Highly regioselective synthesis of 2,3-disubstituted 2H-1-benzopyrans: Brønsted acid catalyzed [4+2] cycloaddition reaction with a variety of arylalkynes via ortho-quinone methides

Tetrahedron 73 (2017) 6456e6464

Contents lists available at ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Highly regioselective synthesis of 2,3-disubstituted 2H-1benzopyrans: Brønsted acid catalyzed [4þ2] cycloaddition reaction with a variety of arylalkynes via ortho-quinone methides Kenta Tanaka, Mayumi Sukekawa, Yosuke Shigematsu, Yujiro Hoshino, Kiyoshi Honda* Graduate School of Environment and Information Sciences, Yokohama National University, Tokiwadai, Hodogaya-ku, Yokohama, 240-8501, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 July 2017 Received in revised form 20 September 2017 Accepted 26 September 2017 Available online 28 September 2017

A highly regioselective one-pot synthesis of 2,3-disubstituted-2H-1-benzopyrans has been developed through Brønsted acid catalyzed [4þ2] cycloaddition reaction with a variety of arylalkynes via orthoquinone methides. A catalytic amount of trifluoromethanesulfonic acid effectively promotes the [4þ2] cycloaddition reaction of salicylaldehydes with arylalkynes to afford the corresponding 2H-1benzopyrans in good yields with high regioselectivities. Treatment of the cycloadduct 2,3-diphenyl2H-1-benzopyran with some nucleophiles led to 4H-1-benzpyrans and 2H-1-benzopyran according to reagents. The present reactions provide versatile access to functionalized 2,3-disubstituted-2H-1benzopyrans that would be a useful tool for the synthesis of biologically and photochemically active molecules. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Regioselective synthesis Brønsted acid catalyst [4þ2] Cycloaddition 2H-1-Benzopyran ortho-Quinone methide

1. Introduction 2,3-Disubstituted-2H-1-benzopyrans are important structural motifs found in a wide range of biologically active compounds1 and photochemical materials2 (Fig. 1). Their importance and usefulness have prompted the development of a number of methods for the regioselective synthesis of 2,3-disubstituted-2H-1-benzopyrans in recent years. The typical synthetic methods for regioselective 2,3disubstituted-2H-1-benzopyrans include condensation reactions of domino oxa-Michael/aldol reaction in the presence of 1,5,7Triazabicyclo[4.4.0]dec-5-ene (TBD) under solvent free condition (Scheme 1a),3 insertion of arynes into DMF followed by multicomponent coupling reaction,4 Lewis acid catalyzed cycloaddition of methylenecyclopropanes,5 catalytic Petasis reaction,6 DBUcatalyzed reaction of ethyl 2-methylbuta-2,3-dienoate,7 microwave-assisted catalyst-free synthesis,8 bifunctional acidebase ionic liquid induced Michael addition reaction,9 combining nanocatalysis with base catalysis.10 Despite the availability of these existing methods, they usually suffer from limited substrate range, including lack of reactivity of olefins having electron-rich groups, or use of strong base catalysts. Recently, L-proline catalyzed

* Corresponding author. E-mail address: [email protected] (K. Honda). https://doi.org/10.1016/j.tet.2017.09.045 0040-4020/© 2017 Elsevier Ltd. All rights reserved.

convenient synthesis of 2H-1-benzopyrans by three-component reaction has been developed.11 Furthermore, L-proline catalyzed intermolecular cyclization of electron-poor alkynes such as methyl perfluoroalk-2-ynoates with salicylaldehydes was reported by Weiguo and coworkers in 2016.12 Very recently, we have investigated a direct synthesis of 3-silyl-2H-1-benzopyrans by [4þ2] cycloaddition of in situ generated o-quinonemethides with alkynylsilanes, and reported that salicylaldehydes react with alkynylsilanes in CH2Cl2 in the presence of BF3$OEt2 and trimethyl orthoformate at reflux to give 3-silyl-2H-1-benzopyrans in moderate yields.13 In the course of this study we found that when diphenylacetylene, which has symmetrical distribution of electron density, was subjected to this reaction condition, only a trace amount of the desired 2H-1-benzopyran was obtained. The literature survey shows that diphenylacetylene exhibits the relatively low reactivity toward Diels-Alder reaction and its reaction requires harsh reaction conditions such as high pressure and high temperature.14 Recently, transition metal-catalysts activated [4þ2] cycloaddition reaction of diphenylacetylenes has been intensively investigated.15 On the other hand, the reports of that reaction under metal-free condition are rare and very recently, Verma and co-workers developed a stoichiometric base-promoted [4þ2] cycloaddition reaction of diphenylacetylenes.16 These previous reports and our observations

K. Tanaka et al. / Tetrahedron 73 (2017) 6456e6464

6457

Table 1 Optimization of reaction conditions.a

Fig. 1. Selected examples of 2,3-disubstituted-2H-1-benzopyrans.

Entry

Catalyst

Solvent

Yield (%)

1 2 3 4b 5b 6 7 8 9 10 11c

TfOH TfOH TfOH TfOH TfOH TfOH Benzenesulfonic acid HBF4$OEt2 BF3$OEt2 Sc(OTf)3 TfOH

DMF THF Acetonitrile CH2Cl2 Benzene Toluene Toluene Toluene Toluene Toluene Toluene

N.R 2 2 9 23 38 29 14 16 10 52

a All reactions were carried out with 1a (2.0 mmol), 2a (1.0 mmol), CH(OMe)3 (2.0 equiv.), and catalyst (20 mol%) in solvent (5.0 mL) under nitrogen. b Reflux. c MeOH (5.0 mL) was added during work-up.

Scheme 1. Regioselective synthesis of 2,3-disubstituted-2H-1-benzopyrans.

described above prompted us to develop metal-free, acid-catalyzed [4þ2] cycloaddition of various alkynes for the synthesis of 2,3disubstituted-2H-1-benzopyrans. Herein, we report that a Brønsted acid catalyzed [4þ2] cycloaddition reaction with a variety of arylalkynes via ortho-quinone methides afforded highly regioselective one-pot synthesis of 2,3-disubstituted 2H-1-benzopyrans (Scheme 1b).

solvents such as benzene and toluene, all led to the formation of the desired product 3aa in moderate yields (entries 5 and 6). In those cases, a small amount of byproducts 4aa and 5aa were isolated in 4 and 12% yields, respectively (Fig. 2). When other Brønsted acids like benzenesulfonic acid and HBF4$OEt2 were used instead of TfOH, the desired products were obtained in moderate yields (entries 7 and 8). On the other hand, when Lewis acids such as BF3$OEt2 and Sc(OTf)3 were used, the yields of product 3aa decreased (entries 9 and 10). Finally, when excess MeOH was added during the work-up procedure, the highest yield of the product could be obtained (entry 11, 52% yield). With the optimal reaction conditions in hand, we evaluated the scope of alkynes, as summarized in Scheme 2. Various alkynes with 4-alkyl or 4-aryl groups on benzene ring gave the corresponding products in good yields with high regioselectivities (3aa-3ad). The unbalance of electron distribution on the CeC triple bond of the unsymmetrical alkynes plays an important role in the regioselective formation of 2H-1-benzpryrans.17 Regioselectivity of all products was confirmed by analysis of 13C NMR chemical shift data of the corresponding benzene rings, which were assigned by comparison with 13C NMR data of the parent 2,3-diaryl-2H-1benzopyran 3aa.18 2,3-Diaryl-2H-1-benzopyran 3aa was fully characterized by 1H NMR, 13C NMR, COSY, HMBC, HSQC, IR and HRMS.18 Alkynes with methoxy groups on benzene ring afforded the desired products in moderate yields (3ae, 3ag and 3ah). However, 1-methoxy-3-(phenylethynyl)benzene failed to participate in the reaction (3af). The reaction with 2-(phenylethynyl)naphthalene

2. Result and discussion We initially investigated the reaction of 5-nitrosalicylaldehyde (1a) with diphenylacetylene (2a) in the presence of acid catalysts in various solvents (Table 1). When polar solvents such as DMF, acetonitrile, THF, CH2Cl2 were used in the presence of a catalytic amount of trifluoromethanesulfonic acid (TfOH, 20 mol%), the reactions scarcely proceed (entries 1e4). However, several non-polar

Fig. 2. Byproducts of the reaction.

