Halohydrins, reaction with

Reaction with base brings the alcohol function of the halohydrin into equilibrium with Its corresponding alkoxide... 

The high degree of stereoselectivity associated with most syntheses and reactions of oxiranes accounts for the enormous utility of these systems in steroid syntheses. Individual selectivity at various positions in the steroid nucleus necessitates the discussion of a collection of uniquely specific reactions used in the synthesis of steroidal epoxides. The most convenient and generally applicable methods involve the peracid, the alkaline hydrogen peroxide and the halohydrin reactions. Several additional but more limited techniques are also available. 

Epoxides can also be opened by reaction with acids other than H30+. If anhydrous HX is used, for instance, an epoxide is converted into a trans halohydrin. 

The chlorohydrin reaction with sodium hydroxide is assumed to be a two-step process in which a rate-determining intramolecular displacement of chloride ion by negatively charged oxygen follows a prior equilibrium between the hydroxide ion and the hydroxyl group of the halohydrin (5). 

Chiral halohydrins epoxides.1 The esters (2) of the chiral alcohol 1 derived from camphor-10-sulfonic acid, are converted to a-chloro esters (3) by O-silylation and reaction with NCS with high diastereoselectivity. Reduction of 3 with Ca(BH4)2 results in the recovered auxiliary and the chlorohydrin 4 with clean retention. Cyclization of 4 to the terminal epoxide 5 proceeds with clean inversion. 

The halohydrin 3-bromo-2-butanol undergoes the following reactions with hydrobromic acid. 

Normant, J. F. Preparation of propargylic carbenoids and reactions with carbonyl compounds. A stereoselective synthesis of propargylic halohydrins and oxiranes. Eur. J. Org. Chem. 2001, 3295-3300. 

Several recent publications describe cleavage of 1,3,2-dioxathiolane. S -dioxides (cyclic sulfates) by halide nucleophiles that furnish halohydrines, which can be used as synthetic intermediates, primarily for preparation of corresponding epoxides or for further reactions with nucleophiles (Table 6). Similar reactions with chloride have been studied for 1,3,2-dioxathiolane J-oxides (cyclic sulfites) <1996ACS832>. 

Fig. 6.8 Activation of halogens by CPO (a) reactions with 1,3-dicarbonyl compounds (b) halohydrins formation...

The reaction with A -bromosuccinimide or Af-bromoacetamide with or without added acid, on the other hand, leads predominantly to the same epoxide trans-6 as formed in the reaction with peracids. It is proposed that in the formation of cis-6 with acetyl hypobromite, hypobromous acid or A -chlorosuccinimide, nucleophilic attack of the halonium ion is fast. The epoxide ratio therefore is governed by the kinetically favored tran.v-halohydrin. However, in the reaction with A -bromosuccinimide or A -bromoacetamide the nucleophilic attack on the bromonium ion species becomes rate determining, attack of the nucleophile therefore follows the path of lowest activation energy. This is the attack on the c/.v-bromonium ion distant to the bulky tert-butyl group leading to the trans-diaxial bromohydrin, according to the Fiirst-Plattner rule, hence giving trans-6. 

At somewhat higher pH, direct nucleophilic attack of halide ion on diol epoxide 81 (fci[X-]) becomes important, and a rate plateau is reached in which this term is the main one. If the pH is sufficiently low, the pH-dependent equilibrium between halohydrin 131 and diol epoxide 81 (shown in Scheme 41) favors halohydrin, which reacts via an SnI reaction (k3) to form tetrols 129. As the pH is increased, however, the pH-dependent equilibrium between halohydrin 131 and diol epoxide 81 shifts to favor diol epoxide, and there is a resulting rate decrease that gives an inflection point in the pH-rate profile at intermediate pH that resembles those in the profiles in Figs 4 and 5. Rate and product observations are rationalized by the mechanism of Scheme 40, and comparable mechanisms can be expected for reactions of other epoxides susceptible to reaction with nucleophiles. 

Treatment of diethyl 1,2-epoxyethylphosphonate with R MgBr failed to result in the formation of the expected hydroxy alky Iphosphonate. The oxirane ring is opened by reaction with MgBr2 to yield the halohydrin, which is hydrolyzed to the glycol during workup. ... 

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