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Article

Copper-Catalyzed Benzothiazolyldifluoroalkylation of Arylidenemalonitriles or para-Quinone Methides

by
Jilin Xiao
,
Ying Cai
,
Rongfu Xu
,
Fumin Liao
* and
Jinbiao Liu
*
Jiangxi Provincial Key Laboratory of Functional Crystalline Materials Chemistry, School of Chemistry and Chemical Engineering, Jiangxi University of Science and Technology, Ganzhou 341000, China
*
Authors to whom correspondence should be addressed.
Catalysts 2024, 14(11), 777; https://doi.org/10.3390/catal14110777
Submission received: 30 September 2024 / Revised: 29 October 2024 / Accepted: 1 November 2024 / Published: 3 November 2024
(This article belongs to the Section Catalysis in Organic and Polymer Chemistry)
Browse Figures
Versions Notes

Abstract

:
We reported copper-catalyzed the 1,4- or 1,6-conjugate additions of arylidenemalonitriles or para-quinone methides with 2-bromodifluoromethylbenzo-1,3-thiazole for the preparation of benzothiazolyldifluoroalkyl containing (di)arylmethine compounds in moderate to excellent yields, providing a facile route for the synthesis of gem-difluoroalkylatated (di)arylmethine compounds. The synthetic utility of the current method was also demonstrated by a gram-scale reaction.

1. Introduction

The selective introduction of a fluoroalkyl group into biologically active molecules has emerged as a reliable strategy to modulate pharmacological properties in drug discovery and development [1,2,3,4,5,6]. Therefore, establishing new efficient methods for the synthesis of fluoroalkyl-containing compounds is currently a hot topic in the field of synthetic chemistry. The incorporation of a gem-difluoroalkyl group substantially influences the electronic properties of its neighboring groups, which may produce beneficial effects such as an enhancement in lipophilicity, metabolic stability, bioavailability [7]. For instance, eflornithine [8] and gemcitabine [9] are drugs containing a gem-difluoroalkyl group. Furthermore, the difluoromethylene analogs of both Vitamin D [10] and docetaxel [11] show improved properties. Despite considerable progress in selective trifluoromethylation [12], the development of methods for selective gem-difluoroalkylation is still highly desirable [13,14,15,16,17].
2-Bromodifluoromethylbenzo-1,3-thiazoles 1, as stable and readily available difluoroalkyl reagents for the selective introduction of gem-difluoromethylene benzo-1,3-thiazole moiety, have gained increasing attention in the past decade. A variety of reactions using 1 as a substrate have been reported, including the SRN1 reaction [18,19], aldol reaction [20], cross-coupling reaction [21,22,23,24], (di)functionalization of alkenes reaction [25,26,27,28,29,30], and Truce–Smiles rearrangement reaction [31].
The significance of functional malononitrile [32,33] and diarylmethine frameworks scaffolds [34,35,36,37] has been studied, while combining the gem-difluoroalkyl group with arylidenemalonitriles or para-quinone methides (p-QMs) scaffold remains less explored [38,39,40,41,42]. Given the importance of difluoroalkylated (di)arylmethine skeletons in medicinal research, it is highly important to combine them in one molecule for future drug development. As a continuation of our interest in selective fluoroalkylation with 2-Bromodifluoromethylbenzo-1,3-thiazoles 1 [43,44], we have recently completed the efficient synthesis of 1 and its aryl selenylation to furnish gem-difluoromethyl linked aryl seleno compounds [45], as shown in Scheme 1. Herein, the copper-catalyzed 1,4 or 1,6-conjugate addition reaction of 1 with arylidenemalonitriles or p-QMs was developed to furnish gem-difluoroalkylated (di)arylmethine compounds.

2. Results

2.1. The Reaction Conditions Optimization of 1 and 2

Initially, we chose 2-Bromodifluoromethylbenzo-1,3-thiazole 1 and 2-benzylidenemalononitrile 2a as the model substrates to investigate reaction conditions. As outlined in Table 1, firstly, using 20 mol% CuI as the catalyst only, the product 3a was obtained in only an 18% yield (Table 1, entry 1).
Then, we added four common N,N-bidentate ligands to the reaction and found 1,10-phenanthroline (L1) better than other dipyridyl ligands (39% yield, Table 1, entry 2 vs. 3–5). Using CuI/L1 complex as the catalyst, we then screened different solvents and temperatures. After the screening of various solvents, N-methyl-2-pyrrolidone (NMP) proved to be better than other solvents, such as N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, and toluene, providing the desired product 3a in a 57% yield (Table 1, entry 8). Whether it was due to raising the reaction temperature to 100 °C or lowering the reaction temperature to 60 °C, the yield of 3a decreased (Table 1, entry 8 vs. 9–10).
A series of copper catalysts [e.g., CuBr, CuCl, and Cu(OAc)2] were also tested (Table 1, entries 11–13), and CuI was determined to be the best. It is worth mentioning that the addition of 20 mol% copper powder was beneficial for improving the yield of 3a from 57% to 81% (Table 1, entry 14 vs. 8). In addition, increasing or decreasing the amount of copper powder both diminished the reaction yield of 3a (Table 1, entry 14 vs. 15–16).

