Tin Powder-Promoted Cascade Condensation/Allylation/Lactamization: Synthesis of Isoindolinones and Pyrazoloisoindol-8-ones

Article abstract of DOI:10.1021/acs.joc.9b00733

An efficient tin powder-promoted cascade condensation/allylation/lactamization of 2-formylbenzoic acids, hydrazides, and allyl bromides was developed for the 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.

Full text of DOI:10.1021/acs.joc.9b00733

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Article
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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Page 1 of 46
The Journal of Organic Chemistry
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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,† Yulai Hu*†‡
†College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning East Road, Lanzhou
730070, P. R. China
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‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
E-mail: huangdf@nwnu.edu.cn; huyl@nwnu.edu.cn.
Abstract
O
O
COOH
CHO
O
R2
R1
37 examples up to 94% yield
four-component "one pot"
gram-scale synthesis
R2 NHNH2
Sn
R1
N
NH
+
THF, reflux
R4
R4
R5
R3
Br
R5
R3
I2, K2CO3 DCE, rt
O
O
O
12 examples up to 83% yield
mild reaction condition
transition metal-free
N
N
R2
I
N
N
KOH
R1
R1
EtOH, reflux
R3
R3
R4 R5
R4 R5
5 examples up to 86% yield
An efficient tin powder promoted cascade 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
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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.
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O
O
O
MeO
MeO
N
N
N
N
N
N
N
Cl
O
O
O
O
A
B
C
Pagoclone
GABAA receptor
JM-1232 (MR04A3)
Hypnotic drug
CRR-224
PARP-1 inhibitor
O
MeO
MeO
O
HN
N
NH2
N
N
N
N
O
OMe
O
D
E
F
Lennoxamine
Alkaloid
DPX1840
Plant growth regulator
Pyrazolo[5,1-a]isoindole
Antihypotensive agent
Figure 1. Examples of biologically active isoindolinones and pyrazoloisoindol-8-ones.
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The Journal of Organic Chemistry
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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
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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
HN
O
N
R3
HN
O
N
O
O
O
O
O
Sn
EtOH,
reflux
Br
or
or
+
+
(1)
R1 H(R2)
R3 NHNH2
n
COOEt
R1
n = 0, 1, 2, 3
(R2)H
n
n = 0, 1, 2, 3
This work
R2 NHNH2
O
O
O
O
O
O
N
R2
I2, K2CO3
COOH
R2
R1
N
N
N
KOH
N
NH
R3
Sn
(2)
R3
+
CHO
Br
THF
reflux
EtOH
reflux
R4
R1
DCE, rt
R3
I
R4
R5
R1
R1
R4 R5
R4 R5
R5
R3
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RESULTS AND DISCUSSION
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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).
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Table 1. Optimization of the Reaction Conditionsa
O
O
O
COOH
CHO
O
Sn
NH
N
+
+
+
N NH
NHNH2
Br
Solvent, reflux
1a
2a
3a
4a
5a
yield (%)b
entry mole ratio of 1a:2a:3a:Sn
solvent
time (h)
4a
45
76
81
87
5a
0
0
0
0
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
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The Journal of Organic Chemistry
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1:1:2.0:2.0
1:1:2.0:2.5
1:1:2.5:2.5
1:1:2.0:2.5
1:1:2.0:2.5
1:1:2.0:2.5
1:1:2.0:2.5
1:1:2.0:2.5
1:1:2.0:2.5
1:1:2.0:2.5
1:1:2.0:2.5
THF
THF
THF
EtOH
MeOH
DCM
13
13
13
13
13
13
14
16
13
13
16
89
94
92
90
91
58
70
7
0
0
0
0
0
0
0
82
27
21
32
1
2
3
4
5
6
7
8
CH3CN
1,4-dioxane
toluene
DMF
9
10
11
12
13
14
56
37
21
H2O
aReaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), 3a and tin powder were refluxed in THF (4
mL). bIsolated yields.
