Facile Synthesis of Indolizines via 1,3-Dipolar Cycloadditions in [Omim

Aug 26, 2017 - On the other hand, imidazolium ILs can lower the LUMO of dipolarophiles through hydrogen bonding(61-64) or π–π+ interactions (Schem...
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Research Article pubs.acs.org/journal/ascecg

Facile Synthesis of Indolizines via 1,3-Dipolar Cycloadditions in [Omim]Br: The Promotion of the Reaction through Noncovalent Interactions Xiao Zhang, Guo-ping Lu,* Zhu-bing Xu, and Chun Cai Chemical Engineering College, Nanjing University of Science & Technology, Xiaolingwei 200, Nanjing 210094, P. R. China S Supporting Information *

ABSTRACT: Various indolizines are synthesized through one-pot, twostep 1,3-dipolar cycloadditions in recyclable [Omim]Br with high yields and a broad substrate scope. The promotion of noncovalent interactions between ionic liquids and substrates or intermediates on the reaction is discovered on the basis of the results of control and NMR experiments. Moreover, the 3-arylindolizines can also be prepared from low-activity arylmethylpyridinium ylides in the protocol.

KEYWORDS: Indolizine, 1,3-Dipolar cycloaddition, [Omim]Br, Noncovalent interactions, Pyridinium ylides

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INTRODUCTION

not performed well in the data. To solve these issues, we envisage the exploration of an efficient route for the formation of indolizines via 1,3-dipolar cycloadditions in green solvents. On the other hand, imidazolium ILs can lower the LUMO of dipolarophiles through hydrogen bonding61−64 or π−π+ interactions (Scheme 1a),65 accelerate the Menschutkin reaction to in situ generate pyridinium ylides, and enhance the process to afford the 1,3-dipoles derived from pyridinium ylides

Imidazolium ionic liquids (ILs), as one of the first to find applications on an industrial scale, play multiple roles in organic synthesis.1−5 Although the environmental fate of ILs is a complex situation, such as their modes of toxicity, biodegradation pathways, and behavior concerning biosorption,6−9 imidazolium ILs are considered to be a greener solvent than other organic solvents because of their negligible vapor pressure, nonflammability, and recyclability.10−12 Moreover, the noncovalent interactions between ILs and substrates (or intermediates) such as electrostatic association, hydrogen bonding, and π−π stacking, exhibit a crucial promotion in some organic reactions.13−23 Therefore, the exploration of organic reactions in imidazolium ILs, in which noncovalent interactions can promote the reaction, is an appealing and greener alternative to organic synthesis.11,13−23 Indolizines have diverse biological activities,24−26 and photophysical properties,27,28 and can be used as intermediates of other nitrogen heterocycles,29,30 so many approaches have been developed for the synthesis of these compounds.31−37 Among them, 1,3-dipolar cycloadditions of pyridinium ylides with unsaturated hydrocarbons are one of the most convergent and straightforward approaches toward functionalized indolizines.38−44 Nevertheless, a major drawback of this method is that toxic, flammable, and volatile solvents such as DMF, THF, and CHCl3 are often required,45−48 which is obviously contrary to the principle of green chemistry.49−55 Furthermore, the scope of unsaturated hydrocarbons and low-activity arylmethylpyridinium ylides is limited. Although several approaches for 1,3-dipolar cycloadditions from arylmethylpyridinium ylides have been explored,56−60 the advances of these strategies have © 2017 American Chemical Society

Scheme 1. Working Hypothesis: The Noncovalent Interactions between ILs and Substrates (Intermediates or Transition States) in 1,3-Polar Cycloadditions

Received: July 6, 2017 Revised: August 18, 2017 Published: August 26, 2017 9279

DOI: 10.1021/acssuschemeng.7b02241 ACS Sustainable Chem. Eng. 2017, 5, 9279−9285

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Table 1. Optimization Reaction Conditionsa

(Scheme 1b).14,65−67 Moreover, 1,3-dipoles can also be stabilized via electrostatic interactions (Scheme 1b).67 On the basis of these results, we reasoned that imidazolium-based ILs could be ideal solvents for the 1,3-dipolar cycloadditions of pyridinium ylides, in which the reaction may be reinforced by the noncovalent interactions between ILs and substrates (intermediates or transition states). To the best of our knowledge, this is the first example on 1,3-dipolar cycloadditions for the synthesis of indolizines in ILs and exploration of the activation mechanism of ILs in this transformation.68−70

