LiAlH4, reaction with alkyl halides

Nitriles are common nitrogen-containing compounds. In Chapter 11 (Section 11.3.6), cyanide ion reacted as a nucleophile in an Sn2 reaction with alkyl halides to give a nitrile. When 2-bromohexane (22) is treated with NaCN in DMF, the product is 2-cyanohexane, 23. Reduction of this nitrile with LiAlH4 gives a primary amine, in this case l-amino-2-methylhexane 24. 

Azide anion, which is more nucleophilic than amines, reacts with alkyl halides and activated alcohols giving the corresponding alkyl azides. Phase-transfer conditions can also be utilized. For details, readers are referred to a comprehensive review. Alkyl azides thus formed can be readily transformed into primary amines by a variety of reagents or reaction systems which involve catalytic hydrogenation, LiAlH4, NaBH4 under phase-transfer conditions, NaBH /THF/MeOH, PhsP ... 

When steric hindrance in substrates is increased, and when the leaving anion group in substrates is iodide, SET reaction is much induced (Cl < Br < I). This reason comes from the fact that steric hindrance retards the direct nucleophilic reduction of substrates by a hydride species, and the a energy level of C-I bond in substrates is lower than that of C-Br or C-Cl bond. Therefore, metal hydride reduction of alkyl chlorides, bromides, and tosylates generally proceeds mainly via a polar pathway, i.e. SN2. Since LUMO energy level in aromatic halides is lower than that of aliphatic halides, SET reaction in aromatic halides is induced not only in aromatic iodides but also in aromatic bromides. Eq. 9.2 shows reductive cyclization of o-bromophenyl allyl ether (4) via an sp2 carbon-centered radical with LiAlH4. 

Reduction of aryl and alkyl halides.5 This reaction can be conducted in generally good yield with LiAlH4 by a free-radical process initiated by irradiation of di-r-butyl peroxide. The order of reactivity of aryl halides is Arl > ArBr > ArCl > ArF. Alkyl and cycloalkyl halides are reduced efficiently, but vinyl bromides are reduced in only modest yield. 

A better method for preparing primary amines is to use the azide synthesis, in which azide ion, is used for 8 2 displacement of a halide ion from a primary or secondary alkyl halide to give an alkyl azide, RNj. Since alkyl azides are not nucleophilic, overalkylation can t occur. Reduction of the alkyl azide, either by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlH4, leads to the desired primary amine. Although the method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. 

Reaction of hydrazoic acid with the monoaryl sulphoxides (345) affords benzothiazine oxides (346) and benzothiadiazepine oxides (347), and the same reagent converts the diaryl sulphoxides (348) into the benzothiadiazine oxides (349), which undergo a base-catalysed rearrangement to (350), cf. (228) - (229a). JV-5-Alkylation of the latter occurs on treatment with sodamide and alkyl halides, and reduction of the lactam moiety is brought about by LiAlH4. ... 

Unfortunately, these reactions don t stop cleanly after a single alkylation has occurred. Because ammonia and primary amines have similar reactivity, the initially formed monoalkylated substance often undergoes further reaction to yield a mixture of mono-, di-, and trialkylated products. A better method for preparing primary amines from alkyl halides is to use azide ion, N3, as the nucleophile rather than ammonia. The product is an alkyl azide, which is not nucleophilic, so overalkylation can t occur. Subsequent reduction of the alkyl azide with LiAlH4 then leads to the desired primary amine. 

Arylamines are prepared by nitration of an aromatic ring followed by reduction. Alkylamines are prepared by Sn2 reaction of ammonia or an amine with an alkyl halide as well as by a number of reductive methods, including LiAlH4 reduction of amides and nitriles. Also important is the reductive amination reaction in which an aldehyde or ketone is treated with an amine in the presence of a reducing agent. 

Reactions of Halogeno-compounds.— In a reappraisal of the reduction of organic halides to alkanes with lithium aluminium hydride, clear solutions of LiAlH in THF have been observed to perform the reduction quantitatively and more rapidly than when using slurries of the reagent, as described in previous reports. The preferred stoicheiometry is LiAlH4 RHal = 1 1, so that the byproduct is aluminium hydride [equation (16)], which is inert to alkyl halides. 

Primary and secondary alkyl bromides, iodides, and sulfonates can be reduced to the corresponding alkanes with LiBHEt3 (superhydride) or with lithium aluminum hydride (LiAlH4, other names lithium tetrahydridoaluminate or lithium alanate). If such a reaction occurs at a stereocenter, the reaction proceeds with substantial or often even complete stereoselectivity via backside attack by the hydride transfer reagent. The reduction of alkyl chlorides to alkanes is much easier with superhydride than with LiAlH4. The same is true for sterically hindered halides and sulfonates ... 

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