Assembly of Indolenines, 3-Amino Oxindoles, and Aldehydes into

Mar 29, 2017 - Theory Comput. ..... 109.2, 73.0, 71.4, 64.6, 54.2, 52.5, 43.8, 22.8, 20.9; HRMS (ESI) for C40H36N3O [M + ...... The Supporting Informa...
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Assembly of Indolenines, 3‑Amino Oxindoles, and Aldehydes into Indolenine-Substituted Spiro[pyrrolidin-2,3′-oxindoles] via 1,3Dipolar Cycloaddition with Divergent Diastereoselectivities Guodong Zhu, Siyuan Liu, Shiqi Wu, Lianghong Peng, Jingping Qu, and Baomin Wang* State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, P. R. China S Supporting Information *

ABSTRACT: A novel one-pot 1,3-dipolar cycloaddition of indolenines, 3-aminooxindoles, and aldehydes is reported. The reaction provides indolenine-substituted spiro[pyrrolidin-2,3′oxindoles] containing four contiguous stereogenic centers in high yields (up to 99%) and excellent diastereoselectivities (up to >20:1 dr) under mild conditions. Remarkably, the inversion of diastereoselectivity could be readily achieved through slightly modifying the reaction conditions.

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INTRODUCTION The synthesis of complex products with potential bioactivities via short synthetic pathways is a very important yet challenging task in synthetic and medicinal chemistry. Therefore, the development of atom- and step-economical reaction routes toward constructing complex structures has drawn considerable attention from synthetic chemists. Spiro[pyrrolidin-2,3′-oxindoles] and indolenines are important core structures of a wide range of natural and synthetic products exhibiting versatile bioactivities, such as anticancer,1 antitumor,2 acetylcholinesterase inhibitory,3 potent monoamine oxidase inhibitory,4 analgesic,5 and antibacterial6 activities (Figure 1). To date, although a number of synthetic methodologies have been developed for the respective synthesis of spiro[pyrrolidin-2,3′oxindoles] and indolenines,7,8 the union of these two medicinally relevant motifs has not been reported. In this context together with our interest in the construction and modification of pharmacophore heterocycles,9 we aimed to develop an efficient reaction protocol to build indoleninemodified spiro[pyrrolidin-2,3′-oxindoles]. The 1,3-dipolar cycloaddition of azomethine ylides with electron-deficient alkenes has proved to be a powerful tool for the preparation of substituted pyrrolidines over the past decades.10 In such cycloadditions, various activated alkenes, such as nitroalkenes,11 maleates,12 maleimides,13 and methyleneindolinones,14 have been utilized as dipolarophiles and recent research has started to focus on finding novel dipolarophiles. We recently reported 1,3-dipolar cycloaddition reactions of azomethine ylides derived from 3-aminooxindole with nitroalkenes or methyleneindolinones, affording spiro[pyrrolidin-2,3′-oxindoles].9d,h To the best of our knowledge, 2-alkenylindolenines have not yet been employed as dipolar© 2017 American Chemical Society

ophiles in cycloadditions. In addition, utilization of indolenine derivatives to build novel structures in synthetic chemistry has been rarely reported except for a few hydrogenation reactions.15,16 Considering the electron-withdrawing effect of the carbon−nitrogen double bonds in indolenines, we considered whether 2-alkenylindolenines could be used as dipolarophiles to react with azomethine ylides. Subsequent investigations aiming to validate this idea revealed that 2alkenylindolenines, either generated in situ from 2-methylindolenines and aldehydes or preformed, are prominent dipolarophiles, delivering indolenine-substituted spiro[pyrrolidin-2,3′-oxindoles] with high yields and excellent diastereoselectivities under mild conditions. Notably, the diastereoselectivity of the reaction could be switched through adjusting the reaction conditions. Herein we document the first 1,3-dipolar cycloaddition with 2-alkenylindolenines toward constructing the indolenine-substituted spiro[pyrrolidin-2,3′oxindoles] via the direct assembly of indolenines, 3-aminooxindoles, and aldehydes.

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RESULTS AND DISCUSSION Our investigation began with the one-pot cycloaddition of 3aminooxindole hydrochloride 1, benzaldehyde 2a, and 2methylindolenine 3a (Table 1). At the outset, we were pleased to find that the reaction proceeded well in the absence of any catalyst, giving high yield and excellent diastereoselectivity (entry 1). Molecular sieves (4 Å) added into the reaction increased the chemical yield (entry 2). Then a brief screening of molecular sieves revealed that 3 Å MS could promote the Received: February 10, 2017 Published: March 29, 2017 4317

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

Article

The Journal of Organic Chemistry

Figure 1. Representative bioactive molecules containing the spiro[pyrrolidin-2,3′-oxindole] or indolenine core.

Table 1. Optimization of Reaction Conditionsa

entry

R

MS

solvent

t (h)

yield (%)b

drc

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

Me Me Me Me Me Me Me Me Me Me Bn H

− 4Å 4Å 3Å 5Å 3Å 3Å 3Å 3Å 3Å 3Å 3Å

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DCE CHCl3 THF EtOH EtOAc CH2Cl2 CH2Cl2

24 24 24 24 24 24 24 24 24 24 16 95

85 89 90 94 92 82 88 97 50 52 96 74

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 3.5:1 3:1 3:1 >20:1 11:1

a

Reactions were carried out on a 0.1 mmol scale in 1.0 mL of solvent, with the ratio of 1/2a/3a being 1.0:3.0:1.1. bIsolated yield. cThe dr was determined by 1H NMR of the crude products. d10 mol % DPP was added (DPP = diphenyl phosphate).

substitution on the benzaldehydes imposed no obvious effect on the reactivity and yield, but decreased diastereoselectivity compared to meta- and para- substitution was observed (5h). βNaphthaldehyde also worked well under the optimal conditions (5i). Heteroaromatic aldehyde as represented by 2-thenaldehyde also participated in the reaction smoothly with good yield and excellent diastereoselectivity (5j). In addition, we explored the effect on the results of the substituents in the benzene ring of 3-aminooxindole, as exemplified by the cases with 5-methyl and 5-fluoro groups, respectively. Good yields and excellent diastereoselectivities were offered under the same conditions (5k and 5l). The relative configuration of 5e was determined by single-crystal X-ray analysis (see details in Supporting Information).17 Further extension of the substrate scope was focused on 2methylindolenines 3 bearing different substituents (Scheme 2). Indolenines with electron-withdrawing or electron-donating groups such as fluoro, bromo, and methyl groups at the C5-

reaction more effectively (entries 4 and 5) with excellent yield and diastereoselectivity. The addition of acidic catalyst diphenyl phosphate (DPP) into the reaction mixture made no difference to the results (entry 3). A survey of solvents showed that dichloromethane was most suitable for the reaction (entries 6− 10). While the N-nonsubstituted substrate exhibited poor reactivity (entry 12), the N-benzyl substitution gave the best yield and diastereoselectivity in the shortest reaction time (entry 11). With the optimal reaction conditions in hand, we investigated the substrate scope with respect to aldehyde and 3-aminooxindole partners (Scheme 1). In general, a series of benzaldehydes bearing various substituents of different electronic properties and substitution patterns were well tolerated. In detail, the electronically deficient benzaldehydes afforded moderately lowered yields and reactivity than the neutral and electron-rich derivatives, but diastereoselectivities are uniformly high (5d and 5e vs 5c, 5f, and 5g). Ortho 4318

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

Article

The Journal of Organic Chemistry Scheme 1. Substrate Scope of 3-Aminooxindoles and Aldehydesa,b,c

a

Reactions were carried out on a 0.2 mmol scale in 2.0 mL of CH2Cl2, with the ratio of 1/2/3a being 1.0:3.0:1.1. bIsolated yield was given. cThe dr was determined by 1H NMR of the crude products.

Having established optimized methods for the current [3 + 2] cycloaddition reaction (entry 3, Table 2), next the substrate scope was investigated (Scheme 3). In all cases, the [3 + 2] cycloaddition proceeded smoothly and gave indoleninesubstituted spiro[pyrrolidin-2,3′-oxindole] 5 in excellent yields and diastereoselectivities (5s−z). Under the optimal reaction conditions for the epimer 6 (entry 9, Table 2), we simply extended some representative substrates of the reaction (Scheme 4). In all cases, the major products 6 could be achieved with high yields and reactivity as well as moderate to good diastereoselectivities (6a−h). The relative configuration of 6a was determined by single-crystal X-ray analysis (see details in Supporting Information).17 To further evaluate the utility of the cycloaddition process, gram-scale reactions were conducted. Excellent yields were maintained (Scheme 5), but the diastereoselectivity for the preformed alkenylindolenine became poor (Scheme 5B). The synthetic versatility was demonstrated via converting spirooxindole 5c to dihydropyrrole derivative 7, pyrrole derivative 8, and nitrone 9 (Scheme 6).18 The proposed pathway of the [3 + 2] cycloaddition of 3aminooxindole hydrochloride 1c, benzaldehyde 2a, and 2methylindolenine 3a was depicted in Scheme 7A. Acid−base neutralization reaction of 3-aminooxindole hydrochloride 1c and 2-methylindolenine 3a could enhance their reactivity with benzaldehyde. The condensation reaction with benzaldehyde

position reacted smoothly with azomethine ylides, affording desirable products with excellent yields and diastereoselectivities (5m, 5n, and 5q), although a nitro group at the same position reduced the activity (5o). Notably, indolenine bearing a C3 quaternary chiral center was also investigated, and 5r was obtained in good yield and diasteroselectivity. The occurrence of the same aromatic group at C3 and C5 positions of the pyrrolidine ring indeed limits the structural diversity of the spiro[pyrrolidin-2,3′-oxindole] product to some degree. In order to address this limitation, we envisioned the use of preformed 2-alkenylindolenines 4 in the cycloaddition reaction, thus enabling the differentiation of the C3 and C5 substituents. Guided by the above results, we began our optimization of reaction conditions (Table 2). Under the optimal reaction conditions established in Table 1, we found that the cycloaddition proceeded smoothly in excellent yield, but with moderate diastereoselectivity (entry 1). Pleasingly, the addition of catalyst DPP enhanced both the efficiency and the diastereoselectivity (entry 3). Interestingly, we found that the addition of base additives had significant effect on the diastereoselctivity of the [3 + 2] reaction (entry 4). After a detailed screening process, we were pleased to find that the diastereomeric ratio could be switched to 1:6 by the addition of NaHCO3 and catalyst DPP, favoring the formation of the epimer 6 as the major product (entry 9). 4319

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

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The Journal of Organic Chemistry Scheme 2. Substrate Scope of 2-Methylindoleninesa,b,c

ification process of 2-methylindolenine 3a, thus affecting the progress of the whole reaction. At this stage, the origin of the switchable diastereoselectivity remains unclear and would be the future effort together with the development of an asymmetric version of this process.

