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Article Cite This: ACS Omega 2018, 3, 9020−9026

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Ppm Cu Catalyst Enables tert-Alkylation Followed by C−H Cyclization To Synthesize Substituted Oxindoles Kohei Yoshinaga, Naoya Tsubaki, Yumi Murata, Yushi Noda, and Takashi Nishikata* Graduate School of Science and Engineering, Yamaguchi University, Ube, Yamaguchi 755-8611, Japan

ACS Omega 2018.3:9020-9026. Downloaded from pubs.acs.org by 5.188.217.53 on 08/30/18. For personal use only.

S Supporting Information *

ABSTRACT: In this paper, we established highly efficient Cu-catalyzed tandem tert-alkylation C−H cyclization of αbromocarbonyls and methacrylamides to produce substituted oxindoles. The maximum turnover number was up to 48 000 with reasonable yield. Although the catalyst loadings were very low, the reaction was not involving radical chain reaction. The resulting oxindoles were able to transform into aza-multicyclic compound via a reduction.

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oxindoles 3 from the reaction of methacrylamides 1 and αbromocarbonyls 2 as a tertiary alkyl source under high turnover number (TON) conditions, in which a radical reaction occurs, has not yet been reported14 (Scheme 2).

INTRODUCTION Oxindoles are a nitrogen-containing heterocycle and widely found in bioactive molecules.1 There are many reports on the synthesis of oxindoles,2 but the exploitations of straightforward synthetic methodology to prepare oxindoles containing a variety of functionalities are still challenging and important in synthetic organic chemistry. In this context, aniline derivatives possessing acrylamide moiety are one of the most attractive substrates. Various functionalities (functional group (FG)) can be introduced to oxindoles via tandem addition C−H cyclization process (Scheme 1).

Scheme 2. This Work

Scheme 1. Retrosynthesis of Substituted Oxindoles We previously reported atom-transfer radical addition followed by elimination reaction to give Heck-like olefin product (atom-transfer radical substitution (ATRS)).15 Generally, copper-catalyzed atom-transfer radical reactions using alkyl halides have suffered from a large amount of catalyst loadings (10−30 mol %) to obtain reasonable product yields, which might be the limited development of this protocol for industrial processes.16−19 In this context, we have developed ATRS with high catalyst efficiency.20 The reaction of styrenes and α-bromocarbonyls in the presence of amine undergoes ATRS, and TONs were reached up to 8900 with reasonable yields (>70%). Initiators for continuous activator regeneration 21 or activators regenerated by electron-transfer (ARGET)22 process using α,α′-azobisisobutyronitrile, 2,2′azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) or an inorganic reductant have been employed to lower the catalyst loadings,23 but our previous protocol did not need such reductants. The next issue in this field is to accomplish higher

After the discovery of Liu’s oxidative difunctionalization of alkenes in acrylamides with alkyl nitriles using Pd(OAc)2/ PhI(OAc)2 catalyst system,3 various reactions have been reported. For example, primary and secondary alkyl groups,4 aryl and alkenyl groups,5 phosphorus,6 nitrogen,7 sulfur,8 halomethyl groups,9 silicon,10 carbonyl groups,11 and other functional groups12 can be introduced as a functional group (FG). Various FG can be employed in this reaction but the reaction with tertiary alkyl group is still challenging. Li’s group has reported the reaction of acrylamides with cumene or αbromocarbonyls as a tertiary alkyl group in the presence of Pd or Ir catalyst or oxidants.13 Despite the usefulness of the reaction of acrylamides for the synthesis of substituted oxindoles, a copper-catalyzed radical reaction to synthesize © 2018 American Chemical Society

Received: June 20, 2018 Accepted: August 1, 2018 Published: August 13, 2018 9020

DOI: 10.1021/acsomega.8b01397 ACS Omega 2018, 3, 9020−9026

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TON in tandem tert-alkylation C−H cyclization process. In this report, we will describe the copper-catalyzed tertiary alkylation followed by C−H cyclization to synthesize oxindoles. From the chemical process points of view, our findings could be useful to carry out copper-catalyzed radical reactions in industrial scales.

