An Economical, Sustainable Pathway to Indole-Containing Oxindoles: Iron-Catalyzed 1,6-Conjugate Addition in Glycerol

sustainability

Article An Economical, Sustainable Pathway to Indole-Containing Oxindoles: Iron-Catalyzed 1,6-Conjugate Addition in Glycerol

Lan Tan 1,2,* and Abdul Rahman 3,*

1 Business School, Zhejiang University City College, Hangzhou 310015, China 2 Research Base of Philosophy and Social Science in Hangzhou, Center for Research of CSR and Sustainable Development, Zhejiang University City College, Hangzhou 310015, China 3 Faculty of Science, Zhejiang University, Hangzhou 310027, China * Correspondence: [email protected] (L.T.); [email protected] (A.R.); Tel.: +86-571-8828-4363 (L.T.)

Received: 28 July 2018; Accepted: 10 August 2018; Published: 17 August 2018

Abstract: The search for economical, sustainable and practical pathways in synthetic science would contribute to improving resource efficiency, developing a recycling economy and driving new-type urbanization. Green synthesis has established firm ground providing the right green yardstick for development of a sustainable approach to bioactive high-added value molecules and drug discovery, and further development of sustainable manufacturing processes in the pharmaceutical industry toward a green resource efficient economy. In this study, the combination of FeCl3 and glycerol exhibits a versatile and high catalytic activity in the atom economical 1,6-conjugated addition of para-quinone methides derived from isatins with indoles using the right green yardstick. The sustainable pathway provides the preparation of bioactive indole-containing oxindoles in excellent yields with superior advantages, such as the ready availability, low price and environmentally benign character of iron catalysis, easy product separation, cheap and safe bio-renewable glycerol as a green solvent, and catalytic system recycling under mild conditions.

Keywords: atom economy; sustainable pathway; recycling economy; resource efﬁcient economy; glycerol; iron; catalysis; 1,6-conjugate addition

1. Introduction Resource efficiency is the maximising of the supply of funds, materials, staff, and other assets in order to function effectively in a sustainable manner, with minimum wasted resource expenses to minimise environmental impact [1]. In today’s environment, the demand for the production of high-quality products with minimum waste and energy demands is a very important challenge to the coordinated development of new urbanization and employment growth via the economic analysis of resource efficiency policies [2,3]. In the field of synthetic science, the concept of sustainability is clearly expressed by the use of low-waste organic transformations to achieve high incorporation of the starting materials into the final product, avoiding the formation of waste by-products, plus the use of catalysts to reduce energy needed [4–6]. Atom economy [7] has become one of 12 principles of green synthetic science [8]. Both green synthesis and resource efficiency are two key factors towards a green sustainable economy [9,10]. Thus, developing sustainable and practical pathways will be a long-term concerted and challenging task for scientists. In this regard, the 1,6-conjugated addition reaction catalyzed by Brønsted acids or Lewis acids for new chemical bond formation can provide a variety of bioactive compounds, and has complete atom economy [11]. Thus, the 1,6-conjugated addition reaction is attracting much research interest in academia [12–14].

Sustainability 2018, 10, 2922; doi:10.3390/su10082922 www.mdpi.com/journal/sustainability Sustainability 2018, 10, 2922 2 of 11

The development of sustainability has led to the resurrection of iron catalysis in synthetic science. Currently, iron catalysis has been recognized as an environmentally friendly methodology in organic synthesis, due to its ready availability, low price and low toxicity, which is of great importance for many practical applications especially in the pharmaceutical industry, the food industry, and cosmetics. Thus, iron-catalyzed reactions have drawn much attention, which reflects an increasing demand for sustainable synthesis [15,16]. Developments in green reaction media with the ultimate goal of solving the environment problem are strongly needed [17]. In this regard, glycerol as a solvent derived from biomass is drawing increasing interest in the scientific community [18–22]. The bio-renewable glycerol is considered as “organic water”. Glycerol behaves like water, but it is better than water because of its high boiling point, lower vapor pressure and also dissolutions of most of the organic compound which are insoluble in water. Furthermore, it is abundant and inexpensive, non-toxic, highly polar, recyclable, biodegradable, immiscible with ether and hydrocarbons (this ability makes it possible remove the reaction products simply through liquid–liquid extraction), and compatible with most inorganic compounds (salts and transition metal complexes) [23]. 3,3-Disubstituted oxindoles represent an important family of bioactive and pharmaceutical molecules, and their synthesis has drawn much attention [24–26]. In this paper, we report a highly efficient FeCl3 dissolved in glycerol catalyzed 1,6-conjugated addition reaction of para-quinone methides derived from isatins with indoles to afford bioactive indole-containing oxindoles in excellent yields. The superior advantages of the sustainable approach mainly include: (i) the environmentally benign character of iron catalysis; (ii) the first example of 1,6-conjugated addition reaction in glycerol; (iii) oxindoles containing an indolyl unit; (iv) complete atom economy, and easy product separation; (v) a recyclable catalytic system. The current sustainable iron catalysis meets the increasing demand of sustainability, such as energy resources, cheap catalysts, non-toxic reagents and green solvents.

2. Materials and Methods

2.1. General Information 1H NMR (nuclear magnetic resonance), and 13C NMR spectra were measured at 400, 100 MHz spectrometer, respectively. The Supplementary Materials are NMR Spectra for all products. The shifts were reported relative to internal standard tetramethylsilane (TMS, 0 ppm) and referenced to solvent peaks in the NMR solvent (CDCl3 = δ 7.26 ppm; δ 77.16 ppm; d6-DMSO = δ 2.50 ppm; δ 39.52 ppm). Data are reported as: multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant in hertz (Hz) and signal area integration in natural numbers. High-resolution mass spectrometry (HRMS) spectra was obtained using EI ionization. Infrared spectra were recorded on an ATR-FTIR spectrometer. HRMS were obtained using EI or ESI ionization. All the reagents used were of analytical grade without further puriﬁcation. Oxoindole-derived methide derivatives was obtained following the literature [12].

2.2. General Sustainable Procedure for Atom-Economical Synthesis of of 3,3-Disubstituted Oxindoles As shown in Figure1, para-Quinone methides derived from isatins 1 (2 mmol) and indoles 2 or pyrrole (2 mmol) were added to a solution of FeCl3 (0.2 mmol) in glycerol (4 mL), and the resulting mixture was stirred at 120 ◦C under an air atmosphere for 24 h (Table1, entry 8). Complete consumption of starting materials was observed by thin-layer chromatography (TLC). After cooling, the reaction mixture was extracted with 2-methyltetrahydrofuran (an immiscible solvent, 2 × 4 mL), to separate the product, while the residue (glycerol layer), still containing the catalyst FeCl3 dissolved in the glycerol, was used as such for the recycling experiments. The collected organic phases were concentrated by distillation to recover 2-methyltetrahydrofuran and give the solid crude products 3 after washing with water (10 mL) and drying under a vacuum. The analytically pure products 3 could be obtained by Sustainability 2018, 10, 2922 3 of 11

ﬂash silica gel column chromatography (petroleum ether/ethyl acetate = 4:1 as the eluent). The yield obtained in each experiment is reported in Table2.

