Recent Strategies in the Nucleophilic Dearomatization of Pyridines, Quinolines, and Isoquinolines.

Dearomatization reactions have become fundamental chemical transformations in organic synthesis since they allow for the generation of three-dimensional complexity from two-dimensional precursors, bridging arene feedstocks with alicyclic structures. When those processes are applied to pyridines, quinolines, and isoquinolines, partially or fully saturated nitrogen heterocycles are formed, which are among the most significant structural components of pharmaceuticals and natural products. The inherent challenge of those transformations lies in the low reactivity of heteroaromatic substrates, which makes the dearomatization process thermodynamically unfavorable. Usually, connecting the dearomatization event to the irreversible formation of a strong C-C, C-H, or C-heteroatom bond compensates the energy required to disrupt the aromaticity. This aromaticity breakup normally results in a 1,2- or 1,4-functionalization of the heterocycle. Moreover, the combination of these dearomatization processes with subsequent transformations in tandem or stepwise protocols allows for multiple heterocycle functionalizations, giving access to complex molecular skeletons. The aim of this review, which covers the period from 2016 to 2022, is to update the state of the art of nucleophilic dearomatizations of pyridines, quinolines, and isoquinolines, showing the extraordinary ability of the dearomative methodology in organic synthesis and indicating their limitations and future trends.

Two Decades of Progress in the Asymmetric Intramolecular aza-Michael Reaction.

The asymmetric intramolecular aza-Michael reaction (IMAMR) is a very convenient strategy for the generation of heterocycles bearing nitrogen-substituted stereocenters. Due to the ubiquitous presence of these skeletons in natural products, the IMAMR has found widespread applications in the total synthesis of alkaloids and biologically relevant compounds. The development of asymmetric versions of the IMAMR are quite recent, most of them reported in this century. The fundamental advances in this field involve the use of organocatalysts. Chiral imidazolidinones, diaryl prolinol derivatives, Cinchone-derived primary amines and quaternary ammonium salts, and BINOL-derived phosphoric acids account for the success of those methodologies. Moreover, the use of N-sulfinyl imines with a dual role, as nitrogen nucleophiles and as chiral auxiliaries, appeared as a versatile mode of performing the asymmetric IMAMR.

Nickel-Mediated Synthesis of Non-Anomeric C-Acyl Glycosides through Electron Donor-Acceptor Complex Photoactivation.

The preparation of nonanomeric C-acyl-saccharides has been developed from two different carboxylic acid feedstocks. This transformation is driven by the synergistic interaction of an electron donor-acceptor complex and Ni catalysis. Primary-, secondary-, and tertiary redox-active esters are incorporated as coupling partners onto preactivated pyranosyl- and furanosyl acids, preserving their stereochemical integrity. The reaction occurs under mild conditions, without stoichiometric metal reductants or exogenous catalysts, using commercially available Hantzsch ester as the organic photoreductant.

Double asymmetric intramolecular aza-Michael reaction: a convenient strategy for the synthesis of quinolizidine alkaloids.

A new methodology to access the quinolizidine skeleton in an asymmetric fashion was devised. It involves two consecutive intramolecular aza-Michael reactions of sulfinyl amines bearing a bis-enone moiety, in turn generated by a monodirectional cross metathesis reaction. The sequence, which takes place with excellent yields and diastereocontrol, was applied to the total synthesis of alkaloids lasubine I and myrtine.

Synthesis of substituted piperidines by enantioselective desymmetrizing intramolecular aza-Michael reactions.

An organocatalytic enantioselective intramolecular aza-Michael reaction has been described for the first time in a desymmetrization process employing substrates different from cyclohexadienones. By using 9-amino-9-deoxy-epi-hydroquinine as the catalyst and trifluoroacetic acid as a co-catalyst, a series of enantiomerically enriched 2,5-and 2,6-disubstituted piperidines have been obtained in good yields and with moderate diastereoselectivity. Depending on the catalyst/co-catalyst loading ratio, either the major or the minor diastereoisomer of the final piperidine products was achieved with high levels of enantioselectivity. Finally, some mechanistic insights have been considered by means of theoretical calculations which were in agreement with the experimental results obtained in the desymmetrization reaction.

Intramolecular Nitrone Cycloaddition of α-(Trifluoromethyl)styrenes. Role of the CF3 Group in the Regioselectivity.

