One-Pot Synthesis of Polycyclic Spirooxindoles via ... - ACS Publications

Research Article Cite This: ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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One-Pot Synthesis of Polycyclic Spirooxindoles via Montmorillonite K10-Catalyzed C−H Functionalization of Cyclic Amines Xiaofeng Zhang,† Miao Liu,† Weiqi Qiu,† Jason Evans,† Manpreet Kaur,‡ Jerry P. Jasinski,‡ and Wei Zhang*,† †

Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, Massachusetts 02125, United States ‡ Department of Chemistry, Keene State College, 229 Main Street, Keene, New Hampshire 03435, United States S Supporting Information *

ABSTRACT: A method for pot and atom economic synthesis of polycyclic spirooxindoles through α-C−H functionalization of cyclic amines has been developed. This highly efficient three-component [3+2] cycloaddition reaction was catalyzed by recyclable montmorillonite K10 and only water was produced as a byproduct.

KEYWORDS: [3+2] Cycloaddition, Spirooxindoles, Montmorillonite K10, Heterogeneous catalysis, Recyclable, α-C−H functionalization

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INTRODUCTION

diverse heterocyclic structures, including spirooxindole-containing compounds.10−18 The 1,3-dipolar azomethine ylides used for [3+2] cycloadditions were generated from the reaction of α-amino esters with aldehydes.19 It has been reported that 1,3-dipolar azomethine ylides could also be generated from cyclic amines instead of α-amino esters.20−23 Brønsted acids were used as catalysts for the activation of α-C−H of cyclic amines.24−31 Introduced in this paper is our effort on the development of a new synthetic method for polycyclic spirooxindole compounds through one-pot [3+2] cycloaddition of cyclic amines, isatins and maleimides using a low cost, environmentally compatible, and recyclable montmorillonite K10 as a catalyst.32−41

Spirooxindole is a biologically interested scaffold that can be found in a variety of natural products and medicinal chemicals, such as horsfiline, elacomine, spirotryprostatin A, MDM2 inhibitor pteropodine, antibacterial agent and antimalarial drug NITD609 (Figure 1).1−6 The development of cyclization, cycloaddition and asymmetric reactions for spirooxindole-based structures with potential biological activity continuously attracts attention of synthetic chemists.7−9 In recent years, we have developed a series of [3+2] cycloadditions and organocatalysis reactions in the synthesis of

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RESULTS AND DISCUSSION The development of one-pot [3+2] cycloaddition conditions for heterocyclic spirooxindole 1a was explored using isatin 2a, 1,2,3,4-tetrahydroisoquinoline (THIQ) 3a, and N-ethylmaleimide 4a as model compounds. After screening reaction temperatures and times, solvents, and acid catalysts, it was found that under microwave heating at 150 °C for 25 min and in the presence of 3 Å molecular sieves, 1:1.3:1.2 of 2a:3a:4a in EtOH using zeolite YH, montmorillonite K30 or K10 as a heterogeneous catalyst, the one-pot reactions gave 1a in >81% LC yields (Table 1, entries 8−10). A slightly excess amount of 3a and 4a were used to push the reaction to completion. Received: February 2, 2018 Revised: February 19, 2018 Published: February 26, 2018

Figure 1. Bioactive polycyclic spirooxindoles. © XXXX American Chemical Society

A

DOI: 10.1021/acssuschemeng.8b00555 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering

and maleimides 4 were carried out for the synthesis of polycyclic spirooxindoles 1 with different R1−R3 groups (Table 2). The isolated yields of products 1a−h were in the range of

Table 1. [3+2] Cycloaddition Conditions for 1a

Table 2. [3+2] Cycloaddition for Polycyclic Spirooxindoles 1a entry

solvent

cat.

T (°C)

t (min)

1a (%)a

drb

1 2 3 4 5 6 7c 8c 9c 10c 11 12 13

toluene dioxane EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH

BzOH BzOH BzOH − Rf8CO2H TfOH AlCl3 Zeolite YH K30 K10 (2nd rd) (3rd rd) (4th rd)

150 135 125 125 150 150 150 150 150 150 150 150 150

35 50 50 50 25 25 25 25 25 25 25 25 25

50 33 71 63 81 77 50 80 86 86 (80) 83 88 86

67:33 75:25 70:30 66:34 78:28 71:29 75:25 89:11 85:15 89:11 88:12 85:15 82:18

a Detected by LC, isolated yield in parentheses. bDetermined by 1H NMR of crude reaction mixture. cCatalyst loading 100 mg/1 mmol.