2.3. General Procedure for Catalytic System Recycling The recyclability of our catalytic system was investigated using the 1,6-conjugated addition reaction of para-quinone methide derived from isatin 1a and indole 2a as a model reaction. To the residue (the retained glycerol layer) obtained as described above, still containing the catalyst FeCl3 dissolved in glycerol, was added 1a (2 mmol) and 2a (2 mmol), and the resulting mixture was stirred at 120 ◦C under an air atmosphere for 24 h. Complete consumption of starting materials was observed bySustainability TLC. After 2018, cooling, 10, x FOR thePEER reaction REVIEWmixture was extracted with 2-methyltetrahydrofuran (2 × 47mL), of 11 and the collected organic phases were concentrated and gave the crude products 3a after washing reaction at 25 °C because of the insolubility of substrate (1a) in high viscous glycerol (Table 1, entry with water (10 mL) and drying under vacuum. The analytically pure product 3a was obtained after 1). When we increased the reaction temperature from 25 to 60 °C to make the solvent low viscous ﬂash silica gel column chromatography (petroleum ether/ethyl acetate = 4:1 as the eluent). To the and improved the solubility of substrate (1a), a rare amount of desired product (3a) was observed on retained glycerol layer, the substrates were again added, and the mixture was stirred under the same SustainabilityTLC (Table 2018 1, entry, 10, x FOR 2). APEER continuous REVIEW increase of temperature to 80 °C and 120 °C increased the 3yield of 11 conditions described above to provide the desired product 3a after the same work up. This procedure of the required product to rare, 60% and 86% respectively (Table 1, entries 3 and 4). When we set the purewas repeated product ups 3 to could ﬁve consecutive be obtained times. by The flash yield silica obtained gel in column each recycling chromatography experiment (petroleum is reported temperature of reaction according to the yield, then we screened the different type of catalyst to ether/ethylin Table3. acetate = 4:1 as the eluent). The yield obtained in each experiment is reported in Table 2. identify the best reaction protocol. After further screening the different catalysts like H3PO4, PhCO2H, FeCl3, we found that FeCl3 could be easily dissolved in glycerol and became the best choice of catalysts according to the yield (Table 1, entries 5–7). After the loading of FeCl3 catalyst was investigated, we found that 10 mol% is the best loading of catalyst to give the desired indole-containing oxindole 3a in 93% yield (Table 1, entries 7–9). For comparison, we have studied the catalytic activity of FeCl3 in different conventional volatile organic solvents, such as toluene, xylene and 1,2-dichloroethane under reflux, finding that the efficiency of the 1,6-conjugate addition reaction was remarkably lowered (Table 1, entries 10–12). Thus, the optimized reaction conditions were identified (Table 1, entryFigure 8). 1. Synthesis of of 3,3 3,3-Disubstituted-Disubstituted Oxindole Oxindoles.s.

2.3. General Procedure for Catalytic System Recycling a TableTable 1.1. Optimized reactionreaction conditionsconditions a.. The recyclability of our catalytic system was investigated using the 1,6-conjugated addition reaction of para-quinone methide derived from isatin 1a and indole 2a as a model reaction. To the residue (the retained glycerol layer) obtained as described above, still containing the catalyst FeCl3 dissolved in glycerol, was added 1a (2 mmol) and 2a (2 mmol), and the resulting mixture was stirred at 120 °C under an air atmosphere for 24 h. Complete consumption of starting materials was observed by TLC. After cooling, the reaction mixture was extracted with 2-methyltetrahydrofuran (2 × 4 mL), and the collected organic phases were concentrated and gave the crude products 3a after washing with water (10 mL) and drying under vacuum. The analytically pure product 3a was ◦ obtained after flashEntryEntry silica gelCatalyst Catalyst column chromatographyx xTemperature Temperature (petroleum [°C] [Isolated C]ether/ethyl Yield Isolated [%] acetate Yield [%]= 4:1 as the 1 (PhO)2PO2H 15 25 no reaction 1 (PhO) PO H 15 25 no reaction eluent). To the retained2 glycerol(PhO)2PO layer,2 2H2 the15 substrates 60were again added, traceand the mixture was stirred 2 (PhO) PO H 15 60 trace under the same conditions3 (Ph describedO)2PO2 2H2 above15 to provide80 the desired product60 3a after the same work 3 (PhO) PO H 15 80 60 up. This procedure 4was repeated(PhO)2PO2 up2H2 to five15 consecutive120 times. The yield 86obtained in each recycling 4 (PhO)2PO2H 15 120 86 experiment is reported5 in TableH3PO4 (385%. ) 15 120 trace 56 HPhCO3PO42H(85%) 15 15120 12085 trace 67 PhCOFeCl3 2H15 15120 12093 85 2.4. Characterization7 8Data of ProductFeCl FeCl3 3 Is Listed10 Below15 120 12093 93 89 FeCl FeCl3 3 5 10120 12080 93 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3,3′-biindolin-2-one (3a) [27], 93% yield; 1H NMR (400 MHz, 910 b FeCl FeCl3 3 10 5110 12045 80 b CDCl3) δ 8.88 (s, 101H),11 c 8.12 (s, 1H),FeClFeCl3 7.283 (s,10 2H), 107.25–7.21220 (m, 2H), 110 7.16 (t, J =50 7.6 Hz, 451H), 7.07 (t, J = 7.5 c Hz, 1H), 7.00 (d, 11J =12 8.0 d Hz, 1H),FeClFeCl 6.93 43 (t, J =10 7.5 Hz,10 1H),80 6.87 (t, 120J = 7.5 Hz, 2H),76 6.78 (s, 50 1H), 5.17 (s, 1H), d a 12 FeCl3 10 80 76 b 1.32 (s, Reactions 18H); 13C were NMR performed (101 MHz, with CDCl 1 (2 3mmol)) δ 180.9,, 2 (2 153.0, mmol 140.) and2, catalyst136.9, 135. in glycerol4, 134.9, ( 4130.0, mL) for127.89, 24 h; 125.9, c d 125.8,aWith Reactions124.9, toluene 124.6, were ( 4122. performed mL)5 ,as 122.0, the with solvent 120.9,1 (2 mmol),; 119. With52, (2117.0,xylene mmol) 111. ( and4 mL)3, catalyst 110. as the1, in57.7, solvent glycerol 34.;5 (4, With30.3; mL) for ClCHinfrared 24 h;2CHb With (IR)2Cl toluene( 4(film): mL) γ = c d 3648,(4as 335 mL)the3 , assolvent. 2956, the solvent; 2925, 17With10, xylene 1618, (4 15 mL)80, as 1491, the solvent; 1436, 1261,With ClCH 826,2 CH7822 Clcm (4− mL)1; HRMS as the solvent.(electron impact time of flight (EI-TOF)): calculated (calcd.) for C30H32N2O2 452.2464, found 452.2462. With the optimized reaction conditions in hand, our next step was to investigate the scope 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-4′-methyl-3,3′-biindolin-2-one (3b), 91% yield; 1H NMR (400 MHz, of substrate with a different type and at different position of substitutions. To our delight, FeCl3 CDCl3) δ 8.73 (s, 1H), 8.08 (s, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.11 (t, J = 7.0 Hz, 2H), 7.04 (s, 1H), 6.97 (t, J = dissolved in glycerol showed near-perfect performance for such an organic transformation and the 7.6results Hz, 2H), are 6.87 summarized (d, J = 7.7 Hz, in 1H), Table 6.7 21. (d, First J =ly, 7.1 we Hz, observed 1H), 6.49 that(s, 1H), a wide5.19 (s, range 1H), 1.9 of 4indole (s, 3H),s with1.32 13 (s,electron 18H);- withdrawingC NMR (101 MHz,or electron CDCl3)- donatingδ 153.0, 140.1, groups 138.0, are 136.0, suitable 127.9, 126.1,nucleophile 124.8, 122.2,s to 122.1,afford 110.3, the 109.1,corresponding 58.3, 34.5, products 30.3, 20.4; withIR (film): high γ yields = 3637, (8 3348–93%2, 2956,, Table 2925, 2, 1706,entries 1618, 1– 81322,). Meanwhile, 1021, 910, 747,we also664 −1 cmexamined; HRMS the (EI effect-TOF): of calcdsubstitution. for C31 Hon34 Npara2O-2quinone 466.2620 ,methid found e466.2621.s derived from isatins, and no obvious 3electron-(3,5-Di - effecttert-butyl was-4 - observedhydroxyphenyl). Various-5′- methylelectron-3,3′-withdrawing-biindolin-2-one or (electron3c), 93%- donatingyield, 1H NMR groups (400, such MHz, as CDClMe, Cl3) andδ 8.86 Br, (s, could 1H), 7.95also (d,be successfullyJ = 1.7 Hz, 1H), employed 7.21 (s, in2H), the 7.15 1,6–-conjugate7.07 (m, 2H), addition 7.05 (d, reaction J = 8.3 Hz,to reveal 1H), 6.88excellent (dd, Jresults = 11.0, 4.1(85 –Hz,93% 1H),, Table 6.84 2–,6.80 entries (m, 2H), 9–18). 6.68 It (s, is noteworthy1H), 6.66 (d, thatJ = 2.5 the Hz, effect 1H), of5.09 protecting (s, 1H), 2.14 the (s,group 3H), on 1.24 the (s, reaction 18H); 13 protocolC NMR (101was MHz,also examined CDCl3) δ to181.1, show 153.0, that 140.2,there was135.3, no 135.2, significant 135.1, effect130.0, on128.5, the 127.8,yield of126.1, required 125.8, product 125.0, 124.7,s when 123.6, indole 122.4, or para 120.4,-quinone 116.4, 110.9,methid 110.0,e derived 57.7, 34.4,from 30.3, isatin 21.5; was IR protected (film): γ =with 3637, N -2956,methylation 2925, 1706, consecutively 1618, 1471, (Table 1157, 2 910,, entries 747, 16959–20 cm). −1; HRMS (EI-TOF): calcd. for C31H34N2O2 466.2623, found 466.2621.

