed by alkaline hydrolysis af-forded the corresponding selenoxides or telluroxides. Asuggested mechanism involves formation of chloroseleni-um and chlorotellurium species that are stabilized in com-parison to chlorosulfonium compounds, which tend torearrange to the a-sulfides.85 The procedure is compatiblewith several sensitive groups, including alkenes, alcohols,ketones and esters.

Scheme 45

NCS treatment of a-phenylselanylesters 135 in carbon tet-rachloride was shown to be an efficient method for thepreparation of a-chloro-a-phenylselanylesters 136 and a-chloro-a,b-unsaturated esters 137 (Scheme 46).86 Treat-ment with 1.2 equivalents of NCS afforded mainly a-chloro-a-phenylselanyl esters, whereas with 2 molarequivalents of NCS, a-chloro-a,b-unsaturated esters wereobtained.

The chlorination of alkyl methyl sulfoxide 138 with NCSafforded mainly 1-chloroalkyl methyl sulfoxides 140. Inthe presence of a base, the regioselectivity was reversedand alkyl chloromethyl sulfoxides 139 were isolated asthe major products; this was rationalized by assuming ab-

straction of a more acidic and less hindered proton by thebase (Scheme 47).87

Sulfones were shown to undergo a-chlorination by treat-ment with n-butyllithium and inverse addition of theformed carbanion to NCS, which was present in excess.88

Sulfonate-stabilized carbanions were chlorinated by NCSin hexamethylphosphoramide (HMPA) in good yields. Aone-pot procedure was developed for the conversion ofphenols 141 into aryl trichloromethanesulfonates 142using NCS, p-methylsulfonylphenyl chloromethane-sulfonate (143) for transfer of chloromethylsulfonylgroup, and a base (Scheme 48).89

Scheme 48

3 Replacement of Other Groups by Chlorine

Using NCS, the replacement of several groups such asOH, COOH and NH2 by chlorine was demonstrated. Site-selective deoxyhalogenation at C-6 of the carbohydrate N-phthaloylchitosan (143) to halides 144 with an NXS–triphenylphosphine system was described. The reactiontook place in polar aprotic solvents (N-methyl-2-pyrroli-done or N,N-dimethylformamide) and proceeded mosteasily with NCS as compared to the other N-halosuccin-imides (NCS > NBS > NIS), reflecting the order of halideion nucleophilicity in this type of solvent (Scheme 49).90

SPh

t-Bu

t-Bu

NCS

Cl

SPh

t-Bu

t-Bu

NaHCO3

H

O

t-Bu

t-Bu

Ph2MNCS

NaOH

131 132

85%

133a M = Se b M = Te

134a 79% b 89%

Ph2M O

Scheme 46

SePh

CO2Et

R

R1

Cl

SePhCO2Et

R

R11.2 equiv NCS

+Cl

CO2Et

R

R1

Cl

ClR1

SePh

CO2Et

R

H

Y–

+

2 equiv NCS

– PhSeCl

135 136 137

R, R1 = H, alkylY = succinimide anion

Scheme 47

O

R1

H

R2

SMe

O

R1

H

R2

SClH2C

O

R1

Cl

R2

SMe

+

O

R1

H

R2

S

Cl–

baseCl–

R1

R2O

SMe

+

O

R1

H

R2

SMe

O ON

R1, R2 = H, alkyl

138 139 140

+

+

SO2Me Cl3CSO2OArNCS

base141 143 142

ArOH + ClCH2SO2O



The reagent is useful also in the preparation of halidesfrom other carbohydrates, nucleosides and other substitut-ed alcohols.91

Scheme 49

Cyclic secondary alcohols undergo kinetic resolution byenantioselective SN2 displacement of hydroxyl groupswith chlorides in the presence of chiral BINAP to affordinverted chlorides in 54–94% ee and unreacted alcohols in69–98% ee and 82–98% yield. NCS was the optimal chlo-rinating agent for achieving good enantioselectivity,while tetrahydrofuran was the best solvent in this re-spect.92

