Regular Articles
Aryne Generation from o-Triazenylarylboronic Acids Induced by Brønsted Acid
2022 Volume 70 Issue 8 Pages 566-572
Details
2022 Volume 70 Issue 8 Pages 566-572
We report aryne generation from 2-triazenylarylboronic acids using an activator such as Brønsted acids, Lewis acids, and solid acids. With the use of (±)-Camphorsulfonic acid [(±)-CSA], the aryne precursors provided cycloadducts with a range of arynophiles in high yields. Aryne generated under the acidic conditions underwent chemoselective cycloaddition with a furan in the presence of a basic arynophile, namely an amine. Hammett plot analyses revealed that an aryne generation mechanism induced by (±)-CSA is distinct from the mechanism induced by silica gel.
Arynes, which include strained triple bond in aromatic rings, are widely used as unique reactive intermediates in organic synthetic chemistry, because they are capable of simultaneous formation of two bonds on adjacent aromatic carbons.1–4) Owing to high reactivity of arynes, they are usually formed in situ from corresponding precursors, and exposed to the reactions with various arynophiles leading to nucleophilic/electrophilic addition, [4 + 2], [3 + 2], and [2 + 2] cycloaddition. Consequently, a judicious choice of precursors, which generate arynes under conditions compatible with the selected arynophiles, is crucial for achieving the desired transformations. Among aryne precursors developed so far, o-silylaryl triflates are now regarded as one of the most practical precurosors because of the salient features as follows.4,5) (1) Availability: the precursors are synthesized from readily available phenol derivatives in two steps. (2) Stability: the precursors are usually storable at room temperature. (3) Mild reaction conditions for aryne generation: the use of fluoride salts induce aryne generation in excellent compatibility with a range of arynophiles (Chart 1a). In addition to fluoride-induced conditions, Hosoya and colleagues developed an alternative conditions using alkali metal carbonates as an activating agent.6) The presence of two reaction conditions each having distinctive arynophile compatibility allows the precursors to adapt broader transformations.7–9) Similarly, o-borylaryl triflates are reported as useful aryne precursors which generate arynes under various mild conditions involving the use of fluoride salts,10) Pd catalyst,11) or Ni catalyst.12)
On the other hand, as represented by benzenediazonium 2-carboxylates, aryne precursors derived from anilines had made a great contribution on the growth of early aryne chemistry prior to the development of o-silylaryl triflates13,14) (Chart 1b). Despite their availability and applicability, in the present day, the use of benzenediazonium 2-carboxylates is avoided due to their explosive character.15) Consequently, development of stable and practical aniline-based aryne precursors has remained underexplored. In this context, we recently developed new aniline-based precursors, namely, o-triazenylarylboronic acids 116,17) (Chart 1c). These precursors are synthesized from o-iodoarylamines in two steps, obtained as stable solids storable at room temperature in air, and generate arynes under remarkably mild conditions using neutral silica gel as the sole reagent at room temperature. Thus, the precursors 1 are complementary to o-silylaryl triflates in terms of both starting material and aryne generation conditions, and successfully applied to the reactions with a range of arynophiles having various functional groups. Furthermore, our precursors 1 are superior to reported precursors such as o-silylaryl triflates and o-iodoaryl triflates in terms of handling,4,18) because our protocol does not require the use of hygroscopic reagents (fluoride salts, 18-crown-6), strictly anhydrous conditions, and phase separation after the reaction. In our preceding results,17) it is also demonstrated that the precursor generated aryne using Brønsted acid instead of silica gel. Herein, we describe the detail of aryne generation from o-triazenylarylboronic acids 1 using Brønsted or Lewis acid under homogeneous or heterogeneous conditions. Furthermore, Hammett plot analyses of reactions between 1 and 2,5-dimethylfuran revealed that an aryne generation mechanism induced by Brønsted acid is distinct from the mechanism induced by silica gel.
