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O-alkylation reactions of para-quinone methides
Tetrahedron 74 (2018) 1492e1496
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Facile synthesis of 3-aryl 2,3-dihydrobenzofurans via novel domino 1,6-addition/O-alkylation reactions of para-quinone methides Jing Zhou, Guojuan Liang, Xiangnan Hu, Liping Zhou, Hui Zhou* School of Pharmaceutical Science, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing 400016, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 December 2017 Received in revised form 25 January 2018 Accepted 2 February 2018 Available online 3 February 2018
A facile K2CO3-promoted novel domino 1,6-addition/O-alkylation reaction of orthohydroxyphenylsubstituted p-QMs and diethyl bromomalonate is described. A variety of new 3-aryl 2,3-dihydrobenzofurans were obtained in excellent yields (up to 99%) under simple and mild conditions. The structure of the new compound 3f was determined by single crystal X-ray analysis. © 2018 Elsevier Ltd. All rights reserved.
Keywords: 1,6-Addition/O-alkylation Domino reaction Ortho-Hydroxyphenylsubstituted p-QMs Diethyl bromomalonate 3-Aryl 2,3-dihydrobenzofurans
1. Introduction 2,3-dihydrobenzofuran derivatives are core structural motifs in a wide array of natural products and biologically active molecules.1 They are present in molecules acting as antifungal, insecticidal, antitrypanosomal agents,1c,1d potent inducers of anticarcinogenic marker enzyme, quinone reductase1e and anti-multidrug resistant agents.1g The significance of these molecules has led to a variety of methodologies for the construction of 2,3-dihydrobenzofurans, including transition metal-mediated cyclization,2 electrocyclization,3 radical cyclization,4 organocatalytic and dehydrative techniques,5 biomimetic coupling,6 benzyne,7 anionic,8 and cycloaddition.9 However, most of these existing routes have drawbacks involving poor chemoselectivities, unsatisfactory yields, tedious processes and harsh reaction conditions, impeding their wider application. Thus, the development of an efficient, convenient and mild method for the preparation of these derivatives is strongly useful and desirable. Recently, para-quinone methides (p-QMs) have increasingly been investigated to construct diarylmethine compounds via 1,6conjugate addition.10 Applications of the p-QMs in domino
* Corresponding author. E-mail address: [email protected] (H. Zhou). https://doi.org/10.1016/j.tet.2018.02.008 0040-4020/© 2018 Elsevier Ltd. All rights reserved.
reactions have less been explored and all these reports are 1,6conjugate addition induced dearomatization domino reactions to construct spiro-cyclohexadienones.11 Enders and co-workers firstly designed ortho-hydroxyphenylsubstituted p-QMs as ideal donorMichael acceptor substrates and applied this p-QMs in organocatalytic oxa-Michael/1,6-addition domino reactions to construct chromans bearing oxindole scaffolds.12 Shortly after this report, Li's group applied this ortho-hydroxyphenylsubstituted p-QMs with azlactones,13 malononitrile and b-functionalized ketones14 in 1,6addition/aromatization domino reactions to generate various chroman skeletons. Furthermore, Jiang's group reported Ag/BiNPO4H co-catalyzed 1,6-addition/aromatization domino reactions between this p-QMs and b-alkynyl ketones for highly diaseteroselective synthesis of spiro[chromane-2,10 -isochromene] derivatives.15 These few reports demonstrated orthohydroxyphenylsubstituted p-QMs was ideal donor-Michael acceptor synthons, which could be effectively used in 1,6addition/aromatization domino processes to construct various aryl substituted oxygen-containing benzoheterocycles. However, in these reports, reaction substrate scope was limited, and cyclization products were also limited to chroman skeletons. Given the appeal for exploring new methodology with this p-QMs and as part of our continued interest in the construction of novel drug candidates,16 herein, we envisioned that a new 1,6-addition/O-alkylation domino reaction of ortho-hydroxyphenylsubstituted p-QMs with
J. Zhou et al. / Tetrahedron 74 (2018) 1492e1496
diethyl bromomalonate might provide a novel approach for the construction of 3-aryl 2,3-dihydrobenzofurans skeletons (Scheme 1). Our preliminary studies involved 1a and diethyl bromomalonate 2a as model substrates to examine the feasibility of this process, these were allowed to react in dichloromethane at room temperature in the presence of 200 mol% K2CO3. The reaction worked smoothly and afforded the desired product 3a in 92% yield via 1,6-addition/O-alkylation domino process (Table 1, entry 1).
2. Results and discussion To evaluate the reactivity of this system, the reaction of 1a with diethyl bromomalonate 2a was used as a model reaction, and a series of bases were investigated in dichloromethane at room temperature, and the results were shown in Table 1. Strong base KOH gave trace product because side products were produced (Table 1, entry 2). Et3N and DABCO both decreased reaction rate. Et3N afforded moderate yield. DABCO gave trace product (Table 1, entries 3 and 4). K2CO3 gave the highest yield and was chosen as the most suitable base (92% yield, Table 1, entry 1). Next, the reaction was conducted in various solvents (Table 1, entries 5e9). The solvents have great influence on the reaction rate. CH3CN and THF greatly accelerated the reaction rate. THF gave higher yield. CH3CN gave lower yield, because side products were produced. CH2Cl2, CHCl3, toluene and EtOAc gave good yields but poor reactivities, needed longer reaction time. In terms of yield and reactivity, THF was the most suitable reaction media and was selected for further optimization (Table 1, entry 6). Afterward, the loading of K2CO3 was investigated. Decreasing the loading of K2CO3 to 100 mol%, lower yield was obtained (Table 2, entry 2). Increasing the loading of K2CO3 didn't obtain higher yield (Table 2, entry 3). Having identified 200 mol% K2CO3 as the optimal loading for the reaction, we next examined the effect of the reaction temperature (Table 2, entries 4 and 5). A screening of different reaction temperatures showed that the reaction gave the best results at room temperature (Table 2, entry 1). Decreasing reaction temperature slowed down the reaction rate, needed longer reaction time (Table 2, entry 4). Increasing the reaction temperature also slightly decreased the yield because side products were produced (Table 2, entry 5). Finally, the substrate concentration was examined (Table 2, entries 6 and 7). It was found that increasing the substrate concentration slightly decreased the yield (Table 2, entry 6), lowering the substrate concentration decreased the reaction rate and gave lower yield (Table 2, entry 7), 0.2 M was the optimal substrate concentration. Consequently, the following reaction conditions are recommended: 200 mol% K2CO3 with 0.2 M substrate in THF at room temperature (Table 2, entry 1) (see Table 3). With optimized reaction conditions established, the substrate scope of this domino reaction was explored. First, we evaluated the generality of various functional groups substituted orthohydroxyphenylsubstituted p-QMs 1 (3a-3k). In general, the substrates bearing both electron-withdrawing groups and electron-
Scheme 1. Domino 1,6-addition/O-alkylation reactions to form functionalized 3-aryl 2,3-dihydrobenzofurans.
