Stereodivergent Synthesis of 3-Aminooxindole Derivatives Containing

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Article Cite This: J. Org. Chem. 2018, 83, 8936−8952

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Stereodivergent Synthesis of 3‑Aminooxindole Derivatives Containing Vicinal Tetrasubstituted Stereocenters via the Mannich Reaction Koilpitchai Sivamuthuraman and Venkitasamy Kesavan* Chemical Biology Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India

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S Supporting Information *

ABSTRACT: A highly enantioselective stereodivergent synthesis of 3aminooxindole derivatives was accomplished via asymmetric Mannich reaction between 2-substituted benzofuran-3-one and isatin-derived ketimines. Both anti and syn-selective chiral 3,3-disubstituted amino oxindoles bearing two adjacent tetrasubstituted stereogenic centers with high yield and excellent enantioselectivities were obtained using readily available cinchona-alkaloid derived organocatalysts. The control experiment revealed that oxygen atom present in the benzofuran ring played an important role in switching diastereodivergence. The obtained Mannich product was further transformed into a biologically important 2,3dihydrobenzofuran derivative having three contiguous stereocenters with no loss of enantioselectivity.

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aminooxindoles.10,11 These protocols invariably yield inherently preferred diastereomers. However, due to the varying biological activity of diastereomers,12 it is pertinent to synthesize complementary diastereomers also. To date, there have been only two reports in the literature for the diastereodivergent synthesis of 3-aminooxindole derivatives. In 2012, Guo et al.13 reported a Mannich reaction where solvent played a crucial role in the addition of hydroxyacetone with isatin-derived ketimines to synthesize 3-aminooxindoles. It was observed that the antiadduct was preferred in ether, whereas syn-selective addition occurred in toluene (Scheme 1a). In 2017, Shao et al.14 reported chiral amine-catalyzed asymmetric Mannich reaction with isatin-derived ketimine and aldehyde. While a primary amine catalyst yielded anti-addition product, syn-addition product was catalyzed by a secondary amine (Scheme 1b). These reports indicate that diastereodivergent or stereodivergent synthesis of molecules having multiple stereocenters is not trivial and is a formidable task. To the best of our knowledge, Mannich reaction between isatin derived ketimine and 2-substituted benzofuran-3-one to synthesize structurally diverse oxindole derivatives is yet to be reported. For the first time in the literature, we have identified organocatalyst(s) and reaction conditions for stereodivergent (synthesis of all the possible stereoisomers) synthesis of vicinal tetrasubstituted stereocenter bearing benzofuran-3-one and oxindole scaffolds (Scheme 1c).

INTRODUCTION Seminal contributions have been made over the past 30 years in asymmetric catalysis to control diastereo- and enantioselectivity of the reaction.1 Identification of suitable catalyst/additive for a transformation involving the formation of multiple stereocenters is a formidable task which will enable the full control of both absolute and relative configuration. A reaction is considered to be stereodivergent2 if high selectivity is achieved for all of the possible stereoisomers. However, it is often indeed very difficult to achieve this feat. Thus, identification of catalyst(s) and reaction(s) conditions which would result in the formation of all possible stereoisomers or diastereomers is an emerging field of research in asymmetric catalysis.3 Hence, a few notable researchers have engaged in the development of catalytic system(s), engineering, or identification of catalysts to generate every possible stereoisomers in an asymmetric reaction.4 The 3-aminooxindole skeleton bearing adjacent tetrasubstituted stereogenic centers is of great importance due to its wide biological activity (Figure 1A−C).5 Similarly 2, 2-disubstituted benzofuran-3(2H)-ones and related frameworks are characteristic of a quaternary stereogenic center at the C2 position present in a number of natural products and bioactive molecules (Figure 1D−F).6−8 The combination of biologically important oxindole and benzofuran-3-one scaffolds will result in hybrid molecules. Due the importance of hybrid molecules9 (incorporation of two drug pharmacophores in a single molecule) in polypharmacology, we wish to synthesize hybrid molecules bearing oxindole and benzofuran-3-one in an enantioselective manner. Isatin-derived ketimines in combination with various nucleophiles led to the syntheses of structurally diverse 3© 2018 American Chemical Society

Received: May 5, 2018 Published: July 2, 2018 8936

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

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The Journal of Organic Chemistry

Figure 1. Selected example of biologically active 3-aminooxindole and benzofuran-3-one.

Scheme 1. Diastereodivergent Methods for the Synthesis of 3-Substituted 3-Aminooxindoles

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DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

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Table 1. Screening Studies for Syn-Selective Mannich Reaction of 1a and 2aa

RESULTS AND DISCUSSION

Optimization of Syn-Selective Mannich Reaction. Our efforts were dedicated to identifying a suitable catalyst for the Mannich reaction between 2-substituted benzofuran-3(2H)one 1 and isatin-derived ketimine 2 with 10 mol % of catalyst in dichloromethane at room temperature. The observed results are summarized in Table 1. To begin, commonly used cinchona alkaloid derived bifunctional thiourea organocatalysts C1−C4 were employed. Although moderate diastereoselectivity (Table 1, entries 1−4) was observed, the enantioselectivity of the syn addition product was found to be excellent. Encouraged by these results, various organocatalysts were utilized to improve the diastereoselectivity. To our disappointment, except for cinchonine- and quinine-derived thioureas, other organocatalysts fail to improve the diastereoselectivity (Table 1, entries 5−14). Since the enantioselectivity of syn addition product was very good with catalyst C1, it was chosen for further optimization studies. When 4-nitrobenzoic acid was used an additive, we observed reversal of diastereoselectivity but with lower enantioselectivity (Table 1, entry 15). Next, the effect of reaction medium has been tested to improve diastereoselectivity (results summarized in Table 2). During solvent screening, dichloromethane was found to be most suitable solvent. Neither lowering nor increasing the catalyst loading had no effect in diastereoselectivity (Table 2, entries 10 and 11). To further improve the diastereoselectivity, the reaction was carried out at lower temperature at 0 °C (Table 2, entry 12) which led to a slight improvement in diastereoselectivity. Upon further lowering the reaction temperature to −23 °C using catalyst C1 in dichloromethane, the syn addition product (Table 2, entry 13) was isolated with good diastereoselectivity (80:20 dr) in excellent enantioselectivity (96% ee). Under identical conditions, catalyst C2 yielded the same adduct with opposite configuration with good diastereoselectivity (85:15) in excellent enantioselectivity (Table 2, entry 14). Thus, we accomplished the synthesis of both enantiomers of syn-adduct 3 using readily available quinineand cinchonine-derived organocatalysts. Optimization of Anti-Selective Mannich Reaction. We began our optimization studies for anti-selective Mannich reaction of 5-chloroisatin derived ketimines 2c with 2substituted benzofuran-3-one 1 in dichloromethane at room temperature. Initially, natural cinchona bases (C15−C18) were investigated for their ability to synthesize our target molecule. However, syn-diastereomer 3 was only obtained as a major product in excellent yield, with poor diastereo- and enantioselectivity (Table 3, entries 1−4). Protection of the 9-hydroxyl group of catalyst C18 with a benzyl group (C19) and 1-methylnaphthyl group neither reversed the diastereoselectivity nor improved the enantioselectivity (Table 3, entries 5 and 6). Interestingly, when the Mannich reaction was catalyzed by cinchona alkaloid derivatives C21 and C22 which consist of 6′-hydroxyquinoline ring, antiselective diastereomer 4a was obtained as the main product in excellent yield with moderate diastereoselectivity and poor enantioselectivity (Table 3, entries 7 and 8). Intrigued by the role of 6′-hydroxy-containing catalyst in reversing the diastereoselectivity, other similar catalysts C23−C26, were examined for their ability to enhance the enantioselectivity. To our delight β-ICD, catalyst C25, efficiently catalyzed the formation of anti-product 4b with very good enantioselectivity and good diastereoselectivity (21:79 dr) (Table 3, entry 11). To

entry

catalyst

yieldb (%)

drc (%) (syn/anti)

eed (%) (syn/antik)

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

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C1

96 90 90 90 81 78 89 86 80 81 78 74 86 81 80

75:25 70:30 75:25 71:29 49:51 47:53 78:22 79:21 64:36 70:30 46:54 46:54 48:52 57:43 32:68

92 92e 92 84e 4 12 84e 90 18e 84e 21 4 48 6 34

a

The reactions were carried out with 1 (0.13 mmol), 2 (0.14 mmol), and catalyst (0.013 mmol) in 0.5 mL of CH2Cl2 at 25 °C. bIsolated yield. c,dDetermined by chiral HPLC. eSignifies the opposite enantiomer. fAdditive 4-nitrobenzoic Acid used. kMinor diastereomer was not separable by chiral HPLC.

obtain the opposite enantiomer of anti-product 4b, the reaction was performed with α-ICN, catalyst C26. The expected antiadduct was isolated with fair diastereoselectivity and moderate enantioselectivity (Table 3, entry 12). In the case of β-ICD, lowering the reaction temperature improved both diastereo- and enantioselectivity (Table 3, entry 13). Although diastereoselectivity did not fare better while lowering the reaction 8938

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The Journal of Organic Chemistry Table 2. Screening of Solventsa

entry 1 1 2 3 4 5 6 7 8 9 10f 11g 12h 13i 14j

solvent CH2Cl2 CHCl3 DCE MTBE diethyl ether diisopropyl ether dioxane toluene CF3-toluene acetonitrile CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

Table 3. Optimization Studies of Anti-Selective Mannich Reaction of 1a and 2ca

time (h)

yieldb (%)

drc (%) (syn/ anti)

eed (%) (syn/ antie)

3 3 3 6 6 6

96 90 86 82 88 80

80:20 78:28 75:25 62:38 60:40 60:40

96 90 92 92 92 92

5 8 6 3 3 3 3 6 6

75 93 90 78 87 90 96 96 95

63:37 62:38 62:38 72:28 71:29 70:30 78:22 80:20 85:15

96 96 94 88 90 90 94 96 96k

a The reactions were carried out with 1 (0.13 mmol), 2 (0.14 mmol), and catalyst C1(0.013 mmol) in 0.5 mL of solvent at 25 °C. bIsolated yield. c,dDetermined by chiral HPLC. eMinor diastereomer was not separable by Chiral HPLC. fCatalyst (0.0065 mmol) used. gCatalyst (0.026 mmol) used. hReaction performed at 0 °C. iReaction performed at −23 °C for 6h. jCatalyst C2(0.013 mmol) used. k signifies the opposite enantiomer.

temperature, enantioselectivity considerably improved for ent4b (Table 3, entry 14). These results suggest that anti-selective addition product 4b could well be synthesized by the employment of readily available β-ICD (10 mol %) in dichloromethane at −23 °C in very good diastereoselectivity and excellent enantioselectivity. α-ICN was employed to synthesize ent-4b. Having identified catalysts capable of forming all of the diastereomers of the given transformation, the substrate scope was studied further. Substrate Scope for Syn-Selective Mannich Reaction. The effects of substitution on both nucleophiles and electrophiles were investigated for the synthesis of syn-selective product 3 and its enantiomer ent-3 (Scheme 2) under optimized reaction conditions (Table 2, entry 13 and 14). First, the effect of substitutions in the aromatic ring of the N-methyl-protected isatin ketimines was studied. Different halogen and electrondonating (OMe) or electron-withdrawing (OCF3) groups substituted at the fifth position of the isatin-derived ketimine were tolerated in the Mannich reaction. The corresponding products (3a−g) were obtained with very good yields (88− 96%) with moderate to good diastereoselectivity (68:32 to 83:17 dr) and excellent enantioselectivity (up to 97/97% ee). Moreover, the fluoro substituent at the seventh position of the oxindole ring afforded the corresponding product (3h) with very good yield and stereoselectivity. Having established that substitutions on the oxindole ring do not influence stereoselectivity, we next probed the effect of substitutions on the benzofuran-3-one. It is evident that increasing the size of

entry

catalyst

yieldb (%)

drc (%) (syn/anti)

eed (%) (syn/anti)

1 2 3 4 5 6 7 8 9 10 11 12 13f 14f

C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C25 C26

90 85 95 91 92 88 90 93 92 87 96 85 96 90

64:36 64:36 64:36 72:28 61:39 59:41 23:77 17:83 19:81 64:36 21:79 32:68 17:83 35:65

