t-Butyl Chloromethyl Ether

[40556-01-2]  · C5H11ClO  · t-Butyl Chloromethyl Ether  · (MW 122.59)

(reagent for introducing an acid-labile alcohol- or an imidazole-protecting group1)

Physical Data: decomposes upon attempted isolation.

Solubility: sol CH2Cl2, CHCl3, CCl4.

Form Supplied in: generated immediately prior to use.

Analysis of Reagent Purity: 1H NMR (CCl4, d 5.61 or 5.42 (2H, s), 1.2 (9H, s)).

Preparative Methods: chlorination of t-butyl methyl ether using NCS,1 treatment of t-butyl methylthiomethyl ether with sulfuryl chloride,2 or cleavage of t-butyl methoxymethyl ether with BCl3.4

Handling, Storage, and Precautions: solutions in CH2Cl2 appear to remain unchanged upon standing at rt for several days.2 Concentration apparently leads to decomposition. The structurally similar Chloromethyl Methyl Ether is a putative carcinogen.

Protection of Alcohols.

This reagent was introduced in 1978 as a reagent for protecting alcohols as t-butoxymethyl ethers.1 An acetal protecting group analogous to the more common methoxymethyl (MOM) group, the t-butoxymethyl moiety can be removed under significantly milder conditions (see below). The initial report described its preparation via treatment of methyl t-butyl ether (MTBE) with N-Chlorosuccinimide in CCl4 under sunlamp irradiation. Removal of succinimide by filtration gave a crude CCl4 solution of t-butyl chloromethyl ether which was stable under nitrogen at rt. A subsequent report highlighted the importance of excluding both oxygen and acid during the chlorination, recommending carrying out the reaction under dry nitrogen and advocating the addition of N,N-diisopropyl-3-pentylamine as a proton scavenger.3 An interesting study detailing a general entry into a variety of chloromethyl ethers described the conversion of t-butyl methoxymethyl ether into t-butyl chloromethyl ether using Boron Trichloride (eq 1).4 A related procedure has been reported, entailing preparation of t-butyl methylthiomethyl ether and its nearly quantitative conversion to the desired reagent by treatment with Sulfuryl Chloride in CH2Cl2 (eq 2).2

Protection of alcohols proceeds by addition of the crude solution of t-butyl chloromethyl ether to a THF solution of the alcohol and 4 equiv Triethylamine at -20 °C (eq 3), followed by warming to rt.1 The product t-butoxymethyl ethers can be chromatographed on alumina. Deprotection is effected by treatment with aqueous Trifluoroacetic Acid in THF at rt, conditions which do not lead to deprotection of methoxymethyl ethers (eq 4). The imidazole N-H of histidine derivatives can also be protected using t-butyl chloromethyl ether.3 This group is stable to nucleophilic or basic reagents and catalytic hydrogenolysis, conditions which might be encountered during peptide synthesis, but can be removed with trifluoroacetic acid or with anhydrous Hydrogen Chloride or Hydrogen Bromide in acetic acid.

1. Pinnick, H. W.; Lajis, N. H. JOC 1978, 43, 3964.
2. Jones, J. H.; Thomas, D. W.; Thomas, R. M.; Wood, M. E. SC 1986, 16, 1607.
3. Colombo, R.; Colombo, F.; Jones, J. H. CC 1984, 292.
4. Goff, D. A.; Harris, R. N., III; Bottaro, J. C.; Bedford, C. D. JOC 1986, 51, 4711.

F. G. West & John A. Bender

University of Utah, Salt Lake City, UT, USA

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