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Table 1 Optimization of reaction conditions.a
Entry
Base
Solvent
Time (h)
Yieldb (%)
1 2 3 4 5 6 7 8 9
K2CO3 KOH Et3N DABCO K2CO3 K2CO3 K2CO3 K2CO3 K2CO3
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 THF toluene EtOAc CH3CN
24 24 24 24 24 7 18 14 5
92 trace 55 trace 90 96 93 89 80
a Unless otherwise noted, reactions were conducted with 0.2 mmol 1a, 0.2 mmol 2a, 200 mol % base, in 1.0 mL solvent at rt. b Isolated yields.
Table 2 Optimization of reaction conditions.a
Entry
x
Temp ( C)
Yieldb(%)
1 2 3 4c 5 6d 7e
200 100 300 100 100 100 100
25 25 25 0 50 25 25
96 78 94 85 90 91 88
a Unless otherwise noted, reactions were conducted with 0.2 mmol 1a, 0.2 mmol 2a, x mol % K2CO3, in 1.0 mL THF. b Isolated yields. c Reaction time was 24 h. d 0.5 mL CHCl3 was used. e 2.0 mL CHCl3 was used.
donating groups in para, meta and ortho positions of the phenyl ring were all tolerated in this reaction to afford the corresponding products in good yields (3a-3i). The position of the substituents on the phenyl ring affected the reaction rate slightly. The substrates bearing groups in ortho positions of the phenyl ring needed longer reaction time compared with para and meta positions (3g and 3i). Furthermore, the substrate 1j, which contained naphthyl moiety, also participated in this process and gave the desired product 3j in 97% yield. When we replaced the tertbutyl group of the QMs by isopropyl group, the desired product 3k was obtained in 98% yield with longer reaction time. In addition, diethyl chloromalonate was also tested, also provided good yield with longer reaction time. The structure of 3f was determined by an X-ray analysis of single crystal (Fig. 1).17 We also attempted to develop a catalytic asymmetric version of this process to access chiral 3-aryl 2,3-dihydrobenzofuran product. After a series of efforts, we found the reaction of 1a and 2a with quinine as chiral catalyst could afford the product 3a in 93% yield but with only 10% ee (Scheme 2). Despite the result is not satisfactory, this example indicates this catalytic enantioseclective domino reaction is promising.
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J. Zhou et al. / Tetrahedron 74 (2018) 1492e1496
Table 3 Scope of substratesa.
Scheme 2. A tentative study of the catalytic asymmetric version for the domino reaction.
Fig. 1. X-ray crystal structure of product 3f.
3. Conclusions We have developed a facile K2CO3-promoted novel domino 1,6-
addition/O-alkylation reaction of ortho-hydroxyphenylsubstituted p-QMs and diethyl bromomalonate. The reaction conditions are simple and mild. With this protocol, a wide range of new 3-aryl 2,3dihydrobenzofurans were smoothly obtained in excellent yields (up to 99%). This new methodology was also extended to asymmetric organocatalysis. Further studies on the application of highly reactive ortho-hydroxyphenylsubstituted p-QMs as bifunctional substrates in organic synthesis and the asymmetric version of the reactions are in progress in our laboratory.
J. Zhou et al. / Tetrahedron 74 (2018) 1492e1496
4. Experimental section 4.1. General method Various functional groups substituted orthohydroxyphenylsubstituted p-QMs 1 were prepared according to literature method.1 Diethyl bromomalonate 2a and diethyl chloromalonate 2b were purchased from commercial suppliers and used without further purification. Commercial grade solvents were dried and purified by standard procedures as specified in Purification of Laboratory Chemicals, 4th Ed (Armarego, W. L. F.; Perrin, D. D. Butterworth Heinemann: 1997). 1H NMR spectra were recorded on commercial instruments (400 MHz). Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3, d ¼ 7.26). Spectra are reported as follows: chemical shift (d ppm), multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), coupling constants (Hz), integration, and assignment. 13C NMR spectra were collected on commercial instruments (100 MHz) with complete proton decoupling. Chemical shifts are reported in ppm from the tetramethylsilane with the solvent resonance as internal standard (CDCl3, d ¼ 77.0). Mass spectra were recorded on Xevo G2-S QTof tandem mass spectrometer. Reactions were monitored by TLC and visualized with ultraviolet light. 4.2. General procedure for the domino Michael/O-alkylation reaction A solution of ortho-hydroxyphenylsubstituted p-QMs 1 (0.2 mmol, 1 equiv), diethyl halogenated-malonate 2 (0.2 mmol, 1 equiv) in THF (1.0 mL) was stirred at room temperature and K2CO3 (0.4 mmol, 200 mol%) was added at the same temperature. The reaction mixture was stirred at room temperature for certain time and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent PE: EtOAc ¼ 10:1) to afford pure products 3. 4.2.1. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran2,2(3H)-dicarboxylate (3a) Light yellow solid; 96% yield; mp 121.5e122.6 C. HPLC conditions: Chiralcel IA column, Hexane/i-PrOH ¼ 98:2, flow rate 1.0 mL/ min, UV detection at 210 nm, retention time: 6.72 min (major) and 5.25 min (minor). 