(1; R1 = Me, R2 = Me)

[21124-13-0]  · C8H11N3  · 3-Methyl-1-p-tolyltriazene  · (MW 149.22) (2; R1 = NO2, R2 = Me)

[40643-39-8]  · C7H8N4O2  · 3-Methyl-1-p-nitrophenyltriazene  · (MW 180.19) (3; R1 = Me, R2 = Et)

[50707-40-9]  · C9H13N3  · 3-Ethyl-1-p-tolyltriazene  · (MW 163.25) (4; R1 = OMe, R2 = Pr)

[74849-15-3]  · C10H15N3O  · 3-Propyl-1-p-methoxyphenyltriazene  · (MW 193.28) (5; R1 = Me, R2 = i-Pr)

[118399-01-2]  · C10H15N3  · 3-Isopropyl-1-p-tolyltriazene  · (MW 177.28) (6; R1 = Br, R2 = Bn)

[85013-27-0]  · C13H12BrN3  · 3-Benzyl-1-p-bromophenyltriazene  · (MW 290.18)

(methylating agent for carboxylic acids,2 other acids, alcohols, phenols, and thiols3)

Physical Data: mp: (1) 79-81 °C; (2) 112-114 °C; (3) 36-38 °C; (4) 28-30 °C; (5) 29-30 °C; (6) 87-88 °C.

Alternate Name: MTT.

Solubility: in general, slightly sol hexane; sol Et2O, chloroform, acetone, DMSO. May undergo degradation in protic media.

Form Supplied in: (1) colorless solid; commercially available in 98% purity.

Preparative Methods: disubstituted triazenes can be prepared by the reaction of Grignard4 or organolithium reagents5 with azides, or by the reaction of aryl diazonium salts with primary amines.6 Chief impurities present in the latter case are the pentazadienes (2:1 condensation products) and diaryltriazenes.

Handling, Storage, and Precautions: can be safely stored for reasonable periods. Alkyltriazenes are potent biological alkylating agents and should be treated as toxic and potentially carcinogenic. Efficient fumehoods and use of reasonable precautions are recommended when handling these compounds.

Alkylation by Triazenes.

N-Methyltriazenes can achieve low temperature methylation of acidic substances including benzoic acids,2b,6 fatty acids,7 enols,8 polymeric carboxylic acids,2a,2c and presumably any compound that can be methylated by Diazomethane. Succinimide and phenols are also methylated directly by 3-methyl-1-p-tolyltriazene, but methylation of alcohols and thiols requires aluminum alcoholate catalysis.3

In nonpolar solvents the alkylations probably involve displacement reactions on the methyldiazonium ion (eq 1); yields are essentially quantitative. The reaction intermediate is probably identical or very similar to the corresponding intermediate generated from diazomethane. The triazene approach is of special advantage in the case of higher homologs (alkyltriazenes) since most alkyl-substituted diazomethanes are quite unstable; in contrast, primary and secondary alkyltriazenes can be readily prepared.4,9 1-Bicyclo[2.2.1]heptyltriazenes are quite stable,10 but tertiary alkyltriazenes that would lead to relatively stable carbocations, e.g. R2 = t-butyl, are generally not isolable under normal circumstances.

The triazenes have several advantages over diazoalkanes. They are crystalline; they are more stable and need not be freshly prepared; they are far less volatile and thus less toxic via the pulmonary route; they are less prone to explosion; and they do not normally lead to the cycloaddition reactions observed for diazomethane.11 Finally, chiral triazenes can form chiral esters with retention of configuration12 (the reactive center of diazoalkanes is achiral) (see eq 3).

Reactions of Higher Triazene Homologs.

Triazenes with alkyl groups bearing b-hydrogens may give elimination products, which can account for ~20-60% (values estimated for reactions of free carbocations) of the alkyl groups (eq 2) (the diazoalkane approach would yield similar amounts of elimination).