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CONCLUSION We developed a novel [3 + 2] cycloaddition of 3-aminooxindoles, aldehydes, and indolenines. The reaction proceeded smoothly, affording the desired indolenine-substituted spiro[pyrrolidin-2,3′-oxindoles] in high yields (up to 99%) and excellent diastereoselectivities (up to >20:1 dr) under mild conditions. Notably, the switch of the diastereoselectivity of the reaction can be readily achieved through adjusting the reaction conditions.

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EXPERIMENTAL SECTION

General Information. All solvents and aldehydes were purified according to standard methods prior to use. Reactions were monitored by thin layer chromatography (TLC) using silica gel plates. Flash chromatography was carried out utilizing silica gel 200−300 mesh. 1H NMR and 19F NMR spectra were recorded on a Bruker Avance II 400 MHz and Bruker Avance III 471 MHz, respectively, 13C NMR spectra were recorded on a Bruker Avance II 101 MHz or Bruker Avance III 126 MHz. The solvent used for NMR spectroscopy was CDCl3 or CD3COCD3, using tetramethylsilane as the internal reference. Data for 1 H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, br = broad singlet, dd = double doublet, coupling constants in hertz, integration). Data for 13C NMR and 19F NMR are reported in terms of chemical shift (δ, ppm). HRMS (ESI) was determined by a HRMS/ MS instrument (LTQ Orbitrap XL TM). The relative configurations of 5e and 6a were assigned by the X-ray analysis. General Procedure for the Synthesis of Spiro[pyrrolidin-2,3′oxindoles] (5) via the Cycloaddition of 1, 2, and 3. To a reaction tube were added 3-aminooxindole hydrochloride 1 (0.2 mmol), 3 Å (200 mg) and 2-methylindolenines 3 (0.22 mmol), followed by CH2Cl2 (2 mL) at room temperature. Then aldehyde 2 (0.6 mmol) was added, and the reaction mixture was stirred at the same temperature. After the reaction was complete (monitored by TLC),

a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of CH2Cl2, with the ratio of 1c/2a/3 being 1.0:3.0:1.1. bIsolated yield was given. c The dr was determined by 1H NMR of the crude products.

respectively led to the formation of azomethine ylide I and 2alkenylindolenine hydrochloride II. Then the [3 + 2] cycloaddition of I and II proceeded to give the cycloadduct 5c. To prove that acid−base neutralization reaction of 3aminooxindole hydrochloride 1c and 2-methylindolenine 3a could enhance their reactivity with benzaldehyde, 1.5 equiv of NaHCO3 was added under standard conditions (Scheme 7B). As a consequence, the reaction gave the desired product 5c with only 55% yield. We think that the reaction of NaHCO3 and 3-aminooxindole hydrochloride 1c impaired the acidTable 2. Optimization of Reaction Conditionsa

entry

cat. (10 mol %)

base (1.5 equiv)

t (h)

yield (%)b

drc

1d 2 3 4 5 6 7e 8e 9 10

− − DPP − − − − − DPP DPP

− − − NaHCO3 Na2CO3 K2CO3 TMG Et3N NaHCO3 Na2CO3

16 30 6 16 16 16 16 20 16 16

99 85 99 88 80 90 95 72 99 85

5:1 >20:1 >20:1 1:1 1:5 12:1 15:1 16:1 1:6 1:5

a

The reaction was carried out on a 0.1 mmol scale in 1.0 mL of CH2Cl2, with the ratio of 1c/2a/4a being 1.0:1.5:1.1. bIsolated yield. cThe dr was determined by 1H NMR of the crude products. d100 mg of 3 Å MS was added. eThe reaction was conducted under argon atmosphere. 4320

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

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The Journal of Organic Chemistry Scheme 3. Substrate Scope of the DPP-Catalyzed Reactiona,b,c

a

Reactions were carried out on a 0.2 mmol scale in the presence of 10 mol % DPP in 2.0 mL of CH2Cl2 at rt, with the ratio of 1c/2/3 being 1.0:1.5:1.1. bIsolated yield was given. cThe dr was determined by 1H NMR of the crude products.

Scheme 4. Substrate Scope of the DPP-Catalyzed Reaction in the Presence of NaHCO3a,b,c

a Reactions were carried out on a 0.2 mmol scale in the presence of 10 mol % DPP and 1.5 equiv of NaHCO3 in 2.0 mL of CH2Cl2 at rt, with the ratio of 1c/2/3 was 1.0:1.5:1.1. bIsolated yield was given. cThe dr was determined by 1H NMR of the crude products.

157 °C; 1H NMR (400 MHz, CDCl3) δ 7.82−7.74 (m, 3H), 7.70 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.22 (d, J = 7.7 Hz, 2H), 7.20−7.15 (m, 2H), 7.15−7.06 (m, 3H), 7.04−6.97 (m, 4H), 6.61−6.54 (m, 1H), 5.20−5.06 (m, 1H), 4.55−4.39 (m, 2H), 2.78 (br,

the crude product was purified by column chromatography (ethyl acetate/petroleum ether = 1/10) on silica gel to give the product 5. 4-(3,3-Dimethyl-3H-indol-2-yl)-3,5-diphenylspiro[pyrrolidin-2,3′oxindole] (5a). Yield: 72% (70 mg); 11:1 dr; white solid, mp: 155− 4321

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

Article

The Journal of Organic Chemistry Scheme 5. Gram-Scale Reactions

Scheme 6. Derivatization of the Cycloaddition Product

Scheme 7. Proposed Pathway of the [3 + 2] Cycloaddition Reaction and Control Experiment

