Imidazole

[288-32-4]  · C3H4N2  · Imidazole  · (MW 68.09)

(nucleophilic catalyst for silylations and acylations; buffer; weak base; iodination methods)

Alternate Names: Im; iminazole; 1,3-diazole; glyoxaline.

Physical Data: mp 90-91 °C; bp 255 °C, 138 °C/12 mmHg.

Solubility: sol water, alcohols, ether, acetone, chloroform.

Form Supplied in: colorless crystalline solid; widely available. Drying: 40 °C in vacuo over P2O5.

Purification: can be crystallized from C6H6, CCl4, CH2Cl2, EtOH, petroleum ether, acetone-petroleum ether, or water; can also be purified by vacuum distillation, sublimation, or by zone refining.

Introduction.

Imidazole has a pKa of 7.1 and is thus a stronger base than thiazole (pKa 2.5), oxazole (pKa 0.8), and pyridine (pKa 5.2). It is both a good acceptor and donor of hydrogen bonds. The pKa for loss of the N-H is ~14.2, i.e. imidazole is a very weak acid.

Silylations.

Imidazole is a standard component in silylations of alcohols as well as carboxylic acids, amines, and a variety of other functions, typically in combination with a silyl chloride in DMF (eq 1).1 A very widely used procedure for alcohol protection is by conversion into the corresponding t-butyldimethylsilyl (TBDMS or TBS) ether using the method;2 in other solvents such as pyridine or THF the reactions are much slower, probably because the primary silylating reagent is t-BuMe2Si-Im. In this and many other aspects, imidazole resembles another very useful transfer catalyst, 4-Dimethylaminopyridine (DMAP). Similarly, bulkier and hence more stable silyl groups, such as t-butyldiphenylsilyl (TBDPS)3 and triisopropylsilyl (TIPS),4 can be introduced. Times for completion of reaction at 20 °C vary (0.5-20 h); these silylating agents, originally developed for nucleoside protection,5 usually react faster with primary alcohols and with certain secondary alcohols, thus allowing selective protection of polyols to be achieved efficiently. (A faster alternative involves the use of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in place of imidazole, in a variety of solvents such as CH2Cl2, C6H6, or MeCN, in combination with R3SiCl).6 1,3-Diones can be efficiently O-silylated using TBDMSCl-Im7 or Hexamethyldisilazane (HMDS) and imidazole;8 other reagents are not as suitable, even in cases where the enol content is high. The products are useful as trans-silylating agents.7 The HMDS-Im combination is also useful for the silylation of thiols.9

Ester Hydrolysis.

Inspired by evidence that the imidazole ring of histidine residues present in various hydrolytic enzymes is responsible for their proteolytic activities, imidazole itself has been shown to be an excellent catalyst of ester hydrolysis (e.g. eq 2).10 In intramolecular transesterifications and hydrolyses of 2-hydroxymethylbenzoic acid derivatives, the accelerating role of imidazole is due to its ability to act as a proton transfer catalyst rather than as a nucleophile.11

Peptide Coupling.

Peptide couplings involving p-nitrophenyl and related esters (see p-Nitrophenol) are dramatically accelerated by the addition of imidazole.12 However, such reactions, which probably proceed by way of an acylimidazole, can be prone to racemization, in which case 1,2,4-Triazole can be a superior activator.13 Imidazole also catalyzes peptide coupling using the Triphenyl Phosphite method, with negligible racemization when the reactions are carried out in dioxane or DMF,14 and is useful for the activation of phosphomonoester groups in nucleotide coupling, in combination with an arylsulfonyl chloride.15

Acylimidazoles and Nucleophiles.

Acylimidazoles are readily prepared from the parent carboxylic acids by reaction of the derived acid chloride with imidazole or directly using N,N-Carbonyldiimidazole. These intermediates react smoothly with a variety of nucleophiles including Grignard reagents (eq 3),16 Lithium Aluminum Hydride (eq 4),16 and nitronates (eq 5).17 At -20 °C, aroylimidazoles can be reduced to the corresponding aldehydes in the presence of an ester function.16

The activation provided by an imidazole substituent is further illustrated in a route to 1,3-oxathiole-2-thiones from sodium 1-imidazolecarbodithioate, derived from the sodium salt of imidazole and CS2 (eq 6).18

Other Uses.

Imidazole is one of the best catalysts for the preparation of acid chlorides from the corresponding carboxylic acids and phosgene.19 Aryl triflates can be obtained from phenols, or better phenolates, using Trifluoromethanesulfonic Anhydride in combination with imidazole; N-triflylimidazole is the reactive species.20 Photochemical deconjugations of enones can be erratic but are promoted by the presence of a weak base such as imidazole or pyridine in polar solvents.21

Iodination of Alcohols.

Imidazole, Triphenylphosphine, and Iodine in hot toluene,22 or preferably toluene-acetonitrile mixtures,23 is an excellent combination for the conversion of alcohols into iodides, ROH -> RI. Secondary alcohols react with inversion (but see below), although the method can be used for the selective iodination of primary hydroxyls. Applications in the area of natural product synthesis24 emphasize the mildness and generality of the method as well as providing alternative recipes; sometimes, 2,4,5-triiodoimidazole can be a superior reagent.22 Similarly, Ph3P-Cl2-Im can be used for the preparation of alkyl chlorides, ROH -> RCl, and the addition of imidazole in the Triphenylphosphine-Carbon Tetrachloride method for alcohol chlorination has a beneficial effect.25

Diol Deoxygenation.

