Mediated Reductive Epoxidation between Two ... - ACS Publications

Subscriber access provided by Kaohsiung Medical University

Article

Chemoselective P(NMe2)3-Mediated Reductive Epoxidation between Two Different Carbonyl Electrophiles: Synthesis of Highly Functionalized Unsymmetrical Epoxides Rong Zhou, Honghui Zhang, Jialin Liu, Rongfang Liu, Wen-Chao Gao, Yan Qiao, and Ruifeng Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00995 • Publication Date (Web): 05 Jun 2018 Downloaded from http://pubs.acs.org on June 5, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 29 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

The Journal of Organic Chemistry

Chemoselective P(NMe2)3-Mediated Reductive Epoxidation between Two Different Carbonyl Electrophiles: Synthesis of Highly Functionalized Unsymmetrical Epoxides Rong Zhou,*, † Honghui Zhang, † Jialin Liu,† Rongfang Liu,† Wen-Chao Gao,* ,† Yan Qiao,†† and Ruifeng Li† † College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan, 030024, P. R. China †† The State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan, 030001, P. R. China E-mail: [email protected]; [email protected] TOC graphic

Abstract Herein, we report a chemoselective P(NMe2)3-mediated reductive epoxidation of α-dicarbonyl compounds such as isatins, α-keto esters, and α-diketones with aldehydes and ketones, leading to an efficient synthesis of a wide range of highly functionalized unsymmetrical epoxides in moderate to excellent yields and diastereoselectivities. The Kukhtin-Ramirez adduct, which is exclusively generated in situ from α-dicarbonyl compound and P(NMe2)3, plays a key role in governing the chemoselectivity.

ACS Paragon Plus Environment

1

The Journal of Organic Chemistry 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

Page 2 of 29

It represents the first practical synthesis of unsymmetrical epoxides via direct reductive epoxidation of two different carbonyl electrophiles and also complements the existing methods to epoxides. Introduction Epoxides are highly important structural components in many naturally occurring and pharmacologically active molecules, and also serve as versatile intermediates in organic synthesis.1 Intensive research efforts in the past several decades have led to the development of many efficient strategies to this class of compounds.2-6 Among them, the alkene epoxidations such as Sharpless3 and Shi4 epoxidations have been demonstrated to be powerful tools in both industrial- and academic-scale syntheses for olefinic substrates (Scheme 1, eq a). Furthermore, the cyclization of sulfur ylides5 or αhaloenolates6 with carbonyl compounds provides alternative valuable approaches to epoxides in an oxidant-free manner (Scheme 1, eq b and c). Despite the efficiency of the existing methods, there remains significant room for the development of additional complementary epoxidation strategies, especially aiming at synthesis of highly functionalized epoxides from readily available and bench stable precursors under oxidant-free conditions. Scheme 1. Different Epoxidation Methodologies


2

Page 3 of 29 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


The direct reductive epoxidation of two different carbonyl electrophiles such as aldehydes and ketones represents a straightforward approach to epoxides from readily available starting material.7 However, chemoselective epoxidation would be challenging due to the competing reactions between homo- and hetero-coupling between the two carbonyls.7d To achieve a highly chemoselective epoxidation, a reactive intermediate should be chemoselectively generated first from one carbonyl compound, and then once generated it can directly couple with the other carbonyl molecule to deliver the epoxide product. Keeping this in mind, we envisioned that a chemoselective reductive epoxidation of α-dicarbonyl compounds such as α-keto esters/amides, and α-diketones with carbonyls including aldehydes and ketones under the influence of trivalent phosphorus reagents would be feasible. It is well known that the α-dicarbonyl compounds could readily undergo the Kukhtin-Ramirez addition with trivalent phosphorus reagents to afford the reactive dipolar adducts.8 Our group and others have recently demonstrated in a series of documents that the Kukhtin-Ramirez adducts could serve as a versatile C1 synthon in reactions with both nucleophiles9 and electrophiles10,11 due to their dipolar structural properties. We therefore proposed that the Kukhtin-Ramirez adduct would be selectively generated first from α-dicarbonyl compound and trivalent phosphorus reagent even in the presence of carbonyls such as aldehydes or ketones. This adduct would then proceed to trigger a dipolar epoxidation with the other carbonyl molecule to afford the desired unsymmetrical epoxide product (Scheme 1, eq d). Herein we report a chemoselective P(NMe2)3-mediated reductive epoxidation of readily available α-dicarbonyl compounds such as isatins, α-keto esters, and α-diketones with aldehydes and ketones, leading to an efficient synthesis of a wide range of highly functionalized unsymmetrical epoxides in moderate to excellent yields and diastereoselectivities. It represents the first practical synthesis of unsymmetrical epoxides via direct reductive epoxidation of two different carbonyl electrophiles and also complements the existing methods to epoxides.7,12 Results and Discussion


3


Page 4 of 29

We commenced the proposed epoxidation by treating N-methyl isatin 1a with benzaldehyde 2a under the predetermined conditions listed in Table 1. Delightfully, the expected spirooxindole-epoxide 3aa was exclusively afforded in 60% isolated yield and 88:12 diastereoselectivity with trans-3aa (the functional groups with higher priority on the epoxide moiety such as the phenyl and the amide groups are on the opposite side) being the major diastereomer, without formation of any homo-coupling byproducts (Table 1, entry 1). It therefore represents a highly chemoselective reductive epoxidation between two different carbonyls and also provides a facile synthesis of multi-functionalized unsymmetrical epoxides. The reaction conditions were subsequently surveyed to improve the reaction efficiency. Among several common solvents such as CH2Cl2, CHCl3, toluene, THF, and acetonitrile surveyed, CHCl3 was the optimal reaction medium, affording the product 3aa in 88% yield and 90:10 diastereoselectivity (entries 1-5). The influence of the trivalent phosphorus reagents was also investigated. Replacement of P(NMe2)3 with P(OMe)3 resulted in decreased reactivity, whereas both tributylphosphine and triphenylphosphine afforded no desired product (entries 6-8). Other substituents R instead of methyl group on the nitrogen atom of the isatin 1 were examined as well. Both the yields and diastereoselectivities decreased when either an allyl or a benzyl group was introduced to the nitrogen atom (entries 9 and 10). Table 1. Screening of the Reaction Conditionsa

entry

isatin 1

solvent

PR'3

yield (%)b

drc

1

1a

CH2Cl2

P(NMe2)3

3aa, 60

88:12

2

1a

CHCl3

P(NMe2)3

3aa, 88

90:10

3

1a

Toluene

P(NMe2)3

3aa, 56

75:25


4

Page 5 of 29 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

1a

THF

P(NMe2)3

3aa, 20

70:30

5

1a

CH3CN

P(NMe2)3

3aa, 36

89:11

6

1a

CHCl3

P(OMe)3

3aa, 44

80:20

7

1a

CHCl3

PBu3

3aa, 0

-

8

1a

CHCl3

PPh3

3aa, 0

-

9

1b

CHCl3

P(NMe2)3

3ba, 51

62:38

10

1c

CHCl3

P(NMe2)3

3ca, 65

52:48

a

Reaction conditions: isatin 1 (0.2 mmol), benzaldehyde 2a (0.24 mmol), PR'3 (0.22 mmol), and 4Å molecular sieves in solvent (2.0 mL), -78 oC to r.t., 12 h. b The combined yields of two isolated diastereomers based on 1. c Determined by 1H NMR assay of the crude mixture and referring to the ratio of trans-3 versus cis-3

Employing the optimal reaction conditions listed in Table 1, entry 2, the generality of the epoxidations was investigated (Table 2). The isatins bearing different R1 group on the phenyl ring of the oxindole framework were first examined. Both electron-donating and electron-withdrawing R1 groups were well tolerated, readily affording the corresponding spiro-epoxides 3 with representative aldehyde 2a in moderate to good yields and diastereoselectivities (entries 1-9). Furthermore, substituted aldehydes with different electronic and steric properties were investigated with representative isatin 1a. Aromatic aldehydes bearing either electron-donating or electron-withdrawing aryl groups proceeded smoothly in the epoxidation (entries 10-15). Notably, the steric-demanding substrates such as aldehydes 2e and 2f afforded the corresponding epoxides in higher diastereoselectivities without any loss in reactivity (entries 13 and 14). Heteroaromatic aldehydes such as furylaldehyde, thienylaldehyde, and pyridylaldehyde were readily accommodated as well (entries 16-20). An α,β-unsaturated aldehyde such as (E)-cinnamylaldehyde was also effective, affording the desired product in a moderate yield with a good diastereoselectivity (entry 21). Aliphatic aldehydes such as propylaldehyde were applicable to this protocol, giving the epoxide 3an in moderate yield and diastereoselectivity (entry 22). Phenylpropioaldehyde 2o was also a feasible substrate, readily delivering its corresponding product 3ao in good yield and moderate diastereoselectivity (entry 23). ACS Paragon Plus Environment

5


Page 6 of 29

Gratifyingly, ketones such as ynones 4 were viable substrates in this epoxidation reaction, which therefore afforded the desired epoxides bearing adjacent quaternary carbon stereocenters (Scheme 2). However, efforts attempting to extend this methodology to other common ketones such as acetophenone and 2-butanone gave negative results, and no reactions occurred. Furthermore, activated ketones such as trifluoroacetophenone also failed to give the desired epoxide product. Fortunately, majority of the two diastereomeric products listed in Table 2 and Scheme 2 were separable using column chromatography isolations. Table 2. P(NMe2)3-Mediated Reductive Epoxidation of Isatins 1 and Aldehydes 2a

entry

R1 in 1

R2 in 2

time (h)

yield (%)b

drc

1

H (1a)

Ph (2a)

24

3aa, 88

90:10

2

5-MeO (1d)

2a

8

3da, 78

74:26

3

5-Me (1e)

