Letter pubs.acs.org/acscatalysis
A Convenient Synthesis of 2‑Arylbenzo[b]furans from Aryl Halides and 2‑Halophenols by Catalytic One-Pot Cascade Method Mariusz Jan Bosiak*,†,‡ †
Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University in Toruń, 7 Gagarin Street, 87-100 Toruń, Poland ‡ Synthex Technologies Sp. z o.o., 7/134B Gagarin Street, 87-100 Toruń, Poland S Supporting Information *
ABSTRACT: The development of a multicatalytic one-pot synthesis of 2-arylbenzofurans starting from aryl halides and 2-halophenols is described. The protocol involves two Sonogashira coupling reactions, followed by 2-ethynylphenol cyclization leading to 2-arylbenzofuran derivatives. The process occurs smoothly under mild conditions, giving products in good yields, and can be applied to many 2-arylbenzofurans substituted both at 2-aryl position and in the benzodifuran moiety. Substituents such as halogens, hydroxyl, cyano, nitro, and amino groups are tolerated, enabling further functionalization of the system.
KEYWORDS: benzofuran synthesis, one-pot synthesis, Sonogashira reaction, multicatalytic reaction, cascade reactions, intramolecular O-arylation
B
compounds couple easily with terminal alkynes, in the presence of palladium and copper salts, by the Sonogashira-type reaction. Trimethylsilylacetylene (TMSA) also undergoes this reaction to give trimethylsilyl (TMS) protected arylacetylene. The TMS group can be easily removed by basic hydrolysis or fluorides to give arylacetylene which could be further coupled with another halogenated aromatic compound by the second Sonogashira reaction. If the haloaromatic compound, added after TMS cleavage, is 2-halophenol the furan ring closing occurs (Scheme 2).
enzofuran derivatives are important heterocyclic compounds, mainly due to their diverse biological profile, exhibiting antihyperglycemic, analgesic, antiparasitic, antimicrobial, antitumor, and kinase inhibitor activities.1−6 Recently, we also proved their utility in photovoltaics7 and optoelectronics8−10 due to light absorption and emission properties. During the past years, new methods of synthesis of benzofurans and their derivatives have attracted much attention.11−23 The most convenient method for new benzofuran ring formation seems to be the Sonogashira reaction of 2-halophenols and alkynes, followed by heterocyclization of the hydroxyl group with the triple bond (Scheme 1).24−33 Although recently this
Scheme 2. One-Pot, Four-Step Method for 2-Substituted Benzofurans, from Aryl Halides and 2-Halophenols
Scheme 1. Synthesis of 2-Substituted Benzofurans via the Sonogashira Reaction
reaction was supplemented by various catalysts and conditions, a convenient method for benzofuran synthesis starting from aryl halides and 2-halophenols is desirable.34−46 Herein, the development of a new one-pot, four-step method for the synthesis of 2-substituted benzofurans from aryl halides and 2-halophenols is described. The method involves the two Sonogashira couplings and a tandem reaction of their products leading to benzofuran derivatives. Bromo- and iodoaryl © XXXX American Chemical Society
Received: January 20, 2016 Revised: March 2, 2016
2429
DOI: 10.1021/acscatal.6b00190 ACS Catal. 2016, 6, 2429−2434
Letter
ACS Catalysis
Table 1. Influence of the Palladium Catalyst Type and Phosphine Load on the Sonogashira Reaction between Iodophenol and TMSAa
palladium catalyst [2 mol %]
PPh3 load [mol %]
reaction time [min]
palladium catalyst [2 mol %]
PPh3 load [mol %]
reaction time [min]
Pd(PPh3)4
0 200 400 0 200 400 0 100 150 200 300 0 200 250 300 350 400 150 0 50
100 1500 no reaction 12 60 no reaction no reaction 13 10 15 50 6000 20 11 4.5 6 13 10 9 10
PdCl2
0 50 100 150 200 300 XPhos 100b XPhos 200b JohnPhos 100b JohnPhos 200b PHOX 100b 150c 0 50 100 150 200 0 50 100
no reaction 720 12 12 20 40 35 45 21 60 no reaction no reaction no reaction 23 9 6 8 10 8 20
Pd(PPh3)2Cl2
Na2PdCl4
Pd2(dba)3
Pd2(dba)3 [1 mol %] Pd(PPh3)2(OAc)2
Pd(OAc)2
Pd(dppf)Cl2
a
The reaction has been monitored by GC and continued until disappearance of all starting materials. Products have not been isolated. bThe Buchwald phosphines were used instead of PPh3. cWithout CuI.