10/40 rac/16e 10/rac 4/33 46/5 43/37 rac/12 rac/10 6/10 2/25 84/95 80/50e 90/96 88/74e

a

The reaction was carried out with 1 (0.13 mmol), 2c (0.14 mmol), catalyst (0.013 mmol) in 0.5 mL of CH2Cl2 at 25 °C. bIsolated yield. c,d Determined by chiral HPLC. eSignifies the opposite enantiomer. f At −23 °C.

halogen on the fifth position of the benzofuran-3-one ring led to the decrease in diastereo- and enantioselectivity (3i−k) (Scheme 2). To be more specific, substitution of iodo at the fifth position drastically reduced the enantioselectivity and may be due to increase the steric hindrance in the transition state. However, in the presence of an electron-releasing substituent (OMe), the enantioselectivity (3l) remained unaffected. Gratifyingly, having ethyl ester substitution on benzofura-3one derivatives (3m) did not lower the enantioselectivity; however, the diastereoselectivity remained almost the same. Similar effects were observed for product 3n and 3o. The influence of N1-substitution of isatin ketimines on stereoselectivity and yield was investigated. It is evident that various N1-substitutions like ethyl, benzyl, allyl, methyl acetate, ethyl 8939

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

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The Journal of Organic Chemistry Scheme 2. Substrate Scope for Syn-Selective Mannich Reaction of 1 and 2a,b

Reaction conditions: The reactions were carried out with 1 (0.26 mmol), 2 (0.31 mmol), catalyst C1 (0.026 mmol) in 0.5 mL of CH2Cl2 at −23 °C. Isolated yield after column chromatography. Diastereoselectivity and enantioselectivity was determined by HPLC using chiral stationary phase. Note: dr values for compound 3i, 3j, 3k, and 3n were ascertained by 1H NMR of crude reaction mixture. Compound 3v major and minor diastereomers were separable in silica gel column chromatography. bReaction conditions: The reactions were carried out with 1 (0.13 mmol), 2 (0.16 mmol), catalyst C2 (0.013 mmol) in 0.5 mL of CH2Cl2 at −23 °C. a

acetate, and tert-butyl acetate are well tolerated, and expected products (3p−u) were isolated with more than 85% yield and

excellent enantioselectivity (up to 98/99% ee) and moderate to good diastereoselectivity (65:35 to 83:17 dr). In the case of 8940

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

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The Journal of Organic Chemistry Scheme 3. Substrate Scope for Anti-Selective Mannich Reaction of 1 and 2a,b

Reaction conditions: The reactions were carried out with 1 (0.26 mmol), 2 (0.31 mmol), catalyst C25 (0.026 mmol) in 0.5 mL of CH2Cl2 at −23 °C. Isolated yield after column chromatography. Diastereoselectivity and enantioselectivity were determined by HPLC using a chiral stationary phase. bReaction conditions: The reactions were carried out with 1 (0.13 mmol), 2 (0.16 mmol), catalyst C26 (0.013 mmol) in 0.5 mL of CH2Cl2 at −23 °C. a

product 3v, the minor diastereomer was isolated, and absolute configuration was unambiguously determined by X-ray crystallographic analysis. Under identical conditions, the enantiomers of compounds 3 were synthesized using catalyst C2 as depicted in Scheme 2 with good diastereo- and enantioselectivities. Substrate Scope for Anti-Selective Mannich Reaction. Under the optimized reaction conditions (Table 3, entry 13 and 14), the study of substrate scope was examined for the synthesis of anti-selective Mannich products 4 and its enantiomers (Scheme 3). To our delight, anti-selective products (4a−g) were

obtained in excellent yield (up to 98%) and enantioselectivity (up to 99% ee) with better diastereoselectivity (up to 14:86 dr) when various substituted N-methylisatin-derived ketimines underwent Mannich reaction with methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate (1). Identical to the observation of drastic reduction in enantioselectivity for syn-selective product with increase in size of halogen substitution on nucleophile was observed in case of anti-selective product also (4h−j). Similarly ethyl ester substituted nucleophile and N-substituted ketimine such as N−CH2COOMe yielded the respective product (4k− m) with identical stereoselectivities. We are happy to note that 8941

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

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Control Experiment. The switch in diastereomer takes place by using either acid additive or the 6′-hydroxyl group of the catalyst but which alone is not enough to induce the switch in diastereomer, and the presence of oxygen atom in benzofuranone also plays a vital role in switching diastereoselectivity which was explained by control experiment. To prove the role oxygen atom present in the benzofuran-3-one to switch the diastereomer, we synthesized a substrate which lacks oxygen atom such as ethyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate(5), which reacted smoothly with isatin ketamine (2a) to yield syn-selective product (6) as major product in the presence of catalyst C1 or C26 and also catalyst C1 with acid additive (Scheme 4). This observation suggests that not only catalyst or additive but also the presence of oxygen atom in the nucleophile is also played a crucial role in switching diastereoselectivity. Gram-Scale Synthesis. The practical utility of our synselective Mannich addition strategy was demonstrated by performing the reaction on a 1 g scale. We are delighted to observe that under optimized conditions the corresponding product 3c was obtained without any loss of yield (92%) and stereoselectivity (72:28 dr, 96/98%ee) (Scheme 5). Derivatization of the Mannich Adduct. Natural products such as avicenol A, smyrindiol, vaginidiol, and vaginol (Figure 4)18 contain the 2.3-dihydrobenzofuran moiety. To obtain similar pharmaceutically active moiety, the Mannich adduct 3c was reduced using substoichiometric sodium borohydride (0.5 equiv) to yield compound 7 with no loss of stereoselectivity (Scheme 6). Reduction using 2 equiv of sodium borohydride leads to the formation of product 8 having a primary hydroxyl at the quaternary center. Thus, we have established the synthetic versatility of compound 3c in synthesizing structurally diverse the compounds containing three contiguous stereocenters with excellent enantioselectivity. The absolute configuration of the three chiral centers in compound 8 was determined as (8R,10S,11R) on the basis of Xray crystallographic analysis (see the Supporting Information)

the enantiomers of anti-selective product 4 were also obtained using C26 with moderate diastereoselectivities. Plausible Transition State for Syn-Selective Mannich Product. The X-ray crystallographic analysis of compound 3i led to the identification of absolute configuration as (8R,11R),15 and by analogy, absolute configuration of other products were assigned accordingly. On the basis of the stereochemical outcome of the reaction, the plausible transition-state model11b for major syn-selective Mannich product is proposed herein (Figure 2). Thiourea moiety of catalyst C1 interacts with isatin

Figure 2. Plausible transition state for syn-selective Mannich product.

ketimines (2) via hydrogen bonding. The chiral tertiary-amine part of catalyst interacts with nucleophile (1) and thus preorients the substrate. The transition state formed by dual activation facilitates Re face attack of nucleophile to the ketimines leading to the desired syn-selective product 3 with an (8R,11R) configuration. Plausible Transition State for Anti-Selective Mannich Product. The X-ray crystallographic analysis revealed the absolute configuration of compound 3v (minor diastereomer) as (8S,11R).16 We proposed the transition-state model (Figure 3) based on the on the work of Li et al.17 to rationalize the stereochemical outcome of asymmetric Mannich reaction between 1 and 2c in the presence of β-ICD. Dual activation of electrophile and nucleophile can happen via hydrogen bonding with a 6-hydroxy group in the quinoline ring of catalyst C25. The nucleophile also becomes activated by hydrogen bonding through the chiral tertiary amine part of the catalyst. This orientation led to the Siface attack of nucleophile resulting in anti-selective product 4b with (8S,11R) configuration.

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CONCLUSIONS In summary, we have described the first stereodivergent synthesis of 3-aminooxindole bearing a vicinal tetrasubstituted sterocenter through operationally simple Mannich reaction of 2substituted benzofuran-3-one with isatin-derived N-Boc-ketimines using readily available cinchona alkaloid derived organocatalysts. This new methodology provides an opportunity to access all possible diastereomers of 3-aminooxindole derivatives. Both enantiomers of syn-selective 3-substituted 3-aminooxindole (up to 97% yield, 99% ee, dr = 87:13) were obtained

Figure 3. Plausible transition state for anti-selective Mannich product. 8942

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

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The Journal of Organic Chemistry Scheme 4. Control Experiment with Ethyl 1-Oxo-2,3-dihydro-1H-indene-2-carboxylate

Scheme 5. Gram-Scale Reaction for Syn-Selective Mannich Reaction

Figure 4. Important 2,3-dihydro-3-hydroxy-2-hydroxyalkylbenzofurans in natural products.

Scheme 6. Synthesis of 2,3-Dihydro-3-hydroxy-2-hydroxyalkylbenzofuran

using quinine- and cinchonine-derived organocatalysts, whereas anti-selective 3-substituted 3-aminooxindole (up to 96% yield, 98% ee, dr = 13:87) can be accessed using either β-ICD or αICN. The reaction displayed a wide range of substrate scope for different N-Boc-istain ketimines and 2-substituted benzofuran3-ones. The yield and enantioselectivity were not diminished even when the reaction was performed for a gram-scale synthesis. The present study on the asymmetric Mannich reaction with isatin-derived ketimines, provide a new class of

biologically important amino oxindole derivatives having benzofuran-3-one for the first time in the literature.

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EXPERIMENTAL SECTION

General Remarks. All reactions were carried out in a flame-dried flask. Solvents used for reactions and column chromatography were commercial grade and distilled prior to use. THF, toluene, and dioxane were dried over sodium/benzophenone, whereas dichloromethane (DCM) and dichloroethane (DCE) were dried over CaH2. Solvents used were hexane and ethyl acetate. TLC was performed on precoated 8943

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Article

The Journal of Organic Chemistry

conditions: dr 82:18. Major diastereomer (94% ee) Chiralpak AD-H, hexane/i-PrOH = 95:05, flow rate = 0.50 mL/min, λ = 254 nm, retention time: 65.14 min (major) and 36.36 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 95:05, flow rate = 0.50 mL/min, λ = 254 nm, retention time: 60.49 min (major) and 82.25 min (minor). Methyl (S)-2-((S)-3-((tert-Butoxycarbonyl)amino)-5-fluoro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3b). Compound ent-3b. Yellow foamy solid, actual mass 56 mg, yield 92%. 1H NMR (500 MHz, CDCl3) corresponding to 3b.13C NMR (125 MHz, CDCl3) corresponding to 3b. [α]D26 −68.50 (c 0.5, CHCl3). HPLC conditions: dr 80:20. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 30.69 min (major) and 60.94 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 78.21 min (major) and 56.12 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-chloro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3c). Compound 3c. Yellow solid, actual mass 116 mg, yield 92%. Mp: 155−160 °C. 1H NMR (500 MHz, CDCl3): δ = 7.69 (dd, J = 0.9, 7.9 Hz, 1 H), 7.64 (ddd, J = 1.4, 7.2, 8.4 Hz, 1 H), 7.33 (dd, J = 2.0, 8.4 Hz, 1 H), 7.18−7.07 (m, 5 H), 6.86−6.82 (m, 1 H), 6.78 (d, J = 8.2 Hz, 1 H), 3.93 (s, 1 H), 3.87 (s, 3 H), 3.28 (s, 1 H), 3.12 (s, 3 H), 1.33 (s, 13 H). 13C NMR (125 MHz, CDCl3): δ = 191.9, 191.2, 172.1, 171.5, 171.2, 170.9, 164.2, 153.3, 143.5, 139.3, 138.7, 130.1, 129.7, 128.2, 127.5, 125.0, 124.6, 124.0, 123.6, 123.6, 123.4, 120.4, 119.8, 112.9, 112.8, 109.5, 108.9, 86.4, 86.0, 80.8, 66.2, 64.9, 54.1, 53.9, 28.1, 26.9, 26.6. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3405, 2978, 1721, 1610, 1491, 1432, 1392, 1162, 1098, 969, 817, 760, 736, 687, 543. HRMS (ESI) m/z: [M + Na]+ calcd for C24H23ClN2O7 Na 509. 1086, found 509. 1101. [α]D26 +66.40 (c 0.5, CHCl3). HPLC conditions: dr 69:31 Major diastereomer (95% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 15.52 min (major) and 10.40 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 12.89 min (major) and 26.64 min (minor). Methyl (S)-2-((S)-3-((tert-Butoxycarbonyl)amino)-5-chloro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3c). Compound ent-3c. Yellow foamy solid, actual mass 60 mg, yield 95%. 1H NMR (500 MHz, CDCl3) corresponding to 3c.13C NMR (125 MHz, CDCl3) corresponding to 3c. [α]D26 −65.30 (c 0.5, CHCl3). HPLC conditions: dr 74:26. Major diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 9.15 min (major) and 14.14 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 24.69 min (major) and 11.54 min (minor). Methyl (R)-2-((R)-5-Bromo-3-((tert-butoxycarbonyl)amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3d). Compound 3d. Yellow solid, actual mass 124 mg, yield 90%. Mp: 175−180 °C. 1H NMR (500 MHz, CDCl3): δ = 7.66−7.63(m, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 7.52−7.45 (m, 2 H), 7.28−7.22 (m, 2 H), 7.16−7.05 (m, 4 H), 6.82 (d, J = 8.5 Hz, 1 H), 6.72 (d, J = 8.2 Hz, 1 H), 6.61 (d, J = 8.2 Hz, 1 H), 3.91 (s, 1 H), 3.85 (s, 3 H), 3.26 (s, 1 H), 3.09 (s, 3 H), 1.31 (s, 15 H). 13C NMR (125 MHz, CDCl3): δ = 191.9, 191.2, 172.0, 171.5, 171.1, 170.8, 169.8, 164.2, 163.5, 153.3, 144.0, 139.3, 138.7, 133.0, 132.6, 127.8, 126.7, 126.2, 125.0, 124.6, 123.6, 123.6, 122.8, 120.4, 119.8, 86.4, 86.0, 80.8, 69.5, 66.1, 64.8, 54.1, 53.9, 53.8, 28.1, 26.9, 26.5. Visible peaks of minor diastereoisomer present in 1H and 13 C NMR. IR (ν, cm−1): 3404, 2977, 1721, 1608, 1483, 1362, 1257, 1163, 1096, 968, 883, 817, 735, 601. HRMS (ESI) m/z: [M + H]+ calcd for C24H24BrN2O7 531.0761, found 531.0781. [α]D26 +88.40 (c 0.5, CHCl3). HPLC conditions: dr 69:31. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 15:08 min (major) and 10.65 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 12.78 min (major) and 30.25 min (minor).