2a

12

3ea, 58

73:27

4

4-Br (1f)

2a

12

3fa, 61

75:25

5

5-Br (1g)

2a

8

3ga, 67

80:20

6

6-Br (1h)

2a

24

3ha, 53

71:29

7

4-Cl (1i)

2a

12

3ia, 56

66:34

8

5-Cl (1j)

2a

12

3ja, 63

69:31

9

5-NO2 (1k)

2a

21

3ka, 59

80:20

10

1a

4-MeOC6H4 (2b)

8

3ab, 84

62:38

11

1a

4-MeC6H4 (2c)

8

3ac, 85

51:49

12

1a

4-ClC6H4 (2d)

12

3ad, 60

64:36

13

1a

2-ClC6H4 (2e)

7

3ae, 82

90:10

14

1a

2,4-Cl2C6H4 (2f)

7

3af, 78

96:4

15

1a

4-BrC6H4 (2g)

12

3ag, 67

78:22


6

Page 7 of 29 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


16

1a

2-Furyl (2h)

24

3ah, 45

86:14

17

1a

2-Thienyl (2i)

24

3ai, 53

75:25

18

1a

2-Pyridyl (2j)

8

3aj, 65

60:40

19

1a

3-Pyridyl (2k)

7

3ak, 98

95:5

20

1a

4-Pyridyl (2l)

8

3al, 43

94:6

21

1a

E-cinnamyl (2m)

12

3am, 48

90:10

22

1a

Et (2n)

8

3an, 67

74:26

23

1a

Phenylethynyl (2o)

7

3ao, 89

60:40

a

Reaction conditions: isatin 1 (0.2 mmol), aldehyde 2 (0.24 mmol), P(NMe2)3 (0.22 mmol), and 4Å molecular sieves in CHCl3 (2.0 mL), -78 oC to r.t. b The combined yields of two isolated diastereomers based on 1. c Determined by 1H NMR assay of the crude mixture and referring to the ratio of trans-3 versus cis-3.

Scheme 2. P(NMe2)3-Mediated Reductive Epoxidation of Isatin 1a With Ynones 4

The scope of this epoxidation was further extended to other α-dicarbonyl compounds such as α-keto esters and α-diketones. Under the standard reaction conditions (Table 3), aryl-substituted α-keto esters 6a-c bearing either electron-donating or electron-withdrawing aryl groups, and α-diketones such as benzil 6d and acenaphthoquinone 6e were all capable to afford their corresponding epoxides 7 with representative aldehydes 2 in good to excellent yields with moderate to excellent diastereoselectivities (entries 1-8). Table 3. P(NMe2)3-Mediated Reductive Epoxidation of α-Keto Esters and α-Diketones 6 with Aldehydes 2a


7


Page 8 of 29

entry

R3, R4 in 6

R2 in 2

time (h)

yield (%)b

drc

1

Ph, OEt (6a)

Ph (2a)

7

7aa, 71

80:20

2

6a

4-MeC6H4 (2c)

12

7ac, 67

71:29

3

6a

4-BrC6H4 (2g)

12

7ag, 72

90:10

4

6a

3-Pyridyl (2k)

7

7ak, 93

82:18

5

4-MeC6H4, OEt (6b)

2k

7

7bk, 92

71:29

6

4-BrC6H4, OEt (6c)

2k

7

7ck, 94

68:32

7

Ph, Ph (6d)

2k

8

7dk, 88

51:49

8

Acenaphthoquinone (6e)

2k

8

7ek, 99

98:2

a

Reaction conditions: α-dicarbonyl compound 6 (0.2 mmol), aldehyde 2 (0.24 mmol), P(NMe2)3 (0.22 mmol), and 4Å molecular sieves in CHCl3 (2.0 mL), -78 oC to r.t. b The combined yields of two isolated diastereomers based on 6. c Determined by 1H NMR assay of the crude mixture and referring to the ratio of trans-7 versus cis-7.

The structures of epoxides 3, 5, and 7 were identified by 1H,

13

C NMR and HRMS-ESI/MALDI

measurements. Representative compounds were further confirmed by NOESY (7ag and 7ck) and X-ray crystallographic analyses (for crystal structure of 3af, see Supporting Information). A proposed mechanism to account for the formation of epoxides is exemplified in Scheme 3 based on the experimental results and the closely related reports from our group and others.10,11 Presumably, the epoxidation is initiated with the in situ generation of the Kukhtin-Ramirez adduct I or II from αdicarbonyl compound such as isatin 1a and hexamethylphosphorous triamide. Through its dipolar structure II, the Kukhtin-Ramirez adduct then triggers a nucleophilic addition in a manner similar to Aldol reaction to aldehyde such as 2a via two different modes, affording intermediate IIIa and IIIb, respectively. Due to the possible π−π stacking interaction between the phenyl groups and less steric hindrance between the small hydrogen and the bulky phosphonium moiety, the intermediate IIIa is ACS Paragon Plus Environment

8

Page 9 of 29 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


predominantly generated, which then undergoes an intramolecular substitution similar to SN2 to finish the ring closure, affording the major product trans-3aa and the phosphoric triamide by-product.10e,11b,c On the other hand, ring closure of intermediate IIIb through the similar process provides the minor product cis-3aa. The chemoselectivity of this epoxidation was attributed by the exclusive KukhtinRamirez addition of hexamethylphosphorous triamide to α-dicarbonyl compound such as 1a among the two carbonyl electrophiles such as 1a and 2a. Scheme 3. A Proposed Mechanism for the Formation of Epoxide R' O P R' R' O

O O N 1a Me

PR'3 R' = NMe2

R'3P=O trans-3aa major

ring closure

R'3P=O cis-3aa minor

ring closure

O PR'3 O

N I Me

Ph

O

H

PR'3

O N IIIa O Me H

O

N II Me

Ph

PR'3

O Ph

2a

nucleophilic addn.

O N O Me IIIb

Conclusion In summary, a chemoselective P(NMe2)3-mediated reductive epoxidation of α-dicarbonyl compounds such as isatins, α-keto esters, and α-diketones with aldehydes and ketones has been developed, which provides an efficient synthesis of highly functionalized unsymmetrical epoxides in moderate to excellent yields and diastereoselectivities. The chemoselectivity of this epoxidation originates from the exclusive Kukhtin-Ramirez addition of α-dicarbonyl compounds with trivalent phosphorus reagents. It represents the first practical synthesis of unsymmetrical epoxides via direct reductive epoxidation of two different carbonyl electrophiles. The reaction benefits from its broad substrates scope, mild and oxidant-free conditions, readily available and bench stable starting material, and also complements the existing


9


Page 10 of 29

approaches to epoxides. Future efforts in our laboratory will be directed toward further expanding this methodology to other more challenging substrates, and the relevant results will be reported in due course. Experimental Section Unless otherwise noted, all reactions were carried out in nitrogen atmosphere under anhydrous conditions. All solvents were purified according to standard procedures. 1H and 13C NMR spectra were recorded in CDCl3 with tetramethylsilane (TMS) as the internal standard. HRMS spectra were acquired in the ESI mode with the mass analyzer of TOF used. Column chromatography was performed on silica gel (200 ∼ 300 mesh) using a mixture of petroleum ether/ethyl acetate as eluant. Isatins 1,13 and arylsubstituted α-keto esters 614 were prepared according to the reported procedures. General Procedure for the Chemoselective Epoxidation of α-Dicarbonyl Compounds 1 or 6 with Aldehyde 2 or Ynone 4: Under a N2 atmosphere and at -78 oC, P(NMe2)3 (40 µL, 0.22 mmol) in chloroform (0.5 mL) was added dropwise to a mixture of α-dicarbonyl compound 1 or 5 (0.2 mmol), aldehyde 2 or ynone 4 (0.24 mmol), and 4Å molecular (150 mg) in chloroform (1.5 mL) by means of syringe. The resulting reaction mixture was then slowly warmed up to room temperature and stirred at rt for a time indicated in Table 2, 3 or Scheme 2. The solvent was removed on a rotary evaporator under reduced pressure and the residue was subjected to column chromatographic isolation on silica gel by gradient elution using petroleum ether /ethyl acetate (20:1 ∼ 3:1) to give the epoxide 3, 5 or 7. 1-Methyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3aa). Table 1, entry 2; prepared according to the typical procedure, N-Methyl isatin 1a (32 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3aa as two separable diastereomers (combined yields 88%, dr 90:10). The major isomer trans-3aa (40 mg, 79%), a white solid; mp: 158-159 oC; 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.34 (m, 5H), 7.27 (dt, J = 7.8, 1.6 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.47 (dd, J = 7.5, 0.6 Hz, 1H), 4.83 (s, 1H), 3.29 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 171.7, 145.2, 133.1,

130.1, 128.6, 128.4, 126.6, 123.6, 122.4, 120.8, 108.7, 65.0, 61.5, 26.6. the minor isomer cis-3aa (4 mg, 9%), a white solid; 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.57 (m, 2H), 7.43 – 7.34 (m, 4H), 7.25 – 7.21 ACS Paragon Plus Environment

10

Page 11 of 29 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


(m, 1H), 7.16 – 7.09 (m, 1H), 6.89 (d, J = 7.8 Hz, 1H), 4.67 (s, 1H), 3.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.8, 144.6, 131.7, 130.2, 128.8, 127.7, 127.4, 123.6, 122.6, 121.6, 108.6, 67.5, 61.9, 26.5; HRMS−ESI ([M + H]+) Calcd for C16H14NO2 252.1019, found 252.1017. Allyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3ba). Table 1, entry 9; prepared according to the typical procedure, N-allylic isatin 1b (37 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3ba as two separable diastereomers (combined yields 51%, dr 62:38). The major isomer trans-3ba (18 mg, 33%), a yellow colloid; 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.33 (m, 5H), 7.23 (dd, J = 7.8, 1.2 Hz, 1H), 6.89 (t, J = 9.8 Hz, 1H), 6.76 (td, J = 7.6, 0.7 Hz, 1H), 6.48 (dd, J = 7.5, 0.6 Hz, 1H), 5.88 (ddt, J = 17.1, 10.5, 5.4 Hz, 1H), 5.36 – 5.22 (m, 2H), 4.85 (s, 1H), 4.54 – 4.35 (m, 2H);

