Palladium catalyzed Suzuki cross-coupling of 3-iodo-2-(methylthio)-benzo[b]furan derivatives: synthesis of 3-aryl-2-(methylthio)benzo[b]furans

ARTICLE

Palladium catalyzed Suzuki cross-coupling of 3-iodo-2-(methylthio)-benzo[b]furan derivatives: synthesis of 3-aryl-2-(methylthio)benzo[b]furans

Rafaela M. Gay; Flávia Manarin; Ricardo Brandão; Gilson Zeni^*

Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil

ABSTRACT

A selective and efficient method for the synthesis of 3-aryl-2-(methylthio)benzo[b]furans derivatives by palladium catalyzed cross-coupling reaction with boronic acids has been developed. The reaction proceeded cleanly under mild conditions and was performed with aryl boronic acids bearing electron-withdrawing, electron donating and neutral substituents.

Keywords: palladium, Suzuki cross-coupling, benzofuran, boronic acids

RESUMO

Neste trabalho desenvolvemos um método seletivo e eficiente para a síntese de derivados de 3-aril-2-(tiometil)-benzo[b]furanos, via reação de acoplamento com ácidos borônicos, catalisada por paládio. As condições reacionais usadas foram brandas e compatíveis com ácidos borônicos contendo substituintes retiradores, doadores de elétrons ou neutros.

Introduction

The construction of benzo[b]furans substituted in the 2,3 positions is of great synthetic interest due to the presence of this moiety in many complex compounds, which have potential therapeutic applications.¹ In this context, the preparation of 2,3-disubstituted benzo[b]furans represents a synthetic challenge and the palladium-catalyzed Suzuki coupling is one of the most straightforward methodologies to synthesize 3-arylated-benzofurans.² The palladium-catalyzed Suzuki cross-coupling reaction of aryl halides with organoboron reagents has become a common and convenient synthetic method in organic chemistry.³ Many examples of Suzuki coupling reaction of heterocyclic halides with boronic acids have appeared in the literature over the past two decades as a promising synthetic tool.⁴ More recently, significant advances have been made in the use of organoboron reagents as coupling partners in a number of palladium-mediated carbon-carbon bond formation. Among them, the use of potassium organotrifluoroborates, as the organoboron coupling partner, has some of these advantages are higher nucleophilicity, air-stability and ready access in comparison to boronic acids and boronic esters.⁵

In addition, the presence of a sulfide group at the 2-position of benzo[b]furan is significant, since it could be easily oxidized to 2-sulfonylbenzofurans,⁶ a class of compounds which has attracted tremendous interest from the pharmaceutical industry. During the course of our research program aiming at structure-activity relationship studies in order to evaluate the pharmacology activity of heterocycles,^7,8 we required the synthesis of benzofurans having an organochalcogen group at the 2-position and a substituted aromatic ring at the 3-position. Since the Suzuki reaction has proven to be successful for the selective arylation of heterocyles,² it was of interest to explore this reaction to obtain 3-aryl-2-(methylthio)benzo[b]furan derivatives. To our knowledge this methodology has not been explored and we now wish to report the application of 3-iodo-2-(methylthio)benzo[b]furans 1a-c as substrates on the cross-coupling reaction with boronic acids 2a-k in the presence of a palladium salt to obtain 3-aryl-2-(methylthio)benzo[b]furans 3a-u (Scheme 1).

The starting materials 1a-c were readily available by using the electrophilic cyclization protocol⁹ of 2-(methylthio)alkynylanisoles (Scheme 2). The treatment of 2-(methylthio)alkynylanisoles with iodine in CH₂Cl₂, at room temperature, led to the formation of 1a-c, isolated in 87-95% yield after purification (Scheme 2).¹⁰

Results and Discussion

Our initial studies on Suzuki cross-coupling focused on the development of an optimum set of reaction conditions. In this way, 3-iodo-2-(methylthio)benzo[b]furan 1a and phenylboronic acid 2a were used as standard substrates. Thus, the reaction of 1a (0.5 mmol), boronic acid 2a (0.75 mmol), and a solution of K₂CO₃ (1.0 mmol) in H₂O (0.4 mL), using DMF (4.0 mL) as solvent, at reflux with different palladium catalysts was tested (Table 1). As shown in Table 1, both Pd(0) and Pd(II) catalysts with different ligands were tested. The best result was obtained using Pd(PPh₃)₄ (5 mol%) which gave the desired product 3a in 97% yield (Table 1; entry 1). It is important to note that when the amount of catalyst was reduced from 5 to 2 mol%, a small decrease in the yield was observed (Table 1; entry 7). Our experiments also showed that in the absence of catalyst the product was not detected, and the starting material was recovered (Table 1; entry 8).

