Diastereoselective Synthesis of Oxazoloisoindolinones via Cascade

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Diastereoselective Synthesis of Oxazoloisoindolinones via Cascade Pd-Catalyzed ortho-Acylation of N-Benzoyl #-Amino Acid Derivatives and Subsequent Double Intramolecular Cyclizations Kun Jing, Xiang-Nan Wang, and Guan-Wu Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02509 • Publication Date (Web): 04 Dec 2018 Downloaded from http://pubs.acs.org on December 4, 2018

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The Journal of Organic Chemistry

Diastereoselective Synthesis of Oxazoloisoindolinones via Cascade Pd-Catalyzed ortho-Acylation of N-Benzoyl α-Amino Acid Derivatives and Subsequent Double Intramolecular Cyclizations

Kun Jing,† Xiang-Nan Wang,† and Guan-Wu Wang*,†,‡

†CAS

Key Laboratory of Soft Matter Chemistry, Collaborative Innovation Center of

Chemistry for Energy Materials (iChEM), Hefei National Laboratory for Physical Sciences at Microscale, and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China E-mail: [email protected]; ‡State

Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China

ABSTRACT R2

O R

N H

1

O

O COOH

OH + R

3

DCE, 70 oC, 12 h

O

H

Pd(OAc)2 K2S2O8, PTSA

R2 N

R1

O

O

R3

large-scale synthesis broad substrate scope high regioselectivity excellent diastereoselectivity

(rac) 36 examples cis isomer, dr > 99:1 up to 91% yield

1

ACS Paragon Plus Environment

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

The first cascade diastereoselective synthesis of oxazoloisoindolinones via the palladium-catalyzed decarboxylative ortho-acylation of N-benzoyl α-amino acid derivatives followed by double intramolecular cyclizations has been demonstrated. This reaction, using α-amino acids as directing groups and α-oxocarboxylic acids as the acylation source, features broad substrate scope, good functional group tolerance, high regioselectivity, and excellent diastereoselectivity.

INTRODUCTION Isoindolinones are an important subclass of nitrogen-containing heterocycles found in natural products and biologically active compounds such as lennoxamine,1 pestalachloride,2 and pagoclone.3 Additionally, isoindolinone derivatives display versatile biological activities including antihypertensive,4 antipsychotic,5 antitumoral,6 and so on.7 Among them, oxazoloisoindolinones represent the core unit of a wide range of promising bioactive compounds like antidiabetic agents, antitumor agents, and cancer drug candidates SLMP53-1/DIMP53-1 (Figure 1).8 Oxazoloisoindolinones bearing the bicyclic lactam and N,O-acetal moiety have proven to be exceptional building blocks for the asymmetric construction of various natural and unnatural carbocyclic and heterocyclic compounds containing one or more stereogenic centers.9 Given the widespread utility of oxazoloisoindolinones, it is not surprising that a variety of methods have been developed for their synthesis. The early employed methods for the synthesis of oxazoloisoindolinones were the cyclodehydration process between amino alcohols and ketoacids under azeotropic removal of water10 and the reaction of 2


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N-(2-bromoethyl)phthalimide with organolithiums or Grignard reagents.11 In 1997, the Shim group developed the palladium-catalyzed stereoselective synthesis of oxazoloisoindolinones via carbonylative cyclization between 2-bromobenzaldehyde and amino alcohols.12 Another approach is the intramolecular cationic cyclization with N-acyliminium species.13 However, from a synthetic point of view, these methods suffer from some intrinsic drawbacks including poor functional group tolerance, harsh reaction conditions, bad stereoselectivity, and the requirement of prefunctionalization of the coupling partners. Therefore, it is highly desirable to develop novel and efficient protocols with fewer synthetic steps and better stereoselectivity for the synthesis of oxazoloisoindolinones.

O O

N

N O

O H N

O N

antidiabetic agent

NH O

N

antitumor agent

NH

O N

N

R

O SLMP53-1 (R = H) DIMP53-1 (R = Bn)

Figure 1. Representative bioactive oxazoloisoindolinones

The transition-metal-catalyzed C−H bond activation/cyclization reactions have been recognized as one of the most powerful methods for the construction of heterocycles in modern synthetic organic chemistry due to their practical and environment-friendly properties.14 In 2012, Kim and co-workers reported the tandem Rh(III)-catalyzed ortho-acylation and intramolecular cyclization of secondary 3



benzamides and aryl aldehydes to synthesize 3-hydroxylisoindolinones.15 Soon after, a more efficient approach to 3-hydroxylisoindolinones was realized by Zhao and coworkers via the Pd-catalyzed C−H activation/annulation reaction of secondary benzamides and aldehydes.16 In our previous work of the Pd-catalyzed decarboxylative ortho-acylation of benzamides with α-oxocarboxylic acids,17 when secondary benzamides were employed as the substrates, the formed ortho-acylated benzamides underwent further intramolecular cyclization to provide similar hydroxylisoindolinone derivatives. However, to the best of our knowledge, further cyclization utilizing the reactive hydroxyl to construct tricyclic isoindolinone derivatives has not been reported yet now. Amino acid derivatives are widespread and structurally diverse in natural products, and functionalized molecules bearing amino acid moieties are of interest as potential bioactive substrates.18 More recently, pioneering work utilizing environmentally friendly and inexpensive amino acid moieties as novel directing groups in C−H activation for the modification of amino acid derivatives has been realized by the Chatani, Yu, and Hong groups, respectively.19 The special structure of amino acid made itself a feasible directing group without the necessity of being removed, and the products were very useful building blocks for assembling bioactive molecules. In 2016, Liu and co-workers disclosed the Pd-catalyzed alkoxylation of N-benzoyl α-amino acid derivatives at room temperature.20 With our continuing interest in developing more C−H bond activation protocols,14a,14c,17,21 herein we present the first one-step diastereoselective synthesis of oxazoloisoindolinones via cascade Pd-catalyzed 4


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decarboxylative ortho-acylation of N-benzoyl α-amino acid derivatives and subsequent double intramolecular cyclizations.

RESULTS AND DISCUSSION In our initial investigation, when racemic N-benzoyl-DL-valine (1a) and phenylglyoxylic acid (2a) were conducted under our previous conditions (10 mol % Pd(OAc)2 as the catalyst, 2.0 equiv of K2S2O8 as the oxidant, 0.5 equiv of ptoluenesulfonic acid (PTSA) as the additive, and 1,2-dichloroethane (DCE) as the solvent),17 the desired product 3aa was successfully isolated in 67% yield after 12 h at 70 oC (Table 1, entry 1). Solvent screening showed that DCE was the optimal solvent compared to other solvents such as CH3CN, toluene, 1,4dioxane, hexafluoroisopropanol (HFIP), and N,N-dimethylformamide (DMF) (Table 1, entries 2−6). When PTSA was replaced with other acids including trifluoacetic acid (TFA), acetic acid (AcOH), methanesulfonic acid (CH3SO3H), D-camphorsulfonic acid (D-CSA), or trifluoromethanesulfonic acid (TfOH), the yield of 3aa was reduced (Table 1, entries 7−11). Other persulfate oxidants including Na2S2O8, (NH4)2S2O8, and Oxone were inferior to K2S2O8 and other types of oxidants such as Ag2CO3, Cu(OAc)2, and 1,4-benzoquinone (BQ) failed to provide the desired product, which indicated the superiority of K2S2O8 for decarboxylation in our catalyst system (Table 1, entries 12−17). Other palladium catalysts were also examined, and the results showed that Pd(TFA)2 could afford the desired product 3aa albeit in a slightly lower yield, whereas using 5



Pd(CH3CN)2Cl2 or Pd(PhCN)2Cl2 as the catalysts gave only trace amount of 3aa (Table 1, entries 18−20). Increasing the amount of K2S2O8 from 2.0 to 2.5 equiv. resulted in a better yield of 73%, but further increase to 3.0 equiv. gave a worse result (Table 1, entries 21 and 22). Similarly, when the amount of PTSA was increased from 0.5 equiv. to 1.0 equiv. and 1.5 equiv., 3aa was obtained in 80% and 84% yields, respectively, while further increasing to 2.0 equiv. gave a lower yield (Table 1, entries 23−25). Then the reaction temperature was examined, decreasing the temperature from 70 oC to 60 oC or increasing the temperature to 80 oC both reduced the yield slightly (Table 1, entries 26 and 27). When the reaction time was shortened to 10 h, the desired product 3aa was obtained in only 75% yield, and prolonging the reaction time to 14 h had no further improvement of the yield (Table 1, entries 28 and 29). Control experiment revealed that PTSA was essential for this reaction (Table 1, entry 30). PTSA may tune the electrophilicity of the Pd(II) center and promote the insertion of Pd(II) into the aromatic C−H bonds.22 On the other hand, PTSA may favor the second intramolecular cyclization process to generate the desired lactone.23 Therefore, the optimized reaction conditions were as follows: 10 mol % Pd(OAc)2 as the catalyst, 2.5 equiv. of K2S2O8 as the oxidant, 1.5 equiv. of PTSA as the additive, and 2.0 equiv. of 2a as the partner of 1a. The reaction performed best at 70 oC for 12 h with DCE as the solvent. Table 1. Optimization of the Reaction Conditionsa

