Synlett 2017; 28(12): 1463-1466
DOI: 10.1055/s-0036-1588168
letter
© Georg Thieme Verlag Stuttgart · New York

Novel One-Pot Cyclization of the Blaise Reaction Intermediate and Arylglyoxals: The Synthesis of Substituted NH-Pyrroles

Zhiwei Chen*
a   National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
b   Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: chenzhiwei@zjut.edu.cn
,
Hao Chen
a   National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
b   Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: chenzhiwei@zjut.edu.cn
,
Xiaofeng Yang
a   National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
b   Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: chenzhiwei@zjut.edu.cn
,
Xiangqing Chang
a   National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
b   Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: chenzhiwei@zjut.edu.cn
› Author Affiliations
Supported by: We are grateful for financial support from the National Natural Science Foundation of China Grant / Award number ‘21276237’, ‘21676253’
Further Information

Publication History

Received: 06 March 2017

Accepted after revision: 12 March 2017

Publication Date:
11 April 2017 (online)


Abstract

A novel tandem Blaise reaction for the one-pot synthesis of substituted NH-pyrroles was described. The Blaise reaction intermediate, generated in situ from Reformatsky reagent and nitrile, reacted with arylglyoxals chemoselectively to afford a wide variety of substituted NH-pyrroles in good yields.

Supporting Information

 
  • References and Notes

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  • 16 General Procedure for the One-Pot Synthesis of 4a To a stirred suspension of commercial zinc dust (1.26 g, 19.5 mmol) was added methanesulfonic acid (3.7 mg, 0.37 mmol) in anhydrous THF (20 mL). After 10 min of reflux, benzonitrile (1.0 g, 9.7 mmol) was added all at once. While maintaining reflux temperature, ethyl bromoacetate (2.43 g, 14.5 mmol) was added over 1 h with use of a syringe pump, and the reaction mixture was further heated at reflux for 1 h. The reaction mixture was cooled to r.t., and then arylglyoxal (1.62 g, 10.6 mmol) was added. After being stirred for 0.5 h at r.t., the reaction mixture was quenched with sat. aq NH4Cl at r.t. and extracted with EtOAc (3 × 30 mL). The combined organic layer was dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc–hexane, 1:7 v/v) to afford product 4a (2.47 g, 8.0 mmol; 83%); light yellow solid, mp 156.6–157.4 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 11.42 (s, 1 H), 8.68 (s, 1 H), 7.84 (dd, J = 8.4, 1.0 Hz, 2 H), 7.60–7.53 (m, 2 H), 7.46–7.30 (m, 5 H), 7.11 (t, J = 7.4 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 1.14 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 165.83, 143.72, 132.94, 131.17, 130.99, 129.18, 127.80, 127.47, 126.99, 124.26, 123.36, 112.97, 59.23, 13.62. ESI-MS: m/z 308.1 [M + H]+. ESI-HRMS: m/z calcd for C19H17NO3 [M + H]+: 308.1253; found: 308.1258.