Copper acetate monohydrate: a cheap but efficient oxidant for synthesizing multi-substituted indolizines from pyridinium ylides and electron deficient alkenes

Abstract

We report a highly practical one-pot method for synthesizing multi-substituted indolizines from α-halide carbonyl compounds, pyridines and electron deficient alkenes in the presence of copper acetate monohydrate and sodium acetate in DMF. A variety of function groups are tolerable in standard reaction conditions, including aldehyde. 36 examples were presented. The yield of indolizine was from moderate to high. Furthermore, multi-substituted indolizines can be prepared at gram scale by this method.

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Introduction

The indolizine skeleton is abundant in many natural products,¹ such as Erythrinan alkaloids,^2a swainsonine,^2b slaframine,^2c gephyrotoxine,^2d cryptowoline,^2e and Myrmicarin.^2f These natural products as well as their synthetic derivatives have been found to exhibit a variety of biological activities, including antibacterial,^3a phosphatase and aromatase inhibiting,^3b–c antioxidant,^3d antidepressant^3e and antitumor activities.^3f They are also known as calcium entry blockers^3g and 5-hydroxytryptamine receptor antagonists.^3h Furthermore, indolizine derivatives were observed to have long wavelength absorption and fluorescence with high quantum efficiency in the visible light region.^4a–c Therefore, the successful synthesis of these types of compounds has facilitated the development of novel classes of dyes and biological markers.⁴

It is well recognized that 1,3-dipolar cycloaddition⁵ was one of the most efficient methods to construct five member heterocycles.⁶ This synthetic strategy has been applied to synthesizing indolizines since the work of Boekelheide and co-workers in 1961.⁷ However, this kind of reaction has drawbacks relating to the reaction scope due to the involvement of electron deficient alkynes. Compared with electron deficient alkynes, electron deficient alkenes are more readily available. Therefore, replacing electron deficient alkynes with electron deficient alkenes can dramatically extend the reaction scope and decrease the cost of synthesis. However, when electron deficient alkenes are applied to synthesize indolizines through 1,3-dipolar cycloaddition, the corresponding indolizines can be obtained only by adding an excess amount of oxidant, including freshly prepared MnO₂⁸ and tetrakispyridinecobalt(II) dichromate (TPCD).⁹ These two kinds of reagents are not commercially available and need to be prepared in the laboratory. Furthermore, indolizines were synthesized from pyridine in two steps instead of through a more efficient one-pot reaction. Therefore, a cheap and commercially available oxidant which could be applied in a one-pot reaction for synthesizing indolizines from electron deficient alkenes is in great demand.

Copper acetate monohydrate [Cu(OAc)₂·H₂O] is the kind of reagent that meets the above requirement. It's priced at $350.0 per 5 Kg by Alfa Aesar in the US as chemical reagent¹⁰ and at about $4000 per ton in China as an industrial product.¹¹ Copper acetate monohydrate has also been known as an oxidant for many reactions for a long time, including dehydrogenated aromatization reactions.¹² As a follow-up to our reported method,¹³ we herein report that copper acetate monohydrate is an efficient oxidant for synthesizing multi-substituted indolizines from electron deficient alkenes.

Results and discussion

In the preliminary study, in order to optimize the reaction conditions, we chose 1-(2-oxo-2-phenylethyl)pyridinium bromide 4a (2.0 eq.) and ethyl acrylate 3a (1.0 eq.) as our model reaction system. When potassium carbonate was used as the base and N,N-dimethylformamide (DMF) as the solvent, the known product 5a was isolated in good yield (Table 1, entry 1).^14a The result showed that copper acetate monohydrate was the most efficient reagent among five kinds of copper salts (Table 1, entries 1–5). Encouraged by this result, we then optimized the reaction conditions by changing the solvent and base.

