Letter Cite This: Org. Lett. 2018, 20, 4430−4433
pubs.acs.org/OrgLett
Synthesis of Multisubstituted Furans via a Catalyst- and AdditiveFree Tandem Reaction of Enynones with Sulfinic Acids in Water Yue Ren,† Ling-Guo Meng,*,† Tao Peng,† and Lei Wang*,†,‡ †
Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. China
‡
Org. Lett. 2018.20:4430-4433. Downloaded from pubs.acs.org by UNIV OF MISSOURI COLUMBIA on 08/04/18. For personal use only.
S Supporting Information *
ABSTRACT: A facile and efficient tandem reaction of enynones with arylsulfinic acids was developed. A variety of multisubstituted furans were obtained in satisfactory yields via an O2-oxidative single-electron-transfer process without any catalyst and additive in water.
uran, as a classic five-membered aromatic heterocyclic compound, extensively exists in natural molecules, biological compounds, and pharmaceutical ingredients, showing significant activity such as antipneumocystis carinii activity, Plasmodium falciparum inhibitors, phytotoxicity toward Raphanus sativus, and a potent glucagon receptor antagonist (Figure 1).1 Furthermore, furan and its derivatives can also be used as
F
emerging as focal substrates due to their good diversity of reaction activity in the construction of furan molecules. Among this research area, the mainstream furan syntheses rely on a transition-metal catalyst to induce intramolecular carbonyl oxycyclization onto an alkyne bond in enynones, and representative examples are shown in Scheme 1a−c. For example, Wang reported a cycloaddition of enynones with a halogenated hydrocarbon to form a substituted furan in the presence of a Pd-catalyst;4a Chang and Zhu achieved the Scheme 1. Representative Examples for the Synthesis of Substituted Furans
Figure 1. Biologically active molecules with a furan framework.
an important synthetic precursor for producing complicated compounds. 2 Accordingly, many protocols have been developed for the synthesis of substituted furans.3 Nevertheless, most reported transformations require an expensive or scarce catalyst, an additive, a toxic solvent, high temperature, and intricate operations. Due to these drawbacks, the development of more simple and environment-friendly methodology to construct a furan skeleton from simple and readily available starting materials has become an important challenge for organic chemists. Recently, ene-yne-ketones are prepared easily through condensation of propargyl aldehyde with 1,3-diketones, © 2018 American Chemical Society
Received: May 31, 2018 Published: July 20, 2018 4430
DOI: 10.1021/acs.orglett.8b01714 Org. Lett. 2018, 20, 4430−4433
Letter
Organic Letters
as THF, EtOH, and DMF were used as solvents (Table 1, entries 5−7). When the reaction time was reduced or prolonged, no better yields were obtained (Table 1, entries 9 and 10). Only a trace amount of 3aa was observed when the reaction was conducted at room temperature, and a 90% yield of 3aa was generated when the reaction was performed at 120 °C for 3 h (Table 1, entries 11 and 12). With the optimized reaction conditions in hand, the generality of this tandem reaction was investigated, as shown in Scheme 2. Different arylsulfinic acids were subjected to the
construction of furan derivatives from cyclization of amine compounds with conjugated enynones using a Rh-catalyst;5 Zhou and Jiang developed a Cu-catalyzed tandem annulation to give phosphorylated and boronated furans, respectively.6 Significant progress was found by synthesizing multisubstituted furans under mild conditions using Zn-,7 Ag-,8 or Au-salt9 as the catalyst. Another significant breakthrough for the construction of furans was by using organocatalytic approaches, shown in Scheme 1d, with better operability.10 Therefore, development of a more convenient and environmentally benign method for the preparation of substituted furans is highly desirable. Arylsulfinic acids are stable and widely used substrates owing to their diversity of structural variability (such as sulfonyl radical, sulfoxide cation, and sulfonyl anion) during organic transformations.11−13 We attempted the reaction of arylsulfinic acids with ene-yne-ketones; gratifyingly, sulfonyl substituted furans were obtained without any catalyst and additive under an air atmosphere (Scheme 1e). Although there were a few reports for the synthesis of furans without catalyst, the reactions often occur in the presence of auxiliary conditions and poisonous solvent.11 Herein, we report a facile strategy for the synthesis of sulfonyl substituted furans from ene-yneketones and arylsulfinic acids under metal-, catalyst-, and additive-free conditions in water. Initially, 3-(3-phenylprop-2-yn-1-ylidene)pentane-2,4-dione (1a) and 4-methylbenzenesulfinic acid (2a) were selected as the model substrates for optimization of the reaction conditions. When the mixture of 1a and 2a was stirred in CH2Cl2 at 80 °C under air for 3 h, the reaction resulted in the formation of the sulfonyl substituted furan 3aa in 64% yield (Table 1, entry 1), and its structure was determined by NMR spectroscopy and HRMS analysis. Further survey of different solvents demonstrated that H2O was the best choice among those tested (Table 1, entries 1−8). Much lower yields (27− 34%) were obtained when the model reaction was performed in toluene, EtOAc, and DMSO (Table 1, entries 2−4). The reaction failed, and most of the raw materials were recovered,
Scheme 2. Scope of Arylsulfinic Acidsa,b
Table 1. Optimization of the Reaction Conditionsa
entry
solvent
temp (°C)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12
CH2Cl2 toluene EtOAc DMSO THF EtOH DMF H2O H2O H2O H2O H2O
80 80 80 80 80 80 80 80 80 80 rt 120
64 34 30 27 NDc NDc NRd 94 37e 81f trace 90
a Reaction conditions: 1 (0.25 mmol), 2 (0.20 mmol), and H2O (2.0 mL), in air, at 80 °C for 3 h. bIsolated yield. cAt 120 °C. dHAc (0.20 mmol) was added.
