Article pubs.acs.org/joc
In Situ Generation of Quinolinium Ylides from Diazo Compounds: Copper-Catalyzed Synthesis of Indolizine Rongxiang Chen,† Yanwei Zhao,† Hongmei Sun,*,† Ying Shao,†,‡ Yudong Xu,† Meihua Ma,† Liang Ma,† and Xiaobing Wan*,† †
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China ‡ Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Advanced catalysis and Green Manufacturing Collaborative Innovation Center, Changzhou University, Changzhou 213164, P. R. China. S Supporting Information *
ABSTRACT: The Cu-catalyzed three-component reaction between quinolines, diazo compounds, and alkenes has been established for direct construction of indolizine derivatives via quinolinium ylides. This methodology is distinguished by the use of a commercially inexpensive catalyst and readily available starting materials, wide substrate scope, and operational simplicity.
■
INTRODUCTION
inexpensive transition metal as a catalyst with a wide substrate scope presents an important challenge in this field. Indolizine derivatives are particular structural units in the heterocycle class, some of which widely occur in natural products and biologically active substances.10 In particular, synthetic pharmaceuticals bearing this structural unit have been widely applied to clinical treatment as antifungal,11 anticancer,12 anti-inflammatory,13 and antitubercular agents.14 Based on these applications, development of efficient methodologies for the synthesis of indolizines has attracted great attention in recent years. Traditionally, indolizines are synthesized by cyclization of pyridines with a free C-2 position,15 cyclization of pyridines with specific C-2 functionalization,16 cycloisomerization from alkynylpyridine derivatives,17 the reaction of pyridotriazoles with alkynes,18 and 1,3-dipolar cycloaddition.4g,19 Although a variety of synthetic methods for construction of indolizines have been reported, these methods often have drawbacks. Thus, it is still highly valuable to develop more simple and efficient strategies for construction of indolizines. Herein, we report in situ generation of quinolinium ylides from quinolines and diazo compounds using inexpensive copper as a catalyst and subsequent oxidative cyclization to give indolizine derivatives with a broad substrate scope under mild conditions (Scheme 1e).
As special nitrogen ylides, pyridinium ylides are a class of important intermediates with wide applications in organic synthesis.1 They are readily accessible nucleophiles and can undergo a wide range of conversion reactions, such as the Michael addition,2 cyclopropanation,3 and 1,3-dipolar cycloaddition.4 Traditionally, methods to generate pyridinium ylides mainly involve the use of pyridinium salts with the aid of bases (Scheme 1a).5 However, these methods usually suffer from some inherent limitations, including the formation of large amounts of conjugate-acid waste, a narrow substrate scope, and the need for polar solvents. The catalytic formation of pyridinium ylides from pyridine and diazo compounds6 is definitely a more efficient and green strategy than traditional strategies with respect to step economy. In 1993, Padwa et al. reported the Rh(II)-catalyzed reaction of α-diazoacetophenone, pyridine, and dimethyl acetylenedicarboxylate,7 which proceeds through the in situ generation of pyridinium ylide (Scheme 1b). Afterward, the group of Barluenga and Tomás disclosed the first successful example of the metal-catalyzed cyclization of pyridine with alkenyldiazo compounds, leading to substituted indolizines (Scheme 1c).8 Recently, Dowden’s group developed an iron- and copper-catalyzed stereoselective synthesis of tetrahydroindolines by using pyridines, diazo compounds, and electrophilic alkenes, which made a contribution for developing the multicomponent reactions of pyridinium ylides from metal carbenes (Scheme 1d).9 To our surprise, little attention has been paid to the generation of quinolinium ylides from quinolines and diazo compounds. In addition, using an © 2017 American Chemical Society
Received: May 1, 2017 Published: August 1, 2017 9291
DOI: 10.1021/acs.joc.7b01042 J. Org. Chem. 2017, 82, 9291−9304
Article
The Journal of Organic Chemistry Scheme 1. In Situ Formation of Pyridinium Ylides
■