Reactions with other catalysts including BzOH, TfOH, AlCl3 gave significantly lower yields (Table 1, entries 1−7). Homogenous catalyst perfluorononanoic acid (Rf8CO2H) afforded 1a in 81% LC yield and 78:28 dr (entry 5). The dr is lower than that from the reaction of solid catalysts such as K10 of 89:11 (Table 1, entry 10). K10 has a three-dimensional pore structure that may be more stereoselective than homogeneous catalysts. Because K10 was the choice of catalyst for the [3+2] cycloaddition, its recyclability test was conducted. After the reaction was over, the K10 powder was isolated from the reaction mixture by centrifuge, and used for three more rounds of reactions for the evaluation of product yield and dr. Results shown in Figure 2 indicate that no significant yield

a

Isolated yield, reaction conditions are the same as Table 1, entry 10.

43−83% and dr 83:17 to 91:9. Only a trace amount of product 1i was detected from the reaction mixture, probably due to the steric hindrance of 4-bromo in the isatin interacting with the THIQ moiety. The stereochemistry of the major diastereomers was established by X-ray crystal structure analysis of 1f (Figure 3). As a solid catalyst, K10 has surface Brønsted acid centers, peculiar charge characteristics, and three-dimensional pore structure. It has been widely used for chemical transformations in research and production scales. The mechanism of K10catalzed [3+2] cycloaddition for polycyclic spirooxindoles 1 is proposed in Scheme 1. The acid-catalyzed nucleophilic addition of THIQ to isatin followed by dehydration results an iminium ion. It is then converted to an azomethine ylide after deprotonation and then undergoes 1,3-dipolar cycloaddition with a maleimide to afford polycyclic spirooxindoles 1. The stereorigid solid catalyst may provide a good environment for more diastereoselective cycloaddition than using homogeneous catalysts such as BzOH, TfOH, and Rf8CO2H. The applications of the one-pot [3+2] cycloaddition for the synthesis of diverse polycyclic spirooxindoles 5 were attempted by conducting the reaction of isatins with cyclic amines 6 including isoindoline piperidine, morpholine, methyl prolinate, and 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, and with differ-

Figure 2. Recyclability of K10 catalyst.

change in four rounds, but the dr decreased slightly from 89:11 to 82:18. The one-pot reaction has an inherit high pot economy. This three-component [3+2] cycloaddition also has a good atom economy because all the starting materials were incorporated in the product and only one equiv of water was released as a side-product. Under the optimized reaction conditions using K10 as a catalyst, [3+2] cycloadditions of THIQ with diverse isatins 2 B


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Table 3. [3+2] Cycloaddition for Polycyclic Spirooxindoles 5a

Figure 3. X-ray structure of 1f.

Scheme 1. α-C−H Activation of THIQ by K10 for [3+2] Cycloaddition

a b

Isolated yield. Reaction conditions are the same as Table 1, entry 10. 180 °C, 35 min.

hydroquinone, which is no longer a dipolarophile,43 and acyclic dibenzylamine may not efficiently generate azomethine ylide for the [3+2] cycloaddition.

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CONCLUSION This study has established a practical and highly efficient synthesis for polycyclic spirooxindoles with diverse structures. Readily available, environmentally benign and recyclable montmorillonite K10 was used as a heterogeneous catalyst to activate α-C−H of cyclic amines in the formation of azomethine ylides for the [3+2] cycloaddition. Reactions with K10 were found to afford products with a better diastereoselectivity than with homogeneous acid catalysts. This new reaction process also has high pot and atom economy that only produced water as a byproduct.

ent activated alkenes 7 such as Z-dimethyl maleate, naphthalene-1,4-dione, and benzoquinone (Table 3). Heavily polycyclic spirooxindoles 5a and 5b derived from 2,3,4,9tetrahydro-1H-pyrido[3,4-b]indole were produced in 73% and 71% yield, respectively. Reactions using isoindoline, piperidine, morpholine, or methyl prolinate as a cyclic amine afforded products 5c−5f in 40−83% yields. Except 5b, which has a dr of 86:14, other products have dr values greater than 90:10. However, the reactions of benzoquinone or naphthalene-1,4dione only resulted a trace amount of products 5g and 5h. Reaction with an acyclic dibenzylamine failed to give expected product 5i. It is postulated that the electron-rich benzene ring of benzoquinone reduced its reactivity as a dipolarophile,42 whereas aphthalene-1,4-dione could easily be converted to

