LiAlH4, reaction with azides

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. 

Deprotonation of indoles 128 followed by alkylation with 2-methyloxirane led to the secondary alcohols 129 that were used as starting compounds in the preparation of substituted 2-(l//-indol-l-yl)-l-methylethylamines 130, novel agonists of 5HT2C receptors. Sn2 reaction of the corresponding mesylates with sodium azide and reduction of the azides with either hydrogen or LiAlH4 produced amines 130 in excellent yields (Scheme 28) <1997JME2762>. 

Other aminoferrocene precursors are Af-ferrocenyl phthalimide, which can be converted to FC-NH2 by N2H4 H2O in boiling ethanol (82% yield) [16, 44], and ferrocenyl azide, FC-N3, which has been reduced with LiAlH4 (72% yield) (cf. Scheme 5-6) [45]. Ferrocenyl amine, FC-NH2, is generally formed among other products in the thermal or photochemical decomposition of FC-N3 [56] and in the thermolysis of ferrocenyl isocyanate, Fc-NCO [57], in solvents such as cyclohexane, cyclohexene and benzene, probably by reaction of the intermediate nitrene, [Fc-N], with the solvent [56, 57]. The reduction of nitroferrocene, FC-NO2, provides another route to aminoferrocene, FC-NH2 [58 — 61] however, FC-NO2 is not an easily accessible starting material. 

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 ... 

Transformation into azide groups was achieved for polystyrene, poly(MA), and poly(nBA) with the use of sodium azide (EC-18)351 353 or trimethylsilyl azide (EC-19)161-351-354 in the presence of tetrabutylammo-nium fluoride. The azide groups can be further converted into amino (— NH2) groups by treatment with PPh3/H20351 or LiAlH4.354 The reaction between the azide end group in polystyrene and Ceo was also examined.353... 

The azide ion is a better nucleophile than amines, but it has to be reduced to the amine after nucleophilic substitution. Lithium aluminum hydride (LiAlH4) in ether followed by treatment with water reduces the azide ion to the amine. Figures 13-11 and 13-12 illustrate two examples of this reaction. 

Methyl 5,6-(A-acetylepimino)-2,3-di-C-benzyl-5,6-dideoxy-a-L-altrofuranoside (395) gave the 5,6-diacetamido derivative 396 after reaction successively with sodium azide, LiAlH4, and acetylation. The yields of intermediary products and the regioselectivity of the cleavage were not reported. 

Azide 65, an intermediate of the synthesis of lycoposerramine-V, was converted into primary amine by the Staudinger reaction and the resulting amine was directly treated with methyl chloroformate to give methyl carbamate derivative 69 (Scheme 13). Reduction of the carbamate with LiAlH4 gave A-methyl derivative 70 and then the resulting secondary amine was acylated with chloroacetylchloride... 

Stereospecific ring closure. 2/ -Azido-3a-iodocholestane in benzene added to tri-methyl phosphite, allowed to stand at room temp, until spectroscopy shows disappearance of the IR-azide band, solvent and most of the excess trimethyl phosphite removed in vacuo, the ethereal soln. of the residue added to a stirred soln. of LiAlH4 in anhydrous ether at a rate to maintain reflux, and stirred 2 hrs. at room temp. 2, 3i -iminocholestane. Y 16%. - This convenient reaction sequence may be successful in cases where other methods fail. F. e., also isolation of the intermediate, and ring closure with other phosphorus(III) nucleophiles such as phosphines, s. A. Hassner and J. E. Galle, Am. Soc. 92, 3733 (1970). 

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. 

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