Lactamization

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Tin Powder Promoted Cascade Condensation/Allylation/Lactamization: Synthesis of Isoindolinones and Pyrazoloisoindol-8-ones Xiaoping Wang, Danfeng Huang, Ke-Hu Wang, Yingpeng Su, and Yulai Hu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00733 • Publication Date (Web): 15 May 2019 Downloaded from http://pubs.acs.org on May 15, 2019

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The Journal of Organic Chemistry

Tin Powder Promoted Cascade Condensation/Allylation/Lactamization: Synthesis of Isoindolinones and Pyrazoloisoindol-8-ones Xiaoping Wang,† Danfeng Huang,*† Ke-Hu Wang,† Yingpeng Su,† Yulai Hu*†‡ †College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning East Road, Lanzhou 730070, P. R. China ‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China E-mail: [email protected]; [email protected].

Abstract COOH CHO

O

O

R1

R +

2

NHNH2

Sn

R

1

N NH R4 R5

R5 R

3

I2, K2CO3

N N R1

R3 R4 R5 5 examples up to 86% yield

efficient

tin

DCE, rt

powder

EtOH, reflux

promoted

O R2

N N

KOH R1

cascade

37 examples up to 94% yield four-component "one pot" gram-scale synthesis

R3

O

O

An

R2

THF, reflux

R4

Br

O

R4 R5

R3 I

12 examples up to 83% yield mild reaction condition transition metal-free

condensation/allylation/lactamization

of

2-formylbenzoic acids, hydrazides and allyl bromides was developed for synthesis of isoindolinones in good to excellent yields under mild conditions without any other additives or catalysts. Further manipulation

of

isoindolinones

by

iodocyclization

process

afforded

the

tricyclic

tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one derivatives, which could be converted into more complicated tetracyclic tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-ones.

INTRODUCTION Nitrogen heterocycle skeletons are undoubtedly one of the most important structural scaffolds in a large number of pharmaceuticals, agrochemicals and natural products.1 Among various nitrogen heterocycles, isoindolinones and pyrazoloisoindol-8-ones are key structural scaffolds in many ACS Paragon Plus Environment

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medicinal molecules, and show a wide range of biological activities such as antihypertensive,2 antipsychotic,3 antiviral,4 anxiolytic,5 antileukemic6 and anticancer activities.7 For instance, Pagoclone (A), JM-1232 (B), CRR-224 (C), Lennoxamine (D), and Pyrazolo[5,1-a]isoindole (F) are drug candidates, especially, JM-1232 (B) is hypnotic drug candidate, which is currently in phase I clinical trials (Figure 1).8 Consequently, the development of efficient and facile methodologies for the construction of isoindolinone derivatives with structural complexity and diversity has been the focus of intensive efforts from organic chemists.9-13 Current approaches to obtain isoindolinones involve the reductive dehydroxylation of phthalimide derivatives,9 the addition of N-acylimines,10 the multicomponent reaction,11 the transition-metal-catalyzed C−H functionalization12 and others.13 As for the synthesis of pyrazoloisoindol-8-ones, only a handful of examples were reported,14 which included the multi-step reaction of 2-formylbenzoic acid, acetophenone and hydrazine,14a,b the intramolecular Friedel–Crafts acylation of N-formyl-pyrazolines,14c and phosphine-catalyzed cyclization between alkynes and N-aminophthalimide.14d In view of the biological activities of isoindolinones, the development of new and efficient methodologies for diversely functionalized construction of isoindolin-1-ones and tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one derivatives is still highly desired. O

O

N

MeO

N

Cl

N

N

O

O

A Pagoclone GABAA receptor MeO MeO

N

MeO

N N

O

O

B JM-1232 (MR04A3) Hypnotic drug

O

C CRR-224 PARP-1 inhibitor

O O

N

HN N N

O

N N

NH2

OMe

O D Lennoxamine Alkaloid

E DPX1840 Plant growth regulator

F Pyrazolo[5,1-a]isoindole Antihypotensive agent

Figure 1. Examples of biologically active isoindolinones and pyrazoloisoindol-8-ones. ACS Paragon Plus Environment

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On the other hand, organotin compounds such as allylstannanes have been widely applied in organic synthesis due to their good stability toward heat, hydrolysis and oxidation, the tolerance to functional groups, and high selectivity in organic reactions.15 However, most allylstannanes are toxic.16 In 1981, Teruaki Mukaiyama firstly reported tin powder-promoted allylation reaction of aldehydes and ketones.17 This method not only kept the advantages of organotin reagents, but also avoided the use of toxic allylstannanes. Afterwards, tin powder-promoted organic reactions have been studied widely by organic chemists.18 These advantages encouraged us to investigate the application of tin powder-promoted reactions in the construction of nitrogen-containing heterocycles. Recently,

we

successfully

developed

tin

powder-promoted

one-pot

construction

of

α‑methylene-γ-lactams.19 Based on our previous research results (Scheme 1, equation 1), we envisioned that 3-substituted isoindolin-1-ones should be accessible via tin powder-promoted cascade condensation/allylation/lactamization (Scheme 1, equation 2). We describe herein our exploration of tin powder-promoted cascade condensation/allylation/lactamization reaction of 2-formylbenzoic acids, hydrazides and allyl bromides for the synthesis of 3-homoallylic isoindolin-1-ones. In particular, homoallylic isoindolinones could be further converted into tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one

derivatives

and

tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-ones (Scheme 1, equation 2). Scheme 1. Tin Powder Promoted Synthesis of Nitrogen-Containing Heterocycles Our previous work19 R3

O O R1

H(R2)

or

n n = 0, 1, 2, 3

+

O R3

NHNH2

+ Br

Sn

O

HN

COOEt EtOH, reflux

R3 O or

N

HN

O

O

N

(1)

1

R (R2)H

n n = 0, 1, 2, 3

This work R2 COOH R1 CHO

O + R

THF reflux

4

O

O

R2 I2, K2CO3 N NH

Sn

R5

Br

O

NHNH2

R

R4 R5

N N

DCE, rt

1

R3

R1

R3

ACS Paragon Plus Environment

O

O

R4 R5

R2 R3 I

N N

KOH EtOH reflux

R1

R4 R5

(2) R3


Page 4 of 46

RESULTS AND DISCUSSION In our initial investigations, a mixture of 2-formylbenzoic acid (1a, 1.0 equiv) and benzoylhydrazine (2a, 1.0 equiv) in THF was refluxed for 8 hours, and then allyl bromide (3a, 1.0 equiv) and tin powder (1.0 equiv) were added. After refluxing for another 8 hours, product 4a was obtained in 45% yield (Table 1, entry 1). In order to improve the yield, the reaction conditions were optimized (Table 1). The molar ratio of allyl bromide 3a and tin powder was examined first, which was found to influence the yield of 4a greatly (Table 1, entries 2−7). When the mole ratio of 1a:2a:3a:Sn reached to 1:1:2.0:2.5, the yield of 4a increased to 94% (Table 1, entry 6). Next, different solvents were screened (Table 1, entries 8−15). The reaction in protic solvents such as ethanol and methanol were also found to give the product 4a in high yields (Table 1, entries 8 and 9). The other solvents such as dichloromethane and acetonitrile gave the product 4a in lower yields (Table

1,

entries

10

and

11).

In

particular,

the

reaction

in

1,4-dioxane,

toluene,

N,N-dimethylformamide and water produced another side product 5a except for the product 4a in low yields (Table 1, entries 12−15). The side product 5a came from the condensation reaction between 1a and 2a. Therefore, the optimized reaction conditions were found to be the use of 1a, 2a, 3a, and tin powder in a molar ratio of 1:1:2.0:2.5 in THF under reflux (Table 1, entry 6). Table 1. Optimization of the Reaction Conditionsa

+

1a

2a

O

Sn

NHNH2 + Br

CHO

O

O

O

COOH

3a

4a

entry

mole ratio of 1a:2a:3a:Sn

solvent

time (h)

1 2 3 4

1:1:1:1 1:1:1:1.5 1:1:1.5:1.5 1:1:1.5:2.0

THF THF THF THF

16 15 14 14


NH N

+

N NH

Solvent, reflux

5a

yield (%)b 4a 45 76 81 87

5a 0 0 0 0

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5 1:1:2.0:2.0 THF 13 89 0 6 1:1:2.0:2.5 THF 13 94 0 7 1:1:2.5:2.5 THF 13 92 0 8 1:1:2.0:2.5 EtOH 13 90 0 9 1:1:2.0:2.5 MeOH 13 91 0 10 1:1:2.0:2.5 DCM 13 58 0 11 1:1:2.0:2.5 CH3CN 14 70 0 12 1:1:2.0:2.5 1,4-dioxane 16 7 82 13 1:1:2.0:2.5 toluene 13 56 27 14 1:1:2.0:2.5 DMF 13 37 21 15 1:1:2.0:2.5 H2O 16 21 32 aReaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), 3a and tin powder were refluxed in THF (4 mL). bIsolated yields. With the optimal reaction conditions in hand, the different substituted 2-formylbenzoic acids were used to investigate the generality of the substrates. The results were summarized in Table 2. The electronic properties of substituents on the phenyl ring of 2-formylbenzoic acids had little effects on the reactions. All of the 2-formylbenzoic acids with both of electron-donating and electron-withdrawing groups on their phenyl rings gave the corresponding products in good to excellent yields. However, the position of substituents on the phenyl ring of 2-formylbenzoic acids had some influence on the yields. The 3-substituted and 6-substituted 2-formylbenzoic acids gave the

products

in

slightly

lower

yields

because

of

steric

hindrance.

For

instance,

2-formyl-3-methylbenzoic acid and 2-formyl-6-methylbenzoic acid gave the products 4b and 4e in 71% and 78% yields respectively. 2-Formyl-4-methylbenzoic acid and 2-formyl-5-methylbenzoic acid gave the corresponding products in 87% and 90% yields (Table 2, 4c and 4d). Finally, when 2-acetylbenzoic acid 1k and 2-benzoyl benzoic acid 1l were used as substrates, there were no products 4k and 4l obtained (Scheme 2). At the same time, we found that the condensation of 1k or 1l with 2a did not produce the corresponding acylhydrazones. Table 2. Substrate Scope of 2-Formylbenzoic Acidsa



R1

O

O

COOH +

NHNH2

CHO

1

O

Sn Br

3a

H N N

O

H N N

4e 15 h, 78%

O

F3C

4f 13 h, 90%

O

O

H N N

4c 13 h, 87%

O

O

O

H N N

4b 16 h, 71%

O

O

4

O

H N N

O

H N N

R1

THF, reflux

O O

4a 13 h, 94%

Cl

+

2a

H N N

Page 6 of 46

O H N N

O

O

4d 13 h, 90% O

F

H N N

4g 13 h, 94%

O

4h 13 h, 92%

O

H N N

O

H N N

O

Cl

4i 13 h, 91%

4j 13 h, 88%

aReaction

conditions: 1 (0.3 mmol), 2a (0.3 mmol), 3a (0.6 mmol) and tin powder (0.75 mmol) were refluxed in THF (4 mL). Isolated yields.

