Catalyst-Free Ring Opening of Spiroaziridine Oxindoles by

A simple catalyst-free method was developed for the ring opening of spiroaziridine oxindoles ... opened regio- and stereospecifically through the pseu...
4 downloads 5 Views 2MB Size
Download PDF
Article Cite This: J. Org. Chem. 2018, 83, 3633−3644

pubs.acs.org/joc

Catalyst-Free Ring Opening of Spiroaziridine Oxindoles by Heteronucleophiles: An Approach to the Synthesis of Enantiopure 3‑Substituted Oxindoles Saumen Hajra,* Somnath Singha Roy, Anurag Biswas, and Sk Abu Saleh Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226014, India S Supporting Information *

ABSTRACT: A simple catalyst-free method was developed for the ring opening of spiroaziridine oxindoles by three different nucleophiles, namely, amines, thiols, and methanol, to produce enantiopure (up to 99%) vicinal diaminooxindoles, β-aminosulfides, and β-amino-3-methoxyoxindole, respectively, in good to excellent yields. In contrast to the spiroepoxides, spiroaziridines are opened regio- and stereospecifically through the pseudobenzylic spirocenter under catalyst-free conditions. Moreover, unlike simple 2-substituted aziridines, these spiroaziridines are opened up with retention in configuration at the C3-spirocenter.

■

INTRODUCTION New drug candidates always emerge from the efforts to synthesize structurally diverse organic moieties.1 Therefore, such efforts are always the focus of organic and medicinal chemists. Substituted oxindoles, featuring C3 stereocenters, are attractive targets not only due to their presence in various alkaloids but also because they serve as precursors for a number of naturally occurring molecules.2 Among various oxindoles, the disubstituted enantiopure 3-aminoxindoles,3 3-hydroxyoxindoles,4 and 3-alkoxyoxindoles5 are privileged pharmacophores and are present in many biologically active natural products and synthetic compounds. A few examples are depicted in Figure 1, which includes antimalarial agent NITD609,6a donaxaridine, dioxibrassinine,4a a p53/Hdm2 antagonist,6b spirobrassinin,6c and CPC-1.5 In the past few years, various methodologies have been developed to access chiral disubstituted 3-aminoxindoles 7−11 The main strategy has been asymmetric nucleophilic addition to isatin-derived imines7a,c−e or simple isatins.7b,c,10 Amination7a,c,8,11 of 3-monosubstituted oxindoles can also produce 3-aminoxindoles. Our previously developed12 spiroaziridine oxindole13 was anticipated to be an advantageous precursor, as we can directly access a diverse array of pharmacologically important molecular motifs through the judicious opening of these activated aziridines by a suitable nucleophile. Although nucleophilic addition to spiroaziridines appears simple, controlling the regioand stereoselectivity of the reaction, which governs the enantiopurity of the C3-carbon center, is a challenge. Previously, we have described the water-mediated catalyst-free regio- and stereoselective ring opening of spiroaziridine © 2018 American Chemical Society

Figure 1. Representative examples of vicinal diamino oxindoles, βaminosulfides, and β-amino-3-hydroxy oxindoles, and other natural molecules containing 3-substituted oxindoles.

oxindoles with carbon nucleophiles such as indole.14 Therefore, we anticipated that heteronucleophiles could act in a similar Received: December 29, 2017 Published: March 1, 2018 3633

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry

the ee due to its instability during HPLC analysis. We presumed that the ee of 1 (99%) is the same as that of the starting aziridine 4. Similar to our earlier report,14 a suspended mixture of spiroaziridine 1a and aniline 2a in water was stirred without any catalyst at 25 °C. Under these conditions, the reaction was completed in 2 h. The yield and ee of the desired vicinal diamino oxindole product 3aa were found to be 87% and 95%, respectively (Table 1, entry 1). Lowering of reaction temper-

manner under the same reaction conditions (water-mediated and catalyst-free) to generate the desired products with the predicted stereoselectivity. The water-mediated stereoselective ring-opening reactions of simple nonracemic aziridines with heteronucleophiles are well established in the literature.15 However, to the best of our knowledge, there have been no reports of methods that preserve the chirality of the substrate in the product under water-mediated and catalyst-free reaction conditions. Moreover, under these conditions, the aziridine ring opening was reported to occur from the less hindered side.16 Spiroepoxyoxindole also showed a similar kind of ring opening from the less hindered side with amine nucleophiles in water under catalyst-free conditions (Scheme 1).17 Here, for the first time, we report the catalyst-free ring opening of spiroaziridine oxindoles with heteronucleophiles, namely, amines, thiols, and methanol.

Table 1. Optimization of the Reaction Conditionsa

Scheme 1. Water-Mediated Catalyst-Free Ring Opening of Aziridine, Spiroepoxide, and Spiroaziridine

entry

solvent

temp (°C)

time (h)

yield (%)

eeb (%)

1 2 3 4 5

water water water water trifluoroethanol

25 0 10 45 0

2 17 4 1 14

87 80 84 86 83

95 83 93 94 79

a

N-Methyl spiroaziridine oxindole 1a (0.34 mmol), aniline 2a (0.68 mmol), and solvent (3 mL) were stirred at a specified temperature. b Determined by HPLC analysis on a chiral stationary phase. 3aa: the first letter “a” originates from structure 1a, and the second letter “a” originates from structure 2a.

ature, however, led to decreases in both yield and ee with partial recovery of the starting material (entries 2 and 3). Elevated temperature (45 °C) shortened the reaction time, but there was no significant change in the yield and ee of 3aa. Reaction in trifluoroethanol, a strong H-bonding protic solvent, gave comparable yield and ee of 3aa to those of the reaction in water (entry 5). With the optimal conditions determined, we next explored the scope of amines for this regio- and stereoselective ringopening reaction of spiroaziridine oxindole 1a. Electronwithdrawing and electron-donating functionalities as well as aromatic and aliphatic amines were well-tolerated and provided vicinal diamino compounds in good yields with high ee’s (Table 2). We observed that a strong H-bond donor such as fluorine at the ortho- or para-position of the aniline increased the enantioselectivity and yield of the desired product (Table 2, entries 2, 4, and 6). The formation of strong H-bonds involving the substrate, nucleophile, and water molecules may help position the nucleophile and substrate in such a way that favors attack from the easily accessible side. On the other hand, electrondonating substituents such as −OMe diminished the yield and selectivity of the reaction (Table 2, entries 7, 8, and 9). Bulky groups such as bromo at the ortho-position decreased the yield of the reaction (entry 10). Moreover, the reaction took a longer time to complete, and the product was only isolated in 87% ee. Using N-methylaniline as the nucleophile decreased the yield and ee of the desired product; however, the reaction time was much shorter (Table 2, entry 11). Surprisingly, fluorine substitution at the meta-position of the aniline dramatically reduced the ee and yield of the desired product, but the reasons for this are unclear (Table 2, entries 3 and 5). The reaction of methylamine with spiroaziridine afforded the amination

■

RESULTS AND DISCUSSION We began our study by examining the reaction of spiroaziridine oxindole 1a and aniline 2a. Compound 1a was prepared by oxidizing the sulfinyl aziridine 4a with m-CPBA in CH2Cl2 (Scheme 2). We started with 99% enantiopure sulfinyl aziridine 4; however, after conversion to 1, we were unable to measure Scheme 2. Synthesis of Spiroaziridine Oxindoles 1 from Sulfinyl Aziridines 4

3634

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry Table 2. Reaction of N-Methyl Aziridine 1a with Aromatic and Aliphatic Aminesa

entry

Ar/RNHR1

product

time (h)

yield (%)

eeb (%)

1 2 3 4 5 6 7 8 9 10 11 12c,d 13 14d

C6H5NH2 2-F-C6H4NH2 3-F-C6H4NH2 4-F-C6H4NH2 3,4-F2C6H3NH2 3-Cl-4-F-C6H3NH2 2-MeOC6H4NH2 4-MeOC6H4NH2 3,5-(MeO)2C6H3NH2 2-Br-C6H4NH2 C6H5NHMe 2-NO2C6H4NH2 MeNH2 n-C6H13NH2

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai 3aj 3ak ent-3al 3aa′ ent-3ab′

2 4 4.5 2 6 12 1 1 1 48 1.5 48 10 4

87 94 86 94 81 94 83 81 88 91 88 27 82 74

96 99 91 99 85 99 90 91 94 87 92 75 87 95

a N-Methyl spiroaziridine oxindole 1a (0.34 mmol), amine (0.68 mmol), and water (3 mL) were stirred at 25 °C. bDetermined by HPLC analysis on a chiral stationary phase. c40% conversion based on 1H NMR analysis of the crude reaction mixture. dThe reaction was carried out with (S)spiroaziridine ent-1a. The 1st set of letters of 3aa−3al originates from structures 1a and the 2nd set from structures 2a−l.

Figure 2. Exploration of the substrate scope with substituted spiroaziridines and a number of aromatic as well as aliphatic amines. The 1st set of letters of 3bb−3gk originates from structures 1b−g and the 2nd set from structures 2b−k. ent-3bb was produced from the ring-opening reaction of (S)-spiroaziridine ent-1b.

3635

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry Table 3. Exploration of the Scope of the Reaction with Spiroaziridines and Various Thiolsa

entry c

1 2 3 4c 5c 6

R

1

ArSH 6

product

time (h)

yield (%)

eeb (%)

H H H 5-F 5-F 5-Cl

ent-1a 1a 1a ent-1b ent-1b 1f

C6H5SH 4-MeOC6H4SH 2-mercaptopyridine C6H5SH 4-MeOC6H4SH 4-MeOC6H4SH

ent-5aa 5ab 5ac ent-5ba ent-5bb 5fb

1 0.5 2 3 1 0.8

92 81 97 95 94 82

93 93 94 95 96 92

Reaction conditions: 1a (0.34 mmol), PhSH (0.68 mmol), and water (3 mL) were stirred at 25 °C. bDetermined by HPLC analysis on a chiral stationary phase. cThe reaction was carried out with (S)-spiroaziridine ent-1.