As the electron-donating capacity of the alkyl group increases and as the solvent becomes more polar, the mechanism shifts from SN2 to SN1, leading to carbenium ion pair intermediates (eq 3),12,13 which form the esters with net retention of configuration. In these cases, alkylation of the arylamine also occurs (as well as the elimination reaction), and alkylation of the solvent may become a major reaction,14 especially when a removable b-hydrogen is not available. This fact can be turned to advantage since, in this way, weakly acidic or nonacidic compounds can be alkylated.14

Other Reactions of Triazenes.

The common acylating agents react with mono- and disubstituted triazenes to give the corresponding acyl derivatives; Phenyl Isocyanate (eq 4) and Acetic Anhydride have been particularly widely used.15 These acyl derivatives obtained from dialkyltriazenes still have alkylating capabilities.16

Salts of disubstituted triazenes can be alkylated, and with unsymmetrical triazenes alkylation can occur at either or both terminal nitrogens.17 Triazenes are readily reduced to a mixture of amines and hydrazines (the reaction cannot be stopped at the triazane stage).18 Oxidation of disubstituted triazenes with permanganate produces hexazadienes.19 Triazenes form complexes with transition metals in the capacity of mono- and bidentate ligands and as bridging agents.20

The Triazene Moiety as an Amino Blocking Group.

The isomeric bromoanilines have been converted into the corresponding triazenes, which were subjected to lithium-halogen exchange to yield triazenylaryllithiums.21 These react with a variety of electrophiles; subsequent deblocking of the products by hydrolysis regenerates the arylamino function.21

Biological Alkylation.

Alkyltriazenes are cytotoxic compounds which have carcinogenic,22 mutagenic,23 teratogenic,24 antifungal,25 bactericidal,25 and antitumor26 properties. This broad spectrum of biological activity is commonly attributed to their capacity to alkylate biomolecules, in particular DNA.27 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (MTIC) (7), for example, possesses antitumor activity,26,27 methylating DNA primarily at N-7 and O-6 of the guanine residues.27

Related Methylating Agents.

A number of mechanistically related alkylating agents are available, but they are not generally competitive with the triazenes or diazomethane except under specific conditions. For example, acidic compounds are methylated by syn and anti methanediazoate salts28 and by N-methyl-N-nitrososulfamates.29 Conditions can be found for alkylation by N-methyl-N-nitro-O-acylhydroxylamines30 and by the corresponding N-nitroso analogs.31 Finally, an elegant approach suitable for isotopically labeled compounds and other valuable compounds involves the prior incorporation of the incipient methylating group and the acidic group (carboxylic acids, carbonic and carbamic acids, sulfonic acids, etc.) into a single molecule, followed by first-order decomposition32 (see N-Methyl-N-nitrosoacetamide).

Related Reagents.

2-Diazopropane; 1-Methyl-3-nitro-1-nitrosoguanidine; N-[N-Methyl-N-nitroso(aminomethyl)]benzamide; N-Methyl-N-nitroso-p-toluenesulfonamide; N-Nitrosodimethylamine; Phenyldiazomethane; Trimethylsilyldiazomethane.

