Diphenyl Cyanocarbonimidate

[79463-77-7]  · C14H10N2O2  · Diphenyl Cyanocarbonimidate  · (MW 238.26)

(preparation of heterocycles,1,2 1,2,4-triazoles,1 4-oxa-1,3-diazoles,2 benzimidazoles,1 hexahydropyrimidines,3 and hydroquinazolines;3 synthesis of O-phenylisoureas,1 N-cyanoguanidines,2 and guanidines;4 modification of peptides;5 reverse electron demand Diels-Alder heterodieneophile6)

Alternate Names: DPCC; diphenoxymethylenecyanamide; diphenyl N-cyanoimidocarbonate.

Physical Data: mp 156-158 °C,1 161-163 °C (Aldrich).

Solubility: sol THF, propan-2-ol.

Form Supplied in: commercially available in ca. 97% purity.

Preparative Method: from diphenyl carbonate by treatment with PCl5 followed by cyanamide.1

Handling, Storage, and Precautions: harmful if swallowed and irritating to the eyes and respiratory system. Care should be taken not to inhale the powder nor to allow it to come in contact with the skin. It is sensitive to moisture. It should be disposed of by dissolving in a solvent and burning the solution in an approved incinerator. Use in a fume hood.

Synthesis of Heterocycles.

Diphenyl cyanocarbonimidate was originally described as a synthon for heterocyclic synthesis by Webb and Labaw.1 With o-phenylenediamine in boiling propan-2-ol, 2-cyanoaminobenzimidazole is formed. At rt the O-phenylisourea, the product of a single displacement, can be isolated and converted to the benzimidazole on warming (eq 1). The sequential displacement of the two phenoxide ions illustrates a major advantage of DPCC as a reagent. Sequential reaction of aniline followed by Hydrazine gives 5-phenylamino-3-amino-1,2,4-triazole (eq 1). A variety of 1,2,4-triazoles have been prepared by this method.7

Treatment of the O-phenylisourea with Hydroxylamine gives two isomeric oxadiazoles, the predominant isomer arising from initial nucleophilic attack by the hydroxylamine nitrogen (eq 2).2 Cyclization to give six-membered rings also occurs, forming substituted hydropyrimidines (eq 3).8 Imidazole ring formation to give a tricyclic structure has been accomplished by reaction of DPCC with a diamine (eq 4).9

Oxadiazole ring formation occurs with a hydrazide in the presence of Triethylamine, presumably involving the enol in the second nucleophilic displacement (eq 5).10 Reaction of DPCC with 2-aminobenzyl alcohol gives a six-membered benzoazine.11

An alternative mode of ring formation involves sequential substitution with two different nitrogen nucleophiles, followed by ring closure between one nitrogen and a reactive center on the other nucleophile. Thus b-alanine methyl ester gives an O-phenylisourea, which on treatment with benzylamine gives a hexahydropyrimidine (eq 6).3

If two modes of ring closure are possible then the five-membered ring is favored,12 and this can only partially be reversed by discriminating between the ester functions (eq 7).13 Rearrangement of the five-membered imidazolone to the corresponding acid of the hexahydropyrimidine takes place under mild base treatment, but racemization occurs.14

A combination of these two modes of cyclization occurs in the reaction of hydrazine with certain O-phenylisoureas to give 1,2,4,6-tetraazabicyclo[3.3.0]octanes (eq 8).15

Synthesis of N-Cyanoguanidines and Guanidines.

The N-cyanoguanidine drug cimetidine was prepared by Webb and Labaw from the sequential reaction of two different amines, and was their original reason for preparing DPCC (eq 9).2 Guanidines can be prepared from the N-cyanoguanidines by acid hydrolysis.16 Treatment of the N-cyanoguanidines with Trifluoroacetic Acid gives N-trifluoroacetates or, in the presence of water, the corresponding ureas.5,11,17

Modification of Peptides.