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EXPERIMENTAL SECTION

Chemicals and solvents were purchased from Sigma and Oakwood. Montmorillonite K10 from Sigma, surface area, 220−270 m2/g, pH = 3−4. 1H NMR (400 MHz) and 13C NMR spectra (101 MHz) were recorded on Agilent NMR spectrometers. Chemical shifts were reported in parts per million (ppm). LC-MS were performed on an Agilent 2100 LC with a 6130 quadrupole MS spectrometers. A C18 column (5.0 μm, 6.0 × 50 mm) was used for the separation. The mobile phases were MeOH and H2O both containing 0.05% CF3CO2H. Low resolution mass spectra were recorded in APCI (atmospheric pressure chemical ionization). Flash chromatography C


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ACS Sustainable Chemistry & Engineering separations were performed on YAMAZEN AI-580 flash column system with Agela silica gel columns (230−400 μm mesh). General Procedure for the One-Pot Synthesis of Compounds 1 and 5. To a solution of isatin 2 (1.2 mmol), cyclic amine 3 (1.3 mmol), and activated alkene 4 (1.0 mmol) in 2.5 mL of EtOH was added montmorillonite K10 (100 mg/mmol). The reaction mixture was heated under microwaves at 150 or 180 °C for 25 min. Upon the completion of the reaction as monitored by LC-MS, the reaction mixture was centrifuged to separate the K10, and the concentrated reaction solution was isolated on YAMAZEN AI-580 flash column system to give product 1 or 5. Compound 1a was obtained as a white solid (80% yield, 89:11 dr). MP: 230−232 °C. 1H NMR (400 MHz, CDCl3): δ 7.98−7.91 (m, 2H), 7.32−7.26 (m, 3H), 7.20 (ddd, J = 7.4, 2.1, 1.3 Hz, 1H), 7.09 (m, 2H), 6.87−6.80 (m, 1H), 4.95 (d, J = 8.0 Hz, 1H), 3.77 (d, J = 9.7 Hz, 1H), 3.64−3.56 (m, 3H), 3.00−2.88 (m, 1H), 2.81−2.65 (m, 2H), 2.65−2.58 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 176.9, 176.8, 175.4, 141.7, 136.8, 133.8, 130.0, 128.6, 127.8, 126.9, 126.6, 126.3, 124.4, 123.4, 110.2, 71.2, 61.4, 54.0, 49.7, 42.4, 34.1, 29.5, 12.7. HRMS (EI, m/z): calcd. for C23H21N3O3 (M + H)+ 388.1661. Found: 388.1659. Compound 1b was obtained as a white solid (83% yield, 83:17 dr). MP: 197−199 °C. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.7 Hz, 1H), 7.38−7.26 (m, 3H), 7.19 (m, 2H), 7.10 (m, 2H), 6.86 (t, J = 9.7 Hz, 1H), 4.97 (d, J = 8.0 Hz, 1H), 3.75 (d, J = 9.7 Hz, 1H), 3.58 (dd, J = 9.7, 8.1 Hz, 1H), 3.52−3.45 (m, 2H), 3.15 (s, 3H), 2.93 (m, 2H), 2.72−2.62 (m, 2H), 2.52 (dd, J = 10.4, 6.9 Hz, 1H), 1.68−1.57 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 177.0, 175.5, 175.0, 144.7, 136.9, 133.9, 130.0, 128.6, 127.5, 126.8, 126.7, 126.3, 123.9, 123.4, 108.4, 71.0, 61.6, 