Synthesis of Diiodo-Functionalized Benzo[<i>b</i>]furans via Electrophilic Iodocyclization

Frota, Carlise; Rossini, Allan F. C.; Casagrande, Gleison A.; Pizzuti, Lucas; Raminelli, Cristiano

doi:10.21577/0103-5053.20170035

Abstract

An electrophilic iodocyclization reaction involving alkynylated 2-iodoanisoles and molecular iodine in the presence of sodium bicarbonate was developed and diiodo-functionalized benzo[b]furans were obtained in yields from 45 to 99%.

Keywords:
electrophilic iodocyclization; molecular iodine; diiodo-functionalized benzo[b]furans; functionalized heteroaromatics; diiodinated compounds

Introduction

Heterocyclic aromatic compounds constitute a class of substances with a considerable diversity of pharmacological properties.¹1 Li, J. In Heterocyclic Chemistry in Drug Discovery; Li, J., ed.; John Wiley & Sons, Inc.: Hoboken, USA, 2013 p. 1. Accordingly, natural and synthetic heteroaromatic compounds have been employed as drugs.²2 Neumeyer, L. In Foye’s Principles of Medicinal Chemistry, 7th ed.; Lemke, L.; Williams, A.; Roche, F.; Zito, W., eds.; Lippincott Williams & Wilkins: Philadelphia, USA, 2013 p. 1. Focusing on benzo[b]furans (1), we came across an important subclass of heterocyclic aromatic compounds, which comprises various biological activities, such as anticancer,³3 Swamy, G.; Prasad, R.; Ashvini, M.; Giles, D.; Shashidhar, V.; Agasimundin, S.; Med. Chem. Res. 2015, 24, 3437.

4 Abdelhafez, M.; Amin, M.; Ali, I.; Abdallad, M.; Ahmed, Y.; RSC Adv. 2014, 4, 11569.

5 Bazin, M.-A.; Bodero, L.; Tomasoni, C.; Rousseau, B.; Roussakis, C.; Marchand, P.; Eur. J. Med. Chem. 2013, 69, 823.^-⁶6 Hranjec, M.; Sović, I.; Ratkaj, I.; Pavlović, G.; Ilić, N.; Valjalo, L.; Pavelić, K.; Pavelić, K.; Karminski-Zamola, G.; Eur. J. Med. Chem. 2013, 59, 111. antiviral,⁷7 He, S.; Jain, P.; Lin, B.; Ferrer, M.; Hu, Z.; Southall, N.; Hu, X.; Zheng, W.; Neuenswander, B.; Cho, C.-H.; Chen, Y.; Worlikar, A.; Aubé, J.; Larock, C.; Schoenen, J.; Marugan, J.; Liang, J.; Frankowski, J.; ACS Comb. Sci. 2015, 17, 641.

8 Takaya, D.; Yamashita, A.; Kamijo, K.; Gomi, J.; Ito, M.; Maekawa, S.; Enomoto, N.; Sakamoto, N.; Watanabe, Y.; Arai, R.; Umeyama, H.; Honma, T.; Matsumoto, T.; Yokoyama, S.; Bioorg. Med. Chem2011, 19, 6892.^-⁹9 Galal, A.; El-All, A.; Hegab, H.; Magd-El-Din, A.; Youssef, S.; El-Diwani, I.; Eur. J. Med. Chem. 2010, 45, 3035. anti-inflammatory,¹⁰10 Hassan, S.; Abou-Seri, M.; Kamel, G.; Ali, M.; Eur. J. Med. Chem. 2014, 76, 482.

11 Yadav, P.; Singh, P.; Tewari, K.; Bioorg. Med. Chem. Lett. 2014, 24, 2251.^-¹²12 Wu, S.-F.; Chang, F.-R.; Wang, S.-Y.; Hwang, T.-L.; Lee, C.-L.; Chen, S.-L.; Wu, C.-C.; Wu, Y.-C.; J. Nat. Prod. 2011, 74, 989. and immunosuppressive.¹³13 Dawood, M.; Expert Opin. Ther. Pat. 2013, 23, 1133.^,¹⁴14 Lee, S.-M.; Lee, W.-G.; Kim, Y.-C.; Ko, H.; Bioorg. Med. Chem. Lett. 2011, 21, 5726. In this sense, we present the structures of the benzo[b]furans obovaten (2), a natural product with pronounced antitumor activity,¹⁵15 Kao, C.-L.; Chern, J.-W.; J. Org. Chem. 2002, 67, 6772.^,¹⁶16 Tsai, I.-L.; Hsieh, C.-F.; Duh, C.-Y.; Phytochemistry 1998, 48, 1371. and amiodarone (3), a commercial antiarrhythmic drug¹⁷17 Vardanyan, S.; Hruby, J.; Synthesis of Essential Drugs; Elsevier: Amsterdam, NL, 2006 p. 252. (Figure 1).

