N-Sulfinyl-p-toluenesulfonamide1

[4104-47-6]  · C7H7NO3S2  · N-Sulfinyl-p-toluenesulfonamide  · (MW 217.29)

(used to generate electrophilic N-tosyl aldimines;4-7 can act as an enophile in ene reactions2,8 and as a dienophile in Diels-Alder reactions;10,11 participates in Wittig-type reactions17)

Alternate Name: 4-methyl-N-sulfinylbenzenesulfonamide.

Physical Data: mp 53 °C; bp 130-140 °C/0.06 mmHg.

Solubility: sol benzene, toluene, halogenated solvents.

Form Supplied in: bright yellow solid; commercially available.

Preparative Methods: the most common method of preparing N-sulfinyl-p-toluenesulfonamide (TsNSO) (1) is by heating p-toluenesulfonamide with excess Thionyl Chloride in benzene (eq 1).2

An alternative procedure is the treatment of p-toluenesulfonamide with N-chlorosulfinylimidazole, which is derived from thionyl chloride and Imidazole (eq 2).3 The latter method benefits from shorter reaction times and better yields.

Handling, Storage, and Precautions: should be weighed out in a glove bag or dry box, since it readily hydrolyzes to p-toluenesulfonamide. Can be prepared just prior to use and used in situ or stored for extended periods of time in an inert environment.

Formation of N-Tosyl Aldimines.

A number of years ago it was reported by Kresze that nonenolizable aldehydes could be converted to the corresponding N-tosylimine using the title reagent (1) in the presence of a Lewis acid.4 Recently, it has been shown that this transformation can also be effected with enolizable aldehydes both under Lewis acid catalysis at low temperature and thermally.5 Thus treatment of propionaldehyde with (1) leads to the N-tosyl aldimine (2) or its Lewis acid complex (eq 3).

The imines (2) can be trapped in situ with 1,3 dienes,5a organometallic reagents,5b allyl silanes,5c or reduced with Triethylsilane (eq 3).5d Vinyl silanes also add intramolecularly to N-tosylimines in the presence of Boron Trifluoride Etherate or Tin(IV) Chloride to give cyclohexenylsulfonamides (eq 4).6

Intramolecular ene-like reactions of Lewis acid complexed N-tosyliminium intermediates can be effected to afford cyclization products, presumably via a cationic, stepwise pathway (eq 5).7

Ene Reaction.

The ene reaction of (1) and b-pinene in benzene at rt to give the N-tosylsulfinamide (3) (eq 6)2a is reversible under these conditions and has been exploited specifically to introduce deuterium into the allylic position of an alkene.

A more reactive N-sulfinyl compound, N-sulfinylnonafluorobutanesulfonamide, undergoes intermolecular ene reactions with alkenes over 103 times faster than the corresponding tosyl derivative (eq 7).8

In addition, this perfluoro-N-sulfinyl compound undergoes thermal, intermolecular ene reactions with 1-aryl-2-alkanones under neutral conditions to give N-sulfinyl-2-oxoalkanesulfonamides in high yields (eq 8).8a,9

Diels-Alder Reactions.

N-Sulfinyl compound (1) is an effective dienophile in the regioselective [4 + 2] cycloaddition of unsymmetrical dienes.1b,10,11 For example, 2-substituted dienes were found to yield only 5-substituted dihydrothiazine oxides (eq 9). The cycloaddition of (1) with simple 1-substituted 1,3-dienes is often dependent on the reaction temperature. At low temperatures, 3-substituted dihydrothiazine oxides are usually formed as kinetic products, but at higher temperatures the more stable 6-substituted heterocycles are produced (eq 10).12

The dihydrothiazine oxides derived from this hetero Diels-Alder process are valuable synthetic intermediates in constructing homoallylic amines and vicinal amino alcohols in a stereorational manner.11 For instance, in a system involving the diastereoselective synthesis of unsaturated acyclic amines, (1) was combined with (E,E)-tetramethylbutadiene to give cycloadduct (4), whereupon hydrolysis and retro-ene loss of SO2 via a rigid chair-like transition state afforded exclusively the (E)-homoallylic amine derivative (5) (eq 11).11,13 Similarly, (E,Z)-tetramethylbutadiene produced 3,6-dihydrothiazine oxide (6), which was hydrolyzed to give (E)-homoallylic sulfonamide (7).

In a related system involving the diastereoselective synthesis of unsaturated vicinal amino alcohols, the Diels-Alder cycloaddition of (E,E)-hexadiene with benzyl N-sulfinylcarbamate14 gave a 15:1 mixture of epimeric adducts (eq 12). Ring opening of these cycloadducts with Phenylmagnesium Bromide, followed by the [2,3]-sigmatropic rearrangement of the intermediate allylic sulfoxide in the presence of trimethyl phosphite, yielded the (E)-threo vicinal amino alcohol derivative (8). Similarly, (E,Z)-hexadiene underwent the N-sulfinyl Diels-Alder reaction and subsequent steps to give the (E)-erythro hydroxy carbamate (9) exclusively.