4322

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

Article

The Journal of Organic Chemistry 1H), 0.72 (s, 3H), 0.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.1, 181.3, 153.2, 145.7, 142.4, 140.4, 134.1, 132.2, 129.3, 128.9, 128.6, 128.3, 128.1, 127.8, 127.6, 127.3, 125.3, 123.8, 123.1, 121.0, 120.1, 109.5, 73.2, 71.3, 65.0, 54.1, 52.3, 22.5, 20.8; HRMS (ESI) for C33H30N3O [M + H]+ calcd 484.2383, found 484.2372. 4-(3,3-Dimethyl-3H-indol-2-yl)-1′-methyl-3,5-diphenylspiro[pyrrolidin-2,3′-oxindole] (5b). Yield: 94% (93 mg); >20:1 dr; white solid, mp: 178−180 °C; 1H NMR (400 MHz, CDCl3) δ 7.86−7.81 (m, 2H), 7.79 (dd, J = 7.1, 1.2 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.31−7.27 (m, 2H), 7.21−7.15 (m, 2H), 7.14−7.05 (m, 4H), 7.01− 6.97 (m, 4H), 6.55−6.46 (m, 1H), 5.13 (d, J = 9.2 Hz, 1H), 4.54 (dd, J = 12.2, 9.2 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 2.86 (s, 4H), 0.71 (s, 3H), 0.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.1, 179.5, 153.3, 145.7, 143.1, 142.5, 134.0, 131.7, 129.1, 128.9, 128.6, 128.3, 128.1, 127.5, 127.3, 125.3, 123.2, 123.1, 121.0, 120.1, 107.7, 73.4, 71.5, 65.1, 54.1, 52.0, 25.8, 22.5, 20.8; HRMS (ESI) for C34H32N3O [M + H]+ calcd 498.2540, found 498.2529. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-diphenylspiro[pyrrolidin-2,3′-oxindole] (5c). Yield: 96% (110 mg); >20:1 dr; white solid, mp: 213-215 °C; 1H NMR (400 MHz, CDCl3) δ 7.86−7.80 (m, 3H), 7.61 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.25−7.16 (m, 4H), 7.15−7.04 (m, 7H), 7.02−6.99 (m, 3H), 6.53 (d, J = 7.3 Hz, 2H), 6.31 (d, J = 7.6 Hz, 1H), 5.22−5.13 (m, 1H), 5.09 (d, J = 16.0 Hz, 1H), 4.60 (d, J = 4.4 Hz, 2H), 4.29 (d, J = 16.0 Hz, 1H), 3.65 (br, 1H), 0.78 (s, 3H), 0.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.3, 179.4, 153.1, 145.7, 142.7, 142.4, 135.2, 134.1, 131.8, 129.6, 129.0, 128.7, 128.6, 128.3, 128.2, 128.0, 127.7, 127.4, 127.1, 126.6, 125.4, 123.4, 123.2, 121.1, 120.1, 109.2, 73.0, 71.4, 64.6, 54.2, 52.5, 43.8, 22.8, 20.9; HRMS (ESI) for C40H36N3O [M + H]+ calcd 574.2853, found 574.2845. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-bis(4-fluorophenyl)spiro[pyrrolidin-2,3′-oxindole] (5d). Yield: 68% (83 mg); >20:1 dr; white solid, mp: 215−217 °C; 1H NMR (400 MHz, CDCl3) δ 7.85− 7.74 (m, 3H), 7.59 (d, J = 7.7 Hz, 1H), 7.27−7.23 (m, 1H), 7.20−7.08 (m, 8H), 7.04 (d, J = 7.1 Hz, 1H), 6.99 (t, J = 8.6 Hz, 2H), 6.68 (t, J = 8.7 Hz, 2H), 6.60 (d, J = 6.9 Hz, 2H), 6.41 (d, J = 7.1 Hz, 1H), 5.14 (d, J = 8.6 Hz, 1H), 5.08 (d, J = 16.0 Hz, 1H), 4.55−4.45 (m, 2H), 4.32 (d, J = 16.0 Hz, 1H), 2.73 (s, 1H), 0.78 (s, 3H), 0.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.7, 179.3, 162.6 (d, J = 266.6 Hz), 162.5 (d, J = 227.3 Hz), 153.1, 145.6, 142.8, 138.4 (d, J = 3.0 Hz), 135.1, 131.3, 131.1 (d, J = 8.2 Hz), 129.9 (d, J = 8.1 Hz), 129.8 (d, J = 3.0 Hz), 129.2, 128.6, 127.4, 126.6, 125.5, 123.3, 121.1, 120.2, 115.5(d, J = 21.2 Hz), 114.9 (d, J = 21.2 Hz), 109.2, 72.7, 70.4, 63.5, 54.1, 52.4, 43.8, 22.8, 21.1; 19F NMR (377 MHz, CDCl3) δ −114.69, −115.02; HRMS (ESI) for C40H34F2N3O [M + H]+ calcd 610.2664, found 610.2650. 1′-Benzyl-3,5-bis(4-bromophenyl)-4-(3,3-dimethyl-3H-indol-2-yl)spiro[pyrrolidin-2,3′-oxindole] (5e). Yield: 65% (95 mg); >20:1 dr; white solid, mp: 226−228 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 7.1, 1.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.27−7.23 (m, 1H), 7.21−7.19 (m, 3H), 7.17−7.08 (m, 5H), 7.03 (t, J = 8.6 Hz, 3H), 6.58 (dd, J = 6.6, 2.8 Hz, 2H), 6.42−6.40 (m, 1H), 5.14−5.11 (m, 2H), 4.53−4.45 (m, 2H), 4.30 (d, J = 16.0 Hz, 1H), 2.75 (s, 1H), 0.79 (s, 3H), 0.46 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.4, 179.1, 153.1, 145.5, 142.8, 141.7, 135.0, 133.0, 131.7, 131.2, 130.1, 130.1, 129.4, 128.7, 127.5, 127.4, 126.5, 125.6, 123.3, 123.2, 121.9, 121.1, 120.2, 109.3, 72.5, 70.5, 63.7, 54.0, 52.0, 43.9, 22.9, 21.2; HRMS (ESI) for C40H34Br2N3O [M + H]+ calcd 730.1063, found 730.1053. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-di-p-tolylspiro[pyrrolidin-2,3′-oxindole] (5f). Yield: 95% (114 mg); >20:1 dr; white solid, mp: 211−213 °C; 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 7.3, 0.9 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.24−7.20 (m, 1H), 7.16−7.00 (m, 11H), 6.81 (d, J = 7.9 Hz, 2H), 6.55 (d, J = 7.3 Hz, 2H), 6.31 (d, J = 7.4 Hz, 1H), 5.15−5.07 (m, 2H), 4.55 (d, J = 5.0 Hz, 2H), 4.27 (d, J = 16.0 Hz, 1H), 2.89 (br, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 0.80 (s, 3H), 0.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.4, 179.6, 153.4, 145.8, 142.7, 139.3, 137.7, 137.0, 135.3, 132.2, 131.1, 129.5, 129.3, 128.8, 128.6, 128.4, 128.2, 127.3, 127.1, 126.7, 125.2, 123.4, 123.1, 121.0, 120.1, 109.1, 72.9, 71.2, 64.2, 54.2,

52.3, 43.8, 22.9, 21.3, 21.1; HRMS (ESI) for C42H40N3O [M + H]+ calcd 602.3166, found 602.3152. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-di-m-tolylspiro[pyrrolidin-2,3′-oxindole] (5g). Yield: 85% (102 mg); >20:1 dr; white solid, mp: 116−118 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 7.3, 0.9 Hz, 1H), 7.61−7.58 (m, 3H), 7.26−7.21 (m, 1H), 7.21−7.00 (m, 10H), 6.93−6.86 (m, 3H), 6.50 (d, J = 7.3 Hz, 2H), 6.31 (d, J = 7.4 Hz, 1H), 5.14 (d, J = 16.0 Hz, 1H), 5.10 (d, J = 8.7 Hz, 1H), 4.63− 4.53 (m, 2H), 4.25 (d, J = 16.0 Hz, 1H), 2.90 (br, 1H), 2.33 (s, 3H), 2.06 (s, 3H), 0.83 (s, 3H), 0.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.3, 179.4, 153.4, 145.8, 142.8, 142.3, 138.2, 137.3, 135.3, 134.0, 132.0, 130.0, 128.9, 128.8, 128.5, 128.3, 127.8, 127.3, 127.1, 126.9, 126.4, 125.4, 125.2, 123.4, 123.1, 121.0, 120.1, 109.1, 72.9, 71.4, 64.5, 54.2, 52.1, 43.8, 22.8, 21.5, 21.2, 21.1; HRMS (ESI) for C42H40N3O [M + H]+ calcd 602.3166, found 602.3150. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-bis(2methoxyphenyl)spiro[pyrrolidin-2,3′-oxindole] (5h). Yield: 80% (101 mg); 7:1 dr; white solid, mp: 121−123 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.22−7.18 (m, 1H), 7.17− 6.99 (m, 10H), 6.78−6.72 (m, 2H), 6.53 (d, J = 7.8 Hz, 3H), 6.31 (d, J = 7.7 Hz, 1H), 5.67 (d, J = 9.6 Hz, 1H), 5.41 (d, J = 12.2 Hz, 1H), 5.12 (d, J = 16.0 Hz, 1H), 4.60 (dd, J = 12.1, 9.7 Hz, 1H), 4.23 (d, J = 16.0 Hz, 1H), 3.68 (s, 3H), 3.18 (s, 3H), 1.72 (br, 1H), 0.86 (s, 3H), 0.50 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 189.1, 179.3, 158.4, 157.7, 153.8, 145.9, 142.4, 135.5, 132.9, 130.0, 129.9, 128.6, 128.5, 128.2, 128.1, 127.1, 127.0, 126.6, 124.9, 124.3, 123.7, 122.6, 121.2, 120.8, 120.1, 120.0, 111.0, 110.5, 108.6, 72.5, 64.6, 55.4, 53.3, 54.9, 54.0, 51.0, 43.8, 22.9, 20.9; HRMS (ESI) for C42H40N3O3 [M + H]+ calcd 634.3064, found 634.3057. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-di(naphthalen-2-yl)spiro[pyrrolidin-2,3′-oxindole] (5i). Yield: 86% (116 mg); >20:1 dr; white solid, mp: 121−123 °C; 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.5 Hz, 1H), 7.96−7.92 (m, 3H), 7.84−7.79 (m, 1H), 7.77−7.45 (m, 1H), 7.68 (d, J = 5.9 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.45−7.31 (m, 5H), 7.19 (q, J = 7.4 Hz, 2H), 7.07 (td, J = 7.7, 1.0 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.92−6.87 (m, 2H), 6.50 (t, J = 7.7 Hz, 2H), 6.26 (t, J = 8.3 Hz, 3H), 5.39 (d, J = 8.4 Hz, 1H), 5.14 (d, J = 16.0 Hz, 1H), 4.94−4.80 (m, 2H), 4.19 (d, J = 16.0 Hz, 1H), 3.01 (br, 1H), 0.79 (s, 3H), 0.31 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 189.1, 179.4, 153.2, 145.7, 142.8, 139.8, 134.8, 133.4, 133.2, 133.0, 132.9, 131.8, 129.1, 128.9, 128.7, 128.2, 128.0, 127.7, 127.5, 127.4, 127.3, 127.0, 126.2, 126.0, 125.9, 125.3, 123.4, 123.2, 121.0, 120.1, 109.2, 73.0, 71.6, 64.5, 54.2, 51.9, 43.9, 23.0, 21.3; HRMS (ESI) for C48H40N3O [M + H]+ calcd 674.3166, found 674.3154. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-di(thiophen-2-yl)spiro[pyrrolidin-2,3′-oxindole] (5j). Yield: 70% (82 mg); >20:1 dr; white solid, mp: 125−127 °C; 1H NMR (400 MHz, CDCl3) δ 7.76− 7.72 (m, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.30−7.25 (m, 1H), 7.25−7.23 (m, 1H), 7.20−7.07 (m, 8H), 6.94 (d, J = 3.4 Hz, 1H), 6.92−6.89 (m, 1H), 6.84 (dd, J = 5.1, 3.5 Hz, 1H), 6.82−6.77 (m, 2H), 6.69 (dd, J = 5.1, 3.6 Hz, 1H), 6.46−6.40 (m, 1H), 5.43 (d, J = 9.2 Hz, 1H), 5.11 (d, J = 16.0 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.60 (dd, J = 11.9, 9.2 Hz, 1H), 4.47 (d, J = 16.0 Hz, 1H), 2.82 (s, 1H), 0.83 (s, 3H), 0.66 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.7, 179.0, 153.2, 146.5, 146.0, 143.1, 136.2, 135.3, 131.0, 129.3, 128.6, 127.3, 127.2, 126.9, 126.7, 126.5, 126.1, 125.6, 125.5, 124.3, 123.3, 123.2, 121.1, 120.2, 109.2, 72.2, 65.9, 58.9, 54.6, 54.4, 43.9, 22.1, 20.4; HRMS (ESI) for C36H32N3OS2 [M + H]+ calcd 586.1981, found 586.1987. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5′-methyl-3,5diphenylspiro[pyrrolidin-2,3′-oxindole] (5k). Yield: 99% (84 mg); >20:1 dr; white solid, mp: 235−237 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.1 Hz, 2H), 7.68 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.25−7.19 (m, 4H), 7.14−7.00 (m, 8H), 6.86 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 7.3 Hz, 2H), 6.20 (d, J = 7.9 Hz, 1H), 5.15 (d, J = 8.0 Hz, 1H), 5.06 (d, J = 16.0 Hz, 1H), 4.65−4.51 (m, 2H), 4.28 (d, J = 16.0 Hz, 1H), 2.81 (br, 1H), 2.38 (s, 3H), 0.78 (s, 3H), 0.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.2, 179.4, 153.3, 145.8, 142.4, 140.3, 135.3, 134.2, 132.7, 131.9, 129.6, 129.2, 128.6, 128.5, 128.3, 128.1, 127.9, 127.6, 127.3, 127.1, 126.6, 125.3, 124.1, 4323

