p-Toluenesulfonyl Azide1

[941-55-9]  · C7H7N3O2S  · p-Toluenesulfonyl Azide  · (MW 197.24)

(introduction of azide and diazo groups into organic compounds;2 serves as a source of nitrene and 1,3-azide dipoles for [3 + 2] cycloadditions;3 used for the synthesis of N-tosylphosphinimines,4 -sulfimines, and -sulfoximines5)

Alternate Names: tosyl azide.

Physical Data: mp 21-22 °C; bp 110-115 °C/0.001 mmHg;6 d25 1.286 g cm-3; n25589 1.55010.

Solubility: sol chloroform, diethyl ether, acetone.

Form Supplied in: oily colorless liquid.

Analysis of Reagent Purity: IR (neat) n = 2130 (strong, N=N=N), 1380 and 1180 (strong, SO2) cm-1; 1H NMR (CDCl3) d = 2.47 (s, CH3), 7.40 (d, J = 8 Hz, m-SO2C6H4), 7.84 (d, J = 8 Hz, o-SO2C6H4).7

Preparative Methods: the simplest synthetic method for tosyl azide is the reaction of p-Toluenesulfonyl Chloride with Sodium Azide. Tosyl azide prepared in ethanol may contain 7-20% of ethyl p-toluenesulfonate;8 the formation of this byproduct can be avoided by working in aqueous acetone instead of ethanol.9,10 The 1H NMR spectrum of tosyl azide prepared (99% yield) according to Curphey exhibits signals for traces of dichloromethane (<1%);10 the compound is pure by TLC, while HPLC reveals traces (>1.5%) of an impurity. Polymer-bound tosyl chloride can be transformed to polymer-bound tosyl azide.11 A polymer-bound phase-transfer catalyst may also be employed (94% yield).12 Further methods for the preparation of tosyl azide are the oxidation of p-Toluenesulfonylhydrazide by Iron(III) Nitrate-K10 Montmorillonite Clay (83% yield),13 by Nitrogen Dioxide in CCl4 (95% yield),14 or by Nitrosonium Tetrafluoroborate (85% yield). 15

Handling, Storage, and Precautions: crystallizes to a white solid at -20 °C and can be stored indefinitely at this temperature. Particular care is required for all reactions in which tosyl azide is heated at or above 100 °C. The initial temperature of the explosive decomposition is about 120 °C.16 Severe explosions during the attempted distillation of tosyl azide have been reported.6,17 Polymer-bound tosyl azide can be stored indefinitely at room temperature and, in contrast to tosyl azide itself, is not sensitive to mechanical shock. Use in a fume hood.

Synthesis of Azides.

Tosyl azide acts as a transfer reagent to introduce the azide group to anions of C-H acidic compounds such as malonate derivatives (eq 1);18 aryl azides are obtained from the reactions of aryl Grignard reagents with tosyl azide after cleavage of the primarily formed triazene salt intermediates with sodium pyrophosphate (eq 2);19 azidothiophenes and -bithiophenes20 or azidotetrazolium salts21 can be prepared similarly (using organolithium compounds). The anions of primary amines, generated from the latter by treatment with Grignard reagents22 or preferably with Sodium Hydride in THF,23 also react with tosyl azide to furnish azides (diazo group transfer to primary amines, eq 3). a-Azido sulfones are formed in one step by reactions of aliphatic nitro compounds with Potassium Hydride in THF and subsequent treatment with tosyl azide (eq 4).24

Synthesis of Diazo Compounds.2

The synthesis of diazo compounds from a carbon nucleophile and an arenesulfonyl azide, preferably tosyl azide (eq 5), is known as diazo group transfer.25 The actual reaction in a somewhat different form has been known for a long time;26 it was first employed for the synthesis of diazocyclopentadiene from the cyclopentadienide anion and tosyl azide27 and has since been developed intensively.

When X and Y are suitable electron-attracting groups such as CO2R, COR, NO2, SO2R, Ar, etc., the required carbanion can be generated by treatment of the corresponding methylene compound with an appropriate base (NEt3, pyridine/piperidine, NaOEt, t-BuOK). The synthesis of t-butyl diazoacetate is an explicit example.8 The use of a phase-transfer catalyst is sometimes advantageous for the generation of the carbanion.28 When only one electron-attracting, activating group is present in the substrate, diazo group transfer can be effected by an indirect route in which, for example, a ketone is transformed to an a-formyl ketone which is, in turn, converted by treatment with tosyl azide in the presence of a base to the desired diazo compound by cleavage of N-formyltosyl amide (deformylating diazo group transfer, eq 6).29