6


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O O

O N H

COOH

OH

+

catalyst oxidant, additive solvent, 70 oC, 12 h

O

N O

O

(rac)

1a

2a

3aa

oxidant (equiv)

additive (equiv)

catalyst (10 mol %)

1

Pd(OAc)2

K2S2O8 (2.0)

PTSA (0.5)

DCE

67

2

Pd(OAc)2

K2S2O8 (2.0)

PTSA (0.5)

CH3CN

0

3

Pd(OAc)2

K2S2O8 (2.0)

PTSA (0.5)

Toluene

31

4

Pd(OAc)2

K2S2O8 (2.0)

PTSA (0.5)

1,4-dioxane

56

5

Pd(OAc)2

K2S2O8 (2.0)

PTSA (0.5)

HFIP

45

6

Pd(OAc)2

K2S2O8 (2.0)

PTSA (0.5)

DMF

0

7

Pd(OAc)2

K2S2O8 (2.0)

TFA (0.5)

DCE

8

8

Pd(OAc)2

K2S2O8 (2.0)

AcOH (0.5)

DCE

trace

9

Pd(OAc)2

K2S2O8 (2.0)

CH3SO3H (0.5)

DCE

44

10

Pd(OAc)2

K2S2O8 (2.0)

D-CSA (0.5)

DCE

trace

11

Pd(OAc)2

K2S2O8 (2.0)

TfOH (0.5)

DCE

47

12

Pd(OAc)2

Na2S2O8 (2.0)

PTSA (0.5)

DCE

7

13

Pd(OAc)2

(NH4)2S2O8 (2.0)

PTSA (0.5)

DCE

63

14

Pd(OAc)2

Oxone (2.0)

PTSA (0.5)

DCE

27

15

Pd(OAc)2

Ag2CO3 (2.0)

PTSA (0.5)

DCE

0

16

Pd(OAc)2

Cu(OAc)2 (2.0)

PTSA (0.5)

DCE

0

17

Pd(OAc)2

BQ (2.0)

PTSA (0.5)

DCE

0

18

Pd(TFA)2

K2S2O8 (2.0)

PTSA (0.5)

DCE

54

7


solvent

yield (%)b

entry


Page 8 of 46

19

Pd(CH3CN)2Cl2

K2S2O8 (2.0)

PTSA (0.5)

DCE

trace

20

Pd(PhCN)2Cl2

K2S2O8 (2.0)

PTSA (0.5)

DCE

trace

21

Pd(OAc)2

K2S2O8 (2.5)

PTSA (0.5)

DCE

73

22

Pd(OAc)2

K2S2O8 (3.0)

PTSA (0.5)

DCE

66

23

Pd(OAc)2

K2S2O8 (2.5)

PTSA (1.0)

DCE

80

24

Pd(OAc)2

K2S2O8 (2.5)

PTSA (1.5)

DCE

84

25

Pd(OAc)2

K2S2O8 (2.5)

PTSA (2.0)

DCE

78

26c

Pd(OAc)2

K2S2O8 (2.5)

PTSA (1.5)

DCE

71

27d

Pd(OAc)2

K2S2O8 (2.5)

PTSA (1.5)

DCE

79

28e

Pd(OAc)2

K2S2O8 (2.5)

PTSA (1.5)

DCE

75

29f

Pd(OAc)2

K2S2O8 (2.5)

PTSA (1.5)

DCE

83

30

Pd(OAc)2

K2S2O8 (2.5)

-

DCE

trace

aReaction

conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (0.03 mmol),

oxidant, additive, solvent (3 mL), 70 °C, 12 h. bIsolated yields based on 1a. c60 °C. d80 °C. e10 h. f14 h.

Having established the optimal reaction conditions, the substrate scope of N-benzoyl α-amino acid derivatives was investigated, and the results are shown in Table 2. Generally, various substituents on either the α-amino acid moiety or the aromatic ring were well tolerated to afford the corresponding products in moderate to excellent yields. α-Mono-substituted amino acid derivatives 1b−e proceeded smoothly to give products 3ba−ea in 51−73% yields, and the desired 8


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product 3fa was obtained in 56% yield when R2 was the phenyl group. α-Disubstituted amino acid derivative 1g gave the corresponding product 3ga in 55% yield. To our satisfaction, cyclic amino acid derivatives 1h and 1i also worked well under our optimal conditions, providing products 3ha and 3ia in 67% and 66% yields, respectively. The functional group tolerance of the aromatic ring was also explored. To our delight, either electron-rich or electron-deficient groupsubstituted amino acid derivatives were well tolerated with our optimized conditions. Substrates 1j−l with para-substituted electron-donating groups gave the corresponding oxazoloisoindolinones 3ja−la in good to high yields of 74−91%. This reaction was also compatible with α-amino acids bearing halogen substituents on the phenyl ring and furnished products 3ma−oa in high yields of 79−90%. Particularly noteworthy was the tolerance of the reaction conditions to chloro and bromo atoms, which provide a versatile synthetic handle for further functionalization of the products. Substrates 1p and 1q with strong electronwithdrawing groups (CF3 and NO2) proceeded well and delivered the desired products 3pa and 3qa in 69% and 54% yields, respectively. In addition, the cleavage of C−H bonds in meta-substituted substrates (1r−t) occurred predominantly at the less hindered sites to give 3ra−ta in 61−82% yields with excellent regioselectivities. What is more, this reaction could also be expanded to ortho-substituted substrates and provided the desired products 3ua−xa in good yields (62−78%). Finally, the α-amino acid derivatives bearing a disubstituted benzoyl moiety proved to be feasible for this procedure and afforded the 9



corresponding products 3ya and 3za in 64% and 78% yields, respectively. However, to our disappointment, N-benzoyl-DL-glycine was not compatible for this reaction. When R2 was replaced with other functional groups such as OMe, Br, and CN, the corresponding substrates also failed to give the desired products, probably due to their instability under our conditions. To demonstrate the synthetic utility of this method, a large-scale reaction was conducted, and a satisfactory yield of 73% for product 3ja was obtained under our optimized reaction conditions.

Table 2. Scope of N-Benzoyl α-Amino Acid Derivativesa,b

10


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O R

O R

2

N H

1

O


OH

+

COOH

R1

DCE, 70 oC, 12 h

O

R2 N O

O

(rac)

1a-z

3aa-za

2a O

O

N

N O

O

(rac)

(rac)

3ba, 60%

O

O

(rac)

(rac)

O N

N O

O

N

O

O

O

(rac)

3ha, 67%d

3ga, 55%

O

MeO

O

O

O

F

(rac)

3la, 76%

O

O 2N

O

O

(rac)

3qa, 54%c O

F N

(rac)

3va, 62%c,d aReaction

(rac)

(rac)

3ra, 74%

3sa, 82%

O

Cl N

O

O

O

O

O

O

N O

O

3ua, 77% O

O N

N O

(rac)

(rac)

3wa, 78%

3xa, 78%

O

O

(rac)

(rac)

3ta, 61%

O

O

O

3pa, 69%

N

F3C

O

(rac)

O

O

O

F3C

3oa, 79%

N

Cl

O

(rac)

O N

N

N

O

Br

3na, 90%

O

O

O

(rac)

3ma, 84%

O N

O

Cl

(rac)

3ka, 74%

O N

N

N

MeO

O

O

O

O

(rac)

3ja, 91% (73%)e

3ia, 66%

O

3fa, 56%c

O

O

O

O

3da, R = H, 63% 3ea, R = Me, 51%c

O

O

N

R

O

(rac)

N

O

O

3ca, 73%

O N

Ph

O

3aa, 84%

O N

N

O

O

O

O

O

(rac)

3ya, 64%

Cl

N

O

O

Cl

O

(rac)