Scheme 2. Scope of Other Substrates O

O

COOH +

NHNH2

+

Sn Br

H N N

O

THF, reflux

O 1k

2a

Ph

O

O

COOH +

4k 13 h, 0%

3a

NHNH2

+

Sn Br

THF, reflux

H N N Ph

O

O 1l

2a

3a


4l 13 h, 0%

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Next, different hydrazides 2 were reacted with 1a to check the generality of hydrazides under the optimized reaction conditions. As shown in Table 3, all of the aromatic hydrazides gave the corresponding products in good to excellent yields. However, the aromatic hydrazides with electron-withdrawing substituents on their phenyl rings usually gave the products in slightly higher yields than those with electron-donating substituents (Table 3, 6c−d vs 6g−i). The positions of substituents on the phenyl ring of benzoyl hydrazines also affected the results. When the substituents on the phenyl rings were the same ones, the para-substituted benzoylhydrazines produced the products in higher yields (Table 3, 6a−c and 6e−g). For instance, o-chlorobenzoylhydrazine gave the product 6e in 80% yield, but the yield of product 6g increased to 94% when p-chlorobenzoylhydrazine was used as the substrate. Heteroaromatic hydrazides also afforded the corresponding products in good yields (Table 3, 6k−m). The aliphatic hydrazides such as acetohydrazide and 2,2,2-trifluoroacetohydrazide did not give the corresponding products, and only the side product 5a was obtained through the condensation reaction between 1a and 2a (Table 3, 6n and 6o). When cyclohexanecarbohydrazide and long chain aliphatic hydrazides such as dodecanehydrazide were used, the desired products were obtained in low yields, and the side product 5a was also produced at the same time (Table 3, 6p and q). Table 3. Substrate Scope of Hydrazidesa O COOH + CHO

1a

R2

NHNH2

+

2

O H N N

O

Br

H N N

THF, reflux

3a O

O

Sn

H N N

R2

6 O

O

O

H N N

O O

H N N

O

O 6a 14 h, 76%

6b 13 h, 87%

6c 13 h, 88%


6d 13 h, 87%


O

O

H N N

O

Page 8 of 46

O

H N N

O

O

H N N

O

H N N

O

Cl Cl 6f 13 h, 90%

6e 14 h, 80%

O H N N

Cl 6g 13 h, 94%

O O

O

H N N

O

H N N

Br 6h 13 h, 94%

O O

H N N

O

N

O

F 6i 13 h, 92%

6j 15 h, 75%

O H N N

6k 13 h, 67%

O O

O

H N N

O

H N N

CH3

S

6m 13 h, 81%

6l 13 h, 87%

6n 17 h, 0% (5a, 80%)

O O

H N N

O

CF3

6o 17 h, 0% (5a, 73%)

6p 17 h,41% (5a, 52%)

O H N N

O C11H23

6q 17 h, 27% (5a, 64%) aReaction

conditions: 1a (0.3 mmol), 2 (0.3 mmol), 3a (0.6 mmol) and tin powder (0.75 mmol) were refluxed in THF (4 mL). Isolated yields. To further expand the scope of the substrates, various allyl bromides were applied in the reaction.

As shown in Table 4, all of the examined β- and γ-substituted allyl bromides could afford the corresponding products in good to excellent yields. In this process, the γ-addition products were obtained exclusively, and γ-substituted allyl bromides gave the products in lower yields than those of the β-substituted allyl bromides because of the steric hindrance (Table 4, 7a−c vs 7d−l). In particularly, both of cinnamyl bromide and 3-bromocyclohexene gave the products with high diastereoselectivities (Table 4, 7b and c).


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Table 4. Substrate Scope of Allyl Bromidesa O

COOH +

NHNH2 + Br

CHO

O

R4

Sn R

R3

1a

2a

O H N N

O

H N N

THF, reflux R3

3

R4 R5 7

O O

5

O O

H N N

O O

H N N

O

H N N

Ph 7a 16 h, 69%

7b 17 h, 67%, dr = 81:19b

O

7c 16 h, 73%, dr > 99:1b

O O

H N N

7d 13 h, 90%

O O

H N N

O

H N N

O

O

H N N

O

EtOOC 7e 14 h, 77%

7f 14 h, 85%

O

O

H N N

O

F

O

H N N Cl

7i 14 h, 81%

7h 16 h, 82%

7g 15 h, 86%

O

H N N

O O

O

H N N

Br

7j 13 h, 84%

7k 14 h, 79%

7l 15 h, 78%

aReaction

conditions: 1a (0.3 mmol), 2a (0.3 mmol), 3 (0.6 mmol) and tin powder (0.75 mmol) were refluxed in THF (4 mL). Isolated yields. bDetermined by 1H NMR analysis. As we can see, the products from the above reactions are highly functionalized molecules. Thus,

we try to further convert them into tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one derivatives by iodocyclization in view of their pharmaceutical importance. As shown in Table 5, isoindolin-1-one 4a was stirred with 2 equiv of iodine in DCM at room temperature, there was no reaction occurred (Table 5, entry 1). To our delight, when 2 equiv of K2CO3 was added into the reaction mixture, the reaction

really

occurred

to

give

the

iodocyclization

product

tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one 8a in 69% yield (Table 5, entry 2). Brief optimization of the reaction conditions revealed that the optimal reaction conditions were to carry out the reaction ACS Paragon Plus Environment


Page 10 of 46

in DCE at room temperature in the presence of 2 equiv of iodine and 2 equiv of K2CO3 (Table 5, entry 5). To increase the solubility of K2CO3 in organic solvent, phase transfer catalyst Bu4NI (0.1 equiv) was added into the reaction mixture, but the yield of 8a was not improved (Table 5, entry 17).

The cis relative configuration of 8a was confirmed by X-ray single crystal structural analysis. In the light of literature20, formation of cis-product 8a could be explained as in Scheme 3. Addition of iodine to C=C bond of 4a formed the iodonium 17. In the next cyclization reaction, two transition states 18 and 19 would be adopted. The more bulky iodonium species in transition state 18 was on pseudo axial bond, and it was on pseudo equatorial bond in transition state 19, which made the transition state 19 more favoured. Thus, the cis-product 8a was formed after the cyclization. Table 5. Optimization of Iodination/Cyclization Reaction Conditionsa O H N N

O

O + I2

Base

O N N

Solvent, rt I

4a

8a

CCDC: 1889343

entry mole ratio of 4a:I2:base base solvent time (h) yield (%)b 1 1:2:0 DCM 20 0 2 1:2:2 K2CO3 DCM 6 69 3 1:2:2 K2CO3 CHCl3 7 65 4 1:2:2 K2CO3 CCl4 20 17 5 1:2:2 K2CO3 DCE 6 78 6 1:2:2 K2CO3 CH3CN 20 41 7 1:2:2 K2CO3 THF 20 45 8 1:2:2 K2CO3 toluene 20 29 9 1:2:2 K2CO3 1,4-dioxane 20 53 10 1:2:2 K2CO3 DMF 20 8 11 1:2:2 K2CO3 EtOH 20 trace 12 1:2:2 Na2CO3 DCE 20 trace 13 1:2:2 Cs2CO3 DCE 20 33 14 1:2:2 DBU DCE 20 39 15 1:2.5:2 K2CO3 DCE 6 78 16 1:2:2.5 K2CO3 DCE 6 77 17c 1:2:2 K2CO3 DCE 6 77 aReaction conditions: 4a (0.2 mmol), I , base, and solvent (3 mL) were stirred at rt. bIsolated yields. 2 cIn the presence of Bu NI (0.1 equiv). 4


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Scheme 3. Formation of cis-Product 8a O

O K2CO3, I2

N

O

I

Bz

H

Disfavoured transition state 18

O

H N N Bz

N

H

I H

N

N

Bz

H

trans-product 8a' not detected

N N Bz I

4a

17 O

N

H N

H Bz I

O

Favoured transition state 19

N

H N

H Bz

I

cis-product 8a

Under the optimized reaction conditions, generality of iodocyclization of isoindolin-1-ones was examined, and the results were summarized in Table 6. In general, most isoindolin-1-one derivatives could

perform

the

iodocyclization

reaction

smoothly

to

afford

tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-ones in good yields (Table 6, 8a−h). The steric hindrance around C=C bond had little effects on the yields of the corresponding products (Table 6, 8i−l). Table 6. Substrate Scopea O H N N

R1

R R5

N N

K2CO3

I2

+

4

R3

O

O

O R

DCE, rt

1

R4 R5

4, 7

O

O

8a 6 h, 78%

F

I

8b 8 h, 73%

Cl I

O

N N I

I

8d 7 h, 83 %

O

O

O

8g 6 h, 75%


I

O N N

N N I

O N N

F3C

8c 7 h, 76%

N N

8f 6 h, 80%

O

O

O

O

N N

8e 6 h, 80%

O N N

O

O

O

8

O

N N

R3 I

I

Cl

8h 6 h, 79%

I


O

O

O

O

O

N N

N N

Page 12 of 46

O

O

O

N N

N N I COOEt

I I

I Ph 8i 8 h, 77%, dr = 70:30b

8j 6 h, 76%

8k 7 h, 73%

8l 8 h, 69%

aReaction

conditions: 4, 7 (0.2 mmol), I2 (0.4 mmol), K2CO3 (0.4 mmol) and DCE (3 mL) were stirred at rt. Isolated yields. bDetermined by 1H NMR analysis. The C=C bond of product 4a could be reduced to alkyl group by palladium catalyzed

hydrogenation to afford 9a in 90% yield without any change of other functional groups. It could also be treated with 3-chlorobenzenecarboperoxoic acid (m-CPBA) to afford epoxide 10a in 84% yield (Scheme 4). Scheme 4. Further Transformations of Allylation Product 4a O H N N

O

H2 (1 atm) Pd/C (10 mol%) MeOH, rt, 24 h 90% yield

O H N N

O

O

m-CPBA (3 equiv)

H N N

DCM, rt, 24 h 84% yield

O

O 9a

4a

10a

As a further extension of our investigation, the products 8 from the above iodocyclization process were refluxed in ethanol in the presence of KOH (2 equiv), and it was found that products tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-ones 11 were produced in good yields through the deprotection/cyclization process (Table 7, 11a−e). However, when 8k and 8l were used as substrates respectively, there were no desired products 11f and 11g formed except some inseparable mixtures after the reaction. The relative configuration of 11a was confirmed by X-ray single crystal structural analysis. To compare with the configuration of 8a, the configuration of 11a came from the epimerization of 8a. In order to determine the position of the epimerization, deuterated ethanol was used as solvent. When deuterated ethanol was used as solvent, the product 11a', which was deuterated at benzylic position, was obtained in 88% yield (Scheme 5). This revealed that epimerization occurred at the benzylic position of the cis-8a. The epimerization process ACS Paragon Plus Environment

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could be described as in Scheme 6. Deprotonation of cis-8a at benzylic position by KOH gave the carbon anion 20, which could transform to carbon anion 21. Proton extraction of carbon anion 21 from ethanol produced the intermediate 22. Deacylation of 22 by KOH gave the nitrogen anion 23, which performed internal SN2 reaction to afford the trans-product 11a. Table 7. Substrate Scope of the Deprotection/Cyclization Reactiona O

O

O

N N R

1 4

R R

5

N N

KOH (2 equiv) R

EtOH, reflux

R3 I

1

R4 R5

R3

11

8

O

O N N

O N N

N N

Cl

11b 0.5 h, 83%

CCDC: 1900569

O O

N N

F

11a 0.5 h, 86%

O

11c 0.5 h, 84%

O

O N N

N N

N N COOEt

11d 0.5 h, 81% aReaction

11e 0.6 h, 79%

11f 1 h, 0%

11g 1 h, 0%

conditions: 8 (0.2 mmol) and KOH (0.4 mmol) were refluxed in EtOH (3 mL). Isolated

yields. Scheme 5. Deuterium Labeling Experiment O

O

O KOH (2 equiv)

