n-Butyl N-(p-Toluenesulfonyl)iminoacetate1

(R = Bu)

[2292-87-7]  · C13H17NO4S  · n-Butyl N-(p-Toluenesulfonyl)iminoacetate  · (MW 283.34) (R = Me)

[89366-20-1]  · C10H11NO4S  · Methyl N-(p-Toluenesulfonyl)iminoacetate  · (MW 241.26) (R = Et)

[83670-53-5]  · C11H13NO4S  · Ethyl N-(p-Toluenesulfonyl)iminoacetate  · (MW 255.29)

(easily prepared N-tosyl imines of glyoxylate esters2 are useful as enophiles in inter-3,4 and intramolecular5 imino ene reactions and as dienophiles in achiral6 and asymmetric7,8,20-23 hetero Diels-Alder reactions)

Physical Data: bp R = Bu, 130-135 °C/0.001 mmHg; R = Et, 145-150 °C/0.02 mmHg.

Solubility: sol various organic solvents, usually used in benzene or toluene; reactions often run without solvent.

Form Supplied in: viscous yellow oil.

Handling, Storage, and Precautions: usually prepared and distilled directly before use or generated and used in situ.

Preparations.

Although a variety of alkyl glyoxylates have been utilized for the preparation of N-tosyliminoacetates, the most widely used compound has been the butyl derivative (1). Albrecht and Kresze1 published the first preparation of (1) in 1965, when butyl glyoxylate was found to react with N-Sulfinyl-p-toluenesulfonamide9 under Lewis acid catalysis to produce the N-tosyliminoacetate (1) (eq 1). This reaction presumably proceeds through an initial [2 + 2] cycloaddition, followed by extrusion of sulfur dioxide.

Two groups have independently published preparations of N-tolyliminoacetates by reactions of glyoxylates and p-Toluenesulfonyl Isocyanate. Le Goffic and Baillarge10a found that Lewis acid catalysis of the reaction in refluxing benzene produced (1) in 95% isolated yield (eq 2). A few years later, Holmes and co-workers10b found that the reaction could be effected without catalysis in refluxing toluene to produce the corresponding methyl ester in good yield. The mechanism of this reaction is thought to parallel the pathway in eq 1.

Imino Ene Reactions.

The first report of an ene reaction of an N-tosylimine with an alkene appeared in 1976, when Achmatowicz and Pietraszkiewicz3 showed that imino ene reactions could be effected thermally or under Lewis acid conditions to produce g,d-unsaturated amino acid derivatives (2) (eq 3).

Interestingly, Kresze and Braxmeier11 have found that the same ene reactions can be effected using N-perfluorobutylsulfonyliminoacetate (3), resulting in a reaction rate increase relative to (1) of approximately three orders of magnitude.

More recently, Weinreb and co-workers4,5 investigated the stereochemical features of the intermolecular ene reaction of (1). It was found that the reactions are stereospecific when conducted thermally, apparently proceeding through a pericyclic mechanism. When ethyl N-tosyliminoacetate was heated at 170 °C with cyclohexene, only sulfonamido ester (4), derived from the endo transition state A, was isolated (eq 4). None of the diastereomer (5), derived from an exo transition state B, was detected. When the reaction was run under Lewis acid catalysis, however, a mixture of (4) and (5) was isolated. It is presumed that the addition of a Lewis acid induces a change in mechanism from a pericyclic to an ionic process.

Weinreb and co-workers5a,12 also found that ene reactions could be effected intramolecularly with unsaturated alkyl esters of N-tosyliminoacetates. The N-tosylimine derived from (E)-crotyl glyoxylate was prepared in situ and heated in o-dichlorobenzene to afford the single ene product (7),13 arising from a cyclization through the intermediate N-tosylimine (6) (eq 5).

In an attempt to construct the framework of polyoxamic acid (10), Baumann and Duthaler14 reacted ethyl N-tosyliminoacetate with methallene (eq 6). While only isolating minor amounts of the desired [2 + 2] adduct (9), a 33% yield of (8), derived from an imino ene reaction, was isolated.

Hetero Diels-Alder Reactions.

The first example of an N-tosyliminoacetate as a dienophile was reported by Kresze1 in 1965. The reaction was found to be generally regioselective (eq 7).

Other groups have explored the addition of (1) to cyclic dienes in a study of the stereochemistry of the reaction.15 Barco and co-workers16 found that when an N-tosyliminoacetate (1) was allowed to react with Cyclopentadiene, only the exo adduct (11) was formed (eq 8). This compound was further elaborated upon to produce 8-aza-9,11-etheno-PGH1, a prostaglandin endoperoxide analog.