3za, 78%

conditions: 1 (0.3 mmol), 2a (0.6 mmol), Pd(OAc)2 (0.03 mmol),

K2S2O8 (0.75 mmol), PTSA (0.45 mmol), DCE (3 mL), 70 oC, 12 h. bIsolated yields based on 1. c24 h. d80 oC. e3.0 mmol scale. 11



Next, we investigated the reaction of representative racemic N-benzoyl αamino acid derivative 1j with a variety of α-oxocarboxylic acids 2b−k to further explore the substrate scope and limitation, which demonstrated wide generality and good yields, as depicted in Table 3. Phenylglyoxylic acids bearing electronrich or electron-deficient groups at the para-position proceeded smoothly and provided the desired products 3jb−jd in 55−78% yields. Meta-substituted phenylglyoxylic acids with different functional groups also worked well under the optimal conditions, delivering the corresponding products 3je−jh in 58−81% yields. The reaction could be extended to ortho-substituted phenylglyoxylic acids to give oxazoloisoindolinones 3ji and 3jj in 75% and 60% yields, respectively. The disubstituted phenylglyoxylic acids proved to be feasible for this procedure and afforded product 3jk in 73% yield. Unfortunately, the attempt to extend the substrates from aromatic oxocarboxylic acids to aliphatic oxocarboxylic acids (such as pyruvic acid) under our optimized conditions failed to give the desired products.

Table 3. Scope of α-Oxocarboxylic Acidsa,b

12


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O O

O N H


OH

COOH

+

N O

O

DCE, 70 oC, 12 h

O R

R (rac)

1j

2b-k

O

O

3jb-jk

N

N O

O

O

O

O N

N O

MeO (rac)

(rac)

O

O

O

N O

O

O

OMe

F (rac)

(rac)

(rac)

3jb, 78%

3jc, 55%

3jd, 60%

3je, 75%

3jf, 69%

O

O

O

O

O

N O

O

N

N

N O

O

O

O

O

N O

O

O

O

Cl Br

CF3

(rac)

3jg, 81% aReaction

(rac)

(rac)

(rac)

3jh, 58%

3ji, 75%

3jj, 60%

Cl

Cl (rac)

3jk, 73%

conditions: 1j (0.3 mmol), 2 (0.6 mmol), Pd(OAc)2 (0.03 mmol), K2S2O8

(0.75 mmol), PTSA (0.45 mmol), DCE (3 mL), 70 oC, 12 h. bIsolated yields based on 1j.

To probe whether the chirality of α-amino acids could be efficiently transferred to products, and hence facile access to chiral oxazoloisoindolinones with two stereogenic centers, including a quaternary one, enantiomerically pure N-benzoyl-L-alanine (L-1b) was employed under the same reaction conditions used for the racemic substrate DL-1b (Scheme 1). To our great delight, the reaction proceeded well to afford the corresponding chiral oxazoloisoindolinone

13



Page 14 of 46

3ba with excellent diastereomeric excess (>99%), guaranteeing the practical importance of our method.

Scheme 1. Determination of the Diastereoselectivity of Pure N-Benzoyl-Lalanine O O

O N H

COOH

L-1b >99% ee


OH +

DCE, 70 oC, 12 h

O

2a

(R)

N

(S)

O

O

(3S,9bR)-3ba

61% yield >99% de

The structures of the obtained products 3 were identified by 1H NMR,

13C

NMR, and HRMS. Particularly, all products 3 were formed as a single diastereoisomer by the analyses of their 1H NMR spectra. For products 3ra−ta, 3ya, and 3za, the regioselectivities could be established by the diagnostic singlets at 7.33−8.18 ppm in their 1H NMR spectra, indicating that the C−H bond cleavage primarily occurred at the less hindered position. Furthermore, the stereoscopic configurations of the products were unambiguously established by the single-crystal X-ray diffraction analyses of representative 3aa and 3ra (Figure 2),24 showing that the phenyl ring at C4 and the isopropyl group at C15 (for 3aa) or C11 (for 3ra) were in the cis-form.

14


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3aa CCDC 1819885

3ra CCDC 1829339

Figure 2. Single-crystal X-ray structures of compounds 3aa and 3ra

Control experiments were performed to gain insight into the reaction mechanism of this transformation (Scheme 2). First, the reaction of 1a and 2a under our optimal conditions was retarded severely in the presence of 3.0 equiv. of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and the corresponding TEMPO-2a adduct was isolated in 29% yield, indicating that this reaction probably involved a free radical process. Second, the kinetic isotope effect (KIE) was determined as kH/kD = 3.8 by an intermolecular competition experiment with 1a and [D5]-1a, hinting that the C−H cleavage might be involved in our catalytic system as the rate-determining step. In order to further probe the source of the ester oxygen atom in the product, the 18O-labeled experiment was also performed under the standard conditions. When [18O]-2a (20%

18O-labled)

was employed

in the reaction, no 18O incorporation was observed in product 3aa by analysis of its HRMS, indicating that the ester oxygen atom introduced into the products

15



Page 16 of 46

came from the α-amino acids. This result also implied that a cationic intermediate might be involved in the second intramolecular cyclization process.25 Scheme 2. Preliminary Mechanistic Studies (a) Trapping experiment with TEMPO O

O

O N H

COOH

OH +

1a

O

N

standard conditions

O

TEMPO (3.0 equiv)

2a

3aa , trac e

(b) Kinetic isotope effect experiment

O

O +

N

O

TEMPO-2a, 29%

O N H

COOH

1a

N H

D5

OH +

O

O

O

O N O

DCE, 70 oC, 1 h 13% yield kH/kD = 3.8

O

COOH


2a

O +

N D4

O

O

[D4]-3aa

3aa [D5]-1a

(c) 18O-labeled experiment 18

O N H

1a

COOH

O

O OH

+

N

standard conditions

O

O

[18O]-2a 20% 18O-labled

O

3aa no 18O incorporation

Based on the above experimental results and the previous literature, a plausible reaction mechanism is proposed (Scheme 3). First, the palladium intermediate I is generated by the coordination of nitrogen atom and oxygen atom of substrate 1 to the Pd catalyst, followed by concerted metalation deprotonation process to produce intermediate II.20 Then, II undergoes oxidative coupling with 16


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the acyl radical III, which is produced by decarboxylation of 2 with the aid of K2S2O8,17,26 to furnish a high-valent Pd intermediate IV. After reductive elimination, a new C−C bond is formed, and the Pd atom coordinates to the nitrogen atom of benzamide, as shown in species V. Intramolecular cyclization of V provides intermediate VI, which is followed by protonation to give hydroxyisoindolinone VII with the simultaneous release of a Pd(II) species to complete the catalytic cycle.16,17 Finally, intramolecular lactonization of the hydroxyisoindolinone VII generated the desired product 3 via a cationic intermediate VIII promoted by PTSA.25

Scheme 3. Plausible Mechanism

17



O

O R

1

R2

N O

PTSA R1 - H 2O

R2

OH

R3

R3

VIII

N

R1

2

O

O

COOH

1

Pd(II)X2

COOH

N X Pd X

R1

R3 VI

R3

R1

O

HX

N COOH Pd X O

R

R2

O R1 O

R3 V

O

I

R2

O

3

R2

O

O Pd X

N R1

N H

R1

VII

R2

O

R

COOH

HX

-H

R2

O

N

HO

O

Page 18 of 46

1

X

R

2

O

N Pd

II

K2S2O8

O O

O

O

O K2S2O8

O IV R3

N Pd X

III

R3 CO2

OH R3

O 2

Trapped by TEMPO O O

N

TEMPO-2a

CONCLUSIONS In conclusion, we have successfully developed the first one-step synthesis of oxazoloisoindolinones via cascade Pd-catalyzed ortho-acylation of N-benzoyl α-amino acid derivatives and subsequent double intramolecular cyclizations. This reaction features broad substrate scope, good functional group tolerance, high regioselectivity, and excellent diastereoselectivity. Of practical importance is the complete stereoretention of enantiomerically pure α-amino acids and hence chiral induction to oxazoloisoindolinones with two stereogenic centers, including a quaternary one. We anticipate that this efficient method will be of great importance to drug synthesis for medicinal chemists. 18


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EXPERIMENTAL SECTION General Information. NMR spectra were recorded on a 400 MHz NMR spectrometer (400 MHz for 1H NMR; 101 MHz for 13C NMR). 1H NMR chemical shifts were determined relative to internal TMS at δ 0.0 ppm. 13C NMR chemical shifts were determined relative to CDCl3 at δ 77.16 ppm. Data for 1H NMR and