N N

N N

CD3CD2OD, reflux D

I 8a

11a', 0.5 h, 88%

Scheme 6. Formation of trans-Product 11a



O

NH

N

H Bz

O

I

KOH

N

N

H Bz

Page 14 of 46 O

I

N

H I

21

20

cis-8a

Bz

N

EtOH EtOK O N N

H

Internal SN2 reaction

O

KOH

N H

I

23

trans-11a

Bz

N

H

N

H

O N H

PhCOOH

H I

22

To explore the practical utility of this method, a gram-scale experiment was performed by using 2-formylbenzoic acid 1a (2.00 g, 13.32 mmol), benzoylhydrazine 2a (1.81 g, 13.32 mmol) and allyl bromide 3a (3.22 g, 26.64 mmol) as substrates. The desired product 4a could be obtained in 85% yield under the optimized reaction conditions. Further manipulation of 4a by iodocyclization afforded

pyrazoloisoindol-8-one

8a

in

61%

yield,

which

could

be

converted

to

tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-one 11a in 76% yield. This demonstrated that the protocol was scalable and practical (Scheme 7). Scheme 7. Gram-Scale Synthesis

COOH CHO 1a, 2.00 g

O 2a, 3a, Sn THF, reflux, 13 h

H N N

O O

I2, K2CO3,

O

O KOH

N N

DCE, rt, 20 h I

4a, 3.31 g, 85%

8a, 2.89 g, 61%

EtOH, reflux, 0.5 h

N N

11a, 0.98 g, 76%

In order to get insight into the mechanism, some control experiments were conducted as showed in Scheme 8. When 2-formylbenzoic acid 1a and benzoylhydrazine 2a were refluxed in THF for 8 h, the acylhydrazone 12a was formed in 96% yield (Scheme 8, equation A). The acylhydrazone 12a was then used as substrate to be refluxed with allyl bromide 3a and tin powder in THF for 5 h, and the product 4a was obtained in 95% yield (Scheme 8, equation B). These meant the acylhydrazone 12a was formed first, and then the allylation/lactamization occurred to give the final product. In ACS Paragon Plus Environment

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order to investigate how the side product 5 was formed, the acylhydrazone 12a was just refluxed in 1,4-dioxane or in the presence of tin powder, and there was no the side product 5a formed. However, when SnCl2 (10 mol%) or SnCl4 (10 mol%) was added into the mixture, the side product 5a was obtained in 84% or 81% yield respectively, and benzoic acid was also obtained at the same time (Scheme 8, equation C). These indicated that the side product 5a was formed through deacylation/cyclation of acylhydrazone 12a in the presence of in-situ formed tin salts. Thus, a possible mechanism was proposed as in Scheme 9 on the basis of our experiment results and the literature.18 Acylhydrazones 12 were formed from condensation of 2-formylbenzoic acids 1 and hydrazides 2, and nucleophilic addition of in-situ formed organotin reagents 14 to acylhydrazones 12 produced intermediates 16, which were then cyclized to afford products 4. During the process, some tin salts would be produced, which promoted the deacylation/cyclation of acylhydrazones 12 to form the side products 5 and corresponding carboxylic acids 13 (Scheme 9). Scheme 8. Control Experiments for Mechanism O

COOH +

A

COOH NHNH2

CHO

N H 12a, 8 h, 96%

2a

1a

O

N

THF, reflux

O COOH B

N

O

N H

+

Br

12a COOH C

N

N H 12a

H N N

Sn THF, reflux

3a O

O

4a, 5 h, 95% O

additive 1,4-dioxane, reflux

O NH N

+

OH

5a 13a Yield: 5a, 0%; 13a, 0%, 20 h (Without additive) Yield: 5a, 0%; 13a, 0%, 20 h (Sn, 10 mol%) Yield: 5a, 84%; 13a, 77%,15 h (SnCl2, 10 mol%) Yield: 5a, 81%; 13a, 73%, 20 h (SnCl4, 10 mol%)

Scheme 9. Proposed Mechanistic Pathway



Page 16 of 46

O

O

OH O SnBr N NH R2

R1 R4 R5

COOH

16

R1

R

1

O

R2

N NH R4 R5

R3

R3

4

CHO 1 +

-H2O

O R2

NHNH2

COOH R

1

N 12

N H

R3

O

BrSn R

2

R4

Br 3 R5

14 R5 R3

Sn

2

R

R3

Sn

4

(II)

R4

Br2Sn or

Sn

(IV

)

15

O R

NH N

1

5

R5

2

O +

R2

OH 13

CONCLUSION In summary, we established a convenient method for the synthesis of 3-allylisoindolin-1-ones from cascade condensation/allylation/lactamization reactions of 2-formylbenzoic acids, hydrazides and allyl bromides promoted by tin powder. The reaction proceeded smoothly under mild reaction conditions to give the corresponding products in good to excellent yields in the absence of transition metal catalysts. Further manipulation of 3-allylisoindolin-1-ones by iodocyclization process afforded the tricyclic pyrazoloisoindol-8-one derivatives, which could be converted into more complicacted tetracyclic tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-ones. The method further extended the application of tin powder-promoted allylation reactions in organic synthesis, especially in the synthesis of heterocyclic compounds.

EXPERIMENTAL SECTION General Methods. The solvents were distilled by standard methods. Reagents were obtained from commercial suppliers and used without further purification unless otherwise noted. Silica gel column chromatography was carried out using silica gel 60 (230−400 mesh). Analytical thin layer chromatography (TLC) was done using silica gel GF254. TLC plates were analyzed by an exposure ACS Paragon Plus Environment

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to ultraviolet (UV) light and/or submersion in phosphomolybdic acid solution or submersion in KMnO4 solution or in I2. High-resolution mass spectra were recorded on Fourier transform ion cyclotron resonance mass spectrometer. NMR experiments were carried out in Chloroform-d1 (CDCl3), Dimethyl sulfoxide-d6 ((CD3)2SO) and Acetone-d6 ((CD3)2CO). 1H NMR, 13C{1H} NMR spectra were recorded at 400 or 600 MHz and 100 or 150 MHz spectrometers, respectively.

19F

NMR spectra were recorded at 376 MHz spectrometers. Chemical shifts are reported as δ values relative to internal TMS (δ 0.00 for 1H NMR), chloroform (δ 7.26 for 1H NMR), dimethyl sulfoxide (δ 2.50 for 1H NMR), acetone (δ 2.05 for 1H NMR), chloroform (δ 77.16 for

13C{1H}

NMR),

dimethyl sulfoxide (δ 39.52 for 13C{1H} NMR), and acetone (δ 206.26 for 13C{1H} NMR) in parts per million (ppm). The following abbreviations are used for the multiplicities: s: singlet, d: doublet, dd: doublet of doublet, t: triplet, q: quartet, m: multiplet, br: broad signal for proton spectra. Coupling constants (J) are reported in Hertz (Hz). Melting points were uncorrected. The 2-formylbenzoic acids 1b−j,9c hydrazides 2b−q,21a and allyl bromides 3f−l21b were prepared according to the reported literature procedures. General Procedure for the Synthesis of 4, 6 and 7. 2-formylbenzoic acids 1 (0.3 mmol, 1 equiv), hydrazides 2 (0.3 mmol, 1.0 equiv), and THF (4 mL) were put into a dried round-bottom flask (50 mL), the mixture was stirred at reflux. The reaction was monitored by TLC until the starting material disappeared, and then tin powder (0.75 mmol, 2.5 equiv) and allyl bromides 3 (0.6 mmol, 2.0 equiv) were added, the mixture was stirred at reflux for another 5−9 h. After completion of the reaction, the mixture was cooled to room temperature, and THF was removed under vacuum. The saturated NH4Cl solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using petroleum ether / ethyl acetate (2/ 1) as the eluent furnished the pure products 4, 6 and 7. ACS Paragon Plus Environment


Page 18 of 46

N-(1-Allyl-3-oxoisoindolin-2-yl)benzamide (4a). 82 mg, 94% yield, white solid, mp 101−103 oC; 1H

NMR (600 MHz, CDCl3) δ 10.68 (s, 1H), 7.85−7.82 (m, 3H), 7.57 (t, J = 7.2 Hz, 1H), 7.46−7.44

(m, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.25 (t, J = 7.8 Hz, 2H), 5.61−5.54 (m, 1H), 5.10 (d, J = 17.4 Hz, 1H), 5.09 (t, J = 5.4 Hz, 1H), 4.90 (d, J = 10.2 Hz, 1H), 2.79−2.74 (m, 1H), 2.68−2.63 (m, 1H); 13C{1H}

NMR (150 MHz, CDCl3) δ 168.3, 166.5, 144.5, 132.5, 132.1, 131.8, 131.0, 130.0, 128.5,

128.3, 127.7, 124.1, 123.0, 119.3, 60.9, 35.4; HRMS (ESI) m/z calcd for C18H17N2O2 [M + H]+ 293.1285, found 293.1289. N-(3-Allyl-4-methyl-1-oxoisoindolin-2-yl)benzamide (4b). 65 mg, 71% yield, white solid, mp 133−135 oC; 1H NMR (600 MHz, CDCl3) δ 10.62 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.68−7.65 (m, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.36−7.35 (m, 2H), 7.28 (t, J = 7.8 Hz, 2H), 5.33−5.26 (m, 1H), 5.21 (t, J = 3.6 Hz, 1H), 5.06 (d, J = 16.8 Hz, 1H), 4.71 (d, J = 9.6 Hz, 1H), 2.96−2.91 (m, 1H), 2.80−2.75 (m, 1H), 2.40 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.2, 166.7, 142.2, 134.1, 133.0, 132.2, 131.2, 131.1, 130.5, 128.5, 128.4, 127.7, 121.7, 118.8, 60.9, 32.9, 18.6; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+ 307.1441, found 307.1427. N-(3-Allyl-5-methyl-1-oxoisoindolin-2-yl)benzamide (4c). 80 mg, 87% yield, white solid, mp 169−170 oC; 1H NMR (600 MHz, CDCl3) δ 10.56 (s, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.26−7.24 (m, 4H), 5.61−5.54 (m, 1H), 5.10 (d, J = 17.4 Hz, 1H), 5.03 (t, J = 5.4 Hz, 1H), 4.90 (d, J = 10.2 Hz, 1H), 2.75−2.71 (m, 1H), 2.66−2.62 (m, 1H), 2.44 (s, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 168.4, 166.5, 144.8, 143.3, 132.1, 131.2, 131.1, 129.3,

128.5, 127.7, 127.5, 124.0, 123.4, 119.1, 60.8, 35.5, 22.2; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+ 307.1441, found 307.1449. N-(1-Allyl-5-methyl-3-oxoisoindolin-2-yl)benzamide (4d). 83 mg, 90% yield, white solid, mp 145−146 oC; 1H NMR (600 MHz, CDCl3) δ 10.61 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.62 (s, 1H), ACS Paragon Plus Environment

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7.39−7.36 (m, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 2H), 5.63−5.56 (m, 1H), 5.10 (d, J = 16.8 Hz, 1H), 5.04 (t, J = 5.4 Hz, 1H), 4.92 (d, J = 10.2 Hz, 1H), 2.77−2.72 (m, 1H), 2.64−2.59 (m, 1H), 2.41 (s, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 168.4, 166.5, 141.7, 138.3, 133.4, 132.1,

132.0, 131.1, 130.1, 128.4, 127.7, 124.3, 122.7, 119.1, 60.8, 35.6, 21.4; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+ 307.1441, found 307.1448. N-(1-Allyl-4-methyl-3-oxoisoindolin-2-yl)benzamide (4e). 72 mg, 78% yield, white solid, mp 132−133 oC; 1H NMR (600 MHz, CDCl3) δ 10.54 (s, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.43−7.38 (m, 2H), 7.27−7.24 (m, 3H), 7.18 (d, J = 7.8 Hz, 1H), 5.67−5.61 (m, 1H), 5.09 (d, J = 17.4 Hz, 1H), 5.03 (t, J = 5.4 Hz, 1H), 4.93 (d, J = 10.2 Hz, 1H), 2.75−2.71 (m, 1H), 2.69 (s, 3H), 2.67−2.62 (m, 1H); 13C{1H}