Merck silica gel aluminum plates with 60F254 indicator, visualized by irradiation with UV light. Column chromatography was performed using silica gel Merck 100−200 and 230−400 mesh. 1H NMR and 13C NMR were recorded on 400, 500, and 100 and 125 MHz using CDCl3 and DMSO-d6 as solvent and multiplicity indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), dt (doublet of triplet), ddd (doublet of doublet of doublet) qd (quartet of doublet). Coupling constants J are reported in hertz. Chemical shifts are represented in δ. High-resolution mass spectra were obtained by ESI using an Orbitrap Elite mass spectrometer. IR spectra were recorded on a FT/IR-420 spectrometer and are reported in terms of frequency of absorption (cm−1). Melting points were measured in open capillaries and are uncorrected. Optical rotations are reported as follows: [α]Drt (c in g per 100 mL, solvent). The 2-substituted benzofuran-3-(2H)-ones,19 isatin-derived ketimines,20 and catalysts21 were synthesized according to the literature procedure. Representative Experimental Procedure for the Synthesis of Syn-Selective 3-Substituted 3-Amino-2-oxindoles (3). To a 30 min stirred solution of isatin-derived ketimines (1.2 equiv) and catalyst C1 or C2 (0.1 equiv) in dry CH2Cl2 (0.5 mL) was added methyl 3-oxo2,3-dihydrobenzofuran-2-carboxylate (1 equiv) at −23 °C. The reaction mixture was stirred at −23 °C until the consumption of methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate, which was monitored by TLC. The crude mixture was purified by flash column chromatography over silica gel (85:15 to 70:30 hexane/EtOAc) to furnish 3a−v. Analytical Data for Syn-Selective 3-Substituted 3-Amino-2oxindoles. Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3a). Compound 3a. Yellow foamy solid, actual mass 114 mg, yield 96%. 1H NMR (500 MHz, CDCl3): δ = 7.68−7.60 (m, 2 H), 7.35 (dt, J = 1.3, 7.7 Hz, 1 H), 7.19−7.00 (m, 6 H), 6.86−6.83 (m, 1 H), 3.93 (s, 1 H), 3.85 (s, 3 H), 3.29 (s, 1 H), 3.13 (s, 3 H), 1.28 (s, 13 H). 13C NMR (125 MHz, CDCl3): δ = 192.3, 191.5, 172.5, 171.6, 171.5, 171.3, 170.9, 164.3, 162.1, 153.3, 144.9, 139.2, 139.0, 138.6, 135.9, 130.7, 130.3, 129.8, 125.9, 125.3, 124.9, 124.4, 123.4, 123.3, 123.2, 123.1, 122.9, 122.8, 122.0, 120.5, 119.9, 119.1, 117.4, 113.5, 113.0, 112.9, 108.6, 107.98, 86.8, 80.5, 66.3, 65.1, 54.0, 53.8, 28.1, 26.7, 26.4. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3407, 2976, 1750, 1714, 1608, 1479, 1360, 1325, 1296, 1255, 1164, 1098, 971, 861, 759. HRMS (ESI) m/z: [M + Na]+ calcd for C24H24N2O7Na 475.1476, found 475.1476. [α]D26 +90.20 (c 0.5, CHCl3). HPLC conditions: dr 80:20. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 41.21 min (major) and 26.69 min (minor). Methyl (S)-2-((S)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent3a). Compound ent-3a. Yellow foamy solid, actual mass 56 mg, yield 95%. 1H NMR (500 MHz, CDCl3) corresponding to 3a.13C NMR (125 MHz, CDCl3) corresponding to 3a. [α]D26 −85.60 (c 0.5, CHCl3). HPLC conditions: dr 84:16. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 24.54 min (major) and 39.41 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-fluoro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3b). Compound 3b. Yellow foamy solid, actual mass 110 mg, yield 90%. 1H NMR (500 MHz, CDCl3): δ = 7.69−7.64(m, 1 H), 7.63 (ddd, J = 1.4, 7.3, 8.4 Hz, 1 H), 7.61 (t, J = 7.6 Hz, 2 H), 7.17−7.03 (m, 2 H), 6.96 (dd, J = 2.5, 7.9 Hz, 1 H), 6.86−6.83 (m, 1 H), 6.78 (dd, J = 4.1, 8.5 Hz, 1 H), 3.92 (s, 1 H), 3.86 (s, 3 H), 3.28 (s, 1 H), 3.12 (s, 3 H), 1.32 (s, 12 H). 13C NMR (125 MHz, CDCl3): δ = 192.0, 191.3, 172.3, 171.6, 171.4, 170.9, 164.2, 160.1(d, J = 266.9 Hz), 159.6, 157.6, 153.3, 140.9, 139.3, 138.7, 127.4, 125.0 (d, J = 178.5 Hz),, 124.6, 123.5, 120.4, 119.7, 116.5(d, J = 23.6 Hz),116.1, 115.9, 113.0, 112.8, 111.8 (d, J = 25.8 Hz), 111.3, 111.1, 109.1 (d, J = 7.7 Hz), 108.5, 86.5, 86.1, 80.7, 66.3, 65.1, 53.9, 53.8, 28.1, 26.9, 26.6. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3407, 2978, 1718, 1613, 1496, 1386, 1324, 1269, 1196, 1164, 1046, 973, 905, 877, 761, 691. HRMS (ESI) m/z: [M + Na]+ calcd for C24H23FN2O7Na 493.1382, found 493.1398. [α]D26 +70.60 (c 0.5, CHCl3). HPLC 8944

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

Article

The Journal of Organic Chemistry Methyl (S)-2-((S)-5-Bromo-3-((tert-butoxycarbonyl) amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3d). Compound ent-3d. White solid, actual mass 62 mg, yield 90%. 1H NMR (500 MHz, CDCl3) corresponding to 3d.13C NMR (125 MHz, CDCl3) corresponding to 3d. [α]D26 −78.50 (c 0.5, CHCl3). HPLC conditions: dr 69:31. Major diastereomer (94% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 9.8 min (major) and 14.19 min (minor). Minor diastereomer (84% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 29.08 min (major) and 12.22 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-iodo-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3e). Compound 3e. Yellow solid, actual mass 132 mg, yield 88%. Mp: 140−145 °C. 1H NMR (500 MHz, CDCl3): δ = 7.69−7.62 (m, 3 H), 7.54- 7.51 (m, 1 H), 7.47 (s, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 7.18− 7.07 (m, 3 H), 6.83 (d, J = 8.5 Hz, 1 H), 6.64 (d, J = 8.2 Hz, 1 H), 6.53 (d, J = 8.2 Hz, 1 H), 3.93 (s, 2 H), 3.88 (s, 3 H), 3.27 (s, 2 H), 3.10 (s, 3 H), 1.33 (s, 14 H). 13C NMR (125 MHz, CDCl3): δ = 191.9, 191.1, 171.8, 171.5, 170.9, 170.8, 164.2, 153.3, 144.6, 139.3, 138.9, 138.7, 138.5, 132.2, 131.7, 125.0, 124.5, 123.6, 120.4, 119.9, 112.9, 112.8, 110.6, 109.9, 86.4, 86.0, 85.1, 83.9, 80.8, 66.0, 64.7, 54.0, 53.8,28.1, 26.8, 26.5. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3404, 2977, 1717, 1606, 1481, 1391, 1326, 1162, 1093, 968, 814, 759, 735, 598, 531. HRMS (ESI) m/z: [M + Na]+ calcd for C24H23IN2O7 Na 601.0442, found 601.0463. [α]D26 +122.60 (c 0.5, CHCl3). HPLC conditions: dr 68:32. Major diastereomer (94% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 16.16 min (major) and 12.20 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 14.32 min (major) and 33.63 min (minor). Methyl (S)-2-((S)-3-((tert-Butoxycarbonyl)amino)-5-iodo-1-methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3e). Compound ent-3e. Yellow foamy solid, actual mass 64 mg, yield 85%. 1H NMR (500 MHz, CDCl3) corresponding to 3e.13C NMR (125 MHz, CDCl3) corresponding to 3e. [α]D26 −112.30 (c 0.5, CHCl3). HPLC conditions: dr 67:33. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.29 min (major) and 15.31 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 32.74 min (major) and 13.30 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-methoxy-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3f). Compound 3f. Yellow foamy solid, actual mass 115 mg, yield 92%. 1H NMR (500 MHz, CDCl3): δ = 7.61−7.47 (m, 2 H), 7.15 (t, J = 7.3 Hz, 2 H), 7.09−7.06 (m, 1 H), 6.88−6.83 (m, 1 H), 6.81 (d, J = 2.5 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 6.66 (s, 1 H), 3.93 (s, 1 H), 3.86 (s, 3 H), 3.74 (s, 3 H), 3.48 (s, 1 H), 3.27 (s, 1 H), 3.11 (s, 3 H), 1.30 (s, 13 H). 13C NMR (125 MHz, CDCl3): δ = 192.3, 191.4, 172.2, 171.7, 171.2, 170.9, 164.3, 156.1, 155.4, 153.3, 139.1, 138.5, 138.4, 125.0, 124.3, 123.5, 123.3, 120.5, 120.0, 115.2, 114.5, 113.1, 112.8, 110.9, 109.9, 108.9, 108.5, 86.8, 86.3, 80.5, 66.5, 65.4, 55.9, 55.8, 54.0, 53.8, 28.1, 26.8, 26.5. Visible peaks of minor diastereoisomer present in 1H and 13 C NMR. IR (ν, cm−1): 3407, 2976, 2837, 1750, 1718, 1609, 1497, 1366, 1258, 1164, 1045, 971, 906, 880, 762, 587. HRMS (ESI) m/z: [M + Na]+ calcd for C25H26N2O8 Na 505.1581, found 505.1592. [α]D26 +66.40 (c 0.5, CHCl 3). HPLC conditions: dr 78:22. Major diastereomer (97% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 109.97 min (major) and 76.40 min (minor). Minor diastereomer (97% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 70.73 min (major) and 193.26 min (minor). Methyl (S)-2-((S)-3-((tert-Butoxycarbonyl)amino)-5-methoxy-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3f). Compound ent-3f. White foam solid, actual mass 57 mg, yield 90%. 1H NMR (500 MHz, CDCl3) corresponding to 3f. 13C NMR (125 MHz, CDCl3) corresponding to 3f. [α]D26 −60.80 (c 0.5, CHCl3). HPLC conditions: dr 82:18. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ =

