Annulations toward Aminooxylated Oxindoles - ACS Publications

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Transition-Metal-Free Oxidative Aminooxyarylation of Alkenes: Annulations toward Aminooxylated Oxindoles Ming-Zhong Zhang,*,† Na Luo,† Rui-Yang Long,† Xian-Tao Gou,† Wen-Bing Shi,† Shu-Hua He,† Yong Jiang,† Jin-Yang Chen,† and Tieqiao Chen*,‡ †

School of Chemistry and Chemical Engineering, Yangtze Normal University, Chongqing 408100, China State Key Laboratory of Marine Resource Utilization in South China Sea, College of Materials and Chemical Engineering, Hainan University, Haikou 570100, China

‡

S Supporting Information *

ABSTRACT: An efficient oxidative aminooxyarylation of alkenes under a transition-metal-free condition was described. Under the reaction conditions, N-hydroxyphthalimide (NHPI) reacted readily with N-arylacrylamides to produce cyclic products via a radical C−H functionalization process, achieving both C−O and C−C bonds formation in one pot. This reaction provided a facile access to the valuable aminooxylated oxindoles. The benzylic and α-methylene C(sp3)-H bonds were also aminooxylated under the reaction conditions.

T

Scheme 1. Difunctionalization of Alkenes with NHPI

he oxygen-containing compounds are ubiquitous and important chemicals.1 They can be widely found in pharmaceuticals, agro-chemicals and materials.2 Thus, synthesizing these compounds with high step- and atom-economic efficiency is highly desirable. The 1,2-difunctionalization of alkenes has been emerging as a powerful strategy for constructing various functional molecules. In recent years, many metal-free and transition-metal-catalyzed transformations such as dioxylation, oxyphosphorylation, oxyamidation, and oxyamination, etc. have been developed.3,4 The 1,2difunctionalization of alkenes with NHPI was also reported (Scheme 1); however, this reaction was limited to dioxylation of alkenes to produce β-oxo alcohols,5 α-oxo ketones,5,6 β-oxo peroxides,5a,7 and β-oxo aryl ethers8 and oxyazidation of alkenes to generate β-oxo alkyl azides.9 Application of this method in oxyarylation of alkenes via C−H functionalization to yield substituted oxindoles has not been achieved. As our continuous interest in green oxidation grows,10 we herein communicate an oxidative aminooxyarylation of electrondeficient alkenes (Scheme 1). This transformation was carried out under a transition-metal-free reaction condition via a radical process, realizing C−H functionalization and C−O and C−C bonds formation in one pot to produce the valuable aminooxylated oxindoles. The resulting products could be easily converted to oxindol-3-yl methanols, which are key synthetic intermediates of esermethole and physostigmine, but usually were synthesized through several steps in low atomeconomic efficiency.11 Under the reaction conditions, benzylic and α-methylene C−H bonds were also aminooxylated with NHPI. K2S2O8/quaternary ammonium salt is an elegant oxidative system which upon heating can generate sulfate radical anions © 2018 American Chemical Society

and thus is applied to induce radical cyclizations under transition-metal-free reaction conditions as exemplified by the tandem acylation/cyclization of alkynoates with aldehydes.12 We envisioned that the aminooxyarylation of N-arylacrylamides with NHPI could also be realized by using a similar strategy. To explore the feasibility of our proposed hypothesis, we started the investigations by screening the radical-trigger system. It was found that in the presence of K2S2O8 (3.0 equiv) and TBAHS (1.5 equiv), the reaction of N-methyl-Nphenyl acrylamide 1a with NHPI took place in DCE at 60 °C Received: October 30, 2017 Published: February 5, 2018 2369

DOI: 10.1021/acs.joc.7b02740 J. Org. Chem. 2018, 83, 2369−2375

Note

The Journal of Organic Chemistry Table 1. Optimization Studiesa

entry

oxidant (equiv)

TBAX (equiv)

temp (°C)

yield (%)b

1 2 3 4c 5d 6e 7f 8 9g 10 11 12 13 14 15 16 17 18 19 20h

3.0

TBAHS (1.5) TBAHS (1.5)

60 60 60 60 60 60 60 90 90 90 90 90 90 90 90 90 90 90 90 100

28 n.r. n.r. 25 10 trace 41 55 trace 55 57 61 35 27 65 71 77 81 79 80

3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 2.5 2.0 1.5 1.2 1.0 1.2

TBAHS (1.5) TBAHS (1.5) TBAHS (1.5) TBAHS (0.2) TBAHS (0.2) TBAF (0.2) TBAC (0.2) TBAB (0.2) TBAI (0.2) TBAOAc (0.2) TBABF4 (0.2) TBAI (0.2) TBAI (0.2) TBAI (0.2) TBAI (0.2) TBAI (0.2) TBAI (0.2)

