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

Abstract

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 (SCF₃) group could significantly improve the lipophilicity of organic molecules as shown by its high Hansch constant (π = 1.44 for SCF₃, 0.88 for CF₃, and 0.61 for SMe) [1] that helps permeation across biological membranes. Furthermore, the strong electron-withdrawing properties of the SCF₃ 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 industries [3–5]. Traditional methods to access these compounds mainly include halogen–fluorine exchange of halomethyl sulfides and trifluoromethylation of sulfur-containing compounds [6–8]. Over the last decade, tremendous efforts have been triggered to develop methods for the direct incorporation of the SCF₃ group into organic compounds [9–16], 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 SCF₃-containing compounds, especially those featuring medicinally promising scaffolds.

Pyrrolo[1,2-a]indol-3-ones are prevalent scaffolds that widely exist in many bioactive compounds and natural products [17–20]. Representative examples of biologically active pyrrolo[1,2-a]indol-3-one derivatives are shown in Figure 1. Recently, the development of efficient methods for the synthesis of pyrrolo[1,2-a]indol-3-one derivatives has attracted considerable attention. For instance, Song [21] and Liang [22] reported the one-pot synthesis of novel phosphorylated and sulfonylated pyrrolo[1,2-a]indol-3-ones from N-[(3-phenyl)propioloyl]indole and N-propargylindoles, respectively. Inspired by these elegant results, we became interested in the preparation of SCF₃-substituted pyrrolo[1,2-a]indol-3-ones, which might be potentially useful in medicinal chemistry.

Figure 1.

Representative examples of biologically active pyrrolo[1,2-a]indol-3-one derivatives.

Radical cascade reactions constitute highly efficient strategies for the construction of compounds with structural diversity and complexity. In 2014, Wang reported the first radical cascade trifluoromethylthiolation and cyclization of activated alkenes (Scheme 1a) [23]. Afterward, Nevado [24], Hopkinson and Glorius [25], Dagousset and Magnier [26], as well as Fu [27] applied this strategy in the synthesis of a series of CH₂SCF₃-substituted heterocycles. For the construction of SCF₃-substituted cyclic compounds, normally proper alkynes are chosen as the substrates for cascade reactions [28–32]. In 2015, Wang developed an oxidative radical cyclization of aryl alkynoate esters with AgSCF₃ for the synthesis of trifluoromethylthiolated coumarins (Scheme 1b) [28]. In 2016, Liu exploited the tandem trifluoromethylthiolation/cyclization of N-arylpropiolamides to construct the SCF₃-substituted spiro[4,5]trienones (Scheme 1c) [29]. In the same year, Zhang and Chen disclosed the transformation of arylpropynones to SCF₃-substituted indenones through the tandem trifluoromethylthiolation/cyclization processes (Scheme 1d) [30]. As part of our continuing research interest in radical trifluoromethylthiolation reactions [33–38], herein we disclose a cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles to access SCF₃-substituted pyrrolo[1,2-a]indol-3-ones (Scheme 1e).

Scheme 1.

Radical cascade trifluoromethylthiolation and cyclization reactions.

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 AgSCF₃ in the presence of K₂S₂O₈ and KHCO₃ 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) [36,39–41] and cascade cyclization reactions has not been reported before. Thus, the amounts of AgSCF₃ and K₂S₂O₈ were increased to deliver 2a in 52% yield (Table 1, entry 2). Other oxidants including Na₂S₂O₈ and (NH₄)₂S₂O₈ afforded 2a in slightly higher yields, respectively (Table 1, entries 3 and 4). Switching KHCO₃ to NaHCO₃ could enhance the yield (Table 1, entry 6), whereas K₂CO₃ and DBU reduced the reaction efficiency (Table 1, entries 5 and 7). Subsequent evaluation of solvents revealed that MeCN and DMF were inferior to DMSO (Table 1, entries 8 and 9). Gratifyingly, the yield was improved to 80% by reducing the amount of base to 1.0 equivalent (Table 1, entry 10).

Table 1.

Optimization of the reaction conditions^a.

entry	oxidant	base	solvent	yield (%)b
1	K2S2O8	KHCO3	DMSO	28
2c	K2S2O8	KHCO3	DMSO	52
3c	Na2S2O8	KHCO3	DMSO	55
4c	(NH4)2S2O8	KHCO3	DMSO	58
5c	(NH4)2S2O8	K2CO3	DMSO	40
6c	(NH4)2S2O8	NaHCO3	DMSO	72
7c	(NH4)2S2O8	DBU	DMSO	34
8c	(NH4)2S2O8	NaHCO3	MeCN	8
9c	(NH4)2S2O8	NaHCO3	DMF	trace
10d	(NH4)2S2O8	NaHCO3	DMSO	80

^aReaction conditions: 1a (0.1 mmol), AgSCF₃ (0.15 mmol), oxidant (0.2 mmol), base (0.15 mmol), solvent (2.0 mL), 80 °C, 12 h. ^bYield was determined by ¹⁹F NMR using trifluorotoluene as an internal standard. ^cAgSCF₃ (0.3 mmol), oxidant (0.3 mmol). ^dAgSCF₃ (0.3 mmol), oxidant (0.3 mmol), base (0.1 mmol).

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.

Scheme 2.

Cascade bis(trifluoromethylthiolation) and cyclization of N-[(3-aryl)propioloyl]indoles 1. Reaction conditions: 1 (0.25 mmol), AgSCF₃ (0.75 mmol), (NH₄)₂S₂O₈ (0.75 mmol), NaHCO₃ (0.25 mmol), DMSO (5.0 mL), 80 °C, 12 h, isolated yields.

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.

Scheme 3.

Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles 3. Reaction conditions: 3 (0.25 mmol), AgSCF₃ (0.75 mmol), (NH₄)₂S₂O₈ (0.75 mmol), NaHCO₃ (0.25 mmol), DMSO (5.0 mL), 80 °C, 12 h, isolated yields.

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 ¹⁹F NMR spectra of the crude reaction mixtures. On the basis of these results and literature studies [21,23,42–47], a plausible reaction mechanism was proposed in Scheme 4. First, oxidation of AgSCF₃ by (NH₄)₂S₂O₈ generates Ag^IISCF₃, which could be further transformed to the CF₃S radical or CF₃SSCF₃ [23,36]. Then, the addition of a CF₃S radical to the alkyne function of substrates 1 or 3 afforded intermediate A. Subsequently, cyclization of intermediate A, followed by oxidation with (NH₄)₂S₂O₈, gave intermediate C [21,42–47]. Finally, deprotonation of intermediate C (R² ≠ H) with NaHCO₃ delivered the aromatized product 4. In the case of intermediate C (R² = H), intermediate D was probably formed, and further underwent electrophilic trifluoromethylthiolation with CF₃SSCF₃ [48–49] to furnish the bis(trifluoromethylthiolated) product 2.

Scheme 4.

Proposed reaction mechanism.

Conclusion

We have reported the cascade trifluoromethylthiolation and cyclization reactions for the preparation of novel and potentially useful SCF₃-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 AgSCF₃ 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.

Supporting Information

File 1

Experimental procedures, spectroscopic and X-ray data (CCDC 1968129 for compound 2a) and copies of NMR spectra.

This article is part of the thematic issue "Organo-fluorine chemistry V".

Funding Statement

National Natural Science Foundation of China (21991121, 21421002), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000), and Youth Innovation Promotion Association CAS (No. 2016234) are greatly acknowledged for funding this work.