Figure 1
Structures of benzo[b]furan compounds.

A number of approaches have been developed towards the efficient construction of benzo[b]furan scaffolds.¹⁸18 Yamaguchi, M.; Akiyama, T.; Sasou, H.; Katsumata, H.; Manabe, K.; J. Org. Chem. 2016, 81, 5450.

19 Zhou, R.; Wang, W.; Jiang, Z.-J.; Wang, K.; Zheng, X.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X.; Chem. Commun. 2014, 50, 6023.

20 Moure, J.; SanMartin, R.; Domínguez, E.; Adv. Synth. Catal. 2014, 356, 2070.

21 Schumacher, F.; Honraedt, A.; Bolm, C.; Eur. J. Org. Chem. 2012, 3737.

22 Bernini, R.; Cacchi, S.; Salve, D.; Fabrizi, G.; Synthesis 2007, 873.

23 Mehta, S.; Larock, C.; J. Org. Chem. 2010, 75, 1652.

24 Mehta, S.; Waldo, P.; Larock, C.; J. Org. Chem. 2009, 74, 1141.

25 Manarin, F.; Roehrs, A.; Gay, M.; Brandão, R.; Menezes, H.; Nogueira, W.; Zeni, G.; J. Org. Chem. 2009, 74, 2153.^-²⁶26 Yue, D.; Yao, T.; Larock, C.; J. Org. Chem. 2005, 70, 10292. Among them we highlight the metal-catalyzed cross-coupling/cyclization reactions¹⁸18 Yamaguchi, M.; Akiyama, T.; Sasou, H.; Katsumata, H.; Manabe, K.; J. Org. Chem. 2016, 81, 5450.

19 Zhou, R.; Wang, W.; Jiang, Z.-J.; Wang, K.; Zheng, X.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X.; Chem. Commun. 2014, 50, 6023.

20 Moure, J.; SanMartin, R.; Domínguez, E.; Adv. Synth. Catal. 2014, 356, 2070.

21 Schumacher, F.; Honraedt, A.; Bolm, C.; Eur. J. Org. Chem. 2012, 3737.^-²²22 Bernini, R.; Cacchi, S.; Salve, D.; Fabrizi, G.; Synthesis 2007, 873. and the electrophilic cyclization reactions employing alkynylanisoles.²³23 Mehta, S.; Larock, C.; J. Org. Chem. 2010, 75, 1652.

24 Mehta, S.; Waldo, P.; Larock, C.; J. Org. Chem. 2009, 74, 1141.

25 Manarin, F.; Roehrs, A.; Gay, M.; Brandão, R.; Menezes, H.; Nogueira, W.; Zeni, G.; J. Org. Chem. 2009, 74, 2153.^-²⁶26 Yue, D.; Yao, T.; Larock, C.; J. Org. Chem. 2005, 70, 10292. The latter approach can be illustrated by the iodocyclization reaction developed by Larock and co-workers.²⁶26 Yue, D.; Yao, T.; Larock, C.; J. Org. Chem. 2005, 70, 10292. Nevertheless, in the course of our research activities aiming to the synthesis of diiodo-functionalized compounds,²⁷27 Ferreira, M.; Casagrande, A.; Pizzuti, L.; Raminelli, C.; Synth. Commun. 2014, 44, 2094.

28 Gallo, C.; Ferreira, M.; Casagrande, A.; Pizzuti, L.; Oliveira-Silva, D.; Raminelli, C.; Tetrahedron Lett. 2012, 53, 5372.^-²⁹29 Gallo, C.; Gebara, S.; Muzzi, M.; Raminelli, C.; J. Braz. Chem. Soc. 2010, 21, 770. for application in selective cross-coupling reactions,³⁰30 Moreira, V.; Muraca, A.; Raminelli, C.; Synthesis 2016, 48, A. DOI: 10.1055/s-0036-1588332.^,³¹31 Rossini, C.; Frota, C.; Casagrande, A.; Pizzuti, L.; Raminelli, C.; J. Braz. Chem. Soc. 2014, 25, 2125. we observed that diiodo-functionalized benzo[b]furans could not be achieved through the reaction between alkynylated 2-iodoanysoles and molecular iodine, using the Larock's conditions for the preparation of iodinated benzo[b]furans.²⁶26 Yue, D.; Yao, T.; Larock, C.; J. Org. Chem. 2005, 70, 10292. In this context, we focused on development of a novel methodology to obtain diiodo-functionalized benzo[b]furans via electrophilic iodocyclization reaction, employing alkynylated 2-iodoanysoles and molecular iodine.