With the optimized reaction conditions in hand, the substrate scope was subsequently explored. As shown in Table 2, a variety of N-arylacrylamides were suitable substrates in the current K2S2O8/TBAI-triggered reaction. Substrates with halo-substituents (F, Cl, Br, and I) on the para-position of the aromatic ring served well under similar reaction conditions to produce the aminooxylated products in good to high yields (2b−2e, 57−73%), facilitating further functionalization of products via cross coupling. As expected, the paraNO2 substituted substrate which is usually inert in radical cyclizations,10c afforded only a trace amount of the desired product 2f as determined by TLC analyze. Other reactants with electron-withdrawing groups, as exemplified by N-(4cyanophenyl)-N-methylmethacrylamide and N-methyl-N-(4(trifluoromethyl) phenyl)methacrylamide, could react readily with NHPI, generating the desired products 2g and 2h in 70% and 58% yields, respectively. To our delight, substrates with electron-donating groups, such as a MeO group on the para-position of N-aryl moiety, underwent the aminooxyarylation smoothly, generating the corresponding aminooxylated oxindole 2i in 79% yield. meta-Substituted Nphenylacrylamide was found reactive to give a mixture of regioisomers in a good yield (the ratio of 2j/2j′ was ca. 1:1.5). Of note, pure 2j and 2j′ could be separated through a silica chromatographic column using DCM/methanol as an eluent. However, the ortho-position substituted N-arylacylamides did not work well in this aminooxyarylation, and only trace amounts of the desired products could be obtained (2k and 2l). The results perhaps were ascribed to the particularly distinct steric hindrance effect.13 Under similar reaction conditions, N-methyl-N-(naphthalen-1-yl)methacrylamide also served well and were converted to product 2m in 68% yield with C2-position being occupied regioselectivity.13,14 Interestingly, the N-arylacrylamide with a 1,3-dioxoisoindolin-2-yl group at the α-position of carbon−carbon double bond showed reactivity despite the lower yield (2n, 42%); whereas, on switching the substituent positions by replacement of 1n with a terminal methyl substituted substrate, the desired product 2o was obtained in a trace amount. The substitute effect at the N atom (R2) of N-arylacrylamides was next investigated. It was found that several N-substituted substrates bearing different functional groups, such as ethyl, isopropyl, phenyl, and benzyl, were proved to be good substrates in this aminooxyarylation and afforded the desired products in satisfactory to good yields (2p−2s). This K2S2O8/TBAItriggered protocol is also applicable to N-hydroxysuccinimide (NHS). For example, the cyclization of N-arylacrylamides 1a and 1i with NHS delivered the corresponding products 2t and 2u in 85% and 88% yields, respectively. The reaction of paraF and -CF3 substituted N-arylacrylamides with NHS also proceeded smoothly to deliver the desired products in good yields (2v and 2w, 71% and 69%). It is noteworthy that the substrate having a long alkyl chain substituent, that is, a nbutyl group, at the N atom also showed good reactivity in this system (2x, 80%). It should be noted that when a N-arylacrylamide bearing a methyl group on the para-position of benzene ring was used as a substrate, a complicated mixture was given. The result perhaps was ascribed to the reaction of benzylic C−H bonds with NHPI under the reaction conditions. Indeed, when ethylbenzene and isochromane, which could couple with NHPI in the presence of a copper catalyst,15 were subjected to the present conditions, the corresponding aminooxylated

a

General reaction conditions: NHPI (0.2 mmol), 1a (1.5 equiv), DCE (1.0 mL), N2; TBAHS, n-Bu4NHSO4; TBAF, n-Bu4NF; TBAC, nBu 4 NCl; TBAB, n-Bu 4 NBr; TBAI, n-Bu 4 NI; TBAOAc, nBu4NOOCMe; TBABF4, n-Bu4NBF4; n.r., no reaction. bIsolated yields based on NHPI. c(NH4)2S2O8. dNa2S2O8. eOxone. fWhen 10 mol % of TBAHS was used, 39% of 2a was produced. gTBAF (1 mol/ L in THF). h15 h.

to produce the corresponding aminooxyarylated product 2a in 28% yield (Table 1, entry 1). Both K2S2O8 and TBAHS are essential to this reaction. In the absence of either species, no reaction was observed (Table 1, entries 2 and 3). With (NH4)2S2O8, a similar result was given, however, when Na2S2O8 or oxone was used as the oxidant, the reaction proceeded sluggishly under similar reaction conditions (Table 1, entries 4−6). The loading of TBAHS was further investigated, and an increased yield of 2a was given with a catalytic amount (20 mol %) of TBAHS (Table 1, entry 7). By elevating the temperature to 90 °C, product 2a could be generated in 55% yield (Table 1, entry 8). Subsequently, a series of quaternary ammonium salts as catalysts were investigated, TBAI displayed the best catalytic efficiency in this tandem reaction (Table 1, entries 9−14). To our delight, the highest yield (81%) was achieved by reducing the amount of K2S2O8 to 1.2 equiv (Table 1, entries 15−18); however, further reducing the amount of K2S2O8 led to a slight decrease in yield (Table 1, entry 19). With continued use of K2S2O8/TBAI system, the reaction of 1a with NHPI was performed in DCE at 100 °C for 15 h, producing the cyclic product 2a in 80% yield (Table 1, entry 20). Finally, various solvents were also tested, revealing that DCE is the best choice as compared to other solvents such as DMF, MeNO2, MeCN, and MeCN/H2O (for details, see Table S1 in the Supporting Information). 2370