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

Article

The Journal of Organic Chemistry

127.6, 127.1, 126.6, 126.5, 123.4, 123.2, 119.9, 114.5, 109.1, 73.0, 71.3, 64.5, 55.8, 52.8, 43.8, 22.6, 20.8; HRMS (ESI) for C40H35BrN3O [M + H]+ calcd 652.1958, found 652.1958. 1′-Benzyl-3,5-diphenyl-4-(3,3,5-trimethyl-3H-indol-2-yl)spiro[pyrrolidin-2,3′-oxindole] (5q). Yield: 86% (101 mg); >20:1 dr; white solid, mp: 141−143 °C; 1H NMR (400 MHz, CDCl3) δ 7.89−7.76 (m, 3H), 7.47 (d, J = 7.9 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.23−7.20 (m, 1H), 7.19−6.98 (m, 11H), 6.82 (s, 1H), 6.53 (d, J = 7.2 Hz, 2H), 6.32 (d, J = 7.5 Hz, 1H), 5.18−5.13 (m, 1H), 5.08 (d, J = 16.0 Hz, 1H), 4.61−4.50 (m, 2H), 4.29 (d, J = 16.0 Hz, 1H), 2.81 (br, 1H), 2.28 (s, 3H), 0.76 (s, 3H), 0.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.1, 179.4, 151.1, 145.9, 142.7, 142.5, 135.2, 135.1, 134.2, 131.9, 129.6, 129.0, 128.6, 128.3, 128.1, 128.0, 127.9, 127.6, 127.1, 126.6, 123.4, 123.2, 121.9, 119.7, 109.2, 72.9, 71.4, 64.6, 53.9, 52.4, 43.8, 22.8, 21.4, 21.0; HRMS (ESI) for C41H37N3NaO [M + Na]+ calcd 610.2829, found 610.2825. 1′-Benzyl-4-(3-ethyl-3-methyl-3H-indol-2-yl)-3,5-diphenylspiro[pyrrolidin-2,3′-oxindole] (5r). Yield: 79% (93 mg); 6:1 dr; white solid, mp: 201−203 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 7.1 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.24−7.20 (m, 3H), 7.20−6.99 (m, 10H), 6.96 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 7.2 Hz, 2H), 6.31 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 16.0 Hz, 1H), 4.60−4.50 (m, 2H), 4.29 (d, J = 16.0 Hz, 1H), 2.78 (br, 1H), 1.45 (q, J = 7.3 Hz, 2H), 0.41 (s, 3H), −0.63 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 188.6, 179.4, 154.2, 143.8, 142.7, 142.4, 135.2, 134.6, 132.1, 129.4, 128.9, 128.6, 128.3, 128.1, 128.0, 127.7, 127.2, 127.1, 126.6, 125.1, 123.4, 123.1, 121.5, 120.0, 109.1, 73.5, 72.4, 64.4, 58.8, 52.5, 43.8, 29.3, 19.4, 7.3; HRMS (ESI) for C41H38N3O [M + H]+ calcd 588.3009, found 588.3014. General Procedure for the Synthesis of Spiro[pyrrolidin-2,3′oxindoles] (5 and 6) via the Cycloaddition of 1, 2, and 4. To a reaction tube were added 3-aminooxindole hydrochloride 1 (0.2 mmol), DPP (0.02 mmol), and 2-alkenylindolenines 4 (0.22 mmol), followed by CH2Cl2 (2 mL) at room temperature. Then aldehyde 2 (0.3 mmol) was added, and the reaction mixture was stirred at the same temperature. After the reaction was complete (monitored by TLC), some drops of NEt3 were added to the reaction solution, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether = 1/10) on silica gel to give the product 5. To a reaction tube were added 3-aminooxindole hydrochloride 1 (0.2 mmol), NaHCO3 (0.3 mmol), DPP (0.02 mmol), and 2alkenylindolenines 4 (0.22 mmol), followed by CH2Cl2 (2 mL) at room temperature. Then aldehyde 2 (0.3 mmol) was added, and the reaction mixture was stirred at the same temperature. After the reaction was complete (monitored by TLC), the crude product was purified by column chromatography (ethyl acetate/petroleum ether = 1/10) on silica gel to give the product 6. 1′-Benzyl-5-(4-bromophenyl)-4-(3,3-dimethyl-3H-indol-2-yl)-3phenylspiro[pyrrolidin-2,3′-oxindole] (5s). Yield: 90% (117 mg); >20:1 dr; white solid, mp: 144−146 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.24−7.22 (m, 1H), 7.19−6.98 (m, 12H), 6.53 (d, J = 7.3 Hz, 2H), 6.33 (d, J = 7.6 Hz, 1H), 5.20−5.12 (m, 1H), 5.08 (d, J = 16.0 Hz, 1H), 4.54 (d, J = 4.8 Hz, 2H), 4.30 (d, J = 16.0 Hz, 1H), 2.75 (br, 1H), 0.77 (s, 3H), 0.47 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.9, 179.3, 153.2, 145.7, 142.8, 141.9, 135.1, 133.9, 131.7, 131.4, 130.1, 129.6, 129.2, 128.6, 128.0, 127.7, 127.4, 127.2, 126.6, 125.5, 123.3, 123.2, 121.8, 121.1, 120.2, 109.3, 72.8, 70.5, 64.5, 54.1, 52.2, 43.8, 22.7, 21.3; HRMS (ESI) for C40H35BrN3O [M + H]+ calcd 652.1958, found 652.1950. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3-phenyl-5-(p-tolyl)spiro[pyrrolidin-2,3′-oxindole] (5t). Yield: 97% (114 mg); >20:1 dr; white solid, mp: 201−203 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.24−7.20 (m, 1H), 7.19−6.98 (m, 14H), 6.52 (d, J = 7.1 Hz, 2H), 6.31 (d, J = 7.6 Hz, 1H), 5.17−5.02 (m, 2H), 4.62−4.51 (m, 2H), 4.29 (d, J = 16.0 Hz, 1H), 2.74 (s, 1H), 2.28 (s, 3H), 0.79 (s, 3H), 0.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.2, 179.5, 153.4, 145.8, 142.7, 139.3, 137.7, 135.2, 134.2, 132.0, 129.6, 129.3, 128.9, 128.6,

