Elsevier

Science Bulletin

Volume 67, Issue 16, 31 August 2022, Pages 1688-1695
Science Bulletin

Article
Ag2O/squaramide cocatalyzed asymmetric interrupted Barton-Zard reaction of 8-nitroimidazo[1,2-a]pyridines

https://doi.org/10.1016/j.scib.2022.07.019Get rights and content

Abstract

Imidazo[1,2-a]pyridines are present in numerous biologically active compounds as the core structural motif. Herein, we report an asymmetric interrupted Barton-Zard reaction of electron-deficient imidazo[1,2-a]pyridines with α-substituted isocyanoacetates. The reaction enables the dearomatization of 8-nitroimidazo[1,2-a]pyridines and hence offers straightforward access to an array of optically active highly functionalized imidazo[1,2-a]pyridine derivatives that possess three contiguous stereogenic centers in good yields (up to 98%) with high stereoselectivities (>19:1 dr, >99% ee). It is worth noting that the catalytic system consisting of a chiral squaramide and silver oxide displays remarkable reactivity and stereoselectivity, and a gram-scale reaction is compatible with the catalyst loading of 0.5 mol%. In addition, the synthetic potential of this method was showcased by versatile transformations of the product.

Introduction

Imidazo[1,2-a]pyridine is a unique heteroaromatic skeleton, which is ubiquitous in luminescent materials, natural products, and biologically active compounds [1], [2], [3], [4], [5]. In particular, many optically active imidazo[1,2-a]pyridine derivatives are found in pharmacologically important molecules (Fig. 1) [6], [7], [8]. In addition, imidazo[1,2-a]pyridine derivatives are also widely used in organic synthesis. For example, the Birman group [9], [10] developed an acyl transfer catalyst based on a 2,3-dihydroimidazo[1,2-a]pyridine backbone for the kinetic resolution of alcohols. Furthermore, Andersson and co-workers [11] developed a series of chiral P,N-ligands based on this framework, which showed high reactivity and excellent enantioselectivities in Ir-catalyzed hydrogenations and Pd-catalyzed intermolecular Heck reactions. Although a variety of synthetic methods have been developed for the synthesis of this important framework [12], [13], [14], [15], [16], [17], [18], [19], [20], most optically active imidazo[1,2-a]pyridine derivatives rely on the use of enantioenriched starting materials or chiral-resolution techniques [21], [22], [23], [24]. Accordingly, the development of efficient synthesis of optically active imidazo[1,2-a]pyridines is highly desirable [25], [26], [27].

Catalytic asymmetric dearomatization (CADA) reaction has attracted enormous attention because of its potential to access enantioenriched three-dimensional molecules from readily available planar aromatic compounds [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. However, the CADA reaction of imidazo[1,2-a]pyridines remains underdeveloped. To the best of our knowledge, the only example was reported by Glorius and co-workers [38], where asymmetric hydrogenation of imidazo[1,2-a]pyridines was realized by using a ruthenium/N-heterocyclic carbene (NHC) catalyst, leading to chiral tetrahydroimidazo[1,2-a]pyridine derivatives (Scheme 1a).

We recently reported a silver/phosphine complex-catalyzed interrupted Barton-Zard reaction of 3-nitroindoles with α-substituted isocyanoacetates [39]. Although imidazo[1,2-a]pyridines are known as electron-rich 10π-electron aromatic compounds and are generally used as nucleophiles, we envisioned that introducing an electron-withdrawing nitro group might make them electrophiles suitable for interrupted Barton-Zard reaction with α-substituted isocyanoacetates. Recently, we realized this design plan by identifying an efficient catalytic system consisting of Ag2O and a chiral squaramide, where phosphine ligand was not necessary (Scheme 1b). Herein, we report the details of this study.

Section snippets

Experimental

Unless stated otherwise, the title reactions were carried out in flame-dried glassware under a dry argon atmosphere. All solvents were purified and dried according to standard methods prior to use. The ligands L1L7, and catalysts C1C5 were prepared following known procedures. The squaramide C6C10 were purchased from Daicel Chiral Technologies (China).

1H and 13C NMR spectra were recorded on a Varian instrument (400 and 100 MHz; 600 and 151 MHz, respectively) or an Agilent instrument (400 and

Results and discussion

Initial studies were performed by employing 8-nitro-imidazo[1,2-a]pyridine (1a) and α-phenyl isocyanoacetate (2a) as the substrates (Table 1). The previous optimal catalytic system for interrupted Barton-Zard reaction of 3-nitroindoles that consists of Ag2O (5 mol%) and cinchonine-derived amino-phosphine L1 (5 mol%) was first examined in Et2O at room temperature (rt) [39], [40], [41]. Gratifyingly, the target reaction proceeded well, delivering the dearomatized product 3aa in 51% NMR yield with

Conclusion

We have developed an efficient diastereo- and enantioselective synthesis of highly functionalized imidazo[1,2-a]pyridine derivatives possessing three contiguous stereogenic centers through an interrupted Barton-Zard reaction of 8-nitroimidazo[1,2-a]pyridine and α-substituted isocyanoacetates by a Ag2O/squaramide cooperative catalytic system. The protocol features operational simplicity, mild reaction conditions, and wide substrate scope. The loading of Ag2O and squaramide can be lowered to

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgments

This work was supported by the National Key R&D Program of China (2021YFA1500100), the National Natural Science Foundation of China (21821002, 22031012, and 22171282), and the Science and Technology Commission of Shanghai Municipality (19590750400 and 21520780100).

Author contributions

Qian Wan carried out the experiments and drafted the manuscript. Chao Zheng, Yao-Feng Yuan, and Shu-Li You revised the manuscript. Shu-Li You and Yao-Feng Yuan supervised the whole study. All of the authors discussed the results and commented on the manuscript.

Qian Wan received her M.S. degree in Organic Chemistry from Fuzhou University in 2015, supervised by Prof. Yao-Feng Yuan. Then, she completed her Ph.D. degree in Organic Chemistry jointly supervised by Prof. Yao-Feng Yuan at Fuzhou University and Prof. Shu-Li You at Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences in 2022. Her research focuses on the development of asymmetric synthetic methodology and applications.

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  • Qian Wan received her M.S. degree in Organic Chemistry from Fuzhou University in 2015, supervised by Prof. Yao-Feng Yuan. Then, she completed her Ph.D. degree in Organic Chemistry jointly supervised by Prof. Yao-Feng Yuan at Fuzhou University and Prof. Shu-Li You at Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences in 2022. Her research focuses on the development of asymmetric synthetic methodology and applications.

    Yao-Feng Yuan obtained his Ph.D. degree of Organic Chemistry at Nankai University in 1993. He worked as a Professor at Nankai University in 1998. Subsequently he collaborated with Prof. Luis A. Oro in Zaragoza University, Prof. Meir Lahav in Weizmann Institute of Science, Prof. C. Goerller-Walrand and K. Binnemans in KU Leuven as a postdoctoral researcher (1999–2005). Since 2005, he has been appointed as the Director of Organic Chemistry Discipline at Fuzhou University. His research focuses on synthetic and application of organic functional molecules.

    Shu-Li You obtained his Ph.D. degree from the Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences in 2001 under the supervision of Prof. Li-Xin Dai before doing postdoctoral studies with Prof. Jeffery W. Kelly at the Scripps Research Institute. From 2004, he worked at the Genomics Institute of the Novartis Research Foundation as a Principal Investigator before returning to SIOC in 2006. His current research interest includes asymmetric catalysis, synthetic methodology, natural product synthesis, as well as medicinal chemistry.

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