N-Heterocyclic Carbene (NHC)-Catalyzed Transformations Involving Azolium Enolates.

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.

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.

N-Heterocyclic Carbene-Catalyzed Enantioselective Synthesis of Spiro-glutarimides via α,ß-Unsaturated Acylazoliums.

NHC-catalyzed enantioselective [3 + 3] spiro-annulation of α,ß-unsaturated aldehydes with cyclic ß-ketoamides allowing the preparation of synthetically and biologically important spiro-glutarimide derivatives has been reported. The interception of the ketoamides with catalytically generated chiral α,ß-unsaturated acylazoliums proceeds in a Michael addition-intramolecular amidation pathway to deliver the spirocyclic products with good yield, diastereoselectivity, and enantioselectivity.

Base-Free and Catalyst-Free Synthesis of Functionalized Dihydrobenzoxazoles via Vinylogous Carbonate to Carbamate Rearrangement.

An unexpected, catalyst-free, and base-free intramolecular cyclization of N-aryloxyacrylate aldimines, under thermal conditions leading to the synthesis of functionalized dihydrobenzoxazoles, is reported. The reaction features a unique rearrangement of vinylogous carbonates to vinylogous carbamates resulting in a new carbon-oxygen and carbon-nitrogen bond construction. The reaction tolerates a broad range of functional groups and the desired products are formed in moderate to good yields.

Enantioselective Synthesis of Functionalized ß-Lactones by NHC-Catalyzed Aldol Lactonization of Ketoacids.

N-Heterocyclic carbene (NHC)-catalyzed intramolecular aldol lactonization of readily available ketoacids leading to the enantioselective synthesis of cyclopentane-fused ß-lactones is presented. The reaction proceeds via the generation of NHC-bound enolate intermediates formed from the ketoacids in the presence of the peptide coupling reagent HATU and NHC generated from the chiral triazolium salt. The functionalized ß-lactones are formed under mild conditions in high yields and enantioselectivities.

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 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.

N-Heterocyclic carbene-catalyzed diastereoselective synthesis of ß-lactone-fused cyclopentanes using homoenolate annulation reaction.

NHC-catalyzed annulation of enals with 2-enoylpyridines or 2-enoylpyridine N-oxides leading to the diastereoselective synthesis of ß-lactone-fused cyclopentanes is reported. The reaction proceeds via the generation of homoenolate equivalent intermediates and tolerates a broad range of functional groups.

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.