1,3-Dipolar cycloaddition of isatin-derived azomethine ylides with 2H

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1,3-Dipolar cycloaddition of isatin-derived azomethine ylides with 2H-azirines: stereoselective synthesis of 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindoles Aniko Angyal, Andras Demjen, Veronika Harmat, Janos Wolfling, Laszlo G. Puskas, and Ivan Kanizsai J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Mar 2019 Downloaded from http://pubs.acs.org on March 12, 2019

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The Journal of Organic Chemistry

1,3-Dipolar cycloaddition of isatin-derived azomethine ylides with 2Hazirines: stereoselective synthesis of 1,3diazaspiro[bicyclo[3.1.0]hexane]oxindoles Anikó Angyal,†,‡ András Demjén†, Veronika Harmat§, János Wölfling‡, László G. Puskás†, Iván Kanizsai†,* † AVIDIN

Ltd., Alsó kikötő sor 11/D, Szeged, H-6726, Hungary; ‡ Department of Organic Chemistry, University of Szeged, Dóm tér 8, H6720, Szeged, Hungary; § Institute of Chemistry, Eötvös Loránd University, Laboratory of Structural Chemistry and Biology, and MTAELTE Protein Modeling Research Group, Pázmány P. sétány 1/A, H-1117, Budapest, Hungary Tel.: +36-62/202107; fax: +36-62/202108; e-mail: [email protected]

Abstract A regio- and diastereoselective 1,3-dipolar cycloaddition of 2H-azirines with azomethine ylides generated in situ from isatins and α-amino acids has been elaborated, affording an unprecedented aziridine-fused spiro[imidazolidine-4,3’-oxindole] framework. This onepot three-component reaction tolerates a wide range of substrates, and enables the construction of highly-diverse 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindoles in isolated yields up to 81% under mild conditions.

of isatin-derived azomethine ylides has not been studied yet. Previous reports: O (a)

R5

R4

R1 N R2

O+

R3

X N H X: H, COOH

NR7

4

R

N R6

N R6 O

N

R1

Ar

COOEt (b) R1

N R2

O+

H2N

COOEt

+

R1

N R2

O +

R3

NH COOH

+

NH O N R2

R6 R4

COOEt COOEt

N

Ar2 CHO

Our work:

(c)

1

R1

O

R R6 R1

R3

N

5

N R5

O

R2 Ar2

1 N Ar

Introduction The synthesis of spiroheterocycles containing oxindole scaffold is regarded as a growing field of interest. It is due to their pronounced biological and pharmaceutical activity,1 in particular, the spiro-oxindolopyrrolidine framework, which constitutes the core unit of numerous alkaloids and pharmaceutics.2 Among the known synthetic strategies, the 1,3-dipolar cycloaddition (1,3-DC) of isatin-derived azomethine ylides with dipolarophiles has been proved to be the main tool for the construction of spirocyclic oxindoles.3 In terms of dipolarophiles, a considerable amount of alkenes4 and alkynes5 have been subjected to 1,3-DC leading to the formation of various spiro-oxindolopyrrolidines and spiropyrrolines. In contrast, the assembly of analogous spirooxindoloimidazolidines by the utilization of imines as dipolarophiles is scarcely explored.6-9 Additionally, the few reported efforts focus mainly on the synthesis of dispirooxindole derivatives, exploiting the reaction of an electron-deficient isatin-derived ketimine with an azomethine ylide generated from isatin and amines or αamino acids (Scheme 1a).7 Other approaches involve a different route for the in situ formation of the azomethine ylide, employing diazooxindoles, amines and aldehydes as starting materials.8 An alternative protocol, established recently by the Shi group, relies on the three-component reaction of isatin-derived imines, amino ester and aldehydes via 1,3-DC catalyzed by phosphoric acid. It enables the construction of the spirooxindoloimidazolidine scaffold with a different regiochemical outcome (Scheme 1b).9 Although the scope of 1,3-DC in the synthesis of spirocyclic oxindoles has been broadened by various dipolarophiles, to the best of our knowledge, the utilization of 2H-azirines as dipolarophiles in cycloaddition reactions

N

R3 N

O

+

R5

R7

N

R4 O

N R2

unprecedented f ramework

Scheme 1. Synthesis of spiro-oxindoloimidazolidines As a continuation of our interest in constructing aziridine-based heterocycles,10 here we report the first synthesis of 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindole framework through the one-pot three-component reaction of isatins, α-amino acids and 2H-azirines in a diastereoand regioselective manner (Scheme 1c). Results and Discussion At the outset of the study, the feasibility of the azirinebased 1,3-DC was investigated by performing the model three-component reaction of isatin 1a, D-(-)-2phenylglycine 2a and (±)-ethyl 3-methyl-2H-azirine-2carboxylate 3a in polar solvents at room temperature (Table 1, entries 1‒5). To our delight, the cycloaddition proceeded smoothly in DMSO and led to desired endocycloadducts 4a and 4b as racemic diastereomers, in acceptable HPLC yield and high diastereoselectivity (92:8 dr) (Table 1, entry 5). The structures of diastereomers 4a and 4b were unambiguously confirmed by NMR spectroscopy and single-crystal X-ray diffraction (See Supporting Information).

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Table 1. Optimization of reaction conditions EtOOC

O

N H 1a

O+

+

N

NH O

COOEt

NH2

HOOC

N NH

+

O

N H (±)-4a major

(±)-3a

2a

EtOOC

N

N H (±)-4b minor

entrya

solvent

temp. (°C)

time (h)

conv. (%)

yield (%)b

drc

1

MeOH

rt

36

91

44

87:13

2

EtOH

rt

36

81

9

85:15

3

TFE

rt

36

83

10

62:38

4

DMF

rt

36

84

11

90:10

5

DMSO

rt

36

93

54 (47)d

92:8

6

MeOH

60

36

98

53

84:16

7

EtOH

60

36

98

71

82:18

8

IPA

60

36

90

49

74:26

9

t-BuOH

60

36

85

13

59:41

10

MeCN

60

36

84

4

74:26

11

DMF

60

36

97

37

90:10

12

THF

60

36

83

2

52:48

13

toluene

60

36

-

-

-

14

CHCl3

60

36

82

2

52:48

15

TFE

60

36

94

31

53:47

16

DMSO

60

36

100

73

92:8

17

DMSO

60

8

100

51

92:8

18

DMSO

f

60

8

100

61

92:8

19

DMSO

60

8

100

72 (65)d

92:8

20

DMSOg

60

8

100

68

92:8

21

DMSOh

60

8

100

69

92:8

e

Reaction conditions: isatin (0.25 mmol), D-(-)-2-phenylglycine (0.3 mmol), 2H-azirine (0.25 mmol), 1 ml anhydrous solvent, argon atmosphere. bCombined yield of 4a and 4b determined by HPLC analysis. cThe diastereomeric ratio (dr) was determined by HPLC analysis. Both diastereomers were calibrated. dIsolated yield of 4a in parenthesis. e0.25 ml anhydr. solvent was applied. f0.5 ml anhydr. solvent was applied. g2 ml anhydr. solvent was applied. h4 ml anhydr. solvent was applied.