NMR (150 MHz, CDCl3) δ 169.0, 166.5, 145.0, 138.3, 132.4, 132.1, 132.0, 131.2, 130.3,

128.5, 127.7, 127.2, 120.3, 118.9, 60.1, 35.9, 17.6; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+ 307.1441, found 307.1430. N-(1-Allyl-5-methoxy-3-oxoisoindolin-2-yl)benzamide (4f). 87 mg, 90% yield, white solid, mp 73−74 oC; 1H NMR (400 MHz, CDCl3) δ 10.54 (s, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.27 (t, J = 8.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 5.65−5.42 (m, 1H), 5.10 (d, J = 17.2 Hz, 1H), 5.02 (t, J = 4.4 Hz, 1H), 4.93 (d, J = 10.4 Hz, 1H), 3.84 (s, 3H), 2.78−2.72 (m, 1H), 2.64−2.57 (m, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 168.3,

166.5, 160.0, 136.8, 132.2, 132.1, 131.2, 131.1, 128.5, 127.7, 124.0, 120.8, 119.2, 106.9, 60.7, 55.8, 35.6; HRMS (ESI) m/z calcd for C19H19N2O3 [M + H]+ 323.1390, found 323.1402. N-(1-Allyl-3-oxo-5-(trifluoromethyl)isoindolin-2-yl)benzamide (4g). 102 mg, 94% yield, white solid, mp 213−214 oC; 1H NMR (600 MHz, CDCl3) δ 10.51 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 7.8 Hz, 2H), 5.60−5.54 (m, 1H), 5.17−5.12 (m, 2H), 4.97 (d, J = 10.2 Hz, 1H), 2.84−2.80 (m, 1H), ACS Paragon Plus Environment


Page 20 of 46

2.71−2.67 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.8, 166.5, 147.7, 132.4, 131.3, 131.2 (q, J = 33.0 Hz), 130.9, 130.8, 129.3 (q, J = 3.0 Hz), 128.6, 127.7, 123.8, 123.7 (q, J = 271.5 Hz), 121.5 (q, J = 3.0 Hz), 120.0, 61.1, 35.2; 19F NMR (376 MHz, CDCl3) δ −62.87 (s); HRMS (ESI) m/z calcd for C19H16F3N2O2 [M + H]+ 361.1158, found 361.1160. N-(1-Allyl-5-fluoro-3-oxoisoindolin-2-yl)benzamide (4h). 86 mg, 92% yield, white solid, mp 157−159 oC; 1H NMR (600 MHz, CDCl3) δ 10.39 (s, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.49 (dd, J = 7.2, 2.4 Hz, 1H), 7.44−7.40 (m, 2H), 7.30−7.26 (m, 3H), 5.60−5.53 (m, 1H), 5.12 (d, J = 16.8 Hz, 1H), 5.06 (t, J = 5.4 Hz, 1H), 4.97 (d, J = 10.2 Hz, 1H), 2.78−2.74 (m, 1H), 2.67−2.62 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.2, 166.5, 162.8 (d, J = 246.0 Hz), 139.9 (d, J = 3.0 Hz), 132.4, 132.1 (d, J = 9.0 Hz), 131.7, 130.9, 128.6, 127.7, 124.8 (d, J = 7.5 Hz), 120.1 (d, J = 24.0 Hz), 119.6, 110.9 (d, J = 22.5 Hz), 60.7, 35.5;

19F

NMR (376 MHz, CDCl3) δ −112.81 (m); HRMS (ESI) m/z

calcd for C18H16FN2O2 [M + H]+ 311.1190, found 311.1180. N-(1-Allyl-5-chloro-3-oxoisoindolin-2-yl)benzamide (4i). 89 mg, 91% yield, white solid, mp 124−125 oC; 1H NMR (600 MHz, CDCl3) δ 10.50 (s, 1H), 7.80−5.76 (m, 3H), 7.53 (d, J = 7.8 Hz, 1H), 7.42−7.39 (m, 2H), 7.26 (t, J = 7.8 Hz, 2H), 5.60−5.53 (m, 1H), 5.12 (d, J = 16.8 Hz, 1H), 5.06 (t, J = 5.4 Hz, 1H), 4.97 (d, J = 10.2 Hz, 1H), 2.78−2.74 (m, 1H), 2.65−2.61 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.9, 166.4, 142.6, 134.6, 132.7, 132.3, 131.8, 131.5, 130.9, 128.5, 127.7, 124.4, 124.2, 119.7, 60.8, 35.3; HRMS (ESI) m/z calcd for C18H16ClN2O2 [M + H]+ 327.0895, found 327.0884. N-(3-Allyl-5-chloro-1-oxoisoindolin-2-yl)benzamide (4j). 86 mg, 88% yield, white solid, mp 157−158 oC; 1H NMR (600 MHz, (CD3)2CO) δ 10.17 (s, 1H), 7.99 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.60−7.59 (m, 2H), 7.49 (t, J = 7.8 Hz, 2H), 5.79−5.72 (m, 1H), 5.15 (d, J = 16.8 Hz, 1H), 5.05 (t, J = 4.8 Hz, 1H), 4.99 (d, J = 10.2 Hz, 1H), 2.90−2.86 (m, 1H), 2.83−2.78 (m, ACS Paragon Plus Environment

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1H); 13C{1H} NMR (150 MHz, (CD3)2CO) δ 167.1, 166.5, 147.1, 138.8, 133.4, 133.2, 133.0, 130.2, 129.6, 129.4, 128.5, 125.9, 124.6, 119.3, 61.4, 35.8; HRMS (ESI) m/z calcd for C18H16ClN2O2 [M + H]+ 327.0895, found 327.0883. Data of side product 5a Phthalazin-1(2H)-one (5a). 36 mg, 82% yield (Table 1, entry 12), white solid, mp 183−185 oC; 1H NMR (600 MHz, CDCl3) δ 11.58 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 161.1, 139.2, 133.8, 131.9, 130.4, 128.1, 126.6, 126.4; HRMS (ESI) m/z calcd for C8H6N2ONa [M + Na]+ 169.0372, found 169.0366. N-(1-Allyl-3-oxoisoindolin-2-yl)-2-methylbenzamide (6a). 70 mg, 76% yield, white solid, mp 162−163 oC; 1H NMR (600 MHz, CDCl3) δ 8.95 (s, 1H), 7.74 (d, J = 5.4 Hz, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.44−7.42 (m, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.17−7.13 (m, 2H), 5.66−5.59 (m, 1H), 5.10 (d, J = 17.4 Hz, 1H), 5.04 (t, J = 4.2 Hz, 1H), 4.97 (d, J = 10.2 Hz, 1H), 2.77−2.73 (m, 1H), 2.68−2.63 (m, 1H), 2.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.3, 167.7, 144.2, 137.6, 132.8, 132.4, 132.2, 131.3, 130.8, 129.9, 128.2, 127.5, 125.8, 124.2, 122.8, 119.2, 60.8, 35.8, 20.1; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+ 307.1441, found 307.1450. N-(1-Allyl-3-oxoisoindolin-2-yl)-3-methylbenzamide (6b). 80 mg, 87% yield, white solid, mp 57−58 oC; 1H NMR (600 MHz, CDCl3) δ 10.64 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.45−7.43 (m, 2H), 7.18 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 5.61−5.54 (m, 1H), 5.11−5.08 (m, 2H), 4.89 (d, J = 10.2 Hz, 1H), 2.79−2.75 (m, 1H), 2.68−2.63 (m, 1H), 2.26 (s, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 168.2, 166.6, 144.5, 138.1,

132.8, 132.4, 131.9, 130.9, 130.1, 128.4, 128.3, 128.2, 124.7, 124.1, 123.0, 119.3, 60.9, 35.5, 21.3; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+ 307.1441, found 307.1454. ACS Paragon Plus Environment


Page 22 of 46

N-(1-Allyl-3-oxoisoindolin-2-yl)-4-methylbenzamide (6c). 81 mg, 88% yield, white solid, mp 155−156 oC; 1H NMR (600 MHz, CDCl3) δ 10.43 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.46−7.44 (m, 2H), 7.05 (d, J = 7.8 Hz, 2H), 5.61−5.54 (m, 1H), 5.10−5.06 (m, 2H), 4.90 (d, J = 10.2 Hz, 1H), 2.78−2.74 (m, 1H), 2.67−2.62 (m, 1H), 2.32 (s, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 168.3, 166.5, 144.5, 142.6, 132.4, 132.0, 130.1, 129.0, 128.3,

128.2, 127.7, 124.1, 123.0, 119.2, 61.0, 35.4, 21.6; HRMS (ESI) m/z calcd for C19H19N2O2 [M + H]+ 307.1441, found 307.1456. N-(1-Allyl-3-oxoisoindolin-2-yl)-4-methoxybenzamide (6d). 84 mg, 87% yield, white solid, mp 164−166 oC; 1H NMR (600 MHz, CDCl3) δ 10.52 (s, 1H), 7.85−7.82 (m, 3H), 7.56 (t, J = 7.2 Hz, 1H), 7.45−7.44 (m, 2H), 6.76−6.73 (m, 2H), 5.60−5.53 (m, 1H), 5.11−5.06 (m, 2H), 4.89 (d, J = 9.6 Hz, 1H), 3.80 (s, 3H), 2.79−2.75 (m, 1H), 2.68−2.63 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.4, 166.1, 162.7, 144.5, 132.4, 131.9, 130.1, 129.7, 128.3, 124.1, 123.5, 123.0, 119.3, 113.7, 61.1, 55.5, 35.4; HRMS (ESI) m/z calcd for C19H19N2O3 [M + H]+ 323.1390, found 323.1394. N-(1-Allyl-3-oxoisoindolin-2-yl)-2-chlorobenzamide (6e). 78 mg, 80% yield, white solid, mp 195−196 oC; 1H NMR (600 MHz, CDCl3) δ 9.07 (s, 1H), 7.72−7.65 (m, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.46−7.42 (m, 2H), 6.38−6.32 (m, 2H), 7.23 (t, J = 7.2 Hz, 1H), 5.64−5.57 (m, 1H), 5.14−5.10 (m, 2H), 5.01 (d, J = 10.2 Hz, 1H), 2.84−2.81 (m, 1H), 2.75−2.71 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.3, 166.2, 144.1, 132.8, 132.5, 132.1, 132.0, 131.5, 130.4, 130.3, 129.8, 128.3, 127.1, 124.3, 122.8, 119.5, 60.7, 35.6; HRMS (ESI) m/z calcd for C18H16ClN2O2 [M + H]+ 327.0895, found 327.0891. N-(1-Allyl-3-oxoisoindolin-2-yl)-3-chlorobenzamide (6f). 88 mg, 90% yield, white solid, mp 133−134 oC; 1H NMR (600 MHz, (CD3)2CO) δ 10.28 (s, 1H), 7.97 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70−7.63 (m, 3H), 7.56−7.52 (m, 2H), 5.77−5.70 (m, 1H), 5.12 (d, J = ACS Paragon Plus Environment