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-7′-methyl-3,3′-biindolin-2-one (3d), 90% yield, 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.28 (s, 2H), 7.16 (ddd, J = 14.8, 13.7, 8.0 Hz, 3H), 6.96 (t, J = 7.3 Hz, 1H), 6.92–6.87 (m, 2H), 6.76 (s, 1H), 6.73 (d, J = 2.5 Hz, 1H), 5.16 (s, 1H), 2.22 (s, 3H), 1.32 (s, Sustainability 2018, 10, 2922 4 of 11 Sustainability 2018, 10, x FOR PEER REVIEW 8 of 11

Table 2. Sustainable approachapproach for synthesis ofof indole-containingindole-containing oxindolesoxindoles aa.

EntryEntry 1 1 R1 R1R2 R2 2 R3 R3 R4 RP4roduct Product(3) (3)Isolated Isolated Yield [%] Yield [%] 1 1a H H 2a H H 3a 93 12 1a 1a H HHH 2b 2a4-Me HHH 3b 3a 91 93 23 1a 1a H HHH 2c 2b5-Me 4-MeH H 3c 3b 93 91 34 1a 1a H HHH 2d 2c7-Me 5-MeH H 3d 3c 90 93 45 1a 1a H HHH 2e 2d6-Br 7-MeH H 3e 3d 88 90 56 1a 1a H HHH 2f 2e7-Cl 6-BrH H 3f 3e 89 88 67 1a 1a H HHH 2g 2f5-OMe 7-ClH H 3g 3f 92 89 78 1a 1a H HHH 2h 2g7-OMe5-OMe H H 3h 3g 90 92 89 1b 1a Me HHH 2a 2hH 7-OMeH H 3i 3h 89 90 109 1b 1b Me MeH H2b 2b4-Me HHH 3j 3i 87 89 1011 1b 1b Me MeH H2d 2b7-Me 4-MeH H 3k 3j 91 87 1112 1b 1b Me MeH H2e 2d6-Br 7-MeH H 3l 3k 85 91 1213 1b 1b Me MeH H2f 2e7-Cl 6-BrH H 3m 3l 87 85 13 1b Me H 2f 7-Cl H 3m 87 Sustainability 201814, 10 , x FOR1b PEERMe REVIEWH 2i 4-Br H 3n 88 9 of 11 1415 1c 1b Cl MeH H2b 2i4-Me 4-BrH H 3o 3n 90 88 1516 1c 1c Cl ClH H2e 2b6-Br 4-MeH H 3p 3o 93 90 such as, long1617 life time1d 1c andBr highClH level H2a of2e reusabilityH 6-BrH . When H 3q the reaction3p between87 931a and 2a was completed under1718 the1d 1d standardBr BrH reaction H2b 2a 4 conditions-Me HHH , the final3r product3q 3a 8was8 extracted87 using 2-methyltetrahydrof1819 1euran, 1d H and Br theMe retained H2a 2b glycerolH 4-MeH phase H with3s FeCl3r3 was reused92 by 88just adding the substrates again1920 under1f 1e theH sameHH reaction Me2j 2a H protocol. HHMe As shown3t in 3s Table 3, w94e observed92 that this a 20 1f HH 2j H Me 3t 94 procedure Reactions could were be repeatedperformed up with to 15 (2times mmol) with, 2 (2no mmol loss )of and catalytic FeCl3 ( 0.activity2 mmol), andin glycerol the desired (4 mL) product at 120a °C for 24 h. ◦ 3a wasReactions obtained were in performed excellent with yield1 (2 every mmol), time2 (2 mmol), which and bears FeCl3 (0.2 witness mmol) into glycerolthe catalyst’s (4 mL) at robustness. 120 C for 24 h.

Furthermore, we then expandedTable 3.3. Study the of generality catalytic systemsystem of the recyclingrecycling FeCl3 dissolved aa.. in glycerol catalyzed 1,6-conjugate addition reaction by using new nucleophile pyrrole, and the results obtained are shown in Scheme 1. The different para-quinone methides derived from isatins could react with pyrrole to afford the corresponding product pyrrole-containing oxindoles in excellent yields (94– 97%) under the above standard conditions.

RunRun Crude Crude Yield Yield (%) (%) Isolated Isolated Yield Yield (%) (%) 1 97 93 1 97 93 2 299 9995 95 3 398 9894 94 4 498 9893 93 5 599 9994 94

a 3 a Reactions were performed using FeCl (0.2 mmol) in glycerol (4 mL)◦ at 120 °C for 24 h, and 2 mmol Reactions were performed using FeCl3 (0.2 mmol) in glycerol (4 mL) at 120 C for 24 h, and 2 mmol of 1a and 2a wasof 1a always and 2 employed.a was always employed. Scheme 1. 1,6-Conjugate addition reaction with pyrrole. 4. Conclusions 3.22.4.. Catalytic Characterization System DataRecycling of Product 3 Is Listed Below A highly efficient and atom-economical0 synthesis of bioactive indole1-containing oxindoles was 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3,3The good results prompted us to -biindolin-2-onestudy the recyclability(3a)[27], of 93% the yield; catalyHtic NMR system(400 in MHz, a batch. CDCl W3e) δdeveloped8.88 (s, 1H), by 8.12 using (s, 1H), a FeCl 7.283 dissolved (s, 2H), 7.25–7.22 in glycerol (m, 2H), catalyzed 7.16 (t, J 1,6= 7.6-conjugated Hz, 1H), 7.07 addition (t, J = 7.5reaction Hz, 1H), of developed FeCl3 dissolved in glycerol as a the catalytic system recycling for 1,6-conjugate addition para-quinone methides derived from isatins and indoles. Pyrrole was also applicable to afford the reaction7.00 (d, Jof= oxoindole 8.0 Hz, 1H),-derived 6.94 (t, methidJ = 7.5e Hz,s and 1H), indole 6.87s (t,forJ the= 7.5 construction Hz, 2H), 6.78 of 3,3 (s,- 1H),disubstituted 5.17 (s, 1H), oxindole 1.32 (s,s. corresponding13 pyrrole-containing oxindoles in excellent yields with this protocol. The desired 18H);The separationC NMR of (101 the MHz, product CDCls was3) δ 180.9,realized 153.0, by a140.2, simple 136.9, extraction 135.4, 134.9, with 130.0,2-methyltetrahydrofuran 127.89, 125.9, 125.8,, 3,3-disubstituted oxoindoles could be extracted using the biomass-derived solvent which is an immiscible solvent with glycerol, while the retained glycerol layer still contained the 2-methyltetrahydrofuran and the retained glycerol layer with FeCl3 could be reused up to 5 times with catalyst FeCl3. The catalytic system with FeCl3 dissolved in glycerol has some obvious advantages, very high efficiency. The superior advantages of the sustainable methodology include the ready availability, low price and environmentally benign character of iron catalysis, easy product separation, and a recyclable catalyst system. The current iron catalysis meets the increasing demand of sustainability, such as energy resources, cheap catalysts, non-toxic reagents and green solvents. Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1, NMR spectra for all products.