13

C NMR (101 MHz, CDCl3) δ 171.4, 144.4, 133.1, 131.1, 130.0, 128.7, 128.4, 126.7, 123.7,

122.4, 120.9, 118.1, 109.5, 65.1, 61.5, 42.9. The minor isomer cis-3ba (10 mg, 18%), a pale yellow solid; mp: 156-158 oC; 1H NMR (400 MHz, CDCl3) δ 7.60 (t, J = 6.8 Hz, 2H), 7.44 – 7.30 (m, 4H), 7.23 (d, J = 11.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.89 – 5.70 (m, 1H), 5.28 – 5.16 (m, 2H), 4.69 (s, 1H), 4.27 (d, J = 5.4 Hz, 2H);

13

C NMR (101 MHz, CDCl3) δ 169.6, 143.8, 131.7,

131.2, 130.1, 128.8, 127.7, 127.4, 123.6, 122.6, 121.7, 118.0, 109.5, 67.6, 61.8, 42.7. HRMS−ESI ([M + H]+) Calcd for C18H16NO2 278.1176, found 278.1180. Benzyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3ca). Table 1, entry 10; prepared according to the typical procedure, N-benzylic isatin 1c (47 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3ca as two separable diastereomers (combined yields 65%, dr 52:48). The major isomer trans-3ca (22 mg, 34%), a white solid; mp: 140-142 oC; 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 7.7, 1.1 Hz, 2H), 7.45 – 7.36 (m, 4H), 7.35 – 7.24 (m, 4H), 7.15 (td, J = 7.8, 1.1 Hz, 1H), 6.79 – 6.68 (m, 2H), 6.47 (d, J = 7.4 Hz, 1H), 5.06 – 4.93 (m, 2H), 4.90 (s, 1H);

13

C NMR (101 MHz, CDCl3) δ

171.8, 144.4, 135.3, 133.1, 130.1, 128.9, 128.7, 128.4, 127.8, 127.4, 126.7, 123.7, 122.5, 120.9, 109.6, 65.2, 61.5, 44.3. The minor isomer cis-3ca (20 mg, 31%), a pale yellow solid; mp: 151-153 oC; 1H NMR (400 MHz, CDCl3)δ 7.63 (d, J = 7.7 Hz, 2H), 7.45 – 7.34 (m, 3H), 7.32 – 7.23 (m, 7H), 7.08 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 4.71 (s, 1H); 13C ACS Paragon Plus Environment

11


Page 12 of 29

NMR (101 MHz, CDCl3) δ 170.0, 143.7, 135.4, 131.7, 130.1, 128.9, 128.8, 127.8, 127.7, 127.5, 127.4, 122.7, 121.7, 109.6, 67.7, 61.9, 44.1. HRMS−ESI ([M + H]+) Calcd for C22H18NO2 328.1332, found 328.1342. 5-Methoxy-1-methyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3da). Table 2, entry 2; prepared according to the typical procedure, isatin 1d (38 mg,0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3da as two separable diastereomers (combined yields 78%, dr 74:26). The major isomer trans-3da (34 mg, 60%), a white solid; mp: 155-157 oC; 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.30 (m, 5H), 6.89 – 6.64 (m, 2H), 6.04 (d, J = 2.3 Hz, 1H), 4.83 (s, 1H), 3.47 (s, 3H), 3.27 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.3, 155.4, 138.5, 133.2, 128.6, 128.4, 126.7, 122.0, 115.1, 110.3, 109.0, 64.9, 61.6, 55.4, 26.7. The minor isomer cis-3da (10 mg, 18%), a white solid; mp: 167-169 oC; 1H NMR (400 MHz, CDCl3) δ 7.53 (dt, J = 3.7, 2.1 Hz, 2H), 7.39 – 7.24 (m, 3H), 6.84 (dd, J = 8.5, 2.6 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 4.56 (s, 1H), 3.76 (s, 3H), 3.05 (s, 3H);

13

C NMR

(101 MHz, CDCl3) δ 169.6, 156.1, 138.0, 131.7, 128.8, 127.7, 127.4, 124.8, 114.9, 109.1, 108.6, 67.6, 62.1, 55.9, 26.6. HRMS−ESI ([M + H]+) Calcd for C17H16NO3 282.1125, found 282.1137. 1,5-Dimethyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3ea). Table 2, entry 3; prepared according to the typical procedure, isatin 1e (35mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3ea as two separable diastereomers (combined yields 58%, dr 73:27). The major isomer trans-3ea (24 mg, 46%), a white solid; mp: 172-173 oC; 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.33 (m, 5H), 7.06 (dd, J = 7.9, 0.8 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 6.40 – 6.13 (m, 1H), 4.81 (s, 1H), 3.27 (s, 3H), 2.06 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 171.6, 142.8, 133.2, 131.9, 130.3, 128.6,

128.3, 126.7, 124.5, 120.8, 108.3, 64.9, 61.6, 26.6, 20.9. The minor isomer cis-3ea (7 mg, 12%), a white solid; mp: 179-181 oC; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.1 Hz, 2H), 7.37 (dt, J = 8.5, 6.9 Hz, 3H), 7.19 (dd, J = 7.9, 0.6 Hz, 1H), 7.06 (s, 1H), 6.78 (d, J = 7.9 Hz, 1H), 4.64 (s, 1H), 3.13 (s, 3H), 2.38 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 169.8, 142.2, 132.3, 131.8, 130.4, 128.77, 127.7, 127.4,

123.6, 122.3, 108.3, 67.4, 62.0, 26.5, 21.0. HRMS−ESI ([M + H]+) Calcd for C17H16NO2 266.1176, found 266.1187. ACS Paragon Plus Environment

12

Page 13 of 29 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-Bromo-1-methyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3fa). Table 2, entry 4; prepared according to the typical procedure, isatin 1f (48 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3fa as two separable diastereomers (combined yields 61%, dr 75:25). The major isomer trans-3fa (30 mg, 46%), a white solid; mp: 165-167 oC; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.25 (m, 5H), 7.16 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.74 (s, 1H), 3.32 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 171.9, 146.9, 130.9, 128.7, 128.3, 128.2, 127.8, 119.7,

119.6, 107.6, 66.4, 62.4, 26.9. The minor isomer cis-3fa (10mg, 15%), a white solid; mp: 175-177 oC; 1

H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 7.9, 1.2 Hz, 2H), 7.44 – 7.31 (m, 3H), 7.24 – 7.18 (m, 2H),

6.93 – 6.78 (m, 1H), 5.49 (s, 1H), 3.12 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 169.1, 146.6, 131.3,

131.1, 128.7, 127.6, 127.6, 127.2, 120.9, 117.7, 107.7, 62.6, 62.1, 26.6. HRMS−ESI ([M + H]+) Calcd for C16H13BrNO2 330.0124, found 330.0135. 5-Bromo-1-methyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3ga). Table 2, entry 5; prepared according to the typical procedure, isatin 1g (48 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3ga as two separable diastereomers (combined yields 67%, dr 80:20). The major isomer trans-3ga (36 mg, 55%), a white solid; mp: 177-179 oC; 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.39 (m, 5H), 7.38 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 4.83 (s, 1H), 3.28 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 171.1, 144.2, 132.9, 132.6, 129.0, 128.6, 126.7, 126.6,

123.0, 115.1, 109.9, 65.3, 61.2, 26.7. The minor isomer cis-3ga (8 mg, 12%), a white solid; mp: 168170 oC; 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 7.7, 1.6 Hz, 2H), 7.35 – 7.26 (m, 3H), 7.19 (dd, J = 7.9, 1.6 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 1.6 Hz, 1H), 4.58 (s, 1H), 3.05 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.6, 145.7, 131.3, 128.9, 127.7, 127.4, 125.4, 123.9, 122.8, 122.5, 112.2, 67.5, 61.6, 26.6. HRMS−ESI ([M + H]+) Calcd for C16H13BrNO2 330.0124, found 330.0131. 6-Bromo-1-methyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3ha). Table 2, entry 6; prepared according to the typical procedure, isatin 1h (48 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3ha as two separable diastereomers (combined yields 53%, dr 71:29). The major isomer trans-3ha (26 mg, 39%), a pale yellow solid; mp: 163-165 oC; 1H NMR (400 MHz, CDCl3) δ 13 ACS Paragon Plus Environment


Page 14 of 29

7.59 (dd, J = 7.9, 1.5 Hz, 2H), 7.43 – 7.32 (m, 3H), 7.28 – 7.26 (m, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 4.65 (s, 1H), 3.13 (s, 3H); 13C NMR (101 MHz, CDCl3)δ 169.6, 145.8, 131.3, 128.9, 127.8, 127.4, 125.4, 123.9, 122.8, 122.5, 112.2, 67.6, 61.6, 26.6. The minor isomer cis-3ha (9 mg, 14%), a pale yellow solid; mp: 168-170 oC;1H NMR (400 MHz, CDCl3) δ 7.50 – 7.32 (m, 5H), 7.02 (d, J = 1.5 Hz, 1H), 6.90 (dd, J = 8.0, 1.5 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.82 (s, 1H), 3.28 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.5, 146.4, 132.9, 128.9, 128.5, 126.6, 125.3, 124.7, 124.2, 119.9, 112.2, 65.1, 61.3, 26.8. HRMS−ESI ([M + H]+) Calcd for C16H13BrNO2 330.0124, found 330.0130. 4-Chloro-1-methyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3ia). Table 2, entry 7; prepared according to the typical procedure, isatin 1i (39mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3ia as two separable diastereomers (combined yields 56%, dr 66:34). The major isomer trans-3ia (21 mg, 37%), a white solid; mp: 165-167 oC; 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.29 (m, 4H), 7.24 (dd, J = 13.9, 5.9 Hz, 2H), 6.82 (dd, J = 8.0, 4.5 Hz, 2H), 4.75 (s, 1H), 3.32 (s, 3H); 13

