Carbonylation Access to Phthalimides Using Self-Sufficient Directing Group and Nucleophile

Article abstract of DOI:10.1021/acs.joc.7b02433

Herein we report a novel palladium-catalyzed oxidative carbonylation reaction for the synthesis of phthalimides with high atom- and step-economy. In our strategy, the imine and H₂O, which are generated in situ from the condensation of aldehyde and amine, serve as self-sufficient directing group and nucleophile, respectively. This method provides rapid access to phthalimides starting from readily available materials in a one-pot manner. Various phthalimide derivatives are constructed efficiently, including medicinally and biologically active phthalimide-containing compounds.

Full text of DOI:10.1021/acs.joc.7b02433

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Article
Carbonylation Access to Phthalimides Using
Self-Sufficient Directing Group and Nucleophile
Fanghua Ji, Jianxiao Li, Xianwei Li, Wei Guo, Wanqing Wu, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02433 • Publication Date (Web): 12 Dec 2017
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Carbonylation Access to Phthalimides Using
Self-Sufficient Directing Group and Nucleophile
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Fanghua Ji,a Jianxiao Li,a Xianwei Li,a Wei Guo,a Wanqing Wu,*,a
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Huanfeng Jiang*,a,b
a Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of
Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640,
P. R. China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R.
China
Fax: (+86) 20ꢀ8711ꢀ2906; Eꢀmail: cewuwq@scut.edu.cn, jianghf@scut.edu.cn
Abstract: Herein we report a novel palladiumꢀcatalyzed oxidative carbonylation
reaction for the synthesis of phthalimides with high atomꢀ and stepꢀ economy. In our
strategy, the imine and H2O, which are generated in situ from the condensation of
aldehyde and amine, serve as selfꢀsufficient directing group and nucleophile
respectively. This method provides rapid access to phthalimides starting from readily
available materials in a oneꢀpot manner. Various phthalimide derivatives are
constructed efficiently, including medicinally and biologically active
phthalimideꢀcontaining compounds.
INTRODUCTION
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Transition metalꢀcatalyzed CꢀH functionalization has emerged as a powerful tool in
organic synthesis.1 Although this method eliminates the need for preactivation of the
starting materials, high reactivity and regioselectivity is still a challenging issue. To
overcome this limitation, directing groupꢀassisted CꢀH bond cleavage is considered to
be a promising and fundamental protocol (Scheme 1a).2 Despite of the significant
progress in this field, the introduction of an external directing group usually requires
tedious preparations and results in limited substrate applicability.
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Scheme 1. Two strategies for directed C-H functionalization
(a) Traditional pre-installed directing groups
DG
H
DG
[M]
DG
FG
DG: directing group
FG: functional group
[M]
coupling
C
C
C
FG
(b) Self-sufficient directing group generated in-situ
A
DG
[M]
A
B
FG
A + B
H
=
=
DG
B
+
coupling
[M]
C
H
C
C
C
Advantages: directing groups are generated in-situ and react as functional groups
In addition, sometimes the reaction conditions for installing and removing
directing groups are incompatible with other functional groups in the same reaction
system. Owing to the concept of “green chemistry” and the increasing pressure to
reduce energy consumption,3 the development of novel, efficient and selfꢀsufficient
directing strategy with maximized atomꢀ and stepꢀeconomy is highly desirable.
Consequently, we envisioned that the directing group could be generated in situ4 and
incorporated into the target molecule playing the role of coupling partner without
further synthetic manipulations (Scheme 1b).
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Within this reaction class, Pdꢀcatalyzed direct oxidative carbonylation has
attracted considerable attention due to the prevalent presence of carbonylꢀcontaining
compounds in organic molecules.5 In recent years, several approaches have been
reported for the synthesis of phthalimides by palladiumꢀcatalyzed carbonylation.6
Moreover, oxidative carbonylation of simple nucleophiles such as CꢀH and YꢀH (Y=
O, N, etc), has been considered as an ideal carbonylation protocol in recent years.
Employing this strategy, Chatani and Rovis reported rutheniumꢀ and
rhodiumꢀcatalyzed oxidative carbonylation for the synthesis of phthalimides via
directing group assisted CꢀH bond activation (Scheme 2a, 2b). Despite of their
advantages, these methods have one drawback: complicated starting materials is
required. On the basis of our previous work,7 we report a straightforward oxidative
carbonylation reaction for the construction of Nꢀsubstituted phthalimides (Scheme 2c).
