Catalyst-Free Ring Opening of Spiroaziridine Oxindoles by

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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03288 • Publication Date (Web): 01 Mar 2018 Downloaded from http://pubs.acs.org on March 1, 2018

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The Journal of Organic Chemistry

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.

yield up to 97% ee up to 96 % R1

Ar

Bus N H O

S

R1

N R2

Ar SH

Me O

Bus R/Ar

N

NH2 1

Ar/R R1

R NH

NH O Bus

N R2 yield up to 94% ee up to 99 %

R2 O

N R2

HO

N

Me

O HN

Bus yield 79% ee 85 %

# Catalyst-free # Water-mediated # High regioselectivity # High enantioselectivity

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 catalystfree conditions. Again, unlike simple 2-substituted aziridines, these spiroaziridines are opened up with retention in configuration at 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 1 ACS Paragon Plus Environment

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to their presence in various alkaloids but they serve also as precursors for a number of naturally occurring molecules.2 Among various oxindoles, the disubstituted enantiopure 3aminoxindoles,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 anti-malarial agent NITD609,6a donaxaridine, dioxibrassinine,4a,d 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-aminoxindoles7-11 The main strategy has been asymmetric nucleophilic addition to isatin-derived imines7a,c,d,e or simple isatins.7b,c,10 Amination7a,c,8,11 of 3-monosubstituted oxindoles can also produce 3-aminoxindoles.

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

Our previously developed12 spiroaziridine oxindole13 was anticipated to be an advantageous precursor, as we can directly access a diverse array of pharmacologically important molecular 2 ACS Paragon Plus Environment

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motifs through the judicious opening of these activated aziridines by a suitable nucleophile. Although nucleophilic addition to spiroaziridines appears simple, controlling the regio- and stereoselectivity of the reaction, which govern 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 oxindoles with carbon nucleophiles such as indole.14 Therefore, we anticipated that heteronucleophiles could act in a similar manner under the same reaction conditions (water-mediated and catalyst-free) to generate the desired products with the predicted stereoselectivity. The water-mediated stereoselective ringopening reactions of simple non-racemic 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 watermediated 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.

Scheme 1. Water-mediated catalyst-free ring opening of aziridine, spiroepoxide, and spiroaziridine.

=

= 3 ACS Paragon Plus Environment


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=

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 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.

Scheme 2. Synthesis of spiroaziridine oxindoles 1 from sulfinyl aziridines 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 temperature, 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). 4 ACS Paragon Plus Environment

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Table 1. Optimization of the reaction conditionsa

entry

solvent

temp

time

yield

eeb

(°C)

(h)

(%)

(%)

1

water

25

2

87

95

2

water

0

17

80

83

3

water

10

4

84

93

4

water

45

1

86

94

5

trifluoroethanol

0

14

83

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.

With the optimal conditions determined, we next explored the scope of amines for this regioand stereoselective ring-opening reaction of spiroaziridine oxindole 1a. Electron-withdrawing and electron-donating functionalities as well as aromatic and aliphatic amines were welltolerated 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). Table 2. Reaction of N-methyl aziridine 1a with aromatic and aliphatic aminesa

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entry

Ar/RNHR1

product

time (h)

yield (%)

eeb (%)

1

C6H5NH2

3aa

2

87

96

2

2-F-C6H4NH2

3ab

4

94

99

3

3-F-C6H4NH2

3ac

4.5

86

91

4

4-F-C6H4NH2

3ad

2

94

99

5

3,4-F2C6H3NH2

3ae

6

81

85

6

3-Cl-4-F-C6H3NH2

3af

12

94

99

7

2-MeOC6H4NH2

3ag

1

83

90

8

4-MeOC6H4NH2

3ah

1

81

91

9

3,5-(MeO)2C6H3NH2

3ai

1

88

94

10

2-Br-C6H4NH2

3aj

48

91

87

11

C6H5NHMe

3ak

1.5

88

92

12c,d

2-NO2C6H4NH2

ent-3al

48

27

75

13

MeNH2

3aa'

10

82

87

n-C6H13NH2

ent-3ab'

4

74

95

14

d

a

N-Methyl spiroaziridine oxindole 1a (0.34 mmol), amine (0.68 mmol), and water (3 mL) were stirred at 25 °C. b Determined by HPLC analysis on a chiral stationary phase. c40% conversion based on 1H NMR analysis of the crude reaction mixture. d The 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.