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17.4 Hz, 1H), 5.03 (t, J = 5.4 Hz, 1H), 4.96 (d, J = 10.8 Hz, 1H), 2.88−2.84 (m, 1H), 2.82−2.77 (m, 1H); 13C{1H} NMR (150 MHz, (CD3)2CO) δ 167.6, 165.8, 145.3, 135.2, 135.0, 133.6, 133.2, 132.8, 131.3, 131.2, 129.1, 128.5, 126.9, 124.3, 124.2, 119.0, 61.6, 36.1; HRMS (ESI) m/z calcd for C18H16ClN2O2 [M + H]+ 327.0895, found 327.0889. N-(1-Allyl-3-oxoisoindolin-2-yl)-4-chlorobenzamide (6g). 92 mg, 94% yield, white solid, mp 154−155 oC; 1H NMR (600 MHz, CDCl3) δ 10.94 (s, 1H), 7.83−7.78 (m, 3H), 7.58 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.22 (d, J = 7.2 Hz, 2H), 5.58−5.51 (m, 1H), 5.11 (d, J = 16.8 Hz, 1H), 5.05 (t, J = 5.4 Hz, 1H), 4.88 (d, J = 10.2 Hz, 1H), 2.78−2.75 (m, 1H), 2.69−2.64 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.6, 165.3, 144.5, 138.6, 132.7, 131.6, 129.8, 129.2, 129.1, 128.7, 128.4, 124.1, 123.0, 119.5, 61.1, 35.3; HRMS (ESI) m/z calcd for C18H16ClN2O2 [M + H]+ 327.0895, found 327.0897. N-(1-Allyl-3-oxoisoindolin-2-yl)-4-bromobenzamide (6h). 104 mg, 94% yield, white solid, mp 165−167 oC; 1H NMR (600 MHz, CDCl3) δ 10.89 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 5.58−5.51 (m, 1H), 5.11 (d, J = 17.4 Hz, 1H), 5.04 (t, J = 5.4 Hz, 1H), 4.89 (d, J = 9.6 Hz, 1H), 2.78−2.74 (m, 1H), 2.69−2.64 (m, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 168.6, 165.4, 144.5, 132.7, 131.7, 131.6,

129.8, 129.6, 129.2, 128.4, 127.3, 124.2, 123.0, 119.5, 61.1, 35.3; HRMS (ESI) m/z calcd for C18H16BrN2O2 [M + H]+ 371.0390, found 371.0386. N-(1-Allyl-3-oxoisoindolin-2-yl)-4-fluorobenzamide (6i). 86 mg, 92% yield, white solid, mp 192−193 oC; 1H NMR (600 MHz, CDCl3) δ 10.93 (s, 1H), 7.90−7.88 (m, 2H), 7.82 (d, J = 7.2 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 6.93 (t, J = 8.4 Hz, 2H), 5.58−5.51 (m, 1H), 5.11 (d, J = 16.8 Hz, 1H), 5.06 (t, J = 5.4 Hz, 1H), 4.88 (d, J = 10.2 Hz, 1H), 2.79−2.74 (m, 1H), 2.69−2.64 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.6, 165.2, 165.1 (d, J = 252.0 Hz), 144.5, ACS Paragon Plus Environment


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132.6, 131.6, 130.2 (d, J = 9.0 Hz), 129.9, 128.4, 127.1 (d, J = 3.0 Hz), 124.1, 123.0, 119.4, 115.5 (d, J = 22.5 Hz), 61.1, 35.3;

19F

NMR (376 MHz, CDCl3) δ −107.31 (m); HRMS (ESI) m/z calcd for

C18H16FN2O2 [M + H]+ 311.1190, found 311.1195. N-(1-Allyl-3-oxoisoindolin-2-yl)-1-naphthamide (6j). 77 mg, 75% yield, white solid, mp 179−180 oC; 1H

NMR (600 MHz, CDCl3) δ 8.89 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H),

7.76 (t, J = 7.8 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.47−7.40 (m, 3H), 7.32 (t, J = 7.2 Hz, 1H), 5.68−5.61 (m, 1H), 5.10 (d, J = 16.8 Hz, 1H), 5.03 (t, J = 5.4 Hz, 1H), 5.00 (d, J = 10.2 Hz, 1H), 2.75−2.71 (m, 1H), 2.64−2.60 (m, 1H);

13C{1H}

NMR

(150 MHz, CDCl3) δ 169.1, 167.6, 144.2, 133.7, 132.5, 132.4, 131.6, 130.9, 130.5, 129.7, 128.3, 128.2, 127.5, 126.6, 126.1, 125.5, 124.6, 124.3, 122.8, 119.2, 60.9, 36.0; HRMS (ESI) m/z calcd for C22H19N2O2 [M + H]+ 343.1441, found 343.1436. N-(1-Allyl-3-oxoisoindolin-2-yl)picolinamide (6k). 59 mg, 67% yield, white solid, mp 112−113 oC; 1H

NMR (600 MHz, CDCl3) δ 9.88 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.91

(d, J = 7.8 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.51−7.48 (m, 3H), 5.65−5.59 (m, 1H), 5.16 (d, J = 17.4 Hz, 1H), 5.09−5.07 (m, 2H), 2.84−2.79 (m, 1H), 2.73−2.68 (m, 1H); 13C{1H}

NMR (150 MHz, CDCl3) δ 166.9, 163.6, 148.6, 148.5, 144.1, 137.5, 132.4, 132.2, 130.3,

128.5, 127.2, 124.4, 122.9, 122.8, 119.4, 60.8, 35.8; HRMS (ESI) m/z calcd for C17H16N3O2 [M + H]+ 294.1237, found 294.1227. N-(1-Allyl-3-oxoisoindolin-2-yl)furan-2-carboxamide (6l). 74 mg, 87% yield, white solid, mp 139−140 oC; 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48−7.41 (m, 3H), 7.15 (d, J = 3.6 Hz, 1H), 6.40 (dd, J = 3.6, 2.0 Hz, 1H), 5.63−5.53 (m, 1H), 5.14−5.06 (m, 2H), 4.96 (d, J = 10.0 Hz, 1H), 2.84−2.77 (m, 1H), 2.71−2.64 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.8, 157.9, 145.9, 145.3, 144.3, 132.5, 131.8, 130.0, 128.3, 124.2, ACS Paragon Plus Environment

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123.0, 119.4, 115.9, 111.9, 61.1, 35.3; HRMS (ESI) m/z calcd for C16H15N2O3 [M + H]+ 283.1077, found 283.1081. N-(1-Allyl-3-oxoisoindolin-2-yl)thiophene-2-carboxamide (6m). 72 mg, 81% yield, white solid, mp 90−91 oC; 1H NMR (600 MHz, CDCl3) δ 10.94 (s, 1H), 7.89 (d, J = 3.6 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.47−7.45 (m, 2H), 7.38 (d, J = 4.8 Hz, 1H), 6.95 (t, J = 4.2 Hz, 1H), 5.57−5.50 (m, 1H), 5.12−5.07 (m, 2H), 4.88 (d, J = 10.2 Hz, 1H), 2.81−2.76 (m, 1H), 2.70−2.66 (m, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 168.5, 161.7, 144.4, 136.0, 132.6, 131.6,

131.5, 130.0, 129.9, 128.3, 128.1, 124.2, 123.0, 119.5, 61.2, 35.2; HRMS (ESI) m/z calcd for C16H15N2O2S [M + H]+ 299.0849, found 299.0857. N-(1-Allyl-3-oxoisoindolin-2-yl)cyclohexanecarboxamide (6p). 37 mg, 41% yield, white solid, mp 145−147 oC; 1H NMR (600 MHz, CDCl3) δ 9.06 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.45−7.41 (m, 2H), 5.51−5.44 (m, 1H), 5.04 (d, J = 17.4 Hz, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.87 (d, J = 10.2 Hz, 1H), 2.70−2.66 (m, 1H), 2.59−2.54 (m, 1H), 2.37 (tt, J = 12.0, 3.6 Hz, 1H), 1.97 (d, J = 12.6 Hz, 1H), 1.88 (d, J = 13.2 Hz, 1H), 1.80 (d, J = 13.2 Hz, 1H), 1.73 (d, J = 11.4 Hz, 1H), 1.65 (d, J = 11.4 Hz, 1H), 1.59−1.51 (m, 2H), 1.33−1.14 (m, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 176.1, 167.7, 144.2, 132.4, 131.8, 130.1, 128.2, 124.0, 122.8, 119.3, 60.6, 43.2, 35.4, 29.9, 29.1, 25.7, 25.7, 25.4; HRMS (ESI) m/z calcd for C18H23N2O2 [M + H]+ 299.1754, found 299.1742. N-(1-Allyl-3-oxoisoindolin-2-yl)dodecanamide (6q). 30 mg, 27% yield, white solid, mp 64−65 oC; 1H

NMR (600 MHz, CDCl3) δ 9.21 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.45 (t,

J = 8.4 Hz, 2H), 5.50−5.43 (m, 1H), 5.07 (d, J = 17.4 Hz, 1H), 5.01 (t, J = 5.4 Hz, 1H), 4.90 (d, J = 10.2 Hz, 1H), 2.74−2.70 (m, 1H), 2.64−2.59 (m, 1H), 2.42−2.31 (m, 2H), 1.74−1.66 (m, 2H), 1.38−1.26 (m, 16H), 0.88 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 173.0, 167.4,

144.0, 132.3, 131.7, 130.0, 128.2, 124.0, 122.7, 119.2, 60.5, 35.2, 34.2, 31.9, 31.9, 29.6, 29.6, 29.5, ACS Paragon Plus Environment


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29.3, 29.3, 25.4, 22.7, 14.1; HRMS (ESI) m/z calcd for C23H35N2O2 [M + H]+ 371.2693, found 371.2708. N-(1-(2-Methylbut-3-en-2-yl)-3-oxoisoindolin-2-yl)benzamide (7a). 66 mg, 69% yield, white solid, mp 116−117 oC; 1H NMR (600 MHz, CDCl3) δ 10.58 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 2H), 5.99 (dd, J = 12.0, 4.8 Hz, 1H), 5.09−5.04 (m, 2H), 4.91 (s, 1H), 1.18 (s, 3H), 1.00 (s, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 170.1, 165.8, 145.3, 143.9,

132.1, 132.0, 131.3, 130.5, 128.5, 128.3, 127.6, 124.6, 124.2, 113.2, 69.4, 41.6, 24.4, 22.7; HRMS (ESI) m/z calcd for C20H20N2O2Na [M + Na]+ 343.1422, found 343.1419. N-(1-Oxo-3-(1-phenylallyl)isoindolin-2-yl)benzamide (7b). Mixture of two isomers: 74 mg, 67% yield, white solid, mp 118−120 oC; 1H NMR (600 MHz, CDCl3) δ (major isomer) 10.32 (s, 1H), 7.87−7.84 (m, 1H), 7.81−7.78 (m, 2H), 7.45−7.38 (m, 3H), 7.29−7.17 (m, 7H), 6.94−7.92 (m, 1H), 5.70−5.64 (m, 1H), 5.47−5.45 (m, 1H), 5.31 (d, J = 17.4 Hz, 1H), 4.97 (d, J = 10.2 Hz, 1H), 4.14 (dd, J = 9.0, 4.8 Hz, 1H); δ (minor isomer) 10.08 (s, 1H), 7.81−7.78 (m, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.45−7.38 (m, 2H), 7.29−7.17 (m, 5H), 7.07−7.01 (m, 3H), 6.28−6.22 (m, 1H), 5.47−5.45 (m, 1H), 5.19−5.16 (m, 2H), 4.01 (dd, J = 7.8, 5.4 Hz, 1H);

13C{1H}

NMR (150

MHz, CDCl3) δ (major isomer) 168.5, 166.6, 142.7, 139.5, 133.9, 132.2, 132.1, 131.1, 130.6, 128.7, 128.5, 128.5, 128.4, 127.8, 127.2, 124.2, 123.9, 119.9, 65.6, 50.6; δ (minor isomer) 168.9, 166.3, 143.7, 139.0, 136.5, 132.3, 132.1, 130.3, 128.6, 128.4, 128.4, 127.6, 127.0, 124.2, 123.8, 118.4, 65.5, 52.1; HRMS (ESI) m/z calcd for C24H20N2O2Na [M + Na]+ 391.1422, found 391.1419. N-(1-(Cyclohex-2-en-1-yl)-3-oxoisoindolin-2-yl)benzamide (7c). 73 mg, 73% yield, white solid, mp 174−175 oC; 1H NMR (600 MHz, CDCl3) δ 10.83 (s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.52−7.48 (m, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.2 Hz, ACS Paragon Plus Environment

