Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles

A cascade oxidative trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles with AgSCF3 is described. This protocol allows for the synthesis of novel bis(trifluoromethylthiolated) or trifluoromethylthiolated pyrrolo[1,2-a]indol-3-ones in moderate to good yields. Mechanistic investigations indicated that radical processes were probably involved in these transformations.


Introduction
The trifluoromethylthio (SCF 3 ) group could significantly improve the lipophilicity of organic molecules as shown by its high Hansch constant (π = 1.44 for SCF 3 , 0.88 for CF 3 , and 0.61 for SMe) [1] that helps permeation across biological membranes. Furthermore, the strong electron-withdrawing properties of the SCF 3 group (Hammett constants: σ p = 0.50, σ m = 0.40) [2] with respect to metabolic stability have attracted considerable interest in pharmaceutical and agrochemical indus-tries [3][4][5]. Traditional methods to access these compounds mainly include halogen-fluorine exchange of halomethyl sulfides and trifluoromethylation of sulfur-containing compounds [6][7][8]. Over the last decade, tremendous efforts have been triggered to develop methods for the direct incorporation of the SCF 3 group into organic compounds [9][10][11][12][13][14][15][16], such as alkynes, alkenes, arenes, and alkanes. Despite these impressive advances, there is a continued strong demand for new methods that enable the efficient synthesis of SCF 3 -containing compounds, especially those featuring medicinally promising scaffolds.

Results and Discussion
On the outset, 1-(1H-indol-1-yl)-3-phenylprop-2-yn-1-one (1a) was chosen as the model substrate for optimization of the reaction conditions (Table 1). To our surprise, the reaction of 1a and AgSCF 3 in the presence of K 2 S 2 O 8 and KHCO 3 in DMSO at 80 °C gave bis(trifluoromethylthiolated) product 2a in 28% yield ( Table 1, entry 1). Only trace of mono(trifluoromethylthiolated) product was detected, and most of the substrate 1a was not converted. To the best of our knowledge, the combination of bis(trifluoromethylthiolation) [36,[39][40][41] and cascade cycli- With the optimized reaction conditions in hand, we then set out to explore the substrate scope of N-[ (3-aryl)propioloyl]indoles (Scheme 2). First, we explored the effect of the substitution on the indole ring. Both electron-donating and withdrawing groups at different positions of the indole ring produced the bis(trifluoromethylthiolated) products 2a-o in moderate to good yields. A wide range of functionalities such as alkyl, alkoxy, nitro, nitrile, ester, aldehyde, fluoro, chloro, and bromo were well-tolerated and compatible under the mild reaction conditions. Substrate 1p containing a methyl substituent on the phenyl ring could also participate in the reaction and furnish the desired product in moderate yield. However, attempts to prepare the substrates bearing an alkyl or electron-deficient aryl substituent on the alkynone were not successful. The structure of product 2a was unambiguously identified by single-crystal X-ray analysis.
When the N-[ (3-aryl)propioloyl]indole substrates (3a-d) with different substituents at the 3-position of the indole ring were subjected to the standard conditions, the cascade trifluoromethylthiolation and cyclization occurred to yield trifluoromethylthiolated pyrrolo[1,2-a]indol-3-ones (4a-d) in moderate yields (Scheme 3). The functionalities including alkyl, aryl, nitrile, and acyl were also well tolerated in this reaction.
In order to gain insight into the reaction mechanism, the radical scavenger 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) was added to the standard reactions of 1a and 3b, respectively. The desired product 2a was not formed and only trace of 4b was detected (see the Supporting Information File 1), which suggested that the radical process was probably involved in these transformations. Notably, no TEMPO-trapped product was detected by 19

Conclusion
We have reported the cascade trifluoromethylthiolation and cyclization reactions for the preparation of novel and poten-tially useful SCF 3 -containing pyrrolo[1,2-a]indol-3-ones. Oxidative trifluoromethylthiolation of N-[ (3-aryl)propioloyl]indoles without substituent at the 3-position of the indole ring with AgSCF 3 afforded the bis(trifluoromethylthiolated) products in moderate to good yields, whereas the substrates with a substituent at the 3-position of the indole ring were converted to the mono(trifluoromethylthiolated) products in moderate yields. Further studies on applying radical cascade reactions to the construction of fluorine-containing heterocyclic scaffolds are in progress in our laboratory.