1H NMR (CDCl3, 400 MHz) d 0.78 (t, J ¼ 7.16 Hz, 3H), 1.29e1.37 (m, 21H), 3.50e3.58 (m, 1H), 3.71e3.77 (m, 1H), 4.24e4.37 (m, 2H), 5.15 (s, 1H), 5.47 (s, 1H), 6.81 (m, 3H), 6.93 (t, J ¼ 7.40 Hz, 2H), 7.02e7.19 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 13.5, 14.1, 29.7, 30.3, 34.2, 54.1, 61.5, 62.6, 93.6, 109.9, 122.1, 125.3, 126.1, 128.8, 135.5, 153.4, 158.1, 166.1, 167.6; HRMS (ESI-TOF) Calcd. for C28H37O6[MþH]þ: 469.2590; Found: 469.2597. 4.2.2. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5methoxybenzofuran-2,2(3H)-dicarboxylate (3b) Yellow solid; 99% yield; mp 89.1e90.7 C. 1H NMR (CDCl3, 400 MHz) d 0.71 (t, J ¼ 7.16 Hz, 3H), 1.21e1.30 (m, 21H), 3.43e3.52 (m, 1H), 3.64 (s, 3H), 3.68e3.70 (m, 1H), 4.16e4.29 (m, 2H), 5.08 (s, 1H), 5.35 (s, 1H), 6.54 (s, 1H), 6.68 (m, 1H), 6.85e6.89 (m, 2H), 7.19 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 13.5, 14.0, 30.3, 34.3, 54.5, 56.0, 61.4, 62.6, 94.0, 110.2, 110.8, 114.7, 126.1, 128.3, 129.5, 135.5, 152.2, 153.3, 155.2, 166.1, 167.7; HRMS (ESI-TOF) Calcd. for C29H39O7[MþH]þ: 499.2696; Found: 499.2672. 4.2.3. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5methylbenzofuran-2,2(3H)-dicarboxylate (3c) White solid; 97% yield; mp 192.0e193.0 C. 1H NMR (CDCl3,
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400 MHz) d 0.78 (t, J ¼ 7.16 Hz, 3H), 1.26e1.37 (m, 21H), 2.24 (s, 3H), 3.51e3.59 (m, 1H), 3.71e3.77 (m, 1H), 4.22e4.36 (m, 2H), 5.12 (s, 1H), 5.40 (s, 1H), 6.87e7.01 (m, 4H), 7.26 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 13.5, 14.0, 15.3, 30.3, 34.3, 54.5, 61.5, 62.4, 93.4, 120.0, 121.8, 122.7, 126.3, 127.8, 128.5, 130.1, 135.4, 153.2, 156.8, 166.3, 167.8; HRMS (ESI-TOF) Calcd. for C29H39O6[MþH]þ: 483.2747; Found: 483.2758. 4.2.4. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5fluorobenzofuran-2,2(3H)-dicarboxylate (3d) White solid; 93% yield; mp 192.0e193.0 C. 1H NMR (CDCl3, 400 MHz) d 0.70 (t, J ¼ 7.16 Hz, 3H), 1.22e1.30 (m, 21H), 3.44e3.52 (m, 1H), 3.64e3.72 (m, 1H), 4.17e4.30 (m, 2H), 5.10 (s, 1H), 5.37 (s, 1H), 6.69 (d, J ¼ 7.84 Hz, 1H), 6.80e6.89 (m, 3H), 7.19 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 13.4, 14.0, 30.2, 34.3, 54.2, 61.6, 62.7, 94.2, 110.3 (d, J ¼ 8.5 Hz), 112.2 (d, J ¼ 25.1 Hz), 115.2, 115.4, 126.0, 127.8, 130.2 (d, J ¼ 8.7 Hz), 135.7, 153.5 (d, J ¼ 55.0 Hz), 157.2 (d, J ¼ 237.3 Hz), 165.9, 167.4; 19F NMR (376 MHz, CDCl3) d -122.7. HRMS (ESI-TOF) Calcd. for C28H36FO6[MþH]þ: 487.2496; Found: 487.2487. 4.2.5. Diethyl 5-chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl) benzofuran-2,2(3H)-dicarboxylate (3e) Yellow solid; 98% yield; mp 103.6e104.8 C. 1H NMR (CDCl3, 400 MHz) d 0.70 (t, J ¼ 7.16 Hz, 3H), 1.22e1.30 (m, 21H), 3.44e3.52 (m, 1H), 3.64e3.72 (m, 1H), 4.17e4.30 (m, 2H), 5.11 (s, 1H), 5.35 (s, 1H), 6.86e6.96 (m, 4H), 7.10 (d, J ¼ 9.76 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 13.4, 14.0, 30.2, 34.3, 54.0, 61.6, 62.8, 94.1, 111.0, 125.4, 126.0, 126.9, 127.8, 128.8, 135.7, 153.5, 156.7, 165.7, 167.2; HRMS (ESITOF) Calcd. for C28H36ClO6[MþH]þ: 503.2200; Found: 503.2231. 4.2.6. Diethyl 5-bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl) benzofuran-2,2(3H)-dicarboxylate (3f) Light yellow solid; 95% yield; mp 107.6e108.5 C. 1H NMR (CDCl3, 400 MHz) d 0.70 (t, J ¼ 7.12 Hz, 3H), 1.22e1.31 (m, 21H), 3.44e3.52 (m, 1H), 3.64e3.70 (m, 1H), 4.17e4.30 (m, 2H), 5.11 (s, 1H), 5.36 (s, 1H), 6.83e6.86 (m, 3H), 7.10 (s, 1H), 7.23 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 13.4, 14.0, 30.2, 34.3, 53.9, 61.6, 62.8, 94.1, 111.7, 114.0, 126.0, 127.6, 127.7, 128.3, 131.3, 135.7, 153.5, 157.2, 165.7, 167.2; HRMS (ESI-TOF) Calcd. for C28H36BrO6[MþH]þ: 547.1695; Found: 547.1706. 4.2.7. Diethyl 5,7-dichloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl) benzofuran-2,2(3H)-dicarboxylate (3g) Yellow solid; 91% yield; mp 129.5e130.9 C. 1H NMR (CDCl3, 400 MHz) d 0.76 (t, J ¼ 7.12 Hz, 3H), 1.30e1.38 (m, 21H), 3.50e3.58 (m, 1H), 3.71e3.77 (m, 1H), 4.26e4.40 (m, 2H), 5.21 (s, 1H), 5.52 (s, 1H), 6.94 (m, 2H), 7.25 (d, J ¼ 7.92 Hz, 2H); 13C NMR (CDCl3, 100 MHz) d 13.4, 13.9, 30.2, 34.3, 54.7, 61.7, 62.9, 94.3, 99.9, 116.0, 123.6, 126.1, 126.9, 129.0, 131.8, 135.9, 153.3, 153.7, 165.1, 166.8; HRMS (ESI-TOF) Calcd. for C28H35Cl2O6[MþH]þ: 537.1811; Found: 537.1802. 4.2.8. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-6methoxybenzofuran-2,2(3H)-dicarboxylate (3h) Yellow solid; 96% yield; mp 107.5e108.6 C. 1H NMR (CDCl3, 400 MHz) d 0.77 (t, J ¼ 7.12 Hz, 3H), 1.29e1.37 (m, 21H), 3.48e3.56 (m, 1H), 3.72e3.75 (m, 1H), 3.80 (s, 3H), 4.26e4.40 (m, 2H), 5.14 (s, 1H), 5.40 (s, 1H), 6.49 (d, J ¼ 9.40 Hz, 1H), 6.62 (s, 1H), 6.91e6.96 (m, 2H), 7.26 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 13.2, 14.0, 30.3, 34.2, 53.5, 55.5, 61.5, 62.6, 94.3, 96.2, 108.1, 120.4, 125.6, 126.0, 128.8, 135.4, 153.3, 159.4, 160.8, 166.0, 167.6; HRMS (ESI-TOF) Calcd. for C29H39O7[MþH]þ: 499.2696; Found: 499.2672.
