Vinyl Chloroformate

[5130-24-5]  · C3H3ClO2  · Vinyl Chloroformate  · (MW 106.51)

(selective N-dealkylation of tertiary amines; amino protection in peptide synthesis; protection of alcohols; polymerization and polymers)

Alternate Names: vinyl chlorocarbonate; VOC-Cl.

Physical Data: bp 68-69 °C; d 1.163 g cm-3.

Form Supplied in: colorless liquid, often stabilized with ca. 0.05% BHT; widely available.

Preparative Methods: the high price of VOC-Cl warrants some comments on its synthesis. Two processes have been used commercially. In the first, ethylene glycol is converted to its bis(chloroformate) with phosgene. This fragments to VOC-Cl in 30-40% yield when passed through a hot tube packed with glass helices at 480 °C.1 More recently, VOC-Cl has been made commercially by a two-step route involving oxymercuration of vinyl acetate (eq 1).2

Handling, Storage, and Precautions: is slightly light-sensitive and even more reactive than other chloroformates toward trace moisture. Because the hydrolysis products, HCl and acetaldehyde, interfere in some applications, the reagent is often distilled before use. It is a strong lachrymator and skin vesicant; inhalation is particularly dangerous. Use in a fume hood.

Amino Protection in Peptide Synthesis.3

Amino acids are converted to their N-VOC derivatives by standard acylation with vinyl chloroformate (VOC-Cl), e.g. by Schnabel's pH-stat process.4 Like Boc-amino acids, VOC-amino acids often are oils but can be characterized and stored as the crystalline dicyclohexylammonium (DCHA) salts and regenerated by acidification-extraction. The yields of VOC-peptides from the free acids or directly from the salts using 1,3-Dicyclohexylcarbodiimide, N-Ethyl-5-phenylisoxazolium-3-sulfonate, and active esters as the amide coupling agents are similar to those with other amine blocking groups (e.g. Boc-peptides). The crystalline products are stable and can be stored indefinitely (see Table 1).

The high reactivity of the VOC amide C=C bond toward electrophiles is the key to the method used for deprotection.3 Acid-induced hydrolysis with HCl or HBr in HOAc or by bubbling HCl through an inert solvent containing the peptide, followed by warming the intermediate HCl adduct in EtOH, affords the deblocked peptide salt in excellent yield. These procedures are mild enough to avoid transesterification of side chain esters (eq 2). Unmasking also can be achieved by titration of the vinyl group with Br2 followed by warming the intermediate adduct with EtOH (eq 3). Under these conditions, Boc-protected secondary functions and t-butyl esters remain intact. A third scission with Mercury(II) Acetate in aqueous HOAc is rarely recommended. Carboxyl unmasking prior to removal of an N-VOC group can be performed with Zinc-Acetic Acid when the carboxyl is masked as a phenacyl ester. However, the VOC group is unstable to conditions required for modification-removal of most other esters (e.g. hydrazinolysis, saponification). The related isopropenyl chloroformate has no value in amine protection but is an excellent reagent of the mixed anhydride class for peptide amide bond formation (eq 4).5

N-Dealkylation of Tertiary Amines.

The N-dealkylation procedure is illustrated by the selective N-deethylation of N-ethylpiperidine to obtain piperidine.HCl in 90% yield (eq 5).6 The VOC-Cl is added to the piperidine in dichloroethane at 0 to -20 °C and the intermediate VOC-piperidine salt is then heated to reflux for a short period to obtain the intermediate carbamate. This can be isolated, but the VOC moiety usually is quantitatively removed in situ by bubbling HCl through a CH2Cl2 or 1,2-dichloroethane (DCE) solution and then warming the adduct in MeOH or EtOH, or by titrating the vinyl group with Br2 and then again warming in the alcohol. Among other dealkylating agents which operate by the same principle, Cyanogen Bromide (method of von Braun) is not selective in this rigorous test system and the amine catalyzes the self-destruction of ethyl and benzyl chloroformate [ROC(O)Cl -> RCl + CO2].7 With phenyl chloroformate, the yield of carbamate under similar conditions is only 34%.