Scheme 3. Control Experiment

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RESULTS AND DISCUSSION At the first stage of this research, we optimized the reaction conditions in the presence of 10 ppm (0.001 mol %) of the Cu catalyst (Table 1). This reaction did not occur without an

Under optimal conditions, tandem tert-alkylation C−H cyclization reactions smoothly proceeded by using low catalyst loadings (20−100 ppm) (Table 2). The reaction of various αbromoesters 1 and methacrylamide derivatives 2 to give oxindoles (3b−p) achieved TON’s of up to 48 000. We have tried the reaction with 20, 50, and 100 ppm of CuI catalyst. When the reactions of methacrylamides 1 possessing an electron-donating or -withdrawing group and 2a were carried out, electron-rich substrates 1 gave 3c−e and 3h in good yields with high TONs (up to 48 000 for 3h). 1 possessing p-tolyl group gave 3b in moderate yields. We expected that electronrich substrates have high reactivities, and electron-poor substrates tends to decrease the reactivities, according to our previous reactions.15 But methacrylamide 1 possessing fluorine atom or ester group gave 3f and 3g in moderate yields though the catalyst loadings were very low. The reaction of 1 possessing m-MeOC6H4− group did not show good selectivity and gave the regio isomers (3d and 3d′). The effects of substituents on the nitrogen of 1 were tested, and Et- or Ph group of 1 also gave the corresponding oxindoles (3i and 3j) in good yields with high TONs. We next examined various combinations of substituted 1 and 2. As a result, 2 possessing cyclic, malonate, amide structures resulted in high TONs up to 45 000 (3k−p). Overall, the catalyst loadings can be reduced to 20 ppm. In those cases, high catalyst loadings were able to increase the yields when the yields were low. The rationale behind the attention given to the synthesis of oxindole 3 as a building block has been based, in part, on its potential to streamline routes toward challenging synthetic targets, including complex amine compounds (Scheme 4). For example, when the reduction of 3p with BH3-THF was carried out, aminated oxindole 4 was obtained in good yield. On the other hand, the reaction of 3p in the presence of LiAlH4 underwent reduction followed by cyclization to afford a multicyclic compound 5 in 54% yield.

a

Table 1. Optimization

run

Cu (ppm)

ligand

amine

3a (%)

TON

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

0 10 10 10 10 10 10 10 10 10 (80 °C) 10 (60 °C) 20 5

none none PMDETA Me6TREN TPMA TPEN TPMA TPMA TPMA TPMA TPMA TPMA TPMA

iPr2EtN iPr2EtN iPr2EtN iPr2EtN iPr2EtN iPr2EtN Et3N iPr2NH Hex3N iPr2EtN iPr2EtN iPr2EtN iPr2EtN

trace trace 4 4 59 14 13 57 27 38 12 94(78)b 35

0 0 4000 4000 59 000 14 000 13 000 57 000 27 000 38 000 12 000 47 000 70 000

All reactions were carried out at 100 °C for 20 h with 0−20 ppm (20 ppm: 0.002 mol %) CuI (5 × 10−4 M in MeCN), ligand (5 mol %), amine (1.5 equiv), 1a (1.0 equiv), and 2a (2.0 equiv) in MeCN (sealed tube). Yields were determined by 1H NMR analysis. b5 mmol scale. a

amine base, a catalyst, and a multidentate nitrogen ligand (runs 1 and 2). Although a ligand is very important for this reaction, N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA), tris[2-(dimethylamino)ethyl]amine (Me 6 TREN), and N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) were not effective (runs 3, 4, and 6). Moderate yield (59%) and high TON (59 000) were obtained by using tris(2pyridylmethyl)amine (TPMA) (run 5). Et3N, iPr2NH, and Hex3N were used instead of iPr2EtN (Hünig’s base), but the yield was not improved (runs 7−9). To obtain more reasonable yield, we screened various reaction temperatures (runs 10 and 11) and solvents, such as toluene, 1,2dichloroethene, AcOEt, 1,2-dimethoxyethane, and dimethylformamide, but MeCN at 100 °C was the best. When the reaction was carried out with 20 and 5 ppm of CuI, 94 and 35% of 3a with TONs of 47 000 and 70 000 were achieved (runs 12 and 13). We also used dimethyl 2,2′-azobis(isobutyrate) (AZO) instead of the Cu catalyst, but no reaction occurred. This result could show that our reaction does not involve a radical chain reaction (Scheme 3).

