Trichloromethyl Chloroformate1

[503-38-8]  · C2Cl4O2  · Trichloromethyl Chloroformate  · (MW 197.82)

(convenient substitute for phosgene; an effective reagent for the synthesis of isocyanates,2 carbamoyl chlorides,3 carboxylic acid chlorides,4 N-carboxy-a-amino acid anhydrides,5 chloroformates,6 carbonates,7 isocyanides,8 nitriles,9 and various heterocyclic compounds)

Alternate Names: diphosgene; TCF

Physical Data: bp 128 °C, 53-55 °C/53 mmHg; d 1.65 g cm-3.

Solubility: sol most organic solvents, but insol water.

Form Supplied in: commercially available as a colorless liquid.

Analysis of Reagent Purity: IR (neat) 1815, 1054, 968, 912, 814, and 764 cm-1; 13C NMR (CDCl3) d 143.9 and 108.4.

Preparative Method: most conveniently prepared by photochlorination of methyl chloroformate.10

Purification: distillation at reduced pressure is recommended to avoid possible decomposition to phosgene which occurs at elevated temperatures.10

Handling, Storage, and Precautions: although the vapor pressure is low, care should be taken to handle this toxic compound, as in the case of phosgene.11 It readily decomposes to phosgene in some cases, particularly rapidly on contact with activated charcoal or iron(III) oxide. It is best to store the reagent in a refrigerator to avoid spontaneous decomposition. The reagent should be used in a fume hood.

Carbonylation of Amines to Form Isocyanates.

Both aromatic and aliphatic primary amines (as the free amines or hydrochlorides) give the corresponding isocyanates on treatment with TCF. As in the case of other reactions of TCF, inert solvents such as THF, dioxane, dichloromethane, 1,2-dichloroethane, benzene, and toluene are commonly used. Phenyl isocyanate, for example, is prepared from aniline and 0.5 molar amount of TCF in dioxane (eq 1).2 In a similar manner, diisocyanates are readily derived from diamines.

Various kinds of isocyanates are prepared from esters of a-amino acids by heating with TCF in toluene in the presence of activated charcoal, which promotes the decomposition of TCF to phosgene. Use of amine hydrochlorides may be effective to avoid the formation of 1,3-disubstituted ureas.12

Secondary amines give carbamoyl chlorides, as exemplified by the formation of bis(2-chloroethyl)carbamoyl chloride.3 Monochloroformylation takes place with a urea (eq 2).13 TCF is also useful for synthesizing various kinds of heterocycles including cyclic ureas,14 pyrazolooxadiazines,15 and oxadiazolinones16 from amine derivatives.

Synthesis of Acid Chlorides.

Carboxylic acids are easily converted into acid chlorides by the action of TCF. Benzoic acid gives benzoyl chloride when heated with TCF.4 Treatment of amino acids with TCF results in the formation of isocyanato acid chlorides. 3-Aminopropanoic acid, for example, gives 3-isocyanatopropanoyl chloride (eq 3).2,10 2-Isocyanatobenzoyl chloride is prepared similarly from anthranilic acid in 85% yield in the presence of Phosphorus(V) Chloride,2 although anthranilic acid and the pyridine analogs are cyclized to anhydrides by TCF quantitatively in the absence of PCl5 (eq 4).2,17

Synthesis of N-Carboxy-a-amino Acid Anhydrides (NCAs) from a-Amino Acids.

Various a-amino acids afford NCAs on treatment with TCF in an appropriate solvent such as THF, and addition of activated charcoal has been suggested to improve the synthesis (eq 5).5 The reactions, however, proceed smoothly in some cases in the absence of activated charcoal, as evidenced by the quantitative formation of NCAs. Starting from L-glutamic acid, a seven-membered g-NCA is produced instead of the ordinary five-membered NCAs.18

Synthesis of Chloroformates and Carbonates from Alcohols.

Chloroformates are readily prepared from aromatic or aliphatic alcohols and TCF in high yields.19 N-Hydroxyphthalimide is also converted into the chloroformate quantitatively.6

Depending on the reaction conditions (particularly in aqueous alkali solution), however, symmetric carbonates are obtained.7 When bisphenols in aqueous alkali are treated with TCF in 1,2-dichloroethane in the presence of a phase-transfer catalyst, polycarbonates can be synthesized.20

Both 1,2- and 1,3-diols favorably cyclize with TCF to form carbonates. For instance, methyl a-L-rhamnoside gives a five-membered cyclic carbonate almost quantitatively with TCF in pyridine (eq 6).21 Similarly, 1,3-diols form six-membered cyclic carbonates.22

When 2-aminoethanol and 3-aminopropanol are treated with TCF in dioxane, isocyanato chloroformates are synthesized. In the reaction with 2-aminoethanol at 55 °C, however, a cyclic carbamate, 2-oxazolidinone, is also obtained as a minor product.2 Amino alcohols, prepared by reducing a-amino acids, are converted into oxazolidinones efficiently at -15 °C (eq 7).23 2-Aminobenzyl alcohol gives rise to a six-membered cyclic carbamate in a similar way.24

Dehydration of Formamides and Amides to Isocyanides and Nitriles.

Dehydration of N-alkyl- or N-arylformamides with TCF or phosgene is an effective way to synthesize isocyanides (eq 8), and the yields are generally higher with TCF than with phosgene, as shown in Table 1.8

Aromatic diisocyanides can be synthesized in a similar manner.25 In the preparation of unstable diisocyanides such as o-diisocyanobenzene, however, the reaction should be carried out at low temperatures, and the yield is improved to 92% by starting at -78 °C from 26% at rt.26

Both aromatic and aliphatic amides are dehydrated with TCF in Trimethyl Phosphate to give nitriles in high yields (eq 9).9 This preparative procedure is superior to the conventional transformation carried out with p-Toluenesulfonyl Chloride in pyridine.