a

Scheme 3. Reaction of N-Methyl Aziridine ent-1a with Methanol

product in good yield (82%) with good enantioselectivity (87%) (Table 2, entry 13). The longer chain length of nhexylamine, however, resulted in faster reaction rate (Table 2, entry 14) and higher ee of the diamine product 3ab′ compared to 3aa′. This may be attributed to the lipophilic character of nhexylamine and established the water-mediated chemistry.18 We also intended to examine the reaction with aryl amines substituted with an electron-withdrawing group like nitro. And as expected, the reaction with ortho-nitroaniline (entry 12) was too slow and only produce 27% (incomplete conversion up to 48 h) of the expected product 3al with 75% ee. Spiroaziridines substituted with both electron-donating and withdrawing groups smoothly underwent reactions with various amines to afford the corresponding functionalized vicinal diamino compounds with excellent optical purities (Figure 2). For example, 2-F, 4-F, and 3-Cl,4-F anilines and para-anisidine underwent reaction with 5-F aziridine to give the desired products ent-3bb, 3bd, 3bf, and 3bh, respectively, in greater than 90% ee. The reaction of substituted anilines with Nmethylaziridines containing electron-donating 5-OMe or 5-Me groups also produced the corresponding vicinal diamino compounds 3ca, 3cg, and 3db in excellent yields and ee’s (>90%). However, changing the protecting group on the spiroaziridine from N-methyl to N-benzyl resulted in a small erosion of ee in the desired products (3ga and 3gk). As initially demonstrated, we have extended our work to the opening of spiroaziridine 1 with various other heteronucleophiles such as thiols and methanol to directly access the core structures of various other natural and bioactive molecular motifs. With the previously optimized reaction condition, Nmethyl protected spiroaziridines 1 reacted rapidly with various thiol compounds 6 to afford the corresponding β-aminosulfides 5 (Table 3) in excellent yield (up to 97%) and enantioselectivity (up to ee = 96%). On the other hand, the reaction with MeOH was very sluggish, which may be associated with the weak nucleophilicity of MeOH, and we isolated the 3-methoxy oxindole product ent7aa in 79% yield and 85% ee from ent-1a (Scheme 3). The reactivity of methanol restricted us from further exploration of its nucleophilic chemistry toward the opening of spiroaziridines. The regioselectivity of the spiroaziridine ring opening by heteronucleophiles at the C3-spirocenter is in line with our previous report on catalyst-free and water-mediated spiroaziridine ring opening by indoles.14 It was confirmed by 1H NMR analysis of the products, in particular, for the compounds 5 and

7. In these compounds, the protons attached to the carbon in CH2NHSO2But appeared as two doublet-of-doublets (dd) due to the coupling with NH. On D2O-exchange experiment, the corresponding peak (dd) of NH disappeared while two doublet-of-doublets (dd) transformed to two doublets (d). In principle, these types of coupling patterns are unusual if the nucleophilic attack on the spiroaziridine occurs from the less hindered terminal site. Similarly, in line with our previous report,14 this ring opening chemistry of spiroaziridines 1 with heteronucleophiles is also assumed to be a retention in configuration at the C3stereocenter. Thus, the absolute stereochemistry of the C3center of products 3, 5, and 7 is assigned as (R)-configuration derived from (R)-spiroaziridine oxindoles 1. Ring-opening chemistry of 2-substituted aziridines in particular of 2-arylaziridines has extensively been studied.19,20 Lewis acid catalyzed opening of this aziridine generally occurs through the benzylic center via an SN2 mechanism with inversion of configuration at the stereocenter.15,19,20 However, the chemistry of spiroaziridineoxindole was unexplored until recently.14 On the basis of Marcus’ report18 and our own work,14 we proposed that the formation of H-bonds between water and spiroaziridine 1 along with heteronucleophile could activate the spiroaziridine toward the ring-opening reaction at the C3-center, but with retention in configuration (Scheme 4). The activation through hydrogen-bonding might generate a partial carbenium ion species 1′ which is stabilized by the benzylic nature and destabilized by the oxindole-carbonyl. Thus, similar to Lewis acid mediated ring opening of 2substituted aziridines, the spiroaziridines might opened up via path A involving a direct SN2 mechanism (intermediate A; Scheme 4). But this SN2 pathway is expected to afford an inversion in configuration,15,19,20 which is in contrary to our result of retention in configuration. Moreover, this pathway might also be unfavorable due to the excess steric crowding at 3636

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry Scheme 4. Proposed Mechanism for Water-Mediated Ring Opening of Spiroaziridine Oxindole 1 by Heteronucleophiles with Retention in Configuration at the Spirocenter

Scheme 5. Effect of N1-Protection in Ring-Opening Reaction of Spiroaziridine 1

substrates (1i and 1j) took 8 h. However, high enantioselectivity was maintained irrespective of the protecting groups. On the contrary, reaction with N-benzyl substrate 1g (R2 = Bn) was found to be very slow. It took 24 h and resulted in lower enantioselectivity (ee = 86%). As the molecular modeling suggests (not shown), this might be due to the steric effect imparted by the phenyl unit at the spirocenter. Hence, longer reaction time and steric hindrance compel the spiroaziridine 1g to adopt an alternate mechanism such as indol-2-one intermediate B, which led to the lower enantioselectivity. Moreover, the enantiomeric leakage for the ring-opening reactions in a few substrates might also be attributed due to the partial reaction via indol-2-one intermediate B and subsequent nucleophilic attack from both sides. To demonstrate the general applicability and the robustness of the method, the ring-opening reaction of spiroaziridine 1a and aniline was performed in 3 mmol (near gram-scale) under optimized conditions. It was found that the product 3aa could be isolated in 91% yield, higher than the small scale reaction and without any loss of enantioselectivity (ee = 95%; Scheme 6). We also sought to use the vicinal diamino compound 3aa to deliver medicinally relevant and structurally diverse imidazolidine-spiroxindoles.23 Deprotection of the sulfonyl auxiliary group of compound 3aa was carried out with TFA and anisole in CH2Cl2 at room temperature to give free vicinal diamine 8. Crude 8 was treated with either CS2 or 1,1′-carbonyldiimidazole (CDI) to give the spirocyclic compounds 9 and 10, respectively, in good yield (Scheme 6).

the spiro-stereocenter. The partial carbenium character can alternatively be dispersed by pathway B through the formation of indol-2-one intermediate B.21 However, if the reaction goes through the intermediate B, it will definitely produce racemic ring-opening products. The attack of the nucleophile occurs from either side of the planar sp2-hybridized benzylic center of the intermediate B. Hence, the ring opening of spiroaziridine with heteronucleophiles might involve the anchimeric assistance of tethered N− or O− of the oxindole unit via the formation of an α-lactum-type aziridinone intermediate C or an oxireno indole intermediate D, respectively.22 This double SN2 mechansim (SN2′-type) led to the retention in configuration at the stereocenter of the product and strongly suggests the formation of either intermediate C or D (pathway C or D). The effect of substitution (R2) at N1 on the reaction rate also supports the notion of anchimeric assistance (double SN2). Spiroaziridine 1h without N-protection (R2 = H) underwent facile reaction within 1 h (Scheme 5). It may be, in part, due to the ease of availability of a nitrogen lone pair, which facilitated the formation of intermediate C and D through deprotonation. In comparison, the N-methyl substrate 1a took 2 h, whereas an electron-withdrawing group such as −Boc and −Ts containing

■

CONCLUSION In conclusion, we have developed an efficient water-mediated and catalyst-free strategy for the regio- and enantioselective ring opening of spiroaziridine oxindoles by amine nucleophiles. In addition, ring opening with other heteronucleophiles such as thiols and methanol to enantioselectively produce β-aminosulfides and 3-methoxy oxindole products, respectively, is also reported. In contrast to the spiroepoxides, water mediated catalyst-free reaction of spiroaziridines with heteronucleophiles are opened regio- and stereospecifically through the pseudobenzylic spirocenter. Moreover, unlike simple 2-substituted aziridine, the ring-opening reaction of spiroaziridine proceeds with retention in configuration at the C3-stereocenter, based on which a plausible double SN2 mechanism (SN2′) is proposed. Due to the importance of spirooxindole scaffolds in the fields of both synthetic and medicinal chemistry, we envision that this work will furnish a simple, cost-effective strategy to produce a broad spectrum of functionalized enantiopure spirooxindole compounds. Our efforts toward the synthesis of various other 3637

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry Scheme 6. Synthesis of Spirooxindoles 9 and 10 from Vicinal Diamino Compound 3aa

of pure 1i, which was used for ring-opening reactions without further purification. 1H NMR (400 MHz, CDCl3) δ 7.97 (dt, J = 8.3, 0.9 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.39 (ddd, J = 8.2, 7.5, 1.4 Hz, 1H), 7.19 (td, J = 7.7, 1.1 Hz, 1H), 3.33 (s, 1H), 3.19 (s, 1H), 1.64 (s, 8H), 1.52 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 141.3, 130.3, 124.6, 124.3, 115.6, 85.0, 61.9, 46.5, 42.4, 28.1, 24.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H25N2O5S+ 381.1479; found 381.1469. (S)-1-(tert-Butylsulfonyl)-1′-tosylspiro[aziridine-2,3′-indolin]-2′one (ent-1j). To a solution of spiroaziridine ent-4h (0.20 g, 0.76 mmol) in THF (8 mL), Et3N (0.16 mL, 1.14 mmol), 4-DMAP (0.02 g, 0.15 mmol), and TsCl (0.22 g, 1.14 mmol) were successively added at −10 °C. The reaction mixture was brought to rt and stirred. Reaction was monitored with TLC, and after completion of the reaction (16 h), THF was evaporated. Silica-gel flash column chromatographic (hexanes/EtOAc 90:10) purification gave a gummy liquid ent-4j (0.29 g, 92%; dr > 99:1). To a stirred solution of ent-4j (0.274 g, 0.65 mmol) in CH2Cl2 at −78 °C, m-CPBA (55%, 0.307 g, 0.98 mmol) was added portion wise. The solution was stirred for 0.5 h at this temperature. The reaction mixture was then transferred to 0 °C and stirred for 3 h. After completion, Na2S2O5 (15 mL) was added, followed by NaHCO3 (15 mL), and stirred for another 10 min. The reaction mixture was then extracted with Et2O (3× 20 mL). The combined organic phase was dried over Na2SO4, filtered, and evaporated in vacuo to yield 0.264 g (93% yield) of pure ent-1j, which was used for ring-opening reactions without further purification. 1H NMR (400 MHz, CDCl3) δ 8.00−7.98 (m, 3H), 7.53 (d, J = 7.9 Hz, 1H), 7.42 (ddd, J = 8.5, 7.6, 1.4 Hz, 1H), 7.35−7.34 (m, 1H), 7.33 (d, J = 8.1 Hz, 2H), 3.25 (s, 1H), 3.12 (s, 1H), 2.43 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 168.4, 146.0, 140.6, 134.8, 130.7, 129.9, 128.1, 124.9, 114.1, 61.9, 46.3, 42.3, 23.9, 21.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H22N2NaO5S2+ 457.0862; found 457.0859. General Procedure for the Synthesis of Vicinal Diamino Oxindoles from Spiroaziridine Oxindoles. All the reactions were done in a 0.1 g scale. To show the versatility of the methodology, we have carried out the reaction with both (R)- and (S)-spiroaziridine oxindoles derived from (R)- and (S)-ketemines. Unless otherwise described, the reactions were carried out with (R)-spiroaziridine. The substrates, spiroaziridine and amine (1:2), and degassed Milli-Q H2O (3 mL) were added to a 10 mL round-bottom flask with a magnetic stirring bar. After stirring at 25 °C for a specific time, as mentioned in Table 2 and Figure 2 of the main text (monitored by TLC for complete consumption of the substrate aziridine), the mixture was extracted with EtOAc, dried over Na2SO4, filtered, and purified by flash column chromatography (SiO2, EtOAc Hexanes) to afford the product. Synthesis of (R)-Vicinal Diamino Oxindoles 3aa from 1a. Under an argon atmosphere, 1a (0.9 g, 3.04 mmol) and 2a (0.7 mL, 7.61 mmol) were taken. 30 mL of degassed Milli-Q H2O was added to it and stirred at 25 °C for 2 h. After completion, the reaction mixture was

functionalized spirooxindoles by spiroaziridine ring opening will be reported soon.