13C

NMR are

reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet). High-resolution mass spectra (HRMS) were measured with FTMS-ESI or TOF-ESI in

positive mode on a LTQ-Orbitrap or Q-

TOF mass spectrometer. HPLC analysis was performed on Agilent 1260. Chiralpak IC and IE columns from Daicel Chemical Industries, LTD were employed for the chiral HPLC analyses. Optical rotation was measured with a polarimeter. K2S2O8, PTSA, 1,2dichloroethene (DCE), N-benzoyl-L-alanine (L-1b), and 2a were purchased from J&K, Adamas-beta, Alfa Aesar, Sinopharm Chemical Reagent Co. Ltd., and TCI and used directly. 1, 2b−k, and [18O]-2a were prepared according to the reported protocols.20,27,28 General Procedure for the Palladium-Catalyzed Decarboxylative orthoAcylation of N-Benzoyl α-Amino Acids with α-Oxocarboxylic Acids. A mixture of N-benzoyl α-amino acid 1 (0.3 mmol), α-oxocarboxylic acid 2 (0.6 mmol), Pd(OAc)2 (6.9 mg, 0.03 mmol), K2S2O8 (202.8 mg, 0.75 mmol), and PTSA (85.8 mg, 0.45 mmol) in DCE (3 mL) was stirred at 70 oC or 80 oC in an oil bath for 12−24 h. After this, the reaction mixture was cooled to room temperature. Then, the reaction mixture was filtered through a silica gel plug with ethyl acetate as the eluent and evaporated in vacuo. 19



Page 20 of 46

Product 3 was purified by column chromatography over silica gel using petroleum ether and ethyl acetate (10:1−6:1) as the eluent. 3-Isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione

(3aa).

By

following the general procedure, the reaction of 1a (66.8 mg, 0.3 mmol) with 2a (90.0 mg, 0.6 mmol) at 70 oC for 12 h gave 3aa (77.5 mg, 84% yield): white solid, mp 142.1−142.5 oC; 1H NMR (400 MHz, CDCl3) δ 7.94−7.89 (m, 1H), 7.62−7.56 (m, 2H), 7.52−7.47 (m, 2H), 7.43−7.37 (m, 3H), 7.36−7.33 (m, 1H), 4.22 (d, J = 9.9 Hz, 1H), 1.68−1.58 (m, 1H), 1.11 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 172.6, 146.6, 138.1, 134.2, 131.2, 130.3, 129.5, 129.1 (2C), 125.2 (2C), 124.8, 124.7, 98.9, 63.6, 29.9, 20.3, 18.9; HRMS (FTMS-ESI) calcd for C19H17NO3Na [M+Na]+ 330.1101, found 330.1092. 3-Methyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione

(3ba).

By

following the general procedure, the reaction of 1b (58.0 mg, 0.3 mmol) with 2a (90.6 mg, 0.6 mmol) at 70 oC for 12 h gave 3ba (50.4 mg, 60% yield): white solid, 153.9−154.6 oC; 1H NMR (400 MHz, CDCl3) δ 7.94−7.88 (m, 1H), 7.64−7.52 (m, 4H), 7.45−7.36 (m, 4H), 4.75 (q, J = 7.4 Hz, 1H), 1.32 (d, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.5, 173.7, 146.0, 137.8, 134.3, 131.3, 130.4, 129.7, 129.1 (2C), 125.4 (2C), 124.9, 124.7, 99.4, 53.3, 17.0; HRMS (FTMS-ESI) calcd for C17H14NO3 [M+H]+ 280.0968, found 280.0962. When N-benzoyl-L-alanine (L-1b) was employed as the substrate, the corresponding chiral product (3S,9bR)-3ba was obtained (50.9 mg, 61% yield). Diastereomeric excess: >99%, determined by HPLC (Daicel Chirapak IE column, hexane/isopropanol = 70/30 v/v, flow rate 0.7 mL/min, T = 30 oC, 254 nm): tR 20


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(minor) = 14.276 min; tR (major) = 16.946 min. [α]D20 = +262.1 (c = 0.314, CHCl3). 3-(Tert-butyl)-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ca). By following the general procedure, the reaction of 1c (70.6 mg, 0.3 mmol) with 2a (90.4 mg, 0.6 mmol) at 70 oC for 12 h gave 3ca (70.7 mg, 73% yield): white solid, 94.9−96.1 oC; 1H

NMR (400 MHz, CDCl3) δ 7.93−7.88 (m, 1H), 7.60−7.54 (m, 2H), 7.51−7.42

(m, 2H), 7.41−7.33 (m, 3H), 7.33−7.28 (m, 1H), 4.29 (s, 1H), 0.90 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.6, 172.1, 147.9, 139.1, 134.3, 131.1, 129.8, 129.2, 129.0 (2C), 125.3 (2C), 124.72, 124.71, 98.8, 67.8, 34.7, 27.3 (3C); HRMS (FTMS-ESI) calcd for C20H19NO3Na [M+Na]+ 344.1257, found 344.1249. 9b-Phenyl-3-propyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione

(3da).

By

following the general procedure, the reaction of 1d (66.7 mg, 0.3 mmol) with 2a (90.3 mg, 0.6 mmol) at 70 oC for 12 h gave 3da (58.2 mg, 63% yield): white colloidal solid; 1H

NMR (400 MHz, CDCl3) δ 7.94−7.88 (m, 1H), 7.62−7.57 (m, 2H), 7.56−7.50 (m,

2H), 7.44−7.36 (m, 4H), 4.59 (dd, J = 11.2, 4.6 Hz, 1H), 1.74−1.64 (m, 1H), 1.62−1.51 (m, 2H), 1.31−1.20 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.02, 173.97, 146.2, 137.9, 134.2, 131.3, 130.4, 129.7, 129.1 (2C), 125.2 (2C), 124.9, 124.7, 99.4, 57.7, 32.3, 19.6, 13.3; HRMS (FTMS-ESI) calcd for C19H18NO3 [M+H]+ 308.1281, found 308.1278. 3-Isobutyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione

(3ea).

By

following the general procedure, the reaction of 1e (70.8 mg, 0.3 mmol) with 2a (90.2 mg, 0.6 mmol) at 70 oC for 24 h gave 3ea (49.2 mg, 51% yield): white solid, 111.9−112.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.93−7.88 (m, 1H), 7.62−7.57 (m, 2H), 21



7.56−7.50 (m, 2H), 7.44−7.36 (m, 4H), 4.67 (dd, J = 12.1, 4.0 Hz, 1H), 1.94−1.83 (m, 1H), 1.53−1.45 (m, 1H), 1.23−1.13 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 172.9, 145.1, 136.8, 133.2, 130.3, 129.5, 128.7, 128.1 (2C), 124.2 (2C), 123.9, 123.7, 98.4, 55.6, 37.7, 24.6, 21.9, 20.1; HRMS (FTMS-ESI) calcd for C20H19NO3Na [M+Na]+ 344.1257, found 344.1249. 3,9b-Diphenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3fa). By following the general procedure, the reaction of 1f (76.6 mg, 0.3 mmol) with 2a (90.3 mg, 0.6 mmol) at 70 oC for 24 h gave 3fa (57.3 mg, 56% yield) : white solid, 147.6−148.3 oC; 1H

NMR (400 MHz, CDCl3) δ 8.02−7.96 (m, 1H), 7.68−7.63 (m, 2H), 7.44−7.39 (m,

1H), 7.37−7.32 (m, 2H), 7.29−7.20 (m, 5H), 7.18−7.12 (m, 3H), 5.81 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.0, 171.8, 146.4, 137.2, 134.5, 132.7, 131.5, 130.4, 129.5, 128.8 (2C), 128.5 (2C), 128.3, 126.8 (2C), 125.7 (2C), 125.0, 124.9, 99.8, 60.3; HRMS (TOF-ESI) calcd for C22H16NO3 [M+H]+ 342.1130, found 342.1127. 3,3-Dimethyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ga). By following the general procedure, the reaction of 1g (62.3 mg, 0.3 mmol) with 2a (90.3 mg, 0.6 mmol) at 70 oC for 12 h gave 3ga (48.4 mg, 55% yield): white solid, 152.2−153.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.90−7.85 (m, 1H), 7.60−7.54 (m, 2H), 7.53−7.49 (m, 2H), 7.42−7.35 (m, 4H), 1.88 (s, 3H), 1.27 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.2, 170.8, 145.6, 138.5, 133.9, 131.4, 131.0, 129.5, 129.1 (2C), 125.1 (2C), 124.6, 124.1, 97.9, 61.3, 25.3, 23.0; HRMS (FTMS-ESI) calcd for C18H15NO3Na [M+Na]+ 316.0944, found 316.0938. 9b'-Phenyl-2'H-spiro[cyclopentane-1,3'-oxazolo[2,3-a]isoindole]-2',5'(9b'H)22