Results and Discussion

Initially, the reaction between the alkynylated 2-iodoanysole 4a and 2 equiv. of iodine in dichloromethane at room temperature for 3 h provided the diiodo-functionalized benzo[b]furan 5a in a yield lower than 5% (Table 1, entry 1). In an attempt to improve the yield, we performed the reaction between compound 4a and 2 equiv. of iodine in dichloromethane at room temperature for 12 h and obtained the desired product 5a in 34% yield (entry 2). When the same transformation was carried out at 40 °C, the diiodo-functionalized benzo[b]furan 5a was isolated in 44% yield (entry 3).

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Table 1
Preparation of diiodo-functionalized benzo[b]furan (5a)^a a Reaction conditions: 0.25 mmol of compound 4a, the indicated amount of I2, the indicated amount of base, and 5 mL of solvent were maintained under stirring at the temperature shown for the indicated time.

Allowing the reaction between the alkynylated 2-iodoanysole 4a, 2 equiv. of iodine, and 2 equiv. of NaHCO₃ in dichloromethane at 40 °C for 12 h, we obtained the diiodo-functionalized benzo[b]furan 5a in 65% yield (Table 1, entry 4). By employing other bases, namely 2 equiv. of K₂CO₃ and 2 equiv. of n-Bu₄NI, the heteroaromatic compound 5a was obtained in yields of 51 and 63%, respectively (entries 5 and 6). In order to increase the reaction temperature, we decided to evaluate another solvent. Thus, we carried out the reaction between the alkynylated 2-iodoanysole 4a, 2 equiv. of iodine, and 2 equiv. of NaHCO₃ in 1,2-dichloroethane at 70 °C for 12 h and obtained the diiodo-functionalized benzo[b]furan 5a in 82% yield (entry 7). By using 3 equiv. of NaHCO₃, compound 5a was isolated in 85% yield (entry 8). When the alkynylated 2-iodoanysole 4a was allowed to react with 2 equiv. of iodine and 3 equiv. of NaHCO₃ in 1,2-dichloroethane at 70 °C for 24 h, the diiodo-functionalized benzo[b]furan 5a was obtained in 89% yield (entry 9). By using 3 equiv. of iodine for 12 h, compound 5a was isolated in 87% (entry 10). Ultimately, the reaction between the alkynylated 2-iodoanysole 4a, 3 equiv. of iodine, and 3 equiv. of NaHCO₃ in 1,2-dichloroethane at 70 °C for 24 h provided the heteroaromatic compound 5a in 97% isolated yield (entry 11).

Employing the optimal conditions (Table 1, entry 11), we examined the scope of the transformation using alkynylated 2-iodoanysoles 4 with electron-donating and -withdrawing groups attached to the aromatic ring as well as alkyl and aryl groups bonded to the triple bond (Table 2).

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Table 2
Diiodo-functionalized benzo[b]furans (5a-i) prepared by the electrophilic iodocyclization reaction^a a Reaction conditions: 0.25 mmol of compound 4a-i, 0.75 mmol of I2, 0.75 mmol of NaHCO3, and 5 mL of ClCH2CH2Cl were maintained under stirring at 70 ºC for 24 h;

Allowing compounds 4a and 4b to react with 3 equiv. of iodine and 3 equiv. of NaHCO₃ in 1,2-dichloroethane at 70 °C for 24 h, we obtained the desired products 5a and 5b in 97 and 71% yields, respectively (Table 2, entries 1 and 2). The reactions between chloro-containing compounds 4c and 4d were more sluggish than the transformations presented in entries 1 and 2 and the chloro-containing heteroaromatic compounds 5c and 5d were isolated in 57 and 46% yields, respectively (entries 3 and 4). When compounds 4c and 4d were allowed to react for 48 h, the desired products 5c and 5d were obtained in 92 and 52% yields, respectively (Table 2, entries 3 and 4). Reactions with methyl-containing compounds 4e and 4f in the presence of 3 equiv. of iodine and 3 equiv. of NaHCO₃ in 1,2-dichloroethane at 70 °C for 24 h gave the methyl-containing heteroaromatic compounds 5e and 5f in isolated yields of 99 and 75%, respectively (entries 5 and 6). When the alkynylated 2-iodoanysole 4g bearing an electron-rich aromatic ring bonded to the triple bond was subjected to the reaction, the heteroaromatic compound 5g was obtained in 99% yield (entry 7). We did not try to perform the iodocyclization of an alkynylated 2-iodoanysole bearing an electron-poor aromatic ring bonded to the triple bond. In addition, when the alkynylated 2-iodoanysole 4h bearing an alkyl group attached to the triple bond was allowed to react, the heteroaromatic compound 5h was isolated in 69% yield (entry 8). Treatment of the chloro-containing alkynylated 2-iodoanysole 4i having an alkyl group bonded to the triple bond with 3 equiv. of iodine and 3 equiv. of NaHCO₃ in 1,2-dichloroethane at 70 °C for 24 h afforded the desired product 5i in a moderate yield of 45% (entry 9). Alkynylated anisoles bearing an alkyl group attached to the triple bond fail to undergo electrophilic cyclizations employing the protocol published by Larock and co-workers.²⁶26 Yue, D.; Yao, T.; Larock, C.; J. Org. Chem. 2005, 70, 10292. However, using our protocol the alkynylated 2-iodoanysoles bearing an alkyl group (4b, 4d, 4f, 4h, and 4i) provided diiodo-functionalized benzo[b]furan (5b, 5d, 5f, 5h, and 5i) in reasonable yields (Table 2, entries 2, 4, 6, 8, and 9).