■

EXPERIMENTAL SECTION

General Information. All the reactions were carried out using oven-dried glassware under an atmosphere of argon (Ar). The sulfinyl spiroaziridines were prepared following the literature procedure.12,14 Commercially available reagents were used without further purification. We have used Milli-Q H2O obtained from a QGARD00R1, QGard 1 purification cartridge. The pH and the resistivity were 6.9 and 18.2 MΩ·cm, respectively, at 25 °C. Solvents were dried and distilled following a standard procedure. Flash column chromatography was performed in all the cases using silica gel (230−400 mesh). Analytical TLC was performed on aluminum-backed plates coated with silica gel 60 with an F254 indicator, and compounds were visualized by irradiation of UV light. The 1H NMR spectra were recorded with 400 MHz/600 MHz/800 MHz and 13C NMR spectra recorded with 100 MHz/150 MHz/200 MHz using CDCl3 or DMSO-d6. 1H NMR chemical shifts are expressed in ppm(δ) relative to δ = 7.26 for CDCl3 and δ = 2.50 for DMSO-d6. 13C NMR chemical shift is expressed in ppm(δ) relative to CDCl3 and DMSO-d6 resonance at δ = 77.00 and δ = 39.52, respectively. Electron spray ionization (ESI) mass spectrometry (MS) experiment was performed on an Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS. Enantiomeric excess (ee) was measured by chiral HPLC analysis. Synthesis of Spiroaziridines 1. Compounds 1a−h were prepared from spiroaziridines 4, which were synthesized from (R)-isatine derived N-tert-butanesulfinyl ketimines as discussed previously.12,14 Similarly, enantiomeric spiroaziridines ent-1 were synthesized from (S)-isatine derived N-tert-butanesulfinyl ketimines. Spiroaziridines 1i and ent-1j were synthesized from the compounds 4h and ent-4h, respectively. Ring-opening reactions are mostly carried out with (R)spiroaziridines 1, unless otherwise noted. (R)-tert-Butyl 1-(tert-Butylsulfonyl)-2′-oxospiro[aziridine-2,3′-indoline]-1′-carboxylate (1i). To a solution of spiroaziridine 4h (0.20 g, 0.76 mmol), prepared by an earlier report,12,14 in THF (8 mL) were added Boc2O (0.33 g, 1.5 mmol) and a catalytic amount of 4-DMAP (0.01 g, 0.076 mmol) at −10 °C. The mixture was stirred and slowly raised to rt. After completion of the reaction (16 h), THF was evaporated and the residue was crystallized with EtOAc-hexanes and afforded a brownish solid compound 4i (0.26 g, 94%; dr > 99:1). To a stirred solution of 4i (0.206 g, 0.56 mmol) in CH2Cl2 at −78 °C, m-CPBA (55%, 0.27 g, 0.85 mmol) was added portion wise. The solution was stirred for 0.5 h at this temperature. The reaction mixture was then transferred to 0 °C and stirred for 3 h. After completion, Na2S2O5 (15 mL) was added, followed by NaHCO3 (15 mL), and stirred for another 10 min. The reaction mixture was then extracted with Et2O (3× 20 mL). The combined organic phase was dried over Na2SO4, filtered, and evaporated in vacuo to yield 0.202 g (94% yield) 3638

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry extracted with EtOAc (3 × 50 mL). The combined organic phase was dried over Na2SO4, filtered, and evaporated in vacuo. Flash column chromatography (SiO2, Hexanes/EtOAc 60:40) was done to afford the product 3aa (91% yield, 1.08 g). Characterization Data for Compounds. (R)-2-Methyl-N-((1methyl-2-oxo-3-(phenylamino)indolin-3-yl)methyl)propane-2-sulfonamide (3aa). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure. The reaction was carried out at 25 °C and took 2 h to complete. The product was obtained as a white solid (1.07 g; 91% yield); mp 186−187 °C; 1H NMR (600 MHz, CDCl3) δ 7.40 (dd, J = 7.7, 1.2 Hz, 1H), 7.37 (dd, J = 8.1, 4.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.01−6.94 (m, 3H), 6.65 (t, J = 7.3 Hz, 1H), 6.20 (dd, J = 7.7, 0.9 Hz, 2H), 5.20 (s, 1H), 5.08 (d, J = 8.1 Hz, 1H), 3.68−3.62 (m, 1H), 3.34−3.26 (m, 1H), 3.26 (s, 3H), 1.41 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 177.1, 144.9, 142.7, 130.0, 129.1, 127.9, 124.3, 123.8, 119.2, 114.7, 109.1, 63.0, 60.4, 51.5, 26.7, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H26N3O3S 388.1695; found 388.1689. HPLC analysis: ee = 95%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 70/30 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 7.13 min, minor enantiomer tR = 8.51 min. (R)-N-((3-((2-Fluorophenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3ab). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.129 g; 94% yield); mp 201−203 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (td, J = 7.8, 1.2 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.97−6.91 (m, 1H), 6.60 (pd, J = 7.6, 3.8 Hz, 2H), 5.73− 5.65 (m, 1H), 5.50 (d, J = 3.6 Hz, 1H), 4.98 (dd, J = 9.0, 3.1 Hz, 1H), 3.68 (dd, J = 13.6, 9.1 Hz, 1H), 3.35 (dd, J = 13.6, 3.2 Hz, 1H), 3.30 (s, 3H), 1.44 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.73, 152.4 (d, J = 239 Hz) 142.7, 133.6 (d, J = 10 Hz), 130.3, 127.60, 124.3, 124.3 (d, J = 3 Hz), 123.9, 118.9 (d, J = 6 Hz), 114.9 (d, J = 20 Hz), 113.6 (d, J = 2 Hz), 109.2, 62.7, 60.5, 51.4, 26.7, 24.5. HRMS (ESITOF) m/z: [M + Na]+ Calcd for C20H24FN3NaO3S 428.1420; found 428.1421. HPLC analysis: ee = 99%; 25 cm Chiralpak IB-3 column, nhexane/i-PrOH = 90/10 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 16.10 min, minor enantiomer tR = 19.61 min. (R)-N-((3-((3-Fluorophenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3ac). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.118 g; 86% yield); mp 162−164 °C; 1H NMR (600 MHz, CDCl3) δ 7.41 (td, J = 7.8, 1.0 Hz, 1H), 7.37−7.33 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.91 (dd, J = 14.9, 8.2 Hz, 1H), 6.32 (td, J = 8.3, 1.9 Hz, 1H), 6.04 (dd, J = 8.2, 1.8 Hz, 1H), 5.78 (dt, J = 11.5, 2.2 Hz, 1H), 5.45 (s, 1H), 5.09 (dd, J = 8.4, 3.4 Hz, 1H), 3.62 (dd, J = 13.9, 8.6 Hz, 1H), 3.31−3.29 (m, 1H), 3.30 (s, 3H) 1.40 (s, 9H).13C {H} NMR (150 MHz, CDCl3) δ 176.7, 163.7 (d, J = 242 Hz), 146.8 (d, J = 10 Hz), 142.6, 130.3 (d, J = 9 Hz), 130.3, 127.4, 124.2, 123.9, 110.4 (d, J = 3 Hz), 109.3, 105.4 (d, J = 21 Hz), 101.1 (d, J = 25 Hz), 62.9, 60.5, 51.5, 26.7, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H25FN3O3S 406.1601; found 406.1589. HPLC analysis: ee = 91%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 8.46 min, minor enantiomer tR = 10.52 min. (R)-N-((3-((4-Fluorophenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3ad). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.129 g; 94% yield); mp 200−201 °C; 1H NMR (600 MHz, CDCl3) δ 7.41 (td, J = 7.8, 1.1 Hz, 1H), 7.38−7.33 (m, 1H), 7.12 (dd, J = 11.0, 4.0 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.91 (dd, J = 14.9, 8.2 Hz, 1H), 6.32 (td, J = 8.3, 1.9 Hz, 1H), 6.04 (dd, J = 8.2, 1.7 Hz, 1H), 5.78 (dt, J = 11.5, 2.2 Hz, 1H), 5.45 (s, 1H), 5.09 (dd, J = 8.4, 3.4 Hz, 1H), 3.62 (dd, J = 13.9, 8.6 Hz, 1H), 3.31−3.29 (m, 1H), 3.30 (s, 3H), 1.40 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.9, 156.8 (d, J = 236 Hz), 142.72, 141.0, 130.0, 127.5, 124.3, 123.7, 116.8 (d, J = 8 Hz), 115.5 (d, J = 22 Hz), 109.0, 63.5, 60.3, 51.3, 26.5, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H25FN3O3S 406.1601; found 406.1610. HPLC analysis:

ee = 99%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 8.78 min, minor enantiomer tR = 11.67 min. (R)-N-((3-((3,4-Difluorophenyl)amino)-1-methyl-2-oxoindolin-3yl)methyl)-2-methylpropane-2-sulfonamide (3ae). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.116 g; 81% yield); mp 180−182 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.82−6.70 (m, 1H), 6.00−5.87 (m, 2H), 5.31 (s, 1H), 5.09 (s, 1H), 3.61 (dd, J = 13.9, 8.6 Hz, 1H), 3.32−3.28 (m, 1H), 3.29 (s, 3H), 1.39 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.6, 150.5 (dd, J = 243 Hz, 13 Hz), 144.2 (dd, J = 238 Hz, 13 Hz), 142.6, 141.9 (dd, J = 9 Hz, 2 Hz), 130.3, 127.2, 124.2, 123.9, 117.4 (d, J = 18 Hz), 110.4 (dd, J = 9 Hz, 3 Hz), 109.3, 103.7 (d, J = 21 Hz), 63.4, 60.5, 51.5, 26.7, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H24F2N3O3S 424.1506; found 424.1510. HPLC analysis: ee = 85%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 9.40 min, minor enantiomer tR = 13.14 min. (R)-N-((3-((3-Chloro-4-fluorophenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3af). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.140 g; 94% yield); mp 178−180 °C; 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 12.0, 4.2 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.69 (t, J = 8.8 Hz, 1H), 6.19 (dd, J = 6.1, 2.9 Hz, 1H), 5.98 (dt, J = 8.9, 3.3 Hz, 1H), 5.23 (s, 1H), 4.99 (dd, J = 8.5, 3.4 Hz, 1H), 3.58 (dd, J = 13.9, 8.6 Hz, 1H), 3.29−3.24 (m, 1H), 3.25 (s, 3H) 1.37 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.6, 152.1 (d, J = 239 Hz), 142.7, 141.9 (d, J = 3 Hz), 130.4, 127.2, 124.3, 124.0, 120.9 (d, J = 18 Hz), 116.7 (d, J = 21 Hz), 116.7, 114.3 (d, J = 8 Hz), 109.3, 63.3, 60.5, 51.4, 26.7, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H24ClFN3O3S 440.1211; found 440.1195. HPLC analysis: ee = 99%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 8.92 min, minor enantiomer tR = 11.99 min. (R)-N-((3-((2-Methoxyphenyl)amino)-1-methyl-2-oxoindolin-3yl)methyl)-2-methylpropane-2-sulfonamide (3ag). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.117 g; 83% yield); mp 163−165 °C; 1H NMR (400 MHz, CDCl3) δ 7.40 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.78−6.71 (m, 1H), 6.62 (td, J = 7.8, 1.1 Hz, 1H), 6.46 (td, J = 7.7, 1.0 Hz, 1H), 5.73 (s, 1H), 5.62 (dd, J = 7.9, 1.2 Hz, 1H), 5.04 (dd, J = 9.4, 1.9 Hz, 1H), 3.89 (s, 3H), 3.72 (dd, J = 13.1, 9.6 Hz, 1H), 3.33−3.28 (m, 1H), 3.28 (s, 3H), 1.45 (s, 9H).13C {H} NMR (150 MHz, CDCl3) δ 177.2, 148.0, 142.7, 135.1, 130.1, 128.2, 124.2, 123.8, 121.0, 118.8, 111.6, 110.2, 109.1, 62.6, 60.5, 55.8, 51.4, 26.6, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H28N3O4S 418.1801; found 418.1800. HPLC analysis: ee = 90%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 11.45 min, minor enantiomer tR = 14.13 min. (R)-N-((3-((4-Methoxyphenyl)amino)-1-methyl-2-oxoindolin-3yl)methyl)-2-methylpropane-2-sulfonamide (3ah). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.114 g; 81% yield); mp 187−189 °C; 1H NMR (400 MHz, CDCl3) δ 7.44−7.39 (m, 1H), 7.37 (dd, J = 7.8, 0.7 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 8.9 Hz, 2H), 6.27 (d, J = 8.9 Hz, 2H), 5.08 (d, J = 6.9 Hz, 1H), 4.77 (s, 1H), 3.69−3.63 (m, 4H), 3.31 (dd, J = 13.4, 2.8 Hz, 1H), 3.22 (s, 3H), 1.40 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 177.4, 154.0, 143.0, 138.4, 130.0, 128.0, 124.6, 123.7, 118.5, 114.5, 109.0, 64.1, 60.4, 55.6, 51.2, 26.5, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H28N3O4S 418.1801; found 418.1799. HPLC analysis: ee = 91%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/30 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 11.77 min, minor enantiomer tR = 15.39 min. 3639

