2,2,2-Trichloroethyl Chloroformate

[17341-93-4]  · C3H2Cl4O2  · 2,2,2-Trichloroethyl Chloroformate  · (MW 211.85)

(protecting agent for many functional groups;1-5 agent for the net carboxylation of organometallic reagents;18 achieves the N-demethylation and N-debenzylation of tertiary amines;19,20 activates N-heteroaromatic rings toward reaction with organostannanes25-28)

Alternate Names: troc-Cl; Troc-Cl; TrOC-Cl; Teoc-Cl; TCEC-Cl.

Physical Data: colorless liquid, bp 171-172 °C/760 mmHg, 75-76 °C/60 mmHg; d25 1.539 g cm-3; n20D 1.4700.

Preparative Methods: widely available commercially. It can be readily prepared by passing Phosgene into a solution of 2,2,2-Trichloroethanol in benzene/diethylaniline1a or benzene/ether/pyridine.1b An alternate two-step approach (93% yield) has been described that employs S-Ethyl Chlorothioformate instead of phosgene.2

Handling, Storage, and Precautions: highly toxic, lachrymatory, and corrosive; it should be handled with caution in a fume hood.

Functional Group Protection.

Alcohols,1,3 phenols,1,4 and thiols5 are readily protected as their trichloroethyl (troc) carbonates/thiocarbonates using 2,2,2-trichloroethyl chlorofomate and Pyridine or pyridine/4-Dimethylaminopyridine. Chemoselective protection of the less crowded of two alcohols is possible (eq 1).6 Electron-deficient alcohols7 and thiols8 (but not phenols)9 are readily protected. Alkyl- and arylamines are protected as their N-troc-carbamate derivatives using troc-Cl/pyridine (eq 2)1,10 or under Schotten-Baumann conditions.1 a-Amino acids are typically N-troc-protected under Schotten-Baumann conditions (eq 3);11 however, refluxing a suspension of the a-amino acid in EtOAc containing troc-Cl is reported to be more convenient and high yielding.12 It should be noted that other reagents are more commonly employed for N-a-amino acid protection (see Benzyl Chloroformate, t-Butyl Azidoformate).

Protection of the usually recalcitrant aryl a-keto acids as their trichloroethyl esters can be achieved using troc-Cl under basic conditions (eq 4).13 However, the efficiency of such reactions with other carboxylic acids is typically much below those using other chloroformates.2,14 Both O- and N-troc-protecting groups are stable under a wide variety of reaction conditions;1,15 deprotection is usually effected using Zinc-Acetic Acid/rt,1 or under milder conditions using Zn/MeOH/reflux1 or Zn/THF-H2O/pH 4.2/25 °C.16 Troc-protected alcohols are cleaved ten times more slowly than the corresponding tribromoethyl carbonates (see 2,2,2-Tribromoethyl Chloroformate). Troc thiocarbonates can be deprotected to either the thiol or disulfide by electrolysis.17 2,2,2-Tribromoethyl esters are cleaved at significantly lower voltages than are needed for electrolytic cleavage of the corresponding trichloroethyl esters.

Carboxylation of Organometallic Reagents.

Troc-Cl has proved useful in the trichloroethoxycarbonylation of alkynyllithium18 species, although analogous methoxycarbonylation reactions are much more common (see Methyl Chloroformate.) The facile reductive cleavage of the resulting trichloroethyl ester to the corresponding carboxylic acid (see above) makes this an attractive overall C-carboxylation protocol.

N-Dealkylation of Tertiary Amines.

Tertiary amines can be readily N-demethylated using troc-Cl.19,20 The common practice of adding mild base appears unnecessary and may actually promote unwanted side reactions.20 Facile cleavage of the resulting N-troc carbamate to the free secondary amine is typically performed using Zn/HOAc,19 although milder conditions have also proved useful.16,21 This N-demethylation protocol is cleaner and more selective than the classical von Braun reaction (see Cyanogen Bromide), avoids the strongly basic conditions required for the cleavage of carbamates derived from other chloroformates, and is compatible with a variety of sensitive functionalities.19 The N-debenzylation of tertiary benzylamines using troc-Cl appears always to be favored over other N-dealkylation pathways (eq 5)22 and is an attractive alternative to hydrogenolytic N-debenzylation. Selective N-deallylation is also often preferred over loss of a simple alkyl group,22b although steric encumbrance can reverse this trend.23 The troc-Cl-mediated N-dealkylative removal of primary alkyl groups can be unreliable24 and Vinyl Chloroformate should be considered for such conversions. In reactions of troc-Cl with tertiary cyclohexylamines bearing only simple N-alkyl substituents, deamination to the cyclohexene can compete effectively with N-dealkylative removal of a methyl or primary alkyl group.22b

Activation of N-Heteroaromatic Rings Toward Reaction with Organostannanes.