Author Contributions: L.T. conceived and directed the project, and analyzed the data; A.R. performed the experiments and the characterizations. Both authors co-wrote the manuscript.

Funding: This research was funded by the Social Science Planning Project of Zhejiang Province grant number 16ZJQN052YB.

Acknowledgments: This work is supported by Zhejiang Social Science Planning Zhi Jiang Youth Project. Financial support from the Social Science Planning Project of Zhejiang Province (Project No. 16ZJQN052YB) is gratefully acknowledged. We thank Xu. Lin for assistance with designing the research and analyzing the data.

Conflicts of Interest: The authors declare no conflict of interest.

Sustainability 2018, 10, 2922 5 of 11

124.9, 124.6, 122.5, 122.0, 120.9, 119.5, 117.0, 111.3, 110.1, 57.7, 34.5, 30.3; infrared (IR) (film): γ = 3648, 3353, 2956, 2925, 1710, 1618, 1580, 1491, 1436, 1261, 826, 782 cm−1; HRMS (electron impact time of flight (EI-TOF)): calculated (calcd.) for C30H32N2O2 452.2464, found 452.2462. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-40-methyl-3,30-biindolin-2-one (3b), 91% yield; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.08 (s, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.11 (t, J = 7.0 Hz, 2H), 7.04 (s, 1H), 6.97 (t, J = 7.6 Hz, 2H), 6.87 (d, J = 7.7 Hz, 1H), 6.71 (d, J = 7.1 Hz, 1H), 6.49 (s, 1H), 5.19 (s, 1H), 1.94 (s, 13 3H), 1.32 (s, 18H); C NMR (101 MHz, CDCl3) δ 153.0, 140.1, 138.0, 136.0, 127.9, 126.1, 124.8, 122.2, 122.1, 110.3, 109.1, 58.3, 34.5, 30.3, 20.4; IR (film): γ = 3637, 3342, 2956, 2925, 1706, 1618, 1322, 1021, 910, −1 747, 664 cm ; HRMS (EI-TOF): calcd. for C31H34N2O2 466.2620, found 466.2621. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-50-methyl-3,30-biindolin-2-one (3c), 93% yield, 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.21 (s, 2H), 7.15–7.07 (m, 2H), 7.05 (d, J = 8.3 Hz, 1H), 6.88 (dd, J = 11.0, 4.1 Hz, 1H), 6.84–6.80 (m, 2H), 6.68 (s, 1H), 6.66 (d, J = 2.5 Hz, 1H), 5.09 (s, 13 1H), 2.14 (s, 3H), 1.24 (s, 18H); C NMR (101 MHz, CDCl3) δ 181.1, 153.0, 140.2, 135.3, 135.2, 135.1, 130.0, 128.5, 127.8, 126.1, 125.8, 125.0, 124.7, 123.6, 122.4, 120.4, 116.4, 110.9, 110.0, 57.7, 34.4, 30.3, 21.5; IR (film): γ = 3637, 2956, 2925, 1706, 1618, 1471, 1157, 910, 747, 695 cm−1; HRMS (EI-TOF): calcd. for C31H34N2O2 466.2623, found 466.2621. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-70-methyl-3,30-biindolin-2-one (3d), 90% yield, 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.28 (s, 2H), 7.16 (ddd, J = 14.8, 13.7, 8.0 Hz, 3H), 6.96 (t, J = 7.3 Hz, 1H), 6.92–6.87 (m, 2H), 6.76 (s, 1H), 6.73 (d, J = 2.5 Hz, 1H), 5.16 (s, 1H), 2.22 (s, 3H), 13 1.32 (s, 18H); C NMR (101 MHz, CDCl3) δ 181.1, 153.0, 140.1, 135.3, 135.2, 135.1, 130.0, 128.5, 127.8, 126.1, 125.8, 125.0, 124.7, 123.6, 122.4, 120.5, 116.4, 110.8, 110.0, 57.7, 34.4, 30.3, 21.5; IR (film): γ = 3537, −1 3241, 2956, 2925, 1706, 1618, 1471, 1236, 1157, 910, 747 cm ; HRMS (EI-TOF): calcd. for C31H34N2O2 466.2620, found 466.2621. 60-Bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3,30-biindolin-2-one (3e), 88% yield, 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.24 (s, 1H), 7.38 (s, 1H), 7.21 (s, 2H), 7.19 (dd, J = 7.4, 3.2 Hz, 2H), 7.02–6.96 (m, 2H), 6.89 (dd, J = 8.1, 5.1 Hz, 2H), 6.74 (d, J = 2.3 Hz, 1H), 5.18 (s, 1H), 1.31 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 153.1, 139.9, 137.7, 135.5, 134.6, 129.7, 128.0, 125.6, 125.0, 124.8, 124.7, 122.7, 122.6, 122.3, 117.2, 115.7, 114.1, 110.1, 57.5, 34.4, 30.2; IR (film): γ = 3537, 3441, 2956, 2925, 1706, 1618, 1471, −1 1322, 1157, 910, 750 cm ; HRMS (EI-TOF): calcd. for C30H31BrN2O2 530.1569, found 530.1570. 70-Chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3,30-biindolin-2-one (3f), 89% yield, 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.32 (s, 1H), 7.26 (s, 2H), 7.19 (t, J = 8.1 Hz, 2H), 7.10 (d, J = 7.5 Hz, 1H), 6.97 (dd, J = 14.3, 6.9 Hz, 1H), 6.91 (dd, J = 6.8, 4.2 Hz, 3H), 6.83 (t, J = 7.8 Hz, 1H), 5.19 (s, 1H), 1.32 (s, 13 18H); C NMR (101 MHz, CDCl3) δ 180.6, 153.1, 140.2, 135.5, 134.5, 134.1, 129.7, 128.0, 127.3, 125.7, 125.1, 124.8, 122.5, 121.5, 120.3, 119.7, 118.4, 116.5, 110.2, 57.6, 34.4, 30.2; IR (film): γ = 3437, 3241, −1 3056, 2925, 1706, 1618, 1471, 1256, 1157, 910 cm ; HRMS (EI-TOF): calcd. for C30H31ClN2O2 486.2074, found 486.2075. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-50-methoxy-3,30-biindolin-2-one (3g), 92% yield, 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.02 (s, 1H), 7.29 (d, J = 6.4 Hz, 2H), 7.26 (s, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.8, 13 2.4 Hz, 1H), 6.36 (d, J = 2.3 Hz, 1H), 5.17 (s, 1H), 3.53 (s, 3H), 1.33 (s, 18H); C NMR (101 MHz, CDCl3) δ 180.3, 153.5, 152.9, 140.0, 135.4, 134.8, 131.9, 130.0, 127.9, 126.4, 125.9, 124.9, 122.5, 116.9, 112.3, 111.8, 109.8, 102.5, 57.5, 55.4, 34.4, 30.2; IR (film): γ = 3337, 3141, 2956, 2870, 1706, 1618, 1471, 1206, 1157, 910, −1 750, 624 cm ; HRMS (EI-TOF): calcd. for C31H34N2O3 482.2569, found 482.2570. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-70-methoxy-3,30-biindolin-2-one (3h), 90% yield, 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.59–8.20 (m, 1H), 7.29 (s, 1H), 7.22 (d, J = 6.0 Hz, 1H), 7.15 (t, J = 8.2 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 5.16 (s, 1H), 3.88 (s, 1H), 1.32 (s, 1H); 13C NMR Sustainability 2018, 10, 2922 6 of 11