Table 1 The optimization of reaction conditions

Entry	Cu Salt (equiv.)	Base (equiv.)	Solvent	Yield(%)^a
a Isolated yield. b DMSO = dimethyl sulfoxide. c DMA = N,N-dimethylacetamide. d NMP = 1-methylpyrrolidin-2-one. e Salt 4a was synthesized in situ by mixing pyridine 1a with 2-bromo-1-phenylethanone 2a at 60 °C for 2 h and without further purification.
1	Cu(OAc)2·H2O, 3.0	K2CO3, 4.0	DMF	82
2	Cu(NO3)2·3H2O, 3.0	K2CO3, 4.0	DMF	53
3	CuSO4, 3.0	K2CO3, 4.0	DMF	77
4	CuBr2, 3.0	K2CO3, 4.0	DMF	trace
5	CuCl2, 3.0	K2CO3, 4.0	DMF	trace
6	Cu(OAc)2·H2O, 3.0	NaHCO3, 4.0	DMF	89
7	Cu(OAc)2·H2O, 3.0	t-BuOK, 4.0	DMF	69
8	Cu(OAc)2·H2O, 3.0	NaH, 4.0	DMF	88
9	Cu(OAc)2·H2O, 3.0	Li2CO3, 4.0	DMF	90
10	Cu(OAc)2·H2O, 3.0	Na2CO3, 4.0	DMF	93
11	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	DMF	98
12	Cu(OAc)2·H2O, 3.0	No	DMF	76
13	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	1,4-dioxane	56
14	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	benzene	trace
15	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	DMSO^b	60
16	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	DMA^c	86
17	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	MeCN	75
18	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	NMP^d	92
19	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	H2O	6
20	Cu(OAc)2·H2O, 2.0	NaOAc, 4.0	DMF	74
21^e	Cu(OAc)2·H2O, 3.0	NaOAc, 4.0	DMF	96

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Entries 6–19 in Table 1 demonstrated that DMF was the best solvent and sodium acetate was the best base, while entry 20 showed that when the amount of copper acetate decreased from 3.0 equiv. to 2.0 equiv., the yield of 5a also decreased from 98 to 74%. Notably, when the isolated salt 4a was replaced by in situ formed salt 4a, the yield of 5a did not change markedly (Table 1, entry 21). This result indicated that more efficient one-pot reaction could be applied to this transformation.

With the optimal reaction conditions in hand (Table 1, entry 21), the scope and generality of pyridine derivatives in this transformation were examined (Table 2). A wide range of substituents, either electron-donating or electron-withdrawing groups in the pyridine ring, such as p-CO₂Me, o-Me, m-CN, p-Me, p-NMe₂, etc., were tolerable in this transformation. Interestingly, 2-methylpyridine 1b gave corresponding indolizine 5b in a high yield of 90%, although 2-phenylindolizine was also found in the reaction mixture. This result should be attributed to the reaction speed of pyridinium ylide with ethyl acrylate, which was much faster than its intermolecular cyclization under standard conditions (Table 2, entry 1). When the pyridine bore a cyano group at the meta position, two isomers (5d and 5d′) were isolated in the ratio of 4 : 5 (Table 2, entry 3). Fused pyridines also gave the corresponding fused indolizine with good yield (Table 2, entries 6–8). The reason that 4-vinylpyridine 1k did not give any designed product could be attributed to polymerization of 1k.

Scheme 1 The formation of 5b, 5d and 5d′.

Table 2 The scope and generality of pyridine derivatives

Entry	Pyridine	Product	Yield (%)^a	Ref.
a Isolated yield. b DMAP = N,N-dimethylpyridin-4-amine.
1	2-methylpyridine 1b	5b	90	—
2	4-methylpyridine 1c	5c	54	—
3	nicotinonitrile 1d	5d; 5d′	39; 50	—
4	DMAP 1e^b	5e	50	—
5	methyl isonicotinate 1f	5f	91	—
6	quinoline 1g	5g	63	14b
7	4-methylquinoline 1h	5h	61	—
8	isoquinoline 1i	5i	95	14c
9	4-chloropyridine 1j	5j	26	—
10	4-vinylpyridine 1k	Complex mixture	N. D.^d	—

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Then, we turned to check the scope of alkenes. The results were listed in Table 3. Many kinds of alkenes bearing a variety of electron-withdrawing groups, including ester, aldehyde, amide, cyano group, ketone and nitro group, were applied in this reaction. Both terminal and non-terminal alkenes reacted with pyridinium ylide smoothly. Some non-terminal alkenes such as 3l and 3p, however, couldn't give corresponding indolizines at high yield even when the reaction time was extended to 72 h. The fused conjugated alkenes 3l also gave indolizine at low yield. Moreover, cyclic alkenes 3m and 3k gave complex mixtures from which the corresponding indolizines could not be isolated. Interestingly, aldehyde could survive under standard reaction conditions and gave corresponding inlodizine at moderate yield (Table 3, entries 17–18). Furthermore, alkenes bearing a nitro group could also be applied in this transformation. When (E)-(2-nitrovinyl) benzene 3t was used, two isomers were isolated. One of the products 6t, which keeps the nitro group, was isolated in a yield of 54%, while the other product 6t′, which loses the nitro group, was isolated in a yield of 28%. When (E)-(2-nitroprop-1-enyl) benzene 3u was used, the only product 6u′ was isolated in a yield of 72%. This result should be attributed to the trend of aromatizing the tetra-hydrogen indolizine intermediate.

