Asymmetric Darzens Reaction of Isatins with Diazoacetamides

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Asymmetric Darzens Reaction of Isatins with Diazoacetamides Catalyzed by Chiral BINOL−Titanium Complex Guo-Li Chai,† Jian-Wei Han,†,§ and Henry N. C. Wong*,†,‡,∥ †

Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China ‡ Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China § Key Laboratory for Advanced Materials, Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China ∥ Shenzhen Municipal Key Laboratory of Chemical Synthesis of Medicinal Organic Molecules & Shenzhen Center of Novel Functional Molecules, Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10, Second Yuexing Road, Shenzhen 518507, China S Supporting Information *

ABSTRACT: An efficient catalytic asymmetric Darzens reaction of N-protected isatins with diazoacetamides using a chiral BINOL/Ti(OiPr)4 complex as the catalyst has been developed. This reaction is a straightforward method for the synthesis of spiro-epoxyoxindoles in 40−95% yields, up to >20:1 dr and up to >99% ee. A gram-scale reaction was also achieved in 95% yield with excellent stereoselectivity and enantioselectivity (>20:1 dr, >99% ee).

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INTRODUCTION Spiro-epoxyoxindole derivatives have been identified to exhibit important biological activities,1 and they are also very important precursors for the synthesis of a wide variety of indole compounds.2 For this reason, syntheses of optically active spiro-epoxyoxindoles have become an important research area. However, efficient catalytic approaches to construct this privileged skeleton in a high enantio- and diastereoselective fashion are few.1e In 2007, the group of Brière and Metzner first developed a stereoselective Darzens reaction between a stoichiometric amount of a C2 symmetric chiral sulfide and αbromoacetamides, but the spiro-epoxyoxindole was achieved in only 30% ee.3 In 2011, the research group of Gasperi succeeded in asymmetric epoxidation of α-ylideneoxindoles by using (S)α,α-diphenylprolinol as catalyst with tert-butylhydroperoxide as the oxidant, leading to the formation of epoxy-oxindoles with moderate to good stereoselectivities (up to 88% ee, up to 71:29 dr).4 In 2014, Xiao’s group reported an asymmetric synthesis of diethylacetamide-substituted epoxyoxindoles (>95:5 dr, up to 93% ee) by employing stoichiometric chiral sulfur ylides generated in situ from camphor-derived sulfonium salts.5 Later on, an elegant work of Feng and co-workers involving the Co(acac)2-N,N′-dioxide-catalyzed asymmetric Darzens reaction of phenacyl bromide with N-protected isatins was reported to afford benzyl-substituted trans-spiro-oxiraneoxindoles with © 2017 American Chemical Society

good to excellent stereoselectivities (>99:1 dr, up to 95% ee).6 Although these approaches did lead to diverse types of chiral spiro-epoxyoxindoles in a stoichiometric or catalytic manner, there is still much room for improvement of the stereoselectivity and enantioselectivity. Furthermore, the development of green, economical, and highly efficient synthetic methods for asymmetric syntheses of novel optically active spiro-epoxyoxindoles is still highly in demand. The Darzens reaction has been frequently used in the syntheses of optically pure epoxides.7 Recently, our research group disclosed an asymmetric Darzens reaction between aldehydes and diazoacetamides by employing a chiral Lewis acid catalyst from (R)-1,16-dihydroxytetraphenylenes (DHTP) and Ti(OiPr)4, giving solely cis-glycidic amides in good yields with excellent enantioselectivities (eq 1, Scheme 1).8 However, Darzens reaction of isatins with diazo-N,N-dimethylacetamide was still unknown (eq 2, Scheme 1); herein we report that the catalyst systems of chiral titanium complexes could also mediate the reaction of N-protected isatins with diazoacetamides, resulting in the formation of enantiopure spiro-epoxyoxindoles. Noteworthy is that nitrogen is produced as the sole byproduct in this reaction. Received: September 26, 2017 Published: October 20, 2017 12647

DOI: 10.1021/acs.joc.7b02439 J. Org. Chem. 2017, 82, 12647−12654

Article

The Journal of Organic Chemistry

out using a mixture of (R)-DHTP (L1, 40 mol %) and Ti(OiPr)4 (2:1) as catalyst with 4 Å molecular sieves (MS) as a water scavenger in dichloromethane (CH2Cl2) at a temperature of 20 °C under an argon atmosphere. To our delight, the desired product of trans-3a was obtained in 35% yield with 82% ee (entry 1, Table 1). Encouraged by the preliminary results, reaction conditions such as various solvents and different reaction temperatures were examined by making use of the model substrate (see the Supporting Information for details, Table S1).9 The Darzens reaction proceeded with excellent enantioselectivities (up to 98% ee) in THF (entry 2, Table 1), but in all cases, the chemical yield was very low (up to 35%). Then we turned to use (R,R)-1,8,9,16-tetrahedroxytetraphenylene (THTP, L2) as chiral ligand to optimize the reaction conditions (see the Supporting Information for details, Tables S2 and S3).9 A lower temperature of 0 °C and a longer reaction time of 48 h are required to implement the conversion of an NBn-substituted substrate 1a into product trans-3a in 70% yield and 94% ee (entries 3 and 4, Table 1). In the subsequent studies, we turned our attention to catalytic systems derived from chiral BINOL (L3, L4) and Ti(OiPr)4. Gratifyingly, the catalyst complex formed in situ between (R)-BINOL (L3) and Ti(OiPr)4 (2:1) was highly

