[726-42-1]  · C15H14N2  · Di-p-tolylcarbodiimide  · (MW 222.31)

(synthesis of nitrogen heterocycles)

Physical Data: bp 221-223 °C/20 mmHg, 114 °C/0.02 mmHg; mp 56-58 °C.

Solubility: sol diethyl ether, benzene, pyridine, t-butanol.

Form Supplied in: off-white crystalline solid.

Preparative Methods: although di-p-tolylcarbodiimide is commercially available, it is quite expensive. It can be conveniently prepared from di-p-tolylthiourea by oxidation with Mercury(II) Oxide,1 Triphenylphosphine in the presence of Diethyl Azodicarboxylate,2 or with mercury(II) benzamide.3 A synthetic method dimerizing p-tolyl isocyanate has been reported.4

Purification: recrystallizations from diethyl ether and other solvents have been reported.1

Handling, Storage, and Precautions: harmful by inhalation, ingestion, or skin absorption and exposure causes strong eye and lung irritation. The solid is light- and moisture-sensitive and should be stored refrigerated in dark, well-sealed containers under an inert atmosphere. It should be used in a fume hood.

Heterocycle Synthesis.

Di-p-tolylcarbodiimide is a potent electrophile which reacts with a wide variety of nucleophiles to yield formamidine derivatives substituted at the central carbon. This reactivity has been exploited to prepare a large number of nitrogen heterocycles. Treatment of di-p-tolylcarbodiimide (1) with ethyl allophanate, for example, results in the formation of 2-substituted quinazolin-4(3H)-ones (eq 1).5 b-Lactams can also be prepared by the reaction of carbodiimides with a-halo esters in a Reformatsky-type reaction (eq 2).6

The reaction of (1) with thiazolium ylides related to thiamine has been extensively studied by Takimazawa and co-workers. They have found that, depending upon reaction conditions and the substrate used, a wide variety of thiamine-annulated heterocycles can be prepared (eq 3).7

Treatment of (1) with amidrazones in MeCN at 80-90 °C yields 5-tolylamino-1,2,4-triazoles in good yields.8 Similarly, Molina and co-workers have found that (1) reacts with a variety of N-amino heterocycles to yield triazoles from N-amino-2-thioxo-4-imidazolidinones (eq 4),9 ring annulated [1,2,4]triazolo[4,3-b]triazoles from [1,2,4]triazoles,10 and [1,2,4] triazolo[5,1-c][1,2,4]triazines from 3,4-diamino[1,2,4]triazine.11 Related additions have also been reported for thiadiazolines.12

Other Reactions with Nucleophiles.

Di-p-tolylcarbodiimide reacts with sulfonic acids to afford the corresponding sulfonic anhydride (and di-p-tolylurea).13 Treatment of (1) with an alcohol in the presence of base yields the corresponding N,N-di-p-tolyl-O-alkyl pseudourea ethers. These ethers decompose in the presence of mono- and disubstituted hydrogen phosphates to afford tertiary phosphates in high yields (eq 5).14 A variation of this methodology has been widely applied for the preparation of nucleoside phosphites.15

Other Reactions.

Di-p-tolylcarbodiimide is reduced with Sodium Borohydride in isopropanol to afford formamidines in good yields.16 Diarylcarbodiimides have been found to help carboxylate active methylene compounds such as fluorene, where the diimide acts as model for biotin.17

1. (a) Zetzsche, F.; Meyer, H. E.; Overbeck, H.; Nerger, W. CB 1938, 71, 1512. (b) Will, W. CB 1881, 14, 1485.
2. (a) Mitsunobu, O.; Kato, K.; Tomari, M. T 1970, 26, 5731. (b) Mitsunobu, O.; Kato, K.; Kakese, F. TL 1969, 2473.
3. Mitsunobu, O.; Tomari, M.; Morimoto, H.; Sato, T.; Sudo, M. BCS 1972, 45, 3607.
4. Hunger, K. TL 1966, 5929.
5. Svétlik, J. H 1981, 16, 1281.
6. Piotrowska, K.; Mostowicz, D. CC 1981, 41.
7. (a) Takamizawa, A.; Hiroi, K.; Matsumoto, S. TL 1968, 4027. (b) Takamizawa, A.; Matsumoto, S.; Sakai, S. CPB 1974, 22, 299. (c) Takamizawa, A.; Matsumoto, S. CPB 1974, 22, 305. (d) Takamizawa, A.; Matsumoto, S.; Makiyo, I. CPB 1974, 22, 311.
8. Doyle, K. M.; Kurzer, F. T 1976, 32, 2343.
9. (a) Molina, P.; Arques, A.; Alias, A. T 1990, 46, 4353. (b) Molina, P.; Alajarin, M.; Ferao, A.; Pérez de Vega, M. J. JCS(P1) 1987, 2667.
10. Molina, P., Alajarín, M.; Ferao, A.; Lorenzo, A.; Vilaplana, M. J.; Aller, E.; Planes, J. H 1988, 27, 161.
11. Molina, P.; Alajarín, M., Pérez de Vega, M. P.; López, A. H 1989, 29, 1607.
12. L'abbé, G.; Albrecht, E. JHC 1992, 29, 451.
13. Khorana, H. G. CJC 1953, 31, 585.
14. (a) Khorana, H. G. CJC 1954, 32, 227. (b) Khorana, H. G.; Todd, A. R. JCS 1953, 2257.
15. Schofield, J. A.; Todd, A. R. JCS 1961, 2257.
16. Kaji, K.; Matsubara, H.; Nagashima, H.; Kikugawa, Y.; Yamada, S.-I. CPB 1978, 26, 2246.
17. Chiba, K.; Tagaya, H.; Karasu, M.; Ono, T.; Hashimoto, K.; Moriwaki, Y. BCS 1991, 64, 966.

Eric J. Stoner

Abbott Laboratories, Chicago, IL, USA

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