54.1, 49.6, 42.3, 40.7, 29.4, 25.8, 20.9, 11.4. HRMS (EI, m/z): calcd. for C25H25N3O3 (M + H)+ 416.1974. Found: 416.1979. Compound 1c was obtained as a white solid (76% yield, 88:12 dr). MP: 173−176 °C. 1H NMR (400 MHz, CDCl3): δ 7.51 (dd, J = 13.6, 4.5 Hz, 1H), 7.37−7.25 (m, 7H), 7.21−7.14 (m, 1H), 7.10−7.00 (m, 2H), 6.81 (dt, J = 8.5, 4.3 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.49 (d, J = 6.6 Hz, 1H), 5.15−5.05 (d, J = 8.3, 1H), 4.65 (d, J = 13.4 Hz, 1H), 4.03−3.95 (m, 1H), 3.64 (d, J = 7.5 Hz, 1H), 2.96 (s, 3H), 2.65 (ddd, J = 11.2, 9.1, 3.7 Hz, 2H), 2.59−2.49 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 176.7, 175.5, 174.8, 143.4, 135.5, 133.9, 132.9, 130.1, 128.9, 128.8, 127.8, 127.7, 127.2, 126.6, 125.6, 125.0, 124.8, 123.0, 109.4, 70.6, 61.0, 51.7, 46.3, 43.7, 42.5, 30.1, 24.9. HRMS (EI, m/z): calcd. for C29H25N3O3 (M + H)+ 464.1974. Found: 464.1968. Compound 1d was obtained as a white solid (77% yield, 89:11 dr). MP: 201−203 °C. 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.36−7.26 (m, 5H), 7.22−7.14 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.75 (td, J = 7.6, 1.0 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.20 (d, J = 6.9 Hz, 1H), 5.40 (d, J = 6.5 Hz, 1H), 4.71 (d, J = 13.9 Hz, 1H), 4.52 (d, J = 13.9 Hz, 1H), 3.95 (dd, J = 7.4, 6.6 Hz, 1H), 3.66 (d, J = 7.5 Hz, 1H), 2.91−2.78 (m, 1H), 2.65−2.53 (m, 2H), 2.51−2.42 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 178.4, 175.1, 174.7, 141.1, 135.6, 134.1, 132.9, 129.8, 129.3, 128.8, 128.5, 128.0, 127.7, 126.6, 126.3, 125.1, 125.1, 122.9, 109.9, 70.8, 60.8, 51.2, 46.3, 42.5, 42.3, 30.2. HRMS (EI, m/z): calcd. for C28H23N3O3 (M + H)+ 450.1818. Found: 450.1819. Compound 1e was obtained as a white solid (61% yield, 90:10 dr). MP: 233−236 °C. 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.31−7.25 (m, 1H), 7.24−7.21 (m, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.00 (dd, J = 8.1, 7.6 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 5.38 (d, J = 6.5 Hz, 1H), 3.97−3.91 (m, 1H), 3.64 (d, J = 7.6 Hz, 1H), 3.52−3.48 (m, 2H), 2.94−2.84 (m, 1H), 2.62 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 177.3, 174.9, 174.3, 138.9, 133.8, 132.6, 130.0, 128.8, 127.8, 126.9, 126.7, 125.1, 124.2, 123.7, 115.3, 71.7, 60.9, 51.5, 46.0, 42.6, 34.0, 30.0, 13.0. HRMS (EI, m/z): calcd. for C23H20ClN3O3 (M + H)+ 422.1272. Found: 422.1273. Compound 1f was obtained as a white solid (79% yield, 91:9 dr). MP: 260−263 °C. 1H NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 8.3, 2.0 Hz, 1H), 7.30−7.21 (m, 1H), 7.22−7.14 (m, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H),

