[3144-09-0]  · CH5NO2S  · Methanesulfonamide  · (MW 95.14)

(methanesulfonamide-derived reagents are used in the synthesis of porphyrins1 and in Mitsunobu reactions;2 methanesulfonamide itself is useful in the synthesis of nitriles,4 N-sulfonyloxaziridines,5 macrocycles,6 site-directed antagonists,7,8 and as a catalyst turnover reagent in osmium-catalyzed asymmetric dihydroxylations9,10)

Physical Data: mp 91-92 °C.

Form Supplied in: white crystalline solid; widely available.

Handling, Storage, and Precautions: should be stored in a cool dry place. It is an irritant and should be handled carefully. Use in a fume hood.

Methanesulfonamide-Derived Reagents.

N-(2-Methylthio-1-p-toluenesufonyl)methanesulfonamide, derived from methanesulfonamide, methylthioacetaldehyde dimethyl acetal and p-toluenesulfenic acid, has been used as a key intermediate in the synthesis of symmetrically substituted porphyrins (eq 1).1

t-Butyl ((2-(trimethylsilyl)ethyl)sulfonyl)carbamate (3), a reagent for use in the Mitsunobu reaction, has been prepared from methanesulfonamide (eq 2).2 Treatment of methanesulfonamide with n-Butyllithium in THF, followed by acylation with t-Butyl Azidoformate in the presence of Sodium Hydride and N,N,N,N-Tetramethylethylenediamine, gave sulfonamide (1). Treatment of (1) with 2 equiv of Lithium Diisopropylamide gave the dianion (2). Addition of (Iodomethyl)trimethylsilane to (2) gave (3). An alternate route to (3) involves deprotonation of the known sulfonamide (4)3 with Methyllithium, followed by acylation with t-butyl azidoformate in the presence of sodium hydride (eq 3). The use of this reagent in Mitsunobu reactions has been well demonstrated.2

Use in Synthetic Transformations.

The classical procedure for conversion of carboxylic acids to the corresponding nitriles through amides is simplified by the use of methanesulfonamide as the nitrogen source.4 A variety of chlorobenzonitrile isomers and homologs, which are otherwise difficult to prepare, are made accessible through this route (eq 4).

N-Sulfonyloxaziridines are gaining importance as potential neutral chiral oxidants. N-Methanesulfonylimines, the precursors for the synthesis of N-sulfonyloxaziridines, are conveniently prepared by the reaction of methanesulfonamide with aromatic aldehydes (eq 5).5

Methanesulfonamide has been used as a locking fragment in the template synthesis of the azacyclam family of macrocycles. Methanesulfonamide in the presence of Formaldehyde, Triethylamine, and CuII effectively closes the open-chain tetramine 1,9-diamino-3,7-diazanonane to give (3-methanesulfonyl-1,3,5,8,12-pentaazacyclotetradecane)dinitratocopper(II) as a crystalline solid (eq 6).6

Methanesulfonamide reacts with 6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid to give the corresponding N-methylsulfonyl derivative, which is a well-characterized antagonist at the glycine site of the NMDA receptor and AMPA receptor (eq 7).7

A highly potent histamine H2 receptor antagonist has been prepared by reaction of methanesulfonamide with the corresponding imidate (eq 8).8

Use as a Catalyst Turnover Reagent.

In the case of osmium-catalyzed asymmetric dihydroxylation of nonterminal trisubstituted alkenes, 1,2-disubstituted alkenes,9 and a,b- and b,g-unsaturated amides,10 where the hydrolysis of the osmate ester is turnover limiting, the presence of methanesulfonamide leads to shorter reaction times (eq 9).

1. Kinoshita, H.; Tanaka, S.; Inomata, K. CL 1989, 1107.
2. Campbell, J. A.; Hart, D. J. JOC 1993, 58, 2900.
3. Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. JACS 1990, 112, 3475.
4. Grivsky, E. M. BSB 1971, 80, 245.
5. Jennings, W. B.; Lovely, C. J. TL 1988, 29, 3725.
6. Blas, A. D.; Santis, G. D.; Fabbrizzi, L.; Licchelli, M.; Lanfredi, A. M. M.; Morosini, P.; Pallavicini, P.; Ugozzoli, F. JCS(D) 1993, 1411.
7. Hays, S. J.; Boxter, P. A.; Talor, C. P.; Vartanian, M. G.; Robichaud, L. J.; Nielsen, E. O. BML 1993, 3, 77.
8. Yanagisawa, I.; Hirata, Y.; Ishii, Y. JMC 1987, 30, 1787.
9. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K-S.; Kwong, H-L.; Morikawa, K.; Wang, Z-M.; Xu, D.; Zhang, X-L. JOC 1992, 57, 2768.
10. Bennani, Y. L.; Sharpless, K. B. TL 1993, 34, 2079.

Nachimuthu Soundararajan

Bristol-Myers Squibb, New Brunswick, NJ, USA

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