Organocatalytic Domino Reaction of Spiroaziridine ... - ACS Publications

May 29, 2019 - ... on the ACS Publications website at DOI: 10.1021/acs.joc.9b01226. ... Medical Sciences Campus, Raebareli Road, Lucknow 226014, INDIA...
0 downloads 0 Views 989KB Size
Download PDF
Article Cite This: J. Org. Chem. 2019, 84, 8194−8201

pubs.acs.org/joc

Organocatalytic Domino Reaction of Spiroaziridine Oxindoles and Malononitrile for the Enantiopure Synthesis of Spiro[dihydropyrrole-3,3′-oxindoles] Saumen Hajra,*,† SK Abu Saleh,†,‡ Atanu Hazra,†,‡ and Maya Shankar Singh‡ †

Downloaded via NOTTINGHAM TRENT UNIV on July 17, 2019 at 16:46:36 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226014, India ‡ Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India S Supporting Information *

ABSTRACT: The first organocatalytic regio- and stereoselective domino reactions of spiroaziridine oxindoles and malononitrile have been developed using DBU as a catalyst without any metal/Lewis acid activation for the enantiopure synthesis of spiro[dihydropyrrole-3,3′-oxindoles] (ee up to >99%). The protocol is also equally effective for the phenyl aziridine with excellent regio- and stereoselectivity.

■

INTRODUCTION The spiro[pyrrolidine-3,3′-oxindole] is a prevalence heterocyclic motif that constitutes the core of various family of alkaloids natural products and unnatural compounds with strong bioactivity profiles (Figure 1).1,2 The presence of an

synthesis of various nitrogen-containing spirooxindole-based heterocycles. We realized that tricyclic spiro[pyrrolidine-3,3′oxindoles] can be synthesized via ring opening followed by cyclization of spiroaziridine oxindoles with carbon pronucleophiles in a domino fashion. Over the years, domino reaction has become a powerful tool for the synthesis of structurally complex bioactive molecules in a conducive manner.7 It has substantial advantages over conventional linear synthesis because of its flexible, convergent, and atom-economic nature. Again, organocatalytic domino reaction represents the state of art in organic chemistry. There are some elegant reports on domino ring opening and cyclization of aziridine using Lewis acid and/or strong base (Scheme 1, eq 1),8 but the organocatalytic ring opening reaction of aziridine with carbon pronucleophiles is sparse in the literature.9 Moreover, the chemistry of the spiroaziridine oxindoles toward synthesis of higher spiro-N-heterocycle oxindoles is still unexplored. The Dixon group first reported the organic phosphorine base-catalyzed ring opening reaction of unsubstituted simple N-sulfonyl aziridine with active methylene carbon for the racemic synthesis of compounds with an all-carbon quaternary center and later the same group developed the catalytic asymmetric ring opening reaction using a phase transfer catalyst (PTC) where the ring opening occurs from the less hindered site (Scheme 1, eq 2).9b Similar reaction using PTC was also reported by the Jørgensen group varying only the protecting group of unsubstituted aziridines.9c To the best of our knowledge, base/organo-catalytic domino ring opening reaction of aziridine, in particular, at the more substituted site has not been reported. In this context, we report the first organocatalytic regio- and stereocontrolled

Figure 1. Representative spiro[dihydropyrrole-3,3′-oxindoles] containing natural/unnatural products.

additional double bond in a spiro-pyrrolidinyl unit, that is, spiro[dihydropyrrole-3,3′-oxindole], is a unique feature of some of the important natural products such as spirotrypsostatin B, cyanogramide, and so forth.3 Considering the important bioactivities, huge efforts have been devoted to synthesize the spiro[pyrrolidine-3,3′-oxindole], where 1,3-dipolar cycloaddition of azomethine ylides and its equivalent with the 3-alkylidene oxindoles was the major successful strategies.4 Our continued research experiences in the aziridine chemistry5,6 led us to presume that spiroaziridines could be the suitable choice of substrate for the © 2019 American Chemical Society

Received: May 7, 2019 Published: May 29, 2019 8194

DOI: 10.1021/acs.joc.9b01226 J. Org. Chem. 2019, 84, 8194−8201

Article

The Journal of Organic Chemistry

deprotonate another molecule of malononitrile and thus continue the catalytic cycle. To validate our concept, we began our studies of domino reaction initially with racemic spiroaziridine (±)-1a altering solvents, temperature, and base (Table 1). To our delight, the

Scheme 1. Previous Reports and the Present Study

Table 1. Optimization of Reaction Conditionsa

domino ring opening and cyclization reaction of spiroaziridine oxindoles with malononitrile at the spirocenter that provides easy access of enantiopure spiro[dihydropyrrole-3,3′-oxindoles] (ee up to >99%). This organocatalytic protocol is also effective for the regio- and stereoselective domino reaction of phenyl aziridine at the benzylic center.

entry

1

base

solvent

temp (°C)

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9 10

(±)-1a (±)-1a (±)-1a (±)-1a (±)-1a (±)-1a (±)-1a (±)-1a (±)-1b (±)-1c

t-BuOK t-BuOK t-BuOK NaH Cs2CO3 Cs2CO3 DBU DBUc DBUc DBUc

THF DMF DMF DMF DMF DMF DMF DMF DMF DMF

25 25 0 25 25 0 25 25 25 25

10 10 12 8 5 6 4.5 5 9 11

35 40 42 37 80 81 95 95 85 84

a

A solution of spiroaziridine (±)-1a (0.05 g, 0.16 mmol), malononitrile (1.5 equiv) and base (1.5 equiv) in 1 mL solvent was stirred at specified temperature. bIsolated yield. c35 mol % base was used.

■

RESULTS AND DISCUSSION The unprecedented reactivity of spiroaziridine oxindoles toward the regio- and stereoselective ring-opening reaction at the spirocenter with retention of configuration without any Lewis acid activation led us to envision that spiroaziridines 1 could undergo nucleophilic addition followed by cyclization with malononitrile in the presence of a base to produce enantiopure spiro[pyrroline-3,3′ oxindoles 3 with retention of configuration (Scheme 2). We further wondered whether an organic base could catalyze this domino reaction. After the ring opening of spiroaziridine at the spirocenter with the anion of malonitrile followed by cyclization, the adduct 4 should be sufficiently basic either to abstract the proton from the conjugate acid BH+ to regenerate the free base or to

domino reaction of spiroaziridine (±)-1a gave exclusively spiro[pyrroline-3,3′ oxindoles] product (±)-3a in good yield with Cs2CO3 as a base in dimethylformamide (DMF) at rt (Table 1; entry 5). Using a catalytic amount of 1,8biazabicyclo[5.4.0]undec-7-ene (DBU; 35 mol %) also gave full consumption of starting material with excellent yield (Table 1; entry 8). Lowering the catalyst loading to 20 mol % or lower led to incomplete conversion even after 24 h. Among the inorganic base, none of the other bases can improve the yield of the reaction even by using a stoichiometric amount. Changing the protecting group from N-Me to N-Bn, N-allyl does not improve the yield of this reaction (Table 1; entry 9, 10). Interestingly, no regio-isomer of the domino product was detected by the 1H NMR analysis of the crude reaction mixture. After successful domino reaction of spiroaziridine (±)-1a, the conditions were implemented to the enantiopure spiroaziridine 1d (Table 2). It was found that not only DBU but also other organic base like DIPEA, TMEDA, and DABCO gave the desired domino product with excellent ee (Table 2, entries 3−5). However, the best yield (95%) and enantioselectivity (>99%) were achieved when DBU (35 mol %) was used as a base (Table 2, entry 2). To our delight, reactions with Cs2CO3 in DMF also afforded the desired domino product 3d with 97% ee, but in little lower yield (Table 2, entry 1). On the basis of optimal reaction conditions, we explored the substrate generality of this domino reaction with various spiroaziridine oxindoles 1d−1s (Figure 2). Irrespective of the Nprotection of spiroaziridines, N-methyl, N-benzyl, and N-allyl gave excellent yields and enantioselectivities. Unlike earlier works on tertiary nucleophilic fluorination,6e domino reaction of N-unprotected spiroaziridine ent-1h produced the desired

