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Article

Visible Light Promotes Cascade Trifluoromethylation/Cyclization, Leading to Trifluoromethylated Polycyclic Quinazolinones, Benzimidazoles and Indoles

by
Ransong Ma
1,
Yuanyuan Ren
1,
Zhoubin Deng
1,
Ke-Hu Wang
1,
Junjiao Wang
1,
Danfeng Huang
1,
Yulai Hu
1,2,* and
Xiaobo Lv
3
1
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China
2
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
3
Shanghai Sinofluoro Chemicals Co., Ltd., Shanghai 201321, China
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(23), 8389; https://doi.org/10.3390/molecules27238389
Submission received: 31 October 2022 / Revised: 22 November 2022 / Accepted: 24 November 2022 / Published: 1 December 2022
(This article belongs to the Special Issue Insights for Organofluorine Chemistry)
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Abstract

:
Efficient visible-light-induced radical cascade trifluoromethylation/cyclization of inactivated alkenes with CF3Br, which is a nonhygroscopic, noncorrosive, cheap and industrially abundant chemical, was developed in this work, producing trifluoromethyl polycyclic quinazolinones, benzimidazoles and indoles under mild reaction conditions. The method features wide functional group compatibility and a broad substrate scope, offering a facile strategy to pharmaceutically produce valuable CF3-containing polycyclic aza-heterocycles.

1. Introduction

Organofluorides are ubiquitous in pharmaceuticals, agrochemicals and functional materials owing to their high lipophilicity, improved metabolic stability and enhanced bioactivity compared with their parent molecules [1,2,3,4,5,6]. Until now, more than 340 fluorinated pharmaceuticals and 420 fluorinated agrochemicals have been registered and used commercially, which account for 20% of clinical drugs and 35% of commercial agrochemicals, respectively [7,8]. Thus, organofluorides have become increasingly important in developing new pharmaceuticals and agrochemicals. Among the various organofluorides, trifluoromethyl compounds are of great importance due to their frequent appearance in drug and pesticide molecules. This fact has stimulated intensive investigations of trifluoromethylation in organic compounds, and various trifluoromethylation methodologies have been developed. In particular, the appearance of versatile trifluoromethylation reagents such as the Togni [9,10,11], Umemoto [12], Ruppert–Prakash [13,14] and Langlois [15] reagents [16,17] have greatly pushed forward the development of trifluoromethylation methodologies through electrophilic, nucleophilic and radical processes. However, all of these reagents are expensive, and none of them are commercially available in bulk quantities for the time-being. Hence, the exploration of new cost-effective and atom-economic trifluoromethylation methods using easily available trifluoromethylation reagents in bulk quantities in industry is of great value. To address this question, cost-effective and readily available trifluoroacetic acid (TFA), trifluoroacetic anhydride (TFAA) and triflic anhydride (Tf2O) have recently been investigated as trifluoromethylation reagents under diverse catalysis by Zhang, Stephenson, Qing and Ritter, etc. [18,19,20,21,22,23,24,25,26,27,28,29].
As an extinguishant and refrigerant (R-13B1), CF3Br is available in large quantities at a low price (21 USD/kg) in industry. Although CF3Br has been tested as a trifluoromethylation reagent before, it has not been fully investigated in the trifluoromethylation process compared to other trifluoromethylation reagents. Screening of the literature shows that CF3Br can be reduced to a trifluoromethyl anion via electrochemical reduction [30,31], active metal reduction [32,33], or by P(NEt2)3 [34] to react with aldehydes or ketones to give alcohols, or to react with TMSCl to give TMSCF3 (Scheme 1a). Secondly, CF3Br can be reduced to a trifluoromethyl radical by Na2S2O4 [35] or the transition metal complex [36,37,38,39] to couple with aromatic rings or alkenes to give trifluoromethyl compounds (Scheme 1b). In 2018, Zhang′s group reported that CF3Br could be activated by visible-light catalysis to produce a trifluoromethyl radical and induce a radical addition reaction with alkenes and alkynes (Scheme 1c) [40]. This process features an environmentally friendly and sustainable strategy to activate CF3Br. In our previous work, the visible-light-induced trifluoromethylation of O-silyl enol ether was initially tested using CF3Br as trifluoromethyl reagent under visible-light catalysis (Scheme 1d) [41]. As our research on CF3Br is on-going, we herein report a visible-light-induced radical cascade trifluoromethylation/cyclization reaction, which provides a series of trifluoromethylated polycyclic quinazolinones, benzimidazoles and indoles, using CF3Br as a trifluoromethyl source (Scheme 1e). This transformation provides a facile way to construct polycyclic aza-heterocycles, which are usually found in various pharmaceutical compounds (Scheme 2). Moreover, this approach features a low-cost trifluoromethyl source and wide substrate tolerance compared with other methods [42,43,44,45,46,47,48].

