Chlorosulfonyl Isocyanate1

ClSO2NCO

[1189-71-5]  · CClNO3S  · Chlorosulfonyl Isocyanate  · (MW 141.53)

(most chemically reactive isocyanate;1 CSI can undergo two types of nucleophilic addition, namely to the carbonyl carbon and to the sulfur of the sulfonyl chloride; the isocyanate portion can undergo formal cycloaddition)

Alternate Name: CSI.

Physical Data: mp -44 to -43 °C; bp 107-108 °C/760 mmHg, 38 °C/50 mmHg; d204 = 1.626 g cm-3; n27D = 1.4435.

Solubility: sol most organic solvents; reacts violently with water.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: reacts explosively with water to form sulfamic acid, hydrogen chloride, and carbon dioxide; fumes slightly in air, has a choking smell, and undergoes thermal decomposition only above about 300 °C. Glass stoppers of bottles used for storage of CSI stick fast after a short time, even when covered with silicone grease, so that polyethylene bottles with screw caps are best for longer storage times (a few weeks); can be kept indefinitely in sealed glass ampules. Suitable solvents include saturated aliphatic hydrocarbons (more or less limited solubility below 0 °C), aromatic hydrocarbons such as benzene and toluene, chlorinated hydrocarbons such as CH2Cl2, CHCl3, CCl4, and chlorobenzene, diethyl ether, diisopropyl ether, and acetonitrile. Liquid sulfur dioxide is particularly favorable, since it increases the reactivity of CSI still further. Solvents such as acetone and ethyl acetate can be used to a limited extent, but only at low temperatures.

Classification of Reactions.

CSI is probably the most chemically reactive isocyanate known, and has been the subject of several reviews.1 It can be synthesized by reaction of sulfur trioxide with cyanogen chloride.2

Reactions with CSI are classified according to the probable site of reaction. The CSI molecule has two electrophilic sites for attack by nucleophilic reagents, namely the carbonyl carbon (Class I) and the sulfur of the sulfonyl chloride group (Class III). The isocyanate portion can also undergo formal cycloaddition reactions (Class II), which makes CSI a very versatile reagent (eq 1).

Class I: Addition Involving Initial Attack on the Isocyanate Carbon.

CSI undergoes nucleophilic additions by alcohols (thiols/phenols) and amines to yield N-chlorosulfonyl carbamates and urea derivatives, respectively, which can undergo further transformations with water/alcohol/amine (eq 2; X = OR, SH, or NR2).1 Primary alcohols can be selectively derivatized with CSI in the presence of other groups without affecting, in general, other sterocenters in complex molecules (eqs 3 and 4).3a,3b

The reagent obtained by reaction of CSI with methanol followed by treatment of the intermediate with Triethylamine (eq 5) has been used to synthesize carbamates from primary alcohols and to dehydrate secondary alcohols.4 The above intermediate itself has been used for the synthesis of various heterocycles.5 Similar intermediates obtained from reaction of CSI and 2,4,6-trichlorophenol are found to be useful bactericides and fungicides,6 and can be further transformed to the isocyanates by treatment with alcohols followed by pyrolysis of the resultant carbamates (eq 6).7

The reaction of CSI with hydroxy groups of a-hydroxy ketones, followed by thermal ring closure of the intermediate carbamate, results in the formation of oxazolones (eq 7).8

Thiocarbamates are obtained from the reaction of CSI with thiols (eq 8), and have been used for the synthesis of potential herbicides.9

CSI also undergoes reaction with amides, sulfonamides (eq 9), and certain phosphoramides.10,1b The addition products can be readily converted to the corresponding isocyanates by pyrolytic elimination of the sulfamoyl chloride. However, the dipolar intermediate postulated for the reaction of N,N-dialkylamides produces amidines through loss of carbon dioxide (eq 10).11 The amidines were further derivatized to prepare insecticidal and acaricidal compounds.12