C NMR (101 MHz, CDCl3) δ 171.8, 146.9, 134.0, 131.9, 130.9, 128.6, 128.2, 127.5, 124.9, 117.7,

107.1, 66.3, 62.4, 26.9. The minor isomer cis-3ia (11 mg, 19%), a pale yellow solid; mp: 173-175 oC; 1

H NMR (400 MHz, CDCl3) δ 7.69 – 7.52 (m, 2H), 7.46 – 7.27 (m, 4H), 7.04 (dd, J = 8.3, 0.7 Hz, 1H),

6.79 (dd, J = 7.8, 0.6 Hz, 1H), 5.43 (s, 1H), 3.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 146.4, 131.3, 131.0, 130.3, 128.7, 127.6, 127.6, 124.1, 119.3, 107.1, 62.4, 62.3, 26.7. HRMS−ESI ([M + H]+) Calcd for C16H13ClNO2 286.0629, found 286.0639. 5-Chloro-1-methyl-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3ja). Table 2; entry 8; prepared according to the typical procedure, isatin 1j (39 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3ja as two separable diastereomers (combined yields 63%, dr 69:31). The major isomer trans-3ja (25 mg, 44%), a white solid; mp: 188-189 oC; 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.34 (m, 5H), 7.24 (dd, J = 8.3, 2.1 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 4.83 (s, 1H), 3.28 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.2, 143.7, 132.6, 129.9, 129.0, 128.6, 127.9, 126.5, 124.0, 122.6, 109.5, 65.2, 61.2, 26.7. The minor isomer cis-3ja (11 mg, 19%), a white solid; mp: 180182 oC; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.3 Hz, 2H), 7.49 – 7.31 (m, 4H), 7.21 (d, J = 1.3 14 ACS Paragon Plus Environment

Page 15 of 29 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


Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.65 (s, 1H), 3.14 (d, J = 0.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.4, 143.0, 131.2, 130.0, 129.0, 128.2, 127.8, 127.4, 125.3, 122.1, 109.5, 67.7, 61.6, 26.6. HRMS−ESI ([M + H]+) Calcd for C16H13ClNO2 286.0629, found 286.0636. 1-Methyl-5-nitro-3'-phenylspiro[indoline-3,2'-oxiran]-2-one (3ka). Table 2, entry 9; prepared according to the typical procedure, isatin 1k (41 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give 3ka as two separable diastereomers (combined yields 64%, dr 80:20). The major isomer trans-3ka (28 mg, 47%), a white solid; mp: 180-181 oC; 1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 8.6, 2.3 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.65 – 7.48 (m, 2H), 7.46 – 7.37 (m, 3H), 6.99 (d, J = 8.6 Hz, 1H), 4.79 (s, 1H), 3.23 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 169.8, 149.7, 143.5, 130.5, 129.3,

127.9, 127.5, 127.0, 124.5, 117.7, 108.3, 68.0, 61.2, 27.0. The minor isomer cis-3ka (10 mg, 17%), a white solid; mp: 189-190 oC; 1H NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 8.6, 2.3 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 7.6, 1.8 Hz, 2H), 7.46 – 7.37 (m, 3H), 6.99 (d, J = 8.6 Hz, 1H), 4.79 (s, 1H), 3.23 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 169.8, 149.7, 143.5, 130.5, 129.3, 127.9, 127.5, 127.0,

124.5, 117.6, 108.3, 100.0, 68.0, 61.2, 27.0. HRMS−ESI ([M + H]+) Calcd for C16H13N2O4 297.0870, found 297.0879. 3'-(4-Methoxyphenyl)-1-methylspiro[indoline-3,2'-oxiran]-2-one (3ab). Table 2, entry 10; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2b (33 mg, 0.24 mmol) were employed to give 3ab as two separable diastereomers (combined yields 84%, dr 62:38). The major isomer trans-3ab (29 mg, 52%), a white solid; mp: 148-150 oC; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 2H), 7.38 (td, J = 7.7, 1.3 Hz, 1H), 7.22 (dd, J = 7.4, 0.8 Hz, 1H), 7.12 (td, J = 7.6, 0.8 Hz, 1H), 6.94 – 6.87 (m, 3H), 4.62 (s, 1H), 3.81 (s, 3H), 3.15 (s, 3H);13C NMR (101 MHz, CDCl3) δ 170.1, 159.9, 144.4, 130.0, 128.8, 123.7, 123.5, 122.5, 121.4, 113.1, 108.5, 67.6, 62.0, 55.2, 26.4. The minor isomer cis-3ab (18 mg, 32%), a white solid; mp: 164-166 oC; 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.50 (m, 2H), 7.38 (td, J = 7.8, 1.3 Hz, 1H), 7.22 (dd, J = 7.4, 0.7 Hz, 1H), 7.11 (td, J = 7.6, 0.8 Hz, 1H), 6.99 – 6.85 (m, 3H), 4.61 (s, 1H), 3.81 (s, 3H), 3.15 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 170.1, 159.9,


15


Page 16 of 29

144.4, 130.0, 128.8, 123.7, 123.6, 122.5, 121.4, 113.1, 108.5, 67.6, 62.0, 55.2, 26.4. HRMS−ESI ([M + H]+) Calcd for C17H16NO3 282.1125, found 282.1125. 1-Methyl-3'-(p-tolyl)spiro[indoline-3,2'-oxiran]-2-one (3ac). Table 2, entry 11; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2c (29 mg, 0.24 mmol) were employed to give 3ac as two separable diastereomers (combined yields 85%, dr 51:49). The major isomer trans3ac (22 mg, 43%), a white solid; mp: 159-160 oC; 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 2H), 7.27 (td, J = 7.8, 1.3 Hz, 1H), 7.21 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 7.8 Hz, 1H), 6.78 (td, J = 7.6, 0.9 Hz, 1H), 6.51 (dd, J = 7.5, 0.7 Hz, 1H), 4.79 (s, 1H), 3.29 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.8, 145.1, 138.5, 130.1, 130.0, 129.1, 126.6, 123.7, 122.4, 121.0, 108.5, 65.1, 61.6, 26.6, 21.29. The minor isomer cis-3ac (21 mg, 42%), a white solid; mp: 167-168 oC; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.1 Hz, 2H), 7.38 (ddd, J = 7.7, 6.1, 1.3 Hz, 1H), 7.21 (dd, J = 9.4, 4.4 Hz, 3H), 7.13 – 7.08 (m, 1H), 6.89 (d, J = 7.8 Hz, 1H), 4.64 (s, 1H), 3.14 (s, 3H), 2.35 (s, 3H);

13

C NMR (101

MHz, CDCl3) δ 169.9, 144.5, 138.5, 130.0, 128.6, 128.4, 127.3, 123.7, 122.5, 121.5, 108.5, 67.6, 61.9, 26.4, 21.35. HRMS−ESI ([M + H]+) Calcd for C17H16NO2 266.1176, found 266.1188. 3'-(4-Chlorophenyl)-1-methylspiro[indoline-3,2'-oxiran]-2-one (3ad). Table 2, entry 12; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2d (34 mg, 0.24 mmol) were employed to give 3ad as two separable diastereomers (combined yields 60%, dr 64:36). The major isomer trans-3ad (21 mg, 38%), a white solid; mp: 162-164 oC; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 9.3 Hz, 4H), 7.29 (td, J = 7.8, 1.1 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 7.3 Hz, 1H), 4.77 (s, 1H), 3.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.3, 145.2, 134.5, 131.7, 130.3, 128.7, 128.1, 123.4, 122.5, 120.4, 108.7, 64.3, 61.5, 26.6. The minor isomer cis-3ad (12 mg, 22%), a white solid; mp: 175-177 oC; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.44 – 7.33 (m, 3H), 7.23 (d, J = 7.3 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 4.63 (s, 1H), 3.16 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 169.7, 144.5, 134.7, 130.3, 130.2, 128.8, 128.0, 123.2,

122.7, 121.6, 108.7, 66.8, 61.9, 26.5. HRMS−ESI ([M + H]+) Calcd for C16H13ClNO2 286.0629, found 286.0633. ACS Paragon Plus Environment