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CONCLUSIONS In conclusion, we discovered that the reaction of methacrylamides 1 and α-bromocarbonyls 2 underwent tandem tertalkylation followed by C−H cyclization to give substituted oxindoles 3 in good yields with high TONs through Cucatalyzed ARGET process, in which Hünig’s base could improve the catalyst activity. The maximum TON was 48 000 with 96% yield. We were able to obtain TON, 70 000, but yield was not reasonable. Moreover, substituted oxindoles 3 can be transformed into amine-substituted oxindole 4 and multicyclic compound 5, which indicated the potential usefulness of oxindoles 3 as a building block. These reactions are useful to synthesize oxindoles 3 with the minimal amounts of Cu metals. Further improvements, including our original ligand design and activator for a Cu catalyst, will be described in due course. 9021

DOI: 10.1021/acsomega.8b01397 ACS Omega 2018, 3, 9020−9026

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Article

Table 2. Substrate Scopea

All reactions were carried out at 100 °C for 20 h with 20−100 ppm CuI (5 × 10−4 M in MeCN), TPMA (5 mol %), iPr2EtN (1.5 equiv), 1 (1.0 equiv), and 2 (2.0 equiv) in MeCN (sealed tube).

a

were obtained using a JEOL 500 MHz NMR spectrometer. 1H NMR and 13C NMR spectra were obtained in CDCl3 by using CHCl3 (for 1H, δ = 7.26 ppm) and CDCl3 (for 13C, δ = 77.16 ppm) as an internal standard. High-resolution mass analyses were obtained using a ACQUITY UPLC/time-of-flight (TOF)-mass spectrometry for electrospray ionization (ESI). Anhydrous MeCN was purchased from Kanto Chemical Co., Ltd. Other chemicals obtained from TCI, Sigma-Aldrich and Wako and copper salts obtained from Sigma-Aldrich, and Wako were used directly as supplied. General Procedure for the Synthesis of 3a−p. 1 (0.50 mmol), CuI (MeCN solution), TPMA (0.075 mmol, 5 mol %), and diisopropylmethylamine (0.75 mmol) were sequentially added to the dram vial equipped with a stir bar and a screw cap. MeCN (1.0 mL) and 2 (0.75 mmol) were added to

Scheme 4. Transformations of 3p

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EXPERIMENTAL SECTION General Information. All reactions were carried out under nitrogen (99.95%) atmosphere. For thin-layer chromatography analyses, precoated Kieselgel 60 F254 plates (Merck, 0.25 mm thick) were used; for column chromatography, silica gel 60 (Kanto chemical, 63−210 μm) was used. Visualization was accomplished by UV light (254 nm), 1H and 13C NMR spectra 9022