We initially examined the reaction of o-triazenylphenylboronic acid 1a and 2,5-dimethylfuran (2a) (Table 1). While the use of silica gel lead to the formation of product 3aa in 94% yield (determined by 1H-NMR using 1,1,2,2-tetrachloroethane as internal standard) within 4 h at room temperature,17) acetic acid displayed much lower activity, and 3aa was obtained only in 47% even with the use of excess amount of acetic acid (entries 2 and 3). Stronger Brønsted acid displayed higher activity, and 2 equivalent (equiv.) of trifluoroacetic acid (TFA) and (±)-camphorsulfonic acid [(±)-CSA] provided 67 and 96% yield, respectively (entries 4 and 5). Although Lewis acids such as BF3·Et2O or trimethylsilyl trifluoromethanesulfonate (TMSOTf) also generated aryne from 1a, they are less effective than Brønsted acids in terms of the product yield (entries 6 and 7). Next, we turned our attention to heterogeneous reactions using solid acids from a viewpoint of ease of purification. Ion-exchange resin such as DOWEX 50W × 4 and Amberlyst 15 displayed virtually no activity for this transformation (entries 8 and 9). In contrast, the use of 200 mg/mL of phosphotungstic acid or Montmorillonite K10 (MK10) displayed moderate activity (entries 10 and 11). The yield of 3aa was improved with the use of increased amount of MK10 (entry 12).
 |
Next, performance of (±)-CSA (2 equiv., conditions A) and MK10 (400 mg/mL, conditions B) in the reactions of a range of aryne precursors 1 with 2a were compared to that of silica gel (200 mg/mL, conditions C) (Table 2). Aryne precursors 1b–e and 1b′, c′ have electron-donating or electron-withdrawing group at C5 and C4 position of parent aryne precursor 1a, respectively. 4,5-Indolyne precursor 1f was also examined. With (±)-CSA, all precursors 1 were smoothly consumed, and provided comparable yield to those obtained with silica gel except for the case of 1c′ bearing methoxy group at C4 position. On the other hand, the yields obtained with MK10 were generally lower than those obtained with silica gel or (±)-CSA, although parent 1a and 1b–d bearing chloro, methoxy and trifluoromethyl group at C5 position provided high yields.
 |
(±)-CSA and MK10 were also applicable to the reactions of 1a with arynophiles other than 2a (Table 3). In the reactions with pyrrole 2b or azide 2c or nitrone 2d, both (±)-CSA and MK10 provided cycloadducts 3ab–ad in comparable yields to silica gel. β-Ketoester 2e, which was inert in the conditions using silica gel, did not furnish desired product 3ae with the use of (±)-CSA or MK10, too. When silica gel was used, 3ae was obtained in 51% yield by exploiting enamine 2e′ instead of 2e.19) While MK 10 did not provide 3ae even with the use of 2e′, (±)-CSA lead to a formation of 3ae from 2e′ albeit in low yield. We consider the low yields attributed to decrease of nucleophilicity of 2e′ by protonation of the enamine moiety and/or hydrolytic decomposition of 2e′ promoted by acid.
 |
To demonstrate an advantage of the use of acid for aryne generation against the use of silica gel, we then performed competitive experiments between furan 2a and N-methylaniline (2f) using 1a as the aryne precursor (Chart 2). With silica gel, 2f reacted much faster than 2a and N-methyldiphenylamine (3af) was obtained as the sole product. In contrast, the use of (±)-CSA inactivate 2f by protonation, and 3aa was obtained in 59% yield along with formation of 3af in 11% yield. The use of MK 10 resulted in the formation of 3aa only in 15%, and 3af was obtained as the major product in 56% yield. Thus, MK 10 only partially inactivated 2f.