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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
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O
O
1
2
3
4
COOH
CHO
O
Sn
H
R1
R1
+
+
N N
NHNH2
Br
THF, reflux
5
6
7
1
2a
3a
4
8
9
O
O
O
O
O
O
H
O
O
H
H
H
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N N
N N
N N
N N
4a
4b
16 h, 71%
4c
4d
13 h, 90%
13 h, 94%
13 h, 87%
O
O
O
O
F
O
F3C
O
O
O
O
H
H
H
H
N N
N N
N N
N N
4e
4f
4g
13 h, 94%
4h
13 h, 92%
15 h, 78%
13 h, 90%
O
O
Cl
O
O
H
H
N N
N N
Cl
4i
4j
13 h, 91%
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
O
O
Sn
H
+
+
N N
NHNH2
Br
THF, reflux
1k
2a
3a
4k
13 h, 0%
O
O
COOH
Ph
O
Sn
H
+
+
N N
NHNH2
Br
THF, reflux
Ph
O
1l
2a
3a
4l
13 h, 0%
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The Journal of Organic Chemistry
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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).
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Table 3. Substrate Scope of Hydrazidesa
O
COOH
CHO
O
O
Sn
H
N N
+
+
Br
R2 NHNH2
R2
THF, reflux
1a
2
3a
6
O
O
O
O
O
O
O
O
H
H
H
H
N N
N N
N N
N N
O
6a
6b
6c
6d
14 h, 76%
13 h, 87%
13 h, 88%
13 h, 87%
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O
O
O
O
1
2
3
O
O
O
O
H
H
H
H
N N
N N
N N
N N
4
5
Cl
6
7
8
9
Cl
Cl
Br
6e
6f
6g
13 h, 94%
6h
13 h, 94%
14 h, 80%
13 h, 90%
O
O
O
O
10
11
12
13
14
15
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O
O
O
O
H
H
H
H
N N
N N
N N
N N
N
O
F
6i
6j
6k
6l
13 h, 92%
15 h, 75%
13 h, 67%
13 h, 87%
O
O
O
O
O
O
O
O
H
H
H
H
N N
N N
N N
N N
CH3
CF3
S
6m
13 h, 81%
6n
17 h, 0%
6o
17 h, 0%
5a
, 73%)
6p
17 h,41%
5a
, 52%)
5a
(
, 80%)
(
(
O
O
C11H23
H
N N
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
2
3
4
5
6
7
8
9
O
R4
O
COOH
CHO
O
Sn
THF, reflux
H
+
+
N N
Br
R5
NHNH2
R3
R4
R5
R3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
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34
35
36
37
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60
1a
2a
3
7
O
O
O
O
O
O
O
H
O
H
H
H
N N
N N
N N
N N
Ph
7a
7b
7d
7c
17 h, 67%, dr = 81:19b
16 h, 73%, dr > 99:1b
16 h, 69%
13 h, 90%
O
O
O
O
O
O
H
O
H
O
H
H
N N
N N
N N
N N
O
EtOOC
7e
7f
7h
7g
14 h, 77%
14 h, 85%
16 h, 82%
15 h, 86%
O
O
O
O
O
O
O
O
H
H
H
H
N N
N N
N N
N N
F
Cl
Br
7i
14 h, 81%
7j
13 h, 84%
7l
7k
14 h, 79%
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
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2
3
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5
6
7
8
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.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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31
32
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34
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40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Optimization of Iodination/Cyclization Reaction Conditionsa
O
O
O
O
H
N N
Base
N N
I2
+
Solvent, rt
I
4a
8a
CCDC: 1889343
entry
1
2
3
4
5
6
7
8
mole ratio of 4a:I2:base
base
-
solvent
DCM
DCM
CHCl3
CCl4
DCE
CH3CN
THF
time (h)
20
6
yield (%)b
1:2:0
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2.5:2
1:2:2.5
1:2:2
0
69
65
17
78
41
45
29
53
8
trace
trace
33
39
78
77
77
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
DBU
7
20
6
20
20
20
20
20
20
20
20
20
6
toluene
9
1,4-dioxane
DMF
EtOH
DCE
10
11
12
13
14
15
16
17c
DCE
DCE
DCE
DCE
K2CO3
K2CO3
K2CO3
6
6
DCE
aReaction conditions: 4a (0.2 mmol), I2, base, and solvent (3 mL) were stirred at rt. bIsolated yields.
cIn the presence of Bu4NI (0.1 equiv).
