Catalytic photochemical enantioselective α-alkylation with pyridinium salts.

We have developed a chiral amine catalyzed enantioselective α-alkylation of aldehydes with amino acid derived pyridinium salts as alkylating reagents. The reaction proceeds in the presence of visible light and in the absence of a photocatalyst via a light activated charge-transfer complex. We apply this photochemical stereoconvergent process to the total synthesis of the lignan natural products (-)-enterolactone and (-)-enterodiol. Mechanistic studies support the ground-state complexation of the reactive components followed by divergent charge-transfer processes involving catalyst-controlled radical chain and in-cage radical combination steps.

Reusable Pd@PEG Catalyst for Aerobic Dehydrogenative C-H/C-H Arylations of 1,2,3-Triazoles.

Dehydrogenative C-H arylations of 1,2,3-triazoles were accomplished with the aid of a reusable palladium catalyst in PEG. The widely applicable oxidative palladium catalysis enabled the synthesis of fully decorated 1,2,3-triazoles with a broad functional-group tolerance and ample substrate scope. The sustainability of the aerobic C-H arylation was reflected by the use of PEG as green reaction medium and demonstrated by recycling studies of the catalyst and the reaction medium.

Micellar Catalysis for Ruthenium(II)-Catalyzed C-H Arylation: Weak-Coordination-Enabled C-H Activation in H2 O.

Chemoselective C-H arylations were accomplished through micellar catalysis by a versatile single-component ruthenium catalyst. The strategy provided expedient access to C-H-arylated ferrocenes with wide functional-group tolerance and ample scope through weak chelation assistance. The sustainability of the C-H arylation was demonstrated by outstanding atom-economy and recycling studies. Detailed computational studies provided support for a facile C-H activation through thioketone assistance.

NHC-Catalyzed Generation of α,ß-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles.

This Account is aimed at highlighting the recent developments in the N-heterocyclic carbene (NHC)-catalyzed generation of α,ß-unsaturated acylazolium intermediates and their subsequent reactivity with (bis)nucleophiles thereby shedding light on the power of this NHC-bound intermediate in organocatalysis. This key intermediate can be generated by the addition of NHCs to α,ß-unsaturated aldehyde or acid derivatives. A wide variety of bisnucleophiles can add across the α,ß-unsaturated acylazoliums to form various five and six-membered heterocycles and carbocycles. Moreover, suitably substituted nucleophiles can add to this intermediate and result in valuable products following cascade processes. Employing chiral NHCs in the process can result in the enantioselective synthesis of valuable compounds. In 2013, we developed a unified strategy for the enantioselective synthesis of dihydropyranones and dihydropyridinones by the NHC-catalyzed formal [3 + 3] annulation of 2-bromoenals with readily available 1,3-dicarbonyl compounds or primary vinylogous amides. This reaction takes place under mild conditions with low catalyst loading. Interestingly, employing enolizable aldehydes as the bisnucleophiles in this annulation afforded chiral 4,5-disubstituted dihydropyranones in spite of the competing benzoin/Stetter pathways. Moreover, the use of cyclic 1,3-dicarbonyl compounds such as 4-hydroxy coumarin/pyrazolone afforded the coumarin/pyrazole-fused dihydropyranones. In addition, a [3 + 2] annulation for the synthesis of spiro γ-butyrolactones was demonstrated using 3-hydroxy oxindoles as the bisnucleophile. The interception of α,ß-unsaturated acylazolium intermediates with malonic ester derivatives having a γ-benzoyl group resulted in the enantioselective synthesis of functionalized cyclopentenes via a cascade process involving a Michael-intramolecular aldol-ß-lactonization-decarboxylation sequence. The use of cyclic ß-ketoamides as the coupling partner for catalytically generated α,ß-unsaturated acylazoliums resulted in the enantioselective synthesis of spiro-glutarimide and the reaction proceeds in a Michael addition-intramolecular amidation pathway. We have recently demonstrated the enantioselective synthesis of tricyclic δ-lactones with three contiguous stereocenters by the reaction of enals with dinitrotoluene derivatives bearing electron-withdrawing groups, under oxidative conditions. This atom-economic cascade reaction proceeds in a Michael/Michael/lactonization sequence tolerating a range of functional groups. This technique was also used for the N-H functionalization of indoles for the enantioselective synthesis of pyrroloquinolines following the aza-Michael/Michael/lactonization sequence. The use of α-arylidene pyrazolinones as the bisnucleophiles for the tandem generation of dienolate/enolates combined with the NHC-catalyzed generation of α,ß-unsaturated acylazoliums resulted in the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones. This formal [3 + 3] annulation proceeds via the vinylogous Michael/spiroannulation/dehydrogenation sequence to afford spirocyclic compounds with an all-carbon quaternary stereocenter. It is reasonable to believe that the chemistry of α,ß-unsaturated acylazoliums, catalytically generated through NHCs, will continue to flourish and will lead to amazing results. Future challenges in this area include the applications of this key intermediate in the synthesis of biologically active natural products and drugs.

