Nucleophilic Ring Opening of Donor–Acceptor Cyclopropanes with

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Cite This: J. Org. Chem. 2018, 83, 8695−8709

Nucleophilic Ring Opening of Donor−Acceptor Cyclopropanes with the Cyanate Ion: Access to Spiro[pyrrolidone-3,3′-oxindoles] Sergey V. Zaytsev,† Konstantin L. Ivanov,† Dmitry A. Skvortsov,† Stanislav I. Bezzubov,‡ Mikhail Ya. Melnikov,† and Ekaterina M. Budynina*,† †

Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991 Russia Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninskiy pr. 31, Moscow 119991 Russia

‡

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S Supporting Information *

ABSTRACT: The nucleophilic ring opening of donor−acceptor cyclopropanes with the cyanate ion is reported for the first time. Cyclopropanes, spiro-activated with oxindole fragments as acceptors, are shown to undergo transformations into biologically relevant spiro[pyrrolidone-3,3′-oxindoles] while being treated with potassium cyanate under microwave assistance.

T

Scheme 1. Strategy of This Work

he strain-driven ring opening of donor−acceptor (DA) cyclopropanes1 with nucleophiles is of great importance as a simple stereocontrolled pathway toward 1,3-functionalized compounds.2 In a broad range of nucleophiles studied as initiators of DA cyclopropane ring opening, N-nucleophiles are of particular significance since they provide numerous opportunities to synthesize structurally diverse N-containing molecules, especially the most privileged and significant Nheterocycles.3 Most N-nucleophiles that were investigated in reactions with DA cyclopropanes are organic compounds, such as amines,4 hydrazines,5 amides,6 nitriles,7 and N-heterocycles8 (Scheme 1a). Among inorganic salts, only sodium azide was systematically studied in DA cyclopropane ring opening toward the synthesis of functionalized organic azides and, subsequently, N-heterocycles.9 Our previous study revealed that, in general, nucleophilic ring opening of commonly used 2-arylcyclopropane-1,1-diesters triggered by an SN2-like attack of the azide ion proceeded under prolonged heating at 100 °C.9b In this regard, less reactive nucleophiles can require more demanding conditions, additionally activating undesired side processes that invalidate the utility of the target reaction. Despite these challenges, we attempted to design a new type of a nucleophilic ring opening of DA cyclopropanes with the cyanate ion, which is isoelectronic to the azide ion (Scheme 1b). Among DA cyclopropanes of several subclasses, cyclopropanes 1 spiro-activated with the oxindole were found to tolerate severe reaction conditions. The discovered reaction allowed for a new rapid access to spiro[pyrrolidone-3,3′oxindoles] 2, which are representatives of a large family of biologically relevant spiro[pyrrolidine-3,3′-oxindoles] (Scheme 1c).10 Spontaneous assembly of the pyrrolidone unit in 2 should be obvious when accounting for intermediate formation of acyclic © 2018 American Chemical Society

isocyanate with an anionic center stabilized with an electronwithdrawing group (EWG) (Scheme 1b). Therefore, this process can be compared with (3+2)-cycloadditions and related reactions between DA cyclopropanes and isocyanates Received: April 12, 2018 Published: June 12, 2018 8695

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

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The Journal of Organic Chemistry

obtained results are in agreement with those reported by Kerr and co-workers and related to lactonization of cyclopropanes proceeding presumably via SN2-like ring opening with the chloride ion.16 Therefore, for the ester-substituted DA cyclopropanes, lactonization and dealkoxycarbonylation are more preferable under the studied conditions, while the tendency of such cyclopropanes to undergo ring opening with NCO− is much lower than that for the isoelectronic N3−. We recently revealed that the SN2-like ring opening of DA cyclopropanes with N3− is a convenient model to estimate their relative reactivity.9b According to this model, 2-phenylcyclopropane-1,1-dinitrile is more reactive than the diester analogue. However, its reaction with NCO− led only to products of oligomerization. In this regard, we recognized that two key conditions should be satisfied. First, cyclopropane should not be functionalized with an EWG prone to participate in Cloke-type ring enlargements 17 or reactions with nucleophiles, e.g., Krapcho dealkoxycarbonylation. Second, the use of an EWG with lower acceptor properties requires additional activation of the DA cyclopropane. Since one of the common tricks for this is spiro-activation,18 we examined cyclopropanes 1 spiro-activated with oxindole as an EWG in reaction with NCO−, giving priority to biologically relevant structures. Recently, similar cyclopropanes were found to exhibit reactivity against N3− that was comparable to arylcyclopropane-1,1-diesters.9a Our initial experiments displayed that, despite significant tarring, the reaction of cyclopropane 1a with KNCO in DMF at 150 °C indeed resulted in the product of nucleophilic ring opening/cyclization 2a in 20 and 50% yields for conventional and microwave heating, respectively (Table 1, entries 1 and 2). Due to the demonstrated superiority of microwave heating, further optimization was carried out under microwave assistance. A further study revealed that only 85% conversion of 1a could be achieved, regardless of duration of heating and

as well as their thio analogues (Scheme 2). As early as the late 1980s, Graziano and co-workers demonstrated that (3+2)Scheme 2. Pyrrolidine Core Formation via Reactions of DA Cyclopropanes with Iso(thio)cyanates

cycloadditions of dialkoxy-activated DA cyclopropanes to iso(thio)cyanates provided the formation of γ-(thio)lactams.11 Reissig et al. carried out a related process with cyclopropyl anions yielding pyrroline derivatives.12 At the same time, Tsuji et al. revealed a similar reactivity for vinyl-substituted DA cyclopropanes when activated with Pd(0) catalysts.13 Recently, Stoltz and co-workers reported analogous (3+2)-cycloaddition between isocyanates and aryl-substituted DA cyclopropanes,14 which have been intensively studied in the recent years. A more relevant example of this reaction with spirocyclopropaneoxindole being used was reported by Marti and Carreira.15 Our initial attempts were directed toward determining reaction conditions for the chemoselective nucleophilic ring opening and, thus, were related to the screening of starting DA cyclopropanes with appropriate donor (EDG) and acceptor (EWG) activating groups tolerant to these conditions. First, we examined the common dimethyl 2-phenylcyclopropane-1,1diester, which was treated with KNCO in DMF at several temperatures. Its visible conversion was detected starting from 140 °C. However, Krapcho dealkoxycarbonylation was found to be the main process (also caused by a nucleophilic attack but on the ester group). Since the nucleophilic ring opening of DA cyclopropanes with N3− was proved to be a reversible step, requiring a H+ source to complete the reaction, we checked whether protic additives influenced the reaction of 2phenylcyclopropane-1,1-diester with NCO− as well. We found that the presence of Et3N·HCl did not allow for reducing the temperature of the reaction, ultimately leading to significant tarring along with detectable lactonization. The

Table 1. Optimization of the Reaction Conditions

entry 1 2 3 4 5 6 7 8 9 10

solvent DMF DMF DMF NMP DMSO DMF DMSO DMF DMF THF

additive (equiv)

18-crown-6 (2) 18-crown-6 (2) 18-crown-6 (2)

Et3N·HCl (1) Et3N·HCl (1) MgBr2·OEt2 (1)

t (h) 9.5 7 1.5 1.5 1 3 4 7 10e 3

T (°C)a c

150 150 150 170 170 130 150c 150 150 130

yield (%)b 20 50d 56d 55d 25 46 trace 42 62 f

a

Microwave heating. bNMR yield. cConventional heating. dIsolated yield. eAn extra portion of KNCO (2 equiv) was added in 4 h. fA mixture of unidentified products.

8696

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

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The Journal of Organic Chemistry extra amounts of KNCO. Suspecting poor solubility of KNCO under studied conditions, we carried out experiments with 18crown-6 (entries 3−5); however, only modest yields of 2a were obtained at incomplete conversions of 1a, along with further drops in 2a yields at additional heating. Varying solvents and reaction temperatures did not provide enhancements in the 2a yield (entries 4−7). Since the obtained results pointed to reversibility, we carried out the reactions in the presence of Et3N·HCl (entries 8 and 9), which would protonate the intermediate anion A. Due to a high probability of KNCO decomposition under the studied conditions, an extra amount of KNCO was added in 4 h after initiation. In this case, the reaction afforded a 96% conversion of 1a and a 62% isolated yield of 2a (entry 9). A pilot experiment with a Lewis acid, MgBr2·OEt2, produced a mixture of unidentified products (entry 10). Consequently, the heating of 1a, KNCO (2 equiv), and Et3N·HCl (1 equiv) in DMF at 150 °C (with an extra amount of KNCO (2 equiv) in 4 h after initiation) was considered optimal for nucleophilic ring opening of 1a with NCO− (entry 9). Under the optimized conditions, spiro[cyclopropane-1,3′oxindoles] 1 were examined to assess compatibilities of substituents in spirooxindole and cyclopropane units (Scheme 3). A series of N-PMB-substituted cyclopropanes 1b−j (PMB = para-methoxybenzyl), containing both donor and acceptor groups in the cyclopropane aryl fragment, generally provided products 2b−i in good yields, despite harsh reaction conditions. Cyclopropanes 1b,c,i,j, containing electron-abun-

dant aryls, as well as their counterparts 1d,e with electrondeficient aryls, underwent nucleophilic ring opening with NCO− more efficiently (3−6 h) than their phenyl analogue 1a (10 h). The exception is para-NO2-substituted cyclopropane 1f, which did not produce the corresponding product 2f, undergoing complete decomposition in 2 h instead. αNaphthyl derivative 1h was the slowest to react, due to the ortho-bulkiness affecting the kinetics unfavorably. Its complete conversion was observed in 16 h, leading to significant tarring and, thus, decreasing the isolated yield of 2h down to 34%. 2Thienyl derivative 1k was also sufficiently tolerant toward harsh reaction conditions, affording 2k in 3 h with a 56% yield. The introduction of substituents in the benzene core of the oxindole moiety allowed for more significant manipulations of the reaction rate. Although 5-methyl derivative 1l underwent ring opening by NCO− with a rate similar to that for 1a, complete conversions of 5-halogen derivatives 1m−p were achieved in 100−120 min. Competitive reactions of two cyclopropanes 1l and 1p with KNCO allowed us to reveal that for 90 min, 95% conversion of the Br derivative 1p was achieved, whereas the Me derivative 1l exhibited only 18% conversion. This tendency is in accordance with results of our DFT calculations of SN2-like ring opening of 1 with NCO−: the replacement of H or Me by halogens leads to lowering of the corresponding energy barriers.19 Replacing the N-PMB group with a Me one (1q−u) did not influence the reaction times and the yields of the products 2q−u. The structure of 2r was unambiguously proved by single crystal X-ray analysis. The combination of N-unprotected pyrrolidone and Nprotected oxindole units in 2 allows for selective protection/ deprotection of both cyclic amides. The presence of the PMB N-protecting group in oxindole allowed for the deprotection of 2,20 producing doubly N-unprotected spiro[pyrrolidone-3,3′oxindoles] 3 (Scheme 4). The evolution of 2 can also be related to their selective reduction into the corresponding pyrrolidines.21

Scheme 3. Reaction Scope

Scheme 4. N-Deprotection of PMB Derivatives 2a,i,o

Preliminary in vitro tests of compounds 2 and 3 revealed their moderate antiproliferative activity toward HEK293T, MCF7, and A549 cell lines.19 In conclusion, we have demonstrated the use of the cyanate ion as a new N-nucleophile for DA cyclopropane ring opening. In comparison with the isoelectronic azide ion, the cyanate ion was found to be less reactive toward small ring opening that required a delicate trade-off between harsh reaction conditions and DA cyclopropane reactivity. Based on the obtained results, a method for nucleophilic ring opening of DA cyclopropanes, spiro-activated with oxindole, with the cyanate ion was developed. A series of cyclopropanes containing various substituents in the oxindole and cyclopropane units exhibited a good tolerance toward reaction conditions, ultimately 8697

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

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The Journal of Organic Chemistry

°C; E/Z = 85:15; Rf = 0.36 (E), 0.46 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1c: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 3.90 (s, 3H, CH3O), 4.95 (s, 2H, CH2), 6.77 (d, 3J = 7.6 Hz, 1H, Ar), 6.86 (d, 3J = 8.7 Hz, 2H, Ar), 6.88 (t, 3J = 7.6 Hz, 1H, Ar), 7.01 (d, 3J = 8.7 Hz, 2H, Ar), 7.16 (t, 3J = 7.6 Hz, 1H, Ar), 7.29 (d, 3J = 8.7 Hz, 2H, Ar), 7.68 (d, 3J = 8.7 Hz, 2H, Ar), 7.76 (d, 3J = 7.6 Hz, 1H, Ar), 7.88 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.2 (CH2), 55.2 (CH3O), 55.4 (CH3O), 109.1 (CH), 114.07 (2 × CH), 114.09 (2 × CH), 121.58 (C), 121.64 (CH), 122.4 (CH), 125.2 (C), 127.3 (C), 128.2 (C), 128.7 (2 × CH), 129.2 (CH), 131.4 (2 × CH), 137.7 (CH), 143.1 (C), 159.0 (C), 160.8 (C), 168.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H22NO3+ 372.1605, found 372.1594. 3-(4-Bromobenzylidene)-1-(4-methoxybenzyl)-1,3-dihydro-2Hindol-2-one (S1d). This compound was obtained from 4bromobenzaldehyde (322 mg, 1.74 mmol) and 1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (400 mg, 1.58 mmol): reaction time 3 h; yield 285 mg (43%); yellow solid, mp 166−167 °C; E/Z = 86:14; Rf = 0.54 (E), 0.66 (Z) (petroleum ether−ethyl acetate, 3:1). (E)S1d: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 4.94 (s, 2H, CH2), 6.77 (d, 3J = 7.6 Hz, 1H, Ar), 6.85−6.87 (m, 3H, Ar), 7.18 (td, 3J = 7.6, 4J = 1.1 Hz, 1H, Ar), 7.28−7.30 (m, 2H, Ar), 7.52−7.54 (m, 2H, Ar), 7.58 (d, 3J = 7.6 Hz, 1H, Ar), 7.60−7.62 (m, 2H, Ar), 7.81 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.2 (CH2), 55.2 (CH3O), 109.3 (CH), 114.1 (2 × CH), 120.9 (C), 121.8 (CH), 122.7 (CH), 123.7 (C), 127.6 (C), 127.9 (C), 128.7 (2 × CH), 130.0 (CH), 130.8 (2 × CH), 131.9 (2 × CH), 133.8 (C), 135.7 (CH), 143.4 (C), 159.0 (C), 168.2 (CO); HRMS (ESI) m/z [M + H]+ calcd for C23H19BrNO2+ 420.0594, found 420.0601. 4-{[1-(4-Methoxybenzyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl}benzonitrile (S1e). This compound was obtained from 4cyanobenzaldehyde (285 mg, 2.174 mmol) and 1-(4-methoxybenzyl)1,3-dihydro-2H-indol-2-one (500 mg, 1.976 mmol): reaction time 2 h; yield 343 mg (47%); orange solid, mp 171−172 °C; E/Z = 80:20; Rf = 0.39 (E), 0.48 (petroleum ether−ethyl acetate, 3:1). (E)-S1e: 1H NMR (600 MHz, CDCl3) δ 3.77 (s, 3H, CH3O), 4.92 (s, 2H, CH2), 6.78 (d, 3J = 7.8 Hz, 1H, Ar), 6.84−6.87 (m, 3H, Ar), 7.20 (t, 3J = 7.8 Hz, 1H, Ar), 7.29 (d, 3J = 8.5 Hz, 2H, Ar), 7.43 (d, 3J = 7.6, 1H, Ar), 7.73 (d, 3J = 8.3 Hz, 2H, Ar), 7.76 (d, 3J = 8.3 Hz, 2H, Ar), 7.82 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.2 (CH2), 55.2 (CH3O), 109.5 (CH), 112.7 (C), 114.1 (2 × CH), 118.3 (C), 120.4 (C), 121.9 (CH), 122.8 (CH), 127.7 (C), 128.6 (2 × CH), 129.3 (C), 129.6 (2 × CH), 130.6 (CH), 132.3 (2 × CH), 134.0 (CH), 139.7 (C), 143.8 (C), 159.0 (C), 167.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H19N2O2+ 367.1441, found 367.1452. 1-(4-Methoxybenzyl)-3-(4-nitrobenzylidene)-1,3-dihydro-2Hindol-2-one (S1f). This compound was obtained from 4-nitrobenzaldehyde (3.28 g, 21.7 mmol) and 1-(4-methoxybenzyl)-1,3dihydro-2H-indol-2-one (5 g, 19.8 mmol): reaction time 2 h; yield 4.30 g (56%); orange solid, mp 165−166 °C; E/Z = 73:27; Rf = 0.29 (E) (petroleum ether−ethyl acetate, 3:1). (E)-S1f: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 4.94 (s, 2H, CH2), 6.79 (d, 3J = 7.9 Hz, 1H, Ar), 6.84−6.88 (m, 3H, Ar), 7.20−7.23 (m, 1H, Ar), 7.28−7.30 (m, 2H, Ar), 7.43−7.45 (m, 1H, Ar), 7.79−7.82 (m, 1H, Ar), 7.86 (s, 1H, CH), 8.32−8.34 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 43.3 (CH2), 55.2 (CH3O), 109.6 (CH), 114.2 (2 × CH), 120.4 (C), 122.0 (CH), 122.9 (CH), 124.0 (2 × CH), 127.7 (C), 128.7 (2 × CH), 129.8 (C), 129.9 (2 × CH), 130.8 (CH), 133.5 (CH), 141.7 (C), 144.0 (C), 147.9 (C), 159.1 (C), 167.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for C23H19N2O4+ 387.1339, found 387.1342. 3-(Biphenyl-4-ylmethylidene)-1-(4-methoxybenzyl)-1,3-dihydro2H-indol-2-one (S1g). This compound was obtained from 4phenylbenzaldehyde (396 mg, 2.174 mmol) and 1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (500 mg, 1.976 mmol): reaction time 2.5 h; yield 460 mg (56%); yellow solid, mp 123−124 °C; E/Z = 81:19; Rf = 0.53 (E), 0.63 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1g: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 4.98 (s, 2H, CH2), 6.82 (d, 3J = 7.8 Hz, 1H, Ar), 6.90−6.93 (m, 3H, Ar), 7.21 (td, 3J = 7.7, 4J = 1.0 Hz, 1H, Ar), 7.35−7.37 (m, 2H, Ar), 7.43 (tt, 3J

affording spiro[pyrrolidone-3,3′-oxindoles] with the N-unprotected pyrrolidone unit.