16

Page 17 of 29 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


3'-(2-Chlorophenyl)-1-methylspiro[indoline-3,2'-oxiran]-2-one (3ae). Table 2, entry 13; prepared according to the typical procedure,isatin 1a (32 mg, 0.2 mmol) and aldehyde 2e (34 mg, 0.24 mmol) were employed to give 3ae as two separable diastereomers (combined yields 82%, dr 90:10). The major isomer trans-3ae (42 mg, 74%), a pale red solid; mp: 166-168 oC; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.3 Hz, 1H), 7.45 – 7.25 (m, 4H), 6.87 (d, J = 7.8 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 4.81 (s, 1H), 3.31 (s, 3H);13C NMR (101 MHz, CDCl3) δ 171.2, 145.2, 133.2, 131.8, 130.2, 129.9, 129.1, 128.2, 126.7, 122.8, 122.4, 120.5, 108.6, 63.5, 61.3, 26.7; HRMS−ESI ([M + H]+) Calcd for C16H13ClNO2 286.0629, found 286.0628. 3'-(2,4-Dichlorophenyl)-1-methylspiro[indoline-3,2'-oxiran]-2-one (3af). Table 2, entry 14; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2f (35 mg, 0.24 mmol) were employed to give 3af (combined yields 78%, dr 96:4). The major isomer trans-3af (47 mg, 76%), a white solid; mp: 171-173 oC; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.3, 1.6 Hz, 1H), 7.35 – 7.26 (m, 2H), 6.89 (d, J = 7.9 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.24 (d, J = 7.5 Hz, 1H), 4.76 (s, 1H), 3.31 (s, 3H); 13CNMR (101 MHz, CDCl3) δ 170.9, 145.2, 135.2, 134.0, 130.6, 130.4, 129.2, 129.1, 127.2, 122.7, 122.5, 120.2, 108.8, 63.1, 61.3, 26.7; HRMS−ESI ([M + H]+) Calcd for C16H12Cl2NO2 320.0240, found 320.0246 . 3'-(4-Bromophenyl)-1-methylspiro[indoline-3,2'-oxiran]-2-one (3ag). Table 2, entry 15; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2g (44 mg, 0.24 mmol) were employed to give 3ag as two separable diastereomers (combined yields 67%, dr 78:22). The major isomer trans-3ag (32 mg, 51%), a white solid; mp: 158-160 oC; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.36 – 7.24 (m, 3H), 6.88 (d, J = 7.8 Hz, 1H), 6.81 (td, J = 7.7, 0.8 Hz, 1H), 6.45 (d, J = 7.5 Hz, 1H), 4.75 (s, 1H), 3.29 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 171.3, 145.2, 132.2, 131.6,

130.3, 128.8, 123.5, 122.7, 122.6, 120.5, 108.7, 64.4, 61.5, 26.6. The minor isomer cis-3ag (12 mg, 16%), a pale yellow solid; mp: 166-168 oC; 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.44 (m, 4H), 7.41 (td, J = 7.8, 1.2 Hz, 1H), 7.24 – 7.20 (m, 1H), 7.13 (dd, J = 11.0, 4.1 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.61 (s, 1H), 3.16 (s, 3H);

13

C NMR (101 MHz, CDCl3)δ 169.7, 144.6, 130.9, 130.7, 130.4, 129.1, 123.2, 17 ACS Paragon Plus Environment


Page 18 of 29

123.0, 122.7, 121.6, 108.7, 66.8, 61.8, 26.5. HRMS−ESI ([M + H]+) Calcd for C16H13BrNO2 330.0124, found 330.0133. 3'-(Furan-2-yl)-1-methylspiro[indoline-3,2'-oxiran]-2-one (3ah). Table 2, entry 16; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2h (23 mg, 0.24 mmol) were employed to give 3ah as a diastereomeric mixture with trans-3ah being the major (22 mg, 45%, dr 86:14), a pale red solid, mp: 167-171 oC; 1H NMR (400 MHz, CDCl3) for the major isomer: δ 9.37 (s, 1H), 8.15 (dd, J = 8.0, 1.4 Hz, 1H), 7.63 – 7.48 (m, 3H), 7.39 – 7.28 (m, 2H), 6.62 (dd, J = 3.5, 1.9 Hz, 1H), 3.74 (s, 3H); 1H NMR (400 MHz, CDCl3) for the minor isomer: δ 7.48 – 7.44 (m, 1H), 7.25 – 7.19 (m, 2H), 6.97 (td, J = 7.6, 0.7 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.59 (d, J = 3.3 Hz, 1H), 6.44 (dd, J = 3.3, 1.8 Hz, 1H), 4.67 (s, 1H), 3.27 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.3, 155.7, 147.1, 145.4, 143.4, 139.7, 138.4, 131.3, 130.5, 124.3, 124.1, 122.7, 121.9, 120.5, 115.8, 113.8, 112.1, 111.2, 111.1, 110.6, 108.7, 101.3, 59.5, 29.5, 26.7; HRMS−ESI ([M + H]+) Calcd for C14H12NO3 242.0812, found 242.0823. 1-Methyl-3'-(thiophen-2-yl)spiro[indoline-3,2'-oxiran]-2-one (3ai). Table 2, entry 17; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2i (27 mg, 0.24 mmol) were employed to give 3ai (combined yields 53%, dr 75:25). The major isomer trans-3ai (20 mg, 39%), a pale yellow solid; mp: 136-138 oC; 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 2H), 7.17 (d, J = 3.5 Hz, 1H), 7.06 (dd, J = 5.0, 3.6 Hz, 1H), 6.87 (dd, J = 16.6, 7.8 Hz, 2H), 6.72 (d, J = 7.5 Hz, 1H), 4.89 (s, 1H), 3.29 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 171.2, 145.2, 135.8, 130.4, 127.0, 126.8,

125.9, 123.7, 122.5, 120.5, 108.6, 62.2, 61.7, 26.6; HRMS−ESI ([M + H]+) Calcd for C14H12NO2S 258.0583, found 258.0599. 1-Methyl-3'-(pyridin-2-yl)spiro[indoline-3,2'-oxiran]-2-one (3aj). Table 2, entry 18; prepared according to the typical procedure, isatin 1a (32.2 mg, 0.2 mmol) and aldehyde 2j (26 mg, 0.24 mmol) were employed to give 3aj as two separable diastereomers (combined yields 65%, dr 60:40). The major isomer trans-3aj (20 mg, 39%), a white solid; mp: 159-161 oC; 1H NMR (400 MHz, CDCl3) δ 8.60 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.36 – 7.24 (m, 18 ACS Paragon Plus Environment

Page 19 of 29 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


2H), 6.86 (d, J = 7.8 Hz, 1H), 6.81 – 6.73 (m, 1H), 6.60 (dd, J = 7.5, 0.7 Hz, 1H), 4.85 (s, 1H), 3.28 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 171.0, 153.4, 149.7, 145.4, 136.5, 130.4, 123.5, 123.3, 122.4,

121.8, 120.5, 108.7, 65.1, 61.7, 26.6. The minor isomer cis-3aj (13 mg, 26%), a white solid; mp: 176177 oC; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.7 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.72 (td, J = 7.8, 1.5 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.4 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 4.73 (s, 1H), 3.07 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 169.7, 152.3, 148.7, 144.6,

135.7, 130.4, 123.5, 123.0, 122.8, 121.9, 108.7, 67.0, 61.6, 26.5. HRMS−ESI [([M + H]+) Calcd for C15H13N2O2 253.0972, found 253.0983. 1-Methyl-3'-(pyridin-3-yl)spiro[indoline-3,2'-oxiran]-2-one (3ak). Table 2; entry 19; prepared according to the typical procedure, isatin 1a (32.2 mg, 0.2 mmol) and aldehyde 2k (26 mg, 0.24 mmol) were employed to give 3ak as two separable diastereomers (combined yields 98%, dr 95:5). The major isomer trans-3ak (45 mg, 93%), a purple solid, mp: 120-122 oC; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 1.5 Hz, 1H), 8.64 (d, J = 3.6 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.33 (ddd, J = 15.5, 7.8, 2.2 Hz, 2H), 6.90 (d, J = 7.8 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 4.81 (s, 1H), 3.30 (s, 3H); 13C NMR (101 MHz, CDCl3 δ 171.0, 149.9, 148.3, 145.2, 134.4, 130.5, 129.1, 123.3, 123.1, 122.5, 120.0, 108.8, 62.8, 61.5, 26.6; HRMS−ESI ([M + H]+) Calcd for C15H13N2O2 253.0972, found 253.0984. 1-Methyl-3'-(pyridin-4-yl)spiro[indoline-3,2'-oxiran]-2-one (3al). Table 2, entry 20; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2l (26 mg, 0.24 mmol) were employed to give 3al as two separable diastereomers (combined yields 43%, dr 94:6). The major isomer trans-3al (20 mg, 40%), a white solid; mp: 135-137 oC; 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.9 Hz, 2H), 7.40 (t, J = 9.7 Hz, 2H), 7.31 (dd, J = 14.4, 6.6 Hz, 1H), 6.89 (t, J = 9.0 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 7.5 Hz, 1H), 4.78 (s, 1H), 3.31 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ

170.9, 149.9, 145.3, 142.3, 130.7, 123.4, 122.7, 121.6, 119.9, 108.9, 63.4, 61.5, 26.7; HRMS−ESI ([M + H]+) Calcd for C15H13N2O2 253.0972, found 253.0986 . (E)-1-methyl-3'-styrylspiro[indoline-3,2'-oxiran]-2-one (3am). Table 2, entry 21; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2m (32 mg, 0.24 mmol) were 19 ACS Paragon Plus Environment


Page 20 of 29

employed to give 3am as two separable diastereomers (combined yields 48%, dr 90:10). The major isomer trans-3am (25 mg, 43%), a pale yellow solid; mp:166-168 oC; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 2H), 7.41 – 7.24 (m, 4H), 7.16 (d, J = 7.3 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.95 – 6.82 (m, 3H), 4.20 (d, J = 7.2 Hz, 1H), 3.26 (d, J = 0.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.1, 144.5, 138.0, 135.8, 130.1, 128.6, 128.5, 126.9, 123.3, 122.7, 121.7, 121.6, 108.7, 67.1, 62.2, 26.6; HRMS−ESI ([M + H]+) Calcd for C18H16NO2 278.1176, found 278.1188. 3'-Ethyl-1-methylspiro[indoline-3,2'-oxiran]-2-one (3an). Table 2, entry 22; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2n (17 mg, 0.24 mmol) were employed to give 3an as two separable diastereomers (combined yields 67%, dr 74:26). The major isomer trans3an (20 mg, 50%), a yellow colloid; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.33 (m, 1H), 7.12 – 7.04 (m, 2H), 6.90 (d, J = 7.8 Hz, 1H), 3.65 – 3.54 (m, 1H), 3.27 (s, 3H), 2.30 – 1.96 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H);

13

C NMR (101 MHz, CDCl3) δ 171.7, 144.3, 129.9, 124.2, 122.6, 121.5, 108.5, 68.5, 59.7, 26.6,