Presumably, the iodocyclization reported proceed through the formation of the iodonium ion A, followed by a five endo-dig cyclization leading to the oxonium ion B, which undergoes methyl group removal via SN₂ displacement by a nucleophile present in the reaction mixture²³23 Mehta, S.; Larock, C.; J. Org. Chem. 2010, 75, 1652.

24 Mehta, S.; Waldo, P.; Larock, C.; J. Org. Chem. 2009, 74, 1141.

25 Manarin, F.; Roehrs, A.; Gay, M.; Brandão, R.; Menezes, H.; Nogueira, W.; Zeni, G.; J. Org. Chem. 2009, 74, 2153.^-²⁶26 Yue, D.; Yao, T.; Larock, C.; J. Org. Chem. 2005, 70, 10292. (Scheme 1).

Scheme 1
Proposed mechanism for the electrophilic iodocyclization developed.

The structures of compounds 5a-i were assigned according to their ¹H nuclear magnetic resonance (NMR), ¹³C NMR, infrared (IR), and mass spectra. All new compounds (5b-i) provided high-resolution mass spectra (HRMS) that are in agreement with the proposed structures.

Conclusions

In summary, an electrophilic iodocyclization reaction involving alkynylated 2-iodoanisoles and molecular iodine in the presence of sodium bicarbonate was developed and diiodo-functionalized benzo[b]furans were obtained in yields from 45 to 99%. Our transformation provided benzo[b]furans even when alkynylated 2-iodoanisoles bearing alkyl groups attached to the triple bond were employed. The iodocyclization reported can be considered a convenient approach to prepare diiodo-functionalized benzo[b]furans and should find use in the construction of molecules with interesting biological properties and applications in materials science.

Experimental

General methods

¹H and ¹³C NMR spectra were recorded on spectrometer operating at 200 and 50 MHz, respectively. ¹H NMR spectra were taken in CDCl₃, and the chemical shifts were given in ppm with respect to tetramethylsilane (TMS) used as an internal standard. ¹³C NMR spectra were taken in CDCl₃, and the chemical shifts were given in ppm with respect to the deuterated solvent used as a reference. Infrared spectra were obtained using attenuated total reflectance (ATR) technique or KBr pellets in the 4000-400 cm^-1 region. Mass spectra were carried out employing a gas chromatograph connected to a mass spectrometer using electron impact ionization (EI) at 70 eV. High resolution mass spectra were obtained using a time-of-flight (TOF) mass spectrometer. Melting point values are uncorrected. Column chromatography separations were carried out using 70-230 mesh silica gel. Commercially obtained reagents and solvents were employed without purification. Alkynylated 2-iodoanysoles (4a-i) were prepared according to the literature.³¹31 Rossini, C.; Frota, C.; Casagrande, A.; Pizzuti, L.; Raminelli, C.; J. Braz. Chem. Soc. 2014, 25, 2125.

General procedure for the preparation of diiodo-functionalized benzo[b]furans (5a-i)

To a vial (20 mL) were added the alkynylated 2-iodoanysole 4 (0.25 mmol), NaHCO₃ (63 mg, 0.75 mmol), and a solution of iodine (190 mg, 0.75 mmol) in 1,2-dichloroethane (5 mL). The vial was sealed using a cap, and the mixture was stirred at 70 °C for 24 hours. Afterwards, a saturated solution of sodium thiosulfate (10 mL) was added to the reaction, which was extracted with ethyl acetate (3 × 10 mL). The organic phase was dried over MgSO₄. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane as eluent, affording the diiodo-functionalized benzo[b]furan 5.