DOI: 10.1021/acsomega.8b01397 ACS Omega 2018, 3, 9020−9026

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29.57, 41.60, 46.84, 47.20, 55.56, 60.40, 95.98, 105.94, 123.82, 125.15, 144.53, 160.05, 177.40, 181.45. HRMS (ESI-TOF) anal. calcd for C18H26NO4 (M + H): 320.1862. Found: 320.1861. Ethyl 3-(7-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)-2,2dimethylpropanoate (3e). Viscous oil (140 mg, 88%); IR (neat) ν 2972, 1705, 752 cm−1; 1H NMR (CDCl3) δ: 0.83 (s, 3H), 1.03 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H), 1.26 (s, 3H), 2.20 (d, J = 14.3 Hz, 1H), 2.48 (d, J = 14.3 Hz, 1H), 3.47 (s, 3H), 3.67−3.77 (m, 2H), 3.83 (s, 3H), 6.70 (dd, J = 7.4 and 0.9 Hz, 1H), 6.10 (d, J = 8.3 and 0.8 Hz, 1H), 6.91 (d, J = 7.4 and 8.2 Hz, 1H). 13C NMR (CDCl3) δ: 14.15, 22.72, 28.36, 29.63, 29.94, 41.93, 47.45, 47.61, 56.24, 60.54, 111.96, 117.50, 122.63, 131.46, 134.20, 145.70, 177.49, 181.21. HRMS (ESITOF) anal. calcd for C18H26NO4 (M + H): 320.1862. Found: 320.1862. Ethyl 3-(7-Fluoro-1,3-dimethyl-2-oxoindolin-3-yl)-2,2-dimethylpropanoate (3f). Viscous oil (93 mg, 61%); IR (neat) ν 2974, 1715, 1234, 776 cm−1; 1H NMR (CDCl3) δ: 0.84 (s, 3H), 1.05 (s, 3H), 1.09 (t, J = 7.3 Hz, 3H), 1.30 (s, 3H), 2.22 (d, J = 14.6 Hz, 1H), 2.52 (d, J = 14.6 Hz, 1H), 3.42 (d, J = 2.7 Hz, 3H), 3.66−3.79 (m, 2H), 6.87−6.98 (m, 3H). 13 C NMR (CDCl3) δ: 14.13, 22.67, 28.28, 29.09, 29.13, 29.72, 41.87, 47.47, 47.90, 47.92, 60.67, 116.1 (d, J = 19.6 Hz), 120.6 (d, J = 3.2 Hz), 122.6 (d, J = 6.4 Hz), 130.1 (d, J = 18.1 Hz), 135.4 (d, J = 3.0 Hz), 148 (d, J = 243.4 Hz), 177.42, 180.59. HRMS (ESI-TOF) anal. calcd for C17H23NO3F (M + H): 308.1662. Found: 308.1662. Ethyl 3-(3-Ethoxy-2,2-dimethyl-3-oxopropyl)-1,3-dimethyl-2-oxoindoline-5-carboxylate (3g). Viscous oil (77 mg, 43%); IR (neat) ν 2972, 1703, 1609, 1280, 1224, 1094, 772 cm−1; 1H NMR (CDCl3) δ: 0.80 (s, 3H), 1.05 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H), 1.32 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H), 2.25 (d, J = 14.7 Hz, 1H), 2.58 (d, J = 14.5 Hz, 1H), 3.24 (s, 3H), 3.72−3.76 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 7.76 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H). 13C NMR (CDCl3) δ: 13.90, 14.52, 22.47, 26.60, 27.67, 29.44, 41.52, 46.94, 47.19, 60.44, 60.93, 107.79, 124.32, 125.42, 130.89, 131.96, 147.39, 166.51, 176.86, 181.05. HRMS (ESI-TOF) anal. calcd for C20H28NO5 (M + H): 362.1967. Found: 362.1969. Ethyl 3-(4,6-Dimethoxy-1,3-dimethyl-2-oxoindolin-3-yl)2,2-dimethylpropanoate (3h). Viscous oil (167 mg, 96%); IR (neat) ν 3080, 2981, 2846, 1727 cm−1; 1H NMR (CDCl3) δ: 0.92 (s, 3H), 0.92 (s, 3H), 1.11 (t, J = 7.15 Hz, 3H), 1.33 (s, 3H), 2.15 (d, J = 14.1 Hz, 1H), 2.53 (d, J = 14.1 Hz, 1H), 3.16 (s, 3H), 3.74−3.77 (m, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.10 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3) δ: 13.98, 24.39, 24.88, 26.46, 26.93, 41.82, 45.84, 46.91, 55.20, 55.62, 60.29, 88.08, 92.19, 110.62, 145.00, 157.00, 161.52, 177.05, 181.30. HRMS (ESI-TOF) anal. calcd for C19H28NO5 (M + H): 350.1967. Found: 350.1967. Ethyl 3-(1-Ethyl-3-methyl-2-oxoindolin-3-yl)-2,2-dimethylpropanoate (3i). Viscous oil (118 mg, 78%); IR (neat) ν 2973, 1706, 1610, 1354, 1128 cm−1; 1H NMR (CDCl3) δ: 0.82 (s, 3H), 1.05 (s, 3H), 1.05 (t, J = 7.3 Hz, 3H), 1.26 (t, J = 7.3 Hz, 3H), 1.27 (s, 3H), 2.21 (d, J = 4.5 Hz, 1H), 2.53 (d, J = 4.5 Hz, 1H), 3.63−3.87 (m, 4H), 6.85 (d, J = 7.8 Hz, 1H), 6.97 (dt, J = 0.9 and 7.5 Hz, 1H), 7.10 (dd, J = 1.1 and 7.3 Hz, 2H), 7.21 (dt, J = 1.3 and 7.8 Hz, 1H). 13C NMR (CDCl3) δ: 12.24, 13.85, 22.36, 28.12, 29.56, 34.68, 41.68, 46.80, 47.29, 60.32, 108.24, 121.68, 124.69, 127.83, 132.25, 142.36, 177.33,