■

EXPERIMENTAL SECTION

General Information. NMR spectra were acquired either on a Bruker Avance 400 MHz spectrometer or on a Bruker Avance 600 MHz spectrometer at room temperature; the chemical shifts (δ) were measured in ppm with respect to the solvent (1H CDCl3, δ = 7.27 ppm, DMSO-d6, δ = 2.50 ppm; 13C CDCl3, δ = 77.0 ppm, DMSO-d6, δ = 39.5 ppm). Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet. Coupling constants (J) are given in hertz. The structures of the synthesized compounds were elucidated with the aid of 1D (1H, 13C, APT, Gated 1H-Decoupling) and 2D (1H−1H COSY, 1H−13C HMBC) NMR spectroscopy. High resolution mass spectra (HRMS) were obtained using Thermo ScientificTM LTQ Orbitrap and AB Sciex TripleTOF 5600+ mass spectrometers with a TurboV ESI source. Single crystal X-ray analysis was performed with a Bruker SMART APEX II diffractometer. Crystallographic data were collected at 150 K using graphite monochromatized Mo Kα radiation (λ = 0.71073 A) using a ω-scan mode. Absorption corrections based on measurements of equivalent reflections were applied (APEX II). The structures were solved by direct methods and refined by full matrix least-squares on F2 with anisotropic thermal parameters for all nonhydrogen atoms. Melting points (mp) were determined using an Electrothermal IA 9100 capillary melting point apparatus. Microwave reactions were performed in a Monowave 300-Anton Paar microwave reactor in sealed reaction vessels. The temperature was monitored with an installed IR detector. Analytical thin layer chromatography (TLC) was carried out with silica gel plates (silica gel 60, F254, supported on aluminum) visualized with an ultraviolet lamp (254 nm). Column chromatography was performed on silica gel 60 (230− 400 mesh). General Procedure for the Synthesis of Alkenes S1. NaOH (158 mg, 3.95 mmol) was dissolved in a mixture of EtOH (7.9 mL) and water (7.9 mL). The corresponding 1-(4-methoxybenzyl)-1Hindole-2,3-dione or 1-methyl-1H-indole-2,3-dione (1.98 mmol) and aldehyde (2.18 mmol) were then added successively to the mixture under vigorous stirring. To ensure solubility of product under the reaction conditions, CH2Cl2 (ca. 20% of the initial solvent volume, 3 mL) was added. The reaction mixture was stirred vigorously at room temperature for the time specified. Then reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether−ethyl acetate). Spectral data for alkenes S1a,22 S1j,23 and S1q−u9a are consistent with those reported previously. 1-(4-Methoxybenzyl)-3-(4-methylbenzylidene)-1,3-dihydro-2Hindol-2-one (S1b). This compound was obtained from 4-methylbenzaldehyde (209 mg, 0.205 mL, 1.74 mmol) and 1-(4methoxybenzyl)-1,3-dihydro-2H-indol-2-one (400 mg, 1.58 mmol): reaction time 2 h; yield 362 mg (64%); yellow solid, mp 172−173 °C; E/Z = 84:16; Rf = 0.50 (E), 0.60 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1b: 1H NMR (600 MHz, CDCl3) δ 2.44 (s, 3H, CH3), 3.78 (s, 3H, CH3O), 4.95 (s, 2H, CH2), 6.76 (d, 3J = 7.9 Hz, 1H, Ar), 6.85−6.88 (m, 3H, Ar), 7.16 (t, 3J = 7.7 Hz, 1H, Ar), 7.29−7.31 (m, 4H, Ar), 7.60 (d, 3J = 7.8 Hz, 2H, Ar), 7.72 (d, 3J = 7.6 Hz, 1H, Ar), 7.92 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 21.5 (CH3), 43.2 (CH2), 55.2 (CH3O), 109.1 (CH), 114.1 (2 × CH), 121.4 (C), 121.7 (CH), 122.7 (CH), 126.3 (C), 128.1 (C), 128.7 (2 × CH), 129.3 (3 × CH), 129.4 (2 × CH), 132.0 (C), 137.8 (CH), 140.0 (C), 143.2 (C), 159.0 (C), 168.6 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H22NO2+ 356.1641, found 356.1645. 1-(4-Methoxybenzyl)-3-(4-methoxybenzylidene)-1,3-dihydro-2Hindol-2-one (S1c). This compound was obtained from 4-methoxybenzaldehyde (118 mg, 0.106 mL, 0.87 mmol) and 1-(4methoxybenzyl)-1,3-dihydro-2H-indol-2-one (200 mg, 0.79 mmol): reaction time 2.5 h; yield 181 mg (62%); yellow solid, mp 166−167 8698

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry = 7.4, 4J = 1.1 Hz, 1H, Ar), 7.49−7.52 (m, 2H, Ar), 7.70−7.72 (m, 2H, Ar), 7.73−7.75 (m, 2H, Ar), 7.79−7.80 (m, 2H, Ar), 7.82 (d, 3J = 7.6, 1H, Ar), 8.02 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.0 (CH2), 55.0 (CH3O), 109.0 (CH), 113.9 (2 × CH), 121.1 (C), 121.6 (CH), 123.0 (CH), 126.7 (C), 126.8 (2 × CH), 127.0 (2 × CH), 127.7 (CH), 127.9 (C), 128.5 (2 × CH), 128.7 (2 × CH), 129.5 (CH), 129.8 (2 × CH), 133.6 (C), 136.8 (CH), 139.8 (C), 142.1 (C), 143.2 (C), 158.8 (C), 168.3 (CO); HRMS (ESI) m/z [M + H]+ calcd for C29H24NO2+ 418.1802, found 418.1804. 1-(4-Methoxybenzyl)-3-(naphth-1-ylmethylidene)-1,3-dihydro2H-indol-2-one (S1h). This compound was obtained from 1naphthaldehyde (339 mg, 0.295 mL, 2.174 mmol) and 1-(4methoxybenzyl)-1,3-dihydro-2H-indol-2-one (500 mg, 1.976 mmol): reaction time 2 h; yield 598 mg (77%); yellow solid, mp 166−167 °C; E/Z = 97:3; Rf = 0.49 (E), 0.58 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1h: 1H NMR (600 MHz, CDCl3) δ 3.80 (s, 3H, CH3O), 5.00 (s, 2H, CH2), 6.72 (td, 3J = 7.7, 4J = 1.0 Hz, 1H, Ar), 6.78 (br d, 3 J = 7.8 Hz, 1H, Ar), 6.89−6.91 (m, 2H, Ar), 7.13 (td, 3J = 7.7, 4J = 1.1 Hz, 1H, Ar), 7.17−7.19 (m, 1H, Ar), 7.35−7.37 (m, 2H, Ar), 7.54−7.59 (m, 3H, Ar), 7.85 (dt, 3J = 7.1, 4J = 1.0 Hz, 1H, Ar), 7.94− 7.98 (m, 2H, Ar), 8.06−8.08 (m, 1H, Ar), 8.44 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.2 (CH2), 55.2 (CH3O), 109.1 (CH), 114.1 (2 × CH), 121.3 (C), 121.7 (CH), 123.1 (CH), 124.8 (CH), 125.1 (CH), 126.5 (CH), 126.7 (CH), 126.8 (CH), 128.1 (C), 128.6 (CH), 128.75 (2 × CH), 128.79 (C), 129.6 (CH), 129.9 (CH), 131.3 (C), 132.2 (C), 133.6 (C), 135.4 (CH), 143.4 (C), 159.0 (C), 168.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C27H22NO2+ 392.1645, found 392.1650. 3-(1,3-Benzodioxol-5-ylmethylidene)-1-(4-methoxybenzyl)-1,3dihydro-2H-indol-2-one (S1i). This compound was obtained from 3,4-(methylenedioxy)benzaldehyde (261 mg, 1.739 mmol) and 1-(4methoxybenzyl)-1,3-dihydro-2H-indol-2-one (400 mg, 1.581 mmol): reaction time 3 h; yield 215 mg (35%); yellow solid, mp 159−160 °C; E/Z = 78:22; Rf = 0.47 (E), 0.56 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1i: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 4.94 (s, 2H, CH2), 6.06 (s, 2H, OCH2O), 6.76 (d, 3J = 7.6 Hz, 1H, Ar), 6.85−6.96 (m, 2H, Ar), 6.88−6.92 (m, 2H, Ar), 7.15−7.19 (m, 2H, Ar), 7.22−7.24 (m, 1H, Ar), 7.27−7.29 (m, 2H, Ar), 7.76−7.77 (m, 1H, Ar), 7.82 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.2 (CH2), 55.2 (CH3O), 101.5 (OCH2O), 108.6 (CH), 109.1 (CH), 109.4 (CH), 114.1 (2 × CH), 121.3 (C), 121.7 (CH), 122.6 (CH), 124.7 (CH), 125.7 (C), 128.1 (C), 128.7 (2 × CH), 128.8 (C), 129.4 (CH), 137.5 (CH), 143.2 (C), 147.9 (C), 148.9 (C), 159.0 (C), 168.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H20NO4+ 386.1387, found 386.1392. 1-(4-Methoxybenzyl)-3-(thien-2-ylmethylidene)-1,3-dihydro-2Hindol-2-one (S1k). This compound was obtained from 2-thiophenecarboxaldehyde (244 mg, 0.205 mL, 2.174 mmol) and 1-(4methoxybenzyl)-1,3-dihydro-2H-indol-2-one (500 mg, 1.976 mmol): reaction time 2.5 h; yield 569 mg (83%); brown oil; E/Z = 63:37; Rf = 0.48 (E), 0.59 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1k: 1H NMR (600 MHz, CDCl3) δ 3.69 (s, 3H, CH3O), 4.90 (s, 2H, CH2), 6.76 (d, 3J = 7.8 Hz, 1H, Ar), 6.82−6.84 (m, 2H, Ar), 6.98−7.01 (m, 1H, Ar), 7.10−7.11 (m, 1H, Ar), 7.15−7.17 (m, 1H, Ar), 7.27−7.28 (m, 2H, Ar), 7.51−7.52 (m, 1H, Ar), 7.54−7.55 (m, 1H, Ar), 8.02 (s, 1H, CH), 8.22 (d, 3J = 7.7 Hz, 1H, Ar); 13C NMR (150 MHz, CDCl3) δ 42.8 (CH2), 54.7 (CH3O), 108.7 (CH), 113.7 (2 × CH), 120.7 (C), 121.5 (CH), 122.9 (C), 123.1 (CH), 127.7 (CH), 127.8 (C), 128.1 (CH), 128.3 (2 × CH), 129.0 (CH), 130.3 (CH), 134.3 (CH), 137.4 (C), 142.6 (C), 158.6 (C), 168.6 (CO); HRMS (ESI) m/z [M + H]+ calcd for C21H18NO2S+ 348.1053, found 348.1050. 3-Benzylidene-5-methyl-1-(4-methoxybenzyl)-1,3-dihydro-2Hindol-2-one (S1l). This compound was obtained from benzaldehyde (3.5 g, 3.4 mL, 33 mmol) and 5-methyl-1-(4-methoxybenzyl)-1,3dihydro-2H-indol-2-one (8.01 g, 30 mmol): reaction time 2.5 h; yield 5.19 g (58%); yellow foam; E/Z = 85:15; Rf = 0.43 (E), 0.51 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1l: 1H NMR (600 MHz, CDCl3) δ 2.20 (CH3), 3.73 (s, 3H, CH3O), 4.92 (s, 2H, CH2), 6.67 (br d, 3J = 7.8 Hz, 1H, Ar), 6.86−6.88 (m, 2H, Ar), 6.96−6.98 (m, 1H, Ar), 7.31−7.33 (m, 2H, Ar), 7.43−7.45 (m, 1H, Ar), 7.46−7.49

(m, 2H, Ar), 7.51−7.52 (m, 1H, Ar), 7.68−7.70 (m, 2H, Ar), 7.96 (br s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 20.78 (CH3), 42.8 (CH2), 54.75 (CH3O), 108.6 (CH), 113.8 (2 × CH), 120.9 (C), 123.1 (CH), 127.0 (C), 127.91 (CH), 127.93 (C), 128.3 (2 × CH), 128.37 (2 × CH), 129.0 (2 × CH), 129.8 (CH), 130.7 (C), 134.7 (C), 136.6 (CH), 140.9 (C), 158.7 (C), 168.1 (CO). (Z)-S1l: 1H NMR (600 MHz, CDCl3) δ 2.36 (CH3), 3.72 (s, 3H, CH3O), 4.90 (s, 2H, CH2), 6.65 (br d, 3J = 7.6 Hz, 1H, Ar), 6.84−6.87 (m, 2H, Ar), 6.98−7.00 (m, 1H, Ar), 7.30−7.32 (m, 2H, Ar), 7.35−7.36 (m, 1H, Ar), 7.42−7.44 (m, 3H, Ar), 7.46−7.49 (m, 2H, Ar), 7.54 (br s, 1H, CH), 8.40−8.42 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 20.81 (CH3), 42.6 (CH2), 54.74 (CH3O), 108.2 (CH), 113.7 (2 × CH), 119.4 (CH), 124.1 (C), 125.8 (C), 128.1 (C), 128.41 (2 × CH), 128.9 (CH), 129.2 (2 × CH), 130.1 (CH), 130.8 (C), 131.8 (2 × CH), 133.6 (C), 136.5 (CH), 139.0 (C), 158.6 (C), 165.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H22NO2+ 356.1645, found 356.1651. 3-Benzylidene-5-fluoro-1-(4-methoxybenzyl)-1,3-dihydro-2Hindol-2-one (S1m). This compound was obtained from benzaldehyde (2.16 g, 2.1 mL, 20.4 mmol) and 5-fluoro-1-(4-methoxybenzyl)-1,3dihydro-2H-indol-2-one (5 g, 18.5 mmol): reaction time 2.5 h; yield 3.45 g (52%); yellow foam; E/Z = 90:10; Rf = 0.45 (E), 0.58 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1m: 1H NMR (600 MHz, CDCl3) δ 3.79 (s, 3H, CH3O), 4.93 (s, 2H, CH2), 6.66 (dd, 3J = 8.5, 4 J = 4.3 Hz, 1H, Ar), 6.85−6.89 (m, 3H, Ar), 7.27−7.29 (m, 2H, Ar), 7.35 (dd, 3J = 9.0, 4J = 2.5 Hz, 1H, Ar), 7.45−7.52 (m, 3H, Ar), 7.63− 7.65 (m, 2H, Ar), 7.99 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.3 (CH2), 55.2 (CH3O), 109.5 (3JCF = 8 Hz, CH), 110.4 (2JCF = 26 Hz, CH), 114.2 (2 × CH), 115.8 (2JCF = 24 Hz, CH), 122.3 (3JCF = 9 Hz, C), 126.8 (4JCF = 3 Hz, C), 127.8 (C), 128.7 (2 × CH), 128.8 (2 × CH), 129.1 (2 × CH), 129.9 (CH), 134.5 (C), 138.9 (CH), 139.4 (C), 158.4 (1JCF = 239 Hz, C), 159.1 (C), 168.3 (CO); HRMS (ESI) m/z [M + H]+ calcd for C23H19FNO2+ 360.1394, found 360.1401. Ethyl 4-{[5-Fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-3Hindol-3-ylidene]methyl}benzoate (S1n). This compound was obtained from methyl 4-formylbenzoate (3.54 g, 21.6 mmol) and 5fluoro-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (5.32 g, 19.6 mmol): reaction time 2 h; transesterification of the methyl ester into the ethyl one under the reaction conditions; yield 3.13 g (37%); orange solid, mp 145−146 °C; E/Z = 81:19; Rf = 0.25 (E), 0.35 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1n: 1H NMR (600 MHz, CDCl3) δ 1.44 (t, 3J = 7.2 Hz, 3H, CH3), 3.79 (s, 3H, CH3O), 4.44 (q, 3J = 7.2 Hz, 2H, CH2O), 4.92 (s, 2H, CH2), 6.66 (dd, 3J = 8.5, 4J = 4.3 Hz, 1H, Ar), 6.85−6.90 (m, 3H, Ar), 7.24 (dd, 3J = 8.9, 4J = 2.6 Hz, 1H, Ar), 7.25−7.28 (m, 3H, Ar), 7.68−7.70 (m, 2H, Ar), 7.96 (s, 1H, CH), 8.16−8.18 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 14.3 (CH3), 43.4 (CH2), 55.2 (CH3O), 61.3 (CH2O), 109.8 (3JCF = 8 Hz, CH), 110.6 (2JCF = 26 Hz, CH), 114.2 (2 × CH), 116.4 (2JCF = 24 Hz, CH), 121.8 (3JCF = 9 Hz, C), 127.6 (C), 128.2 (4JCF = 3 Hz, C), 128.7 (2 × CH), 129.0 (2 × CH), 130.0 (2 × CH), 131.4 (C), 137.2 (CH), 138.9 (C), 139.7 (C), 158.4 (1JCF = 239 Hz, C), 159.1 (C), 165.9 (CO), 167.9 (CO); HRMS (ESI) m/z [M + H]+ calcd for C26H23FNO4+ 432.1606, found 432.1613. 3-Benzylidene-5-chloro-1-(4-methoxybenzyl)-1,3-dihydro-2Hindol-2-one (S1o). This compound was obtained from benzaldehyde (2.16 g, 2.1 mL, 20.4 mmol) and 5-chloro-1-(4-methoxybenzyl)-1,3dihydro-2H-indol-2-one (5.33 g, 18.5 mmol): reaction time 2.5 h; yield 4.25 g (61%); yellow foam; E/Z = 88:12; Rf = 0.44 (E), 0.56 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1o: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 4.93 (s, 2H, CH2), 6.67 (d, 3J = 8.4 Hz, 1H, Ar), 6.86−6.88 (m, 2H, Ar), 7.13 (dd, 3J = 8.4, 4J = 2.1 Hz, 1H, Ar), 7.26−7.27 (m, 2H, Ar), 7.46−7.52 (m, 3H, Ar), 7.60 (br d, 2 J = 2.1 Hz, 1H, Ar), 7.64−7.66 (m, 2H, Ar), 7.98 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.3 (CH2), 55.2 (CH3O), 110.0 (CH), 114.2 (2 × CH), 122.6 (C), 122.8 (CH), 126.2 (C), 127.1 (C), 127.6 (C), 128.6 (2 × CH), 128.8 (2 × CH), 129.2 (2 × CH), 129.3 (CH), 130.0 (CH), 134.4 (C), 139.1 (CH), 141.8 (C), 159.1 (C), 168.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C23H19ClNO2+ 376.1099, found 376.1105. 8699

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry 3-Benzylidene-5-bromo-1-(4-methoxybenzyl)-1,3-dihydro-2Hindol-2-one (S1p). This compound was obtained from benzaldehyde (2.16 g, 2.1 mL, 20.4 mmol) and 5-bromo-1-(4-methoxybenzyl)-1,3dihydro-2H-indol-2-one (6.14 g, 18.5 mmol): reaction time 2.5 h; yield 3.77 g (49%); yellow foam; E/Z = 95:5; Rf = 0.35 (E), 0.44 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1p: 1H NMR (600 MHz, CDCl3) δ 3.79 (s, 3H, CH3O), 4.93 (s, 2H, CH2), 6.63 (d, 3J = 8.4 Hz, 1H, Ar), 6.86−6.87 (m, 2H, Ar), 7.25−7.27 (m, 3H, Ar), 7.48− 7.53 (m, 3H, Ar), 7.64−7.66 (m, 2H, Ar), 7.75 (br d, 2J = 1.9 Hz, 1H, Ar), 7.97 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.3 (CH2), 55.3 (CH3O), 110.5 (CH), 114.2 (2 × CH), 114.5 (C), 123.1 (C), 125.6 (CH), 126.1 (C), 127.6 (C), 128.7 (2 × CH), 128.8 (2 × CH), 129.2 (2 × CH), 130.1 (CH), 132.1 (CH), 134.4 (C), 139.2 (CH), 142.2 (C), 159.1 (C), 168.0 (CO); HRMS (ESI) m/z [M + H]+ calcd for C23H19BrNO2+ 420.0594, found 420.0599. General Procedure for the Synthesis of Cyclopropanes 1. Trimethylsulfoxonium iodide (660 mg, 3.00 mmol, 2.0 equiv) was added to a suspension of NaH (120 mg, 3.00 mmol, 2.0 equiv) in anhydrous DMF (2.5 mL) under an argon atmosphere. The resulting suspension was stirred for 20 min, and then a solution of alkene S1 (1.50 mmol, 1.0 equiv) in DMF (15 mL) was added in one portion. The reaction mixture was stirred at room temperature for the time specified. The resulting mixture was poured into 30 mL of ice water and extracted with EtOAc (3 × 30 mL). Combined organic layers were washed with brine (5 × 15 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether−ethyl acetate). Spectral data for cyclopropanes 1q−u9a are consistent with those reported previously. 1′-(4-Methoxybenzyl)-2-phenylspiro[cyclopropane-1,3′-indol]2′(1′H)-one (1a). This compound was obtained from S1a (550 mg, 1.61 mmol): reaction time 2 h; yield 500 mg (87%); yellowish foam; dr 70:30; Rf = 0.83 (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.05 (dd, 2J = 4.5, 3J = 7.9 Hz, 1H, CH2, A), 2.13 (dd, 2J = 4.9, 3J = 9.1 Hz, 1H, CH2, B), 2.28 (dd, 2J = 4.5, 3J = 9.4 Hz, 1H, CH2, A), 2.49 (dd, 2J = 4.9, 3J = 8.7 Hz, 1H, CH2, B), 3.20 (dd, 3J = 9.1 3J = 8.7 Hz, 1H, CH, B), 3.42 (dd, 3J = 9.4, 3J = 7.9 Hz, 1H, CH, A), 3.77 (s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.81 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.84 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.95 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.02 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.97 (dd, 3J = 7.6, 4J = 0.8 Hz, 1H, Ar, A), 6.65−6.68 (m, 1H, Ar, A), 6.80−6.84 (m, 2H + 1H, Ar, A, B), 6.88−6.90 (m, 2H, Ar, A), 6.98−6.99 (m, 1H, Ar, B), 7.04−7.07 (m, 1H + 1H, Ar, A, B), 7.18− 7.22 (m, 3H + 1H, Ar, A, B), 7.26−7.37 (m, 3H + 9H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 22.6 (CH2), 33.2 (C), 36.0 (CH), 43.6 (CH2), 55.22 (CH3O), 108.72 (CH), 114.1 (2 × CH), 120.7 (CH), 121.4 (CH), 126.4 (CH), 127.4 (CH), 127.5 (C), 128.32 (C), 128.34 (2 × CH), 128.7 (2 × CH), 129.9 (2 × CH), 135.1 (C), 142.9 (C), 159.0 (C), 176.5 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.3 (CH2), 33.8 (C), 38.4 (CH), 43.3 (CH2), 55.18 (CH3O), 108.73 (CH), 114.0 (2 × CH), 118.1 (CH), 121.8 (CH), 126.6 (CH), 127.2 (CH), 127.9 (2 × CH), 128.5 (C), 128.8 (2 × CH), 129.3 (2 × CH), 130.8 (C), 134.4 (C), 142.5 (C), 158.9 (C), 173.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H22NO2+ 356.1645, found 356.1630. 1′-(4-Methoxybenzyl)-2-(p-tolyl)spiro[cyclopropane-1,3′-indol]2′(1′H)-one (1b). This compound was obtained from S1b (310 mg, 0.873 mmol): reaction time 2 h; yield 250 mg (76%); yellow oil; dr 72:28; Rf = 0.58 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.12 (dd, 2J = 4.4, 3J = 7.9 Hz, 1H, CH2, A), 2.17 (dd, 2J = 4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.36 (dd, 2J = 4.4, 3J = 9.2 Hz, 1H, CH2, A), 2.42 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.56 (dd, 2J = 4.9, 3 J = 8.6 Hz, 1H, CH2, B), 3.25 (dd, 3J = 9.0, 3J = 8.6 Hz, 1H, CH, B), 3.50 (dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH, A), 3.81 (s, 3H, CH3O, B), 3.83 (s, 3H, CH3O, A), 4.92 (d, 2J = 15.7 Hz, 1H, CH2, B), 4.95 (d, 2J = 15.7 Hz, 1H, CH2, B), 5.04 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.11 (d, 2 J = 15.4 Hz, 1H, CH2, A), 6.15 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.75− 6.78 (m, 1H, Ar, A), 6.90−6.93 (m, 2H + 1H, Ar, A, B), 6.97−6.98 (m, 2H, Ar, A), 7.03−7.04 (m, 1H, Ar, B), 7.11−7.15 (m, 1H + 1H, Ar, A, B), 7.19−7.20 (m, 2H + 5H, Ar, A, B), 7.24−7.26 (m, 1H, Ar,