2.2. Reaction Conditions Optimization of 1 and 4

We then investigated the reaction conditions of 2-Bromodifluoromethylbenzo-1,3-thiazole 1 with para-quinone methides (p-QMs) 4 for the synthesis of diarylmethine frameworks, as outlined in Table 2.
Firstly, by using 20 mol% Cu/CuI/L1 as the catalyst, the product 5a was obtained in a 43% yield (Table 2, entry 1). When the amount of copper powder was increased to 1.0 equivalent, the yield of 5a increased to 53% (Table 2, entry 2). On this basis, we investigated different copper salts and ligands and found that Cu(OAc)2 was better (Table 2, entry 4). Further investigation revealed that the ligands were not necessary (Table 2, entry 8 vs. 4).
Next, the addition of bases could increase the yield of 5a, and adding 4.0 equivalents of DIPEA was necessary (Table 2, entry 14). Similarly, both increasing and decreasing the temperature decreased the reaction yield (Table 2, entry 14 vs. 16–17). It was crucial to use both the copper powder and copper salt simultaneously, and the product yield significantly decreased without either (Table 2, entry 14 vs. 18–19). To our surprise, increasing the concentration of NMP could reduce the amount of copper powder to 20 mol% while maintaining almost the same yield of 5a (Table 2, entry 21 vs. 14).

2.3. Substrate Scope

With the optimized conditions in hand, we investigated the generality of this reaction. As shown in Table 3, the substrate scope with respect to arylidenemalonitriles 2 was examined. And, we found that the different nature and position of the substituted arylidenemalonitriles 2 all reacted well with the 2-Bromodifluoromethylbenzo-1,3-thiazole 1 to give rise to the corresponding products 3a–3f in 66–90% yields. We further developed the reaction of 1 with para-quinone methides (p-QMs) 4 for diarylmethine synthesis frameworks. As shown in Table 3, the substrate scope with respect to p-QMs was examined. And, we found that aryl-substituted p-QMs 4 all reacted well with the 2-Bromodifluoromethylbenzo-1,3-thiazole 1 to give rise to the corresponding gem-difluoroalkyl-substituted diarylmethine frameworks 5a–5g in 62–66% yields, whatever the nature of the substituent on the phenyl ring.

2.4. Gram-Scale Synthesis

Subsequently, in order to examine the practicality and simplicity of the developed method, the gram-scale reaction was conducted, as Shown in Scheme 2. To our delight, the desired product 3a was obtained in a 78% yield (1.06 g) and the 5a was furnished in a 63% yield (1.23 g).

2.5. The Proposed Mechanism

It has previously been shown that a copper catalyst can initiate the generation of radicals from difluoroalkyl halides through single electron transfer. By employing 2.0 eq of TEMPO as the radical scavenger under standard reaction conditions, the products 3a and 5a were not obtained. This result suggests that free radical pathways may be involved in this reaction. We tried to obtain some information about active intermediates. Unfortunately, this idea could not be confirmed.
Based on the above experimental data and the mechanisms reported in the literature, the proposed reaction mechanisms are described in Scheme 3. Firstly, a copper catalyst can initiate the generation of difluoroalkyl radicals I from 1 through single electron transfer [46,47,48,49] upon the loss of bromine, which undergoes an additional reaction with the active olefins 2 or 4 to form intermediate II. Secondly, II is then reduced by copper(I) to form intermediate III and copper(II). Lastly, the copper(II) is reduced by the solvent NMP to the copper catalyst, along with the generation of protons, which then combine with intermediate III to generate product 3 or 5. In the reaction of 1 with 4, on the one hand, Cu(II) may be reduced by copper powder to generate Cu(I), and, on the other hand, it may also serve as a Lewis acid activation for the substrate 4.

