A general route to fluorinated 3,3-disubstituted 2-oxindoles via a photoinduced radical cyclization of N-arylacrylamides under catalyst-free conditions

Abstract

A catalyst-free radical cyclization of N-arylacrylamides with fluorinated alkyl iodides or the Togni reagent enabled by photoenergy is presented for the first time. Under ultraviolet irradiation, the generation of fluorinated 3,3-disubstituted 2-oxindoles proceeds smoothly without any metals or photoredox catalysts. The broad reaction scope is demonstrated with good functional group tolerance. During the process, fluorinated alkyl groups can be easily incorporated.

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Introduction

So far, visible-light photocatalysis has attracted growing interest in organic transformations.¹ Usually, reactive radicals or ionic species are involved during the reaction process, and photocatalysis is essential for the transformation. Recently, transition-metal-free reactions enabled by photoenergy were discovered.² During the reaction process, no photocatalysis was needed and aryl/alkyl radicals could be generated easily from the corresponding aryl/alkyl halides. For example, aryl alkyne and alkyl iodide could be coupled in water under ultraviolet irradiation in the absence of a transition-metal.^2a A photoinduced halogen exchange in aryl or vinyl halides could happen under metal-free conditions as well.^2b It was demonstrated that these reactions proceeded through alkyl or aryl radicals from alkyl/aryl halides enabled by photoenergy. These results opened a new window for the coupling of aryl/alkyl halides under metal-free conditions, since these reactions were simply promoted by ultraviolet irradiation.

Currently, the rapid generation of natural product-like small molecules is in high demand for studies of chemical genetics.³ In the meantime, much attention has been paid to the introduction of fluorinated substituents into privileged scaffolds, with the expectation to alter their physical, chemical, and biological properties.⁴ Consistent with our continuing interest in the library construction of natural product-like compounds and fluorinated molecules, we initiated a program for the synthesis of fluorinated isatin derivatives. Among the isatin derivatives, 3,3-disubstituted 2-oxindole attracted our attention due to its importance in pharmaceuticals.^5,6 So far, the synthesis of trifluoromethyl-substituted 3,3-disubstituted 2-oxindoles have been reported by using the Togni reagent,⁷ TMSCF₃,⁸ or CF₃SO₂Na⁹ as the fluoro source. The incorporation of other fluorinated groups into the skeleton was also developed,^10a which proceeded through the reaction of N-arylacrylamides with fluoroalkylsulfonyl chlorides in the presence of photoredox catalysts. During the reaction process, fluorinated radicals were generated from R_fSO₂Cl by photoredox catalysis with the release of SO₂. Very recently, fluoroalkyl iodides as the fluoro source were reported as well in the metal-catalyzed or AIBN-promoted process.^10b,c Although the above transformations are efficient, metal catalysts are usually crucial in the reactions. Moreover, the process is not atom economical.

Prompted by the advancement of metal-free coupling reactions of alkyl/aryl halides enabled by photoenergy,² we postulated that the fluorinated 3,3-disubstituted 2-oxindoles could be generated directly from the reaction of N-arylacrylamides 1 with fluoroalkyl iodides 2 under catalyst-free conditions. This hypothesis is shown in Scheme 1. We reasoned that the fluoroalkyl radical would be produced efficiently under ultraviolet irradiation. The subsequent addition of the fluoroalkyl radical to the double bond of N-arylacrylamide 1 would afford intermediate A. The further intramolecular attack of the aromatic ring would give rise to intermediate B. The subsequent aromatization would provide the corresponding fluorinated 3,3-disubstituted 2-oxindole 3. If this hypothesis is feasible, this proposed route would provide an efficient pathway to fluorinated heterocycles, since the transformation would proceed in the absence of metal catalysts or organocatalysts under mild conditions. Considering the importance of economic and environmental issues, this photochemistry is certainly a valuable alternative for the construction of fluorinated heterocycles, especially in the metal-free drug-discovery process.

Scheme 1 A proposed photoinduced radical cyclization of N-arylacrylamides 1 with fluoroalkyl iodides 2.

Results and discussion

Our initial studies focused on the model reaction of N-methyl-N-phenylmethacrylamide 1a with n-nonafluorobutyl iodide 2a under ultraviolet irradiation at room temperature. The reaction occurred at 25 °C under ultraviolet irradiation (mercury lamp) at an intensity of 0.67 W cm⁻² by using a standard photoreactor (see the ESI†). At the outset, the reaction was performed in the presence of sodium carbonate as the base in 1,2-dichloroethane (Table 1, entry 1). To our delight, the desired fluorinated 3,3-disubstituted 2-oxindole 3a was obtained in 24% yield. The yield was increased to 35% when 1,4-dioxane was used as a replacement (Table 1, entry 2). Further screening of solvents indicated that acetonitrile was the best choice, affording the expected product 3a in 73% yield (Table 1, entry 3). We also examined other bases (Table 1, entries 4–8), however, the results were inferior. Only a trace amount of product 3a was detected in a control experiment without the addition of base (Table 1, entry 9). The conversion was inert when the reaction occurred in the dark or under visible light irradiation (Table 1, entries 10 and 11). The advantages of this transformation are attractive: (1) mild conditions at room temperature; (2) without any metals or photoredox catalysts; (3) green process under ultraviolet irradiation.