reaction, and the expected products were generated with satisfactory yields. It should be noted that arylsulfinic acids with either an electron-rich or -poor group on the paraposition of benzene rings could be converted to corresponding products with good functional group tolerance in most cases. When the benzenesulfinic acid was employed in the reaction, the desired product 3ab was produced in 78% yield. A modest yield of 3ac was obtained using arylsulfinic acid with a strong electron-donating group (MeO) on the aromatic ring. Furthermore, arylsulfinic acids with an electron-withdrawing group, such as F, Cl, Br, I, or CN on the para-position of the benzene rings, reacted with 1a to afford corresponding
a
Reaction conditions: 1a (0.25 mmol), 2a (0.20 mmol), and solvent (2.0 mL) in air at 80 °C for 3 h. bIsolated yield. cND = No desired product was detected. dNR = No reaction. eThe reaction for 1 h. fThe reaction for 12 h. 4431
DOI: 10.1021/acs.orglett.8b01714 Org. Lett. 2018, 20, 4430−4433
Letter
Organic Letters products (3ad−ah) in 70−86% yields. Meanwhile, substrates 2 with F, Cl, or CN on the meta-position of the phenyl rings gave the desired products 3ai−ak in 72−85% yields. When a Cl or Br group was located at the ortho-position of the benzene rings in arylsulfinic acids, the corresponding products 3al and 3am were obtained in 90% and 84% yields, respectively, indicating no obvious ortho-position effect. Furthermore, naphthalene-2sulfinic acid and 4-acetamidobenzenesulfinic acid reacted with 1a to produce the anticipated products (3an and 3ao) in 79% and 82% yields, respectively. Next, disubstituted arylsulfinic acids, such as 2,4-difluoro-, 3,5-difluoro-, 2,4-dichloro-, 3,4dichloro-, 3,5-dichloro-, 3-chloro-2-methyl-, and 3-fluoro-4methyl-benzenesulfinic acids, were also suitable for this transformation, and 50−89% yields of 3ap−av were achieved. When the scope of sulfinic acid was switched to aliphatic ones, the anticipant products 3aw and 3ax were obtained in 84% and 70% yields, respectively. When the model reaction was performed on a gram scale, a 72% yield of 3aa was obtained. Subsequently, the range of substrates was expanded to a variety of enynones 1, and the detailed results are listed in Scheme 3. The enynones 1 bearing a methyl (1b) or halide (F
Scheme 4. Control Experiments
reaction was mainly achieved via an O2-oxidative free radical process. Natural light had no obvious effect on the reaction as determined through a light avoidance experiment (Scheme 4c). Meanwhile, no obvious difference in product yield was observed when the reaction occurred in CH2Cl2 under N2, compared with the reaction in H2O under N2 (Scheme 4d vs 4b). Further consideration of the results in Scheme 4e and 4f of the control experiments indicate that the hydrogen atom in 3aa located at the α-position of the sulfonyl group is from water or sulfinic acid, and the O2-oxidative single-electrontransfer radical procedure during formation of substituted furans is the main process. Based on the above results and previous related reports,10,11 a plausible reaction mechanism is proposed for the tandem reaction, as shown in Scheme 5. First, 4-methylbenzenesulfinic
Scheme 3. Scope of Enynonesa,b
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1 (0.25 mmol), 2a (0.20 mmol), and H2O (2.0 mL), in air at 120 °C for 3 h. bIsolated yield.