3. Materials and Methods

All the commercially available reagents were purchased from Shanghai Energy Chemical and used without further purification. The solvents were treated prior to use according to standard methods. All the reactions were performed under nitrogen using solvents dried by standard methods. NMR spectra were recorded on a Bruker Avance AV400 (400/100/376 MHz 1H/13C/19F) spectrometer (Bruker, Billerica, MA, USA). The 1H and 13C chemical shifts were reported in ppm relative to the residual solvent peak. HR- MS data were obtained using a Thermo Scientific Q Exactive Orbitrap Mass Spectrometer. Silica gel (200–300 mesh) was used for the chromatographic separations.
General Procedure A: All the catalytic reactions were performed in a 10 mL Schlenk tube under N2. Typically, a mixture of 2-Bromodifluoromethyl-benzo-1,3-thiazole 1 (0.45 mmol), arylidenemalonitriles 2 (0.30 mmol), CuI (0.06 mmol), Cu (0.06 mmol), and 1,10-Phenanthroline (L1, 0.06 mmol) was used, with the following addition of 3.0 mL of anhydrous NMP as a solvent. The reaction mixture was stirred at 80 °C until the full disappearance of 1 by TLC analysis (24–36 h), and, then, it was purified by flash column chromatography (petroleum ether:ethyl acetate = 7:1), affording the corresponding product 3.
General Procedure B: All the catalytic reactions were performed in a 10 mL Schlenk tube under N2. Typically, a mixture of 2-Bromodifluoromethyl-benzo-1,3-thiazole 1 (0.20 mmol), p-QMS 4 (0.20 mmol), Cu(OAc)2 (0.04 mmol), Cu (0.04 mmol), and DIPEA (0.80 mmol) was used, with the following addition of 1.0 mL of anhydrous NMP as a solvent. The reaction mixture was stirred at 100 °C until the full disappearance of 1 by TLC analysis (4–5 h), and, then, it was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1), affording the corresponding product 5.
The analytical data for compounds 3 and 5 (available in the Supplementary Materials) are as follows.
2-(2-(benzo[d]thiazol-2-yl)-2,2-difluoro-1-phenylethyl)malononitrile (3a): Prepared according to the general procedure A as described above in an 81% yield (82 mg) as a yellow solid. Mp. 137.7–138.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.61–7.57 (m, 1H), 7.53–7.48 (m, 3H), 7.38–7.36 (m, 3H), 5.02 (d, J = 8.0 Hz, 1H), 4.62–4.54 (m, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 161.45 (t, J = 33.3 Hz, 1C), 152.11, 134.94, 130.08, 129.65, 129.33, 127.16, 127.13, 124.45, 122.07, 117.60 (t, J = 249.4 Hz, 1C), 111.04, 110.77, 51.54 (t, J = 23.2 Hz, 1C), 24.67 (t, J = 4.0 Hz, 1C) ppm. 19F NMR (376 MHz, CDCl3) δ −87.11 (d, J = 270.7 Hz, 1F), −94.67 (d, J = 270.7 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C18H11F2N3S [M+H]+, 340.0705; found, 340.0715.
2-(2-(benzo[d]thiazol-2-yl)-2,2-difluoro-1-(p-tolyl)ethyl)malononitrile (3b): Prepared according to the general procedure A as described above in an 86% yield (91 mg) as a yellow solid. Mp. 120.4–120.7 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8 Hz, 1H), 7.91 (d, J = 8 Hz, 1H), 7.60–7.56 (m, 1H), 7.52–7.48 (m, 1H), 7.36 (d, J = 8 Hz, 2H), 7.16 (d, J = 8 Hz, 2H), 4.98 (d, J = 4 Hz, 1H), 4.50–4.58 (m, 1H), 2.30 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 161.59 (t, J = 33.3 Hz, 1C), 152.14, 140.15, 134.95, 130.03, 129.47, 127.12, 127.06, 126.19, 124.44, 122.06, 117.67 (t, J = 249.4 Hz, 1C), 111.14, 110.86, 51.26 (t, J = 23.7 Hz, 1C), 24.75 (t, J = 4.0 Hz, 1C), 21.15 ppm. 19F NMR (376 MHz, CDCl3) δ −86.87 (d, J = 266.9 Hz, 1F), −94.78, −95.13 (d, J = 266.9 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C19H13F2N3S [M+H]+, 354.0862; found, 354.0871.