a dram vial. The resulting mixture was vigorously stirred under nitrogen atmosphere (purity 99.95%) for 20 h at 100 °C. After this time, the contents of the flask were filtered through the plug of silica gel with EtOAc as an eluent and then concentrated by rotary evaporation. The crude residue was purified by flash chromatography (or gel permeation chromatography (GPC) with CHCl3), eluting with EtOAc/ hexane to afford the product 3. Ethyl 3-(1,3-Dimethyl-2-oxoindolin-3-yl)-2,2-dimethylpropanoate (3a). White solid (122 mg, 94%); mp 86−87 °C; 1H NMR (CDCl3) δ: 0.81 (s, 3H), 1.05 (s, 3H), 1.06 (t, J = 7.15 Hz, 3H), 1.30 (s, 3H), 2.22 (d, J = 14.1 Hz, 1H), 2.53 (d, J = 14.1 Hz, 1H), 3.21 (s, 3H), 3.64−3.79 (m, 2H), 6.84 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H). 13C NMR (CDCl3) δ: 13.79, 22.30, 26.31, 27.73, 29.45, 41.59, 47.09, 47.28, 60.31, 108.1, 121.9, 124.5, 127.9, 132.1, 143.3, 177.3, 180.8. High-resolution mass spectrometry (HRMS) (ESI-TOF) anal. calcd for C17H24NO3 (M + H): 290.1756. Found: 290.1756. Ethyl 2,2-Dimethyl-3-(1,3,5-trimethyl-2-oxoindolin-3-yl)propanoate (3b). Viscous oil (95 mg, 66%); IR (neat) ν 2960, 1704, 1478, 1174, 813 cm−1; 1H NMR (CDCl3) δ: 0.78 (s, 3H), 1.04 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H), 1.26 (s, 3H), 2.18 (d, J = 14.5 Hz, 1H), 2.30 (s, 3H), 2.51 (d, J = 14.5 Hz, 1H), 3.17 (s, 3H), 3.67−3.72 (m, 2H), 6.71 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 7.03 (d, J = 7.9 Hz, 1H). 13C NMR (CDCl3) δ: 13.85, 21.15, 22.06, 26.40, 27.82, 29.67, 41.58, 47.05, 47.37, 60.19, 107.88, 125.34, 128.24, 131.24, 131.99, 140.95, 177.29, 180.77. HRMS (ESI-TOF) anal. calcd for C18H26NO3 (M + H): 304.1913. Found: 304.1912. Ethyl 3-(5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)-2,2dimethylpropanoate (3c). White solid (127 mg, 80%); mp: 93−94 °C; IR (neat) ν 2969, 1702, 1492, 1239, 1120, 1036 cm−1; 1H NMR (CDCl3) δ: 0.80 (s, 3H), 1.05 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 2.20 (d, J = 14.5 Hz, 1H), 2.50 (d, J = 14.5 Hz, 1H), 3.18 (s, 3H), 3.67−3.81 (m, 2H), 3.77 (s, 3H), 6.72−6.77 (m, 3H). 13C NMR (CDCl3) δ: 13.86, 22.12, 26.46, 27.80, 29.61, 41.62, 47.00, 47.75, 55.77, 60.34, 108.28, 111.83, 112.36, 133.37, 136.81, 155.61, 177.38, 180.46. HRMS (ESI-TOF) anal. calcd for C18H26NO4 (M + H): 320.1862. Found: 320.1863. Ethyl 3-(6-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)-2,2dimethylpropanoate (3d). The mixture product of 3d and 3d′ (118 mg, 74% (3d/3d′ = 1.8:1)). The pure product was obtained by GPC. White solid; mp: 77−78 °C; IR (neat) ν 2970, 1713, 1606, 1474, 1260, 1067 cm−1; 1H NMR (CDCl3) δ: 0.91 (s, 3H), 0.92 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H), 1.36 (s, 3H), 2.17 (d, J = 14.1 Hz, 1H), 2.60 (d, J = 14.1 Hz, 1H), 3.17 (s, 3H), 3.63−3.70 (m, 1H), 3.75−3.81 (m, 1H), 3.83 (s, 3H), 6.50 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 7.8 and 8.4 Hz, 1H). 13C NMR (CDCl3) δ: 13.98, 24.37, 24.62, 26.49, 27.00, 41.84, 45.62, 47.32, 55.23, 60.24, 101.53, 105.50, 118.50, 129.20, 144.45, 156.40, 176.97, 180.66. HRMS (ESI-TOF) anal. calcd for C18H26NO4 (M + H): 320.1862. Found: 320.1862. Ethyl 3-(4-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)-2,2dimethylpropanoate (3d′). White solid; mp: 130−131 °C; IR (neat) ν 2975, 1708, 1625, 1379, 906 cm−1; 1H NMR (CDCl3) δ: 0.79 (s, 3H), 1.04 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H), 1.26 (s, 3H), 2.17 (d, J = 14.5 Hz, 1H), 2.50 (d, J = 14.5 Hz, 1H), 3.18 (s, 3H), 3.69−3.80 (m, 2H), 3.81 (s, 3H), 6.41 (d, J = 3.3 Hz, 1H), 6.50 (dd, J = 8.1 and 2.6 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H). 13C NMR (CDCl3) δ: 13.88, 22.20, 26.40, 27.89, 9023