Scheme 2 The formation of 6t, 6t′ and 6u′.

Table 3 The scope and generality of alkene derivatives

Entry	Alkene	Product	Yield (%)^a	Ref.
a Isolated yield. b Complex mixture. c 72 h, the yield in parentheses was based on recovered starting material. d Two isomers were isolated.
1	methyl acrylate 3b	6b	95	14a
2	tert-butyl acrylate 3c	6c	80	—
3	n-butyl acrylate 3d	6d	85	14a
4	acrylonitrile 3e	6e	78	14a
5	N,N-dimethylacrylamide 3f	6f	82	14d
6	(E)-methyl but-2-enoate 3g	6g	90	—
7	diethyl fumarate 3h	6h	92	14a
8	dimethyl maleate 3i	6i	80	14a
9	dibutyl maleate 3j	6j	80	—
10	1-phenyl-1H-pyrrole-2,5-dione 3k	Complex mixture	C. M.^b	—
11	2H-chromen-2-one 3l	6l	43 (59)^c	13c
12	naphthalene-1,4-dione 3m	Complex mixture	C. M.^b
13	(E)-1-phenyl-3-p-tolylprop-2-en-1-one 3n	6n	66	—
14	(E)-3-(4-fluorophenyl)-1-phenylprop-2-en-1-one 3o	6o	50	—
15	ethyl cinnamate 3p	6p	25 (32)^c	14e
16	(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one 3q	6q′ (see Scheme 3)	35	—
17	(E)-but-2-enal 3r	6r	54	—
18	cinnamaldehyde 3s	6s	39	—
19	(E)-(2-nitrovinyl)benzene 3t	6t; 6t′	45; 28^d	—; 14f
20	(E)-(2-nitroprop-1-enyl)benzene 3u	6u′	72	—

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At last, to demonstrate the scope of the reaction, we replaced 2-bromo-1-phenylethanone by several similar reagents. The results were presented in Table 4. All of them gave indolizines at moderate to high yield.

Table 4 The scope and generality of α-halide carbonyl derivatives

Entry	R, X	Product	Yield (%)^a	Ref.
a Isolated yield.
1	4-nitrobenzoyl, Br 2b	7b	80	—
2	4-methoxybenzoyl, Br 2c	7c	88	14g
3	2-bromo-1-(4-bromophenyl)ethanone 2d	7d	96	—
4	CO2Et, Cl 2e	7e	75	14h
5	CO2Et, Br 2f	7e	38	14h
6	CN, Br 2g	7g	55	—
7	1-(bromomethyl)-4-nitrobenzene 2h	7h	58	14i
8	1,3-dichloropropan-2-one 2i	7i′ (see Scheme 3)	33	—

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Moreover, (E)-(2-nitroprop-1-enyl)benzene 3q gave (1,1′-carbonylbis(2-phenylindolizine-3,1-diyl))bis(phenylmethanone) 6q′ in a yield of 35% (Table 3, entry 16), and 1,3-dichloropropan-2-one 2i also gave diethyl 3,3′-carbonyldiindolizine-1-carboxylate 7i′ in a yield of 33% (Table 4, entry 8).

Scheme 3 The formation of 6q′ and 7i′.

Furthermore, the reaction scale was easily enlarged to gram scale and the yield did not decrease (Scheme 4).

Scheme 4 The synthesis of indolizine 6f on the gram scale.

Conclusions

In conclusion, we have demonstrated that copper acetate monohydrate is a cheap and efficient reagent for synthesizing multi-substituted indolizines from simple starting materials, such as pyridines, α-halide ketones and electron-deficient alkenes. The reaction runs under mild conditions and is easy to handle. This reaction can be applied on the gram scale and without reducing the yield. At last, further study of a catalytic version of this transformation is now under thorough investigation.

