COMMUNICATION DOI: 10.1002/asia.201402096

A Reagent-Free Oxidative Cyclization Approach to Indolizine Derivatives from a-Picoline Derivatives and Nitroolefins Meng Gao,[a] Jun Tian,[a] and Aiwen Lei*[a, b]

Abstract: A reagent-free oxidative cyclization between a-picoline derivatives and nitroolefins has been developed. This approach, in which the nitro group acts as an internal oxidant, provides an extremely simple, efficient, and atom-economic way to construct heteroaromatic indolizine derivatives.

herent advantage of avoiding prefunctionalization of the substrates, and thus represent an ideal chemical synthesis.[3] However, these approaches often require transition-metal catalysts and a relatively large amount of external oxidants which are disfavored by the pharmaceutical industry. Seeking a reagent-free oxidative cyclization strategy is highly desirable with regard to practical significance and green chemistry. Nitroolefins, as easily available and versatile substrates, have been ubiquitously used in many synthetic strategies,[4] and the nitro group is also versatile in organic synthesis since it can be applied to further functionalization. In recent years, the application of nitroolefins in cycloaddition reactions has been particularly valued.[5] However, the potential oxidizing capacity of the nitro group on nitroolefins has been rarely studied. As part of our goal to obtain a general and practical oxidative cyclization strategy for the synthesis of heterocycles, we envisioned that nitroolefins could be the perfect starting materials in oxidative cross-coupling/cyclization reactions, in which the nitro group serves as an internal oxidant. Herein, we communicate our efforts in the reagent-free synthesis of polysubstituted indolizines through oxidative C C/C N cyclization between a-picoline derivatives and nitroolefins. This protocol addresses the previous limitations and furnishes a diverse collection of valuable polysubstituted indolizines from basic chemical starting materials (Scheme 1).

Indolizines and their partially saturated derivatives, with important antibacterial, antiviral, and anti-inflammatory properties, are key structural moieties in several pharmaceutical drugs such as the lamellarin alkaloids, a new family of marine natural products containing a pyrroloACHTUNGRE[2,1-a]isoquinoline core, which were found to exhibit a wide spectrum of biological activities (Figure 1).[1] As a result, numerous

Figure 1. Examples of important natural lamellarin alkaloids.

methods have been developed for the construction and modification of the indolizine structure,[2] although most of them suffer from low efficiency and selectivity, and require the use of complicated heterocyclic starting materials. Very recently, several new approaches using an oxidative cyclization strategy through direct C H and N H activation have been reported. Undoubtedly, these approaches have the in-

Scheme 1. Reagent-free oxidative C C/C N cyclization.

[a] M. Gao, J. Tian, Prof. Dr. A. Lei College of Chemistry and Molecular Sciences Wuhan University, Wuhan, 430072 (P. R. China) Fax: (+ 86) 27-68754672 E-mail: [email protected]

Our initial efforts focused on the reaction of methyl 2(pyridin-2-yl)acetate (1 a) and 1-(2-nitroprop-1-enyl)benzene (2 a) using copper(II) or ironACHTUNGRE(III) as the promoter. To our delight, we found that the corresponding indolizine cyclization product was obtained when either copper(II) or ironACHTUNGRE(III) salts were employed in the reaction, albeit in moderate yields (Table 1, entries 1 and 2). This interesting transformation prompted us to further examine the feasibility of this oxidative cross-coupling/cyclization.

[b] Prof. Dr. A. Lei National Research Center for Carbohydrate Synthesis Jiangxi Normal University Nanchang 330022, Jiangxi (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402096.

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Table 1. Optimization of the reaction conditions.[a]

Entry Additive 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

CuACHTUNGRE(OAc)2 (0.1 equiv) FeCl3 (0.1 equiv) CuACHTUNGRE(OAc)2 (0.1 equiv) CuACHTUNGRE(OAc)2 (0.1 equiv) – – – – – – – – – – –

Atmosphere t [h] T [8C] Solvent Yield [%][b] air

6

100

DMSO 67

air

6

100

DMSO 41

O2

6

100

DMSO 37

N2

6

100

DMSO 80

N2 N2 N2 N2 air N2 N2 N2 N2 N2 N2

6 10 15 24 15 15 15 15 15 15 15

100 100 100 100 100 100 100 100 80 40 120

DMSO DMSO DMSO DMSO DMSO DMF DCE toulene DMSO DMSO DMSO

44 61 78 75 56 67 37 31 70 17 79

[a] Reaction conditions: 1 a (0.3 mmol, 45.3 mg), 2 a (0.2 mmol, 32.6 mg) in 1 ml solvent. [b] Isolated yield.