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J. Zhou et al. / Tetrahedron 74 (2018) 1492e1496
4.2.9. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-7methylbenzofuran-2,2(3H)-dicarboxylate (3i) White solid; 90% yield; mp 115.8e117.3 C. 1H NMR (CDCl3, 400 MHz) d 0.77 (t, J ¼ 7.12 Hz, 3H), 1.29e1.37 (m, 21H), 2.35 (s, 3H), 3.47e3.55 (m, 1H), 3.69e3.73 (m, 1H), 4.27e4.42 (m, 2H), 5.14 (s, 1H), 5.49 (s, 1H), 6.81e6.88 (m, 2H), 6.97e7.03 (m, 2H), 7.26 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 13.4, 13.9, 15.3, 30.2, 34.3, 54.4, 61.4, 62.4, 93.3, 120.2, 121.6, 122.6, 126.3, 128.3, 135.5, 153.3, 156.9, 166.2, 167.6; HRMS (ESI-TOF) Calcd. for C29H39O6[MþH]þ: 483.2747; Found: 483.2758.
2.
3. 4.
4.2.10. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)naphtho [2,3b]furan-2,2(3H)-dicarboxylate (3j) Light yellow solid; 97% yield; mp 140.1e142.8 C. 1H NMR (CDCl3, 400 MHz) d 0.82 (t, J ¼ 7.08 Hz, 3H), 1.22e1.31 (m, 21H), 3.58e3.66 (m, 1H), 3.74e3.82 (m, 1H), 4.23e4.36 (m, 2H), 5.09 (s, 1H), 5.76 (s, 1H), 6.94 (s, 2H), 7.25e7.32 (m, 4H), 7.76e7.78 (m, 2H); 13 C NMR (CDCl3, 100 MHz) d 13.5, 14.0, 30.2, 34.2, 53.9, 61.6, 62.7, 94.5, 112.0, 119.8, 123.3, 126.6, 128.7, 130.3, 135.5, 153.0, 155.3, 166.0, 167.6; HRMS (ESI-TOF) Calcd. for C32H39O6[MþH]þ: 519.2747; Found: 519.2729. 4.2.11. Diethyl 3-(4-hydroxy-3,5-diisopropylphenyl)benzofuran2,2(3H)-dicarboxylate (3k) Light yellow solid; 98% yield; mp 138.7e140.0 C. 1H NMR (CDCl3, 400 MHz) d 0.80 (t, J ¼ 7.16 Hz, 3H), 1.16e1.22 (m, 12H), 1.32 (t, J ¼ 7.12 Hz, 3H), 3.05e3.12 (m, 2H), 3.50 (m, 1H), 3.73e3.79 (m, 1H), 4.24e4.41 (m, 2H), 4.76 (s, 1H), 5.49 (s, 1H), 6.84 (s, 2H), 6.93 (t, J ¼ 7.52 Hz, 1H), 7.03 (t, J ¼ 6.28 Hz, 2H), 7.20e7.24 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 13.5, 14.0, 22.7, 27.2, 53.9, 61.5, 62.6, 93.5, 110.0, 122.1, 124.8, 128.6, 128.8, 133.3, 149.5, 158.2, 166.0, 167.6; HRMS (ESI-TOF) Calcd. for C26H33O6[MþH]þ: 441.2277; Found: 441.2299. Conflicts of interest
5.
6.
7. 8.
9. 10.
11.
There are no conflicts to declare. Acknowledgement 12.
We appreciate the financial support from National Natural Science Foundation of China (No. 21672031), Fundamental and Advanced Research Projects of Chongqing City (No. cstc2016jcyjA0267), Scientific and Technological Research Program of Chongqing Municipal Education Commission (No. KJ1600211).
13. 14. 15. 16.
Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.tet.2018.02.008. References 1. (a) Ward RS. Chem Soc Rev. 1982;11:75e125; (b) Trost BM, Thiel OR, Tsui H-C. J Am Chem Soc. 2003;125:13155e13164; (c) Luize PS, Ueda-Nakamura T, Filho BPD, Cortez DAG, Nakamura CV. Biol
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Pharm Bull. 2006;29:2126e2130; (d) Bertolini F, Pineschi M. Org Prep Proced Int. 2009;41:385e418; (e) Coy ED, Jovanovic L, Sefkow M. Org Lett. 2010;12:1976e1979; (f) Baragona F, Lomberget T, Duchamp C, et al. Tetrahedron. 2011;67: 8731e8739; (g) Vinosha B, Perumal S, Renuga S, Almansour AI. Tetrahedron Lett. 2012;53: 962e966. (a) Szlosek-Pinaud M, Diaz P, Martinez J, Lamaty F. Tetrahedron. 2007;63: 3340e3349; (b) Ren O, Lapointe D, Fagnou K. Org Lett. 2009;11:4560e4563; (c) Wang X, Lu Y, Dai H-X, Yu J-Q. J Am Chem Soc. 2010;132:12203e12205. Ponpipom MM, Yue BZ, Bugianesi RL, Brooker DR, Chang MN, Shen TY. Tetrahedron Lett. 1986;27:309e312. (a) Vaillard SE, Postigo A, Rossi RA. J Org Chem. 2002;67:8500e8506; (b) Kurono N, Honda E, Komatsu F, Orito K, Tokuda M. Tetrahedron. 2004;60: 1791e1801; (c) Lin H, Schall A, Reiser O. Synlett. 2005:2603e2606; (d) Kuethe JT, Wong A, Journet M, Davies IW. J Org Chem. 2005;70:3727e3729; (e) Park D-Y, Gowrisankar S, Kim J-N. Bull Kor Chem Soc. 2005;26:1440e1442. (a) Stafford JA, Valvano NL. J Org Chem. 1994;59:4346e4349; (b) Bertolini F, Crotti P, Di Bussolo V, Macchia F, Pineschi M. J Org Chem. 2007;72:7761e7764. (a) Benbow JW, Katoch-Rouse R. J Org Chem. 2001;66:4965e4972; ndez V, Gotor V. Org Lett. 2010;12: (b) Mangas-S anchez J, Busto E, Gotor-Ferna 3498e3501. Birkett MA, Knight DW, Mitchell MB. Tetrahedron Lett. 1993;34:6939e6940. (a) Plotkin M, Chen S, Spoors PG. Tetrahedron Lett. 2000;41:2269e2273; (b) Kneisel FF, Monguchi Y, Knapp KM, Zipse H, Knochel P. Tetrahedron Lett. 2002;43:4875e4879. (a) Nair V, Rajesh C, Dhanya R, Rath NP. Org Lett. 2002;4:953e955; (b) Lomberget T, Baragona F, Fenet B, Barret R. Org Lett. 2006;8:3919e3922. (a) Dong N, Zhang Z-P, Xue X-S, Li X, Cheng J-P. Angew Chem Int Ed. 2016;55: 1460e1464; (b) He F-S, Jin J-H, Yang Z-T, Yu X, Fossey JS, Deng W-P. ACS Catal. 2016;6: 652e656; (c) Zhao K, Zhi Y, Wang A, Enders D. ACS Catal. 2016;6:657e660; (d) Deng Y-H, Zhang X-Z, Yu K-Y, et al. Chem Commun. 2016;52:4183e4186; (e) Li X, Xu X, Wei W, Lin A, Yao H. Org Lett. 2016;18:428e431; (f) Chen M, Sun J-W. Angew Chem. 2017;129:1; (g) Goswami P, Singh G, Vijaya Anand R. Org Lett. 2017;19:1982e1985; (h) Ke M-L, Song Q-L. Adv Synth Catal. 2017;359:384e389; (i) Li S-H, Liu Y-Y, Huang B, et al. ACS Catal. 2017;7:2805e2809; (j) Lin C, Shen Y-Y, Huang B, Liu Y, Cui S-L. J Org Chem. 2017;82:3950e3956. (a) Yuan Z-B, Liu L-N, Pan R, Yao H-Q, Lin A-J. J Org Chem. 2017;82:8743e8751; (b) Roiser L, Waser M. Org Lett. 2017;19:2338e2341; (c) Gai K, Fang X, Li X, et al. Chem Commun. 2015;51:15831e15834; (d) Yuan Z, Fang X, Li X, Wu J, Yao H, Lin A. J Org Chem. 2015;80:11123e11130; (e) Zhang X-Z, Du J-Y, Deng Y-H, et al. J Org Chem. 2016;81:2598e2606; (f) Ma C, Huang Y, Zhao Y. ACS Catal. 