In our protocol, we suppose that the inꢀsitu generated imine could be used as
selfꢀsufficient directing group, which is derived from the condensation of aldehyde
and amine, furnishing the carbonylation reaction with high efficiency. H2O as benign
byproduct is liberated in the first condensation step and consumed in the second
nucleophilic step. The process employing inꢀsitu generated imine and H2O as
directing group and nucleophile respectively is coherent with the principle of high
atomꢀ and stepꢀ economy. Furthermore, the use of simple aldehyde and amine as
substrates makes this approach particularly attractive. The transformation provides a
concise and convenient entry to the core structure of phthalimides, which are the key
structural motif in many drug candidates.8
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Scheme 2. New strategy of carbonylation for N-substituted phthalimides
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RESULTS AND DISCUSSION
We began our investigation by utilizing benzaldehyde (1a) and tertꢀbutylamine
(2a) as model substrates under the treatment of PdCl2 with CuO/O2 as oxidant under
CO atmosphere. After screening several parameters (e.g., catalyst, oxidant, solvent
and
temperature),
we
found
that
the
corresponding
product
2ꢀ(tertꢀbutyl)isoindolineꢀ1,3ꢀdione (3a) was obtained in 67% yield in the presence of
PdCl2(CH3CN)2 (7.5 mol %), 1 atm of CO/O2, and CuO (1 equiv) in a mixture of
toluene and DMF (10: 1) (see the Supporting Information for details).
Subsequently, the scope of the arylꢀsubstituted benzaldehydes was investigated.
As summarized in Table 1, mono or diꢀsubstituted substrates bearing
electronꢀdonating groups (R1 = Me, OMe, tꢀbutyl) or electronꢀwithdrawing groups (R1
= Cl, NO2) on benzaldehyde moiety were wellꢀtolerated under the optimal reaction
conditions, and transferred to the corresponding products 3a-3k in moderate to good
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yields. In addition, the reaction started from 1ꢀnaphthaldehyde or 2ꢀnaphthaldehyde
also proceeded efficiently and provided 3l and 3m in good yields. It was found that
the electronic and steric properties have significant effects on the reaction efficiency.
Electronꢀrich substrates are more efficient than those with electronꢀdeficient
substituents, which suggested the CꢀH bond activation might be electrophilic in
nature.9 Meanwhile, this transformation favored less steric position (3i, 3k, 3l).
We next examined the scope of the amines (Table 2). A variety of aliphatic
amines could be efficiently converted into the corresponding products (3n-3u). To our
delight, the substrate decanꢀ1ꢀamine bearing tenꢀcarbon chain could be converted to
the corresponding product 3q in 75% yield. Pleasingly, all the tested cyclic amines,
such as cyclobutanamine, cyclopentanamine and cyclohexanamine, transferred to the
desired phthalimides in moderate to good yields (3r-3t). Heterocyclic aliphatic amine
was also reactive in this catalytic system, and converted to 3u in 76% yield. It is
important that the aromatic amines are also wellꢀtolerated in this reaction. Different
substituted aromatic amines with important functional groups were compatible to this
catalytic system, such as methyl, phenoxyl and halogen (F, Cl, Br), which could be
subjected to further synthetic transformations (3v-3ab). Naphthalenꢀ1ꢀamine and
1ꢀnaphthaldehyde could also transfer to the corresponding products with extended
πꢀsystem (3ac, 3ad). Moreover, this transformation was compatible with benzylamine
to give the desired product 3ae in 68% yield.
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Table 1. Scope of aryl-substituted benzaldehydes
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Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), PdCl2(CH3CN)2 (7.5 mol %), CuO (0.2
mmol), and toluene/DMF (10: 1) (2.5 mL) at room temperature and then added a balloon with
CO/O2 at 100 oC. Yields referred to isolated yields.
Table 2. Scope of amines
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Reaction conditions: [a] 1a (0.2 mmol), 2 (0.24 mmol), PdCl2(CH3CN)2 (7.5 mol %), CuO
(0.2 mmol), and toluene/DMF (10: 1) (2.5 mL) at room temperature. [b] 2 (0.2 mmol), 1a (1.2
equiv), PdCl2(CH3CN)2 (7.5 mol %), CuO (0.2 mmol), and toluene/DMF (10: 1) (2.5 mL) at
o
room temperature and then added a balloon with CO/O2 at 100 C. Yields referred to isolated
yields.