Table 2. Influence of Copper Cocatalyst on the Reaction Time and Amount of the Glaser Byproducta
Table 3. continued solvent
Pd(OAc)2 reaction time [min] Pd(dppf)Cl2 reaction time [min]
1,4-dioxane
60
12
a
The reaction has been monitored by GC and continued until the disappearance of all starting materials. Products have not been isolated. Abbreviations: THF, tetrahydrofuran; DMSO, dimethyl sulfoxide; DMF, dimethylformamide; dppf, 1,1′-bis(diphenylphosphino)ferrocene.
Table 4. Influence of the Base Type on the Sonogashira Coupling CuI amount [mol %.]
reaction time [min]
Glaser reaction product percentage
0 25 50 100 200 400
no reaction 22 13 5 4.5 3
2.2% 2.9% 3.4% 3.5% 3.6%
a
The reaction has been monitored by GC and continued until the disappearance of all starting materials. Products have not been isolated.
Table 3. Influence of the Solvent Type on the Sonogashira Reaction Ratea
base
equiv per PhI
reaction time [min]
Et3N morpholine piperidine TMEDA Cs2CO3 i-Pr2NH i-Pr2NH i-Pr2NH
2.5 2.5 2.5 2.5 2.5 1.25 2.5 5.0
12 40 18 1200 no reaction 40 6 3
a
The reaction has been monitored by GC and continued until disappearance of all starting materials. Products have not been isolated. Abbreviation: TMEDA, tetramethylethylenediamine.
solvent DMSO THF DMF acetonitrile toluene
Pd(OAc)2 reaction time [min] Pd(dppf)Cl2 reaction time [min] reaction stops 120 100 90 18
The palladium catalyst type, copper iodide and phosphine load, base, and solvent type have been examined. Most papers concerning the Sonogashira reaction report 400−1000 mol % of phosphine load per palladium atoms as the optimal amount. The palladium catalyst type and influence of the phosphine
22 45 40 32 8 2430
DOI: 10.1021/acscatal.6b00190 ACS Catal. 2016, 6, 2429−2434
Letter
ACS Catalysis
Table 5. One-Pot Synthesis of 2-Arylbenzofurans Containing Substituents on the Benzene Ring of the Benzofuran Moiety
Concerns the second Sonogashira reaction at 80 °C. b0.75 equiv of 2,6-diiodophenol derivative was used. cReaction time 2 h at 40 °C and 1 h at 80 °C.
a
Beside the desired product 1, 1,4-bis(trimethylsilyl)buta-1,3diyne (2) is also formed by the competitive Glaser reaction. The main influence on the formation of this byproduct has the amount of copper cocatalyst (Table 2). As expected, the Sonogashira coupling reaction accelerates with the increase of copper catalyst load, but the amount of the Glaser reaction byproduct is also increased. The reaction proceeds smoothly when 100−400 mol % of CuI are used relative to Pd(OAc)2, and the Glaser byproduct amount is almost constant in this range, 3.4−3.6%.
load have been examined for the reaction of iodobenzene and TMSA in 1,4-dioxane at the presence of diisopropylamine as a base (Table 1). It was found that the reaction proceeds smoothly when ∼150 mol % of triphenylphosphine per palladium atoms is used. A larger amount of triphenylphosphine slows down the reaction. Other phosphines, such as Buchwald ligands, gave worse results. The reaction proceeded fastest when catalyzed by Pd(OAc)2, but other palladium sources can be taken into account for specific aryl halides. 2431
DOI: 10.1021/acscatal.6b00190 ACS Catal. 2016, 6, 2429−2434
Letter
ACS Catalysis Table 6. One-Pot Synthesis of 2-Arylbenzofurans Substituted at 2-Aryl Position
a Concerns the second Sonogashira reaction at 80 °C. b1.5 equiv of 2,4-dichloro-6-iodophenol was used instead of 2-iodophenol. c1.5 equiv of 2-iodo-4,6-dimethylphenol was used instead of 2-iodophenol. dThe first Sonogashira reaction was proceed at 80 °C for 1.5 h and ethyl 5-hydroxy-6iodo-2-methylbenzofuran-3-carboxylate was used instead of 2-iodophenol.