A), 7.28−7.29 (m, 2H, Ar, B), 7.34−7.36 (m, 2H, Ar, B), 7.40−7.41 (m, 2H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 20.9 (1JCH = 125 Hz, CH3), 22.4 (1JCH = 165 Hz, CH2), 33.0 (C), 35.7 (1JCH = 165 Hz, CH), 43.3 (1JCH = 139 Hz, CH2), 54.90 (1JCH = 144 Hz, CH3O), 108.47 (CH), 113.9 (2 × CH), 120.5 (CH), 121.2 (CH), 126.2 (CH), 127.4 (C), 128.1 (C), 128.4 (2 × CH), 128.8 (2 × CH), 129.5 (2 × CH), 131.7 (C), 136.7 (C), 142.7 (C), 158.8 (C), 176.3 (CO). B: 13C NMR (150 MHz, CDCl3) δ 21.0 (1JCH = 125 Hz, CH3), 22.1 (1JCH = 165 Hz, CH2), 33.6 (C), 38.1 (1JCH = 162 Hz, CH), 43.0 (1JCH = 139 Hz, CH2), 54.87 (1JCH = 144 Hz, CH3O), 108.49 (CH), 113.7 (2 × CH), 117.9 (CH), 121.6 (CH), 126.3 (CH), 128.3 (C), 128.4 (2 × CH), 128.5 (2 × CH), 128.9 (2 × CH), 130.6 (C), 131.1 (C), 136.5 (C), 142.2 (C), 158.7 (C), 173.5 (CO); HRMS (ESI) m/ z [M + H]+ calcd for C25H24NO2+ 370.1802, found 370.1795. 1′-(4-Methoxybenzyl)-2-(4-methoxyphenyl)spiro[cyclopropane1,3′-indol]-2′(1′H)-one (1c). This compound was obtained from S1c (1.02 g, 3.85 mmol): reaction time 2.5 h; yield 0.90 g (84%); yellow viscous oil; dr 68:32; Rf = 0.59 (petroleum ether−ethyl acetate, 1:1); 1 H NMR (600 MHz, CDCl3) δ 2.04 (dd, 2J = 4.4, 3J = 8.0 Hz, 1H, CH2, A), 2.12 (dd, 2J = 4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.31 (dd, 2J = 4.4, 3J = 9.2 Hz, 1H, CH2, A), 2.49 (dd, 2J = 4.9, 3J = 8.5 Hz, 1H, CH2, B), 3.18 (dd, 3J = 9.0 3J = 8.5 Hz, 1H, CH, B), 3.42 (dd, 3J = 9.2, 3J = 8.0 Hz, 1H, CH, A), 3.75 (s, 3H, CH3O, B), 3.78 (s, 3H, CH3O, A), 3.79 (s, 3H, CH3O, A), 3.81 (s, 3H, CH3O, B), 4.84 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.88 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.99 (d, 2 J = 15.4 Hz, 1H, CH2, A), 5.05 (d, 2J = 15.4 Hz, 1H, CH2, A), 6.08 (br d, 3J = 7.4 Hz, 1H, Ar, A), 6.70−6.73 (m, 1H, Ar, A), 6.84−6.90 (m, 3H + 3H, Ar, A, B), 6.91−6.94 (m, 2H + 2H, Ar, A, B), 6.98− 6.99 (m, 1H, Ar, B), 7.05−7.08 (m, 1H, Ar, B), 7.07−7.10 (m, 1H, Ar, A), 7.16−7.17 (m, 2H, Ar, A), 7.19−7.22 (m, 1H, Ar, B), 7.22− 7.24 (m, 2H, Ar, B), 7.31−7.33 (m, 2H, Ar, B), 7.35−7.36 (m, 2H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 22.6 (CH2), 33.1 (C), 35.4 (CH), 43.3 (CH2), 54.85 (CH3O), 54.88 (CH3O), 108.4 (CH), 113.5 (2 × CH), 113.9 (2 × CH), 120.5 (CH), 121.2 (CH), 126.1 (CH), 126.8 (C), 127.3 (C), 128.2 (C), 128.4 (2 × CH), 130.7 (2 × CH), 142.7 (C), 158.6 (C), 158.8 (C), 176.2 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.1 (CH2), 33.6 (C), 38.0 (CH), 42.9 (CH2), 54.8 (CH3O), 54.85 (CH3O), 108.4 (CH), 113.1 (2 × CH), 113.7 (2 × CH), 117.8 (CH), 121.6 (CH), 126.3 (CH), 128.3 (C), 128.5 (2 × CH), 128.6 (C), 130.1 (2 × CH), 130.6 (C), 142.1 (C), 158.4 (C), 158.7 (C), 173.5 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H24NO3+ 386.1751, found 386.1759. 2-(4-Bromophenyl)-1′-(4-methoxybenzyl)spiro[cyclopropane1,3′-indol]-2′(1′H)-one (1d). This compound was obtained from S1d (413 mg, 0.983 mmol): reaction time 3 h; yield 231 mg (54%); yellow solid, mp 123−124 °C; dr 60:40; Rf = 0.66 (petroleum ether− ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.00 (dd, 2J = 4.6, 3 J = 7.9 Hz, 1H, CH2, A), 2.13 (dd, 2J = 5.0, 3J = 9.0 Hz, 1H, CH2, B), 2.30 (dd, 2J = 4.6, 3J = 9.2 Hz, 1H, CH2, A), 2.45 (dd, 2J = 5.0, 3J = 8.5 Hz, 1H, CH2, B), 3.13 (dd, 3J = 9.0, 3J = 8.5 Hz, 1H, CH, B), 3.35 (dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH, A), 3.76 (s, 3H, CH3O, B), 3.78 (s, 3H, CH3O, A), 4.82 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.85 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.96 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.04 (d, 2J = 15.5 Hz, 1H, CH2, A), 6.03 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.72−6.74 (m, 1H, Ar, A), 6.84−6.89 (m, 2H + 2H, Ar, A, B), 6.90−6.92 (m, 2H, Ar, A), 6.98−6.99 (m, 1H, Ar, B), 7.05−7.08 (m, 1H, Ar, B), 7.09−7.11 (m, 2H + 2H, Ar, A, B), 7.20−7.22 (m, 2H, Ar, B), 7.23− 7.25 (m, 2H, Ar, B), 7.33−7.34 (m, 2H, Ar, A), 7.44−7.45 (m, 2H, Ar, A), 7.46−7.48 (m, 2H, Ar, B). A: 13C NMR (150 MHz, CDCl3) δ 22.2 (1JCH = 165 Hz, CH2), 32.9 (C), 35.0 (1JCH = 165 Hz, CH), 43.4 (1JCH = 139 Hz, CH2), 54.99 (1JCH = 144 Hz, CH3O), 108.71 (CH), 114.0 (2 × CH), 120.5 (CH), 121.2 (C), 121.4 (CH), 126.5 (CH), 126.8 (C), 128.0 (C), 128.3 (C), 128.5 (2 × CH), 131.3 (2 × CH), 131.4 (2 × CH), 134.0 (C), 142.7 (C), 158.8 (C), 176.0 (CO). B: 13 C NMR (150 MHz, CDCl3) δ 22.0 (1JCH = 165 Hz, CH2), 33.6 (C), 37.4 (1JCH = 165 Hz, CH), 43.1 (1JCH = 139 Hz, CH2), 54.97 (1JCH = 144 Hz, CH3O), 108.68 (CH), 113.8 (2 × CH), 118.0 (CH), 121.0 (C), 121.8 (CH), 126.7 (CH), 128.1 (C), 128.6 (2 × CH), 130.2 (C), 130.78 (2 × CH), 130.80 (2 × CH), 131.2 (C), 133.3 (C), 8700

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry 142.2 (C), 158.7 (C), 173.3 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H21BrNO2+ 434.0750, found 434.0768. 4-[1′-(4-Methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]benzonitrile (1e). This compound was obtained from S1e (291 mg, 0.795 mmol): reaction time 2 h; yield 250 mg (83%); beige solid, mp 136−137 °C; dr 58:42; Rf = 0.31 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.03 (dd, 2J = 4.7, 3J = 7.8 Hz, 1H, CH2, A), 2.15 (dd, 2J = 5.2, 3J = 8.8 Hz, 1H, CH2, B), 2.30 (dd, 2J = 4.7, 3J = 9.1 Hz, 1H, CH2, A), 2.44 (dd, 2J = 5.2, 3J = 8.4 Hz, 1H, CH2, B), 3.17 (dd, 3J = 8.8, 3J = 8.4 Hz, 1H, CH, B), 3.38 (dd, 3J = 9.1, 3J = 7.8 Hz, 1H, CH, A), 3.70 (s, 3H, CH3O, B), 3.72 (s, 3H, CH3O, A), 4.76 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.80 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.93 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.00 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.96 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.67−6.70 (m, 1H, Ar, A), 6.80−6.81 (m, 2H, Ar, B), 6.85−6.87 (m, 4H, Ar, A), 6.92−6.99 (m, 1H, Ar, B), 7.03−7.08 (m, 1H + 1H, Ar, A, B), 7.16−7.20 (m, 3H, Ar, B), 7.29−7.32 (m, 3H + 1H, Ar, A, B), 7.42−7.43 (m, 2H, Ar, B), 7.54−7.57 (m, 2H + 2H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 21.5 (1JCH = 165 Hz, CH2), 33.0 (C), 35.0 (1JCH = 166 Hz, CH), 43.2 (1JCH = 139 Hz, CH2), 54.75 (1JCH = 144 Hz, CH3O), 108.7 (CH), 110.7 (C), 113.8 (2 × CH), 118.3 (C), 120.1 (CH), 121.2 (CH), 126.0 (C), 126.6 (CH), 127.7 (C), 128.32 (2 × CH), 130.3 (2 × CH), 131.7 (2 × CH), 140.3 (C), 142.6 (C), 158.7 (C), 175.3 (CO). B: 13C NMR (150 MHz, CDCl3) δ 21.7 (1JCH = 165 Hz, CH2), 33.9 (C), 37.0 (1JCH = 163 Hz, CH), 42.9 (1JCH = 139 Hz, CH2), 54.73 (1JCH = 144 Hz, CH3O), 108.6 (CH), 110.3 (C), 113.6 (2 × CH), 118.1 (CH), 118.6 (C), 121.8 (CH), 126.8 (CH), 127.8 (C), 128.33 (2 × CH), 129.5 (C), 129.7 (2 × CH), 131.1 (2 × CH), 139.8 (C), 142.1 (C), 158.6 (C), 172.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H21N2O2+ 381.1598, found 381.1598. 1′-(4-Methoxybenzyl)-2-(4-nitrophenyl)spiro[cyclopropane-1,3′indol]-2′(1′H)-one (1f). This compound was obtained from S1f (830 mg, 2.2 mmol): reaction time 2 h; yield 675 mg (77%); yellow foam; dr 72:28; Rf = 0.33 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.07 (dd, 2J = 4.8, 3J = 8.0 Hz, 1H, CH2, A), 2.22 (dd, 2J = 5.2, 3J = 8.9 Hz, 1H, CH2, B), 2.35 (dd, 2J = 4.8, 3J = 9.1 Hz, 1H, CH2, A), 2.50 (dd, 2J = 5.2, 3J = 8.5 Hz, 1H, CH2, B), 3.22 (dd, 3J = 8.9, 3J = 8.5 Hz, 1H, CH, B), 3.41 (dd, 3J = 9.1, 3J = 8.0 Hz, 1H, CH, A), 3.76 (s, 3H, CH3O, B), 3.79 (s, 3H, CH3O, A), 4.79 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.82 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.94 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.03 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.95 (br d, 3J = 7.6 Hz, 1H, Ar, A), 6.68−6.70 (m, 1H, Ar, A), 6.81−6.83 (m, 2H, Ar, B), 6.85−6.87 (m, 1H + 1H, Ar, A, B), 6.87− 6.90 (m, 2H, Ar, A), 7.00−7.02 (m, 1H, Ar, B), 7.06−7.10 (m, 1H + 1H, Ar, A, B), 7.15−7.18 (m, 2H, Ar, B), 7.20−7.23 (m, 1H, Ar, B), 7.28−7.32 (m, 2H, Ar, A), 7.37−7.39 (m, 2H, Ar, A), 7.50−7.52 (m, 2H, Ar, B), 8.16−8.19 (m, 2H + 2H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 22.1 (CH2), 33.3 (C), 35.0 (CH), 43.6 (CH2), 55.13 (CH3O), 109.1 (CH), 114.1 (2 × CH), 120.3 (CH), 121.6 (CH), 123.5 (2 × CH), 126.2 (C), 127.0 (CH), 128.0 (C), 128.6 (2 × CH), 130.7 (2 × CH), 142.8 (C), 143.0 (C), 147.0 (C), 159.0 (C), 175.6 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.2 (CH2), 34.3 (C), 37.0 (CH), 43.3 (CH2), 55.11 (CH3O), 109.0 (CH), 114.0 (2 × CH), 118.3 (CH), 122.0 (CH), 122.1 (CH), 123.0 (2 × CH), 128.0 (C), 128.7 (2 × CH), 129.7 (C), 130.1 (2 × CH), 142.2 (C), 142.5 (C), 146.8 (C), 158.9 (C), 173.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H21N2O4+ 401.1496, found 401.1501. 2-([1,1′-Biphenyl]-4-yl)-1′-(4-methoxybenzyl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one (1g). This compound was obtained from S1g (395 mg, 0.947 mmol): reaction time 2.5 h; yield 320 mg (78%); light yellow solid, mp 158−160 °C; dr 65:35; Rf = 0.43 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.18 (dd, 2J = 4.5, 3J = 7.9 Hz, 1H, CH2, A), 2.22 (dd, 2J = 4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.42 (dd, 2J = 4.5, 3J = 9.2 Hz, 1H, CH2, A), 2.63 (dd, 2J = 4.9, 3J = 8.6 Hz, 1H, CH2, B), 3.30 (dd, 3J = 9.0, 3J = 8.6 Hz, 1H, CH, B), 3.58 (dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH, A), 3.80 (s, 3H, CH3O, B), 3.84 (s, 3H, CH3O, A), 4.91 (d, 2J = 15.7 Hz, 1H, CH2, B), 4.94 (d, 2J = 15.7 Hz, 1H, CH2, B), 5.07 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.13 (d, 2J = 15.4 Hz, 1H, CH2, A), 6.22 (br d,

3

J = 7.6 Hz, 1H, Ar, A), 6.76−6.79 (m, 1H, Ar, A), 6.91−6.95 (m, 1H + 3H, Ar, A, B), 6.98−7.01 (m, 2H, Ar, A), 7.06 (d, 3J = 7.4 Hz, 1H, Ar, B), 7.13−7.17 (m, 1H + 1H, Ar, A, B), 7.28−7.31 (m, 1H + 1H, Ar, A, B), 7.36−7.41 (m, 2H, Ar, A), 7.42−7.45 (m, 2H + 3H, Ar, A, B), 7.51−7.55 (m, 2H + 4H, Ar, A, B), 7.64−7.68 (m, 2H, Ar, A), 7.69−7.71 (m, 1H + 4H, Ar, A, B), 7.73 (d, 3J = 7.8 Hz, 1H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 22.4 (1JCH = 165 Hz, CH2), 33.1 (C), 35.6 (1JCH = 166 Hz, CH), 43.4 (1JCH = 139 Hz, CH2), 54.91 (1JCH = 144 Hz, CH3O), 108.57 (CH), 113.9 (2 × CH), 120.6 (CH), 121.3 (CH), 126.30 (CH), 126.33 (CH), 126.68 (2 × CH), 126.72 (2 × CH), 127.17 (C), 128.1 (C), 128.48 (2 × CH), 128.6 (2 × CH), 130.1 (2 × CH), 133.9 (C), 139.8 (C), 140.2 (C), 142.7 (C), 158.8 (C), 176.1 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.2 (1JCH = 165 Hz, CH2), 33.9 (C), 38.1 (1JCH = 163 Hz, CH), 43.0 (1JCH = 139 Hz, CH2), 54.87 (1JCH = 144 Hz, CH3O), 108.56 (CH), 113.8 (2 × CH), 118.0 (CH), 121.7 (CH), 126.5 (CH), 126.8 (2 × CH), 126.9 (CH), 127.15 (2 × CH), 128.2 (C), 128.45 (2 × CH), 128.6 (2 × CH), 129.5 (2 × CH), 130.5 (C), 133.3 (C), 139.6 (C), 140.6 (C), 142.2 (C), 158.7 (C), 173.4 (CO); HRMS (ESI) m/z [M + H]+ calcd for C30H26NO2+ 432.1958, found 432.1952. 1′-(4-Methoxybenzyl)-2-(naphthalen-1-yl)spiro[cyclopropane1,3′-indol]-2′(1′H)-one (1h). This compound was obtained from S1h (570 mg, 1.46 mmol): reaction time 2.5 h; yield 540 mg (91%); orange solid, mp 137−138 °C; dr 86:14; Rf = 0.45 (petroleum ether− ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.25 (dd, 2J = 4.6, 3 J = 8.8 Hz, 1H, CH2, B), 2.30 (dd, 2J = 4.5, 3J = 8.0 Hz, 1H, CH2, A), 2.54 (dd, 2J = 4.6, 3J = 9.0 Hz, 1H, CH2, A), 2.68 (dd, 2J = 4.7, 3J = 8.5 Hz, 1H, CH2, B), 3.49 (dd, 3J = 8.8, 3J = 8.5 Hz, 1H, CH, B), 3.74 (s, 3H, CH3O, B), 3.77 (dd, 3J = 9.0, 3J = 8.0 Hz, 1H, CH, A), 3.80 (s, 3H, CH3O, A), 4.45 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.92 (d, 2J = 15.4 Hz, 1H, CH2, A), 4.96 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.31 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.97 (dd, 3J = 7.6, 4J = 0.8 Hz, 1H, Ar, A), 6.44−6.47 (m, 1H, Ar, A), 6.71−6.74 (m, 2H, Ar, B), 6.77 (d, 3J = 7.8 Hz, 1H, Ar, A), 6.87−6.93 (m, 1H + 3H, Ar, A, B), 6.98−7.00 (m, 2H, Ar, A), 7.13−7.18 (m, 2H, Ar, B), 7.14−7.27 (m, 1H, Ar, A), 7.26−7.32 (m, 2H, Ar, B), 7.34−7.37 (m, 1H, Ar, A), 7.42−7.45 (m, 2H, Ar, A), 7.49−7.52 (m, 2H, Ar, B), 7.54 (dd, 3J = 8.0, 3J = 7.2 Hz, 1H, Ar, A), 7.60 (dd, 3J = 8.0, 3J = 7.2 Hz, 1H, Ar, B), 7.62−7.63 (m, 1H, Ar, A), 7.67 (br d, 3J = 8.5 Hz, 1H, Ar, A), 7.72−7.73 (m, 1H, Ar, B), 7.77 (br d, 3J = 8.1 Hz, 1H, Ar, A), 7.82 (br d, 3J = 8.1 Hz, 1H, Ar, A), 7.87 (br d, 3J = 8.2 Hz, 1H, Ar, B), 7.91 (br d, 3J = 8.1 Hz, 1H, Ar, B). A: 13C NMR (150 MHz, CDCl3) δ 21.7 (1JCH = 165 Hz, CH2), 33.3 (C), 34.3 (1JCH = 166 Hz, CH), 43.2 (1JCH = 139 Hz, CH2), 54.9 (1JCH = 144 Hz, CH3O), 108.4 (CH), 113.9 (2 × CH), 119.3 (CH), 121.1 (CH), 123.2 (CH), 124.8 (CH), 125.6 (CH), 125.8 (CH), 126.1 (CH), 126.2 (CH), 126.9 (C), 128.08 (2 × CH), 128.2 (C), 128.33 (2 × CH), 131.6 (C), 132.9 (C), 133.1 (C), 142.2 (C), 158.8 (C), 176.1 (CO). B: 13C NMR (150 MHz, CDCl3) δ 21.8 (1JCH = 165 Hz, CH2), 33.2 (C), 35.9 (1JCH = 163 Hz, CH), 42.8 (1JCH = 139 Hz, CH2), 54.8 (1JCH = 144 Hz, CH3O), 108.6 (CH), 113.5 (2 × CH), 118.1 (CH), 121.8 (CH), 123.1 (CH), 125.0 (CH), 125.1 (CH), 126.0 (CH), 126.7 (CH), 126.8 (CH), 127.86 (CH), 127.94 (C), 128.05 (C), 128.29 (2 × CH), 128.6 (CH), 130.0 (C), 131.4 (C), 133.2 (C), 142.4 (C), 158.5 (C), 173.1 (CO); HRMS (ESI) m/ z [M + H]+ calcd for C28H24NO2+ 406.1802, found 406.1803. 2 -( 1 , 3 - B e nz od i ox o l -5 - yl )- 1′-(4-methoxybenzyl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one (1i). This compound was obtained from S1i (370 mg, 0.961 mmol): reaction time 2.5 h; yield 320 mg (83%); yellow oil; dr 64:36; Rf = 0.40 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.00 (dd, 2J = 4.4, 3J = 7.9 Hz, 1H, CH2, A), 2.08 (dd, 2J = 4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.26 (dd, 2J = 4.4, 3J = 9.1 Hz, 1H, CH2, A), 2.42 (dd, 2J = 4.9, 3J = 8.5 Hz, 1H, CH2, B), 3.14 (dd, 3J = 9.0, 3J = 8.5 Hz, 1H, CH, B), 3.37 (dd, 3J = 9.1, 3J = 7.9 Hz, 1H, CH, A), 3.74 (s, 3H, CH3O, B), 3.76 (s, 3H, CH3O, A), 4.82 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.90 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.97 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.03 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.87−5.88 (m, 2H, OCH2O, B), 5.89−5.90 (m, 2H, OCH2O, A), 6.18 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.69 (br s, 1H, Ar, A), 6.73−6.75 (m, 3H, Ar, B), 6.76 (br s, 1H, Ar, B), 6.76−6.78 (m, 1H, Ar, B), 6.79−6.80 (m, 1H, Ar, B), 6.84−6.89 8701

