Alkyl halides haloalkylation

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. 

The nature of alkyl halide and the environment of the phosphorus atom make a substantial contribution to the direction of the reaction. Thus, cyclic phosphites [108], like trialkyl phosphites [110], react with preservation of the coordination of the P(III) phosphorus atom (126-132 ppm). If the alkoxyl group is substituted by amide, alkyl, or aryl, the nucleophilicity of the phosphorus atom in the corresponding amidophosphite (phosphonite) increases in comparison with the trialkyl phosphite. This probably promotes attack by 1 -haloalkyl-2-pyrrolidone at the phosphorus atom and not the oxygen, and this was confirmed experimentally. As a result of the investigated reactions amidophosphonates or ethyl phenyl phosphinates llOa-c were isolated compounds with P(III) were not detected in these cases. 

Dialkylaminoalkylphenothiazines may be prepared replacing the usual condensating agent, sodamide, by an excess of sodium hydroxide. In the case of alkyl or haloalkyl halides the V-substitution of phenothiazine in the presence of sodium hydroxide fails. The formation of intermediate cyclic quaternary ammonium salts (133) from the dialkylaminoalkyl halides was suggested to explain this effect. Quaternary ammonium salts appear to catalyze the condensation of alkyl halides with phenothiazine in the presence of NaOH. ... 

The proof given in support of dianion formation does not however seem to be sufficients Nevertheless the single step process is reasonably efficient when primary alkyl halides are used but none of the dialkylated compound is produced with isopropyl iodide and benzyl bromide. 2-(o>-Haloalkyl)-l,3-di-thianes have proved to be valuable precursors of 1,3-dithianes derived from cyclic ketoncs. Haloge-nated 1,3-dithianes have been in turn prepared from 2-lithio-l,3-dithiane and stoichiometric amounts of u-chloro- or bromo-alkyl iodides or with an excess of the corresponding dichloride (Scheme 64, entry c). Use of u-bromoalkyldithianes is often impractical because of the ease with which these compounds are transformed into cyclic sulfonium salts. ... 

One of the limitations of the intramolecular Barbier reaction of a>-haloalkyl p-keto ester substrates, as developed in our laboratory, was the inability to utilize secondary alkyl halides. Under the aprotic conditions utilized, a retroaldol reaction transpired that led to undesired transformations of the intermediate generated (Eq. 2). 

Isolation of alkoxyphosphonium intermediates has been achieved recently by the use of reagents which enter into the Michaelis-Arbuzov reaction at room temperature or below. Thus, Abramov et al. (3,4,8) obtained noncrystalline adducts from trialkyl phosphites and o ,iS-di-haloalkyl ethers. Razumov and Bankovskaya (278) found that reaction of alkyl dialkylphosphinite esters with alkyl halides carried cut at low temperature gave crystalline 1 1 adducts convertible to phosphine oxides on gentle warming. These latter adducts were sufficiently stable Tor measurement of their dipole moments and other properties. They should prove valuable for the study of valency expansion. Also of potential value for this purpose are the stable trialkoxyphosphonium fluoroborates (96,97), e.g., [EtP(OEt)s] BF4 , obtained by interaction of EtsO BF4" or Ph3C+ BF4 with phosphites at room temperature. 

Unsymmetrical a-haloalkyl p-tolyl sulfones have likewise been prepared under phase transfer conditions (see Eq. 13.14) [24]. Thus, a-halomethyl p-tolyl sulfones are deprotonated to form a carbanion which reacts with an alkyl halide to give product. a-Halo-a-sulfonylcarbanions apparently are not prone to undergo facile a-elimina-... 

A haloalkyl carbonate structure is formed by the initial ring-opening reaction of the monomer with alkyl halide, which was shown by using ethyl 3-iodopropyl carbonate as the initiator for cyclic carbonate polymerization. The obtained polymer contained both ethyl and iodopropyl end-groups. 

A -(l-Haloalkyl)pyridinium halides have been advantageously employed in the Hantzsch multicomponent synthesis, yielding alkyl 1,4-dihydropyri-dine-3,5-dicarboxylates, which are a well-known class of calcium channel modulators (81AGE762). Tire halides readily interact with an excess of an ethyl 3-aminobut-2-enoate 82 (R = H) in dichloromethane at room temperature to afford the heterocycles 83 (R = H) in good to excellent yields (65-95%) (92T1263). Tliis observation has been exploited to perform a quantitative study of the reactivity of the salts (93CB1251).Tlie results have... 

---