Experimental

General

Unless otherwise noted, all commercial reagents and solvents were obtained from commercial providers and used without further purification. ¹H NMR and ¹³C NMR spectra were recorded on Bruker 400 MHz spectrometers. Chemical shifts were reported relative to internal tetramethylsilane (δ 0.00 ppm) or CDCl₃ (δ 7.26 ppm) for ¹H NMR and CDCl₃ (δ 77.0 ppm) for ¹³C NMR. Flash column chromatography was performed on 300–400 mesh silica gels. Analytical thin layer chromatography was performed with pre-coated glass baked plates (250 μ) and visualized by fluorescence. HRMS was recorded on a Bruker micrOTOF-Q spectrometer. IR spectra were recorded on a Nicolet Avatar 360 spectrometer.

General procedure for the preparation of indolizines 4

Pyridine (1a) 0.40 mmol and 2-bromo-1-phenylethanone (2a) 0.42 mmol were mixed in a test tube and the mixture was heated to 60 °C for 4 h. Then copper acetate monohydrate 0.60 mmol, NaOAc 1.20 mmol, DMF 2.0 mL and ethyl acrylate (3a) 0.20 mmol were added to the mixture. The mixture was then heated at 80 °C for another 4 h (the reaction course was monitored by TLC). Then the mixture was cooled to r.t., poured into water and extracted with CHCl₃ (10 mL × 3). The extractions were combined and washed with saturated brine, dried with Na₂SO₄, and filtered. The solvent was removed by reduce pressure. The residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (the ratio depends on product's polarity) as eluate.

Preparation of indolizine 6f at gram scale

Pyridine (1a) 20.0 mmol and 2-bromo-1-phenylethanone (2a) 21.0 mmol and 10.0 mL DMF were mixed in a round bottom flask at r.t.. The mixture was stirred for 2 h (the temperature of mixture rose to 80 °C automatically and then cooled down to r.t.), and white solid was precipitated. Then copper acetate monohydrate 30.0 mmol, NaOAc 60.0 mmol, DMF 70.0 mL and N,N-dimethylacrylamide (3f) 10.0 mmol were added to the mixture. The mixture was then heated at 80 °C for another 4 h (the reaction course was monitored by TLC). Then the mixture was cooled to r.t., poured into 160 mL water and filtered. The mother liquid was extracted with CHCl₃ (30 mL × 3) and the filter cake was washed with CHCl₃ (10 mL × 3). The organic layers were combined and washed with saturated brine, dried with Na₂SO₄, and filtered. Then the solvent was removed by reduce pressure. The residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (1 : 1, v : v) as eluate to give the corresponding indolizine 6f as a yellow solid.

Ethyl 3-benzoyl-7-methylindolizine-1-carboxylate (5b)

Yellow solid; mp 154–155 °C; ¹H NMR (CDCl₃, 400 MHz): 9.87 (d, J = 7.1 Hz, 1H), 8.20 (s, 1H), 7.82 (dd, J = 6.9, 1.4 Hz, 2H), 7.78 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.3 Hz, 2H), 6.94 (dd, J = 7.1, 1.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 185.2, 164.2, 140.5, 140.1, 139.4, 131.3, 129.3, 128.9, 128.7, 128.3, 122.2, 118.3, 117.7, 105.2, 60.0, 21.6, 14.6; IR (NaCl): 2978, 2919, 1697, 1643, 1611, 1575, 1524, 1481, 1464, 1428, 1344; HRMS Calculated for [C19H17NO3+Na]⁺: 330.1101, Found: 330.1089.

Ethyl 3-benzoyl-5-methylindolizine-1-carboxylate (5c)

Yellow oil; ¹H NMR (CDCl₃, 400 MHz): 8.39 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.76 (s, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.44 (dd, J = 8.6, 7.1 Hz, 1H), 6.94 (d, J = 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.62 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 182.9, 164.1, 141.9, 139.8 138.6, 132.6, 130.3, 129.6, 128.4, 127.4, 125.4, 117.2, 116.7, 105.5, 60.0, 23.2, 14.6; IR (NaCl): 3059, 2977, 2926, 1698, 1632, 1596, 1577, 1524, 1480, 1422, 1335; HRMS Calculated for [C₁₉H₁₇NO₃+Na]⁺: 330.1101, Found: 330.1105.

Ethyl 3-benzoyl-6-cyanoindolizine-1-carboxylate (5d)

Yellow solid; mp 163–164; ¹H NMR (CDCl₃, 400 MHz): 10.39 (s, 1H), 8.49 (d, J = 9.2 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.5 Hz, 2H), 7.50 (dd, J = 9.3, 1.2 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 185.9, 163.3, 138.9, 138.7, 134.8, 132.3, 129.8, 128.0, 128.6, 126.5, 123.4, 120.5, 116.3, 108.3, 101.3, 60.7, 14.5; IR (NaCl): 3102, 2963, 2918, 2849, 2235, 1704, 1630, 1598, 1576, 1541, 1481, 1431, 1366, 1326; HRMS Calculated for [C₁₉H₁₄N₂O₃+Na]⁺: 341.0897, Found: 341.0879.

