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Communication

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

by
Suguru Yoshida
,
Yuki Hazama
,
Yuto Sumida
,
Takahisa Yano
and
Takamitsu Hosoya
*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
*
Author to whom correspondence should be addressed.
Molecules 2015, 20(6), 10131-10140; https://doi.org/10.3390/molecules200610131
Submission received: 1 May 2015 / Accepted: 28 May 2015 / Published: 1 June 2015
(This article belongs to the Special Issue Development and Application of Aryne Chemistry in Organic Synthesis)
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Versions Notes

Abstract

:
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.

Graphical Abstract

1. Introduction

Arynes are highly reactive intermediates useful for preparing diverse aromatic compounds [1,2,3,4,5,6,7,8]. Novel transformations of arynes have been achieved and applied to the synthesis of a wide range of complex aromatic compounds. In line with the growing importance of aryne chemistry, a variety of methods and precursors to generate arynes have been developed. In particular, activation of ortho-silylaryl triflates with a fluoride ion is one of the most widely-used methods for generating arynes [9]. Due to the increased availability of ortho-silylaryl triflates [10,11], numerous transformations via arynes have been developed based on this method [12,13,14,15,16,17,18,19,20,21,22,23,24].
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.

2. 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).
Table
Table 1. Base-mediated benzyne generation from 2-(trimethylsilyl)phenyl triflate (1a).
Molecules 20 10131 i001
Table 1. Base-mediated benzyne generation from 2-(trimethylsilyl)phenyl triflate (1a).
Molecules 20 10131 i001
EntryActivatorAdditiveSolventTemp. (°C)Yield (%) a
1Cs2CO3–––THF251
2Cs2CO3–––THF6032
3Cs2CO3–––MeCN2538
4Cs2CO3–––MeCN6079
5Cs2CO318-crown-6THF2588 (86) b
6Cs2CO318-crown-6MeCN2572
7Cs2CO318-crown-6CH2Cl22513
8Cs2CO318-crown-6toluene2559
9Cs2CO318-crown-6DME2588
10CsHCO318-crown-6THF250
11K2CO318-crown-6THF2537
12 cK2CO318-crown-6THF2576
13K3PO418-crown-6THF2537
14KF18-crown-6THF2599
15CsF–––MeCN25quant.
a Yields determined by 1H-NMR analyses unless otherwise noted; b Isolated yield in parentheses; c 4.0 equivalents of 18-crown-6 were used.
Table
Table 2. Reactions of benzyne generated from 1a with various arynophiles.
Molecules 20 10131 i002
Table 2. Reactions of benzyne generated from 1a with various arynophiles.
Molecules 20 10131 i002
EntryArynophile Product Yield (%) a
1 Molecules 20 10131 i0034 Molecules 20 10131 i0085a73
2 Molecules 20 10131 i0046 Molecules 20 10131 i009787
3 Molecules 20 10131 i0058 Molecules 20 10131 i010974
4 Molecules 20 10131 i00610 Molecules 20 10131 i0111184
5 Molecules 20 10131 i00712 Molecules 20 10131 i0121375
a Isolated yields.
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 2,3- and 1,2-naphthalyne precursors, 1f and 1g, also proceeded smoothly to afford the cycloadducts 5d–g in high yields (entries 3–6).
Table
Table 3. Cycloaddition of various arynes with furan.
Molecules 20 10131 i013
Table 3. Cycloaddition of various arynes with furan.
Molecules 20 10131 i013
EntryArynophile Product Yield (%) a
1 Molecules 20 10131 i0141b Molecules 20 10131 i0205b89
2 Molecules 20 10131 i0151c Molecules 20 10131 i0215c86
3 Molecules 20 10131 i0161d Molecules 20 10131 i0225d88
4 Molecules 20 10131 i0171e Molecules 20 10131 i0235e89
5 Molecules 20 10131 i0181f Molecules 20 10131 i0245f76
6 Molecules 20 10131 i0191g Molecules 20 10131 i0255g85
a Isolated yields.
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.
Molecules 20 10131 g001 550
Figure 1. Generation of benzyne from 1a using various alkali metal carbonates or fluorides and crown ethers. (A) Efficiency of the reactions between 1a and 2 using various bases in combination with different crown ethers (N: without crown ethers; 15: with 15-crown-5; 18: with 18-crown-6; 24: with 24-crown-8). Yields determined by 1H-NMR analyses; (B) Hole size of crown ethers; (C) Diameter of alkali metal ions.
Figure 1. Generation of benzyne from 1a using various alkali metal carbonates or fluorides and crown ethers. (A) Efficiency of the reactions between 1a and 2 using various bases in combination with different crown ethers (N: without crown ethers; 15: with 15-crown-5; 18: with 18-crown-6; 24: with 24-crown-8). Yields determined by 1H-NMR analyses; (B) Hole size of crown ethers; (C) Diameter of alkali metal ions.
Molecules 20 10131 g001
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.
Molecules 20 10131 g002 550
Figure 2. Efficiency of the reactions between 1a and 2 using cesium carbonate in combination with different ethers. Yields determined by 1H-NMR analyses.
Figure 2. Efficiency of the reactions between 1a and 2 using cesium carbonate in combination with different ethers. Yields determined by 1H-NMR analyses.
Molecules 20 10131 g002