DOI: 10.1021/acs.joc.7b02740 J. Org. Chem. 2018, 83, 2369−2375

Note

The Journal of Organic Chemistry Table 2. Scope of the Aminooxyarylation Reactiona

Scheme 2. Reactivity Investigations Using sp3Hydrocarbons

current reaction conditions, providing an attractive complement to previous transition-metal-catalyzed ones. Under similar reaction conditions, propiophenone was a good coupling partner as well (5, 73%). In order to further demostrate the synthetic value of our protocol, a 2 mmol scale reaction was performed (Scheme 3). Under the reaction conditions, N-methyl-N-phenylmethacrylamide 1a reacted with NHPI readily to deliver the desired product 2a in 72% yield. In addition, we were pleased to find that the oxindol-3-yl methanol 6 could be synthesized in 71% yield from 2a through only one step (Scheme 3). Worth noting is that compound 6 is a key synthetic intermediate of natural products esermethole and physostigmine and usually were synthesized through five steps in low atom-economic efficiency.11 Scheme 3. Synthetic Utility Demonstration

As reported, N-hydroxyphthalimide (NHPI) can be easily oxidized into the active phthalimide N-oxyl (PINO) radical,15 therefore, the present reaction might be a radical process. The hyperthesis was further supported by two radical verification experiments. When radical scavengers, such as 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO), and hydroquinone (HQ) were added to the reaction system, the desired transformation was completely suppressed (Scheme 4).

a

General reaction conditions: NHPI (0.2 mmol), 1 (1.5 equiv), K2S2O8 (1.2 equiv), TBAI (20 mol %), DCE (1.0 mL), N2, 90 °C, 24 h. Isolated yields based on NHPI.

coupling products 3 and 4 were produced in 69% and 85% yields, respectively (Scheme 2). Those results indicated that benzylic C−H bonds could also be aminooxylated under the 2371

DOI: 10.1021/acs.joc.7b02740 J. Org. Chem. 2018, 83, 2369−2375

Note

The Journal of Organic Chemistry

functionalization process. Various aminooxylated oxindoles were produced by using the present strategy. The benzylic and α-methylene C−H bonds could also couple with NHPI in the current oxidative system to generate the corresponding aminooxylated coupling products in good to high yields. Further experimental studies to elucidate the mechanistic details and further investigation of relevant reactions based on this K2S2O8/tetrabutyl quaternary ammonium salts combined strategy are currently underway, and these studies will be reported in due course.

Scheme 4. Radical Verification Experiments

■

EXPERIMENTAL SECTION

General Information. All reagents used were obtained commercially and used without further purification unless indicated otherwise. Solvents were dried and distilled prior to use according to the standard protocols. Column chromatography was carried out on silica gel (300−400 grading). 1H NMR and 13C NMR were recorded in CDCl3 and DMSO-d6 at room temperature on the Bruker spectrometer (400 MHz 1H). The chemical-shifts scale is based on internal TMS. Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q (quintet), and m (multiplet), and coupling constants (J) are reported in hertz. HRMS was measured on an electrospray ionization (ESI) apparatus using time-of-flight (TOF) mass spectrometry. Melting points were determined using XT-4 apparatus and are uncorrected. Preparation of N-Arylacrylamides. N-Arylacrylamide substrates 1a−n were prepared according to the literature.20 A Typical Procedure for the Direct Annulations Toward Aminooxylated Oxindoles. N-Arylacrylamide 1 (52.5 mg, 0.3 mmol), N-hydroxyphthalimide (NHPI: 34 mg, 0.2 mmol), K2S2O8 (65.5 mg, 0.24 mmol), TBAI (15 mg, 20 mol %), and anhydrous 1,2-dichloroethane (DCE: 1.0 mL) were added to a 25 mL Schlenk flask equipped with a high-vacuum PTFE valve-to-glass seal. Then the flask was evacuated and backfilled with nitrogen for three times. After that, the mixture was stirred at 90 °C under a nitrogen atmosphere for 24 h. Upon completion, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the desired products 2. 2-((1,3-Dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3dione (2a). By following the typical procedure, the product was isolated as a white solid, 54.5 mg (81% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 155−157 °C; 1H NMR (400 MHz, CDCl3) δ 7.77−7.68 (m, 4H), 7.41 (d, J = 7.2 Hz, 1H), 7.29−7.25 (m, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.44 (d, J = 9.2 Hz, 1H), 3.26 (s, 3H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.5, 162.8, 143.5, 134.4, 130.9, 128.7, 128.4, 123.5, 123.4, 122.6, 108.3, 80.7, 48.6, 26.4, 20.2; HRMS m/z (ESI) calcd for C19H16N2O4+[M+]: 336.1110; found 336.1093. 2-((5-Fluoro-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3-dione (2b). By following the typical procedure, the product was isolated as a white solid, 40.4 mg (57% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 160−161 °C; 1H NMR (400 MHz, CDCl3) δ 7.78−7.71 (m, 4H), 7.19 (d, J = 8.0 Hz, 1H), 7.02−6.96 (m, 1H), 6.80−6.77 (m, 1H), 4.55 (d, J = 9.6 Hz, 1H), 4.43 (d, J = 9.6 Hz, 1H), 3.24 (s, 3H), 1.47 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 177.1, 162.8, 139.4, 134.5, 132.6, 132.5, 128.7, 123.4, 114.7, 114.5, 112.1, 111.8, 108.8, 108.7, 80.5, 49.0, 26.6, 20.1; HRMS m/z (ESI) calcd for C19H15FN2O4+[M+]: 354.1016; found 354.1011. 2-((5-Chloro-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3-dione (2c). By following the typical procedure, the product was isolated as a white solid, 46 mg (62% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 162−163 °C; 1H NMR (400 MHz, CDCl3) δ 7.77−7.70 (m, 4H), 7.38 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 6.78 (d, J = 8.4 Hz,