254 nm, retention time: 77.97 min (major) and 112.48 min (minor). Minor diastereomer (94% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 191.46 min (major) and 70.25 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl) amino)-1-methyl-2oxo-5-(trifluoromethoxy)indolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3g). Compound 3g. Yellow solid, actual mass 132 mg, yield 95%. Mp: 100−105 °C. 1H NMR (500 MHz, CDCl3): δ = 7.62−7.48(m, 2 H), 7.22−7.20 (m, 1 H), 7.18−7.15 (m, 2 H), 7.12− 7.00 (m, 1 H), 6.84−6.74 (m, 1 H), 3.94 (s, 1 H), 3.85 (s, 3 H), 3.31 (s, 1 H), 3.16 (s, 3 H), 1.32 (s, 12 H). 13C NMR (125 MHz, CDCl3): δ = 191.1, 172.4, 171.5, 171.4, 170.9, 164.2, 144.7, 144.0, 143.6, 139.3, 138.8, 125.0, 124.7, 123.6, 123.5, 123.4, 123.2, 121.5, 120.4, 119.6, 119.4, 117.6, 117.1, 112.9, 112.8, 109.0, 108.4, 86.5, 80.8, 66.0, 54.1, 53.8, 28.1, 26.9, 26.6. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3406, 2978, 1721, 1613, 1496, 1469, 1384, 1324, 1252, 1163, 1091, 1016, 971, 884, 759, 622, 549. HRMS (ESI) m/z: [M + Na]+ calcd for C25H23F3N2O8Na 559.1299, found 559.1315. [α]D26 +53.60 (c 0.5, CHCl3). HPLC conditions: dr 83:17. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 37.15 min (major) and 26.73 min (minor). HPLC conditions: Minor diastereomer (93% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 40.37 min (major) and 111.11 min (minor). Methyl (S)-2-((S)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2oxo-5-(trifluoromethoxy)indolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3g). Compound ent-3g. Yellow solid, actual mass 65 mg, yield 92%. 1H NMR (500 MHz, CDCl3) corresponding to 3g. 13C NMR (125 MHz, CDCl3) corresponding to 3g. [α]D26 −49.20 (c 0.5, CHCl3). HPLC conditions: dr 79:21. Major diastereomer (ee 98%) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 18.79 min (major) and 28.15 min (minor). Minor diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 94.05 min (major) and 29.38 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-7-fluoro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3h). Compound 3h. White solid, actual mass 110 mg, yield 90%. Mp: 115−120 °C. 1H NMR (500 MHz, CDCl3): δ = 7.64(d, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.18 (t, J = 7.4 Hz, 2 H), 7.13−7.06 (m, 2 H), 7.00−6.91 (m, 2 H), 6.89−6.58 (m, 1 H), 3.93 (s, 1 H), 3.86 (s, 3 H), 3.51 (s, 1 H), 3.33 (s, 3 H), 1.32 (s, 12 H). 13C NMR (125 MHz, CDCl3): δ = 192.1, 191.2, 172.3, 171.6, 171.4, 170.9, 164.1, 153.3, 148.8 (d, J = 241.2 Hz), 146.4, 139.1, 138.7, 131.7, 131.6, 128.9, 125.0, 124.4 (d, J = 178.8 Hz),123.4, 123.3 (d, J = 2.6 Hz),122.4, 120.5, 119.8, 119.1, 118.7, 118.4 (d, J = 19.36 Hz), 118.0, 117.9, 113.1, 112.9, 86.6, 86.2, 80.7, 66.3, 54.0, 53.8, 29.3, 29.0, 28.1. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3407, 2978, 1721, 1629, 1610, 1481, 1368, 1325, 1240, 1164, 1098, 1021, 970, 759, 697. HRMS (ESI) m/z: [M + Na]+ calcd for C24H23FN2O7Na 493.1382, found 493.1373. [α]D26 + 134.40 (c 0.5, CHCl3). HPLC conditions: dr 76:24. Major diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 59.29 min (major) and 32.27 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/ min, λ = 254 nm, retention time: 64.44 min (major) and 73.60 min (minor). Methyl (S)-2-((S)-3-((tert-Butoxycarbonyl)amino)-7-fluoro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3h). Compound ent-3h. Yellow foamy solid, actual mass 56 mg, yield 92%. 1H NMR (500 MHz, CDCl3) corresponding to 3h.13C NMR (125 MHz, CDCl3) corresponding to 3h. [α]D26 −127.70 (c 0.5, CHCl3). HPLC conditions: dr 81:19. Major diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 27.46 min (major) and 55.46 min (minor). Minor diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min,λ = 254 nm, retention time: 68.56 min (major) and 60.88 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl) amino)-1-methyl-2oxoindolin-3-yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3i). Compound 3i. Yellow solid, actual mass 112 mg, yield 89%. 8945

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

Article

The Journal of Organic Chemistry

in 1H and 13C NMR. IR (ν, cm−1): 3407, 2976, 1718, 1611, 1486, 1369, 1275, 1162, 1090, 973, 831, 759, 699, 608, 533. HRMS (ESI) m/z: [M + Na]+ calcd for C25H26N2O8Na 505.1581, found 505.1595. [α]D26 +100.00 (c 0.5, CHCl3). HPLC conditions: dr 77:23. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 38.08 min (major) and 33.00 min (minor). Methyl (S)-2-((S)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-5-methoxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3l). Compound ent-3l. White foamy solid, actual mass 57 mg, yield 90%. 1H NMR (500 MHz, CDCl3) corresponding to 3l.13C NMR (125 MHz, CDCl3) corresponding to 3l. [α]D26 −95.80 (c 0.5, CHCl3). HPLC conditions: dr 79:21 Major diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 29.25 min (major) and 33.84 min (minor). Ethyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3m). Compound 3m. Yellow solid, actual mass 110 mg, yield 90%. Mp: 125−130 °C. 1H NMR (500 MHz, CDCl3): δ = 7.69−7.59 (m, 2 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.22 (d, J = 7.3 Hz, 1 H), 7.16−7.13 (m, 1 H), 7.09−7.07 (m, 1 H), 7.05−7.00 (m, 1 H), 6.86−6.75 (m, 2 H), 4.38− 4.28 (m, 3 H), 3.30 (s, 1 H), 3.13 (s, 3 H), 1.41 (t, J = 7.1 Hz, 1 H), 1.39−1.27 (m, 14 H). 13C NMR (125 MHz, CDCl3): δ = 191.6, 172.4, 171.7, 171.6, 171.0, 163.8, 153.3, 144.9, 138.9, 138.4, 130.2, 129.7, 124.9, 124.4, 123.5, 123.3, 123.1, 122.8, 122.7, 121.9, 120.6, 119.9, 113.0, 112.9, 108.5, 86.7, 80.4, 66.3, 65.0, 63.6, 63.4, 28.1, 26.4, 14.0,13.9. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3409, 2978, 1718, 1610, 1496, 1370, 1254, 1165, 1089, 932, 885, 756, 695, 612, 538, 513. HRMS (ESI) m/z: [M + Na]+ calcd for C25H26N2O7 Na 489.1632, found 489.1646. [α]D26 +89.60 (c 0.5, CHCl3). HPLC conditions: dr 78:22. Major diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 15.65 min (major) and 13.52 min (minor). Minor diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 18.91 min (major) and 22.35 min (minor). Ethyl (S)-2-((S)-3-((tert-Butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent3m). Compound ent-3m. Yellow foamy solid, actual mass 56 mg, yield 92%. 1H NMR (500 MHz, CDCl3) corresponding to 3m.13C NMR (125 MHz, CDCl3) corresponding to 3m. [α]D26 −82.50 (c 0.5, CHCl3). HPLC conditions: dr 80:20. Major diastereomer (88% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 12.48 min (major) and 14.78 min (minor). Minor diastereomer (94% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 21.00 min (major) and 18.07 min (minor). Ethyl (R)-5-Bromo-2-((R)-3-((tert-butoxycarbonyl)amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3n). Compound 3n. Yellow solid, actual mass 122 mg, yield 85%. Mp: 120−125 °C. 1H NMR (500 MHz, CDCl3): δ = 7.79−7.69 (m, 1 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.16 (t, J = 7.6 Hz, 2 H), 7.05−6.98 (m, 2 H), 6.87−6.82 (m, 1 H), 6.77−6.71 (m, 1 H), 4.44−4.28 (m, 3 H), 3.29 (s, 2 H), 3.13 (s, 3 H), 1.40 (t, J = 7.1 Hz, 2 H), 1.38−1.15 (m, 16 H). 13C NMR (125 MHz, CDCl3): δ = 191.2, 190.2, 172.2, 171.5, 170.4, 169.6, 153.2, 144.9, 141.5, 141.0, 130.4, 130.0, 127.4, 126.8, 123.5, 122.9, 122.8, 122.3, 122.2, 121.6, 116.1, 115.8, 114.7, 114.6, 108.6, 108.1, 87.5, 87.2, 80.5, 66.4, 65.0, 63.9, 63.7, 28.1, 26.8, 26.5,13.9. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3401, 2979, 1725, 1609, 1496, 1368, 1260, 1170, 1091, 1014, 827, 755, 698, 650. HRMS (ESI) m/z: [M + Na]+ calcd for C25H25BrN2O7Na 567.0737, found 567.0755. [α]D28 +42.40 (c 0.5, CHCl3). HPLC conditions: dr 65:35. Major diastereomer (90% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 13.16 min (major) and 11.29 min (minor). Minor diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.06 min (major) and 14.69 min (minor). Ethyl (S)-5-Bromo-2-((S)-3-((tert-butoxycarbonyl)amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carbox-

Mp: 185−190 °C. 1H NMR (500 MHz, CDCl3): δ = 7.66−7.59 (m, 1 H), 7.55 (dd, J = 1.9, 8.8 Hz, 1 H), 7.42−7.35 (m, 1 H), 7.17 (d, J = 7.6 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.86−6.82 (m, 1 H), 6.78 (dd, J = 8.4, 14.0 Hz, 1 H), 6.72−6.69 (m, 1 H), 3.93 (s, 1 H), 3.86 (s, 3 H), 3.29 (s, 1 H), 3.14 (s, 3 H), 1.27 (s, 14 H). 13C NMR (125 MHz, CDCl3): δ = 191.1, 190.3, 172.3, 171.4, 169.9, 169.1, 163.9, 153.2, 144.9, 138.9, 138.4, 130.0, 129.1, 128.9, 124.3, 123.7, 123.3, 123.0, 122.8, 122.2, 121.8, 121.0, 114.3, 114.2, 108.6, 108.1, 87.7, 87.3, 80.6, 66.4, 65.0, 54.1, 53.9, 28.1, 26.8, 26.5. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3409, 3059, 2978, 1754, 1719, 1610, 1494, 1370, 1256, 1164, 1017, 910, 884, 826, 755, 735, 519. HRMS (ESI) m/z: [M + Na]+ calcd for C24H23ClN2O7Na 509.1086, found 509.1101. [α]D28 +59.20 (c 0.5, CHCl3). HPLC conditions: dr 70:30. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 16.22 min (major) and 11.44 min (minor). Minor diastereomer (90% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 12.29 min (major) and 15.95 min (minor). Methyl (R)-5-bromo-2-((R)-3-((tert-Butoxycarbonyl) amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3j). Compound 3j. Yellow solid, actual mass 108 mg, yield 78%. Mp: 165−170 °C. 1H NMR (500 MHz, CDCl3): δ = 7.83−7.75 (m, 1 H), 7.72−7.67 (m, 1 H), 7.54 (dd, J = 1.9, 8.8 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.18−7.15 (m, 2 H), 7.05−7.00 (m, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 6.86−6.82 (m, 1 H), 6.77−6.70 (m, 1 H), 3.93 (s, 1 H), 3.86 (s, 3 H), 3.29 (s, 1H), 3.14 (s, 3 H), 1.27 (s, 15 H). 13C NMR (125 MHz, CDCl3): δ = 190.9, 190.1, 172.3, 171.4, 170.3, 169.6, 163.9, 153.2, 144.9, 141.5, 141.1, 130.4, 130.0, 127.4, 126.8, 125.7, 123.3, 123.0, 122.8, 122.3, 122.2, 121.6, 116.2, 115.9, 114.7, 114.6, 108.6, 108.1, 87.6, 87.1, 80.6, 66.3, 65.0, 54.1, 53.9, 28.1, 26.8, 26.5. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3408, 2977, 1722, 1608, 1496, 1496, 1387, 1266, 1116, 1109, 1101, 973, 826, 754, 651. HRMS (ESI) m/z: [M + Na]+ calcd for C24H23BrN2O7 Na 553.0581, found 553.0601. [α]D28 +64.40 (c 0.5, CHCl3). HPLC conditions: dr 60:40. Major diastereomer (88% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 16.28 min (major) and 11.79 min (minor). Minor diastereomer (80% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ= 254 nm, retention time: 12.93 min (major) and 16.11 min (minor). Methyl (R)-5-Iodo-2-((R)-3-((tert-butoxycarbonyl)amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3k). Compound 3k. Yellow solid, actual mass 105 mg, yield 70%. 1 H NMR (500 MHz, CDCl3): δ = 7.93−7.82 (m, 1 H), 7.69 (dd, J = 1.9, 8.8 Hz, 1 H), 7.35−7.13 (m, 3 H), 7.02 (t, J = 7.4 Hz, 1 H), 6.88−6.80 (m, 2 H), 6.75−6.69 (m, 2 H), 6.63 (d, J = 8.8 Hz, 1 H), 3.91 (s, 3 H), 3.85 (m, 1 H), 3.27 (m, 3 H), 3.12 (s, 1 H), 1.26 (s, 15 H). 13C NMR (125 MHz, CDCl3): δ = 191.2, 172.3, 171.0, 147.1, 146.7, 144.8, 133.5, 133.0, 130.4, 130.0, 123.3, 123.0, 122.8, 122.2, 122.2, 115.1, 115.0, 109.9, 108.1, 85.5, 80.6, 65.0, 54.2, 53.9, 53.8, 28.2, 28.1, 26.8, 26.5. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3402, 2978, 1722, 1608, 1492, 1342, 1261, 1128, 1100, 970, 885, 738, 678. HRMS (ESI) m/z: [M + Na]+ calcd for C24H23IN2O7Na 601.0442, found 601.0434. HPLC conditions: dr 60:40. Major diastereomer (24% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 16.40 min (major) and 12.87 min (minor). Minor diastereomer (rac) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 13.99 min (major) and 16.90 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-5-methoxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3l). Compound 3l. Foamy solid, actual mass 106 mg, yield 85%. 1 H NMR (500 MHz, CDCl3): δ = 7.35 (t, J = 7.7 Hz, 1 H), 7.23−7.13 (m, 3 H), 7.09−6.98 (m, 4 H), 6.85 (d, J = 7.9 Hz, 1 H), 6.76−6.66(m, 1 H), 3.92 (s, 1 H), 3.85 (s, 3 H), 3.79 (s, 4 H), 3.29 (s, 1 H), 3.13 (s, 3 H), 1.27 (s, 13 H). 13C NMR (125 MHz, CDCl3): δ = 192.4, 191.6, 172.5, 171.5, 167.2, 166.3, 164.4, 155.9, 155.8, 153.3, 144.9, 130.2, 129.8, 129.0, 128.5, 123.3, 122.8, 122.7, 122.0, 120.7, 119.9, 113.9, 113.7, 108.5, 107.9, 104.6, 103.8, 87.5, 87.1, 80.4, 66.3, 65.1, 55.9, 55.8, 53.9, 53.7, 28.1, 26.7, 26.4. Visible peaks of minor diastereoisomer present 8946