Ethyl 3-benzoyl-8-cyanoindolizine-1-carboxylate (5d′)

Yellow solid; mp 147–148; ¹H NMR (CDCl₃, 400 MHz): 10.19 (d, J = 6.7 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 7.2 Hz, 2H), 7.15 (t, J = 7.2 Hz,1H), 4.47 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz):185.8, 162.7, 139.0, 136.8, 134.4, 133.0, 132.2, 130.4, 129.1, 128.6, 123.2, 116.3, 113.7, 108.6, 104.7, 60.8, 14.4; IR (NaCl): 3114, 2979, 2925, 2233, 1715, 1627, 1599, 1527, 1476, 1436, 1355; HRMS Calculated for [C₁₉H₁₄N₂O₃+Na]⁺: 341.0897, Found: 341.0919.

Ethyl 3-benzoyl-7-(dimethylamino)indolizine-1-carboxylate (5e)

Yellow solid; mp 162–164 °C; ¹H NMR (CDCl₃, 400 MHz): 9.77 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 6.7 Hz, 2H), 7.67 (s, 1H), 7.56–7.46 (m, 3H), 7.37 (d, J = 2.7 Hz, 1H), 6.63 (dd, J = 7.8, 2.8 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.14 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 183.8, 164.6, 149.5, 143.3, 140.6, 130.8, 130.7, 130.3, 128.8, 128.2, 120.8, 104.2, 102.8, 95.6, 59.6, 39.9, 14.6; IR (NaCl): 3058, 2978, 2930, 1690, 1646, 1597, 1532, 1490, 1440, 1340; HRMS Calculated for [C₂₀H₂₀N₂O₃+H]⁺: 337.1547, Found: 337.1533.

1-Ethyl 7-methyl 3-benzoylindolizine-1,7-dicarboxylate (5f)

Yellow solid; mp 149–151 °C; ¹H NMR (CDCl₃, 400 MHz): 9.88 (d, J = 7.3 Hz, 1H), 9.00 (s, 1H), 7.87–7.79 (m, 3H), 7.63–7.55 (m, 2H), 7.52 (t, J = 7.4 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 185.8, 165.1, 163.5, 139.4, 138.2, 131.9, 129.0, 128.9, 128.49, 128.46, 128.0, 123.6, 121.7, 114.1, 109.1, 60.5, 52.7, 14.5; IR (NaCl): 2983, 1724, 1627, 1573, 1527, 1473, 1432, 1347; HRMS Calculated for [C₂₀H₁₇NO₅+Na]⁺: 374.0999, Found: 374.0988.

Ethyl 1-benzoyl-5-methylpyrrolo[1,2-a]quinoline-3-carboxylate (5h)

Yellow solid; mp 164–166 °C; ¹H NMR (CDCl₃, 400 MHz): 8.21 (s, 1H), 8.14–8.09 (m, 3H), 7.95 (dd, J = 8.0, 0.9 Hz, 1H), 7.67 (t, J = 7.4 Hz, 1H), 7.62 (s, 1H), 7.61–7.50 (m, 4H), 4.38 (q, J = 7.1 Hz, 2H), 2.71 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 184.7, 164.2, 140.5, 138.6, 136.5, 133.0, 132.7, 130.1, 129.9, 128.5, 128.4, 127.9, 125.4, 125.3, 125.2, 120.6, 117.3, 106.7, 60.1, 19.6, 14.6; IR (NaCl): 3060, 2978, 2926, 2855, 1699, 1633, 1597, 1556, 1538, 1499, 1465, 1447, 1416; HRMS Calculated for [C₂₃H₁₉NO₃+Na]⁺: 380.1257, Found: 380.1256.

