Alkylation side chain base catalyzed

Based on the high efficiency of the (dialkylamino)alkyl side chain on the fer-rocenylphosphines, a series of /3-(diaIkylamino)alkylphosphines 10 was prepared and used for Ni-catalyzed cross-coupling. Those substituted with a sterically bulky alkyl group at the chiral carbon center are more effective than the ferrocenylphosphine ligands. Valphos (10c) and Meuphos (lOd), which were prepared starting with valine and tert-leucine, respectively, gave the product 3 with over 81% Use of polymer-... 

The synthesis in Scheme 13.21 starts with a lactone that is available in enantiomer-ically pure form. It was first subjected to an enolate alkylation that was stereocontrolled by the convex shape of the cis ring junction (Step A). A stereospecific Pd-mediated allylic substitution followed by LiAlH4 reduction generated the first key intermediate (Step B). This compound was oxidized with NaI04, converted to the methyl ester, and subjected to a base-catalyzed conjugation. After oxidation of the primary alcohol to an aldehyde, a Wittig-Horner olefination completed the side chain. 

Two anionic mechanisms may be proposed for base-catalyzed nuclear alkylation. One, which is analogous to side-chain alkylation, is Reaction (30a, b). 

Acylation of the theophylline diamine intermediate (26-6) with phenylacetyl chloride affords the corresponding amide (28-2). Base catalyzed cyclization then leads to the purine (28-3) that now includes a quite lipophilic benzyl group on the fused imidazole ring. The molecule is then provided with a side chain that incorporates basic nitrogen, arguably to improve water solubility. The anion from (28-3) is thus first alkylated with bromochloroethane to afford the chloroethyl product (28-4). The displacement of chlorine with ethanolamine affords the bronchodilator bamifylline (28-5) [28]. 

Base-catalyzed carbanionic alkylation, isomerization, polymerization reactions are of major significance. Base-catalyzed alkylation of alkylarenes, in contrast to acid-catalyzed ring alkylation, leads to alkylation of the side chain in the benzylic position [Eq. (1.28) see also Chapter 5] of particular interest is the alkylation of toluene to ethylbenzene (for styrene production). 

In contrast to acid-catalyzed alkylation of arenes, where alkylation of the aromatic nucleus occurs, the base-catalyzed reaction of alkylarenes leads to alkylation of the side chain.231-234 Alkenes (straight-chain 1-alkenes, isobutylene), conjugated... 

A facile route to isothiochromans involves the base-catalyzed reaction of a benzyl dibromide with an a-thiocarbonyl compound. The method has been extended to the synthesis of an anthraceno[2,3-f]thiopyran, a heterocyclic analogue of an anthracyclinone (Equation 169) <1994S363>. In like manner, alkylation of the 2-aryl-1-bromoethane 491 by thiourea and subsequent liberation of the thiol function creates an isothiochroman precursor. An intramolecular Michael addition to the cr, )-unsaturated ester side chain yields the 1-substituted heterocycle (Scheme 179) <1992JOC1727>. 

A material such as Na°/NaY catalyzes the aldol condensation of acetone, to form mesityl oxide and eventually isophorone. Another strong base catalyzed reaction is the side chain alkylation of toluene with ethylene. In contrast with acid catalysis, side chain reaction is strongly preferred over ring alkylation. With a Na°/NaX in the gas phase at 473 K, toluene reacts to give n-propylbenzene (66%) and the dialkylated product, 3-phenylpentane (32%) (41). 

Alkyl nitroarenes may on reduction lose a proton from the side chain either during the acid-catalyzed rearrangement of the arylhydroxylamine or from the parent compound, from which an electrogenerated base (EGB) may abstract one of the relatively acidic protons a. to the nitroaryl. 

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