The synthetic utility of the resultant phthalimides is then demonstrated by
conducting further transformations of 3v (Scheme 3).10 For example, the reduction
of 3v with an excess of NaBH4 resulted in the hydrogenation of imides, leading to
amide 4a in 89% yield. When 3v was submitted to hydrazine hydrate, the
phthalhydrazide product 4b, an important intermediate for the synthesis of
phthalazinones, was obtained in high yield. In addition, aminolysis reaction could
also occur upon 3v, and provided the diamide product 4c in 79% yield. It should be
noted that compound 4d bearing a trifluolomethyl group, which might profoundly
alter the biological and pharmaceutical properties of substrates,11 could be also
constructed from 3v via a trifluolomethylation process.
Scheme 3. Further transformations of 3v
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Reaction conditions: (i) 2ꢀPhenylisoindolineꢀ1,3ꢀdione (3v) (0.5 g, 2.2 mmol), NaBH4 (3 equiv,
0.25 g, 6.6 mmol) , and methanol (25 mL) at 0 °C for 4 h. Yields referred to isolated yields; (ii)
2ꢀPhenylisoindolineꢀ1,3ꢀdione (3v) (0.5 g, 2.2 mmol) , hydrazine hydrate (1.2 equiv, 2.6 mmol) in
methanol (20 mL) refluxed at 70 °C for 16 h. Yields referred to isolated yields; (iii)
2ꢀPhenylisoindolineꢀ1,3ꢀdione (3v) (0.50 g, 2.2 mmol), cyclopentamine (2 equiv, 0.37 g, 4.4 mmol)
in dioxane (20 mL) refluxed at 80 °C for 3 h. Yields referred to isolated yields; (iv)
2ꢀPhenylisoindolineꢀ1,3ꢀdione (3v) (0.5 g, 2.2 mmol), (Trifluoromethyl)trimethyl silane (CF3TMS,
0.3 g, 2.6 mmol), 1.0 M solution of TBAF in dry THF (10 mL) under N2 atmosphere. Yields
referred to isolated yields.
Notably, phthalimides containing a 4ꢀamino substituent have been recognized to
be an important class of fluorescent bioactive compounds.12 The synthesis of this kind
of compounds is generally realized with three steps (methylation; dehydration;
amination) using 4ꢀaminophthalic acid as the starting material [Scheme 4, Eq. (1)].12a
Under our catalytic system, 4ꢀamino substituted phthalimides 4e and 4f could be
achieved efficiently in a oneꢀstep manner starting from available and inexpensive
4ꢀ(dimethylamino)benzaldehyde (4) [Scheme 4, Eq. (2)], thus providing novel and
straightforward access to different fluorescent bioactive compounds.
Scheme 4. The synthesis of 4-amino substituted phthalimides
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Reaction conditions: 4 (0.2 mmol), amine (0.24 mmol), PdCl2(CH3CN)2 (7.5 mol %), CuO (0.2
mmol), and toluene/DMF (10: 1) (2.5 mL) at room temperature and then added a balloon with
CO/O2 at 100 oC. Yields referred to isolated yields.
This tandem oxidative carbonylation reaction was also applied to the
construction of a series important drug candidates bearing phthalimide skeleton, such
as cycloxygenaseꢀ2 (COXꢀ2) enzyme inhibitor (I),13 inhibitor of tumor necrosis
factorꢀα (TNFꢀα) (II),14 2ꢀquinolinephthalimide (III), TRPA1 (Transient Receptor
Potential subfamily A1) modulators (IV)15 and antiꢀglucosidase16(V). As shown in
Figure 1, 5ꢀmethylꢀ2ꢀ(3,4,5ꢀtrimethoxyphenyl)isoindolineꢀ1,3ꢀdione (I), which is
responsible for the formation of different biological mediators, was obtained
efficiently in 78% yield. Moreover, II as an important inhibitor of αꢀTNF was also
synthesized from benzaldehyde with this newly developed method. Gratifyingly, the
precursor of 2ꢀquinolinephthalimide (III), an important bioactive compound, could be
achieved conveniently and the yield was up to 68%. Moreover, the precursor of
TRPA1 (IV), which is a peripheral damage receptor involved in prolonged pain
response, was also prepared directly in 55% yield under the standard conditions.
Besides, αꢀglucosidase inhibitory compound (V) could be also synthesized from the
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corresponding materials 4ꢀnitrobenzaldehyde using our present method after three
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step transformation (Figure 1).
Figure 1. The synthesis of bioactive phthalimides
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Having demonstrated the synthetic utility of this process, a series of mechanistic
experiments were performed to gain further insight into the mechanistic pathway. The
results of 18Oꢀlabeling experiments proved that the oxygen atom in the carbonyl group
should be originated from molecular water [Scheme 5, Eq. (1) and Eq. (2)].
