One‐Pot Hydroxy Group Activation/Carbon‐Carbon Bond Forming Sequence Using a Brønsted Base/Brønsted Acid System

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.

Enolizable Carbonyls and N,O‐Acetals: A Rational Approach for Room‐Temperature Lewis Superacid‐Catalyzed Direct α‐Amidoalkylation of Ketones and Aldehydes

“…The two reactivity scales that were established empirically, as well as meticulous observations made on the outcome of the reaction of these preliminary experiments, were then utilized to demonstrate the potential of this approach by addressing particularly challenging catalytic amidoalkylations. As an illustration of our rational approach, we considered the direct alkylation of parent hemiaminals 1 , which, as stated above, are intrinsically much less reactive than their acetoxy counterparts 2 under acid catalysis at room temperature ,. Indeed, in our feasibility experiments we often observed incomplete conversions caused by the competitive formation of 1 in the course of the reaction, even with ketones of promising reactivity such as 3 a and 3 e – j (giving products 4 aa and 4 ae – aj in Scheme ).…”

“…Our interest in developing a direct amidoalkylation reaction mainly comes from our previous discovery that triflimidate‐based catalysts display high catalytic activity in the alkylation of silyl enol ethers –. Following these preliminary results, we were logically eager to expand the chemistry to the most challenging use of ketones and aldehydes and were pleased to report the first examples of direct α‐amidoalkylation of a small range of ketones using 1 mol % Sn(NTf 2 ) 4 .…”

Rearrangement of Benzylic Trichloroacetimidates to Benzylic Trichloroacetamides

“…Like other primary trichloroacetimidates, this substrate was found to be less reactive and had to be treated with 10% BF 3 •OEt 2 at reflux for 48 hours to achieve rearrangement. More highly substituted imidates with a neighboring nitrogen are reported to be unstable, having to be prepared in situ and used immediately, 18 and so these substrates were not pursued further. Rearrangement of ethyl trichloroacetimidate was also evaluated, but only trace amounts of rearrangement were observed.…”

Synthesis of 3,3′-Disubstituted Indolenines Utilizing the Lewis Acid Catalyzed Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates

“…11 Indoles provide an interesting heterocyclic regime to explore, as they may undergo alkylation at different sites depending on their substitution pattern. A number of Friedel-Crafts alkylation reactions between imidates and indoles have been previously reported, 11g,11h,12 but there have been no reports on the use of imidates to form 3,3′-indolenine structures. Indole itself provides C3-alkylation products with a variety of imidates.…”

“…Indole itself provides C3-alkylation products with a variety of imidates. 11g,11h In cases where the indole C3 position is substituted C2-alkylation usually predominates, 12d although in some cases N-alkylation is observed. 12c …”