DOI: 10.1021/acsomega.8b01397 ACS Omega 2018, 3, 9020−9026

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111.78, 116.72, 122.48, 131.04, 133.57, 145.46, 171.30, 172.16, 180.24. HRMS (ESI-TOF) anal. calcd for C20H28NO6 (M + H): 378.1917. Found: 378.1919. Diethyl 2-((4,6-Dimethoxy-1,3-dimethyl-2-oxoindolin-3yl)methyl)-2-methylmalonate (3o). Viscous oil (148 mg, 73%); IR (neat) ν 2979, 1719, 1606, 1455, 11552, 1106, 908 cm−1; 1H NMR (CDCl3) δ: 1.01 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H), 1.39 (s, 3H), 2.58 (d, J = 14.5 Hz, 1H), 2.86 (d, J = 14.5 Hz, 1H), 3.14 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 3.84 (q, J = 7.1 Hz, 2H), 4.03−4.16 (m, 2H), 6.08 (d, J = 2.0 Hz, 1H), 6.09 (d, J = 2.0 Hz, 1H). 13C NMR (CDCl3) δ: 13.86, 13.94, 18.91, 25.06, 26.38, 39.72, 46.05, 52.97, 55.25, 55.63, 61.04, 61.33, 88.14, 92.24, 110.35, 145.05, 156.91, 161.64, 171.80, 172.18, 180.51. HRMS (ESI-TOF) anal. calcd for C21H30NO7 (M + H): 408.2022. Found: 408.2022. 3-(1,3-Dimethyl-2-oxoindolin-3-yl)-2,2-dimethyl-N-phenylpropanamide (3p). White solid (151 mg, 90%); mp: 137− 139 °C; IR (neat) ν 3347, 3054, 2969, 1695, 752 cm−1; 1H NMR (CDCl3) δ: 0.94 (s, 3H), 1.14 (s, 3H), 1.30 (s, 3H), 2.25 (d, J = 14.5 Hz, 1H), 2.70 (d, J = 14.5 Hz, 1H), 3.19 (s, 3H), 6.72 (dt, J = 7.5 and 1.0 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.81 (brs, 1H), 7.05−7.08 (m, 2H), 7.17 (d, J = 7.5 Hz, 1H), 7.24−7.25 (m, 4H). 13C NMR (CDCl3) δ: 22.82, 26.72, 28.24, 30.03, 42.95, 46.98, 47.82, 108.14, 120.31, 122.95, 124.39, 128.91, 138.09, 142.95, 175.56, 181.43. HRMS (ESITOF) anal. calcd for C21H25N2O2 (M + H): 337.1916. Found: 337.1916. N-(3-(1,3-Dimethylindolin-3-yl)-2,2-dimethylpropyl)aniline (4). To a solution of 3p (33.4 mg, 0.1 mmol) was added 1 M BH3 in tetrahydrofuran (THF, 1.0 mmol, 1.0 mL) at 0 °C. The mixture was stirred at 100 °C for 14 h and then treated with MeOH (1 mL). The organic layers were collected and dried by anhydrous Na2SO4. After concentration under reduced pressure, the crude product was purified by column chromatography to afford the title compound 4 (23.2 mg, 76%, viscous oil); IR (neat) ν 3316, 2953, 2868, 2807, 1719, 1601, 1491 cm−1; 1H NMR (CDCl3) δ: 1.01 (s, 6H), 1.37 (s, 3H), 1.75 (d, J = 14.7 Hz, 1H), 1.88 (d, J = 14.7 Hz, 1H), 2.74 (s, 3H), 2.85 (d, J = 12.1 Hz, 1H), 2.95 (d, J = 12.1 Hz, 1H), 3.08 (d, J = 8.7 Hz, 1H), 3.33 (d, J = 8.7 Hz, 1H), 3.61 (brs, 1H), 6.48 (d, J = 7.8 Hz, 1H), 6.57 (dd, J = 8.1 and 1.1 Hz, 2H), 6.64−6.70 (m, 2H), 6.67 (dd, J = 7.3 and 1.2 Hz, 1H), 7.09 (dt, J = 7.6 and 1.3 Hz, 1H), 7.15 (dd, J = 7.3 and 1.2 Hz, 2H). 13 C NMR (CDCl3) δ: 27.04, 27.65, 28.46, 35.99, 36.19, 44.27, 49.76, 55.52, 69.02, 107.49, 112.83, 117.05, 117.92, 122.33, 127.79, 129.31, 139.65, 149.10. HRMS (ESI-TOF) anal. calcd for C21H29N2 (M + H): 309.2331. Found: 309.2331. 3,3,4a,9-Tetramethyl-1-phenyl-2,3,4,4a,9,9a-hexahydro1H-pyrido[2,3-b]indole (5). To a solution of the LiAlH4 (37.5 mg, 1.0 mmol) in toluene (1.0 mL) was added 3p (33.7 mg, 0.1 mmol) at 0 °C. The mixture was stirred at 110 °C for 72 h and then treated with saturated Na2SO4 aq (2.0 mL). The organic layers were collected and dried by anhydrous Na2SO4. After concentration under reduced pressure, the crude product was purified by column chromatography to afford the title compound 5 (16.5 mg, 54%, viscous oil); IR (neat) ν 3024, 2951, 2862, 2799, 1726, 1596, 1481, 1363, 751 cm−1; 1H NMR (CDCl3) δ: 0.87 (s, 3H), 1.10 (s, 3H), 1.4 (d, J = 8.5 Hz, 2H), 1.52 (s, 3H), 2.52 (s, 3H), 3.16 (dd, J = 12.1 and 10.3 Hz, 2H), 4.88 (s, 1H), 6.46 (d, J = 7.6 Hz, 1H), 6.72 (t, J = 7.4 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 7.00 (t, J = 7.2 Hz, 3H), 7.15 (dt, J = 7.7 and 1.1 Hz, 1H), 7.24 (t, J = 8.1 Hz,

