LiAlH4, reaction with amides

With primary or secondary amides, reaction with LiAlH4 is wasteful in that hydrogen gas is evolved and reduction usually proceeds through to the amine. Nevertheless, it has been shown that r-butylamides, refluxed with an excess of LiAlD4 for 15 h in diethyl ether, give very good yields of deuteriated aldehydes, RCDO. O ... 

Pyridine is an aromatic 6n electron heterocycle, which is isoelectronic with benzene, but electron deficient. Nucleophiles thus add almost invariably to carbon C2 of the imine-like C=N double bond. Perhaps the best known nucleophilic addition is the Chichibabin reaction with sodium amide in liquid ammonia, giving 2-aminopyr-idine. Reactions of the quinoline moiety of cinchona alkaloids can be more complex. Although expected 2 -addition can be achieved easily with organolithium reagents to yield 13 (Scheme 12.6) [9], LiAlH4, for example, has been shown to attack C4 en route to quincorine and quincoridine (Schemes 12.4 and 12.5). C4 selectivity is due to chelation of aluminum by the C9 OH oxygen. 

N-Alkylation of amides. Benzotriazol-l-ylmethylation on the nitrogen atom of an amide is accomplished in refluxing acetic acid. Benzotriazole can then be displaced by reaction with an organometallic reagent (R2Zn, etc.). On LiAlH4 reduction A -methylamines are obtained. 

Methoxyamine solid supports 7x can be used to anchor carboxylic acids in the presence of BOP/DIEA as Weinreb amides [338,339]. The resultant anchor is compatible with peptide assembly using Boc or Fmoc strategies, and treatment of the final sequence with LiAlH4 in THF led to release of peptide aldehydes. A related support with RAM as the base resin has also been used to prepare resin-bound Weinreb amides, which afforded ketones on cleavage induced by reaction with Grignard reagents [340]. 

Amides react with LiAlH4 differently than do other carbonyl derivatives. Reaction with LiAlH4 gives an intermediate iminium salt, which is further reduced to an amine as the final product. The net result of this two-step process is complete removal of oxygen from the molecule, illustrated by the reduction of amide 28, which gave amine 29 in 85% yield from Quirion s asymmetric synthesis of 1,4-disubstituted tetrahydroiso-quinolines.36 The reaction proceeds by initial transfer of hydride to the amide, forming a complex such as... 

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. 

Amides require vigorous reaction conditions for reduction by LiAlH4 so that little selectivity can be achieved with this reagent. Diborane, however, permits the reduction of amides in the presence of ester and nitro groups. 

Another application of cyclic peptides is their conversion to polyazamacrocycles via reduction of the amide bonds with LiAlH4 (Scheme 41)J626 627] This reaction proceeds without racemization and yields compounds that are otherwise hard to access. 

All reactions are carried out under an atmosphere of dry nitrogen gas unless otherwise stated. Lithium bis(trimethylsilyl)amide (Aldrich), 1,4-dicyanoben-zene (Aldrich), chlorotrimethylsilane (Aldrich), and 1,3,5-triazine (Aldrich) are used as received. Benzonitrile (Fisher) is vacuum distilled from P2Os prior to use. Solvents are purified by distillation as follows hexane, over calcium hydride diethyl ether, over LiAlH4 ( Caution. Reacts violently with water) toluene, over sodium acetonitrile, over P2Os. 

Primary and secondary amines also react with epoxides (or in situ produced episulfldes >r aziridines)to /S-hydroxyamines (or /S-mercaptoamines or 1,2-diamines). The Michael type lddition of amines to activated C—C double bonds is also a useful synthetic reaction. Finally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-cylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH4 (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

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