Alkali metal acetates catalyze the Hunsdiecker reaction,in this case the halodecarboxylation of a,b-unsaturatedcarboxylic acids 145 with N-halosuccinimides that led tohaloalkenes 146 (Scheme 50). The reactions, carried outin acetonitrile–water at room temperature, proceeded ingood yields and good stereoselectivities through an ionicpathway.93

Scheme 50

A mild conversion of primary amines into the correspond-ing halides was achieved via a halodeamination reactionof N-substituted N-tosylhydrazines 147 with NCS (orNBS) in anhydrous tetrahydrofuran in the presence oflight (Scheme 51). A suggested reaction mechanism in-volves a stabilized hydrazyl radical which undergoes ha-logenation. Elimination of p-toluenesulfonic acid andnitrogen then affords the alkyl halide.94

Scheme 51

4 Halocyclizations

a-Substituted g,d-unsaturated amides and thioamides 148underwent halocyclization to g-butyrolactones 149 and

150 with several electrophiles, including NCS and NBS(Scheme 52). 1,3-Asymmetric trans induction was mostpronounced for NBS (>99:1); for NCS the ratio of 149 to150 was reduced to 3:2.95

Scheme 52

Haloenol lactones 153 and 154 were prepared from cyclicanhydrides 151 via lactonization of the correspondingketo phosphoranes 152 in the presence of halosuccinim-ides. 1H NMR and 31P NMR studies of the reaction led toa proposed mechanism for the reaction (Scheme 53). Theproducts of this reaction show biological activity and areuseful intermediates in organic synthesis.96

Scheme 53

Chlorolactonization of unsaturated acids was performedwith NCS and phenylselenyl chloride, or with NBS anddiphenyl diselenide, in acetonitrile.61

N-Halosuccinimides were used to carry out the halocy-clization of 4-allyl-1,2,3,4-tetrahydroisoquinoline (155)to azabicyclo[3.2.1]heptanes 156 via a 5-exo-trig route(Scheme 54).97

Scheme 54

NPhthO

OH

HO

O

n NPhthO

X

HO

O

nPPh3, NMP

NXS

X = Cl, Br, I; Phth = phthaloyl

143 144

+ NXSLiOAc (cat.)

R1, R2 = H, Me; X = Cl, Br, I

145 146

R1

Ar

X

R2

R1

Ar

CO2H

R2

NH2R3.

Ts

NH2RN2 NXS

hνXR XTs

O2N

ONH2O2N147

R = alkyl, aralkyl; X = Cl, Br

+

1. TsCl2. base

R2

NMe2

R1Y

NXS

O

X

R2

H

R1Y +

O

X

H

R2

R1Y

R1 = Me, Bn; R2 = Me, H; Y = O, S; X = Cl, Br

148 149 150

O

O

OPh3P=CHCO2R

CO2RH

PPh3

COO–

O

CO2R

PPh3

COOH

O

NXSCO2R

X

PPh3

COO–

O CO2RX

O

O +

XRO2C

O

O

X = Cl, Br, I

151 152

153 154

+

+

NH

NXS

THF

X

N

X = Cl, Br, I

155 156



5 Rearrangements and Functional Group Transformations

NCS can be used to mediate several types of rearrange-ments and functional group transformations.

Cyclic dithiane alcohols 157, with a fused aromatic ring,have been shown to undergo rearrangement to 1,3-dike-tones 158 with a one-carbon ring extension upon treat-ment with excess of NCS (Scheme 55). A key step in theproposed mechanism is conversion of the intermediate binto c with migration of bond ‘a’, a step which is favoredby high electron density on the adjacent carbon atom.98

The treatment of 3-indolecarboxylate 159 with NCS anddifferent primary and secondary alkenols afforded 3-ally-lated 2-indolones 161 in good yield (Scheme 56).99 Thisnovel transformation involves a-chlorination, addition ofalcohol to the imine bond, and [3,3]-sigmatropic rear-rangement of the intermediate 160. This Claisen rear-rangement is highly stereoselective for Z-alkenols.