3. Experimental Section

3.1. General Remarks

All reactions were performed in dried glassware under an argon atmosphere unless otherwise noted. All chemical reagents used were commercial grade and used as received. Aryne precursors 1a–1g were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Analytical thin-layer chromatography (TLC) was performed on precoated (0.25 mm) silica-gel plates (Silica Gel 60 F254, Cat. No. 1.05715, Merck Millipore, Darmstadt, Germany). Column chromatography was conducted using a ZIP sphere cartridge [silica], 10 g (Cat. No. 445-1000-FZ-20, Biotage®, Uppsala, Sweden), with a medium pressure liquid chromatograph (W-Prep 2XY A-type Yamazen, Osaka, Japan). 1H-NMR spectra were obtained with an AVANCE 400 spectrometer or an AVANCE 500 spectrometer at 400 or 500 MHz, respectively (Bruker BioSpin K.K., Karlsruhe, Germany). 13C-NMR spectra were obtained with a Bruker AVANCE 500 spectrometer at 126 MHz. CDCl3 (Cat. No. 368651000, Acros Organics, Geel, Belgium) was used as a solvent for obtaining NMR spectra. 1H-NMR yields were determined using 1,1,2,2-tetrachloroethane as an internal standard. The spectra obtained for products 3 [28], 5a [43], 5b–d [44], 5e [45], 5f [46], 5g [47], 7 [28], 9 [28], 11 [28], and 13 [48] were identical to those reported in the corresponding references.

3.2. Typical Procedure for Aryne Generation from ortho-Silylaryl Triflate with Cesium Carbonate in the Presence of 18-Crown-6

To a mixture of 2-(trimethylsilyl)phenyl triflate (1a, 150 mg, 0.503 mmol) and benzyl azide (2, 333 mg, 2.50 mmol) dissolved in tetrahydrofuran (2.5 mL) was added cesium carbonate (326 mg, 1.00 mmol) and 18-crown-6-ether (265 mg, 1.00 mmol) at room temperature. After stirring for 24 h at 25 °C, water (10 mL) was added to the mixture. The mixture was then extracted with ethyl acetate (15 mL × 3), and the combined organic extract was washed with brine (10 mL), dried (Na2SO4), and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica-gel 10 g, n-hexane/EtOAc = 5/1) to give 1-benzyl-1H-benzo[d][1,2,3]triazole (3, 90.0 mg, 0.431 mmol, 85.6%) as a colorless solid.

4. 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 (JSPS Research Fellowships for Young Scientists) during August–October 2009 at the group of Mark Lautens (Department of Chemistry, University of Toronto, Toronto, ON, Canada), to whom we express special thanks. This work was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from MEXT, Japan; JSPS KAKENHI Grant Numbers 15H03118 (T.H.) and 26350971 (S.Y.); and Azuma Medical & Dental Research Grant (S.Y.).

Author Contributions

Y.H., Y.S., and T.Y. performed the experiments; S.Y. and T.H. designed the experiments and wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

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MDPI and ACS Style

Yoshida, S.; Hazama, Y.; Sumida, Y.; Yano, T.; Hosoya, T. An Alternative Method for Generating Arynes from ortho-Silylaryl Triflates: Activation by Cesium Carbonate in the Presence of a Crown Ether. Molecules 2015, 20, 10131-10140. https://doi.org/10.3390/molecules200610131

AMA Style

Yoshida S, Hazama Y, Sumida Y, Yano T, Hosoya T. An Alternative Method for Generating Arynes from ortho-Silylaryl Triflates: Activation by Cesium Carbonate in the Presence of a Crown Ether. Molecules. 2015; 20(6):10131-10140. https://doi.org/10.3390/molecules200610131

Chicago/Turabian Style

Yoshida, Suguru, Yuki Hazama, Yuto Sumida, Takahisa Yano, and Takamitsu Hosoya. 2015. "An Alternative Method for Generating Arynes from ortho-Silylaryl Triflates: Activation by Cesium Carbonate in the Presence of a Crown Ether" Molecules 20, no. 6: 10131-10140. https://doi.org/10.3390/molecules200610131

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