RESULTS AND DISCUSSION First, we investigated the reaction of quinoline 1a, dimethyl fumarate 2a, and ethyl diazoacetate 3a. It was found that the reaction gave the desired product 4a in 73% yield using CuF2 as catalyst and DCE as solvent at 80 °C after 24 h, along with the formation of byproduct 4a′ from the dimerization of ethyl diazoacetate 3a and subsequent reaction with quinoline 1a (Table 1, entry 1). Encouraged by this promising result, further solvent screening was performed and 1,1,2-trichloroethane gave the higher yield of 83% (Table 1, entries 2−14). The mixed solvent system of DCE/1,1,2-trichloroethane (1:1) gave 87% yield (entry 15). Subsequently, investigation of different copper catalysts showed that other copper catalysts also gave product but in lower yield (entries 16−22). It should be noted that no desired product 4a was produced in the absence of copper catalyst (entry 23). Other common metal catalysts were found to not be suitable for this transformation (entry 24). Further examination on reducing reaction time and amount of catalyst showed less efficient results (entries 25−31). No desired product 4a was detected under a N2 atmosphere (entry 32, see Scheme 2 later). In sharp contrast, product 4a was isolated in 85% yield under O2 atmosphere, indicating that molecular oxygen acts as an essential oxidant for this indolizine formation reaction (entry 33). When dimethyl maleate was used instead of dimethyl fumarate, 4a was generated in 69% yield (entry 34). Notably, 80% yield of 4a was obtained even in the absence of PPh3 (entry 35), indicating it served as an additive in this transformation. The exact structure of 4a was unambiguously determined by X-ray crystallography (see Supporting Information). With the optimal reaction conditions in hand (Table 1, entry 15), the scope and generality of the quinoline, electrondeficient olefin, and diazo compound derivative in this transformation were investigated. As shown in Table 2,
quinoline substrates with substituents at 4, 6, and 8 positions could be converted to the corresponding products (4b−4g) in satisfactory yields. In addition to dimethyl fumarate, we investigated the substrate scope with respect to alkenes. A variety of mono- and disubstituted electron-deficient alkenes, including acrylic ester and fumarate esters, gave the corresponding products (4h−4r) in moderate to excellent yields. It is noteworthy that a variety of functional groups, such as cyano (4i), trifluoromethyl (4l), and hydroxyl (4m), were tolerated under the standard conditions. Furthermore, isobornyl acrylate with rigid structure was also a suitable substrate in this transformation (4o). Next, the scope of the synthesis of pyrrolo[1,2-a]quinolines for different diazo compounds was evaluated. In all of the cases, the different ester groups in the αdiazo compounds reacted well to give the corresponding pyrrolo[1,2-a]quinolines in modest to good yields (4s−4aa). Diazo compound containing furan heteroaryl was also compatible with this transformation, giving the desired product 4y in 81% yield. In addition, a variety of functional groups, such as allyl (4v, 4x) and propargyl (4z) groups, did not affect the reaction profile. Dimethyl diazoacetamide also gave the corresponding product 4w in 20% yield. As well as pyrrolo[1,2-a]quinoline, pyrrolo[2,1-a]isoquinoline derivatives20 are also the focus of this research. With the optimized reaction conditions established (see Table S1), we investigated the generality and limitations of representative substrates containing synthetically useful functional groups. As shown in Table 3, the reaction is not significantly affected by the substituents on the aromatic ring of isoquinoline, giving the corresponding pyrrolo[2,1-a]isoquinolines (6b−6e) in reasonable yields. For various substituted acrylates, the groups on the acrylates were tolerated under standard conditions (6f−6n). Notably, isobornyl acrylate and dodecaperfluoroheptyl acrylate were also suitable and gave 9292
DOI: 10.1021/acs.joc.7b01042 J. Org. Chem. 2017, 82, 9291−9304
Article
The Journal of Organic Chemistry Table 1. Optimizations of Reaction Conditions of Quinoline 1a, Olefin 2a, and Diazo Compound 3aa
entry
catalyst
loading of catalyst (mol %)
solvent
t (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24c 25 26 27 28 29 30 31 32d 33e 34f 35g
CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuI CuCl2 CuBr2 Cu(OAc)2 CuO Cu(acac)2 Cu(OTf)2
20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20
other metal CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2
20 20 20 20 20 10 5 1 20 20 20 20
DCE 1,1,2-C2H4Cl3 CH3CN THF toluene dioxane DMF DMSO EtOH i-PrOH H2O Acetone hexane cyclohexane 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE
24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 12 6 4 2 24 24 24 24 24 24 24
73 83 56
In Situ Generation of Quinolinium Ylides from Diazo Compounds: Copper-Catalyzed Synthesis of Indolizine Rongxiang Chen,† Yanwei Zhao,† Hongmei Sun,*,† Ying Shao,†,‡ Yudong Xu,† Meihua Ma,† Liang Ma,† and Xiaobing Wan*,† †
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China ‡ Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Advanced catalysis and Green Manufacturing Collaborative Innovation Center, Changzhou University, Changzhou 213164, P. R. China. S Supporting Information *
ABSTRACT: The Cu-catalyzed three-component reaction between quinolines, diazo compounds, and alkenes has been established for direct construction of indolizine derivatives via quinolinium ylides. This methodology is distinguished by the use of a commercially inexpensive catalyst and readily available starting materials, wide substrate scope, and operational simplicity.