(101 MHz, CDCl3) δ 181.1, 153.0, 145.9, 140.3, 135.3, 135.1, 135.0, 130.1, 127.8, 127.4, 127.2, 125.8, 125.0, 124.1, 122.4, 119.8, 117.6, 113.7, 110.1, 101.9, 57.7, 55.2, 34.5, 30.3; IR (film): γ = 3537, 3241, 3056, 2925, −1 2870, 1706, 1618, 1236, 1157, 910, 747, 650 cm ; HRMS (EI-TOF): calcd. for C31H34N2O3 482.2569, found 482.2568. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-5-methyl-3,30-biindolin-2-one (3i), 89% yield; 1H NMR (400 MHz, DMSO) δ 10.94 (d, J = 2.0 Hz, 1H), 10.48 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.17 (s, 2H), 7.04–6.97 (m, 2H), 6.92 (dd, J = 11.4, 6.3 Hz, 3H), 6.86 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 2.19 (s, 3H), 1.28 (s, 18H); 13C NMR (101 MHz, DMSO) δ 179.1, 152.6, 138.8, 138.3, 136.7, 134.7, 131.0, 130.1, 128.0, 125.8, 125.6, 124.7, 124.1, 120.9, 120.2, 118.2, 115.9, 111.5, 109.3, 56.9, 34.5, 30.2, 20.7; IR (film): γ = 3423, 2968, 2254, 1657, 1487, 1435, 1386, 825, 763, 630 cm−1; HRMS (EI-TOF): calcd. for C31H34N2O2 466.2620, found 466.2619. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-40,5-dimethyl-3,30-biindolin-2-one (3j), 87% yield; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 6.97 (t, J = 7.5 Hz, 2H), 6.92 (s, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.1 Hz, 1H), 6.46 (s, 1H), 13 2.24 (s, 3H), 1.97 (d, J = 5.4 Hz, 3H), 1.34 (d, J = 4.6 Hz, 18H); C NMR (101 MHz, CDCl3) δ 153.0, 138.0, 137.5, 136.0, 131.5, 128.2, 126.9, 124.9, 122.2, 122.1, 109.8, 109.1, 34.6, 30.2, 21.1; IR (film): γ = 3403, −1 2956, 2925, 1699, 1622, 1464, 1238, 1076, 1016 cm ; HRMS (EI-TOF): calcd. for C32H36N2O2 480.2777, found 480.2776. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-5,50-dimethyl-3,30-biindolin-2-one (3k), 91% yield; 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.31 (s, 2H), 7.02 (d, J = 3.8 Hz, 2H), 6.96 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.72 (dd, J = 5.9, 1.8 Hz, 13 2H), 5.15 (s, 1H), 2.35 (s, 3H), 2.21 (s, 3H), 1.33 (s, 18H); C NMR (101 MHz, CDCl3) δ 181.0, 152.9, 137.7, 137.3, 135.2, 135.0, 131.7, 131.6, 130.2, 128.1, 126.5, 125.0, 124.0, 123.8, 121.2, 120.5, 117.0, 111.1, 109.7, 57.8, 34.5, 30.3, 21.6, 21.2; IR (film): γ = 3627, 3403, 2956, 1701, 1624, 1492, 1390, 1322, 1160, 1096, −1 1051, 881 cm ; HRMS (EI-TOF): calcd. for C32H36N2O2 480.2777, found 480.2775. 60-Bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-3,30-biindolin-2-one (3l), 85% yield, 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.21 (s, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.23 (s, 2H), 7.03–6.96 (m, 3H), 6.89 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 5.17 (s, 1H), 2.24 (s, 3H), 13 1.32 (s, 18H); C NMR (101 MHz, CDCl3) δ 180.5, 153.0, 137.7, 137.5, 135.4, 134.6, 132.0, 129.9, 128.4, 126.3, 125.1, 124.8, 124.7, 122.7, 122.4, 117.3, 115.6, 114.1, 109.7, 57.6, 34.4, 30.2, 21.2; IR (film): γ = 3437, 3141, 2956, 2925, 1706, 1618, 1471, 1322, 1157, 1021, 910, 747, 644 cm−1; HRMS (EI-TOF): calcd. for C31H34BrN2O2 545.1804, found 545.1805. 70-Chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-3,30-biindolin-2-one (3m), 87% yield, 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.28 (s, 1H), 7.27 (s, 2H), 7.11 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 6.9 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.88–6.79 (m, 1H), 5.18 (s, 1H), 2.25 (s, 3H), 1.33 (s, 18H); 13 C NMR (101 MHz, CDCl3) δ 180.3, 153.0, 137.6, 135.4, 134.5, 134.1, 131.9, 129.8, 128.4, 127.4, 126.4, 125.1, 124.9, 121.4, 120.3, 119.8, 118.6, 116.4, 109.7, 57.6, 34.4, 30.2, 21.2. IR (film): γ = 3137, 3041, 2956, −1 2870, 1706, 1618, 1378, 1322, 1157, 910, 744, 603 cm ; HRMS (EI-TOF): calcd. for C31H34ClN2O2 501.2309, found 501.2308. 40-Bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-3,30-biindolin-2-one (3n), 88% yield, 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.40 (s, 1H), 7.92 (s, 1H), 7.17–7.05 (m, 2H), 7.02 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.81 (t, J = 7.4 Hz, 2H), 6.70 (d, J = 7.6 Hz, 1H), 6.35 (s, 1H), 5.21 (s, 1H), 13 2.23 (s, 3H), 1.34 (d, J = 33.0 Hz, 18H); C NMR (101 MHz, CDCl3) δ 183.7, 153.1, 138.9, 138.5, 135.9, 135.3, 134.9, 131.0, 130.0, 128.1, 126.4, 125.9, 124.9, 124.7, 122.8, 113.8, 110.7, 110.0, 57.7, 34.6, 30.4, 30.1, 21.2; IR (film): γ = 3537, 3241, 3024, 2956, 2870, 1706, 1471, 1322, 1157, 1021, 910, 747, 644 cm−1; HRMS (EI-TOF): calcd. for C31H34BrN2O2 545.1804, found 545.1805. Sustainability 2018, 10, 2922 7 of 11

