Abstract
A facile route to 3-sulfonylated and 3-(1-benzotriazolyl)-benzofurans is achieved from readily available o-hydroxyphenyl propargyl alcohols (o-HPPAs) and bench-top sodium sulfonylates and benzotriazoles with no assistance of any reagent or catalyst. Bifunctional o-quinone methides (o-QMs) were the putative reaction intermediates ensued from dehydration of o-HPPA. Our study revealed that the o-QM was so choosy in selection of the nucleophiles for the key Michael addition reaction.
Introduction
Electrophilic cyclizations1 of functionalized alkynes often offer an opportunity for tandem reactions through post cyclization couplings and additions toward complex outcomes in short routes.1 Reverse to this strategy, some precyclization events such as couplings or additions are done in such a way that the resultant adducts readily cyclize in the same conditions to furnish again the complex but usually the complimentary structures in short pathways.2 Using the former approaches, a long list of several highly sought after cyclic scaffolds were synthesized. Benzofurans, for their frequent occurrence in natural products as well as in pharmaceutically active molecules,3 with a variety of substitutions at both C2 and C3 could be easily synthesized using this approach. Recently, some groups reported the synthesis of the same scaffold with different substitution patterns, usually complimentary, through the latter approach. For example, Bi et al. reported a silver-catalyzed benzylic tosylation of o-hydroxyphenyl propargyl alcohols (o-HPPA) as the precyclization event to get the cyclized product (3-tosylbenzofuran) in tandem.4 The A3 coupling5 has also been successfully utilized by Sharghi,5b Rawat5d and Hajra5e as a tandem precyclization event to get 3-substituted benzofurans.
On the other hand, o-quinone methides (o-QMs) are found to be highly reactive transitory intermediates and have become a linchpin in the development of efficient synthetic methods for various natural products and bioactive molecules.6 These momentary intermediates were extensively used in nucleophilation with various nucleophiles toward diverse orthohydroxybenzyl derivatives (Scheme 1a).7 Cycloaddition of the same with some selected bifunctional nucleophilic counterparts for benzopyrans and benzo-ε-lactones were also unveiled (Scheme 1b).8 Appendage of an additional reactive finger to these o-QMs would pave avenues for novel series of tandem reactions toward complex molecular architectures. For example, the alkyne tether to these o-QMs would amplify the reactive area which can result in tandem cyclization after initial additions toward unusual outcomes.9o-HPPAs are ready precursors (under reagent-/catalyst-free conditions) for alkyne-tethered o-QMs which can be used as nucleophile accepters prior to cyclization toward 3-substituted benzofurans. In a seminal instance in this line, Du et al. reported metal-free 3-phosphinoylbenzofurans through in situ generated o-QMs from the above readily available starting materials (Scheme 1c).9b In protraction of our interest in uncovering novel discoveries around functionalized alkynes,10 we developed a curiosity to investigate the possibility of reactivities of other interesting nucleophiles which end up with the installation of useful hetero tethers at C3 of benzofurans.
Scheme 1. (a–c) Reactions of o-QMs with Various Nucleophiles.
Results and Discussion
On the basis of the above postulate, we commenced optimizing the nucleophilic sulfonylative (with TsNa 2a) cyclization of o-QM, an active in situ generated intermediate from o-HPPA 1a (Table 1). We initially used the conditions developed by Du et al. Thus, a reaction of 1a with 2a in DCE in the presence of K2CO3 at 70 °C was initially conducted. Pleasingly, the desired product was formed but only in moderate yield of 50% (entry 1). Change of base (both inorganic and organic) did not incur much change in the reaction outcome (entries 2–5). We reasoned that the in situ formed sulfonylative o-HPPA intermediate might underwent a reversible desulfonylation (vide infra) before cyclization under high basic condition (to give back o-QM followed by slow decomposition). To our surprise and delight, the absence of any external base indeed led to a clean conversion to afford 3-tosyl 2-benzyl benzofuran in 93% yield (entry 6). We suppose that the byproduct NaOH, resulted from tosylation, must have acted as a base required for oxy-cyclization event. DCE was found as the most suitable solvent over the other tested solvents (entries 7–12).
Table 1. Optimization Studiesa.
| entry | base | solvent | temp (°C) | yield (%)b |
|---|---|---|---|---|
| 1 | K2CO3 | DCE | 70 | 50 |
| 2 | Na2CO3 | DCE | 70 | 62 |
| 3 | Cs2CO3 | DCE | 70 | 25 |
| 4 | DBU | DCE | 70 | trace |
| 5 | Et3N | DCE | 70 | 45 |
| 6 | DCE | 80 | 93 | |
| 7 | THF | 80 | 64 | |
| 8 | toluene | 80 | 72 | |
| 9 | CH3CN | 80 | 14 | |
| 10 | DMSO | 80 | 15 | |
| 11 | dioxane | 80 | trace | |
| 12 | DMF | 80 | trace |
Reaction conditions: 1a (0.5 mmol), TsNa (0.75 mmol) in solvent (3 mL).
Isolated yield.
We next assessed the generality of this sulfa-Michael addition/oxy-cyclization process. We first planned to vary the reaction scope of o-HPPA (1a–1m) with TsNa 2a under the above optimized reaction conditions. The results are evidenced in Table 2. Initially, the effect of substitution on alkyne terminus of o-HPPA was studied. Electronically neutral alkyl-phenyl substrates 1b–c gave desired adducts in excellent yields (3ba–ca in 85–86%). The electron-rich methoxy phenyl substitution (1d) showed transformation with similar high yield (3da, 84%). However, the halo (F and Cl) phenyl moieties (1e–f) led to slight erosion of yields (3ea–fa in 71–74%). Pleasingly, the thiophenyl- and cyclohexenyl-substituted analogues 1g–h were found to be equally viable substrates for the reaction to afford the desired products 3ga–ha in 82–86% yield. Proceeding further, the cyclic, acyclic, and aliphatic alkyne (cyclohexyl, cyclopentyl, 3-phenybutyl, and octyl) functionalities (1i–1l) were well tolerated by this metal-free sulfonylative cyclization (75–81%). Quite interestingly, the TMS-tethered alkyne motif (1m) was also well tolerated to give the corresponding product 3ma in 48% yield (along with desillylative component 3mai in 20%). Next, setting a limitation, our efforts to extend the reaction toward the synthesis of 3-sulfonylative indole variants were proved to be totally unfruitful.
