Silver-catalyzed tandem radical acylarylation of cinnamamides in aqueous media

Abstract

A mild silver-catalyzed regioselective radical addition/cyclization reaction of cinnamamides with α-oxocarboxylic acids has been developed. The procedure proceeded well under very mild conditions, leading to a diverse range of 3-acyl-4-aryldihydroquinolin-2(1H)-ones in moderate to good yields.

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Introduction

Over the past few decades, the transition metal-catalyzed oxidative vicinal difunctionalization of alkenes has been widely used for carbon–carbon and carbon–heteroatom bond formations.^1,2 In this field, the metal-catalyzed intramolecular difunctionalization of alkenes has proven to be most efficient and versatile tool for the synthesis of heterocycles.³ For example, one of the traditional routes to N-containing heterocyclic compounds involved the coupling of carbon electrophiles or nucleophiles with unsaturated amines and other related nucleophiles. Therein, aryl halides and hypervalent iodine reagents have been used as common sources of carbon electrophiles in these transformation (Scheme 1, route a).⁴ Recently, the oxidative radical difunctionalization of activated alkenes has emerged as an alternative strategy for the construction of functionalized oxindoles (Scheme 1, route b).⁵ However, only a few types of activated alkenes have been found to react with specific radicals to afford different heterocycles.⁶ Therefore, further development of direct difunctionalization of alkenes via tandem radical process to access diverse valuable heterocycles, and in particular catalytic systems capable of using readily available and stable reagents, are still highly desirable.

Scheme 1 Catalytic intramolecular difunctionalization of alkenes to heterocycles.

α-oxocarboxylic acids are environmentally benign and easily handled carboxylic acids that have been utilized extensively in organic synthesis. Pioneering work by Minisci in the 1990s demonstrated that the silver-catalyzed decarboxylation of α-oxocarboxylic acids generated acyl radicals that were capable of homolytic acylation of heteroarenes.⁷ In recent years, considerable advances have been made in decarboxylative cross-coupling and decarboxylative dehydrogenative couplings of α-oxocarboxylic acids or its salts.⁸ Recently, our group^9a and Lei's group^9b have reported silver-catalyzed tandem decarboxylative acylarylation of acrylamides and isocyanides with α-oxocarboxylic acids for the synthesis of functionalized oxindoles and phenanthridines, respectively. In addition, we found that dihydroquinolinones could also be constructed successfully via a similar radical cyclization process when cinnamamides were used instead of acrylamides.^6d The reversed regioselectivity of this transformation could be attributed to the stability of the newly generated radical intermediate. The excellent regiochemical result and our continuing interest in decarboxylative coupling of α-oxocarboxylic acids^8e,9c–f prompted us to explore analogous methodology for the synthesis of acylated dihydroquinolinones (Scheme 2). Herein, we wish to report the synthesis of functionalized dihydroquinolinones from cinnamamides and α-oxocarboxylic acids under mild conditions.¹⁰

Scheme 2 Decarboxylative acylarylation of cinnamamides.

Results and discussion

Based on our previous reports on the decarboxylative coupling of α-oxocarboxylic acids with other reactants,^9a,f we initially started our investigation of N-methyl-N-phenylcinnamamide (1a) and phenylglyoxylic acid (2a) under silver catalysis. Thus, treatment of 1a with 2a in the presence of 10 mol% of AgNO₃ and 1 equiv. of K₂S₂O₈ as oxidant in acetone/H₂O (1 : 1) at room temperature for 24 h under nitrogen, afforded the desired dihydroquinolin-2(1H)-one 3a in 47% yield (Table 1, entry 1). Changing the solvent to DMF/H₂O, THF/H₂O or dioxane/H₂O led to lower yields of 3a (entries 2–4). Further investigation showed that two-phase system was ineffective for this reaction (entry 5).¹¹ When employing different persulfates as oxidants, Na₂S₂O₈ gave the best yield (entries 6–8). A screening of the catalysts indicated that Ag₂O and Ag₂CO₃ were also effective for this transformation (entries 9 and 10). When the reaction temperature was increased to 50 °C, a similar yield was obtained (entry 11). Reduced catalyst loading to 5 mol% and 2 mol% also gave satisfactory yields (entries 12 and 13). To our delight, switching the ratio of 1a and 2a from 1.0/1.0 to 1.0/1.2 resulted in better yield (entry 14), while further increasing the amount of 2a was unsatisfactory (entry 15). It should be noted that the reaction could also be scaled up to 1 mmol, and the desired product 3a, was isolated in 77% yield. Finally, in the absence of a catalyst, the reaction did not occur at all (entry 16).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (mol%)	Oxidant (equiv.)	Solvent	Yield^b (%)
a Reaction conditions: 10 mol% of catalyst, 1a (0.2 mmol, 1 equiv.), 2a (0.2 mmol, 1 equiv.), solvent (2 mL), oxidant (1 equiv.), room temperature, 24 h.b Yield of isolated product, only trans isomers were observed, for details see the ESI.c n.r. = no reaction.d At 50 °C.e 2a (0.24 mmol, 1.2 equiv.).f Yield on a 1 mmol scale is given in parentheses.g 2a (0.3 mmol, 1.5 equiv.).
1	AgNO3 (10)	K2S2O8 (1)	Acetone/H2O (1 : 1)	47
2	AgNO3 (10)	K2S2O8 (1)	DMF/H2O (1 : 1)	20
3	AgNO3 (10)	K2S2O8 (1)	THF/H2O (1 : 1)	39
4	AgNO3 (10)	K2S2O8 (1)	Dioxane/H2O (1 : 1)	28
5	AgNO3 (10)	K2S2O8 (1)	DCE/H2O (1 : 1)	n.r.^c
6	AgNO3 (10)	(NH4)2S2O8 (1)	Acetone/H2O (1 : 1)	39
7	AgNO3 (10)	Na2S2O8 (1)	Acetone/H2O (1 : 1)	64
8	AgNO3 (10)	Oxone (1)	Acetone/H2O (1 : 1)	n.r.^c
9	Ag2O (10)	Na2S2O8 (1)	Acetone/H2O (1 : 1)	52
10	Ag2CO3 (10)	Na2S2O8 (1)	Acetone/H2O (1 : 1)	58
11^d	AgNO3 (10)	Na2S2O8 (1)	Acetone/H2O (1 : 1)	65
12	AgNO3 (5)	Na2S2O8 (1)	Acetone/H2O (1 : 1)	73
13	AgNO3 (2)	Na2S2O8 (1)	Acetone/H2O (1 : 1)	72
14^e	AgNO3 (2)	Na2S2O8 (1)	Acetone/H2O (1 : 1)	78 (77)^f
15^g	AgNO3 (2)	Na2S2O8 (1)	Acetone/H2O (1 : 1)	62
16^e	—	Na2S2O8 (1)	Acetone/H2O (1 : 1)	n.r.^c