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry

(C), 128.3 (2 × CH), 138.5 (C), 142.6 (C), 158.7 (C), 175.3 (CO). B: 13C NMR (150 MHz, CDCl3) δ 23.3 (1JCH = 165 Hz, CH2), 32.3 (1JCH = 166 Hz, CH), 33.9 (C), 42.9 (1JCH = 139 Hz, CH2), 54.72 (1JCH = 144 Hz, CH3O), 108.49 (CH), 113.7 (2 × CH), 117.8 (CH), 121.5 (CH), 124.4 (CH), 126.3 (CH), 126.52 (CH), 126.8 (CH), 128.0 (C), 128.4 (2 × CH), 129.6 (C), 137.6 (C), 142.1 (C), 158.6 (C), 172.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for C22H20NO2S+ 362.1209, found 362.1213. 5-Methyl-1′-(4-methoxybenzyl)-2-phenylspiro[cyclopropane1,3′-indol]-2′(1′H)-one (1l). This compound was obtained from S1l (5.3 g, 15 mmol): reaction time 2.5 h; yield 4.72 g (85%); white foam; dr 65:35; Rf = 0.50 (petroleum ether−ethyl acetate, 2:1); 1H NMR (600 MHz, CDCl3) δ 2.05 (dd, 2J = 4.4, 3J = 8.0 Hz, 1H, CH2, A), 2.04 (s, 3H, CH3, A), 2.12 (dd, 2J = 4.9, 3J = 9.1 Hz, 1H, CH2, B), 2.29 (dd, 2J = 4.4, 3J = 9.2 Hz, 1H, CH2, A), 2.39 (s, 3H, CH3, B), 2.50 (dd, 2J = 4.9, 3J = 8.6 Hz, 1H, CH2, B), 3.20 (dd, 3J = 9.1, 3J = 8.6 Hz, 1H, CH, B), 3.44 (dd, 3J = 9.2, 3J = 8.0 Hz, 1H, CH, A), 3.78 (s, 3H, CH3O, B), 3.81 (s, 3H, CH3O, A), 4.81 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.84 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.97 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.03 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.81−5.82 (m, 1H, Ar, A), 6.72 (d, 3J = 7.9 Hz, 1H, Ar, A), 6.75 (d, 3J = 7.9 Hz, 1H, Ar, B), 6.83−6.85 (m, 3H, Ar, B), 6.87−6.89 (m, 1H, Ar, A), 6.90−6.92 (m, 2H, Ar, A), 7.01−7.02 (m, 1H, Ar, B), 7.19−7.22 (m, 2H, Ar, B), 7.23−7.25 (m, 2H, Ar, A), 7.28−7.40 (m, 5H + 5H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 20.8 (CH3), 22.4 (CH2), 33.1 (C), 35.8 (CH), 43.5 (CH2), 55.10 (CH3O), 108.3 (CH), 114.0 (2 × CH), 121.6 (CH), 126.6 (CH), 127.2 (CH), 127.5 (C), 128.2 (2 × CH), 128.4 (C), 128.52 (2 × CH), 129.9 (2 × CH), 130.7 (C), 135.1 (C), 140.5 (C), 158.9 (C), 176.3 (CO). B: 13C NMR (150 MHz, CDCl3) δ 21.0 (CH3), 22.1 (CH2), 33.7 (C), 38.3 (CH), 43.2 (CH2), 55.07 (CH3O), 108.4 (CH), 113.9 (2 × CH), 118.9 (CH), 126.8 (CH), 127.1 (CH), 127.8 (2 × CH), 128.50 (C), 128.7 (2 × CH), 129.2 (2 × CH), 131.3 (C), 130.8 (C), 134.4 (C), 140.1 (C), 158.8 (C), 173.6 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H24NO2+ 370.1802, found 370.1808. 5-Fluoro-1′-(4-methoxybenzyl)-2-phenylspiro[cyclopropane1,3′-indol]-2′(1′H)-one (1m). This compound was obtained from S1m (3.40 g, 9.5 mmol): reaction time 2.5 h; yield 3.05 g (86%); yellow foam; dr 74:26; Rf = 0.63 (petroleum ether−ethyl acetate, 2:1); 1H NMR (600 MHz, CDCl3) δ 2.06 (dd, 2J = 4.5, 3J = 8.0 Hz, 1H, CH2, A), 2.12 (dd, 2J = 5.0, 3J = 9.1 Hz, 1H, CH2, B), 2.32 (dd, 2J = 4.5, 3J = 9.2 Hz, 1H, CH2, A), 2.53 (dd, 2J = 5.0, 3J = 8.7 Hz, 1H, CH2, B), 3.18 (dd, 3J = 9.1, 3J = 8.7 Hz, 1H, CH, B), 3.47 (dd, 3J = 9.2, 3J = 8.0 Hz, 1H, CH, A), 3.78 (s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.79 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.83 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.94 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.01 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.73 (dd, 3J = 8.6, 4J = 2.6 Hz, 1H, Ar, A), 6.69 (dd, 3 J = 8.6, 4J = 4.3 Hz, 1H, Ar, A), 6.71−6.76 (m, 1H + 2H, Ar, A, B), 6.82−6.85 (m, 2H, Ar, B), 6.86−6.89 (m, 1H, Ar, B), 6.89−6.92 (m, 2H, Ar, A), 7.16−7.18 (m, 2H, Ar, B), 7.21−7.22 (m, 2H, Ar, A), 7.28−7.31 (m, 2H + 4H, Ar, A, B), 7.32−7.35 (m, 2H + 1H, Ar, A, B), 7.35−7.36 (m, 1H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 22.9 (1JCH = 165 Hz, CH2), 33.5 (4JCF = 2 Hz, C), 36.4 (1JCH = 165 Hz, CH), 43.7 (1JCH = 139 Hz, CH2), 55.14 (1JCH = 144 Hz, CH3O), 108.7 (2JCF = 26 Hz, CH), 109.0 (3JCF = 8 Hz, CH), 112.5 (2JCF = 24 Hz, CH), 114.1 (2 × CH), 127.6 (CH), 128.0 (C), 128.5 (2 × CH), 128.6 (2 × CH), 129.3 (3JCF = 9 Hz, C), 129.7 (2 × CH), 134.4 (C), 138.7 (C), 158.3 (1JCF = 239 Hz, C), 159.0 (C), 176.1 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.4 (1JCH = 165 Hz, CH2), 34.1 (4JCF = 2 Hz, C), 38.9 (1JCH = 164 Hz, CH), 43.3 (1JCH = 139 Hz, CH2), 55.11 (1JCH = 144 Hz, CH3O), 106.3 (2JCF = 25 Hz, CH), 109.1 (3JCF = 8 Hz, CH), 112.7 (2JCF = 23 Hz, CH), 114.0 (2 × CH), 127.4 (CH), 127.7 (2 × CH), 128.1 (C), 128.7 (2 × CH), 129.2 (2 × CH), 132.5 (3JCF = 9 Hz, C), 133.9 (C), 138.3 (C), 158.9 (C), 159.0 (1JCF = 239 Hz, C), 173.3 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H21FNO2+ 374.1551, found 374.1560. Ethyl 4-(5′-Fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′dihydrospiro[cyclopropane-1,3′-indol]-2-yl)benzoate (1n). This compound was obtained from S1n (6.87 g, 16 mmol): reaction time 2.5 h; yield 4.27 g (60%); yellow foam; dr 65:35; Rf = 0.29

(m, 4H, Ar, A), 6.90−6.91 (m, 2H, Ar, A), 6.94−6.96 (m, 1H, Ar, B), 7.03−7.06 (m, 1H, Ar, B), 7.07−7.10 (m, 1H, Ar, A), 7.18−7.20 (m, 1H, Ar, B), 7.23−7.24 (m, 2H, Ar, B), 7.33−7.34 (m, 2H, Ar, A). A: 13 C NMR (150 MHz, CDCl3) δ 22.5 (1JCH = 165 Hz, CH2), 33.1 (C), 35.6 (1JCH = 165 Hz, CH), 43.2 (1JCH = 139 Hz, CH2), 54.82 (1JCH = 144 Hz, CH3O), 100.8 (1JCH = 174 Hz, OCH2O), 107.7 (CH), 108.5 (CH), 110.0 (CH), 113.8 (2 × CH), 120.5 (CH), 121.2 (CH), 122.7 (CH), 126.1 (CH), 127.1 (C), 128.06 (C), 128.4 (2 × CH), 128.53 (C), 142.7 (C), 146.5 (C), 147.3 (C), 158.7 (C), 176.0 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.2 (1JCH = 165 Hz, CH2), 33.5 (C), 38.1 (1JCH = 162 Hz, CH), 42.9 (1JCH = 139 Hz, CH2), 54.79 (1JCH = 144 Hz, CH3O), 100.7 (1JCH = 174 Hz, OCH2O), 107.5 (CH), 108.4 (CH), 109.4 (CH), 113.7 (2 × CH), 117.8 (CH), 121.5 (CH), 122.4 (CH), 126.3 (CH), 128.07 (C), 128.18 (C), 128.46 (2 × CH), 130.4 (C), 142.1 (C), 146.4 (C), 147.1 (C), 158.6 (C), 173.4 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H22NO4+ 400.1543, found 400.1553. 1′-(4-Methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one (1j). This compound was obtained from S1j (395 mg, 0.917 mmol): reaction time 2.5 h; yield 360 mg (88%); yellow viscous oil; dr 65:35; Rf = 0.16 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 1.98 (dd, 2J = 4.4, 3J = 7.9 Hz, 1H, CH2, A), 2.05 (dd, 2J = 4.8, 3J = 9.1 Hz, 1H, CH2, B), 2.20 (dd, 2J = 4.4, 3J = 9.2 Hz, 1H, CH2, A), 2.38 (dd, 2J = 4.8, 3J = 8.6 Hz, 1H, CH2, B), 3.08 (dd, 3J = 9.1, 3J = 8.6 Hz, 1H, CH, B), 3.32 (dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH, A), 3.63 (s, 3H, CH3O, B), 3.64 (s, 6H, CH3O, B), 3.68 (s, 6H, CH3O, A), 3.75 (s, 3H, CH3O, A), 3.795 (s, 3H, CH3O, A), 3.801 (s, 3H, CH3O, B), 4.68 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.81 (d, 2J = 15.5 Hz, 1H, CH2, A), 4.84 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.00 (d, 2J = 15.5 Hz, 1H, CH2, A), 6.12 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.39 (s, 2H, Ar, A), 6.54 (s, 2H, Ar, B), 6.63−6.66 (m, 1H, Ar, A), 6.71−6.73 (m, 2H, Ar, B), 6.77−6.79 (m, 3H + 1H, Ar, A, B), 6.88−6.90 (m, 1H, Ar, B), 6.94−6.97 (m, 1H, Ar, B), 6.98−7.00 (m, 1H, Ar, A), 7.08−7.11 (m, 1H, Ar, B), 7.11−7.13 (m, 2H, Ar, B), 7.23−7.24 (m, 2H, Ar, A). A: 13 C NMR (150 MHz, CDCl3) δ 22.4 (1JCH = 165 Hz, CH2), 32.8 (C), 35.8 (1JCH = 163 Hz, CH), 43.0 (1JCH = 139 Hz, CH2), 54.53 (1JCH = 144 Hz, CH3O), 55.5 (1JCH = 144 Hz, 2 × CH3O), 60.3 (1JCH = 144 Hz, CH3O), 106.6 (2 × CH), 108.3 (CH), 113.5 (2 × CH), 120.3 (CH), 121.0 (CH), 126.0 (CH), 126.8 (C), 127.8 (C), 128.18 (2 × CH), 130.2 (C), 136.9 (C), 142.3 (C), 152.5 (2 × C), 158.5 (C), 175.8 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.2 (1JCH = 164 Hz, CH2), 33.4 (C), 38.4 (1JCH = 164 Hz, CH), 42.6 (1JCH = 139 Hz, CH2), 54.52 (1JCH = 144 Hz, CH3O), 55.4 (1JCH = 144 Hz, 2 × CH3O), 60.2 (1JCH = 144 Hz, CH3O), 106.0 (2 × CH), 108.2 (CH), 113.4 (2 × CH), 117.7 (CH), 121.4 (CH), 126.2 (CH), 128.0 (C), 128.16 (2 × CH), 128.4 (C), 129.8 (C), 136.6 (C), 141.9 (C), 152.2 (2 × C), 158.4 (C), 173.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C27H27NO5+ 446.1962, found 446.1964. 1′-(4-Methoxybenzyl)-2-(thien-2-yl)spiro[cyclopropane-1,3′indol]-2′(1′H)-one (1k). This compound was obtained from S1k (547 mg, 1.58 mmol): reaction time 2.5 h; yield 490 mg (86%); yellow oil; dr 68:32; Rf = 0.44 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.12 (dd, 2J = 4.5, 3J = 7.6 Hz, 1H, CH2, A), 2.20 (dd, 2J = 4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.40 (dd, 2J = 4.5, 3J = 9.2 Hz, 1H, CH2, A), 2.49 (dd, 2J = 4.9, 3J = 8.2 Hz, 1H, CH2, B), 3.26 (dd, 3J = 9.0, 3J = 8.2 Hz, 1H, CH, B), 3.44 (dd, 3J = 9.2, 3J = 7.6 Hz, 1H, CH, A), 3.74 (s, 3H, CH3O, B), 3.76 (s, 3H, CH3O, A), 4.83 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.94 (d, 2J = 15.5 Hz, 1H, CH2, A), 4.97 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.06 (d, 2J = 15.5 Hz, 1H, CH2, A), 6.34 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.78−6.80 (m, 1H, Ar, A), 6.87−6.89 (m, 2H, Ar, A), 6.91−6.94 (m, 2H + 1H, Ar, A, B), 6.96− 6.97 (m, 3H, Ar, B), 6.98−7.00 (m, 1H, Ar, A), 7.03−7.04 (m, 1H, Ar, B), 7.05−7.07 (m, 1H, Ar, B), 7.12−7.15 (m, 1H + 1H, Ar, A, B), 7.19−7.20 (m, 1H, Ar, A), 7.21−7.23 (m, 2H, Ar, B), 7.27−7.28 (m, 2H, Ar, B), 7.35−7.36 (m, 2H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 23.4 (1JCH = 165 Hz, CH2), 29.9 (1JCH = 169 Hz, CH), 33.7 (C), 43.2 (1JCH = 139 Hz, CH2), 54.74 (1JCH = 144 Hz, CH3O), 108.52 (CH), 113.8 (2 × CH), 120.0 (CH), 121.3 (CH), 125.0 (CH), 126.4 (CH), 126.49 (CH), 126.50 (C), 127.1 (CH), 127.9 8702

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 1.39 (t, 3J = 7.2 Hz, 3H, CH3, A), 141 (t, 3J = 7.2 Hz, 3H, CH3, A), 2.06 (dd, 2J = 4.8, 3J = 8.1 Hz, 1H, CH2, A), 2.15 (dd, 2J = 5.1, 3J = 9.0 Hz, 1H, CH2, B), 2.33 (dd, 2J = 4.8, 3J = 9.1 Hz, 1H, CH2, A), 2.54 (dd, 2J = 5.1, 3J = 8.6 Hz, 1H, CH2, B), 3.18 (dd, 3J = 9.0, 3J = 8.6 Hz, 1H, CH, B), 3.44 (dd, 3J = 9.0, 3J = 8.1 Hz, 1H, CH, A), 3.77 (s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.39 (q, 3J = 7.2 Hz, 2H + 2H, CH2O, A, B), 4.75 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.80 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.90 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.01 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.70 (dd, 3J = 8.5, 4J = 2.5 Hz, 1H, Ar, A), 6.68 (dd, 3J = 8.5, 4J = 4.4 Hz, 1H, Ar, A), 6.71−6.77 (m, 1H + 2H, Ar, A, B), 6.80−6.84 (m, 2H, Ar, B), 6.84−6.86 (m, 1H, Ar, B), 6.86−6.90 (m, 2H, Ar, A), 7.11−7.15 (m, 2H, Ar, B), 7.26−7.28 (m, 4H, Ar, A), 7.39−7.41 (m, 2H, Ar, B), 8.00−8.03 (m, 2H + 2H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 13.9 (1JCH = 127 Hz, CH3), 22.12 (1JCH = 165 Hz, CH2), 33.4 (C), 35.8 (1JCH = 166 Hz, CH), 43.4 (1JCH = 139 Hz, CH2), 54.77 (1JCH = 144 Hz, CH3O), 60.7 (1JCH = 147 Hz, CH2O), 108.3 (2JCF = 26 Hz, CH), 108.96 (3JCF = 7 Hz, CH), 112.6 (2JCF = 24 Hz, CH), 113.9 (2 × CH), 127.6 (C), 128.3 (2 × CH), 128.5 (3JCF = 9 Hz, C), 129.10 (C), 129.43 (2 × CH), 129.44 (2 × CH), 138.6 (C), 139.4 (C), 158.0 (1JCF = 239 Hz, C), 158.8 (C), 165.7 (CO2Et), 175.4 (CO). B: 13C NMR (150 MHz, CDCl3) δ 14.0 (1JCH = 127 Hz, CH3), 22.05 (1JCH = 165 Hz, CH2), 34.1 (C), 38.0 (1JCH = 162 Hz, CH), 43.0 (1JCH = 139 Hz, CH2), 54.75 (1JCH = 144 Hz, CH3O), 60.5 (1JCH = 148 Hz, CH2O), 106.2 (2JCF = 25 Hz, CH), 109.01 (3JCF = 7 Hz, CH), 112.7 (2JCF = 24 Hz, CH), 113.7 (2 × CH), 127.7 (C), 128.4 (2 × CH), 128.8 (2 × CH), 129.05 (C), 129.5 (2 × CH), 131.8 (3JCF = 9 Hz, C), 138.1 (C), 139.1 (C), 158.7 (C), 158.7 (1JCF = 240 Hz, C), 165.9 (CO2Et), 172.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for C27H25FNO4+ 446.1762, found 446.1767. 5-Chloro-1′-(4-methoxybenzyl)-2-phenylspiro[cyclopropane1,3′-indol]-2′(1′H)-one (1o). This compound was obtained from S1o (4.20 g, 11.2 mmol): reaction time 2.5 h; yield 3.54 g (81%); yellow foam; dr 69:31; Rf = 0.65 (petroleum ether−ethyl acetate, 2:1); 1H NMR (600 MHz, CDCl3) δ 2.07 (dd, 2J = 4.6, 3J = 7.9 Hz, 1H, CH2, A), 2.13 (dd, 2J = 5.0, 3J = 9.1 Hz, 1H, CH2, B), 2.32 (dd, 2J = 4.6, 3J = 9.2 Hz, 1H, CH2, A), 2.53 (dd, 2J = 5.0, 3J = 8.8 Hz, 1H, CH2, B), 3.20 (dd, 3J = 9.1, 3J = 8.8 Hz, 1H, CH, B), 3.47 (dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH, A), 3.77 (s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.78 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.82 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.94 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.01 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.93 (dd, 4J = 2.1, 5J = 0.4 Hz, 1H, Ar, A), 6.70 (br d, 3J = 8.4 Hz, 1H, Ar, A), 6.73 (br d, 3J = 8.4 Hz, 1H, Ar, B), 6.82−6.84 (m, 2H, Ar, B), 6.89−6.91 (m, 2H, Ar, A), 6.96 (dd, 4J = 2.1, 5J = 0.4 Hz, 1H, Ar, B), 7.01 (dd, 3J = 8.3, 4J = 2.1 Hz, 1H, Ar, A), 7.14 (dd, 3J = 8.3, 4J = 2.1 Hz, 1H, Ar, B), 7.14−7.17 (m, 2H, Ar, B), 7.20−7.22 (m, 2H, Ar, A), 7.27−7.29 (m, 2H, Ar, A), 7.29−7.32 (m, 4H, Ar, B), 7.33−7.36 (m, 3H + 1H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 22.9 (1JCH = 165 Hz, CH2), 33.2 (C), 36.5 (1JCH = 165 Hz, CH), 43.6 (1JCH = 139 Hz, CH2), 55.2 (1JCH = 144 Hz, CH3O), 109.5 (CH), 114.1 (2 × CH), 121.0 (CH), 126.2 (CH), 126.8 (C), 127.7 (CH), 127.8 (C), 128.45 (2 × CH), 128.53 (2 × CH), 129.3 (C), 129.7 (2 × CH), 134.4 (C), 141.4 (C), 159.0 (C), 175.9 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.4 (1JCH = 165 Hz, CH2), 33.8 (C), 38.9 (1JCH = 162 Hz, CH), 43.3 (1JCH = 139 Hz, CH2), 55.1 (1JCH = 144 Hz, CH3O), 109.6 (CH), 114.0 (2 × CH), 118.6 (CH), 126.4 (CH), 127.2 (C), 127.4 (CH), 127.88 (2 × CH), 127.92 (C), 128.7 (2 × CH), 129.2 (2 × CH), 132.5 (C), 133.8 (C), 140.9 (C), 158.9 (C), 173.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H21ClNO2+ 390.1255, found 390.1264. 5-Bromo-1′-(4-methoxybenzyl)-2-phenylspiro[cyclopropane1,3′-indol]-2′(1′H)-one (1p). This compound was obtained from S1p (2.99 g, 7.14 mmol): reaction time 2.5 h; yield 2.36 g (76%); yellow foam; dr 69:31; Rf = 0.60 (petroleum ether−ethyl acetate, 2:1); 1H NMR (600 MHz, CDCl3) δ 2.06 (dd, 2J = 4.6, 3J = 8.0 Hz, 1H, CH2, A), 2.13 (dd, 2J = 5.1, 3J = 9.1 Hz, 1H, CH2, B), 2.29 (dd, 2J = 4.6, 3J = 9.2 Hz, 1H, CH2, A), 2.51 (dd, 2J = 5.1, 3J = 8.7 Hz, 1H, CH2, B), 3.19 (dd, 3J = 9.1, 3J = 8.7 Hz, 1H, CH, B), 3.44 (dd, 3J = 9.1, 3J = 8.0 Hz, 1H, CH, A), 3.77 (s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.77