1. (a) Vaughan, K.; Stevens, M. F. G. CSR, 1978, 7, 377. (b) Tisdale, M. J. In Triazenes [Proc. Int. Conf.] 1989 (pub. 1990), 15.
2. (a) Cohen, H. L. J. Polym. Sci., Polym. Chem. Ed., 1976, 14, 7. (b) Isaacs, N. S.; Rannala, E. JCS(P2) 1974, 899. (c) Blumstein, R.; Murphy, G. J.; Blumstein, A.; Watterson, A. C. J. Polym. Sci., Polym. Lett. Ed. 1973, 11, 21.
3. (a) Pochinok, V. Y.; Limarenko, L. P. UKZ 1955, 21, 628. (b) Pochinok, V. Y.; Portayagina, V. A. UKZ 1952, 18, 631.
4. Dimroth, O. CB 1903, 36, 909.
5. Smith, R. H.; Michejda, C. J. S 1983, 476.
6. (a) White, E. H.; Baum, A. A.; Eitel, D. E. OSC 1973, 5, 797. (b) White, E. H.; Scherrer, H. TL 1961, 758.
7. Henrick, C. A. U.S. Patent 3 873 586 (CA 1975, 82, 170 098y).
8. Vyas, D. M.; Benigni, D.; Partyka, R. A.; Doyle, T. A. JOC 1986, 51, 4307.
9. (a) Zverina, V.; Matrka, M. Chem. Listy 1969, 63, 51. (b) Bublitz, D. E. JOM 1970, 23, 225.
10. Dzadzic, P. M. Ph.D. Thesis, The Johns Hopkins University, 1975 (Diss. Abstr. DA1-B 36/07, p 3783, June 1976).
11. Wulfman, D. S.; Linstrumelle, G.; Cooper, D. F. In The Chemistry of Diazonium and Diazo Groups; Patai, S., Ed.; Wiley: New York, 1978, Part 2, p 823.
12. White, E. H.; Maskill, H.; Woodcock, D. J.; Schroeder, M. A. TL 1969, 1713.
13. White, E. H. JACS 1955, 77, 6215.
14. (a) White, E. H.; DePinto, J. T.; Polito, A. J.; Bauer, I.; Roswell, D. F. JACS 1988, 110, 3708. (b) White, E. H.; Field, K. W.; Hendrickson, W. H.; Dzadzic, P; Roswell, D. F.; Paik, S.; Mullen, P. W., JACS 1992, 114, 8023.
15. (a) Dimroth, O. CB 1907, 40, 2376. (b) Dimroth, O. CB 1905, 38, 677.
16. Smith, R. H.; Wladkowski, B. D.; Herling, J. A.; Pfaltzgraff, T. D.; Taylor, J. E.; Thompson, E. J.; Pruski, B.; Klose, J. R.; Michejda, C. J. JOC 1992, 57, 6448.
17. Smith, C.; Watts, C. H. JCS 1910, 97, 562.
18. (a) Nölting, E.; Binder, F. CB 1887, 20, 3004. (b) Clusius, K.; Weisser, H. R. HCA 1952, 35, 1524.
19. Theilacker, W.; Fintelmann, E. C. CB 1958, 91, 1597.
20. Moore, D. S.; Robinson, S. D. Adv. Inorg. Chem. Radiochem. 1986, 30, 1.
21. Gross, M. L.; Blank, D. H.; Welch, W. M. Abstracts of Papers, Part 2, 200th ACS National Meeting, Washington, D.C., August 26-31, 1990.
22. Preussman, R.; von Hodenberg, A.; Hengy, H. Biochem. Pharmacol. 1969, 18, 1.
23. Ong, T.; deSerres, F. J. Mutation Res. 1971, 13, 276.
24. Druckrey, H.; Ivankovic, S.; Preussman, R.; Brunner, U. E 1967, 23, 1042.
25. Zlochevskaya, I. V.; Rukhadze, E. G.; Bobkoval, T. S.; Chekunova, L. N. Vestn. Mosk. Univ., Biol. Pochvoved. 1973, 28, 42 (CA 1974, 81, 21 539v).
26. Schmid, F. A.; Hutchinson, D. J. Cancer Res. 1974, 34, 1671.
27. Meer, L.; Janzer, R. C.; Kleihues, P.; Kolar, G. F. Biochem. Pharmacol. 1973, 22, 1855.
28. (a) White, E. H.; Ryan, T. J.; Field, K. W. JACS 1972, 94, 1360. (b) Suhr, H. CB 1963, 96, 1720.
29. White, E. H.; Li, M.; Lu, S. JOC 1992, 57, 1252.
30. White, E. H.; Reefer, J.; Erickson, R. H.; Dzadzic, P. M. JOC 1984, 49, 4872.
31. White, E. H.; Ribi, M. A.; Cho, L.; Egger, N.; Dzadzic, P. M.; Todd, M. D. JOC 1984, 49, 4866.
32. White, E. H.; Woodcock, D. J. In The Chemistry of the Amino Group; Patai, S., Ed.; Wiley: New York, 1968; Chapter 8.

Emil H. White & Ron W. Darbeau

The Johns Hopkins University, Baltimore, MD, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.