Scheme 1. Asymmetric Darzens Reactions of Aldehydes and Ketones of Isatins

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RESULTS AND DISCUSSION Initially, racemic trans-N-phenyl-1-benzyl-2-oxospiro[indoline3,2′-oxirane]-3′-carboxamide (trans-3a) was obtained by the Zn(OTf)2/DCE system with 70% yield, and trans-3a and cis-3a were separable by silica gel chromatography with a stereoselectivity of >20/1 dr. A model reaction comprising N-benzylprotected isatin 1a and N-phenyl-diazoacetamide 2a was carried Table 1. Optimization of the Reaction Conditionsa

entry

L

solvent

temp (°C)

time (h)

yieldb (%)

eec (%)

1 2 3d 4d 5 6 7 8 9 10 11 12 13e 14 15 16f

L1 L1 L2 L2 L3 L3 L3 L3 L3 L3 L3 L3 L3 L3 L3 L4

CH2Cl2 THF CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 toluene o-xylene THF Et2O MTBE MeCN toluene toluene toluene toluene

20 20 20 0 20 20 20 20 20 20 20 20 20 0 40 20

48 48 24 48 24 24 4 4 24 24 24 10 24 22 4 4

35 34 59 70 54 48 95 94 nr 59 29 nr 54 89 62 94

82 98 91 94 94 93 99 98 − 95 91 − 94 98 95 −99

a

Unless otherwise stated, reactions were performed with 1a (0.12 mmol), 2a (0.1 mmol), 20 mol % Ti(OiPr)4, 40 mol % L, 4 Å MS (250 mg) in a dry solvent (5 mL) at 20 °C under an argon atmosphere. bIsolated yield of trans-3a; diastereomer ratios (dr > 20/1) were determined by 1H NMR analysis of unpurified reaction mixture. cDetermined by HPLC on a chiral stationary phase. dUsing 30 mol % Ti(OiPr)4, 30 mol % L2. eUsing 10 mol % Ti(OiPr)4, 20 mol % (R)-BINOL. fUsing 20 mol % Ti(OiPr)4, 40 mol % L4 ((S)-BINOL). MTBE = methyl tert-butyl ether, nr = no reaction, MS = molecular sieves. 12648

DOI: 10.1021/acs.joc.7b02439 J. Org. Chem. 2017, 82, 12647−12654

Article

The Journal of Organic Chemistry Scheme 2. Reaction Scope of the Catalytic Asymmetric Darzens Reactiona,b,c

a

Unless otherwise stated, the reactions were performed with 1 (0.12 mmol), 2 (0.1 mmol), 20 mol % Ti(OiPr)4, 40 mol % L3, and 4 Å MS (250 mg) in dry toluene (5 mL) at 20 °C under an argon atmosphere for 4−24 h. bIsolated yield of trans-products; diastereomer ratios (dr) were determined by 1H NMR analysis of the unpurified reaction mixture. cDetermined by HPLC on a chiral stationary phase. dThe reactions were performed with 1 (0.12 mmol), 2 (0.1 mmol), 30 mol % Ti(OiPr)4, 30 mol % L2, and 4 Å MS (250 mg) in dry CH2Cl2 (5 mL) at 0 °C under an argon atmosphere for 48 h.

active and enantioselective. With 20 mol % catalytic loading of the titanium complexes from L3, the reaction in DCM showed high enantioselectivity (94% ee) and moderate efficiency, giving 54% yield (entry 5, Table 1). As depicted in Table 1, reaction

media played a key role in the reaction efficiency (entries 5−12, Table 1). While chlorinated solvents resulted in moderate yields of 3a (entries 5 and 6, Table 1), ethereal solvents led to low or moderate yields (entries 10 and 11, Table 1) and polar 12649

DOI: 10.1021/acs.joc.7b02439 J. Org. Chem. 2017, 82, 12647−12654

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The Journal of Organic Chemistry

2b, which gave product 3v in 62% yield and 95% ee. Moreover, products 3a (70% yield, 12:1 dr, 94% ee), 3d (67% yield, 13:1 dr, 93% ee), and 3q (76% yield, 17:1 dr, 93% ee) were generated in moderate yields and in high enantioselectivities under the optimal conditions of dichloromethane as solvent at the temperature of 0 °C for 48 h by using L2 as chiral ligand (entry 4 Table 1). The absolute configurations of the newly formed products were determined to be trans-(3S,3′S) by an X-ray crystallographic analysis of 3e and 3s (Figure 1). It was also found that all other products exhibited similar Cotton effects in their CD spectra.9