(d, 2J = 15.6 Hz, 1H, CH2, B), 4.79 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.91 (d, 2J = 15.5 Hz, 1H, CH2, A), 4.99 (d, 2J = 15.5 Hz, 1H, CH2, A), 6.02 (dd, 4J = 2.0, 5J = 0.4 Hz, 1H, Ar, A), 6.64 (br d, 3J = 8.3 Hz, 1H, Ar, A), 6.67 (br d, 3J = 8.3 Hz, 1H, Ar, B), 6.80−6.82 (m, 2H, Ar, B), 6.87−6.89 (m, 2H, Ar, A), 7.08 (dd, 4J = 2.0, 5J = 0.4 Hz, 1H, Ar, B), 7.11−7.14 (m, 2H, Ar, B), 7.15 (dd, 3J = 8.3, 4J = 2.0 Hz, 1H, Ar, A), 7.18−7.20 (m, 2H, Ar, A), 7.24−7.26 (m, 2H, Ar, A), 7.27−7.32 (m, 4H, Ar, B), 7.33−7.35 (m, 3H + 1H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 22.7 (CH2), 33.0 (C), 36.4 (CH), 43.4 (CH2), 55.0 (CH3O), 109.85 (CH), 113.96 (C), 114.00 (2 × CH), 123.6 (CH), 127.5 (CH), 127.6 (C), 127.7 (CH), 128.3 (2 × CH), 128.4 (2 × CH), 129.5 (C), 129.6 (2 × CH), 134.2 (C), 141.7 (C), 158.9 (C), 175.6 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.3 (CH2), 33.6 (C), 38.8 (CH), 43.1 (CH2), 54.9 (CH3O), 109.91 (CH), 113.8 (2 × CH), 114.3 (C), 121.2 (CH), 127.2 (CH), 128.1 (C), 128.46 (C), 128.50 (2 × CH), 129.0 (2 × CH), 129.12 (2 × CH), 132.8 (CH), 133.7 (C), 141.2 (C), 158.8 (C), 172.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H21BrNO2+ 434.0750, found 434.0761. General Procedure for the Synthesis of Spiro[Pyrrolidone3,3′-oxindoles] 2. A solution of cyclopropane 1 (0.20 mmol, 1.0 equiv) in dry DMF (2.0 mL, 0.1 M), KNCO (33 mg, 0.40 mmol, 2.0 equiv), and triethylamine hydrochloride (28 mg, 0.20 mmol, 1.0 equiv) was placed in a microwave vessel. The reaction mixture was stirred (800 rpm) under the heating by microwave irradiation at 150 °C for a specified time; then it was cooled down to ambient temperature, and an extra portion of KNCO (33 mg, 0.40 mmol, 2.0 equiv) was added (excluding synthesis of 2m−p). The resulting mixture was further heated under microwave irradiation at 150 °C for a specified time, cooled to ambient temperature, poured into water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (5 × 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on conventional or neutralized (2c−e,i−k,s−u) silica gel (petroleum ether−ethyl acetate). For the preparation of neutralized silica gel, in an Erlenmeyer flask, silica gel (ca. 12 g), petroleum ether (90 mL), ethyl acetate (5 mL), and triethylamine (1 mL) were mixed. The suspension was then shaken vigorously and left overnight. The column was packed with the resulting silica gel slurry. In order to remove the leftover polar solvent, petroleum ether was passed through the column. (The total volume is approximately 8−10 volumes of silica gel.) 1-(4-Methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (2a). This compound was obtained from 1a (424 mg, 1.20 mmol): reaction time 4 + 6 h; yield 294 mg (62%); white solid, mp 216−217 °C; dr 52:48; Rf = 0.38 (petroleum ether− ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.41 (dd, 2J = 13.3, 3J = 8.2 Hz, 1H, CH2, A), 2.81 (dd, 2J = 13.5, 3J = 7.5 Hz, 1H, CH2, B), 2.88 (dd, 2J = 13.5, 3J = 8.3 Hz, 1H, CH2, B), 3.11 (dd, 2J = 13.4, 3J = 7.2 Hz, 1H, CH2, A), 3.76 (s, 3H, CH3O), 3.77 (s, 3H, CH3O), 4.83 (d, 2J = 15.6 Hz, 1H, CH2), 4.84 (d, 2J = 15.6 Hz, 1H, CH2), 4.92 (d, 2J = 15.6 Hz, 1H, CH2), 4.98 (d, 2J = 15.6 Hz, 1H, CH2), 5.10 (dd, 3J = 8.3, 3J = 7.5 Hz, 1H, CH, B), 5.34 (dd, 3J = 8.2, 3 J = 7.2 Hz, 1H, CH, A), 6.74−6.77 (m, 2H, Ar), 6.81−6.86 (m, 4H, Ar), 6.89 (br s, 1H, NH), 6.95 (br s, 1H, NH), 7.04−7.09 (m, 2H, Ar), 7.17−7.19 (m, 1H, Ar), 7.19−7.23 (m, 2H, Ar), 7.24−7.29 (m, 4H, Ar), 7.34−7.39 (m, 3H, Ar), 7.41−7.45 (m, 6H, Ar), 7.51−7.53 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 41.4 (CH2), 42.1 (CH2), 43.4 (CH2), 43.6 (CH2), 55.20 (CH3O), 55.21 (CH3O), 55.4 (CH), 56.5 (CH), 58.5 (C), 58.6 (C), 109.6 (CH), 109.8 (CH), 114.2 (2 × CH), 114.3 (2 × CH), 122.5 (CH), 123.0 (CH), 123.2 (CH), 123.3 (CH), 125.8 (2 × CH), 126.4 (2 × CH), 127.3 (2 × C), 128.3 (CH), 128.4 (3 × CH), 128.5 (2 × CH), 128.6 (C), 128.99 (CH), 129.02 (2 × CH), 129.08 (CH), 129.11 (2 × CH), 130.1 (C), 141.1 (C), 141.5 (C), 143.2 (C), 143.8 (C), 159.0 (C), 159.1 (C), 173.6 (CO), 173.8 (CO), 175.1 (CO), 175.5 (CO); HRMS (ESI) m/ z [M + H]+ calcd for C25H23N2O3+ 399.1703, found 399.1698. 1-(4-Methoxybenzyl)-5′-(p-tolyl)-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (2b). This compound was obtained from 1b (77 mg, 0.21 mmol): reaction time 2 + 4 h; yield 57 mg (66%); yellowish 8703

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry solid, mp 195−196 °C; dr 51:49; Rf = 0.40 (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.36 (CH3), 2.38 (CH3), 2.39 (dd, 2J = 13.4, 3J = 8.4 Hz, 1H, CH2, A), 2.77 (dd, 2J = 13.3, 3J = 7.4 Hz, 1H, CH2, B), 2.85 (dd, 2J = 13.3, 3J = 8.3 Hz, 1H, CH2, B), 3.09 (dd, 2J = 13.4, 3J = 7.1 Hz, 1H, CH2, A), 3.75 (s, 3H, CH3O), 3.76 (s, 3H, CH3O), 4.81 (d, 2J = 15.6 Hz, 1H, CH2), 4.83 (d, 2J = 15.7 Hz, 1H, CH2), 4.92 (d, 2J = 15.6 Hz, 1H, CH2), 4.98 (d, 2 J = 15.7 Hz, 1H, CH2), 5.06 (dd, 3J = 8.3, 3J = 7.4 Hz, 1H, CH, B), 5.29 (dd, 3J = 8.4, 3J = 7.1 Hz, 1H, CH, A), 6.73−6.76 (m, 2H, Ar), 6.80−6.84 (m, 4H, Ar), 6.91 (br s, 1H, NH), 6.98 (br s, 1H, NH), 7.03−7.08 (m, 2H, Ar), 7.17−7.29 (m, 11H, Ar), 7.32−7.33 (m, 2H, Ar), 7.35−7.36 (m, 1H, Ar), 7.39−7.40 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 21.0 (1JCH = 127 Hz, 2 × CH3), 41.4 (1JCH = 138 Hz, CH2), 42.1 (1JCH = 138 Hz, CH2), 43.3 (1JCH = 138 Hz, CH2), 43.5 (1JCH = 138 Hz, CH2), 55.13 (1JCH = 144 Hz, 2 × CH3O), 55.14 (1JCH = 140 Hz, CH), 56.2 (1JCH = 140 Hz, CH), 58.5 (C), 58.6 (C), 109.5 (CH), 109.6 (CH), 114.1 (2 × CH), 114.2 (2 × CH), 122.5 (CH), 122.9 (CH), 123.1 (CH), 123.3 (CH), 125.7 (2 × CH), 126.3 (2 × CH), 127.3 (2 × C), 128.36 (2 × CH), 128.41 (2 × CH), 128.76 (C), 128.84 (CH), 128.9 (CH), 129.6 (2 × CH), 129.7 (2 × CH), 130.2 (C), 138.0 (C), 138.10 (C), 138.12 (C), 138.5 (C), 143.2 (C), 143.7 (C), 158.9 (C), 159.0 (C), 173.4 (CO), 173.5 (CO), 175.1 (CO), 175.6 (CO); HRMS (ESI) m/z [M + H]+ calcd for C26H25N2O3+ 413.1860, found 413.1864. 1-(4-Methoxybenzyl)-5′-(4-methoxyphenyl)-2′H-spiro[indole3,3′-pyrrolidine]-2,2′(1H)-dione (2c). This compound was obtained from 1c (73 mg, 0.19 mmol): reaction time 2 + 2 h; purification performed on neutralized silica gel; yield 45 mg (56%); orange solid, mp 223−224 °C; dr 51:49; Rf = 0.42 (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.38 (dd, 2J = 13.3, 3J = 8.3 Hz, 1H, CH2, A), 2.77 (dd, 2J = 13.4, 3J = 7.4 Hz, 1H, CH2, B), 2.85 (dd, 2 J = 13.4, 3J = 8.3 Hz, 1H, CH2, B), 3.06 (dd, 2J = 13.3, 3J = 7.0 Hz, 1H, CH2, A), 3.75 (s, 3H, CH3O), 3.76 (s, 3H, CH3O), 3.81 (s, 3H, CH3O), 3.83 (s, 3H, CH3O), 4.81 (d, 2J = 15.6 Hz, 1H, CH2), 4.83 (d, 2J = 15.6 Hz, 1H, CH2), 4.92 (d, 2J = 15.6 Hz, 1H, CH2), 4.98 (d, 2 J = 15.6 Hz, 1H, CH2), 5.05 (dd, 3J = 8.3, 3J = 7.4 Hz, 1H, CH, B), 5.29 (dd, 3J = 8.3, 3J = 7.0 Hz, 1H, CH, A), 6.69 (br s, 1H, NH), 6.74−6.76 (m, 2H + 1H, Ar, NH), 6.81−6.84 (m, 4H, Ar), 6.93−6.96 (m, 4H, Ar), 7.04−7.08 (m, 2H, Ar), 7.19−7.22 (m, 3H, Ar), 7.24− 7.28 (m, 4H, Ar), 7.34−7.37 (m, 3H, Ar), 7.43−7.45 (m, 2H, Ar); 13 C NMR (150 MHz, CDCl3) δ 41.5 (1JCH = 138 Hz, CH2), 42.3 (1JCH = 138 Hz, CH2), 43.4 (1JCH = 138 Hz, CH2), 43.6 (1JCH = 138 Hz, CH2), 54.9 (1JCH = 144 Hz, CH), 55.16 (1JCH = 144 Hz, CH3O), 55.18 (1JCH = 144 Hz, CH3O), 55.28 (1JCH = 144 Hz, CH3O), 55.30 (1JCH = 144 Hz, CH3O), 55.9 (1JCH = 144 Hz, CH), 58.5 (C), 58.6 (C), 109.5 (CH), 109.7 (CH), 114.15 (2 × CH), 114.21 (2 × CH), 114.3 (2 × CH), 114.4 (2 × CH), 122.5 (CH), 122.9 (CH), 123.2 (CH), 123.3 (CH), 127.1 (2 × CH), 127.3 (2 × C), 127.7 (2 × CH), 128.39 (2 × CH), 128.44 (2 × CH), 128.7 (C), 128.9 (CH), 129.0 (CH), 130.2 (C), 133.0 (C), 133.3 (C), 143.2 (C), 143.7 (C), 158.97 (C), 159.01 (C), 159.5 (C), 159.7 (C), 173.2 (CO), 173.3 (CO), 175.2 (CO), 175.6 (CO); HRMS (ESI) m/z [M + H]+ calcd for C26H25N2O4+ 429.1809, found 429.1816. 5′-(4-Bromophenyl)-1-(4-methoxybenzyl)-2′H-spiro[indole-3,3′pyrrolidine]-2,2′(1H)-dione (2d). This compound was obtained from 1d (78 mg, 0.18 mmol): reaction time 2 + 2 h; purification performed on neutralized silica gel; yield 41 mg (48%); orange solid, mp 199− 200 °C; dr 53:47; Rf = 0.58 (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.32 (dd, 2J = 13.3, 3J = 8.1 Hz, 1H, CH2, A), 2.77 (dd, 2J = 13.5, 3J = 8.0 Hz, 1H, CH2, B), 2.82 (dd, 2J = 13.5, 3 J = 7.6 Hz, 1H, CH2, B), 3.09 (dd, 2J = 13.3, 3J = 7.1 Hz, 1H, CH2, A), 3.75 (s, 3H, CH3O), 3.77 (s, 3H, CH3O), 4.80 (d, 2J = 15.6 Hz, 1H, CH2), 4.82 (d, 2J = 15.6 Hz, 1H, CH2), 4.91 (d, 2J = 15.6 Hz, 1H, CH2), 4.96 (d, 2J = 15.6 Hz, 1H, CH2), 5.05 (dd, 3J = 8.3, 3J = 7.4 Hz, 1H, CH, B), 5.29 (dd, 3J = 8.3, 3J = 7.0 Hz, 1H, CH, A), 6.73−6.76 (m, 2H, Ar), 6.79−6.84 (m, 4H, Ar), 7.04−7.08 (m, 2H, Ar), 7.13− 7.14 (m, 1H, Ar), 7.18 (br s, 1H, NH), 7.19−7.26 (m, 6H + 1H, Ar, NH), 7.30−7.33 (m, 3H, Ar), 7.37−7.38 (m, 2H, Ar), 7.51−7.55 (m, 4H, Ar); 13C NMR (150 MHz, CDCl3) δ 41.1 (1JCH = 138 Hz, CH2), 41.9 (1JCH = 138 Hz, CH2), 43.4 (1JCH = 138 Hz, CH2), 43.6 (1JCH =

138 Hz, CH2), 54.9 (1JCH = 144 Hz, CH), 55.21 (1JCH = 144 Hz, CH3O), 55.23 (1JCH = 144 Hz, CH3O), 55.8 (1JCH = 144 Hz, CH), 58.3 (C), 58.5 (C), 109.7 (CH), 109.8 (CH), 114.2 (2 × CH), 114.3 (2 × CH), 122.1 (C), 122.3 (C), 122.5 (CH), 123.0 (CH), 123.2 (2 × CH), 127.2 (2 × C), 127.5 (2 × CH), 128.1 (2 × CH), 128.39 (2 × CH), 128.44 (2 × CH), 128.5 (C), 129.1 (CH), 129.2 (CH), 130.0 (C), 132.1 (2 × CH), 132.2 (2 × CH), 140.4 (C), 140.6 (C), 143.3 (C), 143.7 (C), 159.0 (C), 159.1 (C), 173.6 (CO), 173.7 (CO), 175.0 (CO), 175.4 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H22BrN2O3+ 477.0808, found 477.0821. 4-[1-(4-Methoxybenzyl)-2,2′-dioxo-1,2-dihydrospiro[indole-3,3′pyrrolidin]-5′-yl]benzonitrile (2e). This compound was obtained from 1e (71 mg, 0.19 mmol): reaction time 2 + 1 h; purification performed on neutralized silica gel; yield 32 mg (48%); orange solid, mp 184−186 °C; dr 53:47; Rf = 0.46 (A), 0.39 (B) (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.30 (dd, 2J = 13.4, 3J = 8.1 Hz, 1H, CH2, A), 2.74 (dd, 2J = 13.6, 3J = 7.4 Hz, 1H, CH2, B), 2.88 (dd, 2J = 13.6, 3J = 7.9 Hz, 1H, CH2, B), 3.14 (dd, 2J = 13.4, 3J = 7.4 Hz, 1H, CH2, A), 3.75 (s, 3H, CH3O), 3.77 (s, 3H, CH3O), 4.78 (d, 2J = 15.6 Hz, 1H, CH2), 4.79 (d, 2J = 15.6 Hz, 1H, CH2), 4.90 (d, 2J = 15.6 Hz, 1H, CH2), 4.95 (d, 2J = 15.6 Hz, 1H, CH2), 5.11−5.13 (m, 1H, CH), 5.35−5.37 (m, 1H, CH), 6.74−6.81 (m, 6H, Ar), 7.03−7.10 (m, 3H, Ar), 7.20−7.24 (m, 6H, Ar), 7.32− 7.33 (m, 1H, Ar), 7.51−7.52 (m, 2H, Ar), 7.57−7.58 (m, 2H, Ar), 7.61 (br s, 1H, NH), 7.63−7.65 (m, 2H, Ar), 7.66−7.67 (m, 2H, Ar), 7.70 (br s, 1H, NH); 13C NMR (150 MHz, CDCl3) δ 40.6 (CH2), 41.5 (CH2), 43.4 (CH2), 43.6 (CH2), 55.1 (CH), 55.19 (CH3O), 55.21 (CH3O), 55.9 (CH), 58.2 (C), 58.4 (C), 109.7 (CH), 109.9 (CH), 112.07 (C), 112.11 (C), 114.2 (2 × CH), 114.3 (2 × CH), 118.3 (C), 118.4 (C), 122.5 (CH), 123.13 (CH), 123.15 (CH), 123.3 (CH), 126.5 (2 × CH), 127.0 (2 × CH, 2 × C), 128.2 (C), 128.3 (2 × CH), 128.4 (2 × CH), 129.2 (CH), 129.3 (CH), 129.7 (C), 132.8 (2 × CH), 132.9 (2 × CH), 143.3 (C), 143.7 (C), 146.7 (C), 147.0 (C), 159.06 (C), 159.10 (C), 174.0 (CO), 174.1 (CO), 174.9 (CO), 175.3 (CO); HRMS (ESI) m/z [M + H]+ calcd for C26H22N3O3+ 424.1656, found 424.1667. 5′-(Biphenyl-4-yl)-1-(4-methoxybenzyl)-2′H-spiro[indole-3,3′pyrrolidine]-2,2′(1H)-dione (2g). This compound was obtained from 1g (86 mg, 0.20 mmol): reaction time 2 + 4 h; yield 53 mg (56%); yellow solid, mp 244−245 °C; dr 53:47; Rf = 0.38 (petroleum ether− ethyl acetate, 1:1); 1H NMR (600 MHz, DMSO-d6) δ 2.31 (dd, 2J = 13.3, 3J = 8.1 Hz, 1H, CH2, A), 2.50 (dd, 2J = 13.3, 3J = 8.5 Hz, 1H, CH2, B), 2.83 (dd, 2J = 13.3, 3J = 7.3 Hz, 1H, CH2, B), 3.07 (dd, 2J = 13.3, 3J = 7.3 Hz, 1H, CH2, A), 3.71 (s, 3H, CH3O, B), 3.72 (s, 3H, CH3O, A), 4.78 (d, 2J = 15.7 Hz, 1H, CH2, B), 4.81 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.90 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.95 (d, 2J = 15.7 Hz, 1H, CH2, B), 5.17 (dd, 3J = 8.1, 3J = 7.3 Hz, 1H, CH, A), 5.26 (dd, 3J = 8.5, 3J = 7.3 Hz, 1H, CH, B), 6.87−6.90 (m, 2H + 2H, Ar, A, B), 6.92−6.94 (m, 1H + 1H, Ar, A, B), 7.01−7.04 (m, 1H, Ar, B), 7.07−7.10 (m, 1H, Ar, A), 7.22−7.32 (m, 3H + 4H, Ar, A, B), 7.37− 7.40 (m, 1H + 1H, Ar, A, B), 7.47−7.50 (m, 2H + 2H, Ar, A, B), 7.52−7.53 (m, 1H, Ar, A), 7.57−7.59 (m, 2H, Ar, A), 7.61−7.62 (m, 2H, Ar, B), 7.69−7.71 (m, 2H + 2H, Ar, A, B), 7.73−7.75 (m, 2H + 2H, Ar, A, B), 8.91 (br s, 1H, NH, B), 8.93 (br s, 1H, NH, A). A: 13C NMR (150 MHz, DMSO-d6) δ 41.1 (CH2), 42.2 (CH2), 54.4 (CH), 55.0 (CH3O), 58.36 (C), 109.3 (CH), 114.03 (2 × CH), 122.7 (CH), 123.4 (CH), 126.7 (2 × CH), 126.9 (2 × CH), 126.69 (CH), 127.00 (2 × CH), 127.5 (CH), 127.9 (C), 128.5 (2 × CH), 129.0 (2 × CH), 129.4 (C), 139.7 (C), 139.78 (C), 141.6 (C), 143.5 (C), 158.58 (C), 172.4 (CO), 175.4 (CO). B: 13C NMR (150 MHz, DMSO-d6) δ 40.7 (CH2), 42.4 (CH2), 54.8 (CH), 55.0 (CH3O), 58.41 (C), 109.4 (CH), 113.99 (2 × CH), 122.7 (CH), 122.8 (CH), 126.7 (2 × CH), 126.9 (2 × CH), 126.69 (CH), 127.00 (2 × CH), 127.5 (CH), 127.8 (C), 128.5 (2 × CH), 129.0 (2 × CH), 130.6 (C), 139.7 (C), 139.81 (C), 141.8 (C), 142.9 (C), 158.55 (C), 172.5 (CO), 175.2 (CO); HRMS (ESI) m/z [M + H]+ calcd for C31H27N2O3+ 475.2016, found 475.2015. 1-(4-Methoxybenzyl)-5′-(naphthalen-1-yl)-2′H-spiro[indole-3,3′pyrrolidine]-2,2′(1H)-dione (2h). This compound was obtained from 1h (86 mg, 0.21 mmol): reaction time 4 + 4 + 8 h; yield 32 mg 8704