The o-amino function of lysine in peptides has been modified by treatment with DPCC to give the isourea, followed by an amine to give the N-cyanoguanidine (eq 10).5 Capsaicin analogs containing N-cyanoguanidine groups have been prepared,18 and methods have been described to prepare various N-guanidino-modified arginines.19

Diels-Alder Reaction.

The cyano group of DPCC acts as a heterodienophile in a reverse electron-demand Diels-Alder reaction with 3,6-bis(methoxycarbonyl)-1,2,4,5-tetraazabenzene to give a 1,2,4-triazabenzene derivative (eq 11).6

Related Reagents.

Aminoiminomethanesulfonic Acid; Cyanamide; N-Dichloromethylene-N,N-dimethyliminium Chloride; Guanidine; S-Methylisothiosemicarbazide; S-Methylisothiourea; O-Methylisourea; 1H-Pyrazole-1-carboxamidine Hydrochloride.

1. Webb, R. L.; Labaw, C. S. JHC 1982, 19, 1205.
2. Webb, R. L.; Eggleston, D. S.; Labaw, C. S.; Lewis, J. J.; Wert, K. JHC 1987, 24, 275.
3. Garratt, P. J.; Hobbs, C. J.; Wrigglesworth, R. JOC 1989, 54, 1062.
4. Elz, S.; Schunack, W. AP 1987, 320, 182.
5. Theobald, P.; Porter, J.; Rivier, C.; Corrigan, A.; Hook, W.; Siraganian, R.; Perrin, M.; Vale, W.; Rivier, J. JMC 1991, 34, 2395.
6. Seitz, G.; Wassmuth, H. CZ 1988, 112, 281.
7. Keller, F.; Buschauer, A.; Schunack, W. PZ Wiss 1988, 1, 48 (CA 1990, 112, 98 466k).
8. Buschauer, A.; Sattler, H. J.; Schunack, W. CB 1984, 117, 2597.
9. Kukla, M. J.; Breslin, H. J.; Diamond, C. J.; Grous, P. P.; Ho, C. Y.; Miranda, M.; Rodgers, J. D.; Sherrill, R. G.; De Clercq, E.; Pauwels, R.; Andries, K.; Moens, L. J.; Janssen, M. A. C.; Janssen, P. A. J. JMC 1991, 34, 3187.
10. Boschelli, D. H.; Connor, D. T.; Bornemeier, D. A.; Dyer, R. D.; Kennedy, J. A.; Kuipers, P. J.; Okonkwo, G. C.; Schrier, D. J.; Wright, C. D. JMC 1993, 36, 1802.
11. Garratt, P. J.; Hobbs, C. J.; Wrigglesworth, R. T 1989, 45, 829.
12. Besse, R.; Garratt, P. J.; Hobbs, C. J.; Rogers, H. M.; Sueleiman, A. M.; Walpole, C. J. S.; Wrigglesworth, R. T 1990, 46, 7803.
13. Garratt, P. J.; Thorn, S. N.; Wrigglesworth, R. TL 1991, 32, 691.
14. Delisser, V. M.; Garratt, P. J.; Thorn, S. N.; Wrigglesworth, R. BML 1992, 2, 421.
15. Garratt, P. J.; Thorn, S. N.; Wrigglesworth, R. T 1993, 49, 165.
16. Elz, S.; Kimmel, U.; Buschauer, A.; Schunack, W. Sci. Pharm. 1988, 56, 229.
17. Garratt, P. J.; Thorn, S. N.; Wrigglesworth, R. T 1993, 49, 6885.
18. Walpole, C. S. J.; Wrigglesworth, R.; Bevan, S.; Campbell, E. A.; Dray, A.; James, I. F.; Masdin, K. J.; Perkins, M. N.; Winter, J. JMC 1993, 36, 2373.
19. Wagenaar, F. L.; Kerwin, J. F., Jr. JOC 1993, 58, 4331.

Peter J. Garratt

University College London, UK

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