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

Article

The Journal of Organic Chemistry ylate (ent-3n). Compound ent-3n. White solid, actual mass 60 mg, yield 85%. 1H NMR (500 MHz, CDCl3) corresponding to 3n. 13C NMR (125 MHz, CDCl3) corresponding to 3n. HPLC conditions: dr 60:40. Major diastereomer (88% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 10.45 min (major) and 12.13 min (minor). Minor diastereomer (84% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 13.09 min (major) and 10.17 min (minor). Ethyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-6-methyl-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3o). Compound 3o. Foamy solid, actual mass 98 mg, yield 90%. 1 H NMR (500 MHz, CDCl3): δ = 7.54−7.49 (m, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.11−6.98 (m, 1 H), 6.94−6.92 (m, 1 H), 6.85−6.82 (m, 3 H), 6.74−6.60 (m, 1 H), 4.35−4.25 (m, 3 H), 3.27 (s, 1 H), 3.12 (s, 3 H), 2.40 (s, 3 H), 2.28 (s, 1 H), 1.38 (t, J = 7.1 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 13H). 13C NMR (125 MHz, CDCl3): δ = 191.9, 190.9, 172.5, 172.3, 171.90, 171.6, 171.5, 164.0, 153.3, 151.5, 150.9, 144.9, 130.1, 129.7, 125.0, 124.8, 124.4, 123.9, 123.4, 122.9, 122.7, 121.9, 118.2, 117.5, 113.6, 112.9, 108.5, 107.9, 86.9, 80.3, 66.2, 63.5, 63.4, 28.1, 26.4, 22.6, 22.6, 14.1,14.0. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3407, 3057, 2978, 1719, 1614, 1470, 1369, 1258, 1164, 1119, 1092, 939, 860, 733, 607, 535. HRMS (ESI) m/z: [M + Na]+ calcd for C26H28N2O7Na 503.1789, found 503.1805. [α]D29 +36.90 (c 3.0, CHCl3). HPLC conditions: dr 81:19. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 18.04 min (major) and 12.70 min (minor). Minor diastereomer (99% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 28.55 min (major) and 20.29 min (minor). Ethyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-ethyl-2-oxoindolin-3-yl)-6-methyl-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3p). Compound 3p. Foamy solid, actual mass 103 mg, yield 92%. 1H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 7.9 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 2 H), 7.05 (t, J = 7.4 Hz, 1 H), 6.97 (d, J = 7.9 Hz, 1 H), 6.87−6.59 (m, 2 H), 4.37−4.29 (m, 2 H), 3.87 (dd, J = 7.1, 14.0 Hz, 1 H), 3.45 (s, 1 H), 2.42 (s, 3 H), 2.31 (s, 1 H), 1.41−1.27 (m, 15 H), 1.18 (t, J = 7.1 Hz, 4 H). 13C NMR (125 MHz, CDCl3): δ = 191.0, 172.3, 172.1, 171.5, 171.2, 163.9, 153.3, 151.3, 150.7, 144.0, 143.9, 130.1, 129.6, 124.9, 124.7, 124.5, 123.9, 123.6, 123.1, 122.6, 121.6, 118.3, 117.6, 112.9, 108.5, 108.0, 87.0, 86.8, 80.2, 66.3, 65.0, 63.4, 63.3, 35.2, 34.9, 28.1, 22.6, 22.5, 14.0, 12.7. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3407, 2979, 2934, 1719, 1614, 1492, 1466, 1329, 1253, 1165, 1094, 938, 858, 754, 612. HRMS (ESI) m/z: [M + Na]+ calcd for C27H30N2O7Na 517.1945, found 517.1957. [α]D26 +123.20 (c 0.5, CHCl3). HPLC conditions: dr 79:21. Major diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 12.25 min (major) and 9.96 min (minor). Ethyl (R)-2-((R)-1-Benzyl-3-((tert-butoxycarbonyl)amino)-2-oxoindolin-3-yl)-6-methyl-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3q). Compound 3q. White solid, actual mass 120 mg, yield 95%. Mp: 185−190 °C. 1H NMR (500 MHz, CDCl3): δ = 7.56 (d, J = 7.9 Hz, 1 H), 7.49 (dd, J = 7.7, 19.7 Hz, 1 H), 7.39−7.30 (m, 1 H), 7.29−7.24 (m, 8 H), 7.05−6.96 (m, 1 H), 6.94−6.85 (m, 1 H), 6.77 (dd, J = 7.9, 13.9 Hz, 1 H), 6.74 (d, J = 7.9 Hz, 1 H), 6.70 (s, 1 H), 6.61−6.50 (m, 1 H), 5.06 (d, J = 15.4 Hz, 1 H), 4.43−4.29 (m, 3 H), 2.39 (s, 3 H), 2.28 (s, 1 H), 1.42−1.39 (m, 3 H), 1.33−1.28 (m, 12 H). 13C NMR (125 MHz, CDCl3): δ = 191.8, 191.1, 172.7, 172.2, 172.0, 171.9, 171.4, 164.0, 163.2, 153.4, 151.5, 151.4, 150.6, 144.4, 143.9, 135.8, 130.1, 129.6, 128.5, 128.5, 127.6, 127.6, 127.4, 125.0, 124.8, 124.5, 124.0, 123.5, 122.9, 122.9, 121.9, 118.2, 117.6, 113.4, 112.8, 109.5, 109.0, 86.9, 86.7, 80.3, 66.3, 65.2, 63.5, 63.4, 44.3, 44.3, 28.2, 22.7, 22.6, 14.0. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3408, 3061, 2979, 2934, 1717, 1614, 1491, 1366, 1254, 1118, 1098, 939, 858, 817, 735, 699. HRMS (ESI) m/z: [M + Na]+ calcd for C32H32N2O7 Na 579.2120, found 579.2122. [α]D29 +98.40 (c 0.5, CHCl3). HPLC conditions: dr 77:23. Major diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 24.10 min (major) and 12.50 min (minor).

Minor diastereomer (94% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 20.28 min (major) and 14.14 min (minor). Ethyl (R)-2-((R)-1-Allyl-3-((tert-butoxycarbonyl)amino)-2-oxoindolin-3-yl)-6-methyl-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3r). Compound 3r. Yellow foamy solid, actual mass 103 mg, yield 90%. 1 H NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 7.9 Hz, 1 H), 7.33−7.28 (m, 1 H), 7.23 (d, J = 7.3 Hz, 1 H), 7.05 (t, J = 7.6 Hz, 1 H), 6.96 (d, J = 7.9 Hz, 1 H), 6.86−6.58 (m, 3 H), 5.77−5.75 (m, 1 H), 5.35 (d, J = 17.3 Hz, 1 H), 5.21 (d, J = 10.4 Hz, 1 H), 4.38 (d, J = 15.4 Hz, 1 H), 4.35− 4.27 (m, 3 H), 2.41 (s, 3 H), 2.31 (s, 1 H), 1.38 (t, J = 7.1 Hz, 2 H), 1.36−1.27 (m, 13 H). 13C NMR (125 MHz, CDCl3): δ = 191.0, 172.3, 172.2, 171.5, 171.4, 163.9, 153.3, 151.4, 150.7, 144.2, 144.0, 131.4, 131.2, 130.0, 129.5, 125.0, 124.8, 124.5, 124.0, 123.5, 122.9, 122.7, 121.8, 118.3, 117.6, 117.4, 117.2, 113.1, 112.9, 109.4, 108.8, 86.9, 86.7, 80.3, 66.3, 65.0, 63.4, 63.4, 42.7, 42.7, 28.1, 22.6, 22.5, 14.0. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1):3408, 2979, 2931, 1716, 1613, 1492, 1386, 1252, 1164, 1098, 935, 858, 817, 752, 611, 533. HRMS (ESI) m/z: [M + Na]+ calcd for C28H30N2O7Na 529.1945, found 529.1960. [α]D26 +140.00 (c 0.5, CHCl3). HPLC conditions: dr 75:25. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 44.32 min (major) and 36.92 min (minor). Minor diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/ min, λ = 254 nm, retention time: 48.43 min (major) and 57.76 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-(2-methoxy2-oxoethyl)-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2carboxylate (3s). Compound 3s. Yellow solid, actual mass 113 mg, yield 85%. 1H NMR (500 MHz, CDCl3): δ = 7.62−7.58 (m, 1 H), 7.49 (t, J = 7.4 Hz, 2 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.30−7.27 (m, 1 H), 7.16 (d, J = 7.3 Hz, 1 H), 7.12−7.06 (m, 1 H), 7.02 (t, J = 7.4 Hz, 2 H), 6.95− 6.67 (m, 2H), 6.57 (d, J = 7.9 Hz, 1 H), 4.62 (d, J = 17.7 Hz, 1 H), 3.95 (d, J = 15.8 Hz, 1 H), 3.82 (s, 1 H), 3.77 (s, 1 H), 3.76 (s, 3 H), 3.68 (s, 3 H), 1.22 (m, 11 H). 13C NMR (125 MHz, CDCl3): δ = 191.7, 172.4, 171.9, 171.5, 171.2, 167.5, 164.3, 153.2, 143.6, 143.5, 139.1, 138.3, 132.0, 132.0, 130.2, 129.7, 128.5, 128.4, 125.9, 124.4, 124.2, 123.4, 123.3, 123.3, 123.1, 122.2, 120.3, 119.6, 114.1, 113.2, 108.5, 108.2, 86.4, 80.4, 66.3, 53.9, 53.7, 52.4, 52.3, 41.5, 28.0. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3408, 2978, 1714, 1609, 1494, 1469, 1363, 1259, 1164, 1015, 976, 875, 755, 697, 579, 537. HRMS (ESI) m/z: [M + Na]+ calcd for C26H26N2O9 Na 533.1531, found 533.1550. [α]D26 +156.00 (c 0.5, CHCl3). HPLC conditions: dr 84:16. Major diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 14.72 min (major) and 11.55 min (minor). Minor diastereomer (99% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 16.92 min (major) and 19.02 min (minor). Methyl (S)-2-(S)-3-((tert-Butoxycarbonyl)amino)-1-(2-methoxy2-oxoethyl)-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2carboxylate (ent-3s). Compound ent-3s. White solid, actual mass 60 mg, yield 90%. 1H NMR (500 MHz, CDCl3) corresponding to 3s.13C NMR (125 MHz, CDCl3) corresponding to 3s. HPLC conditions: dr 87:13. Major diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 15.23 min (major) and 19.90 min (minor). Minor diastereomer (99% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 25.67 min (major) and 22.90 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-(2-ethoxy-2oxoethyl)-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3t). Compound 3t. Yellow solid, actual mass 123 mg, yield 90%. Mp: 205−210 °C. 1H NMR (500 MHz, CDCl3): δ = 7.71 (d, J = 7.9 Hz, 1 H), 7.63−7.58 (m, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 1 H), 7.14 (t, J = 7.4 Hz, 1 H), 7.09 (t, J = 7.6 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H), 4.70 (d, J = 17.7 Hz, 1 H), 4.22 (q, J = 6.9 Hz, 2 H), 4.01 (d, J = 19.5 Hz, 1 H), 3.92 (s, 1 H), 3.84 (s, 3 H), 1.39−1.34 (m, 2 H), 1.29 (t, J = 6.9 Hz, 12 H). 13C NMR (125 MHz, CDCl3): δ = 191.8, 172.5, 172.0, 171.6, 171.3, 167.0, 164.4, 153.3, 143.8, 139.0, 138.3, 130.2, 129.7, 124.5, 124.3, 123.5, 123.3, 123.2, 123.2, 123.0, 122.2, 120.4, 119.8, 114.2, 113.3, 86.5, 86.2, 80.5, 8947