solvents such as MeCN inhibited the reaction (entries 9 and 12, Table 1), but the use of nonpolar solvents such as toluene and o-xylene appeared to be beneficial. In these nonpolar solvents, the desired trans-(S,S)-product of 3a was obtained in excellent yields and enantioselectivities (entries 7 and 8, Table 1). Toluene was the most suitable solvent of choice for the reaction; the product of trans-3a was achieved in 95% yield with 99% ee. On the other hand, catalytic loadings also impart significant effect on the yields. Reducing the catalytic loading to 10 mol%, however, had a detrimental effect on the reaction course, leading to a lengthy reaction time (entry 13, Table 1). Decreasing the reaction temperature from 20 to 0 °C resulted in a slower reaction efficiency (entry 14, Table 1), and increasing the temperature to 40 °C led to side reactions. As a result, the yield and ee value of the desired product both decreased (entry 15, Table 1). On the other hand, (R,R)-3a, the enantiomer of (S,S)-3a, was obtained in high yield with excellent enantioselectivity (94% yield, 99% ee) when L4 [(S)BINOL] was applied as the chiral ligand (entry 16, Table 1). It is worthwhile to note that the ability to employ commercially available chiral ligands of BINOL under mild reaction conditions makes this a simple protocol for the asymmetric construction of enantiopure spiro-epoxyoxindoles. Scheme 2 summarizes the application of the optimized reaction conditions, which are reported in Table 1 (entry 7), to a variety of N-protected isatins. When 5-substituted N-benzyl isatins 1b−h were employed, the reaction proceeded efficiently to yield products 3b−h in moderate to high yields with excellent enantioselectivities. The electronic properities of the aromatic ring of the N-Bn-isatins 1 affected slightly the selectivity and yield of the desired products 3b−n (Scheme 2). Electron-withdrawing groups (such as fluoro, chloro, bromo, and iodo) and electron-donating groups (such as methoxy, methyl, and trifluoromethyl) were found to be welltolerated, but 5-nitro-N-benzyl isatin 1m reacted very sluggishly to form 3m in only 40% yield and 87% ee. Moreover, variation of steric properties was also readily exploited on the benzene ring, e.g., 7-substituted N-benzyl isatins and 6-substituted Nbenzyl isatins. It was discovered that these substrates were converted into the corresponding products in good yields with excellent enantiomeric purity (Scheme 2, 3b and 3i; 3c and 3j; 3d, 3k, and 3l). Notably, halogen-substituted substrates are well-tolerated in this asymmetric reaction, allowing further structural modification of the products. A diminished reaction rate was also observed from the reaction of a disubstituted reactant such as N-benzyl-5-chloro-7-methylisatin 1n, which gave product 3n in 46% yield with 95% ee. Isatins 1 bearing other N-substituents were also able to undergo a catalytic asymmetric reaction with diazoacetamide (3o−3s, Scheme 2). The catalytic efficiency of the reaction was dependent upon the nature of the N-substituents. All N-Bnsubstituted isatins 1a (R1 = Bn), 1o (R1 = 4-FC6H4CH2), and 1p (R1 = 4-MeOC6H4CH2) reacted with 2a to yield the corresponding products 3a, 3o, and 3p with a high level of enantioselectivity. However, the reaction of an N-substituent with an electron-donating group on the benzene ring gave a lower yield (3p) in comparison to 3o and 3a. It is noteworthy that when the N-Bn group was replaced by an N-Me substituent, products 3q−3u were obtained in moderate yields with high enantioselectivities, as shown in Scheme 2 (98% ee for 3q, 93% ee for 3r, 97% ee for 3s, 91% ee for 3t, and 98% ee for 3u). This catalytic asymmetric reaction was readily expanded to the other N-(p-methoxylphenyl)-diazoacetamide

Figure 1. X-ray structure of 3e (left) and 3s (right); the thermal ellipsoids are at the probability level of 30% for the crystal structures.

The reported catalytic asymmetric reaction was scalable. This was demonstrated by the high-yielding reaction of 2a (3.0 mmol) with 1d, which afforded the gram-scale product 3d (1.29 g, >20:1 dr, >99% ee), without decrease in enantioselectivity (eq 1, Scheme 3). Furthermore, we performed several synthetic transformations on chiral spirolepoxyoxindoles (eq 2, Scheme 3). Thus, treatment of (3S,3′S)3a and (3S,3′S)-3e with di-tert-butyl dicarbonate [(Boc)2O] and N,N-dimethylpyridin-4-amine (DMAP) and subsequent alcoholysis with sodium ethoxide afforded esters 4 and 5, respectively, in good yields and with the high level of stereoselectivity maintained (99% ee for 4 and 98% ee for 5), which are better results when compared to the previous reports (4, 66:34 dr, 56% ee; 5, 64:36 dr, 82% ee).4

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CONCLUSION In conclusion, we have successfully developed a general and efficient asymmetric Darzens reaction of N-protected isatins with diazoacetamides catalyzed by chiral BINOL-Ti(OiPr)4 complex under mild reaction conditions. The reaction proceeded well with a variety of substituted isatins, affording optically pure desired trans-spiro-epoxyoxindoles (dr > 20:1, ee up to >99%). Transformations of 3a and 3q were achieved to afford 4 and 5 smoothly without any loss of enantioselectivity. Further development of this method for the synthesis of related compounds is under investigation in our laboratories.

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EXPERIMENTAL SECTION

General Information. Unless otherwise noted, materials were purchased from commercial suppliers and without further purification. All the solvents were treated according to general methods. All reactions were carried out under an atmosphere of argon using standard Schlenk techniques. Flash chromatography (FC) was carried out using Merck silica gel 60 (230−400 mesh). HPLC analysis was performed on a Dionex UltiMate 3000, ThermoScientific. Chiral HPLC data for the epoxidation products could be obtained using a Chiralpak IC or Chiralpak IA column. These chiral columns were purchased from Daicel Chemical Industries, Ltd. Optical rotations were measured on an Autopol I polarimeter. 1H NMR spectra were recorded with a Varian Mercury 400 MHz or Agilent 400 MHz 12650

DOI: 10.1021/acs.joc.7b02439 J. Org. Chem. 2017, 82, 12647−12654

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The Journal of Organic Chemistry Scheme 3. Gram-Scale Reaction and Further Transformations of the Products 3a and 3q