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry

A), 4.88 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.94 (d, 2J = 15.7 Hz, 1H, CH2, B), 5.09 (dd, 3J = 8.1, 3J = 7.0 Hz, 1H, CH, A), 5.15 (dd, 3J = 8.1, 3J = 7.4 Hz, 1H, CH, B), 6.81 (s, 2H, Ar, A), 6.83 (s, 2H, Ar, B), 6.87−6.90 (m, 2H + 2H, Ar, A, B), 6.92−6.93 (m, 1H + 1H, Ar, A, B), 7.02−7.04 (m, 1H, Ar, A), 7.06−7.09 (m, 1H, Ar, B), 7.22−7.24 (m, 1H, Ar, A), 7.24−7.27 (m, 1H, Ar, B), 7.28−7.31 (m, 3H + 2H, Ar, A, B), 7.48−7.49 (m, 1H, Ar, B), 8.87 (br s, 1H, NH, B), 8.88 (br s, 1H, NH, A). A: 13C NMR (150 MHz, DMSO-d6) δ 41.1 (CH2), 42.1 (CH2), 54.9 (CH), 55.0 (CH3O), 56.0 (2 × CH3O), 58.4 (C), 60.00 (CH3O), 103.3 (2 × CH), 109.2 (CH), 114.02 (2 × CH), 122.60 (CH), 123.6 (CH), 127.9 (CH), 128.52 (2 × CH), 128.6 (C), 129.2 (C), 136.9 (C), 137.9 (C), 143.5 (C), 153.11 (2 × C), 158.57 (C), 172.4 (CO), 175.4 (CO). B: 13C NMR (150 MHz, DMSO-d6) δ 40.6 (CH2), 42.4 (CH2), 55.0 (CH3O), 55.2 (CH), 55.9 (2 × CH3O), 58.3 (C), 60.02 (CH3O), 103.4 (2 × CH), 109.4 (CH), 113.97 (2 × CH), 122.62 (CH), 122.8 (CH), 127.8 (CH), 128.50 (2 × CH), 128.53 (C), 130.6 (C), 136.9 (C), 138.3 (C), 142.9 (C), 153.05 (2 × C), 158.55 (C), 172.4 (CO), 175.2 (CO); HRMS (ESI) m/z [M + H]+ calcd for C28H29N2O6+ 489.2020, found 489.2027. 1-(4-Methoxybenzyl)-5′-(thien-2-yl)-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (2k). This compound was obtained from 1k (77 mg, 0.21 mmol). Purification was performed on neutralized silica gel. Reaction time 2 + 1 h; yield 48 mg (56%); orange solid, mp 194− 196 °C; dr 52:48; Rf = 0.42 (A), 0.38 (B) (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.55 (dd, 2J = 13.4, 3J = 7.8 Hz, 1H, CH2, A), 2.84 (ddd, 2J = 13.3, 3J = 7.3, 5J = 0.7 Hz, 1H, CH2, B), 3.00 (dd, 2J = 13.3, 3J = 8.2 Hz, 1H, CH2, B), 3.15 (ddd, 2J = 13.4, 3J = 7.2, 5J = 0.6 Hz, 1H, CH2, A), 3.76 (s, 3H, CH3O, B), 3.77 (s, 3H, CH3O, A), 4.81 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.83 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.92 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.98 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.39 (dd, 3J = 8.2, 3J = 7.3 Hz, 1H, CH, B), 5.59 (dd, 3J = 7.8, 3J = 7.2 Hz, 1H, CH, A), 6.74−6.76 (m, 1H + 1H, Ar, A, B), 6.82−6.86 (m, 2H + 2H, Ar, A, B), 6.87 (br s, 1H, NH, A), 6.94 (br s, 1H, NH, B), 7.00−7.02 (m, 1H + 1H, Ar, A, B), 7.05−7.08 (m, 1H + 1H, Ar, A, B), 7.11−7.12 (m, 1H, Ar, A), 7.19−7.23 (m, 1H + 1H, Ar, A, B), 7.24−7.26 (m, 2H, Ar, A), 7.28−7.29 (m, 2H, Ar, B), 7.30−7.33 (m, 1H + 2H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 42.3 (CH2), 43.4 (CH2), 51.5 (CH), 55.20 (CH3O), 58.43 (C), 109.6 (CH), 114.22 (2 × CH), 123.2 (CH), 123.4 (CH), 125.0 (CH), 125.3 (CH), 127.12 (CH), 127.2 (C), 128.4 (2 × CH), 128.5 (C), 129.1 (CH), 143.7 (C), 145.4 (C), 159.02 (C), 172.6 (CO), 175.4 (CO). B: 13C NMR (150 MHz, CDCl3) δ 41.6 (CH2), 43.6 (CH2), 52.1 (CH), 55.18 (CH3O), 58.40 (C), 109.8 (CH), 114.16 (2 × CH), 122.5 (CH), 123.0 (CH), 125.2 (CH), 125.5 (CH), 127.09 (CH), 127.3 (C), 128.5 (2 × CH), 129.0 (CH), 129.8 (C), 143.2 (C), 144.5 (C), 158.98 (C), 172.8 (CO), 174.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for C23H21N2O3S+ 405.1267, found 405.1271. 5-Methyl-1-(4-methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′pyrrolidine]-2,2′(1H)-dione (2l). This compound was obtained from 1l (369 mg, 1.0 mmol): reaction time 7 + 3 h; yield 260 mg (63%); white foam; dr 52:48; Rf = 0.24 (petroleum ether−ethyl acetate, 1:1); 1 H NMR (600 MHz, CDCl3) δ 2.29 (s, 3H, CH3, A), 2.34 (s, 3H, CH3, B), 2.40 (dd, 2J = 13.3, 3J = 8.5 Hz, 1H, CH2, A), 2.80 (dd, 2J = 13.4, 3J = 7.5 Hz, 1H, CH2, B), 2.88 (dd, 2J = 13.4, 3J = 8.3 Hz, 1H, CH2, B), 3.08 (dd, 2J = 13.3, 3J = 7.0 Hz, 1H, CH2, A), 3.76 (s, 3H, CH3O, B), 3.77 (s, 3H, CH3O, A), 4.81 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.83 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.90 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.96 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.10 (dd, 3J = 8.3, 3J = 7.56.9 Hz, 1H, CH, B), 5.35 (dd, 3J = 8.5, 3J = 7.0 Hz, 1H, CH, A), 6.52 (br s, 1H, NH, A), 6.55 (br s, 1H, NH, B), 6.63−6.64 (m, 1H + 1H, Ar, A, B), 6.81−6.85 (m, 2H + 2H, Ar, A, B), 7.00−7.02 (m, 2H + 2H, Ar, A, B), 7.17−7.18 (m, 1H, Ar, B), 7.21−7.28 (m, 2H + 2H, Ar, A, B), 7.35−7.47 (m, 4H + 3H, Ar, A, B), 7.53−7.54 (m, 1H + 1H, Ar, A, B); 13C NMR (150 MHz, CDCl3) δ 21.1 (2 × CH3), 41.4 (CH2), 42.3 (CH2), 43.4 (CH2), 43.6 (CH2), 55.2 (2 × CH3O), 55.4 (CH), 56.4 (CH), 58.4 (C), 58.6 (C), 109.3 (CH), 109.5 (CH), 114.15 (2 × CH), 114.21 (2 × CH), 123.3 (CH), 124.1 (CH), 125.9 (2 × CH), 126.4 (2 × CH), 127.4 (2 × C), 128.3 (CH), 128.4 (2 × CH), 128.46 (3 × CH), 128.49 (C), 129.0 (2 × CH), 129.1 (2 × CH), 129.2 (CH), 129.4 (CH), 130.2 (C), 132.6 (C), 132.8 (C),

(34%); orange viscous oil; dr 52:48; Rf = 0.47 (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.45 (dd, 2J = 13.5, 3J = 6.8 Hz, 1H, CH2, A), 2.91 (dd, 2J = 13.5, 3J = 7.8 Hz, 1H, CH2, B), 3.12 (dd, 2J = 13.5, 3J = 7.8 Hz, 1H, CH2, B), 3.51 (dd, 2J = 13.5, 3J = 8.0 Hz, 1H, CH2, A), 3.70 (s, 3H, CH3O), 3.73 (s, 3H, CH3O), 4.82 (d, 2J = 15.5 Hz, 1H + 1H, CH2, A. B), 4.93 (d, 2J = 15.5 Hz, 1H, CH2), 4.98 (d, 2J = 15.5 Hz, 1H, CH2), 5.93 (dd, 3J = 7.8, 3J = 7.8 Hz, 1H, CH, B), 6.06 (dd, 3J = 8.0, 3J = 6.8 Hz, 1H, CH, A), 6.71 (d, 3J = 7.8 Hz, 1H, Ar), 6.75−6.78 (m, 3H, Ar), 6.80−6.81 (m, 2H, Ar), 6.94−6.97 (m, 1H, Ar), 6.96 (br s, 1H, NH), 6.99 (br s, 1H, NH), 7.01−7.02 (m, 1H, Ar), 7.12−7.17 (m, 2H, Ar), 7.23−7.25 (m, 5H, Ar), 7.48−7.49 (m, 1H, Ar), 7.52−7.60 (m, 6H, Ar), 7.73 (br d, 3J = 7.1 Hz, 1H, Ar), 7.82 (br d, 3J = 7.1 Hz, 1H, Ar), 7.85 (br d, 3J = 8.2 Hz, 1H, Ar), 7.87 (br d, 3J = 8.1 Hz, 1H, Ar), 7.92−7.94 (m, 2H, Ar), 8.05−8.08 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 40.5 (CH2), 40.7 (CH2), 43.5 (CH2), 43.6 (CH2), 52.2 (CH), 52.9 (CH), 55.15 (CH3O), 55.17 (CH3O), 58.38 (C), 58.41 (C), 109.6 (CH), 109.8 (CH), 114.1 (2 × CH), 114.2 (2 × CH), 121.4 (CH), 122.2 (CH), 122.55 (CH), 122.61 (CH), 122.7 (CH), 123.06 (CH), 123.10 (CH), 123.4 (CH), 125.6 (CH), 125.85 (CH), 125.87 (CH), 126.1 (CH), 126.5 (CH), 126.7 (CH), 127.2 (C), 127.3 (C), 128.39 (2 × CH), 128.43 (2 × CH), 128.6 (2 × CH), 128.98 (CH), 129.04 (C), 129.06 (CH), 129.07 (CH), 129.2 (CH), 130.11 (C), 130.14 (C), 130.2 (C), 134.0 (C), 133.9 (C), 136.7 (C), 138.0 (C), 143.4 (C), 143.7 (C), 158.97 (C), 159.01 (C), 173.6 (CO), 173.7 (CO), 174.9 (CO), 175.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for C29H25N2O3+ 449.1860, found 449.1862. 5′-(1,3-Benzodioxol-5-yl)-1-(4-methoxybenzyl)-2′H-spiro[indole3,3′-pyrrolidine]-2,2′(1H)-dione (2i). This compound was obtained from 1i (92 mg, 0.23 mmol): reaction time 2 + 4 h; purification performed on neutralized silica gel; yield 55 mg (54%); yellowish solid, mp 237−239 °C; dr 56:44; Rf = 0.49 (A), 0.55 (B) (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.35 (dd, 2J = 13.3, 3J = 8.3 Hz, 1H, CH2, A), 2.75 (dd, 2J = 13.4, 3J = 7.4 Hz, 1H, CH2, B), 2.82 (dd, 2J = 13.4, 3J = 8.1 Hz, 1H, CH2, B), 3.04 (dd, 2J = 13.3, 3J = 7.0 Hz, 1H, CH2, A), 3.75 (s, 3H, CH3O, B), 3.76 (s, 3H, CH3O, A), 4.81 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.82 (d, 2J = 15.7 Hz, 1H, CH2, B), 4.91 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.97 (d, 2J = 15.7 Hz, 1H, CH2, B), 5.00 (dd, 3J = 8.1, 3J = 7.4 Hz, 1H, CH, B), 5.23 (dd, 3J = 8.3, 3J = 7.0 Hz, 1H, CH, A), 5.95 (d, 2J = 1.3 Hz, 1H, OCH2O, B), 5.96 (d, 2J = 1.3 Hz, 1H, OCH2O, B), 5.97 (d, 2J = 1.3 Hz, 1H, OCH2O, A), 5.98 (d, 2J = 1.3 Hz, 1H, OCH2O, A), 6.73− 6.75 (m, 1H + 1H, Ar, A, B), 6.78−6.84 (m, 4H + 3H, Ar, NH, A, B), 6.88−6.93 (m, 1H + 3H, Ar, A, B), 7.04−7.07 (m, 2H + 1H, Ar, A, B), 7.18−7.22 (m, 2H + 1H, Ar, A, B), 7.23−7.25 (m, 2H, Ar, A), 7.26−7.28 (m, 2H, Ar, B), 7.32−7.33 (m, 1H, Ar, B). A: 13C NMR (150 MHz, CDCl3) δ 42.2 (CH2), 43.4 (CH2), 55.17 (CH3O), 55.23 (CH), 58.6 (C), 101.3 (OCH2O), 106.1 (CH), 108.5 (CH), 109.5 (CH), 114.22 (2 × CH), 119.4 (CH), 123.2 (CH), 123.3 (CH), 127.29 (C), 128.38 (2 × CH), 128.7 (C), 129.0 (CH), 135.3 (C), 143.8 (C), 147.6 (C), 148.32 (C), 159.03 (C), 173.3 (CO), 175.5 (CO). B: 13C NMR (150 MHz, CDCl3) δ 41.4 (CH2), 43.6 (CH2), 55.16 (CH3O), 56.2 (CH), 58.4 (C), 101.2 (OCH2O), 106.7 (CH), 108.3 (CH), 109.7 (CH), 114.16 (2 × CH), 119.9 (CH), 122.4 (CH), 122.9 (CH), 127.31 (C), 128.43 (2 × CH), 128.9 (CH), 130.2 (C), 135.1 (C), 143.2 (C), 147.7 (C), 148.28 (C), 159.00 (C), 173.4 (CO), 175.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C26H23N2O5+ 443.1601, found 443.1603. 1-(4-Methoxybenzyl)-5′-(3,4,5-trimethoxyphenyl)-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (2j). This compound was obtained from 1j (210 mg, 0.47 mmol): reaction time 2 + 4 h; purification performed on neutralized silica gel; yield 145 mg (63%); yellow solid, mp 166−168 °C; dr 54:46; Rf = 0.21 (A), 0.25 (B) (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, DMSOd6) δ 2.29 (dd, 2J = 13.1, 3J = 8.1 Hz, 1H, CH2, A), 2.47 (dd, 2J = 13.2, 3J = 8.1 Hz, 1H, CH2, B), 2.80 (dd, 2J = 13.2, 3J = 7.4 Hz, 1H, CH2, B), 2.99 (dd, 2J = 13.1, 3J = 7.0 Hz, 1H, CH2, A), 3.669 (s, 3H, CH3O, A), 3.673 (s, 3H, CH3O, B), 3.709 (s, 3H, CH3O, B), 3.713 (s, 3H, CH3O, A), 3.82 (s, 6H, CH3O, B), 3.84 (s, 6H, CH3O, A), 4.78 (d, 2J = 15.7 Hz, 1H, CH2, B), 4.81 (d, 2J = 15.6 Hz, 1H, CH2, 8705