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry

3H), 1.34 (s, 9H). 13C {H} NMR (150 MHz, CDCl3): δ 178.0, 143.7, 129.7, 126.7, 124.8, 123.2, 108.5, 65.9, 60.1, 50.2, 30.4, 26.1, 24.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H24N3O3S 326.1538; found 326.1547. HPLC analysis: ee = 87%; 25 cm. Chiralpak OD-H column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 8.35 min, minor enantiomer tR = 7.11 min. (S)-2-Methyl-N-((1-methyl-2-oxo-3-(propylamino)indolin-3-yl)methyl)propane-2-sulfonamide (ent-3ab′). The product was prepared from (S)-spiroaziridine ent-1a by following the general procedure and was obtained as a brownish gummy liquid (0.099 g; 74% yield). 1H NMR (600 MHz, CDCl3) δ 7.42 (dd, J = 7.4, 1.2 Hz, 1H), 7.34 (td, J = 7.8, 1.2 Hz, 1H), 7.13 (dd, J = 8.1, 7.1 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 4.87−4.82 (m, 1H), 3.45 (dd, J = 12.7, 9.3 Hz, 1H), 3.30 (dd, J = 12.6, 2.1 Hz, 1H), 3.21 (m, 3H), 2.21 (ddd, J = 10.7, 7.8, 6.1 Hz, 1H), 2.07 (ddd, J = 10.8, 8.1, 6.4 Hz, 1H), 1.27−1.15 (m, 8H), 0.85−0.81 (m, 3H). 13C {H} NMR (150 MHz, CDCl3) δ 178.4, 143.6, 129.7, 127.4, 124.9, 123.3, 108.6, 65.5, 60.2, 50.6, 44.0, 31.7, 30.3, 26.8, 26.3, 24.4, 22.6, 14.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H34N3O3S 396.2321; found 396.2331. HPLC analysis: ee = 95%; 25 cm Chiralpak IA-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 7.637 min, minor enantiomer tR = 5.85 min. (S)-N-((5-Fluoro-3-((2-fluorophenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (ent-3bb). The product was prepared from (S)-spiroaziridine ent-1b by following the general procedure and was obtained as a white solid (0.119 g; 88% yield); mp 223−226 °C; 1H NMR (400 MHz, CDCl3) δ 7.14 (dd, J = 10.9, 8.0 Hz, 2H), 6.95 (dd, J = 13.9, 5.8 Hz, 2H), 6.65 (d, J = 4.4 Hz, 2H), 5.71 (d, J = 7.2 Hz, 1H), 5.52 (s, 1H), 5.05 (d, J = 7.5 Hz, 1H), 3.70 (dd, J = 13.5, 9.3 Hz, 1H), 3.42−3.34 (m, 1H), 3.32 (s, 3H), 1.46 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 176.3, 159.8 (d, J = 242 Hz), 152.22 (d, J = 24 Hz), 138.4 (d, J = 2.2 Hz), 133.1 (d, J = 12 Hz), 129.3 (d, J = 8 Hz), 124.2 (d, J = 4 Hz), 119.06, 118.99 (d, J = 7 Hz), 116.5 (d, J = 24 Hz), 114.9 (d, J = 18 Hz), 113.17, 112.4 (d, J = 24 Hz), 109.7 (d, J = 8 Hz), 62.88, 60.47, 51.18, 26.79, 24.37. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H24F2N3O3S 424.1506; found 424.1504. HPLC analysis: ee = 91%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 9.72 min, minor enantiomer tR = 8.66 min. (R)-N-((5-Fluoro-3-((4-fluorophenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3bd). The product was prepared from (R)-spiroaziridine oxindole 1b by following the general procedure and was obtained as a white solid (0.116 g; 86% yield); mp 196−198 °C ; 1H NMR (600 MHz, CDCl3) δ 7.14 (dd, J = 7.3, 2.6 Hz, 1H), 7.09 (td, J = 8.7, 2.7 Hz, 1H), 6.87 (dd, J = 8.5, 3.9 Hz, 1H), 6.69 (t, J = 8.7 Hz, 2H), 6.24−6.14 (m, 2H), 5.13 (dd, J = 8.9, 3.3 Hz, 1H), 5.08 (s, 1H), 3.63 (dd, J = 13.7, 8.9 Hz, 1H), 3.30 (dd, J = 13.8, 3.3 Hz, 1H), 3.25 (s, 3H), 1.40 (s, 9H).13C {H} NMR (150 MHz, CDCl3) δ 176.81, 159.9(d, J = 243 Hz), 157.1 (d, J = 237 Hz), 140.9 (d, J = 3 Hz), 138.7 (d, J = 2 Hz), 129.6 (d, J = 7.5 Hz), 116.8 (d, J = 7.5 Hz), 116.6, 116.4 (d, J = 24 Hz), 115.8, 115.6 (d, J = 23 Hz), 112.7, 112.6 (d, J = 25 Hz), 109.8, 109.8 (d, J = 9 Hz), 64.0, 60.5, 51.3, 26.8, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H24F2N3O3S 424.1506; found 424.1505. HPLC analysis: ee = 91%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 9.45 min, minor enantiomer tR = 12.01 min. (R)-N-((3-((3-Chloro-4-fluorophenyl)amino)-5-fluoro-1-methyl-2oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3bf). The product was prepared from (R)-spiroaziridine oxindole 1b by following the general procedure and was obtained as a white solid (0.137 g; 94% yield); mp 209−210 °C; 1H NMR (400 MHz, CDCl3) δ 7.17−7.08 (m, 2H), 6.92 (dd, J = 9.2, 4.0 Hz, 1H), 6.75 (t, J = 8.8 Hz, 1H), 6.21 (dd, J = 6.1, 3.0 Hz, 1H), 6.02 (dt, J = 8.9, 3.4 Hz, 1H), 5.32 (s, 1H), 5.13 (dd, J = 8.7, 3.5 Hz, 1H), 3.61 (dd, J = 14.0, 8.8 Hz, 1H), 3.32−3.27 (m, 1H), 3.28 (s,3H), 1.40 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.34, 159.9 (d, J = 243 Hz), 152.1 (d, J = 239 Hz), 141.7 (d, J = 3 Hz), 138.56, 129.1 (d, J = 7.5 Hz), 121.0 (d, J = 18 Hz), 116.8 (d, J = 23 Hz), 116.7 (d, J = 23 Hz), 116.4, 114.0 (d, J = 4.5 Hz), 112.6 (d, J = 25 Hz), 110.0, (d, J = 7.5 Hz), 63.7, 60.5, 51.3,

(R)-N-((3-((3,5-Dimethoxyphenyl)amino)-1-methyl-2-oxoindolin3-yl)methyl)-2-methylpropane-2-sulfonamide (3ai). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.133 g; 88% yield); mp 161−163 °C; 1H NMR (400 MHz, CDCl3) δ 7.39 (ddd, J = 9.5, 7.6, 1.6 Hz, 2H), 7.13 (td, J = 7.5, 0.9 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 5.80 (t, J = 2.1 Hz, 1H), 5.38 (d, J = 2.1 Hz, 2H), 5.24 (s, 1H), 5.08 (dd, J = 8.7, 3.3 Hz, 1H), 3.64 (dd, J = 13.7, 8.7 Hz, 1H), 3.54 (s, 6H), 3.30 (s, 4H), 1.40 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.9, 161.3, 146.7, 142.5, 130.0, 127.9, 124.1, 123.8, 108.9, 92.9, 92.1, 62.7, 60.3, 54.9, 51.3, 26.5, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H30N3O5S 448.1906; found 448.1906. HPLC analysis: ee = 94%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 10.76 min, minor enantiomer tR = 16.17 min. (R)-N-((3-((2-Bromophenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3aj). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.143 g; 91% yield); mp 182−183 °C; 1H NMR (600 MHz, CDCl3) δ 7.44 (t, J = 7.9 Hz, 2H), 7.37 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 7.7 Hz, 1H), 6.59−6.52 (m, 1H), 5.75 (s, 1H), 5.68 (dd, J = 8.2, 1.0 Hz, 1H), 5.11 (d, J = 7.6 Hz, 1H), 3.78 (dd, J = 13.3, 9.4 Hz, 1H), 3.36−3.33 (m, 1H), 3.34 (s, 3H), 1.47 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.5, 142.6, 142.3, 132.9, 130.3, 128.2, 127.4, 124.1, 124.0, 119.7, 112.6, 111.5, 109.2, 62.8, 60.5, 51.5, 26.8, 24.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H24BrN3NaO3S 490.0599; found 490.0579. HPLC analysis: ee = 87%; 25 cm Chiralpak IA-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 10.27 min, minor enantiomer tR = 12.02 min. (R)-2-Methyl-N-((1-methyl-3-(methyl(phenyl)amino)-2-oxoindolin-3-yl)methyl)propane-2-sulfonamide (3ak). The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a gummy liquid (0.120 g; 88% yield). 1 H NMR (600 MHz, CDCl3) δ 7.37 (d, J = 7.0 Hz, 1H), 7.31 (td, J = 7.7, 1.1 Hz, 1H), 7.19 (dd, J = 10.9, 4.5 Hz, 2H), 7.17−7.13 (m, 2H), 7.11−7.06 (m, 2H), 6.78 (d, J = 7.8 Hz, 1H), 4.59 (dd, J = 7.6, 2.6 Hz, 1H), 3.68 (dd, J = 12.7, 7.9 Hz, 1H), 3.62 (dd, J = 12.7, 3.1 Hz, 1H), 3.16 (s, 3H), 2.90 (s, 3H), 1.34 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 175.9, 148.9, 143.4, 129.7, 128.7, 127.4, 127.1, 125.7, 125.4, 122.9, 108.4, 68.6, 60.4, 48.4, 38.6, 26.1, 24.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H28N3O3S 402.1851; found 402.1824. HPLC analysis: ee = 92%; 25 cm Chiralpak IC-3 column, n-hexane/i-PrOH = 65/35 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 13.09 min, minor enantiomer tR = 21.46 min. (S)-2-Methyl-N-((1-methyl-3-((2-nitrophenyl)amino)-2-oxoindolin-3-yl)methyl)propane-2-sulfonamide (ent-3al). The product was prepared from (S)-spiroaziridine ent-1a by following the general procedure and was obtained as a yellow solid (0.039 g; 27% yield); mp 194−196 °C; 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.18 (dd, J = 8.6, 1.6 Hz, 1H), 7.45 (td, J = 7.8, 1.3 Hz, 1H), 7.32−7.29 (m, 1H), 7.15 (td, J = 7.6, 1.0 Hz, 1H), 7.09 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.67 (ddd, J = 8.4, 7.1, 1.2 Hz, 1H), 5.77 (dd, J = 8.6, 1.2 Hz, 1H), 4.88 (d, J = 8.5 Hz, 1H), 3.76 (dd, J = 13.0, 9.5 Hz, 1H), 3.41 (dd, J = 13.0, 2.7 Hz, 1H), 3.37 (s, 3H), 1.48 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 175.30, 142.36, 142.19, 135.94, 133.91, 130.60, 127.09, 126.55, 124.13, 123.76, 117.36, 114.40, 109.52, 62.32, 60.64, 51.46, 26.90, 24.26. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H25N4O5S 433.1546; found 433.1539. HPLC analysis: ee = 75%; 25 cm Chiralpak IA-3 column, n-hexane/i-PrOH = 85/15 (v/ v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 18.11 min, minor enantiomer tR = 21.00 min. (R)-2-Methyl-N-((1-methyl-3-(methylamino)-2-oxoindolin-3-yl)methyl)propane-2-sulfonamide (3aa′). The product was prepared by following the general procedure and was obtained as a pale yellow gummy liquid (0.09 g; 82% yield). 1H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 7.3 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.87 (d, J = 8.4 Hz, 1H), 3.49 (dd, J = 12.7, 9.1 Hz, 1H), 3.31 (d, J = 12.7 Hz, 1H), 3.23 (s, 3H), 2.05 (s, 3640