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With the optimized condition in hand, a variety of cinnamamides 1 were examined. As shown in Table 2, all of the cinnamamides derived from different cinnamylic acids were compatible with this transformation (3b–i and 3k–o). Both electron-rich and electron-poor aromatic rings at β-position of cinnamamides afforded the desired products in moderate to good yields (3b–i). Cinnamamides bearing ortho-substituents also proceeded well under the standard condition and no obvious steric effects were observed in these cases (3g and 3h). The meta-substituted cinnamamides such as 1i, also gave the corresponding product 3i in 57% yield. However, unprotected N-aryl cinnamamide 1j was found to be an unsuitable substrate. Furthermore, cinnamamides containing electron-donating or -withdrawing groups at the para-position of the anilide moiety were also effective for this transformation (3k–n). Unexpectedly, the cinnamamide derived from m-tolylamine afforded the desired product 3o in 92% yield with excellent regioselectivity, probably due to the steric effect. It is noteworthy that the cyclization procedure tolerated a variety of functional groups on the cinnamamide, such as bromo (3e and 3n) and cyano (3f) groups.

Table 2 Scope of N-aryl cinnamamides^a

a Reaction conditions: 2 mol% of catalyst, 1 (0.2 mmol, 1 equiv.), 2a (0.24 mmol, 1.2 equiv.), solvent (2 mL), Na₂S₂O₈ (1 equiv.), room temperature, 24 h.

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Subsequently, the scope of α-oxocarboxylic acids were also explored. The results were summarized in Table 3. Phenylglyoxylic acids having electron-donating or -withdrawing groups at the para-position on the aromatic ring proved to be good substrates for this transformation, leading to the corresponding dihydroquinolinones 4 in moderate to high yields (4a–f). Notably, even the bromo and iodo substituted phenylglyoxylic acid were also tolerated well and furnished the desired products 4e and 4f in 88% and 92% yields, respectively. These results were significant because the halo groups retained in the heterocycles provide opportunities for further transformation under palladium catalysis. When 2-thienylglyoxylic acid and furoyl formic acid were used, the desired product 4g and 4h were isolated in somewhat lower yields under the above conditions. Remarkably, aliphatic α-oxocarboxylic acids such as pyruvic acid proceeded smoothly to give 4i in 95% yield.

Table 3 Scope of α-oxocarboxylic acids^a

a Reaction conditions: 2 mol% of catalyst, 1a (0.2 mmol, 1 equiv.), 2 (0.24 mmol, 1.2 equiv.), solvent (2 mL), Na₂S₂O₈ (1 equiv.), room temperature, 24 h.

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To gain more insights into the reaction mechanism, TEMPO and BHT, well-known radical scavengers, were added to the reaction under standard conditions, respectively (eqn (1) and (2)). The reactions were suppressed remarkably, which implied that the reaction involves radical intermediates, which was consistent with the mechanisms proposed in previous reports.^7c,9a,b A plausible mechanism of the reaction was shown in Scheme 3. Firstly, the nucleophilic acyl radical 2a′ was generated in the presence of Ag(I)/Na₂S₂O₈.⁷ Secondly, the radical 2a′ selectively attacks the α-position of the C=C double bond of cinnamamide 1a to produce more stable radical intermediate II,^6d which undergoes an intramolecular cyclization to generate radical III. Finally, radical III was converted to the corresponding carbocation via single-electron oxidation by Ag(II) followed by the loss of H⁺, which lead to the desired product 3a and regenerate Ag(I). This high stereoselectivity probably explained by the stable radical intermediate III, which leads to the trans isomer due to minimizing the strain of phenyl and benzoyl groups on six-membered ring.

Scheme 3 Proposed mechanism.

Conclusions

In summary, we have developed a regioselective acylarylation of cinnamamides using readily available α-oxocarboxylic acids as acyl sources. This decarboxylative coupling/cyclization reaction exhibited low catalyst loading, mild reaction conditions as well as the excellent functional groups tolerance. A variety of valuable substituted dihydroquinolinones could be easily prepared in moderate to good yields with high stereoselectivity in aqueous solution.

Acknowledgements

Financial support from National Natural Science Foundation of China (no. 21102110, 21102111) and the Natural Science Basic Research Plan in Shaanxi Province of China (no. 2014JQ2071) are greatly appreciated.

Notes and references

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11. When other two-phase solvents such as Tol/H₂O, PhCF₃/H₂O and DCM/H₂O were used, no reaction occurred.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra08529a

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