2,2,2-Tribromoethyl Chloroformate

[17182-43-3]  · C3H2Br3ClO2  · 2,2,2-Tribromoethyl Chloroformate  · (MW 345.20)

(protecting agent for alcohols1,2 and carboxylic acids3)

Physical Data: bp 47-50 °C/0.05 mmHg, 103 °C/10 mmHg.

Form Supplied in: no longer commercially available.

Preparative Method: prepared1 by the reaction of 2,2,2-tribromoethanol with Phosgene in benzene under pyridine catalysis.

Handling, Storage, and Precautions: although no details are available, the high toxicity and the lachrymatory and corrosive nature of the closely related 2,2,2-Trichloroethyl Chloroformate suggest that 2,2,2-tribromoethyl chloroformate should be handled with caution.

Protection of Alcohols.

2,2,2-Tribromoethyl chloroformate has found application in the protection of primary and secondary alcohols. The attraction of the resulting tribromoethoxycarbonyl protecting group includes its stability to the acidic conditions (e.g. 80% acetic acid at 100 °C for 35 min, or at rt for 6 h) used for the removal of many other O-protecting groups (e.g. the trityl group).1 In addition, it is readily removed via b-elimination using a Zinc/Copper Couple, preferably in acetic acid but also (albeit more slowly) in ethanol or DMF, under conditions where many common protecting groups (e.g. O-acetyl, N-benzoyl, and O-trityl)1 survive. Deprotection of tribromoethyl carbonates using a Zn/Cu couple in acetic acid (complete in 20 min at rt) proceeds an order of magnitude faster than cleavage of the more widely used trichloroethyl (troc) carbonates (see 2,2,2-Trichloroethyl Chloroformate) suggesting that it has potential (as yet untapped) as a complementary protecting group to the troc group. Selective protection of primary over secondary alcohols can be accomplished, albeit in only modest yield, using tribromoethyl chloroformate in the presence of either N,N-diethylaniline or 2,6-lutidine as base (eq 1).2

Tribromoethyl chloroformate is useful for the protection of primary and secondary hydroxyl groups in nucleosides and their derivatives;1 reactions are generally complete in 0.5-2.0 h at 0 °C in anhydrous pyridine/DMF and typically proceed in good to excellent yield. Since tribromoethyl chloroformate reacts vigorously with DMF at rt and reacts slowly even at 0 °C, DMF solutions must be prepared at 0 °C and then immediately be added to the nucleoside in pyridine in order to avoid significant chloroformate decomposition. Selective 5-protection of 2-deoxynucleosides is possible (eq 2). Attempts to protect 2,3-dihydroxynucleosides lead to the formation of a 2,3-cyclic carbonate in addition to the desired 2,3-bis(tribromoethyl) carbonate (eq 3). Prior N-protection of nucleosides containing amino-substituted bases is necessary; nucleosides containing free amino groups give complex mixtures of products.

Protection of Carboxylic Acids.

Tribromoethyl chloroformate has been used for the protection of benzoic acid as its tribromoethyl ester.3 An attractive feature of the tribromoethyl ester protecting group is its facile cleavage by electrolytic reduction (-0.70 V, 85% yield). In contrast, cleavage of the related trichloroethyl ester requires much higher voltages (-1.65 V) and often results in the formation of small amounts of dichloroethyl ester byproduct (see 2,2,2-Trichloroethyl Chloroformate).3

1. Cook, A. F. JOC 1968, 33, 3589.
2. Stouwe, C.; Schafer, H. J. CB 1981, 114, 946.
3. Semmelhack, M. F.; Heinsohn, G. E. JACS 1972, 94, 5139.

Paul Sampson

Kent State University, OH, USA

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