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entry

oxidant (x)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

AIBNc (3.0) TBHP (3.0) DTBP (3.0) K2S2O8 (3.0) TBHP (3.0) TBHP (3.0) TBHP (3.0) TBHP (3.0) TBHP (3.0) TBHP (3.0) TBHP (3.0) TBHP (2.0) TBHP (1.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0)

EXPERIMENTAL DETAILS

General Remarks. All chemical reagents were obtained from commercial suppliers and used without further purification. All known compounds were identified by using appropriate techniques such as 1 H NMR, 13C NMR, and MS. All unknown compounds were characterized by 1H NMR, 13C NMR, MS, and elemental analyses. Analytical thin-layer chromatography was performed on glass plates precoated with silica gel impregnated with a fluorescence indicator (254 nm). GC analyses were performed on an Agilent 7890A instrument (column, Agilent 19091J-413, 30 m × 320 μm × 0.25 μm, H. FID). All NMR spectra were recorded on an AVANCE 500 Bruker spectrometer operating at 500 and 125 MHz in CDCl3, respectively, and chemical shifts were reported in ppm. GC−MS data was recorded on a 5975C mass-selective detector, coupled with a 7890A gas chromatograph (Agilent Technologies). Elemental analyses were performed on a Yanagimoto MT3CHN recorder. General Procedure for the 1,3-Diploar Cycloadditions of Alkenes in [Omim]Br. A mixture of organic bromide 2 0.75 mmol, and pyridine 3 0.75 mmol were added in [Omim]Br (1.0 mL), which was stirred at 50 °C for 2 h. Then, alkene 1 0.5 mmol, Na2CO3 1.5 mmol, and TBHP (tert-butyl hydroperoxide) 1.0 mmol were added and further stirred for 22 h at 110 °C. Upon completion, the reaction mixture was extracted by methyl tert-butyl ether (MTBE) (3 × 2 mL). The organic phase was collected and removed in vacuo to afford the crude product. Further column chromatography on silica gel was needed to afford the pure product 4, 7, or 8a. General Procedure for the 1,3-Diploar Cycloadditions of Alkynes in [Omim]Br. A mixture of organic bromide 2 0.75 mmol, and pyridine 3 0.75 mmol were added in [Omim]Br (1.0 mL), which was stirred at 50 °C for 2 h. Then, alkyne 5 0.5 mmol and Cs2CO3 0.6 mmol were added and further stirred for 6 h at 50 °C. Upon completion, the reaction mixture was extracted by methyl tert-butyl ether (MTBE) (3 × 2 mL). The organic phase was collected and removed in vacuo to afford the crude product. Further column chromatography on silica gel was needed to afford the pure product 6, 7, or 8b. Procedure of Recycling [Omim]Br. After reaction completion, the mixture was then extracted with MTBE (3 × 10 mL). The organic layer was collected, and removed in vacuo to afford the crude product 8b. A portion of 1-(benzofuran-3-yl)-2-bromoethanone 11 mmol and pyridine 11 mmol was added to the phase of IL, and stirred at 50 °C for 2 h. Then, methyl propiolate 10.0 mmol and Cs2CO3 10.0 mmol were added at the same temperature and the reaction stirred for 10 h at 50 °C. The extraction cycle was then repeated for the separation of 8b.

base

solvent

yieldb (%)

K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 Cs2CO3 Na2CO3 DBUf NaOH t-BuOK NEt3

[Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omimm]Br [Omim]I [Omim]Cl [Omim]OAc [Omim]OAc [Omim]NTf2 [Omim]MeSO3 [Omim]HSO4 [Hmim]Br [Bmim]Br DMF 1,4-dioxane THF H2O hexane acetonitrile

15 17 28 21 nr 28 40, 26d, 21e 24 28 31 13 trace 45, 46g, 27h 25 74 57 68 75 77 33 59 73 trace 72 71 36 trace 45 nri trace 26

Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3

a

Conditions for entries 1−14: [step 1] 2a 1.0 mmol, 3a 1.0 mmol, [OmimBr] 1.0 mL, 50 °C, 2 h; [step 2] 1a 0.5 mmol, oxidant x equiv, base 3.0 equiv, 110 °C, 4 h. Conditions for entries 15−27: [step 1] 2a 0.75 mmol, 3a 0.75 mmol, solvent 1.0 mL, 50 °C, 2 h; [step 2] 1a 0.5 mmol, TBHP 2.0 equiv, Na2CO3 3.0 equiv, 110 °C, 22 h. bIsolated yields. cAIBN = 2,2′-azobis(2-methylpropionitrile). d2.0 equiv of Na2CO3 was used. e1.0 equiv of Na2CO3 was used. fDBU = 1,8-diazabicyclo[5.4.0]undec-7-ene. g2a 0.75 mmol and 3a 0.75 mmol were used. h2a 0.5 mmol and 3a 0.5 mmol were used. inr = not recorded.

