Haloalkylation Reactions

The reaction is completed by the coordination of AICI3 to the oxygen atom, making it easier to displace in an 5 2 substitution by chloride. The reason for the selectivity for the/ ara-position over the ortho-site in the reaction of the polymer is clearly steric. 

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The last group of reactions uses ring opening of carbonyl or 1-hydroxyalkyl substituted cyclopropanes, which operate as a -synthons. d -Synthons, e.g. hydroxide or halides, yield 1,4-disubstituted products (E. Wenkert, 1970 A). (1-Hydroxyalkyl)- and (1-haloalkyl)-cyclopropanes are rearranged to homoallylic halides, e.g. in Julia s method of terpene synthesis (M. Julia, 1961, 1974 S.F. Brady, I968 J.P. McCormick, 1975). 

Each of the following dihaloalkanes gives an N (haloalkyl)phthahmide on reaction with one equivalent of the potassium salt of phthalimide Write the structure of the phthahmide denvative formed m each case and explain the basis for your answer... 

This method is also used with alcohols of the stmcture Cl(CH2) OH (114). HaloaLkyl chlorosulfates are likewise obtained from the reaction of halogenated alkanes with sulfur trioxide or from the chlorination of cycHc sulfites (115,116). Chlorosilanes form chlorosulfate esters when treated with sulfur trioxide or chlorosulfuric acid (117). Another approach to halosulfates is based on the addition of chlorosulfuric or fluorosulfuric acid to alkenes in nonpolar solvents (118). 

To the best of our knowledge, the hrst paper which mentioned an A-(l-haloalkyl)pyridinium compound appeared 66 years ago in the Chemische Berichte (Krohnke 33CB1386). Tlie author described the reaction of phenacyl pyridinium derivatives 1 with bromine in acetic acid to give the halides 2 (36CB2006 37CB864). Tire addition of bromine to the double bonds of A-vinylpyridinium salts 3 and 4 giving the adducts 5 and 6 has also been reported (51CB399) (Scheme 1). 

Trichloro- and dichloromethane, ether, dioxane, benzene, toluene, chlorobenzene, acetonitrile, or even pyridine itself has been employed to carry out the one-pot syntheses. Tliese solvents allow straightforward preparation of the salts. The temperature range between 0° and 20°C is usually employed and the salts formed are sufficiently soluble. In the case of slow reactions, selection of a solvent with a higher boiling point is prohtable since thermal instability of the A -(l-haloalkyl)heteroarylium halides has not been reported. Addition of water or an aqueous solution of sodium acetate does not cause a rapid decomposition of the salts so that this constitutes a useful step in the optimization of some procedures. 

Not many reactions between A-(l-haloalkyl)heteroarylium halides and anionic nucleophiles are reported in the literature. In trichloromethane or... 

The traditional means of assessment of the sensitivity of radical reactions to polar factors and establishing the electrophilicity or nucleophilieity of radicals is by way of a Hammett op correlation. Thus, the reactions of radicals with substituted styrene derivatives have been examined to demonstrate that simple alkyl radicals have nucleophilic character38,39 while haloalkyl radicals40 and oxygcn-ccntcrcd radicals " have electrophilic character (Tabic 1.4). It is anticipated that electron-withdrawing substituents (e.g. Cl, F, C02R, CN) will enhance overall reactivity towards nucleophilic radicals and reduce reactivity towards electrophilic radicals. Electron-donating substituents (alkyl) will have the opposite effect. 

Secondly, the rates and modes of reaction of the intermediates are dependent on their detailed structure. For example, the stability of the cation radical formed by the oxidation of tertiary aromatic amines is markedly dependent on the type and degree of substitution in the p-position (Adams, 1969b Nelson and Adams, 1968 Seo et al., 1966), and the rate of loss of halogen from the anion radical formed during the reduction of haloalkyl-nitrobenzenes is dependent on the size and position of alkyl substituent and the increase in the rate of this reaction may be correlated with the degree to which the nitro group is twisted out of the plane of the benzene ring (Danen et al., 1969). 