5-Chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-40-methyl-3,30-biindolin-2-one (3o), 90% yield; 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.28 (s, 1H), 7.27 (s, 2H), 7.11 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 6.9 Hz, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.89–6.79 (m, 1H), 13 5.18 (s, 1H), 2.25 (s, 3H), 1.33 (s, 18H); C NMR (101 MHz, CDCl3) δ 180.3, 153.0, 137.6, 135.4, 134.5, 134.1, 131.9, 129.8, 128.43, 127.4, 126.4, 125.1, 124.8, 121.4, 120.3, 119.8, 118.6, 116.4, 109.7, 57.6, 34.4, 30.2, 21.2; IR (film): γ = 3403, 2955, 2924, 2254, 1714, 1613, 1472, 1435, 1160, 1007, 763, 630 cm−1; HRMS (EI-TOF): calcd. for C31H34ClN2O2 501.2309, found 501.2308. 60-Bromo-5-chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3,30-biindolin-2-one (3p), 93% yield; 1H NMR (400 MHz, DMSO) δ 11.17 (d, J = 2.1 Hz, 1H), 10.79 (s, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.30 (dd, J = 8.3, 2.1 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.09 (s, 2H), 7.03–6.99 (m, 3H), 6.94–6.86 (m, 2H), 1.28 (s, 18H); 13C NMR (101 MHz, DMSO) δ 178.6, 152.9, 140.1, 138.7, 137.7, 136.4, 130.1, 127.9, 125.9, 125.5, 124.9, 124.4, 123.8, 121.9, 121.3, 115.1, 114.3, 113.9, 111.3, 57.1, 34.5, 30.2; IR (film): γ = 3628, −1 3345, 2957, 2925, 1711, 1615, 1436, 1375, 1079, 1021, 1007, 808 cm ; HRMS (EI-TOF): calcd. for C30H30 BrClN2O2 564.1179, found 564.1179. 5-Bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3,30-biindolin-2-one (3q), 87% yield; 1H NMR (400 MHz, DMSO) δ 11.02 (d, J = 2.0 Hz, 1H), 10.77 (s, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 7.14 (s, 2H), 7.08–7.02 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.86–6.79 (m, 2H), 1.28 (s, 18H); 13C NMR (101 MHz, DMSO) δ 178.7, 152.9, 140.6, 138.6, 137.0, 136.8, 130.6, 130.1, 127.7, 125.3, 24.8, 123.9, 121.1, 119.8, 118.4, 115.0, 113.1, 111.7, 57.1, 34.6, 30.2; IR (film): −1 γ = 3404, 2983, 2356, 1677, 1472, 1359, 1251, 905, 826, 764 cm ; HRMS (EI-TOF): calcd. for C30H31 BrN2O3 530.1569, found 530.1572. 5-Bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-40-methyl-3,30-biindolin-2-one (3r), 88% yield; 1H NMR (400 MHz, DMSO) δ 10.99 (d, J = 1.9 Hz, 1H), 10.68 (s, 1H), 7.44 (dd, J = 8.2, 1.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 15.5 Hz, 2H), 6.95 (t, J = 7.9 Hz, 3H), 6.63 (d, J = 7.1 Hz, 1H), 6.45 (s, 1H), 1.86 (s, 3H), 1.31 (s, 18H); 13C NMR (101 MHz, DMSO) δ 152.9, 140.4, 138.5, 137.9, 130.6, 127.9, 124.4, 121.3, 121.1, 112.9, 111.9, 109.6, 57.9, 34.6, 30.2; IR (film): γ = 3421, 2924, 2256, 1655, 1472, −1 1379, 1051, 1005, 826, 764 cm ; HRMS (EI-TOF): calcd. for C31H33 BrN2O2 544.1725, found 544.1721. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1-methyl-3,30-biindolin-2-one (3s), 92% yield; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.29 (q, J = 7.9 Hz, 3H), 7.25 (d, J = 1.3 Hz, 1H), 7.22–7.16 (m, 1H), 7.15–7.05 (m, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.94 (dd, J = 7.6, 4.2 Hz, 2H), 6.91–6.84 (m, 1H), 6.80 13 (d, J = 2.5 Hz, 1H), 5.14 (s, 1H), 3.32 (s, 3H), 1.32 (s, 18H); C NMR (101 MHz, CDCl3) δ 178.2, 152.9, 143.0, 136.9, 135.2, 134.2, 130.1, 127.9, 125.9, 125.6, 124.9, 124.3, 124.1, 122.5, 121.9, 120.8, 120.7, 119.8, 119.4, 117.5, 111.1, 108.1, 102.5, 57.1, 34.5, 30.2, 26.6; IR (film): γ = 3637, 3301, 2956, 2925, 1706, 1471, 1436, −1 1237, 1143, 909, 803, 750, 668 cm ; HRMS (EI-TOF): calcd. for C31H34N2O2 466.2620, found 466.2617. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-10-methyl-3,30-biindolin-2-one (3t), 94% yield; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.29 (q, J = 7.9 Hz, 3H), 7.25 (d, J = 1.3 Hz, 1H), 7.22–7.16 (m, 1H), 7.15–7.05 (m, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.94 (dd, J = 7.6, 4.2 Hz, 2H), 6.91–6.84 (m, 1H), 6.80 13 (d, J = 2.5 Hz, 1H), 5.14 (s, 1H), 3.32 (s, 3H), 1.32 (s, 18H); C NMR (101 MHz, CDCl3) δ 178.2, 152.9, 143.0, 136.9, 135.2, 134.2, 130.1, 127.9, 125.9, 125.6, 124.9, 124.3, 124.1, 122.5, 121.9, 120.8, 120.7, 119.7, 119.4, 117.5, 111.1, 108.1, 102.5, 57.1, 34.4, 30.2, 26.6; IR (film): γ = 3637, 3301, 2956, 1706, 1619, 1471, −1 1321, 1237, 1143, 909, 803, 750 cm ; HRMS (EI-TOF): calcd. for C31H34N2O2 466.2620, found 466.2617. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(1H-pyrrol-2-yl)indolin-2-one (3u), 94% yield; 1H NMR (400 MHz, DMSO) δ 10.57 (s, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.22 (td, J = 7.7, 1.1 Hz, 1H), 7.01 (td, J = 7.6, 0.8 Hz, 1H), 6.95–6.89 (m, 2H), 6.83 (s, 2H), 6.68 (dd, J = 4.3, 2.6 Hz, 1H), 5.91 (dd, J = 5.6, 2.6 Hz, 1H), 5.82 (dd, J = 4.5, 3.0 Hz, 1H), 1.26 (s, 18H); 13C NMR (101 MHz, DMSO) δ 177.9, 152.8, 141.2, 138.5, 133.7, 132.1, 129.3, 127.8, 125.3, 123.6, 121.6, 118.9, 109.5, 107.3, 106.2, 57.3, 34.4, 30.1; IR (film): γ = 3637, −1 3201, 2956, 1706, 1645, 1540, 1436, 955, 803, 750, 608 cm ; HRMS (EI-TOF): calcd. for C26H30 N2O2 402.2707, found 402.2701. Sustainability 2018, 10, 2922 8 of 11

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-5-methyl-3-(1H-pyrrol-2-yl)indolin-2-one (3v), 95% yield, 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.71 (dd, J = 28.4, 6.2 Hz, 1H), 7.10 (s, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.88 (s, 2H), 6.81 (d, J = 8.0 Hz, 2H), 6.13 (dd, J = 5.2, 2.5 Hz, 1H), 6.05 (t, J = 2.8 Hz, 1H), 5.15 (s, 1H), 13 2.31 (s, 3H), 1.33 (s, 18H); C NMR (101 MHz, CDCl3) δ 180.4, 180.4, 153.0, 135.7, 134.0, 132.3, 132.1, 128.4, 126.3, 123.9, 118.6, 109.9, 108.6, 107.7, 57.8, 34.3, 30.2, 21.3. IR (ﬁlm): γ = 3337, 3141, 3025, 2956, −1 2870, 1706, 1618, 1471, 1378, 1322, 910, 750, 644 cm ; HRMS (EI-TOF): calcd. for C27H32N2O2 416.2464, found 416.2464. 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-5-methoxy-3-(1H-pyrrol-2-yl)indolin-2-one (3w), 97% yield, 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.62 (s, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.87 (s, 2H), 6.84 (d, J = 8.5 Hz, 1H), 6.81 (dd, J = 3.9, 2.4 Hz, 1H), 6.75 (dd, J = 8.5, 2.5 Hz, 1H), 6.14 (dd, J = 5.9, 2.8 Hz, 1H), 13 6.08 (t, J = 3.5 Hz, 1H), 5.14 (s, 1H), 3.77 (s, 3H), 1.32 (s, 18H); C NMR (101 MHz, CDCl3) δ 180.2, 155.9, 153.1, 135.7, 135.3, 133.3, 131.9, 128.2, 123.8, 118.7, 112.9, 112.5, 110.5, 108.6, 107.8, 58.1, 55.8, 34.3, 30.2; IR (ﬁlm): γ = 3037, 3141, 2956, 2925, 2770, 1706, 1618, 1471, 1436, 1378, 1322, 1236, 1157, 1021, 850, −1 747, 624 cm ; HRMS (EI-TOF): calcd. for C27H32N2O3 432.2413, found 432.2414.