180.31. HRMS (ESI-TOF) anal. calcd for C18H26NO3 (M + H): 304.1913. Found: 304.1913. Ethyl 2,2-Dimethyl-3-(3-methyl-2-oxo-1-phenylindolin-3yl)propanoate (3j). Viscous oil (133 mg, 73%); IR (neat) ν 3049, 2973, 1715, 861 cm−1; 1H NMR (CDCl3) δ: 0.99 (s, 3H), 1.07 (t, J = 7.3 Hz, 3H), 1.11 (s, 3H), 1.43 (s, 3H), 2.32 (d, J = 14.5 Hz, 1H), 2.62 (d, J = 14.1 Hz, 1H), 3.67−3.79 (m, 2H), 6.82 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.0 Hz, 1H), 7.16 (d, J = 7.2 Hz, 2H), 7.40−7.43 (m, 3H), 7.52 (t, J = 7.8 Hz, 2H). 13 C NMR (CDCl3) δ: 14.12, 23.01, 28.65, 29.83, 42.02, 47.58, 47.76, 60.68, 109.75, 122.63, 125.05, 126.71, 128.07, 128.26, 129.91, 132.12, 135.05, 143.48, 177.56, 180.28. HRMS (ESITOF) anal. calcd for C22H26NO3 (M + H): 352.1913. Found: 352.1916. Ethyl 1-((1-Ethyl-3-methyl-2-oxoindolin-3-yl)methyl)cyclobutane-1-carboxylate (3k). Viscous oil (169 mg, 90%); IR (neat) ν 2974, 1706, 1611, 1488, 1358, 1209 cm−1; 1H NMR (CDCl3) δ: 1.09 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.31 (s, 3H), 1.66−1.75 (m, 2H), 1.92−2.05 (m, 3H), 2.08−2.17 (m, 1H), 2.46 (d, J = 14.1 Hz, 1H), 2.53 (d, J = 14.1 Hz, 1H), 3.56−3.69 (m, 3H), 3.77−3.84 (m, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.96 (dt, J = 0.8 and 7.5 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H). 13C NMR (CDCl3) δ: 12.46, 13.86, 16.49, 26.23, 28.09, 34.70, 35.03, 45.82, 47.14, 47.28, 60.19, 108.09, 121.55, 124.34, 127.93, 132.32, 142.74, 176.35, 179.90. HRMS (ESI-TOF) anal. calcd for C19H26NO3 (M + H): 316.1913. Found: 316.1915. Ethyl 1-((3-Methyl-2-oxo-1-phenylindolin-3-yl)methyl)cyclobutane-1-carboxylate (3l). Viscous oil (162 mg, 86%); IR (neat) ν 2977, 1712, 1499, 1203, 1175 cm−1; 1H NMR (CDCl3) δ:1.09 (t, J = 7.1 Hz, 3H), 1.45 (s, 3H), 1.70−1.76 (m, 2H), 1.96−2.12 (m, 3H), 2.25−2.31 (m, 1H), 2.55 (d, J = 4.1 Hz, 1H), 2.60 (d, J = 4.1 Hz, 1H), 3.58 (q, J = 7.2 Hz, 2H), 6.75 (dd, J = 1.0 and 8.6 Hz, 1H), 7.01 (dt, J = 0.9 and 7.6 Hz, 1H), 7.13−7.16 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.43−7.45 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H). 