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry 26.85, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H23ClF2N3O3S 458.1117; found 458.1116. HPLC analysis: ee = 97%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 9.03 min, minor enantiomer tR = 11.38 min. (R)-N-((5-Fluoro-3-((4-methoxyphenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3bh). The product was prepared from (R)-spiroaziridine oxindole 1b by following the general procedure and was obtained as a white solid (0.115 g; 83% yield); 192−194 °C; 1H NMR (600 MHz, CDCl3) δ 7.18 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 8.7 Hz, 1H), 6.82 (dd, J = 8.5, 3.9 Hz, 1H), 6.60−6.53 (m, 2H), 6.31−6.24 (m, 2H), 5.10 (dd, J = 14.7, 8.9 Hz, 1H), 4.75 (s, 1H), 3.68−3.62 (m, 1H), 3.65 (s, 3H) 3.31 (dt, J = 13.5, 2.5 Hz, 1H), 3.20 (s, 3H), 1.42−1.37 (m, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 177.1, 159.8 (d, J = 241 Hz), 154.1, 138.9, 138.1, 129.9 (d, J = 7.5 Hz), 118.4, 116.3 (d, J = 24), 114.6, 112.9 (d, J = 24 Hz), 109.6 (d, J = 7.5 Hz), 64.5, 60.5, 55.6, 51.1, 26.7, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H27FN3O4S 436.1706; found 436.1706. HPLC analysis: ee = 93%; 25 cm Chiralpak IB-3 column, nhexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 11.65 min, minor enantiomer tR = 15.75 min. (R)-N-((3-((3,5-Dimethoxyphenyl)amino)-5-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3bi). The product was prepared from (R)-spiroaziridine oxindole 1b by following the general procedure and was obtained as a white solid (0.123 g; 83% yield); mp 185−187 °C; 1H NMR (600 MHz, CDCl3) δ 7.13 (dd, J = 7.3, 2.6 Hz, 1H), 7.09 (td, J = 8.7, 2.7 Hz, 1H), 6.89 (dd, J = 8.5, 3.9 Hz, 1H), 5.82 (t, J = 2.1 Hz, 1H), 5.37 (d, J = 2.2 Hz, 2H), 5.26 (s, 1H), 5.14 (dd, J = 8.9, 3.3 Hz, 1H), 3.62 (dd, J = 13.8, 8.8 Hz, 1H), 3.56 (s, 6H), 3.29−3.26 (m, 1H), 3.28 (s,3H) 1.40 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.8, 161.5, 160.0 (d, J = 241.5 Hz), 146.6, 138.5, 130.0, 116.5 (d, J = 24 Hz), 112.6 (d, J = 24 Hz), 109.7 (d, J = 7.8 Hz), 93.0, 92.1, 63.2, 60.5, 55.1, 51.3, 26.8, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H29FN3O5S 466.1812; found 466.1812. HPLC analysis: ee = 95%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 14.85 min, minor enantiomer tR = 22.93 min. (R)-N-((5-Fluoro-1-methyl-3-(methylamino)-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3ba′). The product was prepared from (R)-spiroaziridine oxindole 1b by following the general procedure and was obtained as a gummy liquid (0.087 g; 80% yield). 1 H NMR (600 MHz, CDCl3) δ 7.19 (dd, J = 7.7, 2.7 Hz, 1H), 7.05 (td, J = 8.7, 2.7 Hz, 1H), 6.80 (dd, J = 8.5, 4.0 Hz, 1H), 4.90 (d, J = 9.0 Hz, 1H), 3.46 (dd, J = 12.9, 9.0 Hz, 1H), 3.30 (d, J = 12.9 Hz, 1H), 3.21 (s, 3H), 2.04 (s, 3H), 1.34 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 177.9, 159.7 (d, J = 242 Hz), 139.7, 128.7 (d, J = 9 Hz), 116.1 (d, J = 24 Hz), 113.2 (d, J = 24 Hz), 109.2 (d, J = 7.5 Hz), 66.4, 60.3, 50.3, 30.7, 26.4, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H23FN3O3S 344.1444; found 344.1441. HPLC analysis: ee = 88%; 25 cm Chiralpak IA-3 column, n-hexane/i-PrOH = 75/25 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 7.16 min, minor enantiomer tR = 8.98 min. (R)-N-((5-Methoxy-1-methyl-2-oxo-3-(phenylamino)indolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3ca). The product was prepared from (R)-spiroaziridine oxindole 1c by following the general procedure and was obtained as a white solid (0.108 g; 84% yield); mp 142−145 °C; 1H NMR (600 MHz, CDCl3) δ 7.19 (dd, J = 7.7, 2.7 Hz, 1H), 7.05 (td, J = 8.7, 2.7 Hz, 1H), 6.80 (dd, J = 8.5, 4.0 Hz, 1H), 4.90 (d, J = 9.0 Hz, 1H), 3.46 (dd, J = 12.9, 9.0 Hz, 1H), 3.30 (d, J = 12.9 Hz, 1H), 3.21 (s, 3H), 2.04 (s, 3H), 1.34 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 177.9, 159.7 (d, J = 242 Hz), 139.7, 128.7 (d, J = 9 Hz), 116.1 (d, J = 24 Hz), 113.2 (d, J = 24 Hz), 109.2 (d, J = 7.5 Hz), 66.4, 60.3, 50.3, 30.7, 26.4, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H28N3O4S 418.1801; found 418.1799. HPLC analysis: ee = 92%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 75/25 (v/ v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 8.03 min, minor enantiomer tR = 9.26 min. (R)-N-((5-Methoxy-3-((2-methoxyphenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3cg). The

product was prepared from (R)-spiroaziridine oxindole 1c by following the general procedure and was obtained as a white solid (0.114 g; 83% yield): mp 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 2.3 Hz, 1H), 6.90 (dt, J = 14.1, 5.4 Hz, 2H), 6.74 (dd, J = 8.1, 0.9 Hz, 1H), 6.63 (td, J = 7.8, 1.3 Hz, 1H), 6.47 (td, J = 7.7, 1.1 Hz, 1H), 5.72 (s, 1H), 5.64 (dd, J = 7.9, 1.3 Hz, 1H), 5.09 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.77−3.69 (m, 1H), 3.76 (s, 3H), 3.29 (d, J = 2.1 Hz, 1H), 3.26 (s, 3H), 1.45 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.9, 156.9, 147.9, 135.9, 135.2, 129.6, 121.0, 118.8, 115.1, 111.6, 110.7, 110.2, 109.7, 62.9, 60.5, 55.9, 55.8, 51.5, 26.7, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H30N3O5S 448.1906; found 448.1899. HPLC analysis: ee = 94%; 25 cm Chiralpak IB-3 column, n-hexane/iPrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 17.80 min, minor enantiomer tR = 24.31 min. (R)-N-((5-Methoxy-1-methyl-3-(methylamino)-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3ca′). The product was prepared from (R)-spiroaziridine oxindole 1c by following the general procedure and was obtained as a white solid (0.087 g; 80% yield); mp 165−167 °C; 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 6.94−6.71 (m, 2H), 4.92 (d, J = 7.9 Hz, 1H), 3.81 (s, 3H), 3.55−3.43 (m, 1H), 3.27 (d, J = 12.7 Hz, 1H), 3.20 (s, 3H), 2.04 (s, 3H), 1.35 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 177.9, 156.6, 137.1, 128.0, 115.0, 111.4, 109.2, 77.4, 77.1, 76.8, 66.36, 60.2, 56.0, 50.5, 30.7, 26.3, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H26N3O4S 356.1644; found 356.1642. HPLC analysis: ee = 90%; 25 cm Chiralpak IA-3 column, n-hexane/i-PrOH = 75/25 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 7.63 min, minor enantiomer tR = 8.50 min. (R)-N-((3-((2-Fluorophenyl)amino)-1,5-dimethyl-2-oxoindolin-3yl)methyl)-2-methylpropane-2-sulfonamide (3db). The product was prepared from (R)-spiroaziridine oxindole 1d by following the general procedure and was obtained as a white solid (0.108 g; 80% yield); mp 205−207 °C; 1H NMR (400 MHz, CDCl3) δ 7.25−7.15 (m, 2H), 7.00−6.84 (m, 2H), 6.69−6.53 (m, 2H), 5.79−5.63 (m, 1H), 5.52 (s, 1H), 5.07 (d, J = 12.0 Hz, 1H), 3.69 (q, J = 9.2 Hz, 1H), 3.41−3.20 (m, 1H), 3.30 (s, 3H) 2.33 (s, 3H), 1.44 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 176.5, 152.2 (d, J = 239 Hz), 140.2, 133.7, 133.70, 130.5, 127.5, 124.9, 124.3 (d, J = 3 Hz), 118.7 (d, J = 7.5 Hz), 114.9 (d, J = 20 Hz), 113.4, 109.0, 62.5, 60.5, 51.4, 26.7, 24.5, 21.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H27FN3O3S 420.1757; found 420.1756. HPLC analysis: ee = 91%; 25 cm Chiralpak IA-3 column, nhexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 5.88 min, minor enantiomer tR = 11.99 min. (R)-N-((7-Fluoro-3-((4-methoxyphenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3eh). The product was prepared from (R)-spiroaziridine oxindole 1e by following the general procedure and was obtained as a white solid (0.125 g; 90% yield); mp 140−141 °C; 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 6.9, 1.4 Hz, 1H), 7.18−7.02 (m, 2H), 6.63−6.56 (m, 2H), 6.34−6.28 (m, 2H), 5.10 (dd, J = 8.9, 3.0 Hz, 1H), 4.80 (s, 1H), 3.68−3.62 (m, 4H), 3.44 (d, J = 2.7 Hz, 3H), 3.35 (dd, J = 13.5, 3.1 Hz, 1H), 1.42 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 177.13, 154.01, 1489.1 (d, J = 243 Hz), 138.13, 130.9 (d, J = 2.4 Hz) 129.5 (d, J = 9 Hz), 124.3 (d, J = 6 Hz), 120.5 (d, J = 3 Hz), 118.36, 117.90 (d, J = 20 Hz), 114.58, 64.5, 60.50, 55.58, 51.28, 24.50. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H27FN3O4S 436.1706; found 436.1703. HPLC analysis: ee = 84%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 7.78 min, minor enantiomer tR = 10.68 min. (R)-N-((3-((3,4-Dimethoxyphenyl)amino)-7-fluoro-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3em). The product was prepared from (R)-spiroaziridine oxindole 1e by following the general procedure and was obtained as a white solid (0.125 g; 84% yield); mp 167−169 °C; 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 6.9 Hz, 1H), 7.16−7.00 (m, 2H), 6.51 (d, J = 8.5 Hz, 1H), 6.02 (d, J = 2.3 Hz, 1H), 5.73 (dd, J = 8.6, 2.5 Hz, 1H), 5.10 (dd, J = 8.6, 2.8 Hz, 1H), 4.84 (s, 1H), 3.71 (s, 3H), 3.67−3.62 (m, 1H), 3.62 (s, 3H), 3.43 (d, J = 2.6 Hz, 3H), 3.33 (dd, J = 13.6, 3.1 Hz, 1H), 1.40 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 177.1, 149.4, 148.1 (d, J = 243 Hz), 143.2, 138.7, 131.1, 129.4 (d, J = 20 Hz), 124.3 (d, J = 6 Hz), 120.4 (d, J = 3 Hz), 117.9 (d, J = 9 Hz), 112.2, 107.2, 102.1, 64.2, 60.5, 56.30, 3641