■
INTRODUCTION
inexpensive transition metal as a catalyst with a wide substrate scope presents an important challenge in this field. Indolizine derivatives are particular structural units in the heterocycle class, some of which widely occur in natural products and biologically active substances.10 In particular, synthetic pharmaceuticals bearing this structural unit have been widely applied to clinical treatment as antifungal,11 anticancer,12 anti-inflammatory,13 and antitubercular agents.14 Based on these applications, development of efficient methodologies for the synthesis of indolizines has attracted great attention in recent years. Traditionally, indolizines are synthesized by cyclization of pyridines with a free C-2 position,15 cyclization of pyridines with specific C-2 functionalization,16 cycloisomerization from alkynylpyridine derivatives,17 the reaction of pyridotriazoles with alkynes,18 and 1,3-dipolar cycloaddition.4g,19 Although a variety of synthetic methods for construction of indolizines have been reported, these methods often have drawbacks. Thus, it is still highly valuable to develop more simple and efficient strategies for construction of indolizines. Herein, we report in situ generation of quinolinium ylides from quinolines and diazo compounds using inexpensive copper as a catalyst and subsequent oxidative cyclization to give indolizine derivatives with a broad substrate scope under mild conditions (Scheme 1e).
As special nitrogen ylides, pyridinium ylides are a class of important intermediates with wide applications in organic synthesis.1 They are readily accessible nucleophiles and can undergo a wide range of conversion reactions, such as the Michael addition,2 cyclopropanation,3 and 1,3-dipolar cycloaddition.4 Traditionally, methods to generate pyridinium ylides mainly involve the use of pyridinium salts with the aid of bases (Scheme 1a).5 However, these methods usually suffer from some inherent limitations, including the formation of large amounts of conjugate-acid waste, a narrow substrate scope, and the need for polar solvents. The catalytic formation of pyridinium ylides from pyridine and diazo compounds6 is definitely a more efficient and green strategy than traditional strategies with respect to step economy. In 1993, Padwa et al. reported the Rh(II)-catalyzed reaction of α-diazoacetophenone, pyridine, and dimethyl acetylenedicarboxylate,7 which proceeds through the in situ generation of pyridinium ylide (Scheme 1b). Afterward, the group of Barluenga and Tomás disclosed the first successful example of the metal-catalyzed cyclization of pyridine with alkenyldiazo compounds, leading to substituted indolizines (Scheme 1c).8 Recently, Dowden’s group developed an iron- and copper-catalyzed stereoselective synthesis of tetrahydroindolines by using pyridines, diazo compounds, and electrophilic alkenes, which made a contribution for developing the multicomponent reactions of pyridinium ylides from metal carbenes (Scheme 1d).9 To our surprise, little attention has been paid to the generation of quinolinium ylides from quinolines and diazo compounds. In addition, using an © 2017 American Chemical Society
Received: May 1, 2017 Published: August 1, 2017 9291
DOI: 10.1021/acs.joc.7b01042 J. Org. Chem. 2017, 82, 9291−9304
Article
The Journal of Organic Chemistry Scheme 1. In Situ Formation of Pyridinium Ylides
■
RESULTS AND DISCUSSION First, we investigated the reaction of quinoline 1a, dimethyl fumarate 2a, and ethyl diazoacetate 3a. It was found that the reaction gave the desired product 4a in 73% yield using CuF2 as catalyst and DCE as solvent at 80 °C after 24 h, along with the formation of byproduct 4a′ from the dimerization of ethyl diazoacetate 3a and subsequent reaction with quinoline 1a (Table 1, entry 1). Encouraged by this promising result, further solvent screening was performed and 1,1,2-trichloroethane gave the higher yield of 83% (Table 1, entries 2−14). The mixed solvent system of DCE/1,1,2-trichloroethane (1:1) gave 87% yield (entry 15). Subsequently, investigation of different copper catalysts showed that other copper catalysts also