p-Toluenesulfonyl Chloride1

[98-59-9]  · C7H7ClO2S  · p-Toluenesulfonyl Chloride  · (MW 190.66)

(sulfonyl transfer reagent; O-sulfonylation of alcohols2 for conversion to chlorides3 or intermolecular4 and intramolecular5 displacements, vicinal diols for epoxidation,6 1,3-diols for oxetane formation,7 carboxylic acids for esterification8 or decarboxylation,9 oximes for Beckmann rearrangements10 or fragmentations11 and Neber rearrangements,12 hydroxamic acids for Lossen rearrangements,13 nitrones for rearrangements,14 conversion of N-cyclopropylhydroxylamines to b-lactams;15 N-sulfonylation of aliphatic amines16 for subsequent deamination17 or displacement,18 aromatic amines for protection;19 C-sulfonylation of alkenes20 and silylalkynes;21 dehydration of ureas,22 formamides,23 and amides24)

Alternate Names: tosyl chloride.

Physical Data: mp 67-69 °C; bp 146 °C/15 mmHg.

Solubility: insol H2O; freely sol ethanol, benzene, chloroform, ether.

Form Supplied in: white solid, widely available.

Purification: upon prolonged standing the material develops impurities of p-toluenesulfonic acid and HCl. Tosyl chloride is purified by dissolving 10 g in a minimum volume of CHCl3 (ca. 25 mL), filtering, and diluting with five volumes (ca. 125 mL) of petroleum ether (bp 30-60 °C) to precipitate impurities (mostly tosic acid, mp 101-104 °C). The solution is filtered, clarified with charcoal, and concentrated to ca. 40 mL by evaporation. Further evaporation to a very small volume gives 7 g of pure white crystals (mp 67.5-68.5 °C).25

Tosyl chloride may also be recrystallized from petroleum ether, from benzene, or from toluene/petroleum ether (bp 40-60 °C) in the cold. Tosyl chloride in diethyl ether can be washed with aqueous 10% NaOH until colorless, then dried with Na2SO4 and crystallized by cooling in powdered dry ice. It can also be purified by dissolving in benzene, washing with aqueous 5% NaOH, drying with K2CO3 or MgSO4, and distilling under reduced pressure.26

Handling, Storage, and Precautions: freshly purified tosyl chloride should be used for best results. Tosyl chloride is a moisture-sensitive, corrosive lachrymator.

General Discussion.

The tosylation of alcohols is one of the most prevalent reactions in organic chemistry.1 Optimized conditions for this reaction include the use of a 1:1.5:2 ratio of alcohol/tosyl chloride/pyridine in chloroform (eq 1).2a This procedure avoids formation of unwanted pyridinium salts inherent to reactions where higher relative quantities of pyridine have been employed.2b

Good yields (81-88%) for tosylation have also been observed under biphasic conditions where Benzyltriethylammonium Chloride is employed as a phase-transfer catalyst between benzene and aqueous sodium hydroxide solution.2c

It has long been known that it is possible to selectively tosylate primary over secondary alcohols (eq 2).2d

It is also possible to regioselectively mono-O-tosylate various nonprotected hydroxyl functionalities, as illustrated in Scheme 1.2e This method employs a preliminary activation of a glycopyranoside with Di-n-butyltin Oxide and usually requires the use of a basic catalyst such as 4-Dimethylaminopyridine (DMAP) in conjunction with tosyl chloride. Regioselectivity differs markedly from acylation reactions and is thought to be a function of changes in the kinetics of the reactions with the various tin intermediates which are in equilibrium.

Regioselective mono- and ditosylation of aldonolactones has also been reported.2f A few of these products are shown in Scheme 2. In no instances was the b-hydroxy function tosylated.

The regioselective tosylation of various cyclodextrins has been reported. The two major products resulting from the tosylation of b-cyclodextrin are heptakis(6-O-(p-tosyl))-b-cyclodextrin (1) and heptakis(6-O-(p-tosyl))-2-O-(p-tosyl))-b-cyclodextrin (2).2g,h Yamamura has also prepared hexakis(6-O-(p-tosyl))-a-cyclodextrins2i as well as polytosylated g-cyclodextrins.2j

By proper choice of base it is possible to selectively O-tosylate in the presence of a free amine or N-tosylate in the presence of a free hydroxyl, with yields in excess of 94% (eq 3). The probable explanation for selective O-tosylation in the presence of the stronger base is formation of an adequate amount of phenoxide to allow the anion to act as the nucleophile.2k

Tosyl chloride has been used in the preparation of allylic chlorides from their respective alcohols, leaving in place sensitive groups and with no rearrangement of the allylic substrate (eq 4).21

Studies on reactions of various types of alcohols with the related tosyl chloride/dimethylaminopyridine (TsCl/DMAP) system have led to the following conclusions: allylic, propargylic, and glycosidic hydroxyls quickly react to form the corresponding chlorides, 2,3-epoxy and selected primary alcohols yield chlorides but at a slower rate, and reactions of aliphatic secondary alcohols stop at the tosylate stage. Example reactions are illustrated in eqs 5-10.3a

Attempted tosylation of 3b-methoxy-21-hydroxy-5a-pregnan-20-one afforded its a-chloro derivative.3b This reinforces the rule that as hybridization a to the alcohol increases in s character, displacement of the intermediate tosylate is facilitated (eq 11).