Table 2. Scope of o-HPPA for 3-Ts Benzofuransa.
Reaction conditions: 1a (0.5 mmol), TsNa (0.75 mmol), in DCE (3 mL).
Isolated yield.
We subsequently investigated the scope of the conjugate addition/oxy-cyclization mode with respect to salicylaldehyde derivatives (Table 3). The electron-donating −OEt-bearing analogue 1n with TsNa gave the expected product 3na in 79% yield. Gratifyingly, highly reactive hydroxyl functional group on core phenyl ring 1o contentedly survived in given reaction condition. Further, the halo (Cl and Br) substituted (irrespective of position) motifs 1p–s were cleanly converted to the anticipated 3-tosyl benzyl benzofurans (3pa–sa) in 68–73% yields. The electron-deficient NO2 counterpart 1t was transformed to the desired product 3ta in 66% yield. In further continuation, we next examined the reaction scope with respect of sodium sulfinates. Thus, the neutral as well as electron-rich aryl sulfinate salts 2b–c fruitfully engaged with o-HPPA to form 3ab–ac in 78–82%, respectively. Sterically hindered napthyl sulfinate 2d also functioned well to yield 3ar in 69%. The methyl sodium sulfinate salt (2e), as alkyl counterpart, similarly delivered the final desired adduct in 68% yield.
Table 3. Scope of Salicylaldehydes & Sodium Sulfinate Saltsa.
Reaction conditions: 1a (0.5 mmol), RSO2Na (0.75 mmol), in DCE (3 mL).
Isolated yield.
Further, we identified that the other sulfonyl synthons such as toluenesulfonylmethyl isocyanide and tosyl hydrazines also successfully deliver (eq 1) the desire product (3aa from 1a), but the presence of K2CO3 as base was essential and the reaction totally failed in its absence.
 |
1 |
To ascertain the applicability of this nucleophilation/oxy-cyclization path, we then quested after the other potential nucleophilic precursors to act on o-QM to deliver benzofuran adducts with unusual C3-substitution. Thus, various hetero and carbophilic nucleophiles have been extensively screened as shown in Scheme 2. Regrettably, these nucleophiles were ineffective in the desired conjugate addition/oxy-cyclization process of o-QM (Scheme 2i–iv). Presumably, these strong nucleophiles are inapt to react with in situ generated ephemeral and highly reactive o-QM intermediate. Finally, though unusual, the 1H-benzotriazoles (Scheme 2v) were found as new nucleophilic counterparts for this aza-Michael addition/oxy-cyclization of o-QM to deliver diheterocyclic adduct 5a. Use of K2CO3 as base was essential in this case.
Scheme 2. Screening of Various Nucleophiles with o-QM.
1a (0.5 mmol), NuX (0.75 mmol), base (1.5 mmol), DCE (3 mL). For detailed description see Experimental Section.
We then explored its generality with a series of benzotriazoles (4) and o-HPPA, and the results are outlined in Table 4. Thus, 1b in presence of base reacted well with 4 and the expected product 5b was obtained in 81% yield.
Table 4. Synthesis of 3-(1-Benzotriazolyl)-benzofuransa.
Reaction conditions: 1a (0.5 mmol), 4 (0.75 mmol), base (1.5 mmol) in solvent (3 mL).
Isolated yield.
The substrates with electron-rich functionalities such as OMe and OEt on alkyne terminus as well as core aryl group efficiently underwent the desired transformation to produce expected products in good yields (5c–d in 72–74%). However, in case of halo (F, Cl, and Br) substituted counterparts (irrespective of the position), the products were obtained in slightly diminished yields when compared with electronically neutral substrates (5e–h in 62–68%). In contrast, the thiophenyl substitution on alkyne terminal 1d showed good reactivity to afford the desired product 5i in 73% yield. In addition, the 5-methyl-substituted benzotriazole reacted with electronically neutral and slightly electronically poor (F) o-HPPA (1a & 1e) and gave 5j–k (in 67 and 59%, respectively) in almost a 1:1 mixture of regioisomeric ratio (because of nucleophilic shuttling state in triazole ring). Nevertheless, the alkyl-substituted alkynes were found to be ineffective in this conversion.
On the basis of the investigational results and previous reports, we proposed a possible reaction path for the title reaction (Scheme 3). Initially, o-QM intermediate is generated from o-HPPA by expelling the water molecule. Conjugate addition of sulfinate salt on o-QM gave sodium phenoxide intermediate b, which with liberated H2O produced NaOH (and c). This NaOH infact acted as the base required for the subsequent deprotonation at benzylic position (allenyl isomerization) to give allene intermediate d. As the in situ base formation is not possible in case of benzotriazole as nucleophile, the external base was essential. Intramolecular oxy-cyclization of d and 1,3-proton migration led to 3-hetero-substituted benzylbenzofuran 3 or 5.
Scheme 3. Proposed Reaction Mechanism.
Conclusions
In summary, we have illustrated a practically simple and efficient approach for the synthesis of 3-heterosubstituted benzylbenzofurans from readily available o-HPPA and sulfinate salts or benzotriazoles. The reaction likely proceeds though sulfa-/aza-Michael addition and oxy-cyclization of in situ generated o-QM as bifunctional ephemeral intermediate. The hetero nucleophiles are thus embedded on somewhat electronically rich third position of benzofurans through a catalyst-free process. Further investigations on the enlargement of metal-free hetero-Michael addition reactions are currently underway.