6458

K. Tanaka et al. / Tetrahedron 73 (2017) 6456e6464

Scheme 2. Evaluation of the scope of the various alkynes.

smoothly underwent to give the corresponding product in good yield (3ai). On the other hand, interestingly, when 1-(phenylethynyl)naphthalene was used, the reaction did not sufficiently proceed (3aj). When various diarylacetylenes with electron withdrawing groups were used, the corresponding adducts were formed in low yields with high regioselectivities (3ak-3am). Interestingly, 4-bromo diphenylacetylene gave the mixture of 2and 3-(4-bromophenyl)chromenes (3an). The ratio of isomerization to 2-bromophenyl and 3-bromophenyl products was 1: 1, which was investigated with the view of comparing the integration ratio of the protons associated with 4-position of chromenes in 1H NMR spectrum. In this case, almost no regioselectivity may relate to small difference of electron distribution on the CeC triple bond of 4-bromo diphenylacetylene.19 The combination of the electron withdrawing group and electron donating group gave moderate yield (3ao). Furthermore, the reactivity of other general alkynes was also investigated. When terminal alkyne, phenylacetylene, was used, the complex mixture was obtained (3ap). However, the reaction with internal alkynes that have alkyl and aryl groups smoothly underwent to afford the cycloadducts in high yields (3aq3as). Trimethylsilylethynylbenzene gave the product in low yield (3at). In addition, the reaction with aliphatic alkynes having no aryl group did not proceed (3au-3av). When dimethyl acetylenedicarboxylate was used, the cycloadduct was not obtained (3aw). Alkynes with hetero rings were poor dienophiles in the present reaction (3ax and 3ay). We next examined a variety of salicylaldehydes (Scheme 3). 5-

a

Mixture of 2- and 3-bromo aryl products.

Nitrosalicylaldehyde afforded the product in moderate yield (3aa). Other strong withdrawing groups such as 5-nitrile, 5tosyloxy, 4-tosyloxy groups gave the products in low yields (3ba3da). The reaction of salicylaldehydes having medium withdrawing groups, such as 5-methoxycarbonyl, 4-acetoxy, and 4-bromo groups, did not smoothly proceed (3ea-3ga). 5Methoxysalicylaldehyde gave no product (3ha). Next, the reaction of salicylaldehydes with 1-phenyl-1-butyne has been examined. 5Nitrosalicylaldehyde smoothly led to the formation of the desired product in 99% (3ar). In addition, 5-methoxycarbonyl group afforded the desired product in high yield (3er). When halogen groups such as 5-bromo, 5-chloro were used, the desired products were obtained in moderate yields (3ir and 3jr). In addition, a high yield was obtained when the reaction of 5-bromosalicylaldehyde was carried out (3gr). In contrast, electron donating group such as 5methoxy group gave the trace amount of the product (3hr). Finally, we investigated further transformations of methoxy group at C-2 position of 2,3-diaryl-2H-1-benzopyrans by various nucleophiles (Scheme 4).20 When 2H-1-benzopyran 3aa was treated with Et3SiH, 4H-1-benzopyran 6aa was obtained in 77%. Treatment of [1-[(trimethylsilyl)oxy]ethenyl]benzene, which is known as a soft nucleophile, gave no 2-substituted product but 4substituted 4H-1-benzopyrans 7aa in 42% yield.21 1,4Dimethoxybenzene gave 4-aryl-4H-1-benzpyran 8aa in 53%. 4aryl-4H-1-benzopyrans and 2,3,4-triarylbenzopyrans has a lot of important bioactivities such as selective estrogen receptor modulation activity.21b,22 On the other hand, the Peason's hard

K. Tanaka et al. / Tetrahedron 73 (2017) 6456e6464

6459

Scheme 5. Plausible mechanism for the synthesis of 2,3-disubstituted-2H-1benzopyrans from salicylaldehydes with alkynes.

Scheme 3. Optimization of salicylaldehydes.

nucleophile such as iPrOH afforded the 2-isopropoxy 2H-1benzopyran 9aa, which is a derivative of Bullataketals,23 in 69%

yield. It is noted that the present reaction is a good method for constructing 2-substituted 2,3-diaryl-2H-1-benzopyrans and 4substituted 2,3-diaryl-4H-1-benzopyrans according to HSAB principle, leading to the effective synthesis of biologically and photochemically active molecules, from the same starting substrate. A plausible reaction mechanism for the cycloaddition of salicylaldehydes with diarylacetylenes is depicted in Scheme 5. First, acid-catalyzed acetal formation of salicylaldehydes 10 with CH(OMe)3 would occurred to afford the intermediates 11, which is amenable to elimination of MeOH under acidic conditions, affording o-quinonemethides 12. It is considered that o-quinonemethides may react with diarylacetylenes by stepwise mechanism to generate stable vinyl cation and give the intermediate 13 followed by smooth cyclization and afford cycloadduct 14. It is known that aaryl groups can stabilize the vinyl cation.24 It is suggested that the step of attack of the more electron-rich carbon of unsymmetrical alkynes into the exo-methylene carbon of o-quinonemethide intermediates would determine the regioselectivity of the products.19 Elimination of methoxy group from 14 with the assistance of Brønsted acid can form flavylium salts 15, which would equilibrate with 17 under the reaction conditions. Then, attack of excess MeOH at 2-position of flavylium salts 15 would generate 17 as the most stable products. When the reaction mixture is quenched by aqueous work-up, nucleophilic water would compete with MeOH in the step of addition of nucleophile to 15, leading to the reduction of the yields of the desired products. 3. Conclusion

Scheme 4. Examination of nucleophilic attack to 2,3-diaryl-2H-1-benzopyran 3aa.

In summary, we demonstrated that the Brønsted acid catalyzed [4þ2] cycloaddition reaction of salicylaldehydes with a variety of arylalkynes via ortho-quinone methides afforded high regioselective one-pot synthesis of 2,3-disubstituted-2H-1-benzopyrans. Electron withdrawing or electron donating substituted aryl groups of diarylacetylenes and alkyl aryl acetylenes such as 1-phenyl-1propyne afforded the high regioselectivities by which 2-(electron-