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry

B), 4.80 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.91 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.96 (d, 2J = 15.7 Hz, 1H, CH2, B), 5.13 (dd, 3J = 8.1, 3J = 6.9 Hz, 1H, CH, A), 5.29 (dd, 3J = 8.2, 3J = 7.4 Hz, 1H, CH, B), 6.87−6.90 (m, 2H + 2H, Ar, A, B), 6.91−6.94 (m, 1H + 1H, Ar, A, B), 7.26−7.28 (m, 2H, Ar, A), 7.29−7.31 (m, 1H + 2H, Ar, A, B), 7.32−7.37 (m, 1H + 2H, Ar, A, B), 7.40−7.41 (m, 1H, Ar, A), 7.43− 7.45 (m, 2H + 2H, Ar, A, B), 7.49−7.50 (m, 2H, Ar, B), 7.56−7.57 (m, 2H, Ar, A), 7.66−7.67 (m, 1H, Ar, B), 8.94 (br s, 1H, NH, B), 8.97 (br s, 1H, NH, A). A: 13C NMR (150 MHz, DMSO-d6) δ 40.9 (CH2), 42.2 (CH2), 54.84 (CH), 55.0 (CH3O), 58.7 (C), 110.6 (CH), 114.1 (2 × CH), 124.0 (CH), 126.6 (2 × CH), 126.9 (CH), 127.53 (C), 127.84 (C), 128.4 (CH), 128.5 (2 × CH), 128.6 (2 × CH), 131.1 (C), 142.0 (C), 142.4 (C), 158.62 (C), 171.7 (CO), 175.04 (CO). B: 13C NMR (150 MHz, DMSO-d6) δ 40.3 (CH2), 42.5 (CH2), 54.81 (CH), 55.0 (CH3O), 58.7 (C), 110.7 (CH), 114.0 (2 × CH), 123.1 (CH), 126.3 (2 × CH), 126.8 (CH), 127.46 (C), 127.76 (C), 128.3 (CH), 128.5 (2 × CH), 128.7 (2 × CH), 132.4 (C), 141.9 (C), 142.0 (C), 158.59 (C), 171.8 (CO), 174.97 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H22ClN2O3+ 433.1313, found 433.1323. 5-Bromo-1-(4-methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′pyrrolidine]-2,2′(1H)-dione (2p). This compound was obtained from 1p (433 mg, 1.0 mmol): reaction time 100 min; yield 300 mg (63%); white solid, mp 228−230 °C; dr 52:48; Rf = 0.56 (A), 0.47 (B) (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, DMSOd6) δ 2.36 (dd, 2J = 13.2, 3J = 8.2 Hz, 1H, CH2, A), 2.43 (dd, 2J = 13.3, 3J = 8.2 Hz, 1H, CH2, B), 2.85 (dd, 2J = 13.3, 3J = 7.5 Hz, 1H, CH2, B), 3.00 (dd, 2J = 13.2, 3J = 7.0 Hz, 1H, CH2, A), 3.710 (s, 3H, CH3O, B), 3.711 (s, 3H, CH3O, A), 4.76 (d, 2J = 15.8 Hz, 1H, CH2, B), 4.79 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.90 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.95 (d, 2J = 15.8 Hz, 1H, CH2, B), 5.12 (dd, 3J = 8.2, 3J = 7.0 Hz, 1H, CH, A), 5.28 (dd, 3J = 8.2, 3J = 7.5 Hz, 1H, CH, B), 6.87−6.90 (m, 3H + 3H, Ar, A, B), 7.25−7.27 (m, 2H, Ar, A), 7.28− 7.30 (m, 2H, Ar, B), 7.34−7.37 (m, 1H + 1H, Ar, A, B), 7.42−7.46 (m, 3H + 3H, Ar, A, B), 7.48−7.49 (m, 2H, Ar, B), 7.51−7.52 (m, 1H, Ar, A), 7.56−7.57 (m, 2H, Ar, A), 7.76−7.77 (m, 1H, Ar, B), 8.94 (br s, 1H, NH, B), 8.97 (br s, 1H, NH, A); 13C NMR (150 MHz, DMSO-d6) δ 40.3 (CH2), 40.8 (CH2), 42.2 (CH2), 42.4 (CH2), 54.79 (CH), 54.84 (CH), 55.0 (2 × CH3O), 58.6 (2 × C), 111.1 (CH), 111.3 (CH), 114.0 (2 × CH), 114.1 (2 × CH), 114.54 (C), 114.56 (C), 125.7 (CH), 126.3 (2 × CH), 126.6 (2 × CH), 126.7 (CH), 127.4 (C), 127.5 (C), 127.75 (CH), 127.83 (CH), 128.5 (4 × CH), 128.6 (2 × CH), 128.7 (2 × CH), 131.2 (CH), 131.3 (CH), 131.4 (C), 132.8 (C), 142.0 (C), 142.3 (C), 142.6 (C), 142.9 (C), 158.59 (C), 158.61 (C), 171.7 (CO), 171.8 (CO), 174.94 (CO), 174.88 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H22BrN2O3+ 477.0808, found 477.0829. 1-Methyl-5′-phenyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)dione (2q).17 This compound was obtained from 1q (397 mg, 1.59 mmol): reaction time 2 + 6 h; yield 280 mg (67%, based on 90% conversion); yellow solid, mp 195−196 °C (lit. 198−200 °C); dr 50:50; Rf = 0.6 (ethyl acetate). A: 1H NMR (600 MHz, CDCl3) δ 2.33 (dd, 2J = 13.5, 3J = 8.0 Hz, 1H, CH2), 3.01 (dd, 2J = 13.5, 3J = 7.4 Hz, 1H, CH2), 3.20 (s, 3H, CH3N), 5.22 (dd, 3J = 8.0, 3J = 7.4 Hz, 1H, CH), 6.84 (d, 3J = 7.8 Hz, 1H, Ar), 7.04−7.06 (m, 1H, Ar), 7.12 (d, 3J = 7.9 Hz, 1H, Ar), 7.28−7.33 (m, 3H, Ar), 7.37−7.40 (m, 3H + 1H, Ar, NH); 13C NMR (150 MHz, CDCl3) δ 26.4 (CH3N), 41.8 (CH2), 55.3 (CH), 58.6 (C), 108.6 (CH), 123.16 (CH), 123.22 (CH), 125.7 (2 × CH), 128.2 (CH), 128.5 (C), 129.0 (2 × CH), 129.2 (CH), 141.4 (C), 144.5 (C), 173.7 (CO), 175.6 (CO). 1-Methyl-5′-(4-tolyl)-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)dione (2r). This compound was obtained from 1r (400 mg, 1.52 mmol): reaction time 2 + 7 h; yield 255 mg (61%, based on 90% conversion); white solid, mp 234−235 °C; dr 50:50; Rf = 0.67 (ethyl acetate); 1H NMR (600 MHz, CDCl3) δ 2.36 (dd, 2J = 13.5, 3J = 8.3 Hz, 1H, CH2, A), 2.37 (CH3), 2.38 (CH3), 2.72 (dd, 2J = 13.4, 3J = 7.2 Hz, 1H, CH2, B), 2.79 (dd, 2J = 13.4, 3J = 8.4 Hz, 1H, CH2, B), 3.02 (dd, 2J = 13.5, 3J = 7.1 Hz, 1H, CH2, A), 3.23 (s, 3H, CH3N, A), 3.26 (s, 3H, CH3N, B), 5.04 (dd, 3J = 8.4, 3J = 7.2 Hz, 1H, CH, B), 5.26 (dd, 3J = 8.3, 3J = 7.1 Hz, 1H, CH, A), 6.43 (br s, 1H, NH, A),

140.8 (C), 141.2 (C), 141.4 (C), 141.5 (C), 158.96 (C), 159.01 (C), 173.5 (CO), 173.6 (CO), 175.0 (CO), 175.4 (CO); HRMS (ESI) m/ z [M + H]+ calcd for C26H25N2O3+ 413.1860, found 413.1873. 5-Fluoro-1-(4-methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′pyrrolidine]-2,2′(1H)-dione (2m). This compound was obtained from 1m (373 mg, 1.0 mmol): reaction time 2 h; yield 266 mg (64%); yellowish foam; dr 51:49; Rf = 0.18 (petroleum ether−ethyl acetate, 2:1); 1H NMR (600 MHz, CDCl3) δ 2.35 (dd, 2J = 13.4, 3J = 8.0 Hz, 1H, CH2, A), 2.79 (dd, 2J = 13.5, 3J = 7.5 Hz, 1H, CH2, B), 2.86 (dd, 2 J = 13.5, 3J = 8.2 Hz, 1H, CH2, B), 3.13 (dd, 2J = 13.4, 3J = 7.2 Hz, 1H, CH2, A), 3.74 (s, 3H, CH3O), 3.76 (s, 3H, CH3O), 4.78 (d, 2J = 15.7 Hz, 1H, CH2), 4.79 (d, 2J = 15.7 Hz, 1H, CH2), 4.91 (d, 2J = 15.7 Hz, 1H, CH2), 4.96 (d, 2J = 15.7 Hz, 1H, CH2), 5.06 (dd, 3J = 8.2, 3J = 7.5 Hz, 1H, CH, B), 5.31 (dd, 3J = 8.0, 3J = 7.2 Hz, 1H, CH, A), 6.63−6.66 (m, 2H, Ar), 6.79−6.84 (m, 4H, Ar), 6.86−6.92 (m, 3H, Ar), 7.11−7.13 (m, 1H, Ar), 7.21−7.26 (m, 4H, Ar), 7.24 (br s, 1H, NH), 7.28 (br s, 1H, NH), 7.32−7.37 (m, 2H, Ar), 7.39−7.44 (m, 6H, Ar), 7.49−7.51 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 41.0 (1JCH = 133 Hz, CH2), 41.9 (1JCH = 133 Hz, CH2), 43.5 (1JCH = 139 Hz, CH2), 43.6 (1JCH = 139 Hz, CH2), 55.13 (1JCH = 144 Hz, CH3O), 55.14 (1JCH = 144 Hz, CH3O), 55.3 (1JCH = 145 Hz, CH), 56.3 (1JCH = 145 Hz, CH), 58.8 (C), 58.9 (C), 110.1 (3JCF = 8 Hz, CH), 110.2 (3JCF = 8 Hz, CH), 110.8 (2JCF = 25 Hz, CH), 111.5 (2JCF = 25 Hz, CH), 114.16 (2 × CH), 114.22 (2 × CH), 115.1 (2JCF = 25 Hz, CH), 115.3 (2JCF = 25 Hz, CH), 125.7 (2 × CH), 126.3 (2 × CH), 126.9 (CH), 128.2 (CH), 128.3 (2 × CH), 128.4 (2 × CH), 129.0 (2 × CH), 129.1 (2 × CH), 130.1 (3JCF = 8 Hz, C), 131.4 (3JCF = 8 Hz, C), 139.1 (C), 139.6 (C), 141.0 (C), 141.3 (C), 158.99 (C), 159.03 (C), 159.2 (1JCF = 242 Hz, C), 159.3 (1JCF = 242 Hz, C), 173.0 (CO), 173.1 (CO), 174.8 (CO), 175.2 (CO); HRMS (ESI) m/ z [M + H]+ calcd for C25H22FN2O3+ 417.1609, found 417.1611. Ethyl 4-[5-Fluoro-1-(4-methoxybenzyl)-2,2′-dioxo-1,2dihydrospiro[indole-3,3′-pyrrolidine]-5′-yl]benzoate (2n). This compound was obtained from 1n (356 mg, 0.80 mmol): reaction time 2 h; yield 165 mg (42%); brown foam; dr 51:49; Rf = 0.47 (A), 0.38 (B) (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 1.38 (t, 3J = 7.1 Hz, 3H, CH3), 1.40 (t, 3J = 7.1 Hz, 3H, CH3), 2.30 (dd, 2J = 13.4, 3J = 8.0 Hz, 1H, CH2, A), 2.78 (dd, 2J = 13.6, 3J = 7.8 Hz, 1H, CH2, B), 2.83 (dd, 2J = 13.6, 3J = 7.8 Hz, 1H, CH2, B), 3.14 (dd, 2J = 13.4, 3J = 7.3 Hz, 1H, CH2, A), 3.71 (s, 3H, CH3O), 3.73 (s, 3H, CH3O), 4.36 (q, 3J = 7.1 Hz, 2H, CH2O), 4.38 (q, 3J = 7.1 Hz, 2H, CH2O), 4.75 (d, 2J = 15.7 Hz, 1H, CH2), 4.76 (d, 2 J = 15.7 Hz, 1H, CH2), 4.88 (d, 2J = 15.7 Hz, 1H, CH2), 4.93 (d, 2J = 15.7 Hz, 1H, CH2), 5.10−5.13 (m, 1H, CH), 5.34−5.37 (m, 1H, CH), 6.61−6.65 (m, 2H, Ar), 6.75−6.79 (m, 4H, Ar), 6.85−6.91 (m, 3H, Ar), 7.09−7.11 (m, 1H, Ar), 7.17−7.22 (m, 4H, Ar), 7.46−7.47 (m, 2H, Ar), 7.53−7.54 (m, 2H, Ar), 7.66−7.71 (m, 1H, NH), 7.71− 7.75 (m, 1H, NH), 8.04−8.07 (m, 4H, Ar); 13C NMR (150 MHz, CDCl3) δ 14.2 (2 × CH3), 40.6 (CH2), 41.5 (CH2), 43.4 (CH2), 43.6 (CH2), 55.07 (CH3O), 55.09 (CH3O), 55.13 (CH), 55.9 (CH), 58.7 (C), 58.8 (C), 60.95 (CH2O), 61.01 (CH2O), 110.2 (3JCF = 9 Hz, CH), 110.3 (3JCF = 9 Hz, CH), 110.8 (2JCF = 25 Hz, CH), 111.4 (2JCF = 25 Hz, CH), 114.1 (2 × CH), 114.2 (2 × CH), 115.1 (2JCF = 24 Hz, CH), 115.4 (2JCF = 24 Hz, CH), 125.5 (2 × CH), 126.1 (2 × CH), 126.7 (C), 126.8 (C), 128.2 (2 × CH), 128.3 (2 × CH), 129.9 (3JCF = 8 Hz, C), 130.2 (2 × CH), 130.3 (2 × CH), 130.4 (3JCF = 8 Hz, 2 × C), 131.1 (3JCF = 8 Hz, C), 139.1 (C), 139.5 (C), 146.0 (C), 146.3 (C), 158.98 (C), 159.02 (C), 159.2 (1JCF = 242 Hz, C), 159.3 (1JCF = 242 Hz, C), 165.96 (CO2Et), 166.01 (CO2Et), 173.3 (CO), 173.4 (CO), 174.7 (CO), 175.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C28H26FN2O5+ 489.1820, found 489.1828. 5-Chloro-1-(4-methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′pyrrolidine]-2,2′(1H)-dione (2o). This compound was obtained from 1o (389 mg, 1.0 mmol): reaction time 100 min; yield 217 mg (50%); white solid, mp 208−210 °C; dr 52:48; Rf = 0.56 (A), 0.43 (B) (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, DMSOd6) δ 2.36 (dd, 2J = 13.2, 3J = 8.1 Hz, 1H, CH2, A), 2.45 (dd, 2J = 13.3, 3J = 8.2 Hz, 1H, CH2, B), 2.85 (dd, 2J = 13.3, 3J = 7.4 Hz, 1H, CH2, B), 3.00 (dd, 2J = 13.2, 3J = 6.9 Hz, 1H, CH2, A), 3.710 (s, 3H, CH3O, B), 3.713 (s, 3H, CH3O, A), 4.77 (d, 2J = 15.7 Hz, 1H, CH2, 8706

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

Note

The Journal of Organic Chemistry

B), 5.04 (dd, 3J = 8.1, 3J = 7.1 Hz, 1H, CH, A), 5.13 (dd, 3J = 8.2, 3J = 7.4 Hz, 1H, CH, B), 6.79 (s, 2H, Ar), 6.82 (s, 2H, Ar), 7.03−7.04 (m, 1H, Ar, A), 7.05−7.08 (m, 1H + 1H, Ar, A, B), 7.09−7.12 (m, 1H, Ar, B), 7.27−7.29 (m, 1H, Ar, A), 7.31−7.37 (m, 1H + H, Ar, A, B), 7.46−7.48 (m, 1H, Ar, B), 8.81 (br s, 1H, NH, B), 8.83 (br s, 1H, NH, A). A: 13C NMR (150 MHz, DMSO-d6) δ 26.2 (CH3N), 41.1 (CH2), 54.8 (CH), 56.0 (2 × CH3O), 58.28 (C), 60.01 (CH3O), 103.3 (2 × CH), 108.6 (CH), 122.55 (CH), 123.4 (CH), 128.71 (CH), 129.2 (C), 136.9 (C), 138.0 (C), 144.6 (C), 153.1 (2 × C), 172.4 (CO), 175.2 (CO). B: 13C NMR (150 MHz, DMSO-d6) δ 26.4 (CH3N), 40.7 (CH2), 55.2 (CH), 55.9 (2 × CH3O), 58.27 (C), 60.02 (CH3O), 103.4 (2 × CH), 108.7 (CH), 122.57 (CH), 122.59 (CH), 128.69 (CH), 130.5 (C), 136.9 (C), 138.3 (C), 144.0 (C), 153.0 (2 × C), 172.4 (CO), 175.0 (CO); HRMS (ESI) m/z [M + H]+ calcd for C21H23N2O5+ 383.1601, found 383.1609. General Procedure20 for PMB-N-deprotection of 2. To solution of 2 (0.20 mmol, 1.0 equiv) in CH2Cl2 (2.50 mL, 0.08 M) were sequentially added TFA (0.75 mL, 10.0 mmol, 50 equiv) and TfOH (44 μL, 5.0 mmol, 2.5 equiv). The resulting solution was stirred at room temperature for the time specified. The reaction mixture was then poured into an ice−water mixture and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on neutralized silica gel (ethyl acetate−petroleum ether). 5′-Phenyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (3a). This compound was obtained from 2a (89 mg, 0.224 mmol): reaction time 54 h; yield 33 mg (53%); white solid, mp 274−275 °C; dr 54:46; Rf = 0.72 (ethyl acetate); 1H NMR (600 MHz, DMSO-d6) δ 2.18 (dd, 2 J = 13.3, 3J = 7.9 Hz, 1H, CH2, A), 2.36 (dd, 2J = 13.2, 3J = 8.6 Hz, 1H, CH2, B), 2.71 (dd, 2J = 13.2, 3J = 7.3 Hz, 1H, CH2, B), 2.98 (dd, 2 J = 13.3, 3J = 7.3 Hz, 1H, CH2, A), 5.03 (dd, 3J = 7.9, 3J = 7.3 Hz, 1H, CH2, A), 5.15 (dd, 3J = 8.6, 3J = 7.3 Hz, 1H, CH2, B), 6.84−6.86 (m, 1H, Ar, A), 6.87−6.90 (m, 1H, Ar, B), 6.94−6.98 (m, 1H, Ar, A), 7.00−7.04 (m, 1H, Ar, B), 7.12−7.15 (m, 1H, Ar, A), 7.19−7.23 (m, 1H, Ar, A), 7.23−7.27 (m, 1H, Ar, B), 7.32−7.37 (m, 1H + 1H, Ar, A, B), 7.41−7.51 (m, 4H + 5H, Ar, A, B), 8.77 (s, 1H, NH, B), 8.80 (s, 1H, NH, A), 10.56 (s, 1H, NH, A), 10.60 (s, 1H, NH, B); 13C NMR (150 MHz, DMSO-d6) δ 40.9 (CH2), 41.2 (CH2), 54.6 (CH), 55.0 (CH), 58.7 (C), 58.8 (C), 109.4 (CH), 109.6 (CH), 121.9 (2 × CH), 122.9 (CH), 123.5 (CH), 126.23 (2 × CH), 126.24 (2 × CH), 127.7 (2 × CH), 128.55 (CH), 128.56 (CH), 128.6 (2 × CH), 128.7 (2 × CH), 130.2 (C), 131.4 (C), 142.5 (C), 142.66 (C), 142.71 (C), 143.1 (C), 172.6 (CO), 172.7 (CO), 176.6 (CO), 177.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C17H15N2O2+ 279.1128, found 279.1133. 5′-(3,4,5-Trimethoxyphenyl)-2′H-spiro[indole-3,3′-pyrrolidine]2,2′(1H)-dione (3b). This compound was obtained from 2j (105 mg, 0.215 mmol): reaction time 114 h; yield 40 mg (51%); yellow solid, mp 249−250 °C; dr 53:47; Rf = 0.45 (ethyl acetate); 1H NMR (600 MHz, DMSO-d6) δ 2.21 (dd, 2J = 13.2, 3J = 8.2 Hz, 1H, CH2, A), 2.38 (dd, 2J = 13.2, 3J = 8.4 Hz, 1H, CH2, B), 2.71 (dd, 2J = 13.2, 3J = 7.4 Hz, 1H, CH2, B), 2.94 (dd, 2J = 13.2, 3J = 7.2 Hz, 1H, CH2, A), 3.66 (s, 6H, CH3O, B), 3.81 (s, 3H + 3H, CH3O, A, B), 5.01 (dd, 3J = 8.2, 3 J = 7.2 Hz, 1H, CH, A), 5.10 (dd, 3J = 8.4, 3J = 7.4 Hz, 1H, CH, B), 6.78 (s, 1H, Ar, A), 6.80 (s, 1H, Ar, B), 6.83−6.87 (m, 1H, Ar, A), 6.87−6.91 (m, 1H, Ar, B), 6.95−7.00 (m, 1H, Ar, A), 7.00−7.05 (m, Ar, 1H, Ar, B), 7.19−7.27 (m, 2H + 1H, Ar, A, B), 7.39−7.42 (m, 1H, Ar, B), 8.76 (br s, 1H, NH, B), 8.78 (br s, 1H, NH, A), 10.56 (br s, 1H, NH), 10.60 (br s, 1H, NH); 13C NMR (150 MHz, DMSO-d6) δ 40.7 (CH2), 41.1 (CH2), 54.8 (CH), 55.2 (CH), 55.9 (2 × CH3O), 56.0 (2 × CH3O), 58.7 (2 × C), 60.0 (2 × CH3O), 103.3 (2 × CH), 103.4 (2 × CH), 109.4 (CH), 109.6 (CH), 121.9 (2 × CH), 122.9 (CH), 123.7 (CH), 128.6 (2 × CH), 130.1 (C), 131.3 (C), 136.9 (2 × C), 138.1 (C), 138.3 (C), 142.5 (C), 143.1 (C), 153.0 (2 × C), 153.1 (2 × C), 172.6 (2 × CO), 176.7 (CO), 177.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C20H21N2O5+ 369.1445, found 369.1446.

