Kai
Kang
,
Chunfa
Xu
and
Qilong
Shen
*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China. E-mail: shenql@sioc.ac.cn
First published on 3rd March 2014
A new high yielding method for the preparation of a shelf-stable electrophilic trifluoromethylthiolating reagent, N-(trifluoromethylthio)phthalimide, is described. Reaction of this reagent with a variety of aryl and vinyl boronic acids in the presence of a copper catalyst generated the trifluoromethylthiolated arenes and alkenes in good to excellent yields.
Traditional methods for arene trifluoromethylthiolation formation include halo-fluorine exchange or radical trifluoromethylation of sulphur-containing compounds.2 These methods usually require harsh reaction conditions that limit functional group tolerance. More recently, efficient direct trifluoromethylthiolation methods utilizing group 10 transition metal catalysts have been developed. For example, Buchwald and coworkers reported a palladium-catalyzed trifluoromethylthiolation of aryl bromides with AgSCF3 under mild conditions.3a Likewise, Vicic and Zhang reported a Ni-catalyzed trifluoromethylthiolation of aryl bromides or iodides by using [NMe4][SCF3] as the nucleophilic CF3S source.3b
In addition to group 10 transition metals, catalysts based on copper provide an alternative approach for trifluoromethylthiolation since copper is much cheaper and readily available. Qing4a,b and Vicic4c have independently reported a Cu-mediated oxidative trifluoromethylthiolation of aryl boronic acids with in situ formed nucleophilic CF3S reagent or [NMe4][SCF3]. Li and Duan have reported an oxidative trifluoromethylthiolation using CF3CO2Na as the trifluoromethyl source, albeit in moderate yields.4f Weng has reported the isolation of a stable trifluoromethylthiolated copper complex that enables the direct trifluoromethylthiolation of aryl iodides in excellent yields.4d Furthermore, a copper-catalyzed C–H activation/trifluoromethylthiolation of directed arenes was reported by Daugulis and co-workers,4l thus providing a powerful and straightforward method for the formation of aryl trifluoromethyl thioethers.
Another strategy for arene trifluoromethylthiolation involves the electrophilic trifluoromethylthiolating reagents (Fig. 1).5–9 In this respect, several electrophilic trifluoromethylthiolating reagents such as reagents 36, 47 and 58b have been developed that were allowed to react with aryl Grignard reagent, aryl lithium or aryl boronic acids to give the trifluoromethylthiolated compounds in excellent yields.
A NBS-like electrophilic trifluoromethylthiolating reagent, N-(trifluoromethylthio)phthalimide 1,9 has been previously prepared by Munavalli and co-workers by nucleophilic substitution of potassium phthalimide with trifluoromethylsulfenyl chloride (CF3SCl) at 0 °C. Owing to its highly toxic and corrosive nature, the use of CF3Cl is limited to those with special equipment and the necessary expertise. This shortcoming limited the use of N-(trifluoromethylthio)phthalimide 1 as a general trifluoromethylthiolating reagent. Herein, we report that N-(trifluoromethylthio)phthalimide 1 and its analog 2 can be prepared by an extremely simple and efficient method. In addition, we demonstrate that N-(trifluoromethylthio)phthalimide 1 was capable of coupling with a variety of aryl or vinyl boronic acids in the presence of a copper catalyst. The reactions proceeded under mild conditions and were compatible with a variety of functional groups.
N-(Trifluoromethylthio)phthalimide 1 and its analog 2 were prepared by treatment of N-bromophthalimide or NBS with AgSCF3 in anhydrous CH3CN at room temperature for 3 h. Reagents 1 and 2 were isolated in 93% and 95% yields, respectively. The reactions can be scaled up to 5.3 g with the same yields. Both reagents are crystalline, air- and moisture-stable compounds that remained unchanged even after one month on shelf as determined by 19F and 1H NMR spectroscopy.
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With these reagents in hand, we then explored the reactivity of reagents 1 and 2 with aryl boronic acids.10,11 The trifluoromethylthiolation of 4-biphenyl boronic acid with reagent 1 was chosen at the start of our investigation as a model reaction. Reaction in the presence of 10 mol% of CuI and 10 mol% of bipyridine (bpy) in THF or diglyme occurred smoothly at 60 °C for 12 h to give the desired product in 79% and 82% yields, respectively (Table 1, entries 1 and 2). Reactions in other solvents such as dioxane, CH2Cl2 or CH3CN were much less effective (Table 1, entries 3–5). Reaction in a polar solvent such as DMF was much slower to give the coupled product in less than 10% yield (Table 1, entry 6). Other copper salts were also evaluated and it was found that using other Cu(I) salts such as CuCl, CuBr or CuSCN resulted in lower yields (Table 1, entries 7–9). When CuCl2·H2O was used, the yield was comparable with those obtained using CuI as the catalyst (Table 1, entry 10). We then further investigated whether the yield could be further improved by adding other chelating ligands. Interestingly, the choice of ligand did not affect the yield of the reaction dramatically. Reactions using L1–L5 resulted in 71–83% yields, while a reaction using tBu-bpy (L3) gave the highest yield (Table 1, entry 13). The reaction was sensitive to the base. Using bases such as NaHCO3, KF, K2CO3, K3PO4, or LiOH·H2O provided the products in 5–75% yields (Table 1, entries 16–20). Lowering the amount of the catalyst to 5 mol% generated the product in 81% yield when the reaction was conducted for 15 h (Table 1, entry 21). Finally, reagent 2 was much less effective than reagent 1 under otherwise identical conditions (Table 1, entry 22).