2-(1-([1,1′-biphenyl]-4-yl)-2-(benzo[d]thiazol-2-yl)-2,2-difluoroethyl)malononitrile (3c): Prepared according to the general procedure A as described above in a 90% yield (112 mg) as a yellow solid. Mp. 140.1–140.4 °C. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8 Hz, 1H), 7.91 (d, J = 8 Hz, 1H), 7.60–7.58 (m, 5H), 7.55–7.48 (m, 3H), 7.43–7.40 (m, 2H), 7.36–7.32 (m, 1H), 5.05 (d, J = 4 Hz, 1H), 4.67–4.59 (m, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 161.44 (t, J = 33.3 Hz, 1C), 152.12, 142.77, 139.60, 134.97, 130.08, 128.81, 127.91, 127.86, 127.18, 127.15, 127.04, 124.46, 122.10, 117.61 (t, J = 249.4 Hz, 1C), 111.08, 110.81, 51.24 (t, J = 23.2 Hz, 1C), 24.72 (t, J = 4.0 Hz, 1C) ppm. 19F NMR (376 MHz, CDCl3) δ −86.85 (d, J = 270.7 Hz, 1F), −94.61 (d, J = 270.7 Hz, 1F) ppm. HRMS (ESI): Exact mass calculated for C24H15 F2N3S [M+H]+, 416.1017; found, 416.1028.
2-(2-(benzo[d]thiazol-2-yl)-1-(4-bromophenyl)-2,2-difluoroethyl)malononitrile (3d): Prepared according to the general procedure A as described above in a 66% yield (82 mg) as a yellow solid. Mp. 133.1–133.4 °C. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8 Hz, 1H), 7.94 (d, J = 12 Hz, 1H), 7.62–7.58 (m, 1H), 7.55–7.51 (m, 3H), 7.40 (d, J = 12 Hz, 2H), 5.01 (d, J = 4.0 Hz, 1H), 4.62–4.54 (m, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 161.09 (t, J = 33.3 Hz, 1C), 152.04, 134.93, 132.62, 131.29, 128.55, 128.22, 127.28, 124.75, 124.47, 122.14, 117.34 (t, J = 249.4 Hz, 1C), 110.82, 110.54, 50.90 (t, J = 24.2 Hz, 1C), 24.52 (t, J = 4.0 Hz, 1C) ppm. 19F NMR (376 MHz, CDCl3) δ −86.79 (d, J = 270.7 Hz, 1F), −95.01 (d, J = 270.7 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C18H1079BrF2N3S [M+H]+, 417.9809; found, 417.9820.
2-(2-(benzo[d]thiazol-2-yl)-1-(4-chlorophenyl)-2,2-difluoroethyl)malononitrile (3e): Prepared according to the general procedure A as described above in an 83% yield (92 mg) as a yellow solid. Mp. 168.8–169.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8 Hz, 1H), 7.935 (d, J = 4 Hz, 1H), 7.58–7.62 (m, 1H), 7.53–7.55 (m, 1H), 7.36 (d, J = 8 Hz, 2H), 5.01 (d, J = 8 Hz, 1H), 4.55–4.63 (m, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 161.08 (t, J = 33.3 Hz, 1C), 152.04, 136.44, 134.93, 131.05, 129.66, 127.73, 127.70, 127.28, 124.46, 122.14, 117.41 (t, J = 249.4 Hz, 1C), 110.84, 110.56, 50.83 (t, J = 23.7 Hz, 1C), 24.59 (t, J = 4.0 Hz, 1C) ppm. 19F NMR (376 MHz, CDCl3) δ −86.84 (d, J = 270.7 Hz, 1F), −95.08 (d, J = 270.7 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C18H1035ClF2N3S [M+H]+, 374.0316; found, 374.0325.