6.49 (br s, 1H, NH, B), 6.86−6.89 (m, 1H + 1H, Ar, A, B), 7.08−7.13 (m, 1H + 1H, Ar, A, B), 7.18−7.24 (m, 3H + 2H, Ar, A, B), 7.30− 7.36 (m, 3H + 2H, Ar, A, B), 7.38−7.39 (m, 2H, Ar, B). A: 13C NMR (150 MHz, CDCl3) δ 21.1 (CH3), 26.5 (CH3N), 42.3 (CH2), 55.1 (CH), 58.5 (C), 108.5 (CH), 123.2 (CH), 123.3 (CH), 125.8 (2 × CH), 128.6 (C), 129.2 (CH), 129.74 (2 × CH), 138.2 (C), 138.5 (C), 144.7 (C), 173.2 (CO), 175.4 (CO). B: 13C NMR (150 MHz, CDCl3) δ 21.1 (CH3), 26.7 (CH3N), 41.8 (CH2), 56.1 (CH), 58.4 (C), 108.7 (CH), 122.4 (CH), 123.0 (CH), 126.4 (2 × CH), 129.1 (CH), 129.65 (2 × CH), 130.1 (C), 138.0 (C), 138.3 (C), 144.2 (C), 173.4 (CO), 174.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for C19H19N2O2+ 307.1441, found 307.1438. 5′-(4-Methoxyphenyl)-1-methyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (2s). This compound was obtained from 1s (120 mg, 0.43 mmol). Reaction time 2 + 4 h; purification performed on neutralized silica gel; yield 89 mg (64%); white solid, mp 231−232 °C; dr 54:46; Rf = 0.11 (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.31 (dd, 2J = 13.3, 3J = 8.1 Hz, 1H, CH2, A), 2.68 (dd, 2J = 13.3, 3J = 7.4 Hz, 1H, CH2, B), 2.73 (dd, 2J = 13.3, 3 J = 8.3 Hz, 1H, CH2, B), 2.99 (dd, 2J = 13.3, 3J = 7.1 Hz, 1H, CH2, A), 3.20 (s, 3H, CH3N, A), 3.23 (s, 3H, CH3N, B), 3.79 (s, 3H, CH3O, B), 3.81 (s, 3H, CH3O, A), 5.00 (dd, 3J = 8.1, 3J = 7.1 Hz, 1H, CH, A), 5.20 (dd, 3J = 8.3, 3J = 7.4 Hz, 1H, CH, B), 6.84−6.93 (m, 3H + 3H, Ar, NH, A, B), 6.96 (br s, 1H, NH, B), 7.07−7.12 (m, 2H + 1H, Ar, A, B), 7.16−7.17 (m, 1H, Ar, B), 7.30−7.35 (m, 2H + 3H, Ar, A, B), 7.37−7.39 (m, 2H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 26.5 (CH3N), 42.2 (CH2), 54.8 (CH), 55.3 (CH3O), 58.52 (C), 108.5 (CH), 114.3 (2 × CH), 123.1 (CH), 123.2 (CH), 127.0 (2 × CH), 128.7 (C), 129.05 (CH), 133.4 (C), 144.5 (C), 159.4 (C), 173.4 (CO), 175.4 (CO). B: 13C NMR (150 MHz, CDCl3) δ 26.6 (CH3N), 41.7 (CH2), 55.2 (CH3O), 55.9 (CH), 58.46 (C), 108.6 (CH), 114.2 (2 × CH), 122.4 (CH), 122.9 (CH), 127.6 (2 × CH), 128.95 (CH), 130.1 (C), 133.0 (C), 144.0 (C), 159.5 (C), 173.5 (CO), 174.9 (CO); HRMS (ESI) m/z [M + H]+ calcd for C19H19N2O3+ 323.1390, found 323.1391. 5′-(1,3-Benzodioxol-5-yl)-1-methyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (2t). This compound was obtained from 1t (86 mg, 0.29 mmol): reaction time 2 + 5 h; purification performed on neutralized silica gel; yield 53 mg (54%); brown solid, mp 243−244 °C; dr 51:49; Rf = 0.67 (ethyl acetate); 1H NMR (600 MHz, CDCl3) δ 2.32 (dd, 2J = 13.4, 3J = 8.3 Hz, 1H, CH2, A), 2.71 (ddd, 2J = 13.5, 3 J = 7.5, 5J = 0.7 Hz, 1H, CH2, B), 2.75 (dd, 2J = 13.5, 3J = 8.1 Hz, 1H, CH2, B), 2.98 (ddd, 2J = 13.4, 3J = 7.1, 5J = 0.8 Hz, 1H, CH2, A), 3.23 (s, 3H, CH3N, A), 3.26 (s, 3H, CH3N, B), 4.98 (dd, 3J = 8.1, 3J = 7.5 Hz, 1H, CH, B), 5.20 (dd, 3J = 8.3, 3J = 7.1 Hz, 1H, CH, A), 5.98 (br s, 2H, OCH2O), 5.99 (br s, 2H, OCH2O), 6.52 (br s, 1H, NH, A), 6.57 (br s, 1H, NH, B), 6.80 (d, 3J = 7.9 Hz, 1H, Ar, B), 6.83 (d, 3 J = 7.8 Hz, 1H, Ar, A), 6.86−6.92 (m, 3H + 2H, Ar, A, B), 7.04−7.05 (m, 1H, Ar, B), 7.09−7.12 (m, 1H + 1H, Ar, A, B), 7.20−7.21 (m, 1H, Ar, A), 7.32−7.35 (m, 1H + 2H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 26.6 (CH3N), 42.3 (CH2), 55.2 (CH), 58.5 (C), 101.30 (OCH2O), 106.1 (CH), 108.6 (2 × CH), 119.4 (CH), 123.2 (CH), 123.3 (CH), 128.5 (C), 129.2 (CH), 135.3 (C), 144.7 (C), 147.6 (C), 148.4 (C), 173.2 (CO), 175.3 (CO). B: 13C NMR (150 MHz, CDCl3) δ 26.8 (CH3N), 41.7 (CH2), 56.2 (CH), 58.3 (C), 101.27 (OCH2O), 106.7 (CH), 108.4 (CH), 108.7 (CH), 120.0 (CH), 122.4 (CH), 123.0 (CH), 129.1 (CH), 130.1 (C), 134.9 (C), 144.2 (C), 147.7 (C), 148.3 (C), 173.3 (CO), 174.9 (CO); HRMS (ESI) m/z [M + H]+ calcd for C19H17N2O4+ 337.1183, found 337.1184. 1-Methyl-5′-(3,4,5-trimethoxyphenyl)-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (2u). This compound was obtained from 1u (100 mg, 0.30 mmol): reaction time 2 + 5 h; purification performed on neutralized silica gel; yield 64 mg (57%); white solid, mp 222−223 °C; dr 51:49; Rf = 0.50 (A), 0.43 (B) (ethyl acetate); 1H NMR (600 MHz, DMSO-d6) δ 2.24 (dd, 2J = 13.3, 3J = 8.1 Hz, 1H, CH2, A), 2.41 (dd, 2J = 13.3, 3J = 8.2 Hz, 1H, CH2, B), 2.73 (dd, 2J = 13.3, 3J = 7.4 Hz, 1H, CH2, B), 2.94 (dd, 2J = 13.3, 3J = 7.1 Hz, 1H, CH2, A), 3.15 (s, 3H, CH3N, A), 3.17 (s, 3H, CH3N, B), 3.67 (s, 3H + 3H, CH3O, A, B), 3.82 (s, 3H + 3H, CH3O, A, B), 3.83 (s, 3H + 3H, CH3O, A, 8707

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

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The Journal of Organic Chemistry 5-Bromo-5′-phenyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)dione (3c). This compound was obtained from 2p (88 mg, 0.185 mmol): reaction time 114 h; yield 28 mg (42%); beige solid, mp 290−291 °C; dr 55:45; Rf = 0.66 (ethyl acetate); 1H NMR (600 MHz, DMSO-d6) δ 2.26 (dd, 2J = 13.2, 3J = 8.2 Hz, 1H, CH2, A), 2.33 (dd, 2J = 13.3, 3J = 8.5 Hz, 1H, CH2, B), 2.75 (dd, 2J = 13.3, 3J = 7.5 Hz, 1H, CH2, B), 2.93 (dd, 2J = 13.2, 3J = 7.0 Hz, 1H, CH2, A), 5.03 (dd, 3J = 8.2, 3J = 7.0 Hz, 1H, CH, A), 5.22 (dd, 3J = 8.5, 3J = 7.5 Hz, 1H, CH, B), 6.81 (d, 3J = 8.2 Hz, 1H, Ar, A), 6.84 (d, 3J = 8.3 Hz, 1H, Ar, B), 7.31−7.37 (m, 1H + 1H, Ar, A, B), 7.38−7.48 (m, Ar, 4H + 5H, Ar, A, B), 7.50−7.55 (m, 2H, Ar, A), 7.67 (d, 4J = 1.9 Hz, 1H, Ar, B), 8.81 (s, 1H, NH, B), 8.86 (s, 1H, NH, A), 10.71 (br s, 1H, NH, B), 10.75 (br s, 1H, NH, A); 13C NMR (150 MHz, DMSO-d6) δ 40.4 (CH2), 40.9 (CH2), 54.8 (2 × CH), 59.0 (C), 111.3 (CH), 111.5 (CH), 113.6 (2 × C), 125.9 (CH), 126.2 (2 × CH), 126.6 (2 × CH), 126.8 (CH), 127.7 (CH), 127.8 (CH), 128.59 (3 × CH), 128.64 (2 × CH), 131.3 (2 × CH), 132.3 (C), 133.6 (C), 141.9 (C), 142.2 (C), 142.5 (C), 142.7 (C), 172.0 (CO), 172.1 (CO), 176.3 (CO), 176.6 (CO); HRMS (ESI) m/z [M + H]+ calcd for C17H14BrN2O2+ 357.0233, found 357.0238.

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Simone, F.; Frei, R.; Benfatti, F.; Serrano, E.; Waser, J. Cyclization and Annulation Reactions of Nitrogen-Substituted Cyclopropanes and Cyclobutanes. Chem. Commun. 2014, 50 (75), 10912−10928. (f) Wang, Z. Polar Intramolecular Cross-Cycloadditions of Cyclopropanes toward Natural Product Synthesis. Synlett 2012, 23 (16), 2311−2327. (3) Budynina, E. M.; Ivanov, K. L.; Sorokin, I. D.; Melnikov, M. Ya. Ring Opening of Donor−Acceptor Cyclopropanes with N-Nucleophiles. Synthesis 2017, 49 (14), 3035−3068. (4) For recent examples of DA cyclopropane ring opening with amines, see: (a) Nambu, H.; Hirota, W.; Fukumoto, M.; Tamura, T.; Yakura, T. An Efficient Route to Highly Substituted Indoles via Tetrahydroindol-4(5H)-One Intermediates Produced by Ring-Opening Cyclization of Spirocyclopropanes with Amines. Chem. - Eur. J. 2017, 23 (66), 16799−16805. (b) Das, S.; Daniliuc, C. G.; Studer, A. Stereospecific 1,3-Aminobromination of Donor−Acceptor Cyclopropanes. Angew. Chem., Int. Ed. 2017, 56 (38), 11554−11558. (c) Xia, Y.; Lin, L.; Chang, F.; Liao, Y.; Liu, X.; Feng, X. Asymmetric Ring Opening/Cyclization/Retro-Mannich Reaction of Cyclopropyl Ketones with Aryl 1,2-Diamines for the Synthesis of Benzimidazole Derivatives. Angew. Chem., Int. Ed. 2016, 55 (40), 12228−12232. (d) Tejeda, J. E. C.; Landschoot, B. K.; Kerr, M. A. Radical Cyclizations for the Synthesis of Pyrroloindoles: Progress toward the Flinderoles. Org. Lett. 2016, 18 (9), 2142−2145. (e) Afanasyev, O. I.; Tsygankov, A. A.; Usanov, D. L.; Chusov, D. Dichotomy of Reductive Addition of Amines to Cyclopropyl Ketones vs Pyrrolidine Synthesis. Org. Lett. 2016, 18 (22), 5968−5970. (f) Han, J.-Q.; Zhang, H.-H.; Xu, P.-F.; Luo, Y.-C. Lewis Acid and (Hypo)iodite Relay Catalysis Allows a Strategy for the Synthesis of Polysubstituted Azetidines and Tetrahydroquinolines. Org. Lett. 2016, 18 (20), 5212−5215. (5) For examples of DA cyclopropane ring opening with hydrazines, see: (a) Sathishkannan, G.; Tamilarasan, V. J.; Srinivasan, K. Nucleophilic Ring-Opening Reactions of trans-2-Aroyl-3-aryl-cyclopropane-1,1-dicarboxylates with Hydrazines. Org. Biomol. Chem. 2017, 15 (6), 1400−1406. (b) Xue, S.; Liu, J.; Qing, X.; Wang, C. Brönsted Acid-Mediated Annulations of 1-Cyanocyclopropane-1-carboxylates with Arylhydrazines: Efficient Strategy for the Synthesis of 1,3,5Trisubstituted Pyrazoles. RSC Adv. 2016, 6 (72), 67724−67728. (c) Lebold, T. P.; Kerr, M. A. Stereodivergent Synthesis of Fused Bicyclopyrazolidines: Access to Pyrazolines and Pyrrolidines. Org. Lett. 2009, 11 (19), 4354−4357. (d) Cao, W.; Zhang, H.; Chen, J.; Deng, H.; Shao, M.; Lei, L.; Qian, J.; Zhu, Y. A Facile Preparation of trans-1,2-Cyclopropanes Containing p-Trifluoromethylphenyl Group and Its Application to the Construction of Pyrazole and Cyclopropane Ring Fused Pyridazinone Derivatives. Tetrahedron 2008, 64 (28), 6670−6674. (6) For examples of DA cyclopropane ring opening with amides, see: (a) Liu, R.-R.; Ye, S.-C.; Lu, C.-J.; Xiang, B.; Gao, J.; Jia, Y.-X. AuCatalyzed Ring-Opening Reactions of 2-(1-Alkynyl-cyclopropyl)pyridines with Nucleophiles. Org. Biomol. Chem. 2015, 13 (17), 4855−4858. (b) Zhang, J.; Schmalz, H.-G. Gold(I)-Catalyzed Reaction of 1-(1-Alkynyl)-cyclopropyl Ketones with Nucleophiles: A Modular Entry to Highly Substituted Furans. Angew. Chem., Int. Ed. 2006, 45 (40), 6704−6707. (7) For examples of DA cyclopropane ring opening with nitriles, see: (a) Schobert, R.; Gordon, G. J.; Bieser, A.; Milius, W. 3Functionalized Tetronic Acids From Domino Rearrangement/ Cyclization/Ring-Opening Reactions of Allyl Tetronates. Eur. J. Org. Chem. 2003, 2003 (18), 3637−3647. (b) Vankar, Y. D.; Kumaravel, G.; Rao, C. T. Ritter Reaction with Cyclopropyl Ketones and Cyclopropyl Alcohols: Synthesis of N-Acyl-γ-keto and N-Acyl Homoallyl Amines. Synth. Commun. 1989, 19 (11−12), 2181− 2198. (c) Caputo, R.; Ferreri, C.; Palumbo, G.; Wenkert, E. Trimethylsilyl Tetrafluoroborate a Convenient Reagent for Solvolysis Reactions. Tetrahedron Lett. 1984, 25 (5), 577−578. Review on (3+2)-cycloaddition of DA cyclopropanes to nitriles, see: (d) Pagenkopf, B. L.; Vemula, N. Cycloadditions of Donor−Acceptor Cyclopropanes and Nitriles. Eur. J. Org. Chem. 2017, 2017 (18), 2561−2567.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00922. X-ray data, results of cell assay, DFT calculations, Cartesian coordinates, and NMR spectra (PDF) Crystal data of 2r (CIF) Accession Codes

CCDC 1832110 contains the supplementary crystallographic data for this paper (2r). These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Konstantin L. Ivanov: 0000-0002-1557-175X Stanislav I. Bezzubov: 0000-0002-2017-517X Ekaterina M. Budynina: 0000-0003-1193-7061 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Russian Science Foundation, grant no. 17-73-10418. The NMR measurements were carried out at the Center for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine of Lomonosov Moscow State University.

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REFERENCES

(1) Reissig, H.; Zimmer, R. Donor−Acceptor-Substituted Cyclopropane Derivatives and Their Application in Organic Synthesis. Chem. Rev. 2003, 103 (4), 1151−1196. (2) For selected reviews on DA cyclopropanes, see: (a) Grover, H. K.; Emmett, M. R.; Kerr, M. A. Carbocycles from Donor−acceptor Cyclopropanes. Org. Biomol. Chem. 2015, 13 (3), 655−671. (b) Novikov, R. A.; Tomilov, Yu. V. Dimerization of Donor− acceptor Cyclopropanes. Mendeleev Commun. 2015, 25 (1), 1−10. (c) Cavitt, M. A.; Phun, L. H.; France, S. Intramolecular Donor− acceptor Cyclopropane Ring-Opening Cyclizations. Chem. Soc. Rev. 2014, 43 (3), 804−818. (d) Schneider, T. F.; Kaschel, J.; Werz, D. B. A New Golden Age for Donor−Acceptor Cyclopropanes. Angew. Chem., Int. Ed. 2014, 53 (22), 5504−5523. (e) de Nanteuil, F.; De 8708

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709

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The Journal of Organic Chemistry

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(8) For recent examples of DA cyclopropane ring opening with Nheterocycles, see: (a) Garve, L. K. B.; Jones, P. G.; Werz, D. B. RingOpening 1-Amino-3-aminomethylation of Donor−Acceptor Cyclopropanes via 1,3-Diazepanes. Angew. Chem., Int. Ed. 2017, 56 (31), 9226−9230. (b) Garve, L. K. B.; Kreft, A.; Jones, P. G.; Werz, D. B. Synthesis of 2-Unsubstituted Pyrrolidines and Piperidines from Donor−Acceptor Cyclopropanes and Cyclobutanes: 1,3,5-Triazinanes as Surrogates for Formylimines. J. Org. Chem. 2017, 82 (17), 9235− 9242. (c) Preindl, J.; Chakrabarty, S.; Waser, J. Dearomatization of Electron Poor Six-Membered N-Heterocycles through [3 + 2] Annulation with Aminocyclopropanes. Chem. Sci. 2017, 8 (10), 7112−7118. (d) Niu, H.; Du, C.; Xie, M.; Wang, Y.; Zhang, Q.; Qu, G.; Guo, H. Diversity-Oriented Synthesis of Acyclic Nucleosides via Ring-Opening of Vinyl Cyclopropanes with Purines. Chem. Commun. 2015, 51 (16), 3328−3331. (e) Selvi, S.; Srinivasan, K. Tandem Ring Opening/Cyclization of trans-2-Aryl-3-nitrocyclopropane-1,1-dicarboxylates with 2-Aminopyridines: Access to Pyrido[1,2-a]pyrimidin4-one Derivatives. Eur. J. Org. Chem. 2017, 2017 (37), 5644−5648. (9) For examples of DA cyclopropane ring opening with the azide ion, see: (a) Akaev, A. A.; Villemson, E. V.; Vorobyeva, N. S.; Majouga, A. G.; Budynina, E. M.; Melnikov, M. Ya. 3-(2-Azidoethyl)oxindoles: Advanced Building Blocks for One-Pot Assembly of Spiro[pyrrolidine-3,3′-oxindoles]. J. Org. Chem. 2017, 82 (11), 5689− 5701. (b) Ivanov, K. L.; Villemson, E. V.; Budynina, E. M.; Ivanova, O. A.; Trushkov, I. V.; Melnikov, M. Ya. Ring Opening of Donor− Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N-Heterocycles. Chem. - Eur. J. 2015, 21 (13), 4975−4987. (c) Flisar, M. E.; Emmett, M. R.; Kerr, M. A. Catalyst-Free Tandem Ring-Opening/Click Reaction of Acetylene-Bearing Donor−Acceptor Cyclopropanes. Synlett 2014, 25 (16), 2297−2300. (d) Emmett, M. R.; Grover, H. K.; Kerr, M. A. Tandem Ring-Opening Decarboxylation of Cyclopropane Hemimalonates with Sodium Azide: A Short Route to γ-Aminobutyric Acid Esters. J. Org. Chem. 2012, 77 (15), 6634−6637. (e) Izquierdo, M. L.; Arenal, I.; Bernabé, M.; Fernández Alvarez, E. Synthesis of E and Z 1-Amino-2-aryl(alkyl)-cyclopropanecarboxylic Acids via Meldrum Derivatives. Tetrahedron 1985, 41 (1), 215−220. (10) (a) Zhao, Y.; Aguilar, A.; Bernard, D.; Wang, S. Small-Molecule Inhibitors of the MDM2−p53 Protein−Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment. J. Med. Chem. 2015, 58 (3), 1038−1052. (b) Yu, B.; Yu, D.-Q.; Liu, H.-M. Spirooxindoles: Promising Scaffolds for Anticancer Agents. Eur. J. Med. Chem. 2015, 97, 673−698. (c) Santos, M. M. M. Recent Advances in the Synthesis of Biologically Active Spirooxindoles. Tetrahedron 2014, 70 (52), 9735−9757. (d) Galliford, C. V.; Scheidt, K. A. Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Angew. Chem., Int. Ed. 2007, 46 (46), 8748−8758. (11) (a) Graziano, M. L.; Iesce, M. R. Ring-opening Reactions of Cyclopropanes. Part 1. Formal [3 + 2] Cycloaddition of trans-Ethyl 2,2-Dimethoxy-3-methylcyclopropane-1-carboxylate to Phenyl Isocyanate. J. Chem. Res. (S) 1987, 19 (11), 362−363. (b) Graziano, M. L.; Cimminiello, G. Ring-opening Reactions of Cyclopropanes. Part 2. Investigation on the Reactivity of Ethyl 2,2-Dimethoxycyclopropane-1-carboxylates towards Phenyl Isothiocyanate. J. Chem. Res. (S) 1989, 21, 42−43. (12) Brückner, C.; Suchland, B.; Reißig, H.-U. Eine neue Synthese von Pyrrolderivaten. Liebigs Ann. der Chemie 1988, 1988 (5), 471− 473. (13) Yamamoto, K.; Ishida, T.; Tsuji, J. Palladium(0)-catalyzed Cycloaddition of Activated Vinylcyclopropanes with Aryl Isocyanates. Chem. Lett. 1987, 16 (6), 1157−1158. (14) Goldberg, A. F. G.; O’Connor, N. R.; Craig, R. A., II; Stoltz, B. M. Lewis Acid Mediated (3 + 2) Cycloadditions of Donor−Acceptor Cyclopropanes with Heterocumulenes. Org. Lett. 2012, 14 (20), 5314−5317. (15) Marti, C.; Carreira, E. M. Total Synthesis of (−)-Spirotryprostatin B: Synthesis and Related Studies. J. Am. Chem. Soc. 2005, 127 (32), 11505−11515. 8709

DOI: 10.1021/acs.joc.8b00922 J. Org. Chem. 2018, 83, 8695−8709