or Cl; 1c or 1d) on the phenyl rings reacted smoothly with 2a, providing the corresponding products (3ba−da) in 76−90% yields. Treatment of 4-(3-phenylprop-2-yn-1-ylidene)heptane3,5-dione 1e with 2a afforded the desired product 3ea in 81% yield. 1,3-Diphenyl-2-(3-phenylprop-2-yn-1-ylidene)propane1,3-dione 1f was also a suitable substrate to give furan product 3fa, albeit only in 32% yield; meanwhile, about 35% of 1f was recovered. Particularly notable is that unsymmetric substrates 1g and 1h could also generate the substituted furans 3ga and 3ha in moderate yields with good regioselectivity. To improve the solubility of the substrates involved in the reaction, the reaction temperature was elevated from 80 to 120 °C to obtain higher yields of the products. In order to gain insight into the reaction mechanism, several control experiments were conducted, as depicted in Scheme 4. When the model reaction of 1a and 2a was in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or under a nitrogen atmosphere, the model reaction was obviously inhibited (Scheme 4a and 4b), which implied that this tandem
acid 2a was decomposed in water to form sulfinyl anion A, which was transformed into radical B in the presence of air. The formed B resonated with sulfonyl radical C under an air atmosphere, but 1O2 was not observed by electron spin resonance (ESR) analysis; see the Supporting Information (SI).11 Subsequently, sulfonyl radical C attacked enynone 1a to generate an enolate radical D, which underwent an intramolecular cyclization to give an radical intermediate E. It should be noted that intermediate D or E was detected by HRMS analysis in Scheme 4a, but we could not be sure which one (D or E) could couple with TEMPO (see SI for detail). When the model reaction included addition of 5,5-dimethyl-1pyrroline-N-oxide (DMPO), a capture agent, a signal for the 4432
DOI: 10.1021/acs.orglett.8b01714 Org. Lett. 2018, 20, 4430−4433
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Organic Letters
(4) (a) Xia, Y.; Qu, S.; Xiao, Q.; Wang, Z.-X.; Qu, P.; Chen, L.; Liu, Z.; Tian, L.; Huang, Z.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2013, 135, 13502. (b) Xia, Y.; Chen, L.; Qu, P.; Ji, G.; Feng, S.; Xiao, Q.; Zhang, Y.; Wang, J. J. Org. Chem. 2016, 81, 10484. (5) (a) Hong, S. Y.; Jeong, J.; Chang, S. Angew. Chem., Int. Ed. 2017, 56, 2408. (b) Luo, H.; Chen, K.; Jiang, H.; Zhu, S. Org. Lett. 2016, 18, 5208. (6) (a) Yang, J.-M.; Li, Z.-Q.; Li, M.-L.; He, Q.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2017, 139, 3784. (b) Yu, Y.; Yi, S.; Zhu, C.; Hu, W.; Gao, B.; Chen, Y.; Wu, W.; Jiang, H. Org. Lett. 2016, 18, 400. (c) Yu, Y.; Chen, Y.; Wu, W.; Jiang, H. Chem. Commun. 2017, 53, 640. (7) (a) Vicente, R.; González, J.; Riesgo, L.; González, J.; López, L. A. Angew. Chem., Int. Ed. 2012, 51, 8063. (b) González, J.; González, J.; Pérez-Calleja, C.; López, L. A.; Vicente, R. Angew. Chem., Int. Ed. 2013, 52, 5853. (c) González, J.; López, L. A.; Vicente, R. Chem. Commun. 2014, 50, 8536. (d) Mata, S.; López, L. A.; Vicente, R. Chem. - Eur. J. 2015, 21, 8998. (e) Song, B.; Li, L.-H.; Song, X.-R.; Qiu, Y.-F.; Zhong, M.-J.; Zhou, P.-X.; Liang, Y.-M. Chem. - Eur. J. 2014, 20, 5910. (8) Dong, J.; Bao, L.; Hu, Z.; Ma, S.; Zhou, X.; Hao, M.; Li, N.; Xu, X. Org. Lett. 2018, 20, 1244. (9) (a) Liu, P.; Sun, J. Org. Lett. 2017, 19, 3482. (b) Luo, H.; Chen, K.; Jiang, H.; Zhu, S. Org. Lett. 2016, 18, 5208. (10) (a) Clark, J. S.; Boyer, A.; Aimon, A.; García, P. E.; Lindsay, D. M.; Symington, A. D. F.; Danoy, Y. Angew. Chem., Int. Ed. 2012, 51, 12128. (b) Liang, L.; Dong, X.; Huang, Y. Chem. - Eur. J. 2017, 23, 7882. (c) Zhu, C.-Z.; Sun, Y.-L.; Wei, Y.; Shi, M. Adv. Synth. Catal. 2017, 359, 1263. (11) (a) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.; Wang, H.; Liu, Z.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 7156. (b) Lu, Q.; Zhang, J.; Zhao, G.; Qi, Y.; Wang, H.; Lei, A. J. Am. Chem. Soc. 2013, 135, 11481. (c) Shen, T.; Yuan, Y.; Song, S.; Jiao, N. Chem. Commun. 