For further improvement of unsatisfactory yields, prolonging the reaction time to 22 h was necessary (entry 15). [Omimm]Br (1,2-dimethyl-3-octyl-1H-imidazolium bromide) was employed as the solvent to confirm the effects of the C2 hydrogen of imidazole. The results suggested that a slight influence was found during the process (entries 15 versus 16), which can be attributed to the hydrogen bonds between the C2 hydrogen of imidazole and substrates.14,20−23 A series of ILs with different anions were screened (entries 17−23). The basic IL is beneficial to the reaction, and a poor yield could be afforded even in the absence of base (entries 19 and 20). Nevertheless, acidic IL can inhibit the reaction since the base is consumed by the IL (entry 23). In view of both yield and cost, [Omim]Br proved to be the best IL. The length of alkyl groups has no evident effect on the chemistry (entries 24 and 25).

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RESULTS AND DISCUSSION To verify the feasibility of our proposed assumption, we started the investigation by selecting the reaction of ethyl cinnamate 1a, ethyl bromoacetate 2a, and pyridine 3a as the model reaction to optimize the reaction conditions (Table 1). Both oxidants and bases could promote the reaction. After a screening of different bases and oxidants (entries 1−12), the combination of Na2CO3 and TBHP emerged as the best option (entry 7). The amounts of Na2CO3, TBHP, 2a, and 3a were also optimized, and 2.0 equiv of TBHP, 3.0 equiv of Na2CO3, and 1.5 equiv of 2a and 3a proved to be the best choice (entry 13). 9280

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smoothly under identical conditions (4k). Other pyridines also worked in the reaction (4j, 4l). Although styrene failed to afford the final indolizine, a moderate yield of 67% was produced in the reaction of α-vinylpyridine (4g). A undesired product 4m was obtained when 4-methoxychalcone was used. In the reaction of 4-nitrochalcone, a mixture of 3n and 3n′ was isolated, whose yields were determined by GC and 1H NMR. To our delight, the 1,3-polar cycloadditions of alkynes with pyridines and organic bromides in [Omim]Br occurred under milder conditions (50 °C). The kinds of bases and solvents were optimized (Table 2). The results indicated that

Several organic solvents were also screened (entries 26−31). As expected, [Omim]Br provided the best results. With the optimized conditions in hand, a series of alkenes and organic bromides were applied to establish the scope and generality of the protocol (Scheme 2). Ethyl bromoacetate, Scheme 2. Reaction of Electron-Deficient Alkenes, Organic Bromides, and Pyridines in [Omim]Bra

Table 2. Optimization Reaction Conditionsa

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

solvent [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br [Omim]Br DMF 1,4-dioxide THF H2O hexane acetonitrile

base (x equiv) K3PO4 (3.0) Cs2CO3 (3.0) Na2CO3 (3.0) DBU (3.0) NaOH (3.0) t-BuOK (3.0) NEt3 (3.0) Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

(1.0) (2.0) (1.2) (1.2) (1.2) (1.2) (1.2) (1.2) (1.2)

yieldb (%) c

20 , 62, 60d, 54e 93 24 89 trace 87 80 nr 88 95 93, 64f, 92g 90g 62g 81g nrg 48g 83g

Conditions: [step 1] 2a 1.0 mmol, 3a 1.0 mmol, 50 °C, 2 h; [step 2] 5a 0.5 mmol, base 1.5 mmol, solvent, 1.0 mL, 50 °C, 6 h. bIsolated yields. cAt room temperature. dAt 80 °C. eAt 110 °C. fThe molar ratio of 5a/2a/3a is 1/1/1. gThe molar ratio of 5a/2a/3a is 1/1.5/1.5.