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, electron-donating 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. 6 ACS Paragon Plus Environment

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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 product in good yield (82%) with excellent enantioselectivity (92%) (Table 2, entry 13). The longer chain length of nhexylamine caused it to slow the reaction rate (Table 2, entry 14). However, the higher ee of the diamine product 3ab' compared to 3aa' 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 3Cl,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. Whereas the reaction of substituted anilines with N-methylaziridines 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).



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.

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, N-methyl 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 (ee = 96%).


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Table 3. Exploration of the scope of the reaction with spiroaziridines and various thiolsa

entry R

1

ArSH 6

product

time (h) yield (%) eeb (%)

1c

H

ent-1a C6H5SH

ent-5aa

1

92

93

2

H

1a

4-MeOC6H4SH

5ab

0.5

81

93

2-mercaptopyridine 5ac

2

97

94

3

H

1a

4

c

5-F

ent-1b C6H5SH

ent-5ba 3

95

95

5

c

5-F

ent-1b 4-MeOC6H4SH

ent-5bb 1

94

96

82

92

6 a

5-Cl 1f

4-MeOC6H4SH

5fb

0.8

Reaction conditions: 1a (0.34 mmol), PhSH (0.68 mmol), and water (3 mL) were stirred at 25 °C. b Determined

by HPLC analysis on a chiral stationary phase. c The reaction was carried out with (S)-spiroaziridine ent-1.

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 ent-7aa 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.

Scheme 3. Reaction of N-methyl aziridine ent-1a with methanol

.

The regioselectivity of the spiroaziridine ring opening by heteronucleophiles at C3spirocenter 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 9 ACS Paragon Plus Environment


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 type 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 ring opening of spiroaziridines 1 with heteronucleophiles are also assumed to be a retention in configuration at the C3-stereocentre. Thus, the absolute stereochemistry of the C3-center of products 3, 5 and 7 are 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 SN2 mechanism with inversion of configuration at the stereocenter.15,19,20 However, the chemistry of spiroaziridineoxindole was unexplored until recently.14 Based on 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 open reaction at the C3-center, but with retention in configuration (Scheme 4). The activation through hydrogen-bonding might generate a partial carbenium ion species 1ˊ which is stabilized by the benzylic nature and destabilized by the oxindole-carbonyl. Thus, similar to Lewis acid mediated ring opening of 2-substituted 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 the spiro-stereocenter. The partial Scheme 4. Proposed mechanism for water-mediated ring-opening of spiroaziridine oxindole 1 by heteronucleophiles with retention in configuration at the spirocenter


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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 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 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 electronwithdrawing group such as -Boc and –Ts containing substrates (1i and 1j) took 8 h. However, high enantioselectivity was maintained irrespective of the protecting groups. In the contrary, reaction with N-benzyl substrate 1g (R2 = Bn) was found to be very slow. It took 24 h and resulted 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 to adopt 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 few substrates might also be attributed due to the partial reaction via indol-2-one intermediate B and subsequent nucleophilic attack from both sides. Scheme 5. Effect of N1-protection in ring opening reaction of spiroaziridine 1


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To demonstrate the general applicability and the robustness of the method, the ringopening 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 imidazolidinespiroxindoles.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 either with CS2 or 1,1′-carbonyldiimidazole (CDI) to give the spirocyclic compounds 9 and 10, respectively, in good yield (Scheme 6).