2. Results and Discussion

The initial investigation commenced with the reaction of 3-(pent-4-en-1-yl)quinazoline-4(3H)-one (1a) and CF3Br (2) in the presence of tris(2-phenylpyridine)iridium (fac-IrIII(ppy)3) in acetonitrile (CH3CN) under the irradiation of a 5 W blue LED (460–465 nm). The anticipated product 3a was obtained with only a 5% yield (Table 1, entry 1). In view of the great influence of solvent effects on the reaction, various commonly used solvents including dichloromethane (DCM), toluene (Tol), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF) and N-methyl pyrrolidone (NMP) were tested; NMP proved to be the most suitable solvent, in which the product 3a was obtained in a 30% yield (Table 1, entries 2–7). Subsequently, the screening of different light sources and their strength showed that the 5 W blue LED was optimal for the reaction (Table 1, entries 8–10). To further improve the product yield, several Lewis acids were examined. Notably, the addition of LiCl (1.0 equiv.) as an additive significantly accelerated the reaction rate, and the desired product 3a was obtained in an 83% yield (Table 1, entries 11–15). Afterwards, the screening of the loading of the photocatalyst (PC) indicated that 1 mol % of fac-IrIII(ppy)3 was still the most suitable amount (Table 1, entries 14, 16 and 17). Finally, control experiments showed that a photocatalyst or light source is necessary for this transformation because there was no product formed in the absence of the photocatalyst or blue LED light (Table 1, entries 18 and 19). Thus, the optimal reaction conditions were to perform the reaction with 1 equiv. of 3-(pent-4-en-1-yl)quinazoline-4(3H)-one, under 1 atm CF3Br, in the presence of fac-IrIII(ppy)3 in NMP, under the irradiation of a 5 W blue LED, with 1 equiv. of LiCl as the additive.
With the optimal reaction conditions in hand, the substrate scopes were investigated. First, various N-alkenyl quinazolinones 1 were examined (Scheme 3). The results indicated that substrates containing both electron-donating (methyl and methoxy) and electron-withdrawing groups (fluoro-, chloro- and trifluoromethyl) at the 5-, 6-, 7- or 8-position of the quinazolinone ring were well tolerated and provided the corresponding ring-fused quinazolinones in 30% to 73% yields (Scheme 3, 3b–3o). N-alkenyl quinazolinones possessing disubstituted benzene rings reacted well to generate the desired products 3p–3r in 32−81% yields (Scheme 3, 3p–3r). In addition, five- and seven-membered cyclized products 3s–3v were acquired in 30−76% yields (Scheme 3, 3s–3v). Finally, when the benzene ring of the quinazolinone was replaced by a pyridine or thiophene moiety, the corresponding products 3w and 3x were isolated in 41% and 69% yields (Scheme 3, 3w and 3x).
Next, various N-alkenyl pyrroles and N-alkenyl indoles 4 were applied in the standard conditions. As illustrated in Scheme 4, N-alkenyl pyrroles with acetyl groups at the 2-position gave five- and six-membered cyclization products (Scheme 4, 5a and 5b). However, pyrroles with methyl at the 2-position and without substituents failed to produce the desired product (Scheme 4, 5c and 5d). These results indicated that electron-withdrawing substitution on the pyrrole was favorable to the reaction. Afterwards, N-alkenyl indoles containing different substituents were also examined in this transformation. Similarly, indoles with electron-withdrawing substituents (e.g., Ac, CF3CO and CO2Me) at the 3-position produced the desired products (Scheme 4, 5e–5h), while no desired product was detected when the R group at the 3-position was H or methyl (Scheme 4, 5i and 5j).
In order to further investigate the substrate generalities, various N-alkenyl benzimidazoles 6 were applied to the reaction (Scheme 5). When 1-(pent-4-en-1-yl)-1H-benzimidazole reacted with CF3Br under the standard reaction conditions, the six-membered cyclic product 7a was produced in a 70% yield. The other derivatives of 1-(pent-4-en-1-yl)-1H-benzimidazole with both electron-donating and electron-withdrawing groups on their phenyl rings also produced the corresponding products in good yields (Scheme 5, 7b–7f). Subsequently, the reaction was extended to linear and branched N-butenyl benzimidazole, and the corresponding five-membered cyclization products 7g and 7h were also generated smoothly, albeit with decreased yields (Scheme 5, 7g and 7h). Moreover, 7-azobenzimidazole and theophylline were successfully used in this reaction to give the products 7i and 7j with good yields of 62% and 70% (Scheme 5, 7i and 7j).