Scheme 2. Presumption of Base-Catalyzed Domino Reaction of Spiroaziridine

8195

DOI: 10.1021/acs.joc.9b01226 J. Org. Chem. 2019, 84, 8194−8201

Article

The Journal of Organic Chemistry

product ent-3h with excellent enantioselectivity by using an additional equivalent of the base. The substrate 1g with the electron-withdrawing N-protecting group such as N-Boc also underwent smooth reaction under the optimized reaction condition and afforded 3g by taking a little more time. It seems that less availability of the electron pair on nitrogen might restrict the neighboring participation to the aziridine moiety. Again, these results support our presumption of the anchimeric assistance of the oxindole unit. To check the versatility, a wide range of spiroaziridines with electron-withdrawing and electron-donating substitutions at C5, C7, and C4 positions were also tested. All underwent smooth reactions and afforded the corresponding spiro[pyrroline-3,3′ oxindoles] 3i−s with excellent yields and enantioselectivities (ee 93 to >99%). Interestingly, the electron-donating groups at the C5 and C7 positions showed the higher reactivity by taking less time than the substrates having the electron-withdrawing groups. It seems that the electron-donating group, in particular, at the C5 and C7 position increases the electron density to the ring and in turn might enhance the donating propensity of oxindole nitrogen/oxygen toward anchimeric assistance leading to the faster reaction. In line with our previous report,6 organic base-catalyzed domino ring opening and cyclization of spiroaziridines 1 and malononitrile are also assumed to be a retention in configuration at the C3-stereocenter. It is further confirmed from the single-crystal X-ray analysis of ent-3m which was recrystallized from ethyl acetate/hexanes (9:1). The crystal structure unambiguously confirms the stereochemistry of the C3-center of ent-3m as (S)-configuration derived from (S)spiroaziridine oxindole ent-1m (Figure 2). To manifest the scalability and to check the withstanding ability of the method, the domino reaction was extended up to gram-scale under the optimized conditions (Scheme 3). The

Table 2. Optimization of Reaction Conditions for Stereocontrolled Domino Reactiona

entry

base (x mol %)

solvent

temp (°C)

time (h)

yieldb (%)

eec (%)

1 2 3 4 5

Cs2CO3 (150) DBU (35) DIPEA (35) TMEDA (35) DABCO (35)

DMF DMF DMF DMF DMF

25 25 25 25 25

5 5 5 5 5

80 95 75 70 80

97 >99 95 ND 97

a

A solution of spiroaziridine 1d (0.05 g, 0.17 mmol), malononitrile (1.5 equiv), and base (x mol %) in 1 mL solvent was stirred at a specified temperature. bIsolated yield. cee determined by HPLC analysis on a chiral stationary phase. ND = not determined.

Scheme 3. Gram-Scale Domino Reaction

spiroaziridine 1d (1 g, 3.14 mmol) underwent smooth reaction with a DBU catalyst in DMF at 25 °C and produced spiro[pyrroline-3,3′ oxindoles] 3d maintaining excellent enantioselectivity and yield (ee >99 and 94%). Further, an organocatalytic domino protocol was executed with phenyl aziridine 5 to compare the reactivity pattern with spiroaziridine 1 (Scheme 4). In contrast to the earlier report where Lewis acid and strong base were found to be mandatory Scheme 4. DBU-Catalyzed Domino Reaction of Phenyl Aziridine 5 Figure 2. Enantiopure synthesis of spiro[pyrroline-3,3′ oxindoles] oxindoles 2; ent-3e, ent-3h, ent-3j, ent-3l, and ent-3m were obtained from (S)-spiroaziridines ent-1e, ent-1h, ent-1j, ent-1l, and ent-1m, respectively.

8196

DOI: 10.1021/acs.joc.9b01226 J. Org. Chem. 2019, 84, 8194−8201

Article

The Journal of Organic Chemistry

General Procedure for the Synthesis of (R)-Spiroaziridine Oxindoles. The starting materials were prepared according to the literature procedure.6a−c,e General Procedure for the Synthesis of Spiro[dihydropyrrole-3,3′ oxindoles] 3. To a stirring suspended solution of malononitrile 2 (0.013 mL, 0.25 mmol) and 4 Å MS in anhydrous DMF (1 mL) under Ar atmosphere at 25 °C, DBU (9 μL, 35 mol %) was added. After 30 min, 1d (0.05 g, 0.17 mmol) was added to the reaction mixture at the same temperature. The resulting mixture was stirred at the same temperature and monitored by TLC. After completion (5 h), the reaction mixture was quenched with brine and extracted with ethyl acetate (3 × 25 mL) and washed with brine. The combined organic layers were dried over Na2SO4 and solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography with hexanes/ethyl acetate (2:1) to afford spiro[dihydropyrrole-3,3′ oxindoles] 3d (0.058 g, 95% yield). Organocatalytic Asymmetric Domino Reaction of Spiroaziridine (±)-1a and Its Kinetic Resolution. In a screw-cap vial, a solution of (±)-1a (0.05 g, 0.16 mmol), 2 (0.013 mL, 0.25 mmol), and quinine (0.005 g, 0.016 mmol, 10 mol %) in anhydrous CH2Cl2 (0.5 mL) was stirred at 25 °C. After about 50% consumption of starting spiroaziridine 1a monitored by TLC (9 h), the reaction mixture was directly loaded on silica gel for flash column chromatography and eluted with hexanes/ethyl acetate (2:1) to afford spiro[dihydropyrrole-3,3′ oxindoles] 3a (0.021 g, 35% yield) and recovered spiroaziridine 1a (0.023 g, 45% yield). Characterization Data for Compounds. 1′-Methyl-1(phenylsulfonyl)spiro[aziridine-2,3′-indolin]-2′-one ((±)-1a). The product was prepared by following the literature procedure and was obtained as a gray solid (0.388 g; 92% yield): mp 126−128 °C; 1H NMR (400 MHz, CDCl3): δ 7.97−7.95 (m, 2H), 7.74 (dd, J = 7.7, 1.3 Hz, 1H), 7.64−7.62 (m, 1H), 7.54−7.50 (m, 2H), 7.41−7.36 (m, 1H), 7.15−7.11 (m, 1H), 6.92 (dd, J = 7.9, 1.2 Hz, 1H), 3.46 (d, J = 1.0 Hz, 1H), 3.27 (d, J = 2.3 Hz, 3H), 3.14 (d, J = 0.9 Hz, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 169.8, 145.1, 139.4, 133.7, 130.3, 129.1, 127.8, 125.3, 123.0, 120.3, 108.9, 48.3, 40.4, 26.9: HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H14N2NaO3S, 337.0623; found, 337.0622. HPLC analysis of recovered 1a: ee = 13 and 18% (in toluene); CHIRALCEL IB-3 column, 250 mm, nhexane/isopropyl alcohol = 90:10; flow rate 1.0 mL/min; 254 nm: tR = 37.30 min (major), tR = 45.53 min (minor). 1′-Benzyl-1-(phenylsulfonyl)spiro[aziridine-2,3′-indolin]-2′-one ((±)-1b). The product was prepared by following the literature procedure and was obtained as a gray solid (0.375 g; 90% yield): mp 140−142 °C; 1H NMR (400 MHz, CDCl3): δ 7.98−7.95 (m, 2H), 7.71 (dd, J = 7.7, 1.2 Hz, 1H), 7.64−7.60 (m, 1H), 7.53−7.49 (m, 2H), 7.35−7.24 (m, 6H), 7.09 (td, J = 7.6, 1.0 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 4.97 (s, 2H), 3.50 (d, J = 0.9 Hz, 1H), 3.27 (d, J = 0.9 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.0, 144.3, 139.4, 135.1, 133.6, 130.2, 129.1, 128.9, 128.7, 127.8, 127.3, 125.3, 123.0, 120.4, 109.9, 48.3, 44.4, 40.4. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H18N2NaO3S, 413.0936; found, 413.0924. 1′-Allyl-1-(phenylsulfonyl)spiro[aziridine-2,3′-indolin]-2′-one ((±)-1c). The product was prepared by following the literature procedure and was obtained as a gray solid (0.378 g; 90% yield): mp 118−120 °C; 1H NMR (400 MHz, CDCl3): δ 7.96−7.94 (m, 2H), 7.73 (dd, J = 7.7, 1.2 Hz, 1H), 7.64−7.60 (m, 1H), 7.52 (dd, J = 8.5, 7.1 Hz, 2H), 7.35 (td, J = 7.8, 1.3 Hz, 1H), 7.12 (td, J = 7.6, 1.0 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 5.88−5.79 (m, 1H), 5.26−5.20 (m, 2H), 4.40 (dt, J = 5.4, 1.7 Hz, 2H), 3.48 (d, J = 0.9 Hz, 1H), 3.19 (d, J = 0.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.6, 144.4, 139.4, 133.6, 130.9, 130.2, 129.1, 127.8, 125.4, 122.9, 120.3, 118.1, 109.8, 48.2, 43.0, 40.4; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H16N2NaO3S, 363.0779; found, 363.0774. 5′-Amino-1-methyl-2-oxo-1′-(phenylsulfonyl)-1′,2′dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile ((±)-3a). The product was prepared by following the general procedure and was obtained as a white solid (0.057 g; 95% yield): mp 200−202 °C; 1H NMR (400 MHz, CDCl3): δ 7.99−7.89 (m, 2H), 7.80 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.7 Hz, 2H), 7.31−7.22 (m, 1H), 6.93 (t, J = 7.5 Hz,

