Epichlorohydrin1

[106-89-8]  · C3H5ClO  · Epichlorohydrin  · (MW 92.53) (R)

[51594-55-9] (S)

[67843-74-7]

(readily available three-carbon unit functionalized on every carbon; convenient HCl or HBr trap; linker for various polymers)

Alternate Name: chloromethyloxirane.

Physical Data: mp -57 °C; bp 115-117 °C; d 1.183 g cm-3.

Solubility: 6.6 wt% in water; sol alcohol, acetone, THF, toluene, n-heptane.

Form Supplied in: neat liquid; both enantiomers available.

Handling, Storage, and Precautions: should only be handled in a well ventilated fume hood because of its low permissible exposure limit of 2 ppm and reports of allergic skin reactions and lung, liver, and kidney damage. MSDSs are available from the two principal manufacturers (Dow and Shell). The material is not moisture or air sensitive.

Introduction.

Epichlorohydrin (1) is most widely used in polymer synthesis.2 Other common uses include an in situ trapping agent for HCl, HBr,3 or the alcohol generated during formation of Meerwein's reagent (eq 1).4

Reactions with Nucleophiles.

The epoxide is, by far, the more reactive site and a wide variety of nucleophiles have been used (eq 2) to open the ring at C-3 such as HCl (96%),5 HOAc (>50%),6 H2S (65% as cyclized product 3-thietanol),7 HCN (66%),8 ethanol (90%),9 t-butanol (86%),10 phenyl or benzyl thiol (99% or 93%, respectively),11 and phenyl selenide (generated in situ from the diselenide and sodium hydroxymethyl sulfite) (>55%).12 If desired, the epoxide is easily formed from the chlorohydrin by treatment with excess KOH or Et3N.

The epoxide is also opened at C-3 by various electrophilic reagents that fit into the generalized scheme in eq 3. Examples include Chlorotrimethylsilane (TMSCl) (85%),13 TMSCl/NaBr (X = Br) (85%),14 Cyanotrimethylsilane (91%),15 Azidotrimethylsilane (83%),16 Thionyl Chloride (70%),17 H2NCOCl (96%),18 and MeCH=CHCOCl (80%).19 The only report of unusual selectivity for opening the epoxide at C-2 was for Sulfuryl Chloride (eq 4).20

A number of special catalysts have been developed to facilitate ring opening and improve the regioselectivity for reaction at C-3. For example, SnII halides are useful in preparations of (2) (X = Cl, 70%; X = Br, 63%; X = I, 90%).21 An equimolar mixture of Lithium Bromide and Copper(II) Bromide gave (2) (X = Br, 93%).22 The ring can be opened selectively by anilines in the presence of other amines when Cobalt(II) Chloride is the catalyst.23 MgSO4 was found to catalyze the addition of 2 mol of CN- to (1) to afford 3-hydroxyglutaronitrile.24 CaF2 supported on KF was used in the conversion of (1) to epifluorohydrin.25 A catalyst composed of a 1:2 mole ratio of Di-n-butyltin Oxide and tributyl phosphate was developed for ring opening by alcohols.26 Other catalysts shown to be of value for the examples given above include FeCl3,6 LiClO4,11 Et3N,11 CAN,9 DDQ,10 Ti(O-i-Pr)4,15b CoCl2,13,19 YbCl3,15a and Al(O-i-Pr)3.16

A variety of carbon nucleophiles react at C-3 with high regioselectivity. Examples include Grignard reagents,27 aryllithium,28 alkynyllithium,29 and others (eqs 5-8).30-33

Compound (1) can be chain extended by one carbon by a Co-catalyzed CO insertion followed by reduction (eq 9).34 A whole class of medicinally important compounds called b-blockers are prepared from (1) as illustrated in eq 10 for the synthesis of a propranolol analog.35

Preparation of Heterocycles.

A wide array of heterocycles are available from (1). A few examples are shown in eqs 11-16).36-41

In some cases the reaction rate and yield are dramatically improved if the product can be trapped as the TMS ether (eq 17).42 Also, (1) lends itself well to nucleophilic opening under phase transfer conditions (eq 18).43

The ready availability44 of both enantiomers of (1) has greatly enhanced its value as a synthetic intermediate. The pheromone (S)-(-)-ipsenol (2), prepared45 in 16% overall yield in four steps from (R)-(1), is just one of many examples of this utility. In practice, either isomer can sometimes be used by adjusting the order of addition of the groups at C-1 and C-3. The synthesis of (-)-anisomycin (3) illustrates this point.46

Related Reagents.

Glycidol.


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2. For example, CA 12th Coll. Index lists 133 pages of references to polymers.
3. Sato, K.; Kojima, Y.; Sato, H. JOC 1970, 35, 2374.
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20. Malinovskii, M. S. JGU 1947, 17, 1559 (CA 1948, 42, 2229b).
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32. Zuidema, G. D.; vanTamelen, E.; VanZyl, G. OSC 1963, 4, 10.
33. Block, E.; Laffitte, J-A; Eswarakrishnan, V. JOC 1986, 51, 3428.
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40. Baba, A.; Shibata, I.; Masuda, K.; Matsuda, H. S 1985, 1144.
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Joel E. Huber

The Upjohn Co., Kalamazoo, MI, USA



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