2-(2-(benzo[d]thiazol-2-yl)-1-(3,5-dimethylphenyl)-2,2-difluoroethyl)malononitrile (3f): Prepared according to the general procedure A as described above in a 75% yield (82 mg) as a yellow solid. Mp. 116.4–116.8 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8 Hz, 1H), 7.91 (d, J = 8 Hz, 1H), 7.60–7.56 (m, 1H), 7.52–7.48 (m, 1H), 7.07 (s, 2H), 6.99 (s, 1H), 4.96 (d, J =8 Hz, 1H), 4.52–4.43 (m, 1H), 2.27 (s, 6H) ppm. 13C NMR (101 MHz, CDCl3) δ 161.72 (t, J = 33.3 Hz, 1C), 152.17, 138.92, 135.02, 131.79, 129.14, 127.33, 127.12, 127.07, 124.45, 122.05, 117.64 (t, J = 249.4 Hz, 1C), 111.13, 110.86, 51.46 (t, J = 23.7 Hz, 1C), 24.76 (t, J = 4.0 Hz, 1C), 21.26 ppm. 19F NMR (376 MHz, CDCl3) δ −87.55 (d, J = 270.7 Hz, 1F), −93.60 (d, J = 270.7 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C20H15 F2N3S [M+H]+, 368.1021; found, 368.1028.
4-(2-(benzo[d]thiazol-2-yl)-1-(4-bromophenyl)-2,2-difluoroethyl)-2,6-di-tert-butylphenol (5a): Prepared according to the general procedure B as described above in a 65% yield (72 mg) as a white solid. Mp. 154–156 °C. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 4.0 Hz, 1H), 7.54–7.51 (m, 1H), 7.46–7.41 (m, 5H), 7.15 (s, 2H), 5.19–5.10 (m, 2H), 1.33 (s, 18H) ppm. 13C NMR (101 MHz, CDCl3) δ 165.04 (t, J = 34.3 Hz, 1C), 153.18, 152.58, 136.14, 135.70, 135.03, 131.56, 131.29, 126.62, 126.35, 126.25, 126.19, 124.05, 121.80, 121.40, 119.80 (t, J = 249.5 Hz, 1C), 56.98 (t, J = 23.2 Hz, 1C), 34.24, 30.12 ppm. 19F NMR (376 MHz, CDCl3) δ −92.37 (d, J = 259.4 Hz, 1F), −93.23 (d, J = 259.4 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C29H2979BrF2NOS [M-H]−, 556.1127; found, 556.1137.
4-(2-(benzo[d]thiazol-2-yl)-1-(4-chlorophenyl)-2,2-difluoroethyl)-2,6-di-tert-butylphenol (5b): Prepared according to the general procedure B as described above in a 66% yield (68 mg) as a yellow solid. Mp. 134–136 °C. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.54–7.50 (m, 1H), 7.46–7.41 (m, 3H), 7.24–7.22 (m, 3H), 7.14 (s, 2H), 5.19–5.10 (m, 2H), 1.32 (s, 18H) ppm. 13C NMR (101 MHz, CDCl3) δ 165.07 (t, J = 33.3 Hz, 1C), 153.17, 152.58, 135.69, 135.61, 135.03, 133.18, 130.94, 128.61, 126.62, 126.36, 126.25, 124.05, 121.80, 119.86 (t, J = 249.5 Hz, 1C), 56.92 (t, J = 23.3 Hz, 1C), 34.25, 30.12 ppm. 19F NMR (376 MHz, CDCl3) δ −92.41 (d, J = 255.7 Hz, 1F), −93.34 (d, J = 255.7 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C29H2935ClF2NOS [M-H]−, 512.1632; found, 512.1650.
4-(2-(benzo[d]thiazol-2-yl)-2,2-difluoro-1-phenylethyl)-2,6-di-tert-butylphenol (5c): Prepared according to the general procedure B as described above in a 62% yield (59 mg) as a yellow solid. Mp. 140–142 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.55–7.50 (m, 3H), 7.44–7.40 (m, 1H), 7.31–7.28 (m, 2H), 7.24–7.21 (m, 3H), 5.21–5.11 (m, 2H), 1.33 (s, 18H) ppm. 13C NMR (101 MHz, CDCl3) δ 165.45 (t, J = 33.3 Hz, 1C), 153.04, 152.61, 137.03, 135.53, 135.07, 129.62, 128.43, 127.23, 126.75, 126.51, 126.49, 126.11, 124.04, 121.74, 120.07 (t, J = 250.5 Hz, 1C), 57.66 (t, J = 23.2 Hz, 1C), 34.23, 30.14 ppm. 19F NMR (376 MHz, CDCl3) δ −92.34 (d, J = 259.4 Hz, 1F), −93.20 (d, J = 259.4 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C29H30F2NOS [M-H]−, 478.2022; found, 478.2046.
