Visible light-driven and substrate-promoted alkenyltrifluoromethylation of alkenes to synthesize CF₃-functionalized 1,4-naphthoquinones

Abstract

The first example of the visible light-driven and substrate-promoted three-component alkenyltrifluoromethylation of alkenes is developed. This approach uses easily available alkenes, 2-arylamino-1,4-naphthoquinones and Togni reagent as the reactants, and describes good functionality tolerance. The reaction offers a precise synthesis of valuable CF₃-functionalized 1,4-naphthoquinones and can be applied in late-stage modification of natural products and pharmaceuticals. Experimental results imply that bifunctional 2-arylamino-1,4-naphthoquinones serve as both substrates and catalysts. In terms of this autocatalytic system, the protocol enables a straightforward intermolecular difunctionalization of alkenes under visible light irradiation without external catalysts.

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Introduction

Quinone- and particularly 1,4-naphthoquinone-containing organic molecules are significant compounds due to their prevalent appearance in natural products, agrochemicals and therapeutic drugs (Fig. 1).¹ As a consequence, a variety of synthetic strategies towards the construction of these compounds have been demonstrated through direct C–H alkylation,² halogenation,³ phosphonylation,⁴ amination⁵ and arylation⁶ of a 1,4-naphthoquinone skeleton, as well as other alternatives.⁷ In addition, several examples of the C–H difunctionalization of 1,4-naphthoquinones, including thioamination⁸ and aminophosphinoylation,⁹ for the synthesis of 2,3-disubstituted-1,4-naphthoquinones have been reported. Given the step-economical and product-diverse superiority, alkene difunctionalization has served as one of the most attractive synthetic protocols. In this context, the establishment of a novel and efficient alkene difunctionalization for the synthesis of 1,4-naphthoquinone derivatives through C–H functionalization of 1,4-naphthoquinones is highly desirable.

Fig. 1 Representative active molecules containing a 1,4-naphthoquinone scaffold.

Because the presence of a trifluoromethyl group (CF₃) in organic molecules usually perfects their metabolic stability and lipophilicity, CF₃-containing organic compounds, in clinical studies, are widely used as active pharmaceutical ingredients.¹⁰ Apart from playing an important role in pharmaceuticals, CF₃-functionalized molecules are prevalently applied in the realm of agrochemicals, materials science and food science.¹¹ Due to the significance of these compounds, recent decades have attested to a booming development of numerous methods for their preparation in the presence of trifluoromethyl reagents.¹² Recently, the direct C–H trifluoromethylation of 1,4-naphthoquinones was achieved under the catalysis of a Cu¹³ or Fe salt.¹⁴ Very recently, we demonstrated a catalyst-free C–H aminotrifluoromethylation of 1,4-naphthoquinones for the synthesis of CF₃-containing naphthoquinones under mild conditions.¹⁵ However, little research interest has been focused on the preparation of CF₃-functionalized 1,4-naphthoquinones through the difunctionalization of alkenes. In 2019, Zhang and co-workers described the Ag-catalyzed difunctionalization of alkenes using 1,4-naphthoquinones and 1-(trifluoromethyl)-1,2-benziodoxol-3(1H)-one (Togni reagent) as coupling partners, leading to the desired CF₃-functionalized 1,4-naphthoquinones in moderate to good yields (Scheme 1A).¹⁶ Subsequently, the application of the difunctionalization of alkenes for the synthesis of CF₃-functionalized 1,4-naphthoquinones was achieved by our group, in which unactivated alkenes could be cross-coupled by 2-amino-1,4-naphthoquinones and sodium trifluoromethanesulfinate (Langlois reagent) in the presence of a Fe catalyst (Scheme 1B).¹⁷ Nevertheless, external transition metal catalysts and relatively high reaction temperatures were required in these methods. From the perspective of green chemistry, catalyst-free reactions are more attractive. Encouraged by our ongoing research on organofluorine chemistry,^15,17,18 we herein demonstrate a substrate-promoted alkenyltrifluoromethylation of alkenes with 2-amino-1,4-naphthoquinones and Togni reagent, in which 2-amino-1,4-naphthoquinones can activate Togni reagent to produce a CF₃ radical under visible light irradiation. Therefore, the reaction proceeds smoothly under mild conditions without external photocatalysts (Scheme 1C).