3,7-Diiodo-2-phenylbenzofuran (5a)

Yield: 108 mg (97%); off-white solid; m.p. 110-112 °C (lit.³¹31 Rossini, C.; Frota, C.; Casagrande, A.; Pizzuti, L.; Raminelli, C.; J. Braz. Chem. Soc. 2014, 25, 2125. m.p. 110-112 °C); ¹H NMR (200 MHz, CDCl₃) δ 8.23-8.18 (m, 2H), 7.70 (dd, 1H, J 7.7, 1.1 Hz), 7.55-7.37 (m, 4H), 7.06 (t, 1H, J 7.7 Hz); ¹³C NMR (50 MHz, CDCl₃) δ 153.9, 153.4, 134.4, 132.4, 129.5, 129.4, 128.5, 127.5, 125.0, 121.9, 74.5, 61.4; IR (KBr) ν_max / cm^-1 3055, 1905, 1485, 1482, 1060; LRMS m/z (%) 446 (100.0), 319 (8.7), 192 (10.0).

2-Butyl-3,7-diiodobenzofuran (5b)

Yield: 75 mg (71%); orange oil; ¹H NMR (200 MHz, CDCl₃) δ 7.63 (dd, 1H, J 7.7, 1.1 Hz), 7.27 (dd, 1H, J 7.8, 1.1 Hz), 7.01 (t, 1H, J 7.7 Hz), 2.89 (t, 2H, J 7.5 Hz), 1.83-1.68 (m, 2H), 1.47-1.25 (m, 2H), 0.96 (t, 3H, J 7.3 Hz); ¹³C NMR (50 MHz, CDCl₃) δ 159.8, 154.3, 133.4, 131.0, 124.7, 120.9, 74.4, 63.0, 29.9, 27.7, 22.2, 13.8; IR (ATR) ν_max / cm^-1 2891, 2893, 2916, 2918, 2920, 3045, 1164; LRMS m/z (%) 426 (100.0), 383 (31.1), 257 (17.4); HRMS (EI-TOF MS) calculated for [C₁₂H₁₂I₂O]⁺: 425.8978; found: 425.8986.

5-Chloro-3,7-diiodo-2-phenylbenzofuran (5c)

Yield: 68 mg (57%); off-white solid; m.p. 125-126 °C; ¹H NMR (200 MHz, CDCl₃) δ 8.20-8.15 (m, 2H), 7.67 (d, 1H, J 2.0 Hz), 7.56-7.45 (m, 3H), 7.38 (d, 1H, J 2.0 Hz); ¹³C NMR (50 MHz, CDCl₃) δ 154.9, 152.8, 133.7, 133.1, 129.9, 129.0, 128.6, 127.6, 121.6, 74.6, 60.3; IR (KBr) ν_max / cm^-1 3064, 1483, 1225, 1058; LRMS m/z (%) 480 (100.0), 353 (16.0), 226 (10.6); HRMS (EI-TOF MS) calculated for [C₁₄H₇ClI₂O]⁺: 479.8275; found: 479.8280.

2-Butyl-5-chloro-3,7-diiodobenzofuran (5d)

Yield: 53 mg (46%); off-white solid; m.p. 95-96 °C; ¹H NMR (200 MHz, CDCl₃) δ 7.59 (d, 1H, J 2.0 Hz), 7.25 (d, 1H, J 2.0 Hz), 2.87 (t, 2H, J 7.5 Hz), 1.78-1.70 (m, 2H), 1.50-1.32 (m, 2H), 0.96 (t, 3H, J 7.3 Hz); ¹³C NMR (50 MHz, CDCl₃) δ 161.4, 153.1, 132.6, 131.7, 129.4, 120.6, 74.5, 62.2, 29.7, 27.7, 22.2, 13.7; IR (KBr) ν_max / cm^-1 3100, 2958, 2945, 1436, 1157; LRMS m/z (%) 460 (100.0), 417 (62.3), 291 (25.8); HRMS (EI-TOF MS) calculated for [C₁₂H₁₁ClI₂O]⁺: 459.8588; found: 459.8599.

3,7-Diiodo-5-methyl-2-phenylbenzofuran (5e)

Yield: 114 mg (99%); off-white solid; m.p. 120-121 °C; ¹H NMR (200 MHz, CDCl₃) δ 8.22 (dd, 2H, J 8.1, 1.6 Hz), 7.54-7.45 (m, 4H), 7.17 (d, 1H, J 0.6 Hz), 2.45 (s, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 153.5, 152.5, 135.4, 135.1, 132.2, 129.6, 129.4, 128.5, 127.5, 121.9, 74.0, 61.1, 20.9; IR (KBr) ν_max / cm^-1 3014, 3018, 2910, 2842, 1236, 1064; LRMS m/z (%) 460 (100.0), 333 (11.2), 207 (5.8); HRMS (EI-TOF MS) calculated for [C₁₅H₁₀I₂O]⁺: 459.8821; found: 459.8825.

