No abstract

A new sequential two-step multicatalytic strategy is presented consisting in the efficient DBU-catalysed trichloroacetimidation of an alcohol followed by a ditriflylamine (Tf 2 NH)-catalysed intermolecular alkylation by silicon-based nucleophiles and C À H nucleophiles. The distinct feature of the trichloroacetimidate group allows use of weaker acid catalysts such as 1,1'-bi-2-naphthol (BINOL)-derived phosphoric acid, pointing out the possible development of an enantioselective variant. This unprecedented sequential one-pot Brønst-ed base-Brønsted acid catalysis further expands the synthetic scope of the trichloroacetimidate group.Keywords: N-acyliminium; alkylation; electrophilic alcohols; sequential organocatalysis; trichloroacet-A C H T U N G T R E N N U N G imidates Due to some specific attributes including good availability and minimum side-products, p-alcohols are ideal electrophilic reagents in modern acid-catalysed alkylative chemistry. Therefore, considerable advances in their Lewis and Brønsted acid-catalysed direct alkylation with carbon nucleophiles have been recently achieved.[1] Because of the poor leaving group ability of the hydroxy group, sometimes even under acidcatalysed conditions, high temperatures and/or long reaction times are frequently required to achieve these reactions with good efficiency. This makes particularly challenging the alkylation of sensitive nucleophiles such as enoxysilanes and ketene silyl acetals, which do not survive under these drastic reaction conditions. Given the greater catalytic activities generally observed in the acid-catalysed alkylation of the more electrophilic acetate derivatives, the latter constitute the common alternative to circumvent the problematic catalytic alkylation of silicon-based nucleophiles. However, the two acylative and alkylative processes are always performed sequentially.[2] Instead, the development of an efficient and reliable tandem reaction sequence combining the installation of a leaving group and its subsequent displacement in a one-pot operation would obviously provide a useful and straightforward novel solution in catalytic alkylative chemistry.Hydroxy lactams derived from phthalimide and benzhydrol are typical examples of such weakly reactive alcohols in acid-catalysed alkylation with siliconbased nucleophiles.[3] We report herein the efficient alkylation of these model substrates by means of a one-pot homogeneous Brønsted base/Brønsted acid (BB/BA) organocatalytic sequence. According to our strategy, the OH group needs to be in situ activated as a transient good leaving group under conditions compatible with the subsequent one-pot catalytic alkylation step (Scheme 1).[4] Scheme 1. Objective: sequential one-pot Brønsted base-catalysed hydroxy group activation/Brønsted acid-catalysed nucleophilic displacement.

Studies indicate that MAO-B is induced in peripheral inflammatory diseases. To target peripheral tissues using MAO-B inhibitors that do not permeate the blood-brain barrier (BBB) the MAO-B-selective inhibitor deprenyl was remodeled by replacing the terminal acetylene with a COH function, and incorporating a para-OCHAr motif (compounds 10a-s). Further, in compound 32 the C-2 side chain corresponded to CHCN. In vitro, 10c, 10j, 10k, and 32 were identified as potent reversible MAO-B inhibitors, and all four compounds were more stable than deprenyl in plasma, liver microsomal, and hepatocyte stability assays. In vivo, they demonstrated greater plasma bioavailability. Assessment of in vitro BBB permeability showed that compound 10k is a P-glycoprotein (P-gp) substrate and 10j displayed mild interaction. Importantly, compounds 10c, 10j, 10k, and 32 displayed significantly reduced BBB permeability after intravenous, subcutaneous, and oral administration. These polar MAO-B inhibitors are pertinent leads for evaluation of efficacy in noncentral nervous system (CNS) inflammatory disease models.

Intramolecular and intermolecular alkylations of carbocation precursors of limited ionization ability, principally N,O-acetals, without the use of an exogenous reagent have been developed. The reactions are carried out in 1,1,2,2-tetrachloroethane (TCE) and take advantage of the ability of this solvent to continuously release small amounts of HCl by thermolytic elimination. A study of the reaction led to several improved protocols such as (1) preheated TCE, (2) microwave-assisted reactions, and (3) flow or sealed-tube conditions, which allow significant reaction rate enhancements and made possible some challenging reactions such as the α-amidoalkylation of ketones. Studies using flow chemistry confirmed not only that very low concentrations of HCl generated from the solvent were responsible for the reactivity but also that TCE had additional beneficial properties in comparison to other chlorinated solvents such as dichloroethane. The method can easily be extended to the alkylation using proelectrophiles such as π-activated alcohols, which are normally unreactive toward HCl catalysis. This work represents the first successful use of HCl, the simplest strong Brønsted acid, as an efficient alkylation catalyst.