Synthesis of Diiodo-Functionalized Benzo [ b ] furans via Electrophilic Iodocyclization

Heterocyclic aromatic compounds constitute a class of substances with a considerable diversity of pharmacological properties. Accordingly, natural and synthetic heteroaromatic compounds have been employed as drugs. Focusing on benzo[b]furans (1), we came across an important subclass of heterocyclic aromatic compounds, which comprises various biological activities, such as anticancer, antiviral, anti-inflammatory, and immunosuppressive. In this sense, we present the structures of the benzo[b]furans obovaten (2), a natural product with pronounced antitumor activity, and amiodarone (3), a commercial antiarrhythmic drug (Figure 1). A number of approaches have been developed towards the efficient construction of benzo[b]furan scaffolds. Among them we highlight the metal-catalyzed cross-coupling/ cyclization reactions and the electrophilic cyclization reactions employing alkynylanisoles. The latter approach can be illustrated by the iodocyclization reaction developed by Larock and co-workers. Nevertheless, in the course of our research activities aiming to the synthesis of diiodo-functionalized compounds, for application in selective cross-coupling reactions, 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. 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.

4][25][26] The latter approach can be illustrated by the iodocyclization reaction developed by Larock and co-workers. 26Nevertheless, in the course of our research activities aiming to the synthesis of diiodo-functionalized compounds, [27][28][29] for application in selective cross-coupling reactions, 30,31 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. 26n 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 diiodofunctionalized 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).
Allowing the reaction between the alkynylated 2-iodoanysole 4a, 2 equiv. of iodine, and 2 equiv. of NaHCO 3 in dichloromethane at 40 °C for 12 h, we obtained the diiodo-functionalized benzo [b] Reaction conditions: 0.25 mmol of compound 4a, the indicated amount of I 2 , the indicated amount of base, and 5 mL of solvent were maintained under stirring at the temperature shown for the indicated time.
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).
Allowing compounds 4a and 4b to react with 3 equiv.of iodine and 3 equiv.of NaHCO 3 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 NaHCO 3 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 NaHCO 3 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 coworkers. 26However, 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 SN 2 displacement by a nucleophile present in the reaction mixture [23][24][25][26] (Scheme 1).
The structures of compounds 5a-i were assigned according to their 1 H nuclear magnetic resonance (NMR), 13 C 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 1 H and 13 C NMR spectra were recorded on spectrometer operating at 200 and 50 MHz, respectively. 1H NMR spectra were taken in CDCl 3 , and the chemical shifts were given in ppm with respect to tetramethylsilane (TMS) used as an internal standard. 13C NMR spectra were taken in CDCl 3 , 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. 31neral 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), NaHCO 3 (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 MgSO 4 .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.
0.25 mmol of compound 4a-i, 0.75 mmol of I 2 , 0.75 mmol of NaHCO 3 , and 5 mL of ClCH 2 CH 2 Cl were maintained under stirring at 70 °C for 24 h; b this yield was obtained after 48 h of reaction.