Experimental Section
General Information
All solvents and reagents were purchased from commercially available sources. NMR spectra were recorded with a 300, 400, or 500 MHz spectrometer for 1H NMR, 100 or 125 MHz for 13C NMR spectroscopy. Chemical shifts are reported relative to the residual signals of deuterated solvent CDCl3 for 1H and 13C NMR spectroscopy. Multiplicities are reported as follows: singlet (s), doublet (d), doublet of doublets (dd), doublet of triplets (dt), triplet (t), quartet (q), and multiplet (m). High-resolution mass spectrometry (HRMS) was recorded by using QTof mass spectrometer. The characterization of compounds was further established by using HRMS. Column chromatography was performed with silica gel (100–200 mesh) as the stationary phase. All reactions were monitored by using thin-layer chromatography.
o-Hydroxyl phenyl propargylic alcohols (1) were prepared from our previously reported methods.10a,10b
General Procedure A for the Synthesis of 2-Benzyl-3-tosylbenzofurans (3aa–3ta and 3ab–3ae) from (1a–1t) Taking Synthesis of 3aa as an Example
To a 15 mL Schlenk tube was added o-hydroxyl phenyl propargylic alcohol 1a (112 mg, 0.5 mmol), sodium tosylate 2a (133 mg, 0.75 mmol) in anhydrous DCE (3 mL), sealing the Schlenk tube without degassing, and reaction mixture was stirred at 80 °C until complete conversion of starting material (8 h for 3aa–3da, 6 h for 3ea–3ga 12 h for 3ma–3la, 10 h for 3ma–3ta and 8 h for 3ab–3ae). After the removal of the solvent under reduced pressure, the crude material was purified on silica gel using 10% EtOAc/hexane to get 3aa (168 mg, 93%) as white solid.
2-Benzyl-3-tosylbenzofuran (3aa)4
mp 185–186 °C; Rf = 0.52 (10% ethyl acetate/hexane); 1H NMR (500 MHz, CDCl3): δ 7.91–7.85 (m, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.44–7.37 (m, 1H), 7.35–7.27 (m, 6H), 7.27–7.25 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 4.58 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.4, 153.5, 144.2, 139.3, 135.8, 129.8, 129.1, 128.7, 127.0, 126.8, 125.4, 124.4, 124.2, 120.6, 118.3, 111.4, 33.2, 21.5.
2-(4-Methylbenzyl)-3-tosylbenzofuran (3ba)
0.160 g was obtained from 1b (0.119 g, 0.5 mmol) following the general procedure A. Yield 85%; white solid, mp 177–179 °C; Rf = 0.56 (SiO2, 10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 6.3, 2.9 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.40 (dt, J = 7.0, 3.1 Hz, 1H), 7.38–7.28 (m, 2H), 7.22 (dd, J = 7.7, 5.5 Hz, 4H), 7.11 (d, J = 7.9 Hz, 2H), 4.54 (s, 2H), 2.37 (s, 3H), 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 161.7, 153.5, 144.2, 139.4, 136.7, 132.7, 129.8, 129.4, 129.0, 126.8, 125.4, 124.3, 124.2, 120.5, 118.1, 111.4, 32.8, 21.5, 21.1.; IR (KBr) ν: 3283, 2317, 1318, 1148, 961, 683 cm–1; HRMS (ESI): calcd for C23H21O3S [M + H]+, 377.1211; found, 377.1201.
2-(4-Ethylbenzyl)-3-tosylbenzofuran (3ca)
0.168 g was obtained from 1c (0.126 g, 0.5 mmol) following the general procedure A. Yield 86%; off white solid, mp 158–160 °C; Rf = 0.54 (SiO2, 15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.91–7.84 (m, 1H), 7.82–7.76 (m, 2H), 7.40 (dt, J = 7.4, 3.4 Hz, 1H), 7.32–7.27 (m, 2H), 7.23 (dd, J = 14.1, 5.9 Hz, 4H), 7.12 (d, J = 8.1 Hz, 2H), 4.54 (s, 2H), 2.62 (q, J = 7.6 Hz, 2H), 2.36 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.7, 153.5, 144.2, 143.1, 139.4, 133.0, 129.8, 129.0, 128.2, 126.8, 125.4, 124.3, 124.2, 120.5, 118.1, 111.4, 32.8, 28.5, 21.5, 15.6; IR (KBr) ν: 3038, 2311, 1565, 1313, 1050, 678 cm–1; HRMS (ESI): calcd for C24H23O3S [M + H]+, 391.1368; found, 391.1371.
2-(4-Methoxybenzyl)-3-tosylbenzofuran (3da)4
0.165 g was obtained from 1d (0.127 g, 0.5 mmol) following the general procedure A. Yield 84%; white solid, mp 136–138 °C; Rf = 0.46 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.90–7.83 (m, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.40 (dt, J = 7.4, 3.5 Hz, 1H), 7.33–7.20 (m, 6H), 6.87–6.80 (m, 2H), 4.51 (s, 2H), 3.78 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.8, 158.7, 153.4, 144.2, 139.4, 130.1, 129.8, 127.8, 126.8, 125.4, 124.3, 124.2, 120.5, 118.0, 114.1, 111.4, 32.3, 21.5.
2-(4-Fluorobenzyl)-3-tosylbenzofuran (3ea)
0.135 g was obtained from 1e (0.121 g, 0.5 mmol) following the general procedure A. Yield 71%; pale yellow solid, mp 120–122 °C; Rf = 0.54 (SiO2, 15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 6.0, 2.9 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.41 (dt, J = 7.5, 3.6 Hz, 1H), 7.34–7.27 (m, 4H), 7.28–7.21 (m, 2H), 7.03–6.93 (m, 2H), 4.54 (s, 2H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 162.9 (d, J = 245.8 Hz) 161.1, 153.5, 144.4, 139.3, 131.5, 130.6 (d, J = 7.8 Hz), 129.8, 126.8, 125.6, 124.4, 124.1, 120.6, 118.3, 115.5 (d, J = 21.3 Hz), 111.4, 32.4, 21.5; IR (KBr) ν: 3212, 2359, 1564, 1295, 1016, 664 cm–1; HRMS (ESI): calcd for C22H18FO3S [M + H]+, 381.0961; found, 381.0965.
2-(3-Chlorobenzyl)-3-tosylbenzofuran (3fa)
0.146 g was obtained from 1f (0.129 g, 0.5 mmol) following the general procedure A. Yield 74%; off white solid, mp 144–146 °C; Rf = 0.52 (SiO2, 10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.93–7.87 (m, 1H), 7.83–7.77 (m, 2H), 7.45–7.40 (m, 1H), 7.35–7.30 (m, 2H), 7.27–7.20 (m, 6H), 4.54 (s, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.35, 153.56, 144.49, 139.25, 137.66, 134.50, 129.97, 129.92, 129.09, 127.34, 126.83, 125.71, 124.54, 124.14, 120.71, 118.85, 111.56, 32.81, 21.59; IR (KBr) ν: 3244, 2315, 1568, 1321, 1037, 681 cm–1; HRMS (ESI): calcd for C22H18ClO3S [M + H]+, 397.0665; found, 397.0661.