Scheme 56

The Beckmann rearrangement of ketoximes with a mix-ture of triphenylphosphine and NCS in dichloromethaneat room temperature afforded secondary amides, whereas

primary amides and aldoximes were rapidly convertedinto their corresponding nitriles (Scheme 57).100

Aromatic and aliphatic acids were converted, in excellentyields, into amides in the presence of NCS and triphe-nylphosphine (Scheme 58). The reaction was conductedunder mild conditions and with a wide variety of sub-strates, including the sensitive and sterically congestedabietic acid and primary as well as secondary amines.101

Scheme 58

Epoxides were regioselectively converted into vic-haloal-cohols 163 with 1.2 equivalents of NXS and triphe-nylphosphine in acetonitrile at room temperature. On theother hand, treatment with 2.5 equivalents of NXS andtriphenylphosphine at reflux temperature afforded sym-

Scheme 55

NCS

R3R2

R1

O

O

n n

S S

R3

R2R1

OH

n

ClS S

R3

R2R1

OH

NCS

n

ClS S

R3

R2R1

OH

R3

H Cl

SS

R2

R1

OH

n

Cl

SS

R2

R1

OH

R3

n n

S

S

R2

R1

O

R3

NCS

H2O

a bc

d

a

158157

158

+ ++

CO2Me

1,4-dimethyl-piperazine

Cl CO2Me

NCSHO

CCl3CO2H

O

CO2Me

159

160 161

NH

NH

N

NH

O

MeO2C

Scheme 57

RCONH2

PPh3, NCS

CH2Cl2RCN

PPh3, NCS

CH2Cl2

R2NOH

R1 PPh3, NCS

CH2Cl2

NHR2

O

R1

R = alkyl, Bn, Ph

R = Cl, Br, NO2, Me

R1, R2, Ph, Me

R

CN

R

HC NOH

PPh3, NCSHNRR1

CH2Cl2RCO2H RCONRR1



metrical vic-dihalides. When different N-haloimides wereused successively, unsymmetrical vic-dihalides 165 wereobtained in high yield (Scheme 59).102

Scheme 59

1,3-Oxathiolanes, 1,3-dithiolanes and 1,3-dithianes wereefficiently converted into the corresponding acetals withNCS or NBS and various alcohols and diols. The transfor-mations occurred rapidly at room temperature, preferen-tially in dichloromethane, without liberation of carbonylcompounds (Scheme 60).103

Scheme 60

A new method was elaborated for the synthesis of acetals167 from carbohydrates and aldehydes. It involved the ad-dition of triphenylphosphine to a solution of aldehyde andNCS (or NBS) in anhydrous N,N-dimethylformamidewith formation of methanium salt 166, followed by addi-tion of the carbohydrate (Scheme 61).104

The oxidative hydrolysis of various vinyl halides with ox-ygen-containing groups to a-halomethyl ketones was de-

scribed (Scheme 62). This reaction, affording products ingood yield and purity, required catalytic amounts of thecorresponding hydrohalic acid.105

Scheme 62

The treatment of a,a-diisopropylhomoallylic alcoholswith tin(II) chloride and NCS in dichloromethane at–40 °C gave allylic trichlorotins, which subsequently un-derwent nucleophilic addition to N-tosylimines to affordthe corresponding a-substituted homoallylic amines(Scheme 63).106

Scheme 63

The reaction of secondary amines with sodium nitrite andNXS under phase-transfer catalysis conditions affordedefficiently the corresponding N-nitrosoamines(Scheme 64). Without the catalyst present, N-chloroam-ines were the major products. The proposed mechanisminvolves initial formation of a nitryl halide followed by akey intermediate, nitrogen dioxide.107

Scheme 64

a-Phenylthio secondary propanoamides were stereospe-cifically transformed to (Z)-a-phenylthio-b-chloroprop-enamides upon treatment with NCS (Scheme 65). Thereaction of analogues with extended alkyl chains was lessefficient and was not stereoselective.108

Scheme 65

6 Formation of New Carbon–Carbon Bonds

NCS has been shown to participate in several reactionswherein new carbon–carbon bonds are formed.

