Halohydrin reaction with base

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

They can also be obtained from alkenes in a two-step process (Fig. A). The first step involves electrophilic addition of a halogen in aqueous solution to form a halohydrin. Treatment of the halohydrin with base then ionises the alcohol group, that can then act as a nucleophile. The oxygen uses a lone pair of electrons to form a bond to the neighbouring electrophilic carbon, thus displacing the halogen by an intramolecular SN2 reaction. 

The reaction of chloro- or bromohydrins with bases provides an economical route for the preparation of epoxides. Halohydrins are readily accessible by treatment of an alkene with either hypochlorous acid (Clj -1- H2O —> HOCl), hypochlorite bleach solution (NaOCl), or hypobromous acid (NBS -1- HjO HOBr). These reactions involve the... 

Reaction of dialkyl halohydrinphosphonates with bases. DiaLkyl-l,2-epoxyphosphonates are exclusively formed in the reaction between dialkyl H-phosphonates and a-halo ketones in the presence of equimolar quantities of sodium alkoxides in methanol at room temperature [254], A two-step mechanism of the above reaction has been proposed based on NMR data, which includes the intermediate formation of the corresponding halohydrin. 

A generally applicable method for the preparation of optically active epoxides makes use of a lipase-catalyzed resolution of halohydrins bearing the halogen in the terminal position (Scheme 3.10). Pseudomonas sp. lipase-catalyzed acylation of racemic halohydrins affords a readily separable mixture of (f )-halohydrin and the corresponding (5)-ester in good to excellent optical purities [193, 194]. Treatment of the latter with base leads to the formation of epoxides with no loss of optical purity. A semiquantitative comparison of the reaction rate obtained with different acyl donors using substrates of this type revealed that they were in the order ethyl... 

We Studied the reaction of alkenes with chlorine or bromine in water to form halohydrins in Section 6.3E and saw that it is both regioselective and stereoselective (for an alkene that shows cis-trans isomerism, it is also stereospecific). Conversion of a halohydrin to an epoxide with base is stereoselective as well and can be viewed as an internal Sj. 2 reaction. Hydroxide ion or another base abstracts a proton from the halohydrin hydroxyl group to form an alkoxide ion, a good nucleophile, which then displaces halogen on the adjacent carbon. As with all S 2 reactions, attack of the nucleophile is from the backside of the C—X bond and causes inversion of configuration at the site of substitution. 

Silica gel-based catalytic systems have been described as efficient promoters for a number of organic reactions.28 Illustrative examples include the oxidative cleavage of double bonds catalyzed by silica-supported KM11O4,29 reaction of epoxides with lithium halides to give /i-halohydrins performed on silica gel,30 selective deprotection of terf-butyldimethylsilyl ethers catalyzed by silica gel-supported phosphomolybdic acid (PMA),31 and synthesis of cyclic carbonates from epoxides and carbon dioxide over silica-supported quaternary ammonium salts.32... 

PEG proves to be an efficient reaction medium for the reaction of vicinal halohydrin with carbon dioxide in the presence of a base to synthesize cyclic carbonates (Scheme 5.9) [42], Notably, PEG400 (MW = 400) as an environmentally friendly solvent exhibits a unique influence on reactivity compared with conventional organic solvents. Various cyclic carbonates can be prepared in high yield employing this protocol. The process presented here has potential applications in the industrial production of cyclic carbonates because of its simplicity, cost benefits, ready availability of starting materials, and mild reaction conditions. 

Based on the (/ )-specific ADH from L. kefir, a recombinant E. coli strain was constructed as a whole-cell biocatalyst, and co-expressed GDH was used for regeneration of NADPH [157]. These designer cells were applied for the reduction of 4-fluoroacetophenone to the corresponding optically active (/ )-4-fluorophe-nylethan-l-ol at 0.5 M educt concentration [158]. After a reaction time of 23 h, a conversion of >95% has been achieved, and the purified isolated chiral alcohol showed an ee value of >99% (87% yield). (S)-p-Halohydrins were obtained with this whole-cell catalyst by means of an enantioselective reduction of the corresponding ketones with both high conversions of >95% and enantioselectivities of >99% (Fig. 40). Base-induced cyclization of the [S-halohydrin led to enantiomeri-cally pure (S)-epoxides in high yield and enantiomeric purity (>99% ee) [159]. 

Of course, aziridines can also be synthesized by the ring-closing reactions of appropriately substituted amines. For example, halohydrins of type 142 are converted to iV-hydroxy-aziridines 144 by treatment with hydroxylamine derivatives, followed by base-catalyzed intramolecular Sn2 reaction of the intermediate p-haloaminoesters 143 under phase-transfer conditions <03TL3259>. A -Bromoethylimines 146, formed from the reaction of benzaldehyde derivatives (e.g., 145) and 2-bromo-2-methylpropylamine hydrobromide, undergo nucleophilic attack by methoxide, followed by intramolecular displacement of bromide to form A -(a-methoxybenzyl)aziridines 147 <03TL1137>. 

As fas as reaction conditions are concerned, two main approaches are usually taken. Either the nucleophilicity of the R5OH to be added is further enhanced by addition of base (normally R50 M +, or nitrogen bases of low nucleophilicity), i.e., base catalysis, or the electrophilicity of the accepting double bond is further increased by adding, e.g., mercuric salts (alkoxymercu-ration), or sources of halonium ions (formation of / -halohydrins). Clearly, the latter protocol, from now on abbreviated as "onium-methods , necessitates a subsequent step for the removal of the auxiliary electrophile, e.g., reductive demercuration of an intermediate /i-alkoxymercu-rial. Whereas base catalysis has successfully been employed with all varieties of acceptors, application of onium-methods thus far appears to be restricted to a,/ -unsaturated carbonyl compounds. Interestingly, conjugate addition of alcohols to a,/l-enones could also be effected photochemically in a couple of cases. 

The mechanistic outline of carbenoid/carbonyl reactivity follows the paradigm illustrated at the outset of this chapter (Scheme 1 X = halogen). The nucleophilic lithium species adds to the carbonyl compound and suffers elimination to provide the epoxide. Competition from molecular rearrangements emanating from the intermediate halohydrin or the product epoxides is sometimes a problem, particularly with cyclic ketones. Also, the initial adduct frequently fails to cyclize when the reaction is quenched at low temperature, but it is usually a simple matter to effect ring closure by treatment of the halohydrin with mild base in a separate step. 

Tin(n) triflate mediated cross aldol reactions between a-bromo ketone (124 Scheme 56) and aldehydes afford iyn-a-bromo-P-hydroxy ketones (125) with high stereoselectivity. The resulting halohydrins are converted to the corresponding (Z)-2,3-epoxy ketones (126). Chiral aldehyde (127) reacts with lithium alkynide (128) followed by mesylation and base treatment to give chirally pure ( )-epoxide (129). The initially formed alkoxide anion should be trapped in situ by mesylation, otherwise partial racemization takes place owing to benzoate scrambling (Scheme 56). ... 

---