Scheme 5. Proposed Mechanism for the K2S2O8/TBAITriggered Reaction

On the basis of these preliminary evidence as well as previous literature, a plausible mechanistic pathway for this reaction is depicted in Scheme 5. Similar to a TEAB-catalyzed dehydrogenative arylation of aldehydes, TBAI might act as an initiator for producing the active sulfate radical anions in our reaction system.16 Being different from that of the radical cyclization between homopropargylic alcohols and sulfonyl hydrazides triggered by K2S2O8/TBAI, the phthalimide N-oxyl radical (PINO) is generated from NHPI by sulfate radical anions.17 Further evidence was provided by two control experiments.18 The addition of phthalimide N-oxyl radical to the carbon−carbon double bond of N-arylacrylamide 1a would produce an oxygenated alkyl radical A. The resulting alkyl radical would then readily aromatize to give the aryl radical B.10b,c Single electron oxidation of B by sulfate radical anions gives rise to a carbocation C, which is deprotonated by the generated sulfate dianion to yield the desired oxygenated product 2a.16 On the other hand, alkyl radicals likely produced upon the H abstraction from sp3-hydrocarbons by PINO radical19 and the resulting NHPI molecules were reoxidized by sulfate radical anions to produce the PINO radical via a similar H abstraction process again. Obviously, the cross-coupling products (i.e., 3, 4, and 5) were produced from the coupling of two radicals (i.e., alkyl radical and PINO radical). In summary, we have developed an efficient aminooxyarylation of N-arylacrylamides with NHPI. This reaction preceded in the presence of K2S2O8/TBAI via a radical C−H 2372