Additionally, amide 6a is one of the most common substrates for the construction of
phthalimides,17 however, no reaction occurred starting from amide 6a, indicating that
amide was not the intermediate in this catalytic system [Scheme 5, Eq. (3)]. To our
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delight, 3ꢀhydroxyꢀ2ꢀphenylisoindolinꢀ1ꢀone (7a),
a
possible precursor of
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phthalimide,18 was detected in this reaction system. When we submitted 7a to the
standard conditions, the corresponding product 3v was obtained in 75% yield
[Scheme 5, Eq. (4)]. Furthermore, it was observed that no reaction occurred in the
absence of Pd catalyst using benzaldehyde as initial material, which suggested that 7a
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was the unique possible intermediate in this process.
Scheme 5 Mechanistic studies
On the basis of the above results and literature precedence,19 a plausible reaction
mechanism is proposed in Figure 2. Initially, the imine is generated in situ as a
directing group from the condensation of aldehyde and amine. Subsequent CꢀH
activation directed by imine group leads to the generation of intermediate A, followed
by CO insertion to afford the intermediate B. H2O, which is also generated in situ
from the condensation process, undergoes nucleophilic reaction to C=N bond to
generate intermediate C.20 The reductive elimination of intermediate C would afford
the annulation product D. Finally, further oxidation of D gives the desired product.
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Finally, Pd(0) species formed from the reductive elimination step is recycled by
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CuO/O2 oxidant.
Figure 2. Proposed mechanism
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CONCLUSION
In summary, we have developed a novel and efficient protocol for the synthesis
of phthalimides in a oneꢀpot manner. The directing group and nucleophile are all
generated in situ, making the reaction feature high atom and step economy. From the
point of “green chemistry”, energyꢀsaving and environmentꢀfriendly strategy, this
method provides an ideal pathway for the synthesis of various medicinally and
biologically active compounds. Further efforts toward the synthetic applications for
the drug delivery as well as mechanistic studies are underway in our laboratory.
EXPERIMENTAL SECTION
General Information. Melting points were measured with a BÜCHI Bꢀ545 melting
point instrument and were uncorrected. 1H and 13C NMR spectra were recorded using
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a Bruker Avance 400 MHz NMR spectrometer. The chemical shifts are referenced to
signals at 7.24 and 77.0 ppm, respectively, and chloroform is solvent with TMS as the
internal standard. IR spectra were obtained either as potassium bromide pellets or as
liquid films between two potassium bromide pellets with a Bruker Vector 22
spectrometer. GC–MS was obtained using electron ionization. HRMS (LCMSꢀITꢀTOF)
was carried out on a MAT 95XP (Thermo). TLC was performed by using
commercially prepared 100–400 mesh silica gel plates (GF254) and visualization was
effected at 254 nm.
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Typical Experimental Procedure for Synthesis of N-substituted phthalimides.
When RNH2 is aliphatic amine with low boiling point, condition A: A mixture of
arylꢀsubstituted aldehyde (0.2 mmol), aliphatic amine (0.24 mmol), PdCl2(CH3CN)2
(4.8 mg, 7.5 mol %), CuO (0.2 mmol), toluene/DMF (10: 1, 2.5 mL) in a test tube (25
mL) equipped with a magnetic stirring bar;When RNH2 is aromatic amine or aliphatic
amine with high boiling point, condition B: A mixture of arylꢀsubstituted aldehyde
(0.24 mmol), aromatic amine (0.2 mmol), PdCl2(CH3CN)2 (4.8 mg, 7.5 mol %), CuO
(0.2 mmol), toluene/DMF (10:1, 2.5 mL) in a test tube (25 mL) equipped with a
magnetic stirring bar; The mixture was stirred under the atmosphere of air at room
temperature for 12 h. After the condensation was completed, a balloon with CO and
o
O2 was added into the tube and the mixture was stirred at 100 C for 48 h. When the
reaction was completed (detected by TLC), the mixture was cooled to room
temperature, and then the solvent was removed under reduced pressure. The residue
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was purified by column chromatography on silica gel to afford the corresponding
products with petroleum ether/ethyl acetate (4:1).
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Experimental Procedure for 4a. 2ꢀPhenylisoindolineꢀ1,3ꢀdione (3v) (0.5 g, 2.2
mmol) was dissolved in methanol in a 25 mL flask and cooled to 0 °C. NaBH4 (3
equiv, 0.25 g, 6.6 mmol) was added and the reaction mixture was stirred at 0 °C for 4
h. When the reaction was completed (detected by TLC), the solvent was removed
under reduced pressure. The residue was purified by column chromatography on silica
gel to afford the corresponding products 4a (0.44 g, 89%) with petroleum ether/ethyl
acetate (2:1).