19.7, 10.5. The minor isomer cis-3an (7 mg, 17%), a white solid; mp: 79-81 oC; 1H NMR (400 MHz, CDCl3) δ 7.32 (td, J = 7.8, 1.1 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 3.61 – 3.50 (m, 1H), 3.20 (s, 3H), 1.98 – 1.67 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.7, 145.3, 130.0, 123.8, 122.5, 121.9, 108.8, 66.6, 60.5, 26.6, 21.6, 10.4; HRMS−ESI ([M + H]+) Calcd for C12H14NO2 204.1019, found 204.1023. 1-Methyl-3'-(phenylethynyl)spiro[indoline-3,2'-oxiran]-2-one (3ao) Table 2, entry 23; prepared according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and aldehyde 2o (31 mg, 0.24 mmol) were employed to give 3ao as a diastereomeric mixture with trans-3ao being the major (44 mg, 89%, dr 60:40), a yellow solid; mp 185-188 oC; 1H NMR (400 MHz, CDCl3) for the major isomer: δ 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.28 (m, 6H), 7.16 – 7.11 (m, 2H), 6.92 (d, J = 7.9 Hz, 1H), 4.29 (s, 1H), 3.30 (s, 3H); 1H NMR (400 MHz, CDCl3) for the minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.45 (m, 7H), 7.10 – 7.05 (m, 1H), 6.95 (d, J = 7.9 Hz, 1H), 4.37 (s, 1H), 3.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ170.4, 169.1, 145.3, 145.0, 132.3, 132.0, 130.7, 129.4, 129.1, 128.5, 128.2, 124.4, 122.8,


20

Page 21 of 29 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


122.7, 121.8, 121.7, 121.6, 121.2, 120.4, 108.8, 88.1, 87.9, 82.0, 80.9, 61.9, 61.6, 53.1, 52.2, 26.8, 26.7; HRMS−ESI ([M + H]+) Calcd for C18H14NO2 276.1019, found 276.1016. 1,3'-Dimethyl-3'-(phenylethynyl)spiro[indoline-3,2'-oxiran]-2-one

(5aa).

Scheme

2;

prepared

according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and ynones 4a (32 mg, 0.24 mmol) were employed to give 5aa as two separable diastereomers (combined yields 35%, dr 71:29). The major isomer trans-5aa (15 mg, 26%), a red solid; mp:140-142 oC; 1H NMR (400 MHz, CDCl3) δ 7.55 (dt, J = 8.7, 4.0 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.35 – 7.28 (m, 3H), 7.21 (d, J = 7.3 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 3.29 (s, 3H), 1.95 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 170.2,

145.6, 132.2, 130.4, 128.8, 128.2, 124.6, 122.1, 122.0, 121.1, 108.7, 86.7, 84.9, 66.4, 58.4, 26.8, 20.6. The minor isomer cis-5aa (5 mg, 9%), a red colloid; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.5 Hz, 1H), 7.48 – 7.30 (m, 6H), 7.10 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 3.29 (s, 3H), 2.09 (s, 3H); 13

C NMR (101 MHz, CDCl3) δ 170.8, 144.8, 131.9, 130.3, 129.1, 128.4, 124.9, 122.3, 122.1, 121.6,

108.4, 86.5, 86.0, 64.8, 60.0, 26.7, 17.9. HRMS−ESI ([M + H]+) Calcd for C19H16NO2 290.1176, found 290.1182. 1,3'-Dimethyl-3'-(p-tolylethynyl)spiro[indoline-3,2'-oxiran]-2-one

(5ab).

Scheme

2;

prepared

according to the typical procedure, isatin 1a (32 mg, 0.2 mmol) and ynones 4b (41 mg, 0.24 mmol) were employed to give 5ab (combined yields 31%, dr 84:16). The major isomer trans-5ab (16 mg, 26%), a red solid; mp: 141-143 oC; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.30 (m, 3H), 7.13 (d, J = 6.6 Hz, 1H), 7.07 – 6.97 (m, 3H), 6.86 (d, J = 7.8 Hz, 1H), 3.22 (s, 3H), 2.27 (s, 3H), 1.87 (s, 3H);

13

C NMR (101

MHz, CDCl3) δ 170.3, 145.6, 139.0, 132.2, 130.3, 129.0, 124.6, 122.1, 118.9, 108.7, 86.9, 84.2, 66.4, 58.5, 26.8, 21.5, 20.7; HRMS−ESI ([M + H]+) Calcd for C20H18NO2 304.1332, found 304.1342. Ethyl 2,3-diphenyloxirane-2-carboxylate (7aa). Table 3, entry 1; prepared according to the typical procedure,α-keto ester 6a (36 mg, 0.2 mmol) and aldehyde 2a (25 mg, 0.24 mmol) were employed to give7aa as a diastereomeric mixture with trans-7aa being the major (38 mg, 71%, dr 80:20), a yellow liquid; 1H NMR (400 MHz, CDCl3) for the major isomer: δ 8.13 (dd, J = 8.2, 1.1 Hz, 1H), 7.58 (ddd, J =


21


Page 22 of 29

5.7, 4.6, 1.7 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.20 (dd, J = 4.1, 2.4 Hz, 3H), 7.15 – 7.09 (m, 3H), 4.56 (s, 1H), 4.34 – 4.23 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H); 1H NMR (400 MHz, CDCl3) for the minor isomer: δ 7.48 (s, 1H), 7.32 – 7.27 (m, 4H), 7.02 (dt, J = 6.0, 2.4 Hz, 5H), 6.14 (s, 1H), 4.24 – 4.11 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H);

13

C NMR (101 MHz, CDCl3) δ 169.3, 137.9, 131.5, 130.0, 129.1, 128.7, 128.5,

128.1, 127.6, 126.7, 65.1, 63.6, 62.1, 21.1, 14.0; HRMS−ESI ([M + H]+) Calcd for C17H17O3269.1172, found 269.1174. Ethyl 2-phenyl-3-(p-tolyl)oxirane-2-carboxylate (7ac).Table 3, entry 2; prepared according to the typical procedure, α-keto ester 6a (36 mg, 0.2 mmol) and aldehyde 2c (29 mg, 0.24 mmol) were employed to give7ac as a diastereomeric mixture with trans-7ac being the major (38 mg, 67%, dr 71:29), a yellow liquid; 1H NMR (400 MHz, CDCl3) for the major isomer: δ 7.26 – 7.19 (m, 2H), 7.16 – 7.09 (m, 3H), 6.83 (q, J = 8.3 Hz, 4H), 4.43 (s, 1H), 4.23 – 4.10 (m, 2H), 2.13 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 1H NMR (400 MHz, CDCl3) for the minor isomer: δ 8.10 – 8.04 (m, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.51 (dd, J = 4.9, 2.7 Hz, 2H), 7.43 – 7.31 (m, 4H), 6.07 (s, 1H), 6.05 (s, 1H), 4.14 – 4.06 (m, 2H), 2.33 (s, 3H), 1.14 (td, J = 7.1, 2.1 Hz, 3H);

13

C NMR (101 MHz, CDCl3)δ 169.3, 165.9, 133.4, 133.1,

131.4, 130.0, 129.2, 128.8, 128.7, 128.4, 128.2, 128.1, 127.8, 127.6, 126.8, 75.0, 65.1, 63.5, 62.2, 61.7, 14.1; HRMS−ESI ([M + H]+) Calcd for C18H19O3 283.1329, found 283.1335. Ethyl 3-(4-bromophenyl)-2-phenyloxirane-2-carboxylate (7ag). Table 3, entry 3; prepared according to the typical procedure, α-keto ester 6a (36 mg, 0.2 mmol) and aldehyde 2g (44 mg, 0.24 mmol) were employed to give 7ag as two separable diastereomers (combined yields 72%, dr 90:10). The major isomer trans-7ag (45 mg, 65%), a colorless liquid; 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.19 (m, 7H), 6.89 (d, J = 8.4 Hz, 2H), 4.51 (s, 1H), 4.30 – 4.21 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H);

13

C NMR (101

MHz, CDCl3) δ 168.9, 132.2, 131.0, 128.6, 128.4, 128.4, 127.8, 122.4, 65.1, 62.9, 62.3, 14.0; HRMS−ESI ([M + H]+) Calcd for C17H16BrO3 347.0277, found 347.0272. Ethyl 2-phenyl-3-(pyridin-3-yl)oxirane-2-carboxylate (7ak). Table 3, entry 4; prepared according to the typical procedure, α-keto ester 6a (36 mg, 0.2 mmol) and aldehyde 2k (26 mg, 0.24 mmol) were


22

Page 23 of 29 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


employed to give 7ak as a diastereomeric mixture with trans-7ak being the major (50 mg, 93%, dr 82:18), a yellow liquid; 1H NMR (400 MHz, CDCl3) for the major isomer: δ 8.46 – 8.35 (m, 2H), 7.68 – 7.60 (m, 1H), 7.46 – 7.38 (m, 1H), 7.33 – 7.28 (m, 2H), 7.23 – 7.15 (m, 2H), 7.01 (dd, J = 7.9, 4.8 Hz, 1H), 4.60 (s, 1H), 4.35 – 4.21 (m, 2H), 1.33 – 1.25 (m, 3H); 1H NMR (400 MHz, CDCl3) for the minor isomer: δ 8.70 (d, J = 1.8 Hz, 1H), 8.59 (dd, J = 4.8, 1.4 Hz, 1H), 7.73 (dt, J = 8.0, 1.8 Hz, 1H), 7.45 – 7.42 (m, 1H), 7.19 (dt, J = 7.9, 1.8 Hz, 4H), 6.99 (s, 1H), 4.18 (s, 1H), 4.09 – 3.98 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H);