At first, with the optimized conditions in hand, the generality of the 1,3-DC with respect to the isatin component was examined, using phenylglycine 2a and azirine 3a as inputs (Scheme 2a). Gratifyingly, both electron-rich and electron-deficient isatins were tolerated well, providing major diastereomers 5a–10a in 44–78% isolated yields (Scheme 2a). Remarkable substituent effect was not observed; however, the presence of electronwithdrawing groups (Br and NO2) at C-7 or the application of N-benzylisatin resulted in lower yields (6a, 7a and 10a). Subsequently, the azirine scope of the 1,3-DC was investigated, employing isatin 1a and phenylglycine 2a as precursors of the azomethine ylide (Scheme 2b, 11a–17a). Scheme 2. Scope of isatins and 2H-azirines R4

O

R1

N R2

NH2 O +

COOH +

a)

EtOOC

N R3

2a

1a–g

EtOOC

O

O

EtOOC

NH

O

O

MeO

Ph NH

O

O

Ph N

N NH O N H (±)-13a, 67% 88:12 dr O O

N

Ph

NH

NH O N H (±)-16a, 66% 92:8 dr

N H (±)-15a, 32% 63:37 dr

N H (±)-14a, 78% 90:10 dr Cl

Ph

MeO

Ph

Cl

N NH

NH

N

NH O

O

N H (±)-17a, 76% 87:13 dr

Ph

N H (±)-12a, 71% 87:13 dr

Ph

O

Ph (±)-10a, 55% 82:18 dr

Cl

N

N H (±)-11a, 65% 80:20 dr

Ph

O N

NH

N

NH

(±)-9a, 70% 87:13 dr

b)

F

N

N

(±)-8a, 63% 72:28 dr

Ph

EtOOC

NH

N

NO2 (±)-7a, 50% 81:19 dr

N

N H

Ph

O N H

(±)-6a, 44% 87:13 dr

N

N NH

N H

Br

NH

O N R2 (±)-5a–19a EtOOC

NH

(±)-5a, 78% 91:9 dr

MeO

DMSO 60 °C, 8 h Ar

N

NH N H

EtOOC

R4

N

3 R1 R

(±)-3a–h

N

Cl

a

To further optimize the reaction conditions, a broader range of anhydrous solvents were screened at elevated temperature (Table 1, entries 6‒16). Generally, the formation of the desired cycloadducts was favored in polar protic and aprotic solvents (Table 1, entries 6‒8, 11 and 16), while nonpolar solvents were not tolerated. In view of combined yields, ethanol and DMSO proved to be the best media (71% and 73% HPLC yields, respectively) (Table 1, entries 7 and 16); however, higher diastereoselectivity (92:8 dr) was achieved in DMSO. Modification of the concentration resulted in inferior or similar yields. Interestingly, however, it had no impact on the diastereomeric ratio (Table 1, entries 17‒21). Therefore, we found that the model reaction in DMSO (0.25 M for 1a) at 60 °C after 8 hours could deliver products 4a and 4b in a high HPLC yield of 72% and with maintained diastereoselectivity (92:8 dr, Table 1, entry 19).

Page 2 of 12

O N H (±)-18a, 68% 80:20 dr

N Cl

NH O N H (±)-19a, 73% 87:13 dr

Reaction conditions: isatin (0.5 mmol), D-(-)-2-phenylglycine (0.6 mmol), 2H-azirine (0.5 mmol), 2 ml anhydrous DMSO, argon atmosphere, 60 °C, 8 h. The dr values were determined by LC-MS analysis.

Pleasingly, 2,3-diphenylazirines furnished the corresponding products 11a–14a in good yields and dr, regardless of the electronic effect of the benzene substituent. Interestingly, 2H-azirine bearing benzyl group at the R3 position resulted in diminished diastereoselectivity (15a, 63:37 dr). The increased formation of the minor diastereomer might be explained


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by the π-π interaction between the benzyl moiety and the phenyl group of the azomethine ylide. On the other hand, the steric properties of the R4 substituent had negligible impact on the stereochemical outcome of the 1,3-DC (16a and 17a). In further exploration of the substrate scope, we focused on the α-amino acid component (Scheme 3). The reaction of isatin 1a, azirine 3a and phenylglycines possessing electron-donating (Me) or electron-withdrawing (Cl, F) substituents at para position proceeded smoothly under the optimal reaction conditions and delivered the expected spirooxindoles 20a–22a in good isolated yields and dr (Scheme 3). Lengthening of the R1 side chain by methylene group(s) had no significant influence on the diastereoselectivity and the efficiency of the 1,3-DC (Scheme 3, 23a–25a). To our delight, trifunctional αamino acids, such as S-benzylcysteine, tryptophan, serine and glutamine, were also compatible with the reaction (Scheme 3, 26a–29a) Although aliphatic norleucine was readily transformed to cycloadduct 30a in 70% isolated yield, it was surprising that L-proline was barely tolerated (31a, 11%). Scheme 3. Scope of amino acids EtOOC O

R2 O +

R1

N H 1a

NH COOH

+

COOEt

DMSO 60 °C, 8 h Ar

(±)-3a

2a-m

R1

N

N

N

R2 O

N H (±)-20a–31a

Cl EtOOC

EtOOC

N

NH

O

O

EtOOC

N

EtOOC NH

O

O

S

EtOOC

NH

O EtOOC

N

N NH

O

O N H (±)-30a, 70% 82:18 dr

OH NH

O N H (±)-28a, 46% 84:16 dr EtOOC

NH N H (±)-29a, 56% 80:20 dr

(±)-25a, 63% 81:19 dr

O N H (±)-27a, 66% 81:19 dr NH2

N

O N H

NH

NH O N H (±)-26a, 37% 76:24 dr

NH

EtOOC

N

N

OH

N H (±)-24a, 61% 81:19 dr EtOOC

N

O N H (±)-22a, 68% 87:13 dr

N

NH

N NH

N H (±)-21a, 72% 82:18 dr

N H (±)-23a, 69% 87:13 dr EtOOC

N

NH N H (±)-20a, 81% 90:10 dr EtOOC

F EtOOC

N N O N H (±)-31a, 11% 89:11 dr

Reaction conditions: isatin (0.5 mmol), amino acid (0.6 mmol), 2Hazirine (0.5 mmol), 2 ml anhydrous DMSO, argon atmosphere, 60 °C, 8 h. The dr values were determined by LC-MS analysis.

Since the pyrrolidine scaffold is a key structure in drug discovery,11 the optimal reaction conditions for the formation of 31a was reinvestigated (See Supporting Information). In dry isopropyl alcohol at room temperature, desired product 31a could be obtained in an improved yield of 60% (Scheme 4). Afterwards, further

cycloadducts were synthesized in moderate to good yields and high diastereoselectivites, demonstrating the general performance of the proline-involved 1,3-DC under the reoptimized conditions (Scheme 4, 32a–36a). Scheme 4. Three-component reactions involving Lproline under reoptimized reaction conditions R4 O

1

R

O

+

N R2

R3

N

R4

N

N

O N H (±)-32a, 55% 95:5 dr Ph

N

N

N

Cl

O N H (±)-31a, 60% 93:7 dr

N R2 31a–36a

EtOOC

N

MeO

N

O

O N H (±)-33a, 68% 88:12 dr Ph

N

Ph

N O

IPA rt, 24 h Ar

(±)-3 EtOOC

N

EtOOC

+

2m

1 EtOOC

COOH

N H

N

3 R1 R

N

Cl

N

Ph

N

O

O

N

N H

N H

(±)-34a, 62% 89:11

(±)-35a, 33% 90:10 dr

(±)-36a, 47% 71:29 dr

Reaction conditions: isatin (0.5 mmol), L-proline (0.6 mmol), 2H-azirine (1.5 mmol), 8 ml anhydrous IPA, argon atmosphere, rt, 24 h. The dr values were determined by LC-MS analysis.