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Experimental Procedure for 4b. 2ꢀPhenylisoindolineꢀ1,3ꢀdione (3v) (0.5 g, 2.2
mmol) was dissolved in 20 mL methanol in a 50mL flask and hydrazine hydrate (1.2
equiv, 2.6 mmol) was added. The solution was refluxed at 70 °C for 16 h. When the
reaction was completed (detected by TLC), the solvent was removed under reduced
pressure. The residue was purified by column chromatography on silica gel to afford
the corresponding products 4b (0.34 g, 95%) with petroleum ether/ethyl acetate (1:1).
Experimental Procedure for 4c. 2ꢀPhenylisoindolineꢀ1,3ꢀdione (3v) (0.50 g, 2.2
mmol) was dissolved in 20 mL dioxane in a 50 mL flask and cyclopentamine (2 equiv,
0.37 g, 4.4 mmol) was added. The solution was refluxed at 80 °C for 3 h. When the
reaction was completed (detected by TLC), the solvent was removed under reduced
pressure. The residue was purified by column chromatography on silica gel to afford
the corresponding products 4c (0.54 g, 79%) with petroleum ether/ethyl acetate (4:1).
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Experimental Procedure for 4d. 2ꢀPhenylisoindolineꢀ1,3ꢀdione (3v) (0.5 g, 2.2
mmol) was dissolved in dry THF (10 mL) in a reaction tube under N2 atmosphere and
cooled to 0 °C. (Trifluoromethyl)trimethyl silane (CF3TMS, 0.3 g, 2.6 mmol) was
added, followed by 1.0 M solution of TBAF in THF (1−2 mol %, 20−34 ꢁL), and the
reaction mixture was warmed to room temperature and stirred for 1 h. The solvent
was removed under reduced pressure. The residue was purified by column
chromatography on silica gel to afford the corresponding products 4d (0.58 g, 89%)
with petroleum ether/ethyl acetate (4:1).
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Experimental Procedure for V. (1) A mixture of benzaldehyde (0.2 mmol),
nꢀbutylamine (0.24 mmol), PdCl2(CH3CN)2 (4.8 mg, 7.5 mol %), CuO (0.2 mmol),
toluene/DMF (10: 1, 2.5 mL) in a test tube (25 mL) equipped with a magnetic stirring
bar; The mixture was stirred under the atmosphere of air at room temperature for 12 h.
After the condensation was completed, a balloon with CO and O2 was added into the
tube and the mixture was stirred at 100 oC for 48 h. When the reaction was completed
(detected by TLC), the mixture was cooled to room temperature, and then the solvent
was removed under reduced pressure. The residue was purified by column
chromatography on silica gel to afford the corresponding crude product.
(2) The crude product from step 1 was dissolved in EtOH (5 mL) in a test tube (25
mL). Iron powder (0.6 mmol) was added, followed by 1.0 M solution of HCl (1.2
mmol), and the reacton mixture was stirred at 100 °C. When the reaction was
completed (detected by TLC), the mixture was cooled to room temperature and
reacted with NaOH until the solution is neutral. Then the mixture was filtrated and
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extracted. The residue was purified by column chromatography on silica gel to afford
the corresponding crude product.
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(3) The crude product from step 2 was dissolved in CH2Cl2 (5 mL) in a test tube (25
mL) and Et3N (0.4 mmol) was added. Tosyl chloride (0.3 mmol) was added and the
reaction mixture was stirred at 0 °C for 1 h. When the reaction was completed
(detected by TLC), the mixture was cooled to room temperature, and then the solvent
was removed under reduced pressure. The residue was purified by column
chromatography on silica gel to afford the corresponding product V (22 mg, 29%)
with petroleum ether/ethyl acetate (10:1).
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2-(tert-Butyl)isoindoline-1,3-dione (3a)21
o
Colorless solid (27 mg, 67 %), mp: 58.9ꢀ60.3 C;1H NMR (400 MHz, CDCl3) δ
7.80ꢀ7.71 (m, 2H), 7.68ꢀ7.66 (m, 2H), 1.70 (s, 9H); 13C NMR (100MHz, CDCl3) δ
169.5, 133.6, 132.1, 122.5, 57.7, 29.1 ppm; IR (KBr) νmax 1708, 1362, 1312, 1094,
715 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C12H13NNaO2 [M+Na]+, 226.0838; found,
226.0837.