Entry | CuX | Ligand | Base | Solvent | Yieldb (%) |
---|---|---|---|---|---|
a Reaction conditions: 4-biphenyl boronic acid (0.05 mmol), reagent 1 (0.075 mmol), copper salt (10 mol%), ligand (10 mol%) and base (0.1 mmol) in diglyme (1.0 mL) at 60 °C for 12 h. b Yields were determined by 19F NMR analysis of the crude reaction mixture with trifluoromethylbenzene as an internal standard. c The reaction was conducted in the presence of 5 mol% of the catalyst using 0.5 equiv. of Na2CO3 for 15 h. d Reagent 2 was used. | |||||
1 | CuI | bpy | Na2CO3 | THF | 79 |
2 | CuI | bpy | Na2CO3 | Diglyme | 82 |
3 | CuI | bpy | Na2CO3 | Dioxane | 68 |
4 | CuI | bpy | Na2CO3 | CH2Cl2 | 65 |
5 | CuI | bpy | Na2CO3 | CH3CN | 65 |
6 | CuI | bpy | Na2CO3 | DMF | 9 |
7 | CuCl | bpy | Na2CO3 | Diglyme | 73 |
8 | CuBr | bpy | Na2CO3 | Diglyme | 72 |
9 | CuSCN | bpy | Na2CO3 | Diglyme | 47 |
10 | CuCl2·2H2O | bpy | Na2CO3 | Diglyme | 81 |
11 | CuI | L1 | Na2CO3 | Diglyme | 79 |
12 | CuI | L2 | Na2CO3 | Diglyme | 78 |
13 | CuI | L3 | Na2CO3 | Diglyme | 83 |
14 | CuI | L4 | Na2CO3 | Diglyme | 71 |
15 | CuI | L5 | Na2CO3 | Diglyme | 80 |
16 | CuI | L3 | Na2CO3 | Diglyme | 77 |
17 | CuI | L3 | KF | Diglyme | 5 |
18 | CuI | L3 | K2CO3 | Diglyme | 26 |
19 | CuI | L3 | K3PO4 | Diglyme | 57 |
20 | CuI | L3 | LiOH·H2O | Diglyme | 75 |
21 | CuI | L3 | Na2CO3 | Diglyme | 81c |
22 | CuI | L3 | Na2CO3 | Diglyme | 70d |
On the basis of the results summarized in Table 1, the reaction conditions of entry 21 in Table 1 were chosen to study the scope of CuI/L3 catalyzed trifluoromethylthiolation of aryl and alkenyl boronic acids, and the results are summarized in Table 2. Reactions of simple aryl boronic acids gave the corresponding trifluoromethylthio-substituted arenes in good to excellent yields (Table 2, entries 1–7). Challenging functionalized aryl boronic acids were compatible with the reaction conditions. Reactions of aryl boronic acids with functional groups such as iodine, bromide, enolizable ketone, ester, amide cyano and alkene resulted in good yields (Table 2, entries 8–13). Pharmaceutically interesting trifluoromethylthio-substituted heteroarenes such as thiophene or pyridine derivatives were synthesized in good yields (Table 2, entries 15 and 16). It is interesting to note that alkenyl boronic acid also converted effectively into trifluoromethylthio substituted olefin in 50% yields (Table 2, entry 17). No isomerization was observed for the vinyl trifluoromethylthioether.
Entry | Product | Yieldb (%) | Entry | Product | Yieldb (%) |
---|---|---|---|---|---|
a Reaction conditions: aryl boronic acid (0.5 mmol), reagent 1 (0.75 mmol), CuI (5 mol%), L3 (5 mol%) and Na2CO3 (0.25 mmol) in diglyme (4.0 mL) at 60 °C for 15 h. b Isolated yields. c Yields were determined by 19F NMR analysis of the crude reaction mixture with trifluoromethylbenzene as an internal standard. d The reactions were conducted at 80 °C for 20 h. | |||||
1 | 80 | 10 | 92 | ||
2 | 85 | 11 | 87 | ||
3 | 77 | 12 | 79 | ||
4 | 82 | 13 | 56 (81c) | ||
5 | 90 | 14 | 84 | ||
6 | 80 | 15 | 74c | ||
7 | 90 | 16 | 62 | ||
8 | 93 | 17 | 50 (74c,d) | ||
9 | 89 |
The reaction can be conducted under air, albeit in much lower yield. For example, a reaction of 4-biphenyl boronic acid with reagent 1 in the presence of 10 mol% of CuI and 10 mol% of L3 using Na2CO3 as the base at 60 °C under air afforded after 15 h the desired product in 62% yield.
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Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3qo00068k |
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