2,4,6-Triisopropylbenzenesulfonyl Azide1

[36982-84-0]  · C15H23N3O2S  · 2,4,6-Triisopropylbenzenesulfonyl Azide  · (MW 309.48)

(agent for diazo2 and azide3 transfer to enolates)

Alternate Name: trisyl azide.

Physical Data: mp 41-43 °C.

Solubility: freely sol most organic solvents.

Preparative Methods: readily prepared by treatment of the commercially available triisopropylbenzenesulfonyl chloride (trisyl chloride) with sodium azide.4

General Considerations.

The reactions of arylsulfonyl azides with enolates have been reported to give a range of products, depending on the fragmentation of the initial adduct.3,5 This may differ according to the nature of the enolate, the particular sulfonyl azide, and the quenching procedure. Net diazo transfer is usually observed for stabilized enolates, while azide transfer is more common with more reactive enolates.

Diazo Transfer to Ketones.

Triisopropylbenzenesulfonyl azide has been used for the direct transfer of the diazo group to ketone enolates under phase transfer conditions to furnish a-diazo ketones (eqs 1-4).2,6-8

The method may be used as a more direct alternative to the stepwise procedure of hydroxymethylenation, followed by treatment with p-Toluenesulfonyl Azide and Triethylamine,9 but its greatest value lies with the reactions of sterically hindered substrates (eqs 5-9),2,10-12 for which the two-stage process is ineffective. The utility of the trisyl azide in these conversions stems from the steric hindrance afforded by the ortho isopropyl groups; simpler arylsulfonyl azides are degraded too rapidly under these conditions to be useful. The method appears to be less effective with cyclopentanones (eq 9)13 and several failures have been reported with such substrates.14

Azide Transfer to Enolates.

Kinetically controlled azide transfer to the lithium enolates of azetidinones was originally demonstrated with tosyl azide using Chlorotrimethylsilane as a quenching reagent,15 but was found not to be general for other enolates. One of the problems is competing diazo transfer. In a systematic study of azide transfer to imide enolates,5 it was found that azide transfer is more strongly favored by more electropositive counterions (K > Na >> Li), and by more electron-rich arylsulfonyl azides (trisyl > tosyl > p-nitrobenzenesulfonyl). The steric requirements of the trisyl group undoubtedly play a role also. Triazenes are implicated as intermediates and it is the treatment of these compounds which determines the product distribution rather than the initial step. Triazene (1) was sufficiently stable to be isolated as a mixture of tautomers and it was found that decomposition to azide (2) could be effected with potassium acetate, but not lithium acetate. Thus the counterion effect noted above is expressed in triazene decomposition, rather than the initial addition of the enolate to the azide.

The most general protocol (eq 10) has therefore been based on Potassium Hexamethyldisilazide (KHMDS) as the base, addition of trisyl azide at -78 °C and then acetic acid at the same temperature.5 Excellent levels of diastereoselectivity are observed with most substrates and the method has been used widely in the enantioselective synthesis of a-amino acids from chiral imides.16 Chemoselective azidation of an imide enolate in the presence of an ester function has been demonstrated (eq 11).17 The product distribution is nevertheless finely balanced, as discovered with the respective dimethyl and dibenzyl ethers of the 3,5-substituted phenylacetyl imide (3) (eq 12).18

The azide transfer methodology may also be applied to a variety of esters19 and is compatible with a number of other functional groups (eqs 13-15).20,21 It may also be used with phosphonates (eq 16),22 and if the counterion to the anion is lithium, as in the earlier imide study, it is possible to isolate the simple adduct retaining the sulfonyltriazine moiety (eq 17). Reaction with an N-hydroxy b-lactam afforded the deoxy-a-azido lactam via the O-sulfonate.23

Related Reagents.

p-Toluenesulfonyl Azide and Methanesulfonyl Azide have been used widely for diazo transfer to stabilized enolates.9 The latter reagent simplifies isolation of the desired product,24 but is potentially explosive and must be handled with care. Relative to other aryl analogs, the electron-deficient p-nitrobenzenesulfonyl analog favors diazo transfer to imide enolates.5