2-Butyl-3,7-diiodo-5-methylbenzofuran (5f)

Yield: 82.5 mg (75%); orange oil; ¹H NMR (200 MHz, CDCl₃) δ 7.47 (d, 1H, J 0.9 Hz), 7.05 (d, 1H, J 0.6 Hz), 2.87 (t, 2H, J 7.5 Hz), 2.41 (s, 3H), 1.81-1.66 (m, 2H), 1.47-1.35 (m, 2H), 0.96 (t, 3H, J 7.2 Hz); ¹³C NMR (50 MHz, CDCl₃) δ 159.9, 152.8, 134.7, 134.3, 130.9, 120.9, 73.9, 62.7, 29.9, 27.7, 22.2, 20.8, 13.7; IR (ATR) ν_max / cm^-1 3002, 2925, 2921, 1518, 1135; LRMS m/z (%) 440 (100.0), 397 (26.6), 271 (11.1); HRMS (EI-TOF MS) calculated for [C₁₃H₁₄I₂O]⁺: 439.9134; found: 439.9140.

3,7-Diiodo-2-(4-methoxyphenyl)benzofuran (5g)

Yield: 118 mg (99%); off-white solid; m.p. 135-137 °C; ¹H NMR (200 MHz, CDCl₃) δ 8.18-8.13 (m, 2H), 7.68 (dd, 1H, J 7.7, 1.1 Hz), 7.37 (dd, 1H, J 7.8, 1.1 Hz), 7.1-7.0 (m, 3H), 3.89 (s, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 160.6, 153.8, 153.7, 133.9, 132.5, 129.2, 125.0, 122.0, 121.6, 114.0, 74.40, 59.6, 55.4; IR (KBr) ν_max / cm^-1 3025, 3010, 2980, 2850, 1250, 1120; LRMS m/z (%) 476 (100.0), 397 (26.6), 271 (11.1); HRMS (EI-TOF MS) calculated for [C₁₅H₁₀I₂O₂]⁺: 475.8770; found: 475.8775.

2-(Cyclopentylmethyl)-3,7-diiodobenzofuran (5h)

Yield: 78 mg (69%); orange oil; ¹H NMR (200 MHz, CDCl₃) δ 7.63 (dd, 1H, J 7.7 0.9 Hz), 7.27 (d, 1H, J 7.7 Hz), 7.01 (t, 1H, J 7.7 Hz) 2.88 (d, 2H, J 7.4 Hz), 2.41-2.33 (m, 1H), 1.82-1.76 (m, 2H), 1.71-1.66 (m, 2H), 1.59-1.53 (m, 2H), 1.35-1.30 (m, 2H); ¹³C NMR (50 MHz, CDCl₃) δ 159.7, 154.4, 133.4, 131.0, 124.7, 120.9, 74.4, 63.4, 39.1, 33.6, 32.4, 24.9; IR (ATR) ν_max / cm^-1 2993, 2920, 2922, 3020, 1591, 1435, 1220; LRMS m/z (%) 452 (100.0), 384 (74.1), 257 (58.7); HRMS (EI-TOF MS) calculated for [C₁₄H₁₄I₂O]⁺: 451.9134; found: 451.9145.

5-Chloro-2-(cyclopentylmethyl)-3,7-diiodobenzofuran (5i)

Yield: 54.7 mg (45%); orange oil; ¹H NMR (200 MHz, CDCl₃) δ 7.60 (d, 1H, J 2.0 Hz), 7.26 (d, 1H, J 2.0 Hz), 2.87 (d, 2H, J 7.4 Hz), 2.39-2.32 (m, 1H), 1.83-1.78 (m, 2H), 1.71-1.67 (m, 2H), 1.60-1.55 (m, 2H), 1.34-1.29 (m, 2H); ¹³C NMR (50 MHz, CDCl₃) δ 161.4, 153.3, 132.7, 131.8, 129.5, 120.8, 74.5, 62.6, 39.1, 33.7, 32.4, 24.9. IR (ATR) ν_max / cm^-1 3090, 2963, 2951, 1495, 1101; LRMS m/z (%) 486 (100.0), 360 (74.1), 233 (38.7); HRMS (EI-TOF MS) calculated for [C₁₄H₁₃ClI₂O]⁺: 485.8744; found: 485.8755.

Acknowledgments

We gratefully acknowledge the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT), and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for financial support.

Supplementary Information

Supplementary data (¹H and ¹³C NMR spectra) are available free of charge at http://jbcs.sbq.org.br as a PDF file.