gave product but in lower yield (entries 16−22). It should be noted that no desired product 4a was produced in the absence of copper catalyst (entry 23). Other common metal catalysts were found to not be suitable for this transformation (entry 24). Further examination on reducing reaction time and amount of catalyst showed less efficient results (entries 25−31). No desired product 4a was detected under a N2 atmosphere (entry 32, see Scheme 2 later). In sharp contrast, product 4a was isolated in 85% yield under O2 atmosphere, indicating that molecular oxygen acts as an essential oxidant for this indolizine formation reaction (entry 33). When dimethyl maleate was used instead of dimethyl fumarate, 4a was generated in 69% yield (entry 34). Notably, 80% yield of 4a was obtained even in the absence of PPh3 (entry 35), indicating it served as an additive in this transformation. The exact structure of 4a was unambiguously determined by X-ray crystallography (see Supporting Information). With the optimal reaction conditions in hand (Table 1, entry 15), the scope and generality of the quinoline, electrondeficient olefin, and diazo compound derivative in this transformation were investigated. As shown in Table 2,
quinoline substrates with substituents at 4, 6, and 8 positions could be converted to the corresponding products (4b−4g) in satisfactory yields. In addition to dimethyl fumarate, we investigated the substrate scope with respect to alkenes. A variety of mono- and disubstituted electron-deficient alkenes, including acrylic ester and fumarate esters, gave the corresponding products (4h−4r) in moderate to excellent yields. It is noteworthy that a variety of functional groups, such as cyano (4i), trifluoromethyl (4l), and hydroxyl (4m), were tolerated under the standard conditions. Furthermore, isobornyl acrylate with rigid structure was also a suitable substrate in this transformation (4o). Next, the scope of the synthesis of pyrrolo[1,2-a]quinolines for different diazo compounds was evaluated. In all of the cases, the different ester groups in the αdiazo compounds reacted well to give the corresponding pyrrolo[1,2-a]quinolines in modest to good yields (4s−4aa). Diazo compound containing furan heteroaryl was also compatible with this transformation, giving the desired product 4y in 81% yield. In addition, a variety of functional groups, such as allyl (4v, 4x) and propargyl (4z) groups, did not affect the reaction profile. Dimethyl diazoacetamide also gave the corresponding product 4w in 20% yield. As well as pyrrolo[1,2-a]quinoline, pyrrolo[2,1-a]isoquinoline derivatives20 are also the focus of this research. With the optimized reaction conditions established (see Table S1), we investigated the generality and limitations of representative substrates containing synthetically useful functional groups. As shown in Table 3, the reaction is not significantly affected by the substituents on the aromatic ring of isoquinoline, giving the corresponding pyrrolo[2,1-a]isoquinolines (6b−6e) in reasonable yields. For various substituted acrylates, the groups on the acrylates were tolerated under standard conditions (6f−6n). Notably, isobornyl acrylate and dodecaperfluoroheptyl acrylate were also suitable and gave 9292
DOI: 10.1021/acs.joc.7b01042 J. Org. Chem. 2017, 82, 9291−9304
Article
The Journal of Organic Chemistry Table 1. Optimizations of Reaction Conditions of Quinoline 1a, Olefin 2a, and Diazo Compound 3aa
entry
catalyst
loading of catalyst (mol %)
solvent
t (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24c 25 26 27 28 29 30 31 32d 33e 34f 35g
CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuI CuCl2 CuBr2 Cu(OAc)2 CuO Cu(acac)2 Cu(OTf)2
20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20
other metal CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2 CuF2
20 20 20 20 20 10 5 1 20 20 20 20
DCE 1,1,2-C2H4Cl3 CH3CN THF toluene dioxane DMF DMSO EtOH i-PrOH H2O Acetone hexane cyclohexane 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE 1,1,2-C2H4Cl3/DCE
24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 12 6 4 2 24 24 24 24 24 24 24
73 83 56