a

an excellent yield 92% could be derived in the model reaction at 50 °C for 6 h in [Omim]Br using Cs2CO3 as the base (entry 11). Further investigations indicated that various arynes could be applied in the process (Scheme 3). Electron-deficient arynes led to good-to-excellent yields of the desired products (6a−6d, 6g, 6i), but the reactions were sluggish in the cases of electron-rich arynes (6e, 6f, 6h), presumably because of their higher LUMO than electron-deficient ones.61−64 Other organic bromides and pyridines still worked under identical conditions to yield the desired products (6j−6l, 6n, 6o); however, no reaction took place in the cases of pyridine with electron-withdrawing groups (such as 4-cyanopyrdine). The reaction of ethynyltriisopropylsilane resulted in a moderate yield of 6m, which could be further modified because of the silicon substitution in the 1-position. A series of internal alkynes also afforded the corresponding 1,2,3-trisubstituted indolizines (6p−6u). In the cases of 6a, 6c, 6d, and 6j, good-to-excellent yields could also be obtained even at room temperature by prolonging the time to 22 h [step 2]. However, no desired

a

Conditions: [step 1] 2 0.75 mmol, 3a 0.75 mmol, [Omim]Br 1.0 mL, 50 °C, 2 h; [step 2] 1 0.5 mmol, Na2CO3 1.5 mmol, TBHP, 1.0 mmol, 110 °C, 22 h, isolated yields. b50 °C, 22 h [step 2]. cIsoquinoline instead of pyridine was used. d4-Methylpyridine instead of pyridine was used. eThe yields were detected by GC and 1H NMR.

bromoacetonitrile, and 2-bromoacetophenone could react with pyridine and acrylic esters to yield the desired products (4b−4d), and the order of reactivity for them is 2-bromoacetophenone > ethyl bromoacetate > bromoacetonitrile. In the cases of α,β-unsaturated esters including acrylic esters and ethyl cinnamate, moderate-to-good yields were obtained (4a−4d, 4j). Likewise, the corresponding indolizines were also afforded with good yields using acrylonitrile (4f, 4l) or acrylamide (4i) as the dipolarophiles. In the cases of 4e and 4h, the lower yields may be due to the stability of thiophene and high tension of five-member rings. However, the reaction of chalcone proceeded 9281

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ACS Sustainable Chemistry & Engineering Scheme 3. Reaction of Alkynes, Organic Halides, and Pyridines in [Omim]Bra

Scheme 4. 1,3-Dipolar Cycloadditions of Pyridines, Benzyl Bromides, and Alkenes (Or Alkynes)a

a

Conditions: [step 1] 2 0.75 mmol, 3 0.75 mmol, [Omim]Br 1.0 mL, 50 °C, 2 h; [step 2] 5 0.5 mmol, Cs2CO3 0.6 mmol, 50 °C, 22 h, isolated yields. bConditions: [step 1] 2 0.75 mmol, 3a 0.75 mmol, [Omim]Br 1.0 mL, 50 °C, 2 h; [step 2] 1 0.5 mmol, Na2CO3 1.5 mmol, TBHP 1.0 mmol, 110 °C, 22 h, isolated yields. c110 °C [step 2]. dGC yield. e80 °C [step 2].

a Conditions: [step 1] 2 0.75 mmol, 3 0.75 mmol, [Omim]Br 1.0 mL, 50 °C, 2 h; [step 2] 5 0.50 mmol, Cs2CO3 0.60 mmol, 50 °C, 6 h, isolated yields. bRoom temperature, 22 h [step 2]. c110 °C, 22 h [step 2]. d22 h [step 2].

two anticonvulsant and anti-inflammatory indolizines (8a and 8b) were synthesized by 1,3-dipolar cycloadditions in [Omim]Br (Scheme 5).25 Further NMR experiments were also performed to confirm the hypothetical interactions between [Omim]Br and substrates (4-ethynylbenzonitrile, ethyl acrylate, and 1-(2-ethoxy-2oxoethyl)pyridin-1-ium bromide) (Figure 1). On the basis of these results, it is found that the proton at the C2 position of

product was observed under optimized conditions using but-1yn-1-ylbenzene as the substrate. It should be noted that benzyl bromides could also react with pyridines and unsaturated hydrocarbons under our optimized conditions (Scheme 4) because of the noncovalent interactions of [Omim]Br.65−67 Benzyl bromides with electron-withdrawing groups provided moderate-to-excellent yields of products (7a, 7c, 7d), but no reaction occurred in the reaction of benzyl bromides with electron-donating groups. To our delight, the reactions of benzyl bromide, 4-fluorobenzyl bromide, and 2-(bromomethyl)pyridine also worked via raising the temperature (7b, 7j, 7k). Unsurprisingly, the reaction happened when other pyridines or electron-deficient alkenes or alkynes were used. A 43% yield of 7g, a crucial intermediate of a xanthine oxidase inhibitor,71 was also obtained in the protocol. Moreover, alkynes have better reactivity than alkenes (7a, 7h, 7i). For further demonstration of the potential of this methodology,