With VOC-Cl, N-dealkylation selectivities follow the order: benzyl, allyl, t-alkyl >> s-alkyl &egt; methyl > n-alkyl >> piperidine ring scission.6,8 Weakly basic tertiary amines like N,N-dimethylaniline do not react with VOC-Cl even in refluxing DCE. Some examples of N-dealkylations accomplished with VOC-Cl include the N-demethylation of alkyl amines (eq 6)9 and other N-alkylpiperidines (eq 7).10,11 Note in eq 7 that the N-VOC is removed by base hydrolysis. This dealkylation process also is part of an asymmetric synthesis of a-amino esters (eq 8),12 as well as the key step of a protocol for resolving tertiary amine enantiomers.13 Also, VOC-Cl-induced dealkylation permits an improved synthesis of the emergency heroin antidote naloxone from oxymorphone (eq 9).6,14 Vinyl chloroformate largely has been replaced for N-dealkylation by 1-Chloroethyl Chloroformate. This latter reagent is cheaper and shows similar dealkylation selectivities and equally facile replacement of the N-alkyl by the carbamate unit.

Protection of Alcohols.

Vinyloxycarbonyl esters (O-VOC) of phenols and alcohols are prepared from VOC-Cl by standard methods.15 Unlike VOC derivatives of amines, O-VOC esters are quite stable in acid but are readily hydrolyzed in mild base, conditions under which N-VOC is stable (eq 10).15 This reactivity-selectivity difference can be useful in complex syntheses involving the simultaneous protection of both amine and alcohol functions with a single blocking moiety, while retaining the flexibility to modify either site without deprotecting the other. In related blocking schemes, attempts to free the amine first usually fail because esters are generally easier to hydrolyze than amides in both acid and base. The value of this selectivity in combination with N-dealkylation by VOC-Cl is illustrated in a synthesis of nalorphine, the classic narcotic antagonist, from morphine in 77% overall yield (eq 11).15

Polymerization and Polymers.

Vinyl chloroformate has been polymerized and copolymerized using standard radical initiators (e.g. peroxydicarbonates, Dibenzoyl Peroxide, and Azobisisobutyronitrile) to yield both high molecular weight poly(vinyl chloroformates) and random copolymers.16,17 The polymerization is inhibited by traces of acetaldehyde. Treatment of poly(vinyl chloroformate) with amines, alcohols, and phenols affords the corresponding poly(vinyl urethanes) and poly(vinyl carbonates).16,18 Urethanes and carbonates of VOC-Cl also can be polymerized to similar materials with radical initiators.16-19 These materials are hard (but not brittle) clear thermoplastics with high decomposition temperatures, excellent chemical resistance, and varying glass transition temperatures.18 Some products have value as liquid crystals20 and detergent builders.21 The divinyl carbonate polymerizes an order of magnitude more easily than the diallyl carbonate to a product of similar properties.19 Polymers of carbonates of VOC-Cl and dermal drugs (e.g. benzocaine, estradiol, dexamethasone, and hydrocortisone) are recommended as hydrolyzable pro-drugs for topical use.22

Pummerer and Other Reactions.

Sulfoxides react with VOC-Cl to give a-chloro sulfides via the Pummerer rearrangement (eq 12). Vinyl chloroformate is more reactive than the conventional reagents, including acetic anhydride, acyl chlorides, and alkyl chloroformates. Additionally, the reaction conditions are neutral and the byproducts are readily removed.

The reaction of penicillin b-sulfoxide with VOC-Cl induces a novel rearrangement which involves cleavage of the C-5-S bond (eq 13).23 Reaction of imidazoles with VOC-Cl in weakly alkaline solution affords the corresponding imidazol-2-ones, presumably via ring opening to the isocyanate intermediate, followed by ring closure (eq 14).24