Troc-Cl strongly activates pyridine toward regioselective 1,4-addition of prenyl25 and benzylstannanes (eq 6),26 while regioselective 1,2-addition is observed with Allyltributylstannane (eq 7).27

Quinoline and isoquinoline ring systems undergo selective 1,2-addition reactions with allenylstannanes.28 Significantly higher yields are obtained when using troc-Cl rather than methyl chloroformate, due to better activation of the aromatic ring toward nucleophilic attack conferred by the strongly electron-withdrawing N-troc group.

1. (a) Windholtz, T. B.; Johnston, D. B. R. TL 1967, 2555. (b) Chauvette, R. R. et al. JOC 1971, 36, 1259.
2. Gilligan, W. H.; Stafford, S. L. S 1979, 600.
3. Shiuey, S. J.; Kulesha, I.; Baggiolini, E. G.; Uskokovic, M. R. JOC 1990, 55, 243.
4. Farina, F.; Noheda, P.; Paredes, M. C. TL 1991, 32, 1109.
5. Aratani, M.; Hashimoto, M. JACS 1980, 102, 6171.
6. Imoto, M.; Kusunose, N.; Kusumoto, S.; Shiba, T. TL 1988, 29, 2227.
7. Johnson, P. Y.; Berman, M. JOC 1975, 40, 3046.
8. Mitsukuchi, M. et al. CPB 1989, 37, 3286.
9. Evens, E. D.; Patterson, R. L. S.; Woodcock, D. TL 1969, 555.
10. Ibuka, T.; Chu, G. N. CPB 1986, 34, 2380.
11. (a) Carson, J. F. S 1981, 268. (b) Kiso, Y.; Inai, M.; Kitagawa, K.; Akita, T. CL 1983, 739. (c) Boyd, S. A.; Thompson, W. J. JOC 1987, 52, 1790.
12. Kruse, C. H.; Holden, K. G. JOC 1985, 50, 2792.
13. Domagala, J. M. TL 1980, 21, 4997.
14. Kim, S.; Lee, J. I.; Kim, Y. C. JOC 1985, 50, 560.
15. Protective Groups in Organic Synthesis; Greene, T. W.; Wuts, P. G. M., Eds.; Wiley: New York, 1991; Chapter 8, pp 406-452.
16. Just, G.; Grozinger, K. S 1976, 457.
17. Semmelhack, M. F.; Heinsohn, G. E. JACS 1972, 94, 5139.
18. Hall, S. E.; Roush, W. R. JOC 1982, 47, 4611.
19. Montzka, T. A.; Matiskella, J. D.; Partyka, R. A. TL 1974, 1325.
20. He, X. S.; Brossi, A. SC 1990, 20, 2177.
21. Donaldson, R. E.; Saddler, J. C.; Byrn, S.; McKenzie, A. T.; Fuchs, P. L. JOC 1983, 48, 2167.
22. (a) Reinecke, M. G.; Daubert, R. G. JOC 1973, 38, 3281. (b) Kapnang, H.; Charles, G. TL 1983, 24, 3233. (c) Flann, C.; Malone, T. C.; Overman, L. E. JACS 1987, 109, 6097.
23. Sundberg, R. J.; Hamilton, G. S.; Laurino, J. P. JOC 1988, 53, 976.
24. Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe, J. P. TL 1977, 1567.
25. Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, M. JOC 1988, 53, 3507.
26. Yamaguchi, R.; Moriyasu, M.; Kawanisi, M. TL 1986, 27, 211.
27. Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, M. JOC 1985, 50, 287.
28. Yamaguchi, R.; Moriyasu, M.; Takase, I.; Kawanisi, M.; Kozima, S. CL 1987, 1519.

Paul Sampson

Kent State University, OH, USA

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