Aqueous and Solvent‐Free Uncatalyzed Three‐Component Vinylogous Mukaiyama–Mannich Reactions of Pyrrole‐Based Silyl Dienolates

Abstract

A catalyst-free, environmentally benign three-component vinylogous Mukaiyama-Mannich reaction of pyrrole-based silyl dienolates is presented, which works effectively in both aqueous and solvent-free environments. Both lipophilic and hydrophilic aldehyde candidates are suitable substrates, allowing access to a rich repertoire of unsaturated vicinal aminolactam structures with virtually complete g-site selectivity and moderate to good anti-diastereoselectivity. The utility of this technology is highlighted by protecting group-free synthesis of densely hydroxylated, sugar-related lactam frameworks. The role of water as an indispensable H-bonding reaction propeller is demonstrated.Keywords: catalyst-free conditions; green chemistry; Mukaiyama-Mannich reaction; synthetic methods; vinylogy; water The development of enabling chemical methodologies that fulfil such emblematic keywords as water, solvent-free, environment awareness, atom economy, and practicality is one of the greatest challenges of contemporary organic synthesis.[1] To this goal, several aqueous and solvent-free versions of leading carboncarbon bond-forming reactions have been successfully explored, [2] including the venerable Diels-Alder cycloaddition, [3] the aldol addition reaction, [4] the Mannich [5] and Michael couplings, [6] the Claisen rearrangement, [3b,7] to mention only a few.As for the Mannich reaction in particular, significant progress has been made for direct and indirect, two-component and three-component executions, few of which adopting neutral water as the reaction medium or even under solvent-free conditions. [5] However, to the best of our knowledge, there are not examples available concerning the development of catalyst-free, aqueous or neat Mukaiyama-type vinylogous Mannich addition methodology, [8,9] in spite of the distinct advantage of being atom conservative and more eco-friendly as compared to the conventional organic-phase, catalyzed counterparts. To address this issue, in connection with our ongoing studies focused on the exploitation of heterocyclic silyl dienolates in the vinylogous addition to C=X bonds, [8d,10] we herein present the first uncatalyzed aqueous and solvent-free three-component vinylogous Mukaiyama-Mannich reaction (VMMnR) employing a pyrrole ketene silyl-N,O-acetal, an aromatic amine, and diverse classes of aldehydes. Two complementary protocols are established, with which both hydrophobic aldehydes (aqueous and solvent-free conditions) and hydrophilic aldehydes (aqueous conditions) operate, furnishing g-substituted d-aminopyrrolinone units in high isolated yields, with excellent levels of g-site selectivity and chemoselectivity, and moderate to high diastereoselectivity in favour of anti-configured adducts.We initiated our journey by evaluating the one-pot three-component VMMnR between N-Boc-protected trimethylsilyloxypyrrole (1a), 3-methylbutanal (2a), and aniline (3a) in pure neutral water under vigorous stirring at room temperature (Table 1, entry 1). Very poor amounts of the Mannich product ...

New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems

“…Along this line, Zanardi et al presented the first catalyst-free three-component vinylogous Mukaiyama–Mannich reaction (VMMnR) employing pyrrole silyl dienolates of type 842a , o -anisidine 869 , and diverse aldehydes 823 , which performed well in both aqueous and solvent-free environments ( Scheme 220 ). 576 Both lipophilic and hydrophilic, aromatic and aliphatic aldehydes proved to be competent substrates giving access to a wide collection of racemic α,β-unsaturated δ-aminolactams 870 in high isolated yields, with excellent levels of γ-site selectivity and chemoselectivity, and moderate to high diastereoselectivity in favor of anti -configured adducts. Of note, aqueous and solvent-free protocols were particularly suited for protected alkoxy aldehydes and highly hydrophilic substrates, leading to the corresponding adducts with promising yields and favorable anti -diastereoselectivity.…”

Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate

“…Focusing better on the initial VMMnR operation, it was previously reported that mixing pyrrole-derived silyloxy diene 7, 14 D-mannitol-derived glyceraldehyde 8 and commercial o-anisidine 9 under neat or on-water conditions at 30 °C under ultrasonic irradiation produced the expected vinylogous Mannich product in a high global yield (neat, 96% yield; onwater, 95% yield) as a mixture of three separable diastereoisomers, namely (3S,4S,5S)-configured 10a (target numbering, 42%), (3S,4R,5R)-isomer 10b (34-39%), and (3S,4R,5S)-isomer 10c (15-20%) (Scheme 2). 15 Parallel application of the designed general plan to each individual isomer 10a, 10b, 10c, plus 10d, derived from 10a by base-promoted C5-epimerization, would in principle deliver 4-epi-oseltamivir, 5-epi-oseltamivir, oseltamivir itself, and 4,5di-epi-oseltamivir, respectively. By including stereoisomers obtained from L-glyceraldehyde precursor ent-8, the execution of the whole plan would ultimately lead to all eight possible stereoisomers of the oseltamivir core.…”

Acetaldehyde Silyl Enol Ethers in Enantioselective Mukaiyama Aldol Reactions: Enzyme‐Like Organocatalysis in Action

“…[5] Over the years, there have been additional advances,i ncluding the development of cascade reactions, [6] vinylogous variants, [7] and onwater protocols. [8] Despite these advances,o ne fundamental piece of the puzzle was still missing:the efficient and truly general use of the smallest enolizable aldehyde,a cetaldehyde.T he use of this substrate was frustrated by seemingly unsolvable issues, in particular,t he inability of the small acetaldehyde SEE to discriminate between the starting aldehyde acceptor and the product aldehyde,t hus leading to extensive polymerization. Thef irst encouraging results from attempts to address this issue were obtained by Yamamoto and co-workers in 2006, [9] who were first to recognize that an extremely bulky tris-(trimethylsilyl) SEE ("super-silyl") of acetaldehyde could be employed to develop asuccessful catalytic (although racemic) MAR.…”