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2H), 5.92−5.89 (m, 1H), 5.71 (d, J = 9.6 Hz, 1H), 5.10 (d, J = 3.0 Hz, 1H), 3.07 (s, 1H), 1.96 (d, J = 18.0 Hz, 1H), 1.84−1.80 (m, 1H), 1.53−1.45 (m, 2H), 1.38−1.36 (m, 1H), 0.63−0.57 (m, 1H); 13C{1H}

NMR (150 MHz, CDCl3) δ 168.8, 166.5, 143.6, 132.3, 132.1, 131.0, 130.9, 130.4, 128.5,

128.1, 127.7, 127.1, 123.9, 123.6, 65.0, 36.8, 25.2, 22.1, 21.6; HRMS (ESI) m/z calcd for C21H20N2O2Na [M + Na]+ 355.1422, found 355.1421. N-(1-(2-Methylallyl)-3-oxoisoindolin-2-yl)benzamide (7d). 83 mg, 90% yield, white solid, mp 163−164 oC; 1H NMR (600 MHz, CDCl3) δ 10.11 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.48−7.41 (m, 3H), 7.30 (t, J = 7.8 Hz, 2H), 5.14 (t, J = 6.6 Hz, 1H), 4.91 (s, 1H), 4.85 (s, 1H), 2.74 (dd, J = 14.4, 6.0 Hz, 1H), 2.40 (dd, J = 13.8, 7.8 Hz, 1H), 1.76 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.1, 166.5, 145.1, 141.1, 132.4, 132.2, 131.3, 129.8, 128.6, 128.3, 127.6, 124.2, 123.2, 114.8, 59.4, 40.9, 22.6; HRMS (ESI) m/z calcd for C19H18N2O2Na [M + Na]+ 329.1266, found 329.1265. Ethyl 2-((2-benzamido-3-oxoisoindolin-1-yl)methyl)acrylate (7e). 84 mg, 77% yield, white solid, mp 60−61 oC; 1H NMR (600 MHz, CDCl3) δ 9.84 (s, 1H), 7.88−7.82 (m, 3H), 7.58 (t, J = 7.2 Hz, 1H), 7.49−7.43 (m, 3H), 7.36 (t, J = 7.2 Hz, 2H), 6.12 (s, 1H), 5.53 (s, 1H), 5.18 (t, J = 5.4 Hz, 1H), 4.16−4.08 (m, 2H), 3.09−3.06 (m, 1H), 2.89 (dd, J = 14.4, 4.8 Hz, 1H), 1.17 (t, J = 7.2 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 167.7, 167.4, 166.2, 143.7, 135.0, 132.3, 132.2, 131.5, 130.4,

129.6, 128.6, 128.4, 127.7, 124.3, 123.0, 61.4, 60.4, 33.7, 14.1; HRMS (ESI) m/z calcd for C21H21N2O4 [M + H]+ 365.1496, found 365.1502. N-(1-Oxo-3-(2-phenylallyl)isoindolin-2-yl)benzamide (7f). 94 mg, 85% yield, white solid, mp 166−168 oC; 1H NMR (600 MHz, CDCl3) δ 9.83 (s, 1H), 7.81−7.78 (m, 3H), 7.49 (t, J = 7.2 Hz, 1H), 7.44−7.40 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.32−7.28 (m, 4H), 7.27−7.22 (m, 3H), 5.36 (s, 1H), 5.14 (s, 1H), 5.02 (dd, J = 7.2, 5.4 Hz, 1H), 3.33 (dd, J = 14.4, 5.4 Hz, 1H), 2.82 (dd, J = 14.4, 7.8 ACS Paragon Plus Environment


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Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.9, 166.3, 144.8, 143.9, 140.3, 132.3, 132.2, 131.3, 129.8, 128.8, 128.6, 128.3, 128.0, 127.7, 126.3, 124.1, 123.3, 116.8, 60.0, 38.4; HRMS (ESI) m/z calcd for C24H20N2O2Na [M + Na]+ 391.1422, found 391.1422. N-(1-(2-(4-Methoxyphenyl)allyl)-3-oxoisoindolin-2-yl)benzamide (7g). 103 mg, 86% yield, white solid, mp 86−87 oC; 1H NMR (600 MHz, CDCl3) δ 9.81 (s, 1H), 7.82−7.79 (m, 3H), 7.51 (t, J = 7.8 Hz, 1H), 7.45−7.41 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.32−7.26 (m, 4H), 6.78 (d, J = 9.0 Hz, 2H), 5.30 (s, 1H), 5.04 (s, 1H), 5.03 (dd, J = 7.2, 5.4 Hz, 1H), 3.76 (s, 3H), 3.30 (dd, J = 14.4, 5.4 Hz, 1H), 2.77 (dd, J = 14.4, 7.8 Hz, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 167.9, 166.3, 159.5, 144.9,

143.2, 132.5, 132.3, 132.3, 131.3, 129.7, 128.6, 128.3, 127.6, 127.4, 124.1, 123.4, 115.2, 114.2, 60.0, 55.4, 38.6; HRMS (ESI) m/z calcd for C25H22N2O3Na [M + Na]+ 421.1528, found 421.1525. N-(1-Oxo-3-(2-(p-tolyl)allyl)isoindolin-2-yl)benzamide (7h). 94 mg, 82% yield, white solid, mp 84−85 oC; 1H NMR (600 MHz, CDCl3) δ 9.60 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.46−7.39 (m, 3H), 7.32 (t, J = 7.8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 5.33 (s, 1H), 5.06 (s, 1H), 5.02 (dd, J = 7.2, 4.8 Hz, 1H), 3.30 (dd, J = 14.4, 4.8 Hz, 1H), 2.81 (dd, J = 14.4, 7.8 Hz, 1H), 2.30 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.9, 166.3, 144.8, 143.7, 137.9, 137.3, 132.3, 132.2, 131.3, 129.8, 129.5, 128.6, 128.3, 127.6, 126.2, 124.1, 123.3, 116.00, 60.0, 38.5, 21.2; HRMS (ESI) m/z calcd for C25H22N2O2Na [M + Na]+ 405.1579, found 405.1572. N-(1-(2-(4-Fluorophenyl)allyl)-3-oxoisoindolin-2-yl)benzamide (7i). 94 mg, 81% yield, white solid, mp 170−172 oC; 1H NMR (600 MHz, CDCl3) δ 10.08 (s, 1H), 7.81−7.79 (m, 3H), 7.50 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.31−7.25 (m, 4H), 6.91 (t, J = 8.4 Hz, 2H), 5.33 (s, 1H), 5.17 (s, 1H), 5.03 (dd, J = 7.8, 5.4 Hz, 1H), 3.28 (dd, J = 14.4, 5.4 Hz, 1H), 2.81 (dd, J = 14.4, 7.8 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.0, 166.3, 162.5 (d, J = 247.5 Hz), ACS Paragon Plus Environment

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144.7, 143.0, 136.3 (d, J = 3.0 Hz), 132.3 (d, J = 7.5 Hz), 131.1, 129.7, 128.6, 128.4, 127.9 (d, J = 9.0 Hz), 127.6, 124.1, 123.3, 116.7, 115.7, 115.6 (d, J = 21.0 Hz), 59.8, 38.6; 19F NMR (376 MHz, CDCl3) δ −114.61 (m); HRMS (ESI) m/z calcd for C24H19FN2O2Na [M + Na]+ 409.1328, found 409.1332. N-(1-(2-(4-Chlorophenyl)allyl)-3-oxoisoindolin-2-yl)benzamide (7j). 101 mg, 84% yield, white solid, mp 147−148 oC; 1H NMR (600 MHz, CDCl3) δ 10.07 (s, 1H), 7.80−7.78 (m, 3H), 7.49 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.2 Hz, 2H), 7.23−7.18 (m, 4H), 5.36 (s, 1H), 5.19 (s, 1H), 5.03 (dd, J = 7.8, 5.4 Hz, 1H), 3.27 (dd, J = 14.4, 5.4 Hz, 1H), 2.82 (dd, J = 14.4, 7.8 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.0, 166.3, 144.7, 142.9, 138.7, 133.8, 132.4, 132.3, 131.1, 129.7, 128.9, 128.6, 128.4, 127.6, 127.5, 124.1, 123.3, 117.3, 59.8, 38.3; HRMS (ESI) m/z calcd for C24H19ClN2O2Na [M + Na]+ 425.1033, found 425.1029. N-(1-(2-(4-Bromophenyl)allyl)-3-oxoisoindolin-2-yl)benzamide (7k). 106 mg, 79% yield, white solid, mp 182−183 oC; 1H NMR (600 MHz, CDCl3) δ 10.05 (s, 1H), 7.80−7.77 (m, 3H), 7.50 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.35−7.33 (m, 3H), 7.30 (t, J = 7.8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.36 (s, 1H), 5.19 (s, 1H), 5.02 (dd, J = 7.8, 5.4 Hz, 1H), 3.27 (dd, J = 14.4, 5.4 Hz, 1H), 2.82 (dd, J = 14.4, 7.8 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.0, 166.3, 144.6, 142.9, 139.2, 132.4, 132.3, 131.8, 131.0, 129.7, 128.6, 128.4, 127.9, 127.6, 124.2, 123.2, 122.0, 117.4, 59.8, 38.3; HRMS (ESI) m/z calcd for C24H19BrN2O2Na [M + Na]+ 469.0528, found 469.0521. N-(1-(2-(Naphthalen-1-yl)allyl)-3-oxoisoindolin-2-yl)benzamide (7l). 98 mg, 78% yield, white solid, mp 181−182 oC; 1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.45−7.40 (m, 3H), 7.36−7.33 (m, 2H), 7.30−7.25 (m, 4H), 6.98 (d, J = 6.6 Hz, 1H), 5.48 (s, 1H), 5.18 (d, J = 1.2 Hz, 1H), 5.09 (t, J = 4.8 Hz, 1H), 3.29−3.28 (m, 2H); ACS Paragon Plus Environment

13C{1H}

NMR (150 MHz,


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CDCl3) δ 167.4, 166.4, 144.0, 143.2, 140.1, 133.7, 132.2, 132.1, 131.2, 130.6, 130.2, 128.7, 128.5, 128.2, 127.9, 127.5, 126.3, 126.0, 125.6, 125.5, 125.4, 124.1, 123.0, 120.4, 60.4, 39.2; HRMS (ESI) m/z calcd for C28H22N2O2Na [M + Na]+ 441.1579, found 441.1566. General Procedure for the Synthesis of 8. Isoindolinones 4, 7 (0.2 mmol, 1 equiv), I2 (0.4 mmol, 2.0 equiv), K2CO3 (0.4 mmol, 2.0 equiv) and DCE (3 mL) were stirred at room temperature. The reaction was monitored by TLC until the starting material disappeared. The saturated Na2S2O3 solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with DCM (3 × 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using petroleum ether / ethyl acetate (2.5 / 1) as the eluent furnished the pure products 8. 1-Benzoyl-2-(iodomethyl)-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one (8a). 65 mg, 78% yield, white solid, mp 151−152 oC; 1H NMR (600 MHz, CDCl3) δ 7.94−7.92 (m, 2H), 7.83 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 5.29−5.24 (m, 1H), 4.80 (t, J = 8.4 Hz, 1H), 3.63 (dd, J = 9.6, 4.2 Hz, 1H), 3.01−2.96 (m, 2H), 1.77−1.73 (m, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 173.4,

173.4, 145.5, 134.2, 133.6, 131.4, 129.5, 128.7, 128.3, 128.1, 125.7, 123.2, 65.1, 63.1, 38.5, 8.5; HRMS (ESI) m/z calcd for C18H16IN2O2 [M + H]+ 419.0251, found 419.0247. 1-Benzoyl-2-(iodomethyl)-6-methoxy-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one (8b). 65 mg, 73% yield, white solid, mp 213−215 oC; 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.30−7.28 (m, 2H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 5.27−5.23 (m, 1H), 4.74 (t, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.62 (dd, J = 9.6, 4.2 Hz, 1H), 3.00 (t, J = 10.2 Hz, 1H), 2.93 (dt, J = 13.2, 8.4 Hz, 1H), 1.75−1.70 (m, 1H);

13C{1H}

NMR (150 MHz,

CDCl3) δ 173.5, 173.4, 160.8, 137.8, 133.6, 131.4, 129.9, 128.3, 128.0, 124.1, 122.4, 108.1, 65.2, ACS Paragon Plus Environment

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62.8, 55.9, 38.5, 8.6; HRMS (ESI) m/z calcd for C19H17IN2O3Na [M + Na]+ 471.0182, found 471.0177. 1-Benzoyl-2-(iodomethyl)-6-methyl-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one

(8c).

