Azidomethyl Phenyl Sulfide

[77422-70-9]  · C7H7N3S  · Azidomethyl Phenyl Sulfide  · (MW 165.22)

(reagent for amination of organomagnesium compounds;1 allows amination and oxidation of a,a-disubstituted ester enolates via 1,2,3-triazol-5-ones;1b a synthetic equivalent of methyl azide for the synthesis of methylaziridines;2 substituted a-azido sulfides undergo Beckmann-type rearrangements to provide lactams and imino thioethers3,4)

Physical Data: bp 104-105 °C/5 mmHg; n20D 1.5904; d 1.168 g cm-3; fp 107 °C.

Solubility: freely sol common organic solvents.

Form Supplied in: colorless to light-gold liquid, ~95% pure.

Analysis of Reagent Purity: 1H NMR.

Preparative Method: chlorination of Thioanisole with Sulfuryl Chloride followed by treatment of the resultant a-chloro sulfide with Sodium Azide in acetonitrile.1a

Handling, Storage, and Precautions: as with all azides of low or moderate molecular weight, heat or shock can cause vigorous, possibly explosive, nitrogen evolution. Distillation should be performed behind a blast shield at reduced pressure and temperatures less than 110 °C. Similar compounds have been shown to decompose with nitrogen evolution at ~120 °C.5 Striking neat azidomethyl phenyl sulfide with a hammer fails to cause detonation. Storage under nitrogen in an amber bottle in a refrigerator is recommended. It is incompatible with strong acids, bases, and oxidizing agents. When the reagent is used for the amination of organomagnesium reagents, an intermediate triazene is formed. Certain triazenes are known to be carcinogenic,6 thus caution in handling these intermediates should be exercised. Rinsing glassware with bleach will dispel the disagreeable odor associated with azidomethyl phenyl sulfide, phenylthiomethyltriazenes, and other sulfur-containing byproducts encountered in the use of this reagent. Handle in a fumehood.

Amination of Organomagnesium Reagents.

Treatment of azidomethyl phenyl sulfide with aryl organomagnesium reagents followed by aqueous workup results in the formation of triazenes. These may be converted to anilines by the action of aqueous Potassium Hydroxide or aqueous Formic Acid (eq 1).1a,c Transmetalation of aryllithium compounds to organomagnesium compounds with Magnesium Bromide etherate is required, since the former are unsuitable for this transformation. The phenylthio group appears to accelerate the reaction with the organomagnesium reagent relative to other substituents.1b Aliphatic organomagnesium reagents may also be aminated, but acylation of the intermediate magnesiotriazene at low temperature is required prior to cleavage, resulting in the amidated product (eq 2).1b A variety of primary and secondary organomagnesium reagents have been amidated, and several different acylating agents have been used.1b

The phenylthio group allows regiocontrol in the acylation and subsequent cleavage reaction. Other reagents for amination of organomagnesium and organolithium reagents have been published, each with its own advantages and limitations.7 Some representative reagents are MeONH2/MeLi,8 ArONH2,9 (PhO)2P(O)ONH2,10 (PhO)2P(O)N3,11 ArSO2N3,12 Me3SiCH2N3,13 vinyl azides,14 and oxime derivatives.15 Amidation with TsON(Li)Boc has been accomplished.16 Introduction of alkylamino, arylamino, or dialkylamino groups by the amination approach has also been studied.17

Amination of Ester Enolates.

Lithium ester enolates react with azidomethyl phenyl sulfide to give 3,5-dihydro-4H-1,2,3-triazol-5-ones, which may be converted to a-amino amides with aqueous Ammonia (eq 3).1b The ester enolate must be a,a-disubstituted to avoid aromatization of the triazolone. Treatment of the triazolones with methanolic Magnesium Methoxide results in the formation of a-methoxy amides.1b Other azides have been used to prepare triazolones, which undergo similar solvolysis reactions.18 Other reagents for the amination of enolates have been examined,7 including BocN=NBoc19 and trisyl azide.20

Dipolar Cycloadditions.

A common strategy for the synthesis of aziridines is the dipolar cycloaddition of azides with alkenes followed by thermal or photochemical decomposition of the resultant triazolines. The synthesis of methylaziridines by this approach would require the hazardous compound methyl azide. Azidomethyl phenyl sulfide is a safer synthetic equivalent of methyl azide, since the phenylthio group can be removed by desulfurization (eq 4).2

Rearrangement of a-Azido Sulfides.

