Reductive alkylation regiochemistry

Two essentially different mechanisms, (i) oxidative cyclization of two 7T-components (formation of metallacycle) and (ii) oxidative addition of reducing or alkylating agents followed by insertion of 7t-components, can operate in these three-component reactions.426 However, the aforementioned phenomena such as the reversal of regiochemistry and the crossover from reductive to alkylative manifolds remain unsolved. 

Terminal monoalkenes were alkylated by stabilized carbanions (p a 10-18) in the presence of 1 equiv. of palladium chloride and 2 equiv. of triethylamine, at low temperatures (Scheme l).1 The resulting unstable hydride eliminate to give the alkene (path b), or treated with carbon monoxide and methanol to produce the ester (path c).2 As was the case with heteroatom nucleophiles, attack at the more substituted alkene position predominated, and internal alkenes underwent alkylation in much lower (=30%) yield. In the absence of triethylamine, the yields were very low (1-2%) and reduction of the metal by the carbanion became the major process. Presumably, the tertiary amine ligand prevented attack of the carbanion at the metal, directing it instead to the coordinated alkene. The regiochemistry (predominant attack at the more sub-... 

Steric and electronic effects on the rate and regiochemistry of the reaction between p-nitrobenzyl substrates and tertiary carbanions were also studied71. Thus, increasing the size of the alkyl groups attached to the benzylic or anionic carbons of the substrates causes substantial decrease in the proportions of C-alkylation product. In contrast with the previous reaction with nitronate anions, formation of reduction products is observed instead of a significant O-alkylation. 

The deactivating effects of alkyl and alkoxy substituents on the regiochemistry of reduction of substituted naphthalenes are exemplified below. ... 

It is well established that 3-alkyl pyridines are selectively reduced at N1-C2, to produce 3-alkyl-l,2-DHPs [58,59,60], 5-Alkyl-l,2-DHPs, which result from hydride addition at C-6, are potentially valuable synthetic intermediates [61]. Substituent effects on the regiochemistry of the reduction of A-carbalkoxypyridinium salts have been studied in detail by Sundberg [62]. These DHPs have served as useful dienes for the synthesis of ISQs. Methyl 2-[l-phenylsulfonyl-lH-indol-2-yl]-2-propenoate (62) served as dienophile in most of these reactions [61,62,63,64,65,66,67,68]. Palladium-catalyzed radical cyclization [63], photocyclization [64] or thermal cyclization [61,65,66,67,68] reactions have all been employed to furnish the Diels-Alder adducts (e.g., 63). 

The enzyme 2-C-methyl-D-erythritol-4-phosphate synthetase appears to catalyse a Bilik reaction (Figure 6.10) the substrate l-deoxyxylulose-5-phosphate is converted to the title compound via an intermediate aldehyde, whose carbonyl derives from C3 of the substrate. The first step is thus a Bilik reaction and the aldehyde is subsequently reduced by the enzyme using NADPH as reductant, The X-ray crystal structure of the Escherichia coli enzyme in complex with the promising antimalarial Fosmidomycin (a hydroxamic acid) reveals a bound Mn " coordinated to oxygens equivalent to the substrate carbonyl and 03. The stereochemistry and regiochemistry follow the normal Bilik course, although the crystallographers favour an alkyl shift rather than a reverse aldol-aldol mechanism. The intermediate aldehyde has been shown to be a catalytically competent intermediate. 

In the forward direction, tetrahydrothiapyrone 146 served as the precursor of both 143 and 144. Metallation of 143 (an allylic sulfide) using -butyllithium, followed by a reaction of the derived carbanion with 144, gave 147 after dehydration of the intermediate tertiary alcohol. Metallation of 147 followed by alkylation of the resulting anion with bromide 145, provided 148. Hydrolysis of the THP ether followed by reduction of the allylic C-S bonds with lithium in diethylamine, gave fe-sulfide 149. This reaction would have been expected to proceed via allyic radical and/or anion intermediates and thus, loss of olefin regiochemistry might have been anticipated, but the reaction seems to have proceeded without a major problem. Esterification of the alcohol (and most likely the thiols) and reduction of the homoallyic C-S bonds with Raney-Ni, gave 150. The synthesis of CJH (1) was completed in the usual manner. 

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