(3S,3′S)-N-Phenyl-1-benzyl-5-fluoro-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3b). Compound 3b was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 95% yield (37 mg): mp 180−183 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 70:30, flow rate 0.7 mL/min, λ = 254 nm) tR (major) = 17.89 min, tR (minor) = 21.75 min, ee = 99%; [α]27 D = 155.1 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.34 (brs, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.39−7.29 (m, 7H), 7.22 (t, J = 7.2 Hz, 1H), 6.98−6.95 (m, 2H), 6.74−6.71 (m, 1H), 4.93 (dd, J = 20.4,15.6 Hz, 2H), 4.41 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.8, 162.3, 159.2 (d, J = 241.5 Hz, 1C), 141.0, 136.0, 134.6, 129.5, 129.2, 128.2, 127.4, 125.7, 120.8 (d, J = 8.7 Hz, 1C), 120.2, 117.9 (d, J = 23.5 Hz, 1C), 112.3 (d, J = 26.3 Hz, 1C), 111.2 (d, J = 8.0 Hz, 1C), 61.6, 61.2, 44.8; 19F NMR (376 MHz, CDCl3) δ −118.23 to −118.26 (m, 1F); HRMS (DART) calcd for C23H18O3N2F ([M + H]+) 389.1296, found 389.1296. (3S,3′S)-N-Phenyl-1-benzyl-5-chloro-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3c). Compound 3c was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 94% yield (38 mg): mp 187−189 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 70:30, flow rate 0.7 mL/min, λ = 254 nm) tR (major) = 19.10 min, tR (minor) = 23.63 min, ee = 99%; [α]27 D = 119.7 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.35 (brs, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.37−7.20 (m, 8H), 6.72 (d, J = 8.4 Hz, 1H), 4.92 (dd, J = 24.4,15.6 Hz, 2H), 4.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.5, 162.3, 143.5, 135.9, 134.4, 131.3, 129.5, 129.2, 129.0, 128.3, 127.5, 125.8, 124.5, 120.9, 120.5, 111.4, 61.6, 61.0, 44.8; HRMS (DART) calcd for C23H18O3N2Cl ([M + H]+) 405.1000, found 405.0999. (3S,3′S)-N-Phenyl-1-benzyl-5-bromo-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3d). Compound 3d was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 95% yield (43 mg): mp 200−202 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 70:30, flow rate 0.7 mL/min, λ = 254 nm) tR (major) = 20.59 min, tR (minor) = 25.03 min, ee = 99%; [α]30 D = 77.1 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.20 (brs, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.42−7.27 (m, 10H), 6.68 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 4.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 162.3, 144.0, 135.8, 134.4, 134.2, 129.5, 129.2, 128.3, 127.5, 127.3, 125.9, 121.3, 120.6, 116.2, 111.9, 61.6, 60.9, 44.8; HRMS (DART) calcd for C23H18O3N2Br ([M + H]+) 449.0495, found 449.0492. (3S,3′S)-N-Phenyl-1-benzyl-5-iodo-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3e). Compound 3e was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 82% yield (41 mg): mp 198−202 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 70:30, flow rate 0.7 mL/min, λ = 254 nm) tR (major) = 23.79 min, tR (minor) = 29.35 min, ee = 99%; [α]30 D = 41.6 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.18 (brs, 1H), 7.60−7.56 (m, 3H), 7.47 (s, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.35− 7.24 (m, 6H), 6.58 (d, J = 8.4 Hz, 1H), 4.93 (s, 2H), 4.38 (s, 1H); 13C

spectrometer. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3, δ = 7.26). 1H NMR spectroscopic data are presented as follows: chemical shift (ppm), multiplicity (brs = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants in hertz (Hz), integration, assignment. 13C NMR spectra were recorded with a Varian Mercury 100 MHz or Agilent 100 MHz spectrometer. Chemical shift were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3, δ = 77.16). Low-resolution mass spectrometry (LRMS) were recorded with an Agilent Single Quad 1260 LC−MS. High-resolution mass spectra (HRMS) were measured on an Agilent Technologies 6224 TOF LC/MS spectrometer, Thermo Fisher Scientific LTQ FT Ultra (ESI) mass spectrometers, or Bruker Daltonics FTMS-7 mass spectrometers. All melting points were determined using a digital melting point apparatus and were uncorrected. TLC was performed on glass-backed silica plates. Substituted 1-benzylisatin and 1-methylisatin were prepared from the reported procedure10 and the starting material of the substituted diazoacetamides was prepared from the literature procedures.7a,g (R)-BINOL and (S)-BINOL were obtained from commercial sources. Chiral 1,8,9,16-tetrahydroxytetraphenylene (THTP) and 1,16-dihydroxytetraphenylene (DHTP) were prepared according to the methods mentioned in the catalyst preparation section of ref 8. General Procedure for the Asymmetric Darzens Reaction. A 25 mL Schlenk tube containing 4 Å molecular sieves (250 mg) was dried under vacuum, and the air was replaced by argon. To the flask was added (R)-BINOL (0.04 mmol), toluene (5 mL), and Ti(O-i-Pr)4 (0.02 mmol). The mixture was stirred at 20 °C for 4 h. Then the corresponding substituted N-protected isatin (0.12 mmol) was introduced directly. After the mixture was stirred at 20 °C for 0.5 h and the diazoacetamide (0.1 mmol) was added. The reaction was kept stirring at 20 °C. After the completion of the reaction (monitored by TLC), H2O (0.1 mL) was added to the mixture to quench the reaction. After evaporation under reduced pressure, the residue was purified through flash column chromatography on silica gel [eluent, petroleum ether (bp 60−90 °C)/EtOAc = 5:1−2:1] to give pure product 3. (3S,3′S)-N-Phenyl-1-benzyl-2-oxospiro[indoline-3,2′-oxirane]-3′carboxamide (3a). Compound 3a was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 94% yield (35 mg): mp 178−181 °C; dr > 20:1; HPLC (Chiralcel IC, hexane/i-PrOH = 70:30, flow rate 0.7 mL/ min, λ = 254 nm) tR (major) = 34.53 min, tR (minor) = 42.83 min, ee 1 = 99%; [α]27 D = 162.2 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.35 (brs, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.33−7.15 (m, 8H), 6.92 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 4.95 (s, 2H), 4.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.9, 162.7, 145.1, 136.3, 134.9, 131.4, 129.5, 129.1, 128.1, 127.5, 125.5, 123.8, 123.5, 120.1, 119.2, 110.5, 61.5, 61.4, 44.6; HRMS (DART) calcd for C23H19O3N2 ([M + H]+) 371.1390, found 371.1391. 12651