OPhO

PPh3, NXS (1.2 equiv)

CH2X

OHPhO

OPhO


CH2X

XPhO

X = Cl, Br, I

X = Cl, Br

1.

2.


PPh3, NX'S (2.5 equiv) CH2X

X'PhO

X' = Cl, Br

162 163

164

165

R2R1

O SNXS

R3OH R2R1

OR3R3O

R2R1

SS

( )n

HO(CH2)3OHCH2Cl2

NXS

R2R1

OO

R1 = aryl, aralkyl, cycloalkyl; R2 = H, Me R3 = Me, Et, -(CH2)n–; X = Br, Cl

R1 = aryl, cycloalkyl; R2 = H, Ph, Me; n = 0, 1

–

Scheme 61

RCHONCS

PPh3

O

O

CHRNMe

MeO

O

OH

CHR

Me

MeO

O

O

– HX

R Me

Me

O

O

O

O

167

166

R = aryl, alkyl; X = Cl, Br

+

+

OH

OH

O

R

O

YNXS

R

Y

Y = Cl, Br; X = Cl, Br, I

SnCl2

NCSTs

NR

OH

i-Pr i-Pr SnCl3

R

NHTs

CH2Cl2, H2O

R = Bn, cyclohexyl, aryl; X = Cl, Br

phase-transfercatalyst

R2NH + NXS + NaNO2 R2NNO

PhS

Me

NHR

ONCS

CCl4Cl

PhSNHR

O

R = p-Tol, alkyl, alkenyl



The aldol-type reaction of aldehydes with propen-2-ylacetate and primary alcohols in the presence of NCS andtin(II) chloride produced 4-substituted 4-alkoxybutan-2-ones 169 in good yield (Scheme 66). When methanol wasused as an alcohol, but-3-en-2-one 170 was also obtainedafter elimination of a molecule of methanol.109 The reac-tion involved the formation of hemiacetal 171 from the al-dehyde and alcohol with the participation of NCS·SnCl2,followed by nucleophilic attack of propen-2-yl acetate.

Dimesitylboron-stabilized carbanions 172 react with ali-phatic aldehydes in the presence of NCS (or trifluoroace-tic acid anhydride) to afford, after an acidic workup, thecorresponding ketones 173 in a type of boron-Wittigtransformation (Scheme 67). This condensation–redox re-action proceeded in satisfactory yields for aldehydes withprimary and secondary alkyl groups; as the only exeption,anion substrates derived from dimesitylmethylborane un-derwent mainly an alternative reaction to afford the corre-sponding alkenes.110

Scheme 67

Nucleophilic displacement on sulfur of dimethylsuccin-imidosulfonium fluorosulfate (174) by morpholine en-amine 175 afforded sulfonium enamine 176 which, upon

heating with sodium cyanide in acetonitrile, furnished iso-meric cyanomorpholine bicyclo[n.1.0]alkanes 177 and/or178 (Scheme 68).111

The regioselective methylthiomethylation of various,mostly 2,6-disubstituted, phenols with excess succinimi-dosulfonium chloride (Corey–Kim reagent) was exam-ined. The reaction, carried out in the presence oftriethylamine, afforded several types of mono-, bis- andtris-substituted cyclohexa-2,4-dien-1-ones in good yieldsvia rearrangement of the oxasulfonium salts 179(Scheme 69).112

Alternatively, reaction of the Corey–Kim reagent with ex-cess monosubstituted phenols furnished the o-methyl-thiomethylated phenols.113 This reagent induced thecyclization of tryptamine derivatives with concomitant in-troduction of the methylthiomethyl group at C-3.114

An oxidative homo-coupling of arylzinc compounds wasachieved in the presence of a catalytic amount of Pd2+ orPd0 through the use of NCS as an oxidant. This reactionrevealed a new and facile synthetic method for the prepa-ration of biaryls from aryl halides or arenes via arylzincintermediates (Scheme 70).115