DOI: 10.1021/acs.joc.7b02740 J. Org. Chem. 2018, 83, 2369−2375

Note

The Journal of Organic Chemistry 1H), 4.58 (d, J = 9.6 Hz, 1H), 4.43 (d, J = 9.6 Hz, 1H), 3.24 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.0, 162.7, 142.1, 134.4, 132.5, 128.6, 128.3, 128.1, 124.1, 123.4, 109.2, 80.3, 48.9, 26.6, 20.2; HRMS m/z (ESI) calcd for C19H15ClN2O4+[M+]: 370.0720; found 370.0716. 2-((5-Bromo-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3-dione (2d). By following the typical procedure, the product was isolated as a white solid, 54.8 mg (66% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 166−167 °C; 1H NMR (400 MHz, CDCl3) δ 7.76−7.70 (m, 4H), 7.50 (d, J = 1.6 Hz, 1H), 7.36 (dd, J = 8.4, 1.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.58 (d, J = 10.0 Hz, 1H), 4.43 (d, J = 9.6 Hz, 1H), 3.23 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.9, 162.7, 142.6, 134.4, 132.9, 131.2, 128.6, 126.8, 123.4, 115.3, 109.8, 80.2, 48.8, 26.5, 20.2; HRMS m/z (ESI) calcd for C19H15BrN2O4+[M+]: 414.0215; found 414.0211. 2-((5-Iodo-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline1,3-dione (2e). By following the typical procedure, the product was isolated as a white solid, 67.5 mg (73% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 175−177 °C; 1H NMR (400 MHz, CDCl3) δ 7.75−7.70 (m, 4H), 7.64 (d, J = 1.6 Hz, 1H), 7.53 (dd, J = 8.2, 1.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 4.58 (d, J = 10.0 Hz, 1H), 4.42 (d, J = 9.6 Hz, 1H), 3.22 (s, 3H), 1.42 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 176.7, 162.6, 143.3, 137.2, 134.4, 133.2, 132.2, 128.6, 123.4, 110.4, 85.1, 80.1, 48.6, 26.5, 20.2; HRMS m/z (ESI) calcd for C19H15IN2O4+[M+]: 462.0076; found 462.0079. 3-(((1,3-Dioxoisoindolin-2-yl)oxy)methyl)-1,3-dimethyl-2-oxoindoline-5-carbonitrile (2g). By following the typical procedure, the product was isolated as a white solid, 50.6 mg (70% yield), flash chromatography (petroleum ether/ethyl acetate, 2/1); mp: 217−219 °C; 1H NMR (400 MHz, CDCl3) δ 7.77−7.71 (m, 4H), 7.66 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 8.0 Hz, 1H), 4.45 (d, J = 8.0 Hz, 1H), 3.28 (s, 3H), 1.47 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 177.2, 162.7, 147.4, 134.6, 133.8, 131.9, 128.6, 127.0, 123.5, 119.0, 108.8, 105.8, 80.2, 48.6, 26.7, 20.0; HRMS m/z (ESI) calcd for C20H15N3O4+[M+]: 361.1063; found 361.1060. 2-((1,3-Dimethyl-2-oxo-5-(trifluoromethyl)indolin-3-yl)methoxy)isoindoline-1,3-dione (2h). By following the typical procedure, the product was isolated as a white solid, 47 mg (58% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 199−201 °C; 1H NMR (400 MHz, CDCl3) δ 7.84−7.70 (m, 4H), 7.62 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.65 (d, J = 9.8 Hz, 1H), 4.47 (d, J = 9.8 Hz, 1H), 3.31 (s, 3H), 1.48 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 177.4, 162.6, 146.5, 134.7, 134.4, 131.4, 128.8, 128.8, 128.5, 126.3, 126.3, 126.2, 126.2, 126.2, 126.1, 126.1, 123.8, 123.5, 123.4, 120.5, 120.5, 108.1, 80.1, 48.6, 26.6, 20.1; HRMS m/z (ESI) calcd for C20H15F3N2O4+[M+]: 404.0984; found 404.0989. 2-((5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3-dione (2i). By following the typical procedure, the product was isolated as a colorless oil, 57.9 mg (79% yield), flash chromatography (petroleum ether/ethyl acetate, 3/1); 1H NMR (400 MHz, CDCl3) δ 7.76−7.69 (m, 4H), 7.05 (s, 1H), 6.76 (t, J = 10.2 Hz, 2H), 4.60 (d, J = 9.2 Hz, 1H), 4.41 (d, J = 9.2 Hz, 1H), 3.77 (s, 3H), 3.23 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.1, 162.8, 156.1, 136.9, 134.3, 132.3, 128.8, 123.4, 113.0, 110.9, 108.7, 80.5, 55.8, 49.0, 26.5, 20.3; HRMS m/z (ESI) calcd for C20H18N2O5+[M+]: 366.1216; found 366.1212. 2-((6-Bromo-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3-dione and 2-((4-Bromo-1,3-dimethyl-2-oxoindolin3-yl)methoxy)isoindoline-1,3-dione (2j + 2j′). By following the typical procedure, the product was isolated as a colorless oil, 58 mg (70% yield), flash chromatography (petroleum ether/ethyl acetate, 4/ 1); 1H NMR (400 MHz, CDCl3) δ 7.75−7.69 (m, 7H), 7.28 (s, 0.45H), 7.18−7.12 (m, 1.71H), 7.06 (d, J = 8.0 Hz, 0.99H), 7.01 (s, 0.62H), 6.85 (d, J = 7.6 Hz, 0.99H), 5.23 (d, J = 10.7 Hz, 1H), 4.57 (dd, J = 17.0, 8.6 Hz, 1.76H), 4.40 (d, J = 9.5 Hz, 0.72H), 3.28 (s, 3H), 3.23 (s, 2.05H), 1.45 (s, 5.02H); 13C NMR (100 MHz, CDCl3) δ 177.4, 177.2, 162.7, 162.5, 146.3, 144.8, 134.5, 134.3, 129.8, 128.7,