References

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⁷
He, S.; Jain, P.; Lin, B.; Ferrer, M.; Hu, Z.; Southall, N.; Hu, X.; Zheng, W.; Neuenswander, B.; Cho, C.-H.; Chen, Y.; Worlikar, A.; Aubé, J.; Larock, C.; Schoenen, J.; Marugan, J.; Liang, J.; Frankowski, J.; ACS Comb. Sci. 2015, 17, 641.
⁸
Takaya, D.; Yamashita, A.; Kamijo, K.; Gomi, J.; Ito, M.; Maekawa, S.; Enomoto, N.; Sakamoto, N.; Watanabe, Y.; Arai, R.; Umeyama, H.; Honma, T.; Matsumoto, T.; Yokoyama, S.; Bioorg. Med. Chem2011, 19, 6892.
⁹
Galal, A.; El-All, A.; Hegab, H.; Magd-El-Din, A.; Youssef, S.; El-Diwani, I.; Eur. J. Med. Chem. 2010, 45, 3035.
¹⁰
Hassan, S.; Abou-Seri, M.; Kamel, G.; Ali, M.; Eur. J. Med. Chem. 2014, 76, 482.
¹¹
Yadav, P.; Singh, P.; Tewari, K.; Bioorg. Med. Chem. Lett. 2014, 24, 2251.
¹²
Wu, S.-F.; Chang, F.-R.; Wang, S.-Y.; Hwang, T.-L.; Lee, C.-L.; Chen, S.-L.; Wu, C.-C.; Wu, Y.-C.; J. Nat. Prod. 2011, 74, 989.
¹³
Dawood, M.; Expert Opin. Ther. Pat. 2013, 23, 1133.
¹⁴
Lee, S.-M.; Lee, W.-G.; Kim, Y.-C.; Ko, H.; Bioorg. Med. Chem. Lett. 2011, 21, 5726.
¹⁵
Kao, C.-L.; Chern, J.-W.; J. Org. Chem. 2002, 67, 6772.
¹⁶
Tsai, I.-L.; Hsieh, C.-F.; Duh, C.-Y.; Phytochemistry 1998, 48, 1371.
¹⁷
Vardanyan, S.; Hruby, J.; Synthesis of Essential Drugs; Elsevier: Amsterdam, NL, 2006 p. 252.
¹⁸
Yamaguchi, M.; Akiyama, T.; Sasou, H.; Katsumata, H.; Manabe, K.; J. Org. Chem. 2016, 81, 5450.
¹⁹
Zhou, R.; Wang, W.; Jiang, Z.-J.; Wang, K.; Zheng, X.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X.; Chem. Commun. 2014, 50, 6023.
²⁰
Moure, J.; SanMartin, R.; Domínguez, E.; Adv. Synth. Catal. 2014, 356, 2070.
²¹
Schumacher, F.; Honraedt, A.; Bolm, C.; Eur. J. Org. Chem. 2012, 3737.
²²
Bernini, R.; Cacchi, S.; Salve, D.; Fabrizi, G.; Synthesis 2007, 873.
²³
Mehta, S.; Larock, C.; J. Org. Chem. 2010, 75, 1652.
²⁴
Mehta, S.; Waldo, P.; Larock, C.; J. Org. Chem. 2009, 74, 1141.
²⁵
Manarin, F.; Roehrs, A.; Gay, M.; Brandão, R.; Menezes, H.; Nogueira, W.; Zeni, G.; J. Org. Chem. 2009, 74, 2153.
²⁶
Yue, D.; Yao, T.; Larock, C.; J. Org. Chem. 2005, 70, 10292.
²⁷
Ferreira, M.; Casagrande, A.; Pizzuti, L.; Raminelli, C.; Synth. Commun. 2014, 44, 2094.
²⁸
Gallo, C.; Ferreira, M.; Casagrande, A.; Pizzuti, L.; Oliveira-Silva, D.; Raminelli, C.; Tetrahedron Lett. 2012, 53, 5372.
²⁹
Gallo, C.; Gebara, S.; Muzzi, M.; Raminelli, C.; J. Braz. Chem. Soc. 2010, 21, 770.
³⁰
Moreira, V.; Muraca, A.; Raminelli, C.; Synthesis 2016, 48, A. DOI: 10.1055/s-0036-1588332.
³¹
Rossini, C.; Frota, C.; Casagrande, A.; Pizzuti, L.; Raminelli, C.; J. Braz. Chem. Soc. 2014, 25, 2125.