On the basis of the experimental and analytical results discussed above, plausible reaction pathways are proposed (Scheme 5). Initially, azomethine ylide is generated from 1a and 2a via a condensation/lactonization/decarboxylation sequence. Although the subsequent regioselective 1,3-dipolar cycloaddition with 2H-azirine 3a can occur through both endo-TS and exo-TS, no evidence was found for exocyclic products. The exclusive formation of endo-cycloadducts 4a and 4b might be accounted for by the steric repulsion emerging in exo-TS between the methyl substituent of the azirine moiety and the phenyl substituent of oxindole. Since the S-shaped conformation of the azomethine ylide is sterically more favored against the U-shaped conformation,12 the endo-selective 1,3-DC leads to the predominant formation of diastereomer 4a. Conclusion In summary, we have successfully developed a one-pot, three-component reaction for the synthesis of a novel aziridine-fused spiro[imidazolidine-4,3’-oxindole] framework through endo-selective 1,3-dipolar cycloaddition of 2H-azirines with azomethine ylides generated from isatins and α-amino acids. The protocol is compatible with a wide range of aliphatic and aromatic αamino acids and 2H-azirines. Furthermore, it tolerates both electron-rich and electron-deficient isatins, and enables the facile assembly of highly-diverse 1,3diazaspiro[bicyclo[3.1.0]hexane]oxindoles in isolated yields up to 81% under mild conditions with complete regio- and high diastereoselectivities.



Scheme 5. Proposed reaction mechanism for 1,3-DC O

Ph O +

N

NH2

HOOC

1a H

N +

COOEt (±)-3a

2a

-CO2, -H2O

S-shaped ylide

U-shaped ylide

H N

H N

O N N HR

NR H

*

H N

O

N H

N

*

R=COOEt

N

*

R

R=COOEt

exo-TS

endo-TS

EtOOC

O

Ph

N

EtOOC

Ph

N

EtOOC

N

NH

NH

NH

O

O

O

Ph

N H

N H

N H

major- 4a

minor- 4b

4c-not observed

Experimental Section General information: The NMR spectra were recorded at 298 K on a Bruker Ascend 500 with 5 mm BBO Prodigy Probe in CDCl3-d1 or DMSO-d6. The chemical shifts are reported in δ (ppm) relative to the internal standard (TMS) or the residual solvent signal. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet etc.), coupling constants and integration. Coupling constants (J) are given in Hertz (Hz). LC/MS analyses were carried out on an Agilent 1100/1200 Series equipment with an Agilent G1946D MS detector (ESI, operated in positive mode) with Kinetex C18 column (100 Å, 5 µm, 250 x 4.6 mm, Phenomenex). Chiral HPLC analyses were conducted on a Shimadzu LC-10 VP series equipment with Phenomenex Lux Cellulose-1 column (5µm, 150 x 4.6 mm) (1 ml/min, hexane:IPA 80:20). Highresolution mass spectra (HRMS) were performed on a Thermo Scientific Q Exactive hybrid quadrupole-Orbitrap mass spectrometer using HESI ion source. Samples (5 µL from 1 µg/ml solution) were injected to the MS using flow injection method (200 µL/min, water: MeCN 1:1, 0.1% TFA). Melting points (mp) were recorded with a Digital Melting Point Apparatus (Electrothermal, IA 9000 Series). Chromatographic purification of the products was performed on Merck silica gel 60, particle size 0.063‒0.200 mm. TLC was performed on fluorescentindicating plates (aluminum sheets precoated with silica gel 60F254, 1.05554, Merck), and visualization was achieved by UV light (254 nm) or by staining with basic potassium permanganate solution. Racemic 2H-azirines (±)-3a–3h were synthesized according to literature procedures.13 All other reagents and solvents were commercially available and used without further purification. General procedure and characterization data for products (±)-4a–31a and (±)-4b Under argon atmosphere, a mixture of the corresponding isatin (0.5

Page 4 of 12

mmol), α-amino acid (0.6 mmol) and 2H-azirine (0.5 mmol) in anhydrous DMSO (2 ml) was stirred at 60 °C for 8 h. After the reaction was complete (monitored by TLC) the resulting mixture was poured into 50 ml water and extracted with diethyl-ether (3x10 ml). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the crude product which was purified by column chromatography on silica gel (eluent: hexane/chloroform or chloroform/MeOH) to afford pure products (±)-4a–31a and (±)-4b. rac-(2R,3'R,5S,6S)-Ethyl 5-methyl-2'-oxo-2-phenyl1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'-indoline]-6carboxylate ((±)-4a): white solid, 118 mg, 65% yield, mp 172–174 °C. Silica gel TLC Rf = 0.44 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.58 (d, J = 7.4 Hz, 2H), 7.41 (d, J = 7.0 Hz, 1H), 7.38 (d, J = 7.5 Hz, 2H), 7.36 – 7.34 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.15 (s, 1H), 4.33 – 4.08 (m, 2H), 3.17 (s, 1H), 2.50 (s, 1H), 1.34 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 179.1, 168.9, 141.7, 137.6, 130.1, 128.6, 128.3, 126.9, 126.4, 124.0, 123.2, 110.5, 79.4, 71.2, 61.3, 56.9, 35.9, 14.3, 10.4. HRMS (ESI) m/z: [M+H]+ Calcd for C21H22N3O3 364.1661; Found 364.1661. rac-(2R,3'S,5R,6R)-Ethyl 5-methyl-2'-oxo-2-phenyl1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'-indoline]-6carboxylate ((±)-4b):The synthesis of (±)-4b was accomplished on a 5 mmol ((±)-3a) scale. White solid, 55 mg, 3% yield, mp 198–199 °C. Silica gel TLC Rf = 0.55 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.56 – 7.50 (m, 3H), 7.41 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.29 (t, J = 7.1 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 5.77 (d, J = 7.4 Hz, 1H), 4.15 – 3.97 (m, 2H), 3.65 (d, J = 7.5 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H), 0.94 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 176.6, 169.3, 141.9, 138.9, 131.2, 129.5, 128.8, 128.5, 127.3, 125.2, 122.7, 110.7, 80.4, 70.3, 60.9, 56.9, 35.5, 14.6, 11.5. HRMS (ESI) m/z: [M+H]+ Calcd for C21H22N3O3 364.1661; Found 364.1663. rac-(2R,3'R,5S,6S)-Ethyl 5'-chloro-5-methyl-2'-oxo-2phenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-5a): beige solid, 155mg, 78% yield, mp 235–236 °C. Silica gel TLC Rf = 0.23 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.37 – 7.32 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 5.79 (d, J = 7.8 Hz, 1H), 4.27 (d, J = 7.8 Hz, 1H), 4.17 – 4.02 (m, 2H), 3.33 (s, 1H), 1.16 (t, J = 7.0 Hz, 3H), 1.11 (s, 3H). 13C NMR (126 MHz, DMSOd6) δ 178.6, 169.1, 142.3, 138.4, 129.9, 128.9, 128.7, 128.4, 127.4, 126.3, 125.5, 111.7, 79.6, 71.7, 61.1, 56.4, 35.3, 14.6, 10.6. HRMS (ESI) m/z: [M+H]+ Calcd for C21H21ClN3O3 398.1271 and 400.1271; Found 398.1275 and 400.1240. rac-(2R,3'R,5S,6S)-Ethyl 7'-bromo-5-methyl-2'-oxo-2phenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'-