To gain insight into mechanism of aryne generation by (±)-CSA, we performed Hammett plot analysis based on competition experiment between 1a and substituted aryne precursors 1b–d and 1b′,c′20) (Fig. 1). Relative reaction rates (kR/kH) were estimated from production ratio of 3aa and 3ba–da determined by 1H-NMR analyses of the crude reaction mixture (Fig. 1a). In the substituted precursors 1b–d and 1b′,c′, each substituent R1 or R2 have Hammett constant against triazenyl group and that against borono group. In this manuscript, the former is denoted as σN and the latter as σB, respectively. Plot of log(kR/kH) against σN displayed a linear relationship in good R2 value (0.930), and negative ρN value was obtained from slope of the line (Fig. 1b). In stark contrast, no linearity was observed with the plot against σB (Fig. 1c). These results suggest that, in the rate-determining step, positive charge is built on the nitrogen atom, while no charge is built on the boron atom. Contrary to the results of Hammett analyses using (±)-CSA, in Hammett analyses using silica gel, log(kR/kH) displayed linear relationship neither against σN nor against σB (Figs. 2a–c). Therefore, when silica gel was used, the electronic perturbation does not occur at just one of triazenyl and borono groups. In contrast, when influence of σN and σB were analyzed in parallel using Jaffé’s equation (4) and (5) derived from Hammett equation (3), the good linearity was obtained17,21–23) (Fig. 2d). Therefore, the electronic perturbation occurred at both triazenyl and borono groups. Furthermore, obtained negative ρN value and positive ρB value indicated build-up of positive and negative charges on the nitrogen and the boron atom in the rate-determining step, respectively. Plausible reaction mechanisms were shown in Charts 3a and 3b. With (±)-CSA, protonation of the terminal nitrogen atom of the triazenyl group lead to the elimination of diisopropylamine from 1 to form diazonium species I24–27) (Chart 3a). Based on the Hammett plot analysis, the formation of I will be the rate-determining step. Next, probably by an attack of nucleophile to boron atom, diazonium species I undergo aryne generation accompanied by release of N2 and borate. On the other hand, upon activation by silica gel, 1 generate zwitterionic intermediate II in the rate-determining step as suggested by Jaffé’s plot (Chart 3b).
In conclusion, we found various Brønsted and Lewis acids including solid acids induced aryne generation from 2-triazenylarylboronic acids under homogeneous and heterogeneous conditions. Among acids examined, (±)-CSA provided cycloadducts with various arynophiles in comparable yields to those obtained with silica gel. Furthermore, under (±)-CSA-mediated conditions, chemoselective reaction of aryne with furan was realized in the presence of amine component. Hammett plot analyses revealed that (±)-CSA induced aryne generation through a stepwise mechanism including the formation of diazonium species as the rate-determining step followed by release of elimination of boronate and N2. This is contrary to silica gel-induced mechanism, in which triazenyl group and borono group were simultaneously activated as diazonio and boronate group, respectively. We consider that the presence of two distinct reaction conditions further increase the utility of 2-triazenylarylboronic acids as aryne precursors. Further studies are currently in progress to extend utility of 2-triazenylarylboronic acids and scope of the arynophiles using these reaction conditions.
1H-NMR spectra were recorded on JEOL JNM-AL 300 (300 MHz) spectrometer or JEOL JNM-ECA 400 (400 MHz) spectrometer or JEOL JNM-ECZ 500 (500 MHz) spectrometer. Chemical shifts are reported relative to internal standard (tetramethylsilane at δH 0.00, CDCl3 at δH 7.26, C6D6 at δH 7.15). Data are presented as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant and integration. Column chromatography was carried out on Kanto silica gel 60 N (40–50 mesh). Analytical TLC was carried out on Merck Kieselgel 60 F254 plates with visualization by ultraviolet, anisaldehyde stain solution or phosphomolybdic acid stain solution. All non-aqueous reactions were carried out in flame-dried glassware under Ar atmosphere unless otherwise noted. Reagents and solvents were used without purification. Spherical silica gel (neutral, 40–50 µm) was purchased from Kanto Chemical and used after heating under vacuum to driness. o-Triazenylphenylboronic acids 1a–f were synthesized by our previously reported method.17) Enamine 3e′ was synthesized according to the literature procedures.28)
General Procedure for (±)-CSA Mediated Reactions of 2-Triazenylarylboronic Acids 1 and Arynophiles 2To a solution of 2-triazenylarylboronic acid 1a (49.8 mg, 0.200 mmol) and 2,5-dimethylfuran (2a, 9.6 mg, 0.100 mmol) in CH2Cl2 (1.0 mL) was added (±)-camphorsulfonic acid (46.5 mg, 0.200 mmol). After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NaHCO3, and the whole mixture was extracted with AcOEt. The combined organic layers were successively washed with saturated aqueous NaHCO3 and brine, were dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product. The yield of cycloadduct 3aa was determined by 1H-NMR analysis of the crude product using 1,1,2,2-tetrachloroethane as an internal standard.
