N,N-Carbonyldiimidazole1

[530-62-1]  · C7H6N4O  · N,N-Carbonyldiimidazole  · (MW 162.15)

(reagent for activation of carboxylic acids;1 synthesis of esters,2 amides,3 peptides,4 aldehydes,5 ketones,6 b-keto thioesters,7 tetronic acids;8 ureas,9 isocyanates,10 carbonates;9 halides from alcohols;11 glycosidation;12 dehydration13-16)

Physical Data: mp 116-118 °C.

Solubility: no quantitative data available. Inert solvents such as THF, benzene, CHCl3, DMF are commonly used for reactions.

Form Supplied in: commercially available white solid.

Analysis of Reagent Purity: purity can be determined by measuring the amount of CO2 evolved on hydrolysis.

Preparative Methods: prepared by mixing phosgene with four equivalents of imidazole in benzene/THF.17

Purification: may be purified by recrystallization from hot, anhydrous THF with careful exclusion of moisture.17

Handling, Storage, and Precautions: moisture sensitive; reacts readily with water with evolution of carbon dioxide. May be kept for long periods either in a sealed tube or in a desiccator over P2O5.

Activation of Carboxylic Acids: Synthesis of Acyl Imidazoles.

N,N-Carbonyldiimidazole (1) converts carboxylic acids into the corresponding acylimidazoles (2) (eq 1).1 The method can be applied to a wide range of aliphatic, aromatic, and heterocyclic carboxylic acids, including some examples (such as formic acid and vitamin A acid) where acid chloride formation is difficult. The reactivity of (2) is similar to that of acid chlorides, but the former have the advantage that they are generally crystalline and easily handled. Isolation of (2) is simple, but often unnecessary; further reaction with nucleophiles is usually performed in the same reaction vessel. Conversion of (2) into acid chlorides (via reaction with HCl),18 hydrazides,3 hydroxamic acids,3 and peroxy esters19 have all been described. Preparation of the more important carboxylic acid d erivatives is described below.

Esters from Carboxylic Acids.

Reaction of equimolar amounts of carboxylic acid, alcohol, and (1) in an inert solvent (e.g. THF, benzene, or chloroform) results in ester formation (eq 2). Since alcoholysis of the intermediate acylimidazole is relatively slow, the reaction mixture must be heated at 60-70 °C for some time. However, addition of a catalytic amount of a base such as Sodium Amide to convert the alcohol to the alkoxide, or a catalytic amount of the alkoxide itself, allows rapid and complete formation of the ester at room temperature.2 The base catalyst must of course be added after formation of (2) from the acid is complete, as indicated by cessation of evolution of carbon dioxide.

Esters of tertiary alcohols may not be prepared from carboxylic acids containing acidic a-protons using this modified procedure, since deprotonation and subsequent condensation, competes. However, the use of stoichiometric 1,8-Diazabicyclo[5.4.0]undec-7-ene as base has been shown to provide good yields of t-butyl esters even for acids with acidic a-protons (eq 3).20 This procedure was unsuccessful for pivalic acid or for N-acyl-a-amino acids.

An alternative approach to increasing the rate of esterification is to activate further the intermediate (2). N-Bromosuccinimide has been used for this purpose,21 but unsaturation in the carboxylic acid or alcohol is not tolerated. More generally useful is the addition of an activated halide, usually Allyl Bromide, to a chloroform solution of (1) and a carboxylic acid, resulting in formation of the acylimidazolium salt (3) (eq 4).22 Addition of the alcohol and stirring for 1-10 h at room temperature or at reflux affords good yields of ester in a one-pot procedure. These conditions work well for the formation of methyl, ethyl, and t-butyl esters of aliphatic, aromatic, and a,b-unsaturated acids. Hindered esters such as t-butyl pivalate can be prepared cleanly (90% yield). The only limitation is that substrates must not contain functionality that can be alkylated by the excess of the reactive halide.

Since the purity of commercial (1) may be variable due to its water sensitivity, it is common to employ an excess in order to ensure complete conversion of the carboxylic acid to the acylimidazole. It has been suggested that alcohols react faster with residual (1) than with the acylimidazole (2), thus reducing the yield of ester. A procedure has been developed for removal of excess (1) before addition of the alcohol.23

Macrolactonization has been accomplished using (1).24 Thiol and selenol esters can also be prepared in one pot from carboxylic acids using (1);25 reaction of the intermediate (2) with aromatic thiols or selenols is complete within a few minutes in DMF, while aliphatic thiols require a few hours. Formation of the phenylthiol ester of N-Cbz-L-phenylalanine was accompanied by only slight racemization. N,N-Carbonyldi-sym-triazine can be used in place of (1), with similar results.

Amides from Carboxylic Acids: Peptide Synthesis.