Domino Michael/aldol processes, which are initiated by the addition of a halide to an enone or enal, have found wide attention. They are valuable building blocks, as they can be easily converted into a variety of extended aldols via subsequent SN2 reactions with nucleophiles or a halide/metal exchange. As an example, a-haloalkyl- 3-hy-droxy ketones such as 2-76 have been obtained in very good yields and selectivities by reaction of enones 2-71 with nBu4NX in the presence of an aldehyde 2-74 and TiCl4as described by the group of Shinokubo and Oshima (Scheme 2.16) [24]. 

A novel route to 3,4-disubstituted piperidines 206 via ring transformation of 2-(haloalkyl)azetidines 207 is shown below. During these reactions, bicyclic azetidinium intermediates are formed and then ring opened by a variety of nucleophiles generating stereospecific substituted piperidines in excellent yields <06OLl 105>. 

A wide range of A-acylbenzotriazoles 915 have been prepared under mild conditions in reactions of carboxylic acids with thionyl chloride in the presence of fourfold excess of benzotriazole, including R = alkyl, a-haloalkyl, a-alkoxyalkyl, alkenyl, alkinyl, aryl, and heteroaryl <2003S2795, 2004RQM275>. They represent convenient acylating agents for variety of nucleophiles. Synthetic applications of such compounds have been reviewed <2005SL1656>. 

The alkylation of 4-amino-l,2,4-triazolo-3-thione derivatives using haloalkyl nitriles to give the S-alkylated product as a result of alkylation of the 3-mercato-l,2,4-triazole tautomer, or the corresponding N-alkylated product resulting from reaction with the 3-thione tautomer, has been studied extensively optimum conditions have been developed to provide either the S- or the N-alkylated products in good yields <2000PS(167)219, 2003BML2601>. 

FIGURE 3.20 Protection of carboxyl groups by esterification of V-protected amino acids (A) by reaction of the anion with an alkyl halide or haloalkyl resin (R = resin) in dimethylformamide51 and (B) by tertiary amine-catalyzed reaction of a symmetrical anhydride with hydroxymethylphenyl-resin (R = resin).53 The intermediate is probably that depicted in Figure 3.19. Reaction (A) is applicable also to the carboxyl groups of peptides. 

An alternative to the above is esterification by reaction of the salt of the Fmoc-amino acid with the halomethylphenyl-support (see Section 3.17). It was established in the 1960s that this method of esterifying A-alkoxycarbonylamino acids, which does not involve electrophilic activation, is not accompanied by enan-tiomerization. Examples of supports with haloalkyl linkers are bromomethylphe-noxymethyl-polystyrene and 2-chlorotrityl chloride resin (see Section 5.23). 

Another reaction of dehalogenation, the oxidative dehalogenation of haloalkyl groups, summarized in Fig. 11.3,b (Chapt. 8 in [50]), has also been observed in mammals and other organisms. Here, the haloalkane is oxidized by a cytochrome P450 enzyme to form a hydroxylated intermediate that loses HX to become a carbonyl derivative. The latter is then reduced by dehydrogenases to the corresponding alcohol (Fig. 11.3,c), or, when the carbonyl derivative is an aldehyde, oxidation to the acid can occur (Fig. 11.3,c). 

Halides are, not surprisingly, also suitable leaving groups for the generation of carbon-metal double bonds by a-abstraction. a-Haloalkyl complexes can be converted into carbene complexes either thermally [459,483] or by treatment with Lewis acids [180], The vinylogous variant of this reaction has also been reported (Figure 3.17). 

Direct treatment of organic geminal dihalides or trihalides with strongly nucleophilic transition metal complexes can also lead to the formation of carbene complexes, presumably via intermediate a-haloalkyl complexes [484-489]. Examples of such reactions are sketched in Figure 3.17. 

The disproportionation of III into IV and V can be rationalized on the basis of the known reaction of phosphoranes with halogen sources giving a-haloalkyl-phosphonium salts. 

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