General Procedure for MK10 Mediated Reactions of 2-Triazenylarylboronic Acids 1 and Arynophiles 2To a solution of 2-triazenylarylboronic acid 1a (49.8 mg, 0.200 mmol) and 2,5-dimethylfuran (2a, 9.6 mg, 0.100 mmol) in CH2Cl2 (1.0 mL) was added Montmorillonite K10 (400 mg). After stirring at room temperature for 4 h, Celite was added to the reaction mixture. Filtration and evaporation in vacuo furnished the crude product. The yield of cycloadduct 3aa was determined by 1H-NMR analysis of the crude product using 1,1,2,2-tetrachloroethane as an internal standard.
4,5-Dimethyl-1,4-dihydro-1,4-epoxynaphthalene (3aa)17)1H-NMR (300 MHz, CDCl3) δ: 1.89 (s, 6H, CH3), 6.77 (s, 2H, CH = CH), 6.97 (dd, J = 3.0, 5.1 Hz, 2H, ArH), 7.13 (dd, J = 3.0, 5.1 Hz, 2H, ArH).
6-Chloro-1,4-dimethyl-1,4-dihydro-1,4-epoxynaphthalene (3ba)17)1H-NMR (400 MHz, CDCl3) δ: 1.86 (s, 3H, CH3), 1.87 (s, 3H, CH3), 6.75 (d, J = 5.2 Hz, 1H, CH = CH), 6.77 (d, J = 5.2 Hz, 1H, CH = CH), 6.94 (dd, J = 7.6, 2.0 Hz, 1H, ArH), 7.01 (d, J = 7.6 Hz, 1H, ArH), 7.09 (d, J = 2.0 Hz, 1H, ArH).
6-Methoxy-1,4-dimethyl-1,4-dihydro-1,4-epoxynaphthalene (3ca)17)1H-NMR (300 MHz, CDCl3) δ: 1.85 (s, 3H, CH3), 1.86 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 6.40 (dd, J = 7.5, 2.1 Hz, 1H, ArH), 6.73 (d, J = 5.1 Hz, 1H, CH = CH), 6.76 (s, 1H, ArH), 6.77 (d, J = 5.1 Hz, 1H, CH = CH), 6.99 (d, J = 7.5 Hz, 1H, ArH).
1,4-Dimethyl-6-(trifluoromethyl)-1,4-dihydro-1,4-epoxynaphthalene (3da)17)1H-NMR (300 MHz, CDCl3) δ: 1.90 (s, 3H, CH3), 1.91 (s, 3H, CH3), 6.77 (d, J = 5.4 Hz, 1H, CH = CH), 6.79 (d, J = 5.4 Hz, 1H, CH = CH), 7.18 (d, J = 7.8 Hz, 1H, ArH), 7.28 (d, J = 7.8 Hz, 1H, ArH), 7.31 (s, 1H, ArH).
6-Cyano-1,4-dimethyl-1,4-dihydro-1,4-epoxynaphthalene (3ea)17)1H-NMR (300 MHz, CDCl3) δ: 1.89 (s, 3H, CH3), 1.90 (s, 3H, CH3), 6.76 (d, J = 5.4 Hz, 1H, CH = CH), 6.79 (d, J = 5.4 Hz, 1H, CH = CH), 7.19 (dd, J = 7.2, 1.2 Hz, 1H, ArH), 7.33 (s, 1H, ArH), 7.36 (dd, J = 7.2, 1.2 Hz, 1H, ArH).