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

Article

The Journal of Organic Chemistry 66.4, 61.6, 61.5, 53.9, 53.7, 41.8,41.7, 28.1, 14.2. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3408, 3058, 2980, 1717, 1610, 1496, 1366, 1260, 1164, 1045, 970, 872, 755, 698, 612. HRMS (ESI) m/z: [M + Na]+ calcd for C27H28N2O9 Na 547.1687, found 547.1702. [α]D26 +152.20 (c 0.5, CHCl3). HPLC conditions: dr 83:17. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 85.46 min (major) and 71.40 min (minor). Ethyl (R)-2-((R)-1-(2-(tert-Butoxy)-2-oxoethyl)-3-((tertbutoxycarbonyl)amino)-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3u). Compound 3u. Yellow foamy solid, actual mass 117 mg, yield 85%. 1H NMR (500 MHz, CDCl3): δ = 7.69 (d, J = 7.9 Hz, 1 H), 7.55 (t, J = 7.7 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.33−7.27 (m, 2 H), 7.22 (d, J = 8.5 Hz, 1 H), 7.12−7.03 (m, 3 H), 6.73 (d, J = 7.9 Hz, 1 H), 4.58 (d, J = 17.7 Hz, 1 H), 4.35−4.31 (m, 3 H), 4.27−4.23 (m, 1 H), 1.54 (s, 2 H), 1.47 (s, 10 H), 1.40−1.36 (m, 2 H), 1.30−1.24 (m, 13 H). 13C NMR (125 MHz, CDCl3): δ = 192.7, 192.1, 172.3, 172.0, 171.5, 171.4, 166.1, 164.0, 153.2, 143.9, 143.9, 139.0, 138.0, 130.2, 129.6, 124.4, 124.2, 123.7, 123.1, 123.0, 123.0, 122.0, 120.4, 119.9, 114.5, 113.3, 108.5, 108.3, 86.5, 86.3, 82.4, 82.3, 80.3, 66.5, 65.0, 63.5, 63.3, 43.0, 42.1, 28.1, 28.0, 13.9. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3411, 3058, 2978, 2932, 1717, 1610, 1496, 1325, 1255, 1096, 931, 883, 734, 698, 879. HRMS (ESI) m/z: [M + Na]+ calcd for C30H34N2O9Na 589.2157, found 589.2178. [α]D26 +163.20 (c 0.5, CHCl3). HPLC conditions: dr 83:17. Major diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 7.93 min (major) and 9.38 min (minor). Ethyl (S)-2-((S)-1-(2-(tert-Butoxy)-2-oxoethyl)-3-((tertbutoxycarbonyl)amino)-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-3u). Compound ent-3u. Yellow foamy solid, actual mass 61 mg, yield 88%. 1H NMR (500 MHz, CDCl3) corresponding to 3u.13C NMR (125 MHz, CDCl3) corresponding to 3u. HPLC conditions: dr 86:14. Major diastereomer (99% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 8.31 min (major) and 7.02 min (minor). Methyl (R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-chloro-1methyl-2-oxoindolin-3-yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran2-carboxylate (3v Major). Compound 3v. Foamy solid, actual mass 108 mg, yield 53%. 1H NMR (500 MHz, CDCl3): δ = 7.65−7.58 (m, 1 H), 7.57 (dd, J = 1.9, 8.8 Hz, 1 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.18 (s, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 3.88 (s, 3 H), 3.12 (s, 3 H), 1.32 (s, 9 H). 13C NMR (125 MHz, CDCl3): δ = 190.1, 171.1, 169.1, 163.8, 153.2, 143.5, 138.5, 130.2, 129.4, 128.4, 127.32, 124.4, 124.0, 121.6, 114.1, 109.6, 87.3, 80.9, 66.3, 54.0, 28.1, 26.6. IR (ν, cm−1):3411, 2977, 2928, 1723, 1608, 1490, 1462, 1391, 1258, 1164, 1098, 975, 887, 736, 693, 604. HRMS (ESI) m/z: [M + Na]+ calcd for C24H22N2O7Cl2Na 543.0696, found 543.0714. [α]D26 +180.60 (c 0.5, CHCl3). HPLC conditions: dr 60:40. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.69 min (major) and 8.73 min (minor). Methyl (R)-2-((S)-3-((tert-Butoxycarbonyl)amino)-5-chloro-1methyl-2-oxoindolin-3-yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran2-carboxylate (3v Minor). Compound 3v. White solid, actual mass 77 mg, yield 38%. Mp: 178−183 °C. 1H NMR (500 MHz, CDCl3): δ = 7.64−7.62 (m, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 6.83 (d, J = 8.5 Hz, 2 H), 6.69 (d, J = 8.2 Hz, 1 H), 3.92 (s, 3 H), 3.27 (s, 3 H), 1.32 (s, 10 H). 13C NMR (125 MHz, CDCl3): δ = 190.8, 171.9, 169.8, 163.1, 153.2, 143.5, 139.2, 130.2, 129.9, 129.3, 127.6, 123.8, 123.4, 120.9, 114.3, 109.1, 87.1, 80.9, 64.8, 54.2, 28.1, 26.9. IR (ν, cm−1): 3411, 2977, 2928, 1723, 1608, 1490, 1462, 1391, 1258, 1164, 1098, 975, 887, 736, 693, 604. HRMS (ESI) m/z: [M + Na]+ calcd for C24H22N2O7Cl2Na 543.0696, found 543.0714. [α]D28 −118.40 (c 0.5, CHCl3). Minor diastereomer (97% ee) Chiralpak AD-H, hexane/iPrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 10.48 min (major) and 21.85 min (minor). General Procedure for Synthesis of Compound 7. To stirred solution of 3-substituted 3-amino-2-oxindole 3c in methanol at 0 °C was portionwise added NaBH4 (0.5 equiv) to the reaction mixture, the mixture was stirred for 30 min. After completion of the reaction, the reaction quenched by aqueous ammonium chloride solution followed

by extraction in dichloromethane, and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography over silica gel (80:20 hexane/EtOAc) to furnish 7. Methyl (2S,3R)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-chloro1-methyl-2-oxoindolin-3-yl)-3-hydroxy-2,3-dihydrobenzofuran-2carboxylate (7 Major). Compound 7 (Major). White solid, actual mass 106 mg, yield 51%. 1H NMR (500 MHz, CDCl3): δ = 7.39 (dd, J = 0.9, 7.9 Hz, 1 H), 7.35(dd, J = 1.4, 7.2, 8.4 Hz, 1 H), 7.21 (ddd, J = 2.0, 8.4 Hz, 1 H), 7.06 (d, 1 H), 7.01 (ddd, 2 J = 2.0, 8.4 Hz, 1H),6.81 (d ,J = 2.0, 8.4 Hz, 1 H), 6.71(d, J = 8.2 Hz, 2 H), 6.40(d, J = 8.2 Hz, 1 H), 5.65 (d, J = 8.2 Hz, 1 H, 3.85 (s, 3 H), 3.11 (s, 3 H), 1.29 (s., 11 H). 13C NMR(125 MHz, CDCl3): δ = 175.2, 171.0, 156.4, 153.3, 142.7, 131.2, 130.5, 129.9, 129.1, 128.8, 128.7, 126.1, 125.6, 125.4, 123.3, 122.7, 111.2, 110.0, 109.6, 109.2, 94.5, 90.4, 80.9, 80.2, 66.4, 53.2, 28.1, 26.8. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3605, 3405, 2978, 1721, 1610, 1491, 1432, 1392, 1162, 1098, 969, 817, 760, 736, 687, 543. HRMS (ESI) m/z: [M + Na]+ calcd for C24H25ClN2O7Na 511.1242, found 511.1233. HPLC conditions: dr 60:40. Major diastereomer (94% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 25.74 min (major) and 8.24 min (minor). Methyl (2R,3R)-2-((R)-3-((tert-Butoxycarbonyl) amino)-5-chloro1-methyl-2-oxoindolin-3-yl)-3-hydroxy-2,3-dihydrobenzofuran-2carboxylate (7 Minor). Compound 7 (Minor). White solid, actual mass 65 mg, yield 31%. 1H NMR (500 MHz, CDCl3): δ = 7.66 (s, 1H) 7.45 (d, J = 8.4 Hz, 1 H), 7.41 (t, J = 2.0, 8.4 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H),7.16 (d, J = 8.2 Hz, 1 H), 7.09 (t, J = 8.2 Hz, 1 H),6.78 (d, J = 8.2 Hz, 1 H), 6.28 (s, 1H), 5.90 (s, 1H), 5.57 (s, 1H), 3.34 (s, 3 H), 3.23 (s, 3 H), 1.29 (s, 9 H). 13C NMR (125 MHz, CDCl3): δ = 175.13, 169.2,158.9, 153.3, 142.1, 131.2, 129.9, 128.7, 126.1, 125.9, 125.6, 122.7, 111.2,109.2, 94.5, 80.7, 64.5, 52.9, 28.1, 26.9. IR (ν, cm−1): 3605, 3405, 2978, 1721, 1610, 1491, 1432, 1392, 1162, 1098, 969, 817, 760, 736, 687, 543. HRMS (ESI) m/z: [M + Na] + calcd for C24H25ClN2O7Na 511.1242, found 511.1233. Minor diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 12.22 min (major) and 16.4 min (minor). General Procedure for Synthesis of Compound 8. To stirred solution of 3-Substituted 3-Amino-2-oxindole 3c in methanol at 0 °C, then portion wise NaBH4(2 equiv) was added to the reaction mixture stirred for 1 h, after completion of the reaction quenched by aqueous ammonium chloride solution followed by extracted in dichloromethane and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography over silica gel (60:40 hexane/EtOAc) to furnish 8. tert-Butyl ((R)-5-Chloro-3-((2S,3R)-3-hydroxy-2-(hydroxymethyl)2,3-dihydrobenzofuran-2-yl)-1-methyl-2-oxoindolin-3-yl)carbamate (8). Compound 8. White solid, actual mass 174 mg, yield 71%. 1H NMR (500 MHz, DMSO-d6): δ = 7.54 (s, 1H), 7.39 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.14 (t, J = 2.0, 8.4 Hz, 1 H), 6.95 (t, J = 8.2 Hz, 1 H), 6.80 (s, 1H), 6.78 (d, J = 8.2 Hz, 1 H), 6.57 (d, J = 8.2 Hz, 1 H), 5.67 (s, 1H), 4.9 (bs, 1H), 4.10 (d, J = 8.2 Hz, 1 H), 3.69 (s, 1 H), 3.57(d, J = 8.2 Hz, 1 H), 3.07 (s, 3 H), 1.25 (s, 9 H). 13C NMR (125 MHz, DMSO-d6): δ = 176.7, 158.5,156.8, 153.5, 142.9, 130.4, 129.7, 128.3, 127.4, 126.4, 125.6, 121.7, 110.5, 109.5, 92.9, 89.3, 80.3, 67.62, 63.95, 28.07, 26.84. IR (ν, cm−1): 3605, 3594, 3405, 2973, 1608, 1489, 1429, 1396, 1159, 1092, 960, 813, 766, 730, 682, 541. HRMS (ESI) m/ z: [M + H]+ calcd for C23H26ClN2O6 461.1474, found 461.1463. HPLC conditions: dr 85:15. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 44.00 min (major) and 9.90 min (minor). Minor diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 16.62 min (major) and 20.96 min (minor). Representative Experimental Procedure for the Synthesis of Anti-Selective 3-Substituted 3-Amino-2-oxindoles (4). To a 30 min stirred solution of isatin-derived ketimines (1.2 equiv) and catalyst C25 or C26 (0.1 equiv) in dry CH2Cl2 (0.5 mL) was added methyl 3oxo-2,3-dihydrobenzofuran-2-carboxylate(1equiv) at −23 °C. The 8948