6460

K. Tanaka et al. / Tetrahedron 73 (2017) 6456e6464

rich aryl)-3-(electron-poor aryl or alkyl)-2H-1-benzopyrans were obtained. The substitution of methoxy group of the product by various nucleophiles led to 2-substituted 2,3-diaryl-2H-1benzopyrans or 4-substituted 2,3-diaryl-4H-1-benzopyran skeleton. Thus, the present reactions provide versatile access to functionalized 2,3-disubstituted-2H-1-benzopyrans that would be a useful tool for the synthesis of biologically and photochemically active molecules. 4. Experimental section 4.1. General Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR PARAGON 1000 spectrometer or a JASCO FT/IR-4100. 1H NMR spectra were recorded on a Bruker DRX-300 (300 MHz) spectrometer, or a Bruker DRX-500 (500 MHz) spectrometer with tetramethylsilane (TMS) as internal standard. Chemical shifts are reported in ppm from TMS. Data are reported as follows: chemical shift, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), coupling constants, integration. 13C NMR spectra were recorded on a Bruker DRX-500 (125 MHz) spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from TMS with the solvent resonance as the internal standard (CDCl3: d 77.0). Column chromatography was carried out with Cicareagent silica gel 60 N (spherical, particle size 63e210 mm). Thinlayer chromatography (TLC) was carried out with Merck TLC plates with silica gel 60 F254. Unless otherwise noted, reagents were commercially available and were used without purification. 4.2. General procedure for the synthesis of 2,3-disubstituted 2H-1benzopyrans To a solution of nitrosalicylaldehyde (2.0 mmol), diphenylacetylene (1.0 mmol) and trimethyl orthoformate (2.0 mmol) in toluene (5.0 mL) under nitrogen, trifluoromethanesulfonic acid (18 mL, 0.20 mmol, 20 mol%) was added. After being stirred at reflux for 15 h, methanol (5.0 mL, 0.12 mol) was added. Then the reaction mixture was quenched with H2O. The organic layer was separated and the aqueous layer was extracted with ethylacetate. The combined organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (hexane/ ethylacetate ¼ 100: 1 to 20: 1) to afford product. 4.2.1. 2-Methoxy-6-nitro-2,3-diphenyl-2H-1-benzopyran (3aa) Yield 52%, yellow solid. IR (ATR): 3063, 2839, 1511, 1480, 1446, 1336, 1249, 1181, 1125, 1107, 1087, 1016, 987, 962, 903, 827, 772, 748, 697, 595, 566 cm1. 1H NMR (300 MHz, CDCl3): d 8.17 (d, 1H, J ¼ 2.6 Hz), 8.11 (dd, 1H, J ¼ 2.6, 9.0 Hz), 7.44e7.55 (m, 2H), 7.31e7.35 (m, 2H), 7.17e7.31 (m, 7H), 7.15 (s, 1H), 7.00 (d, 1H, J ¼ 9.0 Hz), 3.44 (s, 3H). 13C NMR (125 MHz, CDCl3): d 157.3, 142.0, 140.7, 136.3, 134.7, 128.3, 128.1, 127.8, 126.5, 125.5, 124.7, 122.9, 119.7, 115.8, 105.2, 51.2. HRMS (ESIþ): m/z calcd for C21H13NO3 ([MOMe]þ): 327.0895, found: 327.0911. 4.2.2. 4-Methoxy-6-nitro-2,3-diphenyl-4H-1-benzopyran (4aa) Yield 11%, yellow solid. IR (ATR): 3089, 2925, 2844, 1577, 1511, 1485, 1337, 1251, 1108, 1084, 1047, 987, 957, 901, 828, 801, 782, 765, 743, 697, 645, 606, 581, 568 cm1. 1H NMR (500 MHz, CDCl3): d 8.19 (d, 1H, J ¼ 8.8 Hz), 7.92 (s, 1H), 7.35 (s, 3H), 7.25 (d, 1H, J ¼ 9.1 Hz), 7.14e7.23 (m, 7H), 5.72 (s, 1H), 3.64 (s, 3H). 13C NMR (126 MHz, CDCl3): d 155.5, 142.5, 136.6, 135.1, 133.0, 130.4, 128.9, 128.7, 128.2, 128.1, 127.6, 124.6, 124.2, 122.6, 117.5, 100.3, 56.0. HRMS (ESIþ): m/z calcd for C21H13NO3 ([M-OMe]þ): 327.0895, found: 327.0904.

4.2.3. 2-Hydroxy-6-nitro-2,3-diphenyl-2H-1-benzopyran (5aa) Yield 16%, yellow solid. IR (ATR): 3428, 3066, 2924, 1644, 1612, 1577, 1505, 1478, 1446, 1380, 1337, 1268, 1200, 1172, 1129, 1092, 1072, 1036, 996, 969, 947, 910, 899, 829, 767, 748, 728, 693, 651, 592, 566 cm1. 1H NMR (500 MHz, CDCl3): d 8.19 (s, 1H), 8.14 (d, 1H, J ¼ 8.8 Hz), 7.52 (d, 2H, J ¼ 7.6 Hz), 7.26e7.34 (m, 5H), 7.21 (s, 3H), 7.05 (d, 1H, J ¼ 8.8 Hz), 6.94 (s, 1H), 3.76 (s, 1H). 13C NMR (126 MHz, CDCl3): d 155.5, 142.2, 140.6, 138.5, 136.3, 128.8, 128.1, 126.4, 125.2, 122.6, 120.4, 117.0, 101.0. HRMS (ESIþ): m/z calcd for C21H15NO4 ([MþH]þ): 346.1079, found: 346.1079. 4.2.4. 2-Methoxy-2-(4-methylphenyl)-6-nitro-3-phenyl-2H-1benzopyran (3ab) Yield 69%, white solid. IR (ATR): 1515, 1338, 1255, 1183, 1104, 1084, 988, 962, 901, 824, 763, 702, 611, 566 cm1. 1H NMR (500 MHz, CDCl3): d 8.12 (dd, 1H, J ¼ 2.6, 8.7 Hz), 8.03e8.06 (m, 1H), 7.28e7.44 (m, 4H), 7.18e7.20 (m, 3H), 7.12 (s, 1H), 7.04 (d, 2H, J ¼ 7.9 Hz), 6.93 (d, 1H, J ¼ 8.8 Hz), 3.40 (s, 3H), 2.22 (s, 3H). 13C NMR (125 MHz, CDCl3): d 157.3, 141.7, 138.4, 138.0, 136.3, 134.5, 128.7, 128.1, 127.6, 126.2, 125.3, 124.6, 122.7, 119.5, 115.6, 105.3, 51.0, 21.0. HRMS (ESIþ): m/z calcd for C23H20NO4 ([MþH]þ): 374.1392, found: 374.1394. 4.2.5. 2-(4-Isopropylphenyl)-2-methoxy-6-nitro-3-phenyl-2H-1benzopyran (3ac) Yield 70%, yellow solid. IR (ATR): 3089, 2964, 2871, 1614, 1578, 1514, 1479, 1414, 1335, 1258, 1184, 1126, 1090, 1057, 1021, 974, 905, 886, 849, 824, 804, 768, 748, 725, 616, 567 cm1. 1H NMR (300 MHz, CDCl3): d 8.13 (d, 1H, J ¼ 2.6 Hz), 8.05 (dd, 1H, J ¼ 2.6, 9.0 Hz), 7.38e7.48 (m, 2H), 7.31e7.38 (m, 2H), 7.06e7.27 (m, 5H), 6.94 (d, 1H, J ¼ 9.0 Hz), 3.40 (s, 3H), 2.82 (m, 1H), 1.13e1.20 (m, 6H). 13C NMR (126 MHz, CDCl3): d 157.5, 149.5, 141.9, 138.1, 136.4, 134.8, 128.2, 127.8, 126.3, 126.2, 125.4, 124.6, 122.8, 119.8, 115.8, 105.5, 51.2, 33.7, 23.8. HRMS (ESIþ): m/z calcd for C24H20NO3 ([M-OMe]þ): 370.14377, found: 370.14461. 4.2.6. 2-Methoxy-6-nitro-3-phenyl-2-(4-phenylphenyl)-2H-1benzopyran (3ad) Yield 50%, yellow solid. IR (ATR): 2937, 1508, 1480, 1338, 1274, 1252, 1091, 975, 824, 762, 745, 699, 684 cm1. 1H NMR (500 MHz, CDCl3): d 8.23 (d, 1H, J ¼ 2.5 Hz), 8.15e8.17 (d, 1H, J ¼ 8.7 Hz), 7.62e7.63 (m, 2H), 7.54e7.58 (m, 4H), 7.42e7.45 (m, 4H), 7.35e7.38 (m, 1H), 7.28e7.29 (m, 3H), 7.22 (s, 1H), 7.04e7.06 (d, 1H, J ¼ 8.8 Hz), 3.50 (s, 3H). 13C NMR (125 MHz, CDCl3): d157.4, 142.0, 141.5, 140.3, 139.7, 136.3, 134.5, 128.8, 128.4, 127.8, 127.6, 127.1, 126.9, 126.8, 125.5, 124.9, 123.0, 119.7, 115.8, 105.3, 51.28. HRMS (ESIþ): m/z calcd for C27H18NO3 ([M-OMe]þ): 404.1281, found: 404.1269. 4.2.7. 2-Methoxy-2-(2-methoxyphenyl)-6-nitro-3-phenyl-2H-1benzopyran (3ae) Yield 47%, yellow solid. IR (ATR): 1602, 1578, 1517, 1489, 1338, 1271, 1253, 1184, 1128, 1089, 1061, 1027, 970, 888, 833, 749, 699, 595, 562 cm1. 1H NMR (300 MHz, CDCl3): d 8.18 (d, 1H, J ¼ 2.6 Hz) 8.12 (dd, 1H, J ¼ 3.4, 6.4 Hz), 7.84 (dd, 1H, J ¼ 1.7, 7.7 Hz), 7.33e7.40 (m, 2H), 7.17e7.24 (m, 4H), 7.07 (s, 1H), 6.92e6.99 (m, 2H), 6.72 (d, 1H, J ¼ 8.0 Hz), 3.49 (s, 3H), 3.48 (s, 3H). 13C NMR (126 MHz, CDCl3): d 158.9, 157.3, 141.5, 136.8, 133.7, 130.4, 128.1, 127.8, 125.1, 124.0, 122.8, 119.8, 119.6, 114.9, 111.6, 102.7, 55.5, 50.0. HRMS (ESIþ): m/z calcd for C23H20NO5 ([MþH]þ): 390.1341, found: 390.1349. 4.2.8. 2-Methoxy-2-(4-methoxyphenyl)-6-nitro-3-phenyl-2H-1benzopyran (3ag) Yield 52%, yellow solid. IR (ATR): 3009, 2972, 2937, 1667, 1608, 1580, 1509, 1483, 1337, 1246, 1175, 1091, 1054, 1022, 976, 879, 830, 807, 768, 746, 694, 635, 564 cm1. 1H NMR (500 MHz, CDCl3):

