Reductive alkylation, indirect

The direct conversion of 3-methylcyclohex-2-enone into 2-allyl-3-methylcyclohexanone provides an interesting example of the utility of the reduction-alkylation procedure. Synthesis of this compound from 3-methy I cyclohexanone would be difficult because the latter is converted mainly into 2-alkyl-5-methylcyelohexanones either by direct base-catalyzed alkylation11 or by indirect methods such as alkylation of its enamine (see Note 13) or alkylation of the magnesium salt derived from its cyclohexylimine.12... 

Quinoxaline gave l,4-diethyl-l,2,3,4-tetrahydroquinoxaline by indirect reductive alkylation (AcOH, KBHai, <15°C, 1 h, then reflux, 6h 87% presumably by nuclear reduction, A-acylation, and further reduction of the acetyl groups ). ... 

Before discussing the relevant literature, a few qualifiers are mentioned and discussed. Reductive amination is sometimes incorrectly associated with the reduc tion of preformed imines and derivatives thereof. Reductive amination, by definition, is only the one pot conversion of a ketone to an amine in which a reductant coexists in the presence of a ketone starting material [4]. The term indirect reductive amination is occasionally used, but can be more tersely and accurately described as imine reduction [5]. The reader wUl note that depending on the perspective one takes for the transformation, the term reductive amination is applied when considering the reaction course of the ketone starting material, and the term reductive alkylation is applied when describing the starting amine s conversion to the product amine. 

A number of alternative multi-step procedures for the synthesis of a-tert-alkyl ketones are known, none of which possess wide generality. A previous synthesis of 2-tert-penty1cyclopentanone involved reaction of N-1-cyclopentenylpyrrol 1 dine with 3-chloro-3-methy1-l-butyne and reduction of the resulting acetylene (overall yield 46 ). However, all other enamines tested afford much lower yields. Cuprate addition to unsaturated ketones may be useful in certain cases. Other indirect methods have been briefly reviewed. ... 

The alkyl group R of certain carboxylic esters can be reduced to RH by treatment with lithium in ethylamine. The reaction is successful when R is a tertiary or a sterically hindered secondary alkyl group. A free-radical mechanism is likely. Similar reduction, also by a free-radical mechanism, has been reported with sodium in HMPA-r-BuOH. In the latter case, tertiary R groups give high yields of RH, but primary and secondary R are converted to a mixture of RH and ROH. Both of these methods provide an indirect method of accomplishing 10-81 for tertiary R. 

Structures such as (26) were demonstrated [103] to he fairly easily reduced at a Pt electrode. Thus, when R = Ph, an anion radical (E° = —1.26 V vs Ag/Agl/I 0.1 M) of high stahihty is formed. However, macroelectrolyses of the compounds (26) could not he achieved at all since whatever the amount of electricity passed through the cell, the starting material was totally recovered. The compounds (26) are expected to react slowly with the tetraalky-lammonium salt R4N+ and the reaction would correspond to an indirect reduction of the electrolyte. Compounds (26), with R = primary alkyl groups, led - even in DMF-to strong self-inhibition explained by the adsorption of produced... 

The allylic sulfonyl group is regioselectively cleaved in the presence of the alkyl-sulfonyl group by indirect reduction with anthracene as a mediator (Fig. 24) [125]. 

In the case of the benzothiazole system, both aldehydes and mixed ketones have been synthesized by reduction or alkylation of the appropriate carbonyl precursors. The carbonyl compounds are in turn prepared from the benzothiazole-2-anion either directly by reaction with esters or indirectly by reaction with aldehydes followed by PCC oxidation (Scheme 154) (85H2467 91BCJ3256). 

The field of reductive preparations for the formation of nitroso compounds has not yet been adequately explored. For example, only indirect evidence exists that the electrolytic reduction of f-nitroalkanes to tertiary alkyl-hydroxylamines proceeds by way of nitroso compounds. 

It is natural to presuppose that the reduction of nitro compounds should lead to the nitroso compounds, at least as an intermediate stage. Until quite recently, no reductive processes for the formation of nitrosoalkanes were known [3], More recently, some indirect evidence is said to show that, on electrolytic reduction of tertiary aliphatic nitro compounds, the final t-alkyl-hydroxylamines are produced by the intermediate formation of nitroso compounds which were not isolated [99]. 

An indirect 3-alkylation of pyridine [15] is based on accentuation of the donor character of C-3 by reductive dearomatization. 

Several research groups ha ve been involved in the study of ET reactions from an electrochemically generated aromatic radical anion to alkyl halides in order to describe the dichotomy between ET and polar substitution (SN2). The mechanism for indirect reduction of alkyl halides by aromatic mediators has been described in several papers. For all aliphatic alkyl halides and most benzylic halides the cleavage of the carbon-halogen bond takes place concertedly with the... 

The indirect electrochemical reduction of alkyl halides is also possible by use of nickel(I) complexes which may be obtained by cathodic reduction of square planar Ni(n)-complexes of macrocyclic tetradentate ligands (Table 7, No. 10, 11) 2 4-248) Comparable to the Co(I)- and Ni(O)-complexes, the Ni(I)-species reacts with the alkyl halide unter oxidative addition to form an organo nickel(III) compound. The stability of the new nickel-carbon bond dominates the overall behavior of the system. If the stability is low, the alkyl group is lost in form of the radical and the original Ni(II)-complex is regenerated. A large number of regenerative cycles is the result. 

The reduction of hydrazones can also be used as an indirect method of reducing, carbonyl compounds to the corresponding alkyl compounds. In addition, hydrazides have been used in the reductive synthesis of aldehydes. 

Other methods for obtaining complexes of ethylene and other alkenes include ligand substitution reactions, reduction of a higher valent metal in the presence of an alkene, and synthesis from alkyl and related species [reductive elimination, of an allyl or hydride, for example hydride abstraction from alkyls protonation of sigma-allyls from epoxides (indirectly)] [74a],... 

The mechanism of reductive elimination of a hydrido alkyl complex is therefore often approached in an indirect manner. The hydrido-alkyl complex is made not by oxidative addition of the alkane but by some other route. The decomposition of the hydrido-alkyl complex to give alkane is then studied for mechanistic information. Reductive eliminations of an aldehyde from an acyl-hydrido complex, Reaction 2.7, and acetyl iodide from an iodo-acyl complex,... 

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