1. (a) Küng, F. E. U.S. Patent 2 377 085 (CA 1945, 39, 3792). (b) Schaefgen, J. R. U.S. Patent 3 118 862 (CA 1964, 60, 10 883a). (c) Lee, L.-H. JOC 1965, 30, 3943.
2. (a) Piteau, M. D. A.; Malfroot, T. A. Ger. Offen 2 807 338 (CA 1978, 89, 214 914n). (b) Malfroot, T.; Piteau, M. Fr. Demande 2 421 866 (CA 1980, 93, 7667b). (c) Olofson, R. A.; Bauman, B. A.; Wancowicz, D. J. JOC 1978, 43, 752.
3. Olofson, R. A.; Yamamoto, Y. S.; Wancowicz, D. J. TL 1977, 1563.
4. Schnabel, E. LA 1967, 702, 188.
5. Jaouadi, M.; Selve, C.; Dormoy, J.-R.; Castro, B. BSF 1988, 870, and references cited therein.
6. Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe, J. P. TL 1977, 1567.
7. (a) Hageman, H. A. OR 1953, 7, 198. (b) Cooley, J. H.; Evain, E. J. S 1989, 1.
8. Kapnang, H.; Charles, G. TL 1983, 24, 3233.
9. Jung, M. E.; Abrecht, S. JOC 1988, 53, 423.
10. Showell, G. A.; Gibbons, T. L.; Kneen, C. O.; MacLeod, A. M.; Merchant, K.; Saunders, J.; Freedman, S. B.; Patel, S.; Baker, R. JMC 1991, 34, 1086.
11. For other examples, see: (a) Takai, H.; Obase, H.; Teranishi, M.; Karasawa, A.; Kubo, K.; Shuto, K.; Kasuya, Y.; Hashikami, M.; Karashima, N.; Shigenobu, K. CPB 1985, 33, 1129. (b) Barnes, R. D.; Wood-Kaczmar, M. W.; Richardson, J. E.; Lynch, I. R.; Buxton, P. C.; Curzons, A. D. Eur. Pat. Appl. 223 403 (CA 1987, 107, 141 102z). (c) Mitch, C. H.; Zimmerman, D. M.; Snoddy, J. D.; Reel, J. K.; Cantrell, B. E. JOC 1991, 56, 1660.
12. (a) Agami, C.; Couty, F.; Prince, B.; Puchot, C. T 1991, 47, 4343. (b) Agami, C.; Couty, F.; Poursoulis, M.; Vaissermann, J. T 1992, 48, 431.
13. Maibaum, J. J. Chromatogr. 1988, 436, 269.
14. Olofson, R. A.; Pepe, J. P. TL 1977, 1575.
15. Olofson, R. A.; Schnur, R. C. TL 1977, 1571.
16. Schaefgen, J. R. J. Polym. Sci., Polym. Symp. 1968, 75.
17. Meunier, G.; Hémery, P.; Boileau, S.; Senet, J.-P.; Chéradame, H. Polymer 1982, 23, 849.
18. Kassir, F.; Boivin, S.; Boileau, S.; Chéradame, H.; Wooden, G. P.; Olofson, R. A. Polymer 1985, 26, 443, and several references to the publications of S. Boileau therein.
19. (a) Strain, F.; Küng, F. E. U.S. Patent 2 377 111 (CA 1945, 39, 3971); U.S. Patent 2 384 143 (CA 1946, 40, 589). (b) Meunier, G.; Hémery, P.; Senet, J.-P.; Boileau, S. Polym. Bull. 1981, 4, 705, and references cited therein.
20. (a) de Marignan, G.; Teyssié, D.; Boileau, S.; Malthête, J.; Noël, C. Polymer 1988, 29, 1318. (b) Boileau, S.; Teyssié, D. Fr. Demande FR 2 609 999 (CA 1989, 110, 105 169e).
21. Wu, S. R.; Garofalo, A. Eur. Patent Appl. EP 441 563 (CA 1991, 115, 235 228n).
22. (a) Khue, N. V.; Galin, J. C. J. Appl. Polym. Sci. 1985, 30, 2761. (b) Brosse, J.-C.; Soutif, J.-C.; Cardon, F. Makromol. Chem., Rapid Commun. 1985, 6, 567; 1984, 5, 95.
23. Lett, R. TL 1983, 24, 201.
24. Pratt, R. F.; Kraus, K. K. TL 1981, 22, 2431.

Charles B. Kreutzberger & Roy A. Olofson

The Pennsylvania State University, University Park, PA, USA

Keith R. Buszek

Kansas State University, Manhattan, KS, USA

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