2-(Thiophen-3-ylmethyl)-3-tosylbenzofuran (3ga)
0.158 g was obtained from 1g (0.115 g, 0.5 mmol) following the general procedure A. Yield 86%; off white solid, mp 161–163 °C; Rf = 0.48 (SiO2, 10% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3): δ 7.91–7.84 (m, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.47–7.40 (m, 1H), 7.36–7.21 (m, 6H), 7.14 (s, 1H), 7.06 (d, J = 4.9 Hz, 1H), 4.59 (s, 2H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 160.9, 153.4, 144.3, 139.3, 135.3, 129.8, 128.3, 126.8, 125.9, 125.5, 124.4, 124.2, 122.8, 120.6, 118.0, 111.4, 28.0, 21.5; IR (KBr) ν: 3108, 2342, 1572, 1315, 1051, 667 cm–1; HRMS (ESI): calcd for C20H17O3S2 [M + H]+, 369.0619; found, 369.0618.
2-(Cyclohex-1-en-1-ylmethyl)-3-tosylbenzofuran (3ha)
0.150 g was obtained from 1h (0.114 g, 0.5 mmol) following the general procedure A. Yield 82%; white solid, mp 168–170 °C; Rf = 0.58 (SiO2, 15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.94–7.87 (m, 3H), 7.44 (dt, J = 7.4, 3.5 Hz, 1H), 7.34–7.29 (m, 2H), 7.29–7.28–7.26 (m, 2H), 5.41 (d, J = 1.6 Hz, 1H), 3.87 (s, 2H), 2.38 (s, 3H), 1.97 (m, 4H), 1.60 (m, 2H), 1.53 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 161.9, 153.3, 144.1, 139.5, 132.6, 129.7, 126.9, 125.2, 124.9, 124.3, 120.5, 118.6, 111.4, 35.3, 28.5, 25.3, 22.7, 22.0, 21.6; IR (KBr) ν: 3283, 2320, 1605, 1277, 1060, 761 cm–1; HRMS (ESI): calcd for C22H23O3S [M + H]+, 367.1368; found, 367.1365.
2-(Cyclohexylmethyl)-3-tosylbenzofuran (3ia)
0.144 g was obtained from 1i (0.115 g, 0.5 mmol) following the general procedure A. Yield 78%; white solid, mp 125–127 °C; Rf = 0.54 (SiO2, 10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.92–7.85 (m, 3H), 7.46–7.39 (m, 1H), 7.33–7.24 (m, 4H), 3.09 (d, J = 7.3 Hz, 2H), 2.38 (s, 3H), 1.96–1.86 (m, 1H), 1.74–1.64 (m, 5H), 1.28–1.05 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 163.5, 153.2, 144.1, 139.8, 129.8, 126.8, 125.1, 124.4, 124.2, 120.4, 118.5, 111.2, 37.5, 34.7, 33.1, 26.1, 21.5; IR (KBr) ν: 3243, 2343, 1607, 1434, 1057, 698 cm–1; HRMS (ESI): calcd for C22H25O3S [M + H]+, 369.1524; found, 369.1516.
2-(Cyclopentylmethyl)-3-tosylbenzofuran (3ja)
0.136 g was obtained from 1j (0.108 g, 0.5 mmol) following the general procedure A. Yield 77%; off white solid, mp 128–130 °C; Rf = 0.48 (SiO2, 10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.93–7.85 (m, 3H), 7.42 (dt, J = 7.4, 3.4 Hz, 1H), 7.33–7.25 (m, 4H), 3.20 (d, J = 7.5 Hz, 2H), 2.43–2.34 (m, 4H), 1.82–1.65 (m, 4H), 1.56–1.49 (m, 2H), 1.37–1.25 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 164.0, 153.2, 144.1, 139.8, 129.8, 126.7, 125.1, 124.4, 124.2, 120.4, 117.9, 111.2, 39.0, 32.8, 32.5, 24.9, 21.5; IR (KBr) ν: 2921, 2312, 1569, 1315, 1042, 755 cm–1; HRMS (ESI): calcd for C21H23O3S [M + H]+, 355.1368; found, 355.1359.
2-(3-Phenylpropyl)-3-tosylbenzofuran (3ka)
0.158 g was obtained from 1k (0.126 g, 0.5 mmol) following the general procedure A. Yield 81%; white solid, mp 149–151 °C; Rf = 0.55 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.93–7.87 (m, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.41 (dt, J = 7.6, 3.2 Hz, 1H), 7.32–7.26 (m, 6H), 7.20 (dd, J = 5.0, 2.8 Hz, 3H), 3.24 (t, J = 7.7 Hz, 2H), 2.73 (t, J = 7.7 Hz, 2H), 2.38 (s, 3H), 2.15–2.06 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 163.7, 153.2, 144.2, 141.3, 139.7, 129.8, 128.4, 128.4, 126.7, 126.0, 125.2, 124.4, 124.3, 120.4, 118.0, 111.2, 35.4, 29.5, 27.0, 21.6; IR (KBr) ν: 3025, 2320, 1570, 1298, 1014, 677 cm–1; HRMS (ESI): calcd for C24H23O3S [M + H]+, 391.1368; found, 391.1363.
2-Heptyl-3-tosylbenzofuran (3la)
0.139 g was obtained from 1l (0.116 g, 0.5 mmol) following the general procedure A. Yield 75%; white solid, mp 99–101 °C; Rf = 0.50 (SiO2, 15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.95–7.84 (m, 3H), 7.51–7.45 (m, 1H), 7.34–7.24 (m, 4H), 3.26–3.14 (m, 2H), 2.38 (s, 3H), 1.81–1.72 (m, 2H), 1.39–1.25 (m, 8H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.3, 153.2, 144.1, 139.8, 129.8, 126.7, 125.1, 124.4, 124.2, 120.4, 117.7, 111.2, 31.7, 29.3, 28.9, 28.0, 27.3, 22.6, 21.5, 14.1; IR (KBr) ν: 3290, 2311, 1603, 1327, 1054, 753 cm–1; HRMS (ESI): calcd for C22H27O3S [M + H]+, 371.1681; found, 371.1701.
