Copper-catalyzed oxidative cascade coupling of N-alkyl-N-phenylacrylamides with aryl aldehydes

Abstract

An oxidative cascade coupling reaction was developed between N-alkyl-N-phenylacrylamides and aryl aldehydes using CuCl₂/TBHP (tert-butyl hydroperoxide) as a catalyst and oxidant. The reaction involves oxidative cross coupling of the activated alkene Csp²–H from the N-alkyl-N-phenylacrylamide with the aldehyde Csp²–H bond (–CHO), followed by metal-mediated direct aryl Csp²–H functionalization/cyclization to afford 3-(2-oxo-2-arylethyl)indolin-2-ones in good yields under mild reaction conditions without organic solvents involved.

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Transition-metal-catalyzed oxidative cross coupling of activated alkenes has attracted a lot of attention,¹ because these kinds of reactions are normally atom-economic, highly efficient and environment friendly.² When these substrates are carefully designed, the reactions will not stop at the oxidative coupling stage. Instead, it will subsequently undergo metal-mediated functionalization/cyclization catalyzed by the same metal catalyst in one pot. For example, direct aryl C(sp²)–H or alkyl C(sp³)–H cyclization/functionalization can occur. In this way, the cascade reaction can generate a complex product skeleton in a highly efficient way.³ N-Alkyl-N-phenylacrylamides, which contain both an activated double bond (Csp²–H) and an electron-rich aryl substrate (Csp²–H) in one molecule, is a suitable synthetic substrate for planning this kind of cascade reaction. Reports exist of using N-alkyl-N-arylacrylamides as reactants for carrying out cascade reactions to synthesize oxindole derivatives,^4,8–11 but these transformations are still quite rare.

It is known that N-aryl amide substrates are suitable for C(sp²)–H cyclization/functionalization.⁵ Early work was reported by Hennessy and Buchwald,⁶ and later extended by Jia and Kündig.⁷ Recently, more fascinating results were obtained when aryl C(sp²)–H cyclization/functionalization was combined with oxidative cross couplings of activated alkenes. Zhu and Liu independently used N-arylacrylamides as reactants for the oxindole syntheses by Pd(OAc)₂-catalyzed oxidative difunctionalization (Scheme 1).⁸ Li developed a novel FeCl₃-catalyzed oxidative coupling reaction of the alkene function substrate from N-arylacrylamide with either an aryl Csp²–H bond or a Csp³–H bond adjacent to a heteroatom to afford oxindole derivatives (Scheme 1).⁹ Yang reported the preparation of various diphenylphosphoryl oxindoles by AgNO₃-catalyzed difunctionalization of the alkene function on N-arylacrylamides through a carbon phosphorylation and C–H functionalization cascade (Scheme 1).¹⁰ Here, we report a copper-catalyzed oxidative cross coupling reaction of the double bonds' Csp²–H of N-alkyl-N-phenylacrylamides with an aryl aldehyde Csp²–H bond, followed by a Cu-mediated direct aryl Csp²–H functionalization/cyclization to produce the ketone oxindole derivatives, 3-(2-oxo-2-arylethyl)indolin-2-ones. This cascade reaction proceeded under mild, atom-economical and environmental friendly conditions. An inexpensive copper catalyst and aqueous tert-butylhydroperoxide (TBHP) were used without any organic solvents involved.

Scheme 1 Transition-metal catalyzed cascade reactions of using N-aryklacrylamide as one of reactants.

Very recently, Lei reported oxidative cross coupling reactions between phenyl-substituted alkenes with aldehydes.¹¹ We have extended this chemistry using the electron-deficient alkene functions from N-alkyl-N-phenylacrylamides in contrast to a phenyl-substituted alkene. By introducing an arylamide substrate into the reactant structure, a one-pot cascade reaction generating ketone oxindoles in good yield was developed. An inexpensive copper catalyst and aqueous tert-butylhydrogenperoxide (TBHP) were used without any organic solvents involved.

Reaction conditions were screened to search for cascade promoting features. Benzaldehyde and N-methyl-N-phenyl-methacrylamide were selected and various catalysts, solvents, reaction times and yields were screened. Based on previous research,¹² catalyst screening focused mainly on copper catalysts which are capable of promoting oxidative coupling of arylamide via single-electron transfer. There is no prior literature report of using a copper catalyst for this type of cascade reaction.