121.0, 120.1, 108.9, 73.1, 71.5, 64.6, 54.2, 52.5, 43.8, 22.8, 21.2, 20.9; HRMS (ESI) for C41H38N3O [M + H]+ calcd 588.3009, found 588.3010. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5′-fluoro-3,5diphenylspiro[pyrrolidin-2,3′-oxindole] (5l). Yield: 85% (101 mg); >20:1 dr; white solid, mp: 255−257 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.1 Hz, 2H), 7.62−7.58 (m, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.25−6.99 (m, 12H), 6.76 (td, J = 8.8, 2.6 Hz, 1H), 6.52 (d, J = 7.3 Hz, 2H), 6.22 (dd, J = 8.5, 4.0 Hz, 1H), 5.12 (dd, J = 7.1, 1.8 Hz, 1H), 5.05 (d, J = 16.0 Hz, 1H), 4.62−4.51 (m, 2H), 4.28 (d, J = 16.0 Hz, 1H), 2.78 (s, 1H), 0.78 (s, 3H), 0.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.7, 179.3, 159.7 (d, J = 242.2 Hz), 153.3, 145.7, 142.1, 138.4 (d, J = 2.0 Hz), 134.8, 134.0 (d, J = 7.1 Hz), 133.9, 129.5, 128.7, 128.3, 128.2, 128.0, 127.8, 127.3, 126.5, 125.3, 121.0, 120.2, 115.3, 115.2 (d, J = 23.2 Hz), 111.5 (d, J = 24.2 Hz), 109.8 (d, J = 7.1 Hz), 73.3, 71.5, 64.7, 54.1, 52.4, 44.0, 22.7, 20.9; 19F NMR (377 MHz, CDCl3) δ −119.86; HRMS (ESI) for C40H35FN3O [M + H]+ calcd 592.2759, found 592.2753. 1′-Benzyl-4-(5-fluoro-3,3-dimethyl-3H-indol-2-yl)-3,5diphenylspiro[pyrrolidin-2,3′-oxindole] (5m). Yield: 92% (109 mg); >20:1 dr; white solid, mp: 242−244 °C; 1H NMR (400 MHz, CDCl3) δ 7.86−7.78 (m, 3H), 7.50 (dd, J = 8.5, 4.6 Hz, 1H), 7.31 (t, J = 7.3 Hz, 2H), 7.25−7.22 (m, 1H), 7.19−7.06 (m, 8H), 7.06−7.00 (m, 2H), 6.91 (td, J = 9.1, 2.5 Hz, 1H), 6.70 (dd, J = 8.0, 2.5 Hz, 1H), 6.54 (d, J = 7.2 Hz, 2H), 6.33 (d, J = 7.5 Hz, 1H), 5.17−5.11 (m, 1H), 5.08 (d, J = 16.0 Hz, 1H), 4.60−4.51 (m, 2H), 4.30 (d, J = 16.0 Hz, 1H), 2.89 (s, 1H), 0.76 (s, 3H), 0.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.8, 179.4, 161.3 (d, J = 245.4 Hz), 149.2 (d, J = 2.0 Hz), 147.8 (d, J = 8.1 Hz), 142.7, 142.3, 135.2, 134.1, 131.8, 129.5, 129.0, 128.7, 128.6, 128.3, 128.2, 128.0, 127.7, 127.1, 126.6, 123.3, 123.2, 120.7 (d, J = 9.1 Hz), 113.8 (d, J = 24.2 Hz), 109.2, 108.7 (d, J = 24.2 Hz), 72.9, 71.4, 64.5, 54.7, 52.5, 43.8, 22.7, 20.7; 19F NMR (377 MHz, CDCl3) δ −117.47; HRMS (ESI) for C40H35FN3O [M + H]+ calcd 592.2759, found 592.2764. 1′-Benzyl-4-(5-bromo-3,3-dimethyl-3H-indol-2-yl)-3,5diphenylspiro[pyrrolidin-2,3′-oxindole] (5n). Yield: 95% (124 mg); >20:1 dr; white solid, mp: 265−267 °C; 1H NMR (400 MHz, CDCl3) δ 7.87−7.76 (m, 3H), 7.44 (d, J = 8.2 Hz, 1H), 7.37−7.27 (m, 3H), 7.24−7.22 (m, 1H), 7.17−7.00 (m, 11H), 6.54 (d, J = 7.2 Hz, 2H), 6.33 (d, J = 7.5 Hz, 1H), 5.16−5.12 (m, 1H), 5.08 (d, J = 16.0 Hz, 1H), 4.63−4.46 (m, 2H), 4.30 (d, J = 16.0 Hz, 1H), 3.01 (br, 1H), 0.75 (s, 3H), 0.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.7, 179.3, 152.2, 148.0, 142.7, 142.3, 135.1, 134.0, 131.8, 130.4, 129.5, 129.0, 128.7, 128.6, 128.2, 128.0, 127.7, 127.1, 126.6, 124.6, 123.3, 123.2, 121.5, 119.1, 109.2, 72.9, 71.4, 64.6, 54.7, 52.6, 43.8, 22.6, 20.7; HRMS (ESI) for C40H35BrN3O [M + H]+ calcd 652.1958, found 652.1965. 1 ′-Benz yl-4-(3 ,3-di met hyl-5-ni tro -3 H-i ndo l-2-yl) -3 ,5diphenylspiro[pyrrolidin-2,3′-oxindole] (5o). Yield: 75% (93 mg); >20:1 dr; white solid, mp: 272−274 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.5, 2.3 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.86−7.76 (m, 3H), 7.65 (d, J = 8.5 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.28−7.24 (m, 1H), 7.21−7.00 (m, 10H), 6.55 (d, J = 7.2 Hz, 2H), 6.35 (d, J = 7.5 Hz, 1H), 5.14 (d, J = 8.9 Hz, 1H), 5.09 (d, J = 16.0 Hz, 1H), 4.67− 4.56 (m, 2H), 4.32 (d, J = 16.0 Hz, 1H), 2.83 (br, 1H), 0.82 (s, 3H), 0.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.6, 179.2, 158.4, 146.8, 145.6, 142.7, 141.9, 135.1, 133.7, 131.6, 129.5, 129.1, 128.8, 128.6, 128.4, 128.1, 127.9, 127.2, 126.6, 124.3, 123.3, 120.3, 116.9, 109.3, 72.9, 71.7, 64.7, 55.1, 53.1, 43.8, 22.4, 20.4; HRMS (ESI) for C40H35N4O3 [M + H]+ calcd 619.2704, found 619.2704. 1′-Benzyl-4-(7-bromo-3,3-dimethyl-3H-indol-2-yl)-3,5diphenylspiro[pyrrolidin-2,3′-oxindole] (5p). Yield: 93% (121 mg); 7:1 dr; white solid, mp: 129−131 °C; 1H NMR (400 MHz, CDCl3) δ 7.87−7.79 (m, 3H), 7.40−7.34 (m, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.24−7.21 (m, 1H), 7.19−7.05 (m, 8H), 7.02 (t, J = 7.4 Hz, 2H), 6.95−6.89 (m, 2H), 6.56 (d, J = 7.1 Hz, 2H), 6.34 (d, J = 7.6 Hz, 1H), 5.21 (d, J = 8.8 Hz, 1H), 5.08 (d, J = 16.0 Hz, 1H), 4.58 (m, 2H), 4.31 (d, J = 16.0 Hz, 1H), 2.78 (br, 1H), 0.74 (s, 3H), 0.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.0, 179.4, 151.8, 147.7, 142.7, 142.5, 135.2, 134.2, 131.9, 130.8, 129.6, 129.0, 128.6, 128.3, 128.1, 128.0, 4324

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

Article

The Journal of Organic Chemistry

145.7, 142.7, 142.5, 134.9, 133.0, 132.9, 131.9, 131.8, 129.1, 128.7, 128.4, 128.2, 128.0, 127.5, 127.3, 127.0, 126.3, 125.9, 125.3, 123.4, 123.2, 121.0, 120.1, 109.2, 73.0, 71.5, 64.6, 54.2, 52.5, 43.8, 23.0, 21.0; HRMS (ESI) for C44H37N3NaO [M + Na]+ calcd 646.2829, found 646.2814. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5-phenyl-3-(thiophen-2yl)spiro[pyrrolidin-2,3′-oxindole] (5z). Yield: 99% (115 mg); >20:1 dr; white solid, mp: 123−125 °C; 1H NMR (400 MHz, CDCl3) δ 7.83−7.73 (m, 3H), 7.62 (d, J = 7.7 Hz, 1H), 7.31−7.26 (m, 2H), 7.24−7.19 (m, 2H), 7.18−7.13 (m, 3H), 7.13−7.06 (m, 3H), 7.03 (d, J = 6.8 Hz, 1H), 6.93 (d, J = 3.5 Hz, 1H), 6.89 (dd, J = 5.1, 0.9 Hz, 1H), 6.80 (dd, J = 6.6, 2.8 Hz, 2H), 6.68 (dd, J = 5.1, 3.6 Hz, 1H), 6.43 (dd, J = 6.6, 1.9 Hz, 1H), 5.12−5.07 (m, 2H), 4.82 (d, J = 12.0 Hz, 1H), 4.59−4.44 (m, 2H), 2.76 (s, 1H), 0.79 (s, 3H), 0.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.8, 179.4, 153.3, 145.9, 143.0, 142.3, 136.4, 135.3, 131.5, 129.2, 128.7, 128.3, 128.1, 127.4, 127.3, 127.0, 126.9, 126.7, 125.4, 124.3, 123.4, 123.3, 121.1, 120.2, 109.2, 72.4, 71.0, 59.2, 54.3, 54.1, 43.9, 22.3, 20.8; HRMS (ESI) for C38H34N3OS [M + H]+ calcd 580.2417, found 580.2402. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-diphenylspiro[pyrrolidin-2,3′-oxindole] (6a). Yield: 96% (110 mg); 3:1 dr; white solid, mp: 161−163 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 6.6 Hz, 1H), 7.62 (d, J = 7.3 Hz, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.21− 7.00 (m, 16H), 6.54 (d, J = 7.2 Hz, 2H), 6.35 (d, J = 7.2 Hz, 1H), 5.72 (d, J = 9.5 Hz, 1H), 5.08−4.99 (m, 2H), 4.84 (d, J = 11.3 Hz, 1H), 4.28 (d, J = 16.0 Hz, 1H), 2.92 (s, 1H), 1.00 (s, 3H), 0.89 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.1, 179.2, 153.5, 145.3, 143.0, 141.7, 135.4, 135.2, 129.7, 129.2, 128.8, 128.6, 128.1, 127.6, 127.5, 127.3, 127.2, 127.1, 126.6, 124.9, 123.9, 122.9, 120.8, 120.1, 109.1, 72.9, 63.9, 60.5, 54.2, 46.5, 43.4, 23.8, 21.6; HRMS (ESI) for C40H36N3O [M + H]+ calcd 574.2853, found 574.2847. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5-(4-fluorophenyl)-3phenylspiro[pyrrolidin-2,3′-oxindole] (6b). Yield: 92% (109 mg); 9:1 dr; white solid, mp: 158−160 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 6.7 Hz, 1H), 7.60 (dd, J = 8.5, 5.6 Hz, 2H), 7.45 (d, J = 7.7 Hz, 1H), 7.20−7.00 (m, 13H), 6.88 (t, J = 8.7 Hz, 2H), 6.55 (d, J = 7.2 Hz, 2H), 6.36 (d, J = 7.3 Hz, 1H), 5.74 (d, J = 9.6 Hz, 1H), 5.06 (d, J = 16.0 Hz, 1H), 5.02−4.94 (m, 1H), 4.81 (d, J = 11.3 Hz, 1H), 4.30 (d, J = 16.0 Hz, 1H), 2.90 (s, 1H), 0.98 (s, 3H), 0.89 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.0, 179.3, 162.1 (d, J = 246.4 Hz), 153.5, 145.3, 143.0, 137.5 (d, J = 3.0 Hz), 135.2, 131.4 (d, J = 8.1 Hz), 129.5, 129.2, 128.8, 128.6, 128.1, 127.4, 127.3, 127.1, 126.6, 125.1, 123.9, 123.0, 120.9, 120.2, 114.3 (d, J = 21.2 Hz), 109.2, 72.7, 62.9, 60.4, 54.1, 46.2, 43.4, 23.6, 21.6; 19F NMR (377 MHz, CDCl3) δ −117.72; HRMS (ESI) for C40H35FN3O [M + H]+ calcd 592.2759, found 592.2751. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3-phenyl-5-(m-tolyl)spiro[pyrrolidin-2,3′-oxindole] (6c). Yield: 96% (113 mg); 2:1 dr; white solid, mp: 155−157 °C; 1H NMR (400 MHz, acetone-d6) δ 7.87 (d, J = 6.7 Hz, 1H), 7.53 (s, 1H), 7.45−7.39 (m, 2H), 7.22−6.99 (m, 14H), 6.85 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 6.1 Hz, 2H), 6.45 (d, J = 7.3 Hz, 1H), 5.75 (d, J = 9.3 Hz, 1H), 5.01−4.96 (m, 2H), 4.88 (d, J = 10.9 Hz, 1H), 4.44 (d, J = 16.0 Hz, 1H), 3.59 (s, 1H), 2.21 (s, 3H), 0.95 (s, 3H), 0.87 (s, 3H); 13C NMR (101 MHz, acetone) δ 189.0, 178.6, 153.7, 145.6, 143.4, 142.1, 136.2, 136.1, 136.0, 131.1, 130.2, 128.9, 128.8, 128.4, 127.9, 127.6, 127.2, 127.1, 126.9, 126.8, 126.7, 124.8, 123.7, 122.5, 121.0, 119.7, 108.8, 72.5, 63.6, 60.8, 53.9, 46.8, 42.6, 23.2, 20.8, 20.5; HRMS (ESI) for C41H38N3O [M + H]+ calcd 588.3009, found 588.3010. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5-(naphthalen-2-yl)-3phenylspiro[pyrrolidin-2,3′-oxindole] (6d). Yield: 96% (120 mg); 3:1 dr; white solid, mp: 112−114 °C; 1H NMR (400 MHz, acetone-d6) δ 8.07 (dd, J = 8.6, 1.4 Hz, 1H), 8.01 (s, 1H), 7.97−7.91 (m, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.72 (dd, J = 8.0, 3.1 Hz, 2H), 7.40−7.31 (m, 3H), 7.23 (d, J = 7.2 Hz, 2H), 7.20−7.01 (m, 10H), 6.94−6.90 (m, 1H), 6.79−6.68 (m, 2H), 6.46 (d, J = 7.4 Hz, 1H), 5.97 (d, J = 9.7 Hz, 1H), 5.20−5.09 (m, 1H), 5.03−4.98 (m, 2H), 4.46 (d, J = 16.0 Hz, 1H), 3.76 (s, 1H), 0.96 (s, 3H), 0.90 (s, 3H); 13C NMR (101 MHz, acetone) δ 188.5, 178.8, 153.6, 145.5, 143.4, 140.3, 136.0, 132.9, 132.8, 130.2, 129.0, 128.8, 128.0, 128.5, 128.4, 127.9, 127.7, 127.4, 127.3,