Page 22 of 46

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dione (3ha). By following the general procedure, the reaction of 1h (70.2 mg, 0.3 mmol) with 2a (90.6 mg, 0.6 mmol) at 80 oC for 12 h gave 3ha (64.2 mg, 67% yield): white solid, 168.1−169.8 oC; 1H NMR (400 MHz, CDCl3) δ 7.90−7.85 (m, 1H), 7.60−7.54 (m, 2H), 7.50−7.46 (m, 2H), 7.40−7.34 (m, 4H), 3.11−3.02 (m, 1H), 2.28−2.15 (m, 1H), 2.14−2.04 (m, 1H), 2.00−1.75 (m, 3H), 1.71−1.61 (m, 1H), 1.58−1.50 (m, 1H); 13C{1H}

NMR (101 MHz, CDCl3) δ 177.5, 170.5, 145.2, 138.4, 133.8, 131.7, 131.0,

129.5, 129.1 (2C), 125.3 (2C), 124.6, 124.1, 98.0, 70.4, 39.0, 32.4, 25.2, 24.6; HRMS (FTMS-ESI) calcd for C20H17NO3Na [M+Na]+ 342.1101, found 342.1095. 9b'-Phenyl-2'H-spiro[cyclohexane-1,3'-oxazolo[2,3-a]isoindole]-2',5'(9b'H)dione (3ia). By following the general procedure, the reaction of 1i (74.4 mg, 0.3 mmol) with 2a (90.4 mg, 0.6 mmol) at 70 oC for 12 h gave 3ia (66.1 mg, 66% yield): colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.89−7.83 (m, 1H), 7.58−7.49 (m, 4H), 7.41−7.31 (m, 4H), 2.69−2.60 (m, 1H), 2.34−2.22 (m, 1H), 2.06−1.93 (m, 2H), 1.65−1.39 (m, 6H);

13C{1H}

NMR (101 MHz, CDCl3) δ 175.6, 171.2, 145.5, 139.0, 133.8, 131.4,

130.9, 129.3, 129.2 (2C), 124.8 (2C), 124.5, 124.0, 97.8, 65.2, 33.9, 30.3, 24.8, 22.3, 21.4; HRMS (FTMS-ESI) calcd for C21H19NO3Na [M+Na]+ 356.1257, found 356.1250. 3-Isopropyl-8-methyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ja). By following the general procedure, the reaction of 1j (70.8 mg, 0.3 mmol) with 2a (90.6 mg, 0.6 mmol) at 70 oC for 12 h gave 3ja (88.2 mg, 91% yield): white solid, 150.2−151.6 oC; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 1H), 7.52−7.48 (m, 2H), 7.43−7.36 (m, 4H), 7.12 (s, 1H), 4.20 (d, J = 9.8 Hz, 1H), 2.38 (s, 3H), 1.67−1.56 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, 23



CDCl3) δ 174.4, 172.7, 147.0, 145.6, 138.3, 132.3, 129.4, 129.0 (2C), 127.7, 125.2 (2C), 125.0, 124.6, 98.9, 63.5, 29.9, 22.1, 20.2, 18.9; HRMS (FTMS-ESI) calcd for C20H19NO3Na [M+Na]+ 344.1257, found 344.1250. 8-(Tert-butyl)-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ka). By following the general procedure, the reaction of 1k (83.6 mg, 0.3 mmol) with 2a (90.7 mg, 0.6 mmol) at 70 oC for 12 h gave 3ka (80.2 mg, 74% yield): white solid, 176.4−177.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.1, 1.6 Hz, 1H), 7.53−7.48 (m, 2H), 7.44−7.37 (m, 3H), 7.31 (d, J = 1.6 Hz, 1H), 4.19 (d, J = 9.9 Hz, 1H), 1.66−1.56 (m, 1H), 1.27 (s, 9H), 1.10 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 172.7, 158.7, 146.9, 138.3, 129.4, 129.0 (2C), 128.8, 127.7, 125.2 (2C), 124.4, 121.1, 99.1, 63.5, 35.7, 31.2 (3C), 29.9, 20.2, 18.9; HRMS (FTMS-ESI) calcd for C23H25NO3Na [M+Na]+ 386.1727, found 386.1719. 3-Isopropyl-8-methoxy-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3la). By following the general procedure, the reaction of 1l (75.9 mg, 0.3 mmol) with 2a (90.0 mg, 0.6 mmol) at 70 oC for 12 h gave 3la (77.3 mg, 76% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.5 Hz, 1H), 7.52−7.46 (m, 2H), 7.44−7.37 (m, 3H), 7.07 (dd, J = 8.5, 1.9 Hz, 1H), 6.75 (d, J = 1.9 Hz, 1H), 4.18 (d, J = 9.7 Hz, 1H), 3.80 (s, 3H), 1.70−1.55 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H);

13C{1H}

NMR (101 MHz, CDCl3) δ 174.2, 172.7, 164.8, 149.2, 138.3,

129.5, 129.1 (2C), 126.4, 125.2 (2C), 122.6, 118.2, 109.0, 98.5, 63.5, 56.0, 30.0, 20.2, 19.0; HRMS (FTMS-ESI) calcd for C20H19NO4Na [M+Na]+ 360.1206, found 360.1201. 24


Page 24 of 46

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8-Fluoro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ma). By following the general procedure, the reaction of 1m (72.0 mg, 0.3 mmol) with 2a (90.3 mg, 0.6 mmol) at 70 oC for 12 h gave 3ma (82.0 mg, 84% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 8.3, 4.7 Hz, 1H), 7.52−7.46 (m, 2H), 7.45−7.39 (m, 3H), 7.31−7.24 (m, 1H), 7.01 (d, J = 7.5 Hz, 1H), 4.21 (d, J = 9.8 Hz, 1H), 1.68−1.57 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −101.87 (s, 1F); 13C{1H} NMR (101 MHz, CDCl3) δ 173.1, 172.2, 166.4 (d, JC−F = 257.0 Hz), 149.2 (d, JC−F = 9.6 Hz), 137.6, 129.8, 129.2 (2C), 127.1 (d, JC−F = 9.8 Hz), 126.3 (d, JC−F = 2.1 Hz), 125.1 (2C), 119.2 (d, JC−F = 23.7 Hz), 112.2 (d, JC−F = 24.4 Hz), 98.0 (d, JC−F = 2.4 Hz), 63.6, 29.9, 20.2, 18.9; HRMS (TOFESI) calcd for C19H17FNO3 [M+H]+ 326.1192, found 326.1195. 8-Chloro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3na). By following the general procedure, the reaction of 1n (76.9 mg, 0.3 mmol) with 2a (90.4 mg, 0.6 mmol) at 70 oC for 12 h gave 3na (92.3 mg, 90% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 1H), 7.56 (dd, J = 8.1, 1.7 Hz, 1H), 7.51−7.46 (m, 2H), 7.46−7.39 (m, 3H), 7.31 (d, J = 1.7 Hz, 1H), 4.21 (d, J = 9.8 Hz, 1H), 1.69−1.55 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.1, 172.1, 148.1, 140.7, 137.4, 131.9, 129.8, 129.2 (2C), 128.7, 126.0, 125.1 (3C), 98.1, 63.6, 29.8, 20.2, 18.9; HRMS (FTMS-ESI) calcd for C19H1735ClNO3 [M+H]+ 342.0892, found 342.0887. 8-Bromo-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3oa). By following the general procedure, the reaction of 1o (90.2 mg, 0.3 mmol) with 25



Page 26 of 46

2a (90.1 mg, 0.6 mmol) at 70 oC for 12 h gave 3oa (91.1 mg, 79% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 8.1, 1.5 Hz, 1H), 7.51−7.46 (m, 3H), 7.46−7.39 (m, 3H), 4.21 (d, J = 9.9 Hz, 1H), 1.67−1.56 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H);

