2-Chloroethyl Chloromethyl Ether

[1462-33-5]  · C3H6Cl2O  · 2-Chloroethyl Chloromethyl Ether  · (MW 128.98)

(reagent for cyclopropanol synthesis;1,2 formaldehyde equivalent in hydroxymethylation of Grignard reagents;3 used for protection of indoles4)

Alternate Name: 1-chloro-2-(chloromethoxy)ethane.

Physical Data: bp 145-147 °C (66-68 °C/22 mmHg);3 d 1.28 g cm-3.5

Solubility: sol most commonly used organic solvents including ethereal (THF, diethyl ether), halogenated (CH2Cl2, CHCl3, CCl4), and hydrocarbon solvents; incompatible with alcohol solvents.

Analysis of Reagent Purity: best ascertained by 1H NMR [(300 MHz, CDCl3/TMS) d 3.96 (t, J = 5.7 Hz, 2 H), 3.96 (t, J = 5.7 Hz, 2 H), 5.53 (s, 2 H)].3

Preparative Method: most conveniently prepared by reaction of 2-chloroethanol and 1,3,5-trioxane with HCl(g) at 0 °C (1.0 mol scale, 66% yield).3,6

Purification: by distillation.

Handling, Storage, and Precautions: chloromethyl ethers are recognized carcinogens.7 Preparation and handling of the reagent should be carried out in an efficient fume hood, and skin contact should be avoided. Chloromethyl ethers are also moisture-sensitive and should be stored and transferred under inert atmosphere. Excess reagent should be hydrolyzed in water before removing from the fume hood.3

Synthesis of Cyclopropanol Derivatives.

2-Chloroethyl chloromethyl ether serves as a precursor to (2-chloroethoxy)carbene8 via deprotonation of the chloromethylene group with Lithium 2,2,6,6-Tetramethylpiperidide (LiTMP) followed by a-elimination.1 Trapping of the carbene intermediate with an alkene (excess) affords a 2-chloroethyl cyclopropyl ether. The corresponding cyclopropanol is obtained by cleavage of the 2-chloroethyl moiety upon treatment with n-Butyllithium.1,8 This methodology offers an efficient means for preparation of secondary cyclopropanols (eq 1),8 but is not suitable for the synthesis of tertiary derivatives.

This reaction sequence has been applied by Danheiser and co-workers in the synthesis of cyclopentenols via an oxyanion-accelerated vinylcyclopropane rearrangement (eq 2).2 In these cases the alkene is used as the limiting reagent in the cyclopropanation reaction. Upon treatment with n-BuLi the intermediate 2-vinylcyclopropanol alkoxides undergo an accelerated [1,3]-sigmatropic shift to afford the corresponding 3-cyclopentenols in a one-pot synthesis from the (2-chloroethyl) cyclopropyl ethers. The overall transformation is highly stereoselective and can be viewed as a [4 + 1] annulation proceeding via suprafacial exo addition of hydroxycarbene to a diene.

Hydroxymethylation of Grignard Reagents.

Hydroxymethylation of Grignard reagents via reaction with formaldehyde generally proceeds in only moderate yields and is complicated by difficulties in handling formaldehyde. Ogle and co-workers have developed a two-step, one-pot alternative procedure which involves reaction of Grignard reagents with 2-chloroethyl chloromethyl ether, followed by removal of the 2-chloroethyl group by treatment with Sodium-Potassium Alloy (eq 3).3 Use of diethyl ether as solvent gives optimum yields. This two-step protocol can also be applied to alkynyllithium reagents to provide propargyl alcohol derivatives.

Protection of Indoles.

An example of protection of an indole with the 2-chloroethoxymethylene group was reported in the synthesis of (±)-austamide (indole derivative, ClCH2CH2OCH2Cl, KH, DMF-THF, 50% yield).4 Cleavage of this protecting group was effected by treatment with KCN in acetonitrile in the presence of 18-Crown-6 (84% yield).

1. (a) Barber, G. N.; Olofson, R. A. TL 1976, 3783. (b) for a related example, see Dougherty, C. M.; Olofson, R. A. OSC 1988, 6, 571.
2. (a) Danheiser, R. L.; Martinez-Davila, C. E.; Morin, J. M. JOC 1980, 45, 1341. (b) Danheiser, R. L.; Martinez-Davila, C. E.; Auchus, R. J.; Kadonaga, J. T. JACS 1981, 103, 2443.
3. Ogle, C. A.; Wilson, T. E.; Stowe, J. A. S 1990, 495.
4. Hutchison, A. J.; Kishi, Y. JACS 1979, 101, 6786.
5. Farren, J. W.; Fife, H. F.; Clark, F. E.; Garland, C. E. JACS 1925, 47, 2419.
6. For similar procedures, see ref 5 and Holy, A.; Rosenberg, I.; Dvorakova, H. CCC 1989, 54, 2190 (4.6 mol scale, 74% yield).
7. Olah, G. A.; Yu, S.; Liang, G.; Matseescu, G. D.; Bruce, M. R.; Donovan, D. J.; Arvanaghi, M. JOC 1981, 46, 571.
8. (a) Schöllkopf, U.; Paust, J.; Al-Azrak, A.; Schumacher, H. CB 1966, 99, 3391. (b) Schöllkopf, U.; Paust, J.; Patsch, M. R. OSC 1973, 5, 859.

Joanne J. Bronson

Bristol-Myers Squibb, Wallingford, CT, USA

Rick L. Danheiser

Massachusetts Institute of Technology, Cambridge, MA, USA

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