Regarding the influence of solvent, optimal results were achieved using DMF (Table 2, entry 1). By using dioxane, CH₃CN and THF (Table 2, entries 2, 4 and 6) good yields were also obtained, while the use of DME (Table 2, entry 5) did not give the desired product 3a. We also observed that the nature of the base was critical for the success of the coupling. When the reaction was carried out with an aqueous solution of inorganic bases such as K₃PO_4, Cs₂CO₃ and Na₂CO₃ the coupling product was obtained in good yields (Table 2; entries 7-9), while the use of NaOH (Table 2, entry 10) furnished the desired coupling product in low yield. It is also important to mention that when dry base were used in place of an aqueous solution, only 54% of product was obtained (Table 2; entry 11). Careful analysis of the results revealed that the optimum condition for this coupling reaction was found to be the use of Pd(PPh₃)₄ (2 mol%), 3-iodo-2-(methylthio)-benzo[b]furan 1a (0.5 mmol), phenylboronic acid (0.75 mmol) in DMF (4.0 mL) and H₂O (0.4 mL) at room temperature. After that, the base K₃PO₄ (1.0 mmol) was added and the mixture was heated at 100 ºC for 1h. Using this reaction condition we were able to prepare 3-aryl-2-(methylthio)-benzo[b]furan derivative 3a in excellent yield.¹²

In order to demonstrate the efficiency of this protocol, we explored the generality of our method extending the conditions to other aryl boronic acids and 3-iodo-2-(methylthio)-benzo[b]furan derivatives and the results are summarized in Table 3. Inspection of Table 3 shows that the reaction worked well for a variety of arylboronic acids. A closer inspection of the results revealed that the reaction is sensitive to the electronic effect of the aromatic ring attached in the arylboronic acid. For example, arylboronic acids bearing an electron-donating group, methyl or methoxyl, at the para position gave a better yield than the arylboronic acid bearing an electron-withdrawing group, halide and acetyl (Table 3; entries 2, 3 versus 4-6). These results are in full agreement with the fact that electron donating groups increase the nucleophilicity of boronic acids. We have found that steric effects had a little influence on the coupling reaction since boronic acids containing 2-methylphenyl or naphtyl group, gave similar yields than arylboronic acids with no substituent, however an increase in the reaction time was required (Table 3; entries 10, 15, 18 and 21). Differentiation in the reactivity between halogen and boron atoms can be seen by coupling showed in the experiments described in Table 1 (enties 4 and 5), which provide only the Suzuki product, without any homo-coupling product. To the best of our knowledge, aryl halogen could react with boronic acids in the presence of palladium catalysts to afford biaryl products.¹¹ In the example reported in this study, the halogen substituent was not affected. In an attempt to broaden the scope of our methodology, the possibility of performing the reaction with other 3-iodo-2-(methylthio)-benzofurans was also investigated. Then substrates 1b and 1c, which have methyl and fluoro group in the side chain, were efficiently cross-coupled. Under these conditions, both electron-rich and electron-poor arylboronic acids produced the desired products in good yields (Table 3; entries 11-21).

Alternatively, under the same conditions described to boronic acids, we were able to use other organoboron source, the aryltrifluoroborates (Scheme 3).⁵ In this way, 3-iodo-2-(methylthio)-benzofuran 1a underwent palladium cross-coupling with aryltrifluoroborates furnishing the corresponding 3-aryl-2-(methylthio)benzo[b]furan in good yields.

