· (MW 70.05)
(useful heterocycle in medicinal chemistry, pKa similar to a carboxylic acid, serves as a carboxylic acid mimic; nucleophilic amine, undergoes N-alkylation with a variety of electrophilic reagents; used as a catalyst in the synthesis of phosphonate esters)
Solubility: soluble in H2O, alcohol, acetonitrile; limited solubility in ether, benzene, and other organic solvents.
Form Supplied in: white crystalline solid and 0.45 M solution in acetonitrile.
Purification: careful recrystallization from ethanol. Sublimed under high vacuum at ca. 120 °C (Caution: explosion hazard).
Handling, Storage, and Precautions: decomposes upon heating and may explode if heated above 155 °C. Compound is noncombustible and hygroscopic. Store in a cool, dry place. Avoid heat and sunlight. Incompatible with strong acids, oxidizing agents, acid halides, and acid anhydrides.
N-Alkylations and Related Electrophilic Reactions
Tetrazole can exist as a mixture of 1H- and 2H- tautomers (1).1 The ratio of tautomers in solution depends on solvent polarity and, in the case of substituted tetrazoles, the nature of the C5 substituent. Tetrazole is a moderately strong acid, with a pKa value of the order of a carboxylic acid. Tetrazole reacts with a broad spectrum of electrophilic reagents to produce N-substituted derivatives. Various N-alkylation reactions have been studied extensively.2 As expected, N1 and N2-substituted isomers are typically generated. For example, methylation with methyl iodide or diazomethane leads to a mixture of N1 and N2 methyltetrazoles, the latter in slight excess (2).3 Similar ratios of N1 and N2 isomers were observed using BOM-Cl,4 ethyl bromoacetate,5 and o-tert-butyl-N,N´-dicyclohexylisourea.6 The N-alkylation of tetrazole using alkynones7 and formaldehyde8 has also been reported. Mitsunobu condensation between 5-phenyltetrazole and N-hexanol favors N2 over N1 alkylation (3).9 The Mitsunobu reaction of tetrazole and L-rhodinose was also reported to provide N2 glycosyl tetrazole as the major product and the corresponding N1 isomer as a minor component (4).10
An early publication reports silylation of tetrazole using chlorotrimethylsilane and triethylamine giving exclusively N1 trimethylsilyltetrazole (5).11 Amination of tetrazole affords an approximate 2:1 mixture of N1 and N2 aminotetrazole.12
C5 Substitution and Functionalization
5-Alkyl-and 5-acyl-1H-tetrazoles have been prepared from N-protected tetrazoles by deprotonation with N-butyllithium followed by quenching with various electrophilic reagents (6).13 5-Lithiotetrazoles derived from N1-protected tetrazoles are thermally less stable compared to their N2-protected counterparts.14 For example, 1-phenyl-5-lithiotetrazole undergoes rapid and irreversible decomposition to N-phenylcyanamide even at -70 °C (7). In contrast, N2-protected 5-lithiotetrazoles are generally stable at -78 °C (8). Suzuki15 and Stille16 cross-coupling reactions have been used to introduce functionality at the C5 position of tetrazole (eqs 9 and 10).
As a reagent 1H-tetrazole has been used as a condensation agent to mediate the coupling of ribonucleotides and phosphoramidites in the synthesis of oligonucleotides.17 1H-tetrazole has also been used to promote the coupling of phosphoramidite and protected inositols for the synthesis of myo-inositol phosphates (11).18
- 1. (a) Butler, R. N., Adv. Heterocyclic Chem. 1977, 21, 323. (b) Butler, R. N., Comprehensive Heterocyclic Chem.; Potts, K. T., Ed.; Pergamon: New York, 1984; Vol. 5. (c) Wittenberger, S. J., Org. Prep. and Proced. Int. 1994, 26, 499.
- 2. Ostrovskii, V. A.; Koren, A. O., Heterocycles 2000, 53, 1421.
- 3. Spear, R. J., Aust. J. Chem. 1984, 37, 2453.
- 4. Yokoyama, M.; Hirano, S.; Matsushita, M.; Hachiya, T.; Kobayashi, N.; Kubo, M.; Togo, H.; Seki, H., J. Chem. Soc. Perkin Trans. 1 1995, 1747.
- 5. Raap, R.; Howard, J., Can. J. Chem. 1969, 47, 813.
- 6. Henry, R. A., J. Hetreocycl. Chem. 1976, 13, 391.
- 7. Vereshchagin, L. I.; Tikhonova, L. G.; Maksikova, A. V.; Buzilova, S. R.; Shulgina, V. M.; Proidakov, A. G., Zh. Org. Khim. 1979, 15, 1730 (Chem. Abstr. 92, 6477).
- 8. Tselinskii, I. V.; Mel'nikov, A. A.; Varyagina, L. G.; Zhigadlova, I. G., Zh. Org. Khim. 1983, 19, 415 (Chem. Abstr. 100, 22621).
- 9. Purchase, C. F.; White, A. D., Syn. Commun. 1996, 26, 2687.
- 10. Guo, Y.; Sulikowski, G. A., J. Am. Chem. Soc. 1998, 120, 1392.
- 11. Birkofer, L; Ritter, A; Richter P., Chem. Ber. 1963, 96, 2750.
- 12. Raap, R., Can. J. Chem. 1969, 47, 3677.
- 13. (a) Grimmett, M. R.; Iddon, B., Heterocycles 1995, 41, 1525. (b) Satoh, Y.; Marcopulos, N., Tetrahedron Lett. 1995, 36, 1759.
- 14. Raap, R., Can. J. Chem. 1971, 49, 2139.
- 15. Yi, K. Y.; Yoo, S. E., Tetrahedron Lett. 1995, 36, 1679.
- 16. Bookser, B. C., Tetrahedron Lett. 2000, 41, 2805.
- 17. Beaucage, S. L.; Iyer, R. P., Tetrahedron 1993, 49, 6123.
- 18. Yu, K.-L.; Fraser-Reid, B., Tetrahedron Lett. 1988, 29, 979.
Gary A. Sulikowski & Michelle M. Sulikowski
Texas A & M University, College Station, TX, USA
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