3. Gram-Scale Synthesis

To probe the practical utility of this trifluoromethylation process, a gram-scale reaction of 3-(pent-4-en-1-yl) quinazolin-4(3H)-one was performed with 1 mol % catalyst loading, which proceeded smoothly to produce the desired product 3a in a 60% yield (Scheme 6). Experimental details and characterization data for products are in Supplementary Materials.

4. Proposed Mechanism

To probe the reaction mechanism, the radical scavenger 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO, 2.0 equiv.) was added in the reaction of 1a with CF3Br under the standard reaction conditions. The formation of the product 3a was completely inhibited (Scheme 7, a). When radical scavenger 1,1-diphenylethylene (2.0 equiv.) was added to the reaction, product 3a was not formed; only the trifluoromethyl radical trapping compound (3,3,3-trifluoroprop-1-ene-1,1-diyl)dibenzene 8 as produced in a yield of 64% (Scheme 7, b). These results imply that the trifluoromethyl radical was involved as the reactive species in the reaction.
In light of our experimental results and the literature descriptions [47,48], a reaction mechanism is tentatively proposed in Scheme 8. Under the activation of LiCl, N-alkenyl quinazolinones 1a convert to more electrophilic lithium-activated N-alkenyl quinazolinones A. Meanwhile, the visible light induced the transformation of the photocatalyst fac-IIIIr(ppy)3 to the excited-state fac-IIIIr(ppy)3*, which reduced CF3Br to generate a trifluoromethyl radical along with the generation of the fac-IVIr(ppy)3 complex via a single-electron transfer (SET). Then, the addition of the trifluoromethyl radical onto the C = C bond of lithium-activated N-alkenyl quinazolinones A gave radical intermediate B, which underwent intramolecular radical cyclization to offer the intermediate C, followed by a further 1,2-hydrogen shift process to yield the intermediate D. The intermediate D was then oxidized by fac-IVIr(ppy)3 to form the cation E. Finally, product 3a was obtained with the loss of a proton.

5. Conclusions

In conclusion, we have developed efficient visible-light-induced radical trifluoromethylation/cyclization for the synthesis of potential bioactive trifluoromethylated polycyclic quinazolinones, benzimidazoles and indoles. This system has the advantages of high step-economy and low-cost, which renders this protocol highly attractive for the synthesis of CF3-containing polycyclic aza-heterocycles.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27238389/s1, Experimental details and characterization data for products 3a–3x, 5a, 5b, 5e–5h and 7a−7j [42,46,47,49,50,51].