for the regio- and stereoselective reaction at the more hindered site, it interestingly gave the same reaction pattern. N-nosyl aziridine 5a afforded exclusively the domino product 6a with excellent yield, and no terminal product 6a′ was detected in the crude reaction mixture, whereas N-tosyl substrate 5b gave the product 6b as a major one along with a minor amount of terminal product 6b′ (6b/6b′ = 4:1). Gratifyingly, both the reactions showed excellent stereoselectivity (ee >99%). Finally, this strategy was extended toward organocatalytic asymmetric domino reaction of racemic spiroaziridine using different organo-catalysts (for details, see the Supporting Information). On preliminary investigation, the quinine (10 mol %) catalyzed the reaction of (±)-1a and malononitrile at 25 °C furnished the product 3a with the promising enantioselectivity along with a kinetic resolution of spiroaziridine 1a (Scheme 5). Scheme 5. Organocatalytic Asymmetric Domino Reaction and Kinetic Resolution of Spiroaziridine

■

CONCLUSION In conclusion, we have developed the first organocatalytic regio- and stereoselective domino reaction of spiroaziridine and malononitrile as a carbon pronucleophile at the spirocenter using only DBU as a catalyst. The protocol provides easy access of spiro[dihydropyrrole-3,3′-oxindole] with excellent enantiopurity (ee up to >99%) and yields. The organocatalytic protocol is equally effective for the N-sulfonyl phenyl aziridine, which usually needs Lewis acid and strong base. Further preliminary investigation of organocatalytic asymmetric domino reaction of racemic spiroaziridine showed a promising result with concomitant kinetic resolution of spiroaziridine. We intend to continue our research efforts toward this asymmetric reaction and other ring opening reaction of spiroaziridine in our laboratory.

■

EXPERIMENTAL SECTION

General Information. All the reactions were carried out under an atmosphere of argon using oven-dried glass wares. Commercially available reagents were purchased and used without further purification. Solvents were dried and distilled following the standard literature procedure. In all the cases, flash column chromatography was performed using silica gel (230−400 mesh). Analytical TLC was performed on aluminium-backed plates coated with silica gel 60 with an F254 indicator, and compounds were visualized by irradiation of UV light. The 1H NMR and 13C NMR spectra were recorded with Bruker 400 MHz and 100 MHz using CDCl3 and DMSO-d6. FT-IR experiments were performed on PerkinElmer Spectrum Version 10.03.08. HRMS and electron spray ionization (ESI) mass spectrometry (MS) experiments were performed on Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS. Enantiomeric excess (ee) was measured by HPLC analysis with chiral stationary phase. The melting points (Mps) were determined using a STUART SMP30 melting point apparatus and are uncorrected. 8197

