One-pot synthesis of indolizine via 1,3-dipolar cycloaddition using a sub-equivalent amount of K₂Cr₂O₇ as an efficient oxidant under base free conditions

Abstract

A one-pot method for synthesizing multi-substituted indolizines from α-halo-carbonyl compounds, pyridines and electron deficient alkenes was developed. A sub-equivalent amount of potassium dichromate was used as an oxidant under base free conditions. The transformation developed should be of economic efficiency.

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Hydrogenated indolizines, commonly known as indolizidines, are abundant in many natural products and drugs.¹ Also indolizines are important heterocycles that exhibit a broad array of bioactivities, for example, antibacterial, phosphatase and aromatase inhibitory, antioxidant, antidepressant and antitumor activities.² In addition, indolizine derivatives have been extensively applied in analytic chemistry and materials science as fluorescent probes and organic semiconductors respectively.³

Undoubtedly, methods for synthesizing indolizines are attracting great interests of organic chemists.^4,5 Among these reported methods, 1,3-dipolar cycloaddition of electron deficient alkenes with pyridinium ylides in the presence of an oxidant and a base was one of the most efficient because of broad scope and easy availability of starting materials.⁵ However, several drawbacks were still associated with these methods, such as the use of excess amounts of oxidant and base (Scheme 1).

Scheme 1 The schematic comparison of this work with previous works.

As regarding to oxidants, oxidants containing Cr(VI) were widely applied in indolizine synthesis, for example tetrakispyridinecobalt(II) dichromate (TPCD)⁵ⁱ and tetrakispyridinenickel(II) dichromate (TPND).^5k However, the required use of excessive oxidant and base raised the cost and environmental concerns (Table 1). To circumvent these problems and pursue our interests in indolizines green synthesis,^5k,7 we were considered the use of a reagent which could serve as high efficient oxidant and base simultaneously. Under these conditions, the reaction could be base free. Herein, we report the use of sub-equivalent potassium dichromate⁶ as an oxidant for the one-pot synthesis of indolizines from electron deficient alkenes under base free conditions.

Table 1 The comparison of amounts of oxidant and base using in this work with previously reported results

entry	Oxidant (M. W.^a), amount (equiv.)^b	Base, amount (equiv.)^b	Ref. no.
a M. W. = molecular weight.b Based on the limited starting materials.
1	TPCD (811), 1.0	Pyridine, 2.5	5h
2	TPND (812), 1.0	NEt3, 2.2	5i
3	MnO2 (86.9), 8.0	NEt3, 1.1	5j
4	Cu(OAc)2 (200), 3.0	NaOAc, 6.0	5k
5	K2Cr2O7 (294), 0.75	Base free	This work

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In the preliminary study, in order to optimize the reaction condition, we chose 1-(2-oxo-2-phenylethyl)pyridinium bromide 3aa (0.20 mmol, 1.0 equiv.) and butyl acrylate 4a in DMF (N,N-dimethyl formamide, 3.0 mL) as our reaction model system. Several cheap and commercially available Cr(VI) compounds, including potassium dichromate, potassium chromate and chromium trioxide were tested within this system under base free conditions. Fortunately, the desired product 5a was isolated in 68% yield with potassium dichromate as the oxidant. However, using potassium chromate or chromium trioxide, only trace or 36% of 5a were obtained, respectively (Table 2, entry 2 and 3). Furthermore, 0.75 equivalent of potassium dichromate (0.15 mmol) was proven to be most efficient (Table 2, entry 1, 4–6). Further investigation on reaction conditions led us to establish the optimized reaction conditions as follows: 0.75 equivalent of potassium dichromate, 2.0 mL of DMF, heating at 80 °C for 8 h with 1.5 equiv. of 4a (Table 2, entry 10). Notably, the yield of 5aa was just slightly lower when one-pot procedure was applied (Table 1, entry 13).⁸

Table 2 The optimization of reaction conditions

Entry	Oxidant	Amount (mmol)	Ratio (3a/4a)	Solvent (mol L^−1)	Yield^a (%)
a Isolated yield.b Other solvents include water, dimethyl sulfoxide, toluene, acetonitrile, 1,4-dioxane and dimethyl carbonate.c One-pot reaction starting from pyridine (1a, 0.21 mmol) and 2-bromo-1-phenylethan-1-one (2a, 0.20 mmol) in 0.20 mL of DMF: the mixture were heated at 60 °C in a test tube with a stopper for 2 h to form 3aa in situ, and then reacted with butyl acrylate (4a, 0.30 mmol) in the presence of potassium dichromate (0.15 mmol) under 80 °C for 8 h with another 1.80 mL of DMF added as solvent.
1	K2Cr2O7	0.13	1/2	DMF (0.067)	68
2	K2CrO4	0.26	1/2	DMF (0.067)	Trace
3	CrO3	0.26	1/2	DMF (0.067)	36
4	K2Cr2O7	0.15	1/1.5	DMF (0.067)	95
5	K2Cr2O7	0.17	1/1.5	DMF (0.067)	94
6	K2Cr2O7	0.20	1/1.5	DMF (0.067)	90
7	K2Cr2O7	0.15	1/1.2	DMF (0.067)	93
8	K2Cr2O7	0.15	1/3	DMF (0.067)	96
9	K2Cr2O7	0.15	1/1.5	DMF (0.20)	78
10	K2Cr2O7	0.15	1/1.5	DMF (0.10)	96
11	K2Cr2O7	0.15	1/1.5	DMF (0.050)	77
12	K2Cr2O7	0.15	1/1.5	Other solvents^b (0.10)	0–59
13^c	K2Cr2O7	0.15	1/1.5	DMF (0.10)	93