Tosyl azide is the reagent employed most frequently. However, p-Dodecylbenzenesulfonyl Azide,16 p-carboxybenzenesulfonyl azide,30 polymer-bound tosyl azide,11 trifluoromethanesulfonyl azide (triflyl azide),31 (azidochloromethylene)dimethylammonium chloride,32 2,4,6-Triisopropylbenzenesulfonyl Azide (trisyl azide),33 and others34 have also been used. 2-Azido-3-ethyl-1,3-benzothiazolium tetrafluoroborate and 2-azido-1-ethylpyridinium tetrafluoroborate35 have proven to be useful as diazo group transfer reagents since they can also be employed in weakly acidic media with base-sensitive methylene compounds. In addition to the requirement for a less hazardous reagent than tosyl azide, the separation of the inevitably formed amine from the desired diazo compound represents the main stimulant for the continued search for novel diazo group transfer reagents.

Supplementary to the classic diazo group transfer to activated methylene compounds described briefly above, the reactions of tosyl azide with enamines, enol ethers, ynamines, ynethers, activated alkenes and alkynes, cyclopropenes, and methylenephosphoranes may also be included in this reaction type in its widest sense, when the respective reactions give rise to diazo compounds (see the examples in eqs 7 and 8);36 see also cycloaddition reactions (below) as an alternative.

Cycloaddition Reactions.

The 1,3-dipolar cycloadditions of tosyl azide to alkenes primarily furnish the 4,5-dihydrotriazoles which can seldom be isolated.37 Generally, subsequent reactions such as the [3 + 2] cycloreversion to N-tosylimines and diazo compounds (diazo group transfer), the cleavage of nitrogen in N-tosylaziridines, or the concomitant 1,2-shift of a substituent in N-tosylimines with rearranged molecular skeletons (eq 9) predominate.38 All processes can occur in parallel; however, there is a pronounced reaction selectivity in dependence on the group X (the electron donating substituent).

From the plethora of synthetic applications of tosyl azide, its examples of the reactions with nonstrained cycloalkenes leading to N-tosylimines (eq 10),39 with cyclic enamines which give amidines (eq 11),40 with indoles to furnish 2-tosyliminoindoles (eq 12),41 and with enol ethers giving rise to imidates in quantitative yield (eq 13)42 are mentioned as examples. When the alkene carries a further substituent capable of elimination, the cycloadditions give rise to 1,2,3-triazoles directly (eq 14).43 The N-tosyl group can be readily removed by hydrolysis to liberate the corresponding NH compound. Thus in this sense, tosyl azide can be considered as a synthetic equivalent of the difficult to handle hydrogen azide (Hydrazoic Acid, HN3).

Miscellaneous.

The reactions of aryl and heteroaryl hydrazides with tosyl azide in the presence of NaOH under phase-transfer conditions give rise to the corresponding aromatic and heteroaromatic compounds (eq 15).44 After oxidative workup, reactions with trialkylboranes yield alkyl aryl sulfides (eq 16).45


