RESUMEN

Over the past few years, there has been a surge of interest in the chemistry of bicyclobutanes (BCBs). Although BCBs have been used to synthesize bicyclo[2.1.1]hexanes and bicyclo[3.1.1]heptanes, the synthesis of bicyclo[4.1.1]octanes has remained elusive. Herein, we report the first Lewis acid-catalyzed unexpected (4+3) annulation of para-quinonemethides (p-QMs) with BCBs allowing the synthesis of oxabicyclo[4.1.1]octanes proceeding under mild conditions. With 5 mol % of Bi(OTf)3, the reaction afforded the (4+3) annulated product in high regioselectivity and good functional group compatibility via a simultaneous Lewis acid activation of BCBs and p-QMs. The reaction is likely initiated by the 1,6-addition of Lewis acid activated BCBs to p-QMs followed by the C2-selective intramolecular addition of the phenol moiety to the generated cyclobutyl cation intermediate. Moreover, detailed mechanistic studies provided insight into the mechanism of the reaction.

RESUMEN

Bicyclo[1.1.0]butanes (BCBs), featuring two fused cyclopropane rings, have found widespread application in organic synthesis. Their versatile reactivity towards radicals, nucleophiles, cations, and carbenes makes them suitable for various reactions, including ring-opening and annulation strategies. Despite this versatility, their potential as enophiles in an ene reaction remains underexplored. Considering this and given the challenges of achieving diastereoselectivity in ring-opening reactions of BCBs, herein, we present a unique method utilizing BCBs as enophiles in a mild and diastereoselective Sc(OTf)3-catalyzed formal ene reaction with thioindolinones/thiolactams, delivering 1,3-disubstituted cyclobutane derivatives in high yields and excellent regio- and diastereoselectivity. Notably, structurally different thiolactam derivatives underwent diastereoselective addition to BCBs, affording the corresponding cyclobutanes. The synthesized thioindole-substituted cyclobutanes could serve as a versatile tool for subsequent functional group manipulations.

RESUMEN

Traditionally, N-aryl phthalimides are synthesized by the condensation of phthalic anhydride and aniline derivatives, usually proceeding under harsh conditions. The alternative mild and organocatalytic strategies for their synthesis are underdeveloped. Herein, we demonstrate the organocatalytic atroposelective synthesis of N-aryl phthalimides via the traditional N-CC=O disconnection under mild conditions. The in-situ acid activation of phthalamic acid and subsequent N-heterocyclic carbene (NHC)-catalyzed atroposelective amidation allowed the synthesis of well-decorated N-aryl phthalimides in excellent yields and enantioselectivities. Mechanistic studies reveal the addition of NHC to the in situ generated isoimides, thus introducing a unique mode of generating acylazoliums. Interestingly, both enantiomers of the product can be accessed from the same phthalic anhydride and aniline using the same NHC pre-catalyst. Moreover, this strategy has been extended to the atroposelective synthesis of N-aryl maleimides.

RESUMEN

The enantioselective synthesis of tricyclic oxoquinolines via NHC-catalyzed cascade reaction of enals with malonates bearing a 2-aminophenyl group is reported. The chiral α,ß-unsaturated acylazoliums underwent a smooth Michael-aldol-lactamization-dehydration quadruple cascade with the amino malonate derivative to afford the desired tricyclic products.

RESUMEN

Lewis acid-catalyzed one-pot 1,3-thioalkenylation of donor-acceptor (D-A) cyclopropanes has been demonstrated employing in situ generated dithiocarbamates (from amines and CS2) as nucleophilic triggers and alkyl propiolates as electrophiles. This method addresses the limitations of previously known carbothiolation approach, eliminating the need for extra filtration prior to the subsequent trapping with electrophiles. The anticipated thioalkenylated products were obtained in good to excellent yields with a moderate to good E/Z ratio. Three new bonds (C-N, C-S, and C-C) are formed during this 1,3-bisfunctionalization reaction. Notably, employing enantiomerically pure D-A cyclopropanes resulted in enantiopure 1,3-thioalkenylated products, underscoring the stereospecific nature of the developed reaction.

RESUMEN

Bicyclo[1.1.0]butanes (BCBs), strained carbocycles comprising two fused cyclopropane rings, have become well-established building blocks in organic synthesis, medicinal chemistry, and chemical biology due to their diverse reactivity profile with radicals, nucleophiles, cations, and carbenes. The constraints of the bicyclic ring system confer high p-character on the interbridgehead C-C bond, leading to this broad reaction profile; however, the use of BCBs in pericyclic processes has to date been largely overlooked in favor of such stepwise, non-concerted additions. Here, we describe the use of BCBs as substrates for ene-like reactions with strained alkenes and alkynes, which give rise to cyclobutenes decorated with highly substituted cyclopropanes and arenes. The former products are obtained from highly stereoselective reactions with cyclopropenes, generated in situ from vinyl diazoacetates under blue light irradiation (440 nm). Cyclobutenes featuring a quaternary aryl-bearing carbon atom are prepared from equivalent reactions with arynes, which proceed in high yields under mild conditions. Mechanistic studies highlight the importance of electronic effects in this chemistry, while computational investigations support a concerted pathway and rationalize the excellent stereoselectivity of reactions with cyclopropenes.