K. Tanaka et al. / Tetrahedron 73 (2017) 6456e6464

d 8.10e8.19 (m, 2H), 7.38e7.46 (m, 2H), 7.24e7.28 (m, 3H), 7.17 (s,

1H), 7.02 (d, 1H, J ¼ 8.8 Hz), 6.82 (m, 2H), 3.77 (s, 3H), 3.45 (s, 3H). 13 C NMR (125 MHz, CDCl3): d 159.7, 157.4, 141.8, 136.4, 133.1, 131.6, 130.0, 128.2, 127.7, 125.4, 124.6, 122.8, 119.7, 118.9, 115.7, 113.4, 105.3, 55.1, 51.1. HRMS (ESIþ): m/z calcd for C23H19NO5 ([M-OMe]þ): 390.1341, found: 390.1343. 4.2.9. 2-Methoxy-2,3-bis(4-methoxyphenyl)-6-nitro-2H-1benzopyran (3ah) Yield 39%, yellow solid. IR (ATR): 1609, 1336, 1243, 1172, 1090, 1028, 972, 877, 823, 749, 573 cm1. 1H NMR (500 MHz, CDCl3): d 8.09e8.14 (m, 1H) 8.03 (dd, 1H, J ¼ 8.8, 2.5 Hz), 7.39e7.46 (m, 2H), 7.27e7.34 (m, 2H), 7.08 (s, 1H), 6.92 (d, 1H, J ¼ 9.1 Hz), 6.69e6.81 (m, 4H), 3.72 (s, 3H), 3.71 (s, 3H), 3.40 (s, 3H). 13C NMR (125 MHz, CDCl3): d 159.6, 157.2, 141.7, 134.0, 133.3, 128.9, 127.6, 125.0, 123.3, 122.5, 119.8, 115.5, 113.6, 113.3, 105.4, 55.1, 51.1. HRMS (ESIþ): m/z calcd for C24H22NO6 ([MþH]þ): 420.1447, found: 420.1448. 4.2.10. 2-Methoxy-2-(2-naphthyl)-6-nitro-3-phenyl-2H-1benzopyran (3ai) Yield 57%, yellow solid. IR (ATR): 3055, 2932, 1732, 1663, 1611, 1578, 1518, 1338, 1260, 1245, 1175, 1091, 972, 835, 760, 749, 696, 634, 566 cm1. 1H NMR (300 MHz, CDCl3): d 8.29 (d, 1H, J ¼ 2.6 Hz), 8.15 (dd, 1H, J ¼ 2.8, 8.9 Hz), 8.03 (d, 1H, J ¼ 7.5 Hz), 7.97 (d, 1H, J ¼ 7.9 Hz), 7.69e7.82 (m, 2H), 7.35e7.49 (m, 3H), 7.28e7.35 (m, 3H), 7.23 (s, 1H), 7.07e7.16 (m, 2H), 7.04 (d, 1H), 3.55 (s, 3H). 13C NMR (126 MHz, CDCl3): d 157.4, 136.3, 135.4, 134.9, 130.7, 130.3, 128.9, 128.4, 128.2, 128.0, 127.8, 126.2, 125.6, 125.3, 126.1, 124.6124.2, 123.2, 116.1, 60.4, 50.9, 21.1, 14.2. HRMS (ESIþ): m/z calcd for C25H18NO3 ([M-OMe]þ): 378.1132, found: 378.1139. 4.2.11. 2-Methoxy-6-nitro-3-(4-nitrophenyl)-2-phenyl-2H-1benzopyran (3ak) Yield 24%, yellow solid. IR (ATR): 1591, 1505, 1332, 1255, 1108, 972, 851, 831, 748, 696, 584 cm1. 1H NMR (500 MHz, CDCl3): d 8.24 (d, 1H, J ¼ 2.5 Hz) 8.17 (dd, 1H, J ¼ 9.0, 2.7 Hz), 8.02e8.09 (m, 2H), 7.50e7.54 (m, 2H), 7.45e7.49 (m, 2H), 7.25e7.32 (m, 4H), 7.06 (d, 1H, J ¼ 9.1 Hz), 3.45 (s, 3H). 13C NMR (125 MHz, CDCl3): d 157.2, 147.2, 142.8, 142.1, 139.9, 132.6, 129.1, 128.6, 128.3, 126.8, 126.4, 126.3, 123.4, 118.8, 116.0, 104.4, 51.2. HRMS (ESIþ): m/z calcd for C22H17N2O6 ([MþH]þ): 405.1087, found: 405.1087. 4.2.12. 2-Methoxy-3-(4-methoxycarbonylphenyl)-6-nitro-2phenyl-2H-1-benzopyran (3al) Yield 28%, yellow solid. IR (ATR): 1712, 1658, 1602, 1522, 1481, 1434, 1341, 1281, 1190, 1106, 1077, 977, 932, 877, 835, 773, 760, 747, 700, 643, 611 cm1. 1H NMR (300 MHz, CDCl3): d 8.20 (d, 1H, J ¼ 2.6 Hz) 8.15 (dd, 1H, J ¼ 2.6, 6.4 Hz), 7.90 (m, 2H), 7.42e7.48 (m, 4H), 7.23e7.27 (m, 5H), 7.04 (d, 1H, J ¼ 8.7 Hz), 3.89 (s, 3H), 3.45 (s, 3H). 13C NMR (125 MHz, CDCl3): d 166.5, 157.3, 142.0, 140.8, 140.3, 133.7, 129.7, 129.5, 128.2, 127.7, 126.4, 125.9, 125.8, 123.1, 119.2, 115.9, 104.8, 52.1, 51.2. HRMS (ESIþ): m/z calcd for C24H20NO6 ([MþH]þ): 418.1291, found: 418.1287. 4.2.13. 2-Methoxy-6-nitro-2-phenyl-3-(4-trifluorophenyl)-2H-1benzopyran (3am) Yield 38%, white solid. IR (ATR): 1614, 1516, 1480, 1323, 1264, 1164, 1106, 1067, 1017, 990, 969, 911, 834, 746, 700, 608 cm1. 1H NMR (500 MHz, CDCl3): d 8.20 (m, 1H), 8.10e8.14 (m, 1H), 7.47e7.52 (m, 6H), 7.22e7.31 (m, 4H), 7.01 (d, 1H, J ¼ 8.8 Hz), 3.44 (s, 3H). 13C NMR (125 MHz, CDCl3): d 157.2, 142.0, 140.2, 139.8, 133.3, 130.1, 129.8, 128.9, 128.2, 128.0, 126.4, 125.9, 125.2, 125.1, 124.9, 123.1, 122.8, 119.1, 115.9, 104.7, 51.1. HRMS (ESIþ): m/z calcd for C23H17F3NO4 ([MþH]þ): 428.1110, found: 428.1107.

