umpolung chemistry

극반전(umpolung) 반응은 작용기 본연의 극성과 반대되는 극성을 가지는 화학변환을 의미하며, 반응조건을 온화하게 변화시키거나 전통적인 선택성을 뒤집어 새로운 화학공간(chemical space)에 접근하게 해줄 수 있다. 연구진은 C-C치환 혹은 Ar-Ar짝지움 반응을 위한 극반전 개념을 선도적으로 연구하고 있으며, 향후 다른 촉매반응 모드와 결합할 때, 무궁한 가능성을 제공할 수 있을 것이다.

Ynamide Activation and Umpolung Alkylation                                                      Angew. Chem. Int. Ed. 2017, 56, 3670; Org. Chem. Front. 2024, 11, 1790.

In continuation of alkyne oxidation and OAT chemistry by gold catalysis, we conceived that electron-rich alkynes such as ynamides may be activated by Brønsted acids. This turned out to be the case, and the addition of pyridine-N-oxides led to N-enoxypyridinium salts as reactive intermediates. By utilizing the weak N-O bond (55 kcal/mol), this underwent a concerted substitution (SN2’) by various nucleophiles, such as indoles, pyrroles, phenols and silyl enol ethers. Addition of heteroatom nucleophiles, such as alcohols, thiols, and hydrazides was subsequently developed. This reaction corresponds to the 'umpolung' of enolate alkylation, and has several adtantages to the classical approaches. 

• no need for highly basic reagents and cryogenic temperature

• C-H arylation (no need for pre-functionalization into electrophilic R-X) 

• prospects for the enantioselective synthesis of chiral tertiary α-center (no strong base)

Enantioselective version of this reaction con be found here.

Mechanistic Studies into Ynamide Activation and Umpolung Alkylation                                 Chem. Sci. 2019, 10, 8799; Chem. Comm. 2017, 53, 2733 2733

The above oxidative transformation of ynamides requires temporal chemoselectivity, because multiple nucleophiles and electrophiles coexists in the reaction mixture. In Chem. Comm. paper, we studied reversibility of each steps en route to N-enoxypyridinium salts, and described experimental study on the reversibility of each steps. In Chem. Sci. paper, we studied reactions of homologous enynamides, and performed a mechanistic study (Hammett plot) to arrive at the mechanistic duality, depending on the nucleophiles: C-nucleophiles prefer a concerted SN2’' reaction, while O-nucleophiles prefer a carboncation-trapping mechanism.  

Aromatic Umpolung                                                                                                                                                                                Chem. Sci. 2022, 13, 1169

The 'umpolung of enolates' enables alkylation of unmodified nucleophiles. How about C-C cross coupling by way of umpolung? 

We developed N-carboxyindoles as indolyl cross-coupling partners that react with 2-naphthols and phenols in a ortho-selective fashion. The reaction can be promoted with a very low loading of Cu(I)-catalyst (0.001 mol%Cu) or with a Brønsted acid as a catalyst. Recently, we developed this chemistry into asymmetric version, which will be published in due course. 

Radical Chemistry of N-O Bond Substrates                                                                                         ACS Catal. 2022, 12, 8833; Org. Lett. 2022, 24, 1774

We also found that N-carboxyindoles and N-enoxybenzotriazoles functioned as N- and C-radical precursors under photocatalytic conditions. Details of this chemistry can be found here.