13C{1H}

NMR (101 MHz,

CDCl3) δ 173.2, 172.1, 148.1, 137.4, 134.7, 129.8, 129.2 (2C), 129.1 (2C), 128.0, 126.1, 125.1 (2C), 98.1, 63.5, 29.8, 20.2, 18.8; HRMS (FTMS-ESI) calcd for C19H1679BrNO3Na [M+Na]+ 408.0206, found 408.0196. 3-Isopropyl-9b-phenyl-8-(trifluoromethyl)oxazolo[2,3-a]isoindole-2,5(3H,9bH)dione (3pa). By following the general procedure, the reaction of 1p (86.8 mg, 0.3 mmol) with 2a (90.1 mg, 0.6 mmol) at 70 oC for 12 h gave 3pa (77.2 mg, 69% yield): pale yellow colloidal solid; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.53−7.49 (m, 2H), 7.46−7.42 (m, 3H), 4.24 (d, J = 10.0 Hz, 1H), 1.68−1.57 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −62.71 (s, 3F); 13C{1H} NMR (101 MHz, CDCl3) δ 172.6, 171.9, 147.0, 137.0, 135.9 (q, JC−F = 33.1 Hz), 133.5, 130.0, 129.4 (2C), 128.6 (q, JC−F = 3.4 Hz), 125.6, 125.1 (2C), 123.1 (q, JC−F= 273.5 Hz), 121.9 (q, JC−F= 3.8 Hz), 98.3, 63.6, 29.8, 20.2, 18.8; HRMS (FTMS-ESI) calcd for C20H16F3NO3Na [M+Na]+ 398.0975, found 398.0965. 3-Isopropyl-8-nitro-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3qa). By following the general procedure, the reaction of 1q (80.0 mg, 0.3 mmol) with 2a (90.4 mg, 0.6 mmol) at 70 oC for 24 h gave 3qa (57.4 mg, 54% yield): pale yellow solid, 153.8−155.0 oC; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.3 Hz, 1H), 8.16 (s, 26


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1H), 8.10 (d, J = 8.3 Hz, 1H), 7.54−7.42 (m, 5H), 4.25 (d, J = 10.0 Hz, 1H), 1.69−1.58 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.7, 171.5, 151.6, 147.7, 136.5, 135.2, 130.3, 129.5 (2C), 126.8, 126.1, 125.1 (2C), 120.3, 97.9, 63.8, 29.8, 20.3, 18.8; HRMS (FTMS-ESI) calcd for C19H17N2O5 [M+H]+ 353.1132, found 353.1125. 3-Isopropyl-7-methyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ra). By following the general procedure, the reaction of 1r (70.6 mg, 0.3 mmol) with 2a (90.9 mg, 0.6 mmol) at 70 oC for 12 h gave 3ra (71.7 mg, 74% yield): white solid, 154.1−155.0 oC; 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.51−7.45 (m, 2H), 7.42−7.35 (m, 4H), 7.22 (d, J = 7.8 Hz, 1H), 4.20 (d, J = 9.9 Hz, 1H), 2.46 (s, 3H), 1.68−1.56 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.5, 172.7, 144.1, 141.9, 138.3, 135.2, 130.5, 129.4, 129.0 (2C), 125.2 (2C), 124.9, 124.4, 98.9, 63.6, 29.9, 21.6, 20.3, 18.9; HRMS (FTMS-ESI) calcd for C20H19NO3Na [M+Na]+ 344.1257, found 344.1251. 7-Chloro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3sa). By following the general procedure, the reaction of 1s (77.0 mg, 0.3 mmol) with 2a (90.6 mg, 0.6 mmol) at 70 oC for 12 h gave 3sa (84.4 mg, 82% yield): white solid, 132.2−133.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.4 Hz, 1H), 7.55 (dd, J = 8.1, 1.4 Hz, 1H), 7.50−7.45 (m, 2H), 7.44−7.38 (m, 3H), 7.28 (d, J = 8.1 Hz, 1H), 4.21 (d, J = 9.9 Hz, 1H), 1.67−1.56 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H);

13C{1H}

NMR (101 MHz, CDCl3) δ 172.7, 172.1, 144.7, 137.7, 137.5, 134.3,

132.1, 129.7, 129.1 (2C), 125.9, 125.1 (2C), 124.8, 98.3, 63.6, 29.8, 20.2, 18.8; HRMS 27



(FTMS-ESI) calcd for C19H1635ClNO3Na [M+Na]+ 364.0711, found 364.0706. 3-Isopropyl-9b-phenyl-7-(trifluoromethyl)oxazolo[2,3-a]isoindole-2,5(3H,9bH)dione (3ta). By following the general procedure, the reaction of 1t (86.8 mg, 0.3 mmol) with 2a (90.3 mg, 0.6 mmol) at 70 oC for 12 h gave 3ta (68.7 mg, 61% yield): pale yellow colloidal solid; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.53−7.48 (m, 3H), 7.45−7.40 (m, 3H), 4.24 (d, J = 9.9 Hz, 1H), 1.70−1.59 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −62.68 (s, 3F); 13C{1H} NMR (101 MHz, CDCl3) δ 172.6, 171.9, 149.5, 137.2, 133.8 (q, JC−F = 33.4 Hz), 131.2, 131.1 (q, JC−F = 3.4 Hz), 130.0, 129.3 (2C), 125.5, 125.1 (2C), 123.3 (q, JC−F = 273.2 Hz), 122.2 (q, JC−F = 3.8 Hz), 98.2, 63.6, 29.8, 20.2, 18.8; HRMS (FTMS-ESI) calcd for C20H16F3NO3Na [M+Na]+ 398.0975, found 398.0968. 3-Isopropyl-6-methyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ua). By following the general procedure, the reaction of 1u (71.0 mg, 0.3 mmol) with 2a (90.3 mg, 0.6 mmol) at 70 oC for 12 h gave 3ua (73.8 mg, 77% yield): white solid, 142.5−144.0 oC; 1H NMR (400 MHz, CDCl3) δ 7.53−7.47 (m, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.41−7.35 (m, 3H), 7.32 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 4.21 (d, J = 9.8 Hz, 1H), 2.74 (s, 3H), 1.69−1.57 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.2, 172.8, 147.1, 139.1, 138.5, 133.7, 133.1, 129.4, 129.0 (2C), 127.4, 125.2 (2C), 122.2, 98.5, 63.6, 29.8, 20.3, 19.0, 17.6; HRMS (FTMS-ESI) calcd for C20H19NO3Na [M+Na]+ 344.1257, found 344.1254. 3-Isopropyl-6-methoxy-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3va). By following the general procedure, the reaction of 1v (75.3 mg, 0.3 mmol) with 28


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2a (90.1 mg, 0.6 mmol) at 80 oC for 24 h gave 3va (62.3 mg, 62% yield): white solid, 141.4−142.8 oC; 1H NMR (400 MHz, CDCl3) δ 7.55−7.46 (m, 3H), 7.42−7.35 (m, 3H), 7.01 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 4.21 (d, J = 9.6 Hz, 1H), 4.02 (s, 3H), 1.67−1.55 (m, 1H), 1.09 (d, J = 5.9 Hz, 3H), 0.89 (d, J = 5.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.0, 172.7, 157.8, 148.8, 138.3, 136.2, 129.4, 129.0 (2C), 125.2 (2C), 117.2, 116.6, 113.2, 98.2, 63.4, 56.3, 29.8, 20.1, 18.9; HRMS (FTMS-ESI) calcd for C20H19NO4Na [M+Na]+ 360.1206, found 360.1200. 6-Fluoro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3wa). By following the general procedure, the reaction of 1w (71.9 mg, 0.3 mmol) with 2a (90.5 mg, 0.6 mmol) at 70 oC for 12 h gave 3wa (76.4 mg, 78% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.58 ( td, J = 7.9, 4.6 Hz, 1H), 7.53−7.48 (m, 2H), 7.45−7.39 (m, 3H), 7.23 (t, J = 8.5 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 4.22 (d, J = 9.9 Hz, 1H), 1.68−1.56 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 19F

NMR (376 MHz, CDCl3) δ −113.75 (s, 1F); 13C{1H} NMR (101 MHz, CDCl3) δ

172.2, 170.8, 158.7 (d, JC−F = 264.8 Hz), 148.6, 137.7, 136.5 (d, JC−F = 7.6 Hz), 129.7, 129.2 (2C), 125.1 (2C), 120.8 (d, JC−F = 4.3 Hz), 118.5 (d, JC−F = 19.2 Hz), 117.6 (d, JC−F = 14.0 Hz), 98.2, 63.5, 29.8, 20.2, 18.9; HRMS (FTMS-ESI) calcd for C19H17FNO3 [M+H]+ 326.1187, found 326.1187. 6-Chloro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3xa). By following the general procedure, the reaction of 1x (76.8 mg, 0.3 mmol) with 2a (90.8 mg, 0.6 mmol) at 70 oC for 12 h gave 3xa (80.3 mg, 78% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.55−7.47 (m, 4H), 7.45−7.38 (m, 3H), 7.24 (dd, 29