Trimethyl((3-tosylbenzofuran-2-yl)methyl)silane (3ma)
0.86 g was obtained from 1m (0.110 g, 0.5 mmol) following the general procedure A. Yield 48%; light brown gum; Rf = 0.55 (SiO2, 15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.90–7.86 (m, 2H), 7.84–7.78 (m, 1H), 7.39–7.34 (m, 1H), 7.29–7.26 (m, 2H), 7.26–7.22 (m, 2H), 2.76 (s, 2H), 2.38 (s, 3H), 0.14 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 161.2, 152.8, 140.0, 129.7, 126.5, 124.7, 124.3, 124.0, 120.3, 119.8, 115.0, 110.7, 21.5, 19.3, −1.0; IR (neat) ν: 3238, 2319, 1691, 1318, 1148, 762 cm–1; HRMS (ESI): calcd for C19H23O3SSi [M + H]+, 359.1137; found, 359.1134.
2-Methyl-3-tosylbenzofuran (3mai)4
0.28 g was obtained from 1m. Yield 20%; white solid, 122–124 °C; Rf = 0.50 (SiO2, 15% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 7.92–7.85 (m, 3H), 7.43–7.38 (m, 1H), 7.32–7.28 (m, 4H), 2.81 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.4, 153.2, 144.2, 140.8, 129.9, 127.8, 126.7, 125.1, 124.4, 124.3, 120.2, 111.1, 21.5, 13.6.
2-Benzyl-7-ethoxy-3-tosylbenzofuran (3na)
0.160 g was obtained from 1n (0.134 g, 0.5 mmol) following the general procedure A. Yield 79%; off white solid, mp 176–178 °C; Rf = 0.45 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.77–7.70 (m, 2H), 7.45 (dd, J = 8.0, 0.9 Hz, 1H), 7.38–7.25 (m, 6H), 7.21 (dd, J = 12.4, 4.4 Hz, 3H), 6.82 (dd, J = 8.1, 0.8 Hz, 1H), 4.62 (s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 2.37 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.6, 148.7, 144.4, 136.0, 129.7, 129.0, 128.6, 127.4, 126.9, 125.6, 125.2, 112.4, 108.8, 64.7, 33.1, 21.5, 14.8; IR (KBr) ν: 3135, 2340, 1601, 1304, 1049, 771 cm–1; HRMS (ESI): calcd for C24H23O4S [M + H]+, 407.1317; found, 407.1320.
2-Benzyl-3-tosylbenzofuran-5-ol (3oa)
0.142 g was obtained from 1o (0.120 g, 0.5 mmol) following the general procedure A. Yield 75%; white solid, mp 146–148 °C; Rf = 0.44 (SiO2, 30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.3 Hz, 2H), 7.35–7.16 (m, 9H), 6.81 (dd, J = 8.9, 2.6 Hz, 1H), 5.40 (br s, 1H), 4.53 (s, 2H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 162.3, 152.9, 148.4, 144.34, 139.3, 135.7, 129.8, 129.1, 128.7, 127.0, 126.7, 125.1, 117.9, 114.2, 112.1, 105.6, 33.3, 21.5; IR (KBr) ν: 3396, 2316, 1573, 1321, 1147, 659 cm–1; HRMS (ESI): calcd for C22H19O4S [M + H]+, 379.1004; found, 379.1011.
2-Benzyl-5-bromo-3-tosylbenzofuran (3pa)4
0.159 g was obtained from 1p (0.151 g, 0.5 mmol) following the general procedure A. Yield 72%; off white solid, mp 153–155 °C; Rf = 0.50 (SiO2, 10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 8.03 (d, J = 1.9 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 8.7, 2.0 Hz, 1H), 7.27 (m, 8H), 4.55 (s, 2H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 162.6, 152.2, 144.6, 139.0, 135.3, 129.9, 129.1, 128.8, 128.6, 127.2, 126.8, 126.1, 123.3, 118.1, 117.7, 112.9, 33.2, 21.6.
2-Benzyl-5,7-dichloro-3-tosylbenzofuran (3qa)
0.157 g was obtained from 1q (0.146 g, 0.5 mmol) following the general procedure A. Yield 73%; pale yellow solid, mp 166–168 °C; Rf = 0.54 (SiO2, 10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 2.0 Hz, 1H), 7.75–7.71 (m, 2H), 7.36–7.26 (m, 6H), 7.24 (d, J = 8.0 Hz, 2H), 4.57 (s, 2H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 163.4, 148.0, 144.8, 138.7, 135.0, 130.5, 130.0, 129.1, 128.8, 127.3, 126.9, 126.6, 125.8, 118.9, 117.7, 33.2, 21.6; IR (KBr) ν: 3292, 2341, 1578, 1329, 1081, 706 cm–1; HRMS (ESI): calcd for C22H17Cl2O3S [M + H]+, 431.0275; found, 431.0279.
2-Benzyl-7-bromo-5-chloro-3-tosylbenzofuran (3ra)
0.163 g was obtained from 1r (0.167 g, 0.5 mmol) following the general procedure A. Yield 69%; off white solid, mp 185–187 °C; Rf = 0.56 (SiO2, 10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J = 1.9 Hz, 1H), 7.74–7.70 (m, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.35–7.27 (m, 5H), 7.23 (d, J = 8.0 Hz, 2H), 4.58 (s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.3, 149.4, 144.8, 138.7, 135.0, 130.7, 130.0, 129.1, 128.8, 128.5, 127.3, 126.8, 126.2, 119.5, 118.9, 104.6, 33.2, 21.6; IR (KBr) ν: 3306, 2319, 1573, 1329, 1147, 735 cm–1; HRMS (ESI): calcd for C22H17BrClO3S [M + H]+, 474.9770; found, 474.9781.