In further experiments we then found the reaction conditions to be best under a nitrogen atmosphere in DMSO at 100 8C (Table 1, entry 7). The use of CuACHTUNGRE(OAc)2 (0.1 equiv) could accelerate this cyclization, which was complete in 6 hours (Table 1, entries 4–5). Without CuACHTUNGRE(OAc)2, the reaction time had to be extended to 15 hours to obtain a comparable yield. Further extension of the reaction time did not observably improve the yield (Table 1, entries 5–8). Replacement of the nitrogen atmosphere with air led to a lower yield (Table 1, entry 9). Decreases in the reaction temperature reduced the yield distinctly (Table 1, entries 13, 14), while an increase in the temperature did not improve the yield (Table 1, entry 15). The reaction could proceed in other solvents, such as N,N-dimethylformamide (DMF), 1,2dichloroethane (DCE), and toluene, albeit with lower yields (Table 1, entries 10–12). Various nitroolefins 2 were found to be suitable reaction partners for different a-picoline derivatives 1 to provide the corresponding indolizine products 3 in moderate to good yield (Scheme 2). This transformation showed excellent functional group tolerance. Various nitroolefins with methyl, methoxyl, cyano, fluoro, chloro, bromo, N,N-dimethyl, or trifluoromethyl groups on the arene resulted in moderate to good yields, and electronic effects had no significant impact on the yields (Scheme 2, 3 a–3 k). The steric effect of the bromo group lowered the yields slightly (Scheme 2, 3 c, 3 e). Notably, nitroolefins possessing a naphthyl or a furanyl group could also be transformed into the target indolizine product in good yield (Scheme 2, 3 l, 3 m). In addition, the cyclohexyl-substituted nitroolefin could also react smoothly with methyl 2-(pyridin-2-yl)acetate (1 a) to give the corre-

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Scheme 2. Substrate scope of the reaction.

sponding product in a moderate yield (Scheme 2, 3 n). Somewhat disappointingly, the transformation turned out to be less effective with R2 = H (Scheme 2, 3 o). In addition, various a-picoline derivatives 1 were tested to access the indolizine rings. Derivatives with different substitutions on the 2-(pyridin-2-yl)acetate could react with 1-(2-nitroprop-1enyl)benzene (2 a) smoothly to afford the respective products in good yields (Scheme 2, 3 q, 3 r). 1-(Pyridin-2-yl)propan-2-one also led to the corresponding indolizine without any difficulty. Moreover, a derivative bearing a cyano group

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could be transformed into the target indolizine product in good yield (Scheme 2, 3 s). This reaction system could also be applied on a larger scale under the optimized conditions. A mixture of 1 a (3.0 mmol, 0.453 g), 2 a (2.0 mmol, 0.326 g), and DMSO (2 mL) stirred at 100 8C for 18 h afforded the desired product in a yield of 67 % (0.355 g). To gain preliminary mechanistic insight into this transformation, we analyzed the composition of the atmosphere in the flask before and during the reaction by mass spectrometry (Figure 2) and gas chromatography. The results clearly

(2-nitroprop-1-enyl)benzene (2 a) first undergo a Michael addition to produce intermediates 5 and 6. Then, the intermediate 6 experiences an intramolecular nucleophilic attack to form 7, which gives 8 through tautomerization, and finally elimination of nitroxyl (judged by N2O formation)[6a, b] and H2O occurs to generate the product 3 a. In conclusion, we have developed a reagent-free oxidative cyclization between a-picoline derivatives and nitroolefins. This approach, in which the nitro group acts as an internal oxidant, provides a simple and efficient way to construct heteroaromatic indolizine derivatives.

Experimental Section Representative procedure: A mixture of methyl 2-(pyridin-2-yl)acetate (1 a, 0.3 mmol, 45.3 mg) and 1-(2-nitroprop1-enyl)benzene (2 a, 0.2 mmol, 32.6 mg) in DMSO (1 mL) was stirred under an atmosphere of N2 at 100 8C for 15 h. After completion of the reaction, as indicated by TLC and GC-MS, the mixture was diluted with 3 % aqueous Na2CO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over anhyFigure 2. Mass spectra of the atmosphere in the flask before (a) and during (b) the reaction. drous Na2SO4, filtered, and concentrated under vacuum. The residual oil was purified by chromatography (PE/EtOAc = 25:1) to afford the desired product 3 a (78 %, 41.3 mg).

showed that a gas was formed during the reaction. The molecular ion (m/z = 44) and fragments ion (m/z = 30) peaks revealed the generation of N2O (see the Supporting Information for further details). In addition, when we added CoCl2 and KCl to the reaction mixture after completion of the standard reaction, we did not observe the golden yellow precipitate of K3[CoACHTUNGRE(NO2)]6, which illustrates that nitrite was not formed in the system. Based on the experimental results and previous reports,[6] we propose the reaction mechanism shown in Scheme 3. In this mechanism, methyl 2-(pyridin-2-yl)acetate (1 a) and 1-

Acknowledgements This work was supported by the 973 Program (2012CB725302), the National Natural Science Foundation of China (21025206, 21272180 and 21302148). We are also grateful for the support from the Program for Changjiang Scholars and Innovative Research Team in University (IRT1030). We thank Prof. Lin Zhuang for providing the AMETEK Dycor mass spectrometer.

Keywords: green chemistry · indolizines · nitroolefins · oxidative cyclization · reagent-free · synthetic methods

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Scheme 3. Proposed mechanism for the oxidative C C/C N cyclization.

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COMMUNICATION Cyclization Meng Gao, Jun Tian, Aiwen Lei* Simply the best: A reagent-free oxidative cyclization between a-picoline derivatives and nitroolefins has been developed. This approach, in which the

nitro group acts as an internal oxidant, provides a simple and efficient way to construct heteroaromatic indolizine derivatives.

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A Reagent-Free Oxidative Cyclization Approach to Indolizine Derivatives from a-Picoline Derivatives and Nitroolefins

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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