6461

4.2.14. 3-(4-Bromophenyl)-2-methoxy-6-nitro-2-phenyl-2H-1benzopyran, 2-(4-bromophenyl)-2-methoxy-6-nitro-2-phenyl-2H1-benzopyran (3an) Yield 45%, yellow solid. IR (ATR): 1516, 1481, 1335, 1255, 1090, 1073, 1010, 975, 879, 820, 748, 697 cm1. 1H NMR (500 MHz, CDCl3): d 8.06 (s, 1H) 7.99 (dd, 1H, J ¼ 8.8, 2.5 Hz), 7.38 (d, 1H, J ¼ 6.9 Hz), 7.10e7.28 (m, 8H), 7.04 (d, 1H, J ¼ 9.5 Hz), 6.88 (d, 1H, J ¼ 9.1 Hz), 3.32 (s, 3H). 13C NMR (125 MHz, CDCl3): d 157.1, 156.9, 141.9, 140.3, 139.8, 135.9, 135.1, 133.9, 131.3, 131.1, 128.8, 128.3, 126.3, 125.6, 124.9, 122.5, 119.4, 119.3, 115.6, 104.8, 104.6, 51.1. HRMS (ESIþ): m/z calcd for C21H15BrNO3 ([MþH]þ): 438.0343, found: 438.0337. 4.2.15. 2-Methoxy-2-(4-methylphenyl)-6-nitro-3-(4-nitrophenyl)2H-1-benzopyran (3ao) Yield 54%, yellow solid. IR (ATR): 3069, 2927, 2884, 1657, 1614, 1592, 1507, 1474, 1335, 1291, 1259, 1228, 1180, 1092, 1032, 1017, 971, 906, 851, 817, 800, 750, 612, 570 cm1. 1H NMR (500 MHz, CDCl3): d 8.23 (d, 1H, J ¼ 3.0 Hz), 8.15 (dd, 1H, J ¼ 2.6, 9.0 Hz), 8.03e8.10 (m, 2H), 7.52e7.60 (m, 2H), 7.37 (d, 2H, J ¼ 8.3 Hz), 7.29 (s, 1H), 7.01e7.10 (m, 3H), 3.44 (s, 3H), 2.27 (s, 3H). 13C NMR (126 MHz, CDCl3): d 157.3, 147.1, 142.8, 141.9, 139.0, 137.1, 132.5, 131.5, 129.6, 128.9, 128.5, 126.7, 126.2, 123.4, 123.3, 119.3, 118.8, 115.9, 104.6, 51.1, 21.0. HRMS (ESIþ): m/z calcd for C22H15N2O5 ([M-OMe]þ): 387.0975, found: 387.0947. 4.2.16. 2-Methoxy-3-methyl-6-nitro-2-phenyl-2H-1-benzopyran (3aq) Yield 80%, yellow solid. IR (ATR): 3074, 3005, 2942, 2838, 1666, 1577, 1513, 1476, 1450, 1335, 1271, 1234, 1195, 1124, 1092, 1075, 1025, 948, 910, 834, 758, 748, 696, 665, 627, 565 cm1. 1H NMR (500 MHz, CDCl3): d 8.04 (d, 1H, J ¼ 8.7 Hz), 8.02 (s, 1H), 7.50 (d, 2H, J ¼ 7.9 Hz), 7.32e7.41 (m, 3H), 6.97 (d, 1H, J ¼ 8.8 Hz), 6.63 (s, 1H), 3.35 (s, 3H), 1.68 (s, 3H). 13C NMR (126 MHz, CDCl3): d 157.2, 141.7, 140.2, 132.7, 128.7, 128.1, 126.1, 124.6, 122.5, 121.7, 119.6, 115.4, 105.1, 50.5, 18.6. HRMS (ESIþ): m/z calcd for C16H14NO3 ([MþH]þ): 298.1081, found: 298.1074. 4.2.17. 3-Ethyl-2-methoxy-6-nitro-2-phenyl-2H-1-benzopyran (3ar) Yield 99%, yellow oil. IR (ATR): 2969, 2938, 2834, 2360, 1736, 1614, 1579, 1518, 1482, 1450, 1336, 1268, 1091, 1076, 983, 903, 829, 760, 750, 698 cm1. 1H NMR (400 MHz, CDCl3): d 8.04e8.11 (m, 2H), 7.51 (d, 1H, J ¼ 6.8 Hz), 7.49e7.50 (m, 1H), 7.33e7.42 (m, 3H), 6.99 (d, 1H, J ¼ 9.2 Hz), 6.66 (s, 1H), 3.33 (s, 3H), 2.10 (ddd, 1H, J ¼ 1.4, 7.4, 17.3 Hz), 1.71e1.84 (m, 1H), 1.03 (t, 3H, J ¼ 7.3). 13C NMR (126 MHz, CDCl3): d 156.9, 141.8, 140.5, 138.4, 128.7, 128.1, 126.2, 124.5, 121.9, 120.2, 119.8, 115.4, 105.1, 50.6, 23.8, 11.4. HRMS (ESIþ): m/z calcd for C17H16NO3 ([M-OMe]þ): 280.0968, found: 280.0975. 4.2.18. 3-Buthyl-2-methoxy-6-nitro-2-phenyl-2H-1-benzopyran (3as) Yield 52%, yellow oil. IR (ATR): 2957, 2871, 2360, 1738, 1615, 1579, 1519, 1482, 1450, 1336, 1261, 1089, 1075, 1025, 952, 905, 827, 761, 749, 698 cm1. 1H NMR (500 MHz, CDCl3): d 8.06 (s, 1H), 8.06 (d, 2H, J ¼ 5.1 Hz), 7.47e7.55 (m, 2H), 7.32e7.42 (m, 3H), 6.95e7.01 (m, 1H), 6.66 (s, 1H), 3.29e3.36 (m, 3H), 1.98e2.06 (m, 1H), 1.76e1.86 (m, 1H), 1.36e1.46 (m, 1H), 1.18e1.34 (m, 3H), 0.82 (t, 3H, J ¼ 7.3 Hz). 13C NMR (126 MHz, CDCl3): d 156.9, 141.8, 140.4, 137.1, 128.7, 128.1, 126.2, 124.5, 121.9, 120.9, 119.8, 115.4, 105.1, 50.7, 30.5, 29.4, 22.3, 13.7. HRMS (ESIþ): m/z calcd for C19H20NO3 ([M-OMe]þ): 308.1281, found: 308.1299. 4.2.19. 2-Methoxy-6-nitro-2-phenyl-3-trimethylsilyl-2H-1benzopyran (3at) Yield 26%, yellow solid. IR (ATR): 3084, 2954, 2359, 1739, 1612,