66 mg, 76% yield, white solid, mp 137−138 oC; 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 7.8 Hz, 2H), 7.63 (s, 1H), 7.45−7.42 (m, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 5.27−5.23 (m, 1H), 4.76 (t, J = 8.4 Hz, 1H), 3.62 (dd, J = 10.2, 4.2 Hz, 1H), 3.00−2.93 (m, 2H) 2.43 (s, 3H), 1.75−1.70 (m, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 173.6, 173.4, 142.8, 139.8, 135.1, 133.6,

131.3, 128.7, 128.4, 128.0, 125.8, 122.9, 65.1, 62.9, 38.5, 21.5, 8.6; HRMS (ESI) m/z calcd for C19H17IN2O2Na [M + Na]+ 455.0232, found 455.0226. 1-Benzoyl-2-(iodomethyl)-6-(trifluoromethyl)-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-o ne (8d). 81 mg, 83% yield, white solid, mp 145−146 oC; 1H NMR (600 MHz, CDCl3) δ 8.11 (s, 1H), 7.92−7.88 (m, 3H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 5.30−5.25 (m, 1H), 4.86 (t, J = 8.4 Hz, 1H), 3.61 (dd, J = 9.6, 4.2 Hz, 1H), 3.06−3.00 (m, 2H), 1.78−1.74 (m, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 173.5, 171.6, 148.3, 133.4, 132.4 (q, J =

33.0 Hz), 131.6, 130.9 (q, J = 3.0 Hz), 129.8, 128.2, 128.1, 124.0, 123.4 (q, J = 271.5 Hz), 123.0 (q, J = 4.5 Hz), 65.2, 63.0, 38.3, 8.3; 19F NMR (376 MHz, CDCl3) δ −63.06 (s); HRMS (ESI) m/z calcd for C19H14F3IN2O2Na [M + Na]+ 508.9950, found 508.9925. 1-Benzoyl-6-fluoro-2-(iodomethyl)-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one (8e). 70 mg, 80% yield, white solid, mp 151−152 oC; 1H NMR (600 MHz, CDCl3) δ 7.92−7.90 (m, 2H), 7.49 (dd, J = 7.2, 2.4 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.40−7.36 (m, 3H), 7.33 (td, J = 8.4, 2.4 Hz, 1H), 5.28−5.23 (m, 1H), 4.78 (t, J = 8.4 Hz, 1H), 3.62 (dd, J = 10.2, 4.8 Hz, 1H), 3.04−2.95 (m, 2H), 1.75−1.71 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 173.5, 172.2, 163.3 (d, J = 249.0 Hz), 140.9 (d, J = 3.0 Hz), 133.5, 131.5, 130.9 (d, J = 9.0 Hz), 128.3, 128.1, 124.9 (d, J = 9.0 Hz), 121.7 (d, J = ACS Paragon Plus Environment


Page 32 of 46

22.5 Hz), 112.4 (d, J = 24.0 Hz), 65.3, 62.8, 38.5, 8.5; 19F NMR (376 MHz, CDCl3) δ −110.53 (m); HRMS (ESI) m/z calcd for C18H14FIN2O2Na [M + Na]+ 458.9982, found 458.9983. 1-Benzoyl-6-chloro-2-(iodomethyl)-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one

(8f).

72 mg, 80% yield, white solid, mp 140−141 oC; 1H NMR (600 MHz, CDCl3) δ 7.91−7.90 (m, 2H), 7.80 (d, J = 1.8 Hz, 1H), 7.59 (dd, J = 8.4, 2.4 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.39−7.35 (m, 3H), 5.28−5.23 (m, 1H), 4.78 (t, J = 7.8 Hz, 1H), 3.61 (dd, J = 10.2, 4.2 Hz, 1H), 3.03−2.95 (m, 2H), 1.76−1.71 (m, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 173.5, 171.9, 143.4, 135.9, 134.3, 133.5,

131.5, 130.6, 128.3, 128.1, 125.8, 124.5, 65.2, 62.8, 38.5, 8.4; HRMS (ESI) m/z calcd for C18H14ClIN2O2Na [M + Na]+ 474.9686, found 474.9688. 1-Benzoyl-2-(iodomethyl)-5-methyl-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one

(8g).

65 mg, 75% yield, white solid, mp 159−160 oC; 1H NMR (600 MHz, CDCl3) δ 7.94−7.93 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H), 5.28−5.23 (m, 1H), 4.74 (t, J = 8.4 Hz, 1H), 3.63 (dd, J = 9.6, 4.2 Hz, 1H), 2.99−2.93 (m, 2H), 2.46 (s, 3H), 1.77−1.73 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 173.6, 173.4, 146.0, 145.5, 133.7, 131.3, 130.5, 128.4, 128.0, 125.8, 125.5, 123.7, 64.9, 63.0, 38.5, 22.2, 8.6; HRMS (ESI) m/z calcd for C19H17IN2O2Na [M + Na]+ 455.0232, found 455.0220. 1-Benzoyl-5-chloro-2-(iodomethyl)-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one

(8h).

71 mg, 79% yield, white solid, mp 219−220 oC; 1H NMR (600 MHz, CDCl3) δ 7.92−7.90 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.4, 1.8 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.41 (s, 1H), 7.37 (t, J = 8.4 Hz, 2H), 5.29−5.23 (m, 1H), 4.77 (t, J = 8.4 Hz, 1H), 3.61 (dd, J = 9.6, 4.2 Hz, 1H), 3.02−2.95 (m, 2H), 1.79−1.74 (m, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 173.4, 172.2, 146.8,

140.7, 133.5, 131.5, 130.2, 128.3, 128.1, 127.1, 126.9, 123.7, 65.0, 62.6, 38.4, 8.4; HRMS (ESI) m/z calcd for C18H14ClIN2O2Na [M + Na]+ 474.9686, found 474.9689. ACS Paragon Plus Environment

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1-Benzoyl-2-(iodomethyl)-3-phenyl-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one

(8i).

Mixture of two isomers: 76 mg, 77% yield, white solid, mp 248−249 oC; major isomer: 1H NMR (600 MHz, CDCl3) δ 8.05−8.03 (m, 2H), 7.73−7.72 (m, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.37−7.33 (m, 2H), 7.13 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.8 Hz, 2H), 6.85 (d, J = 6.6 Hz, 1H), 6.71 (d, J = 7.2 Hz, 2H), 5.52 (q, J = 7.8 Hz, 1H), 5.13 (d, J = 9.0 Hz, 1H), 4.25 (t, J = 8.4 Hz, 1H), 3.53 (dd, J = 9.6, 8.4 Hz, 1H), 3.07 (dd, J = 10.2, 7.8 Hz, 1H);

13C{1H}

NMR (150 MHz,

CDCl3) δ 175.9, 172.4, 142.5, 133.8, 133.2, 132.3, 131.5, 130.8, 130.7, 129.3, 128.5, 128.3, 128.1, 127.9, 124.9, 124.8, 69.0, 66.5, 50.9, 4.0; HRMS (ESI) m/z calcd for C24H19IN2O2Na [M + Na]+ 517.0389, found 517.0375. 1-Benzoyl-2-(iodomethyl)-3,3-dimethyl-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one (8j). 68 mg, 76% yield, white solid, mp 156−158 oC; 1H NMR (600 MHz, CDCl3) δ 7.96−7.94 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.38−7.34 (m, 3H), 4.88 (dd, J = 9.0, 6.6 Hz, 1H), 4.43 (s, 1H), 3.50 (dd, J = 10.8, 6.6 Hz, 1H), 3.11 (dd, J = 10.2, 9.0 Hz, 1H), 1.56 (s, 3H), 0.71 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 175.1, 172.3, 142.1, 133.9, 133.6, 131.3, 130.5, 129.6, 128.2, 128.1, 125.3, 123.5, 73.0, 72.7, 44.8, 29.6, 18.7, 1.6; HRMS (ESI) m/z calcd for C20H19IN2O2Na [M + Na]+ 469.0389, found 469.0390. 1-Benzoyl-2-(iodomethyl)-2-methyl-1,2,3,3a-tetrahydro-8H-pyrazolo[5,1-a]isoindol-8-one

(8k).

63 mg, 73% yield, white solid, mp 186−187 oC; 1H NMR (600 MHz, CDCl3) δ 7.70−7.68 (m, 3H), 7.62 (t, J = 7.8 Hz, 1H), 7.49−7.46 (m, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 5.09 (dd, J = 9.6, 7.2 Hz, 1H), 4.14 (d, J = 10.2 Hz, 1H), 3.53 (d, J = 10.2 Hz, 1H), 2.68 (dd, J = 12.6, 6.6 Hz, 1H), 2.01 (s, 3H), 1.98 (dd, J = 13.2, 10.2 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.8, 168.1, 144.5, 136.0, 133.7, 130.4, 129.6, 128.7, 127.9, 127.8, 125.6, 123.1, 73.1, 59.7, 47.7, 23.0, 15.5; HRMS (ESI) m/z calcd for C19H17IN2O2Na [M + Na]+ 455.0232, found 455.0237.