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry

was obtained as a white solid (0.048 g; 91% yield); mp 181−184 °C; 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.32−7.29 (m, 1H), 7.23 (d, J = 1.3 Hz, 1H), 7.05 (td, J = 7.5, 1.0 Hz, 1H), 7.01−6.96 (m, 2H), 6.78 (d, J = 7.8 Hz, 1H), 6.66 (t, J = 7.3 Hz, 1H), 6.31−6.26 (m, 2H), 5.41 (dd, J = 8.7, 3.8 Hz, 1H), 5.30 (s, 1H), 3.66 (dd, J = 13.9, 8.7 Hz, 1H), 3.35 (dd, J = 13.9, 3.8 Hz, 1H), 1.40 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 179.1, 144.9, 139.4, 129.7, 129.1, 128.3, 124.2, 123.5, 118.8, 114.4, 111.0, 63.5, 60.4, 51.6, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H24N3O3S+ 374.1533; found 374.1538. HPLC analysis: ee = 99%; 25 cm Chiralpak IA-3 column, n-hexane/i-PrOH = 70/30 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 6.61 min, minor enantiomer tR = 16.69 min. (R)-tert-Butyl 3-((1,1-Dimethylethylsulfonamido)methyl)-2-oxo3-(phenylamino)indoline-1-carboxylate (3ia). The compound was prepared from (R)-spiroaziridine oxindole 1i by following the general procedure and was obtained as a white solid (0.047 g; 76% yield); mp 167−169 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 1H), 7.46−7.33 (m, 2H), 7.24−7.18 (m, 1H), 6.98 (dd, J = 8.6, 7.3 Hz, 2H), 6.67 (t, J = 7.3 Hz, 1H), 6.23 (d, J = 7.6 Hz, 2H), 5.26 (s, 1H), 4.81−4.65 (m, 1H), 3.61 (dd, J = 13.9, 8.6 Hz, 1H), 3.40 (dd, J = 13.9, 3.9 Hz, 1H), 1.64 (s, 9H), 1.41 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 175.7, 148.8, 144.3, 138.7, 130.1, 129.1, 126.8, 125.4, 124.1, 119.2, 115.8, 114.8, 85.2, 63.3, 60.5, 51.7, 28.1, 24.4. HRMS (ESITOF) m/z: [M + H]+ Calcd for C24H32N3O5S+ 474.2057; found 474.2078. HPLC analysis: ee = 98%; 25 cm Chiralpak IA-3 column, nhexane/i-PrOH = 70/30 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 4.71 min, minor enantiomer tR = 12.05 min. (S)-2-Methyl-N-((2-oxo-3-(phenylamino)-1-tosylindolin-3-yl)methyl)propane-2-sulfonamide (ent-3ja). The compound was prepared from (S)-spiroaziridine ent-1j by following the general procedure and was obtained as a brownish solid (0.048 g; 80% yield); mp 77−79 °C; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 7.9 Hz, 1H), 7.32−7.27 (m, 3H), 7.20 (t, J = 7.5 Hz, 1H), 6.58 (t, J = 7.6 Hz, 2H), 6.48 (t, J = 7.4 Hz, 1H), 5.75 (d, J = 8.0 Hz, 2H), 5.31 (s, 1H), 4.68 (b, J = 8.4 Hz, 1H), 3.61 (dd, J = 14.1, 8.8 Hz, 1H), 3.35 (dd, J = 14.1, 4.2 Hz, 1H), 2.43 (s, 3H), 1.40 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 176.1, 146.1, 143.8, 138.2, 134.6, 130.5, 130, 128.7, 127.8, 127.3, 125.8, 124.5, 118.6, 114.2, 114.1, 63.5, 60.6, 51.3, 24.4, 21.7. HRMS (ESI-TOF) m/ z: [M + H]+ Calcd for C26H30N3O5S2 528.1621; found 528.1645. HPLC analysis: ee = 97%; 25 cm Chiralpak IA-3 column, n-hexane/iPrOH = 70/30 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 18.59 min, minor enantiomer tR = 9.38 min. (S)-2-Methyl-N-((1-methyl-2-oxo-3-(phenylthio)indolin-3-yl)methyl)propane-2-sulfonamide (ent-5aa). The product was prepared from (S)-spiroaziridine ent-1a by following the general procedure and was obtained as a gummy liquid (0.126 g; 92% yield). 1H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 6.5 Hz, 2H), 7.25− 7.22 (m, 1H), 7.19 (dd, J = 8.2, 1.4 Hz, 2H), 7.15−7.06 (m, 3H), 6.58 (d, J = 7.8 Hz, 1H), 4.64 (s, 1H), 3.84 (dd, J = 13.0, 8.0 Hz, 1H), 3.76 (dd, J = 13.0, 4.2 Hz, 1H), 2.95 (s, 3H), 1.36 (s, 9H).13C {H} NMR (100 MHz, CDCl3) δ 175.1, 143.1, 136.8, 129.8, 129.6, 128.4, 128.2, 127, 124.8, 123.1, 108.2, 60.5, 57.8, 47.5, 26.2, 24.3. HRMS (ESITOF) m/z: [M + H]+ Calcd for C20H25N2O3S2 405.1307; found 405.1305. HPLC analysis: ee = 93%; 25 cm Chiralcel OD-H column, n-hexane/i-PrOH = 90/10 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 14.97 min, minor enantiomer tR = 18.86 min. (R)-N-((3-((4-Methoxyphenyl)thio)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (5ab). The product was prepared from (R)-spiroaziridine 1a by following the general procedure and was obtained as a gummy liquid (0.147 g; 81% yield). 1H NMR (800 MHz, CDCl3) δ 7.27 (d, J = 7.5 Hz, 1H), 7.24 (td, J = 7.7, 1.2 Hz, 1H), 7.15−7.11 (m, 2H), 7.08 (t, J = 7.5 Hz, 1H), 6.70−6.65 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 4.58 (dd, J = 8.1, 4.1 Hz, 1H), 3.81 (dd, J = 13.1, 8.1 Hz, 1H), 3.74 (s, 4H), 2.99 (s, 3H), 1.35 (s, 9H).13C {H} NMR (200 MHz, CDCl3) δ 175.1, 161.0, 143.1, 138.5, 129.5, 127.0, 124.7, 123.0, 118.8, 113.9, 108.3, 60.4, 57.6, 55.3, 47.4, 26.2, 24.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H27N2O4S2 435.1412; found 435.1401. HPLC analysis: ee = 93%; 25 cm Chiralcel OD-H column, n-hexane/i-PrOH = 90/10 (v/v), flow