Scheme 5. Synthesis of Anticonvulsant and AntiInflammatory Indolizines 8a and 8b in the Protocol

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Figure 2. Recycle studies. Conditions: [step 1] pyridine 12 mmol, 1-(benzofuran-3-yl)-2-bromoethanone 12 mmol, [Omim]Br 20 mL, 50 °C, 2 h; [step 2] methyl propiolate 10 mmol, Cs2CO3 11 mmol, 50 °C, 10 h, isolated yields.

Figure 1. 1H NMR spectra of [Omim]Br (a), the mixing of 4-ethynylbenzonitrile and [Omim]Br (b), 4-ethynylbenzonitrile (c), the mixture of ethyl acrylate and [Omim]Br (d), the mixture of 1-(2-ethoxy-2-oxoethyl)pyridin-1-ium bromide (e), and [Omim]Br (f) 1-(2-ethoxy-2-oxoethyl)pyridin-1-ium bromide (f).

take place in recyclable [Omim]Br under relatively mild conditions with high yields and a broad substrate scope, thereby making it more environmentally friendly and suitable for largescale operations, and offering considerable applications to complex targets in organic and medicinal chemistry. Low-activity arylmethylpyridinium ylides also provide the desired 3-arylindolizines in the protocol. This chemistry can be strengthened by noncovalent interactions in [Omim]Br including hydrogen bonding, π−π+, and electrostatic interactions, which are investigated by control experiments and 1H NMR spectroscopies. Other transformations in ILs are ongoing in our group.

the imidazolium moiety shifts from 10.14 (a) to 10.03 (b) in the presence of 4-ethynylbenzonitrile; meanwhile the proton of the alkinyl group in 4-ethynylbenzonitrile shifts from 3.30 (c) to 3.38 (b), which can be considered as evidence of the π−π+ interactions between the imidazolium moiety and the benzene ring (Scheme 1a).65 Conversely, the proton at the C2 position of the imidazolium moiety shifts from 10.14 (a) to 10.21 (d) in the presence of ethyl acrylate because of the hydrogen bonds between the C2 hydrogen of the imidazolium moiety with the carbonyl oxygen of ethyl acrylate (Scheme 1a).23,61−64 The delocalization of positive charge in the pyridinium moiety is enhance by electrostatic interactions, which increase the pyridine ring’s proton shift (e versus f).66,67 Moreover, the hydrogen bonding makes the C2 proton shift to a low field (10.14 to 10.20; a versus e), which may raise the acidity of 1-(2ethoxy-2-oxoethyl)pyridin-1-ium bromide (6.36 versus 6.34). Finally, investigations were also conducted to assess the potential for recycling of the reaction medium, and the reaction of methyl propiolate, pyridine, and (benzofuran-3-yl)-2-bromoethanone was selected as the model reaction. Meanwhile, the model reaction was scaled up to 10 mmol. After completion of reaction, the product undergoes in-flask extraction with minimum amounts of an organic solvent (MTBE). The phase of [Omim]Br was separated by simple extraction and reuse for next run. The process could be repeated 5 times without an obvious change in yields, but the flowability of [Omim]Br was decreasing along with the increase of the inorganic salt amount (Figure 2). In the first run, 96% [Omim]Br was recycled, and the purity and structure of recovered [Omim]Br remain unchanged on the basis of the 1H NMR results (Figure S1 in the SI).

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.7b02241. Additional experimental details and quantum chemical calculations, and copies of 1H NMR and 13C NMR spectra of all products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Guo-ping Lu: 0000-0003-4476-964X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the Natural Science Foundation of China (21402093), Jiangsu (BK20140776), and Chinese Postdoctoral Science Foundation (2016T90465, 2015M571761) for financial support. This work is a project funded by the Priority Academic Program development of Jiangsu Higher Education Institution.

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CONCLUSIONS In summary, a facile 1,3-dipolar cycloaddition reaction in [Omim]Br is described. These transition-metal-free reactions 9283

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