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

Article

The Journal of Organic Chemistry reaction mixture was stirred at −23 °C until the consumption of methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate, which was monitored by TLC. The crude mixture was purified by flash column chromatography over silica gel (85:15 to 70:30 hexane/EtOAc) to furnish 4a−m. Analytical Data for Anti-Selective 3-Substituted 3-Amino-2oxindoles. Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-fluoro-1-methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2carboxylate (4a). Compound 4a. White foamy solid, actual mass 109 mg, yield 89%. 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 7.7 Hz, 1 H), 7.53−7.48 (m, 1 H), 7.11−7.07 (m, 1 H), 6.86−6.80 (m, 2 H), 6.67 (dd, J = 8.5, 4.0 Hz, 1 H), 6.61 (d, J = 6.0 Hz, 1 H), 3.92 (s, 3 H), 3.28 (s, 3 H), 1.32 (s, 11 H). 13C NMR (100 MHz,, CDCl3): δ = 192.0, 172.3, 171.5, 159.8, 157.4, 140.9, 139.3, 138.7, 125.0, 124.6, 123.5, 119.7, 116.1, 115.9, 113.0, 112.9, 111.3, 111.1, 108.5, 86.1, 80.7, 65.0, 54.1, 28.1, 26.9. [α]D27 −119.80 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C24H23FN2O7Na 493.1382, found 493.1392. HPLC conditions: dr 18:82. Major diastereomer (99% ee) Chiralpak AD-H, hexane/i-PrOH = 95:05, flow rate = 0.50 mL/min, λ = 254 nm, retention time: 64.71 min (major) and 94.96 min (minor). Methyl (R)-2-((S)-3-((tert-Butoxycarbonyl)amino)-5-fluoro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-4a). Compound ent-4a. Yellow foamy solid, actual mass 50 mg, yield 82%. 1H NMR (400 MHz, CDCl3) corresponding to 4a.13C NMR (100 MHz, CDCl3) corresponding to 4a. [α]D27 + 89.80 (c 0.5, CHCl3). HPLC conditions: dr 35:65. Major diastereomer (92/80%ee) Chiralpak AD-H, hexane/i-PrOH = 95:05, flow rate = 0.50 mL/min, λ = 254 nm, retention time: 84.86 min (major) and 59.71 min (minor). Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-chloro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4b). Compound 4b. White solid, actual mass 121 mg, yield 96%. 1 H NMR (400 MHz, CDCl3): δ = 7.69−7.67 (m, 1 H), 7.51 (ddd, J = 8.5, 7.2, 1.3 Hz, 1 H), 7.12−7.07 (m, 2 H), 6.84−6.80 (m, 2 H), 6.67 (d, J = 8.3 Hz, 1 H), 3.92 (s, 3 H), 3.27 (s, 3 H), 1.32. (s, 11 H). 13C NMR (100 MHz,, CDCl3): δ = 191.9, 172.1, 171.5, 144.3, 143.5, 139.3, 138.7, 130.1, 129.7, 127.4, 125.0, 124.6, 123.6, 123.4, 119.7, 112.9, 112.8, 108.9, 86.0, 80.8, 64.9, 54.1, 28.1, 26.9. [α]D27 −75.80 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C24H23ClN2O7Na 509.1086, found 509.1083. HPLC conditions: dr 18:82. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 12.45 min (major) and 27.08 min (minor). Methyl (R)-2-((S)-3-((tert-Butoxycarbonyl)amino)-5-chloro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-4b). Compound ent-4b. Yellow foamy solid, actual mass 56 mg, yield 89%. 1H NMR (400 MHz, CDCl3) corresponding to 4b.13C NMR (100 MHz, CDCl3) corresponding to 4b. [α]D27 +45.80 (c 0.5, CHCl3). HPLC conditions: dr 35:65. Major diastereomer (88/74%ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 23.82 min (major) and 11.37 min (minor). Methyl (S)-2-((R)-5-Bromo-3-((tert-butoxycarbonyl)amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4c). Compound 4c. Yellow solid, actual mass 135 mg, yield 98%. 1 H NMR (400 MHz, CDCl3): δ = 7.69 (dd, J = 7.8, 0.8 Hz, 1 H), 7.51 (ddd, J = 8.5, 7.2, 1.5 Hz, 1 H), 7.23 (dd, J = 8.3, 1.8 Hz, 2 H), 7.13− 7.09 (m, 1 H), 6.93−6.84 (m, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 8.3 Hz, 1 H), 3.92 (s, 3 H), 3.27 (s, 3 H), 1.32 (s, 11 H). 13C NMR (100 MHz,, CDCl3): δ = 191.9, 172.0, 171.5, 143.9, 139.4, 138.8, 133.0, 132.6, 126.1, 125.0, 124.6, 123.7, 123.6, 119.8, 114.5, 112.9, 112.8, 109.4, 86.0, 80.8, 64.8, 54.1, 28.1, 26.9. [α]D27 −48.20 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + H]+ calcd for C24H24BrN2O7 531.0761, found 531.0781. HPLC conditions: dr 17:83. Major diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 12.37 min (major) and 29.61 min (minor). Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-5-iodo-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4d). Compound 4d. Yellow foamy solid, actual mass 126 mg, yield 84%. 1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 7.7 Hz, 1 H), 7.53−7.49 (m, 1 H), 7.41 (d, J = 7.9 Hz, 1 H), 7.14−7.07 (m, 1 H), 7.06 (s, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 6.52 (d, J = 8.2 Hz, 1 H), 3.92 (s, 3 H), 3.26 (s, 3 H), 1.32 (s, 11 H). 13C NMR (100 MHz, CDCl3): δ = 191.9, 171.8, 171.5, 144.6, 139.4, 138.8, 138.5, 132.1, 131.7, 125.0, 124.5, 123.7, 119.8, 112.9, 85.9, 83.9, 80.8, 64.7, 54.1, 28.1, 26.8. [α]D27

−22.80 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C24H23IN2O7Na 601.0442, found 601.0453. HPLC conditions: dr 14:86. Major diastereomer (98% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 13.74 min (major) and 31.55 min (minor). Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl) amino)-5-methoxy-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4e). Compound 4e. White foamy solid, actual mass 122 mg, yield 97%. 1H NMR (400 MHz, CDCl3): δ = 7.65 (dd, J = 7.8, 0.8 Hz, 1 H), 7.50−7.46 (m, 1 H), 7.09−7.05 (m, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.65 (d, J = 1.2 Hz, 2 H), 6.44 (s, 1 H), 3.92 (s, 3 H), 3.47 (s, 3 H), 3.26 (s, 3 H), 1.30 (s, 10 H). 13C NMR (100 MHz,, CDCl3): δ = 192.3, 172.2, 171.6, 155.4, 139.1, 138.6, 138.4, 125.0, 124.3, 123.5, 123.3, 119.9, 115.2, 113.1, 109.8, 108.5, 86.3, 80.5, 65.4, 55.8, 54.1, 28.1, 26.9. [α]D27 −95.20 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C25H26N2O8Na 505.1581, found 505.1578. HPLC conditions: dr 15:85. Major diastereomer (96% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 79.20 min (major) and 216.14 min (minor). Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2oxo-5-(trifluoromethoxy)indolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4f). Compound 4f. White foamy solid, actual mass 132 mg, yield 94%. 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 7.2 Hz, 1 H), 7.51−7.47 (m, 1 H), 7.11−7.06 (m, 2 H), 7.00 (d, J = 7.8 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 8.3 Hz, 2 H), 3.92 (s, 3 H), 3.30 (s, 3 H), 1.32 (s, 11 H). 13C NMR (100 MHz,, CDCl3): δ = 191.9, 172.4, 171.5, 144.0, 143.7, 139.3, 138.8, 125.0, 124.7, 123.7, 123.6, 123.5, 123.2, 119.6, 117.6, 117.1, 112.8, 108.4, 85.8, 80.8, 66.0, 54.1, 28.1, 27.0. [α]D28 −89.60 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C25H23F3N2O8Na 559.1299, found 559.1309. HPLC conditions: dr 24:76. Major diastereomer (97% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 41.60 min (major) and 115.91 min (minor). Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-7-fluoro-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4g). Compound 4g. Yellow foamy solid, actual mass 119 mg, yield 97%. 1H NMR (400 MHz, CDCl3): δ = 7.63 (dd, J = 7.8, 0.9 Hz, 1 H), 7.50 (ddd, J = 8.5, 7.2, 1.5 Hz, 1 H), 7.07 (t, J = 7.5 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 6.84 (dd, J = 11.0, 8.7 Hz, 1 H), 6.63−6.61 (m, 1 H), 6.59−6.54 (m, 1 H), 3.92 (s, 3 H), 3.50 (d, J = 2.6 Hz, 3 H), 1.33(s, 11 H). 13C NMR (100 MHz, CDCl3): d = 192.1, 172.3, 171.6, 148.6, 146.2, 139.1, 138.7, 125.0, 124.5, 123.6, 123.4, 122.5, 122.4, 119.8, 118.7, 118.1, 117.9, 113.1, 112.9, 86.2, 80.7, 65.0, 54.1, 29.4, 28.1. [α]D28 −105.00 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C24H23FN2O7Na 493.1382, found 493.1373. HPLC conditions: dr 25:75. Major diastereomer (95% ee) Chiralpak AD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 65.61 min (major) and 75.10 min (minor). Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4h). Compound 4h. Yellow foamy solid, actual mass 102 mg, yield 81%. 1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 2.3 Hz, 1 H), 7.40 (dd, J = 8.8, 2.3 Hz, 1 H), 7.15 (t, J = 7.6 Hz, 2 H), 6.82−6.77 (m, 2 H), 6.76−6.71 (m, 2 H), 6.71−6.68 (m, 1 H), 3.92 (s, 3 H), 3.28 (s, 3 H), 1.26 (s, 11 H). 13C NMR (100 MHz, CDCl3): d = 191.2, 172.3, 169.9, 144.8, 138.9, 138.4, 130.4, 130.0, 128.9, 124.3, 123.7, 122.7, 122.2, 121.0, 114.3, 108.1, 80.6, 65.0, 54.2, 28.1, 26.8. [α]D28 −164.60 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C24H23ClN2O7Na 509.1086, found 509.1096. HPLC conditions: dr 15:75. Major diastereomer (94% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.89 min (major) and 15.21 min (minor). Methyl (R)-2-((S)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-5-chloro-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent-4h). Compound ent-4h. Yellow foamy solid, actual mass 50 mg, yield 79%. 1H NMR (400 MHz, CDCl3) corresponding to 4h.13C NMR (100 MHz, CDCl3) corresponding to 4h. [α]D28 +9.10 (c 0.5, CHCl3). HPLC conditions: dr 40:60. Major diastereomer (84/80%ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 16.45 min (major) and 12.49 min (minor). 8949