The generality of the reaction of CSI with acetals of aliphatic aldehydes,13 and similar reactivity of orthoesters,1b has been reviewed. The reaction of acetals has been used for the conversion of isopropylidine-protected sugars to the corresponding carbonates (eq 11).14 A similar reaction sequence with carboxylic acids15 sometimes provides intermediate N-chlorosulfonylcarboxamides which are stable enough to be isolated, or which can be treated with N,N-Dimethylformamide to provide a one-pot synthesis of nitriles (eq 12). The reported16 anhydropenicillin rearrangement (eq 13) is believed to proceed by an intermediate similar to that described above. Interestingly, such an intermediate also has been used as a mild reagent for displacement of an N-trimethylsilyl group.17

Aromatic compounds undergo facile reaction with CSI. Treatment of the resultant N-chlorosulfonylcarboxamides with DMF in situ afforded the corresponding nitriles (eq 14).18

Nucleophilic attack by aldehydic carbonyl groups on the isocyanate carbon atom gives products as shown in eq 15, by way of 1,4-dipolar intermediates.13 Reaction of arylmethylene malonaldehydes with CSI has provided bicyclic 1,3-oxazin-2-one derivatives (eq 16).19

Enolizable ketones upon treatment with CSI produce N-chlorosulfonyl-b-ketocarboxamides, which have been used for the synthesis of b-ketonitriles by in situ treatment with DMF (eq 17).20 However, in the presence of excess CSI, ketones with two a-hydrogens have been observed to undergo further transformations (eq 18).21 The final product distribution depends on solvent, substituents, and concentration. Nonenolizable ketones, such as benzophenone and g-pyrones,22 produce azomethines (eq 19). The azomethine intermediate of benzophenone further cyclizes to provide benzoisothiazole (eq 20).13 a,b-Unsaturated ketones are converted into 3,4-dihydro-1,3-oxazin-2-ones (eq 21).13

b-Diketones and b-keto esters react with CSI to produce amides (eqs 22 and 23).13 Heterocycles have been obtained from the reaction of CSI with amino compounds having ester or carbonyl functions.23 The reaction of CSI with ethyl 3-oxo-2-(arylhydrazono)butanoates gives thiazolotriazinediones (eq 24).24

CSI has been used as a dipolar synthon of the type shown in eq 25 in its reaction with cyanohydrins. The final products of this one-pot reaction are 5,5-disubstituted 2,4-oxazolidinediones.25

The reagent has been used to introduce the nitrile functionality in cyclic enamides (eq 26)26 and in some other electron-rich alkenes (eqs 27 and 28).27,28

An attempt to use CSI as a dienophile in its reaction with 2-vinylindole was not successful (eq 29).29 The product obtained was the indole-3-carboxamide, as reported earlier.30 Similar electrophilic substitution on pyrroles31 and thiophene32 using CSI in the presence of DMF has furnished the respective cyanation products.

Brief treatment of CSI with epoxides at low temperature has provided the corresponding 1,3-dioxolan-2-ones (major products) and oxazolidine-2-one derivatives (eq 30).33 This reaction is both regio- and stereospecific. Aziridines have also provided analogous products from their reaction with CSI.33a 1,2-Diols having substituents with good migratory aptitudes gave the rearrangement products, but unsubstituted or alkyl substituted 1,2-diols gave the corresponding carbamates as the major product (eq 31).34

CSI also has been used as a mild chlorinating agent in its reaction with 6-aryl-3(2H)-pyridazinones to produce 6-aryl-3-chloropyridazines (eq 32).35 1-Trimethylsilylalkynes react with CSI to produce primary 2-alkynamides after hydrolysis (eq 33).36 CSI reacts with nitrones derived from cyclic conjugated ketones to produce enamides (eq 34),37 and with substituted nitrones to produce amides (eq 35).38 Similar reactions with substituted 3,4-dihydro-2H-pyrrole 1-oxide produce 2H-pyrroles (eq 36).39