6462

K. Tanaka et al. / Tetrahedron 73 (2017) 6456e6464

1516, 1475, 1449, 1337, 1323, 1268, 1243, 1117, 1095, 1066, 996, 836, 826, 757, 748, 694, 630, 597 cm1. 1H NMR (300 MHz, CDCl3): d 8.18e8.25 (m, 2H), 7.54e7.62 (m, 2H), 7.43e7.51 (m, 3H), 7.22 (s, 1H), 7.04 (d, 1H, J ¼ 8.4 Hz), 3.42 (s, 3H), 0.02e0.02 (m, 9H). 13C NMR (126 MHz, CDCl3): d 158.1, 142.1, 141.4, 137.9, 133.4, 128.9, 128.1, 126.3, 125.8, 122.8, 118.3, 115.8, 105.6, 50.7. HRMS (ESIþ): m/z calcd for C18H20NO3 ([MþH]þ): 356.1324, found:356.1317. 4.2.20. 2-Methoxy-6-nitro-2,3-bis(2-thienyl)-2H-1-benzopyran (3ay) Yield 13%, yellow solid. IR (ATR): 3102, 2963, 2932, 2855, 1732, 1610, 1576, 1515, 1479, 1434, 1336, 1268, 1234, 1183, 1091, 1047, 961, 908, 822, 747, 698, 576 cm1. 1H NMR (500 MHz, CDCl3): d 8.13 (s, 1H), 8.06 (d, 1H, J ¼ 8.6 Hz), 7.31e7.35 (m, 1H), 7.22e7.25 (m, 3H) 6.86e7.00 (m, 4H), 3.47 (s, 3H). 13C NMR (126 MHz, CDCl3): d 156.6, 144.2, 142.1, 138.1, 128.6, 127.8, 127.5, 126.7, 127.0, 126.4, 126.4, 125.3, 122.7, 122.6, 119.3, 116.0, 103.9, 51.8. HRMS (ESIþ): m/z calcd for C17H12NO3S2 ([MþH]þ): 372.0366, found:372.0362. 4.2.21. 6-Carbonitrile-2-methoxy-2,3-diphenyl-2H-1-benzopyran (3ba) Yield 23%, white solid. IR (ATR): 3060, 2937, 2834, 2224, 1599, 1487, 1447, 1258, 1132, 1102, 1076, 977, 895, 824, 757, 736, 695, 591, 574, 543, 510, 502 cm1. 1H NMR (300 MHz, CDCl3): d 7.52 (d, 1H, J ¼ 1.9 Hz), 7.45e7.50 (m, 3H), 7.29e7.33 (m, 2H), 7.18e7.25 (m, 6H), 7.05 (s, 1H), 6.98 (d, 1H, J ¼ 8.3 Hz), 3.42 (s, 3H). 13C NMR (126 MHz, CDCl3): d 155.6, 140.7, 136.4, 134.5, 133.5, 131.0, 128.6, 128.1, 128.1, 128.0, 127.7, 126.4, 124.4, 120.4, 118.9, 116.3, 104.7, 104.7, 51.1. HRMS (ESIþ): m/z calcd for C22H14NO ([M-OMe]þ): 308.1070, found: 308.1058. 4.2.22. 2-Methoxy-2,3-diphenyl-6-(4-tosyloxy)-2H-1-benzopyran (3ca) Yield 32%, white solid. IR (ATR): 2937, 1598, 1484, 1447, 1370, 1247, 1218, 1176, 1133, 1092, 985, 955, 899, 844, 814, 766, 726, 696, 658, 547 cm1. 1H NMR (300 MHz, CDCl3): d 7.74 (d, 2H, J ¼ 8.1 Hz), 7.46 (dd, 2H, J ¼ 7.8, 1.8 Hz), 7.15e7.33 (m, 10H), 6.97 (d, 1H, J ¼ 2.7 Hz), 6.93 (s, 1 Hz), 6.80 (d, 1H, J ¼ 9.0 Hz), 6.70 (dd, 1H, J ¼ 8.4, 2.4 Hz), 3.39 (s, 3H), 2.45 (s, 3H). 13C NMR (126 MHz, CDCl3): d 150.8, 145.3, 143.3, 141.0, 136.9, 133.9, 132.4, 129.7, 128.5, 128.3, 128.0, 127.8, 127.8, 127.7, 126.6, 125.2, 123.2, 120.6, 120.3, 115.9, 103.9, 51.0, 21.7. HRMS (ESIþ): m/z calcd for C28H21O4S ([M-OMe]þ): 453.1155, found: 453.1162. 4.2.23. 2-Methoxy-2,3-diphenyl-7-(4-tosyloxy)-2H-1-benzopyran (3da) Yield 20%, white solid. IR (ATR): 3068, 2983, 2942, 2840, 1597, 1490, 1445, 1372, 1253, 1192, 1178, 1130, 1111, 1091, 1057, 1032, 985, 957, 867, 839, 814, 765, 754, 732, 695, 676, 657, 628, 607, 584, 557 cm1. 1H NMR (300 MHz, CDCl3): d 7.71 (d, 2H, J ¼ 7.4 Hz), 7.44 (d, 2H, J ¼ 6.8 Hz), 7.13e7.29 (m, 11H), 6.99 (s, 1H), 6.70 (d, 1H, J ¼ 8.1 Hz), 6.51 (d, 1H, J ¼ 2.2 Hz), 3.35 (s, 3H), 2.41 (s, 3H). 13C NMR (126 MHz, CDCl3): d 152.7, 150.0, 145.4, 137.1, 133.2, 132.3, 129.7, 129.0, 128.4, 128.3, 128.2, 128.0, 127.8, 127.8, 127.6, 127.6, 126.6, 125.1, 118.8, 155.5, 109.6, 103.9, 50.9, 21.7. HRMS (ESIþ): m/z calcd for C29H24O5S ([MþNa]þ): 507.1242, found: 507.1234. 4.2.24. 2-Methoxy-6-methoxycarbonyl-2,3-diphenyl-2H-1benzopyran (3ea) Yield 14%, yellow solid. IR (ATR): 3394, 2949, 1715, 1609, 1490, 1436, 1239, 1201, 1101, 1075, 976, 891, 836, 763, 695, 566 cm1. 1H NMR (500 MHz, CDCl3): d 7.95e8.00 (m, 1H) 7.91 (d, 1H, J ¼ 8.4 Hz), 7.43e7.58 (m, 2H), 7.30e7.36 (m, 2H), 7.18e7.29 (m, 7H), 7.13 (s, 1H), 6.97 (d, 1H, J ¼ 8.5 Hz), 3.91 (s, 3H), 3.43 (s, 3H). 13C NMR (126 MHz, CDCl3): d 166.6156.2, 141.2, 137.0, 133.1, 131.5, 129.0, 127.9, 128.1,