1. (a) Grundmann, C. MOC 1965, 10/4, 777. (b) The Chemistry of the Azido Group; Patai, S., Ed.; Wiley: London, 1971. (c) Scriven, E. F. V.; Turnbull, K. CRV 1988, 88, 351.
2. (a) Regitz, M.; Maas, G. Diazo Compounds. Properties and Synthesis; Academic: Orlando, 1986; pp 326-435. (b) Böhshar, M.; Fink, J.; Heydt, H.; Wagner, O.; Regitz, M. MOC 1990, E14b, 961.
3. Lwowski, W. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, p 559.
4. (a) Heydt, H.; Regitz, M. MOC 1982, E2, 96. (b) Laszlo, P.; Polla, E. TL 1984, 25, 4651. (c) For the synthesis of arsinimines by the same method, see Cadogan, J. I. G.; Gosney, I. JCS(P1) 1974, 460.
5. (a) Haake, M. MOC 1985, E11, 901. (b) Haake, M. MOC 1985, E11, 1304.
6. Caution: the distillation of p-toluenesulfonyl azide should be avoided if at all possible since severe explosions have been reported: Spencer, H. Chem. Br. 1981, 17, 106.
7. Hua, D. H.; Peacock, N. J.; Meyers, C. Y. JOC 1980, 45, 1717.
8. Regitz, M.; Hocker, J.; Liedhegener, A. OSC 1973, 5, 179.
9. Breslow, D. S.; Sloan, M. F.; Newberg, N. R.; Renfrow, W. B. JACS 1969, 91, 2273.
10. Curphey, T. J. OPP 1981, 13, 112.
11. Roush, W. R.; Feitler, D.; Reb&ebreve;k, J. TL 1974, 1391.
12. Kumar, S. M. SC 1987, 17, 1015.
13. Laszlo, P.; Polla, E. TL 1984, 25, 3701.
14. Kim, Y. H.; Kim, K.; Shim, S. B. TL 1986, 27, 4749.
15. Pozsgay, V.; Jennings, H. J. TL 1987, 28, 5091.
16. Hazen, G. G.; Weinstock, L. M.; Connell, R.; Bollinger, F. W. SC 1981, 11, 947.
17. Rewicki, D.; Tuchscherer, C. AG(E) 1972, 11, 44.
18. (a) Weininger, S. J.; Kohen, S.; Mataka, S.; Koga, G.; Anselme, J.-P. JOC 1974, 39, 1591. (b) Kozikowski, A. P.; Greco, M. N. JOC 1984, 49, 2310.
19. Smith, P. A. S.; Rowe, C. D.; Bruner, L. B. JOC 1969, 34, 3430.
20. (a) Spagnolo, P.; Zanirato, P. JOC 1978, 43, 3539. (b) Spagnolo, P.; Zanirato, P.; Gronowitz, S. JOC 1982, 47, 3177.
21. Weiss, R.; Lowack, R. H. AG(E) 1991, 30, 1162.
22. (a) Fischer, W.; Anselme, J.-P. JACS 1967, 89, 5284. (b) Anselme, J.-P.; Fischer, W. T 1969, 25, 855.
23. Quast, H.; Eckert, P. LA 1974, 1727.
24. Koft, E. R. JOC 1987, 52, 3466.
25. (a) Regitz, M. AG(E) 1967, 6, 733. (b) Regitz, M. S 1972, 351.
26. (a) Dimroth, O. LA 1910, 373, 336. (b) Curtius, T.; Klavehn, W. JPR(2) 1926, 112, 65.
27. von Doering, W.; De Puy, C. H. JACS 1953, 75, 5955.
28. (a) Ledon, H. S 1974, 347. (b) Ledon, H. J. OS 1980, 59, 66. (c) Nakajima, M.; Anselme, J.-P. TL 1976, 4421. (d) Gonzáles, A.; Gálvez, C. S 1981, 741.
29. Regitz, M.; Rüter, J.; Liedhegener, A. OS 1971, 51, 86.
30. Hendrickson, J. B.; Wolf, W. A. JOC 1968, 33, 3610.
31. Cavender, C. J.; Shiner, V. J., Jr. JOC 1972, 37, 3567.
32. Kokel, B.; Viehe, H. G. AG(E) 1980, 19, 716.
33. Lombardo, L.; Mander, L. N. S 1980, 368.
34. Döpp, D.; Döpp, H. MOC 1990, E14B, 1052.
35. (a) Balli, H.; Kersting, F. LA 1961, 647, 1. (b) Balli, H.; Low, R.; Müller, V.; Rempfler, H.; Sezen-Gezgin, G. HCA 1978, 61, 97.
36. Regitz, M.; Maas, G. Diazo Compounds. Properties and Synthesis; Academic: Orlando, 1986; p 384.
37. Example: X = NR2, R1, R2 = cycloalkenyl, R3 = H: Pocar, D.; Ripamonti, M. C.; Stradi, R.; Trimarco, P. JHC 1977, 14, 173.
38. (a) Croce, P. D.; Stradi, R. T 1977, 33, 865. (b) Bourgois, J.; Mathieu, A.; Texier, F. JHC 1984, 21, 513. (c) Quast, H.; Regnat, D.; Balthasar, J.; Banert, K.; Peters, E.-M.; Peters, K.; von Schnering, H. G. LA 1991, 409.
39. Abramovitch, R. A.; Knaus, G. N.; Pavlin, M.; Holcomb, W. D. JCS(P1) 1974, 2169.
40. (a) Ritchie, A. C.; Rosenberger, M. JCS(C) 1968, 227. (b) Warren, B. K.; Knaus, E. E. JHC 1987, 24, 1413.
41. (a) Bailey, A. S.; Scattergood, R.; Warr, W. A. JCS(C) 1971, 2479. (b) Harmon, R. E.; Wellman, G.; Gupta, S. K. JHC 1972, 9, 1191.
42. Gerlach, O.; Reiter, P. L.; Effenberger, F. LA 1974, 1895.
43. Chakrasali, R. T.; Ila, H.; Junjappa, H. S 1988, 851.
44. Stanovnik, B.; Tisler, M.; Kunaver, M.; Gabrijel&cbreve;i&cbreve;, D.; Ko&cbreve;evar, M. TL 1978, 3059.
45. Ortiz, M.; Larson, G. L. SC 1982, 12, 43.

Heinrich Heydt & Manfred Regitz

University of Kaiserslautern, Germany



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