Scheme 66

OCOMeMe + R1CHO

SnCl2, NCS

ROHCH2Cl2

ROHR1CHO

NCS

– ROH

169

SnCl2

168

R1 = aryl, cycloalkyl, alkyl; R1 = alkyl, alkenyl, Bn

171

170 169

MeR1

OR O

168

N SnCl3

O

OR1 OSnCl3

RO H

R1 Me

OCOMe+

OR

R1 Me

OR O

R1 Me

O

Mes2BCHR1 Li R2CHO CH2R1

O

R2C

O–Li+HCR2

Mes2BCHR1

H

R2

CO

CHR1Mes2B

Li

O R2C

Mes2BCHR1

R1CH CR2

OBMes2HCH2R1

O

R2C

O

O

Cl N

R1 = alkyl, H; R2 = alkyl, Bn, aryl

172 173

– +

+

+

–

172 + R2CHO

+

Scheme 68

(CH2)n

O

NNCS·SMe2

FSO3

(CH2)n

SMe2

O

N

FSO3

H

NC

H

O

N

(CH2)n

CN +NC

HH

O

N

(CH2)n

175 176

177 178

n = 4–9

174

+

–

+

–

–

*



Scheme 70

7 Formation of Heterocyclic Systems

N-Halosuccinimides have been used to enable new syn-theses of heterocyclic systems. The treatment of phenylisocyanide with NXS and sodium azide under phase-transfer catalysis conditions afforded 5-halo-1-phenyltet-razoles 180 in good yields (Scheme 71). The active spe-cies are probably halogen azides which add to the phenylisocyanide.116

Scheme 71

The reaction of some cyclopentenes and indenes with di-sulfur dichloride in tetrahydrofuran in the presence ofNCS and a base (DABCO or DIPEA) enabled an effectiveconversion into several unsaturated and chlorinated fusedheterocyclic and carbocyclic compounds (Scheme 72).Cyclopent-1-en-1-ylacetic acid (181) afforded the trichlo-rocyclopenta[1,2]dithiole ester 182 via the correspondingacid as a result of tetrahydrofuran cleavage by disulfurdichloride. Inden-3-ylacetic acid (183) furnished methyl-eneindenes 184 and 185, 1,2-dithiolone 186, and thiophe-none derivative 187, a new liquid crystalline material.117

Scheme 72

3-Amino-1H-indene-2-carbonitrile (188) reacted withsulfur dichloride, triisobutylamine and NCS to give thecorresponding indeno[1,2,6]thiadiazine 189 in a reactionthat involved dehydrogenation and chlorination of the cy-clopentathiazine moiety (Scheme 73).

Scheme 73

Under similar conditions, 2-aminocyclopent-1-enecarbo-nitrile (190) afforded the cyclopenta[1,2,6]thiadiazine191, and 2-aminocyclohept-1-enecarbonitrile yielded aformally antiaromatic cyclohepta[1,2,3]dithiazole.118

Scheme 69

OHSMe2

O

O

NSMe2O

R

Cl

Et3N

R2

SMeR1R3

O

R3 R1

SMe

R2

SMeR4

O

R1

MeS

R2

SMe

SMe

O

179

+ –

+

R

IZn

ZnIPd catalyst

NCS

RR

n-BuLi

THF

ZnX2

Pd catalyst

NCS

RR

62–95%

80–95%

R R

R

NXS + N3 N3X CPhN

N3

XCPhN

N3

XCPhN

X N

N N

N180

X = Cl, Br, I

–+

Ph

CO2H

S2Cl2, NCS

CO2H

S2Cl2 Cl

Cl

Cl

Cl

Cl

+

+

181 182

183 184 185

186 187

baseTHF

S

S

Cl

Cl

Cl

O OCl

NCSbase

ClCl

S

S

O

S

Cl

Cl

O

Cl

COClCl

NH2

CN SCl2, NCS(i-Bu)3N

ClCl

NH2

CNSCl2, NCS

(i-Bu)3N

188 189

190 191

N

N

S

ClCl

N

N

S



Some of the product compounds showed useful featuresas new liquid crystals and near-IR dyes.

