Direct halogenation of alcohols

A variety of reagents are available for the direct replacement of a hydroxyl by a halogeno substituent. Many of these approaches are based on the reaction of an activated triphenyl phosphine derivative with a sugar alcohol to give an alkoxyphosphonium ion, which in turn is 

Mitsunobu conditions [triphenylphosphine/diethyl azodicarboxylate (DEAD)]7 and triphenylphosphite methiochde [(PhO)3P+MeI ] or dihalides [(PhO)3P + XX-j8 have been successfully applied to the synthesis of halogeno sugars. 

The above-discussed methods are mainly used for the synthesis of chloro, bromo and iodo sugars. A different approach has to be taken when a deoxyfluoro sugar derivative is required, and the most commonly applied reagent for direct fluorination is diethylaminosulfur trifluoride 

Tosylate and mesylate displacements at C(2) of a-glycosides are very slow owing to unfavourable dipolar interactions in the SN2 transition state. Both polar bonds of the transition state are inclined at an angle of about 30° to permanent dipoles of the C(l)—0(1) and C(l)—0(5) bonds. Displacement of C(2) sulfonates of p-glycosides is much more facile because, in this case, the transition state experiences only one unfavourable dipolar interaction of the C(l)—0(1) bond.12d,e 

The development of an SN2 transition state at C(3) or C(4) is not affected by dipoles associated with the anomeric centre but is mainly influenced by steric and polar factors from other groups in the sugar ring. For example, the displacement of equatorially oriented tosylates or 

---

Organohalogens can be made in varions ways. Direct halogenation of hydrocarbons with chlorine gives organochlorines with bromine, organobromines. Alcohols can be converted into organohalogens by reaction with hydrogen hahdes. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Before the synthesis of the pseudoureas was published, Bernthsen and Klinger [6] reported a pseudothiourea synthesis involving the reaction of thioureas with alkyl halides. This reaction was briefly reviewed by Dains [16] and Stieglitz [49, 50], and it found many commercial applications [51-53]. The preparation of isothiouronium salts by the direct action of thiourea and halogen acids on alcohols (primary, secondary, and tertiary) was reported by Stevens [8] and further developed by Johnson and Sprague [54, 55] (Eq. 25). 

There is also an apparent trend in manufacturing operations toward simplification by direct processing. Examples of this include the oxidation of ethylene for direct manufacture of ethylene oxide the direct hydration of ethylene to produce ethyl alcohol production of chlorinated derivatives by direct halogenation in place of round-about syntheses and the manufacture of acrolein by olefin oxidation. The evolution of alternate sources, varying process routes, and competing end products has given the United States aliphatic chemical industry much of its vitality and ability to adjust to varying market conditions. 

Cyclization of allylic alcohols to form epoxides has been particularly problematical, and the reactions have been more of mechanistic than of synthetic interest. For reactions conducted under basic conditions, it is possible that epoxide formation involves initial halogen addition followed by nucleophilic displacement to form the epoxide. Early examples of direct formation of epoxides from allylic alcohols with sodium hypobromite," bromine and 1.5 M NaOH,12 and r-butyl hypochlorite13 have been reviewed previously.fr Recently it has been shown that allylic alcohols can be cyclized effectively with bis(jym-collidine)iodine(I) perchlorate (equation 3).14 An unusual example of epoxide formation competing with other cyclization types is shown in equation (4).15 In this case, an allylic benzyl ether competes effectively with a -/-hydroxyl group as the nucleophile. 

---