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Regarding the substrate scope of alkenes, a series of different electron deficient alkenes reacting with 1a and 2a in a one-pot fashion were studied under standard conditions (Scheme 2). It turned out that most of electron deficient alkenes reacted with 3aa and gave the corresponding product 5 smoothly. However, the derivatives of cinnamic acid, chalcone and (E)-1-methyl-4-(2-nitrovinyl)benzene gave corresponding indolizines (5e–g, 5q) in poor yields. The worst case was naphthalene-1,4-dione, only giving 5i in trace yield. On the contrary, the similar cyclic alkene (coumarin) gave 5h in 69% yield. The reason for the difference is under further investigation.

Scheme 2 The scope of electron deficient alkenes.

To study the substrate scope of pyridines and α-halide carbonyl compounds, different such substances were reacted with 4a under standard conditions in a one-pot fashion (Scheme 3). As a result, pyridines produced their corresponding products in a smooth manner (Scheme 3, 6a–f). Pyridines with substituents at 2-position gave the corresponding products 6 in moderate yields, possibly due to associated steric hindrance. On the other hand, several α-halo-carbonyl compounds successfully achieved this transformation, including derivatives of α-bromoacetophenone, ethyl 2-bromoacetate, phenyl 2-chloroacetate and 2-bromoacetonitrile (Scheme 3, 6g–k). Interestingly, 6l was obtained in moderate yield (37%) from 1-(bromomethyl)-4-nitrobenzene, but 6m was not detected. Which may due to the low acidity of 1-benzylpyridin-1-ium bromide formed from pyridine and (bromomethyl)benzene.

Scheme 3 The scope of pyridines and α-halide carbonyl compounds.

The reaction was performed on a 5.0 mmol scale and producing 5c in 86% yield (1.20 g, Scheme 4), which demonstrated the synthetic utility of this method.

Scheme 4 The gram scale experiment.

Based on the results of previous study,⁵ the proposed mechanism of this transformation was presented in Scheme 5. Firstly, pyridinium salt (3) is formed in situ. Then 3 reacts with potassium dichromate to form pyridinium salt 7 with the release of potassium bromide, which would improve the solubility of potassium dichromate in DMF. 9 and 8 are thus generated from 7 by hydrogen abstraction. The dipolar species 9 would readily react with alkene 4 through 1,3-dipolar cycloaddition to form intermediate 10, followed by dehydrogenative aromatization promoted by 8 or 11. Since 8 and 11 contain the same anion with TPCD and TPND which are known to oxidize 10, they are proposed to oxidize 10 to 5 and reduced to Cr(III) species.⁵ The proposed mechanism is consistent with our experimental result.

Scheme 5 The proposed mechanism.

Conclusions

A one-pot method for the synthesis of multi-substituted indolizines was developed, starting from α-halo-carbonyl compounds, pyridines and electron deficient alkenes. In this method, sub-equivalent amount of potassium dichromate was used as an oxidant under base free conditions, which rendered this transformation economically efficient. The substrate scopes of this method were broad, since various electron deficient alkenes, pyridines and α-halo-carbonyl compounds were successfully applied in this stage. At last, the synthetic utility has been successfully raised up to a practical gram scale, which may attract the interests of many medicinal and material chemists.

Acknowledgements

We are grateful to funding of NSFC (no.: 21202058, 21401063), Education Department of Jiangsu Province (no. 13KJA150001), CPSF (no.: 2012M511645, 2013T60483), MOE (no. 13zs1102) and CSCSE (no. 13zs1102) for their financial supports.

Notes and references

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8. Experimental procedure for synthesize indolizines: pyridine derivative (1, 0.21 mmol) and α-halide carbonyl compound (2, 0.20 mmol) in 0.20 mL of DMF were heated at 60 °C in a test tube with a stopper for 2 h to form 3 in situ. Then alkene (4, 0.30 mmol), potassium dichromate (0.15 mmol) and another 1.80 mL of DMF were added to the tube. Then the mixture was heated at 80 °C for another 8 h (the reaction course was monitored by TLC). Then the mixture was cooled to r.t., passed through a layer of silica gel and washed with ethyl acetate to remove the inorganic by-products. Then solvent was removed by reduce pressure. The residue was purified by flash chromatogram on silica gel using petroleum ether/ethyl acetate as eluate to give the corresponding indolizine.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectral data for all new compounds. See DOI: 10.1039/c5ra06019b

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