J = 6.6, 1.8 Hz, 1H), 4.24 (d, J = 9.8 Hz, 1H), 1.68−1.58 (m, 1H), 1.11 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.2, 171.7, 148.7, 137.7, 135.0, 132.7, 132.5, 129.7, 129.1 (2C), 126.6, 125.2 (2C), 123.3, 97.5, 63.6, 29.8, 20.2, 18.9; HRMS (FTMS-ESI) calcd for C19H1735ClNO3 [M+H]+ 342.0892, found 342.0886. 3-Isopropyl-7,8-dimethyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ya). By following the general procedure, the reaction of 1y (75.2 mg, 0.3 mmol) with 2a (90.3 mg, 0.6 mmol) at 70 oC for 12 h gave 3ya (64.6 mg, 64% yield): white solid, 153.8−154.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.51−7.46 (m, 2H), 7.42−7.36 (m, 3H), 7.08 (s, 1H), 4.19 (d, J = 9.8 Hz, 1H), 2.35 (s, 3H), 2.28 (s, 3H), 1.66−1.56 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.7, 172.8, 144.8, 144.3, 140.7, 138.5, 129.3, 129.0 (2C), 128.1, 125.3, 125.24, 125.19 (2C), 99.0, 63.5, 29.9, 20.8, 20.3, 20.2, 18.9; HRMS (FTMSESI) calcd for C21H22NO3 [M+H]+ 336.1594, found 336.1592. 7,8-Dichloro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3za). By following the general procedure, the reaction of 1z (87.0 mg, 0.3 mmol) with 2a (90.4 mg, 0.6 mmol) at 70 oC for 12 h gave 3za (88.0 mg, 78% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.50−7.40 (m, 6H), 4.20 (d, J = 9.9 Hz, 1H), 1.66−1.55 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 171.8, 145.6, 139.0, 137.1, 136.5, 130.0, 129.9, 129.3 (2C), 126.8, 126.5, 125.1 (2C), 97.8, 63.7, 29.8, 20.2, 18.9; HRMS (FTMS-ESI) calcd for C19H1635Cl2NO3 [M+H]+ 376.0502, found 376.0494. 30


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3-Isopropyl-8-methyl-9b-(p-tolyl)oxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3jb). By following the general procedure, the reaction of 1j (70.8 mg, 0.3 mmol) with 2b (98.9 mg, 0.6 mmol) at 70 oC for 12 h gave 3jb (78.9 mg, 78% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.40−7.35 (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 7.12 (s, 1H), 4.18 (d, J = 10.0 Hz, 1H), 2.38 (s, 3H), 2.36 (s, 3H), 1.68−1.57 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.4, 172.8, 147.2, 145.5, 139.4, 135.3, 132.2, 129.7 (2C), 127.7, 125.1 (2C), 125.0, 124.6, 99.0, 63.5, 29.9, 22.1, 21.3, 20.3, 18.9; HRMS (FTMS-ESI) calcd for C21H22NO3 [M+H]+ 336.1594, found 336.1595. 3-Isopropyl-9b-(4-methoxyphenyl)-8-methyloxazolo[2,3-a]isoindole-2,5(3H,9bH)dione (3jc). By following the general procedure, the reaction of 1j (70.8 mg, 0.3 mmol) with 2c (108.2 mg, 0.6 mmol) at 70 oC for 12 h gave 3jc (58.2 mg, 55% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 4.18 (d, J = 9.9 Hz, 1H), 3.82 (s, 3H), 2.39 (s, 3H), 1.70−1.59 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H);

13C{1H}

NMR (101 MHz, CDCl3) δ 174.4, 172.8, 160.4,

147.2, 145.5, 132.2, 130.2, 127.7, 126.6 (2C), 124.9, 124.6, 114.3 (2C), 99.0, 63.5, 55.5, 29.9, 22.1, 20.3, 19.0; HRMS (FTMS-ESI) calcd for C21H22NO4 [M+H]+ 352.1543, found 352.1538. 9b-(4-Fluorophenyl)-3-isopropyl-8-methyloxazolo[2,3-a]isoindole-2,5(3H,9bH)dione (3jd). By following the general procedure, the reaction of 1j (70.9 mg, 0.3 mmol) with 2d (100.8 mg, 0.6 mmol) at 70 oC for 12 h gave 3jd (60.8 mg, 60% yield): white 31



colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 1H), 7.51−7.45 (m, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.13−7.06 (m, 3H), 4.20 (d, J = 9.8 Hz, 1H), 2.40 (s, 3H), 1.68−1.57 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −111.76 (s, 1F);

13C{1H}

NMR (101 MHz, CDCl3) δ 174.3, 172.5,

163.3 (d, JC−F = 249.3 Hz), 146.9, 145.7, 134.3 (d, JC−F = 3.4 Hz), 132.4, 127.6, 127.3 (d, JC−F = 8.5 Hz, 2C), 124.9, 124.7, 116.2 (d, JC−F = 21.9 Hz, 2C), 98.5, 63.5, 29.9, 22.2, 20.2, 19.0; HRMS (FTMS-ESI) calcd for C20H19FNO3 [M+H]+ 340.1344, found 340.1339. 3-Isopropyl-8-methyl-9b-(m-tolyl)oxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3je). By following the general procedure, the reaction of 1j (70.5 mg, 0.3 mmol) with 2e (99.0 mg, 0.6 mmol) at 70 oC for 12 h gave 3je (75.2 mg, 75% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.30 (s, 1H), 7.29−7.24 (m, 2H), 7.21−7.16 (m, 1H), 7.13 (s, 1H), 4.18 (d, J = 9.9 Hz, 1H), 2.39 (s, 3H), 2.36 (s, 3H), 1.67−1.56 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.4, 172.8, 147.1, 145.5, 138.9, 138.2, 132.2, 130.2, 128.9, 127.7, 125.7, 125.0, 124.6, 122.3, 98.9, 63.5, 29.8, 22.1, 21.6, 20.2, 18.9; HRMS (TOF-ESI) calcd for C21H22NO3 [M+H]+ 336.1600, found 336.1602. 3-Isopropyl-9b-(3-methoxyphenyl)-8-methyloxazolo[2,3-a]isoindole-2,5(3H,9bH)dione (3jf). By following the general procedure, the reaction of 1j (71.2 mg, 0.3 mmol) with 2f (108.1 mg, 0.6 mmol) at 70 oC for 12 h gave 3jf (73.1 mg, 69% yield): pale yellow solid, 117.9−119.2 oC; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 32


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7.38 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H), 4.19 (d, J = 9.9 Hz, 1H), 3.80 (s, 3H), 2.39 (s, 3H), 1.71−1.60 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 172.5, 160.0, 146.8, 145.5, 139.8, 132.2, 130.2, 127.6, 124.9, 124.6, 117.4, 114.8, 110.8, 98.6, 63.5, 55.4, 29.8, 22.1, 20.3, 18.9; HRMS (FTMS-ESI) calcd for C21H22NO4 [M+H]+ 352.1543, found 352.1534. 9b-(3-Bromophenyl)-3-isopropyl-8-methyloxazolo[2,3-a]isoindole-2,5(3H,9bH)dione (3jg). By following the general procedure, the reaction of 1j (71.2 mg, 0.3 mmol) with 2g (137.8 mg, 0.6 mmol) at 70 oC for 12 h gave 3jg (97.3 mg, 81% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 1.8 Hz, 1H), 7.52 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.46−7.39 (m, 2H), 7.29 (t, J = 7.9 Hz, 1H), 7.13 (s, 1H), 4.20 (d, J = 9.8 Hz, 1H), 2.41 (s, 3H), 1.67−1.58 (m, 1H), 1.12 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.2, 172.3, 146.5, 145.8, 140.7, 132.7, 132.5, 130.7, 128.3, 127.6, 125.0, 124.8, 123.9, 123.2, 97.9, 63.5, 30.0, 22.1, 20.2, 19.0; HRMS (FTMS-ESI) calcd for C20H1879BrNO3Na [M+Na]+ 422.0362, found 422.0352. 3-Isopropyl-8-methyl-9b-(3-(trifluoromethyl)phenyl)oxazolo[2,3-a]isoindole2,5(3H,9bH)-dione (3jh). By following the general procedure, the reaction of 1j (71.1 mg, 0.3 mmol) with 2h (131.0 mg, 0.6 mmol) at 70 oC for 12 h gave 3jh (67.3 mg, 58% yield): pale yellow colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 4.23 (d, J = 9.7 Hz, 1H), 2.41 (s, 3H), 33