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indoline]-6-carboxylate ((±)-6a): light yellow solid, 97 mg, 44% yield, mp 115–116 °C. Silica gel TLC Rf = 0.29 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.56 – 7.45 (m, 4H), 7.40 (t, J = 7.3 Hz, 2H), 7.38 – 7.31 (m, 1H), 7.01 (t, J = 7.8 Hz, 1H), 5.82 (d, J = 6.8 Hz, 1H), 4.35 (d, J = 6.9 Hz, 1H), 4.16 – 4.00 (m, 2H), 1.18 – 1.08 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 179.0, 169.1, 142.7, 138.6, 132.9, 129.0, 128.8, 128.4, 127.4, 124.2, 124.1, 102.6, 79.0, 72.0, 61.0, 56.4, 35.3, 14.6, 10.6. HRMS (ESI) m/z: [M+H]+ Calcd for C21H21BrN3O3 442.0766 and 444.0766; Found 442.0771 and 444.0749. rac-(2R,3'R,5S,6S)-Ethyl 5-methyl-7'-nitro-2'-oxo-2phenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-7a): yellow solid, 102 mg, 50% yield, mp 158–160 °C. Silica gel TLC Rf = 0.33 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.1 Hz, 1H), 7.53 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.31 – 7.23 (m, 1H), 5.85 (d, J = 6.7 Hz, 1H), 4.46 (d, J = 6.8 Hz, 1H), 4.17 – 4.00 (m, 2H), 3.42 (s, 1H), 1.17 – 1.12 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 179.5, 168.9, 139.8, 138.4, 131.6, 131.3, 130.6, 128.8, 128.5, 127.4, 125.1, 122.6, 79.0, 69.9, 61.1, 56.4, 35.4, 14.6, 10.6. HRMS (ESI) m/z: [M+H]+ Calcd for C21H21N4O5 409.1512; Found 409.1515. rac-(2R,3'R,5S,6S)-Ethyl 6'-methoxy-5-methyl-2'-oxo2-phenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-8a): light yellow solid, 124 mg, 63% yield, mp 218–220 °C. Silica gel TLC Rf = 0.15 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.50 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.39 – 7.30 (m, 2H), 6.63 – 6.52 (m, 1H), 6.43 (s, 1H), 5.77 (d, J = 7.7 Hz, 1H), 4.13 (d, J = 7.8 Hz, 1H), 4.11 – 4.03 (m, 2H), 3.76 (s, 3H), 3.27 (s, 1H), 1.15 (t, J = 7.1 Hz, 3H), 1.09 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 179.4, 169.3, 161.1, 144.6, 138.8, 128.7, 128.3, 127.3, 126.0, 118.4, 107.1, 97.1, 79.2, 71.3, 60.9, 56.2, 55.7, 35.3, 14.6, 10.5. HRMS (ESI) m/z: [M+H]+ Calcd for C22H24N3O4 394.1767; Found 394.1770. rac-(2R,3'R,5S,6S)-Ethyl 1',5-dimethyl-2'-oxo-2phenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-9a): white solid, 132 mg, 70% yield, mp 167–169 °C. Silica gel TLC Rf = 0.38 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 7.52 (t, J = 7.8 Hz, 3H), 7.42 – 7.37 (m, 3H), 7.34 (t, J = 7.3 Hz, 1H), 7.17 – 7.05 (m, 2H), 5.84 (d, J = 7.4 Hz, 1H), 4.26 (d, J = 7.5 Hz, 1H), 4.16 – 4.02 (m, 2H), 3.18 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H), 1.04 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 177.0, 169.2, 144.8, 138.6, 130.2, 128.8, 128.3, 127.3, 126.1, 124.8, 123.0, 109.3, 79.3, 71.2, 61.0, 56.3, 35.4, 26.4, 14.6, 10.5. HRMS (ESI) m/z: [M+H]+ Calcd for C22H24N3O3 378.1818; Found 378.1820. rac-(2R,3'R,5S,6S)-Ethyl 1'-benzyl-5-methyl-2'-oxo-2phenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-10a): beige solid, 104 mg, 55% yield, mp 76–78 °C. Silica gel TLC Rf = 0.21

(Hexane/EtOAc = 2/1); 1H NMR (500 MHz, Chloroformd) δ 7.59 (d, J = 7.3 Hz, 2H), 7.47 – 7.27 (m, 9H), 7.09 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.22 (s, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.78 (d, J = 15.6 Hz, 1H), 4.37 – 4.07 (m, 2H), 3.19 (s, 1H), 2.51 (s, 1H), 1.34 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, Chloroformd) δ 176.9, 168.9, 143.8, 137.7, 135.5, 130.1, 128.9, 128.6, 128.3, 127.8, 127.4, 126.9, 125.9, 123.7, 123.2, 109.7, 79.5, 70.9, 61.3, 56.9, 43.9, 35.9, 14.3, 10.6. HRMS (ESI) m/z: [M+H]+ Calcd for C28H28N3O3 454.2131; Found 454.2127. rac-(2R,3'R,5S,6R)-2,5,6-Triphenyl-1,3diazaspiro[bicyclo[3.1.0]hexane-4,3'-indolin]-2'-one ((±)-11a): white solid, 140 mg, 65% yield, mp 230–232 °C. Silica gel TLC Rf = 0.26 (CHCl₃/MeOH = 19/1); Chiral HPLC Rt = 4.49 min and 4.91 min; 1H NMR (500 MH z, Chloroform-d) δ 7.68 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.0 Hz, 2H), 7.40 – 7.28 (m, 5H), 7.18 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.0 Hz, 2H), 7.06 (t, J = 7.2 Hz, 2H), 7.02 (td, J = 8.1, 7.6, 2.7 Hz, 2H), 6.99 – 6.92 (m, 2H), 6.78 (d, J = 7.7 Hz, 1H), 6.47 (s, 1H), 3.85 (s, 1H), 2.87 (bs, 1H). 13C NMR (126 MHz, Chloroform-d) δ 178.4, 141.7, 138.4, 135.6, 132.2, 130.0, 128.5, 128.0, 127.7, 127.7, 127.6, 127.5, 127.5, 126.9, 126.7, 123.4, 123.0, 110.3, 80.5, 72.4, 64.1, 40.2. HRMS (ESI) m/z: [M+H]+ Calcd for C29H24N3O 430.1919; Found 430.1924. rac-(2R,3'R,5S,6R)-5-(4-Methoxyphenyl)-2,6diphenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indolin]-2'-one ((±)-12a): white solid, 163 mg, 71% yield, mp 174–177 °C. Silica gel TLC Rf = 0.38 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.29 (q, J = 8.1 Hz, 2H), 7.18 – 7.04 (m, 5H), 7.01 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 7.8 Hz, 2H), 6.70 – 6.65 (m, 1H), 6.54 (d, J = 8.2 Hz, 2H), 6.21 (d, J = 7.9 Hz, 1H), 4.39 (d, J = 8.1 Hz, 1H), 4.15 (s, 1H), 3.58 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 178.6, 158.6, 143.4, 139.4, 137.1, 129.9, 128.7, 128.1, 128.0, 128.0, 127.9, 127.4, 126.8, 125.4, 125.3, 122.2, 113.1, 109.9, 79.9, 72.4, 63.4, 55.2. HRMS (ESI) m/z: [M+H]+ Calcd for C30H26N3O2 460.2025; Found 460.2032. rac-(2R,3'R,5S,6R)-5-(4-Chlorophenyl)-2,6-diphenyl1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'-indolin]-2'one ((±)-13a): white solid, 155 mg, 67% yield, mp 222– 224 °C. Silica gel TLC Rf = 0.31 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d ) δ 10.18 (s, 1H), 7.99 (d, J 6 = 7.4 Hz, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.35 – 7.24 (m, 2H), 7.17 – 7.00 (m, 8H), 6.77 (d, J = 7.7 Hz, 1H), 6.22 (d, J = 7.9 Hz, 1H), 4.47 (d, J = 8.0 Hz, 1H), 4.23 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 178.4, 143.3, 139.2, 136.5, 132.8, 132.3, 130.2, 128.7, 128.2, 127.9, 127.8, 127.6, 127.4, 127.0, 125.3, 122.4, 110.1, 79.8, 72.2, 63.2. HRMS (ESI) m/z: [M+H]+ Calcd for C29H23ClN3O 464.1530 and 466.1530; Found 464.1535 and 466.1496. rac-(2R,3'R,5S,6R)-5-(4-Fluorophenyl)-2,6-diphenyl1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'-indolin]-2'-