2-(tert-Butyl)-5-methylisoindoline-1,3-dione (3b)
White solid (26 mg, 61 %), mp: 66.9ꢀ68.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.63 (d,
J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.45 (d, J = 7.2 Hz, 1H), 2.48 (s, 3H), 1.69 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 169.8, 169.7, 144.8, 134.2, 132.6, 129.6, 123.0, 122.5,
57.7, 29.1, 21.9 ppm; IR (KBr) νmax 1708, 1354, 1093, 741 cmꢀ1; HRMS (ESIꢀTOF)
m/z: calcd for C13H15NNaO2 [M+Na]+, 240.0995; found, 240.0994.
2-(tert-Butyl)-5-methoxyisoindoline-1,3-dione (3c)
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White solid (30 mg, 65 %), mp: 131.6ꢀ132.7 C; 1H NMR (400 MHz, CDCl3) δ 7.65
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(d, J = 8.4 Hz, 1H), 7.22 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 1.68 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 169.5, 164.5, 134.7, 124.2, 119.8, 106.9, 57.7, 56.0,
29.1 ppm; IR (KBr) νmax 1703, 1328, 1013, 744 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd
for C13H15NNaO3 [M+Na]+, 256.0944; found, 256.0949.
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2,5-di-tert-Butylisoindoline-1,3-dione (3d)
Colorless solid (31 mg, 60 %), mp: 97.1ꢀ98.5 oC; 1H NMR (400 MHz, CDCl3) δ 7.79
(s, 1H), 7.68 (s, 2H), 1.68 (s, 9H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.1,
169.8, 158.2, 132.4, 130.7, 129.6, 122.4, 119.7, 57.7, 35.7, 31.2, 29.1 ppm; IR (KBr)
νmax 1708, 1351, 1262, 748 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C16H21NNaO2
[M+Na]+, 282.1464; found, 282.1469.
2-(tert-Butyl)-5-fluoroisoindoline-1,3-dione (3e)
1
Colorless solid (20 mg, 45 %), mp: 59.9ꢀ61.0 oC; H NMR (400 MHz, CDCl3) δ
7.78ꢀ7.75 (m, 1H), 7.43 (d, J = 6.8 Hz, 1H), 7.33 (t, J = 8.6 Hz, 1H), 1.69 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 168.6, 168.2, 167.6, 165.0, 134.9, 134.9, 127.9, 125.0,
124.9, 120.9, 120.6, 110.4, 110.1, 58.2, 29.0 ppm; IR (KBr) νmax 1710, 1357, 1012,
748 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C12H12FNNaO2 [M+Na]+, 244.0744;
found, 244.0742.
2-(tert-Butyl)-5-chloroisoindoline-1,3-dione (3f)
o
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White solid (22 mg, 47 %), mp: 89.0ꢀ89.9 C; H NMR (400 MHz, CDCl3) δ
7.78ꢀ7.67 (m, 2H), 7.66ꢀ7.59 (m, 1H), 1.69 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
168.7, 168.3, 140.3, 133.8, 130.2, 123.9, 123.0, 58.2, 29.0 ppm; IR (KBr) νmax 1710,
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1346, 1093, 748 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C12H12ClNNaO2 [M+Na]+,
260.0449; found, 260.0443.
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2-(tert-Butyl)-5-nitroisoindoline-1,3-dione (3g)
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Yellow solid (25 mg, 51 %), mp: 119.5ꢀ120.5 oC; 1H NMR (400 MHz, CDCl3) δ 8.58
(s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 1.71 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 167.5, 167.1, 151.7, 136.5, 133.4, 129.0, 123.9, 118.2, 59.0, 28.9
ppm; IR (KBr) νmax 1711, 1536, 1324, 754, 716 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd
for C12H13N2O4 [M+H]+, 249.0870; found, 249.0869.
2-(tert-Butyl)-4-methoxyisoindoline-1,3-dione (3h)
o
White solid (36 mg, 78 %), mp: 110.1ꢀ111.5 C; 1H NMR (400 MHz, CDCl3) δ 7.57
(t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H),
1.64 (s, 9H); 13C NMR (100MHz, CDCl3) δ 169.1, 168.5, 156.3, 135.7, 134.5, 117.4,
116.8, 114.7, 57.7, 56.2, 29.1 ppm; IR (KBr) νmax 1705, 1315, 1277, 753 cmꢀ1; HRMS
(ESIꢀTOF) m/z: calcd for C13H15NNaO3 [M+Na]+, 256.0944; found, 256.0949.