128.6, 128.2, 126.5, 125.4, 124.8, 123.5, 123.4, 123.3, 122.1, 119.0, 111.9, 107.6, 80.3, 78.0, 50.9, 48.4, 26.7, 26.6, 20.1, 17.5; HRMS m/z (ESI) calcd for C19H15BrN2O4+[M+]: 414.0215; found 414.0212. 2-((6-Bromo-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3-dione (2j). White solid (21 mg), Rf = 0.3 (DCM/ methanol, 50/1); mp 158−160 °C; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 13.4 Hz, 4H), 7.29 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 4.58 (d, J = 9.3 Hz, 1H), 4.41 (d, J = 9.4 Hz, 1H), 3.24 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.3, 162.8, 144.8, 134.5, 129.8, 128.7, 125.4, 124.8, 123. 5, 122.1, 111.9, 80.3, 48.4, 26.6, 20.1; HRMS m/z (ESI) calcd for C19H15BrN2O4+[M+]: 414.0215; found 414.0212. 2-((4-Bromo-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3-dione (2j′). White solid (32 mg), Rf = 0.2 (DCM/ methanol, 50/1); mp 155−156 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 4H), 7.13 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 5.22 (d, J = 10.6 Hz, 1H), 4.54 (d, J = 10.6 Hz, 1H), 3.27 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.4, 162.5, 146.2, 134.3, 129.8, 128.6, 128.1, 126.4, 123.3, 119, 107.6, 77.9, 50.8, 26.6, 17.5; HRMS m/z (ESI) calcd for C19H15BrN2O4+[M+]: 414.0215; found 414.0212. 2-((1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[g]indol-3-yl)methoxy)isoindoline-1,3-dione (2m). By following the typical procedure, the product was isolated as a white solid, 52.6 mg (68% yield), flash chromatography (petroleum ether/ethyl acetate, 4/ 1); mp: 175−177 °C; 1H NMR (400 MHz, CDCl3) δ 7.70−7.41 (m, 9H), 7.00 (d, J = 7.1 Hz, 1H), 4.99 (d, J = 9.4 Hz, 1H), 4.80 (d, J = 9.4 Hz, 1H), 3.60 (s, 3H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 162.69, 136.6, 134.6, 134.2, 133.3, 128.5, 126.8, 126.5, 126.4, 123.1, 122.9, 122.5, 119.6, 108.7, 84.4, 47.6, 29.9, 27.8; HRMS m/z (ESI) calcd for C23H18N2O4+[M+]: 386.1267; found 386.1265. 2-((3-((1,3-Dioxoisoindolin-2-yl)methyl)-1-methyl-2-oxoindolin3-yl)methoxy)isoindoline-1,3-dione (2n). By following the typical procedure, the product was isolated as a white solid, 40.4 mg (42% yield), flash chromatography (petroleum ether/ethyl acetate, 1/1); mp: 267−269 °C; 1H NMR (400 MHz, DMSO) δ 7.82−7.75 (m, 8H), 7.42 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.01−6.93 (m, 2H), 4.81 (d, J = 8.0 Hz, 1H), 4.58 (d, J = 12.0 Hz, 1H), 3.99 (d, J = 16.0 Hz, 1H), 3.89 (d, J = 12.0 Hz, 1H), 3.12 (s, 3H); 13C NMR (100 MHz, DMSO) δ 174.7, 168.1, 162.8, 144.3, 135.2, 135.1, 131.7, 129.04 (d, J = 41.1 Hz), 128.83−128.52 (m), 127.34, 124.69, 123.64 (d, J = 13.2 Hz), 129.2, 128.8, 127.3, 124.7, 123.7, 123.6, 122.4, 109.1, 78.2, 52.6, 40.7, 26.8; HRMS m/z (ESI) calcd for C27H19N3O6+[M+]: 481.1274; found 481.1269. 2-((1-Ethyl-3-methyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3dione (2p). By following the typical procedure, the product was isolated as a white solid, 42 mg (60% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 162−165 °C; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 16.3 Hz, 4H), 7.44 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.57 (d, J = 9.0 Hz, 1H), 4.41 (d, J = 9.0 Hz, 1H), 3.80 (q, J = 7.1 Hz, 2H), 1.48 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.0, 162.7, 142.5, 134.4, 131.2, 128.7, 128.3, 123.8, 123.4, 122.4, 108.4, 80.8, 48.4, 34.9, 20.2, 12.6; HRMS m/z (ESI) calcd for C20H18N2O4+[M+]: 350.1267; found 350.1266. 2-((1-Isopropyl-3-methyl-2-oxoindolin-3-yl)methoxy)isoindoline1,3-dione (2q). By following the typical procedure, the product was isolated as a white solid, 47.4 mg (65% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 170−172 °C; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 18.4 Hz, 4H), 7.45 (d, J = 7.0 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 7.0 Hz, 2H), 4.68 (m, 1H), 4.56 (d, J = 8.6 Hz, 1H), 4.38 (d, J = 8.6 Hz, 1H), 1.50 (dd, J = 15.9, 9.6 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 177.1, 162.8, 142.0, 134.4, 131.4, 128.8, 128.1, 124.0, 123.4, 122.0, 110.0, 81.0, 48.2, 44.0, 20.3, 19.4, 19.3; HRMS m/z (ESI) calcd for C21H20N2O4+[M+]: 364.1423; found 364.1419. 2-((3-Methyl-2-oxo-1-phenylindolin-3-yl)methoxy)isoindoline1,3-dione (2r). By following the typical procedure, the product was isolated as a white solid, 63 mg (79% yield), flash chromatography 2373