55.5, 51.2, 29.2 (d, J = 6 Hz), 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H29FN3O5S 466.1812; found 466.1810. HPLC analysis: ee = 91%; 25 cm Chiralpak IA-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 14.39 min, minor enantiomer tR = 22.46 min. (R)-N-((5-Chloro-3-((3,5-dimethoxyphenyl)amino)-1-methyl-2oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3fi). The product was prepared from (R)-spiroaziridine oxindole 1f by following the general procedure and was obtained as a white solid (0.124 g; 85% yield); mp 168−169 °C; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 2.0 Hz, 1H), 7.35 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.82 (t, J = 2.2 Hz, 1H), 5.35 (d, J = 2.1 Hz, 2H), 5.28 (s, 1H), 5.11 (dd, J = 9.1, 3.3 Hz, 1H), 3.65−3.58 (m, 1H), 3.58 (s, 6H) 3.33−3.21 (m, 1H), 3.28 (s, 3H) 1.40 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 176.6, 161.5, 146.5, 141.0, 130.1, 129.9, 129.5, 124.7, 110.1, 92.9, 92.1, 63.1, 60.6, 55.1, 51.4, 26.9, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H28ClN3O5S 482.1516; found 482.1517. HPLC analysis: ee = 96%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 17.18 min, minor enantiomer tR = 28.72 min. (R)-N-((5-Chloro-1-methyl-3-(methyl(phenyl)amino)-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3fk). The product was prepared from (R)-spiroaziridine oxindole 1f by following the general procedure and was obtained as a white solid (0.095 g; 72% yield); mp 185−187 °C; 1H NMR (600 MHz, CDCl3) δ 7.35 (d, J = 2.1 Hz, 1H), 7.28−7.25 (m, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.16−7.11 (m, 2H), 7.09 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 4.55−4.47 (m, 1H), 3.64−3.56 (m, 2H), 3.11 (s, 3H), 2.85 (s, 3H), 1.30 (s, 9H). 13 C {H} NMR (150 MHz, CDCl3) δ 175.5, 148.5, 141.9, 129.6, 129.3, 128.9, 128.5, 127.2, 126.1, 125.9, 109.4, 68.9, 60.4, 48.3, 38.8, 26.3, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H27ClN3O3S 436.1462; found 436.1459. HPLC analysis: ee = 91%; 25 cm Chiralpak OD-H column, n-hexane/i-PrOH = 90/10 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 13.08 min, minor enantiomer tR = 10.77 min. (R)-N-((1-Benzyl-2-oxo-3-(phenylamino)indolin-3-yl)methyl)-2methylpropane-2-sulfonamide (3ga). The product was prepared from (R)-spiroaziridine oxindole 1g by following the general procedure and was obtained as a white solid (0.113 g; 91% yield); mp 88−90 °C; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.1 Hz, 1H), 7.37−7.30 (m, 3H), 7.30−7.26 (m, 3H), 7.10 (t, J = 7.5 Hz, 1H), 6.95 (dd, J = 8.2, 7.6 Hz, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.25 (d, J = 7.8 Hz, 2H), 5.27 (s, 1H), 5.17 (d, J = 15.3 Hz, 2H), 5.16 (s, 1H), 4.75 (d, J = 15.4 Hz, 1H), 3.71 (dd, J = 13.6, 8.7 Hz, 1H), 3.39 (dd, J = 13.6, 3.4 Hz, 1H), 1.44 (s, 9H). 13C {H} NMR (100 MHz, CDCl3) δ 177.2, 144.9, 141.7, 135.3, 129.9, 129.1, 128.9, 128.0, 127.9, 127.8, 124.4, 123.7, 119.3, 115.3, 110.1, 63.4, 60.5, 51.6, 44.3, 24.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H30N3O3S 464.2008; found 464.2006 4. HPLC analysis: ee = 86%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 12.14 min, minor enantiomer tR = 13.16 min. (R)-N-((1-Benzyl-3-(methyl(phenyl)amino)-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (3gk). The product was prepared from (R)-spiroaziridine oxindole 1g by following the general procedure and was obtained as a white solid (0.109 g; 85% yield); mp 60−63 °C; 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 6.4 Hz, 1H), 7.26 (s, 3H), 7.21−7.09 (m, 6H), 7.05 (d, J = 14.1 Hz, 3H), 6.65 (d, J = 7.2 Hz, 1H), 5.05 (d, J = 15.6 Hz, 1H), 4.73 (s, 1H), 4.63 (d, J = 15.5 Hz, 1H), 3.84−3.70 (m, 1H), 3.64 (d, J = 12.1 Hz, 1H), 2.99 (s, 3H), 1.35 (s, 9H). 13C {H} NMR (150 MHz, CDCl3) δ 175.8, 149.0, 142.6, 135.4, 129.7, 128.9, 128.8, 127.8, 127.6, 127.4, 127.4, 125.8, 125.4, 122.9, 109.6, 68.7, 60.4, 48.6, 43.9, 38.6, 24.4. HRMS (ESITOF) m/z: [M + H]+ Calcd for C27H32N3O3S 478.2164; found 478.2163. HPLC analysis: ee = 85%; 25 cm Chiralpak IA-3 column, nhexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 12.06 min, minor enantiomer tR = 15.39 min. (R)-2-Methyl-N-((2-oxo-3-(phenylamino)indolin-3-yl)methyl)propane-2-sulfonamide (3ha). The compound was prepared from (R)-spiroaziridine oxindole 1h by following the general procedure and 3642

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry

washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. Flash column chromatography (SiO2, Hexanes/EtOAc 70:30) was done to afford the product as a white semi-solid (0.087 g; 79% yield).1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.3 Hz, 1H), 7.42− 7.37 (m, 1H), 7.17 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 4.67 (s, 1H), 3.56−3.50 (m, 2H), 3.23 (s, 3H), 3.05 (s, 3H), 1.35 (s, 9H). 13 C {H} NMR (100 MHz, CDCl3) δ 174.2, 143.9, 130.7, 125.3, 124.5, 123.5, 108.8, 81.1, 60.4, 53.4, 50.3, 26.4, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H23N2O4S 327.1379 found 327.1377. HPLC analysis: ee = 85%; 25 cm Chiralpak IB-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 8.28 min, minor enantiomer tR = 9.24 min. (R)-1′-Methyl-3-phenyl-2-thioxospiro[imidazolidine-4,3′-indolin]2′-one (9). Under an argon atmosphere, at 0 °C, triflic acid was added dropwise to a stirred solution of 3aa (0.2 g, 0.5 mmol) and anisole (1.8 g, 10 mmol) in CH2Cl2 (15 mL). Reaction was monitored by TLC. After completion (4 h), the reaction was quenched with saturated sodium bicarbonate solution. The resultant product was extracted with EtOAc (3 × 15 mL) and washed with sodium bicarbonate solution and brine. The combine organic layers were dried over Na2SO4 and solvent was removed under reduced pressure. The crude diamine compound 8 thus obtained (0.131 g, 96%) was utilized without further purification. To a stirred solution of diamine compound 8 (0.13 g, 0.5 mmol) in EtOH/H2O (5 mL, 4:1) at 25 °C was added carbon disulfide (0.036 mL, 0.6 mmol). The reaction was monitored by TLC. After completion (16 h), the ethanol was evaporated in reduced pressure and extracted with EtOAC (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and purified by column chromatography in silica gel using EtOAC/Hexanes (3:7). The product 9 was obtained as a pinkish-white solid (0.124 g; 77% yield over two steps); mp 136−138 °C; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.18 (dd, J = 16.9, 9.3 Hz, 4H), 7.06 (d, J = 3.5 Hz, 2H), 6.71 (d, J = 7.8 Hz, 1H), 6.26 (s, 1H), 4.22 (d, J = 9.5 Hz, 1H), 3.90 (d, J = 9.7 Hz, 1H), 3.05 (s, 3H).13C {H} NMR (150 MHz, CDCl3) δ 185.0, 173.3, 143.2, 136.9, 130.9, 129.6, 128.9, 128.5, 127.6, 124.7, 123.9, 108.9, 72.6, 52.2, 26.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16N3OS 310.1014; found 310.0995. (R)-1′-Methyl-3-phenylspiro[imidazolidine-4,3′-indoline]-2,2′dione (10). A THF solution of 1,1′-carbonyldiimidazole (CDI) (0.065 g, 0.41 mmol) was added dropwise to a stirred solution of the crude diamine compound 8 (0.1 g, 0.38 mmol) in 1.5 mL of THF at 0 °C. The reaction mixture was then transferred to room temperature. After 8 h, the reaction mixture was evaporated in reduced pressure to get rid of THF. The crude mixture was extracted with EtOAc (3 × 10 mL) and washed thoroughly with water. The combined organic layers were washed with brine, dried over Na2SO4, and purified by column chromatography on silica gel using EtOAC/Hexanes (1:1). The product 10 was obtained as a white solid (0.07 g; 93% yield over two steps); mp 113−115 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.3 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.16 (dd, J = 12.8, 4.9 Hz, 2H), 7.12−7.07 (m, 2H), 7.03 (d, J = 7.5 Hz, 2H), 6.78 (d, J = 7.8 Hz, 1H), 5.30 (s, 1H), 3.95 (d, J = 8.7 Hz, 1H), 3.64 (d, J = 8.8 Hz, 1H), 3.13 (s, 3H). 13C {H} NMR (100 MHz, CDCl3) δ 174.4, 160.8, 142.9, 136.2, 130.4, 128.9, 128.3, 126.8, 126.5, 124.1, 123.7, 108.9, 68.1, 48.8, 26.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16N3O2 294.1243; found 294.1249.

rate: 1 mL/min, 254 nm; major enantiomer tR = 23.28 min, minor enantiomer tR = 20.55 min. (R)-2-Methyl-N-((1-methyl-2-oxo-3-(pyridin-2-ylthio)indolin-3-yl)methyl)propane-2-sulfonamide (5ac). The product was prepared from (R)-spiroaziridine 1a by following the general procedure and was obtained as a gummy liquid (0.137 g; 97% yield).1H NMR (800 MHz, CDCl3) δ 8.29 (dd, J = 5.1, 1.7 Hz, 1H), 7.50 (td, J = 7.7, 1.9 Hz, 1H), 7.43 (dd, J = 7.5, 1.2 Hz, 1H), 7.28 (ddd, J = 9.0, 7.8, 1.2 Hz, 2H), 7.08 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 7.04−7.00 (m, 1H), 6.83 (d, J = 7.7 Hz, 1H), 5.81 (dd, J = 9.2, 3.2 Hz, 1H), 3.76 (dd, J = 13.2, 8.9 Hz, 1H), 3.67 (dd, J = 13.2, 3.2 Hz, 1H), 3.26 (s, 3H), 1.40 (s, 9H).13C {H} NMR (200 MHz, CDCl3) δ 175.3, 153.9, 149.4, 143.5, 136.7, 129.6, 127.4, 127.4, 124.8, 123.0, 122.2, 108.2, 60.3, 56.5, 48.9, 26.7, 24.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19 H24 N3O3 S2 406.1259; found 406.1247. HPLC analysis: ee = 94%; 25 cm CHIRALPAK IC-3 column, n-hexane/i-PrOH = 55/45 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 52.53 min, minor enantiomer tR = 58.70 min. (S)-N-((5-Fluoro-1-methyl-2-oxo-3-(phenylthio)indolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (ent-5ba). The product was prepared from (S)-spiroaziridine ent-1b by following the general procedure and was obtained as a white solid (0.135 g; 95% yield); mp 110−112 °C; 1H NMR (800 MHz, CDCl3) δ 7.28 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 7.15 (t, J = 7.5 Hz, 2H), 7.09−7.04 (m, 1H), 6.96−6.89 (m, 1H), 6.49 (dd, J = 8.5, 4.0 Hz, 1H), 4.77−4.61 (m, 1H), 3.83 (dd, J = 13.3, 7.8 Hz, 1H), 3.75 (dd, J = 13.3, 4.5 Hz, 1H), 2.93 (s, 3H), 1.36 (s, 9H). 13C {H} NMR (200 MHz, CDCl3) δ 174.88, 159.2, (d, J = 240 Hz), 139.0, 136.8, 130.0, 128.7 (d, J = 8 Hz), 128.5, 127.81, 115.9 (d, J = 24 Hz), 113.0, 112.9 (d, J = 26 Hz), 108.7 (d, J = 8 Hz), 60.5, 58.2, 47.4, 26.3, 24.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H24FN2O3S2 423.1212; found 423.1198. HPLC analysis: ee = 95%; 25 cm Chiralcel OD-H column, n-hexane/i-PrOH = 90/10 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 14.04 min, minor enantiomer tR = 17.72 min. (S)-N-((5-Fluoro-3-((4-methoxyphenyl)thio)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (ent-5bb). The product was prepared from (S)-spiroaziridine ent-1b by following the general procedure and was obtained as a gummy liquid (0.144 g; 94% yield). 1H NMR (800 MHz, CDCl3) δ 7.12 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 9.1 Hz, 1H), 6.67 (d, J = 8.2 Hz, 2H), 6.52 (dd, J = 8.8, 3.9 Hz, 1H), 4.72 (t, J = 6.1 Hz, 1H), 3.79 (dd, J = 13.3, 7.6 Hz, 1H), 3.73 (s, 3H), 3.73−3.71 (m, 1H) 2.95 (s, 3H), 1.35 (s, 9H).13C {H} NMR (200 MHz, CDCl3) δ 174.93, 160.4 (d, J = 270 Hz), 158.6, 139.1, 138.4, 128.7 (d, J = 8 Hz), 118.4, 115.7 (d, J = 24 Hz), 114.1, 113.9 (d, J = 26 Hz), 108.7 (d, J = 8 Hz), 60.4, 58.2, 55.3, 47.20 26.4, 24.3, 24.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26FN2O4S2 453.1318; found 453.1305. HPLC analysis: ee = 96%; 25 cm Chiralcel OD-H column, n-hexane/i-PrOH = 90/10 (v/ v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 20.81 min, minor enantiomer tR = 24.26 min. (R)-N-((5-Chloro-3-((4-methoxyphenyl)thio)-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (5fb). The product was prepared from (R)-spiroaziridine 1f by following the general procedure and was obtained as a gummy liquid (0.142 g; 82% yield). 1 H NMR (800 MHz, CDCl3) δ 7.30−7.22 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.74 (d, J = 8.2 Hz, 2H), 6.58 (d, J = 8.2 Hz, 1H), 4.72 (tt, J = 8.3, 4.0 Hz, 1H), 3.84 (dd, J = 13.3, 7.7 Hz, 1H), 3.79 (s, 3H), 3.76 (dd, J = 13.3, 4.6 Hz, 1H), 3.01 (s, 3H), 1.39 (s, 9H). 13C {H} NMR (200 MHz, CDCl3) δ 174.8, 161.2, 141.6, 138.5, 129.3, 128.8, 128.3, 125.3, 118.4, 114.1, 109.2, 60.5, 57.9, 55.3, 47.2, 26.4, 24.3, 24.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26ClN2O4S2 469.1023; found 469.1015. HPLC analysis: ee = 92%; 25 cm Chiralpak IA-3 column, n-hexane/i-PrOH = 80/20 (v/v), flow rate: 1 mL/min, 254 nm; major enantiomer tR = 18.28 min, minor enantiomer tR = 19.53 min. (S)-N-((3-methoxy-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (ent-7aa). Under an argon atmosphere, ent1a (0.100 g, 0.34 mmol) and degassed dry methanol (3.4 mL) were stirred in a sealed tube at 60 °C. After 5 days, the reaction mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03288. NMR spectra and HPLC chromatograms for all new compounds 1i, 1j, 3, 5, 7, 9, and 10 (PDF) 3643