DOI: 10.1021/acs.joc.9b01226 J. Org. Chem. 2019, 84, 8194−8201

Article

The Journal of Organic Chemistry

isopropyl alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm; tR = 15.48 min (major), tR = 14.57 min (minor). (R)-1-Allyl-5′-amino-1′-(tert-butylsulfonyl)-2-oxo-1′,2′dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3f). The product was prepared by following the general procedure and was obtained as a white solid (0.054 g; 90% yield): mp 156−158 °C; 1H NMR (400 MHz, CDCl3): δ 7.30−7.25 (m, 1H), 7.23 (dd, J = 7.7, 1.3 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.85 (s, 2H), 5.77 (ddd, J = 15.9, 10.5, 5.1 Hz, 1H), 5.22−5.12 (m, 2H), 4.33 (dd, J = 4.9, 1.9 Hz, 1H), 4.24−4.05 (m, 3H), 1.52 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.1, 158.4, 142.8, 130.6, 129.7, 128.6, 124.1, 123.7, 117.7, 116.5, 109.5, 65.2, 62.9, 59.2, 51.8, 42.5, 24.4; FT-IR (ν cm−1) 3437, 2920, 2188, 1715, 1643, 1585, 1487, 1364, 1130, 1045, 757, 662, 568; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H22N4NaO3S, 409.1310; found, 409.1304. HPLC analysis: ee >99%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm; tR = 42.01 min (major), tR = 30.14 min (minor). tert-Butyl-(R)-5′-amino-1′-(tert-butylsulfonyl)-4′-cyano-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-1-carboxylate (3g). The product was prepared by following the general procedure and was obtained as a white solid (0.038 g; 65% yield): mp 169−171 °C; 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.8 Hz, 1H), 7.36 (ddd, J = 7.3, 4.4, 2.8 Hz, 2H), 7.25 (d, J = 5.8 Hz, 1H), 5.80 (s, 2H), 4.24 (d, J = 10.9 Hz, 1H), 4.12 (d, J = 10.7 Hz, 1H), 1.65 (s, 9H), 1.57 (s, 9H); 13 C{1H} NMR (100 MHz, CDCl3): δ 176.4, 158.5, 148.6, 139.7, 130.0, 127.1, 125.5, 124.0, 116.3, 115.4, 85.2, 65.3, 63.6, 60.1, 52.3, 28.1, 24.4; FT-IR (ν cm−1) 3350, 2918, 2189, 1734, 1642, 1466, 1338, 1129, 759, 566; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H26N4NaO5S, 469.1522; found, 469.1509. HPLC analysis: ee = 98%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm tR = 14.66 min (major), tR = 17.62 min (minor). (S)-5′-Amino-1′-(tert-butylsulfonyl)-2-oxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3h). The product was prepared by following the general procedure and was obtained as a white solid (0.056 g; 90% yield); mp 214−216 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.07−6.94 (m, 3H), 6.85 (d, J = 7.7 Hz, 1H), 4.16 (d, J = 10.8 Hz, 1H), 3.98 (d, J = 10.8 Hz, 1H), 1.46 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 179.3, 158.2, 142.5, 130.7, 129.6, 124.7, 122.9, 117.7, 110.3, 64.8, 61.3, 58.8, 52.4, 24.1; FT-IR (ν cm−1): 3317, 2924, 2188, 1716, 1641, 1583, 1471, 1329, 1129, 1044, 757, 660, 596; HRMS (ESI-TOF) m/z: [M + Na]+ calcd C16H18N4NaO3S, 369.0997; found, 369.0992. HPLC analysis: ee >99%; CHIRALCEL OJ-H column, 250 mm, n-hexane/isopropyl alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm, tR = 15.12 min (major), tR = 18.80 min (minor). (R)-5′-Amino-1′-(tert-butylsulfonyl)-5-methoxy-1-methyl-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3i). The product was prepared by following the general procedure and was obtained as a white solid (0.055 g; 92% yield); mp 214−216 °C; 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.83 (dd, J = 8.5, 2.5 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 5.85 (s, 2H), 4.18 (d, J = 10.6 Hz, 1H), 4.09 (d, J = 10.5 Hz, 1H), 3.79 (s, 3H), 3.17 (s, 3H), 1.57 (s, 9H); 13 C{1H} NMR (100 MHz, CDCl3): δ 177.0, 158.4, 156.8, 137.0, 129.8, 116.5, 114.4, 111.0, 109.2, 65.2, 62.9, 59.2, 55.9, 52.1, 26.7, 24.4; FT-IR (ν cm−1) 3437, 2925, 2187, 1709, 1643, 1584, 1499, 1435, 1365, 1289, 1129, 1036, 853, 806, 755, 660, 597, 509; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H22N4NaO4S, 413.1259; found, 413.1253. HPLC analysis: ee >99%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 75:25; flow rate: 1.0 mL/min; 254 nm, tR = 21.25 min (major), tR = 31.97 min (minor). (S)-5′-Amino-1′-(tert-butylsulfonyl)-1,5-dimethyl-2-oxo-1′,2′dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3j). The product was prepared by following the general procedure and was obtained as a white solid (0.053 g; 88% yield): mp 225−227 °C; 1H NMR (400 MHz, CDCl3): δ 7.16−7.08 (m, 2H), 6.71 (d, J = 7.9 Hz, 1H), 5.81 (s, 2H), 4.16 (d, J = 10.7 Hz, 1H), 4.10 (d, J = 10.8 Hz, 1H), 3.18 (s, 3H), 2.34 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100

1H), 6.79 (d, J = 7.8 Hz, 1H), 6.45 (d, J = 7.4 Hz, 1H), 5.91 (s, 2H), 4.11 (d, J = 10.9 Hz, 1H), 3.82 (d, J = 10.9 Hz, 1H), 3.17 (s, 3H);13C{1H} NMR (100 MHz, CDCl3): δ 176.3, 156.1, 143.0, 135.6, 134.6, 130.1, 129.9, 129.6, 127.8, 123.5, 123.3, 115.8, 108.6, 65.0, 57.6, 52.4, 26.8; FT-IR (ν cm−1): 3368, 2925, 2191, 1715, 1613, 1468, 1361, 1090, 755, 604, 584; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H16N4NaO3S, 403.0841; found, 403.0828. HPLC analysis of 3a: ee = 12%; CHIRALCEL IA-3 column, 250 mm, n-hexane/ isopropyl alcohol = 80:20; flow rate: 1.0 mL/min; 254 nm; tR = 35.13 min (major), tR = 20.83 min (minor). 5′-Amino-1-benzyl-2-oxo-1′-(phenylsulfonyl)-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile ((±)-3b). The product was prepared by following the general procedure and was obtained as a white solid (0.05 g; 85% yield): mp 204−206 °C; 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 7.6 Hz, 2H), 7.31−7.23 (m, 2H), 7.19 (d, J = 7.6 Hz, 3H), 7.08 (t, J = 7.8 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.96 (s, 2H), 4.92 (d, J = 15.8 Hz, 1H), 4.72 (d, J = 15.8 Hz, 1H), 4.15 (d, J = 10.9 Hz, 1H), 3.82 (d, J = 10.9 Hz, 1H);13C{1H} NMR (100 MHz, CDCl3): δ 176.6, 156.2, 142.0, 135.5, 135.0, 134.6, 130.1, 129.9, 129.6, 128.9, 127.9, 127.8, 127.1, 123.5, 123.4, 116.0, 109.7, 65.0, 57.6, 52.5, 44.2; FT-IR (ν cm−1) 3355, 2924, 2853, 2191, 1715, 1644, 1612, 1467, 1363, 1170, 1089, 753, 687, 581; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C25H20N4NaO3S, 479.1154; found, 479.1138. 1-Allyl-5′-amino-2-oxo-1′-(phenylsulfonyl)-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile ((±)-3c). The product was prepared by following the general procedure and was obtained as a white solid (0.05 g; 84% yield): mp 132−134 °C; 1H NMR (400 MHz, CDCl3): δ 7.94−7.91 (m, 2H), 7.80−7.76 (m, 1H), 7.66 (t, J = 7.8 Hz, 2H), 7.21 (td, J = 7.8, 1.2 Hz, 1H), 6.90 (td, J = 7.6, 0.8 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.44 (d, J = 7.0 Hz, 1H), 6.00 (s, 2H), 5.82−5.72 (m, 1H), 5.20−5.15 (m, 2H), 4.35 (dd, J = 16.5, 4.9 Hz, 1H), 4.20 (dd, J = 16.5, 5.2 Hz, 1H), 4.12 (d, J = 10.9 Hz, 1H), 3.83 (d, J = 10.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.2, 156.1, 142.1, 135.6, 134.6, 130.6, 130.1, 129.9, 129.5, 127.8, 123.4, 123.4, 117.7, 115.9, 109.5, 64.9, 57.5, 52.4, 42.7; FT-IR (ν cm−1) 3445, 2925, 2191, 1716, 1645, 1590, 1487, 1363, 1218, 1171, 1089, 944, 856, 755, 687, 583; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H18N4NaO3S, 429.0997; found, 429.0979. (R)-5′-Amino-1′-(tert-butylsulfonyl)-1-methyl-2-oxo-1′,2′dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3d). The product was prepared by following the general procedure and was obtained as a white solid (small scale: 0.058 g; 95% yield. Gram-scale: 1.15 g, 94% yield): mp 178−181 °C; 1H NMR (400 MHz, CDCl3): δ 7.35− 7.31 (m, 2H), 7.14 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.76 (s, 2H), 4.19 (d, J = 10.8 Hz, 1H), 4.12 (d, J = 10.7 Hz, 1H), 3.21 (s, 3H), 1.58 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.2, 158.3, 143.7, 129.8, 128.5, 124.0, 123.7, 116.4, 108.7, 65.2, 63.1, 59.2, 51.7, 26.6, 24.4. FT-IR (ν cm−1) 3436, 2920, 2188, 1714, 1643, 1585, 1470, 1373, 1262, 1128, 1056, 754, 662, 568; HRMS (ESI-TOF) m/ z: [M + Na]+ calcd for C17H20N4NaO3S, 383.1154; found, 383.1149; HPLC analysis: ee >99%; CHIRALCEL IA-3 column, 250 mm, nhexane/isopropyl alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm, tR = 28.91 min (major), tR = 25.63 min (minor). (S)-5′-Amino-1-benzyl-1′-(tert-butylsulfonyl)-2-oxo-1′,2′dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3e). The product was prepared by following the general procedure and was obtained as a white solid (0.052 g; 88% yield): mp 115−116 °C; 1H NMR (400 MHz, CDCl3): δ 7.35−7.31 (m, 3H), 7.27 (d, J = 6.5 Hz, 3H), 7.21 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.73 (s, 2H), 5.02 (d, J = 15.8 Hz, 1H), 4.81 (d, J = 15.8 Hz, 1H), 4.25 (d, J = 10.7 Hz, 1H), 4.18 (d, J = 10.6 Hz, 1H), 1.60 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.5, 158.2, 146.1, 142.7, 135.0, 129.7, 128.9, 127.8, 127.0, 124.1, 123.8, 116.3, 109.8, 65.3, 63.4, 59.3, 51.9, 44.1, 24.4; FT-IR (ν cm−1) 3350, 2920, 2187, 1713, 1639, 1467, 1129, 756, 665, 568; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H24N4NaO3S, 459.1467; found, 459.1450. HPLC analysis: ee = 98%; CHIRALCEL IB-3 column, 250 mm, n-hexane/ 8198