6.49 (d, J = 8.4 Hz, 1H), 5.30 (d, J = 6.2 Hz, 1H), 3.95 (dd, J = 7.5, 6.3 Hz, 1H), 3.80 (d, J = 7.5 Hz, 1H), 3.55 (q, J = 7.2 Hz, 2H), 2.99−2.87 (m, 1H), 2.71−2.57 (m, 2H), 2.53 (dd, J = 9.9, 6.0 Hz, 1H), 1.21 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 178.2, 175.6, 175.0, 140.3, 133.8, 132.7, 132.6, 128.9, 128.7, 127.9, 127.5, 126.8, 125.1, 115.5, 112.0, 70.8, 61.0, 51.5, 46.4, 42.5, 34.2, 30.0, 13.1. HRMS (EI, m/z): calcd. for C23H20BrN3O3 (M + H)+ 466.0766. Found: 466.0768. Compound 1g was obtained as an off-white solid (43% yield, 83:17 dr). MP: 179−181 °C. 1H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.27−8.18 (m, 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 4.91 (d, J = 8.0 Hz, 1H), 3.83 (d, J = 9.7 Hz, 1H), 3.63 (ddd, J = 21.6, 12.0, 7.7 Hz, 3H), 3.03−2.91 (m, 1H), 2.82−2.67 (m, 2H), 2.58 (dd, J = 10.2, 7.1 Hz, 1H), 1.19 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 177.1, 176.2, 175.2, 147.5, 144.2, 136.0, 133.4, 129.1, 128.6, 127.2, 127.0, 126.5, 126.5, 120.6, 110.2, 70.9, 61.7, 54.4, 49.5, 42.6, 34.2, 29.3, 12.7. HRMS (EI, m/z): calcd. for C23H20N4O5 (M + H)+ 433.1512. Found: 433.1509. Compound 1h was obtained as a white solid (59% yield, 86:14 dr). MP: 270−273 °C. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 9.8 Hz, 1H), 7.08 (d, J = 5.3, 2H), 6.73 (d, J = 7.9 Hz, 1H), 4.94 (d, J = 8.0 Hz, 1H), 3.75 (t, J = 8.4 Hz, 1H), 3.64−3.55 (m, 3H), 3.02−2.90 (m, 1H), 2.78−2.59 (m, 3H), 2.32 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).13C NMR (101 MHz, CDCl3): δ 176.8, 175.4, 139.2, 136.8, 133.9, 133.0, 130.4, 128.6, 127.8, 126.9, 126.6, 126.3, 125.1, 109.9, 71.3, 61.4, 54.0, 49.7, 42.4, 34.0, 29.5, 21.1, 12.7. HRMS (EI, m/ z): calcd. for C24H23N3O3 (M + H)+ 402.1818. Found: 402.1822. Compound 5a was obtained as a light yellow solid (73% yield, 92:8 dr). MP: 240−242 °C. 1H NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 8.00 (s, 1H), 7.48−7.37 (m, 2H), 7.34−7.25 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.03 (d, J = 8.9 Hz, 1H), 3.75 (d, J = 9.3 Hz, 1H), 3.62 (q, J = 7.2 Hz, 2H), 3.50 (dd, J = 14.8, 5.7 Hz, 1H), 2.83−2.65 (m, 4H), 1.22 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 176.8, 176.7, 175.3, 140.1, 136.0, 131.9, 130.2, 129.7, 128.9, 126.8, 124.9, 121.9, 119.6, 118.3, 111.3, 111.3, 107.9, 71.1, 57.7, 54.8, 48.3, 42.4, 34.2, 22.3, 12.8. HRMS (EI, m/z): calcd. for C25H21ClN4O3 (M + H)+ 461.1380. Found: 461.1382. Compound 5b was obtained as a light yellow solid (71% yield, 86:14 dr). MP: 228−230 °C. 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.36 (s, 1H), 7.41 (dd, J = 19.6, 8.0 Hz, 2H), 7.24−7.21 (m, 1H), 7.21−7.12 (m, 1H), 7.12−7.03 (m, 2H), 6.81 (d, J = 8.3 Hz, 1H), 4.97 (dt, J = 10.4, 5.2 Hz, 1H), 3.93−3.87 (m, 2H), 3.87 (s, 3H), 3.31 (s, 3H), 2.92−2.85 (m, 1H), 2.73−2.62 (m, 3H). 13C NMR (101 MHz, CDCl3): δ 179.5, 172.7, 170.0, 139.8, 135.6, 132.8, 129.9, 129.4, 128.5, 126.8, 125.8, 121.7, 119.3, 118.2, 111.2, 110.8, 108.2, 70.8, 57.3, 53.9, 53.1, 52.1, 49.2, 42.5, 22.2. HRMS (EI, m/z): calcd. for C25H22ClN3O5 (M + H)+ 480.1326. Found: 480.1329. Compound 5c was obtained as an off-white solid (83% yield, 92:8 dr). MP: 258−261 °C. 1H NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.38 (dd, J = 8.3, 1.8 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.26−7.21 (m, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.78 (dd, J = 13.1, 5.1 Hz, 2H), 5.62 (d, J = 9.6 Hz, 1H), 4.12−4.01 (m, 1H), 3.95 (q, J = 14.1 Hz, 2H), 3.78−3.62 (m, 2H), 1.93−1.81 (m, 1H), 1.79− 1.65 (m, 3H), 1.55 (d, J = 10.5 Hz, 1H), 1.30 (d, J = 12.3 Hz, 1H), 1.22−1.03 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 177.3, 175.1, 174.6, 140.7, 139.7, 137.8, 133.0, 131.3, 128.2, 127.5, 125.8, 125.3, 122.1, 114.6, 111.6, 73.1, 71.0, 55.2, 53.2, 51.8, 49.2, 28.3, 27.8, 25.6, 24.8. HRMS (EI, m/z): calcd. for C26H24BrN3O3 (M + H)+ 506.1079. Found: 506.1075. Compound 5d was obtained as a white solid (71% yield, 91:9 dr). MP: 138−140 °C. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.51−7.26 (m, 5H), 6.61 (dd, J = 6.9, 5.1 Hz, 2H), 4.71 (dd, J = 52.6, 14.1 Hz, 2H), 3.74−3.67 (m, 1H), 3.51−3.46 (m, 1H), 3.36 (d, J = 7.9 Hz, 1H), 2.30 (d, J = 10.3 Hz, 1H), 2.10 (dd, J = 8.5, 5.4 Hz, 2H), 1.79 (d, J = 6.1 Hz, 1H), 1.45 (t, J = 15.0 Hz, 1H), 1.34−1.13 (m, 3H). 13C NMR (101 MHz, CDCl3): δ 178.2, 175.7, 174.6, 140.2, 135.6, 132.5, 130.0, 128.9, 128.6, 128.1, 127.3, 115.2, 111.2, 72.7, 60.3, 50.2, 47.3, D