The a-chlorination of sulfoxides can also be achieved using tosyl chloride and pyridine, albeit in poor yield (32%), as shown in eq 12.3c

Alcohols treated with tosyl chloride are transformed into their corresponding sulfonate esters without manipulation of existing stereochemistry in the substrate. The p-toluenesulfonyloxy moiety subsequently serves as a good leaving group in intermolecular nucleophilic substitution or elimination reactions.4 Treatment of multifunctional alcohols with tosyl chloride can result in the formation of intermediate O-sulfonylated species, which can undergo intramolecular displacement of the tosylate group. For example, treatment of trans-2-hydroxycyclohexaneacetamide with tosyl chloride in pyridine is the key step in the conversion of the lactone of trans-2-hydroxycyclohexaneacetic acid to its cis isomer (eq 13).5a

Alcohols treated with tosyl chloride can also serve as alkylating agents for thioamides to make thiazolines (eq 14).5b

Several useful one-pot procedures employing the reaction of tosyl chloride with vicinal diols have been used to form epoxides. Treatment of variously substituted diols with 1 equiv of tosyl chloride and sodium hydroxide in monoglyme provides access to a variety of 1-alkynyloxiranes (R1 and/or R3 being terminal or substituted alkynes) in moderate to good yield (eq 15).6a

Another method entails treatment of the diol in THF with 2.2 equiv of Sodium Hydride followed by reaction with a slight molar excess of tosyl chloride. This fast reaction, illustrated in eq 16, can be used to prepare enantiopure epoxides in good to excellent yields.6b

Phase-transfer catalysis has also been successfully employed to achieve epoxidation. A variety of cyclic trans-substituted diols in dichloromethane were treated with a 50% aqueous solution of sodium hydroxide in the presence of the phase-transfer catalyst benzyltriethylammonium bromide. Consistently good yields were achieved for these as well as glycosidic and acyclic substrates (eq 17).6c

A one-pot conversion of a variety of 1,3-diols to oxetanes has also been reported.7 The procedure entailed alcohol deprotonation with one equivalent of n-Butyllithium followed by treatment with tosyl chloride and then a second equivalent of base (eq 18).

When a solution of a carboxylic acid and an alcohol in pyridine is treated with tosyl chloride, an ester is formed rapidly in excellent yield. This procedure is useful especially in the esterification of tertiary alcohols. The combination of a carboxylic acid and tosyl chloride serves as a convenient method of in situ preparation of symmetrical acid anhydrides for further formation of esters and amides (eq 19). The novelty of this protocol is that the acid can be recycled through the anhydride stage in the presence of the alcohol, thereby resulting in complete conversion to the ester (eq 20).8a Reactivity is determined by the strength of the acid: strong acids facilitate the esterifications.8b

Similarly, a two-step procedure employing treatment of a mixture of tosic acid and various amino acids with alcoholic tosyl chloride results in the isolation of the esters of the amino acids as their p-toluenesulfonate salts in excellent yield. The tosic acid used in the esterification is added to make the amino acids more soluble and to prevent N-tosylation (eq 21).8c

A novel formal decarboxylation of the amino acid a-anilino-a,a-diphenylacetic acid has been observed upon treatment with tosyl chloride in pyridine.9 It has been proposed that a mixed anhydride of p-toluenesulfonic acid has undergone an elimination via N-deprotonation and synchronous extrusion of carbon monoxide in this reaction. Interestingly, no N-tosylation occurs (eq 22).

Spontaneous Beckmann rearrangement has been observed upon O-tosylation of oximes. Lactams can therefore be conveniently prepared from cyclic oximes, as shown in eq 23.10a The rearrangement has long been known to proceed with retention of configuration of the migrating group.10b,c This is complementary to the reaction of oximes with Sulfuric Acid (eq 24).10b

A Beckmann fragmentation of oximes using tosyl chloride in a basic ethanol-water system has also been observed.11 Formation of the cyclic product shown in eq 25 was consistent with a base-induced opening of an intermediate lactone followed by rearrangement and incipient extrusion of benzoic acid.