Recently, a facile denitrosation of N-nitrosoamines has been demonstrated by Dhar et al. (eq 37).40 The reactivity of CSI towards sulfoxides41 has been used for the reduction of sulfoxides to sulfides in the presence of Sodium Iodide (eq 38).41c

The new reagent N-carbo(trimethylsilyloxy)sulfamoyl chloride, obtained from CSI as a substitute for sulfamoyl chloride, has been used for the synthesis of 3-amino-4-N-alkyl-5-aryloxy-1,2,4,6-thiatriazine-1,1-dioxides.42

Class II: Cycloaddition to Isocyanate C=N.

The formal [2 + 2] cycloaddition of CSI to a variety of alkenes to produce b-lactams has been the most thoroughly studied reaction (eq 39).43 A competing elimination reaction (path b) forms an alkene byproduct. The ratio of b-lactam to alkene is determined by the pattern and type of substitution on the alkene. Both concerted and nonconcerted 1,4-dipolar mechanisms have been proposed for these reactions. Regiochemistry is dictated by the formation of the most stable carbocation, and the cis adduct is generally formed. Several examples are given in review articles,1 which show the diversity of b-lactams available from this route. An improved procedure for b-lactam formation from volatile alkenes and CSI has been published.44

Reaction of CSI with conjugated or nonconjugated dienes also leads to 2-azetidinones after hydrolysis of the N-chlorosulfonyl group (eqs 40 and 41).45

The reaction of CSI with vinyl acetates leads to 4-acetoxy-2-azetidinones upon hydrolysis (eq 42).46 These b-lactams are ideal building blocks for synthesis of a wide variety of classes of antibiotics. The resulting b-lactams are also convenient precursors to erythro- and threo-amino acids.47

CSI reacts with functionalized allenes to provide a-alkylidene b-lactams (eq 43).48

Alternative acyl and sulfonyl isocyanates that are preparatively useful for b-lactam synthesis include Cl3CH2OSO2NCO, Cl3CH2SO2NCO, and CF3CONCO.49 Methods for deprotection to the core b-lactam are described.

CSI has been useful as a mechanistic probe to study uniparticulate electrophilic addition to a number of fluxional molecules such as bullvalene, barrelene, and homobarrelene.50

CSI yields 2:1 adducts with Schiff's bases to form s-triazinediones (eq 44).51

As a result of their large degree of p character, highly strained carbon-carbon single bonds can undergo formal cycloaddition with CSI (eq 45).52

CSI reacts with most alkynes to give six-membered heterocyclic ring structures. Hydrolysis affords ketones (eq 46), while methanolysis affords b-keto esters. Interestingly, only the alkynic portion of 1-octene-4-yne reacts with CSI.53

Azirines react with CSI to give three products derived from [2 + 2 + 2] cycloadducts (eq 47).54

Amidines react with CSI to form mesionic compounds with an interesting structure (eq 48).55

Regioselective 1,3 dipolar cycloaddition of nitrile oxides with CSI gives 3-aryl-substituted 1,2,4-oxadiazolin-5-ones after hydrolysis (eq 49).56

Transition metal 2-alkenyl and 2-alkynyl complexes undergo [3 + 2] cycloadditions with CSI, which lead to pyrrolidones and pyrrolinones respectively with migration of the metal atom (eqs 50 and 51).57

Type III Reactions.

Type III reactions involve compounds which react with the chlorosulfonyl portion of CSI. These include compounds which are unreactive towards the isocyanate group (eqs 52 and 53)58,59 or which react with the chlorosulfonyl portion under special experimental conditions such as high temperature (eq 54)60 or radical conditions (eq 55).61

By changing the reaction conditions in eq 55, a dramatically different product is obtained (eq 56).1a


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Marvin J. Miller, Manuka Ghosh, Peter R. Guzzo, Paul F. Vogt & Jingdan Hu

University of Notre Dame, IN, USA



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