DOI: 10.1021/acs.joc.7b02439 J. Org. Chem. 2017, 82, 12647−12654

Article

The Journal of Organic Chemistry NMR (100 MHz, CDCl3) δ 169.1, 162.4, 144.8, 140.1, 135.6, 134.5, 132.8, 129.6, 129.2, 128.3, 127.5, 125.9, 121.6, 120.7, 112.4, 85.9, 61.6, 60.8, 44.8; HRMS (DART) calcd for C23H16O3N2I ([M − H]−) 495.0211, found 495.0207. (3S,3′S)-N-Phenyl-1-benzyl-5-methoxy-2-oxospiro[indoline-3,2′oxirane]-3′-carboxamide (3f). Compound 3f was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 90% yield (36 mg): mp 172−175 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 20.08 min, tR (minor) = 27.66 min, ee = 99%; [α]27 D = 105.3 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.37 (brs, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.40−7.27 (m, 7H), 7.19 (t, J = 7.6 Hz, 1H), 6.78−6.75 (m, 2H), 6.70−6.68 (m, 1H), 4.91 (dd, J = 19.2, 15.6 Hz, 2H), 4.40 (s, 1H), 3.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 162.7, 156.2, 138.3, 136.2, 134.9, 129.5, 129.0, 128.1, 127.5, 125.6, 120.1, 119.9, 116.9, 111.2, 110.0, 61.6, 61.5, 55.5, 44.7; HRMS (DART) calcd for C24H19O4N2 ([M − H]−) 399.1350, found 399.1346. (3S,3′S)-N-Phenyl-1-benzyl-5-methyl-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3g). Compound 3g was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 65% yield (25 mg): mp 174−178 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 21.19 min, tR (minor) = 28.84 min, ee = 98%; [α]27 D = 70.2 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.30 (brs, 1H), 7.62 (d, J = 0.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.33−7.19 (m, 7H), 7.04 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.92 (dd, J = 18.4,16.0 Hz, 2H), 4.38 (s, 1H), 2.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 162.8, 142.7, 136.1, 135.0, 133.1, 131.7, 129.5, 129.0, 128.1, 127.5, 125.6, 124.6, 120.3, 119.1, 110.3, 61.5, 61.4, 44.6, 21.1; HRMS (DART) calcd for C24H19O3N2 ([M − H]−) 383.1401, found 383.1399. (3S,3′S)-N-Phenyl-1-benzyl-5-trifluoromethoxy-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3h). Compound 3h was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 5:1] to afford a colorless solid in 80% yield (36 mg): mp 200−203 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 70:30, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 11.18 min, tR (minor) = 13.26 1 min, ee = 98%; [α]32 D = 148.2 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.30 (brs, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.39−7.30 (m, 7H), 7.21 (t, J = 7.6 Hz, 1H), 7.13−7.12 (m, 2H), 6.81−6.78 (m, 1H), 4.95 (dd, J = 19.2, 16.0 Hz, 2H), 4.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.8, 162.1, 145.0, 143.6, 135.8, 134.4, 129.5, 129.2, 128.4, 127.5, 125.8, 124.6, 121.6, 120.8, 120.3, 118.0, 111.1, 61.6, 61.0, 44.9; 19 F NMR (376 MHz, CDCl3) δ −58.56 (s, 3F); HRMS (DART) calcd for C24H16O4N2F3 ([M − H]−) 453.1068, found 453.1072. (3S,3′S)-N-Phenyl-1-benzyl-7-fluoro-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3i). Compound 3i was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 5:1] to afford a colorless solid in 79% yield (30 mg): mp 187−191 °C; HPLC (Chiralcel IA, hexane/i-PrOH = 70:30, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 11.39 min, tR (major) = 14.54 min, ee = 99%; [α]32 D = 72.5 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.26 (brs, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.42−7.30 (m, 7H),7.22 (t, J = 7.2 Hz, 1H), 7.08−7.03 (m, 1H), 6.96−6.95 (m, 1H), 6.91−6.86 (m, 1H), 5.09 (dd, J = 29.6, 15.2 Hz, 2H), 4.38 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.7, 162.2, 149.2, 146.8, 136.1 (d, J = 3.8 Hz, 1C), 131.7 (d, J = 9.2 Hz, 1C), 129.5, 128.9, 128.1, 127.8 (d, J = 1.6 Hz, 1C), 125.7, 124.4 (d, J = 6.4 Hz, 1C), 122.2 (d, J = 3.3 Hz, 1C), 120.1, 119.9, 119.7 (d, J = 3.0 Hz, 1C), 61.8, 61.1 (d, J = 3.5 Hz, 1C), 46.3 (d, J = 5.0 Hz, 1C); 19F NMR (376 MHz, CDCl3) δ −131.75 to −131.79 (m, 1F); HRMS (DART) calcd for C23H16O3N2F ([M − H]−) 387.1150, found 387.1146. (3S,3′S)-N-Phenyl-1-benzyl-7-chloro-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3j). Compound 3j was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 82% yield (33 mg): mp 196−198 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 12.85 min, tR (major) = 14.46 min, ee = 99%; [α]32 D = 98.7 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29 (brs,