The application of the Pummerer reaction methodology toN-acylamino-2-thiophenyl derivatives with NCS andtin(IV) chloride provided a direct synthesis of 5-thiophe-nyloxazoles (Scheme 74).119

Scheme 74

The treatment of triphenylformazanes 192 with NCS (orNBS) resulted in cyclodehydration and formation of2,3,5-triphenylterazolium halides 193. Similarly, syn-phenylhydrazones of 2-pyridinealdehyde 194 afforded 8-azaindazolium salts 195 (Scheme 75).120

Scheme 75

8 Oxidations

The oxidation of alcohols by NCS requires the presence ofappropriate catalysts.

Primary alcohols are chemoselectively oxidized by NCSto aldehydes in the presence of 2,2,6,6-tetramethyl-1-pip-eridinyloxy (TEMPO) catalyst. A broad range of aliphat-ic, benzylic and allylic alcohols were oxidized, withoutany over-oxidation (Scheme 76). The reactions were car-ried out in dichloromethane–aqueous buffer system (pH8.6) at room temperature in the presence of tetrabutylam-monium chloride (TBACl) as a phase-transfer agent. Theoxidation of secondary alcohols proceeds with a muchlower efficiency and at a rate that is at least one order ofmagnitude lower than that observed for primary alco-hols.121

Scheme 76

Japanese chemists examined the use of N-tert-butylben-zenesulfenamide as a catalyst in the oxidation of variousprimary and secondary alcohols to the corresponding car-bonyl compounds.122 The reaction was performed in thepresence of potassium carbonate and molecular sieves.Selective oxidation of primary hydroxy groups took placewhen diols were subjected to the reaction, albeit in mod-erate yields (Scheme 77). A mechanistic investigationsuggested that a key species in the chlorination was N-tert-butylbenzenesulfinimidoyl chloride (formed from N-tert-butylbenzenesulfenamide and NCS), which oxidizedthe alcohols to the carbonyl products while regeneratingthe catalyst.

Scheme 77

In another variant of this approach, polymer-supportedsulfinimidoyl chlorides were used either as catalysts withNCS or in stoichiometric amounts.123 In the first case,longer reaction times were required than in the case ofmonomeric sulfonamide.

The frequently applied oxidation of alcohols by the Co-rey–Kim reagent (NCS·SMe2 complex) is related to theoxidation that is mediated by activated dimethyl sulfoxideand has been reviewed.124 A newer example of this reac-tion is shown in Scheme 78.125 The oxidation of b-hy-droxy ketones (prepared from isoxazolines by reductivehydrogenation) with NCS·SMe2 and triethylamine afford-ed the stabilized sulfonium ylides 196 which were de-sulfurized with zinc in acetic acid. In the search for a moreuser-friendly variant of this reagent, an odorless complexof NCS and dodecyl methyl sulfide was introduced.126

Scheme 78

The kinetics and mechanism of the palladium(II)-cata-lyzed oxidation of allyl alcohol by NCS in aqueous alka-line medium was studied by an Indian research group.127

A mechanism involving the hypochlorite ion as the reac-tive species of the oxidant was proposed.

NCS, PhCl

SnCl4

R

SPh

R1N

O50–77%

R R1

SPh

HN

O

R = aryl, heteroaryl, alkyl; R1 = Ph, alkyl, H

Ph Ph

Ph

N

NN

N

HNXS

Ph Ph

Ph

N

NN

N X

Ph

HNN

NXS

PhN

NX

192 193 194 195

X = Cl, Br

+

– +–

N

RCH2OHNCS, TEMPO

CH2Cl2/H2OTBACl

RCHO

( )8 OH

OH

Me

NCS, TEMPO

CH2Cl2/H2O

TBACl( )8

CHO

OH

Me

R = alkyl, aralkyl, alkenyl, aralkenyl

82%

83–100%

R2

OH

R1PhSNHt-Bu

NCS

K2CO3, 4 Å MS R2

O

R1

R1, R2 = H, aryl, alkyl, alkenyl

96%

PhSNHt-BuNCS

K2CO3, 4 Å MSPh Me Ph Me

OH O

NCS·SMe2

Et3N, –78 °CCH2Cl2

R1, R2 = aryl

Zn

AcOH

196

R1 R2

O OH

R1 R2

O O

SMe2

R1 R2

O O



The oxidation of aryl and alkyl thioacetates, as well asseveral thiols and disulfides, by a combination of NCSand dilute hydrochloric acid afforded the correspondingsulfonyl chlorides in good yield.128 A smooth reactioncourse was envisaged to involve the rapid generation ofreactive molecular chlorine.

