Synlett, Inhaltsverzeichnis

Synlett 2020; 31(04): 363-368
DOI: 10.1055/s-0039-1691567

letter

© Georg Thieme Verlag Stuttgart · New York

Metal-Free Regioselective Alkylation of Imidazo[1,2-a]pyridines with N-Hydroxyphthalimide Esters under Organic Photoredox Catalysis

Bin Sun

^aCollaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China

^cNational Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

,

Tengwei Xu

^bCollege of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

^cNational Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

,

Liang Zhang

^bCollege of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

^cNational Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

,

Rui Zhu

^bCollege of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

^cNational Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

,

Jin Yang

^bCollege of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

^cNational Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

,

Min Xu

^aCollaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China

^cNational Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

,

Can Jin∗

^aCollaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China

^bCollege of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

^cNational Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Zhejiang University of Technology, Hangzhou 310014, P. R. of China eMail: jincan@zjut.edu.cn

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Abstract

A visible-light-induced direct C–H alkylation of imidazo[1,2-a]pyridines has been developed. It proceeds at room temperature by employing inexpensive Eosin Y as a photocatalyst and alkyl N-hydroxyphthalimide (NHP) esters as alkylation reagents. A variety of NHP esters derived from aliphatic carboxylic acids (primary, secondary, and tertiary) were tolerated in this protocol, giving the corresponding C-5-alkylated products in moderate to excellent yields. Mechanistic studies indicate that a radical decarboxylative coupling pathway was involved in this process.

Key words

Key words

photocatalysis - C–H alkylation - NHP esters - regioselectivity - metal-free reactions

References and Notes

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17 5-(tert-Butyl)-7-chloro-2-phenylimidazo[1,2-a]pyridine (3aa); Typical Procedure A 10 mL Schlenk-tube was charged with 7-chloro-2-phenylimidazo[1,2-a]pyridine (1a) (114 mg, 0.5 mmol), tert-butyl NHP ester 2a (247 mg, 1.0 mmol), Eosin Y (3 mg, 0.005 mmol), DMSO (2 mL), and TfOH (37 mg, 0.25 mmol). The tube was evacuated and backfilled with N₂ (3×). The mixture was then irradiated by 3 W blue LEDs at r.t. for 48 h. The reaction mixture was then quenched with 1 M NaOH aq (15 mL) and extracted with CH₂Cl₂ (3 × 10 mL). The organic layer was dried with anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (EtOAc/PE, 1:20) to afford 3aa as a white solid. Yield: 116 mg (82%); mp 141.6–142.4 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.07 (s, 1 H), 7.96 (d, J = 7.2 Hz, 2 H), 7.58 (s, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.35 (t, J = 7.2 Hz, 1 H), 6.71 (s, 1 H), 1.57 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.1, 146.5, 145.7, 133.6, 131.5, 128.8, 128.2, 126.2, 114.3, 110.7, 108.9, 35.6, 27.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₈ClN₂: 285.1153; found: 285.1163.

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