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Scheme 3. Formation of cis-Product 8a
3
4
5
I
O
O
I
H
H
Bz
Bz
N
N
N
H
N
H
6
7
8
9
18
8a'
Disfavoured transition state
trans-product
not detected
O
O
H
K2CO3, I2
N N Bz
N N Bz
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
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49
50
51
52
53
54
55
56
57
58
59
60
I
4a
17
H
Bz
H
O
O
H
H
Bz
I
N
I
N
N
N
19
8a
cis-product
Favoured transition state
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
O
O
O
H
R1
N N
N N
K2CO3
DCE, rt
I2
+
R1
R4
R5
R3
I
R3
R4 R5
4 7
8
,
O
N N
O
O
O
O
O
O
O
N N
N N
N N
O
F3C
I
I
I
I
8a
6 h, 78%
8b
8 h, 73%
8c
7 h, 76%
8d
7 h, 83 %
O
O
O
O
O
O
O
O
N N
N N
N N
N N
F
Cl
Cl
I
I
I
I
8e
6 h, 80%
8f
8g
6 h, 75%
8h
6 h, 79%
6 h, 80%
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O
O
O
O
O
O
O
O
1
2
3
4
5
6
7
N N
N N
N N
N N
I
I
COOEt
I
I
Ph
8i
8j
6 h, 76%
8k
7 h, 73%
8l
8 h, 69%
8 h, 77%, dr = 70:30b
8
9
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.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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58
59
60
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
O
O
H2 (1 atm)
Pd/C (10 mol%)
m-CPBA
(3 equiv)
O
O
O
H
H
H
N N
N N
N N
DCM, rt, 24 h
84% yield
MeOH, rt, 24 h
90% yield
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
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8
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.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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60
Table 7. Substrate Scope of the Deprotection/Cyclization Reactiona
O
O
O
N N
N N
KOH (2 equiv)
EtOH, reflux
R1
R1
R3
R3
I
R4 R5
R4 R5
11
8
O
O
O
N N
N N
N N
F
Cl
11a
0.5 h, 86%
11b
0.5 h, 83%
11c
CCDC: 1900569
0.5 h, 84%
O
O
O
O
N N
N N
N N
N N
O
COOEt
11d
11e
11f
11g
0.5 h, 81%
0.6 h, 79%
1 h, 0%
1 h, 0%
aReaction 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
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H
Bz
H
Bz
O
O
O
1
2
H
N
I
Bz
N
I
N
KOH
N
H
I
N
N
3
4
5
21
8a
20
cis-
6
EtOH
7
8
9
EtOK
O
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
O
O
KOH
Internal
SN2 reaction
Bz
N
N
N
H
H
H
I
N
N
N
H
H
H
I
PhCOOH
11a
23
22
trans-
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
O
O
O
O
COOH
CHO
O
H
I2, K2CO3,
2a 3a
,
, Sn
KOH
N N
N N
N N
EtOH, reflux,
0.5 h
THF, reflux,
13 h
DCE, rt, 20 h
I
1a
4a
8a
11a
, 0.98 g, 76%
, 2.00 g
, 3.31 g, 85%
, 2.89 g, 61%
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
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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).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Control Experiments for Mechanism
O
COOH
CHO
COOH
N
O
A
B
+
NHNH2
THF, reflux
N
H
2a
12a
, 8 h, 96%
1a
O
COOH
N
O
H
O
O
Sn
N N
+
Br
THF, reflux
N
H
12a
3a
4a
, 5 h, 95%
O
O
COOH
N
additive
1,4-dioxane, reflux
C
+
NH
N
OH
N
H
12a
5a
13a
5a
Yield: , 0%;
5a
Yield: , 0%;
13a
13a
, 0%, 20 h (Without additive)
, 0%, 20 h (Sn, 10 mol%)
5a
Yield: , 84%;
5a
Yield: , 81%;
13a
, 77%,15 h (SnCl2, 10 mol%)
13a
, 73%, 20 h (SnCl4, 10 mol%)
Scheme 9. Proposed Mechanistic Pathway
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O
1
2
3
4
5
6
7
8
O
O
R2
OH
O
R1
SnBr
R1
N
NH
N
R2
NH
R4
R5
R4
R5
R3
R3
COOH
CHO
R1
16
4
R3
R3
9
1
COOH
N
-H2O
O
Sn
R4
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
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59
60
R1
Br
R4
BrSn
+
N
R2
Sn
R5
3
R5
O
14
H
12
R2 NHNH2
R3
Br2Sn
O
R4
2
(II)
or
R5
2
Sn
(IV)
15
O
NH
R1
+
R2 OH
N
5
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
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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
8
9
1
13
(CDCl3), Dimethyl sulfoxide-d6 ((CD3)2SO) and Acetone-d6 ((CD3)2CO). H NMR, C{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
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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44
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60
(δ 2.50 for H NMR), acetone (δ 2.05 for H NMR), chloroform (δ 77.16 for 13C{1H} NMR),
1
1
dimethyl sulfoxide (δ 39.52 for C{1H} NMR), and acetone (δ 206.26 for C{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.
