Iminium ions hydride reduction

The reduction of the double bond of an enamine is normally carried out either by catalytic hydrogenation (MS) or by reduction with formic acid (see Section V.H) or sodium borohydride 146,147), both of which involve initial protonation to form the iminium ion followed by hydride addition. Lithium aluminum hydride reduces iminium salts (see Chapter 5), but it does not react with free enamines except when unusual enamines are involved 148). 

Amide reduction occurs by nucleophilic addition of hydride ion to the amicle carbonyl group, followed by expulsion of the oxygen atom as an alumi-nate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by JL1AIH4 to yield the amine. 

The catalytic Pd complex and the aryl bromide together suggest the first step is oxidative addition of Pd(0) to the C5-Br bond. (The reduction of Pd(II) to Pd(0) can occur by coordination to the amine, p-hydride elimination to give a Pd(II)-H complex and an iminium ion, and deprotonation of Pd(IE)-H to give Pd(0).) The C10-C11 k bond can then insert into the C5-Pd bond to give the C5-C10 bond. P-Hydride elimination then gives the Cl 1-C12 n bond and a Pd(II)-H, which is deprotonated by the base to regenerate Pd(0). The overall reaction is a Heck reaction. 

In the LAH reduction sequence, the C=N double bond in the iminium ion now behaves just as the C=0 bond of a carbonyl (see Section 7.7.1) and is also reduced by transfer of hydride from a further equivalent of LAH. The final product is thus an amine. 

In 2004, List reported that several ammonium salts including dibenzylammonium trifluoroacetate catalyzed the chemoselective 1,4 reduction of a, 5-unsaturated aldehydes with Hantszch esters as hydride sources [40]. It is assumed that substrate activation via iminium ion formation results in selective 1,4 addition of hydride. Subsequently, List [41] and MacMillan [42] reported asymmetric versions of this reaction promoted by chiral imidazoUdinone salts. In this context, several reports of this metal-free reductive process catalyzed by chiral phosphoric acids have appeared in the recent literature. 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

Reduction of vinylogous carbamate 36 with sodium cyanoborohydride in acidic methanol gave exclusively the equatorial aminoester 38. Eschenmoser and co-workers (181 have explained this result by invoking a stereoelectroni-cally controlled anti peri planar addition of hydride ion on the iminium ion 37. 

Using LiAlH4 is a widespread method to generate piperidine rings from lactams. Mechanistically the tetrahedral intermediate 46 is formed first, and this then collapses to the iminium ion 47. The iminium ion is of course more electrophilic than the carbonyl group. Thus after a hydride transfer to the iminium ion and repetition of the reaction sequence again, the tertiary amine 49 is formed. As a matter of principle parallel to this reduction sequence the ketone in ring B is reduced to form 50. 

Reduction of the iminium ion proceeds via perpendicular hydride attack (antiparallel) via a chair-like TS minimizing A1,2 strain. 

An enamine intermediate has been proposed as being formed by hydride reduction of a transient iminium ion [14, 15]. The electrophilic capture of the enamine is possible by a Michael acceptor thus, reductive Michael cyclizations of enal enones such as 9 or 11 were described in many cases (intramolecular reactions) (Scheme 11.5) [16]. 

We ve talked about reduction of iminium ions formed from carbonyl compounds plus amines. Iminium ions can also be formed by reducing amides with lithium aluminium hydride. A tetrahedral intermediate is formed that collapses to the iminium ion. 

The reduction of camphor enamines by the same method has been found to be highly selective, leading to the endo isomer as the predominant product (85-87%)204 (Scheme 136). The lack of solvent effect and the incorporation of up to 3 deuterium atoms when using DCOOD, are in favour of a two-step mechanism. This would involve reversible protonation of the / -carbon atom with formation of the iminium ion, followed by irreversible transfer of hydride from the formate ion to this ion. 