3. Results and Discussion

3.1. Sustainable Methodology To start this work, firstly we investigated the model 1,6-conjugate addition reaction between para-quinone methide derived from isatin (1a) and indole (2a) in glycerol, and screened the reaction conditions. The procedure of the reaction was monitored by TLC and the results are summarized in Table1. It is noted that 2-methyltetrahydrofuran as a biomass-derived solvent, is an immiscible solvent with glycerol. The desired product 3a can be extracted with 2-methyltetrahydrofuran from the reaction mixture in glycerol at room temperature, because 3a is insoluble in high viscous glycerol at room temperature although it is soluble in low viscous glycerol at high temperature (>100 ◦C). To optimize the reaction conditions, firstly, we investigated the catalytic effect of diphenyl phosphoric acid on reaction at different temperatures for 24 h, and noted that there was no reaction at 25 ◦C because of the insolubility of substrate (1a) in high viscous glycerol (Table1, entry 1). When we increased the reaction temperature from 25 to 60 ◦C to make the solvent low viscous and improved the solubility of substrate (1a), a rare amount of desired product (3a) was observed on TLC (Table1, entry 2). A continuous increase of temperature to 80 ◦C and 120 ◦C increased the yield of the required product to rare, 60% and 86% respectively (Table1, entries 3 and 4). When we set the temperature of reaction according to the yield, then we screened the different type of catalyst to identify the best reaction protocol. After further screening the different catalysts like H3PO4, PhCO2H, FeCl3, we found that FeCl3 could be easily dissolved in glycerol and became the best choice of catalysts according to the yield (Table1, entries 5–7). After the loading of FeCl 3 catalyst was investigated, we found that 10 mol% is the best loading of catalyst to give the desired indole-containing oxindole 3a in 93% yield (Table1, entries 7–9). For comparison, we have studied the catalytic activity of FeCl3 in different conventional volatile organic solvents, such as toluene, xylene and 1,2-dichloroethane under reflux, finding that the efficiency of the 1,6-conjugate addition reaction was remarkably lowered (Table1, entries 10–12). Thus, the optimized reaction conditions were identified (Table1, entry 8). With the optimized reaction conditions in hand, our next step was to investigate the scope of substrate with a different type and at different position of substitutions. To our delight, FeCl3 dissolved in glycerol showed near-perfect performance for such an organic transformation and the results are summarized in Table2. Firstly, we observed that a wide range of indoles with electron-withdrawing or electron-donating groups are suitable nucleophiles to afford the corresponding products with high yields (88–93%, Table2, entries 1–8). Meanwhile, we also examined the effect of substitution on para-quinone methides derived from isatins, and no obvious electron effect was observed. Various electron-withdrawing or electron-donating groups, such as Me, Cl and Br, could also be successfully employed in the 1,6-conjugate addition reaction to reveal excellent results (85–93%, Sustainability 2018, 10, x FOR PEER REVIEW 8 of 11

Table 2. Sustainable approach for synthesis of indole-containing oxindoles a.

Entry 1 R1 R2 2 R3 R4 Product (3) Isolated Yield [%] 1 1a H H 2a H H 3a 93 2 1a H H 2b 4-Me H 3b 91 3 1a H H 2c 5-Me H 3c 93 4 1a H H 2d 7-Me H 3d 90 5 1a H H 2e 6-Br H 3e 88 6 1a H H 2f 7-Cl H 3f 89 7 1a H H 2g 5-OMe H 3g 92 8 1a H H 2h 7-OMe H 3h 90 9 1b Me H 2a H H 3i 89 10 1b Me H 2b 4-Me H 3j 87 11 1b Me H 2d 7-Me H 3k 91 12 1b Me H 2e 6-Br H 3l 85 13 1b Me H 2f 7-Cl H 3m 87 14 1b Me H 2i 4-Br H 3n 88 15 1c Cl H 2b 4-Me H 3o 90 16 1c Cl H 2e 6-Br H 3p 93 Sustainability 2018, 10, 2922 9 of 11 17 1d Br H 2a H H 3q 87 18 1d Br H 2b 4-Me H 3r 88 19 1e H Me 2a H H 3s 92 Table2, entries20 9–18). 1f It is noteworthyH H 2j that theH effectMe of protecting3t the group on94 the reaction protocol was alsoa Reactions examined were to performed show that with there 1 (2 was mmol) no signiﬁcant, 2 (2 mmol) effect and FeCl on the3 (0. yield2 mmol) of requiredin glycerol products (4 mL) at when indole120 or °Cpara for-quinone 24 h. methide derived from isatin was protected with N-methylation consecutively (Table2, entries 19–20). Furthermore, we then expanded expanded the generality generality of of the the FeCl FeCl33 dissolveddissolved in in glycerolglycerol catalyzed catalyzed 1,6-conjugate1,6-conjugate addition addition reaction reaction by by using using new new nucleophile nucleophile pyrrole, pyrrole, and the and results the results obtained obtained are shown are inshown Scheme in 1 Scheme. The different 1. The differentpara-quinone para- methidesquinone methid derivedes from derived isatins from could isatins react could with react pyrrole with to affordpyrrole the tocorresponding afford the corresponding product pyrrole-containing product pyrrole oxindoles-containing in excellent oxindoles yields in excellent (94–97%) yields under (94 the– above97%) under standard the conditions.above standard conditions.

Scheme 1. 1,6-Conjugate1,6-Conjugate addition reaction with pyrrole.

3.2. Catalytic System Recycling 3.2. Catalytic System Recycling The good results prompted us to study the recyclability of the catalytic system in a batch. We The good results prompted us to study the recyclability of the catalytic system in a batch. developed FeCl3 dissolved in glycerol as a the catalytic system recycling for 1,6-conjugate addition We developed FeCl3 dissolved in glycerol as a the catalytic system recycling for 1,6-conjugate addition reaction of oxoindole-derived methides and indoles for the construction of 3,3-disubstituted oxindoles. reaction of oxoindole-derived methides and indoles for the construction of 3,3-disubstituted oxindoles. The separation of the products was realized by a simple extraction with 2-methyltetrahydrofuran, The separation of the products was realized by a simple extraction with 2-methyltetrahydrofuran, which is an immiscible solvent with glycerol, while the retained glycerol layer still contained the which is an immiscible solvent with glycerol, while the retained glycerol layer still contained the catalyst FeCl3. The catalytic system with FeCl3 dissolved in glycerol has some obvious advantages, catalyst FeCl3. The catalytic system with FeCl3 dissolved in glycerol has some obvious advantages, such as, long life time and high level of reusability. When the reaction between 1a and 2a was completed under the standard reaction conditions, the ﬁnal product 3a was extracted using 2-methyltetrahydrofuran, and the retained glycerol phase with FeCl3 was reused by just adding the substrates again under the same reaction protocol. As shown in Table3, we observed that this procedure could be repeated up to 5 times with no loss of catalytic activity, and the desired product 3a was obtained in excellent yield every time, which bears witness to the catalyst’s robustness.