The oxidation of dialkyl, diaryl and benzylphenyl sulfidesby an equimolar amount of NCS gave sulfoxides. In aque-ous solution containing chloride ion, the first step is chlo-rination by chlorine, formed in the reaction, followed byhydrolysis to afford the corresponding sulfoxides(Scheme 79). In alcoholic solutions, alkoxysulfoniumsalts were postulated as intermediates. Diphenyl sulfox-ides afforded the corresponding sulfones in the presenceof excess NXS, while dialkyl sulfides gave only cleavageproducts.129

Scheme 79

The kinetics and mechanism of the oxidation to sulfoxidesof aromatic sulfides and arylmercaptoacetic acids by NCSwas examined.130 The measurements, carried out in anacetonitrile–water mixture, showed that protonated NCSand NCS are the active oxidizing species in the oxidationof aromatic sulfides, and NCS is the active species in thecase of phenylmercaptoacetic acids. Structure–reactivitycorrelations for the oxidation of the sulfides and arylmer-captoacetic acids indicated that chlorosulfonium ion wasan intermediate.

A similar mechanism was proposed for the oxidation withN-halosuccinimides of diaryl or alkylaryl selenides anddiaryl or dialkyl tellurides.85c NCS was found to be a muchbetter oxidant than NBS. The reactions with a positivehalogen source required a subsequent alkaline hydrolysisto afford the corresponding selenoxides or telluroxides (orhydrates) (see Scheme 45).

The oxidation of the amino acid cysteine and its deriva-tives into cystine was performed with NCS.131 NCS wasfound to be one of two specific reagents capable of oxidiz-ing methionine to the corresponding sulfoxide.132

The kinetics of the palladium(II)-catalyzed oxidation ofmaleic and crotonic acids by NCS in perchloric acid waspresented.133 The oxidation of maleic acid afforded glyox-ylic acid, while that of crotonic acid gave acetaldehydeand glyoxylic acid. Mechanistic steps were discussed onthe basis of kinetic observations and product analysis.

Oxidation of bromide ion with NCS afforded brominechloride, which, in reaction with cyclohexane, yielded amixture of 1-bromo-2-chlorocyclohexane and 1,2-dibro-mocyclohexane.134

9 Deprotections

Both NCS and NBS have been shown to be effectivedeoximating agents. The parent ketones were obtained inexcellent yields by stirring oximes and NCS (or NBS) atroom temperature in carbon tetrachloride.135

A novel method was invented for the chemoselectivedeprotection of S,S- and S,O-acetals and ketals, in thepresence of their O,O-analogues, to the carbonyl com-pounds.136 The reactions were carried out efficiently in achloroform solution at room temperature with catalyticamounts of NCS, NBS, or similar sources of electrophilichalogens, in the presence of dimethyl sulfoxide as thesource of oxygen. The suggested mechanism involves ha-logenation on the sulfur atom and nucleophilic attack ofthe dimethyl sulfoxide oxygen at the central carbon atom.

10 Transformations of NCS

NCS has been used as a convenient source of NIS. Thiselectrophilic iodination reagent was prepared by treat-ment of NCS with sodium iodide in acetone and subse-quent filtration of the precipitated sodium iodide.137

Similarly, NBS was obtained from NCS by reaction withtetraethylammonium bromide.138

The chlorine atom in NCS can be substituted by sulfurnucleophiles, such as tetrahydrothiophene,139 3H-benzo-thiazole-2-thione140 or dialkylsulfides, to result in the for-mation of succinimidosulfonium chloride.141 The reactionof NCS with an equimolar amount of sulfur in dichloro-ethane in the presence of tetrabutylammonium iodideafforded N-chlorothiosuccinimide. A similar reaction oc-curred upon heating of NCS with excess sulfur dichloride.Subsequent heating of the resulting N-chlorothiosuccin-imide in inert solvents was accompanied by loss of sulfurdichloride and formation of disuccinimidosulfide(Scheme 80).142