Miscellaneous Reactions.

In the Swern oxidation using the combination Dimethyl Sulfoxide-Oxalyl Chloride, the latter may be replaced by TCF to facilitate the reaction. Various aldehydes and ketones are thus synthesized from primary and secondary alcohols in moderate to high yields.27

Direct introduction of a chloroformyl group is possible by heating acid chlorides with TCF at 225 °C. 2-Methylpropanoyl chloride, for example, affords dimethylmalonyl chloride in 70% yield. Cyclohexanecarbonyl chloride gives 1,1-cyclohexanedicarboxylic acid in 81% yield by treating with TCF followed by hydrolysis.28 Some alcohols, including benzyl and t-butyl alcohols, are transformed into the corresponding chlorides by chlorination with TCF.2,29

1. Melnikow, N. N. Chem. Zentr. 1935, I, 1650 (CA 1936, 30, 4152).
2. Kurita, K.; Matsumura, T.; Iwakura, Y. JOC 1976, 41, 2070.
3. Brintzinger, H.; Pfannstiel, K.; Koddebusch, H. CB 1949, 82, 389.
4. Kraft, M. Y.; Alekseev, B. A. JGU 1932, 2, 726 (CA 1933, 27, 2426).
5. (a) Oya, M.; Katakai, R.; Nakai, H.; Iwakura, Y. CL 1973, 1143. (b) Katakai, R.; Iizuka, Y. JOC 1985, 50, 715.
6. Imajo, H.; Kurita, K.; Iwakura, Y. J. Polym. Sci., Polym. Chem. Ed. 1981, 19, 1855.
7. Melnikow, N. N. JPR 1930, 128, 233.
8. Skorna, G.; Ugi, I. AG 1977, 89, 267.
9. Mai, K.; Patil, G. TL 1986, 27, 2203.
10. Kurita, K.; Iwakura, Y. OS 1980, 59, 195.
11. Damle, S. B. Chem. Eng. News 1993, 71(6), 4.
12. Ozaki, S.; Ike, Y.; Mizuno, H.; Ishikawa, K.; Mori, H. BCJ 1977, 50, 2406.
13. Turconi, M.; Nicola, M.; Gil Quintero, M.; Maiocchi, L.; Micheletti, R.; Giraldo, E.; Donetti, A. JMC 1990, 33, 2101.
14. (a) Davey, D.; Erhardt, P. W.; Lumma, W. C., Jr.; Wiggins, J.; Sullivan, M.; Pang, D.; Cantor, E. JMC 1987, 30, 1337. (b) Kukla, M. J.; Breslin, H. J.; Pauwels, R.; Fedde, C. L.; Miranda, M.; Scott, M. K.; Sherrill, R. G.; Raeymaekers, A.; Van Gelder, J.; Andries, K.; Janssen, M. A. C.; De Clerq, E.; Janssen, P. A. J. JMC 1991, 34, 746.
15. Giori, P.; Veronese, A. C.; Poli, T.; Vincentini, C. B.; Manfrini, M.; Guarneri, M. JHC 1986, 23, 585.
16. Chau, N.; Saegusa, Y.; Iwakura, Y. JHC 1982, 19, 541.
17. Suzuki, F.; Kuroda, T.; Kawakita, T.; Manabe, H.; Kitamura, S.; Ohmori, K.; Ichimura, M.; Kase, H.; Ichikawa, S. JMC 1992, 35, 4866.
18. Honda, N.; Kawai, T.; Higashi, F. Makromol. Chem. 1978, 179, 1643.
19. (a) Sakamoto, S.; Tsuchiya, T.; Tanaka, A.; Umezawa, S.; Hamada, M.; Umezawa, H. J. Antibiot. 1985, 38, 477. (b) Kurita, K.; Mikawa, N.; Koyama, Y.; Nishimura, S.-I. Macromolecules 1990, 23, 2605.
20. Saegusa, Y.; Kuriki, M.; Kawai, A.; Nakamura, S. J. Polym. Sci., Part A: Polym. Chem. 1990, 28, 3327.
21. Tatsuta, K.; Akimoto, K.; Annaka, M.; Ohno, Y.; Kinoshita, M. BCJ 1985, 58, 1699.
22. (a) Schwarz, G.; Geffken, D. AP 1988, 321, 51. (b) Vloon, W. J.; Van den Bos, J. C.; Koomen, G.-J.; Pandit, U. K. T 1992, 48, 8317.
23. Pridgen, L. N.; Prol, J., Jr.; Alexander, B.; Gillyard, L. JOC 1989, 54, 3231.
24. Uchida, M.; Chihiro, M.; Morita, S.; Yamashita, H.; Yamasaki, K.; Kanbe, T.; Yabuuchi, Y.; Nakagawa, K. CPB 1990, 38, 1575.
25. Efraty, A.; Feinstein, I.; Wackerle, L.; Goldman, A. JOC 1980, 45, 4059.
26. Ito, Y.; Ohnishi, A.; Ohsaki, H.; Murakami, M. S 1988, 714.
27. Takano, S.; Inomata, K.; Tomita, S.; Yanase, M.; Samizu, K.; Ogasawara, K. TL 1988, 29, 6619.
28. Kharasch, M. S.; Eberly, K.; Kleiman, M. JACS 1942, 64, 2975.
29. Nekrassow, W.; Melnikow, N. JPR 1930, 127, 210.

Keisuke Kurita

Seikei University, Tokyo, Japan

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