DOI: 10.1021/acs.joc.7b02740 J. Org. Chem. 2018, 83, 2369−2375

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The Journal of Organic Chemistry (petroleum ether/ethyl acetate, 4/1); mp: 189−191 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.9 Hz, 2H), 7.78 (d, J = 3.0 Hz, 2H), 7.42−7.35 (m, 7H), 7.29−7.27 (m, 2H), 4.76 (d, J = 10.0 Hz, 1H), 4.66 (d, J = 10.0 Hz, 1H), 1.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 163.9, 134.8, 128.9, 128.6, 128.3, 128.1, 127.4, 127.4, 123.9, 85.5, 78.2, 53.4, 19.8; HRMS m/z (ESI) calcd for C24H18N2O4+[M+]: 398.1267; found 398.1265. 2-((1-Benzyl-3-methyl-2-oxoindolin-3-yl)methoxy)isoindoline1,3-dione (2s). By following the typical procedure, the product was isolated as a white solid, 58.6 mg (71% yield), flash chromatography (petroleum ether/ethyl acetate, 4/1); mp: 198−201 °C; 1H NMR (400 MHz, CDCl3) δ 7.72−7.68 (m, 2H), 7.66−7.63 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.24−7.15 (m, 5H), 7.10−7.06 (m, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.96 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.57 (d, J = 8.8 Hz, 1H), 4.42 (d, J = 8.8 Hz, 1H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.7, 162.8, 142.5, 135.8, 134.4, 130.9, 128.8, 128.8, 128.3, 127.5, 127.2, 123.7, 123.4, 122.7, 109.4, 80.8, 48.6, 43.9, 20.4; HRMS m/z (ESI) calcd for C25H20N2O4+[M+]: 412.1423; found 412.1420. 1-((1,3-dimethyl-2-oxoindolin-3-yl)methoxy)pyrrolidine-2,5dione (2t). By following the typical procedure, the product was isolated as a white solid, 49 mg (85% yield), flash chromatography (petroleum ether/ethyl acetate, 2/1); mp: 176−178 °C; 1H NMR (400 MHz, CDCl3) δ 7.34−7.30 (m, 2H), 7.09 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.57 (d, J = 10.0 Hz, 1H), 4.35 (d, J = 10.0 Hz, 1H), 3.24 (s, 3H), 2.54−2.39 (m, 4H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.5, 170.3, 143.6, 130.8, 128.5, 123.0, 122.5, 108.5, 78.7, 48.5, 26.4, 25.2, 20.5; HRMS m/z (ESI) calcd for C15H16N2O4+[M+]: 288.1110; found 288.1113. 1-((5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)pyrrolidine-2,5-dione (2u). By following the typical procedure, the product was isolated as a white solid, 56 mg (88% yield), flash chromatography (petroleum ether/ethyl acetate, 1/1); mp: 149−151 °C; 1H NMR (400 MHz, CDCl3) δ 6.98 (s, 1H), 6.79 (dd, J = 26.0, 8.4 Hz, 2H), 4.52 (d, J = 9.9 Hz, 1H), 4.30 (d, J = 9.8 Hz, 1H), 3.80 (s, 3H), 3.19 (s, 3H), 2.58−2.43 (m, 4H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.1, 170.3, 156.0, 137.0, 132.2, 112.9, 110.6, 108.7, 78.9, 55.8, 49.0, 26.5, 25.3, 20.4; HRMS m/z (ESI) calcd for C16H18N2O5+[M+]: 318.1216; found 318.1218. 1-((5-Fluoro-1,3-dimethyl-2-oxoindolin-3-yl)methoxy)pyrrolidine-2,5-dione (2v). By following the typical procedure, the product was isolated as a white solid, 43 mg (71% yield), flash chromatography (petroleum ether/ethyl acetate, 1/1); mp: 183−185 °C; 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 7.8 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 6.78 (t, J = 8.0 Hz, 1H), 4.45 (d, J = 9.7 Hz, 1H), 4.31 (d, J = 9.7 Hz, 1H), 3.21 (s, 3H), 2.62−2.47 (m, 4H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.1, 170.3, 160.4, 158.0, 139.4, 132.5, 132.4, 114.8, 114.6, 111.8, 111.5, 108.8, 108.8, 78.9, 49.0, 26.5, 25.2, 20.2; HRMS m/z (ESI) calcd for C15H15FN2O4+[M+]: 306.1016; found 306.1012. 1-((1,3-Dimethyl-2-oxo-5-(trifluoromethyl)indolin-3-yl)methoxy)pyrrolidine-2,5-dione (2w). By following the typical procedure, the product was isolated as a white solid, 50 mg (69% yield), flash chromatography (petroleum ether/ethyl acetate, 1/1); mp: 187−190 °C; 1H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 8.0 Hz, 2H), 6.95 (d, J = 7.9 Hz, 1H), 4.55 (d, J = 10.1 Hz, 1H), 4.36 (d, J = 10.2 Hz, 1H), 3.27 (s, 3H), 2.58−2.43 (m, 4H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.5, 170.2, 146.7, 131.4, 126.4, 126.3, 126.3, 126.2, 125.7, 124.9, 124.6, 123.0, 120.3, 108.2, 78.8, 48.6, 26.7, 25.2, 20.2; HRMS m/z (ESI) calcd for C16H15F3N2O4+[M+]: 356.0984; found 356.0985. 1-((1-Butyl-3-methyl-2-oxoindolin-3-yl)methoxy)pyrrolidine-2,5dione (2x). By following the typical procedure, the product was isolated as a white solid, 52.9 mg (80% yield), flash chromatography (petroleum ether/ethyl acetate, 1/1); mp: 187−190 °C; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 7.0 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.07 (t, J = 7.1 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.50 (d, J = 9.3 Hz, 1H), 4.28 (d, J = 9.3 Hz, 1H), 3.83−3.76 (m, 1H), 3.68− 3.62 (m, 1H), 2.58−2.43 (m, 4H), 1.69−1.66 (t, J = 8.0 Hz, 2H), 1.42−1.36 (m, 5H), 0.95 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz,