found that this catalyst guarantee fast subsequent reactions occurring in the process in various solvents. The last factor that had to be determined was the base type (Table 4). As expected, diisopropylamine, widely used in the Sonogashira coupling reaction, proved to be the best choice for this reaction. Using the developed conditions, a group of 2-arylbenzofurans substituted on the benzene ring of the benzofuran moiety has been obtained, starting from iodobenzene and 2iodophenols (Table 5). The reaction for 2-iodophenols proceeds smoothly and generally completes in 2−4 h, giving 2-phenylbenzofurans in
To evaluate the influence of solvent on the coupling reaction rate, more-demanding 2-methoxyiodophenol was used, because the Sonogashira reaction proceeds slower for activated aromatic rings (Table 3). Toluene was the best choice both for palladium acetate and Pd(dppf)Cl2, although in special cases, when more polar environment is necessary, other solvents, such as 1,4-dioxane, acetonitrile, or DMSO, can be used. For further research [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) has been chosen because of short reaction time and no need to add the second phosphine for the reaction progress. It has been also 2432
DOI: 10.1021/acscatal.6b00190 ACS Catal. 2016, 6, 2429−2434
Letter
ACS Catalysis
When 4-ethyl-2,6-diiodophenol was used in half the amount, leaving unchanged amounts of the other reagents, only 19 has been isolated. Using this procedure, five 2-phenyl-7(phenylethynyl)benzofuran derivatives have been obtained in moderate to good yields (Table 5, entries 17−21). 2,6-Diphenylbenzo[1,2-b:5,4-b′]difuran (24) has been obtained starting from 4,6-diiodobenzene-1,3-diol, but elongated reaction time was necessary. Elongated time was also needed for reaction with 2-bromophenol (Table 5, entry 23), but the yield of 2-phenylbenzofuran was still good (78%). A similar procedure was applied for the preparation of 2-arylbenzofurans substituted at 2-aryl position (Table 6). Generally the one-pot, four-step synthesis of benzofurans proceeds smoothly for many different aryl iodides. Even hindered 2,6-dimethyliodophenol (Table 6, entry 4) reacts in good yield. Synthetically important groups, such as hydroxyl, nitro, amino, and bromine atoms, are tolerated, enabling further functionalization of the system. An exception is the carboxyl group in 2-iodocarboxylic acid, which reacts readily with ethynyl group, obtained after TMS cleavage, to give 3-methyleneisobenzofuran-1(3H)-one (40, Table 6, entry 16). The process was used for preparation of benzodifuran ligand (43) of ruthenium-based dye, which proved to be a very efficient sensitizer for dyesensitized solar cells (DSSC).7 Due to the bromoaryl used, instead of iodoaryl as the starting material, the first Sonogashira reaction with TMSA was carried out at 80 °C for 1.5 h, and the second reaction was carried at the same temperature for 20 h. The desired product was obtained in high 78% yield (Table 6, entry 19). The plausible mechanism for the one-pot 2-arylbenzofuran synthesis includes the Sonogashira reaction starting from oxidative addition of Pd0 to an aryl iodide leading to arylpalladium(II) iodide complex (a) and its transmetalation with ((trimethylsilyl)ethynyl)copper (b) to give, after reductive elimination, trimethyl(arylethynyl)silane (c) (Scheme 3). The trimethylsilyl group is immediately cleaved by the action of fluoride ions from tetrabutylammonium fluoride (TBAF), and arylacetylene (d) is transformed into (arylethynyl)copper (e). After addition of 2-iodophenol, it is converted into (2-hydroxyphenyl)palladium(II) iodide complex (f), which undergoes transmetalation with e to give 2-(arylethynyl)phenol (g) complex with palladium(II), after reductive elimination. Due to the strong electron-donating nature of the hydroxyl group, the arene ring reactivity in the Sonogashira reaction, is decreased. Higher