one ((±)-14a): white solid, 174mg, 78% yield, mp 216– 218 °C. Silica gel TLC Rf = 0.32 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d ) δ 10.16 (s, 1H), 7.98 (d, J 6 = 7.4 Hz, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.31 (q, J = 7.1 Hz, 2H), 7.18 – 7.05 (m, 5H), 7.01 (t, J = 7.1 Hz, 1H), 6.91 – 6.79 (m, 3H), 6.76 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 7.9 Hz, 1H), 4.45 (d, J = 8.0 Hz, 1H), 4.21 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 178.5, 161.6 (d, J = 243.3 Hz), 143.3, 143.3, 139.2, 139.2, 136.7, 136.7, 130.2, 129.8, 128.7, 128.1, 127.8, 127.7, 127.4, 126.9, 125.3, 122.4, 114.7 (d, J = 21.4 Hz), 110.1, 79.8, 72.3, 63.1. HRMS (ESI) m/z: [M+H]+ Calcd for C29H23FN3O 448.1825; Found 448.1830. rac-(2R,3'R,5S,6R)-5-Benzyl-2,6-diphenyl-1,3diazaspiro[bicyclo[3.1.0]hexane-4,3'-indolin]-2'-one ((±)-15a): white solid, 71 mg, 32% yield, mp 248–249 °C. Silica gel TLC Rf = 0.26 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.58 – 7.51 (m, 5H), 7.40 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.28 (t, J = 6.3 Hz, 2H), 6.94 (t, J = 7.6 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.69 (t, J = 7.1 Hz, 2H), 6.48 (d, J = 7.3 Hz, 2H), 6.38 (d, J = 7.7 Hz, 1H), 5.96 (d, J = 8.1 Hz, 1H), 4.08 (d, J = 8.2 Hz, 1H), 4.04 (s, 1H), 3.04 (d, J = 15.0 Hz, 1H), 2.75 (d, J = 15.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d ) δ 178.8, 142.7, 139.4, 6 137.6, 135.9, 129.2, 129.0, 128.7, 128.6, 128.6, 128.0, 127.4, 127.3, 126.1, 124.9, 121.6, 109.5, 78.6, 71.0, 59.4, 38.6, 31.8. HRMS (ESI) m/z: [M+H]+ Calcd for C30H26N3O 444.2076; Found 444.2081. rac-(2R,3'R,5S,6S)-tert-Butyl 5-methyl-2'-oxo-2phenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-16a): White solid, 129 mg, 66% yield, mp 135–236 °C. Silica gel TLC Rf = 0.14 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.45 – 7.37 (m, 3H), 7.34 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 5.78 (d, J = 7.7 Hz, 1H), 4.19 (d, J = 7.8 Hz, 1H), 3.18 (s, 1H), 1.37 (s, 9H), 1.09 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 178.9, 168.5, 143.4, 138.9, 130.0, 128.7, 128.2, 127.3, 126.9, 125.1, 122.2, 110.2, 79.2, 71.4, 55.8, 36.2, 28.2, 10.6. HRMS (ESI) m/z: [M+H]+ Calcd for C23H26N3O3 392.1974; Found 392.1976. rac-(2R,3'R,5S)-2,5-Diphenyl-1,3diazaspiro[bicyclo[3.1.0]hexane-4,3'-indolin]-2'-one ((±)-17a): white solid, 134 mg, 76% yield, mp 216–217 °C. Silica gel TLC Rf = 0.20 (CHCl₃/MeOH = 19/1); Chiral HPLC Rt = 4.15 min and 4.73 min; 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.0 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.20 – 7.13 (m, 3H), 7.06 (t, J = 7.6 Hz, 1H), 7.03 – 6.99 (m, 2H), 6.79 (d, J = 7.8 Hz, 1H), 6.02 (d, J = 7.6 Hz, 1H), 4.21 (d, J = 7.7 Hz, 1H), 2.89 (s, 1H), 1.53 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 178.8, 143.3, 139.3, 137.9, 130.0, 128.6, 128.4, 128.3, 128.2, 127.7, 127.6, 127.6, 125.3, 122.2, 110.0, 78.34, 70.5, 55.8, 29.8. HRMS (ESI) m/z: [M+H]+ Calcd for C23H20N3O 354.1606; Found 354.1606.