128.2, 127.9, 127.6, 127.3, 127.1, 126.6, 125.2, 123.4, 123.2, 121.0, 120.1, 109.1, 73.0, 71.3, 64.5, 54.2, 52.3, 43.8, 22.8, 21.3, 21.1; HRMS (ESI) for C41H38N3O [M + H]+ calcd 588.3009, found 588.2995. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5-(naphthalen-2-yl)-3phenylspiro[pyrrolidin-2,3′-oxindole] (5u). Yield: 99% (123 mg); >20:1 dr; white solid, mp: 121−123 °C; 1H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 8.5, 1.5 Hz, 1H), 7.91−7.86 (m, 3H), 7.82−7.76 (m, 1H), 7.73−7.71 (m, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.44−7.33 (m, 2H), 7.23−7.19 (m, 3H), 7.16−6.98 (m, 9H), 6.94 (d, J = 7.2 Hz, 1H), 6.52 (d, J = 7.2 Hz, 2H), 6.31 (d, J = 7.6 Hz, 1H), 5.34 (d, J = 9.1 Hz, 1H), 5.12 (d, J = 16.0 Hz, 1H), 4.75 (dd, J = 12.1, 9.2 Hz, 1H), 4.66 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 16.0 Hz, 1H), 2.88 (s, 1H), 0.78 (s, 3H), 0.28 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.2, 179.4, 153.4, 145.8, 142.8, 139.9, 135.2, 134.2, 133.4, 133.2, 131.8, 129.7, 129.1, 128.9, 128.7, 128.1, 128.0, 127.8, 127.7, 127.4, 127.2, 126.6, 126.0, 125.9, 125.4, 123.4, 123.2, 121.1, 120.2, 109.2, 73.0, 71.6, 64.5, 54.2, 51.9, 43.9, 22.8, 21.3; HRMS (ESI) for C44H38N3O [M + H]+ calcd 624.3009, found 624.2995. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3-phenyl-5-(thiophen-2yl)spiro[pyrrolidin-2,3′-oxindole] (5v). Yield: 86% (100 mg); >20:1 dr; white solid, mp: 159−161 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.1 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 4.8 Hz, 2H), 7.17 (d, J = 7.3 Hz, 2H), 7.15−6.98 (m, 11H), 6.83 (dd, J = 5.0, 3.5 Hz, 1H), 6.52 (d, J = 7.2 Hz, 2H), 6.30 (d, J = 7.6 Hz, 1H), 5.50 (d, J = 9.2 Hz, 1H), 5.11 (d, J = 16.0 Hz, 1H), 4.64 (dd, J = 12.2, 9.2 Hz, 1H), 4.54 (d, J = 12.4 Hz, 1H), 4.27 (d, J = 16.0 Hz, 1H), 3.24 (s, 1H), 0.80 (s, 3H), 0.67 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.1, 179.0, 153.2, 146.7, 145.9, 142.8, 135.2, 133.9, 131.4, 129.6, 129.1, 128.6, 128.0, 127.7, 127.4, 127.1, 126.6, 126.5, 126.1, 125.5, 125.4, 123.4, 123.1, 121.1, 120.2, 109.2, 72.7, 66.4, 64.4, 54.3, 53.1, 43.9, 22.7, 20.4; HRMS (ESI) for C38H34N3OS [M + H]+ calcd 580.2417, found 580.2403. 1′-Benzyl-3-(4-chloro-2-fluorophenyl)-4-(3,3-dimethyl-3H-indol2-yl)-5-phenylspiro[pyrrolidin-2,3′-oxindole] (5w). Yield: 95% (119 mg); >20:1 dr; white solid, mp: 196−198 °C; 1H NMR (400 MHz, CDCl3) δ 7.88−7.82 (m, 1H), 7.81−7.75 (m, 2H), 7.65−7.57 (m, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.26−7.21 (m, 2H), 7.20−7.07 (m, 6H), 7.03 (d, J = 6.8 Hz, 1H), 6.83 (dd, J = 8.5, 1.8 Hz, 1H), 6.72 (dd, J = 9.4, 2.1 Hz, 1H), 6.69−6.61 (m, 2H), 6.49−6.41 (m, 1H), 5.23−5.04 (m, 3H), 4.55 (dd, J = 12.1, 9.4 Hz, 1H), 4.32 (d, J = 16.0 Hz, 1H), 2.85 (s, 1H), 0.79 (s, 3H), 0.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.2, 179.1, 161.1 (d, J = 253.5 Hz), 153.2, 145.6, 142.5, 142.2, 135.2, 133.9 (d, J = 10.1 Hz), 131.5 (d, J = 4.0 Hz), 130.9, 129.3, 128.7, 128.3, 128.2, 127.5, 126.6, 125.5, 123.9, 123.4, 121.1, 120.5 (d, J = 14.1 Hz), 120.4, 116.1 (d, J = 27.3 Hz), 109.0, 72.0, 71.3, 54.0, 52.0, 43.9, 22.9, 20.8; 19F NMR (377 MHz, CDCl3) δ −113.92; HRMS (ESI) for C40H34ClFN3O [M + H]+ calcd 626.2369, found 626.2352. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5-phenyl-3-(p-tolyl)spiro[pyrrolidin-2,3′-oxindole] (5x). Yield: 96% (113 mg); >20:1 dr; white solid, mp: 222−224 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 9.3, 7.7 Hz, 3H), 7.59 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 7.4 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 7.16−7.00 (m, 9H), 6.81 (d, J = 7.9 Hz, 2H), 6.55 (d, J = 7.4 Hz, 2H), 6.31 (d, J = 7.6 Hz, 1H), 5.14 (dd, J = 12.4, 3.5 Hz, 2H), 4.63−4.51 (m, 2H), 4.27 (d, J = 16.0 Hz, 1H), 2.78 (s, 1H), 2.18 (s, 3H), 0.80 (s, 3H), 0.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.2, 179.5, 153.4, 145.8, 142.7, 142.6, 137.1, 135.2, 132.0, 131.0, 129.5, 128.9, 128.6, 128.5, 128.3, 128.1, 127.3, 127.1, 126.7, 125.3, 123.4, 123.1, 121.1, 120.1, 109.2, 72.9, 71.4, 64.3, 54.2, 52.4, 43.8, 22.9, 21.2, 20.9; HRMS (ESI) for C41H38N3O [M + H]+ calcd 588.3009, found 588.2990. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3-(naphthalen-2-yl)-5phenylspiro[pyrrolidin-2,3′-oxindole] (5y). Yield: 99% (123 mg); >20:1 dr; white solid, mp: 139−141 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 9.3 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 8.6 Hz, 1H), 7.38−7.30 (m, 5H), 7.23−7.13 (m, 3H), 7.05−7.01 (m, 2H), 6.96 (d, J = 7.0 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.49 (t, J = 7.7 Hz, 2H), 6.24 (t, J = 6.7 Hz, 3H), 5.21 (d, J = 8.5 Hz, 1H), 5.10 (d, J = 16.0 Hz, 1H), 4.84− 4.67 (m, 2H), 4.17 (d, J = 16.0 Hz, 1H), 2.84 (s, 1H), 0.78 (s, 3H), 0.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.0, 179.4, 153.2, 4325