1H), 7.62 (d, J = 1.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.32−7.22 (m, 7H), 7.12 (dd, J = 7.6, 1.2 Hz, 1H), 6.89 (t, J = 8.0 Hz, 1H), 5.39 (dd, J = 19.6, 16.4 Hz, 2H), 4.39 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.7, 162.1, 141.0, 136.6, 136.2, 134.1, 129.5, 128.8, 127.6, 126.6, 125.7, 124.4, 122.3, 122.2, 120.1, 116.9, 62.1, 60.7, 45.8; HRMS (DART) calcd for C23H16O3N2Cl ([M − H]−) 403.0855, found 403.0850. (3S,3′S)-N-Phenyl-1-benzyl-7-bromo-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3k). Compound 3k was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 5:1] to afford a colorless solid in 78% yield (35 mg): mp 197−201 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 13.46 min, tR (major) = 16.11 min, ee = 98%; [α]32 D = 95.4 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.31 (brs, 1H), 7.62−7.60 (m, 2H), 7.45 (dd, J = 8.4, 1.2 Hz, 1H), 7.41−7.37 (m, 2H), 7.34−7.21 (m, 6H), 7.18 (dd, J = 7.6, 1.2 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 5.45 (s, 2H), 4.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.9, 162.1, 142.4, 137.4, 136.5, 136.2, 129.5, 128.8, 127.6, 126.5, 125.7, 124.8, 122.9, 122.6, 120.1, 103.8, 62.1, 60.6, 45.5; HRMS (DART) calcd for C23H16O3N2Br ([M − H]−) 447.0350, found 447.0349. (3S,3′S)-N-Phenyl-1-benzyl-6-bromo-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3l). Compound 3l was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 89% yield (40 mg): mp 176−178 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 13.46 min, tR (major) = 15.28 min, ee = 99%; [α]30 D = 134.1 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29 (brs, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.41−7.32 (m, 7H), 7.22 (t, J = 7.6 Hz, 1H), 7.07−6.96 (m, 3H), 4.91 (dd, J = 19.6, 15.6 Hz, 2H), 4.39 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.8, 162.3, 146.3, 136.1, 134.3, 129.5, 129.2, 128.4, 127.5, 126.5, 125.7, 125.5, 125.0, 120.1, 118.1, 113.9, 61.5, 61.0, 44.8; HRMS (DART) calcd for C23H16O3N2Br ([M − H]−) 447.0350, found 447.0348. (3S,3′S)-N-Phenyl-1-benzyl-5-nitro-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3m). Compound 3m was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a yellow solid in 40% yield (16 mg): mp 200−203 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 15.58 min, tR (major) = 21.07 min, ee = 87%; [α]30 D = 74.0 (c 0.50, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.28 (brs, 1H), 8.22 (dd, J = 8.4, 4.0 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.38−7.24 (m, 6H), 6.91 (d, J = 8.8 Hz, 1H), 5.02 (dd, J = 20.0, 16.0 Hz, 2H), 4.46 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.0, 161.9, 150.2, 143.8, 135.4, 133.8, 129.6, 129.4, 128.7, 128.0, 127.6, 126.3, 120.9, 120.4, 119.9, 110.2, 61.8, 60.5, 45.1; HRMS (DART) calcd for C23H16O5N3 ([M − H]−) 414.1095, found 414.1095. (3S,3′S)-N-Phenyl-1-benzyl-5-chloro-7-methyl-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3n). Compound 3n was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 5:1] to afford a colorless solid in 46% yield (19 mg): mp 165−168 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 80:20, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 51.82 min, tR (major) = 56.45 1 min, ee = 97%; [α]32 D = 118.1 (c 0.50, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.19 (brs, 1H), 7.62−7.60 (m, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.37−7.33 (m, 2H), 7.28−7.22 (m, 2H), 7.16 (d, J = 7.2 Hz, 2H), 7.06−7.04 (m, 2H), 5.22 (dd, J = 22.0, 17.2 Hz, 2H), 4.40 (s, 1H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 162.3, 141.8, 136.4, 135.9, 135.0, 129.6, 129.3, 128.8, 127.8, 125.9, 125.7, 123.0, 122.0, 121.7, 120.6, 62.1, 60.8, 46.0, 18.8; HRMS (DART) calcd for C24H18O3N2Cl ([M − H]−) 417.1011, found 417.1006. (3S,3′S)-N-Phenyl-1-(4-fluorobenzyl)-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3o). Compound 3o was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 4:1] to afford a colorless solid in 79% yield (30 mg): mp 177−180 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 70:30, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 29.41 min, tR (major) = 38.57 min, ee = 97%; [α]32 D = 131.1 (c 0.50, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.24 (brs, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.34−7.23 (m, 12652