Holmes and co-workers8,17 have studied the hetero [4 + 2]-reaction of N-tosyliminoacetates with various cyclohexadienes and have applied the adducts to natural product syntheses. Cyclohexadiene was found to afford only the expected exo isomer (12) when reacted with ethyl N-tosyliminoacetate (eq 9). This compound was further functionalized to provide (±)-actinobolamine.17a

Advances have also been made toward asymmetric hetero Diels-Alder reactions using chiral ester derivatives of (1). For example, Holmes and co-workers8 have employed the N-tosylimine glyoxylate derivatives of ethyl (S)-lactate (13a) and (R)-pantolactone (13b) (eq 10) in Lewis acid-catalyzed reactions with cyclopentadiene to produce only the exo isomers (14) and (15) with the diastereomeric ratios dependent upon the particular chiral auxiliary employed.

Hamada and co-workers18 have recently reported a diastereoselective hetero Diels-Alder reaction between chiral diene (16) and (1) to produce the single diastereomer (17) in good yield (eq 11). This compound has been further elaborated to the alkaloid (-)-cannabisativine, the enantiomer of the natural product.18b

Recently, Whiting and co-workers19 have achieved modest diastereoselectivity in a reaction of ethyl N-(1R)-camphorsulfonyliminoacetate (18) with Danishefsky's diene (1-Methoxy-3-trimethylsilyloxy-1,3-butadiene) (eq 12). Inseparable mixtures of tetrahydropyridone diastereomers were isolated in varying ratios under both thermal and Lewis acid-catalyzed conditions.


1. Albrecht, R.; Kresze, G. CB 1965, 98, 1431.
2. Hook, J. M. SC 1984, 14, 83.
3. (a) Achmatowicz, O.; Pietraszkiewicz, M. CC 1976, 484. (b) Achmatowicz, O.; Pietraszkiewicz, M. JCS(P1) 1981, 2680.
4. Weinreb, S. M. BSB 1992, 101, 381.
5. (a) Tschaen, D. M.; Turos, E.; Weinreb, S. M. JOC 1984, 49, 5058. (b) Melnick, M. J.; Freyer, A. J.; Weinreb, S. M. TL 1988, 29, 3891.
6. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic: Orlando, 1987. (b) Weinreb, S. M. COS 1991, 5, 401.
7. Maggini, M.; Prato, M.; Scorrano, G. TL 1990, 31, 6243.
8. Hamley, P.; Helmchen, G.; Holmes, A. B.; Marshall, D. R.; MacKinnon, J. W. M.; Smith, D. F.; Ziller, J. W. CC 1992, 786.
9. Hori, T.; Singer, S. P.; Sharpless, K. B. JOC 1978, 43, 1456 (see also: N-N-Sulfinyl-p-toluenesulfonamide).
10. (a) Baillargé, M.; Le Goffic, F. SC 1987, 17, 1603. (b) Hamley, P.; Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith, D. F. SL 1991, 29.
11. Braxmeier, H.; Kresze, G. S 1985, 683.
12. For intramolecular imino ene reactions involving N-acyl imines, see: Koch, K.; Lin, J.-M.; Fowler, F. W. TL 1983, 24, 1581.
13. The stereochemistry originally published for (7)5a was revised by Baumann and Duthaler.14
14. Baumann, H.; Duthaler, R. O. HCA 1988, 71, 1025.
15. (a) Krow, G. R.; Rodebaugh, R.; Marakowski, J.; Ramey, K. C. TL 1973, 1899. (b) Krow, G. R.; Pyun, C.; Rodebaugh, R.; Marakowski, J. T 1974, 30, 2977.
16. Barco, A.; Benetti, S.; Baraldi, P. G.; Moroder, F.; Pollini, G. P.; Simoni, D. LA 1982, 960.
17. (a) Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith, D. F. CC 1990, 1412. (b) Birkinshaw, T. N.; Holmes, A. B. TL 1987, 28, 813. (c) Birkinshaw, T. N.; Tabor, A. B.; Holmes, A. B.; Kaye, P.; Mayne, P. M.; Raithby, P. R. CC 1988, 1599.
18. (a) Hamada, T.; Sato, H.; Hikota, M.; Yonemitsu, O. TL 1989, 30, 6405. (b) Hamada, T.; Zenkoh, T.; Sato, H.; Yonemitsu, O. TL 1991, 32, 1649.
19. McFarlane, A. K.; Thomas, G.; Whiting, A. TL 1993, 34, 2379.
20. Some chiral derivatives of N-alkyliminoacetate esters have also been employed in asymmetric hetero Diels-Alder reactions with excellent selectivity. Examples include a-methylbenzyl derivatives21,22 and a-amino acid derivatives.23
21. Stella, L.; Abraham, H.; Feneau-Dupont, J.; Tinant, B.; Delercq, J. P. TL 1990, 31, 2603.
22. Bailey, P. D.; Wilson, R. D.; Brown, G. R. JCS(P1) 1991, 1337.
23. (a) Waldmann, H.; Braun, M. LA 1991, 1045. (b) Waldmann, H.; Braun, M.; Dräger, M. AG(E) 1990, 29, 1468.

Steven M. Weinreb & R. Jason Herr

The Pennsylvania State University, University Park, PA, USA



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