Analogous to ester formation, reaction of equimolar amounts of a carboxylic acid and (1) in THF, DMF, or chloroform, followed by addition of an amine, allows amide bond formation.3 The method has been applied to peptide synthesis (eq 5).4 One equivalent of (1) is added to a 1 M solution of an acylamino acid in THF, followed after 1 h by the desired amino acid or peptide ester. The amino acid ester hydrochloride may be used directly instead of the free amino acid ester. An aqueous solution of the amino acid salt can even be used, but yields are lower.

As is the case in esterification reactions, the presence of unreacted (1) can cause problems since the amine reacts with this as quickly as it does with the acylimidazole, forming urea byproducts that can be difficult to separate. Use of exactly one equivalent of (1) is difficult due to its moisture sensitivity, and also because of the tendency of some peptides or amino acids to form hydrates. Paul and Anderson solved this problem by use of an excess of (1) to form the acylimidazole, then cooling to -5 °C and adding a small amount of water to destroy the unreacted (1) before addition of the amine.26

For the sensitive coupling of Cbz-glycyl-L-phenylalanine and ethyl glycinate (the Anderson test), Paul and Anderson reported the level of racemization as 5% using THF as solvent at -10 °C, but as <0.5% in DMF.4 Performing the same coupling reaction at room temperature, Beyerman and van den Brink later claimed that the degree of racemization in DMF was in fact as high as 17%, and reported better results (no detectable racemization) using the related reagent N,N-carbonyl di-sym-triazine in place of (1).27 In a comparative study of several reagents, Weygand and co-workers also observed extensive racemization using (1).28 In the formation of tyrosine esters, Paul reported that the mixed anhydride method is to be preferred to use of (1), since O-acylation is a major side reaction with the latter.29

Aldehydes and Ketones from Carboxylic Acids.

Reduction of the derived acylimidazole (2) with Lithium Aluminum Hydride achieves conversion of an aliphatic or aromatic carboxylic acid to an aldehyde (eq 6).5 Diisobutylaluminum Hydride has also been used, allowing preparation of a-acylamino aldehydes from N-protected amino acids.30 Similarly, reaction of (2) with Grignard reagents affords ketones,6 with little evidence for formation of tertiary alcohol.

Reaction of acylimidazoles with the appropriate carbon nucleophile has also been used for the preparation of a-nitro ketones31 and b-keto sulfoxides.32

C-Acylation of Active Methylene Compounds.

Treatment of an acylimidazole, derived from a carboxylic acid and (1), with the magnesium salt of a malonic or methylmalonic half thiol ester results in C-acylation under neutral conditions (eq 7).7 The presence of secondary hydroxyl functionality in the carboxylic acid is tolerated, but primary alcohols require protection. Magnesium salts of malonic esters may be used equally effectively. Intramolecular C-acylation of ketones has also been reported.33

Tetronic Acids.

A synthesis of tetronic acids reported by Smith and co-workers relies on the reaction between (1) and the dianion derived from an a-hydroxy ketone (eq 8).8 The reaction proceeds in moderate yield (31-57%).

Ureas and Carbonates.

Reagent (1) may be used as a direct replacement for the highly toxic Phosgene in reactions with alcohols and amines. Reaction of (1) with two equivalents of a primary aliphatic or aromatic amine at room temperature rapidly yields a symmetrical urea (eq 9).9 If only one equivalent of a primary amine is added to (1), then the imidazole-N-carboxamide (4) is formed (eq 10). These compounds can dissociate into isocyanates and imidazole, even at room temperature, and distillation from the reaction mixture provides a useful synthesis of isocyanates (eq 10).10 Secondary amines react only at one side of (1) at room temperature, again giving the imidazole-N-carboxamide of type (4).

Reaction of (1) with one equivalent of an alcohol provides the imidazole-N-carboxylic ester (5) (eq 11).34 Further treatment with another alcohol or phenol yields an unsymmetrical carbonate; alternatively, reaction with an amine affords a carbamate (eq 12).34

Heating (1) with an excess of an alcohol or phenol gives the symmetrical carbonate.9 This reaction can be accelerated dramatically by the presence of catalytic base (e.g. Sodium Ethoxide). Reaction under these conditions is so exothermic even at room temperature that only t-butanol stops at the imidazole-N-carboxylic ester stage.

1,2-Diamines, 1,2-diols, or 1,2-amino alcohols react with (1) to form cyclic ureas,35 carbonates,36 or oxazolidinones,35 respectively. In the case of cyclohexane-1,2-diols, the cis-diol reacts much more rapidly than the trans, as would be expected.36 Thiazolidinones can also be prepared using (1).37

Halides from Alcohols.

Treatment of an alcohol with (1) and an excess (at least three equivalents) of an activated halide results in its conversion to the corresponding halide (eq 13).11 Any halide more reactive than the product halide may be used, but in practice Allyl Bromide or Iodomethane give best results as they are effective and readily removed after the reaction. Acetonitrile is the best solvent and yields are generally high (>80%). Bromide or iodide formation work well, but not chlorination. Optically active alcohols are racemized.