The intramolecular 1,3-dipolar cycloaddition of ortho-substituted 1,1,1-trifluoromethylstyrene-derived nitrones is described. Tricyclic fused isoxazolidines were obtained as major or exclusive products, in contrast to the case for nonfluorinated substrates, which rendered the bridged derivatives. This change in the regioselectivity was attributed to the electronic and, particularly, steric requirements of the trifluoromethyl group in comparison to the methyl group. It is worth mentioning that trifluoromethylstyrenes have been employed for the first time as dipolarophiles in a 1,3-dipolar intramolecular cycloaddition reaction, leading to the corresponding isoxazolidines bearing a quaternary trifluoromethyl moiety. Finally, the synthetic utility of the developed methodology has been illustrated with the synthesis of a family of bicyclic fluorinated 1,3-amino alcohols.

Enantioselective Synthesis of Fluorinated Indolizidinone Derivatives.

The enantioselective synthesis of fluorinated indolizidinone derivatives has been developed. The process involved an enantioselective intramolecular aza-Michael reaction of conjugated amides bearing a pendant α,ß-unsaturated ketone moiety, catalyzed by the (S)-TRIP-derived phosphoric acid, followed by dimethyltitanocene methylenation and ring closing metathesis (RCM). Final indolizidine-derived products comprise a fluorine-containing tetrasubstituted double bond generated by the RCM reaction, which is a challenging task. The whole synthetic sequence took place in acceptable overall yields with excellent enantioselectivities.

Thianthrenium-Enabled Sulfonylation via Electron Donor-Acceptor Complex Photoactivation.

Sulfone-containing compounds are prevalent building blocks in pharmaceuticals and other biomolecules, and they serve as key intermediates in the synthesis of complex scaffolds. During the past decade, several methods have been developed to access sulfones. These strategies, however, require the use of strong reaction conditions, limiting their substrate scope. Recently, visible light-mediated transformations have emerged as novel platforms to access unprecedented structural motifs. This report demonstrates a thianthrenium-enabled sulfonylation via intra-complex charge transfer to generate transient aryl- and persistent sulfonyl radicals that undergo selective coupling to generate alkyl- and (hetero)aryl sulfones under ambient conditions. Importantly, this strategy allows retention of halide handles, presenting a complementary approach to transition metal-mediated photoredox couplings. Furthermore, this sulfonylation allows high functional group tolerance and is amenable to late-stage functionalization of complex biomolecules. Mechanistic investigations support the intermediacy of electron donor-acceptor (EDA) complexes.

Synthesis of 3,4-Dihydropyrimidin(thio)one Containing Scaffold: Biginelli-like Reactions.

The interest in 3,4-dihydropyrimidine-2(1H)-(thio)ones is increasing every day, mainly due to their paramount biological relevance. The Biginelli reaction is the classical approach to reaching these scaffolds, although the product diversity suffers from some limitations. In order to overcome these restrictions, two main approaches have been devised. The first one involves the modification of the conventional components of the Biginelli reaction and the second one refers to the postmodification of the Biginelli products. Both strategies have been extensively revised in this manuscript. Regarding the first one, initially, the modification of one of the components was covered. Although examples of modifications of the three of them were described, by far the modification of the keto ester counterpart was the most popular approach, and a wide variety of different enolizable carbonylic compounds were used; moreover, changes in two or the three components were also described, broadening the substitution of the final dihydropyrimidines. Together with these modifications, the use of Biginelli adducts as a starting point for further modification was also a very useful strategy to decorate the final heterocyclic structure.

Enantioselective Synthesis of Pyrrolizidinone Scaffolds through Multiple-Relay Catalysis.

A triple-tandem protocol for the synthesis of the pyrrolizidinone skeleton has been devised. It involves a cross metathesis-intramolecular aza-Michael reaction-intramolecular Michael addition tandem sequence, starting from N-pentenyl-4-oxo-2-alkenamides and conjugated ketones. In the presence of two cooperative catalysts, namely the second-generation Hoveyda-Grubbs catalyst and (R)-TRIP-derived BINOL phosphoric acid, this multiple-relay catalytic process takes place in good yields and outstanding levels of diastero- and enantioselectivity with the simultaneous generation of three contiguous stereocenters.

Organocatalytic enantioselective synthesis of 2,5,5-trisubstituted piperidines bearing a quaternary stereocenter. Vinyl sulfonamide as a new amine protecting group.

An organocatalytic desymmetrizing intramolecular aza-Michael reaction with vinyl sulfonamides as nucleophilic nitrogen source has been devised for the synthesis of a new family of 2,5,5-trisubstituted piperidines bearing a quaternary sterocenter. The process takes place with excellent levels of enantioselectivity and moderate to good diastereoselectivity. The vinyl sulfonamide moiety can be removed by means of an ozonolysis reaction.