CDCl3) δ 177.2, 170.3, 142.8, 131.0, 128.3, 123.4, 122.2, 108.6, 78.9, 48.3, 39.8, 29.3, 25.2, 20.4, 20.0, 13.7; HRMS m/z (ESI) calcd for C18H22N2O4+[M+]: 330.1580; found 330.1581. 2-(1-Phenylethoxy)isoindoline-1,3-dione (3).15 White solid (36.9 mg, 69%), Rf = 0.27 (petroleum ether/EtOAc, 6:1); mp: 92−94 °C; 1 H NMR (400 MHz, CDCl3) δ 7.76−7.67 (m, 4H), 7.52−7.50 (m, 2H), 7.36−7.31 (m, 3H), 5.50 (q, J = 6.5 Hz, 1H), 1.72 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 139.0, 134.3, 129.0, 128.8, 128.3, 127.6, 123.3, 85.1, 20.4; HRMS m/z (ESI) calcd for C16H13NO3+[M+]: 267.0895; found 267.0892. 2-(Isochroman-1-yloxy)isoindoline-1,3-dione (4).15 Yellow oil (50.2 mg, 85%), Rf = 0.29 (petroleum ether/EtOAc, 6:1); 1H NMR (400 MHz, CDCl3) δ 7.88−7.86 (m, 2H), 7.78−7.70 (m, 3H), 7.37−7.31 (m, 2H), 7.20 (d, J = 4.0 Hz, 1H), 6.20 (s, 1H), 4.70 (td, J = 12.5, 3.1 Hz, 1H), 4.03 (dd, J = 11.5, 6.0 Hz, 1H), 3.15−3.06 (m, 1H), 2.73 (dd, J = 16.6, 2.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.9, 134.9, 134.4, 129.6, 129.4, 129.2, 128.8, 128.5, 126.6, 123.5, 102.2, 59.6, 27.5; HRMS m/z (ESI) calcd for C17H13NO4+[M+]: 295.0845; found 295.0840. 2-((1-Oxo-1-phenylpropan-2-yl)oxy)isoindoline-1,3-dione (5).6b White Solid (43.1 mg, 73%), Rf = 0.2 (petroleum ether/EtOAc, 5:1); mp: 87−88 °C; 1H NMR (400 MHz, CDCl3) δ 8.18−8.15 (m, 2H), 7.85−7.81 (m, 2H), 7.77−7.73 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 5.75 (q, J = 6.8 Hz, 1H), 1.69 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.3, 163.6, 134.7, 134.6, 133.7, 129.2, 128.8, 128.7, 123.7, 83.6, 16.2; HRMS m/z (ESI) calcd for C17H13NO4+[M+]: 295.0845; found 295.0843. 2-((1,3-Dimethyl-2-oxoindolin-3-yl)methoxy)isoindoline-1,3dione (6).11 White solid; mp: 80−83 °C; 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 3.85 (d, J = 10.8 Hz, 1H), 3.74 (d, J = 10.8 Hz, 1H), 3.23 (s, 3H), 2.22 (s, 1H), 1.42 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 180.0, 143.7, 131.7, 128.4, 122.78, 122.7, 108.3, 67.7, 49.9, 26.2, 19.0. HRMS m/z (ESI) calcd for C11H13NO2+[M+]: 191.0946; found 191.0950.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02740. Copies of 1H and 13C spectra for all products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Ming-Zhong Zhang: 0000-0001-5427-3168 Tieqiao Chen: 0000-0002-9787-9538 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are thankful for the financial support from the Natural Science Foundation of China (no. 21275021), Program for Innovation Team Building at Institutions of Higher Education in Chongqing (no. CXTDX201601039), and the Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJ1601202).

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REFERENCES

(1) (a) Zhang, Y.; Wang, Q.; Wang, T.; He, H.; Yang, W.; Zhang, X.; Cai, Q. J. Org. Chem. 2017, 82, 1458. (b) Figg, T. M.; Webb, J. R.; Cundari, T. R.; Gunnoe, T. B. J. Am. Chem. Soc. 2012, 134, 2332.

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DOI: 10.1021/acs.joc.7b02740 J. Org. Chem. 2018, 83, 2369−2375

Note

The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.7b02740 J. Org. Chem. 2018, 83, 2369−2375