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

Abstract

Conspectus This Account is aimed at highlighting the recent developments in the N-heterocyclic carbene (NHC)-catalyzed generation of α,β-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,β-unsaturated aldehyde or acid derivatives. A wide variety of bisnucleophiles can add across the α,β-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,β-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-β-lactonization-decarboxylation sequence. The use of cyclic β-ketoamides as the coupling partner for catalytically generated α,β-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,β-unsaturated acylazoliums resulted in the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones. This formal [3 + 3] annulation proceeds via the vi...

Construction of Dihydropyrido[2,3-d]pyrimidine Scaffolds via Aza-Claisen Rearrangement Catalyzed by N-Heterocyclic Carbenes

“…N -Heterocyclic carbenes (NHCs) have emerged as versatile organocatalysts for various transformations and constitute convenient methods for carbon–carbon and carbon–heteroatom bond formation. 3 In the recent years, processes in which NHC-catalyzed reactions take place via normal-polarity intermediates have gained importance. There are four well-studied paths of generating α,β-unsaturated acyl azoliums: the reactions of NHCs with α,β-unsaturated enol esters or acyl fluorides, 4 ynals, 5 2-bromoenals, 6 or stoichiometric oxidation of Breslow intermediates.…”

N‐Heterocyclic Carbene‐Catalyzed Formal [6+2] Annulation Reaction via Cross‐Conjugated Aza‐Trienolate Intermediates

“…Compared with the carbene generated from 4,r eaction performed using other carbene precursors 6-9 resulted in the reduced yield of 3a (entries2-5). Moreover,C s 2 CO 3 was found to be the best base for this transformation,a st he reactions carried out using other inorganic (K 2 CO 3 and KOtBu) and organic (DBU and DABCO) bases returned inferiory ields of 3a (entries [6][7][8][9]. Ther eactions carriedo ut in solvents such as THF, 1,2-dichloroethane and toluened id not improve the yield of 3a indicatingt hat CHCl 3 is the optimal solventf or this [6+ +2] annulation (entries 10-12).…”

“…[4] Moreover,a ddition of NHCs to a,b-unsaturateda ldehydesc ould result in the generation of homoenolate equivalents, [5] and a,b-unsaturateda cylazoliums under oxidative conditions. [6] Av ariety of carbocycles and heterocycles can easily be accessed by intercepting the homoenolates/a,bunsaturated acylazoliums.…”

N‐Heterocyclic Carbene‐Catalyzed Enantioselective Intramolecular Annulations to Construct Benzo‐Fused Pyranones with Quaternary Stereocenter

“…Subsequent base screening ( Table 1, entries 10-16) revealed, that different organic bases, even extremely strong ones such as BEMP or P 2 -Et could give the products with high yields and without erosion of stereoselectivity, remaining at < 99%. Additional screening of the reaction solvents did not show further improvements in the reaction outcomes ( Table 1, entries [16][17][18][19][20]. Finally, identification of diisopropylethylamine and toluene as the best-suited reaction conditions were indicated in terms of enantioselectivity for the developed annulation.…”

“…[13,14] In recent years N-heterocyclic carbene catalysis has emerged as an attractive and ideal strategy to synthesize complex heterocyclic molecules via umpolung reactivity. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Among various asymmetric catalytic strategies for the stereoselective construction and selective functionalization of the six-membered motifs, the Stetter reaction proved to be one of the universal and fundamental tool of the N-heterocyclic carbene (NHC) catalysis [30][31][32][33][34][35][36] After Ciganek initial contribution on intramolecular NHC-catalyzed synthesis of chromanones, during next years many highly enantioselective approaches have been developed (Scheme 1, eq a). [30,[37][38][39][40] In the later stage, Rovis and coworkers disclosed a highly enantioselective and diastereoselective Stetter reaction of salicylaldehyde-derived bearing a tethered α,β-disubstituted Michael acceptors (eq b).…”