13

C NMR (101 MHz, CDCl3) δ 168.6, 166.1, 149.7, 149.4, 148.4, 148.1, 134.1, 134.0,

133.6, 130.6, 129.7, 129.1, 129.0, 128.6, 128.5, 127.9, 126.2, 123.1, 122.6, 66.8, 65.1, 63.4, 62.4, 61.7, 61.3, 14.0, 13.8; HRMS−ESI ([M + H]+) Calcd for C16H16NO3 270.1125, found 270.1136. Ethyl 3-(pyridin-3-yl)-2-(p-tolyl)oxirane-2-carboxylate (7bk). Table 3, entry 5; prepared according to the typical procedure, α-keto ester 6b (38 mg, 0.2 mmol) and aldehyde 2k (26 mg, 0.24 mmol) were employed to give 7bk as a diastereomeric mixture with trans-7bk being the major (52 mg, 92%, dr 71:29), a yellow liquid; 1H NMR (400 MHz, CDCl3) for the major isomer: δ 8.45 – 8.34 (m, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.5, 5.0 Hz, 2H), 7.07 – 6.98 (m, 3H), 4.57 (s, 1H), 4.35 – 4.20 (m, 2H), 2.25 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 1H NMR (400 MHz, CDCl3) for the minor isomer: δ 8.69 (d, J = 1.6 Hz, 1H), 8.58 (dd, J = 4.7, 1.3 Hz, 1H), 7.72 (dt, J = 7.9, 1.8 Hz, 1H), 7.29 (q, J = 4.8 Hz, 1H), 7.24 – 7.22 (m, 2H), 7.01 (d, J = 4.3 Hz, 2H), 4.17 (s, 1H), 4.08 – 3.95 (m, 2H), 2.37 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H);

13

C NMR (101 MHz, CDCl3) δ 168.7, 166.1, 149.6, 149.3, 148.4, 148.0, 138.9, 138.2,

134.1, 133.5, 131.0, 129.7, 129.2, 129.1, 128.5, 128.4, 127.6, 127.4, 126.0, 122.9, 122.5, 66.7, 65.0, 63.3, 62.2, 61.5, 61.2, 21.1, 13.9, 13.7; HRMS−ESI ([M + H]+) Calcd for C17H18NO3 284.1281, found 284.1292. Ethyl 2-(4-bromophenyl)-3-(pyridin-3-yl)oxirane-2-carboxylate (7ck). Table 3, entry 6; prepared according to the typical procedure, α-keto ester 6c (51 mg, 0.2 mmol) and aldehyde 2k (26 mg, 0.24 mmol) were employed to give 7ck as a diastereomeric mixture with trans-7bk being the major (63 mg, 94%, dr 68:32), a yellow liquid; 1H NMR (400 MHz, CDCl3) for the major isomer: δ 8.42 (s, 2H), 7.54 (s, 2H), 7.39 – 7.34 (m, 2H), 7.21 – 7.16 (m, 2H), 4.62 (s, 1H), 4.28 (qd, J = 7.1, 1.6 Hz, 2H), 1.29 (t, J 23 ACS Paragon Plus Environment


Page 24 of 29

= 7.1 Hz, 3H); 1H NMR (400 MHz, CDCl3) for the minor isomer: δ 8.69 (d, J = 1.7 Hz, 1H), 8.60 (dd, J = 4.8, 1.4 Hz, 1H), 7.72 (dt, J = 7.9, 1.8 Hz, 1H), 7.34 – 7.30 (m, 1H), 7.22 (t, J = 1.8 Hz, 1H), 7.22 (t, J = 1.8 Hz, 1H), 7.06 (dd, J = 7.9, 4.9 Hz, 2H), 4.14 (s, 1H), 4.09 – 3.95 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H); 13

C NMR (101 MHz, CDCl3) δ 168.1, 165.6, 149.8, 149.6, 148.3, 148.0, 133.9, 133.6, 133.1, 131.7,

131.1, 130.2, 129.7, 129.2, 128.6, 127.9, 123.1, 123.0, 122.8, 122.7, 66.1, 64.5, 63.5, 62.5, 61.8, 61.4, 13.9, 13.7; HRMS- ESI ([M + H]+) Calcd for C16H15BrNO3 348.0230, found 348.0232. Phenyl(2-phenyl-3-(pyridin-3-yl)oxiran-2-yl)methanone (7dk). Table 3, entry 7; prepared according to the typical procedure, benzil 6d (42 mg, 0.2 mmol) and aldehyde 2k (26 mg, 0.24 mmol) were employed to give 7dk as a diastereomeric mixture with trans-7dk being the major (53 mg, 88%, dr 51:49), a yellow liquid; 1H NMR (400 MHz, CDCl3) for the major isomer: δ 8.42 (d, J = 2.1 Hz, 1H), 8.32 (dd, J = 4.8, 1.5 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.36 – 7.25 (m, 8H), 7.16 – 7.09 (m, 2H), 4.18 (s, 1H); 1H NMR (400 MHz, CDCl3) for the minor isomer: δ 8.45 (d, J = 2.0 Hz, 1H), 8.39 (dd, J = 4.8, 1.6 Hz, 1H), 8.05 (dd, J = 5.2, 3.4 Hz, 2H), 7.55 – 7.37 (m, 8H), 7.08 – 6.96 (m, 2H), 4.47 (s, 1H);

13

C NMR

(101 MHz, CDCl3) δ 194.4, 193.0, 149.5, 149.2, 148.3, 148.0, 135.1, 134.8, 134.1, 134.0, 133.9, 133.7, 133.4, 131.2, 130.3, 129.8, 129.5, 129.2, 128.9, 128.7, 128.6, 128.5, 128.4, 128.3, 127.2, 125.4, 123.0, 122.6, 71.1, 70.3, 64.8, 60.9; HRMS−ESI ([M + H]+) Calcd for C20H16NO2 302.1176, found 302.1185. 3'-(Pyridin-3-yl)-2H-spiro[acenaphthylene-1,2'-oxiran]-2-one (7ek). Table 3, entry 8; prepared according to the typical procedure, acenaphthylene-1,2-dione 6e (36 mg, 0.2 mmol) and aldehyde 2k (26 mg, 0.24 mmol) were employed to give 7ek as two separable diastereomers (combined yields 99%, dr 98:2). The major isomer trans-7ek (53 mg, 97%), a pale yellow solid; mp: 174-176 oC; 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 2.0 Hz, 1H), 8.66 (dd, J = 4.8, 1.5 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 6.8 Hz, 1H),7.94 – 7.74 (m, 3H), 7.45 – 7.35 (m, 2H), 6.72 (d, J = 7.0 Hz, 1H), 4.93 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 197.3, 149.9, 148.3, 143.0, 134.5, 132.4, 130.6, 130.4, 129.9, 129.8, 128.2, 128.1, 126.4, 123.2, 122.2, 120.5, 66.1, 63.1; HRMS−ESI ([M + H]+) Calcd for C18H12NO2 274.0863, found 274.0877.


24

Page 25 of 29 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


Supporting Information Available: Copies of NMR (1H, 13C) spectra of new compounds 3, 5, and 7; X-ray crystallographic data (CIF files) for compound 3af. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgment: Financial support from National Natural Science Foundation of China (Grant No. 21502135) is gratefully acknowledged. References: (1) (a) He, J.; Ling, J.; Chiu, P. Vinyl Epoxides in Organic Synthesis. Chem. Rev. 2014, 114, 80378128. (b) Kim, K. B.; Crews, C. M. From Epoxomicin to Carfilzomib: Chemistry, Biology, and Medical Outcomes. Nat. Prod. Rep. 2013, 30, 600-604. (c) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Naturally Occurring Cyclohexane Epoxides: Sources, Biological Activities, and Synthesis. Chem. Rev. 2004, 104, 2857-2900. (d) Jacobsen, E. N. Asymmetric Catalysis of Epoxide Ring-Opening Reactions. Acc. Chem. Res. 2000, 33, 421-431. (e) Triandafillidi, L.; Kokotos, C. G. Green Organocatalytic Synthesis of Isoxazolines via a One-Pot Oxidation of Allyloximes. Org. Lett. 2017, 19, 106-109. (2) For selected reviews, see: (a) Wang, C.; Yamamoto, H. Asymmetric Epoxidation Using Hydrogen Peroxide as Oxidant. Chem. Asian J. 2015, 10, 2056-2068. (b) De Faveri, G.; IIyashenko, G.; Watkinson, M. Recent Advances in Catalytic Asymmetric Epoxidation Using the Environmentally Benign Oxidant Hydrogen Peroxide and Its Derivatives. Chem. Soc. Rev. 2011, 40, 1722-1760. (c) McGarrigle, E. M.; Giheany, D. G. Chromium- and Manganese-Salen Promoted Epoxidation of Alkenes. Chem. Rev. 2005, 105, 1563-1602. (d) Xia, Q. H.; Ge, H. Q.; Ye, C. P.; Liu, Z. M.; Su, K. X. Advances in Homogeneous and Heterogeneous Catalytic Asymmetric Epoxidation. Chem. Rev. 2005, 105, 1603-1662. (e) Rose, E.; Andrioletti, B.; Zrig, S.; Quelquejeu-Ehteve, M. Enantioselective Epoxidation of Olefins with Chiral Metalloporphyrin Catalysts. Chem. Soc. Rev. 2005, 34, 573-583. (f) Denmark, S. E.; Wu, Z. The Development of Chiral, Nonracemic Dioxiranes for the Catalytic, Enantioselective Epoxidation of Alkenes. Synlett 1999, 847-859. (g) Yang, D. Ketone-Catalyzed Asymmetric Epoxidation Reactions. Acc. Chem. Res. 2004, 37, 497ACS Paragon Plus Environment