In 2001, we reasoned that this catalysis strategy might be applicable to the conjugate reduction of a, 3-unsaturated carbonyl compounds if a suitable hydride donor could be identified (Scheme 18). Hantzsch ester 11 seemed to be particularly promising since its reaction with preformed a, 3-unsaturated iminium ions had already been established (Makino et al. 1977 Baba et al. 1980). 

Enamines may be reduced by sodium borohydride to give saturated amines, but only if a protonating species is available to convert the enamine initially into the iminium cation (lo). Steroidal g-amino-g,5-dienes are unreactive to sodium boro-hydride alone, but addition of acetic acid leads to rapid reduction via the iminium ion (10) to give gj -amino-A -steroids [224], The possibility that diborane was the reactive species in the NaBHd/HOAc system was excluded by the virtual non-reactivity of the enamine to externally generated diborane. Reduction of the iminium ion derivative (3) of a 6-formyl enol ether has been exploited in a variant of the Vilsmeier synthesis of 6-methyl steroids [22 ], the reduction product was the 6-aminomethyl enol ether (ii) which suffered hydrogenolysis with Raney nickel to give the 6-methylated enol ether (12). 

Mechanistic details involved in imine and carbonyP - reductions are undoubtedly similar, although thorough investigations of the former are lacking. Certainly, hydride transfer to the electrophilic carbon, with or without prior activation by protonation or complexation is essential for both types of ir-systems (Scheme 1). Whether or not alcohol solvents participate in imine reductions by borohydride (in the absence of added acid) to furnish the amine proton (as is the case with carbonyls) is not known and must await detailed kinetic study and analysis of the initial intermediates formed before hydrolysis. Direct, in situ, reductive amination with NaBHsCN has been attributed to initial, reversible formation (via an intermediate hydroxyamine, (1) of an iminium ion (2) from carbonyls and amines followed by rapid attack by hydride (Scheme 2). However, the inermess of an imine (partial structure 3) to the usual reductive... 

As described above, the reduction of imines often proceeds via iminium ions particularly in acidic media, since protonation enhances the electrophilicity of the imine carbon. Thus, as expected, preformed iminium salts generated from carbonyls and secondary amines are also readily reduced by most hydride reagents. Several examples of synthetic applications with a variety of reagents are illustrated in Table 4. Entries 9-12 illustrate the use of iminium intermediates for the reductive removal of amide carbonyls. Thus, treatment of amides with POCI3 affords the iminium derivatives (e.g. 9 Scheme 3), which are reduced by NaBHt to the corresponding amines (Table 4, entries 9, 10). Likewise, reaction of amides witii trialkyloxonium salts to give imidic esters (entry 12) or thioamides with methyl iodide to give... 

Reduction ofC N to CHNH by Metal Hydrides 1.2.2.4 Reduction of Enamines via Iminium Ion Intermediates... 

Formic acid is an exception among organic acids in having reducing capacity because of its combined acid/aldehyde character and the possibility for exothermic release of carbon dioxide on hydride donation. Ammonium formate, NH4CO2H, has long been used for reductive alkylation of amines. This is the Leuc-kart reaction, which has been reviewed. In this process aldehydes or ketones are used to alkylate ammonia and form a primary amine (11), as depicted in equation (11). The reductive step is the reaction of formate with an iminium ion or its equivalent (equation 12). ... 

Although also a special case of a MPV reduction (Section 1.3.3.3) some unusual reactions of practical import will be considered here because of the heterocyclic characteristics. Donation in an intramolecular reaction of a hydride from a tertiary aniline derivative to generate an iminium ion initiates the reaction. An example is given in Scheme 7. Tertiary aniline derivative (99) rearranges thermally apparently via intermediate (100) to pyrrolo[ 1,2-a]quinoline (101). ° The highly electron-deficient double bond is clearly the hydride acceptor in this case exclusively the most substituted iminium salt is formed. Subsequent ring closure provides the end product (101). Formation of the more substituted iminium ion is not always the case. ° ° ... 

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