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rac-(2R,3'R,5S,6R)-5-(4-Chlorophenyl)-6'-methoxy2,6-diphenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indolin]-2'-one ((±)-18a): white solid, 167 mg, 68% yield, mp 240–241 °C. Silica gel TLC Rf = 0.30 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.17 – 7.06 (m, 6H), 7.03 (t, J = 7.1 Hz, 1H), 6.84 (s, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 6.18 (d, J = 8.3 Hz, 1H), 4.37 (d, J = 8.4 Hz, 1H), 4.18 (s, 1H), 3.78 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 178.8, 161.1, 144.6, 139.2, 136.6, 132.9, 132.2, 128.7, 128.2, 127.9, 127.8, 127.3, 127.0, 126.2, 119.0, 107.2, 96.9, 79.8, 72.1, 62.9, 55.7. HRMS (ESI) m/z: [M+H]+ Calcd for C30H25ClN3O2 494.1635 and 496.1635; Found 494.1642 and 496.1600. rac-(2R,3'R,5S,6R)-5'-Chloro-5-(4-chlorophenyl)-2,6diphenyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indolin]-2'-one ((±)-19a): white solid, 181 mg, 73% yield, mp 246–247 °C. Silica gel TLC Rf = 0.38 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.10 (s, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7.44 – 7.29 (m, 4H), 7.23 – 6.95 (m, 8H), 6.78 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 7.9 Hz, 1H), 4.54 (d, J = 8.0 Hz, 1H), 4.27 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 178.1, 142.2, 138.9, 136.4, 132.4, 130.1, 129.6, 128.7, 128.3, 128.2, 128.1, 127.8, 127.4, 127.1, 126.5, 125.6, 111.6, 80.1, 72.5, 63.3, 23.3. HRMS (ESI) m/z: [M+H]+ Calcd for C29H22Cl2N3O 498.1140, 500.1140 and 502.1140; Found 498.1147, 500.1113 and 502.1066. rac-(2R,3'R,5S,6S)-Ethyl 5-methyl-2'-oxo-2-(p-tolyl)1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'-indoline]-6carboxylate ((±)-20a): white solid, 153 mg, 81% yield, mp 208–209 °C. Silica gel TLC Rf = 0.17 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 7.7 Hz, 2H), 7.27 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 5.78 (d, J = 7.3 Hz, 1H), 4.16 (d, J = 7.4 Hz, 1H), 4.12 – 4.02 (m, 2H), 3.29 (s, 1H), 2.31 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H), 1.09 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 179.0, 169.3, 143.3, 137.5, 135.8, 130.0, 129.3, 127.3, 127.0, 125.1, 122.3, 110.2, 79.0, 71.3, 60.9, 56.4, 35.2, 21.2, 14.6, 10.6. HRMS (ESI) m/z: [M+H]+ Calcd for C22H24N3O3 378.1818; Found 378.1812. rac-(2R,3'R,5S,6S)-Ethyl 2-(4-chlorophenyl)-5-methyl2'-oxo-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-21a): white solid, 143 mg, 72% yield, mp 231–232 °C. Silica gel TLC Rf = 0.19 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.49 – 7.41 (m, 3H), 7.28 (t, J = 7.7 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 5.79 (d, J = 7.2 Hz, 1H), 4.29 (d, J = 7.3 Hz, 1H), 4.16 – 4.01 (m, 2H), 3.32 (d, J = 27.4 Hz, 1H), 1.15 (t, J = 7.0 Hz, 3H), 1.09 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 179.0, 169.1, 143.3, 137.7, 132.9, 130.1, 129.3, 128.7, 126.9, 125.1, 122.3, 110.3, 78.4, 71.3, 61.0, 56.5, 35.3, 14.6, 10.6. HRMS (ESI) m/z: [M+H]+


Page 7 of 12 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


Calcd for C21H21ClN3O3 398.1271 and 400.1271; Found 398.1267 and 400.1234. rac-(2R,3'R,5S,6S)-Ethyl 2-(4-fluorophenyl)-5-methyl2'-oxo-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-22a): white solid, 130 mg, 68% yield, mp 211–212 °C. Silica gel TLC Rf = 0.19 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.55 (dd, J = 8.5, 5.6 Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.31 – 7.19 (m, 3H), 7.03 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 5.80 (d, J = 7.1 Hz, 1H), 4.26 (d, J = 7.3 Hz, 1H), 4.15 – 3.99 (m, 2H), 3.31 (s, 1H), 1.14 (t, J = 7.1 Hz, 3H), 1.09 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 179.0, 169.2, 162.3 (d, J = 243.5 Hz), 143.32, 135.0 (d, J = 2.7 Hz), 130.1, 129.38 (d, J = 8.2 Hz), 126.9, 125.1, 122.3, 115.5 (d, J = 21.2 Hz), 110.2, 78.4, 71.3, 61.0, 56.5, 35.3, 14.6, 10.6. HRMS (ESI) m/z: [M+H]+ Calcd for C21H21FN3O3 382.1567; Found 382.1559. rac-(2R,3'R,5S,6S)-Ethyl 2-benzyl-5-methyl-2'-oxo1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'-indoline]-6carboxylate ((±)-23a): white solid, 130 mg, 69% yield, mp 167–168 °C. Silica gel TLC Rf = 0.26 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.34 – 7.24 (m, 5H), 7.25 – 7.17 (m, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 4.79 – 4.67 (m, 1H), 4.25 – 4.05 (m, 2H), 3.71 (d, J = 9.4 Hz, 1H), 2.95 – 2.75 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.01 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 178.4, 169.4, 143.4, 138.9, 130.1, 129.7, 128.6, 126.7, 126.6, 124.9, 122.1, 110.2, 80.8, 71.9, 60.9, 56.1, 37.5, 34.4, 14.7, 10.5. HRMS (ESI) m/z: [M+H]+ Calcd for C22H24N3O3 378.1818; Found 378.1812. rac-(2R,3'R,5S,6S)-Ethyl 2-(4-hydroxybenzyl)-5methyl-2'-oxo-1,3-diazaspiro[bicyclo[3.1.0]hexane4,3'-indoline]-6-carboxylate ((±)-24a): white solid, 120 mg, 61% yield, mp 206–208 °C. Silica gel TLC Rf = 0.10 (CHCl₃/MeOH = 19/1); Chiral HPLC Rt = 7.28 min and 10.53 min; 1H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.17 (s, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.12 – 7.00 (m, 3H), 6.84 (d, J = 7.8 Hz, 1H), 6.66 (d, J = 7.9 Hz, 2H), 4.71 – 4.63 (m, 1H), 4.22 – 4.04 (m, 2H), 3.63 (d, J = 9.4 Hz, 1H), 3.30 (s, 1H), 2.81 – 2.63 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.00 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 178.5, 169.5, 156.1, 143.4, 130.5, 130.0, 129.0, 126.7, 124.9, 122.1, 115.3, 110.1, 81.1, 71.8, 60.9, 56.1, 36.7, 34.3, 14.7, 10.5. HRMS (ESI) m/z: [M+H]+ Calcd for C22H24N3O4 394.1767; Found 394.1767. rac-(2R,3'R,5S,6S)-Ethyl 5-methyl-2'-oxo-2phenethyl-1,3-diazaspiro[bicyclo[3.1.0]hexane-4,3'indoline]-6-carboxylate ((±)-25a): white solid, 123 mg, 63% yield, mp 171–172 °C. Silica gel TLC Rf = 0.25 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, Chloroformd) δ 8.12 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.33 – 7.27 (m, 3H), 7.23 – 7.17 (m, 3H), 7.10 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.07 (t, J = 6.4 Hz, 1H), 4.32 – 4.12 (m, 2H), 3.14 (s, 1H), 2.97 – 2.74 (m, 2H), 2.17 (s, 1H), 2.08

– 1.97 (m, 1H), 1.92 – 1.80 (m, 1H), 1.32 – 1.27 (m, 6H). NMR (126 MHz, Chloroform-d) δ 179.1, 169.1, 141.7, 141.6, 130.0, 128.5, 128.2, 126.5, 123.9, 123.2, 110.4, 78.5, 71.2, 61.4, 56.4, 35.0, 34.3, 32.7, 14.4, 10.3. HRMS (ESI) m/z: [M+H]+ Calcd for C23H26N3O3 392.1974; Found 392.1977. 13C