13
13
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.
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o
1
2
3
4
5
6
7
8
N-(1-Allyl-3-oxoisoindolin-2-yl)benzamide (4a). 82 mg, 94% yield, white solid, mp 101−103 C;
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.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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59
60
N-(3-Allyl-4-methyl-1-oxoisoindolin-2-yl)benzamide (4b). 65 mg, 71% yield, white solid, mp
o
1
133−135 C; H 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
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145−146 C; H NMR (600 MHz, CDCl3) δ 10.61 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.62 (s, 1H),
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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.
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N-(1-Allyl-4-methyl-3-oxoisoindolin-2-yl)benzamide (4e). 72 mg, 78% yield, white solid, mp
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132−133 C; H 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),
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3.84 (s, 3H), 2.78−2.72 (m, 1H), 2.64−2.57 (m, 1H); C{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),
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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.
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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,
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110.9 (d, J = 22.5 Hz), 60.7, 35.5; F 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
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124−125 C; H 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,
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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.
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Data of side product 5a
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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,
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1H), 7.80 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H); C{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
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162−163 C; H 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),
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2.68−2.63 (m, 1H), 2.26 (s, 3H); C{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.
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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.
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N-(1-Allyl-3-oxoisoindolin-2-yl)-4-methoxybenzamide (6d). 84 mg, 87% yield, white solid, mp
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164−166 C; H 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
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Hz, 1H), 3.80 (s, 3H), 2.79−2.75 (m, 1H), 2.68−2.63 (m, 1H); C{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,
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2H), 5.01 (d, J = 10.2 Hz, 1H), 2.84−2.81 (m, 1H), 2.75−2.71 (m, 1H); C{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 =
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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.
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N-(1-Allyl-3-oxoisoindolin-2-yl)-4-chlorobenzamide (6g). 92 mg, 94% yield, white solid, mp
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154−155 C; H 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),
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2.69−2.64 (m, 1H); C{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
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192−193 C; H 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,
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J = 22.5 Hz), 61.1, 35.3; F NMR (376 MHz, CDCl3) δ −107.31 (m); HRMS (ESI) m/z calcd for
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C18H16FN2O2 [M + H]+ 311.1190, found 311.1195.
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N-(1-Allyl-3-oxoisoindolin-2-yl)-1-naphthamide (6j). 77 mg, 75% yield, white solid, mp 179−180
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oC; H 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); C{1H} NMR
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(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,
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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,
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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),
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2.70−2.66 (m, 1H); C{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),
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1.38−1.26 (m, 16H), 0.88 (t, J = 7.2 Hz, 3H); C{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,
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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
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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.
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N-(1-Oxo-3-(1-phenylallyl)isoindolin-2-yl)benzamide (7b). Mixture of two isomers: 74 mg, 67%
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yield, white solid, mp 118−120 C; H 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,
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1H), 5.47−5.45 (m, 1H), 5.19−5.16 (m, 2H), 4.01 (dd, J = 7.8, 5.4 Hz, 1H); C{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,
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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.
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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,
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mp 60−61 C; H 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
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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.
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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),
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2.77 (dd, J = 14.4, 7.8 Hz, 1H); C{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),
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9.0 Hz), 127.6, 124.1, 123.3, 116.7, 115.7, 115.6 (d, J = 21.0 Hz), 59.8, 38.6; F NMR (376 MHz,
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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
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(dd, J = 14.4, 7.8 Hz, 1H); C{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
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(dd, J = 14.4, 7.8 Hz, 1H); C{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),
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