Thiocarbonyl-enabled ferrocene C-H nitrogenation by cobalt(III) catalysis: thermal and mechanochemical.

Versatile C-H amidations of synthetically useful ferrocenes were accomplished by weakly-coordinating thiocarbonyl-assisted cobalt catalysis. Thus, carboxylates enabled ferrocene C-H nitrogenations with dioxazolones, featuring ample substrate scope and robust functional group tolerance. Mechanistic studies provided strong support for a facile organometallic C-H activation manifold.

Mild Decarboxylative C-H Alkylation: Computational Insights for Solvent-Robust Ruthenium(II) Domino Manifold.

Computational studies on decarboxylative C-H alkenylations provided key insights into the solvent-robust nature of C-H activation/decarboxylation domino reactions. These properties were exploited for ruthenium(II)-catalyzed C-H alkylations by a decarboxylative process with ample scope under copper-free and silver-free reaction conditions.

Organocatalytic Enantioselective Vinylogous Michael-Aldol Cascade for the Synthesis of Spirocyclic Compounds.

Enantioselective synthesis of pyrazolone-fused spirocyclohexenols by the secondary amine-catalyzed cascade reaction of α,ß-unsaturated aldehydes with α-arylidene pyrazolinones is reported. This formal [3 + 3] organocascade reaction proceeds through a vinylogous Michael-aldol sequence to furnish the spiroheterocycles with three stereocenters including an all-carbon quaternary center in good yields and selectivities. The catalytic generation of α,ß-unsaturated iminium ions from enals and tandem dienolate/enolate formation from pyrazolinones are the key for the success of this spiroannulation reaction.

Enantioselective synthesis of spiro γ-butyrolactones by N-heterocyclic carbene (NHC)-catalyzed formal [3 + 2] annulation of enals with 3-hydroxy oxindoles.

The N-heterocyclic carbene (NHC)-catalyzed enantioselective formal [3 + 2] annulation of α,ß-unsaturated aldehydes with 3-hydroxy oxindoles is presented. Under oxidative conditions using the bisquinone oxidant, the reaction resulted in the synthesis of spiro γ-butyrolactones in moderate to good yields, enantioselectivity and diastereoselectivity. The reaction likely proceeds via the generation of the NHC-bound α,ß-unsaturated acylazolium intermediate from enals, which was intercepted by the dioxindoles in a formal [3 + 2] pathway to form the spirocyclic compounds. However, a deeper mechanistic investigation revealed that the reaction can also proceed via the homoenolate intermediate. In this case, the dioxindole was oxidized to the corresponding isatin derivative using traces of air under basic conditions, and was intercepted with the NHC-bound homoenolate intermediate in a formal [3 + 2] pathway to afford the spiro compound.

Facile synthesis of N-acyl 2-aminobenzothiazoles by NHC-catalyzed direct oxidative amidation of aldehydes.

A mild, general, and high yielding synthesis of N-acyl 2-aminobenzothiazoles has been demonstrated by N-heterocyclic carbene (NHC)-organocatalyzed direct amidation of aldehydes with 2-aminobenzothiazoles proceeding via acyl azolium intermediates. The carbene generated from the triazolium salt under oxidative conditions was the key for the success of this reaction. The method was subsequently applied to the synthesis of various biologically important N-acyl 2-aminobenzothiazoles.

Synthesis of 4H-chromenes by an unexpected, K3PO4-mediated intramolecular Rauhut-Currier type reaction.