The Ph3P-Im-I2 combination can also be used to convert vic-diols into the corresponding alkenes, although 2,4,5-triiodoimidazole is more effective than imidazole itself.26 Alternative combinations are Triphenylphosphine-Iodoform-Imidazole, which can deoxygenate cis-diols but which is better suited to trans-isomers,27 and Chlorodiphenylphosphine-I2-Im, which can be used to deoxygenate vic-diols when both are secondary or when one is secondary and one is primary.28

Epoxidation.

t-Butyl Hydroperoxide in combination with MoO2(acac)2 can be used to oxidatively cleave alkenes, but will epoxidize such functions in the presence of a metalloporphyrin or a simple amine, the choice of which depends upon the substrate structure. Imidazole is the most suitable for 1-phenylpropene, Pyridine for stilbene, and N,N-dimethylethylenediamine for 1-alkenes.29


1. Lalonde, M.; Chan, T. H. S 1985, 817. Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991. Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994.
2. Corey, E. J.; Venkateswarlu, A. JACS 1972, 94, 6190.
3. Hanessian, S.; Lavallee, P. CJC 1975, 53, 2975.
4. Cunico, R. F.; Bedell, L. JOC 1980, 45, 4797.
5. Ogilvie, K. K. CJC 1973, 51, 3799. Ogilvie, K. K.; Iwacha, D. J. TL 1973, 317. Ogilvie, K. K.; Sadana, K. L.; Thompson, E. A.; Quilliam, M. A.; Westmore, J. B. TL 1974, 2861. Ogilvie, K. K.; Thompson, E. A.; Quilliam, M. A.; Westmore, J. B. TL 1974, 2865.
6. Aizpurua, J. M.; Palomo, C. TL 1985, 26, 475.
7. Veysoglu, T.; Mitscher, L. A. TL 1981, 22, 1299, 1303.
8. Torkelson, S.; Ainsworth, C. S 1976, 722.
9. Glass, R. S. JOM 1973, 61, 83.
10. Bender, M. L.; Turnquest, B. W. JACS 1957, 79, 1652. Bruice, T. C.; Schmir, G. L. JACS 1957, 79, 1663. Bender, M. L. CRV 1960, 60, 82. Looker, J. H.; Holm, M. J.; Minor, J. L.; Kagal, S. A. JHC 1964, 1, 253.
11. Fife, T. H.; Benjamin, B. M. JACS 1973, 95, 2059. Kirby, A. J.; Lloyd, G. J. JCS(P2) 1974, 637. Chiong, K. N. G.; Lewis, S. D.; Shafer, J. A. JACS 1975, 97, 418. Pollack, R. M.; Dumsha, T. C. JACS 1975, 97, 377. Belke, C. J.; Su, S. C. K.; Shafer, J. A. JACS 1971, 93, 4552.
12. Mazur, R. H. JOC 1963, 28, 2498. Wieland, T.; Vogeler, K. AG(E) 1963, 2, 42; LA 1964, 680, 125. McGahren, W. J.; Goodman, M. T 1967, 23, 2017. Stewart, F. H. C. CI(L) 1967, 1960.
13. Beyerman, H. C.; van der Brink, W. M.; Weygand, F.; Prox, A.; Konig, W.; Schmidhammer, L.; Nintz, E. RTC 1965, 84, 213.
14. Mitin, Y. V.; Glinskaya, O. V. TL 1969, 5267.
15. Berlin, Yu. A.; Chakhmakhcheva, O. G.; Efimov, V. A.; Kolosov, M. N.; Korobko, V. G. TL 1973, 1353.
16. Staab, H. A.; Braunling, H. LA 1962, 654, 119. Staab, H. A.; Jost, E. LA 1962, 655, 90. Staab, H. A. AG(E) 1962, 1, 351.
17. Baker, D. C.; Putt, S. R. S 1978, 478.
18. Ishida, M.; Sugiura, K.; Takagi, K.; Hiraoka, H.; Kato, S. CL 1988, 1705.
19. Hauser, C. F.; Theiling, L. F. JOC 1974, 39, 1134.
20. Effenberger, F.; Mack, K. E. TL 1970, 3947.
21. Eng, S. L.; Ricard, R.; Wan, C. S. K.; Weedon, A. C. CC 1983, 236.
22. Garegg, P. J.; Samuelsson, B. CC 1979, 978; JCS(P1) 1980, 2866.
23. Garegg, P. J.; Johansson, R.; Ortega, C.; Samuelsson, B. JCS(P1) 1982, 681.
24. Corey, E. J.; Pyne, S. G.; Su, W. TL 1983, 24, 4883. Berlage, U.; Schmidt, J.; Peters, U.; Welzel, P. TL 1987, 28, 3091. Corey, E. J.; Nagata, R. TL 1987, 28, 5391. Soll, R. M.; Seitz, S. P. TL 1987, 28, 5457.
25. Garegg, P. J.; Johansson, R.; Samuelsson, B. S 1984, 168.
26. Garegg, P. J.; Samuelsson, B. S 1979, 469, 813.
27. Bessodes, M.; Abushanab, E.; Panzica, R. P. CC 1981, 26.
28. Liu, Z.; Classon, B.; Samuelsson, B. JOC 1990, 55, 4273.
29. Kato, J.; Ota, H.; Matsukawa, K.; Endo, T. TL 1988, 29, 2843.

David W. Knight

Nottingham University, UK



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