2016;6:6408e6412; (g) Yuan Z-B, Wei W-W, Lin A-J, Yao H-Q. Org Lett. 2016;18:3370e3373. Zhao K, Zhi Y, Shu T, Valkonen A, Rissanen K, Enders D. Angew Chem Int Ed. 2016;55:12104e12108. Zhang L-L, Liu Y, Liu K, Liu Z-T, He N-N, Li W-J. Org Biomol Chem. 2017;15: 8743e8747. Zhang L-L, Zhou X, Li P-F, et al. RSC Adv. 2017;7:39216e39220. Liu S, Lan X-C, Chen K, et al. Org Lett. 2017;19:3831e3834. (a) Zhou J, Wang Q-L, Peng L, Tian F, Xu X-Y, Wang L-X. Chem Commun. 2014;50:14601e14604; (b) Zhou J, Jia L-N, Wang Q-L, et al. Tetrahedron. 2014;70:8665e8671; (c) Zhou J, Jia L-N, Peng L, et al. Tetrahedron. 2014;70:3478e3484; (d) Wang W, Liang G-J, Bai Y, et al. Arkivoc. 2017;(part iv):236e248; (e) Zhou J, Bai L-J, Liang G-J, et al. RSC Adv. 2017;7:39885e39888; (f) Wang Q-L, Cai T, Zhou J, Tian F, Xu X-Y, Wang L-X. Chem Commun. 2015;51: 10726e10729; (g) Guo Y-L, Jia L-N, Peng L, et al. RSC Adv. 2013;3:16973e16976; (h) Zhu Y-S, Zhou J, Jin S-J, et al. Chem Commun. 2017;53:11201e11204; (i) Bai L-J, Chen Y-H, Bai Y, Chen Y-J, Zhou J, Huang A-L. Biomaterials. 2017;133: 11e19; (j) Chen Y-j, Luo X-H, Bai L-J, et al. New J Chem. 2017;41:10225e10230. The CCDC number is 1579631.
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Facile synthesis of 3-aryl 2,3-dihydrobenzofurans via novel domino 1,6-addition/O-alkylation reactions of para-quinone methides Jing Zhou, Guojuan Liang, Xiangnan Hu, Liping Zhou, Hui Zhou* School of Pharmaceutical Science, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing 400016, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 December 2017 Received in revised form 25 January 2018 Accepted 2 February 2018 Available online 3 February 2018
A facile K2CO3-promoted novel domino 1,6-addition/O-alkylation reaction of orthohydroxyphenylsubstituted p-QMs and diethyl bromomalonate is described. A variety of new 3-aryl 2,3-dihydrobenzofurans were obtained in excellent yields (up to 99%) under simple and mild conditions. The structure of the new compound 3f was determined by single crystal X-ray analysis. © 2018 Elsevier Ltd. All rights reserved.
Keywords: 1,6-Addition/O-alkylation Domino reaction Ortho-Hydroxyphenylsubstituted p-QMs Diethyl bromomalonate 3-Aryl 2,3-dihydrobenzofurans
1. Introduction 2,3-dihydrobenzofuran derivatives are core structural motifs in a wide array of natural products and biologically active molecules.1 They are present in molecules acting as antifungal, insecticidal, antitrypanosomal agents,1c,1d potent inducers of anticarcinogenic marker enzyme, quinone reductase1e and anti-multidrug resistant agents.1g The significance of these molecules has led to a variety of methodologies for the construction of 2,3-dihydrobenzofurans, including transition metal-mediated cyclization,2 electrocyclization,3 radical cyclization,4 organocatalytic and dehydrative techniques,5 biomimetic coupling,6 benzyne,7 anionic,8 and cycloaddition.9 However, most of these existing routes have drawbacks involving poor chemoselectivities, unsatisfactory yields, tedious processes and harsh reaction conditions, impeding their wider application. Thus, the development of an efficient, convenient and mild method for the preparation of these derivatives is strongly useful and desirable. Recently, para-quinone methides (p-QMs) have increasingly been investigated to construct diarylmethine compounds via 1,6conjugate addition.10 Applications of the p-QMs in domino
* Corresponding author. E-mail address: [email protected] (H. Zhou). https://doi.org/10.1016/j.tet.2018.02.008 0040-4020/© 2018 Elsevier Ltd. All rights reserved.
reactions have less been explored and all these reports are 1,6conjugate addition induced dearomatization domino reactions to construct spiro-cyclohexadienones.11 Enders and co-workers firstly designed ortho-hydroxyphenylsubstituted p-QMs as ideal donorMichael acceptor substrates and applied this p-QMs in organocatalytic oxa-Michael/1,6-addition domino reactions to construct chromans bearing oxindole scaffolds.12 Shortly after this report, Li's group applied this ortho-hydroxyphenylsubstituted p-QMs with azlactones,13 malononitrile and b-functionalized ketones14 in 1,6addition/aromatization domino reactions to generate various chroman skeletons. Furthermore, Jiang's group reported Ag/BiNPO4H co-catalyzed 1,6-addition/aromatization domino reactions between this p-QMs and b-alkynyl ketones for highly diaseteroselective synthesis of spiro[chromane-2,10 -isochromene] derivatives.15 These few reports demonstrated orthohydroxyphenylsubstituted p-QMs was ideal donor-Michael acceptor synthons, which could be effectively used in 1,6addition/aromatization domino processes to construct various aryl substituted oxygen-containing benzoheterocycles. However, in these reports, reaction substrate scope was limited, and cyclization products were also limited to chroman skeletons. Given the appeal for exploring new methodology with this p-QMs and as part of our continued interest in the construction of novel drug candidates,16 herein, we envisioned that a new 1,6-addition/O-alkylation domino reaction of ortho-hydroxyphenylsubstituted p-QMs with
J. Zhou et al. / Tetrahedron 74 (2018) 1492e1496
diethyl bromomalonate might provide a novel approach for the construction of 3-aryl 2,3-dihydrobenzofurans skeletons (Scheme 1). Our preliminary studies involved 1a and diethyl bromomalonate 2a as model substrates to examine the feasibility of this process, these were allowed to react in dichloromethane at room temperature in the presence of 200 mol% K2CO3. The reaction worked smoothly and afforded the desired product 3a in 92% yield via 1,6-addition/O-alkylation domino process (Table 1, entry 1).