2-(tert-Butyl)-5-nitroisoindoline-1,3-dione (3i)
o
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Yellow solid (28 mg, 58 %), mp: 62.0ꢀ63.2 C; H NMR (400 MHz, CDCl3) δ
8.62ꢀ8.53 (m, 2H), 7.97 (d, J = 8.0 Hz, 1H), 1.72 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 167.5, 167.1, 151.7, 136.5, 133.4, 129.0, 123.9, 118.2, 59.0, 28.9 ppm; IR (KBr)
ν
max 1711, 1536, 1336, 1098, 756 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C12H13N2O4
[M+H]+, 249.0870; found, 249.0862.
2-(tert-Butyl)-4,6-dimethylisoindoline-1,3-dione (3j)
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White solid (34 mg, 75 %), mp: 62.3ꢀ63.4 oC; 1H NMR (400 MHz, CDCl3) δ 7.38 (s,
1H), 7.19 (s, 1H), 2.60 (s, 3H), 2.41 (s, 3H), 1.67 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.7, 169.9, 144.1, 137.0, 136.6, 133.1, 126.2, 120.8, 57.5, 29.2, 21.7, 17.5
ppm; IR (KBr) νmax 1703, 1355, 1310, 1011, 750 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd
for C14H17NNaO2 [M+Na]+, 254.1151; found, 254.1155.
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2-(tert-Butyl)-5,6-dichloroisoindoline-1,3-dione (3k)
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Colorless solid (30 mg, 55 %), mp: 105.7ꢀ106.8 C; H NMR (400 MHz, CDCl3) δ
7.83 (s, 2H), 1.67 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 167.6, 138.6, 131.3, 124.8,
58.5, 28.9 ppm; IR (KBr) νmax 1710, 1589, 1349, 1099, 752 cmꢀ1; HRMS (ESIꢀTOF)
m/z: calcd for C12H12Cl2NO2 [M+H]+, 272.0240; found, 272.0233.
2-(tert-Butyl)-1H-benzo[f]isoindole-1,3(2H)-dione (3l)
o
White solid (34 mg, 67 %), mp: 128.5ꢀ129.4 C; 1H NMR (400 MHz, CDCl3) δ 8.24
(s, 2H), 8.08ꢀ7.97 (m, 2H), 7.72ꢀ7.58 (m, 2H), 1.75 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 169.4, 135.6, 130.1, 128.8, 128.2, 123.7, 58.2, 29.1 ppm; IR (KBr) νmax
1708, 1327, 1101, 755 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C16H15NNaO2
[M+Na]+, 276.0995; found, 276.1001.
2-(tert-Butyl)-1H-benzo[e]isoindole-1,3(2H)-dione (3m)
Colorless solid (39 mg, 78 %), mp: 98.6ꢀ99.9 oC; 1H NMR (400 MHz, CDCl3) δ 8.95
(d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0
Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 1.74 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 171.1, 170.2, 136.6, 134.6, 131.5, 129.3, 128.7, 128.4, 127.8,
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127.0, 124.9, 118.1, 57.7, 29.2 ppm; IR (KBr) νmax 1713, 1586, 1346, 1055, 755 cmꢀ1;
HRMS (ESIꢀTOF) m/z: calcd for C16H15NNaO2 [M+H]+, 276.0995; found, 276.0997.
2-Butylisoindoline-1,3-dione (3n)
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Yellow oil (30 mg, 75 %): H NMR (400 MHz, CDCl3) δ 7.84ꢀ7.83 (m, 2H),
7.71ꢀ7.70 (m, 2H), 3.69 (t, J = 7.2, 2H), 1.66ꢀ1.64 (m, 2H), 1.39ꢀ1.34 (m, 2H), 0.95 (t,
J = 7.4, 3H);13C NMR (100 MHz, CDCl3) δ 168.5, 133.8, 132.2, 123.1, 37.8, 30.7,
20.1, 13.6 ppm; IR (KBr) νmax 1712, 1390, 1047, 733 cmꢀ1; HRMS (ESIꢀTOF) m/z:
calcd for C12H14NO2 [M+H]+, 204.1019; found, 204.1018
2-Isobutylisoindoline-1,3-dione (3o)
Colorless solid (29 mg, 71 %), mp: 92.8ꢀ93.8 C; 1H NMR (400 MHz, CDCl3) δ 7.91
o
(d, J = 2.4 Hz, 2H), 7.72 (d, J = 2.4 Hz, 2H), 3.51 (d, J = 7.2 Hz, 2H), 2.16ꢀ2.09 (m,
1H), 0.95 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.6, 133.9, 132.0,
123.2, 45.3, 27.8, 20.1 ppm; IR (KBr) νmax 1706, 1392, 1050, 716 cmꢀ1; HRMS
(ESIꢀTOF) m/z: calcd for C12H13NNaO2 [M+Na]+, 226.0838; found, 226.0835.