4-(2-(benzo[d]thiazol-2-yl)-2,2-difluoro-1-(p-tolyl)ethyl)-2,6-di-tert-butylphenol (5d): Prepared according to the general procedure B as described above in a 66% yield (65 mg) as a yellow solid. Mp. 149–150 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.54–7.50 (m, 1H), 7.44–7.40 (m, 3H), 7.21 (s, 2H), 7.10 (d, J = 8.0 Hz, 2H), 5.17–5.08 (m, 2H), 2.29 (s, 3H), 1.34 (s, 18H) ppm. 13C NMR (101 MHz, CDCl3) δ 165.57 (t, J = 33.3 Hz, 1C), 152.98, 152.62, 136.83, 135.48, 135.09, 133.98, 129.46, 129.16, 126.97, 126.48, 126.42, 126.06, 124.03, 121.74, 120.11 (t, J = 249.5 Hz, 1C), 57.33 (t, J = 23.2 Hz, 1C), 34.23, 30.16, 21.00 ppm. 19F NMR (376 MHz, CDCl3) δ −92.74, −94.34 ppm. HRMS (ESI): exact mass calculated for C30H32F2NOS [M-H]−, 492.2178; found, 492.2184.
4-(2-(benzo[d]thiazol-2-yl)-2,2-difluoro-1-(4-methoxyphenyl)ethyl)-2,6-di-tert-butylphenol (5e): Prepared according to the general procedure B as described above in a 65% yield (66 mg) as a yellow solid. Mp. 127–128 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.54–7.50 (m, 1H), 7.46–7.40 (m, 3H), 7.22 (s, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.17–5.08 (m, 2H), 3.75 (s, 3H), 1.35 (s, 18H) ppm. 13C NMR (101 MHz, CDCl3) δ 165.56 (t, J = 34.5 Hz, 1C), 158.61, 152.96, 152.59, 135.50, 135.06, 130.69, 129.08, 127.05, 126.48, 126.37, 126.06, 123.99, 121.73, 120.12 (t, J = 249.5 Hz, 1C), 113.78, 56.87 (t, J = 23.2 Hz, 1C), 55.06, 34.22, 30.15 ppm. 19F NMR (376 MHz, CDCl3) δ −92.41 (d, J = 259.4 Hz, 1F), −93.40 (d, J = 259.4 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C30H32F2NO2S [M-H]−, 508.2127; found, 508.2154.
4-(1-([1,1′-biphenyl]-4-yl)-2-(benzo[d]thiazol-2-yl)-2,2-difluoroethyl)-2,6-di-tert-butylphenol (5f): Prepared according to the general procedure B as described above in a 63% yield (70 mg) as a yellow solid. Mp. 149–150 °C. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.58–7.51 (m, 5H), 7.45–7.39 (m, 3H), 7.34–7.31 (m, 3H), 7.24 (s, 2H), 5.26–5.12 (m, 2H), 1.35 (s, 18H) ppm. 13C NMR (101 MHz, CDCl3) δ 165.40 (t, J = 33.3 Hz, 1C), 153.10, 152.63, 140.54, 139.93, 136.09, 135.60, 135.10, 129.99, 128.69, 127.24, 127.12, 126.96, 126.70, 126.54, 126.49, 126.14, 124.05, 121.77, 120.09 (t, J = 249.5 Hz, 1C), 57.37 (t, J = 23.2 Hz, 1C), 34.26, 30.16 ppm. 19F NMR (376 MHz, CDCl3) δ −92.18 (d, J = 259.4 Hz, 1F), −93.16 (d, J = 259.4 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C35H34F2NOS [M-H]−, 554.2335; found, 554.2356.
4-(1-(4-bromophenyl)-2-(6-chlorobenzo[d]thiazol-2-yl)-2,2-difluoroethyl)-2,6-di-tert-butylphenol (5g): Prepared according to the general procedure B as described above in a 62% yield (73 mg) as a yellow solid. Mp. 153–155 °C. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 1H), 7.83 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.43–7.37 (m, 4H), 7.15 (s, 2H), 5.15–5.06 (m, 2H), 1.34 (s, 18H) ppm. 13C NMR (101 MHz, CDCl3) δ 165.51 (d, J = 34.3 Hz, 1H), 153.24, 151.08, 136.19, 135.95, 135.77, 132.41, 131.61, 131.24, 127.62, 126.31, 126.01, 124.82, 121.50, 121.39, 119.60 (t, J = 249.5 Hz, 1H), 56.95 (t, J = 23.2 Hz, 1H), 34.26, 30.14 ppm. 19F NMR (376 MHz, CDCl3) δ −92.36 (d, J = 259.4 Hz, 1F), −93.25 (d, J = 259.4 Hz, 1F) ppm. HRMS (ESI): exact mass calculated for C29H28BrClF2NOS [M-H]−, 590.0737; found, 590.0748.

