Benzylic halides, alkylation conversion

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0")2 ] by treatment with a strong base such as LDA. The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCH2COOH and RR"CHCOOH. This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 458),... 

Another way to oxidize primary alkyl halides to aldehydes is by the use of hexamethylenetetramine followed by water. However, this reaction, called the Sommelet reaction. is limited to benzylic halides. The reaction is seldom useful when the R in RCH2CI is alkyl. The first part of the reaction is conversion to the amine ArCH2NH2 (0-44), which can be isolated. Reaction of the amine with excess hexamethylenetetramine gives the aldehyde. It is this last step that is the actual Sommelet reaction, though the entire process can be conducted without isolation of intermediates. Once the amine is formed, it is converted to an imine (ArCH2N=CH2) with formaldehyde liberated from the reagent. The key step then follows transfer of hydrogen from another mole of the arylamine to the imine ... 

A one-pot PTC reaction procedure for the overall conversion of an alkyl halide into a primary amine via an azide is particularly illustrative.204 Thus the reduction of the azide is effected by the addition of sodium borohydride to a reaction mixture arising from the PTC displacement reaction of an alkyl halide with sodium azide (the preparation of 1-octylamine, Expt 5.193). The reaction appears to be applicable to primary and secondary alkyl halides, alkyl methane-sulphonates and benzylic halides. 

Ben2 yl-type chlorides are converted to the corresponding cyanides much more rapidly (85-90%). Ring substituents include alkyl, halo, carbethoxy and nitro groups. The more reactive benzyl halides, particularly the p-methoxy derivatives, are subject to extensive alcoholysis when ethanol is employed as the solvent. The successful use of acetone, acetonitrile, and phenylacetonitrile as solvents has been described. Conversion by cuprous cyanide and pyridine has been successfully applied to benzyl chloride as well as to di-o-tolylchloro-methane. It is interesting to find that treatment of a-chloroethylbenzene, C,H,CH(C1)CH, with cuprous cyanide gives 1,3-diphenyI-l-butene,... 

Sulfones are valuable in carbon-carbon bond formation (see Chapter 10, p. 197) alkylation occurs easily with allyl and benzyl halides, and this can be utilised in the formation of 2-alkenes. The reaction is illustrated by the conversion... 

There is one more way for conversion of ort/to-nitroarylacetonitriles into indoles. Alkylation of such nitriles with allyl or benzyl halides followed by treatment of the compounds obtained with basic agents results in a multistep transformation, which is likely to proceed via intermediate nitrosoarenes, to produce 1-hydroxyindoles. For instance, alkylation of ort/io-nitroarylacetonitriles with 3-phenylallyl bromide gives the compounds that in the presence of chlorotri-methylsilane and triethylamine undergo cyclization into 3-cyano-l-hydroxy-2-vinylindoles (Scheme 70) [188]. Presumably, this reaction proceeds via 0-silylation of the nitronate anion and 1,5-elimination of trimethylsilanol from the intermediate trimethylsilyl nitronate, followed by cyclization and a hydrogen shift. 

A practical and efficient asymmetric synthesis of 2-substituted oxetane-3-ones 46 has been developed by Shipman and co-workers by lithiation of SAMP/RAMP hydrazones of oxetane-3-one 45, followed by interception of the putative azaenolate lithiated intermediate with a range of electrophiles that include alkyl, aUyl and benzyl halides, and an aldehyde (Scheme 13) (2013JOC12243). As for the bases, w-BuLi and <-BuLi were found to be the most suitable for the metalation step providing adducts 46 in good yields and enantioselectivities (up to 84% ee), whereas LDA was less effective. Conversion of hydrazones 46 to the enantiomerically enriched 2-substituted oxetane-3-ones 47 can be achieved without detectable racemization using aqueous oxaHc acid at room temperature. 