rac-(2R,3'R,5S,6S)-Ethyl 2-((benzylthio)methyl)-5methyl-2'-oxo-1,3-diazaspiro[bicyclo[3.1.0]hexane4,3'-indoline]-6-carboxylate ((±)-26a): light yellow solid, 78 mg, 37% yield, mp 144–146 °C. Silica gel TLC Rf = 0.25 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.37 – 7.29 (m, 4H), 7.26 (d, J = 7.6 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.87 – 4.69 (m, 1H), 4.22 – 3.98 (m, 2H), 3.86 (q, J = 13.6 Hz, 2H), 3.82 – 3.71 (m, 1H), 3.26 (s, 1H), 2.66 – 2.56 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H), 1.03 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 178.5, 169.2, 143.4, 139.1, 130.1, 129.3, 128.9, 127.3, 126.6, 124.8, 122.2, 110.3, 80.4, 71.4, 61.0, 56.7, 36.3, 34.5, 31.6, 14.7, 10.5. HRMS (ESI) m/z: [M+H]+ Calcd for C23H26N3O3S 424.1695; Found 424.1701. rac-(2R,3'R,5S,6S)-Ethyl 2-((1H-indol-3-yl)methyl)-5methyl-2'-oxo-1,3-diazaspiro[bicyclo[3.1.0]hexane4,3'-indoline]-6-carboxylate ((±)-27a): beige solid, 137 mg, 66% yield, mp 237–238 °C. Silica gel TLC Rf = 0.11 (CHCl₃/MeOH = 19/1) 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.46 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.22 – 7.18 (m, 1H), 7.06 (q, J = 7.4 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 4.84 (q, J = 6.9 Hz, 1H), 4.27 – 4.00 (m, 2H), 3.67 (d, J = 9.3 Hz, 1H), 3.37 (s, 1H), 2.95 (qd, J = 14.7, 6.5 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.01 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 178.5, 169.5, 143.4, 136.5, 130.0, 127.9, 126.9, 124.8, 123.9, 122.1, 121.2, 118.8, 118.6, 111.7, 111.3, 110.1, 80.4, 71.9, 60.9, 56.3, 34.3, 27.2, 14.7, 10.5. HRMS (ESI) m/z: [M+H]+ Calcd for C24H25N4O3 417.1927; Found 417.1930. rac-(2R,3'R,5S,6S)-Ethyl 2-(hydroxymethyl)-5methyl-2'-oxo-1,3-diazaspiro[bicyclo[3.1.0]hexane4,3'-indoline]-6-carboxylate ((±)-28a): light yellow solid, 73mg, 46% yield, mp 148–149 °C. Silica gel TLC Rf = 0.43(CHCl₃/MeOH = 9/1); 1H NMR (500 MHz, Chloroform-d) δ 8.49 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.04 (t, J = 4.4 Hz, 1H), 4.30 – 4.09 (m, 2H), 3.95 – 3.79 (m, 2H), 3.53 – 3.44 (m, 1H), 3.46 (s, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.22 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 178.9, 169.1, 141.7, 130.0, 126.3, 124.0, 123.1, 110.5, 78.2, 70.8, 62.0, 61.5, 55.5, 35.9, 14.3, 10.1. HRMS (ESI) m/z: [M+H]+ Calcd for C16H20N3O4 318.1454; Found 318.1455. rac-(2R,3'R,5S,6S)-Ethyl 2-(3-amino-3-oxopropyl)-5methyl-2'-oxo-1,3-diazaspiro[bicyclo[3.1.0]hexane4,3'-indoline]-6-carboxylate ((±)-29a): white solid, 101 mg, 56% yield, mp 232–233 °C. Silica gel TLC Rf = 0.26 (CHCl₃/MeOH = 9/1); 1H NMR (500 MHz, DMSO-d6) δ



10.48 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.30 (s, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.74 (s, 1H), 4.60 – 4.47 (m, 1H), 4.20 – 4.01 (m, 2H), 3.61 (d, J = 9.5 Hz, 1H), 3.14 (s, 1H), 2.20 (t, J = 7.7 Hz, 2H), 1.73 (p, J = 7.2, 6.7 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.01 (s, 3H). 13C NMR (126 MHz, DMSOd6) δ 178.5, 174.2, 169.4, 143.4, 130.0, 126.8, 124.9, 122.1, 110.1, 79.3, 71.9, 60.9, 56.1, 34.1, 32.5, 26.9, 14.7, 10.5. HRMS (ESI) m/z: [M+H]+ Calcd for C18H23N4O4 359.1719; Found 359.1722. rac-(2R,3'R,5S,6S)-Ethyl 2-butyl-5-methyl-2'-oxo-1,3diazaspiro[bicyclo[3.1.0]hexane-4,3'-indoline]-6carboxylate ((±)-30a): white solid, 120 mg, 70% yield, mp 168–169 °C. Silica gel TLC Rf = 0.19 (CHCl₃/MeOH = 19/1); Chiral HPLC Rt = 3.63 min and 5.34 min; 1H NMR (500 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 4.97 (t, J = 6.0 Hz, 1H), 4.44 – 3.99 (m, 2H), 3.07 (s, 1H), 2.15 (s, 1H), 1.76 – 1.65 (m, 2H), 1.53 (tdt, J = 13.0, 9.4, 4.2 Hz, 2H), 1.38 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.3 Hz, 3H), 1.26 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 179.1, 169.2, 141.7, 130.0, 126.6, 123.8, 123.1, 110.4, 79.0, 71.2, 61.3, 56.4, 34.9, 32.2, 28.6, 22.8, 14.3, 14.0, 10.3. HRMS (ESI) m/z: [M+H]+ Calcd for C19H26N3O3 344.1974; Found 344.1974. rac-(1R,2aS,3'S,7aR)-Ethyl 7a-methyl-2'-oxo1,2a,3,4,5,7a-hexahydrospiro[azirino[1,2c]pyrrolo[1,2-a]imidazole-7,3'-indoline]-1-carboxylate ((±)-31a): light yellow solid, 98 mg, 60% yield, mp 147– 148 °C. Silica gel TLC Rf = 0.16 (CHCl₃/MeOH = 19/1); Chiral HPLC Rt = 4.18 min and 4.64 min; 1H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 5.03 (t, J = 6.4 Hz, 1H), 4.17 – 4.06 (m, 2H), 3.26 – 3.15 (m, 1H), 2.80 (s, 1H), 2.37 (t, J = 7.5 Hz, 1H), 2.19 – 2.08 (m, 1H), 2.02 – 1.92 (m, 1H), 1.78 – 1.68 (m, 1H), 1.68 – 1.57 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H), 1.01 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 178.1, 168.5, 144.1, 130.4, 126.6, 124.2, 122.0, 110.6, 86.6, 72.8, 61.0, 60.7, 50.2, 38.1, 28.2, 26.8, 14.7, 11.6. HRMS (ESI) m/z: [M+H]+ Calcd for C18H22N3O3 328.1661; Found 328.1660. General procedure and characterization data for products (±)-31a–36a To a solution of L-proline (69 mg, 0.6 mmol) in anhydrous IPA (8 ml), the corresponding isatin (0.5 mmol) and 2H-azirine (1.5 mmol) were added under argon atmosphere. The reaction mixture was stirred for 24 h at room temperature until the reaction was completed (monitored by TLC). Then the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc) to afford pure products (±)-31a–36a. rac-(1R,2aS,3'S,7aR)-Ethyl 5'-chloro-7a-methyl-2'oxo-1,2a,3,4,5,7a-hexahydrospiro[azirino[1,2c]pyrrolo[1,2-a]imidazole-7,3'-indoline]-1-carboxylate ((±)-32a): light yellow solid, 99 mg, 55% yield, mp 235–