Author Contributions

Data curation, K.-H.W., J.W. and D.H.; Funding acquisition, D.H., Y.H. and X.L.; Investigation, R.M.; Methodology, R.M., J.W. and D.H.; Project administration, Y.H.; Validation, Y.R., Z.D., K.-H.W. and D.H.; Writing—original draft, R.M.; Writing—review & editing, Y.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China, grant numbers 22061037 and 21861033; the State Key Laboratory of Applied Organic Chemistry, Lanzhou University; and Shanghai Sinofluoro Chemicals Co., Ltd.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We are thankful for financial support from the National Natural Science Foundation of China (Grant No. 22061037 and 21861033), the State Key Laboratory of Applied Organic Chemistry, Lanzhou University, and Shanghai Sinofluoro Chemicals Co., Ltd.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 27 08389 sch001 550
Scheme 1. Trifluoromethylation with CF3Br as the trifluoromethylation source.
Scheme 1. Trifluoromethylation with CF3Br as the trifluoromethylation source.
Molecules 27 08389 sch001
Molecules 27 08389 sch002 550
Scheme 2. Representative biologically active aza-heterocycles.
Scheme 2. Representative biologically active aza-heterocycles.
Molecules 27 08389 sch002
Molecules 27 08389 sch003 550
Scheme 3. Scope of quinazolinone-derived substrates a. a Reaction conditions: 1a (0.3 mmol, 1 equiv.), PC = fac-Ir(III)(ppy)3 (0.003 mmol, 1 mol %); LiCl (0.3 mmol), NMP (3 mL) and CF3Br (1.0 atm) in a 50 mL Schlenk flask; room temperature, 5 W blue LED light irradiation; time = 16 h. Isolated yield.
Scheme 3. Scope of quinazolinone-derived substrates a. a Reaction conditions: 1a (0.3 mmol, 1 equiv.), PC = fac-Ir(III)(ppy)3 (0.003 mmol, 1 mol %); LiCl (0.3 mmol), NMP (3 mL) and CF3Br (1.0 atm) in a 50 mL Schlenk flask; room temperature, 5 W blue LED light irradiation; time = 16 h. Isolated yield.
Molecules 27 08389 sch003
Molecules 27 08389 sch004 550
Scheme 4. Scope of pyrrole- and indole-derived substrates a. a Reaction conditions: 1a (0.3 mmol, 1 equiv.), PC = fac-Ir(III)(ppy)3 (0.003 mmol, 1 mol %); LiCl (0.3 mmol), NMP (3 mL) and CF3Br (1.0 atm) in a 50 mL Schlenk flask; room temperature, 5 W blue LED light irradiation; time = 16 h. Isolated yield. bN.D.: not detected.
Scheme 4. Scope of pyrrole- and indole-derived substrates a. a Reaction conditions: 1a (0.3 mmol, 1 equiv.), PC = fac-Ir(III)(ppy)3 (0.003 mmol, 1 mol %); LiCl (0.3 mmol), NMP (3 mL) and CF3Br (1.0 atm) in a 50 mL Schlenk flask; room temperature, 5 W blue LED light irradiation; time = 16 h. Isolated yield. bN.D.: not detected.
Molecules 27 08389 sch004
Molecules 27 08389 sch005 550
Scheme 5. Scope of benzimidazole-derived substrates a. aReaction conditions: 1a (0.3 mmol, 1 equiv.), PC = fac-Ir(III)(ppy)3 (0.003 mmol, 1 mol %); LiCl (0.3 mmol), NMP (3 mL) and CF3Br (1.0 atm) in a 50 mL Schlenk flask; room temperature, 5 W blue LED light irradiation; time = 16 h. Isolated yield.