2014, 50, 4115. (d) Lu, Q.; Zhang, J.; Peng, P.; Zhang, G.; Huang, Z.; Yi, H.; Miller, J. T.; Lei, A. Chem. Sci. 2015, 6, 4851. (e) Xia, D.; Li, Y.; Li, P.; Wang, L. Chem. Commun. 2016, 52, 11559. (f) Wang, H.; Lu, Q.; Chiang, C.-W.; Luo, Y.; Zhou, J.; Wang, G.; Lei, A. Angew. Chem., Int. Ed. 2017, 56, 595. (g) Xu, J.; Yu, X.; Yan, J.; Song, Q. Org. Lett. 2017, 19, 6292. (h) Xia, D.; Li, Y.; Miao, T.; Li, P.; Wang, L. Chem. Commun. 2016, 52, 11559. (i) Yuan, Z.; Wang, H.-Y.; Mu, X.; Chen, P.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc. 2015, 137, 2468. (12) Miao, T.; Li, P.; Zhang, Y.; Wang, L. Org. Lett. 2015, 17, 832. (13) (a) Xi, Y.; Dong, B.; McClain, E. J.; Wang, Q.; Gregg, T. L.; Akhmedov, N. G.; Petersen, J. L.; Shi, X. Angew. Chem., Int. Ed. 2014, 53, 4657. (b) Li, W.; Yin, G.; Huang, L.; Xiao, Y.; Fu, Z.; Xin, X.; Liu, F.; Li, Z.; He, W. Green Chem. 2016, 18, 4879. (14) (a) Nakatani, K.; Maekawa, S.; Tanabe, K.; Saito, I. J. Am. Chem. Soc. 1995, 117, 10635. (b) Nakatani, K.; Adachi, K.; Tanabe, K.; Saito, I. J. Am. Chem. Soc. 1999, 121, 8221. (c) González-Pelayo, S.; López, L. A. Adv. Synth. Catal. 2016, 358, 4114. (15) Xie, P.; Wang, J.; Liu, Y.; Fan, J.; Wo, X.; Fu, W.; Sun, Z.; Loh, T.-P. Nat. Commun. 2018, 9, 1321.
hydroxyl radical was observed by electron paramagnetic resonance (EPR) spectrometer (see SI for detail). Finally, intermediate E abstracted a hydrogen atom from H2O and 2a to afford desired product 3aa. On the basis of the results of Scheme 4b and 4d, the desired product 3aa might be formed in the presence of N2 through another reaction pathway, which might be achieved by a cooperative effect between the carbonyl group of 1a and 2a via a hydrogen bond.15 In conclusion, we have developed a convenient and maneuverable synthetic platform for the synthesis of sulfonyl substituted furans through an O2-oxidative radical tandem cycloaddition of enynones with arylsulfinic acids in water without any catalyst and additive. This tandem reaction tolerated a broad range of functional groups and produced a variety of substituted furans with high efficiency. Further efforts on the development of an environment-friendly, practical, and simple synthetic method for obtaining complicated heterocycles from easily available reagents are currently underway in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01714.
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Full experimental details and characterization data for all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Lei Wang: 0000-0001-6580-7671 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21772062, 21572078, 21402061), the Young Talent Key Project of Anhui Province (gxyqZD2016411), and the Natural Science Foundation of Anhui (1708085MB45) for financial support of this work.
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REFERENCES
(1) (a) Rahmathullah, S. M.; Hall, J. E.; Bender, B. C.; McCurdy, D. R.; Tidwell, R. R.; Boykin, D. W. J. Med. Chem. 1999, 42, 3994. (b) Krake, S. H.; Martinez, P. D. G.; McLaren, J.; Ryan, E.; Chen, G.; White, K.; Charman, S. A.; Campbell, S.; Willis, P.; Dias, L. C. Eur. J. Med. Chem. 2017, 126, 929. (c) Matusiak, A.; Lewkowski, J.; Rychter, P.; Biczak, R. J. Agric. Food Chem. 2013, 61, 7673. (d) Hasegawa, F.; Niidome, K.; Migihashi, C.; Murata, M.; Negoro, T.; Matsumoto, T.; Kato, K.; Fujii, A. Bioorg. Med. Chem. Lett. 2014, 24, 4266. (2) (a) Zhang, Z.; Huber, G. W. Chem. Soc. Rev. 2018, 47, 1351. (b) Keay, B. A. Chem. Soc. Rev. 1999, 28, 209. (c) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008, 41, 1001. (3) (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955 and references cited therein. (b) He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A. J. Am. Chem. Soc. 2012, 134, 5766. (c) Tang, S.; Liu, K.; Long, Y.; Qi, X.; Lan, Y.; Lei, A. Chem. Commun. 2015, 51, 8769. 4433
DOI: 10.1021/acs.orglett.8b01714 Org. Lett. 2018, 20, 4430−4433