Ethyl 3-benzoyl-7-chloroindolizine-1-carboxylate (5j)

Yellow solid; mp 134–136 °C; ¹H NMR (CDCl₃, 400 MHz): 9.91 (d, J = 7.5 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 7.0 Hz, 2H), 7.82 (s, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.4 Hz, 2H), 7.07 (dd, J = 7.4, 2.2 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 185.6, 163.7, 139.9, 139.5, 134.5, 131.7, 129.7, 129.3, 129.0, 128.5, 122.7, 118.6, 116.5, 106.1, 60.3, 14.5; IR (NaCl): 3123, 2980, 1700, 1619, 1523, 1473, 1442, 1343; HRMS Calculated for [C₁₈H₁₄ClNO₃+H]⁺: 328.0735, Found: 328.0737.

tert-Butyl 3-benzoylindolizine-1-carboxylate (6c)

Yellow solid; mp 125–126 °C; ¹H NMR (CDCl₃, 400 MHz): 9.99 (d, J = 7.0 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 7.1 Hz, 2H), 7.80 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.44 (dd, J = 7.7, 7.0 Hz, 1H), 7.08 (t, J = 6.8 Hz, 1H), 1.63 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz): 185.5, 163.5, 140.0, 139.6, 131.4, 129.24, 129.18, 129.0, 128.4, 127.4, 122.3, 119.6, 115.1, 108.0, 80.6, 28.5; IR (NaCl): 2976, 2931, 1696, 1616, 1521, 1479, 1449, 1367, 1343; HRMS Calculated for [C₂₀H₁₉NO₃+Na]⁺: 344.1257, Found: 344.1264.

3-Benzoyl-N,N-dimethylindolizine-1-carboxamide (6f)

Yellow solid; mp 91–93 °C; ¹H NMR (CDCl₃, 400 MHz): 9.94 (d, J = 7.0 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.44 (s, 1H), 7.35 (dd, J = 8.1, 7.6 Hz, 1H), 7.04 (t, J = 6.9 Hz, 1H), 3.14 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz): 185.1, 166.5, 140.2, 139.3, 131.3, 128.9, 128.7, 128.3, 126.44, 126.37, 121.5, 119.4, 115.0, 109.7; IR (NaCl): 3057, 2928, 1713, 1609, 1573, 1526, 1474, 1415, 1346; HRMS Calculated for [C₁₈H₁₆N₂O₂+Na]⁺: 315.1104, Found: 315.1106.

Dibutyl 3-benzoylindolizine-1,2-dicarboxylate (6j)

Yellow oil. ¹H NMR (CDCl₃, 400 MHz): 9.63 (d, J = 7.1 Hz, 1H), 8.42 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 7.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.42–7.48 (m, 3H), 7.10 (dd, J = 6.9, 1.0 Hz, 1H), 4.29 (t, J = 6.6 Hz, 2H), 3.55 (t, J = 6.8 Hz, 2H), 1.70 (qu, J = 7.1 Hz, 2H), 1.49–1.35 (m, 4H), 1.31–1.20 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 186.8, 165.0, 163.1, 139.6, 138.5, 131.9, 131.7, 128.8, 128.5, 128.1, 127.9, 120.7, 120.0, 115.9, 104.3, 65.7, 64.4, 30.8, 30.1, 19.2, 19.1, 13.7; IR (NaCl): 3059, 2959, 2872, 1738, 1702, 1624, 1577, 1506, 1447, 1376, 1344; HRMS Calculated for [C₂₅H₂₇NO₅+Na]⁺: 444.1781, Found: 444.1780.

(2-p-Tolylindolizine-1,3-diyl)bis(phenylmethanone) (6n)

Yellow solid; 181–182 °C; ¹H NMR (CDCl₃, 400 MHz): 9.68 (d, J = 7.1 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.41–7.32 (m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.08–7.02 (m, 3H), 6.97 (t, J = 7.7 Hz, 2H), 6.73 (d, J = 7.9 Hz, 2H), 6.49 (t, J = 7.8 Hz, 2H), 2.00 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): 192.9, 188.5, 139.4, 139.2, 139.0, 136.5, 131.5, 131.3, 130.9, 130.3, 129.5, 129.4, 129.4, 127.8, 127.7, 127.5, 127.4, 127.0, 121.1, 119.1, 115.1, 114.1, 20.9; IR (NaCl): 3060, 2923, 1633, 1612, 1597, 1576, 1499, 1386, 1343; HRMS Calculated for [C₂₉H₂₁NO₂+Na]⁺: 438.1465, Found: 438.1469.