Publication Dates

Publication in this collection
Oct 2017

History

Received
27 Nov 2016
Accepted
20 Feb 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[7] ⁷
He, S.; Jain, P.; Lin, B.; Ferrer, M.; Hu, Z.; Southall, N.; Hu, X.; Zheng, W.; Neuenswander, B.; Cho, C.-H.; Chen, Y.; Worlikar, A.; Aubé, J.; Larock, C.; Schoenen, J.; Marugan, J.; Liang, J.; Frankowski, J.; ACS Comb. Sci. 2015, 17, 641.

[8] ⁸
Takaya, D.; Yamashita, A.; Kamijo, K.; Gomi, J.; Ito, M.; Maekawa, S.; Enomoto, N.; Sakamoto, N.; Watanabe, Y.; Arai, R.; Umeyama, H.; Honma, T.; Matsumoto, T.; Yokoyama, S.; Bioorg. Med. Chem2011, 19, 6892.

[9] ⁹
Galal, A.; El-All, A.; Hegab, H.; Magd-El-Din, A.; Youssef, S.; El-Diwani, I.; Eur. J. Med. Chem. 2010, 45, 3035.

[10] ¹⁰
Hassan, S.; Abou-Seri, M.; Kamel, G.; Ali, M.; Eur. J. Med. Chem. 2014, 76, 482.

[11] ¹¹
Yadav, P.; Singh, P.; Tewari, K.; Bioorg. Med. Chem. Lett. 2014, 24, 2251.

[12] ¹²
Wu, S.-F.; Chang, F.-R.; Wang, S.-Y.; Hwang, T.-L.; Lee, C.-L.; Chen, S.-L.; Wu, C.-C.; Wu, Y.-C.; J. Nat. Prod. 2011, 74, 989.

[13] ¹³
Dawood, M.; Expert Opin. Ther. Pat. 2013, 23, 1133.

[14] ¹⁴
Lee, S.-M.; Lee, W.-G.; Kim, Y.-C.; Ko, H.; Bioorg. Med. Chem. Lett. 2011, 21, 5726.

[15] ¹⁵
Kao, C.-L.; Chern, J.-W.; J. Org. Chem. 2002, 67, 6772.

[16] ¹⁶
Tsai, I.-L.; Hsieh, C.-F.; Duh, C.-Y.; Phytochemistry 1998, 48, 1371.

[17] ¹⁷
Vardanyan, S.; Hruby, J.; Synthesis of Essential Drugs; Elsevier: Amsterdam, NL, 2006 p. 252.

[18] ¹⁸
Yamaguchi, M.; Akiyama, T.; Sasou, H.; Katsumata, H.; Manabe, K.; J. Org. Chem. 2016, 81, 5450.

[19] ¹⁹
Zhou, R.; Wang, W.; Jiang, Z.-J.; Wang, K.; Zheng, X.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X.; Chem. Commun. 2014, 50, 6023.

[20] ²⁰
Moure, J.; SanMartin, R.; Domínguez, E.; Adv. Synth. Catal. 2014, 356, 2070.

[21] ²¹
Schumacher, F.; Honraedt, A.; Bolm, C.; Eur. J. Org. Chem. 2012, 3737.

[22] ²²
Bernini, R.; Cacchi, S.; Salve, D.; Fabrizi, G.; Synthesis 2007, 873.

[23] ²³
Mehta, S.; Larock, C.; J. Org. Chem. 2010, 75, 1652.

[24] ²⁴
Mehta, S.; Waldo, P.; Larock, C.; J. Org. Chem. 2009, 74, 1141.

[25] ²⁵
Manarin, F.; Roehrs, A.; Gay, M.; Brandão, R.; Menezes, H.; Nogueira, W.; Zeni, G.; J. Org. Chem. 2009, 74, 2153.

[26] ²⁶
Yue, D.; Yao, T.; Larock, C.; J. Org. Chem. 2005, 70, 10292.

[27] ²⁷
Ferreira, M.; Casagrande, A.; Pizzuti, L.; Raminelli, C.; Synth. Commun. 2014, 44, 2094.

[28] ²⁸
Gallo, C.; Ferreira, M.; Casagrande, A.; Pizzuti, L.; Oliveira-Silva, D.; Raminelli, C.; Tetrahedron Lett. 2012, 53, 5372.

[29] ²⁹
Gallo, C.; Gebara, S.; Muzzi, M.; Raminelli, C.; J. Braz. Chem. Soc. 2010, 21, 770.

[30] ³⁰
Moreira, V.; Muraca, A.; Raminelli, C.; Synthesis 2016, 48, A. DOI: 10.1055/s-0036-1588332.

[31] ³¹
Rossini, C.; Frota, C.; Casagrande, A.; Pizzuti, L.; Raminelli, C.; J. Braz. Chem. Soc. 2014, 25, 2125.

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