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

Article

The Journal of Organic Chemistry 127.0, 126.7, 126.3, 125.5, 124.8, 123.8, 122.5, 120.9, 119.7, 108.8, 72.6, 63.5, 60.6, 53.9, 46.6, 42.7, 23.2, 21.0; HRMS (ESI) for C44H38N3O [M + H]+ calcd 624.3009, found 624.3011. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3-phenyl-5-(thiophen-2yl)spiro[pyrrolidin-2,3′-oxindole] (6e). Yield: 94% (109 mg); 7:1 dr; white solid, mp: 152−154 °C; 1H NMR (400 MHz, acetone-d6) δ 7.88 (dd, J = 7.2, 1.1 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.24−7.10 (m, 11H), 7.09−7.02 (m, 3H), 6.96 (d, J = 3.0 Hz, 1H), 6.75 (dd, J = 5.1, 3.5 Hz, 1H), 6.73−6.67 (m, 2H), 6.44 (d, J = 7.3 Hz, 1H), 5.99 (dd, J = 9.1, 5.1 Hz, 1H), 5.17−5.04 (m, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.81 (d, J = 11.6 Hz, 1H), 4.44 (d, J = 16.0 Hz, 1H), 3.89 (d, J = 6.2 Hz, 1H), 1.23 (s, 3H), 1.06 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 186.7, 179.3, 153.6, 147.4, 145.4, 142.9, 135.1, 134.8, 130.0, 129.2, 128.8, 128.6, 128.1, 127.4, 127.3, 127.1, 126.5, 126.0, 125.6, 125.3, 125.1, 124.2, 123.0, 120.9, 120.4, 109.2, 72.4, 59.3, 59.0, 54.3, 46.2, 43.6, 24.2, 21.6; HRMS (ESI) for C38H34N3OS [M + H]+ calcd 580.2417, found 580.2416. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5-phenyl-3-(p-tolyl)spiro[pyrrolidin-2,3′-oxindole] (6f). Yield: 95% (112 mg); 6:1 dr; white solid, mp: 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.1, 1.2 Hz, 1H), 7.62 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.20−7.03 (m, 11H), 7.00 (d, J = 4.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 6.56 (d, J = 7.3 Hz, 2H), 6.37−6.30 (m, 1H), 5.70 (d, J = 9.6 Hz, 1H), 5.11 (d, J = 16.0 Hz, 1H), 5.01 (dd, J = 11.3, 9.7 Hz, 1H), 4.81 (d, J = 11.4 Hz, 1H), 4.25 (d, J = 16.0 Hz, 1H), 3.07 (br, 1H), 2.20 (s, 3H), 1.01 (s, 3H), 0.89 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.2, 179.4, 153.6, 145.4, 143.1, 141.8, 136.7, 135.3, 132.3, 129.8, 129.7, 129.1, 128.8, 128.7, 128.5, 127.6, 127.5, 127.2, 127.1, 126.7, 124.9, 123.9, 122.9, 120.8, 120.1, 109.1, 72.9, 63.9, 60.2, 54.2, 46.5, 43.5, 23.9, 21.7, 21.1; HRMS (ESI) for C41H38N3O [M + H]+ calcd 588.3009, found 588.3010. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3-(naphthalen-2-yl)-5phenylspiro[pyrrolidin-2,3′-oxindole] (6g). Yield: 99% (123 mg); 10:1 dr; white solid, mp: 128−130 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.2 Hz, 1H), 7.74−7.62 (m, 4H), 7.58 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.45−7.26 (m, 4H), 7.22−7.05 (m, 6H), 6.99 (t, J = 6.1 Hz, 2H), 6.89 (t, J = 7.3 Hz, 1H), 6.52 (t, J = 7.6 Hz, 2H), 6.27 (t, J = 7.5 Hz, 3H), 5.78 (d, J = 9.5 Hz, 1H), 5.18 (t, J = 10.3 Hz, 1H), 5.05 (t, J = 14.5 Hz, 2H), 4.17 (d, J = 16.0 Hz, 1H), 3.00 (br, 1H), 1.03 (s, 3H), 0.91 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.1, 179.3, 153.4, 145.3, 143.1, 141.7, 134.9, 133.2, 131.1, 132.9, 129.8, 129.3, 128.2, 128.1, 127.7, 127.6, 127.5, 127.2, 127.1, 127.0, 126.3, 125.9, 125.8, 125.0, 123.9, 123.0, 120.8, 120.2, 109.2, 73.0, 64.0, 60.6, 54.3, 46.7, 43.5, 24.0, 21.7; HRMS (ESI) for C44H38N3O [M + H]+ calcd 624.3009, found 624.3009. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-5-phenyl-3-(thiophen-2yl)spiro[pyrrolidin-2,3′-oxindole] (6h). Yield: 99% (115 mg); 2:1 dr; white solid, mp: 150−152 °C; 1H NMR (400 MHz, CDCl3) δ 7.85− 7.76 (m, 1H), 7.59 (d, J = 7.4 Hz, 2H), 7.47 (d, J = 7.7 Hz, 1H), 7.20− 7.12 (m, 8H), 7.10−7.01 (m, 3H), 6.98−6.92 (m, 1H), 6.79 (d, J = 3.3 Hz, 1H), 6.77−6.67 (m, 3H), 6.45 (dd, J = 5.8, 2.9 Hz, 1H), 5.69 (d, J = 9.8 Hz, 1H), 5.11 (dd, J = 25.4, 13.7 Hz, 2H), 5.02−4.89 (m, 1H), 4.40 (d, J = 16.0 Hz, 1H), 2.82 (s, 1H), 1.10 (s, 3H), 0.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 187.5, 179.0, 153.4, 145.5, 143.4, 141.5, 138.4, 135.3, 129.9, 129.3, 129.2, 128.7, 127.6, 127.5, 127.2, 126.8, 126.5, 125.7, 125.0, 123.9, 123.0, 120.8, 120.2, 109.2, 72.5, 63.5, 55.4, 54.3, 48.3, 43.5, 24.1, 21.6; HRMS (ESI) for C38H34N3OS [M + H]+ calcd 580.2417, found 580.2415. Procedure for the Synthesis of Compounds 7, 8, and 9. A reaction tube was charged with 5c (0.2 mmol) and dioxane (2 mL), and then DDQ (0.24 mmol) was added at 25 °C. The reaction was stirred for 24 h, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether = 1/8) on silica gel to give the product 7. A reaction tube was charged with 5c (0.2 mmol) and dioxane (2 mL), and then DDQ (0.50 mmol) was added at 80 °C. The reaction was stirred for 3.5 h, the crude product was purified by column chromatography (ethyl acetate/petroleum ether = 1/8) on silica gel to give the product 8.

In a reaction tube, 5c (0.2 mmol) was added into THF (2 mL) at 15 °C. Then m-CPBA (0.5 mmol) was added at the same temperature, and the reaction solution was stirred for 30 min. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/4) to afford product 9. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-diphenyl-3,4dihydrospiro[prorol-2,3′-oxindole] (7). Yield: 90% (103 mg); white solid, mp: 290−292 °C; 1H NMR (400 MHz, CDCl3) δ 7.80−7.69 (m, 3H), 7.57 (d, J = 7.7 Hz, 1H), 7.35−7.24 (m, 6H), 7.24−7.21 (m, 1H), 7.16−7.11 (m, 7H), 7.06 (t, J = 7.3 Hz, 2H), 6.48 (d, J = 7.3 Hz, 2H), 6.42 (dd, J = 5.6, 3.1 Hz, 1H), 5.55 (d, J = 10.4 Hz, 1H), 5.11 (d, J = 16.0 Hz, 1H), 4.42 (d, J = 10.4 Hz, 1H), 4.25 (d, J = 16.0 Hz, 1H), 1.39 (s, 3H), 0.71 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.5, 178.6, 174.2, 153.3, 145.5, 143.3, 135.1, 134.9, 134.8, 130.2, 130.0, 129.5, 129.2, 128.6, 128.4, 128.2, 128.1, 127.8, 127.6, 127.1, 126.5, 125.8, 124.6, 123.2, 121.0, 120.9, 109.2, 85.6, 64.8, 55.1, 54.5, 43.7, 23.3, 22.8; HRMS (ESI) for C40H34N3O [M + H]+ calcd 572.2696, found 572.2693. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-3,5-diphenylspiro[prorol-2,3′-oxindole] (8). Yield: 92% (105 mg); white solid, mp: 150−152 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.7 Hz, 1H), 7.62−7.51 (m, 5H), 7.36−7.26 (m, 7H), 7.25−7.18 (m, 5H), 7.17− 7.07 (m, 3H), 7.01 (d, J = 7.2 Hz, 1H), 6.91−6.82 (m, 1H), 5.48 (s, 2H), 0.56 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 182.5, 153.3, 147.3, 145.7, 136.1, 134.8, 133.8, 132.9, 131.6, 131.3, 130.8, 128.8, 128.4, 127.7, 127.6, 127.5, 127.3, 126.8, 126.4, 125.6, 125.4, 124.3, 123.2, 122.8, 122.2, 120.9, 120.8, 116.3, 115.2, 56.5, 53.4, 47.3, 22.5; HRMS (ESI) for C40H32N3O [M + H]+ calcd 570.2540, found 570.2543. 1′-Benzyl-4-(3,3-dimethyl-3H-indol-2-yl)-2-oxo-3,5-diphenyl-3,4dihydrospiro[pyrrolidin-2,3′-oxindole]-1-oxide (9). Yield: 88% (103 mg); white solid, mp: 288−290 °C; 1H NMR (400 MHz, CDCl3) δ 8.08−8.05 (m, 2H), 7.83 (dd, J = 5.7, 2.9 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.37−7.26 (m, 7H), 7.24−7.10 (m, 7H), 7.07 (t, J = 7.3 Hz, 2H), 6.52 (d, J = 7.3 Hz, 2H), 6.49−6.43 (m, 1H), 5.59 (d, J = 8.8 Hz, 1H), 5.08 (d, J = 16.0 Hz, 1H), 4.41−4.34 (m, 2H), 1.37 (s, 3H), 0.69 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.0, 171.5, 153.0, 145.6, 145.4, 144.4, 134.6, 133.3, 131.0, 130.1, 129.6, 129.2, 128.7, 128.6, 128.5, 128.1, 127.7, 127.2, 126.4, 126.1, 125.1, 124.9, 123.7, 121.1, 121.0, 109.9, 86.6, 57.0, 54.3, 47.8, 44.5, 43.9, 23.4, 22.8, 22.4; HRMS (ESI) for C40H33N3NaO2 [M + Na]+ calcd 610.2465, found 610.2449.

