Enantioselective one-carbon expansion of aromatic rings by simultaneous formation and chromoselective irradiation of a transient coloured enolate

Enantioenriched seven-membered carbocycles are motifs in many molecules of structural and biological interest. We report a simple, practical, transition metal-free and mechanistically unusual method for the enantioselective synthesis of substituted cycloheptatrienes. By forming a coloured enolate with an appropriate absorption band and selectively irradiating in situ, we to initiate a tandem, asymmetric anionic and photochemical ring expansion of readily accessible N-benzylbenzamides. The cascade of reactions leading to the products entails enantioselective benzylic deprotonation with a chiral lithium amide, dearomatizing cyclization of the resulting configurationally defined organolithium to give an extended amide enolate, and photochemically induced formal [1,7]-sigmatropic rearrangement and 6π-electrocyclic ring-opening – the latter all evidently being stereospecific – to deliver enantioenriched cycloheptatrienes with embedded benzylic stereocentres

Base-Mediated Deuteration of Organic Molecules: A Mechanistic Insight

A base-promoted, step-economical, and cost-effective strategy for introducing heavy isotopes into the organic molecules has been developed. The schemes involve the selective deuteration of various electronically distinct molecules that are formed because of deuterioamination, deuteriothiolation, deuteriophenoxylation, and deuterioalkoxylation as well as tandem cyclization using dimethyl sulfoxide (DMSO)-d6 as a deuterium source. The reaction involves a metal-, ligand-, and additive-free route and provides a high level of deuterium incorporation in the presence of DMSO-d6 as an inflammable and ecological reagent. The reaction is well tolerated across the electronically varied substrates for the successful incorporation of deuterium into the product. The proposed mechanistic pathway for various transformations has been well supported by NMR studies

C(sp³)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (S_NAr)

[Image: see text] The asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums. While investigating the lithiation chemistry of ureas (a “Cinderella” sister of the more established amides and carbamates), we noted an unexpected Truce–Smiles (T-S) rearrangement involving the 1,4-N → C transposition of a urea N′-aryl group to the α-carbanion of an adjacent N-benzyl group. Despite this reaction formally constituting an S(N)Ar substitution, we found it to be remarkably tolerant of the electronic properties of the migrating aryl substituent and the degree of substitution at the carbanion. Moreover, in contrast to classical S(N)Ar reactions, the rearrangement was sufficiently rapid that it took place under conditions compatible with configurational stability in an organolithium intermediate, enabling enantiospecific arylation at benzylic stereogenic centers. Experimental and computational studies confirmed a low kinetic barrier to the aryl migration arising from the strong preference for a trans arrangement of the urea N′-aryl and carbonyl groups, populating a reactive conformer in which spatial proximity was enforced between the carbanion and N′-aryl group, hugely accelerating ipso-substitution. This discovery led us to uncover a whole series of conformationally accelerated intramolecular N → C aryl transfers using different anilide-based functional groups, including a diverse range of urea, carbamate, and thiocarbamate-substituted anions. Products included enantioenriched α-tertiary amines (including α-arylated N-heterocycles) and alcohols, as well as rare α-tertiary thiols. Synthetically challenging diarylated centers with differentiated aryl groups featured heavily in all product sets. The absolute enantiospecificity (retention versus inversion) of the reaction was dependent on the heteroatom α to the lithiation site: the origin of this stereodivergence was probed both experimentally and computationally. Asymmetric variants of the rearrangement were realized by enantioselective deprotonation, and connective strategies were developed in which an intermolecular C–C bond-forming event preceded the anionic rearrangement. Substrates where the N′-nucleofuge (at the aryl ipso position) was tethered to the migrating arene allowed us to use the rearrangement as a ring expansion method to generate 8- to 12-membered medium-ring N-heterocycles from very simple precursors. Stabilized carbon nucleophiles such as alkali metal enolates also readily promoted intramolecular N → C aryl transfer in N′-arylureas, opening up access to biologically relevant hydantoins, and enabling a “chiral memory” approach for the (hetero)arylation of chiral α-amino acids with programmable retention or inversion of configuration. Collectively, our studies of electronically versatile T-S rearrangements in anilide-based systems have culminated in a practical and general strategy for transition metal-free C(sp(3))-arylation. More broadly, our results highlight the power of conformational activation to achieve unprecedented reactivity in the construction of challenging C–C bonds

Metal- and Protection-Free [4 + 2] Cycloadditions of Alkynes with Azadienes: Assembly of Functionalized Quinolines

A base promoted, protection-free, and regioselective synthesis of highly functionalized quinolines via [4 + 2] cycloaddition of azadienes (generated in situ from <i>o</i>-aminobenzyl alcohol) with internal alkynes has been discovered. The reaction tolerates a wide variety of functional groups which has been successfully extended with diynes, (2-aminopyridin-3-yl)­methanol, and 1,4-bis­(phenylethynyl)­benzene to afford (<i>Z</i>)-phenyl-2-styrylquinolines, phenylnaphthyridine, and alkyne-substituted quinolines, respectively. The proposed mechanism and significant role of the solvent were well supported by isolating the azadiene intermediate and deuterium-labeling studies

Regioselective Synthesis of C‑3-Functionalized Quinolines via Hetero-Diels–Alder Cycloaddition of Azadienes with Terminal Alkynes

A highly efficient metal and protection-free approach for the regioselective synthesis of C-3-functionalized quinolines from azadienes (in situ generated from 2-aminobenzyl alcohol) and terminal alkynes through [4 + 2] cycloaddition has been developed. An unprecedented reaction of 2-aminobenzyl alcohol with 1,3- and 1,4-diethynylbenzene provided the C-3 tolylquinolines via [4 + 2] HDA and oxidative decarboxylation. The −NH₂ group directed mechanistic approach was well supported by the control experiments and deuterium-labeling studies and by isolating the azadiene intermediate. The reactivity and selectivity of unprotected azadiene in metal-free base-assisted hetero-Diels-Alder reaction is exploited to quickly assemble an important class of C-3-functionalized quinolines, which are difficult to access