Scheme 80

11 Miscellaneous Reactions

Early investigations into the halogenation of saturated hy-drocarbons with NCS were moderately successful in thealicyclic series, where cyclohexyl chloride was preparedin 42% yield from cyclohexane after heating at reflux for12 hours. NBS proved to be less convenient because somedecomposition was observed upon prolonged heating.143

The treatment of N,N-dialkylsulfenamides with NCS insolution with dichloromethane yielded dialkylamino suc-cinimidosulfonium chlorides. These products underwent

RS

Ph+ NCS Cl

RS

Ph H2OO

RS

Ph+ HCl + H+

O

O

ClN

O

O

SClN

O

O

N

O

O

N

SCl2

S8

DCE S



nucleophilic displacement on sulfur by carbanions,formed from active methylene compounds, to afford thenovel stabilized sulfur ylides 197 (Scheme 81).144

Scheme 81

NCS was found to be a more satisfactory reagent than sul-furyl chloride in the conversion of hydrogen phosphatesinto phosphorochloridates 198, since the reaction mediumremains neutral (Scheme 82).145

Scheme 82

N-Halosuccinimides (NCS and NBS) were also shown tomediate the alkoxylation at C-7 of pyrazino[2,3-c][1,2,6]thiadiazine-2,2-dioxides 199 with lower alcohols(Scheme 83). Some evidence indicates that the reactiondoes not involve the 7-halointermediates and may insteadbe mediated by free radicals, since it can be catalyzed bytypical free-radical initiators such as tert-butylhydroper-oxide.146

Scheme 83

The N,N-dimethylformamide-induced reaction of [(Z)-1-bromo-1-alkenyl]dialkylboranes 200 with NXS affordedthe 1,2-disubstituted (E)-vinyl bromides in a stereoselec-tive manner (Scheme 84). The envisaged reaction mecha-nism includes the formation of a halonium ion and the 1,2-migration of the alkylaminoboryl and halogeno groups.147

Scheme 84

The stereoselective synthesis of b-alkyl-a-halocarboxylicacids 202 was achieved by a reaction cascade comprisingthe 1,4-addition of dialkyl aluminum chlorides to a,b-un-

saturated N-acyloxazolidinones substituted with chiralauxiliaries 201, followed by the reaction of aluminumenolates with N-halosuccinimides and, finally, basic hy-drolysis (Scheme 85).148 Oxazolidinones derived fromglucosamine showed the highest stereocontrol.

Scheme 85

12 Biological Activity of NCS

NCS exhibits bacteriostatic and bactericidal activity re-sulting from its strong oxidative action.149 Studies of cel-lular mechanisms in Escherichia coli and Staphylococcusepidermis showed that this chloramine inhibited the ac-tion of enzymes containing sulfhydryl groups that inter-fere with the synthesis of bacterial DNA, RNA andproteins.

13 Conclusions

This review has demonstrated the broad synthetic utilityof NCS. The versatility and selectivity of this reagent canbe further enhanced and modified by the formation ofcomplexes with Lewis bases (PPh3, sulfides), and com-pounds with Lewis acids. The reactivity of NCS can be al-tered within a wide range – from nucleophilic properties(in the presence of Lewis bases), through free-radical re-activity, to electrophilic character – depending on the sub-strate, solvent, reaction conditions and the presence ofcatalysts and additives. NCS possesses general acid–baseproperties and is thermally and photochemically the moststable of the three N-halosuccinimides.

Further applications of NCS and its derivatives can be ex-pected. One of the possible new avenues could be the ap-plication of chiral complexes with participation of NCS.

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Applications of N-Chlorosuccinimide in Organic Synthesis€¦ · of Industrial Organic Chem-istry in Warsaw. Since 2001 he has been carrying out graduate research under su-pervision