127.8, 126.5, 125.8, 123.3, 119.3, 115.2, 104.5, 52.0, 51.0. HRMS (ESIþ): m/z calcd for C23H16O3 ([M-OMe]þ): 340.1099, found: 340.1105. 4.2.25. 3-Ethyl-2-methoxy-6-methoxycarbonyl-2-phenyl-2H-1benzopyran (3er) Yield 94%, IR (ATR): 2967, 2834, 1715, 1610, 1583, 1493, 1441, 1286, 1269, 1247, 1212, 1124, 1092, 984, 907, 835, 759, 732, 698, 512 cm1. 1H NMR (300 MHz, CDCl3): d 7.86e7.88 (m, 2H), 7.53e7.52 (m, 2H), 7.31e7.39 (m, 3H), 6.95 (d, 1H, J ¼ 8.3 Hz), 6.63 (s, 1H), 3.89 (s, 3H), 3.31 (s, 3H), 1.99e2.13 (m, 1H), 1.69e1.82 (m, 1H), 1.00 (t, 3H, J ¼ 7.5 Hz). 13C NMR (126 MHz, CDCl3): d 166.3, 155.6, 140.9, 136.3, 130.4, 128.2, 127.9, 127.8, 126.2, 122.9, 120.8, 119.3, 114.7, 104.3, 51.6, 50.3, 23.6, 11.4. HRMS (ESIþ): m/z calcd for C19H17O3 ([M-OMe]þ): 293.1172, found: 293.1169. 4.2.26. 6-Bromo-3-ethyl-2-methoxy-2-phenyl-2H-1-benzopyran (3ir) Yield 34%, yellow oil. IR (ATR): 2967, 2935, 2831, 1477, 1449, 1413, 1305, 1242, 1188, 1124, 1068, 990, 965, 930, 897, 812, 758, 698, 631, 552 cm1. 1H NMR (500 MHz, CDCl3): d 7.41 (d, 2H, J ¼ 7.0 Hz), 7.22e7.27 (m, 3H), 7.13e7.16 (m, 2H), 6.73 (d, 1H, J ¼ 8.0 Hz), 6.39 (s, 1H), 3.19 (s, 3H), 1.91e1.98 (m, 1H), 1.59e1.1.66 (m, 1H), 0.88 (t, 3H, J ¼ 7.0 Hz). 13C NMR (126 MHz, CDCl3): d 150.8, 140.9, 137.4, 131.1, 128.3, 127.9, 126.5, 121.8, 120.6, 116.8, 113.7, 50.5, 23.9, 11.6. HRMS (ESIþ): m/z calcd for C17H14OBr ([M-OMe]þ): 313.0223, found: 313.0220. 4.2.27. 6-Chloro-3-ethyl-2-methoxy-2-phenyl-2H-1-benzopyran (3jr) Yield 35%, brown oil. IR (ATR): 2968, 2936, 2831, 1479, 1449, 1416, 1305, 1244, 1188, 1123, 1078, 990, 962, 907, 813, 759, 698, 637, 559 cm1. 1H NMR (500 MHz, CDCl3): d 7.42 (d, 2H, J ¼ 7.0 Hz), 7.20e7.28 (m, 3H), 6.99e7.01 (m, 2H), 6.78 (d, 1H, J ¼ 8.5 Hz), 6.40 (s, 1H), 3.20 (s, 3H), 1.92e1.99 (m, 1H), 1.59e1.67, (m, 1H), 0.88 (t, 3H, J ¼ 7.0 Hz). 13C NMR (126 MHz, CDCl3): d 150.8, 140.9, 137.4, 131.1, 128.3, 127.9, 126.5, 121.8, 120.6, 116.8, 113.7, 50.5, 23.9, 11.6. HRMS (ESIþ): m/z calcd for C17H14OCl ([M-OMe]þ): 269.0728, found: 269.0735. 4.2.28. 7-Bromo-3-ethyl-2-methoxy-2-phenyl-2H-1-benzopyran (3gr) Yield 86%, yellow oil. IR (ATR): 2966, 2935, 1595, 1568, 1480, 1448, 1409, 1299, 1227, 1189, 1124, 1063, 985, 920, 856, 802, 759, 698, 582 cm1. 1H NMR (300 MHz, CDCl3): d 7.36e7.38 (m, 2H), 7.15e7.21 (m, 3H), 6.99 (s, 1H), 6.80 (d, 1H,J ¼ 8.0 Hz), 6.37 (s, 1H), 3.15 (s, 3H), 1.87e1.92 (m, 1H), 1.58e1.61 (m, 1H), 0.83 (t, 3H, J ¼ 7.5 Hz). 13C NMR (126 MHz, CDCl3): d 152.4, 140.9, 136.3, 128.2, 127.9, 127.1, 126.4, 124.1, 121.1, 120.4, 118.8, 118.2, 104.0, 50.4, 23.9, 11.5. HRMS (ESIþ): m/z calcd for C17H14OBr ([M-OMe]þ): 313.0223, found: 313.0220. 4.3. Procedure for the synthesis of 6-nitro-2,3-diphenyl-4H-1benzopyran25 (6aa) BF3$OEt2 (6.3 mL, 0.05 mmol) was added dropwise to a stirred solution of 2-methoxy-6-nitro-2,3-diphenyl-2H-1-benzopyran (3aa, 74 mg, 0.2 mmol) in dichloromethane at 78  C under nitrogen atmosphere. The contents were stirred for 30 min at the same temperature, and triethylsilane (48 mL, 0.3 mmol) was added dropwise over a period of 15 min. After 18 h, the reaction was quenched with water and diluted with CHCl3. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (hexane/ethylacetate ¼ 20: 1) to afford 6-nitro-

K. Tanaka et al. / Tetrahedron 73 (2017) 6456e6464

2,3-diphenyl-4H-1-benzopyran (6aa) (0.0519 g, 77%) as yellow solid. IR (ATR): 3084, 3062, 3029, 2960, 2923, 1670, 1586, 1516, 1516, 1496, 1481, 1446, 1426, 1343, 1252, 1108, 1089, 1068, 1003, 991, 926, 888, 830, 789, 764, 745, 696, 635, 572, 552 cm1. 1H NMR (500 MHz, CDCl3): d 8.00e8.12 (m, 2H), 7.16e7.29 (m, 9H), 7.12e7.16 (m, 2H), 7.10 (d, 2H, J ¼ 8.8 Hz), 3.91 (s, 2H). 13C NMR (126 MHz, CDCl3): d 156.5, 146.2, 143.3, 138.9, 133.9, 129.2, 128.7, 128.5, 127.9, 127.2, 124.7, 123.7, 121.3, 116.8, 110.6, 30.8. HRMS (ESIþ): m/z calcd for C21H16NO3 ([MþH]þ): 330.1125, found: 330.1114. 4.4. Procedure for the synthesis of 6-nitro-4-(2-oxo-2-phenylethyl)2,3-diphenyl-4H-1-benzopyran (7aa) To 2-methoxy-6-nitro-2,3-diphenyl-2H-1-benzopyran (3aa, 0.359 g, 1.0 mmol) in toluene under nitrogen, BF3OEt2 (18 mL, 20 mol%) was added and heated to 60  C. Then trimethyl([1phenylvinyl]oxy)silane (0.613 mL, 3.0 mmol) was added. After being stirred at 60  C for 4 h, the reaction mixture was quenched with H2O. The organic layer was separated and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (hexane/ethylacetate ¼ 50: 1) to afford 4-substituted-4H-1-benzopyran product (7aa) (0.187 g, 42%) as a yellow solid. IR (ATR): 3089, 3056, 2887, 1665, 1583, 1524, 1482, 1445, 1338, 1247, 1120, 1091, 1074, 1039, 1009, 983, 939, 928, 914, 834, 788, 764, 747, 703, 691, 634, 586, 570, 553 cm1. 1H NMR (500 MHz, CDCl3): d 8.27 (d, J ¼ 2.6 Hz, 1H), 8.06 (dd, 1H, J ¼ 2.6, 9.0 Hz), 7.78 (s, 1H), 7.76 (s, 1H), 7.42e7.55 (m, 1H), 7.27e7.39 (m, 4H), 7.15e7.27 (m, 8H), 7.12 (d,1H, J ¼ 8.7 Hz), 4.69 (dd, 1H, J ¼ 3.8, 7.9 Hz), 3.28 (m, 1H). 13C NMR (126 MHz, CDCl3): d 197.4, 156.9, 147.4, 143.4, 137.5, 136.6, 133.9, 133.2, 129.6, 128.9, 128.7, 128.5, 127.9, 127.8, 127.4, 125.6, 125.0, 123.7, 116.8, 115.3, 45.2, 36.8. HRMS (ESIþ): m/z calcd for C29H22NO4 ([MþH]þ): 448.1549, found: 448.1532. 4.5. Procedure for the synthesis of 4-(2,5-dimethoxyphenyl)-6nitro-2,3-diphenyl-4H-1-benzopyran (8aa) To 2-methoxy-6-nitro-2,3-diphenyl-2H-1-benzopyran (3aa, 0.179 g, 0.5 mmol) and 1,4-dimethoxybenzene (2.5 g, 18 mmol) under nitrogen were heated to 60  C, then trifluoromethanesulfonic acid (8.8 mL, 0.05 mmol, 10 mol%) was added. After being stirred at 60  C for 7 h, the reaction mixture was quenched with H2O. The organic layer was separated and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (hexane/ ethylacetate ¼ 100: 1) to afford 4-substituted-4H-1-benzopyran product (8aa) (0.120 g, 53%) as a yellow solid. IR (ATR): 1585, 1523, 1497, 1340, 1251, 1236, 695 cm1. 1H NMR (500 MHz, CDCl3): d 8.25 (d, 1H, J ¼ 2.5 Hz), 8.06 (dd, 1H, J ¼ 2.7, 9.0 Hz), 7.37 (d, 2H, J ¼ 6.9 Hz), 7.21e7.29 (m, 5H),7.05e7.12 (m, 3H), 6.82 (d, 2H, J ¼ 9.1 Hz), 6.71 (dd, 1H, J ¼ 3.2, 8.8 Hz), 5.49 (s, 1H), 3.80 (s, 3H), 3.68 (s, 3H). 13C NMR (126 MHz, CDCl3): d 155.7, 154.0, 150.4, 147.6, 143.6, 138.4, 134.1, 133.5, 129.4, 129.3, 128.6, 128.1, 127.9, 127.0, 126.3, 125.1, 123.3, 116.8, 115.4, 114.3, 112.4, 56.1, 55.6. HRMS (ESIþ): m/z calcd for C29H24NO5 ([MþNa]þ): 488.1468, found: 488.1450. 4.6. Procedure for the synthesis of 2-isopropoxy-6-nitro-2,3diphenyl-2H-1-benzopyran (9aa) To 2-methoxy-6-nitro-2,3-diphenyl-2H-1-benzopyran (3aa, 0.359 g, 1.0 mmol) in 2-propanol (5.0 mL) under nitrogen, TfOH