13C NMR (CDCl3) δ: 13.89, 16.58, 26.53, 28.44, 35.10, 46.32, 47.32, 47.35, 60.31, 109.33, 122.23, 124.39, 126.65, 127.93, 128.01, 129.64, 131.85, 134.76, 143.72, 176.39, 179.55. HRMS (ESI-TOF) anal. calcd for C23H26NO3 (M + H): 364.1913. Found: 364.1913. Diethyl 2-((1,3-Dimethyl-2-oxoindolin-3-yl)methyl)-2methylmalonate (3m). Viscous oil (111 mg, 64%); IR (neat) ν 2966, 1705, 758 cm−1; 1H NMR (CDCl3) δ: 1.02 (s, 3H), 1.09 (t, J = 7.12 Hz, 3H), 1.19 (t, J = 7.12 Hz, 3H), 1.36 (s, 3H), 2.72 (d, J = 14.8 Hz, 1H), 2.76 (d, J = 14.8 Hz, 1H), 3.21 (s, 3H), 3.77 (q, J = 7.1 Hz, 2H), 4.11−4.12 (m, 2H), 6.84 (d, J = 7.7 Hz, 1H), 7.00 (dt, J = 0.9 and 7.5 Hz, 1H), 7.10 (dd, J = 0.9 and 7.6 Hz, 1H), 7.24−7.27 (m, 1H). 13 C NMR (CDCl3) δ: 13.89, 14.14, 19.09, 26.54, 28.16, 41.39, 46.51, 53.20, 61.33, 61.76, 108.52, 122.27, 124.34, 128.48, 132.20, 143.60, 171.60, 172.43, 180.33. HRMS (ESI-TOF) anal. calcd for C19H26NO5 (M + H): 348.1811. Found: 348.1811. Diethyl 2-((7-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)methyl)-2-methylmalonate (3n). Viscous oil (107 mg, 57%); IR (neat) ν 2976, 1703, 1464, 1245, 1106, 1021 cm−1; 1H NMR (CDCl3) δ: 1.03 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.32 (s, 3H), 2.68 (d, J = 14.8 Hz, 1H), 2.76 (d, J = 14.8 Hz, 1H), 3.47 (s, 3H), 3.77−3.82 (m, 2H), 3.84 (s, 3H), 4.08−4.14 (m, 2H), 6.70 (dd, J = 0.9 and 7.5 Hz, 1H), 7.00 (dd, J = 0.8 and 8.4 Hz, 1H), 7.10 (dd, J = 8.2 and 7.4 Hz, 1H). 13C NMR (CDCl3) δ: 13.74, 13.99, 18.76, 28.26, 29.69, 41.15, 46.34, 52.99, 55.92, 61.08, 61.53, 9024

DOI: 10.1021/acsomega.8b01397 ACS Omega 2018, 3, 9020−9026

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2H). 13C NMR (CDCl3) δ: 24.14, 26.77, 30.27, 30.30, 33.36, 40.64, 48.18, 52.34, 87.61, 100.50, 107.50, 116.10, 118.24, 118.47, 121.21, 127.47, 129.35, 139.51, 151.94. HRMS (ESITOF) anal. calcd for C21H27N2 (M + H): 307.2174. Found: 307.2177.

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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/acsomega.8b01397. Copies of 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Takashi Nishikata: 0000-0002-2659-4826 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We warmly thank YU and JSPS KAKENHI Grant Number JP 18H04262(TN) in Precisely Designed Catalysts with Customized Scaffolding.

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REFERENCES

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DOI: 10.1021/acsomega.8b01397 ACS Omega 2018, 3, 9020−9026