Scheme 6. Synthesis of spirooxindoles 9 and 10 from vicinal diamino compound 3aa

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. Again, unlike simple 2-substituted aziridine, the 13 ACS Paragon Plus Environment


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ring-opening reaction of spiro-aziridine proceeds with retention in configuration at C3stereocenter, based on which, a plausible double SN2 mechanism (SN2ˊ) 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 functionalized spirooxindoles by spiroaziridine ring opening will be reported soon.

EXPERIMENTAL SECTION General information: All the reactions were carried out using oven dried glass wares 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 QGARD00R1, Q-Gard® 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 standard procedure. Flash column chromatography was performed in all the cases using silica gel (230-400 mesh). Analytical TLC was performed on aluminium-backed plates coated with silica gel 60 with 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

13

C NMR spectra recorded with 100

1

MHz/150 MHz/200 MHz using CDCl3 or DMSO-d6. H NMR chemicals shift 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 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-tertbutanesulfinyl ketimines. Spiroaziridines 1i and ent-1j were synthesized from the compound 4h and ent-4h, respectively. Ring opening reactions are mostly carried out with (R)spiroaziridines 1, otherwise it is noted.


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(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 earlier report,12,14 in THF (8 mL) was added Boc2O (0.33 g, 1.5 mmol) and 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 crystalized 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) 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 15 ACS Paragon Plus Environment


(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 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 bottomed flask with a magnetic stirring bar. After stirring at 25 °C for a specific time, as mentioned in the Table 2 and Fig. 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, EtOAcHexanxes/EtOAc) to afford the product. Synthesis of (R)-vicinal diamino oxindoles 3aa from 1a: Under 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 extracted with EtOAc (3 × 50 mL). The combined organic phase was dried over Na2SO4, filtered and evaporated in vacuo. Flash column chromatography (SiO2, EtOAcHexanxes/EtOAc 60:40) was done to afford the product 3aa (91% yield, 1.08 g). Characterisation data for compounds: (R)-2-Methyl-N-((1-methyl-2-oxo-3-(phenylamino)indolin-3-yl)methyl)propane-2sulfonamide (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 ºC; 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).

13

C {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


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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)-2methylpropane-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 ⁰C; 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, n-hexane/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)-2methylpropane-2-sulfonamide (3ac): The product was prepared from (R)-spiroaziridine oxindole 1a by following the general procedure and was obtained as a white solid (0.118g;

86% yield); mp 162-164 ⁰C; 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)-2methylpropane-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 = 17 ACS Paragon Plus Environment


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).

13

C {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-3-yl)methyl)-2methylpropane-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 ⁰C; 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)-2methylpropane-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 ⁰C; 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-


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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-3-yl)methyl)-2methylpropane-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 ⁰C; 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 forC21H28N3O4S 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-3-yl)methyl)-2methylpropane-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 ⁰C; 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. (R)-N-((3-((3,5-Dimethoxyphenyl)amino)-1-methyl-2-oxoindolin-3-yl)methyl)-2methylpropane-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), 19 ACS Paragon Plus Environment


3.54 (s, 6H), 3.30 (s, 4H), 1.40 (s, 9H).

13

C {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)-2methylpropane-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 ⁰C; 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)propane2-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).

13

C {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)propane2-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 20 ACS Paragon Plus Environment

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(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).

13

C {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-2sulfonamide (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, 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-2sulfonamide (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)-2methylpropane-2-sulfonamide (ent-3bb): The product was prepared from (S)-spiroaziridine 21 ACS Paragon Plus Environment


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)-2methylpropane-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 ⁰C ; 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-2-oxoindolin-3yl)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 ⁰C; 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 22 ACS Paragon Plus Environment

Page 22 of 35

Page 23 of 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


= 4.5 Hz), 112.6 (d, J = 25 Hz), 110.0, (d, J = 7.5 Hz), 63.7, 60.5, 51.3, 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)-2methylpropane-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 ⁰C; 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).

13

C {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, n-hexane/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)-2methylpropane-2-sulfonamide (3baʹ): 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). 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 23 ACS Paragon Plus Environment


Hz, 1H), 3.30 (d, J = 12.9 Hz, 1H), 3.21 (s, 3H), 2.04 (s, 3H), 1.34 (s, 9H).