2-Benzyl-5,7-dibromo-3-tosylbenzofuran (3sa)4
0.176 g was obtained from 1s (0.190 g, 0.5 mmol) following the general procedure A. Yield 68%; off white solid, mp 220–222 °C; Rf = 0.55 (SiO2, 10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 1.8 Hz, 1H), 7.74–7.70 (m, 2H), 7.60 (d, J = 1.8 Hz, 1H), 7.35–7.27 (m, 5H), 7.24 (d, J = 8.0 Hz, 2H), 4.57 (s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.1, 149.8, 144.8, 138.7, 134.9, 131.0, 130.0, 129.1, 128.8, 127.3, 126.8, 122.4, 118.82, 117.9, 105.0, 33.2, 21.6.
2-Benzyl-5-nitro-3-tosylbenzofuran (3ta)4
0.134 g was obtained from 1t (0.135 g, 0.5 mmol) following the general procedure A. Yield 66%; light yellow solid, mp 155–157 °C; Rf = 0.40 (SiO2, 20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 8.77 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 9.1, 2.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 9.1 Hz, 1H), 7.34–7.27 (m, 7H), 4.60 (s, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.4, 156.0, 145.1, 145.0, 138.6, 134.8, 130.1, 129.1, 128.9, 127.4, 127.0, 124.9, 121.4, 119.6, 117.2, 112.1, 33.3, 21.6.
2-Benzyl-3-(phenylsulfonyl)benzofuran (3ab)
0.143 g was obtained from 1a (0.112 g, 0.5 mmol) following the general procedure A. Yield 82%; white solid, mp 160–162 °C; Rf = 0.50 (SiO2, 10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 7.90 (m, 3H), 7.56–7.50 (m, 1H), 7.46–7.40 (m, 3H), 7.29 (m, 7H), 4.58 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 161.7, 153.5, 142.2, 135.7, 133.3, 129.2, 129.1, 128.7, 127.1, 126.8, 125.5, 124.4, 124.2, 120.6, 118.0, 111.5, 33.2; IR (KBr) ν: 3247, 2309, 1566, 1318, 1047, 716 cm–1; HRMS (ESI): calcd for C21H17O3S [M + H]+, 349.0898; found, 349.0903.
2-Benzyl-3-((4-methoxyphenyl)sulfonyl)benzofuran (3ac)
0.147 g was obtained from 1a (0.112 g, 0.5 mmol) following the general procedure A. Yield 78%; off white solid, mp 142–144 °C; Rf = 0.40 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.90–7.79 (m, 3H), 7.40 (dt, J = 7.3, 3.3 Hz, 1H), 7.35–7.23 (m, 7H), 6.91–6.85 (m, 2H), 4.58 (s, 2H), 3.80 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 163.4, 161.1, 153.5, 135.9, 133.9, 129.1, 128.7, 127.0, 125.4, 124.3, 124.2, 120.5, 118.7, 114.3, 111.5, 55.6, 33.2; IR (KBr) ν: 3026, 2316, 1575, 13 448, 1141, 754 cm–1; HRMS (ESI): calcd for C22H19O4S [M + H]+, 379.1004; found, 379.1012.
2-Benzyl-3-(naphthalen-1-ylsulfonyl)benzofuran (3ad)
0.137 g was obtained from 1a (0.112 g, 0.5 mmol) following the general procedure A. Yield 69%; pale yellow solid, mp 175–177 °C; Rf = 0.50 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 7.93 (dt, J = 5.1, 2.9 Hz, 1H), 7.90–7.78 (m, 4H), 7.63–7.55 (m, 2H), 7.41 (dt, J = 6.6, 2.9 Hz, 1H), 7.36–7.32 (m, 2H), 7.32–7.23 (m, 5H), 4.64 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 161.8, 153.5, 139.0, 135.7, 135.1, 132.1, 129.5, 129.4, 129.1, 128.7, 128.2, 127.8, 127.5, 127.1, 125.5, 124.5, 124.2, 121.9, 120.5, 118.0, 111.5, 33.2; IR (KBr) ν: 3141, 2357, 1511, 1327, 1022, 674 cm–1; HRMS (ESI): calcd for C25H19O3S [M + H]+, 399.1055; found, 399.1063.
2-Benzyl-3-(methylsulfonyl)benzofuran (3ae)
0.97 g was obtained from 1a (0.112 g, 0.5 mmol) following the general procedure A. Yield 68%; light yellow solid, mp 90–92 °C; Rf = 0.45 (SiO2, 10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.89–7.79 (m, 1H), 7.52–7.44 (m, 1H), 7.41–7.29 (m, 6H), 7.28–7.22 (m, 1H), 4.52 (s, 2H), 3.05 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.0, 153.4, 135.7, 129.0, 128.8, 127.2, 125.7, 124.6, 124.3, 120.2, 116.8, 111.6, 45.1, 33.0; IR (KBr) ν: 3247, 2343, 1567, 1304, 1016, 702 cm–1; HRMS (ESI): calcd for C16H15O3S [M + H]+, 287.0742; found, 287.0732.
Screening of Various Nucleophiles
We screened various nucleophiles for incorporation on o-QM. We carried out a series of reactions using o-HPPA (1a) with different hetero nucleophiles such as KSCN, ROH (alkynols, phenol, trichlroethanol, and triflouroethanol), amines (TsNH2, aniline, diphenylamine, piperidine-2,6-dione, oxy-indole, indoline, indole, TMSN3, NaN3, imidazole, and benzimidazole), and carbo nucleophiles (allyl silane, dimethyl malonate, ethylcyano acetate, and 1,3-isndandione) in the presence of different bases (organic and inorganic see Table 1 in manuscript) in dry DCE.
Benzotriazoles as Nucleophiles
Benzotriazoles were found as new nucleophilic counterparts for this aza-Michael addition/oxy-cyclization of o-QM. Then, we screened the reaction parameters. Thus, base and solvent K2CO3 gave best results over the other tested bases. DCE is the suitable solvent for this aza-Michael/oxy-cyclization event.
General Procedure B for the Synthesis of 1-(2-Benzylbenzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5a–5k) from (1) Taking Synthesis of 5a as an Example
To a 15 mL Schlenk tube was added o-hydroxyl phenyl propargylic alcohol 1a (112 mg, 0.5 mmol), benzotriazole 4a (89.5 mg, 0.75 mmol), K2CO3 (207 mg, 1.5 mmol) in anhydrous DCE (3 mL), sealing the Schlenk tube without degassing, and the reaction mixture was stirred at 80 °C until complete conversion of the starting material (12 h for 5a–5d, 14 h for 5e–5h and 16 h for 5i–5k). After removal of the solvent under reduced pressure, the crude material was purified on silica gel using 20% EtOAc/hexane to get 5a (140 mg, 86%) as off-white solid.