DOI: 10.1021/acs.joc.9b01226 J. Org. Chem. 2019, 84, 8194−8201

Article

The Journal of Organic Chemistry MHz, CDCl3): δ 177.2, 158.3, 141.3, 133.4, 130.0, 128.5, 124.8, 116.6, 108.4, 65.2, 63.0, 59.3, 51.8, 26.6, 24.4, 21.2; FT-IR (ν cm−1) 3436, 2921, 2188, 1712, 1639, 1585, 1501, 1432, 1327, 1265, 1129, 1055, 808, 751, 661, 597, 552; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H22N4NaO3S, 397.1310; found, 397.1305. HPLC analysis: ee = 99% CHIRALCEL IA-3 column, 250 mm, n-hexane/ isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm, tR = 30.92 min (major), tR = 38.13 min (minor). (R)-5′-Amino-1′-(tert-butylsulfonyl)-1,5,7-trimethyl-2-oxo-1′,2′dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3k). The product was prepared by following the general procedure and was obtained as a white solid (0.054 g; 90% yield): mp 228−230 °C; 1H NMR (400 MHz, CDCl3): δ 6.96 (s, 1H), 6.84 (s, 1H), 5.79 (s, 2H), 4.14 (d, J = 10.6 Hz, 1H), 4.06 (d, J = 10.7 Hz, 1H), 3.44 (s, 3H), 2.50 (s, 3H), 2.28 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.9, 158.2, 138.9, 133.9, 133.1, 129.4, 122.7, 120.0, 116.6, 65.2, 63.5, 59.7, 51.3, 29.9, 24.4, 20.8, 18.7; FT-IR (ν cm−1) 3436, 2920, 2189, 1708, 1644, 1585, 1483, 1338, 1266, 1048, 762, 571; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H24N4NaO3S, 411.1467; found, 411.1463. HPLC analysis: ee >99%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm, tR = 26.65 min (major), tR = 15.39 min (minor). (S)-5′-Amino-1′-(tert-butylsulfonyl)-5-fluoro-1-methyl-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3l). The product was prepared by following the general procedure and was obtained as a white solid (0.052 g; 86% yield): mp 189−191 °C; 1 H NMR (400 MHz, CDCl3): δ 7.10−7.01 (m, 2H), 6.77 (dd, J = 8.5, 4.0 Hz, 1H), 5.85 (s, 2H), 4.19 (d, J = 10.6 Hz, 1H), 4.09 (d, J = 10.6 Hz, 1H), 3.20 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.0, 159.8 (d, JC−F = 243.0 Hz, 2C), 139.6, 139.6, 130.2, 116.3, 116.1, 112.2 (d, JC−F = 25.0 Hz, 2C), 109.4 (d, JC−F = 7.0 Hz, 2C), 65.3, 62.4, 59.1, 52.1 (d, JC−F = 2.0 Hz, 2C), 26.8, 24.3; . 19F NMR (376 MHz, CDCl3): δ −118.546; FT-IR (ν cm−1) 3344, 2919, 2186, 1756, 1584, 1463, 1311, 1128, 667, 597; HRMS (ESI-TOF) m/ z: [M + Na]+ calcd for C17H19FN4NaO3S, 401.1060; found, 401.1054. HPLC analysis: ee = 98%; CHIRALCEL IA-3 column, 250 mm, nhexane/isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm, tR = 52.91 min (major), tR = 46.97 min (minor); . (S)-5′-Amino-1′-(tert-butylsulfonyl)-5-chloro-1-methyl-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3m). The product was prepared by following the general procedure and was obtained as a white solid (0.051 g; 85% yield); mp 239−241 °C; 1 H NMR (400 MHz, CDCl3): δ 7.65 (dd, J = 8.2, 1.7 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.76 (s, 2H), 4.18 (d, J = 10.8 Hz, 1H), 4.10 (d, J = 10.8 Hz, 1H), 3.19 (s, 3H), 1.58 (s, 9H); 13 C{1H} NMR (100 MHz, CDCl3): δ 176.5, 158.4, 143.4, 138.7, 132.9, 130.9, 116.1, 110.7, 86.0, 65.3, 62.7, 59.1, 51.7, 26.7, 24.4; FTIR (ν cm−1) 3435, 2922, 2187, 1716, 1640, 1464, 1341, 1129, 1053, 810, 750, 665, 597; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H19ClN4NaO3S/C17H1937ClN4NaO3S, 417.0764 and 419.0764; found, 417.0757 and 419.0756, respectively. HPLC analysis: ee >99%; CHIRALCEL IB-3 column, 250 mm, n-hexane/isopropyl alcohol = 85:15; flow rate 1.0 mL/min; 254 nm, tR = 23.61 min (major), tR = 27.97 min (minor). (R)-5′-Amino-1′-(tert-butylsulfonyl)-5-bromo-1-methyl-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3n). The product was prepared by following the general procedure and was obtained as a white solid (0.05 g; 85% yield): mp 225−227 °C; 1H NMR (400 MHz, CDCl3): δ 7.45 (dd, J = 4.4, 2.4 Hz, 2H), 6.72 (d, J = 8.8 Hz, 1H), 5.84 (s, 2H), 4.18 (d, J = 10.9 Hz, 1H), 4.10 (d, J = 10.7 Hz, 1H), 3.19 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.7, 158.5, 142.7, 132.7, 130.7, 127.3, 116.3, 110.1, 108.7, 65.3, 62.3, 59.0, 51.8, 26.7, 24.4; FT-IR (ν cm−1) 3436, 2922, 2187, 1716, 1642, 1609, 1583, 1488, 1341, 1268, 1106, 1054, 813, 751, 655, 570; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H19BrN4NaO3S/C17H1981BrN4NaO3S, 461.0259 and 463.0259; found, 461.0243 and 463.0234, respectively. HPLC analysis: ee >99%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate 1.0 mL/min, 254 nm; tR = 44.57 min (major), tR = 50.10 min (minor).