Scheme 1 Difunctionalization of alkenes involved in the synthesis of CF₃-functionalized 1,4-naphthoquinones.

Results and discussion

Our study on visible light- and substrate-promoted alkenyltrifluoromethylation of alkenes, guided by an integrated design, began with exposure of 4-methylstyrene (1a), 2-phenylamino-1,4-naphthoquinone (2a) and Togni reagent (3) to blue light by the use of Na₃PO₄ as a base and DMF as a solvent (Table 1). Initially, different photocatalysts, including transition metal complexes and organic photosensitizers, were evaluated (entries 2 and 3). A relatively low yield of 4aa was obtained when using Ru(bpy)₃Cl₂ as the catalyst. Nevertheless, the reaction was inactive in the presence of Rose Bengal. Subsequent experiments focused on the assessment of different solvents (entries 4–6). The results obtained above indicated that DMF was the optimal solvent. As shown in entries 7–9, no higher yield was obtained when other organic and inorganic bases were employed. When the reaction was conducted under other light sources, the difunctionalization reaction for the formation of 4aa was restrained (entries 10–12). Further control experiments revealed that the base was not a necessity (entry 13). As expected, visible light was necessary for the reaction (entry 14).

Table 1 Optimization of reaction conditions^a

Entry	Variation from standard conditions	Yield^b (%)
a 1a (0.15 mmol, 1.5 equiv.), 2a (0.1 mmol, 1.0 equiv.), 3 (0.175 mmol, 1.75 equiv.), solvent (1 mL), base (0.15 mmol, 1.5 equiv.), room temperature, 24 h, N2 atmosphere, 40 W blue LEDs (450–470 nm). b Isolated yield.
1	None	76
2	Addition of Ru(bpy)3Cl2 (2 mol%)	68
3	Addition of Rose Bengal (2 mol%)	Trace
4	DMSO as a solvent	52
5	MeCN as a solvent	57
6	EtOAc as a solvent	48
7	DABCO as a base	59
8	DMAP as a base	54
9	K2CO3 as a base	63
10	Green LEDs (530–550 nm)	8
11	Yellow LEDs (560–580 nm)	Trace
12	Red LEDs (640–660 nm)	Trace
13	Without Na3PO4	66
14	In the dark	n.d.

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With the optimal reaction conditions in hand, the substrate scope of various alkenes for the difunctionalization reaction was extended (Scheme 2). When the electron-rich substituent acetoxyl appeared on the benzene ring, a relatively low product yield of 4ab was observed. Styrenes bearing weakly electron-donating groups, including methyl and t-butyl, produced the corresponding coupling products in good yields (4aa and 4ac). Weakly electron-withdrawing halogens in styrenes could be readily converted into the alkenyltrifluoromethylation products 4ae–4aj in moderate to good yields. However, a negative steric hindrance effect was observed, as shown in 4ai. Only moderate yields of 4ak–4am were obtained when electron-deficient substituents, such as trifluoromethyl, cyano and carboxyl, appeared on the aromatic rings of styrenes. Furthermore, biphenyl and naphthalenyl were well compatible to give products 4an and 4ao in 65% and 61% yields, respectively. In addition to styrenes, various aliphatic olefins were evaluated. Simple olefins, such as 1-hexene, 1-octene, 3-phenyl-1-propene, 4-phenyl-1-butene and cyclohexylethylene, were also capable of offering the target products 4ap–4at in moderate yields. In addition, sulfonyloxyl- and phenoxyl-containing alkenes served as efficient substrates, leading to 4au–4aw in acceptable yields. Because of the synthetic diversity of this protocol, we were encouraged to investigate bioactive alkenes. The results showed that various products derived from natural products and pharmaceuticals, including undecenoic acid, indomethacin, estrone, menthol and galactose, were obtained (4ax–4da). Attempts to expand the scope of 2-arylamino-1,4-naphthoquinones were also met with success. The desired products 4ea–ha were isolated in moderate to good yields. Due to steric hindrance, a relatively low yield of 4ia was observed, which was similar to the obtained result in 4ai. Pleasingly, a scale-up model reaction could afford 4aa in a 64% yield (1.4 g).