Conclusions

In summary, we have explored the Suzuki cross-coupling reaction of arylboronic acids with 3-iodo-2-(methylthio)-benzofurans using a catalytic amount of Pd(PPh₃)₄. In addition, the same procedure used to aryl boronic acids was efficiently extended to aryltrifluoroborates. The reaction proceeded cleanly under mild reaction conditions, short reaction time and was performed with aryl boronic acids bearing electron withdrawing, electron donating, and neutral substituents. It is important to point out that this route permits an easy and efficient access to highly substituted benzofurans.

Supplementary Information

Supplementary data (Experimental details and caracterization of the compounds) are available free of charge at http://jbcs.sbq.org.br, as PDF file.

Acknowledgments

We are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), for the fellowship and financial support.

References

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12. General procedure for the cross-coupling reaction: To a solution of appropriate 3-iodo-2-(methylthio)Benzo[b]furan (0.5 mmol) in DMF (4.0 mL) and H₂O (0.4 mL) was added to Pd(PPh₃)₄ (0.011g, 2 mol%) and K₂CO₃ (1 mmol), under argon. After this time, boronic acid (0.75 mmol) was added. The mixture was then heated at 100 ºC during 1-4 h, cooled to room temperature, diluted with dichloromethane (20 mL), and washed with brine (2 × 20 mL). The organic phase was separated, dried over MgSO₄, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ ethyl acetate as eluent. Selected spectral and analytical data for 2-(methylthio)-3-phenylBenzo[b]furan 3a: Yield: 0.111 g (93%). ¹H NMR: CDCl₃, 400 MHz, δ (ppm): 7.61-7.59 (m, 3H), 7.50-7.46 (m, 3H), 7.37 (t, J 7.3 Hz, 1H), 7.29 (t, J 7.3 Hz, 1H), 7.23 (dd, J 7.5 Hz and J 2.5 Hz, 1H), 2.52 (s, 3H). ¹³C NMR: CDCl₃, 100 MHz, δ (ppm): 155.9, 147.5, 131.8, 129.1, 128.5, 128.3, 127.4, 124.4, 122.9, 122.5, 119.7, 110.8, 16.9. MS (EI, 70 eV) m/z (relative intensity): 238 (26), 222 (17), 194 (100), 163 (23), 151 (10), 76 (8). Anal. (%) Calc. for C₁₅H₁₂OS: C 74.97, H 5.03. Found: C 75.15, H 5.39.

Submitted: February 4, 2010

Published online: May 11, 2010

Supplementary Information

Experimental

Proton nuclear magnetic resonance spectra (¹H NMR) were obtained at 400 MHz. Spectra were recorded in CDCl₃ solutions. Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl₃ or tetramethylsilane (TMS) as the external reference. Data are reported as follows: chemical shift (δ), multiplicity, coupling constant (J) in Hertz and integrated intensity. Carbon-13 nuclear magnetic resonance spectra (¹³C NMR) were obtained at 100 MHz. Spectra were recorded in CDCl₃ solutions. Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl₃. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sex (sextet) and m (multiplet). High resolution mass spectra were recorded on a double focusing magnetic sector mass spectrometer using EI at 70 eV. Column chromatography was performed using silica gel (230-400 mesh) following the methods described by Still (Still, W.C.; Kahn, M.; Mitra, A.; J. Org. Chem. 1978, 43, 2923). Thin layer chromatography (TLC) was performed using silica gel GF₂₅₄, 0.25 mm thickness. For visualization, TLC plates were either placed under ultraviolet light, or stained with iodine vapor, or acidic vanillin. The following solvents were dried and purified by distillation from the reagents indicated: tetrahydrofuran from sodium with a benzophenone ketyl indicator. All other solvents were ACS or HPLC grade unless otherwise noted. Air- and moisture-sensitive reactions were conducted in flame-dried or oven dried glassware equipped with tightly fitted rubber septa and under a positive atmosphere of dry nitrogen or argon. Reagents and solvents were handled using standard syringe techniques. Temperatures above room temperature were maintained by use of a mineral oil bath with an electrically heated coil connected to a controller.