(R)-5′-Amino-1′-(tert-butylsulfonyl)-5-iodo-1-methyl-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3o). The product was prepared by following the general procedure and was obtained as a white solid (0.052 g; 90% yield): mp 226−228 °C; 1H NMR (400 MHz, CDCl3): δ 7.32−7.30 (m, 2H), 6.78−6.76 (m, 1H), 5.77 (s, 2H), 4.19 (d, J = 10.8 Hz, 1H), 4.10 (d, J = 10.8 Hz, 1H), 3.20 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.8, 158.4, 142.2, 130.3, 129.8, 129.1, 124.6, 116.1, 109.7, 65.3, 62.6, 59.1, 51.9, 26.7, 24.4; FT-IR (ν cm−1) 3436, 2923, 2188, 1717, 1640, 1583, 1465, 1342, 1129, 1053, 812, 751, 654, 597; HRMS (ESITOF) m/z: [M + Na]+ calcd for C17H19IN4NaO3S, 509.0120; found, 509.0104. HPLC analysis: ee >99%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate 1.0 mL/min; 254 nm; tR = 50.00 min (major), tR = 46.12 min (minor). (R)-5′-Amino-1′-(tert-butylsulfonyl)-7-fluoro-1-methyl-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3p). The product was prepared by following the general procedure and was obtained as a white solid (0.048 g; 80% yield): mp 210−212 °C; 1H NMR (400 MHz, CDCl3): δ 7.11−7.10 (m, 1H), 7.06−7.03 (m, 2H), 5.90 (s, 2H), 4.18 (d, J = 10.8 Hz, 1H), 4.08 (d, J = 10.9 Hz, 1H), 3.41 (d, J = 2.7 Hz, 3H), 1.56 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.0, 158.4, 147.7 (d, JC−F = 244.0 Hz, 2C), 131.4, 130.3 (d, JC−F = 8.6 Hz, 2C), 124.3 (d, JC−F = 6.4 Hz, 2C), 119.9 (d, JC−F = 1.2 Hz, 2C), 117.8 (d, JC−F = 19.2 Hz, 2C), 116.2, 65.3, 62.9, 59.3, 52.0 (d, JC−F = 2.5 Hz, 2C), 29.1 (d, JC−F = 5.7 Hz, 2C), 24.3; 19F NMR (376 MHz, CDCl3): δ −135.981; FT-IR (ν cm−1) 3435, 2921, 2189, 1717, 1632, 1585, 1482, 1329, 1128, 1048, 665, 571; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H19FN4NaO3S, 401.1060; found, 401.1046. HPLC analysis: ee = 93%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm; tR = 38.79 min (major), tR = 29.90 min (minor). (R)-5′-Amino-1′-(tert-butylsulfonyl)-7-chloro-1-methyl-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3q). The product was prepared by following the general procedure and was obtained as a white solid (0.051 g; 85% yield): mp 201−203 °C; 1H NMR (400 MHz, CDCl3): δ 7.24−7.21 (m, 2H), 7.04 (dd, J = 8.2, 7.5 Hz, 1H), 5.82 (s, 2H), 4.17 (d, J = 10.8 Hz, 1H), 4.07 (d, J = 10.7 Hz, 1H), 3.58 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.5, 158.4, 139.6, 133.8, 132.1, 124.4, 122.7, 116.3, 116.1, 65.3, 62.9, 59.5, 51.5, 30.0, 24.3; FT-IR (ν cm−1) 3438, 2924, 2189, 1721, 1643, 1585, 1464, 1365, 1259, 1130, 1061, 814, 757, 688, 569; HRMS (ESI-TOF) m/z: [M + Na] + calcd for C17H19ClN4NaO3S/C17H1937ClN4NaO3S, 417.0764 and 419.0764; found, 417.0758 and 419.0756, respectively. HPLC analysis: ee = 95%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm; tR = 29.99 min (major), tR = 22.01 min (minor). (R)-5′-Amino-7-bromo-1′-(tert-butylsulfonyl)-1-methyl-2-oxo1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3r). The product was prepared by following the general procedure and was obtained as a white solid (0.05 g; 85% yield): mp 211−213 °C; 1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.1 Hz, 1H), 7.25 (dd, J = 7.4, 1.3 Hz, 1H), 6.97 (t, J = 7.8 Hz, 1H), 5.88 (s, 2H), 4.16 (d, J = 10.8 Hz, 1H), 4.05 (d, J = 10.7 Hz, 1H), 3.58 (s, 3H), 1.56 (s, 9H); 13 C{1H} NMR (100 MHz, CDCl3): δ 177.7, 158.5, 141.0, 135.4, 131.8, 124.8, 123.2, 116.4, 102.9, 65.3, 62.7, 59.6, 51.5, 30.3, 24.3; FTIR (ν cm−1) 3435, 2921, 2188, 1719, 1643, 1581, 1459, 1329, 1129, 1057, 767, 633, 569; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H19BrN4NaO3S/C17H1981BrN4NaO3S, 461.0259 and 463.0259; found, 461.0249 and 463.0230, respectively. HPLC analysis: ee = 96%; CHIRALCEL IA-3, 250 mm, eluent: n-hexane/isopropyl alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm): tR = 31.96 min (major), tR = 23.60 min (minor). (R)-5′-Amino-1′-(tert-butylsulfonyl)-4,7-dichloro-1-methyl-2oxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3s). The product was prepared by following the general procedure and was obtained as a white solid (0.041 g; 70% yield): mp 180−182 °C; 1 H NMR (400 MHz, CDCl3): δ 7.21 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 5.80 (s, 2H), 4.40 (d, J = 9.9 Hz, 1H), 4.14 (d, J = 10.1 Hz, 1H), 3.58 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, 8199