Page 24 of 35

13

C {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)-2methylpropane-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). 13

C {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)-2methylpropane-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 ⁰C; 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). 13

C {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/i-PrOH = 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)-2methylpropane-2-sulfonamide ( 3caʹ): The product was prepared from (R)-spiroaziridine oxindole 1c by following the general procedure and was obtained as a white solid (0.087 g; 24 ACS Paragon Plus Environment

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80% yield); mp 165- 167 ⁰C; 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).

13

C {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-3-yl)methyl)-2methylpropane-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 ⁰C; 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)-2methylpropane-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).

13

C {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 25 ACS Paragon Plus Environment


Page 26 of 35

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).

13

C {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, 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-2-oxoindolin-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).

13

C {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)-2methylpropane-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. 26 ACS Paragon Plus Environment

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(R)-N-((1-Benzyl-2-oxo-3-(phenylamino)indolin-3-yl)methyl)-2-methylpropane-2sulfonamide (3ga): The product was prepared from (R)-spiroaziridine oxindole 1g by following the general procedure and was obtained as a white solid (0.113g; 91% yield); mp 88-90 ⁰C; 1

H 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).

13

C {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-methylpropane2-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).

13

C {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 (ESI-TOF) m/z: [M+H]+ Calcd for C27H32N3O3S 478.2164; found 478.2163. HPLC analysis: ee = 85%; 25 cm Chiralpak IA-3 column, n-hexane/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 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, 27 ACS Paragon Plus Environment


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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-oxo-3-

(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 (ESI-TOF) m/z: [M+H]

+

Calcd for

C24H32N3O5S+ 474.2057; found 474.2078. HPLC analysis: ee = 98%; 25 cm Chiralpak IA-3 column, n-hexane/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-2sulfonamide (ent-3ja): The compound was prepared from (S)-spiroaziridine ent-1j by following the general procedure and was obtained as a bronish 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/i-PrOH = 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-2sulfonamide (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). 1

H 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,


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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 (ESI-TOF) m/z: [M+H]+ Calcd for C20H25N2O3S2 405.1307; found 405.1305. HPLC analysis: ee = 93%; 25 cm Chiralcel OD-H column, nhexane/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)-2methylpropane-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 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-2sulfonamide (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 C19H24N3O3S2 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-2sulfonamide (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 29 ACS Paragon Plus Environment


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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)-2methylpropane-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)-2methylpropane-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). 1H 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).

13

C {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.


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(S)-N-((3-methoxy-1-methyl-2-oxoindolin-3-yl)methyl)-2-methylpropane-2-sulfonamide (ent-7aa): Under argon atmosphere ent-1a (0.100 g, 0.34 mmol) and degassed dry methanol (3.4 mL) was 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 washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Flash column chromatography (SiO2, Hexanxes/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). 13C {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

argon atmosphere, at 0 °C, triflic acid was added drop wise 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. 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 combine 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 ⁰C; 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): THF solution of 1,1′-carbonyldiimidazole (CDI) (0.065 g, 0.41 mmol) was added drop wise to a stirred solution of the crude diamine compound 8 (0.1 g, 0.38 mmol) in 1.5 mL 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 combine 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).

13

C {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.

ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author *[email protected] Fax: (+91)-522-2668995; Tel.: (+91)-522-2668861 Author Contributions SSR and AB contributed equally. Notes The authors declare no competing financial interest ACKNOWLEDGMENT 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. thanks, DST, New Delhi and UGC, New Delhi for their fellowships. We thank the Director of CBMR for providing research facilities.

Supporting Information 32 ACS Paragon Plus Environment

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NMR spectra and HPLC chromatograms for all new compounds 1i, 1j, 3, 5, 7, 9 and 10. This material is available free of charge via the Internet at http://pubs.acs.org

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Catalyst-Free Ring Opening of Spiroaziridine Oxindoles by

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