Scheme 2 Substrate scope. Reaction conditions: 1 (0.15 mmol, 1.5 equiv.), 2 (0.1 mmol, 1.0 equiv.), 3 (0.175 mmol, 1.75 equiv.), DMF (1 mL), Na₃PO₄ (0.15 mmol, 1.5 equiv.), room temperature, 24 h, N₂ atmosphere, 40 W blue LEDs; isolated yield. ^a 5 mmol of 2a was used.

To further understand the mechanism of the developed protocol, some control experiments were conducted (Scheme 3). The visible light-promoted alkenyltrifluoromethylation of alkenes was obviously inhibited when a radical trapping agent, TEMPO, BHT or 1-phenylvinylcyclopropane, was introduced into the reaction mixture, and the corresponding radical adduct 5, 6 or 7 could be detected by GC-MS (Scheme 3A). The results obtained above revealed that a trifluoromethyl was involved in the process. However, the direct trifluoromethylation of 2a with 3 failed due to the eletrophilicity of the trifluoromethyl (Scheme 3B), which indicated that alkene 1a served as a bridge and played an important role in the process. With the addition of excess MeOH, the oxytrifluoromethylation was not observed (Scheme 3C). This result excluded the possibility of a carbocation intermediate. Furthermore, using 2j as a substrate could not give the desired product 4ja because of the lack of a conjugated phenyl of 2j that could not be excited under blue light irradiation (Scheme 3D).

Scheme 3 Control experiments.

Subsequently, the UV-vis spectrum of 2a showed a typical absorption of blue light with the maximum peak of 460 nm, which indicated that 2a could act as an efficient photosensitizer under the radiation of blue light. Compared to 2a, the spectra of other solutions were not shifted. The results excluded the possibility of an electron-donor–acceptor (EDA) complex (Fig. 2A). The results obtained in the “light/dark” reaction confirmed the necessity of continuous blue light (Fig. 2B). Moreover, the results that a fluorescence quenching effect of 2a with 3 was observed indicated that an oxidative quenching cycle was involved (Fig. 2C and D).

Fig. 2 (A) UV-vis spectra; (B) “light/dark” experiments; (C) emission spectra of 2a containing 3; (D) Stern–Volmer quenching plot for 2a using 3 as a quencher.

According to the experimental results obtained above, a plausible mechanism for the visible light-promoted alkenyltrifluoromethylation of alkenes is proposed (Scheme 4). Firstly, irradiating 2a with blue light generates an excited 2a* species that reduces 3 to the radical ˙CF₃ with the generation of intermediate Avia a single-electron transfer (SET) process. The resulting ˙CF₃ is added to the alkene 1a to produce a radical B, and B is converted to radical C through the addition of B to 2a. Subsequently, C is oxidized to an intermediate D by A, accompanied by the production of 2a. Finally, sequential deprotonation and tautomerization of D gives the product 3aa.

Scheme 4 Proposed mechanism.

Conclusions

This manuscript discloses an efficient and practical photochemical strategy for the external catalyst-free three-component alkenyltrifluoromethylation of alkenes with 2-arylamino-1,4-naphthoquinones and Togni reagent. This protocol employs bifunctional 2-arylamino-1,4-naphthoquinones as both catalyst and substrate and Togni reagent as both an oxidant and a substrate. In this context, the developed reaction proceeds smoothly in the absence of additional catalysts. A wide range of CF₃-functionalized 1,4-naphthoquinones, as well as active molecules, have been prepared through a radical process under mild reaction conditions. In summary, the title protocol is distinguished by easily available reactants, broad substrate scope, no involvement of an external catalyst, mild conditions and operational simplicity.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (no. 21602190), the Foundation of Department of Education of Henan Province (no. 23A150022), the Young Backbone Teachers Program of Institutions of Higher Learning in Henan (no. 2020GGJS154), and the Nanhu Scholars Program for Young Scholars of XYNU.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and characterization of products. See DOI: https://doi.org/10.1039/d4ob01585a

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