DOI: 10.1021/acs.joc.9b01226 J. Org. Chem. 2019, 84, 8194−8201

Article

The Journal of Organic Chemistry CDCl3): δ 177.1, 159.0, 140.9, 133.0, 130.2, 127.2, 125.1, 116.2, 114.8, 65.4, 60.6, 56.3, 52.5, 30.2, 24.5; FT-IR (ν cm−1) 3436, 2919, 2187, 1725, 1642, 1596, 1453, 1329, 1128, 1044, 752, 658, 599; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H18Cl2N4NaO3S/ C 17 H 18 37 Cl 35 ClN 4 NaO 3 S/C 17 H 18 37 Cl 37 ClN 4 NaO 3 S, 451.0374, 453.0374 and 455.0374; found, 451.0361, 453.0353 and 455.0344, respectively. HPLC analysis: ee = 96%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm; tR = 27.25 min (major), tR = 39.36 min (minor). (S)-2-Amino-1-((4-nitrophenyl)sulfonyl)-4-phenyl-4,5-dihydro1H-pyrrole-3-carbonitrile (6a). The product was prepared by following the general procedure and was obtained as a yellow solid (0.053 g; 90% yield): mp 171−173 °C; 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.1 Hz, 3H), 6.85 (d, J = 7.1 Hz, 2H), 5.74 (s, 2H), 4.20 (t, J = 10.4 Hz, 1H), 4.00 (dd, J = 10.0, 4.6 Hz, 1H), 3.60 (dd, J = 10.9, 4.6 Hz, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 154.3, 150.9, 141.4, 141.3, 129.0, 128.9, 127.7, 126.5, 124.8, 117.3, 66.1, 57.4, 42.6; FT-IR (ν cm−1) 3369, 2929, 2190, 1650, 1531, 1349, 1169, 1088, 740, 614, 597; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H14N4NaO4S, 393.0633; found, 393.0614. HPLC analysis: ee >99%; CHIRALCEL OD-H column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm; tR = 41.22 min (major), tR = 54.44 min (minor). (S)-2-Amino-4-phenyl-1-tosyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (6b). The product was prepared by following the general procedure and was obtained as a white solid (0.054 g; 88% yield overall, inseparable Regio-isomers 6b:6b′ = 4:1): mp 93−95 °C; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 6.0 Hz, 3H), 6.82 (d, J = 4.6 Hz, 2H), 5.83 (s, 2H), 4.07 (t, J = 10.3 Hz, 1H), 3.92 (dd, J = 10.1, 5.2 Hz, 1H), 3.47 (dd, J = 10.6, 5.2 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.4, 145.5, 141.8, 132.7, 130.3, 128.8, 127.7, 127.4, 126.8, 118.2, 65.0, 56.9, 42.7, 21.7. FT-IR (ν cm−1) 3447, 3367, 2922, 2189, 1646, 1594, 1426, 1365, 1164, 1089, 1045, 814, 757, 701, 662, 596, 562, 544; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H17N3NaO2S, 362.0939; found, 362.0929. HPLC analysis: ee >99% of 6b and 6b′; CHIRALCEL IA-3 column, 250 mm, n-hexane/ isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm major regio-isomer 6b tR = 28.79 min (major), tR = 24.42 min (minor). Minor regio-isomer 6b′ tR = 23.26 min (major), tR = 22.84 min (minor).

■

are thankful to Prof. P. Banerjee and his research group, IIT Ropar for X-ray crystal analysis.

■

(1) For reviews, see: (a) Galliford, C. V.; Scheidt, K. A. Pyrrolidinylspirooxindole natural products as inspirations for the development of potential therapeutic agents. Angew. Chem., Int. Ed. 2007, 46, 8748− 8758. (b) Marti, C.; Carreira, E. M. Construction of Spiro[pyrrolidine-3,3′-oxindoles] − Recent Applications to the Synthesis of Oxindole Alkaloids. Eur. J. Org. Chem. 2003, 2003, 2209−2219. (c) Cui, C.-B.; Kakeya, H.; Osada, H. Novel Mammalian Cell Cycle lnhibitors, Spirotryprostatins A and B, Produced by Aspergillusfumigatus, Which Inhibit Mammalian Cell Cycle at G2/M Phase1. Tetrahedron 1996, 52, 12651−12666. (d) Cui, C.-B.; Kakeya, H.; Osada, H. Spirotryprostatin B, a novel mammalian cell cycle inhibitor produced by Aspergillus fumigatus. J. Antibiot. 1996, 49, 832−835. (e) Yu, B.; Yu, D.-Q.; Liu, H.-M.; Spirooxindoles. Promising scaffolds for anticancer agents. Eur. J. Med. Chem. 2015, 97, 673−698. (f) Xu, P.-W.; Yu, J.-S.; Chen, C.; Cao, Z.-Y.; Zhou, F.; Zhou, J. Catalytic Enantioselective Construction of Spiro Quaternary Carbon Stereocenters. ACS Catal. 2019, 9, 1820−1882. (g) Cao, Z.-Y.; Wang, X.; Tan, C.; Zhao, X.-L.; Zhou, J.; Ding, K. Highly Stereoselective Olefin Cyclopropanation of Diazooxindoles Catalyzed by a C2-Symmetric Spiroketal Bisphosphine/Au(I) Complex. J. Am. Chem. Soc. 2013, 135, 8197−8200. (h) Liu, Y.-L.; Wang, X.; Zhao, Y.-L.; Zhu, F.; Zeng, X.-P.; Chen, L.; Wang, C.-H.; Zhao, X.-L.; Zhou, J. One-Pot Tandem Approach to Spirocyclic Oxindoles Featuring Adjacent Spiro-Stereocenters. Angew. Chem., Int. Ed. 2013, 52, 13735−13739. (i) Yin, X.-P.; Zeng, X.-P.; Liu, Y.-L.; Liao, F.-M.; Yu, J.-S.; Zhou, F.; Zhou, J. Asymmetric Triple Relay Catalysis: Enantioselective Synthesis of Spirocyclic Indolines through a One-Pot Process Featuring an Asymmetric 6π Electrocyclization. Angew. Chem., Int. Ed. 2014, 53, 13740−13745. (j) Cao, Z.-Y.; Zhou, F.; Zhou, J. Development of Synthetic Methodologies via Catalytic Enantioselective Synthesis of 3,3-Disubstituted Oxindoles. Acc. Chem. Res. 2018, 51, 1443−1454. (2) (a) Girgis, A. S. Regioselective synthesis of dispiro[1H-indene2,3’-pyrrolidine-2’,3’’-[3H]indole]-1,2’’(1’’H)-diones of potential antitumor properties. Eur. J. Med. Chem. 2009, 44, 91−100. (b) Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. A facile synthesis and antimycobacterial evaluation of novel spiro-pyridopyrrolizines and pyrrolidines. Eur. J. Med. Chem. 2009, 44, 3821− 3829. (c) Kouznetsov, V. V.; Arenas, D. R. M.; Arvelo, F.; Forero, J. S. B.; Sojo, F.; Muñoz, A. 4-Hydroxy-3-methoxyphenyl substituted 3methyl-tetrahydroquinoline derivatives obtained through imino dielsalder reactions as potential antitumoral agents. Lett. Drug Des. Discovery 2010, 7, 632−639. (d) Maheswari, S. U.; Balamurugan, K.; Perumal, S.; Yogeeswari, P.; Sriram, D. A facile 1,3-dipolar cycloaddition of azomethine ylides to 2-arylidene-1,3-indanediones: synthesis of dispiro-oxindolylpyrrolothiazoles and their antimycobacterial evaluation. Bioorg. Med. Chem. Lett. 2010, 20, 7278−7282. (e) Prasanna, P.; Balamurugan, K.; Perumal, S.; Yogeeswari, P.; Sriram, D. A regio- and stereoselective 1,3-dipolar cycloaddition for the synthesis of novel spiro-pyrrolothiazolyloxindoles and their antitubercular evaluation. Eur. J. Med. Chem. 2010, 45, 5653−5661. (f) Lo, M. M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.; Schreiber, S. L. A Library of Spirooxindoles Based on a Stereoselective Three-Component Coupling Reaction. J. Am. Chem. Soc. 2004, 126, 16077−16086. (g) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schürmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products. Nat. Chem. 2010, 2, 735−740. (3) (a) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. Total Synthesis of Spirotryprostatin A, Leading to the Discovery of Some Biologically Promising Analogues. J. Am. Chem. Soc. 1999, 121, 2147−2155. (b) Meyers, C.; Carreira, E. M. Total synthesis of (-)-spirotryprostatin B. Angew. Chem., Int. Ed. 2003, 42, 694−696. (c) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.;

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01226.