6463

(18mL, 0.2 mmol, 20 mol%) was added and heated to 60  C. After being stirred at 60  C for 5 h, the reaction mixture was quenched with H2O. The organic layer was separated and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (hexane/ethylacetate ¼ 100: 1 to 20:1) to afford 2-isopropoxy-6-nitro-2,3-diphenyl-2H-1-benzopyran (9aa) (0.265 g, 69%) as a yellow solid. IR (ATR): 3066, 2971, 1634, 1612, 1578, 1516, 1480, 1448, 1334, 1257, 1233, 1178, 1091, 1072, 1042, 1019, 971, 926, 910, 877, 833, 808, 757, 750, 695, 650, 589, 571 cm1. 1H NMR (300 MHz, CDCl3): d 8.16 (s, 1H), 8.07 (dd, 1H, J ¼ 2.6, 8.7 Hz), 7.47e7.63 (m, 2H), 7.32e7.40 (m, 2H), 7.17e7.32 (m, 6H), 7.16 (s, 1H), 6.91 (d, 1H, J ¼ 9.0 Hz), 4.01e4.16 (m, 1H), 1.26 (d, 3H, J ¼ 6.0 Hz), 0.99 (d, 3H, J ¼ 6.0 Hz). 13C NMR (126 MHz, CDCl3): d 156.9, 141.7, 141.5, 136.4, 135.7, 128.6, 128.1, 128.0, 126.4, 125.3, 123.8, 122.8, 119.8, 115.9, 105.4, 68.2, 24.5, 23.3. HRMS (ESIþ): m/z calcd for C24H21NO4 ([MþH]þ): 388.1549, found: 388.1551. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.tet.2017.09.045. References 1. (a) Saeed A, Sharma AP, Durani N, Jain R, Durani S, Kapil RS. J Med Chem. 1990;33:3210; (b) Sharma AP, Saeed A, Durani S, Kapil RS. J Med Chem. 1990;33:3216; (c) Sharma AP, Saeed A, Durani S, Kapil RS. J Med Chem. 1990;33:3222; (d) Gauthier S, Cloutier J, Dory YL, et al. J Enzyme Inhib Med Chem. 2005;20:165; (e) Gauthier S, Caron B, Cloutier J, et al. J Med Chem. 1997;40:2117; (f) Hajela K, Kapil RS. Eur J Med Chem. 1997;32:135; (g) Ishizuka N, Matsumura KI, Sakai K, Fujimoto M, Mihara SI, Yamamori T. J Med Chem. 2002;45:2041; (h) Wang JL, Aston K, Limburg D, et al. Bioorg Med Chem Lett. 2010;20:7164. 2. Arai K, Kobayashi Y, Abe J. Chem Commun. 2015;51:3057. 3. Lanari D, Rosati O, Curini M. Tetrahedron Lett. 2014;55:1752. 4. Yoshioka E, Kohtani S, Miyabe H. Angew Chem Int Ed. 2011;50:6638. 5. Jiang M, Shi M. Org Lett. 2010;12:2606. 6. Wang Q, Finn MG. Org Lett. 2000;2:4063. 7. Dai LZ, Shi YL, Zhao GL, Shi M. Chem Eur J. 2007;13:3701. 8. Likai X, Hongyun C, Yong RL. Tetrahedron. 2015;71:6894. 9. Climent MJ, Iborra S, Sabater MJ, Vidal JD. Appl Catal A: General. 2014;481:27. 10. Pascal DG, Peter JM, Jennifer KE, Graham JH, Sylvain A. ChemCatChem. 2017;9: 70. 11. (a) Chandrasekhara RL, Meshram HM, Satish KN, Nageswara RN, Jagadeesh BN. Tetrahedron Lett. 2014;55:1127; (b) Rao LC, Kumar NS, Meshram HM. Helv Chim Acta. 2015;98:978. 12. Xufeng Y, Dandan S, Jing H, et al. J Fluorine Chem. 2016;188:58. 13. (a) Tanaka K, Hoshino Y, Honda K. Tetrahedron Lett. 2016;57:2448; (b) Tanaka K, Hoshino Y, Honda K. Heterocycles. 2017;95:474. 14. (a) Nakayama J, Yamaoka S, Nakanishi T, Hoshino M. J Am Chem Soc. 1988;110: 6598; (b) Soenen DR, Zimpleman JM, Boger DL. J Org Chem. 2003;68:3593; (c) Kranjc K, Stefane B, Polanc S, Kocevar M. J Org Chem. 2004;69:3190. 15. (a) Horie H, Kurahashi T, Matsubara S. Chem Commun. 2012;48:3866; (b) Asao N, Nogami T, Lee S, Yamamoto Y. J Am Chem Soc. 2003;125:10921; (c) Nakao Y, Morita E, Idei H, Hiyama T. J Am Chem Soc. 2011;133:3264; (d) Zhi-Guang Y, Qiang W, Ang Z, et al. Chem Commun. 2016;52:5128; (e) Matsumoto A, Ilies L, Nakamura E. J Am Chem Soc. 2011;133:6557. 16. Saunthwal RK, Patel M, Verma AK. Org Lett. 2016;18:2200. 17. Rubin M, Trofimov A, Gevorgyan V. J Am Chem Soc. 2005;127:10243. 18. For identification of the regio-isomers and 2D NMR spectral data of product 3aa, see supplementary data. 19. (a) Coefficient values calculated by using Winmostar version 6.015 (MOPAC PM3) are shown in supplementary data; (b) Senda N. Idemitsu Tech Rep. 2006;49:106. 20. (a) Kumar A, Thadkappaly S, Menon RS. J Org Chem. 2015;80:11048; (b) Fichtner C, Remennikov G, Mayr H. Eur J Org Chem. 2001:4451; (c) Chen W, Xie Z, Zheng H, Lou H, Liu L. Org Lett. 2014;16:5988; (d) Saidachary G, Veera PK, Sairam M, Raju BC. Tetrahedron Lett. 2014;55:4753. 21. (a) Aridoss G, Zhou B, Hermanson DL, Bleeker NP, Xing C. J Med Chem. 2012;55: 5566; (b) Kiyani H, Ghorbani F. J Saudi Chem Soc. 2014;18:689. 22. (a) Kumar S, Deshpande S, Chandra V, et al. Bioorg Med Chem. 2009;17:6832; (b) Parthiban A, Kumaravel M, Muthukumaran J, Rukkumani R, Krishna R,

̌

̌

6464

K. Tanaka et al. / Tetrahedron 73 (2017) 6456e6464

Rao HSP. Med Chem Res. 2016;25:1308; (c) Aryapour H, Mahdavi M, Mohebbi SR, Reza ZM, Foroumadi A. Arch Pharm Res (Seoul). 2012;35:1573. 23. (a) Woollard JMR, Perry NB, Weavers RT, Klink JW. Phytochemistry. 2008;69: 1313;

(b) Tan H, Liu H, Chen X, Yuan Y, Chen K, Qiu S. Org Lett. 2015;17:4050. 24. (a) Okuyama T. Acc Chem Res. 2002;35:12; (b) Miranda PO, Ramirez MA, Martin VS, Padron JI. Chem Eur J. 2008;14:6260. 25. Gannerla S, Kasagani VP, Mudulkar S, Bhimapaka CR. Tetrahedron Lett. 2014;55: 4753.