RESUMEN

A general and practical route to the synthesis of functionalized isoindolin-2-ones from commercially available aldehydes and 2-chlorobenzonitriles under mild conditions initiated by N-heterocyclic carbenes is presented. The catalytically generated Breslow intermediates from aldehydes and carbenes underwent smooth SNAr with 2-chlorobenzonitriles followed by annulation triggered by adventitious water present in DMF to furnish the functionalized isoindolin-2-ones in good to excellent yields.

RESUMEN

Axially chiral diaryl ethers, a distinguished class of atropisomers possessing unique dual C-O axis, hold immense potential for diverse research domains. In contrast to the catalytic enantioselective synthesis of conventional single axis bearing atropisomers, the atroposelective synthesis of axially chiral ethers containing flexible C-O axis remains a significant challenge. Herein, we demonstrate the first N-heterocyclic carbene (NHC)-catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde-containing diaryl ethers. Mechanistically, the reaction proceeds via NHC-catalyzed desymmetrization strategy to afford the corresponding axially chiral diaryl ether atropisomers in good yields and high enantioselectivities under mild conditions. The derivatization of the synthesized product expands the utility of present strategy via access to a library of C-O axially chiral compounds. The temperature dependency and preliminary investigations on the racemization barrier of C-O bonds are also presented.

RESUMEN

The N-heterocyclic carbene (NHC)-catalyzed generation of ortho-quinodimethanes (o-QDMs) from 9H-fluorene-1-carbaldehydes followed by the interception with activated ketones resulting in the enantioselective synthesis of tetracyclic δ-lactones is presented. High diastereoselectivity of products, remote C(sp3)-H functionalization, broad substrate scope, and mild reaction conditions are the notable features of the present (4 + 2) annulation.

RESUMEN

Traditional radical-mediated ring-opening of bicyclo[1.1.0]butanes (BCBs) for cyclobutane synthesis suffers from poor diastereoselectivity. Although few reports on BCB ring-opening via polar mechanisms are available, the Lewis acid-catalyzed diastereoselective ring-opening of BCBs using carbon nucleophiles is still underdeveloped. Herein, we report a mild and diastereoselective Bi(OTf)3-catalyzed ring-opening of BCBs employing 2-naphthols. The anticipated carbofunctionalized trisubstituted cyclobutanes were obtained via a bicoordinated bismuth complex and the products are formed in good to excellent yields with high regio- and diastereoselectivity. The scope of the reaction was further extended using electron-rich phenols and naphthylamine. The functionalization of the synthesized trisubstituted cyclobutanes shows the synthetic utility of the present method.

RESUMEN

The use of benzotriazoles as nucleophilic triggers in the three-component Yb(OTf)3-catalyzed ring-opening 1,3-aminofunctionalization of donor-acceptor (D-A) cyclopropanes is presented. Using N-halo succinimide (NXS) as the third component, the reaction afforded the 1,3-aminohalogenation product in up to an 84% yield. Moreover, using alkyl halides or Michael acceptors as the third components, the 3,1-carboaminated products are formed in up to a 96% yield in a one-pot operation. Employing Selectfluor as the electrophile, the reaction furnished the 1,3-aminofluorinated product in a 61% yield.

RESUMEN

The pyridine core is among the most common motifs found in pharmaceuticals and agrochemicals. Consequently, the C-H functionalization of pyridine is a prized reaction, as it can help access a broad spectrum of valuable chemicals. However, the intrinsic electronic properties of pyridines hinder their meta-C-H functionalization, requiring drastic conditions affecting functional group compatibility. A synthetic manoeuvre to overcome this challenge involves the temporary conversion of pyridines into electron-rich intermediates and subsequent regioselective electrophilic functionalization. This was recently accomplished by a ring-opening ring-closing sequence via Zincke imine intermediates by McNally and co-workers, and a dearomatization-rearomatization sequence via oxazino-pyridine intermediates by the Studer group. The mildness and simplicity of these protocols enable them to work with complex molecular setups for synthesizing natural products and bioactive molecules.