■

REFERENCES

NMR spectra for all new compounds 1, 3, and 6 and HPLC chromatogram of compounds 3 and 6 (PDF) Crystal data of compound ent-3m (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: (+91)-5222668861. Fax: (+91)-522-2668995. ORCID

Saumen Hajra: 0000-0003-0303-4647 Maya Shankar Singh: 0000-0002-3199-0823 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank MoES, New Delhi (MoES/09-DS/12/2015 PC-IV) for providing financial support. S.A.S. and A.H. thank UGC and CSIR, New Delhi, respectively, for their fellowships. We 8200

DOI: 10.1021/acs.joc.9b01226 J. Org. Chem. 2019, 84, 8194−8201

Article

The Journal of Organic Chemistry

Lactams. J. Org. Chem. 2010, 75, 6173−6181. (f) Bhattacharyya, A.; Shahi, C. K.; Pradhan, S.; Ghorai, M. K. Stereospecific Synthesis of 1,4,5,6-Tetrahydropyrimidines via Domino Ring-Opening Cyclization of Activated Aziridines with α-Acidic Isocyanides. Org. Lett. 2018, 20, 2925−2928. (g) Shiomi, N.; Kuroda, M.; Nakamura, S. Desymmetrization of aziridine with malononitrile using cinchona alkaloid amide/zinc(II) catalysts. Chem. Commun. 2017, 53, 1817−1820. (9) (a) Moss, T. A.; Alba, A.; Hepworth, D.; Dixon, D. J. Efficient base catalyzed alkylation reactions with aziridine electrophiles. Chem. Commun. 2008, 2474−2476. (b) Moss, T. A.; Fenwick, D. R.; Dixon, D. J. Enantio- and diastereoselective catalytic alkylation reactions with aziridines. J. Am. Chem. Soc. 2008, 130, 10076−10077. (c) Paixão, M. W.; Nielsen, M.; Jacobsen, C. B.; Jørgensen, K. A. Organocatalytic asymmetric ring-opening of aziridines. Org. Biomol. Chem. 2008, 6, 3467−3470.

Roller, P. P.; Wang, S. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J. Med. Chem. 2006, 49, 3432−3435. (d) Zhao, Y.; Liu, L.; Sun, W.; Lu, J.; McEachern, D.; Li, X.; Yu, S.; Bernard, D.; Ochsenbein, P.; Ferey, V.; Carry, J.-C.; Deschamps, J. R.; Sun, D.; Wang, S. Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors. J. Am. Chem. Soc. 2013, 135, 7223− 7234. (e) Fu, P.; Kong, F.; Li, X.; Wang, Y.; Zhu, W. Cyanogramide with a New Spiro[indolinone-pyrroloimidazole] Skeleton from Actinoalloteichus cyanogriseus. Org. Lett. 2014, 16, 3708−3711. (f) Hong, S.; Jung, M.; Park, Y.; Ha, M. W.; Park, C.; Lee, M.; Park, H.-g. Efficient enantioselective total synthesis of (-)-horsfiline. Chem.Eur. J. 2013, 19, 9599−9605. (4) For review, see: (a) Fang, X.; Wang, C.-J. Catalytic asymmetric construction of spiropyrrolidines via 1,3-dipolar cycloaddition of azomethine ylides. Org. Biomol. Chem. 2018, 16, 2591−2601. For selected examples see: (b) Shanmugam, P.; Viswambharan, B.; Madhavan, S. Synthesis of Novel Functionalized 3-Spiropyrrolizidine and 3-Spiropyrrolidine Oxindoles from Baylis−Hillman Adducts of Isatin and Heteroaldehydes with Azomethine Ylides via [3+2]Cycloaddition. Org. Lett. 2007, 9, 4095−4098. (c) Sebahar, P. R.; Williams, R. M. The Asymmetric Total Synthesis of (+)- and (−)-Spirotryprostatin B. J. Am. Chem. Soc. 2000, 122, 5666−5667. (5) (a) Hajra, S.; Maji, B.; Mal, D. A Catalytic and Enantioselective Synthesis of trans-2- Amino-1-aryltetralins. Adv. Synth. Catal. 2009, 351, 859−864. (b) Hajra, S.; Bar, S. Catalytic enantioselective synthesis of A-86929, a dopamine D1 agonist. Chem. Commun. 2011, 47, 3981−3982. (c) Hajra, S.; Sinha, D. Catalytic Enantioselective Aziridoarylation of Aryl Cinnamyl Ethers toward Synthesis of trans-3Amino-4-arylchromans. J. Org. Chem. 2011, 76, 7334−7340. (d) Hajra, S.; Akhtar, S. M. S.; Aziz, S. M. Catalytic asymmetric aminolactonization of 1,2-disubstituted alkenoic acid esters: Efficient construction of aminolactones with an all-carbon quaternary stereocentre. Chem. Commun. 2014, 50, 6913−6916. (6) (a) Hajra, S.; Aziz, S. M.; Jana, B.; Mahish, P.; Das, D. Synthesis of Chiral Spiro-Aziridine Oxindoles via Aza-Corey−Chaykovsky Reaction of Isatin Derived N-tert-Butanesulfinyl Ketimines. Org. Lett. 2016, 18, 532−535. (b) Hajra, S.; Roy, S. S.; Aziz, S. M.; Das, D. Catalyst-Free “On-Water” Regio- and Stereospecific Ring-Opening of Spiroaziridine Oxindole: Enantiopure Synthesis of Unsymmetrical 3,3′-Bisindoles. Org. Lett. 2017, 19, 4082−4085. (c) Hajra, S.; Roy, S. S.; Biswas, A.; Saleh, S. A. Catalyst-Free Ring Opening of Spiroaziridine Oxindoles by Heteronucleophiles: An Approach to the Synthesis of Enantiopure 3-Substituted Oxindoles. J. Org. Chem. 2018, 83, 3633−3644. (d) Hajra, S.; Roy, S.; Saleh, S. A. Domino Corey−Chaykovsky Reaction for One-Pot Access to Spirocyclopropyl Oxindoles. Org. Lett. 2018, 20, 4540−4544. (e) Hajra, S.; Hazra, A.; Mandal, P. Stereocontrolled Nucleophilic Fluorination at the Tertiary sp3-Carbon Center for Enantiopure Synthesis of 3-Fluorooxindoles. Org. Lett. 2018, 20, 6471−6475. (7) For reviews, see: (a) Tietze, L. F. Domino Reactions in Organic Synthesis. Chem. Rev. 1996, 96, 115−136. (b) Pellissier, H. Stereocontrolled Domino Reactions. Chem. Rev. 2013, 113, 442− 524. (c) Chanda, T.; Zhao, J. C.-G. Recent Progress in Organocatalytic Asymmetric Domino Transformations. Adv. Synth. Catal. 2018, 360, 2−79. (8) For review see: (a) Hu, X. E. Nucleophilic ring opening of aziridines. Tetrahedron 2004, 60, 2701−2743. (b) Singh, G. S.; Sudheesh, S.; Keroletswe, N. Recent applications of aziridine ring expansion reactions in heterocyclic synthesis. Arkivoc 2017, 2018, 50−113. (c) Talukdar, R.; Saha, A.; Ghorai, M. K. Domino-Ring Opening-Cyclization (DROC) of DonorAcceptor (DA) Cyclopropanes. Isr. J. Chem. 2016, 56, 445−453. For selected examples see: (d) Ghorai, M. K.; Tiwari, D. P. Enantioselective Synthesis of 4,5Dihydropyrroles via Domino RingOpening Cyclization (DROC) of N-Activated Aziridines with Malononitrile. J. Org. Chem. 2013, 78, 2617−2625. (e) Ghorai, M. K.; Tiwari, D. P. Lewis Acid Catalyzed Highly Stereoselective Domino-Ring-Opening Cyclization of Activated Aziridines with Enolates: Synthesis of Functionalized Chiral γ8201

DOI: 10.1021/acs.joc.9b01226 J. Org. Chem. 2019, 84, 8194−8201