An Alternative Method for Generating Arynes from ortho-Silylaryl Triflates: Activation by Cesium Carbonate in the Presence of a Crown Ether

An alternative method for generating arynes from ortho-silylaryl triflates using cesium carbonate and 18-crown-6 is reported. The method was efficiently applied to a variety of reactions between several arynes and arynophiles. We also demonstrated that the efficiency of aryne generation is significantly affected by the alkali metal countercation of the carbonate.


OPEN ACCESS
As a part of our studies focusing on highly strained alkynes, including arynes [24][25][26][27][28][29][30][31][32][33][34], we have been working on a project to develop new aryne generation methods. For example, we have recently succeeded in efficiently generating arynes from ortho-iodoaryl triflates bearing sensitive functional groups using a trimethylsilylmethyl Grignard reagent as an activator [30,31,33] instead of conventional activators such as n-butyllithium [35] or a turbo-Grignard reagent [36]. Herein, we report that cesium carbonate, in the presence of a crown ether, serves in place of a fluoride ion as an efficient activator for generating arynes from ortho-silylaryl triflates.

Results and Discussion
We first screened efficient conditions for generating benzyne from 2-(trimethylsilyl)phenyl triflate (1a) without the use of a fluoride ion and in the presence of benzyl azide (2), which was employed as an arynophile. Consequently, we found that cesium carbonate slowly triggers the generation of benzyne from 1a to afford benzotriazole 3 ( Table 1, entries 1-4). While the reaction in tetrahydrofuran at 25 °C for 24 h resulted in the generation of a trace amount of benzyne with the recovery of a significant amount of 1a (entry 1), performing the reaction with heating at 60 °C improved the efficiency (entry 2). Further improvement was observed by switching solvent from tetrahydrofuran to acetonitrile (entries 3 and 4). After extensive screening of the conditions to further enhance the efficiency of benzyne generation from 1a using cesium carbonate, we found that addition of 18-crown-6-ether dramatically accelerates benzyne generation, affording the product 3 in high yield, even when the reaction is performed at 25 °C (entry 5) [37]. Among the various solvents examined, tetrahydrofuran and 1,2-dimethoxyethane gave the best results (entries 5-9). Conversely, generation of benzyne was not observed when cesium carbonate was replaced by cesium bicarbonate (entry 10), which was previously used concomitantly with cesium carbonate and 18-crown-6 to generate benzyne from 2-(trimethylsilyl)phenyl nonaflate with moderate efficiency [38]. Moreover, the efficiency of the reaction was reduced when potassium carbonate and 18-crown-6, which can retain a potassium cation inside the molecule, were used (entry 11). In this case, the yield of 3 was improved by using an increased amount of 18-crown-6 (entry 12). Treatment of 1a with tripotassium phosphate in the presence of 18-crown-6 also triggered benzyne generation, albeit slowly (entry 13). Although the efficiency of benzyne generation from 1a mediated by cesium carbonate and 18-crown-6 was slightly inferior to the conventional methods using potassium fluoride and 18-crown-6 (entry 14) or cesium fluoride alone (entry 15), the newly established conditions are worth exploring for optimization of the reactions that use arynes generated from ortho-silylaryl triflates.
The optimized reaction conditions were applicable to the reactions between benzyne and various arynophiles ( Table 2). Diels-Alder reaction of benzyne generated from 1a with furan (4), 2,5-dimethylfuran (6), or N-phenylpyrrole (8) provided the corresponding cycloadducts 5a, 7, and 9, respectively, in good yields (entries 1-3). Nitrone 10 also reacted with benzyne to afford cycloadduct 11 efficiently (entry 4). Amination of benzyne with morpholine (12) proceeded smoothly to yield N-phenylmorpholine (13) in good yield (entry 5).   The aryne generation method mediated by cesium carbonate and 18-crown-6 was also successfully applied to generate arynes from various ortho-(trimethylsilyl)aryl triflates, and this was demonstrated in the reaction with 4 (Table 3). Indeed, 3-and 4-methoxybenzynes were generated efficiently from the corresponding ortho-silylaryl triflates 1b and 1c, respectively, to provide the cycloadducts 5b and 5c in high yields (entries 1 and 2). Reactions of 3-and 4-methylbenzyne precursors, 1d and 1e, as well as 2,3and 1,2-naphthalyne precursors, 1f and 1g, also proceeded smoothly to afford the cycloadducts 5d-g in high yields (entries 3-6). We then turned our attention to the remarkable effect elicited by 18-crown-6-ether, which is able to retain a potassium ion inside the molecule or alternatively coordinate a cesium ion to form a sandwich-type complex [39][40][41][42]. To examine the effects of the countercations of the bases, and the ring size of the crown ether, the efficiencies of benzyne generation from ortho-silylphenyl triflate 1a were compared using several alkali metal carbonates (Na2CO3, K2CO3, Rb2CO3, and Cs2CO3) or fluorides (NaF, KF, RbF, and CsF) in combination with any one of three crown ethers, 15-crown-5, 18-crown-6, and 24-crown-8, in the presence of benzyl azide (2) ( Figure 1A). Consequently, the yield of benzotriazole 3, which reflects the efficiency of benzyne generation, increased as the size of the alkali metal cation of the carbonates became larger. For instance, when 15-crown-5 was employed, the order of the yields of 3 was Na (0%) < K (34%) < Rb (75%) < Cs (86%). A similar trend was observed when 18-crown-6 or 24-crown-8 was used. Fluoride ion-mediated benzyne generation showed the same tendency, Na << K < Rb ≈ Cs, although higher yields of 3 were generally obtained compared with those observed in the carbonate-mediated conditions. These results indicate that the countercation of the base also plays an important role in activating ortho-silylaryl triflate for benzyne generation. Moreover, although the use of a crown ether having a hole size smaller than the size of a metal ion ( Figure 1B,C) was prone to increase the efficiency of benzyne generation from 1a, the use of a larger crown ether, such as 24-crown-8, was less effective, particularly when K2CO3, Rb2CO3, or KF was used as the base. Various other crown ethers, regardless of their ring size and benzene-or cyclohexane-linked structure, also effectively supported the cesium carbonate-mediated generation of benzyne from 1a (Figure 2,  entries 1-7). On the other hand, the use of acyclic tetraethylene glycol dimethyl ether or polyethylene glycol dimethyl ether (average molecular weight 240) instead of the crown ether drastically decreased the efficiency (entries 8 and 9). These results suggest that an appropriate complexation between an alkali metal carbonate and a crown ether, such as between cesium carbonate and 18-crown-6, assists the smooth liberation of the triflyloxy anion. Figure 2. Efficiency of the reactions between 1a and 2 using cesium carbonate in combination with different ethers. Yields determined by 1 H-NMR analyses.

Conclusions
We have demonstrated that cesium carbonate, in the presence of 18-crown-6, triggers the efficient generation of arynes from ortho-silylaryl triflates under mild conditions. The method was applicable to a variety of reactions between several arynes and arynophiles. Various crown ethers other than 18-crown-6 were found to be similarly effective, but the efficiency of aryne generation significantly depended upon the alkali metal countercation of the carbonate. Further studies to demonstrate the advantage of this newly developed method are underway.

Acknowledgments
The initial concept of this work was conceived by one of the authors (Y.S.) during his short stay as a visiting student (

Conflicts of Interest
The authors declare no conflict of interest.