2. Results and discussion To evaluate the reactivity of this system, the reaction of 1a with diethyl bromomalonate 2a was used as a model reaction, and a series of bases were investigated in dichloromethane at room temperature, and the results were shown in Table 1. Strong base KOH gave trace product because side products were produced (Table 1, entry 2). Et3N and DABCO both decreased reaction rate. Et3N afforded moderate yield. DABCO gave trace product (Table 1, entries 3 and 4). K2CO3 gave the highest yield and was chosen as the most suitable base (92% yield, Table 1, entry 1). Next, the reaction was conducted in various solvents (Table 1, entries 5e9). The solvents have great influence on the reaction rate. CH3CN and THF greatly accelerated the reaction rate. THF gave higher yield. CH3CN gave lower yield, because side products were produced. CH2Cl2, CHCl3, toluene and EtOAc gave good yields but poor reactivities, needed longer reaction time. In terms of yield and reactivity, THF was the most suitable reaction media and was selected for further optimization (Table 1, entry 6). Afterward, the loading of K2CO3 was investigated. Decreasing the loading of K2CO3 to 100 mol%, lower yield was obtained (Table 2, entry 2). Increasing the loading of K2CO3 didn't obtain higher yield (Table 2, entry 3). Having identified 200 mol% K2CO3 as the optimal loading for the reaction, we next examined the effect of the reaction temperature (Table 2, entries 4 and 5). A screening of different reaction temperatures showed that the reaction gave the best results at room temperature (Table 2, entry 1). Decreasing reaction temperature slowed down the reaction rate, needed longer reaction time (Table 2, entry 4). Increasing the reaction temperature also slightly decreased the yield because side products were produced (Table 2, entry 5). Finally, the substrate concentration was examined (Table 2, entries 6 and 7). It was found that increasing the substrate concentration slightly decreased the yield (Table 2, entry 6), lowering the substrate concentration decreased the reaction rate and gave lower yield (Table 2, entry 7), 0.2 M was the optimal substrate concentration. Consequently, the following reaction conditions are recommended: 200 mol% K2CO3 with 0.2 M substrate in THF at room temperature (Table 2, entry 1) (see Table 3). With optimized reaction conditions established, the substrate scope of this domino reaction was explored. First, we evaluated the generality of various functional groups substituted orthohydroxyphenylsubstituted p-QMs 1 (3a-3k). In general, the substrates bearing both electron-withdrawing groups and electron-
Scheme 1. Domino 1,6-addition/O-alkylation reactions to form functionalized 3-aryl 2,3-dihydrobenzofurans.
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Table 1 Optimization of reaction conditions.a
Entry
Base
Solvent
Time (h)
Yieldb (%)
1 2 3 4 5 6 7 8 9
K2CO3 KOH Et3N DABCO K2CO3 K2CO3 K2CO3 K2CO3 K2CO3
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 THF toluene EtOAc CH3CN
24 24 24 24 24 7 18 14 5
92 trace 55 trace 90 96 93 89 80
a Unless otherwise noted, reactions were conducted with 0.2 mmol 1a, 0.2 mmol 2a, 200 mol % base, in 1.0 mL solvent at rt. b Isolated yields.
Table 2 Optimization of reaction conditions.a
Entry
x
Temp ( C)
Yieldb(%)
1 2 3 4c 5 6d 7e
200 100 300 100 100 100 100
25 25 25 0 50 25 25
96 78 94 85 90 91 88
a Unless otherwise noted, reactions were conducted with 0.2 mmol 1a, 0.2 mmol 2a, x mol % K2CO3, in 1.0 mL THF. b Isolated yields. c Reaction time was 24 h. d 0.5 mL CHCl3 was used. e 2.0 mL CHCl3 was used.
donating groups in para, meta and ortho positions of the phenyl ring were all tolerated in this reaction to afford the corresponding products in good yields (3a-3i). The position of the substituents on the phenyl ring affected the reaction rate slightly. The substrates bearing groups in ortho positions of the phenyl ring needed longer reaction time compared with para and meta positions (3g and 3i). Furthermore, the substrate 1j, which contained naphthyl moiety, also participated in this process and gave the desired product 3j in 97% yield. When we replaced the tertbutyl group of the QMs by isopropyl group, the desired product 3k was obtained in 98% yield with longer reaction time. In addition, diethyl chloromalonate was also tested, also provided good yield with longer reaction time. The structure of 3f was determined by an X-ray analysis of single crystal (Fig. 1).17 We also attempted to develop a catalytic asymmetric version of this process to access chiral 3-aryl 2,3-dihydrobenzofuran product. After a series of efforts, we found the reaction of 1a and 2a with quinine as chiral catalyst could afford the product 3a in 93% yield but with only 10% ee (Scheme 2). Despite the result is not satisfactory, this example indicates this catalytic enantioseclective domino reaction is promising.
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J. Zhou et al. / Tetrahedron 74 (2018) 1492e1496
Table 3 Scope of substratesa.
Scheme 2. A tentative study of the catalytic asymmetric version for the domino reaction.
Fig. 1. X-ray crystal structure of product 3f.
3. Conclusions We have developed a facile K2CO3-promoted novel domino 1,6-
addition/O-alkylation reaction of ortho-hydroxyphenylsubstituted p-QMs and diethyl bromomalonate. The reaction conditions are simple and mild. With this protocol, a wide range of new 3-aryl 2,3dihydrobenzofurans were smoothly obtained in excellent yields (up to 99%). This new methodology was also extended to asymmetric organocatalysis. Further studies on the application of highly reactive ortho-hydroxyphenylsubstituted p-QMs as bifunctional substrates in organic synthesis and the asymmetric version of the reactions are in progress in our laboratory.