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236 °C. Silica gel TLC Rf = 0.17 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, Chloroform-d) δ 8.70 (s, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.3, 2.1 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 5.36 (t, J = 6.5 Hz, 1H), 4.33 – 4.16 (m, 2H), 3.19 – 3.08 (m, 1H), 2.73 – 2.59 (m, 2H), 2.36 – 2.25 (m, 1H), 2.11 – 2.01 (m, 1H), 2.00 – 1.84 (m, 1H), 1.82 – 1.70 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.27 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 178.5, 168.3, 141.1, 130.2, 127.8, 126.7, 125.7, 111.6, 87.1, 73.3, 61.5, 61.3, 50.4, 38.3, 28.2, 26.7, 14.3, 11.1. HRMS (ESI) m/z: [M+H]+ Calcd for C18H21ClN3O3 362.1271 and 364.1271; Found 362.1275 and 364.1244. rac-(1R,2aS,3'S,7aR)-Ethyl 6'-methoxy-7a-methyl-2'oxo-1,2a,3,4,5,7a-hexahydrospiro[azirino[1,2c]pyrrolo[1,2-a]imidazole-7,3'-indoline]-1-carboxylate ((±)-33a): beige solid, 121 mg, 68% yield, mp 142–144 °C. Silica gel TLC Rf = 0.16 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, Chloroform-d) δ 8.69 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.60 (dd, J = 8.4, 2.3 Hz, 1H), 6.53 (d, J = 2.3 Hz, 1H), 5.34 (t, J = 6.5 Hz, 1H), 4.34 – 4.22 (m, 1H), 4.21 – 4.10 (m, 1H), 3.84 (s, 3H), 3.23 – 3.10 (m, 1H), 2.68 – 2.62 (m, 2H), 2.36 – 2.21 (m, 1H), 2.09 – 1.96 (m, 1H), 1.99 – 1.85 (m, 1H), 1.83 – 1.71 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.26 (s, 3H). 13C NMR (126 MHz, Chloroformd) δ 179.5, 168.7, 161.4, 143.9, 127.1, 115.5, 107.3, 97.6, 86.9, 73.1, 61.4, 61.2, 55.6, 50.6, 38.4, 28.4, 26.6, 14.4, 11.1. HRMS (ESI) m/z: [M+H]+ Calcd for C19H24N3O4 358.1767; Found 358.1768. rac-(1R,2aS,3'S,7aR)-Ethyl 1',7a-dimethyl-2'-oxo1,2a,3,4,5,7a-hexahydrospiro[azirino[1,2c]pyrrolo[1,2-a]imidazole-7,3'-indoline]-1-carboxylate ((±)-34a): white solid, 106 mg, 62% yield, mp 117–118 °C. Silica gel TLC Rf = 0.40 (CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, Chloroform-d) δ 7.49 (d, J = 7.5 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.39 (t, J = 6.5 Hz, 1H), 4.31 – 4.24 (m, 1H), 4.21 – 4.15 (m, 1H), 3.21 (s, 3H), 3.20 – 3.12 (m, 1H), 2.72 (s, 1H), 2.60 (t, J = 7.7 Hz, 1H), 2.34 – 2.23 (m, 1H), 2.07 – 1.98 (m, 1H), 1.96 – 1.86 (m, 1H), 1.81 – 1.75 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.19 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 176.6, 168.7, 145.4, 130.1, 126.0, 123.5, 122.4, 108.6, 86.9, 72.8, 61.4, 61.3, 50.6, 38.4, 28.2, 26.6, 26.1, 14.4, 11.1. HRMS (ESI) m/z: [M+H]+ Calcd for C19H24N3O3 342.1818; Found 342.1819. rac-(1R,2aR,3'R,7aS)-1,7a-Diphenyl-1,2a,3,4,5,7ahexahydrospiro[azirino[1,2-c]pyrrolo[1,2-a]imidazole7,3'-indolin]-2'-one ((±)-35a): white solid, 65 mg, 33% yield, mp 217–218 °C. Silica gel TLC Rf = 0.39(CHCl₃/MeOH = 19/1); 1H NMR (500 MHz, Chloroform-d) δ 7.78 (d, J = 7.5 Hz, 1H), 7.70 (s, 1H), 7.40 – 7.32 (m, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.13 – 6.99 (m, 5H), 7.00 – 6.88 (m, 4H), 6.80 (d, J = 7.7 Hz, 1H), 5.70 (t, J = 6.4 Hz, 1H), 3.55 – 3.46 (m, 1H), 3.45 (s, 1H), 2.81 (t, J = 7.6 Hz, 1H), 2.45 – 2.35 (m, 1H), 2.16 – 2.08 (m, 1H), 2.08 – 1.97 (m, 1H), 1.98 – 1.86 (m, 1H). 13C NMR (126 MHz, Chloroform-d) δ 178.4, 142.6, 135.9, 132.9, 130.0, 127.7, 127.6, 127.5, 127.3, 126.7, 126.2,


Page 9 of 12 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


125.4, 122.2, 110.6, 87.3, 74.0, 69.0, 51.1, 42.9, 28.6, 27.0. HRMS (ESI) m/z: [M+H]+ Calcd for C26H24N3O 394.1919; Found 394.1924. rac-(1R,2aR,3'R,7aS)-5'-Chloro-1,7a-diphenyl1,2a,3,4,5,7a-hexahydrospiro[azirino[1,2c]pyrrolo[1,2-a]imidazole-7,3'-indolin]-2'-one ((±)36a): white solid, 100 mg, 47% yield, mp 218–219 °C. Silica gel TLC Rf = 0.10 (Hexane/EtOAc = 2/1); 1H NMR (500 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.20 – 7.10 (m, 4H), 7.09 – 6.98 (m, 4H), 6.96 – 6.83 (m, 4H), 6.53 (d, J = 8.2 Hz, 1H), 5.53 (t, J = 6.3 Hz, 1H), 3.95 (s, 1H), 3.94 – 3.88 (m, 1H), 2.90 (t, J = 7.8 Hz, 1H), 2.43 – 2.31 (m, 1H), 2.21 – 2.11 (m, 1H), 2.05 – 1.94 (m, 1H), 1.95 – 1.83 (m, 1H). 13C NMR (126 MHz, Chloroform-d) δ 175.1, 137.2, 136.0, 135.2, 133.4, 128.2, 128.1, 127.7, 127.6, 127.5, 127.1, 126.5, 125.3, 110.3, 88.6, 72.2, 70.4, 49.2, 42.7, 28.8, 27.3. HRMS (ESI) m/z: [M+H]+ Calcd for C26H23ClN3O 428.1530 and 430.1500; Found 428.1523 and 430.1489. Associated Content Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Reaction optimization, copies of 1H NMR and 13C NMR spectra for new compounds, 2D NMR spectra and crystallographic data Accession Codes The crystallographic data of compounds 4a and 31a can be obtained free of charge via ww.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223–336–033; or [email protected]) under CCDC deposition numbers CCDC 1890661 and CCDC 1890659, respectively. AUTHOR INFORMATION Corresponding Author * Email: [email protected] ORCID Iván Kanizsai: 0000-0003-0109-7097 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The research within project No. VEKOP-2.3.3-15-201700018 was supported by the European Union and the State

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For Table of Contents Only R6 O

R4 O +

1

R

N R2

3

R

NH COOH

+

R5

N 5

R

R3

N N

6

R

R1

R4 O

N R2

33 examples up to 81% yield, up to 95:5 dr


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1,3-Dipolar cycloaddition of isatin-derived azomethine ylides with 2H

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