Elsevier

Tetrahedron

Volume 76, Issue 33, 14 August 2020, 131353
Tetrahedron

Cascade cyclization of glycine derivatives with β-ketoesters for polysubstituted 1,4-dihydropyridines by visible light photoredox catalysis

https://doi.org/10.1016/j.tet.2020.131353Get rights and content

Highlights

  • Visible light photocatalytic cascade cyclization of N-aryl glycine esters with β-ketoesters to afford diverse polysubstituted 1,4-dihydropyridines at room temperature was disclosed.

  • A possible reaction mechanism for the cascade cyclization by visible light photoredox catalysis was proposed on the basis of control experiments.

  • The synthetic protocol features good functional group tolerance, mild conditions and simple operation.

Abstract

Visible light photocatalytic cascade cyclization reaction between glycine derivatives and β-ketoesters using Ir (ppy)3 as a catalyst and dicumyl peroxide (DCP) as an oxidant was described. A series of N-aryl glycine esters proceeded the cyclization smoothly with β-ketoesters at room temperature, affording the desired 1,4-dihydropyridines (1,4-DHPs) in satisfactory yields. A possible mechanism for the cascade cyclization reaction by visible light photoredox catalysis was also proposed. This protocol not only provides an efficient and convenient approach to synthetize various 1,4-dihydropyridines, but also has potential utilities for the construction of bioactive molecules.

Graphical abstract

Visible light photocatalytic cascade cyclization reaction between glycine derivatives and β-ketoesters using Ir (ppy)3 as a catalyst and dicumyl peroxide (DCP) as an oxidant was described. A series of N-aryl glycine esters proceeded the cyclization smoothly with β-ketoesters at room temperature, affording the desired 1,4-dihydropyridines (1,4-DHPs) in satisfactory yields. A possible mechanism for the cascade cyclization reaction by visible light photoredox catalysis was also proposed. This protocol not only provides an efficient and convenient approach to synthetize various 1,4-dihydropyridines, but also has potential utilities for the construction of bioactive molecules.

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Introduction

Oxidative C–H functionalization has emerged in recent years as a powerful technique to construct complex molecules from simple starting materials in organic synthesis [1]. Among them, much attention has been attracted to the visible light photoredox-mediated C–H functionalization from the chemists due to its inherent characteristics of environmental benignity, sustainability and ease to handle [2]. Glycine is the simplest and readily available natural amino acids. Direct oxidative α-C-H functionalization of glycine via visible light photoredox catalysis provides a reliable and attractive strategy to afford structurally diverse α-amino acid derivatives [3]. In 2015, Wu et al. revealed a cross-coupling hydrogen evolution reaction of glycine derivatives with β-keto esters by the synergistic catalysis of Ru (bpy)3(PF6)2 and Co(dmgH)2pyCl under visible light irradiation [3a]. In 2016, Xiao’s group reported a visible-light-initiated photocatalytic crossing-coupling reaction of glycine derivatives with aryl ketones and aldehyde to 1,2-amino alcohols [3b]. Although much progress has been achieved, the development of simple and efficient methods for the preparation of potentially useful organic molecules through C–H functionalization under mild conditions is still highly desired.

As an important class of nitrogen-containing heterocycles, 1,4-dihydropyridines (1,4-DHPs) are widely prevalent in a great number of natural products, biologically active molecules and pharmaceuticals [4,5]. In particularly, 1,4-DHPs possess a broad range of biological properties such as anticonvulsant activity [6], antitumor [7], antitubercular [8], anti-inflammatory [9], etc. Several commercially available drugs like amlodipine, nicardipine, felodipine, nifedipine and nimodipine contain 1,4-DHP moiety in their core structure. Owing to these intriguing characteristics and utilization, considerable research efforts have been devoted to access various 1,4-dihydropyridine derivatives by synthetic and medicinal chemists over the years [5]. Cascade reaction, which can generate more chemical bonds in a one set of fixed conditions and one-pot process during the reaction, has been extensively applied to the construction of various bioactive molecules, natural products and functional materials [10]. In 2014, Jia et al. disclosed a radical cation salt-prompted C–H oxidation/C–N bond cleavage to access a variety of 1,4-dihydropyridines with TMSCl as an additive [11a]. In 2016, our group developed an aerobic oxidative coupling/cyclization of glycine derivatives with 1,3-dicarbonyl compounds to afford various 1,4-dihydropyridines by copper catalysis [11b]. In view of the biological importance of 1,4-dihydropyridines, and as our ongoing efforts on C–H functionalization reactions [12], we herein present a simple and efficient cascade cyclization reaction of glycine esters with β-ketoesters to synthetize polysubstituted 1,4-dihydropyridines using visible light photoredox catalysis at room temperature.

Section snippets

Results and discussion

Our investigation began with the model reaction of N-4-methylphenylglycine ethyl ester 1a and ethyl acetoacetate 2a in the presence of 1 mol % Acr+-Mes-ClO4- (9-Mesityl-10-methylacridinium Perchlorate) in toluene under irradiation of 18 W blue LED light at room temperature. To our delight, the desired cyclization product 3aa was isolated with a yield of 40% (entry 1, Table 1). Encouraged by this result, a variety of common photocatalysts such as Ir (ppy)3, methylene blue, Ru (bpy3)Cl2·6H2O,

Conclusions

In summary, we have achieved a simple and convenient visible-light-induced photocatalytic cascade cyclization reaction of glycine derivatives with β-ketoesters using dicumyl peroxide (DCP) as an oxidant. A wide range of N-aryl glycine esters proceed the cascade cyclization readily with various β-ketoesters to provide the corresponding polysubstituted 1,4-dihydropyridines in satisfactory yields. A possible mechanism for the cascade cyclization by visible light photoredox catalysis is also

General information

Unless otherwise indicated, all reagents were purchased from commercial distributors and used without further purification. 1H NMR and 13C NMR were recorded at 400 MHz and 100 MHz, respectively, using tetramethylsilane as an internal reference. High-resolution mass spectra (HRMS) were measured on a quadrupole time-of-flight (Q-TOF) mass spectrometer instrument with an electrospray ionization (ESI) source. Melting points were uncorrected. Flash column chromatography was performed over silica gel

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank the National Natural Science Foundation of China (11765002 and 21966003), the Natural Science Foundation of Jiangxi Province (20181BAB203019), the Postdoctoral Science Foundation of Jiangxi Province (2019KY41), the Opening Project of Jiangxi Province Key Laboratory of Polymer Micro/Nano Manufacturing and Devices, and the Innovation Fund Designated for Graduate Students of Jiangxi Province (YC2019–S274) for financial supports.

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