General procedure for the Suzuki coupling reaction

To a solution of appropriate 3-iodo-2-(methylthio)benzo[b]furan (0.5 mmol) in DMF (4.0 mL) and H₂O (0.4 mL) was added to Pd(PPh3)4 (0.011g, 2 mol%) and K₂CO₃ (1 mmol), under argon. After this time, boronic acid (0.75 mmol) was added. The mixture was then heated at 100 ºC during 1-4 h, cooled to room temperature, diluted with dichloromethane (20 mL), and washed with brine (2 x 20 mL). The organic phase was separated, dried over MgSO₄, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ ethyl acetate as eluent.

2-(Methylthio)-3-phenylbenzofuran (3a)

Yield: 0.111 g (93%). ¹H NMR: CDCl₃, 400 MHz, δ (ppm): 7.61-7.59 (m, 3H), 7.50-7.46 (m, 3H), 7.37 (t, J 7.3 Hz, 1H), 7.29 (t, J 7.3 Hz, 1H), 7.23 (dd, J 7.5 Hz and J 2.5 Hz, 1H), 2.52 (s, 3H). ¹³C NMR: CDCl₃, 100 MHz, δ (ppm): 155.9, 147.5, 131.8, 129.1, 128.5, 128.3, 127.4, 124.4, 122.9, 122.5, 119.7, 110.8, 16.9. MS (EI, 70 eV) m/z (relative intensity): 238 (26), 222 (17), 194 (100), 163 (23), 151 (10), 76 (8). Anal. (%) Calc. for C₁₅H₁₂OS: C 74.97, H 5.03. Found: C 75.15, H 5.39.

3-(4-Methoxyphenyl)-2-(methylthio)benzofuran (3b)

Yield: 0.108 g (80%). ¹H NMR: CDCl₃, 400 MHz, δ (ppm): 7.59 (d, J 7.6 Hz, 1H), 7.53 (d, J 8.8 Hz, 2H), 7.47 (d, J 8.0 Hz, 1H), 7.30-7.20 (m, 2H), 7.03 (d, J 8.8 Hz, 2H), 3.85 (s, 3H), 2.49 (s, 3H). ¹³C NMR: CDCl₃, 100 MHz, δ (ppm): 159.0, 155.4, 146.8, 130.2, 128.4, 124.4, 124.0, 122.8, 122.4, 119.7, 114.0, 110.8, 55.2, 17.1. MS (EI, 70 eV) m/z (relative intensity): 269 (14), 267 (100), 252 (48), 224 (46), 181 (14), 150 (21).

2-(Methylthio)-3-p-tolylbenzofuran (3c)

Yield: 0.116 g (92%). ¹H NMR: CDCl₃, 400 MHz, δ (ppm): 7.60 (d, J 7.6 Hz, 1H), 7.50 (d, J 7.8 Hz, 2H), 7.44 (d, J 8.0 Hz, 1H), 7.29 (d, J 7.8 Hz, 2H), 7.25-7.17 (m, 1H), 2.50 (s, 3H), 2.40 (s, 3H). ¹³C NMR: CDCl₃, 100 MHz, δ (ppm): 155.4, 147.1, 137.2, 129.2, 128.9, 128.7, 128.3, 124.3, 122.8, 122.6, 119.7, 110.8, 21.2, 16.9. MS (EI, 70 eV) m/z (relative intensity): 254 (3), 251 (100), 236 (24), 208 (58), 176 (13), 150 (19).

3-(4-Bromophenyl)-2-(methylthio)benzofuran (3e)

Yield: 0.111 g (70%). ¹H NMR: (CDCl₃, 400 MHz) δ (ppm): 7.60 (d, J 8.5 Hz, 2H), 7.54 (d, J 7.6 Hz, 1H), 7.47-7.44 (m, 3H), 7.31-7.21 (m, 2H), 2.51 (s, 3H). ¹³C NMR: (CDCl₃, 50 MHz), δ (ppm): 155.4, 147.7, 131.7, 130.7, 130.5, 124.6, 123.1, 121.4, 121.3, 119.4, 110.9, 16.8. MS (EI, 70 eV) m/z (relative intensity): 318 (10), 221 (100), 193 (11), 161 (14), 150 (33).