In an attempt to develop the umpolung of Michael acceptors using chalcones having an enoate moiety under N-heterocyclic carbene (NHC) catalysis, a K3PO4-mediated intramolecular Rauhut-Currier type reaction was observed. This C(sp(2))-C(sp(2)) coupling reaction afforded the biologically important 4H-chromenes in moderate to good yields. It is likely that the enol ether functionality acts as the nucleophilic trigger in this reaction.

Enantioselective Synthesis of Spirocyclohexadienones by NHC-Catalyzed Formal [3+3] Annulation Reaction of Enals.

The enantioselective synthesis of pyrazolone-fused spirocyclohexadienones was demonstrated by the reaction of α,ß-unsaturated aldehydes with α-arylidene pyrazolinones under oxidative N-heterocyclic carbene (NHC)catalysis. This atom-economic and formal [3+3] annulation reaction proceeds through a vinylogous Michael addition/spiroannulation/dehydrogenation cascade to afford spirocyclic compounds with an all-carbon quaternary stereocenter in moderate to good yields and excellent ee values. Key to the success of the reaction is the cooperative NHC-catalyzed generation of chiral α,ß-unsaturated acyl azoliums from enals, and base-mediated tandem generation of dienolate/enolate intermediates from pyrazolinones.

Enantioselective synthesis of functionalized pyrazoles by NHC-catalyzed reaction of pyrazolones with α,ß-unsaturated aldehydes.

The N-heterocyclic carbene (NHC)-organocatalyzed enantioselective annulation reaction of pyrazolones with α,ß-unsaturated aldehydes proceeding via the chiral α,ß-unsaturated acyl azolium intermediates under oxidative conditions is presented. The reaction afforded dihydropyranone-fused pyrazoles in moderate to good yields and good er values under operationally simple and base-free conditions.

N-Heterocyclic carbene-catalyzed enantioselective synthesis of functionalized cyclopentenes via α,ß-unsaturated acyl azoliums.

Highly enantioselective NHC-organocatalyzed synthesis of functionalized cyclopentenes proceeding via α,ß-unsaturated acyl azolium intermediates is reported. The organocascade reaction of modified enals with malonic ester derivatives having a γ-benzoyl group involves the Michael-intramolecular aldol-ß-lactonization-decarboxylation sequence to deliver cyclopentenes in good yields and excellent ee values.

Synthesis of functionalized coumarins and quinolinones by NHC-catalyzed annulation of modified enals with heterocyclic C-H acids.

N-Heterocyclic carbene (NHC) catalyzed lactonization and lactamization of 2-bromoenals with heterocyclic C-H acids proceeding via the α,ß-unsaturated acyl azolium intermediates is reported. The reaction furnished coumarin- or quinolinone-fused lactone/lactam derivatives. In addition, results of the enantioselective version of this reaction using chiral NHC are presented.

Asymmetric N-heterocyclic carbene (NHC)-catalyzed annulation of modified enals with enolizable aldehydes.

N-Heterocyclic carbene (NHC)-catalyzed highly enantioselective lactonization of modified enals with enolizable aldehydes, proceeding via the α,ß-unsaturated acylazolium intermediates, is reported. The reaction results in the asymmetric synthesis of synthetically important 4,5-disubstituted dihydropyranones.

Efficient synthesis of γ-keto sulfones by NHC-catalyzed intermolecular Stetter reaction.

The N-heterocyclic carbene-catalyzed intermolecular Stetter reaction of aldehydes with α,ß-unsaturated sulfones allows the atom-economic and selective formation of γ-keto sulfones in good yields. Key to the success of this unique transition-metal-free carbon-carbon bond-forming reaction is the right choice of the NHC precursor and base. The reaction tolerates a broad range of different aldehydes.

Recent advances in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using arynes.

This tutorial review is aimed at highlighting recent developments in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions utilizing a versatile class of reactive intermediates, viz., arynes, which hold the potential for numerous applications in organic synthesis. Key to the success of the resurgence of interest in the rich chemistry of arynes is primarily the mild condition for their generation by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates. Consequently, arynes have been employed for the construction of multisubstituted arenes with structural diversity and complexity. The versatile transition-metal-free applications of arynes include cycloaddition reactions, insertion reactions and multicomponent reactions. In addition, arynes have found applications in natural product synthesis. Herein, we present a concise account of the major developments that occurred in this field during the past eight years.