Copper-catalyzed homocoupling of ketoxime carboxylates for synthesis of symmetrical pyrroles

Abstract

A novel and efficient copper-catalyzed homocoupling of ketoxime carboxylates has been developed for the synthesis of symmetrical pyrroles. This reaction tolerates a wide range of functional groups and provides a synthetically useful process to synthesize valuable symmetrical pyrroles under mild conditions.

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Pyrroles are one of the most important heterocycles which are prevalent in numerous natural products, pharmaceuticals and functionalized materials.¹ Particularly, large numbers of symmetrical pyrroles have recently been discovered to have remarkable bioactivity and fluorescence, such as COX-2 isoenzyme inhibitors (a), DNA minor groove recognition reagent DB884 (b), bio-antioxidant (c), fluorophores TPPy (d) and NPANPy (e) (Fig. 1).² Over the past decades, tremendous efforts have been devoted to the synthesis of various substituted pyrroles.³ Apart from the classical protocols,⁴ many new strategies, such as cycloaddition reactions,⁵ multicomponent reactions,⁶ dehydrogenative cyclization reactions,⁷ coupling of enamides with alkynes,⁸ and oxidative cyclization of N-allylimines⁹ have been developed for the synthesis of pyrroles. However, most of these methods are focused on versatile unsymmetrical substituted pyrroles, general protocols for the synthesis of valuable symmetrical pyrroles are rarely developed.¹⁰

Fig. 1 Bioactive or fluorescent symmetrical pyrroles.

Oximes and their derivatives are versatile synthetic building blocks.¹¹ They are well-known fruitful candidates for Beckmann rearrangement reactions in amide preparation,¹² and dehydrations to produce nitriles.¹³ Recently, reductive acylation of ketoximes has been developed as a practical method for the synthesis of enamides.¹⁴ Meanwhile, much attention has been paid to the coupling reactions of oxime carboxylates, because the N–O bond cleavage of oxime carboxylates could be used as an internal oxidant to make reactions proceed under redox-neutral conditions. Thus, transition-metal catalyzed coupling of oxime carboxylates with aldehydes, alkynes and organoboronic acids have emerged for the synthesis of aza-heterocycles.¹⁵ In connection with our interest in oximes^14a,b,15a and green synthesis of pyrroles,⁵ we have developed a novel and efficient copper-catalyzed homocoupling of ketoxime carboxylates for the synthesis of valuable symmetric pyrroles.

Propiophenone oxime acetate 1a was selected as a model substrate in the initial experiments to optimize the reaction conditions. The symmetrical pyrrole 2a was obtained in 37% yield when CuBr was used as the catalyst in DMSO at 120 °C (Table 1, entry 1). Then NaHSO₃, which we found to be a good additive in our previous copper-catalyzed coupling of oxime acetates with aldehydes, was added to the reaction.^15a The yield of pyrrole 2a was dramatically improved to 68% (Table 1, entry 2). Na₂SO₃ shows an inferior yield compared to NaHSO₃. Next, a series of copper catalysts, such as CuI, CuCl, CuCl₂, CuBr₂ and Cu(OAc)₂ were screened to determine if they improved the reaction efficiency (Table 1, entries 4–8). And various solvents, such as DMF and CH₃CN, were screened as well (Table 1, entries 9–10). However, we found that CuBr and DMSO are still the most effective catalyst and solvent respectively. The reaction temperature was also varied; the yield of 2a was further increased to 72% when the reaction was conducted at 140 °C (Table 1, entry 11). Additionally, no reaction was observed in the absence of copper catalyst, confirming that Cu species did indeed act as the catalyst in the reaction (Table 1, entry 12).

Table 1 Optimization of reaction conditions for homocoupling of propiophenone oxime acetate for the synthesis of symmetrical pyrrole^a

Entry	Catalyst	Additive	Solvent	Yield^b (%)
a Reaction conditions: propiophenone oxime acetate 1a (0.3 mmol), catalyst (5 mol%), NaHSO3 (1.2 equiv.) in solvent (3 mL) under Ar at 120 °C for 2 h. b Isolated yields. c The reaction was run at 140 °C.
1	CuBr	—	DMSO	37
2	CuBr	NaHSO3	DMSO	68
3	CuBr	Na2SO3	DMSO	30
4	CuI	NaHSO3	DMSO	35
5	CuCl	NaHSO3	DMSO	64
6	CuCl2	NaHSO3	DMSO	62
7	CuBr2	NaHSO3	DMSO	59
8	Cu(OAc)2	NaHSO3	DMSO	31
9	CuBr	NaHSO3	DMF	24
10	CuBr	NaHSO3	CH3CN	39
11	CuBr	NaHSO3	DMSO	72 ^c
12	—	NaHSO3	DMSO	0

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With the optimized reaction conditions established, the scope of the reaction was investigated (Table 2). The reaction showed good functional group tolerance and proved to be a general methodology for the preparation of symmetrical pyrroles. And the reaction was insensitive to the electronic effects of the substrates. Propiophenone oxime acetates with methyl, alkyl, methoxyl, fluoro and electron-withdrawing groups such as chloro and bromo groups on the aromatic rings all gave the corresponding symmetrical pyrroles 2b–2l in good yields. In this manner, the resulting Cl or Br substituted products 2k–2l, could be further expanded to a wider variety of functionalized symmetrical pyrroles by undergoing subsequent cross-coupling reactions. In addition, ortho-methyl and methoxyl substituted substrates reacted smoothly and resulted in the desired symmetrical pyrroles 2f–2g and 2i in 65–70% yields. These results indicated that steric hindrance on the aromatic rings of the substrates has little influence on the reaction (Table 2, entries 6–7, and 9).