4. Conclusions

In conclusion, copper-catalyzed radical 1,4- or 1,6-conjugate additions of 2-Bromodifluoromethylbenzo-1,3-thiazole with arylidenemalonitriles or para-quinone methides have been developed for the synthesis of benzothiazolyldifluoroalkyl containing (di)arylmethine compounds in moderate to excellent yields. The reaction performed well on a gram scale, indicating that it was a practical tool for the synthesis of gem-difluoroalkylatated (di)arylmethine derivatives. More catalytic reactions involving 2-bromodifluoromethylbenzo-1,3-thiazoles will be reported in due course.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal14110777/s1, Figure S1. 1H-NMR spectrum of the reaction product of 3a; Figure S2. 13C-NMR spectrum of the reaction product of 3a; Figure S3. 19F-NMR spectrum of the reaction product of 3a; Figure S4. 1H-NMR spectrum of the reaction product of 3b; Figure S5. 13C-NMR spectrum of the reaction product of 3b; Figure S6. 19F-NMR spectrum of the reaction product of 3b; Figure S7. 1H-NMR spectrum of the reaction product of 3c; Figure S8. 13C-NMR spectrum of the reaction product of 3c; Figure S9. 19F-NMR spectrum of the reaction product of 3c; Figure S10. 1H-NMR spectrum of the reaction product of 3d; Figure S11. 13C-NMR spectrum of the reaction product of 3d; Figure S12. 19F-NMR spectrum of the reaction product of 3d; Figure S13. 1H-NMR spectrum of the reaction product of 3e; Figure S14. 13C-NMR spectrum of the reaction product of 3e; Figure S15. 19F-NMR spectrum of the reaction product of 3e; Figure S16. 1H-NMR spectrum of the reaction product of 3f; Figure S17. 13C-NMR spectrum of the reaction product of 3e; Figure S18. 19F-NMR spectrum of the reaction product of 3f; Figure S19. 1H-NMR spectrum of the reaction product of 5a; Figure S20. 13C-NMR spectrum of the reaction product of 5a; Figure S21. 19F-NMR spectrum of the reaction product of 5a; Figure S22. 1H-NMR spectrum of the reaction product of 5b; Figure S23. 13C-NMR spectrum of the reaction product of 5b; Figure S24. 19F-NMR spectrum of the reaction product of 5b; Figure S25. 1H-NMR spectrum of the reaction product of 5c; Figure S26. 13C-NMR spectrum of the reaction product of 5c; Figure S27. 19F-NMR spectrum of the reaction product of 5c; Figure S28. 1H-NMR spectrum of the reaction product of 5d; Figure S29. 13C-NMR spectrum of the reaction product of 5d; Figure S30. 19F-NMR spectrum of the reaction product of 5d; Figure S31. 1H-NMR spectrum of the reaction product of 5e; Figure S32. 13C-NMR spectrum of the reaction product of 5e; Figure S33. 19F-NMR spectrum of the reaction product of 5e; Figure S34. 1H-NMR spectrum of the reaction product of 5f; Figure S35. 13C-NMR spectrum of the reaction product of 5f; Figure S36. 19F-NMR spectrum of the reaction product of 5f; Figure S37. 1H-NMR spectrum of the reaction product of 5g; Figure S38. 13C-NMR spectrum of the reaction product of 5g; Figure S39. 19F-NMR spectrum of the reaction product of 5g.

Author Contributions

Prepared the compound and ran the spectra, J.X., Y.C. and R.X.; designed the study, analyzed the data, and wrote the paper, F.L.; helped to discuss the experimental results and process, J.L. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful for financial support from the Jiangxi Provincial Education Department Scientific Research Foundation (No. GJJ190434), National Natural Science Foundation of China (21961014), and Jiangxi Provincial Key Laboratory of Functional Crystalline Materials Chemistry (2024SSY05161).

