Synthesis of 4-Difluoromethylquinolines by NHC-Catalyzed Umpolung of Imines

Patra, Aditya Kumar; Gelat, Fabien; Pannecoucke, Xavier; Poisson, Thomas; Besset, Tatiana; Biju, Akkattu T.

doi:10.1021/acs.orglett.7b04055

Cited by 55 publications

(27 citation statements)

References 51 publications

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“…The resultant enolate 218 would attack the adjacent aldimine scaffold, affording 2,3substituted quinolone product 219 upon oxidation (pathway 2). [86] The NHC-catalyzed umpolung of aldimines for the formation of 4-difluoromethylquinolines 224 was achieved in 2018 by Biju et al [89] Using NHCs, the intramolecular cyclization reaction of aldimines having a moderately electron-poor double bond because of the existence of the À CF 3 substituent probably accomplishes through the intermediacy of the aza-Breslow intermediate. The key to the accomplishment of this aza-Stetter type conversion is the NHC provided from the bicyclic triazolium salt with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base.…”

Section: Application Of Stetter Reaction In Synthesis Of Heterocyclesmentioning

confidence: 99%

“…Since the carbon-carbon bond in 222 is moderately electron-poor, initial NHC addition to the double bond (to form the deoxy-Breslow intermediate) and subsequent interception with the imine scaffold may not occur in this case. [89] Since paullone 237 a and its derivatives 237 b show fascinating biological properties including the glycogen synthase kinase 3 (GSK 3) and also potent inhibition of cyclindependent kinase (CDK), it is significant to establish effective synthetic pathways for paullones. [90] The biological properties of paullones exhibit a robust reliance on the substitution pattern in the indole scaffold, significantly an electron-withdrawing group at the C-9 position of the indole ring; thus, various methods have been reported for providing paullones.…”

Section: Application Of Stetter Reaction In Synthesis Of Heterocyclesmentioning

confidence: 99%

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Recent Advances in Stetter Reaction and Related Chemistry: An update

et al. 2020

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The Stetter reaction is actually a special CÀ C bond forming reaction through a 1,4-addition reaction in the presence of nucleophilic catalyst. It involves a reaction between aldehydes and Michael acceptors catalyzed by Nheterocyclic carbenes (NHC's) leading to preparation of 1,4dicarbonyl compounds via carbon-carbon bond formation. It offers a powerful approach to access 1,4-dicarbonyl compounds which are significant starting materials and inter-mediates in the synthesis of several heterocyclic systems, and bioactive heterocyclic framework which are present in natural products. In this review we try to underscore the recent advances in Stetter reaction and its applications from 2015 till date. Notably, we focused on the applications of Stetter reaction in the synthesis of various heterocyclic systems and total synthesis of natural products, which have largely been overlooked, previously.

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Section: Application Of Stetter Reaction In Synthesis Of Heterocyclesmentioning

confidence: 99%

Section: Application Of Stetter Reaction In Synthesis Of Heterocyclesmentioning

confidence: 99%

Recent Advances in Stetter Reaction and Related Chemistry: An update

et al. 2020

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“…(2)] in the first NHC catalyzed reaction involving imine umpolung ,. Subsequently, the aza‐Breslow intermediate has been invoked in the oxidation of imines to amides, and a quinolone synthesis . While these reports demonstrate the viability of the aza‐Breslow intermediate in reaction discovery, key challenges remain, perhaps most notably regarding enantioselective catalysis.…”

Section: Figurementioning

confidence: 99%

Enantioselective N‐Heterocyclic Carbene Catalysis that Exploits Imine Umpolung

et al. 2019

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The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery.H erein we report an enantioselective aza-Stetter reaction that proceeds via imine umpolung using N-heterocyclic carbene catalysis.T he reaction proceeds with high levels of enantioselectivity (all ! 96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover-limiting addition of the NHC to the imine. Figure 1. Previously and this work.

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“…On the basis of experimental results reported by Biju et al, [15] the model reaction used in this DFT investigation is mentioned in Scheme 1. On the basis of experimental results reported by Biju et al, [15] the model reaction used in this DFT investigation is mentioned in Scheme 1.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Insight towards Mechanism, Role of NHC and DBU in the Synthesis of Substituted Quinolines

Shyam

Mondal

2020

ChemistrySelect

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A plausible mechanism for the conversion of aldimine to 2phenyl-4-difluoromethylquinoline catalyzed by N-heterocyclic carbene (NHC) in association with 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) is investigated in detail by using density functional theory (DFT) method. Six significant stages are proposed to be involved in the whole catalytic cycle, starting from the generation of NHC followed by its nucleophilic interaction with the carbon atom of C═N in aldimine to generate corresponding aza-Breslow intermediate. This aza-Breslow intermediate further undergoes intramolecular umpolung addition followed by several proton transfers to regenerate the NHC along with 2phenyl-4-difluoromethylquinoline. The role of NHC in this intramolecular umpolung addition of aza-Breslow intermediate has been investigated by using conceptual DFT. Apart from NHC; the role of DBU in this catalytic cycle has also been monitored carefully. These theoretical findings are in good agreement with experimental results and also provide a deeper insight into the mechanism of NHC catalyzed synthesis of 2phenyl-4-difluoromethylquinoline.

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Synthesis of 4-Difluoromethylquinolines by NHC-Catalyzed Umpolung of Imines

Cited by 55 publications

References 51 publications

Recent Advances in Stetter Reaction and Related Chemistry: An update

Recent Advances in Stetter Reaction and Related Chemistry: An update

Enantioselective N‐Heterocyclic Carbene Catalysis that Exploits Imine Umpolung

Theoretical Insight towards Mechanism, Role of NHC and DBU in the Synthesis of Substituted Quinolines

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