(2-(4-Fluorophenyl)indolizine-1,3-diyl)bis(phenylmethanone) (6o)

Yellow solid. ¹H NMR (CDCl₃, 400 MHz): 9.69 (d, J = 7.1 Hz, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.47–7.38 (m, 3H), 7.35 (d, J = 7.3 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.11–7.05 (m, 3H), 7.01 (t, J = 7.6 Hz, 2H), 6.82 (dd, J = 8.4, 5.6 Hz, 2H), 6.41 (t, J = 8.6 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz): 192.6, 188.2, 162.9, 160.5, 139.2, 139.1, 139.1, 137.9, 133.2, 133.1, 131.6, 131.3, 129.4, 129.3, 127.8, 127.7, 127.6, 127.4, 121.3, 119.2, 115.4, 114.2, 114.2, 114.0; IR (NaCl): 3062, 1606, 1576, 1525, 1496, 1426, 1386; HRMS Calculated for [C₂₈H₁₈FNO₂+Na]⁺: 442.1214, Found: 442.1162.

(1,1′-Carbonylbis(2-phenylindolizine-3,1-diyl))bis(phenylmethanone) (6q′)

Yellow solid. ¹H NMR (CDCl₃, 400 MHz): 9.41 (d, J = 7.0 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.30–7.22 (m, 6H), 7.09 (t, J = 7.3 Hz, 2H), 6.96–6.88 (m, 6H), 6.85–6.78 (m, 6H), 6.71 (t, J = 7.4 Hz, 4H); ¹³C NMR (CDCl₃, 100 MHz): 187.9, 187.0, 139.2, 138.5, 138.1, 132. 7, 131.2, 131.0, 129.3, 127.5, 127.3, 126.8, 126.6, 126.3, 121.0, 118.7, 116.9, 114.7; IR (NaCl): 3058, 2923, 2851, 1659, 1603, 1575, 1492, 1465, 1449, 1429, 1387, 1340, 1316; HRMS Calculated for [C₄₃H₂₈N₂O₃+H]⁺: 621.2173, Found: 621.2185.

3-Benzoyl-2-methylindolizine-1-carbaldehyde (6r)

Yellow solid; mp 171–173 °C; ¹H NMR (CDCl₃, 400 MHz): 10.17 (s, 1H), 9.55 (d, J = 7.0 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.56–7.46 (m, 3H), 7.08 (t, J = 6.7 Hz, 1H), 2.21 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): 187.7, 184.2, 140.8, 139.3, 137.8, 132.1, 129.1, 128.7, 128.7, 128.6, 122.8, 118.6, 115.8, 113.6, 12.4; IR (NaCl): 3058, 2724, 2854, 1714, 1655, 1609, 1503, 1441, 1391, 1335; HRMS Calculated for [C₁₇H₁₃NO₂+Na]⁺: 286.0838, Found: 286.0834.

3-Benzoyl-2-phenylindolizine-1-carbaldehyde (6s)

Yellow solid; mp 183–185 °C; ¹H NMR (CDCl₃, 400 MHz): 9.79 (s, 1H), 9.76 (d, J = 7.0 Hz, 1H), 8.69 (d, J = 8.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.3 Hz, 2H), 7.23–7.17 (m, 2H), 7.17–7.08 (m, 5H), 7.04 (t, J = 7.7 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz): 188.0, 186.7, 142.6, 139.0, 138.3, 131.5, 131.5, 131.3, 129.4, 129.2, 128.6, 127.9, 127.7, 127.6, 121.5, 119.9, 116.5, 113.2; IR (NaCl): 3058, 2921, 2793, 1657, 1612, 1575, 1497, 1467, 1435, 1390, 1334; HRMS Calculated for [C₂₂H₁₅NO₂+Na]⁺: 348.0995, Found: 348.0983.

(1-Nitro-2-phenylindolizin-3-yl)(phenyl)methanone (6t)

Yellow solid; mp 139–140 °C; ¹H NMR (CDCl₃, 400 MHz): 9.50 (d, J = 7.0 Hz, 1H), 8.69 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 8.2, 7.5 Hz, 1H), 7.42 (d, J = 7.4 Hz, 2H), 7.27–7.17 (m, 4H), 7.11–7.05 (m, 5H); ¹³C NMR (CDCl₃, 100 MHz): 188.4, 138.6, 134.6, 133.9, 132.0, 131.1, 130.9, 130.3, 129.3, 128.2, 128.1, 127.7, 127.7, 127.5, 121.5, 119.4, 116.4; IR (NaCl): 3152, 3056, 2963, 2922, 1624, 1598, 1576, 1500, 1469, 1409, 1370, 1327; HRMS Calculated for [C₂₁H₁₄N₂O₃+Na]⁺: 365.0897, Found: 365.0905.