25


Page 26 of 29

505. (3) (a) Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric Synthesis, Ojima, I. Ed., VCH: New York, 1993, pp. 103-158. (b) Johnson, R. A.; Sharpless, K. B. Addition Reactions with Formation of Carbon-Oxygen Bonds ： Asymmetric Methods of Epoxidation. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I. Eds., Pergamon Press: New York, 1991, Vol. 7, pp. 389-436. (4) (a) Zhu, Y.; Wang, Q.; Cornwall, R. G.; Shi, Y. Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications. Chem. Rev. 2014, 114, 8199-8256. (b) Wong, O. A.; Shi, Y. Organocatalytic Oxidation. Asymmetric Epoxidation of Olefins Catalyzed by Chiral Ketones and Iminium Salts. Chem. Rev. 2008, 108, 3958-3987. (5) (a) Sun, X.-L.; Tang, Y. Ylide-Initiated Michael Addition−Cyclization Reactions beyond Cyclopropanes. Acc. Chem. Res. 2008, 41, 937-948. (b) Aggarwal, V. K.; Winn, C. L. Catalytic, Asymmetric Sulfur Ylide-Mediated Epoxidation of Carbonyl Compounds: Scope, Selectivity, and Applications in Synthesis. Acc. Chem. Res. 2004, 37, 611-620. (6) Ballester, M. Mechanisms of the Darzens and Related Condensations. Chem. Rev. 1955, 55, 283300. (7) For deoxygenative epoxidation to get symmetrical epoxides via trivalent phosphorus reagentsmediated reductive dimerization of aromatic aldehydes see: (a) Liu, X.; Verkade, J. G. P(MeNCH2CH2)3N: A Highly Selective Reagent for Synthesizing trans-Epoxides from Aryl Aldehydes. J. Org. Chem. 2000, 65, 4560-4564. (b) Ramirez, F.; Gulati, A. S.; Smith, C. P. Reaction of Tris(dialkylamino)phosphines with Aromatic Aldehydes. I. Nitrobenzaldehydes. Formation of 2,2,2-Triamino-1,3,2-dioxaphospholanes and Their Conversion into Epoxides. J. Org. Chem. 1968, 33, 13-19. (c) Newman, M. S.; Blum, S. A New Cyclization Reaction Leading to Epoxides of Aromatic Hydrocarbons. J. Am. Chem. Soc. 1964, 86, 5598-5600. (d) Mark, V. Nucleophilic Reactions of Trivalent Phosphorus Compounds: a New Synthesis of Epoxides. J. Am. Chem. Soc. 1963, 85, 1884-1885. ACS Paragon Plus Environment

26

Page 27 of 29 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


(8) (a) Kukhtin, V. A. Some New Types of Arbuzov's Regrouping. Dokl. Akad. Nauk SSSR 1958, 121, 466-469. (b) Ramirez, F. Condensations of Carbonyl Compounds with Phosphite Esters. Pure Appl. Chem. 1964, 9, 337-370. (c) Ramirez, F. Oxyphosphoranes. Acc. Chem. Res. 1968, 1, 168-174. (d) Osman, F. H.; EI-Samahy, F. A. Reactions of α-Diketones and o-Quinones with Phosphorus Compounds. Chem. Rev. 2002, 102, 629-678, and references cited therein. (9) (a) Zhao, W.; Yan, P. K.; Radosevich, A. T. A Phosphetane Catalyzes Deoxygenative Condensation of α-Keto Esters and Carboxylic Acids via PIII/PV=O Redox Cycling. J. Am. Chem. Soc. 2015, 137, 616-619. (b) Zhang, W.-Z.; Xia, T.; Yang, X.-T.; Lu, X.-B. Synthesis of Oxazolidine-2,4-diones by a Tandem Phosphorus-Mediated Carboxylative CondensationCyclization Reaction Using Atmospheric Carbon Dioxide. Chem. Commun. 2015, 51, 6175-6178. (c) Zhao, W.; Fink, D. M.; Labutta, C. A.; Radosevich, A. T. A Csp3–Csp3 Bond Forming Reductive Condensation of α-Keto Esters and Enolizable Carbon Pronucleophiles. Org. Lett. 2013, 15, 3090-3093. (d) Miller, E. J.; Zhao, W.; Herr, J. D.; Radosevich, A. T. A Nonmetal Approach to α-Heterofunctionalized Carbonyl Derivatives by Formal Reductive X−H Insertion. Angew. Chem. Int. Ed. 2012, 51, 10605-10609. (10) (a) Zhou, R.; Han, L.; Zhang, H.; Liu, R.; Li, R. A Deoxygenative [4 + 1] Annulation Involving NAcyldiazenes for an Efficient Synthesis of 2,2,5-Trisubstituted 1,3,4-Oxadiazole Derivatives. Adv. Synth. Cat. 2017, 359, 3977-3982. (b) Zhou, R.; Liu, R.; Zhang, K.; Han, L.; Zhang, H.; Gao, W.; Li, R. Metal-free Formal Carbon-Halogen Bond Insertion: Facile Syntheses of 3-Halo 3,3'Disubstituted Oxindoles and Spirooxindole-γ-butyrolactones. Chem. Commun. 2017, 53, 68606863. (c) Zhou, R.; Zhang, K.; Han, L.; Chen, Y.; Li, R.; He, Z. Unusual Formal [1 + 4] Annulation through Tandem P(NMe2)3-Mediated Cyclopropanation/Base-Catalyzed Cyclopropane Rearrangement: Facile Syntheses of Cyclopentenimines and Cyclopentenones. Chem. Eur. J. 2016, 22, 5883-5887. (d) Zhou, R.; Zhang, K.; Chen, Y.; Meng, Q.; Liu, Y.; Li, R.; He, Z. P(NMe2)3-Mediated Reductive [1 + 4] Annulation of Isatins with Enones: a Facile Synthesis of Spirooxindole-dihydrofurans. Chem. Commun. 2015, 51, 14663-14666. (e) Zhou, R.; Yang, C.; 27 ACS Paragon Plus Environment


Page 28 of 29

Liu, Y.; Li, R.; He, Z. Diastereoselective Synthesis of Functionalized Spirocyclopropyl Oxindoles via P(NMe2)3-Mediated Reductive Cyclopropanation. J. Org. Chem. 2014, 79, 10709-10715. (11) (a) Liu, Y.; Li, H.; Zhou, X.; He, Z. P(NMe2)3-Mediated Reductive (1 + 4) Annulation Reaction of Isatins with Nitroalkenes: an Access to Spirooxindolyl Isoxazoline N-Oxides and Their Corresponding Isoxazolines. J. Org. Chem. 2017, 82, 10997-11007. (b) Jiang, J.; Liu, H.; Lu, C.D.; Xu, Y.-J. P(NMe2)3-Mediated Aziridination of Imines with α-Ketoesters for Synthesis of Aziridine-2-carboxylates. J. Org. Chem. 2017, 82, 811-818. (c) Zhang, L.; Lu, H.; Xu, G.-Q.; Wang, Z.-Y.; Xu, P.-F. PPh3 Mediated Reductive Annulation Reaction between Isatins and Electron Deficient Dienes to Construct Spirooxindole Compounds. J. Org. Chem. 2017, 82, 57825789. (d) Rodriguez, K. X.; Vail, J. D.; Ashfeld, B. L. Phosphorus(III)-Mediated Stereoconvergent Formal [4 + 1]-Cycloannulation of 1,2-Dicarbonyls and o-Quinone Methides: a Multicomponent Assembly of 2,3-Dihydrobenzofurans. Org. Lett. 2016, 18, 4514-4517. (e) Wilson, E. E.; Rodriguez, K. X.; Ashfeld, B. L. Stereochemical Implications in the Synthesis of 3,3′Spirocyclopropyl Oxindoles from β-Aryl/Alkyl-Substituted Alkylidene Oxindoles. Tetrahedron, 2015, 71, 5765-5775. (f) Wang, S. R.; Radosevich, A. T. P(NMe2)3-Mediated Umpolung Alkylation and Nonylidic Olefination of α-Keto Esters. Org. Lett. 2015, 17, 3810-3813. (g) Chavannavar, A. P.; Oliver, A. G.; Ashfeld, B. L. An Umpolung Approach toward N-Aryl Nitrone Construction: a Phosphine-Mediated Addition of 1,2-Dicarbonyls to Nitroso Electrophiles. Chem. Commun. 2014, 50, 10853-10856. (h) Wang, S. R.; Radosevich, A. T. Reductive Homocondensation of Benzylidene- and Alkylidenepyruvate Esters by a P(NMe2)3-Mediated Tandem Reaction. Org. Lett. 2013, 15, 1926-1929. (12) A single example to afford an unsymmetrical epoxide by P(NMe2)3-mediated chemoselective epoxidation of methyl benzoyl formate with 4-methoxylbenzaldehyde was first reported by Ashfeld et al., see ref. 11g. (13) (a) Aikawa, K.; Mimura, S.; Numata, Y.; Mikami, K. Palladium-Catalyzed Enantioselective Ene and Aldol Reactions with Isatins, Keto Esters, and Diketones: Reliable Approach to Chiral ACS Paragon Plus Environment

28

Page 29 of 29 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


Tertiary Alcohols. Eur. J. Org. Chem. 2011, 62-65. (b) Cao, S.-H.; Zhang, X.-C.; Wei, Y.; Shi, M. Chemoselective Reduction of Isatin-Derived Electron-Deficient Alkenes Using Alkylphosphanes as Reduction Reagents. Eur. J. Org. Chem. 2011, 2668-2672. (14) Meng, Q.; Sun, Y.; Ratovelomanana-Vidal, V.; Genêt, J. P.; Zhang, Z. CeCl3·7H2O: an Effective Additive in Ru-Catalyzed Enantioselective Hydrogenation of Aromatic α-Ketoesters. J. Org. Chem. 2008, 73, 3842-3847.


29

Mediated Reductive Epoxidation between Two ... - ACS Publications

Recommend Documents