1-(4-(2-(Methylthio)benzofuran-3-yl)phenyl)ethanone (3f)

Yield: 0.098 g (70%). ¹H NMR: (CDCl₃, 400 MHz) d (ppm): 8.08 (d, J 8.3 Hz, 2H), 7.70 (d, J 8.3 Hz, 2H), 7.61 (d, J 6.8 Hz, 1H), 7.50 (d, J 7.6 Hz, 1H), 7.34-7.25 (m, 2H), 2.65 (s, 3H), 2.56 (s, 3H). ¹³C NMR: (CDCl₃, 50 MHz), δ (ppm): 197.5, 155.5, 148.7, 136.9, 135.8, 129.0, 128.6, 127.8, 124.6, 123.3, 121.1, 119.4, 111.0, 26.6, 16.6. MS (EI, 70 eV) m/z (relative intensity): 280 (17), 279 (100), 264 (35), 221 (12), 150 (21), 43 (58).

1-(3-(2-(Methylthio)benzofuran-3-yl)phenyl)ethanone (3g)

Yield: 0.126 g (90%). ¹H NMR: (CDCl₃, 400 MHz) δ (ppm): 8.02 (t, J 2.0 Hz, 1H), 7.95 (dt, J 7.3 Hz and J 1.2 Hz, 1H), 7.80 (dt, J 7.3 Hz and J 1.2 Hz, 1H), 7.59-7.54 (m, 2H), 7.49-7.47 (m, 1H), 7.30 (td, J 7.3 Hz and J 1.4 Hz, 1H), 7.25 (td, J 7.5 Hz and J 1.3 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H). ¹³C NMR: (CDCl₃, 50 MHz), d (ppm): 197.6, 155.4, 148.0, 137.4, 133.4, 132.3, 128.8, 128.7, 127.8, 127.1, 124.6, 123.1, 121.4, 119.3, 110.9, 26.6, 16.7. MS (EI, 70 eV) m/z (relative intensity): 280 (17), 278 (100), 264 (7), 150 (19).

2-(Methylthio)-3-(3-nitrophenyl)benzofuran (3h)

Yield: 0.081 g (57%). ¹H NMR: (CDCl₃, 400 MHz) δ (ppm): 8.48 (t, J 2.0 Hz, 1H), 8.20 (dd, J 5.8 Hz and J 2.0 Hz, 1H), 7.94 (d, J 7.6 Hz, 1H), 7.64 (t, J 7.8 Hz, 1H), 7.59 (d, J 8.5 Hz, 1H), 7.50 (d, J 7.8 Hz, 1H), 7.35-7.24 (m, 2H), 2.57 (s, 3H). ¹³C NMR: (CDCl₃, 50 MHz), δ (ppm): 155.4, 148.8, 148.4, 134.7, 133.6, 129.4, 127.4, 124.8, 123.5, 123.4, 122.0, 119.9, 119.0, 111.0, 16.5. MS (EI, 70 eV) m/z (relative intensity): 282 (100), 250 (10), 221 (43), 192 (15), 162 (18), 150 (30).

2-(Methylthio)-3-(3-(trifluoromethyl)phenyl)benzofuran (3i)

Yield: 0.137 g (89%). 1H NMR: (CDCl₃, 400 MHz) d (ppm): 7.88 (s, 1H), 7.78 (d, J 7.3 Hz, 1H), 7.63-7.55 (m, 3H), 7.49-7.47 (m, 1H), 7.33-7.23 (m, 2H), 2.53 (s, 3H). ¹³C NMR: (CDCl₃, 50 MHz), δ (ppm): 155.5, 148.4, 132.8, 132.3, 130.8 (q, J 32 Hz), 129.9, 129.0, 125.7 (q, J 3.7 Hz), 124.7, 124.0 (q, J 3.6 Hz), 123.8 (q, J 273 Hz), 123.3, 119.3, 111.0, 16.7. MS (EI, 70 eV) m/z (relative intensity): 305 (100), 289 (8), 262 (95), 221 (15), 150 (13).

