Visible-light-mediated radical aryltrichloromethylation of N-arylacrylamides for the synthesis of trichloromethyl-containing oxindoles

Introduction

Trichloromethyl functionality is widely found in organic chemistry and natural products [1–3]. The introduction of trichloromethyl group into organic framework strongly attracts synthetic pursuit of chemists because of its diverse synthetic applications and important biological properties of the substituted compounds [4, 5]. Nevertheless, up to date, methods for the synthesis of trichloromethylated oxindoles are quite rare [6–8]. Recently, Loh and co-workers reported the Fe-catalyzed coupling of N-arylacrylamides with dichloro- and tetrachloromethane using diaryliodonium salt as oxidant [7]. However, the drawbacks are the use of an oxidant diaryliodonium salt (2.0 equiv.) as well as the requirement of high temperature. A more concise synthesis is highly desirable.

Recently, visible-light photoredox catalysis has attracted substantial attention because of its environmental compatibility and versatility in promoting a large number of synthetically important reactions [9–12]. The visible-light-induced radical reaction of organohalides is an environmentally friendly alternative to traditional radical transformation by avoiding the use of hazardous radical initiators, and substantial achievements have been made [13–18]. Polyhalogenated alkanes, such as tetrachloromethane and bromotrichloromethane have been used as common radical precursors in various transformations leading to trichloromethyl functionalized compounds. For example, Stephenson and co-workers reported a radical addition reaction between tetrachloromethane and unfunctionalized alkenes [18]. Inspired by these results and in connection with our interest in radical cyclizations [19–22], we envisioned the synthesis of trichloromethylated oxindoles by photocatalyzed radical reaction of tetrachloromethane with N-arylacrylamides. This transformation allows the direct formation of a C-CCl₃ bond and the construction of a oxindole ring in one reaction.

Results and discussion

At the outset of this investigation, N-arylacrylamide 1a and tetrachloromethane were chosen as the model substrates to optimize the reaction conditions. The complex [fac-Ir(III)(ppy)₃] (ppy = 2-phenylpyridine) was chosen as the photocatalyst because of its superior reduction capacity in the excited state. Irradiation of the solution of 1a and CCl₄ in DMF with a 5 W blue LED bulb in the presence of [fac-Ir(III)(ppy)₃] and Na₂HPO₄ for 48 h at room temperature afforded the desired product 2a in 75% yield. Using CCl₃Br as ·CCl₃ radical precursor, oxindole 2a was isolated in 63% yield with some unidentifiable products. Other photocatalysts, such as, [Ir(ppy)₂(dtbbpy)]PF₆, Ru(bpy)₃Cl₂, eosin Y were also tested, but none of them gave better results than [fac-Ir(ppy)₃]. A brief screen of the bases revealed that K₂CO₃ was the best choice for the reaction. Other inorganic bases, such as Na₂CO₃, NaOAc, and NaHCO₃ also gave good yields of the isolated products. Indeed, the replacement of inorganic bases by an organic base (triethylamine) had a marked effect on the reaction, affording product 2a in only 52% yield. The reaction proceeds well in DMF and other solvents such as DMSO, CH₃CN. In the control experiments, the reaction was found to be completely restrained without the catalyst or light irradiation.

With the optimized reaction conditions in hand, we further explored the scope of trichloromethylation with a variety of N-arylacrylamides (Scheme 1). It was found that various N-protected substrates, such as ethyl, isopropyl, butyl, benzyl or phenyl could be used as effective substituent group for this transformation (2a–f). Subsequently, the effect of substituents at the N-aryl moiety was examined. Both electron-donating and electron-withdrawing groups located in the para- or ortho position of the aromatic rings were found to be tolerated in this reaction, furnishing the corresponding oxindoles 2g–o in moderate to good yields. N-arylacrylamides 2g–h possessing electron-donating substituents gave the desired products in higher yields than the substrates 2i–l with electron-withdrawing groups. Moreover, the procedure appears to be sensitive to steric effects. Generally, substitutents in the para-position on the benzene are well tolerated. By contrast, the presence of ortho-substituents on the benzene reduce the yields of 2m–n. 3,5-Disubstituted N-arylacrylamide 1o was also transformed into the desired product 2o in 64% yield. Cyclization of meta-chloro-substituted substrates 1p resulted in a mixture of two regioisomers in a 2:1 ratio. Additionally, good results were also obtained with tetrahydroquinoline derivative 1q as a substrate.

Scheme 1

Synthesis of trichloromethylated oxindoles.

Conclusions

We report a facile assembly of 3,3-disubstituted oxindoles by visible-light-promoted aryltrichloromethylation of N-arylacrylamides with tetrachloromethane. The reaction tolerates a wide range of functional groups.

Experimental

All reactions were performed in a 20 mL tube equipped with a rubber septum at room temperature. Photo-irradiation was carried out with a 5 W blue LED. Solvents were purified or dried in a standard manner. ¹H NMR spectra (400 MHz or 500 MHz), ¹³C NMR spectra (100 MHz or 125 MHz), and ¹⁹F NMR spectra were measured in CDCl₃.·HR-MS analyses were recorded on Q-TOF Global mass spectrometer.