1.64−1.53 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −62.67 (s, 3F); 13C{1H} NMR (101 MHz, CDCl3) δ 174.2, 172.2, 146.3, 145.9, 139.8, 132.6, 131.6 (q, JC−F = 32.8 Hz), 129.8, 128.7, 127.6, 126.4 (q, JC−F = 3.6 Hz), 124.9 (2C), 123.7 (q, JC−F = 272.7 Hz), 122.1 (q, JC−F = 3.7 Hz), 98.1, 63.5, 30.0, 22.1, 20.1, 18.9; HRMS (FTMS-ESI) calcd for C21H18F3NO3Na [M+Na]+ 412.1131, found 412.1116. 3-Isopropyl-8-methyl-9b-(o-tolyl)oxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ji). By following the general procedure, the reaction of 1j (71.0 mg, 0.3 mmol) with 2i (98.4 mg, 0.6 mmol) at 70 oC for 12 h gave 3ji (75.6 mg, 75% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 6.3 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.37−7.28 (m, 2H), 7.10 (d, J = 6.2 Hz, 1H), 7.06 (s, 1H), 4.22 (d, J = 9.5 Hz, 1H), 2.39 (s, 3H), 1.84 (s, 3H), 1.63−1.52 (m, 1H), 1.09 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.7, 172.9, 145.9, 145.7, 135.6 (2C), 132.6, 132.4, 129.7, 129.1, 126.54, 126.46, 124.9, 124.4, 98.8, 63.6, 30.1, 22.0, 20.4, 19.4, 19.2; HRMS (FTMS-ESI) calcd for C21H22NO3 [M+H]+ 336.1594, found 336.1587. 9b-(2-Chlorophenyl)-3-isopropyl-8-methyloxazolo[2,3-a]isoindole-2,5(3H,9bH)dione (3jj). By following the general procedure, the reaction of 1j (71.0 mg, 0.3 mmol) with 2j (111.2 mg, 0.6 mmol) at 70 oC for 12 h gave 3jj (63.6 mg, 60% yield): white colloidal solid; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.46−7.30 (m, 4H), 7.04 (s, 1H), 4.23 (d, J = 9.6 Hz, 1H), 2.40 (s, 3H), 1.61−1.50 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.5 Hz, 3H); 13C{1H} NMR 34


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(101 MHz, CDCl3) δ 174.5, 172.8, 145.2, 145.0, 134.9, 132.4, 132.1, 132.0, 131.0, 129.9, 128.2, 127.3, 124.5, 124.3, 97.7, 63.3, 30.4, 22.1, 20.2, 19.2; HRMS (FTMSESI) calcd for C20H1835ClNO3Na [M+Na]+ 378.0867, found 378.0855. 9b-(3,4-Dichlorophenyl)-3-isopropyl-8-methyloxazolo[2,3-a]isoindole2,5(3H,9bH)-dione (3jk). By following the general procedure, the reaction of 1j (70.6 mg, 0.3 mmol) with 2k (132.8 mg, 0.6 mmol) at 70 oC for 12 h gave 3jk (85.0 mg, 73% yield): white solid, 106.5−106.9 oC; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.33 (dd, J = 8.4, 2.2 Hz, 1H), 7.12 (s, 1H), 4.21 (d, J = 9.7 Hz, 1H), 2.42 (s, 3H), 1.70−1.60 (m, 1H), 1.13 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.0, 172.1, 146.1, 145.9, 138.8, 133.9, 133.5, 132.6, 131.2, 127.5, 127.3, 124.9 (2C), 124.6, 97.5, 63.4, 30.0, 22.1, 20.2, 18.9; HRMS (TOF-ESI) calcd for C20H1835Cl2NO3 [M+H]+ 390.0664, found 390.0662. General Procedure for the Large-Scale synthesis of Product 3ja. A mixture of 1j (706.0 mg, 3.0 mmol), phenylglyoxylic acid 2a (900.3 mg, 6.0 mmol), Pd(OAc)2 (69.1 mg, 0.3 mmol), K2S2O8 (2.03 g, 7.5 mmol), and PTSA (855.9 mg, 4.5 mmol) in DCE (30 mL) was stirred at 70 oC in an oil bath for 12 h. After this, the reaction mixture was cooled to room temperature. Then, the reaction mixture was filtered through a silica gel plug with ethyl acetate as the eluent and evaporated in vacuo. The residue was separated by column chromatography over silica gel using petroleum ether and ethyl acetate (10:1−6:1) as the eluent to afford 3ja (706.0 mg, 73% yield). Preliminary Mechanistic Studies 35



1. Trapping Experiment with TEMPO. A mixture of 1a (66.4 mg, 0.3 mmol), phenylglyoxylic acid 2a (90.0 mg, 0.6 mmol), Pd(OAc)2 (7.0 mg, 0.03 mmol), K2S2O8 (202.6 mg, 0.75 mmol), PTSA (85.5 mg, 0.45 mmol), and TEMPO (140.6 mg, 0.9 mmol) in DCE (3 mL) was stirred at 70 oC in an oil bath for 12 h. After cooled to room temperature, the reaction mixture was subsequently analyzed by TLC, and it was found that only a trace amount of the desired product 3aa could be identified. Then, the reaction mixture was filtered through a silica gel plug with ethyl acetate as the eluent, and evaporated in a vacuo. Column chromatography of the residue over silica gel using petroleum ether and ethyl acetate (10:1) as the eluent provided TEMPO-2a adduct (45.3 mg, 29% yield based on 2a). 2,2,6,6-Tetramethylpiperidin-1-yl Benzoate (TEMPO-2a):26 white solid; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 1.84−1.69 (m, 3H), 1.62−1.55 (m, 2H), 1.50−1.42 (m, 1H), 1.28 (s, 6H), 1.12 (s, 6H). 2. Kinetic Isotope Effect Experiment. A mixture of 1a (33.2 mg, 0.15 mmol), [D5]-1a (34.0 mg, 0.15 mmol), phenylglyoxylic acid 2a (90.0 mg, 0.6 mmol), Pd(OAc)2 (7.0 mg, 0.03 mmol), K2S2O8 (202.6 mg, 0.75 mmol), and PTSA (85.5 mg, 0.45 mmol) in DCE (3 mL) was stirred at 70 oC in an oil bath for 1 h. After this, the reaction mixture was subsequently cooled to room temperature, filtered through a silica gel plug with ethyl acetate as the eluent, and evaporated in vacuo. The residue was purified by column chromatography over silica gel using petroleum ether and ethyl acetate (6:1) as the eluent to afford a mixture of 3aa and [D4]-3aa (11.8 mg, 13% yield), which was 36


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analyzed by 1H NMR spectroscopy. Based on the integrations related to different hydrogen resonances, the kinetic isotope effect (KIE) was calculated to be kH/kD = 3.8. 3. 18O-Labeled Experiment. A mixture of 1a (22.1 mg, 0.1 mmol), 18O-labeled phenylglyoxylic acid [18O]-2a (30.6 mg, 0.2 mmol), Pd(OAc)2 (2.7 mg, 0.01 mmol), K2S2O8 (67.6 mg, 0.25 mmol), and PTSA (29.3 mg, 0.15 mmol) in DCE (1 mL) was stirred at 70 oC in an oil bath for 12 h. After this, the reaction mixture was subsequently cooled to room temperature, filtered through a silica gel plug with ethyl acetate as the eluent, and evaporated in vacuo. The residue was purified by column chromatography over silica gel using petroleum ether and ethyl acetate (6:1) as the eluent to afford the product. Then the product was analyzed by HRMS, which indicated that no

18O

incorporation was occurred in the product by compared with the HRMS spectroscopy of 3aa.

ASSOCIATED CONTENT Supporting Information Copies of 1H and 13C NMR spectra, crystallographic data, and chiral HPLC analyses. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author: *Email: [email protected]

Notes 37



The authors declare no competing financial interest.

ACKNOWLEDGMENTS We are grateful for financial support from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000).

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Diastereoselective Synthesis of Oxazoloisoindolinones via Cascade

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