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644

Article

The Journal of Organic Chemistry

■

(11) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488. (b) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593. (c) Zhang, Z.; Zheng, W.; Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 1135. (12) Hajra, S.; Aziz, S. M.; Jana, B.; Mahish, P.; Das, D. Org. Lett. 2016, 18, 532. (13) Other reports on asymmetric synthesis of spiroaziridines: (a) Li, J.; Du, T.; Zhang, G.; Peng, Y. Chem. Commun. 2013, 49, 1330. (b) Marsini, M. A.; Reeves, J. T.; Desrosiers, J.-N.; Herbage, M. A.; Savoie, J.; Li, Z.; Fandrick, K. R.; Sader, C. A.; McKibben, B.; Gao, D. A.; Cui, J.; Gonnella, N. C.; Lee, H.; Wei, X.; Roschangar, F.; Lu, B. Z.; Senanayake, C. H. Org. Lett. 2015, 17, 5614. (14) Hajra, S.; Singha Roy, S.; Aziz, S. M.; Das, D. Org. Lett. 2017, 19, 4082. (15) (a) Wani, I. A.; Sayyad, M.; Ghorai, M. K. Chem. Commun. 2017, 53, 4386. (b) Sengoden, M.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2013, 52, 572. (16) (a) Minakata, S.; Kano, D.; Oderaotoshi, Y.; Komatsu, I. Angew. Chem., Int. Ed. 2004, 43, 79. (b) Somi Reddy, M.; Narender, M.; Rao, K. R. Synlett 2005, 3, 489. (c) Rai, V. K.; Rai, P. K.; Bajaj, S.; Kumar, A. Green Chem. 2011, 13, 1217. (17) (a) Chouhan, M.; Senwar, K. R.; Sharma, R.; Grover, V.; Nair, V. A. Green Chem. 2011, 13, 2553. (b) Zhang, B.; Bao, G.; Li, Y.; Sun, W.; Li, J.; Hong, L.; Wang, R.; Zhu, G.; Wang, J.; Zhang, B. Green Chem. 2017, 19, 2107. (18) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492. (19) (a) Ghorai, M. K.; Bhattacharyya, A.; Das, S.; Chauhan, N. Top. Heterocycl. Chem. 2015, 41, 49. (b) Stanković, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012, 41, 643. (c) Lu, P. Tetrahedron 2010, 66, 2549. (d) Pineschi, M. Eur. J. Org. Chem. 2006, 2006, 4979. (20) (a) Hajra, S.; Maji, B.; Sinha, D.; Bar, S. Tetrahedron Lett. 2008, 49, 4057. (b) Hajra, S.; Maji, B.; Mal, D. Adv. Synth. Catal. 2009, 351, 859. (c) Hajra, S.; Bar, S. Chem. Commun. 2011, 47, 3981. (d) Hajra, S.; Sinha, D. J. Org. Chem. 2011, 76, 7334. (e) Hajra, S.; Aziz, S. M.; Akhtar, S. M. S. Chem. Commun. 2014, 50, 6913. (21) (a) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677. (b) Zhang, H.; Hong, L.; Kang, H.; Wang, R. J. Am. Chem. Soc. 2013, 135, 14098. (22) (a) Lengyel, I.; Sheehan, J. C. Angew. Chem., Int. Ed. Engl. 1968, 7, 25. (b) Smyth, R. M.; Williams, A. J. Chem. Soc., Perkin Trans. 2 1993, 2171. (c) Easton, C. J.; Merrett, M. C. J. Am. Chem. Soc. 1996, 118, 3035. (d) Angus, P. M.; Jackson, W. G. Inorg. Chim. Acta 2003, 343, 95. (e) Calvaresi, M.; Rinaldi, S.; Arcelli, A.; Garavelli, M. J. Org. Chem. 2008, 73, 2066. (f) Proust, N.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 2008, 73, 6279. (23) (a) Lucy, H.; Carmen, L.; Miroslaw, T.; Christopher, W. PCT Int. Appl. WO 2007091948A2 20070816, 2007. (b) Hutchison, A. J. U.S. Pat. US 4464380A 19840807, 1984. (c) Czarna, A.; Beck, B.; Srivastava, S.; Popowicz, G. M.; Wolf, S.; Huang, Y.; Bista, M.; Holak, T. A.; Domling, A. Angew. Chem., Int. Ed. 2010, 49, 5352.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: (+91)-522-2668995. Tel.: (+91)-522-2668861. ORCID

Saumen Hajra: 0000-0003-0303-4647 Author Contributions

S.S.R. and A.B. contributed equally. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank SERB, New Delhi (EMR/2016/001161), and the SERB Young Scientist Award (YSS/2015/000257) for providing financial support. S.S.R. thanks SERB, New Delhi. A.B. and S.A.S. thank DST, New Delhi, and UGC, New Delhi, for their fellowships. We thank the Director of CBMR for providing research facilities.

■

REFERENCES

(1) Eastgate, M. D.; Schmidt, M. A.; Fandrick, K. R. Nat. Rev. Chem. 2017, 1, 0016. (2) For review, see: (a) Ziarani, G. M.; Gholamzadeh, P.; Lashgari, N.; Hajiabbasi, P. ARKIVOC 2013, 470. (b) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (3) For selected examples, see: (a) Kaur, J.; Chimni, S. S.; Mahajan, S.; Kumar, A. RSC Adv. 2015, 5, 52481. (b) Zhu, G.; Liu, S.; Wu, S.; Peng, L.; Qu, J.; Wang, B. J. Org. Chem. 2017, 82, 4317. (4) For selected examples, see: (a) Vintonyak, V. V.; Warburg, K.; Kruse, H.; Grimme, S.; Hubel, K.; Rauh, D.; Waldmann, H. Angew. Chem., Int. Ed. 2010, 49, 5902. (b) Lin, S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, K. M.; Crews, C. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347. (c) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20. (5) (a) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama, H. Tetrahedron Lett. 2006, 47, 3199. (b) Hayashi, M.; Rho, M.-C.; Enomoto, A.; Fukami, A.; Kim, Y.-P.; Kikuchi, Y.; Sunazuka, T.; Hirose, T.; Komiyama, K.; Omura, S. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 14728. (6) (a) van Pelt-Koops, J. C.; Pett, H. E.; Graumans, W.; van der Vegte-Bolmer, M.; van Gemert, G. J.; Rottmann, M.; Yeung, B. K. S.; Diagana, T. T.; Sauerwein, R. W. Antimicrob. Agents Chemother. 2012, 56, 3544. (b) Czarna, A.; Beck, B.; Srivastava, S.; Popowicz, G. M.; Wolf, S.; Huang, Y.; Bista, M.; Holak, T. A.; Doemling, A. Angew. Chem., Int. Ed. 2010, 49, 5352. (c) Takasugi, M.; Monde, K.; Katsui, N.; Shirata, A. Chem. Lett. 1987, 16, 1631. (7) For reviews, see: (a) Chauhan, P.; Chimni, S.-S. Tetrahedron: Asymmetry 2013, 24, 343. (b) Han, W.-Y.; Zhao, J.-Q.; Zuo, J.; Xu, X.Y.; Zhang, X.-M.; Yuan, W.-C. Adv. Synth. Catal. 2015, 357, 3007. (c) Zhou, F.; Liu, Y.-L.; Zhou. Adv. Synth. Catal. 2010, 352, 1381. (d) Chen, D.; Xu, M.-H. Chem. Commun. 2013, 49, 1327. (e) Chen, J.; Wen, X.; Wang, Y.; Du, F.; Cai, L.; Peng, Y. Org. Lett. 2016, 18, 4336. (8) For selected examples, see: (a) Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J. Org. Lett. 2009, 11, 3874. (b) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255. (c) Bui, T.; Hernández-Torres, G.; Milite, C.; Barbas, C. F., III Org. Lett. 2010, 12, 5696. (9) For selected examples, see: (a) Shen, K.; Liu, X.; Wang, G.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2011, 50, 4684. (b) Companyó, X.; Valero, G.; Pineda, O.; Calvet, T.; Font-Bardía, M.; Moyano, A.; Rios, R. Org. Biomol. Chem. 2012, 10, 431. (c) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Kündig, E. P. Chem. Commun. 2008, 4040. (d) Shirai, T.; Ito, H.; Yamamoto, Y. Angew. Chem., Int. Ed. 2014, 53, 2658. (10) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. 3644

DOI: 10.1021/acs.joc.7b03288 J. Org. Chem. 2018, 83, 3633−3644