DOI: 10.1021/acs.joc.7b02439 J. Org. Chem. 2017, 82, 12647−12654

Article

The Journal of Organic Chemistry

1H), 7.65 (dd, J = 8.4, 1.2 Hz, 2H), 7.40−7.36 (m, 2H), 7.19−7.17 (m, 1H), 6.89 (dd, J = 8.8, 2.8 Hz, 1H), 6.81−6.76 (m, 2H), 4.31 (s, 1H), 3.46 (s, 3H), 3.21 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 162.7, 156.3, 139.1, 136.3, 129.5, 125.5, 120.1, 119.9, 116.8, 110.1, 109.9, 61.6, 61.3, 55.6, 26.9; HRMS (DART) calcd for C18H15O4N2 ([M − H]−) 323.1037, found 323.1034. (3S,3′S)-N-Phenyl-1-methyl-6-bromo-2-oxospiro[indoline-3,2′oxirane]-3′-carboxamide (3u). Compound 3u was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 2:1] to afford a colorless solid in 77% yield (29 mg): mp 185−188 °C; HPLC (Chiralcel IA, hexane/i-PrOH = 60:40, flow rate 0.7 mL/min, λ = 234 nm) tR (minor) = 10.58 min, tR (major) = 15.03 min, ee = 98%; 1 [α]27 D = 169.2 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.35 (brs, 1H), 7.63−7.60 (m, 2H), 7.41−7.37 (m, 2H), 7.24−7.19 (m, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.31 (s, 1H), 3.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 162.4, 147.0, 136.1, 129.5, 126.3, 125.6, 125.5, 124.9, 120.1, 118.0, 113.1, 61.3, 61.0, 27.1; HRMS (DART) calcd for C17H12O3N2Br ([M − H]−) 371.0037, found 371.0038. (3S,3′S)-N-(4-Methoxyphenyl)-1-methyl-2-oxospiro[indoline-3,2′oxirane]-3′-carboxamide (3v). Compound 3v was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 2:1] to afford a colorless solid in 62% yield (20 mg): mp 199−201 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 42.03 min, tR (minor) = 51.27 min, ee = 95%; 1 [α]30 D = 133.5 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.21 (brs, 1H), 7.55−7.53 (m, 2H), 7.38 (td, J = 7.6, 1.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.99−6.91 (m, 4H), 4.30 (s, 1H), 3.82 (s, 3H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 162.4, 157.2, 145.9, 131.5, 129.3, 123.6, 123.4, 121.8, 119.2, 114.6, 109.4, 61.4, 61.3, 55.6, 29.8, 26.9; HRMS (ESI) calcd for C18H17O4N2 ([M + H]+) 325.1183, found 325.1182. General Procedure for the Synthesis of Compounds 4 and 5. To a solution of compound 3a (preparation via the Darzens reaction catalyzed by (R)-BINOL titanium complex, >99% ee, 37 mg, 0.1 mmol) in a solvent mixture of CH3CN/CH2Cl2 (9/1, 10 mL) was added DMAP (25 mg, 0.2 mmol), followed by addition of (Boc)2O (66 mg, 0.3 mmol). After being stirred at room temperature for 1 h, the reaction was complete, as monitored by TLC. The solvent was removed in vacuo. The residue was purified through flash column chromatography on silica gel (eluent, petroleum ether/ethyl acetate = 4/1) to give a colorless solid. The product was dissolved in ethanol (10 mL) and then treated with NaOEt in ethanol (1M, 0.2 mL) at 0 °C. After being stirred at 0 °C for 30 min, the reaction was complete, as monitored by TLC. The reaction was quenched with sat. aq NH4Cl (1 mL). Ethanol was removed in vacuo, and the residue was diluted with water (10 mL) and then extracted with CH2Cl2 (2 × 15 mL). The combined organic extracts were dried over Na2SO4, concentrated under vacuum, and purified through flash column chromatography on silica gel (eluent, petroleum ether/ethyl acetate = 5/1) to give compound 4 as a colorless solid (22 mg) in 69% yield: mp 126−127 °C (lit.1f mp 100−102 °C); HPLC (Chiralcel IG, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 14.69 min, tR 4 (major) = 17.81 min, >99% ee; [α]30 D = 168.0 (c 1.00, CH2Cl2) {lit. ee 1 = −110 (c 0.0290, CHCl )}; H NMR (400 MHz, = −56%, [α]20 D 3 CDCl3) δ 7.47 (dd, J = 8.0, 0.8 Hz, 1H), 7.34−7.25 (m, 6H), 7.03 (td, J = 7.6, 0.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.95 (dd, J = 20.4, 15.6 Hz, 2H), 4.27 (s, 1H), 4.36−4.24 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); LRMS (ESI) m/z = 324.1 [C19H17NO4 + H]+. Compound 5 was produced as a colorless solid, in 64% yield: mp 95−97 °C (lit.1f mp 106−108 °C); HPLC (Chiralcel IA, hexane/iPrOH = 90:10, flow rate 0.7 mL/min, λ = 214 nm) tR (minor) = 7.88 min, tR (major) = 8.88 min, ee = 98%; [α]29 D = 208.6 (c 0.53, CH2Cl2) 1 {lit.4 ee = −82%, [α]20 D = −93 (c 1.6, CH2Cl2)}; H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.40−4.28 (m, 2H), 4.21 (s, 1H), 3.28 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); LRMS (ESI) m/z = 248.1 [C13H13NO4 + H]+.