Scheme 5. Scope of benzimidazole-derived substrates a. aReaction conditions: 1a (0.3 mmol, 1 equiv.), PC = fac-Ir(III)(ppy)3 (0.003 mmol, 1 mol %); LiCl (0.3 mmol), NMP (3 mL) and CF3Br (1.0 atm) in a 50 mL Schlenk flask; room temperature, 5 W blue LED light irradiation; time = 16 h. Isolated yield.
Molecules 27 08389 sch005
Molecules 27 08389 sch006 550
Scheme 6. Gram-scale synthesis.
Scheme 6. Gram-scale synthesis.
Molecules 27 08389 sch006
Molecules 27 08389 sch007 550
Scheme 7. Mechanistic experiments.
Scheme 7. Mechanistic experiments.
Molecules 27 08389 sch007
Molecules 27 08389 sch008 550
Scheme 8. Proposed reaction mechanism.
Scheme 8. Proposed reaction mechanism.
Molecules 27 08389 sch008
Table
Table 1. Optimization of Reaction Conditions a.
Table 1. Optimization of Reaction Conditions a.
Molecules 27 08389 i001
EntryPC (x mol%)Light SourceAdditiveSolventYield b (%)
11.0 mol%5 W blue LED-CH3CN5%
21.0 mol%5 W blue LED-DCM15%
31.0 mol%5 W blue LED-Toluene3%
41.0 mol%5 W blue LED-THF3%
51.0 mol%5 W blue LED-DMSOtrace
61.0 mol%5 W blue LED-DMF24%
71.0 mol%5 W blue LED-NMP30%
81.0 mol%10 W blue LED-NMP30%
91.0 mol%15 W blue LED-NMP30%
101.0 mol%5 W white LED-NMP21%
111.0 mol%5 W blue LED20% Sc (OTf)3NMP45%
121.0 mol%5 W blue LED20% In (OTf)3NMP38%
131.0 mol%5 W blue LED100% LiFNMP35%
141.0 mol%5 W blue LED100% LiClNMP83%
151.0 mol%5 W blue LED100% LiBrNMP38%
160.5 mol%5 W blue LED100% LiClNMP78%
170.25 mol%5 W blue LED100% LiClNMP72%
18-5 W blue LED100% LiClNMP0%
191.0 mol%-100% LiClNMP0%
a Reaction conditions: 1a (0.3 mmol, 1 equiv.), PC = fac-Ir(III)(ppy)3; additive, solvent (3 mL) and CF3Br (1.0 atm) in a 50 mL Schlenk flask; room temperature, 5 W blue LED light irradiation; time = 16 h. b Isolated yield.
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Ma, R.; Ren, Y.; Deng, Z.; Wang, K.-H.; Wang, J.; Huang, D.; Hu, Y.; Lv, X. Visible Light Promotes Cascade Trifluoromethylation/Cyclization, Leading to Trifluoromethylated Polycyclic Quinazolinones, Benzimidazoles and Indoles. Molecules 2022, 27, 8389. https://doi.org/10.3390/molecules27238389

AMA Style

Ma R, Ren Y, Deng Z, Wang K-H, Wang J, Huang D, Hu Y, Lv X. Visible Light Promotes Cascade Trifluoromethylation/Cyclization, Leading to Trifluoromethylated Polycyclic Quinazolinones, Benzimidazoles and Indoles. Molecules. 2022; 27(23):8389. https://doi.org/10.3390/molecules27238389

Chicago/Turabian Style

Ma, Ransong, Yuanyuan Ren, Zhoubin Deng, Ke-Hu Wang, Junjiao Wang, Danfeng Huang, Yulai Hu, and Xiaobo Lv. 2022. "Visible Light Promotes Cascade Trifluoromethylation/Cyclization, Leading to Trifluoromethylated Polycyclic Quinazolinones, Benzimidazoles and Indoles" Molecules 27, no. 23: 8389. https://doi.org/10.3390/molecules27238389

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