The chiral N-sulfinyl carbamate prepared from (+)-camphor (eq 13)15 displayed high enantioselectivity in the Titanium(IV) Chloride catalyzed [4 + 2] cycloaddition with 1,3-cyclohexadiene, affording only one cycloadduct. The stereochemistry of compound (12) can be rationalized by a cycloaddition occurring through either conformer (10) via an endo transition state or conformer (11) by an exo transition state. High levels of asymmetric induction have also been reported in the cycloaddition reactions of N-sulfinylcarbamates derived from the chiral auxiliary 8-phenylmenthol.16

Wittig-Type Reaction.

TsNSO undergoes an interesting Wittig-type reaction with triphenylphosphonium fluorenylide to afford thione S-imides in good yields (eq 14).17


1. (a) Bussas, R.; Kresze, G.; Munsterer, H.; Schwobel, A. Sulfur Rep. 1983, 2, 215. (b) Boger, D. L.; Weinreb, S. M. In Hetero Diels-Alder Methodology in Organic Synthesis, Academic: Orlando, 1987; Chapter 1. (c) Schubart, R. MOC 1985, E11, 122.
2. (a) Hori, T.; Singer, S. P.; Sharpless, K. B. JOC 1978, 43, 1456. (b) Kresze, G.; Wucherpfennig, W. AG(E) 1967, 6, 149.
3. Kim, Y. H.; Shin, J. M. TL 1985, 26, 3821.
4. (a) Albrecht, R.; Kresze, G.; Mlakar, B. CB 1964, 97, 483. (b) Albrecht, R.; Kresze, G. CB 1965, 98, 1431. (c) Pozdnyakova, T. M.; Sergeyev, N. M.; Gorodetskaya, N. I.; Zefirov, N. S. IJS(B) 1972, 2, 109.
5. (a) Sisko, J.; Weinreb, S. M. TL 1989, 30, 3037. (b) Sisko, J.; Weinreb, S. M. JOC 1990, 55, 393. (c) Ralbovsky, J. L.; Kinsella, M. A.; Sisko, J.; Weinreb, S. M. SC 1990, 20, 573. (d) Alexander, M. D.; Anderson, R. E.; Sisko, J.; Weinreb, S. M. JOC 1990, 55, 2563. It has also been shown that reductive carbamation of simple aldehydes can be effected in a similar procedure utilizing N-sulfinylbenzyl carbamate.
6. McIntosh, M. C.; Weinreb, S. M. JOC 1993, 58, 4823.
7. Melnick, M. J.; Freyer, A. J.; Weinreb, S. M. TL 1988, 29, 3891.
8. (a) Kresze G.; Bussas, R. AG(E) 1980, 19, 732 and 737. (b) Bussas, R.; Munsterer, H.; Kresze, G. JOC 1983, 48, 2828.
9. For uses of related N-sulfinyl compounds such as N-sulfinyl-(b-(trimethylsilyl)ethyl)sulfonamide and N-sulfinyl-(p-methylphenyl)methanesulfonamide see: Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. JACS 1990, 112, 3475 and Ref. 5a.
10. Kresze, G. In 1,4-Cycloaddition Reactions, the Diels-Alder Reaction in Heterocyclic Synthesis, Hamer, J., Ed.; Academic: New York, 1967; p 453.
11. Weinreb, S. M. ACR 1988, 21, 313.
12. The thermal Diels-Alder reaction of N-alkyl-N-sulfinyl dienophiles with 1,3-dienes fails except in the presence of a Lewis acid catalyst or under high pressure. See: Bell, S. I.; Weinreb, S. M. TL 1988, 29, 4233.
13. Garigipati, R. S.; Morton, J. A.; Weinreb, S. M. TL 1983, 24, 987.
14. This N-sulfinyl compound was prepared from benzyl carbamate with thionyl chloride and pyridine. Garigipati, R. S.; Freyer, A. J.; Whittle, R. R.; Weinreb, S. M. JACS 1984, 106, 7861.
15. Prepared from the corresponding carbamate, thionyl chloride, and pyridine. Remiszewski, S. W.; Yang, J.; Weinreb, S. M. TL 1986, 27, 1853.
16. Whitesell, J. K.; James D.; Carpenter, J. F. CC 1985, 1449.
17. Saito, T.; Motoki, S. JOC 1977, 42, 3922.

Steven M. Weinreb & Robert M. Borzilleri

The Pennsylvania State University, University Park, PA, USA



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