4H), 7.14 (d, J = 7.2 Hz, 1H), 7.04 (t, J = 8.0 Hz, 2H), 6.94 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.93 (s, 2H), 4.39 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 169.8, 163.8, 162.6, 161.4, 145.0, 136.2, 131.5, 130.7 (d, J = 3.4 Hz, 1C), 129.6, 129.4 (d, J = 8.1 Hz, 1C), 125.6, 123.7 (d, J = 16.6 Hz, 1C), 120.1, 119.2, 116.1 (d, J = 21.7 Hz, 1C), 110.4, 61.5, 61.4, 44.0; 19F NMR (376 MHz, CDCl3) δ −113.93 (s, 1F); HRMS (DART) calcd for C23H16O3N2F ([M − H]−) 387.1150, found 387.1148. (3S,3′S)-N-Phenyl-1-(4-methoxybenzyl)-2-oxospiro[indoline-3,2′oxirane]-3′-carboxamide (3p). Compound 3p was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 5:1] to afford a colorless solid in 42% yield (17 mg): mp 185−188 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 22.84 min, tR (minor) = 28.57 min, ee = 93%; 1 [α]28 D = 125.1 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.28 (brs, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.28−7.22 (m, 4H), 7.14 (d, J = 7.6 Hz, 1H), 6.94−6.84 (m, 4H), 4.89 (s, 2H), 4.38 (s, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 162.7, 159.4, 145.2, 136.2, 131.4, 129.5, 129.0, 126.9, 125.6, 123.7, 123.5, 120.1, 119.2, 114.4, 110.5, 61.5, 55.4, 44.1; HRMS (DART) calcd for C24H19O4N2 ([M − H]−) 399.1350, found 399.1346. (3S,3′S)-N-Phenyl-1-methyl-2-oxospiro[indoline-3,2′-oxirane]-3′carboxamide (3q). Compound 3q was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 2:1] to afford a colorless solid in 86% yield (25 mg): mp 200−202 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 23.78 min, tR (minor) = 30.80 min, ee = 98%; [α]28 D = 142.3 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.36 (brs, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.42−7.38 (m, 3H), 7.21 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.31 (s, 1H), 3.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 162.7, 145.9, 136.3, 131.5, 129.5, 125.5, 123.7, 123.5, 120.1, 119.2, 109.5, 61.4, 61.3, 26.9; HRMS (DART) calcd for C17H13O3N2 ([M − H]−) 293.0932, found 293.0931. (3S,3′S)-N-Phenyl-1-methyl-5-fluoro-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3r). Compound 3r was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 2:1] to afford a colorless solid in 64% yield (20 mg): mp 207−209 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 13.53 min, tR (minor) = 16.97 min, ee = 93%; [α]26 D = 145.4 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.28 (brs, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.10 (td, J = 8.8, 2.4 Hz, 1H), 6.94 (dd, J = 7.6, 2.4 Hz, 1H), 6.85 (dd, J = 8.8, 4.0 Hz, 1H), 4.33 (s, 1H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 162.3, 160.4, 159.2 (d, J = 241.5 Hz, 1C), 158.0, 141.8, 136.0, 129.6, 125.8, 120.7 (d, J = 8.4 Hz, 1C), 120.2, 117.9 (d, J = 23.6 Hz, 1C), 112.2 (d, J = 26.3 Hz, 1C), 110.1 (d, J = 8.1 Hz, 1C), 61.4, 61.2, 27.1; 19F NMR (376 MHz, CDCl3) δ −118.37 to −118.40 (m, 1F); HRMS (DART) calcd for C17H12O3N2F ([M − H]−) 311.0837, found 311.0831. (3S,3′S)-N-Phenyl-1-methyl-5-iodo-2-oxospiro[indoline-3,2′-oxirane]-3′-carboxamide (3s). Compound 3s was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 2:1] to afford a colorless solid in 60% yield (25 mg): mp 196−198 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 18.41 min, tR (minor) = 23.93 min, ee = 97%; [α]27 D = 46.8 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.30 (brs, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.61−7.58 (m, 2H), 7.47 (d, J = 1.6 Hz, 1H), 7.42−7.40 (m, 2H), 7.25−7.21 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.31 (s, 1H), 3.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 162.4, 145.5, 140.1, 135.7, 132.7, 129.5, 125.9, 121.5, 120.7, 111.3, 85.8, 61.4, 60.7, 27.0; HRMS (DART) calcd for C17H12O3N2I ([M − H]−) 418.9898, found 418.9891. (3S,3′S)-N-Phenyl-1-methyl-5-methoxy-2-oxospiro[indoline-3,2′oxirane]-3′-carboxamide (3t). Compound 3t was purified by silica gel chromatography [petroleum ether (bp 60−90 °C)/EtOAc = 2:1] to afford a colorless solid in 46% yield (15 mg): mp 153−155 °C; HPLC (Chiralcel IC, hexane/i-PrOH = 50:50, flow rate 0.7 mL/min, λ = 214 nm) tR (major) = 28.37 min, tR (minor) = 45.33 min, ee = 91%; [α]27 D = 131.1 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.37 (brs, 12653

DOI: 10.1021/acs.joc.7b02439 J. Org. Chem. 2017, 82, 12647−12654

Article

The Journal of Organic Chemistry

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2011, 2, 1301. (e) Novacek, J.; Waser, M. Eur. J. Org. Chem. 2013, 2013, 637. (f) Bakó, P.; Rapi, Z.; Keglevich, G. Curr. Org. Synth. 2014, 11, 361. (g) Liu, G.; Zhang, D.-M.; Li, J.; Xu, G.-Y.; Sun, J.-T. Org. Biomol. Chem. 2013, 11, 900. (8) Chai, G.-L.; Han, J.-W.; Wong, H. N. C. Synthesis 2017, 49, 181. (9) More detailed optimization studies are described in the Supporting Information. (10) (a) Kamal, A.; Mahesh, R.; Nayak, V. L.; Babu, K. S.; Kumar, G. B.; Shaik, A. B.; Kapure, J. S.; Alarifi, A. Eur. J. Med. Chem. 2016, 108, 476. (b) Cao, S. H.; Zhang, X. C.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2011, 2011, 2668.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02439. X-ray crystal details in CIF format for compound 3e (CIF) X-ray crystal details in CIF format for compound 3s (CIF) Details of reaction optimization, HPLC data for chiral products, X-ray crystal structure of compounds 3e and 3s, and 1H and 13C NMR spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

* E-mail: [email protected] ORCID

Henry N. C. Wong: 0000-0002-3763-3085 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (NSFC 21472213, 21202186, 21272199), the National Key Program of China (2016YFA0200302), the Shenzhen Science and Technology Innovation Committee (JCYJ20160608151520697), the Chinese Academy of Sciences−Croucher Foundation Funding Scheme for Joint Laboratories, the Innovation and Technology Commission to support State Key Laboratories, an Area of Excellence Scheme established under the University Grants Committee of the Hong Kong SAR, China (Project No. AoE/ P-03/08), and the Research Grants Council of Hong Kong (CRF C4030-14G), the National Natural Science Foundation of China/Research Grants Council Joint Research Scheme (N_CUHK451/13).

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REFERENCES

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DOI: 10.1021/acs.joc.7b02439 J. Org. Chem. 2017, 82, 12647−12654