4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions

In recent years, numerous methods have emerged for the synthesis of trifluoromethylated arenes based on the late-stage introduction of a trifluoromethyl group onto an aryl ring. In sharp comparison, the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon has rarely been addressed. It has been found that 4-trifluoromethyl-p-quinol silyl ethers, the readily available and relatively stable compounds, can act as dielectrophiles to be applied to multi-component reactions for the synthesis of various trifluoromethylated arenes. Catalyzed by In(OTf)3, 4-trifluoromethyl-p-quinol silyl ethers react with C-, N-, and S-nucleophiles, respectively, in a regiospecific 1,2-addition manner to generate the corresponding highly reactive electrophilic intermediates. Further reaction of the in-situ generated electrophiles with a C-nucleophile followed by spontaneous aromatization enables the construction of functionalized trifluoromethyl arenes. This three-component, double nucleophilic addition/aromatization reaction based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon provides a divergent strategy for the synthesis of trifluoromethylated arenes under mild reaction conditions in a single operation.

carbons [31][32][33][34][35] in the ortho and para positions of the CF 3 group of 4-(trifluoromethyl)-p-quinols via a novel meta-double functionalization fashion (Fig. 2b) 32 . Encouraged by the advantage of the 1,3-carbothiolation/ aromatization reaction, such as readily available substrates [31][32][33]38,39 , operational simplicity, and double functionalization on the "aromatic to be" carbons in a single operation [32][33][34][35] , we pursued the three-component, double nucleophilic addition/aromatization reaction of 4-(trifluoromethyl)-p-quinol silyl ethers as dielectrophiles with two nucleophiles, named Nu1 and Nu2 (Fig. 2c). In the double nucleophilic addition/aromatization reactions, Nu1 can be a S-, N-, or C-nucleophile that attacks, in a regiospecific 1,2-addition manner, at the carbonyl carbon of a 4-(trifluoromethyl)-p-quinol silyl ether to form a highly reactive electrophilic intermediate as the crucial step. As a result, the subsequent nucleophilic addition of Nu2 to the in-situ generated electrophilic intermediate followed by spontaneous aromatization can lead to a functionalized trifluoromethyl arene. Herein we present these three-component, double nucleophilic addition/aromatization reactions using 4-(trifluoromethyl)-p-quinol silyl ethers as the versatile dielectrophilic "aromatic to be" precursors. These approaches allow a variety of functional groups, including an alkylthio, an amino, an aryl group or various carbonyl methyl groups to be introduced onto the "aromatic ring" in a single operation under mild reaction conditions (Fig. 2c).
Pseudo three-component, double nucleophilic addition/aromatization reactions using electron-rich arenes as C-nucleophiles. In the case of using 1,3-dimethoxybenzene 4i as the C-nucleophile and performing the reaction of 1a with 4i (6 equiv) at 80 °C for 5 h in the absence of a thiol, the double nucleophilic addition/aromatization products, m-terphenyl compound, 6 and 6′ were obtained in good overall yield as a 1:1 mixture (Fig. 6) 62 . This pseudo-three component reaction provides an efficient route to trifluoromethylated m-terphenyl and o-terphenyl compounds, respectively (Fig. 1).
Reaction mechanism. To our knowledge, there have been no reports so far of 1,3-carboamination reaction 33,[63][64][65][66][67] . To understand the mechanism for the formation of 8, the reaction of 1a with TsNH 2 7a was performed under the identical conditions as used for the synthesis of 8 (Fig. 7) but in the absence of a C-nucleophile. As a result, imine 9 was produced in 35% yield along with 4-(trifluoromethyl)-p-quinol in 32% yield (Fig. 8a). Furthermore, it was proven that 8aa could be formed by the reaction of 9 with pentan-3-one 2c (Fig. 8b), indicating that imine 9 or the 1,2-adduct of 7 with 1a ( Fig. 9) might be the intermediate for the formation of 8aa in the three-component, 1,3-carboamination/aromatization reactions (Fig. 7).
Accordingly, a possible mechanism for the formation of 8 was proposed (Fig. 9), with the reaction of 1a with 7a (RNH 2 ) and 2c (Nu2) as an example), which involves (1) formation of complex I from 1a, In(OTf) 3   (generated in-situ from ketone 2c with TMSCl) at C3 of II in a S N 2′ manner with the release of TMSOH to afford intermediate III 43 , and finally, (4) the release of TMSOH driven by aromatization gives 8 ( Fig. 9) 32,43 .
The proposed mechanism (Fig. 9) tells that the regioselective nucleophilic 1,2-addition (I → II) is the crucial step for the three-component, double nucleophilic addition/aromatization reaction 32 . On the other hand, the addition of TMSCl as an additive is important (Fig. 3) for the activation of ketones through the formation of siloxyalkenes (Figs 4 and 7) 43,63-67 . Therefore, the formation of trifluoromethylated terphenyls 6 using 1,3-dimethoxybenzene 4i as Nu1 should follow a similar mechanism, in which, the 1,2-addition of 4i at the carbonyl group of complex IV (Fig. 10) is to be involved. In this case, complex IV should be formed at first and this mechanism can also be used to interpret the formation of o-terphenyl product 6′ by the generation of complex V  Scientific RepoRts | 6:26957 | DOI: 10.1038/srep26957 (Fig. 10). Furthermore, the formation of trifluoromethylated biaryls 5′ (Fig. 5) via 1,2-carbothiolation/aromatization is easy to understand.
In summary, it has been found that the readily available and relatively stable 4-trifluoromethyl-p-quinol silyl ethers are useful dielectrophiles in tandem and/or multi-component reactions. The three-component reactions of 4-trifluoromethyl-p-quinol silyl ethers with two nucleophiles provide a convenient access to a wide variety of trifluoromethylated arenes in a single operation under mild reaction conditions. The regioselective nucleophilic 1,2-addition of a nucleophile (Nu1) to a 4-trifluoromethyl-p-quinol silyl ether enables the formation of a highly reactive electrophilic intermediate, and thus create a useful template for further elaboration to highly functionalized arenes in a concise process. Further works focused on the synthetic applications of these dielectrophiles and analogues are in progress.