5-Methyl-2-(methylthio)-3-(naphthalen-1-yl)benzofuran (3o)

Yield: 0.139 g (92%). ¹H NMR: (CDCl₃, 400 MHz) δ (ppm): 7.89 (d, J 8.0 Hz, 2H), 7.73 (d, J 8.5 Hz, 1H), 7.54-7.34 (m, 5H), 7.08 (dd, J 7.1 Hz and J 1.5 Hz, 1H), 6.90 (s, 1H), 2.40 (s, 3H), 2.28 (s, 3H). ¹³C NMR: (CDCl₃, 50 MHz), δ (ppm): 153.8, 148.9, 133.7, 132.4, 132.0, 129.9, 129.3, 128.4, 128.3, 128.2, 125.9, 125.8, 125.6, 125.4, 121.4, 119.9, 110.3, 21.1, 16.9. MS (EI, 70 eV) m/z (relative intensity): 300 (100), 285 (27), 270 (11), 258 (32), 242 (12), 223 (7).

5-Fluoro-2-(methylthio)-3-phenylbenzofuran (3p)

Yield: 0.103 g (80%). ¹H NMR: (CDCl₃, 400 MHz) δ (ppm): 7.55-7.53 (m, 2H), 7.46 (t, J 7.8 Hz, 2H), 7.37-7.33 (m, 2H), 7.24 (dd, J 6.1 Hz and J 2.5 Hz, 1H), 6.97 (td, J 6.3 Hz and J 2.9 Hz, 1H), 2.50 (s, 3H). ¹³C NMR: (CDCl₃, 50 MHz), δ (ppm): 160.6, 158.2, 151.6, 149.5, 131.2, 128.7, 128.6, 127.6, 122.1, 111.8 (d, J 26.3 Hz), 111.4 (d, J 9.5 Hz), 105.3 (d, J 25.6 Hz), 16.5. MS (EI, 70 eV) m/z (relative intensity): 255 (100), 239 (64), 212 (92), 192 (12), 168 (30), 150 (6).

5-Fluoro-3-(4-methoxyphenyl)-2-(methylthio)benzofuran (3q)

Yield: 0.130 g (90%). ¹H NMR: (CDCl₃, 400 MHz) δ (ppm): 7.50 (d, J 8.5 Hz, 2H), 7.37 (dd, J 4.9 Hz and J 4.1 Hz, 1H), 7.24 (dd, J 6.1 Hz and J 2.7 Hz, 1H), 7.04-6.97 (m, 3H), 3.86 (s, 3H), 2.51 (s, 3H). ¹³C NMR: (CDCl₃, 50 MHz), δ (ppm): 160.6, 159.1, 158.2, 151.6, 148.8, 130.0, 123.5, 122.3, 114.2, 111.9 (d, J 24.8 Hz), 111.4 (d, J 9.5 Hz), 105.3 (d, J 24.8 Hz), 55.3, 16.7. MS (EI, 70 eV) m/z (relative intensity): 285 (100), 269 (73), 242 (49), 226 (14), 155.6 (17).

2-(Methylthio)-3-(thiophen-2-yl)benzofuran (3x)

Yield: 0.074 g (60%). ¹H NMR: CDCl₃, 400 MHz, δ (ppm): 7.82-7.80 (m, 1H), 7.46-7.44 (m, 2H), 7.37 (dd, J 4.0 Hz and J 1.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.16 (dd, J 4.0 Hz and J 1.4 Hz, 1H), 2.56 (s, 3H).¹³C NMR: CDCl₃, 100 MHz, δ (ppm): 155.3, 147.6, 133.1, 127.6, 127.2, 126.0, 125.0, 124.6, 123.2, 120.0, 116.4, 110.8, 16.8. MS (EI, 70 eV) m/z (relative intensity): 243 (100), 228 (75), 200 (64), 169 (15), 114 (20). HRMS calc. for C₁₃H₁₀OS₂: 246.0173. Found: 246.0177.

Selected Spectra

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Publication Dates

• Publication in this collection
  10 Sept 2010
• Date of issue
  2010

History

• Received
  04 Feb 2010
• Accepted
  11 May 2010