An alternative to the Beckmann rearrangement has been developed involving the protic or Lewis acid promoted rearrangement of a-azido sulfides (eq 5).3,4 Either lactams or imino thioethers may be formed. The thermal-5 and base-promoted21 rearrangement of a-azido sulfides has also been studied (eq 6).5


1. (a) Trost, B. M.; Pearson, W. H. JACS 1981, 103, 2483. (b) Trost, B. M.; Pearson, W. H. JACS 1983, 105, 1054. (c) Trost, B. M.; Pearson, W. H. TL 1983, 24, 269.
2. Benbow, J. W.; Schulte, G. K.; Danishefsky, S. J. AG(E) 1992, 31, 915.
3. Trost, B. M.; Vaultier, M.; Santiago, M. L. JACS 1980, 102, 7929.
4. Still, I. W. J.; Brown, W. L.; Colville, R. J.; Kutney, G. W. CJC 1984, 62, 586.
5. Jarvis, B. B.; Nicholas, P. E.; Midiwo, J. O. JACS 1981, 103, 3878.
6. Smith, R. H., Jr.; Mehl, A. F.; Hicks, A.; Denlinger, C. L.; Kratz, L.; Andrews, A. W.; Michejda, C. J. JOC 1986, 51, 3751 and references cited therein.
7. Review: Erdik, E.; Ay, M. CRV 1989, 89, 1947.
8. (a) Beak, P.; Kokko, B. J. JOC 1982, 47, 2822. (b) Beak, P.; Basha, A.; Kokko, B.; Loo, D. JACS 1986, 108, 6016. (c) Boche, G.; Wagner, H.-U. CC 1984, 1591.
9. (a) Sheradsky, T.; Salemnick, G.; Nir, Z. T 1972, 28, 3833. (b) Radhakrishna, A. S.; Loudon, G. M.; Miller, M. J. JOC 1979, 44, 4836.
10. (a) Colvin, E. W.; Kirby, G. W.; Wilson, A. C. TL 1982, 23, 3835. (b) Boche, G.; Bernheim, M.; Schrott, W. TL 1982, 23, 5399.
11. Mori, S.; Aoyama, T.; Shioiri, T. CPB 1986, 34, 1524.
12. (a) Smith, P. A. S.; Rowe, C. D.; Bruner, L. B. JOC 1969, 34, 3430. (b) Spagnolo, P.; Zanirato, P. JOC 1982, 47, 3177. (c) Reed, J. N.; Snieckus, V. TL 1983, 24, 3795.
13. Nishiyama, K.; Tanaka, N. CC 1983, 1322.
14. Hassner, A.; Munger, P.; Belinka, B. A., Jr. TL 1982, 23, 699.
15. Hagopian, R. A.; Therien, M. J.; Murdoch, J. R. JACS 1984, 106, 5753.
16. Genet, J. P.; Mallart, S.; Greck, C.; Piveteau, E. TL 1991, 32, 2359.
17. Representative examples: (a) Dai, W.; Srinivasan, R.; Katzenellenbogen, J. A. JOC 1989, 54, 2204. (b) Boche, G.; Schrott, W. TL 1982, 23, 5403. (c) Iwao, M.; Reed, J. N.; Snieckus, V. JACS 1982, 104, 5531. (d) Yamamoto, H.; Maruoka, K. JOC 1980, 45, 2739.
18. (a) Quast, H.; Meichsner, G.; Seiferling, B. CB 1987, 120, 217. (b) Quast, H.; Hergenröther, T.; Banert, K.; Peters, E.-M.; Peters, K.; von Schnering, H. G. CB 1993, 126, 103 and earlier work cited therein.
19. (a) Gennari, C.; Colombo, L.; Bertolini, G. JACS 1986, 108, 6394. (b) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. JACS 1986, 108, 6395. (c) Trimble, L. A.; Vederas, J. C. JACS 1986, 108, 6397.
20. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. JACS 1990, 112, 4011.
21. Jarvis, B. B.; Nicholas, P. E. JOC 1980, 45, 2265.

William H. Pearson & P. Sivaramakrishnan Ramamoorthy

The University of Michigan, Ann Arbor, MI, USA



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