Research Article

ACS Sustainable Chemistry & Engineering 46.4, 42.6, 28.7, 25.1, 24.0. HRMS (EI, m/z): calcd. for C24H22BrN3O3 (M + H)+ 480.0923. Found: 480.0925. Compound 5e was obtained as a white solid (53% yield, 92:8 dr). MP: 150−152 °C. 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.46−7.28 (m, 6H), 6.61 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 1.9 Hz, 1H), 4.81−4.60 (m, 2H), 4.29 (dd, J = 11.3, 2.8 Hz, 1H), 3.94−3.85 (m, 1H), 3.70 (dd, J = 11.2, 2.7 Hz, 1H), 3.58 (t, J = 7.8 Hz, 1H), 3.42 (d, J = 7.9 Hz, 1H), 3.36−3.28 (m, 1H), 3.20 (td, J = 11.2, 2.6 Hz, 1H), 2.40 (td, J = 11.0, 3.3 Hz, 1H), 2.15 (d, J = 9.3 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 177.6, 175.0, 174.3, 140.3, 135.5, 133.0, 130.0, 129.0, 128.7, 128.3, 126.1, 115.4, 111.5, 72.4, 69.9, 66.2, 57.7, 50.0, 46.4, 45.8, 42.8. HRMS (EI, m/z): calcd. for C23H20BrN3O4 (M + H)+ 482.0716. Found: 482.0719. Compound 5f was obtained as a white solid (40% yield, 91:9 dr). MP: 105−108 °C. 1H NMR (400 MHz, CDCl3): δ 9.54 (s, 1H), 7.24−7.20 (m, 1H), 7.03 (d, J = 1.9 Hz, 1H), 6.88 (dd, J = 9.4, 4.3 Hz, 1H), 4.23 (t, J = 11.2 Hz, 1H), 4.00 (dt, J = 9.4, 6.8 Hz, 1H), 3.75 (s, 3H), 3.35−3.29 (m, 1H), 3.26 (s, 3H), 2.62 (dt, J = 10.0, 5.8 Hz, 1H), 2.43 (dt, J = 9.9, 7.3 Hz, 1H), 2.14 (td, J = 12.2, 5.9 Hz, 1H), 1.92− 1.84 (m, 2H), 1.76 (dt, J = 7.0, 5.1 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 180.3, 171.5, 169.2, 140.1, 129.9, 127.7, 127.4, 125.8, 111.7, 72.8, 68.1, 57.7, 52.4, 52.0, 50.7, 47.6, 31.9, 27.9. APCIMS m/z: 378.1 (M+ + 1). HRMS (EI, m/z): calcd. for C18H19ClN2O5 (M + H)+ 379.1061. Found: 379.1059.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.8b00555. NMR spectra and X-ray crystal data for compound 1f (PDF)

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AUTHOR INFORMATION

Corresponding Author

*W. Zhang. E-mail: [email protected]. ORCID

Wei Zhang: 0000-0002-6097-2763 Notes

The authors declare no competing financial interest.

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DEDICATION Dedicated to István Horváth on the occasion of his 65th birthday. REFERENCES

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