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ASSOCIATED CONTENT

S Supporting Information *

. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00316. 1 H and 13 C NMR spectra of all products and X-ray crystallography data for compounds 5e and 6a (PDF) CIF data for 5e (CIF) CIF data for 6a (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jingping Qu: 0000-0002-7576-0798 Baomin Wang: 0000-0001-9058-4983 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (no. 21542007), the Program for New Century Excellent Talents in University (NCET-11-0053), and the Fundamental 4326

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327

Article

The Journal of Organic Chemistry

(13) For selected examples, see: (a) Cabrera, S.; Arrayás, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394. (b) Zhao, H.-W.; Yang, Z.; Meng, W.; Tian, T.; Li, B.; Song, X.-Q.; Chen, X.-Q.; Pang, H.-L. Adv. Synth. Catal. 2015, 357, 2492. (c) Liu, H.-C.; Tao, H.-Y.; Cong, H.; Wang, C.-J. J. Org. Chem. 2016, 81, 3752. (14) (a) Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (b) Xiao, J.-A.; Zhang, H.-G.; Liang, S.; Ren, J.-W.; Yang, H.; Chen, X.-Q. J. Org. Chem. 2013, 78, 11577. (c) Xu, Q.; Wang, D.; Wei, Y.; Shi, M. ChemistryOpen 2014, 3, 93. (d) Suman, K.; Thennarasu, S. RSC Adv. 2015, 5, 79413. (e) Dai, W.; Jiang, X.-L.; Wu, Q.; Shi, F.; Tu, S.-J. J. Org. Chem. 2015, 80, 5737. (f) Yin, C.; Lin, L.; Zhang, D.; Feng, J.; Liu, X.; Feng, X. J. Org. Chem. 2015, 80, 9691. (g) Zhang, J.-X.; Wang, H.-Y.; Jin, Q.-W.; Zheng, C.W.; Zhao, G.; Shang, Y.-J. Org. Lett. 2016, 18, 4774. (15) For some examples on transformations of indolenines, see: (a) Heureux, N.; Wouters, J.; Norberg, B.; Markó, I. E. Org. Biomol. Chem. 2006, 4, 3898. (b) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Org. Lett. 2008, 10, 4009. (c) Cai, Q.; Zheng, C.; Zhang, J.-W.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 8665. (d) Kaiser, T. M.; Yang, J. Eur. J. Org. Chem. 2013, 2013, 3983. (e) Li, M.; Woods, P. A.; Smith, M. D. Chem. Sci. 2013, 4, 2907. (16) For examples on the hydrogenation of indolenines, see: (a) Rueping, M.; Brinkmann, C.; Antonchick, A. P.; Atodiresei, I. Org. Lett. 2010, 12, 4604. (b) Rueping, M.; Bootwicha, T.; Beilstein, E. S. J. Org. Chem. 2012, 8, 300. (c) Lackner, A. D.; Samant, A. V.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 14090. (d) Romano, C.; Jia, M.; Monari, M.; Manoni, E.; Bandini, M. Angew. Chem., Int. Ed. 2014, 53, 13854. (e) Yang, Z.; Chen, F.; He, Y.; Yang, N.; Fan, Q.-H. Angew. Chem., Int. Ed. 2016, 55, 13863. (17) CCDC 1525316 (5e), 1525317 (6a). See Supporting Information for details. (18) For reviews, see: (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (b) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213. (c) Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc. Rev. 2010, 39, 4402.

Research Funds of the Central Universities (DUT15TD25) for support of this work.

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REFERENCES

(1) Arun, Y.; Bhaskar, G.; Balachandran, C.; Ignacimuthu, S.; Perumal, P. T. Bioorg. Med. Chem. Lett. 2013, 23, 1839. (2) Girgis, A. S. Eur. J. Med. Chem. 2009, 44, 91. (3) Ali, M. A.; Ismail, R.; Choon, T. S.; Yoon, Y. K.; Wei, A. C.; Pandian, S.; Kumar, R. S.; Osman, H.; Manogaran, E. Bioorg. Med. Chem. Lett. 2010, 20, 7064. (4) Komatsu, Y.; Yoshida, K.; Ueda, H.; Tokuyama, H. Tetrahedron Lett. 2013, 54, 377. (5) Kump, W. G.; Patel, M. B.; Rowson, J. M.; Schmid, H. Helv. Chim. Acta 1964, 47, 1497. (6) Sharma, P.; Kumar, A.; Sahu, V.; Upadhyay, S.; Singh, J. Med. Chem. Res. 2009, 18, 383. (7) For reviews on the synthesis of spiro[pyrrolidine-oxindoles], see: (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2003, 2209. (b) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012, 10, 5165. (c) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (d) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F., III ACS Catal. 2014, 4, 743. (e) Santos, M. M. M. Tetrahedron 2014, 70, 9735. (8) For recent reviews, see: (a) Smith, J. M.; Moreno, J.; Boal, B. W.; Garg, N. K. Angew. Chem., Int. Ed. 2015, 54, 400. (b) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Chem. - Eur. J. 2016, 22, 2856. (9) (a) Zou, L.; Wang, B.; Mu, H.; Zhang, H.; Song, Y.; Qu, J. Org. Lett. 2013, 15, 3106. (b) Zou, L.; Bao, X.; Ma, Y.; Song, Y.; Qu, J.; Wang, B. Chem. Commun. 2014, 50, 5760. (c) Zhang, H.; Wang, B.; Cui, L.; Li, Y.; Qu, J.; Song, Y. Org. Biomol. Chem. 2014, 12, 9097. (d) Zhu, G.; Wang, B.; Bao, X.; Zhang, H.; Wei, Q.; Qu, J. Chem. Commun. 2015, 51, 15510. (e) Bao, X.; Wang, B.; Cui, L.; Zhu, G.; He, Y.; Qu, J.; Song, Y. Org. Lett. 2015, 17, 5168. (f) Zhang, H.; Wei, Q.; Wei, S.; Qu, J.; Wang, B. Eur. J. Org. Chem. 2016, 2016, 3373. (g) Bao, X.; Wei, S.; Zou, L.; He, Y.; Xue, F.; Qu, J.; Wang, B. Chem. Commun. 2016, 52, 11426. (h) Wei, Q.; Zhu, G.; Zhang, H.; Qu, J.; Wang, B. Eur. J. Org. Chem. 2016, 2016, 5335. (i) Xue, F.; Bao, X.; Zou, L.; Qu, J.; Wang, B. Adv. Synth. Catal. 2016, 358, 3971. (10) For reviews on 1,3-dipolar cycloaddition reactions of azomethine ylides, see: (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. (b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484. (c) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132. (d) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (e) Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703. (f) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784. (g) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2011, 50, 8492. (h) Narayan, R.; Potowski, M.; Jia, Z.-J.; Antonchick, A. P.; Waldmann, H. Acc. Chem. Res. 2014, 47, 1296. (11) For examples, see: (a) Arai, T.; Yokoyama, N.; Mishiro, A.; Sato, H. Angew. Chem., Int. Ed. 2010, 49, 7895. (b) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010, 132, 5338. (c) Kim, H. Y.; Li, J.-Y.; Kim, S.; Oh, K. J. Am. Chem. Soc. 2011, 133, 20750. (d) Narayan, R.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew. Chem., Int. Ed. 2013, 52, 12892. (e) Tian, L.; Hu, X.-Q.; Li, Y.-H.; Xu, P.-F. Chem. Commun. 2013, 49, 7213. (f) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462. (g) Bai, X.-F.; Song, T.; Xu, Z.; Xia, C.-G.; Huang, W. S.; Xu, L.-W. Angew. Chem., Int. Ed. 2015, 54, 5255. (h) He, F.-S.; Zhu, H.; Wang, Z.; Gao, M.; Yu, X.; Deng, W.-P. Org. Lett. 2015, 17, 4988. (i) Cayuelas, A.; Ortiz, R.; Nájera, C.; Sansano, J. M.; Larrañaga, O.; Cózar, A.; Cossío, F. P. Org. Lett. 2016, 18, 2926. (12) For selected examples, see: (a) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (b) Zeng, W.; Chen, G.Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129, 750. (c) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 5652. (d) Shi, F.; Tao, Z.-L.; Luo, S.-W.; Tu, S.-J.; Gong, L.-Z. Chem. - Eur. J. 2012, 18, 6885. (e) Wang, H.; Deng, Q.; Zhou, Z.; Hu, S.; Liu, Z.; Zhou, L.-Y. Org. Lett. 2016, 18, 404. 4327

DOI: 10.1021/acs.joc.7b00316 J. Org. Chem. 2017, 82, 4317−4327