Table 2 Cu-catalyzed homocoupling of aryl ethyl ketoxime acetates^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: 1 (0.3 mmol), CuBr (5 mol%), NaHSO3 (1.2 equiv.) in DMSO (3 mL) under Ar at 140 °C. b Isolated yields (averages of two experiments).
1			72
2			74
3			63
4			74
5			76
6			70
7			65
8			65
9			68
10			55
11			70
12			67

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Furthermore, a series of phenyl alkyl ketoxime acetates were investigated to extend the reaction scope (Table 3). Ketoxime acetates derived from butyrophenone, valerophenone and α-tetralone reacted smoothly to give the desired symmetrical pyrroles 2m–2o in 56–68% yields (Table 3, entries 1–3). It should be noted that tetraphenyl pyrrole 2p, which has fluorophores for glassy blue-light-emitting diodes,^2d was obtained in 52% yield when 1,2-diphenylethanone oxime acetate 1p was used as the substrate (Table 3, entry 4). However, acetophenone oxime acetate 1q gave only 10% yield of the corresponding 2,5-diphenyl pyrrole 2q under the aforementioned conditions (Table 3, entry 5). And no desired pyrrole products were obtained when the alkyl alkyl ketoxime acetates, such as cyclohexanone oxime acetate 1r and pentan-2-one oxime acetate 1s were employed as the substrates under the standard conditions (Table 3, entries 6–7). Finally, different propiophenone oxime carboxylates were investigated to determine their reactivity. It was found that the reactivity of the different carboxylates follows the sequence: acetate > propionate > pentafluorobenzoate > benzoate (Table 3, entries 8–10).

Table 3 Cu-catalyzed homocoupling of various ketoxime carboxylates^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: 1 (0.3 mmol), CuBr (5 mol%), NaHSO3 (1.2 equiv.) in DMSO (3 mL) under Ar at 140 °C for 2 h. b Isolated yields (averages of two experiments).
1			56
2			66
3			68
4			52
5			10
6			0
7			0
8			62
9			56
10			45

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On the basis of the above results and previous studies, the tentative mechanisms for this homocoupling reaction are proposed in Scheme 1. Firstly, the reaction starts from a two-step single-electron-transfer reduction of ketoxime acetate 1 by Cu^I to generate imino-Cu^II complex B.^14a,b,15 Tautomerization of the imino-Cu^II complex B gives the enamino-Cu^II intermediate C. Then, two pathways are possible for the following steps. In one case (path a), cleavage of the N–Cu bond of the enamino-Cu^II intermediate C forms a radical intermediate D.¹⁶ Radical coupling of the intermediate D affords diimine intermediate E.¹⁷ Intramolecular cyclization of intermediate E followed by elimination of NH₃ produces the pyrrole 2. Alternatively, condensation of the enamino-Cu^II intermediate C with a second ketoxime acetate 1 gives the intermediate D′.^15a,18 Elimination of intermediate D produces an enimine intermediate E′. Intramolecular radical cyclization of intermediate E′ assisted by Cu^II sequence with tautomerization of intermediate H′ produces the symmetrical pyrrole 2 (path b).^8d,15e,16

Scheme 1 Proposed mechanism for the Cu-catalyzed homocoupling of ketoxime carboxylates.

To gain insight into the mechanism of the reaction, 1,4-diphenylbutane-1,4-dione dioxime diacetate 1w was reacted under the standard conditions (Scheme 2). If the reaction proceeded via path b, we would have expected to observe the pyrrole 2q. However, no pyrrole 2q was observed in the reaction. This result indicated that path b is less likely.

Scheme 2 Intramolecular homocoupling of diketoxime diacetate 1w.

In summary, we have developed a novel and efficient copper-catalyzed homocoupling of ketoxime carboxylates for the synthesis of symmetrical pyrroles. The reaction tolerates a wide range of functional groups and is a reliable method for the rapid elaboration of readily available ketoxime carboxylates into a variety of valuable symmetrical pyrroles. Further scope and mechanistic studies of the reaction are underway and will be reported in due course.

This work was supported by generous grants from the National Natural Science Foundation of China (NSFC-21272183, 21002077), and Fund of the Rising Stars of Shanxi Province (2012KJXX-26).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, ¹H and ¹³C NMR spectra of products 2. See DOI: 10.1039/c3gc41800f

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