J. Zhou et al. / Tetrahedron 74 (2018) 1492e1496
4. Experimental section 4.1. General method Various functional groups substituted orthohydroxyphenylsubstituted p-QMs 1 were prepared according to literature method.1 Diethyl bromomalonate 2a and diethyl chloromalonate 2b were purchased from commercial suppliers and used without further purification. Commercial grade solvents were dried and purified by standard procedures as specified in Purification of Laboratory Chemicals, 4th Ed (Armarego, W. L. F.; Perrin, D. D. Butterworth Heinemann: 1997). 1H NMR spectra were recorded on commercial instruments (400 MHz). Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3, d ¼ 7.26). Spectra are reported as follows: chemical shift (d ppm), multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), coupling constants (Hz), integration, and assignment. 13C NMR spectra were collected on commercial instruments (100 MHz) with complete proton decoupling. Chemical shifts are reported in ppm from the tetramethylsilane with the solvent resonance as internal standard (CDCl3, d ¼ 77.0). Mass spectra were recorded on Xevo G2-S QTof tandem mass spectrometer. Reactions were monitored by TLC and visualized with ultraviolet light. 4.2. General procedure for the domino Michael/O-alkylation reaction A solution of ortho-hydroxyphenylsubstituted p-QMs 1 (0.2 mmol, 1 equiv), diethyl halogenated-malonate 2 (0.2 mmol, 1 equiv) in THF (1.0 mL) was stirred at room temperature and K2CO3 (0.4 mmol, 200 mol%) was added at the same temperature. The reaction mixture was stirred at room temperature for certain time and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent PE: EtOAc ¼ 10:1) to afford pure products 3. 4.2.1. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran2,2(3H)-dicarboxylate (3a) Light yellow solid; 96% yield; mp 121.5e122.6 C. HPLC conditions: Chiralcel IA column, Hexane/i-PrOH ¼ 98:2, flow rate 1.0 mL/ min, UV detection at 210 nm, retention time: 6.72 min (major) and 5.25 min (minor). 1H NMR (CDCl3, 400 MHz) d 0.78 (t, J ¼ 7.16 Hz, 3H), 1.29e1.37 (m, 21H), 3.50e3.58 (m, 1H), 3.71e3.77 (m, 1H), 4.24e4.37 (m, 2H), 5.15 (s, 1H), 5.47 (s, 1H), 6.81 (m, 3H), 6.93 (t, J ¼ 7.40 Hz, 2H), 7.02e7.19 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 13.5, 14.1, 29.7, 30.3, 34.2, 54.1, 61.5, 62.6, 93.6, 109.9, 122.1, 125.3, 126.1, 128.8, 135.5, 153.4, 158.1, 166.1, 167.6; HRMS (ESI-TOF) Calcd. for C28H37O6[MþH]þ: 469.2590; Found: 469.2597. 4.2.2. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5methoxybenzofuran-2,2(3H)-dicarboxylate (3b) Yellow solid; 99% yield; mp 89.1e90.7 C. 1H NMR (CDCl3, 400 MHz) d 0.71 (t, J ¼ 7.16 Hz, 3H), 1.21e1.30 (m, 21H), 3.43e3.52 (m, 1H), 3.64 (s, 3H), 3.68e3.70 (m, 1H), 4.16e4.29 (m, 2H), 5.08 (s, 1H), 5.35 (s, 1H), 6.54 (s, 1H), 6.68 (m, 1H), 6.85e6.89 (m, 2H), 7.19 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 13.5, 14.0, 30.3, 34.3, 54.5, 56.0, 61.4, 62.6, 94.0, 110.2, 110.8, 114.7, 126.1, 128.3, 129.5, 135.5, 152.2, 153.3, 155.2, 166.1, 167.7; HRMS (ESI-TOF) Calcd. for C29H39O7[MþH]þ: 499.2696; Found: 499.2672. 4.2.3. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5methylbenzofuran-2,2(3H)-dicarboxylate (3c) White solid; 97% yield; mp 192.0e193.0 C. 1H NMR (CDCl3,
1495
400 MHz) d 0.78 (t, J ¼ 7.16 Hz, 3H), 1.26e1.37 (m, 21H), 2.24 (s, 3H), 3.51e3.59 (m, 1H), 3.71e3.77 (m, 1H), 4.22e4.36 (m, 2H), 5.12 (s, 1H), 5.40 (s, 1H), 6.87e7.01 (m, 4H), 7.26 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 13.5, 14.0, 15.3, 30.3, 34.3, 54.5, 61.5, 62.4, 93.4, 120.0, 121.8, 122.7, 126.3, 127.8, 128.5, 130.1, 135.4, 153.2, 156.8, 166.3, 167.8; HRMS (ESI-TOF) Calcd. for C29H39O6[MþH]þ: 483.2747; Found: 483.2758. 4.2.4. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5fluorobenzofuran-2,2(3H)-dicarboxylate (3d) White solid; 93% yield; mp 192.0e193.0 C. 1H NMR (CDCl3, 400 MHz) d 0.70 (t, J ¼ 7.16 Hz, 3H), 1.22e1.30 (m, 21H), 3.44e3.52 (m, 1H), 3.64e3.72 (m, 1H), 4.17e4.30 (m, 2H), 5.10 (s, 1H), 5.37 (s, 1H), 6.69 (d, J ¼ 7.84 Hz, 1H), 6.80e6.89 (m, 3H), 7.19 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 13.4, 14.0, 30.2, 34.3, 54.2, 61.6, 62.7, 94.2, 110.3 (d, J ¼ 8.5 Hz), 112.2 (d, J ¼ 25.1 Hz), 115.2, 115.4, 126.0, 127.8, 130.2 (d, J ¼ 8.7 Hz), 135.7, 153.5 (d, J ¼ 55.0 Hz), 157.2 (d, J ¼ 237.3 Hz), 165.9, 167.4; 19F NMR (376 MHz, CDCl3) d -122.7. HRMS (ESI-TOF) Calcd. for C28H36FO6[MþH]þ: 487.2496; Found: 487.2487. 