Tertiary amines are also known to effect the phase transfer addition of cyanide ion to primary, allylic, and benzylic halides [9]. The reported effect of amine structure on catalytic efficiency closely parallels that reported by Hennis for ester formation in a two-phase system (see Sect. 1.7). Both the nitrogen of the amine and the carbon bearing halide of the alkyl bromide must be sterically accessible for the reaction to succeed. Thus, -hexylamine is effective in concert with -butyl bromide but the combinations of either 5-butyl bromide and -hexylamine or -butyl bromide and cyclohexylamine are not. Tertiary amines are generally more effective than secondary or primary amines. In addition, the yields of primary nitriles decrease dramatically with the size of the primary alkyl bromide from quantitative with n-butyl to only 6% with -decyl bromide when -hexylamine is used as phase transfer catalyst. On the other hand, tributylamine was equally useful as a catalyst for the quantitative conversion of either 1-bromohexane or 1-bromodecane to the corresponding nitriles [9]. In general, these observations accord with those of Hennis and coworkers indicating that this reaction is an example of in situ formation of and catalysis by quaternary ammonium salts [10]. 

A new route from alkyl halides to the corresponding amines (as acyl derivatives) involves reaction with A-acyl allylamines (Scheme 34), and subsequent deallylation with Pd salts used catalytically. Palladium species also intervene in the conversion of optically active benzyl halides, with inversion at the original C-halogen bond, to acyl Pd complexes ie.g. 71 ->72) which may be further transformed to carboxylic esters as shown. Alkyl halides give unpredictable results in this sequence. A related conversion can be carried out under phase... 

Two papers this year have described the use of chromate ions for the conversion of alkyl halides or alcohols into aldehydes or ketones (Equation 4). The reaction can be conducted in HMPA in the presence of a crown ether, and although yields are good for allylic and benzylic halides (ca. 80%) they are not so high for saturated halides. " The chromate ion, however, can be supported on an insoluble polymer matrix as the tetra-alkylammonium salt and this both enhances the nucleophilicity of the ion and simplifies the work up procedure. Using the polymer-supported reagent a variety of primary and secondary alcohols were oxidized to the corresponding aldehyde or ketone in excellent yield (ca. 90%). ... 

Jeffrey C. PeUetier of Wyeth Research, Collegeville, PA has developed (Tetrahedron Lett. 2007, 48,7745) a easy work-up Mitsunobu procedure for the conversion of a primary alcohol such as 1 to the corresponding primary amine 2. Shlomo Rozen of Tel-Aviv University has taken advantage (J. Org. Chem. 2007, 72, 6500) of his own method for oxidation of aprimary amine to the nitro compound to effect net conversion of an amino ester 3 to the alkylated amino ester 5. Note that the free amine of 3 or 5 would react immediately with methyl iodide. Keith A. Woerpel of the University of California, Irvine has uncovered (J. Am. Chem. Soc. 2007,129,12602) a Cu catalyst that, with 7, effected direct conversion of sUyl ethers such as 6 to the aUyl silane 8. An Ag catalyst gave 9, which also shows arllyl silane reactivity. Biswanath Das of the Indian Institute of Chemical Technology, Hyderabad has established (Tetrahedron Lett. 2007, 48, 6681) a compact procedure for the direct conversion of an aromatic aldehyde such as 10 to the benzylic halide 11. This will be especially useful for directly generating benzyhc hahdes that are particularly reactive. 

The electrochemistry of cobalt-salen complexes in the presence of alkyl halides has been studied thoroughly.252,263-266 The reaction mechanism is similar to that for the nickel complexes, with the intermediate formation of an alkylcobalt(III) complex. Co -salen reacts with 1,8-diiodo-octane to afford an alkyl-bridged bis[Co" (salen)] complex.267 Electrosynthetic applications of the cobalt-salen catalyst are homo- and heterocoupling reactions with mixtures of alkylchlorides and bromides,268 conversion of benzal chloride to stilbene with the intermediate formation of l,2-dichloro-l,2-diphenylethane,269 reductive coupling of bromoalkanes with an activated alkenes,270 or carboxylation of benzylic and allylic chlorides by C02.271,272 Efficient electroreduc-tive dimerization of benzyl bromide to bibenzyl is catalyzed by the dicobalt complex (15).273 The proposed mechanism involves an intermediate bis[alkylcobalt(III)] complex. 

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