6,9-Dimethyl-3-tosyl-6,9-dihydro-3H-6,9-epoxybenzo[e]indole (3fa)17)1H-NMR (400 MHz, CDCl3) δ: 1.91 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.34 (s, 3H, ArCH3), 6.65 (dd, J = 4.0, 0.8 Hz, 1H, ArH), 6.83 (d, J = 5.2 Hz, 1H, CH = CH), 6.85 (d, J = 5.2 Hz, 1H, CH = CH), 7.12 (d, J = 8.0 Hz, 1H, ArH), 7.20 (d, J = 8.0 Hz, 2H, ArH), 7.58 (d, J = 4.0 Hz, 1H, ArH), 7.60 (dd, J = 8.0, 0.8 Hz, 1H, ArH), 7.72 (d, J = 8.0 Hz, 2H, ArH).
9-(tert-Butoxycarbonyl)-1,4-dihydro-1,4-epiminonaphthalene (3ab)17)1H-NMR (300 MHz, CDCl3) δ: 1.37 (s, 9H, t-Bu), 5.48 (brs, 2H, NCH), 6.92–6.98 (m, 4H, CH = CH and ArH), 7.25 (brs, 2H, ArH).
1-Ethoxycarbonylmethyl-1,2,3-benzotriazol (3ac)17)1H-NMR (400 MHz, CDCl3) δ: 1.27 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 4.26 (q, J = 7.2 Hz, 2H, CO2CH2CH3), 5.43 (s, 2H, NCH2CO2), 7.40 (ddd, J = 8.4, 6.3, 1.5 Hz, 1H, ArH), 7.46–7.56 (m, 2H, ArH), 8.10 (dt, J = 8.4, 0.9 Hz, 1H, ArH).
2-tert-Butyl-3-phenyl-2,3-dihydrobenzo[d]isoxazole (3ad)17)1H-NMR (300 MHz, CDCl3) δ: 1.17 (s, 9H, t-Bu), 5.58 (s, 1H, Ar2CH), 6.76–6.81 (m, 2H, ArH), 6.87 (d, J = 6.6 Hz, 1H, ArH), 7.13 (t, J = 7.8 Hz, 1H, ArH), 7.21–7.26 (m, 1H, ArH), 7.31 (t, J = 7.8 Hz, 2H, ArH), 7.39 (d, J = 7.8 Hz, 2H, ArH).
Ethyl (2-benzoylphenyl)acetate (3ae)17)1H-NMR (300 MHz, CDCl3) δ: 1.11 (t, J = 7.2 Hz, 3H, OCH2CH3), 3.88 (s, 2H, ArCH2), 4.01 (q, J = 7.2 Hz, 2H, OCH2CH3), 7.30–7.49 (m, 6H, ArH), 7.57 (t, J = 7.8 Hz, 1H, ArH), 7.81 (dd, J = 7.8 Hz, 2H, ArH).
N-Methyldiphenylamine (3af)29)1H-NMR (400 MHz, CDCl3) δ: 3.29 (s, 3H, NCH3), 6.92 (dt, J = 8.0, 2.0 Hz, 2H, ArH), 7.01 (d, J = 8.0 Hz, 4H, ArH), 7.24 (t, J = 8.0 Hz, 4H, ArH).
Hammett Plot for the Reactions of 1 with 2a Promoted by (±)-Camphorsulfonic AcidTo a solution of 1a (0.200 mmol), 1b–d or 1b′,c′ (0.200 mmol), and 2,5-dimethylfuran (2a, 0.100 mmol) in CH2Cl2 (1.0 mL) was added (±)-camphorsulfonic acid (46.5 mg, 0.200 mmol). After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NaHCO3, and the whole mixture was extracted with AcOEt. The combined organic layers were successively washed with saturated aqueous NaHCO3 and brine, were dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product. The ratio of products 3aa and 3ba–da were determined by analyses of the crude products on 1H-NMR spectroscopy to determine kR/kH value.
This work is financially supported by a Grant-in-Aid for Scientific Research (C) (No. 21K05077) from JSPS, Japan.
The authors declare no conflict of interest.
