Cyclic halohydrin

Instead of H20, COOH or OH groups of the substrate located at a suitable distance can also open the halonium ion intermediate through a nucleophilic backside reaction. In this way, cyclic halohydrin derivatives are produced (Figure 3.47). They are referred to as halolactones or haloethers. 

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... 

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>. 

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. 

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... 

The study of gas-phase acid-induced nucleophilic displacement on 2,3-dihalobutanes has provided stereochemical evidence for the occurrence of cyclic chloronium and bromo-nium ions (X = Cl, Br), but not fluoronium ions17. Protonation or methylation of the neutral 2,3-dihalobutane by a suitable acid GA+ produces a halonium intermediate 2, which in the presence of water ultimately leads to the corresponding halohydrin neutral product (Scheme 4). Analysis of these neutral products indicated that the reaction proceeds with retention of configuration when X = Cl, Br and with inversion of configuration when X = F. The results were rationalized by the mechanisms sketched in Scheme 4, namely direct bimolecular nucleophilic displacement by H20 on 2 when X= F and intramolecular nucleophilic displacement to convert 2 into the cyclic halonium ion 3 (with inversion of configuation) followed by bimolecular nucleophilic displacement on 3 (with inversion of configuration) when X = Cl and Br. 

Figure 11.5 shows a mechanism that has been postulated for this reaction. First, an electrophilic mercury species adds to the double bond to form a cyclic mercurinium ion. Note how similar this mechanism is, including its stereochemistry and regiochemistry, to that shown in Figure 11.4 for the formation of a halohydrin. The initial product results from anti addition of Fig and OH to the double bond. In the second step, sodium borohydride replaces the mercury with a hydrogen with random stereochemistry. (The mechanism for this step is complex and not important to us at this time.) The overall result is the addition of H and OH with Markovnikov orientation. 

A second synthesis of epoxides and other cyclic ethers involves a variation of the Williamson ether synthesis. If an alkoxide ion and a halogen atom are located in the same molecule, the alkoxide may displace a halide ion and form a ring. Treatment of a halohydrin with base leads to an epoxide through this internal SN2 attack. 

Kinetic Resolution of Racemic Secondary Alcohols. Racemic cyclic and acyclic secondary alcohols and p-halohydrins are kinetically resolved in good chemical yields with modest-to-excellent enantioselectivity (eqs 2 and 3). 

The conversion of halohydrins into epoxides by the action of base is simply an adaptation of the Williamson synthesis (Sec. 17.5) a cyclic compound is obtained because both alcohol and halide happen to be part of the same molecule. In the presence of hydroxide ion a small proportion of the alcohol exists as alkoxide this alkoxide displaces halide ion from another portion of the same molecule to yield the cyclic ether. 

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. 

Cyclic Esters of Phosqphorous Acid.— The cyclic aminophosphite (90), prepared from the corresponding halohydrin and the phosphoramidate (89), slowly forms the novel ammonium salt (91). Both spectroscopic and chemical evidence appear to support the ionic structure over the alternative (92). 

The activation of a diol function could be performed in many different ways. As will be discussed later, vicinal diols can be easily transformed into epoxides, halohydrins and cyclic sulfates, all of them reacting readily and with high stereocontrol with a range of nucleophiles. An intermediate typically generated during the formation of cyclic sulfates [113] is the corresponding cyclic sulfite (Scheme 37). Several nucleophiles, e.g. N3, Cl and Br react readily with activated cychc sulfites to afford in good yield and with clean inversion of stereochemistry, the substitution products. 

The mechanism for halohydrin formation involves the formation of a cyclic bromo-nium ion (or chloronium ion) in the first step of the reaction, because Br (or Cl ) is the only electrophile in the reaction mixture. In the second step, the bromonium ion rapidly reacts with whatever nucleophile it bumps into. In other words, the electrophile and nucleophile do not have to come from the same molecule. There are two nucleophiles present in solution H2O and Br . Because H2O is the solvent, its concentration far exceeds that of Br . Consequently, the bromonium ion is more likely to collide with a molecule of water than with Br . The protonated halohydrin that is formed is a strong acid (Section 1.19), so it loses a proton. 

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