Oximes which are treated with tosyl chloride can also be used as substrates in the Neber rearrangement to a-amino ketones.12a The mixture shown in eq 26 was further subjected to reductive amination to yield 14% of the CNS-active cis-N,N-dimethylated a-amino alcohol.12b

Rearrangements of hydroxamic acids using sulfonyl chlorides have been accomplished, albeit without reported yields, the net result being a unique variation of the Lossen rearrangement (eq 27).13

As an alternative to the Beckmann rearrangement, ketonic nitrones can be treated with tosyl chloride in pyridine in the presence of water, as illustrated in eq 28.14

Rearrangement reactions which utilize tosyl chloride seem to progress in a two-step process: the displacement of chlorine from the sulfonyl halide resulting in the formation of an oxygen-sulfur bond, followed by the migration, elimination, or intramolecular displacement of the sulfonylate anion.8a When the series of carbinolamines depicted in eq 29 were treated with tosyl chloride, they decomposed into the corresponding electron-deficient nitrogen species, which subsequently triggered ring enlargement to the b-lactams in moderate yields.15

N-Tosylation is a facile procedure. For inexpensive amines a useful procedure entails treating 2 equiv of the amine with tosyl chloride. This is the first step in the convenient preparation of Diazald (N-Methyl-N-nitroso-p-toluenesulfonamide), a Diazomethane precursor (eq 30).16a

Protection of 3-amino-3-pyrazoline sulfate, a key intermediate in the preparation of 3(5)-aminopyrazole, was achieved in the presence of an excess of sodium bicarbonate in good yields (eq 31).16b

Sodium Carbonate can also be used as the base in the tosylation of amines, as shown in the reaction of anthranilic acid with tosyl chloride. There was no competing nucleophilic attack at sulfur by the resonance-stabilized carboxylate group (eq 32).16c

Primary, benzyl, and unhindered secondary amines can be ditosylated and deaminated in good to excellent yields, using Sodium Borohydride as the nucleophile, to afford the corresponding alkanes; only highly congested substrates experience competing attack at nitrogen.17 Similarly, primary aliphatic amines, when ditosylated and treated with iodide ion in DMF at 90-120 °C yielded, as their major products, the corresponding alkyl iodides, with some competition arising from elimination reactions (eqs 33 and 34).18

Tosyl chloride has been used in the protection of the imidazole residue of Na-acylhistidine peptides19a,b and the guanidino residue of arginine peptides.19c The resulting nitrogen-protecting group is stable to most conditions but is easily removable in anhydrous hydrogen fluoride at 0 °C.

The tosylation of carbon can be accomplished using electron transfer conditions. Treatment of styrene20a and analogs20b with Copper(II) Chloride and tosyl chloride or Benzenesulfonyl Chloride results in a formal replacement of the vinyl proton by the sulfonyl moiety (eq 35). The intermediacy of a trans-b-chloro sulfone has been demonstrated by 1H NMR. Treatment with base induced the elimination of HCl. A variety of other sulfonyl transfer reagents can be employed in the synthesis of isolated b-chloro sulfones, with good results (60-97% yield) for a variety of alkenes (ethylene, 1-butene, 2-butene, 1-octene, acrylonitrile, methyl acrylate, and 1,3-butadiene).20a

Although it was found that tosyl chloride does not react with 3-sulfolene at temperatures below 110 °C, upon further warming to 140 °C addition to the diene afforded 1-chloro-4-tosyl-2-butene in a convenient procedure that did not require the use of a sealed tube or bomb (eq 36).20c Cycloheptatriene, 1,4-norbornadiene, and phenylacetylene are a few examples of a variety of compounds which are reactive substrates in this protocol.

Radical addition of tosyl chloride to norbornene and aldrin without skeletal rearrangement can be achieved using Dibenzoyl Peroxide as an initiator (eq 37).20a,d Reaction with 1,4-norbornadiene gives rise to a rearranged addition product.

Treatment of bis(trimethylsilyl)acetylene with tosyl chloride and a slight excess of anydrous Aluminum Chloride affords p-tolyl (trimethylsilyl)ethynyl sulfone, a precursor to the reactive Michael acceptor ethynyl p-tolyl sulfone (eq 38).21

The dehydration of ureas employing tosyl chloride provides access to substituted carbodiimides, as depicted in eq 39. The urea made from treatment of ethyl isocyanate with N,N-dimethyl-1,3-propanediamine was treated in situ with 1.1 equiv of tosyl chloride and a large excess of Triethylamine to afford the corresponding carbodiimide in high yield.22a,b

Various ureas upon treatment with tosyl or benzenesulfonyl chloride in the presence of a phase transfer catalyst, benzyltriethylammonium chloride, results in moderate to excellent yields of carbodiimides (eq 40).22c The polymeric carbodiimide in eq 41 offers the advantages of cleaner workup and recyclability if used to prepare aldehydes under Moffatt oxidation conditions.22d

Isocyanides can be made from treatment of formamides with tosyl chloride in pyridine, as illustrated in eq 42.23a,b Similarly, nitriles can be synthesized in moderate to good yields by dehydration of primary amides using tosyl chloride in pyridine23a,b or quinoline (eq 43).23c

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D. Todd Whitaker, K. Sinclair Whitaker & Carl R. Johnson

Wayne State University, Detroit, MI, USA

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