1. Harmon, R. E.; Wellman, G.; Gupta, S. K. JOC 1973, 38, 11.
2. Lombardo, L.; Mander, L. N. S 1980, 5, 368.
3. Evans, D. A.; Britton, T. C. JACS 1987, 109, 6881.
4. Leffler, J. E.; Tsuno, Y. JOC 1962, 28, 902.
5. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. JACS 1990, 112, 4011.
6. Lombardo, L.; Mander, L. N.; Turner, J. V. JACS 1980, 102, 6626.
7. Overman, L. E.; Robertson, G. M.; Robichaud, A. J. JACS 1991, 113, 2598.
8. Taber, D. F.; Schuchardt, J. L. T 1987, 43, 5677.
9. (a) Regitz, M. S 1972, 351. (b) Regitz, M.; Maas, G. Diazo Compounds, Properties and Synthesis; Academic: Orlando, 1986; Chapter 13.
10. Robichaud, A. J.; Meyers, A. I. JOC 1991, 56, 2607.
11. (a) Mander, L. N.; Pyne, S. G. JACS 1979, 101, 3373. (b) Mander, L. N.; Pyne, S. G. AJC 1981, 34, 1899.
12. Nuyttens, F.; Appendino, G.; De Clercq, P. J. SL 1991, 526.
13. Coates, R. M.; Kang, H.-Y. JOC 1987, 52, 2065.
14. (a) Adams, J. L.; Metcalf, B. W. TL 1984, 25, 919. (b) Rao, V. B.; George, C. F.; Wolff, S.; Agosta, W. C. JACS 1985, 107, 5732. (c) Fessner, W.-D.; Sedelmeier, G.; Spurr, P. R.; Rihs, G.; Prinzbach, H. JACS 1987, 109, 4626.
15. Kühlein, K.; Jensen, H. LA 1974, 369.
16. (a) Parry, R. J.; Ju, S.; Baker, B. J. J. Labelled Comp. Radiopharm. 1991, 29, 633. (b) Shaw, A. N.; Dolle, R. E.; Kruse, L. I. TL 1990, 31, 5081. (c) Boteju, L. W.; Wegner, K.; Hruby, V. J. TL 1992, 33, 7491. (d) Chen, H. G.; Beylin, V. G.; Marlatt, M.; Leja, B.; Goel, O. P. TL 1992, 33, 3293. (e) Evans, D. A.; Evrard, D. A.; Rychnovsky, S. D.; Früh, T.; Whittingham, W. G.; DeVries, K. M. TL 1992, 33, 1189. (f) Pearson, A. J.; Park, J. G. JOC 1992, 57, 1744. (g) Beylin, V. G.; Chen, H. G.; Dunbar, J.; Goel. O. P.; Harter, W.; Marlatt, M.; Topliss, J. G. TL 1993, 34, 953. (h) Thompson, W. J.; Ghosh, A. K.; Holloway, M. K.; Lee, H. Y.; Munson, P. M.; Schwering, J. E.; Wai, J.; Darke, P. L.; Zugay, J.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. JACS 1993, 115, 801.
17. Evans, D. A.; Ellman, J. A. JACS 1989, 111, 1063.
18. Stone, M. J.; Maplestone, R. A.; Rahman, S. K.; Williams, D. H. TL 1991, 32, 2663.
19. Stone, M. J.; van Dyk, M. S.; Booth, P. M.; Williams, D. H. JCS(P1) 1991, 1629.
20. Es-Sayed, M.; Gratkowski, C.; Krass, N.; Meyers, A. I.; de Meijere, A. SL 1992, 962.
21. Panek, J. S.; Beresis, R.; Xu, F.; Yang, M. JOC 1991, 56, 7341.
22. Denmark, S. E.; Chatani N.; Pansare, S. V. T 1992, 48, 2191.
23. Gasparski, C. M.; Teng, M.; Miller, M. J. JACS 1992, 114, 2741.
24. Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. JOC 1986, 51, 4077.

Lewis N. Mander

The Australian National University, Canberra, Australia



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