temperature significantly accelerates the reaction. It helps also in the final step: the intramolecular nucleophilic attack of the ortho-oxygen on the carbon−carbon triple bond, leading to the desired 2-arylbenzofuran (3). Although some authors claim that the cyclization step does not require transition metals,24,47 the palladium and/or copper presence significantly accelerates the heteroannulation rate.48,49 In conclusion, a convenient one-pot, four-step synthesis of 2-arylbenzofuran derivatives, starting from aryl halides and 2-halophenols, has been developed. Factors like palladium catalyst type, copper iodide and phosphine load, base, and solvent type have been examined. The developed method involves two Sonogashira coupling reactions, followed by 2-ethynylphenol cyclization, leading to 2-arylbenzofuran derivatives. The process occurs smoothly under mild conditions giving products in good yields and can be applied to many 2-arylbenzofurans substituted both at 2-aryl position and benzodifuran moiety. Many substituents such as halogens, hydroxyl,
Scheme 3. Plausible Mechanism for the One-Pot, Four-Step 2-Arylbenzofuran Synthesis
good yields (Table 5, entries 1−14). The exception is 4-hydroxy-3-iodobenzoic acid (Table 5, entry 15), for which only 26% yield has been obtained after 24 h. When 4-ethyl-2,6diiodophenol was used in the standard amount (1.5 equiv), two products 18 and 19 have been obtained (Table 5, entry 16). 2433
DOI: 10.1021/acscatal.6b00190 ACS Catal. 2016, 6, 2429−2434
Letter
ACS Catalysis
(23) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213− 6284. (24) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280−9288. (25) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, M.B.; Hu, X.-C. J. Org. Chem. 2007, 72, 2053−2057. (26) Cano, R.; Yus, M.; Ramon, D. J. Tetrahedron 2012, 68, 1393− 1400. (27) Ohtaka, A.; Teratani, T.; Fujii, R.; Ikeshita, K.; Kawashima, T.; Tatsumi, K.; Shimomura, O.; Nomura, R. J. Org. Chem. 2011, 76, 4052−4060. (28) Ghosh, S.; Das, J.; Saikh, F. Tetrahedron Lett. 2012, 53, 5883− 5886. (29) Uozumi, Y.; Kobayashi, Y. Heterocycles 2003, 59, 71−74. (30) Pan, W.-B.; Chen, C.-C.; Wei, L.-L.; Wei, L.-M.; Wu, M.-J. Tetrahedron Lett. 2013, 54, 2655−2657. (31) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4, 4727−2729. (32) Moure, M. J.; Sanmartin, R.; Dominguez, E. Adv. Synth. Catal. 2014, 356, 2070−2080. (33) Rossy, C.; Fouquet, E.; Felpin, F.-X. Beilstein J. Org. Chem. 2013, 9, 1426−1431. (34) Yang, J.; Shen, G.; Chen, D. Synth. Commun. 2013, 43, 837− 847. (35) Wang, J.-R.; Manabe, K. J. Org. Chem. 2010, 75, 5340−5342. (36) Genin, E.; Amengual, R.; Michelet, V.; Savignac, M.; Jutand, A.; Neuville, L.; Genet, J.-P. Adv. Synth. Catal. 2004, 346, 1733−1741. (37) Ceylan, S.; Coutable, L.; Wegner, J.; Kirschning, A. Chem. - Eur. J. 2011, 17, 1884−1893. (38) Saha, D.; Dey, R.; Ranu, B. C. Eur. J. Org. Chem. 2010, 2010, 6067−6071. (39) Lin, C.-H.; Wang, Y.-J.; Lee, C.-F. Eur. J. Org. Chem. 2010, 4368−4371. (40) Anga, S.; Kottalanka, R. K.; Pal, T.; Panda, T. K. J. Mol. Struct. 2013, 1040, 129−138. (41) Pal, M.; Subramanian, V.; Yeleswarapu, K. R. Tetrahedron Lett. 2003, 44, 8221−8225. (42) Priyadarshini, S.; Joseph, P. J. A.; Srinivas, P.; Maheswaran, H.; Kantam, M. L.; Bhargava, S. Tetrahedron Lett. 2011, 52, 1615−1618. (43) Dai, W.-M.; Lai, K. W. Tetrahedron Lett. 2002, 43, 9377−9380. (44) Jaseer, E. A.; Prasad, D. J. C.; Sekar, G. Tetrahedron 2010, 66, 2077−2082. (45) Zhou, R.; Wang, W.; Jiang, Z.-J.; Wang, K.; Zheng, X.-L.; Fu, H.Y.; Chen, H.; Li, R.-X. Chem. Commun. 2014, 50, 6023−6026. (46) Cwik, A.; Hell, Z.; Figueras, F. Tetrahedron Lett. 2006, 47, 3023−3026. (47) Kundu, N. G.; Pal, M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1 1997, 2815−2820. (48) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285−2309. (49) Fürstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024− 15025.
