Halohydrins, synthesis

Base promoted cyclization of vicinal halohydrms (Section 16 10) This reaction is an intramolecu lar version of the Williamson ether synthesis The alcohol function of a vicinal halohydrin is con verted to its conjugate base which then displa ces halide from the adjacent carbon to give an epoxide... 

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. 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

The success of the halo ketone route depends on the stereo- and regio-selectivity in the halo ketone synthesis, as well as on the stereochemistry of reduction of the bromo ketone. Lithium aluminum hydride or sodium borohydride are commonly used to reduce halo ketones to the /mm-halohydrins. However, carefully controlled reaction conditions or alternate reducing reagents, e.g., lithium borohydride, are often required to avoid reductive elimination of the halogen. 

Halohydrins are useful intermediates especially in the synthesis of epoxides The main reaction is usually accompanied by the formation of a dihalide... 

Another method for the synthesis of epoxides is through the use of halo-hydrins, prepared by electrophilic addition of HO-X to alkenes (Section 7.3). When a halohydrin is treated with base, HX is eliminated and an epoxide is produced. 

Regioselective anbd Chemoselective Synthesis of Halohydrins by Cleavage of Oxiranes with Metal Halides," Bonini. C. Righi, G. Synthesis, 1994, 225... 

Poessl, T.M., Kosjek, B., Ellmer, U. et al. (2005) Non-racemic halohydrins via biocatalytic hydrogen-transfer reduction of halo-ketones and one-pot cascade reaction to enantiopure epoxides. Advanced Synthesis and Catalysis, 347 (14), 1827-1834. 

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... 

The formation of cholesterol chlorohydrins has been a subject of intense research [99-102]. The role of these compounds is not yet fully understood, but in addition to cytotoxicity and a possible action on atherosclerosis [100], they have been suggested to be biomarkers of myeloperoxidase-derived HOC1 [103]. Moreover, chlorohydrins and other halohydrins are useful intermediates for the synthesis of a vast range of biologically active natural and synthetic products [104, 105], In fact, considering the importance of these compounds, their preparation is of major interest. 

The indirect electrochemical generation of propylene oxide via propylene chloro- or bromohydrin using anodically generated hypochlorite or hypobromite has been studied very intensively. The reason is the lack of a technically useful process for the synthesis of propylene oxide by way of heterogeneous catalysis. The propylene halohydrins are saponified using the cathodically generated sodium hydroxide (Eqs. (42)-(47)) (Table 4. No. 12-15)... 

Mildly basic to neutral conditions for the ring closure of 1,3-halohydrins include tetra-phenylantimony methoxide as an effective non-basic reagent for oxetane synthesis from 1,3-bromohydrins (90S106). The salts of (3-halo acids cyclize in ionizing media to oxetan-2-ones, as do (3-diazonium carboxylates (64HC(l9-2)787). Thietanes are obtained analogously. 

Below are described five approaches to epoxide synthesis by way -.if haLohydrins. These halohydrina may be isol ble purifi ble intermediates or they may be transient, unstable species that undergo spontaneous ring closure under the conditions used to generate them. Jho former are typical of (1) addition of hypobalous acids to olefins 111 chemical reduction of a-h Iocarbonyl compounds, and (3) addition if organometallic reagents to o-halocarbonyl compounds the latter,... 

Halohydrins are useful intermediates especially in the synthesis of epoxides. The main reaction is usually accompanied by the formation of a dihalide. When the reactions are performed in the presence of acetic acid, then acetates of the hydrins can be the predominant products. With several exceptions, alkenes with a nonfluorinated C = C bond have been subjected to halohydrinations. Halogen cations usually undergo addition to the substituted carbon of the C = C bond in (fluoroalkyl)ethenes. 

The first examples of the synthesis of CCs from halohydrins appeared during the early 1930s. In this case, vic-halohydrins were reacted with sodium hydrogen carbonate [190, 191] or sodium alkyl carbonates [192] to afford CCs in good yield (82%), especially when the reaction was carried out under high pressure and temperature. When tetramethylammonium hydrogen carbonate was used in acetonitrile (Equation 7.18) [193], the relevant carbonate could be prepared in high yields under mild conditions. 

An illustrative example of oxirane formation by the action of alkali on a / -halohydrin is to be found in the reaction sequence involved in the Darzens glycidic ester synthesis (Section 5.7.6, p. 598). Three target molecules, namely 2-phenylaziridine (4), methyl (S)-thiiranecarboxylate (5) and cyclooctene sulphide (6), are selected here to exemplify this intramolecular cyclisation reaction type. 

Nakamura T, Nagasawa T et al (1991) A new catalytic function of halohydrin hydrogen-halide-lyase, synthesis of P-hydroxynitriles from epoxides and cyanide. Biochem Biophys Res Commun 180 124—130... 

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. 

Scheme 5.9 Synthesis of cyclic carbonates from halohydrin with C02 catalyzed by PEG/K2C03 system. Reprinted with the permission from Ref. [42].

Wang JL, He LN, Dou XY et al (2009) Poly (ethylene glycol) an alternative solvent for the synthesis of cyclic carbonate from vicinal halohydrin and carbon dioxide. Aust J Chem 62(8) 917-920... 

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