Glycosidation.

A mild glycosidation procedure involving (1) has been reported by Ford and Ley.12 A carbohydrate derivative in ether or dichloromethane reacts with (1) through the anomeric C-1-hydroxyl to give the (1-imidazolylcarbonyl) glycoside (IMG) (6) (eq 14). Isolation of (6) is not usually necessary; treatment with one equivalent of an alcohol and two equivalents of Zinc Bromide in ether at reflux gives the glycoside. Generally, higher a:b ratios are obtained for more hindered alcohols and when ether is used as solvent rather than the less polar dichloromethane. Along with the fact that the a:b ratio is independent of the configuration of (6), this suggests an SN1-type mechanism. In contrast, treatment of (6) with Acetyl Chloride provides the anomeric chloride with essentially exclusive inversion.

Dehydration.

Reagent (1) has been used for the dehydration of various substrates, including aldoximes (to give nitriles),13 b-hydroxy amino acids,14 and b-hydroxy sulfones.15 3-Aryl-2-hydroxyiminopropionic acids undergo dehydration and decarboxylation, to give 2-aryl acetonitriles, upon reaction with (1).16


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2. Staab, H. A.; Mannschreck, A. CB 1962, 95, 1284 (CA 1962, 57, 5846d).
3. Staab, H. A.; Lüking, M.; Dürr, F. H. CB 1962, 95, 1275 (CA 1962, 57, 5908a).
4. Paul, R.; Anderson, G. W. JACS 1960, 82, 4596.
5. Staab, H. A.; Bräunling, H. LA 1962, 654, 119 (CA 1962, 57, 5906c).
6. Staab, H. A.; Jost, E. LA 1962, 655, 90 (CA 1962, 57, 15 090g).
7. Brooks, D. W.; Lu, L. D.-L.; Masamune, S. AG(E) 1979, 18, 72.
8. Jerris, P. J.; Wovkulich, P. M.; Smith, A. B., III. TL 1979, 4517.
9. Staab, H. A. LA 1957, 609, 75 (CA 1958, 52, 7332e).
10. Staab, H. A.; Benz, W. LA 1961, 648, 72 (CA 1962, 57, 4649g).
11. Kamijo, T.; Harada, H.; Iizuka, K. CPB 1983, 31, 4189.
12. Ford, M. J.; Ley, S. V. SL 1990, 255.
13. Foley, H. G.; Dalton, D. R. CC 1973, 628.
14. Andruszkiewicz, R.; Czerwinski, A. S 1982, 968.
15. Kang, S.-K.; Park, Y.-W.; Kim, S.-G.; Jeon, J.-H. JCS(P1) 1992, 405.
16. Kitagawa, T.; Kawaguchi, M.; Inoue, S.; Katayama, S. CPB 1991, 39, 3030.
17. Staab, H. A.; Wendel, K. OS 1968, 48, 44.
18. Staab, H. A.; Datta, A. P. AG(E) 1964, 3, 132.
19. Hecht, R.; Rüchardt, C. CB 1963, 96, 1281 (CA 1963, 59, 1523h).
20. Ohta, S.; Shimabayashi, A.; Aono, M.; Okamoto, M. S 1982, 833.
21. Katsuki, T. BCJ 1976, 49, 2019.
22. Kamijo, T.; Harada, H.; Iizuka, K. CPB 1984, 32, 5044.
23. Morton, R. C.; Mangroo, D.; Gerber, G. E. CJC 1988, 66, 1701.
24. (a) White, J. D.; Lodwig, S. N.; Trammell, G. L.; Fleming, M. P. TL 1974, 3263. (b) Colvin, E. W.; Purcell, T. A.; Raphael, R. A. CC 1972, 1031.
25. Gais, H.-J. AG(E) 1977, 16, 244.
26. Paul, R.; Anderson, G. W. JOC 1962, 27, 2094.
27. Beyerman, H. C.; Van Den Brink, W. M. RTC 1961, 80, 1372.
28. Weygand, F.; Prox, A.; Schmidhammer, L.; König, W. AG(E) 1963, 2, 183.
29. Paul, R. JOC 1963, 28, 236.
30. Khatri, H.; Stammer, C. H. CC 1979, 79.
31. Baker, D. C.; Putt, S. R. S 1978, 478.
32. Ibarra, C. A.; Rodríguez, R. C.; Monreal, M. C. F.; Navarro, F. J. G.; Tesorero, J. M. JOC 1989, 54, 5620.
33. Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. JACS 1985, 107, 7790.
34. Staab, H. A. LA 1957, 609, 83 (CA 1957, 52, 16341e).
35. Wright, W. B., Jr. JHC 1965, 2, 41.
36. Kutney, J. P.; Ratcliffe, A. H. SC 1975, 5, 47.
37. D'Ischia, M.; Prota, G.; Rotteveel, R. C.; Westerhof, W. SC 1987, 17, 1577.

Alan Armstrong

University of Bath, UK



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