cyano, nitro, and amino groups are tolerated, making possible further functionalization of the system.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b00190. Detailed experimental procedures, compound characterization data, IR, 1H, and 13C NMR spectra of the products (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Financial support from The National Centre for Research and Development, Warsaw, POIG.01.04.00-04-097/12 is acknowledged.
■
REFERENCES
(1) Khanam, H.; Shamsuzzaman. Eur. J. Med. Chem. 2015, 97, 483− 504. (2) Naik, R.; Harmalkar, D. S.; Xu, X.; Jang, K.; Lee, K. Eur. J. Med. Chem. 2015, 90, 379−393. (3) Radadiya, A.; Shah, A. Eur. J. Med. Chem. 2015, 97, 356−376. (4) Nevagi, R. J.; Dighe, S. N.; Dighe, S. N. Eur. J. Med. Chem. 2015, 97, 561−581. (5) Knoll, J. CNS Drug Rev. 2001, 7, 317−345. (6) Stehrer-Schmid, P.; Wolf, H.-U. Mutat. Res., Rev. Genet. Toxicol. 1995, 339, 61−72. (7) Bosiak, M. J.; Rakowiecki, M.; Wolan, A.; Szlachta, J.; Stanek, E.; Cycoń, D.; Skupień, K. Dyes Pigm. 2015, 121, 79−87. (8) Bosiak, M. J.; Rakowiecki, M.; Orłowska, K. J.; Kędziera, D.; Adams, J. Dyes Pigm. 2013, 99, 803−811. (9) Bosiak, M. J.; Jakubowska, J. A.; Aleksandrzak, K. B.; Kamiński, S.; Kaczmarek-Kędziera, A.; Ziegler-Borowska, M.; Kędziera, D.; Adams, J. Tetrahedron Lett. 2012, 53, 3923−3926. (10) Kadac, K.; Bosiak, M. J.; Nowaczyk, J. Synth. Met. 2012, 162, 1981−1986. (11) Yin, S.-C.; Zhou, Q.; Zhao, X.-Y.; Shao, L.-X. J. Org. Chem. 2015, 80, 8916−8921. (12) Speckmeier, E.; Padié, C.; Zeitler, K. Org. Lett. 2015, 17, 4818− 4821. (13) Duan, L.; Fu, R.; Zhang, B.; Shi, W.; Chen, S.; Wan, Y. ACS Catal. 2016, 6, 1062−1074. (14) De Luca, L.; Giacomelli, G.; Nieddu, G. J. Comb. Chem. 2008, 10, 517−520. (15) Ackermann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72, 6149− 6153. (16) Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem. 2007, 72, 10283−10286. (17) Mahendar, L.; Satyanarayana, G. J. Org. Chem. 2015, 80, 7089− 7098. (18) Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004, 6, 1761− 1763. (19) Liang, Y.; Tang, S.; Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-X.; Li, J.H. Org. Lett. 2006, 8, 3017−3020. (20) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137−3139. (21) Eidamshaus, C.; Burch, J. D. Org. Lett. 2008, 10, 4211−4214. (22) Zanardi, A.; Mata, J. A.; Peris, E. Organometallics 2009, 28, 4335−4339. 2434
DOI: 10.1021/acscatal.6b00190 ACS Catal. 2016, 6, 2429−2434