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

Article

The Journal of Organic Chemistry Methyl (S)-5-Bromo-2-((R)-3-((tert-butoxycarbonyl)amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4i). Compound 4i. Yellow foamy solid, actual mass 100 mg, yield 73%. 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 2.1 Hz, 1 H), 7.53 (dd, J = 8.8, 2.2 Hz, 1 H), 7.17−7.13 (m, 2 H), 6.83−6.68 (m, 3 H), 3.92 (s, 3 H), 3.28 (s, 3 H), 1.27 (s, 11 H). 13C NMR (100 MHz,, CDCl3): δ = 190.9, 172.3, 170.3, 144.8, 144.3, 141.6, 141.1, 130.0, 127.4, 126.8, 122.7, 122.2, 121.5, 115.9, 114.7, 108.1, 87.1, 80.6, 65.0, 54.2, 28.1, 26.8. [α]D28 −198.00 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C24H23BrN2O7Na 553.0581, found 553.0577. HPLC conditions: dr 14:86. Major diastereomer (92% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.35 min (major) and 14.97 min (minor). Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-5-iodo-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4j). Compound 4j. Yellow foamy solid, actual mass 101 mg, yield 63%. 1 H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 1.6 Hz, 1 H), 7.69 (dd, J = 8.7, 1.8 Hz, 1 H), 7.15 (t, J = 7.2 Hz, 2 H), 6.82 (d, J = 7.6 Hz, 1 H), 6.76−6.69 (m, 2 H), 6.63 (d, J = 8.7 Hz, 1 H), 3.91 (s, 3 H), 3.28 (s, 3 H), 1.26 (s, 12 H). 13C NMR (100 MHz,, CDCl3): δ = 190.6, 172.3, 170.9, 147.1, 146.7, 144.8, 133.0, 130.4, 130.0, 122.7, 122.3, 122.1, 115.1, 108.1, 86.7, 85.5, 80.6, 65.0, 54.2, 28.1, 26.8. [α]D28 −12.60 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C24H23IN2O7Na 601.0442, found 601.0434. HPLC conditions: dr 16:84. Major diastereomer (10% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 14.94 min (major) and 18.89 min (minor). Ethyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4k). Compound 4k. White foamy solid, actual mass 118 mg, yield 97%. 1 H NMR (400 MHz, CDCl3): δ = 7.64−7.62 (m, 1 H), 7.47−7.43 (m, 1 H), 7.13−7.08 (m, 1 H), 7.06−7.02 (m, 1 H), 6.82−6.80 (m, 2 H), 6.73 (d, J = 7.8 Hz, 1 H), 6.62 (t, J = 7.5 Hz, 1 H), 4.46−4.26 (m, 2 H), 3.28 (s, 3 H), 1.40 (t, J = 7.2 Hz, 4 H), 1.30−1.25 (m, 11 H). 13C NMR (100 MHz,, CDCl3): δ = 192.6, 172.4, 171.7, 144.8, 139.0, 138.5, 130.2, 129.8, 124.9, 124.4, 123.4, 123.1, 122.8, 121.9, 119.9, 113.0, 107.9, 80.4, 65.0, 63.7, 28.1, 26.8, 14.0. [α]D28 −112.20 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C25H26N2O7 Na 489.1632, found 489.1646. HPLC conditions: dr 22:78. Major diastereomer (95% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 18.81 min (major) and 21.98 min (minor). Ethyl (R)-2-((S)-3-((tert-Butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (ent4k). Compound ent-4k. White foamy solid, actual mass 48 mg, yield 86%. 1H NMR (400 MHz, CDCl3) corresponding to 4k.13C NMR (100 MHz, CDCl3) corresponding to 4k. [α]D28 −88.60 (c 0.5, CHCl3). HPLC conditions: dr 41:59. Major diastereomer (84/80% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 22.32 min (major) and 19.42 min (minor). Ethyl (S)-5-Bromo-2-((R)-3-((tert-butoxycarbonyl)amino)-1methyl-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (4l). Compound 4l. Yellow foamy solid, actual mass 112 mg, yield 79%. 1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 2.1 Hz, 1 H), 7.52 (dd, J = 8.8, 2.2 Hz, 1 H), 7.17−7.13 (m, 1 H), 6.81 (d, J = 7.3 Hz, 1 H), 6.76−6.68 (m, 3 H), 4.46−4.33 (m, 2 H), 3.28 (s, 3 H), 1.39 (t, J = 7.2 Hz, 4 H), 1.30−1.25 (m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 191.2, 172.2, 170.4, 144.8, 141.5, 141.0, 130.4, 130.0, 127.4, 126.8, 123.4, 122.7, 122.2, 121.6, 115.8, 114.7, 108.1, 87.2, 80.5, 64.9, 63.9, 28.1, 26.8, 14.0. [α]D28 −181.40 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C25H25BrN2O7Na 567.0737, found 567.0749. HPLC conditions: dr 13:87. Major diastereomer (99% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.09 min (major) and 14.96 min (minor). Methyl (S)-2-((R)-3-((tert-Butoxycarbonyl)amino)-1-(2-methoxy2-oxoethyl)-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2carboxylate (4m). Compound 4m. Yellow foamy solid, actual mass 126 mg, yield 96%. 1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 7.8 Hz, 1 H), 7.48−7.44 (m, 1 H), 7.09−7.00 (m, 2 H), 6.92−6.86 (m, 2 H), 6.67−6.60 (m, 2 H), 4.92 (d, J = 17.6 Hz, 1 H), 4.19 (d, J = 15.9 Hz, 1 H), 3.90 (s, 3 H), 3.84 (s, 3 H), 1.29 (s, 11 H). 13C NMR (100 MHz,, CDCl3): δ = 192.3, 172.5, 172.0, 167.7, 153.3, 143.5, 139.1, 138.3,

133.0, 130.3, 129.8, 128.6, 128.4, 124.3, 123.2, 123.1, 122.3, 119.7, 114.1, 113.3, 108.2, 86.2, 80.5, 65.0, 54.0, 52.5, 41.6, 28.1. [α]D28 −172.40 (c 0.5, CHCl3). HRMS (ESI) m/z: [M + Na]+ calcd for C26H26N2O9 Na 533.1531, found 533.1550. HPLC conditions: dr 20:80. Major diastereomer (99% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 25.99 min (major) and 30.42 min (minor). Methyl (R)-2-((S)-3-((tert-Butoxycarbonyl)amino)-1-(2-methoxy2-oxoethyl)-2-oxoindolin-3-yl)-3-oxo-2,3-dihydrobenzofuran-2carboxylate (ent-4m). Compound ent-4m. Yellow foamy solid, actual mass 60 mg, yield 91%. 1H NMR (400 MHz, CDCl3) corresponding to 4m.13C NMR (100 MHz, CDCl3) corresponding to 4m. [α]D28 +113.60 (c 0.5, CHCl3). HPLC conditions: dr 40:60. Major diastereomer (88/80% ee) Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 32.02 min (major) and 22.86 min (minor). Control Experiment. Ethyl (R)-2-((R)-3-((tert-Butoxycarbonyl) amino)-1-methyl-2-oxoindolin-3-yl)-1-oxo-2,3-dihydro-1Hindene-2-carboxylate (6) (Catalyst C1). Compound 6. Yellow liquid, actual mass 57 mg, yield 95%. 1H NMR (CDCl3, 500 MHz): d = 7.72- 7.70 (m, 1 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.36−7.29 (m, 4 H), 7.23 (s, 1 H), 6.97 (s, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 4.28- 4.21(m, J = 34 Hz, 2 H), 3.53 (d, J = 18.2 Hz, 1 H), 3.22 (s, 1 H), 3.21 (s, 1 H), 3.15 (s, 3 H), 1.38−1.20 (m, 17H). 13C NMR (CDCl3, 125 MHz): δ = 198.0, 173.6, 173.3, 153.8, 151.1, 144.5, 135.9, 135.5, 135.5, 129.7, 129.5, 128.0, 127.8, 126.0, 125.7, 124.7, 124.5, 124.1, 122.8, 108.3, 80.0, 62.7, 36.6, 28.1, 26.5, 24.7, 13.9. Visible peaks of minor diastereoisomer present in 1H and 13C NMR. IR (ν, cm−1): 3409, 2978, 1750, 1721, 1610, 1496, 1370, 1254, 1165, 1089, 932, 885, 756, 695, 612, 538, 513. HRMS (ESI) m/z: [M + H]+ calcd for C26H29N2O6 465.2020, found 465.2025. [α]D26 +30.73 (c 1.5, CHCl3). HPLC conditions: dr 82:18. Major diastereomer (98% ee) Chiralpak OD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 34.20 min (major) and 30.12 min (minor). Minor diastereomer (99% ee) Chiralpak OD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 25.24 min (major) and 42.30 min (minor). (Catalyst C25). Compound 6. Yellow liquid, actual mass 56 mg, yield 93%. HPLC conditions: dr 65:35. Major diastereomer (98% ee) Chiralpak OD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 36.01 min (major) and 31.06 min (minor). Minor diastereomer (99% ee) Chiralpak OD-H, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm, retention time: 26.04 min (major) and 42.04 min (minor). Analytical Data for Isatin-Derived Ketimines. The analytical data for known isatin derived ketimines (2a−k) were matched with reported values in the literature.20a‑b The analytical data for other isatin derived ketimines (2l−n) as follows. Methyl (E)-2-(3-((tert-Butoxycarbonyl)imino)-2-oxoindolin-1-yl)acetate (2l). Compound 2l (400 mg from 1g batch), yellow solid. Mp: 155−160 °C. 1H NMR (400 MHz, CDCl3): δ = 7.79−7.61 (m, 1 H), 7.51−7.44 (m, 1 H), 7.13 (s, 1 H), 6.74 (d, J = 7.6 Hz, 1 H), 4.47 (s, 2 H), 3.77 (s, 3 H), 1.62 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 167.3, 146.8, 135.4, 124.6, 123.9, 109.4, 83.7, 52.8, 41.1, 28.0. HRMS (ESI) m/z: [M + Na]+ calcd for C16H18N2O5 Na 341.1108, found 341.1107. Ethyl (E)-2-(3-((tert-Butoxycarbonyl)imino)-2-oxoindolin-1-yl)acetate (2m). Compound 2m (500 mg from 1g batch), yellow solid. Mp:142−145 °C. 1H NMR (400 MHz, CDCl3): δ = 7.68 (s, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.12 (s, 1 H), 6.74 (d, J = 7.7 Hz, 1 H), 4.45 (s, 2 H), 4.23 (q, J = 7.1 Hz, 2 H), 1.62 (s, 10 H), 1.27 (t, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 166.8, 146.9, 135.3, 124.6, 123.8, 109.4, 83.6, 62.1, 41.3, 28.0, 14.1. HRMS (ESI) m/z: [M + Na]+ calcd for C17H20N2O5 Na 355.1264, found 355.1262. tert-Butyl (E)-2-(3-((tert-butoxycarbonyl)imino)-2-oxoindolin-1yl)acetate (2n). Compound 2n (700 mg from 1g batch), yellow solid. Mp: 138−142 °C. 1H NMR (400 MHz, CDCl3): δ = 7.67 (s, 1 H), 7.48 (t, J = 7.7 Hz, 1 H), 7.11 (s, 1 H), 6.72 (d, J = 7.7 Hz, 1 H), 4.36 (s, 2 H), 1.62 (s, 10 H), 1.45 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 165.8, 147.1, 135.3, 124.5, 123.7, 109.5, 83.3, 42.1, 28.0, 27.91. 8950

DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

Article

The Journal of Organic Chemistry HRMS (ESI) m/z: [M + Na]+ calcd for C19H24N2O5 Na 383.1577, found 383.1578.

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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.8b01020. 1 H and 13NMR spectra, CD spectra, and crystallographic data (PDF) Crystallographic data for compound 3i (CIF) Crystallographic data for compound 3v (minor diastereomer) (CIF) Crystallographic data for compound 8 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +91-44-22574102. Tel: +9144-2257-4124. ORCID

Venkitasamy Kesavan: 0000-0002-7720-0268 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the Board of Research in Nuclear Sciences, Mumbai, India (35/14/01/2015-BRNS/10464) for financial support. K.S.M.R. thanks the Council of Scientific & Industrial Research (CSIR) for a fellowship. We thank Dr. Sudha Devi for crystallographic analysis and SAIF-IIT Madras and SAIF-IIT Madras for spectral analysis (NMR and IR). We thank the Department of Biotechnology IIT Madras for LCMS. We thank Prof. Anju Chadha for the AUTOPOL IV polarimeter.

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REFERENCES

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DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952

Article

The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.8b01020 J. Org. Chem. 2018, 83, 8936−8952