Table 1 Initial studies for the reaction of N-methyl-N-phenylmethacrylamide 1a with n-nonafluorobutyl iodide 2a under ultraviolet irradiation^a

Entry	Additive	Solvent	Yield^b (%)
a Reaction conditions: N-methyl-N-phenylmethacrylamide 1a (0.3 mmol), ^nC4F9I (0.3 mmol), base (0.3 mmol), solvent (4.0 mL), irradiation supplied by 600 W Hg light, rt, 12 h. b Isolated yield based on N-methyl-N-phenylmethacrylamide 1a. c The reaction occurred in the dark. d The reaction was performed under visible light irradiation.
1	Na2CO3	DCE	24
2	Na2CO3	1,4-Dioxane	35
3	Na2CO3	MeCN	73
4	NaOAc	MeCN	47
5	KOH	MeCN	61
6	NaHCO3	MeCN	60
7	DBU	MeCN	50
8	DABCO	MeCN	56
9	—	MeCN	Trace
10^c	Na2CO3	MeCN	n.d.
11^d	Na2CO3	MeCN	n.d.

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This promising result encouraged us to explore the scope of the reaction of N-arylacrylamides 1 with fluoroalkyl iodides 2. The result is shown in Table 2. Various N-arylacrylamides 1 reacted with fluoroalkyl iodides 2 efficiently, giving rise to the corresponding fluorinated 3,3-disubstituted 2-oxindoles 3 in moderate to good yields. A range of N-arylacrylamides 1 were examined. N-Arylacrylamides 1 with electron-withdrawing or electron-donating groups on the aromatic ring were all compatible under the standard conditions. Different functional groups were tolerated, including methyl, methoxy, chloro, fluoro, acetyl, and cyano groups. For instance, the cyano-substituted 2-oxindole 3i was obtained in 66% yield, while tert-butyl-substituted 2-oxindole 3g was produced in 76% yield. The chloro and fluoro atoms were remained in the corresponding products. Other fluoroalkyl iodides were employed as substrates as well in the transformation. For example, n-heptafluoropropyl iodide 2b was used in the reaction, leading to the corresponding product 3e in 60% yield.

Table 2 The photoinduced reaction of N-arylacrylamides 1 with fluoroalkyl iodides 2^a

a Isolated yield based on N-arylmethacrylamide 1.

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We further expanded the scope to the reaction of N-arylmethacrylamide 1 with Togni's reagent¹¹ (Table 3). It has been of great synthetic interest for highly efficient and selective incorporation of the trifluoromethyl group into diverse skeletal structures.¹² It was found that this photoinduced reaction of N-arylacrylamides 1 with Togni's reagent 4 also proceeded smoothly to afford the corresponding products as expected. The trifluoromethyl group could be easily installed in the scaffold of 2-oxindole. Again, the substrates featuring various functional groups including fluoro, chloro, trifluoromethyl, and cyano, worked well in this process.

Table 3 The photoinduced reaction of N-arylacrylamides 1 with Togni's reagent 4^a

a Isolated yield based on N-arylmethacrylamide 1.

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Subsequently, this method was extended to N,N-diphenylmethacrylamide 6. As shown in Scheme 2, the reaction of N,N-diphenylmethacrylamide 6 with n-nonafluorobutyl iodide 2a or Togni's reagent worked well under standard conditions, giving rise to the corresponding product 7 or 8, respectively.

Scheme 2 A photoinduced reaction of N,N-diphenylmethacrylamide 6 with n-nonafluorobutyl iodide 2a or Togni's reagent.

Conclusions

In conclusion, we have described a catalyst-free radical cyclization of N-arylacrylamides with fluorinated alkyl iodides or the Togni reagent enabled by photoenergy. Under ultraviolet irradiation, the generation of fluorinated 3,3-disubstituted 2-oxindoles proceeds smoothly without any metals or photoredox catalysts. The broad reaction scope is demonstrated with good functional group tolerance. During the process, fluorinated alkyl groups can be easily incorporated. This approach provides an efficient pathway to fluorinated heterocycles, since the transformation would proceed in the absence of metal catalysts or organocatalysts under mild conditions. Considering the importance of economic and environmental issues, this photochemistry is certainly valuable. The advantages of this method including experimental ease, availability of the starting materials, and mild conditions will make this approach attractive for further applications.

Acknowledgements

Financial support from the National Natural Science Foundation of China (no. 21372046 and 21532001) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00055j

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