RESUMEN

The enantioselective synthesis of functionalized pyrazoloquinolin-3-ones via N-heterocyclic carbene-catalyzed cascade reaction of α-bromoenals with 2-aminoaryl N-tosyl hydrazones is reported. The in situ-generated α,ß-unsaturated acylazoliums underwent an aza-Michael-Mannich-lactamization sequence to afford the tricyclic products bearing three contiguous stereocenters, including a sterically demanding quaternary stereocenter with high enantioselectivity. The unprotected amine-triggered aza-Michael pathway over the competing amidation pathway is noteworthy.

Asunto(s)

RESUMEN

The ubiquity of ε-lactones in various biologically active compounds inspired the development of efficient and enantioselective routes to these target compounds. Described herein is the enantioselective synthesis of indole-fused ε-lactones by the N-heterocyclic carbene (NHC)-Lewis acid cooperative catalyzed dynamic kinetic resolution (DKR) of in situ generated γ,γ-disubstituted indole 2-carboxaldehydes. The Bi(OTf)3-catalyzed Friedel-Crafts reaction of indole-2-carboxaldehyde with 2-hydroxy phenyl p-quinone methides generates γ,γ-disubstituted indole 2-carboxaldehydes, which in the presence of NHC and Bi(OTf)3 afforded the desired tetracyclic ε-lactones in up to 93% yield and >99 : 1 er. Moreover, preliminary studies on the mechanism of this formal [4 + 3] annulation are also provided.

RESUMEN

The N-heterocyclic carbene (NHC)-organocatalyzed [3 + 3] annulation of 2-bromoenals with ß-oxodithioesters resulting in the enantioselective synthesis of dihydrothiopyranones is presented. The chiral α,ß-unsaturated acylazoliums generated from 2-bromoenals and carbenes underwent smooth interception with the sulfur nucleophiles to furnish the sulfur heterocycles in satisfactory yields/selectivity. The regioselective formation of dihydrothiopyranones over the competing dihydropyranones is noteworthy.

RESUMEN

N-Heterocyclic carbene (NHC)-catalyzed umpolung of cyclopent-4-ene-1,3-diones that proceeds via the generation of nucleophilic deoxy-Breslow intermediates is presented. The carbene generated from a commercially available thiazolium salt catalyzed the cross-coupling between cyclopent-4-ene-1,3-diones and isatins to furnish the functionalized oxindoles in moderate to good yields with good functional group compatibility. The key deoxy-Breslow intermediates were isolated and characterized by X-ray analysis. Detailed mechanistic studies are also presented.

RESUMEN

Chiral NHC-catalyzed kinetic resolution of N-aryl aminomaleimides allowing the synthesis of C-N axially chiral N-aryl aminomaleimides via remote chirality control is presented. The catalytically generated α,ß-unsaturated acylazoliums from 2-bromoenals underwent selective [3 + 3] annulation with one of the enantiomers of maleimide to furnish fused-dihydropyridinone (bearing axial/central chirality, up to 6:1 dr, >99:1 er) leaving the enantioenriched opposite enantiomer (up to >99:1 er). Studies on C-N bond rotation barrier and dependence on temperature are also provided.

RESUMEN

A transition-metal-free, [2,3] sigmatropic rearrangement-annulation cascade of 2-substituted thio/amino acetonitriles with arynes allowing the synthesis of 2,4,5-trisubstituted oxazoles under mild conditions has been demonstrated. The key sulfur/nitrogen ylides were generated by the initial S/N arylation followed by proton transfer, which was followed by the selective [2,3] sigmatropic rearrangement involving the -CN moiety and a subsequent annulation to afford the desired products in reasonable yields.

RESUMEN

The recent advances in the N-heterocyclic carbene (NHC)-organocatalyzed generation of azolium enolate intermediates and their subsequent interception with electrophiles are highlighted. The NHC-bound azolium intermediates are generated by the addition of NHCs to suitably substituted aldehydes, acid derivatives or ketenes. A broad range of coupling partners can intercept the azolium enolates to form [2+n] cycloadducts (n=2,3,4) and various α-functionalized compounds. The enantioselective synthesis of the target compounds are achieved with the use of chiral NHCs. Herein, we summarized the development that occurred in this subclass of NHC catalysis.

RESUMEN

Two-step, ring-opening 1,3-carbothiolation of donor-acceptor (D-A) cyclopropanes employing alkyl halides and in situ generated dithiocarbamates (from amines and CS2) has been demonstrated under mild conditions. The reaction is operationally simple and works with good functional group compatibility. Three new bonds including C-N, C-S, and C-C are formed in this 1,3-bifunctionalization strategy. Electron-poor olefins can also be used as electrophiles instead of alkyl halides. The use of enantiomerically pure D-A cyclopropane afforded enantiopure 1,3-carbothiolated product, thus demonstrating the stereospecificity of the reaction.