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Catalysts 14 00777 sch001
Scheme 1. The synthetic application of 2-bromodifluoromethylbenzo-1,3-thiazole.
Scheme 1. The synthetic application of 2-bromodifluoromethylbenzo-1,3-thiazole.
Catalysts 14 00777 sch001
Catalysts 14 00777 sch002
Scheme 2. Gram-scale synthesis.
Scheme 2. Gram-scale synthesis.
Catalysts 14 00777 sch002
Catalysts 14 00777 sch003
Scheme 3. Proposed mechanism for the copper-catalyzed difluoroalkylation.
Scheme 3. Proposed mechanism for the copper-catalyzed difluoroalkylation.
Catalysts 14 00777 sch003
Table 1. Optimization reaction conditions of 1 and 2 a.
Table 1. Optimization reaction conditions of 1 and 2 a.
Catalysts 14 00777 i001
EntryCatalyst[Ligands]SolventTime (h)Yield (%) b
1CuI-DMF7218
2CuIL1DMF7239
3CuIL2DMF4812
4CuIL3DMF4810
5CuIL4DMF4810
6CuIL1DMAc48trace
7CuIL1DMSO4822
8CuIL1NMP4857
9 cCuIL1NMP3641
10 dCuIL1NMP4825
11CuBrL1NMP4643
12CuClL1NMP4645
13Cu(OAc)2L1NMP4645
14CuI + CuL1NMP3681
15 eCuI + CuL1NMP2479
16 fCuI + CuL1NMP4271
Catalysts 14 00777 i002
a Unless otherwise noted, the reaction of 1 (0.45 mmol), 2a (0.30 mmol), the catalyst (20 mol%), and the ligands (20 mol%) was performed at 80 °C in 3.0 mL of NMP. b, isolated yield. c, 100 °C. d, 60 °C. e, copper power (50 mol%). f, copper power (10 mol%).
Table 2. Optimization reaction conditions of 1 and 4 a.
Table 2. Optimization reaction conditions of 1 and 4 a.
Catalysts 14 00777 i003
EntryCatalyst (20 mol%)BaseTime (h)Yield (%) b
1Cu/CuI/L1-4843
2Cu (1.0 eq)/CuI/L1-953
3Cu (1.0 eq)/Cu2O/L1-957
4Cu (1.0 eq)/Cu(OAc)2/L1-960
5Cu (1.0 eq)/Cu(OAc)2/L2-1246
6Cu (1.0 eq)/Cu(OAc)2/L3-1249
7Cu (1.0 eq)/Cu(OAc)2/L4-1245
8Cu (1.0 eq)/Cu(OAc)2-961
9Cu (1.0 eq)/Cu(OAc)2NaHCO3 (2.0 eq)1861
10Cu (1.0 eq)/Cu(OAc)2Et3N (2.0 eq)1859
11Cu (1.0 eq)/Cu(OAc)2Pyridine (2.0 eq)1838
12Cu (1.0 eq)/Cu(OAc)2DIPEA (2.0 eq)662
13Cu (1.0 eq)/Cu(OAc)2DIPEA (3.0 eq)463
14Cu (1.0 eq)/Cu(OAc)2DIPEA (4.0 eq)466
15Cu (1.0 eq)/Cu(OAc)2DIPEA (5.0 eq)445
16 cCu (1.0 eq)/Cu(OAc)2DIPEA (4.0 eq)448
17 dCu (1.0 eq)/Cu(OAc)2DIPEA (4.0 eq)2452
18 e-/Cu(OAc)2DIPEA (4.0 eq)2439
19 fCu (1.0 eq)/-DIPEA (4.0 eq)1453
20Cu (0.2 eq)/Cu(OAc)2DIPEA (4.0 eq)1257
21 gCu (0.2 eq)/Cu(OAc)2DIPEA (4.0 eq) 4 65
a Unless otherwise noted, the reaction of 1 (0.15 mmol) and 4a (0.15 mmol) was performed at 100 °C in 2.0 mL of NMP. b, isolated yield. c, 120 °C. d, 80 °C. e, no copper power. f, no Cu(OAc)2. g, in 1.0 mL of NMP.
Table 3. Substrate scope for the difluoroalkylation of 2 or 4 with 1.
Table 3. Substrate scope for the difluoroalkylation of 2 or 4 with 1.
Catalysts 14 00777 i004
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Xiao, J.; Cai, Y.; Xu, R.; Liao, F.; Liu, J. Copper-Catalyzed Benzothiazolyldifluoroalkylation of Arylidenemalonitriles or para-Quinone Methides. Catalysts 2024, 14, 777. https://doi.org/10.3390/catal14110777

AMA Style

Xiao J, Cai Y, Xu R, Liao F, Liu J. Copper-Catalyzed Benzothiazolyldifluoroalkylation of Arylidenemalonitriles or para-Quinone Methides. Catalysts. 2024; 14(11):777. https://doi.org/10.3390/catal14110777

Chicago/Turabian Style

Xiao, Jilin, Ying Cai, Rongfu Xu, Fumin Liao, and Jinbiao Liu. 2024. "Copper-Catalyzed Benzothiazolyldifluoroalkylation of Arylidenemalonitriles or para-Quinone Methides" Catalysts 14, no. 11: 777. https://doi.org/10.3390/catal14110777

APA Style

Xiao, J., Cai, Y., Xu, R., Liao, F., & Liu, J. (2024). Copper-Catalyzed Benzothiazolyldifluoroalkylation of Arylidenemalonitriles or para-Quinone Methides. Catalysts, 14(11), 777. https://doi.org/10.3390/catal14110777

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