1-(2-Benzylbenzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5a)
mp 166–168 °C; 1H NMR (500 MHz, CDCl3): δ 8.21–8.17 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.52–7.50 (m, 1H), 7.47–7.45 (m, 1H), 7.42–7.39 (m, 1H), 7.37–7.35 (m, 1H), 7.28–7.21 (m, 6H), 7.20–7.16 (m, 1H), 4.15 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 153.4, 153.2, 145.8, 135.7, 134.0, 128.8, 128.6, 128.3, 127.0, 125.2, 124.4, 124.4, 123.7, 120.3, 118.5, 115.4, 112.0, 110.1, 32.6; IR (KBr) ν: 3387, 2311, 1605, 1502, 1050, 678 cm–1; HRMS (ESI): calcd for C21H16N3O [M + H]+, 326.1293; found, 326.1302.
1-(2-(4-Methylbenzyl)benzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5b)
0.137 g was obtained from 1b (0.119 g, 0.5 mmol) following the general procedure B. Yield 81%; light yellow solid, mp 145–147 °C; Rf = 0.50 (SiO2, 20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 8.21–8.17 (m, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.53–7.49 (m, 1H), 7.48–7.44 (m, 1H), 7.42–7.39 (m, 1H), 7.38–7.36 (m, 1H), 7.26–7.24 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.9 Hz, 2H), 4.11 (s, 2H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 153.5, 153.4, 145.8, 136.6, 134.0, 132.6, 129.3, 128.7, 128.2, 125.1, 124.4, 123.7, 120.3, 118.5, 115.2, 112.1, 111.9, 110.1, 32.2, 21.0; IR (KBr) ν: 3399, 2357, 1567, 1605, 1022, 674 cm–1; HRMS (ESI): calcd for C22H18N3O [M + H]+, 340.1450; found, 340.1442.
1-(2-(4-Methoxybenzyl)benzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5c)
0.131 g was obtained from 1d (0.127 g, 0.5 mmol) following the general procedure B. Yield 74%; white solid, mp 139–141 °C; Rf = 0.40 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 8.21–8.17 (m, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.52–7.44 (m, 2H), 7.42–7.38 (m, 1H), 7.38–7.34 (m, 1H), 7.26–7.24 (m, 2H), 7.19–7.14 (m, 2H), 6.79–6.74 (m, 2H), 4.09 (s, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.5, 153.6, 153.4, 145.8, 134.0, 129.9, 128.2, 128.1, 127.7, 125.1, 124.4, 123.7, 120.3, 118.5, 115.1, 114.0, 111.9, 110.1, 55.2, 31.7; IR (KBr) ν: 3283, 2359, 1605, 1505, 1150, 751 cm–1; HRMS (ESI): calcd for C22H18N3O2 [M + H]+, 356.1399; found, 356.1411.
1-(2-Benzyl-7-ethoxybenzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5d)
0.133 g was obtained from 1n (0.134 g, 0.5 mmol) following the general procedure B. Yield 72%; off white solid, mp 152–154 °C; Rf = 0.40 (SiO2, 25% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 8.18–8.14 (m, 1H), 7.52–7.48 (m, 1H), 7.46–7.42 (m, 1H), 7.37–7.34 (m, 1H), 7.22–7.12 (m, 6H), 6.89–6.86 (m, 1H), 6.81 (dd, J = 7.8, 0.8 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H), 4.18 (s, 2H), 1.54 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 153.3, 153.2, 144.8, 142.9, 135.7, 134.0, 128.7, 128.5, 128.2, 126.8, 126.2, 124.5, 124.3, 120.2, 110.5, 110.1, 108.5, 64.8, 32.6, 14.9; IR (KBr) ν: 3398, 2316, 1607, 1435, 1030, 752 cm–1; HRMS (ESI): calcd for C23H20N3O2 [M + H]+, 370.1556; found, 370.1563.
1-(2-(4-Fluorobenzyl)benzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5e)
0.117 g was obtained from 1e (0.121 g, 0.5 mmol) following the general procedure B. Yield 68%; pale yellow solid, mp 160–162 °C; Rf = 0.54 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 8.23–8.16 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.53–7.45 (m, 2H), 7.43–7.35 (m, 2H), 7.28–7.22 (m, 4H), 6.96–6.89 (m, 2H), 4.12 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 161.9 (d, J = 246.0 Hz), 153.4, 152.9, 145.8, 134.0, 131.4, 130.4 (d, J = 8.0 Hz), 128.3, 125.3, 124.5, 124.2, 123.8, 120.4, 118.6, 115.6, 115.3, 112.0, 110.0, 31.8; IR (KBr) ν: 3387, 2340, 1601, 1463, 1049, 671 cm–1; HRMS (ESI): calcd for C21H15FN3O [M + H]+, 344.1199; found, 344.1189.
1-(2-Benzyl-5,7-dichlorobenzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5f)
0.122 g was obtained from 1q (0.146 g, 0.5 mmol) following the general procedure B. Yield 62%; off white solid, mp 164–166 °C; Rf = 0.55 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 8.21–8.17 (m, 1H), 7.56–7.53 (m, 1H), 7.51–7.49 (m, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.34–7.30 (m, 1H), 7.23–7.17 (m, 5H), 7.14 (d, J = 1.9 Hz, 1H), 4.18 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 155.9, 149.8, 147.8, 145.7, 134.7, 133.8, 129.9, 128.8, 128.7, 127.2, 126.8, 125.5, 124.7, 120.5, 118.2, 116.8, 115.3, 109.6, 32.7; IR (KBr) ν: 3387, 2349, 1603, 1444, 1054, 696 cm–1; HRMS (ESI): calcd for C21H14Cl2N3O [M + H]+, 394.0514; found, 394.0533. Found, 394.0546.