4.2.5. Diethyl 5-chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl) benzofuran-2,2(3H)-dicarboxylate (3e) Yellow solid; 98% yield; mp 103.6e104.8 C. 1H NMR (CDCl3, 400 MHz) d 0.70 (t, J ¼ 7.16 Hz, 3H), 1.22e1.30 (m, 21H), 3.44e3.52 (m, 1H), 3.64e3.72 (m, 1H), 4.17e4.30 (m, 2H), 5.11 (s, 1H), 5.35 (s, 1H), 6.86e6.96 (m, 4H), 7.10 (d, J ¼ 9.76 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 13.4, 14.0, 30.2, 34.3, 54.0, 61.6, 62.8, 94.1, 111.0, 125.4, 126.0, 126.9, 127.8, 128.8, 135.7, 153.5, 156.7, 165.7, 167.2; HRMS (ESITOF) Calcd. for C28H36ClO6[MþH]þ: 503.2200; Found: 503.2231. 4.2.6. Diethyl 5-bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl) benzofuran-2,2(3H)-dicarboxylate (3f) Light yellow solid; 95% yield; mp 107.6e108.5 C. 1H NMR (CDCl3, 400 MHz) d 0.70 (t, J ¼ 7.12 Hz, 3H), 1.22e1.31 (m, 21H), 3.44e3.52 (m, 1H), 3.64e3.70 (m, 1H), 4.17e4.30 (m, 2H), 5.11 (s, 1H), 5.36 (s, 1H), 6.83e6.86 (m, 3H), 7.10 (s, 1H), 7.23 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 13.4, 14.0, 30.2, 34.3, 53.9, 61.6, 62.8, 94.1, 111.7, 114.0, 126.0, 127.6, 127.7, 128.3, 131.3, 135.7, 153.5, 157.2, 165.7, 167.2; HRMS (ESI-TOF) Calcd. for C28H36BrO6[MþH]þ: 547.1695; Found: 547.1706. 4.2.7. Diethyl 5,7-dichloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl) benzofuran-2,2(3H)-dicarboxylate (3g) Yellow solid; 91% yield; mp 129.5e130.9 C. 1H NMR (CDCl3, 400 MHz) d 0.76 (t, J ¼ 7.12 Hz, 3H), 1.30e1.38 (m, 21H), 3.50e3.58 (m, 1H), 3.71e3.77 (m, 1H), 4.26e4.40 (m, 2H), 5.21 (s, 1H), 5.52 (s, 1H), 6.94 (m, 2H), 7.25 (d, J ¼ 7.92 Hz, 2H); 13C NMR (CDCl3, 100 MHz) d 13.4, 13.9, 30.2, 34.3, 54.7, 61.7, 62.9, 94.3, 99.9, 116.0, 123.6, 126.1, 126.9, 129.0, 131.8, 135.9, 153.3, 153.7, 165.1, 166.8; HRMS (ESI-TOF) Calcd. for C28H35Cl2O6[MþH]þ: 537.1811; Found: 537.1802. 4.2.8. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-6methoxybenzofuran-2,2(3H)-dicarboxylate (3h) Yellow solid; 96% yield; mp 107.5e108.6 C. 1H NMR (CDCl3, 400 MHz) d 0.77 (t, J ¼ 7.12 Hz, 3H), 1.29e1.37 (m, 21H), 3.48e3.56 (m, 1H), 3.72e3.75 (m, 1H), 3.80 (s, 3H), 4.26e4.40 (m, 2H), 5.14 (s, 1H), 5.40 (s, 1H), 6.49 (d, J ¼ 9.40 Hz, 1H), 6.62 (s, 1H), 6.91e6.96 (m, 2H), 7.26 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 13.2, 14.0, 30.3, 34.2, 53.5, 55.5, 61.5, 62.6, 94.3, 96.2, 108.1, 120.4, 125.6, 126.0, 128.8, 135.4, 153.3, 159.4, 160.8, 166.0, 167.6; HRMS (ESI-TOF) Calcd. for C29H39O7[MþH]þ: 499.2696; Found: 499.2672.
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J. Zhou et al. / Tetrahedron 74 (2018) 1492e1496
4.2.9. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-7methylbenzofuran-2,2(3H)-dicarboxylate (3i) White solid; 90% yield; mp 115.8e117.3 C. 1H NMR (CDCl3, 400 MHz) d 0.77 (t, J ¼ 7.12 Hz, 3H), 1.29e1.37 (m, 21H), 2.35 (s, 3H), 3.47e3.55 (m, 1H), 3.69e3.73 (m, 1H), 4.27e4.42 (m, 2H), 5.14 (s, 1H), 5.49 (s, 1H), 6.81e6.88 (m, 2H), 6.97e7.03 (m, 2H), 7.26 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 13.4, 13.9, 15.3, 30.2, 34.3, 54.4, 61.4, 62.4, 93.3, 120.2, 121.6, 122.6, 126.3, 128.3, 135.5, 153.3, 156.9, 166.2, 167.6; HRMS (ESI-TOF) Calcd. for C29H39O6[MþH]þ: 483.2747; Found: 483.2758.
2.
3. 4.
4.2.10. Diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)naphtho [2,3b]furan-2,2(3H)-dicarboxylate (3j) Light yellow solid; 97% yield; mp 140.1e142.8 C. 1H NMR (CDCl3, 400 MHz) d 0.82 (t, J ¼ 7.08 Hz, 3H), 1.22e1.31 (m, 21H), 3.58e3.66 (m, 1H), 3.74e3.82 (m, 1H), 4.23e4.36 (m, 2H), 5.09 (s, 1H), 5.76 (s, 1H), 6.94 (s, 2H), 7.25e7.32 (m, 4H), 7.76e7.78 (m, 2H); 13 C NMR (CDCl3, 100 MHz) d 13.5, 14.0, 30.2, 34.2, 53.9, 61.6, 62.7, 94.5, 112.0, 119.8, 123.3, 126.6, 128.7, 130.3, 135.5, 153.0, 155.3, 166.0, 167.6; HRMS (ESI-TOF) Calcd. for C32H39O6[MþH]þ: 519.2747; Found: 519.2729. 4.2.11. Diethyl 3-(4-hydroxy-3,5-diisopropylphenyl)benzofuran2,2(3H)-dicarboxylate (3k) Light yellow solid; 98% yield; mp 138.7e140.0 C. 1H NMR (CDCl3, 400 MHz) d 0.80 (t, J ¼ 7.16 Hz, 3H), 1.16e1.22 (m, 12H), 1.32 (t, J ¼ 7.12 Hz, 3H), 3.05e3.12 (m, 2H), 3.50 (m, 1H), 3.73e3.79 (m, 1H), 4.24e4.41 (m, 2H), 4.76 (s, 1H), 5.49 (s, 1H), 6.84 (s, 2H), 6.93 (t, J ¼ 7.52 Hz, 1H), 7.03 (t, J ¼ 6.28 Hz, 2H), 7.20e7.24 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 13.5, 14.0, 22.7, 27.2, 53.9, 61.5, 62.6, 93.5, 110.0, 122.1, 124.8, 128.6, 128.8, 133.3, 149.5, 158.2, 166.0, 167.6; HRMS (ESI-TOF) Calcd. for C26H33O6[MþH]þ: 441.2277; Found: 441.2299. Conflicts of interest
5.
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7. 8.
9. 10.
11.
There are no conflicts to declare. Acknowledgement 12.
We appreciate the financial support from National Natural Science Foundation of China (No. 21672031), Fundamental and Advanced Research Projects of Chongqing City (No. cstc2016jcyjA0267), Scientific and Technological Research Program of Chongqing Municipal Education Commission (No. KJ1600211).
13. 14. 15. 16.
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