Ethyl

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1-benzoyl-2-(iodomethyl)-8-oxo-2,3,3a,8-tetrahydro-1H-pyrazolo[5,1-a]isoindole-

2-carboxylate (8l). 68 mg, 69% yield, white solid, mp 193−194 oC; 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 6.6 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.47−7.45 (m, 2H), 7.36−7.30 (m, 3H), 5.31 (d, J = 14.4 Hz, 1H), 4.84 (dd, J = 10.8, 4.2 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.07−3.04 (m, 1H), 2.76 (d, J = 8.4, Hz, 1H), 1.35−1.30 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 171.1, 169.7, 165.1, 143.4, 134.6, 133.2, 130.5, 129.2, 128.8,

128.2, 127.0, 125.0, 122.4, 63.0, 55.5, 51.9, 44.0, 38.2, 13.9; HRMS (ESI) m/z calcd for C21H19IN2O4Na [M + Na]+ 513.0287, found 513.0289. General Procedure for the Synthesis of 9a. To a solution of 4a (0.2 mmol, 1.0 equiv) in MeOH (3 mL) was added Pd/C (10% w/w). The mixture was purged with hydrogen gas for 2 min and continued stirring under hydrogen atmosphere at room temperature for 24h. After completion of the reaction, the mixture was filtered through celite pad and concentrated under vacuum. Purification of the residue by silica gel column chromatography using petroleum ether / ethyl acetate (3 / 1) as the eluent furnished the pure product 9a in 90 % yield. N-(1-Oxo-3-propylisoindolin-2-yl)benzamide (9a). 53 mg, 90% yield, white solid, mp 122−123 oC; 1H

NMR (600 MHz, CDCl3) δ 10.74 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.52

(t, J = 7.2 Hz, 1H), 7.45−7.41 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 2H), 5.07 (t, J = 4.8 Hz, 1H), 1.97−1.91 (m, 2H), 1.30−1.22 (m, 1H), 1.01−0.92 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 168.6, 166.4, 145.1, 132.5, 132.1, 131.1, 130.1, 128.5, 128.1,

127.7, 124.1, 122.7, 61.5, 32.8, 16.7, 14.3; HRMS (ESI) m/z calcd for C18H18N2O2Na [M + Na]+ 317.1260, found 317.1258. General Procedure for the Synthesis of 10a. m-CPBA (0.6 mmol, 3.0 equiv) was added to a solution of 4a (0.2 mmol, 1.0 equiv) in DCM (3mL) at 0 oC, the mixture was stirred at room temperature for 24 h. After completion of the reaction, the mixture was cooled to 0 oC. The saturated ACS Paragon Plus Environment

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NaHCO3 solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with DCM (3 × 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using petroleum ether / ethyl acetate (1 / 1) as the eluent furnished the pure product 10a in 84 % yield. N-(1-(Oxiran-2-ylmethyl)-3-oxoisoindolin-2-yl)benzamide (10a). Mixture of two isomers: 52 mg, 84% yield, white solid, mp 53−54 oC; 1H NMR (600 MHz, CDCl3) δ (major isomer) 10.00 (s, 1H), 7.87−7.83 (m, 3H), 7.63−7.60 (m, 1H), 7.52−7.41 (m, 3H), 7.35−7.28 (m, 2H), 5.21 (t, J = 4.8 Hz, 1H), 2.84−2.81 (m, 1H), 2.64 (t, J = 4.2 Hz, 1H), 2.47 (dd, J = 4.8, 2.4 Hz, 1H), 2.33 (dt, J = 14.4, 4.8 Hz, 1H), 2.07−2.03 (m, 1H); δ (minor isomer) 10.33 (s, 1H), 7.87−7.83 (m, 3H), 7.63−7.60 (m, 1H), 7.52−7.41 (m, 3H), 7.35−7.28 (m, 2H), 5.15 (t, J = 5.4 Hz, 1H), 2.93−2.91 (m, 1H), 2.69 (t, J = 4.2 Hz, 1H), 2.58 (dd, J = 4.8, 3.0 Hz, 1H), 2.37 (dt, J = 15.0, 4.2 Hz, 1H), 2.00−1.96 (m, 1H); 13C{1H}

NMR (150 MHz, CDCl3) δ (major isomer) 167.8, 166.6, 143.9, 132.8, 132.4, 131.2, 130.1,

129.8, 128.6, 127.7, 124.3, 122.9, 59.7, 48.5, 47.0, 34.8; δ (minor isomer) 168.3, 166.4, 144.0, 132.8, 132.3, 131.0, 130.1, 129.7, 128.7, 128.6, 128.1, 123.1, 59.9, 48.5, 47.2, 34.9; HRMS (ESI) m/z calcd for C18H16N2O3Na [M + Na]+ 331.1053, found 331.1056. General Procedure for the Synthesis of 11. To a solution of 8 (0.2 mmol, 1.0 equiv) in EtOH (3 mL) was added KOH (0.4 mmol, 2.0 equiv), the mixture was stirred at reflux for 0.5−0.6 h. After completion of the reaction, the mixture was cooled to room temperature, and EtOH was removed under vacuum. The saturated NH4Cl solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with DCM (3 × 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using dichloromethane / methanol (30 / 1) as the eluent furnished the pure products 11. 1,8b,9,9a-Tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-one (11a). 32 mg, 86% ACS Paragon Plus Environment


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yield, white solid, mp 139−140 oC; 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 4.66 (dd, J = 9.6, 7.8 Hz, 1H), 3.01 (q, J = 5.4 Hz, 1H), 2.75 (dd, J = 12.6, 7.8 Hz, 1H), 2.17−2.15 (m, 2H), 1.90−1.85 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 172.6, 144.5, 132.8, 131.8, 129.0, 124.8, 122.9, 58.4, 46.0, 32.0, 30.7; HRMS (ESI) m/z calcd for C11H10N2ONa [M + Na]+ 209.0685, found 209.0686. 6-Fluoro-1,8b,9,9a-tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-one (11b). 34 mg, 83% yield, white solid, mp 165−166 oC; 1H NMR (600 MHz, CDCl3) δ 7.46 (dd, J = 7.8, 2.4 Hz, 1H), 7.36 (dd, J = 8.4, 4.8 Hz, 1H), 7.25 (td, J = 8.4, 2.4 Hz, 1H), 4.45 (dd, J = 9.6, 7.8 Hz, 1H), 3.03 (q, J = 6.0 Hz, 1H), 2.75 (dd, J = 12.6, 7.2 Hz, 1H), 2.17 (d, J = 5.4 Hz, 2H), 1.90−1.85 (m, 1H); 13C{1H}

NMR (150 MHz, CDCl3) δ 171.3, 163.2 (d, J = 247.5 Hz), 139.9 (d, J = 1.5 Hz), 134.1 (d, J

= 9.0 Hz), 124.6 (d, J = 9.0 Hz), 120.3 (d, J = 24.0 Hz), 111.5 (d, J = 22.5 Hz), 58.1, 46.3, 32.1, 30.8; 19F

NMR (376 MHz, CDCl3) δ −111.89 (m); HRMS (ESI) m/z calcd for C11H9FN2ONa [M + Na]+

227.0591, found 227.0603. 6-Chloro-1,8b,9,9a-tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-one (11c). 37 mg, 84% yield, white solid, mp 157−158 oC; 1H NMR (600 MHz, CDCl3) δ 7.88 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.63 (dd, J = 9.6, 7.8 Hz, 1H), 3.01 (q, J = 5.4 Hz, 1H), 2.74 (dd, J = 13.2, 7.8 Hz, 1H), 2.19−2.15 (m, 2H), 1.90−1.85 (m, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ

171.1, 142.5, 135.4, 133.9, 133.0, 125.1, 124.2, 58.2, 46.2, 32.2, 30.8; HRMS (ESI) m/z calcd for C11H9N2OClNa [M + Na]+ 243.0296 , found 243.0301. 6-Methoxy-1,8b,9,9a-tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-one (11d). 35 mg, 81% yield, white solid, mp 145−146 oC; 1H NMR (600 MHz, CDCl3) δ 7.29 (d, J = 3.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.4, 2.4 Hz, 1H), 4.61 (dd, J = 9.6, 7.8 Hz, 1H), 3.83 (s, 3H), 3.01 (q, J = 5.4 Hz, 1H), 2.70 (dd, J = 13.2, 7.8 Hz, 1H), 2.15 (d, J = 6.0 Hz, 2H), 1.87−1.82 (m, 1H); ACS Paragon Plus Environment

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13C{1H}

NMR (150 MHz, CDCl3) δ 172.7, 160.6, 136.7, 133.3, 123.8, 121.2, 107.4, 58.2, 55.8, 46.3,

32.1, 30.9; HRMS (ESI) m/z calcd for C12H12N2O2Na [M + Na]+ 239.0791 , found 239.0788. 9,9-Dimethyl-1,8b,9,9a-tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-one (11e). 34 mg, 79% yield, white solid, mp 222−223 oC; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 4.36 (s, 1H), 2.67 (t, J = 4.8 Hz, 1H), 2.21 (t, J = 3.2 Hz, 1H), 2.12−2.10 (m, 1H), 1.52 (s, 3H), 0.65 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.1, 141.4, 133.4, 132.4, 129.0, 124.8, 122.7, 67.2, 55.1, 40.0, 31.0, 23.5, 23.4; HRMS (ESI) m/z calcd for C13H14N2ONa [M + Na]+ 237.0998, found 237.1006. 1,8b,9,9a-Tetrahydro-4H-azirino[1',2':2,3]pyrazolo[5,1-a]isoindol-4-one-8b-d (11a'). 33 mg, 88% yield, white solid, mp 140−141 oC; 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 3.01 (q, J = 5.4 Hz, 1H), 2.74 (d, J = 13.2 Hz, 1H), 2.16 (d, J = 5.4 Hz, 2H), 1.87 (dd, J = 12.6, 4.8 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 172.6, 144.4, 132.8, 131.9, 129.0, 124.8, 122.9, 58.2 (q, J = 22.5 Hz), 46.0, 32.0, 30.6; HRMS (ESI) m/z calcd for C11H9DN2ONa [M + Na]+ 210.0748, found 210.0751. Control Experiments for Mechanism General Procedure for the Reaction A. 2-formylbenzoic acid 1a (0.3 mmol, 1 equiv), benzoylhydrazine 2a (0.3 mmol, 1.0 equiv), and THF (4 mL) were put into a dried round-bottom flask (50 mL), the mixture was stirred at reflux for 8 h. After completion of the reaction, the mixture was cooled to room temperature, and concentrated under vacuum. Purification of the residue by silica gel column chromatography using ethyl acetate as the eluent furnished the pure product 12a in 96% yield. General Procedure for the Reaction B. 12a (0.3 mmol, 1 equiv), 3a (0.6 mmol, 2.0 equiv), tin powder (0.75 mmol, 2.5 equiv), and THF (4 mL) were put into a dried round bottom flask (50 mL), ACS Paragon Plus Environment


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the mixture was stirred at reflux for 5 h. After completion of the reaction, the mixture was cooled to room temperature, and THF was removed under vacuum. The saturated NH4Cl solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using petroleum ether / ethyl acetate (2 / 1) as the eluent afforded product 4a in 95% yield. 2-((2-Benzoylhydrazono)methyl)benzoic acid (12a). 77 mg, 96% yield, white solid, mp 207−209 oC; 1H

NMR (600 MHz, (CD3)2SO) δ 13.32 (s, 1H), 12.08 (s, 1H), 9.22 (s, 1H), 8.10 (d, J = 7.8 Hz,

1H), 7.96 (d, J = 7.2 Hz, 2H), 7.92 (d, J = 7.2 Hz, 1H), 7.67−7.54 (m, 5H); 13C{1H} NMR (150 MHz, (CD3)2SO) δ 168.0, 163.2, 146.5, 134.6, 133.3, 131.9, 131.7, 130.7, 130.2, 129.5, 128.4, 127.7, 126.6; HRMS (ESI) m/z calcd for C15H12N2O3Na [M + Na]+ 291.0746, found 291.0743. General Procedure for the Reaction C. 12a (0.3 mmol, 1 equiv), additive (0.03 mmol, 0.1 equiv), and 1,4-dioxane (4 mL) were put into a dried round bottom flask (50 mL), the mixture was stirred at reflux for 15−20 h. After completion of the reaction, the mixture was cooled to room temperature, and concentrated under vacuum. Purification of the residue by silica gel column chromatography using dichloromethane / methanol (20 / 1) as the eluent furnished the pure products 5a and 13a. Benzoic acid (13a). 28 mg, 77% yield, white solid, mp 119−121 oC; 1H NMR (600 MHz, CDCl3) δ 12.49 (br, 1H), 8.13 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 172.6, 134.0, 130.4, 129.5, 128.6.

Associated Content Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: ACS Paragon Plus Environment

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Copies of the 1H NMR, 13C{1H} NMR and HRMS spectra of 4, 5a, 6, 7, 8, 9a, 10a, 11, 12a, 13a, and crystallography of 8a and 11a (PDF) Crystallographic data for 8a and 11a (PDF)

Author Information Corresponding Authors *E-mail: [email protected]; [email protected]. Notes The authors declare no competing ﬁnancial interest.

Acknowledgments We are thankful for financial support from the National Natural Science Foundation of China (Grant No. 21861033 and 21662030).

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