1-(2-Benzyl-5-bromobenzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5g)
0.133 g was obtained from 1p (0.151 g, 0.5 mmol) following the general procedure B. Yield 66%; off white solid, mp 158–160 °C; Rf = 0.55 (SiO2, 20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 8.21–8.18 (m, 1H), 7.56–7.52 (m, 1H), 7.50–7.45 (m, 2H), 7.42 (d, J = 8.7 Hz, 1H), 7.40–7.36 (m, 2H), 7.25–7.17 (m, 5H), 4.14 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 154.7, 152.2, 145.8, 135.2, 133.9, 128.8, 128.7, 128.6, 128.3, 127.1, 126.3, 124.6, 121.2, 120.5, 117.0, 114.7, 113.5, 109.8, 32.6; IR (KBr) ν: 3386, 2320, 1605, 1432, 1060, 699 cm–1; HRMS (ESI): calcd for C21H15BrN3O [M + H]+, 404.0398; found 404.0414. Found, 404.0398.
1-(2-Benzyl-7-bromo-5-chlorobenzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5h)
0.140 g was obtained from 1r (0.168 g, 0.5 mmol) following the general procedure B. Yield 64%; light brown solid, mp 167–169 °C; Rf = 0.54 (SiO2, 20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 8.20–8.17 (m, 1H), 7.55–7.51 (m, 2H), 7.49–7.46 (m, 1H), 7.33–7.30 (m, 1H), 7.22 (d, J = 4.2 Hz, 4H), 7.19–7.15 (m, 2H), 4.18 (s, 2H); 13C NMR (125 MHz, CDCl3): δ 155.9, 149.2, 145.7, 134.7, 133.8, 130.2, 128.8, 128.7, 128.2, 127.2, 126.5, 124.7, 120.56, 117.4, 115.4, 109.6, 105.3, 32.7; IR (KBr) ν: 3447, 2311, 1691, 1489, 969, 696 cm–1; HRMS (ESI): calcd for C21H14BrClN3O [M + H]+, 438.0009; found, 438.0020.
1-(2-(Thiophen-3-ylmethyl)benzofuran-3-yl)-1H-benzo[d][1,2,3]triazole (5i)
0.121 g was obtained from 1g (0.115 g, 0.5 mmol) following the general procedure B. Yield 73%; white solid, mp 153–155 °C; Rf = 0.50 (SiO2, 15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 8.24–8.15 (m, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.51–7.48 (m, 2H), 7.42–7.35 (m, 2H), 7.30–7.24 (m, 2H), 7.20 (dd, J = 4.9, 3.0 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 4.9, 1.2 Hz, 1H), 4.18 (s, 2H); 13C NMR (125 MHz, CDCl3): δ 153.4, 152.6, 145.8, 135.4, 134.0, 128.3, 128.1, 125.9, 125.2, 124.4, 124.3, 123.8, 122.6, 120.3, 118.6, 115.1, 111.9, 110.0, 27.3; IR (KBr) ν: 3393, 2343, 1692, 1434, 1057, 654 cm–1; HRMS (ESI): calcd for C19H14N3OS [M + H]+, 332.0858; found, 332.0846.
1-(2-Benzylbenzofuran-3-yl)-5-methyl-1H-benzo[d][1,2,3]triazole Compound with 1-(2-Benzylbenzofuran-3-yl)-6-methyl-1H-benzo[d][1,2,3]triazole (1:0.77) (5j)
0.114 g was obtained from 1a (0.112 g, 0.5 mmol) following the general procedure B. Yield 67%; light yellow solid, mp 165–167 °C; Rf = 0.46 (SiO2, 15% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.44 (dd, J = 8.3, 5.3 Hz, 2H), 7.29–7.23 (m, 3H), 7.21–7.18 (m, 2H), 7.18–7.13 (m, 11H), 7.11–7.07 (m, 2H), 7.03 (s, 1H), 4.05 (s, 2H), 4.03 (s, 2H), 2.46 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 153.4, 153.2, 153.0, 146.4, 144.4, 139.1, 135.8, 134.5, 132.5, 130.4, 128.9, 128.6, 126.9, 126.7, 125.1, 124.5, 124.4, 123.7, 119.7, 119.2, 118.6, 115.5, 115.4, 111.9, 109.6, 109.3, 32.5, 22.0, 21.5; IR (KBr) ν: 3394, 2359, 1691, 1445, 1047, 664 cm–1; HRMS (ESI): calcd for C22H18N3O [M + H]+, 340.1450; found, 340.1438.
1-(2-(4-Fluorobenzyl)benzofuran-3-yl)-5-methyl-1H-benzo[d][1,2,3]triazole Compound with 1-(2-(4-Fluorobenzyl)benzofuran-3-yl)-6-methyl-1H-benzo[d][1,2,3]triazole (1:1) (5k)
0.106 g was obtained from 1e (0.121 g, 0.5 mmol) following the general procedure B. Yield 59%; pale yellow solid, mp 167–169 °C; Rf = 0.45 (SiO2, 20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 7.47 (dd, J = 8.3, 3.6 Hz, 2H), 7.33–7.25 (m, 3H), 7.24–7.13 (m, 10H), 7.05 (s, 1H), 6.85 (t, J = 8.6 Hz, 4H), 4.04 (s, 2H), 4.02 (s, 2H), 2.49 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.9, (d, J = 243.9 Hz), 153.4, 152.8, (d, J = 15.0 Hz), 146.4, 144.4, 139.2, 134.6, 134.5, 132.5, 131.5, 130.4, 130.4, 126.7, 125.2, 124.3, (d, J = 12.8 Hz), 123.8, 119.7, 119.3, 118.6, 115.5, 115.3, 111.9, 109.5, 109.2, 31.8, 22.0, 21.5; IR (KBr) ν: 3290, 2311, 1603, 1489, 1153, 753 cm–1; HRMS (ESI): calcd for C22H17FN3O [M + H]+, 358.1356; found, 358.1365.
Acknowledgments
We are thankful to SAIF, CSIR-IICT, for providing the analytical facilities. M.R., M.K.R.S., and R.K.G. thank CSIR for the fellowships. We gratefully acknowledge the financial support by DST (EMR/2017/0002413). IICT Manuscript Communication No IICT/Pubs./2018/341.
Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02480.
Spectroscopic data of all the products is available in the Supporting Information (PDF)
Author Contributions
§ M.R. and M.K.R.S. contributed equally.
The authors declare no competing financial interest.
Supplementary Material
References
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