(1-Methyl-2-phenylindolizin-3-yl)(phenyl)methanone (6u′)

Yellow solid. ¹H NMR (CDCl₃, 400 MHz): 9.90 (d, J = 7.1 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 7.4 Hz, 2H), 7.20 (dd, J = 8.0, 7.4 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.05–6.95 (m, 7H), 6.91 (t, J = 6.8 Hz, 1H), 2.26 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): 186.3, 140.5, 137.8, 136.5, 135.0, 131.0, 130.0, 129.2, 128.3, 127.4, 127.2, 126.4, 123.5, 120.3, 116.8, 113.6, 110.7, 9.2; IR (NaCl): 3058, 2920, 2851, 1593, 1571, 1520, 1452, 1432, 1388, 1371; HRMS Calculated for [C₂₂H₁₇NO+Na]⁺: 334.1202, Found: 334.1208.

Ethyl 3-(4-nitrobenzoyl)indolizine-1-carboxylate (7b)

Yellow solid; mp 144–145 °C; ¹H NMR (CDCl₃, 400 MHz): 10.01 (d, J = 7.0 Hz, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.40 (d, J = 8.6 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H), 7.76 (s, 1H), 7.56 (dd, J = 8.1, 7.1 Hz, 1H), 7.20 (t, J = 6.9 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 182.9, 163.7, 149.4, 145.4, 140.4, 129.7, 129.3, 129.2, 128.6, 123.7, 121.9, 119.7, 116.0, 107.3, 60.3, 14.5; IR (NaCl): 3110, 2924, 2852, 1706, 1619, 1596, 1521, 1482, 1341; HRMS Calculated for [C₁₈H₁₄N₂O₅+Na]⁺: 361.0795, Found: 368.0801.

Ethyl 3-(4-bromobenzoyl)indolizine-1-carboxylate (7d)

Yellow solid; mp 109–110 °C; ¹H NMR (CDCl₃, 400 MHz): 9.95 (d, J = 7.0 Hz, 1H), 8.42 (d, J = 8.9 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.48 (dd, J = 8.0, 7.5 Hz, 1H), 7.12 (t, J = 7.0 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 184.1, 163.9, 140.0, 138.7, 131.7, 130.5, 129.2, 128.8, 127.9, 126.2, 122.2, 119.6, 115.5, 106.6, 60.2, 14.6; IR (NaCl): 3123, 2979, 1700, 1615, 1585, 1521, 1480, 1430, 1342; HRMS Calculated for [C₁₈H₁₄BrNO₃+H]⁺: 372.0230, Found: 372.0239.

Ethyl 3-cyanoindolizine-1-carboxylate (7g)

White solid; mp 102–103 °C; ¹H NMR (CDCl₃, 400 MHz): 8.38–8.33 (m, 2H), 7.81 (s, 1H), 7.36 (dd, J = 8.8, 6.9 Hz, 1H), 7.06 (td, J = 7.3, 1.0 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 163.3, 137.8, 126.0, 125.7, 125.2, 120.5, 115.0, 112.6, 106.1, 96.7, 60.3, 14.5; IR (NaCl): 3119, 2987, 2210, 1691, 1515, 1486, 1445, 1390; HRMS Calculated for [C₁₂H₁₀N₂O₂+Na]⁺: 237.0634, Found: 237.0631.

3,3′-Carbonyldiindolizine-1-carboxylate (7i′)

Yellow solid; mp 223–225 °C; ¹H NMR (CDCl₃, 400 MHz): 9.67 (d, J = 7.0 Hz, 1H), 8.38 (d, J = 9.0 Hz, 1H), 8.00 (s, 1H), 7.38 (dd, J = 8.2, 7.4 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): 174.5, 164.3, 139.6, 128.6, 126.7, 126.1, 122.9, 119.7, 114.6, 106.0, 60.1, 14.6; IR (NaCl): 2981, 2961, 2923, 2852, 1699, 1626, 1520, 1480, 1441, 1369; HRMS Calculated for [C₂₃H₂₀N₂O₅+Na]⁺: 427.1264, Found: 427.1263.

Acknowledgements

We are grateful to Jiangsu Province NSF (No.: BK2011408), Jiangsu Province Department of Education (No.: 10KJB150002), China Postdoctoral Science Foundation funded project (No.: 2012M511645), JSKLCLDM (No.: JSKC11093), HYNU and NBRPC (No.: 2011CB933503) for their financial support.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c2ra21213g

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