4. Conclusions A highly efﬁcient and atom-economical synthesis of bioactive indole-containing oxindoles was developed by using a FeCl3 dissolved in glycerol catalyzed 1,6-conjugated addition reaction of para-quinone methides derived from isatins and indoles. Pyrrole was also applicable to afford the corresponding pyrrole-containing oxindoles in excellent yields with this protocol. The desired 3,3-disubstituted oxoindoles could be extracted using the biomass-derived solvent 2-methyltetrahydrofuran and the retained glycerol layer with FeCl3 could be reused up to 5 times with very high efﬁciency. The superior advantages of the sustainable methodology include the ready availability, low price and environmentally benign character of iron catalysis, easy product separation, and a recyclable catalyst system. The current iron catalysis meets the increasing demand of sustainability, such as energy resources, cheap catalysts, non-toxic reagents and green solvents.

Supplementary Materials: The following are available online at http://www.mdpi.com/2071-1050/10/8/2922/ s1, NMR spectra for all products. Sustainability 2018, 10, 2922 10 of 11

Author Contributions: L.T. conceived and directed the project, and analyzed the data; A.R. performed the experiments and the characterizations. Both authors co-wrote the manuscript. Funding: This research was funded by the Social Science Planning Project of Zhejiang Province grant number 16ZJQN052YB. Acknowledgments: This work is supported by Zhejiang Social Science Planning Zhi Jiang Youth Project. Financial support from the Social Science Planning Project of Zhejiang Province (Project No. 16ZJQN052YB) is gratefully acknowledged. We thank Xu. Lin for assistance with designing the research and analyzing the data. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

1. Tukker, A.; Giljum, S.; Wood, R. Recent progress in assessment of resource efficiency and environmental impacts embodied in trade: An introduction to this special issue. J. Ind. Ecol. 2018, 22, 489–501. [CrossRef] 2. Vanner, R.; Bicket, M. The role of paradigm analysis in the development of policies for a resource efficient economy. Sustainability 2016, 8, 645. [CrossRef] 3. Bicket, M.; Vanner, R. Designing policy mixes for resource efficiency: The role of public acceptability. Sustainability 2016, 8, 366. [CrossRef] 4. Augé, J.; Scherrmann, M.-C. Determination of the global material economy (GME) of synthesis sequences—A green chemistry metric to evaluate the greenness of products. New J. Chem. 2012, 36, 1091–1098. [CrossRef] 5. Dunn, P.J. The importance of green chemistry in process research and development. Chem. Soc. Rev. 2012, 41, 1452–1461. [CrossRef][PubMed] 6. Laird, T. Green chemistry is good process chemistry. Org. Process Res. Dev. 2012, 16, 1–2. [CrossRef] 7. Trost, B.M. The atom economy—A search for synthetic efficiency. Science 1991, 254, 1471–1477. [CrossRef] [PubMed] 8. Tang, S.L.Y.; Smith, R.L.; Poliakoff, M. Principles of green chemistry: Productively. Green Chem. 2005, 7, 761–762. [CrossRef] 9. Wilhelm, R. Sustainable economy—Key factors for sustainable transformations. GAIA Ecol. Perspect. Sci. Soc. 2015, 24, 199–200. 10. Anderson, K. The sustainable economy. Harv. Bus. Rev. 2011, 89, 52–62. 11. Silva, E.M.P.; Silva, A.M.S. 1,6-Conjugate addition of nucleophiles to alpha, beta, gamma, delta-diunsaturated systems. Synthesis 2012, 44, 3109–3128. [CrossRef] 12. Meng, F.; Li, X.; Torker, S.; Shi, Y.; Shen, X.; Hoveyda, A.H. Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups. Nature 2016, 537, 387–393. [CrossRef][PubMed] 13. Chu, W.-D.; Zhang, L.-F.; Bao, X.; Zhao, X.-H.; Zeng, C.; Du, J.-Y.; Zhang, G.-B.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-A. Asymmetric catalytic 1,6-conjugate addition/aromatization of para-quinone methides: Enantioselective introduction of functionalized diarylmethine stereogenic centers. Angew. Chem. Int. Ed. 2013, 52, 9229–9233. [CrossRef][PubMed] 14. Wang, H.; Wang, K.; Man, Y.; Gao, X.; Yang, L.; Ren, Y.; Li, N.; Tang, B.; Zhao, G. Asymmetric intermolecular Rauhut-Currier reaction for the construction of 3,3-disubstituted oxindoles with quaternary stereogenic centers. Adv. Synth. Catal. 2017, 359, 3934–3939. [CrossRef] 15. Bauer, I.; Knölker, H.-J. Iron catalysis in organic synthesis. Chem. Rev. 2015, 115, 3170–3387. [CrossRef] [PubMed] 16. Bisz, E.; Szostak, M. Iron-catalyzed C-O bond activation: Opportunity for sustainable catalysis. ChemSusChem 2017, 10, 3964–3981. [CrossRef][PubMed] 17. Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice; Oxford University Press: New York, NY, USA, 1998. 18. Gu, Y.; Barrault, J.; Jérôme, F. Glycerol as an efficient promoting medium for organic reactions. Adv. Synth. Catal. 2008, 350, 2007–2012. [CrossRef] 19. Gu, Y.; Jérôme, F. Glycerol as a sustainable solvent for green chemistry. Green Chem. 2010, 12, 1127–1138. [CrossRef] 20. Wolfson, A.; Dlugy, C.; Shotland, Y. Glycerol as a green solvent for high product yields and selectivities. Environ. Chem. Lett. 2007, 5, 67–71. [CrossRef] Sustainability 2018, 10, 2922 11 of 11

21. Tagliapietra, S.; Orio, L.; Palmisano, G.; Penoni, A.; Gravotto, G. Catalysis in glycerol: A survey of recent advances. Chem. Pap. 2015, 69, 1519–1531. [CrossRef] 22. Tan, L.; Rahman, A. From technical efficiency to economic efficiency: Development of Aza-Friedel–Crafts reaction using phosphoric acid immobilized in glycerol as a sustainable approach. Sustainability 2017, 9, 1176. [CrossRef] 23. Vidal, C.; García-Álvarez, J. Glycerol: A biorenewable solvent for base-free Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides with terminal and 1-iodoalkynes. Highly efficient transformations and catalyst recycling. Green Chem. 2014, 16, 3515–3521. [CrossRef] 24. Riggio, O.; Mannaioni, G.; Ridola, L.; Angeloni, S.; Merli, M.; Carlà, V.; Salvatori, F.M.; Moroni, F. Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: A study on the pathophysiology of hepatic encephalopathy. Am. J. Gastroenterol. 2010, 105, 1374–1381. [CrossRef][PubMed] 25. Greig, N.H.; Pei, X.-F.; Soncrant, T.T.; Ingram, D.K.; Brossi, A. Phenserine and ring C hetero-analogues: Drug candidates for the treatment of Alzheimer’s disease. Med. Res. Rev. 1995, 15, 3–31. [CrossRef][PubMed] 26. Dalpozzo, R. Catalytic asymmetric synthesis of hetero-substituted oxindoles. Org. Chem. Front. 2017, 4, 2063–2078. [CrossRef] 27. Rahman, A.; Zhou, Q.; Lin, X. Asymmetric organocatalytic synthesis of chiral 3,3-disubstituted oxindoles via 1,6-conjugate addition reaction. Org. Biomol. Chem. 2018, 16, 5301–5309. [CrossRef][PubMed]

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