The synthesis starts with the reaction between benzaldehyde and N-methyl-N-phenyl-methacrylamide (Table 1). Excess benzaldehyde (3.5 equiv.) and aqueous TBHP (70% in water, 2.5 equiv., added in two portions) as an oxidant were used to promote conversion. When CuBr₂, CuI, CuBr (20% mol) were used as catalysts in the absence of solvent (entries 1, 3 and 4), none or only trace amounts of desired product 3a was detected. Using CuO gave only about 5% of 3a. Using solvents DCE, toluene or DMF (entries 5, 6 and 8) with CuCl₂ as the catalyst afforded none or only trace amounts of 3a in acetonitrile (entry 7), the reaction produced a moderate 40% yield of 3a. Using CuCl₂ (10% mol) as the catalyst without solvent (entry 9) gave 3a in 56% yield after 18 h. Increasing the amount of CuCl₂ to 20% mol (entry 10) also increased the rate and gave a good yield of 70%, after 18 h. More catalyst didn't increase the yield. When the reaction time was shortened to 10 h, a 50% yield (entry 11) was obtained. When no catalyst was used, the reaction proceeded but slowly. After 18 h, a 52% yield was observed. Based on the screening results, the optimized reaction conditions are: CuCl₂ (20 mol%), TBHP (2.5 equiv.), 90 °C, 18 h. Ten reactions with different substituents were investigated (Table 2) at the optimized conditions. Besides electron-deficient m-nitrobenzaldehyde gave trace amount of reaction product 3j. All other aromatic aldehydes underwent the oxidative cascade reactions well to give ketone oxindoles in good yields.

Table 1 Optimization of reaction conditions^a

Entry	Cat. (mol%)	Solvent	Reaction time	Yield^b (%)
a Reaction conditions: benzaldehyde (3.5 equiv.), N-methyl-N-phenyl-methacrylamide (1 equiv.), aqueous TBHP (70 wt% in water, 2.5 equiv.), copper catalyst (10 mol%, or 20 mol% of 2a); yield is based on reactant 2a.b Yield of isolated 3a.c The reaction was run with 10 mol% catalyst CuCl2.d The reaction was run for 10 hours.
1	CuBr2 (20)	—	18	Trace
2	CuO (20)	—	18	5%
3	CuI (20)	—	18	Trace
4	CuBr (20)	—	18	Trace
5	CuCl2 (20)	DCE	18	—
6	CuCl2 (20)	Toluene	18	Trace
7	CuCl2 (20)	CH3CN	18	40
8	CuCl2 (20)	DMF	18	Trace
9^c	CuCl2 (10)	—	18	56
10	CuCl2 (20)	—	18	70
11^d	CuCl2 (20)	—	10	50
12	—	—	18	52

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Table 2 Oxidative cascade coupling reaction^a

Entry	R	R^1	Product	Yield^b (%)
a Reaction conditions: aldehyde (3.5 equiv.), N-alkyl-N-phenylacryl-amide (1 equiv.), aqueous TBHP (70 wt% in water, 2.5 equiv.), copper catalyst (20 mol% of 2a–i), yield calculation is based on reactant 2a–i.b Yield of isolated 3a–i.
1	H	Me		70
2	Me	Me		72
3	MeO	Me		62
4	t-Bu	Me		86
5	H	Et		70
6	Me	Et		69
7	MeO	Et		64
8	t-Bu	Et		84
9	MeO	i-Pr		80
10	m-NO2	Me		Trace

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Based on previous reports¹² and these new results, a reaction mechanism is proposed in Scheme 2. First TBHP is reduced by one electron transfer from low valent copper species A to give the tBuO˙ radical and the ˙OH radical, which coordinates to copper species B. The tert-butoxy radical abstracts a hydrogen atom from the aldehyde 1 to generate the acyl radical. This radical adds to the double bond of the N-alkyl-N-phenylacrylamide to give radical 4 which cyclizes to give product 3 via intermediate 5.

Scheme 2 Proposed cascade coupling reaction mechanism.

In summary, we have developed a novel Cu-catalyzed oxidative cascade coupling reaction between N-alkyl-N-phenylacrylamides and aryl aldehydes using CuCl₂/TBHP as catalyst and oxidant respectively. The reaction undergoes oxidative cross coupling reactions of the activated alkenes Csp²–H of the N-alkyl-N-phenylacrylamides with aldehyde Csp²–H bonds, this is subsequently followed by metal-mediated direct aryl Csp²–H functionalization/cyclization process to afford 3-(2-oxo-2-arylethyl)indolin-2-ones in good yields under mild reaction conditions.

Acknowledgements

This investigation was generously supported by funds (1281290006) provided by Jiangsu University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra46915h

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