2-Isopropylisoindoline-1,3-dione (3p)
Colorless solid (29 mg, 77 %), mp: 84.1ꢀ85.0 oC; 1H NMR (400 MHz, CDCl3) δ 7.81
(d, J = 1.6 Hz, 2H), 7.70 (d, J = 2.4 Hz, 2H), 4.57ꢀ4.50 (m, 1H), 1.50 (d, J = 6.8 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 168.3, 133.7, 132.1, 123.0, 43.0, 20.1 ppm; IR
(KBr) νmax 1692, 1369, 1034, 869, 753, 710 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for
C11H11NNaO2 [M+Na]+, 212.0682; found, 212.0684.
2-Decylisoindoline-1,3-dione (3q)
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Colorless solid (43 mg, 75 %), mp: 58.3ꢀ59.6 oC; 1H NMR (400 MHz, CDCl3) δ 7.83
(d, J = 2.4 Hz, 2H), 7.71 (d, J = 2.4 Hz, 2H), 3.67 (t, J = 6.8 Hz, 1H), 1.67ꢀ1.65 (m,
2H), 1.25ꢀ1.23 (m, 14H), 0.87ꢀ0.86 (m, 3H);13C NMR (100 MHz, CDCl3) δ 168.5,
133.8, 132.2, 123.1, 38.1, 31.9, 29.5, 29.5, 29.3, 29.2, 28.6, 26.9, 22.7, 14.1 ppm; IR
(KBr) νmax 1713, 1588, 1390, 717 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for
C18H25NNaO2 [M+Na]+, 310.1777; found, 310.1778.
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2-Cyclobutylisoindoline-1,3-dione (3r)
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Colorless solid (28 mg, 70 %), mp: 108.3ꢀ110.0 C; H NMR (400 MHz, CDCl3) δ
7.81 (d, J = 2.6 Hz, 2H), 7.67 (d, J = 2.6 Hz, 2H), 4.75 (p, J = 8.8 Hz, 1H), 2.93 (p, J
= 9.2 Hz, 2H), 2.26ꢀ2.24 (m, 2H), 1.93 (dd, J = 19.6, 10.0 Hz, 1H), 1.78 (dd, J = 19.6,
10.0 Hz, 1H);13C NMR (100 MHz, CDCl3) δ 168.6, 133.9, 132.0, 123.1, 44.7, 27.7,
15.3 ppm; IR (KBr) νmax 1713, 1591, 1377, 755 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd
for C12H11NNaO2 [M+Na]+, 224.0682; found, 224.0679.
2-Cyclopentylisoindoline-1,3-dione (3s)
o
1
Colorless solid (34 mg, 80 %), mp: 101.5ꢀ102.7 C; H NMR (400 MHz, CDCl3) δ
7.80 (s, 2H), 7.70 (s, 2H), 4.64ꢀ4.61(m, 1H), 2.11ꢀ2.04(m, 2H), 1.96ꢀ1.94 (m, 4H),
1.69ꢀ1.63 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 168.5, 133.7, 132.2, 123, 51.0,
29.6, 25.1 ppm; IR (KBr) νmax 1709, 1593, 1376, 1080, 715 cmꢀ1; HRMS (ESIꢀTOF)
m/z: calcd for C13H13NNaO2 [M+Na]+, 238.0838; found, 238.0841.
2-Cyclohexylisoindoline-1,3-dione (3t)
o
1
Yellow solid (34 mg, 75 %), mp: 166.7ꢀ168.2 C; H NMR (400 MHz, CDCl3) δ
7.88ꢀ7.75 (m, 2H), 7.74ꢀ7.62 (m, 2H), 4.11 (t, J = 8.2 Hz, 1H), 2.21 (q, J = 12.4 Hz,
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1H), 1.87 (d, J = 12.0 Hz, 1H), 1.73 (d, J = 12.8 Hz, 1H), 1.50ꢀ1.13 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 168.4, 133.7, 132.1, 123.0, 50.9, 29.9, 26.0, 25.1 ppm; IR
(KBr) νmax 1708, 1383, 1083, 711 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for
C14H15NNaO2 [M+Na]+, 252.0995; found, 252.0993.
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2-((Tetrahydrofuran-2-yl)methyl)isoindoline-1,3-dione (3u)
White solid (35 mg, 76 %), mp: 88.4ꢀ89.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.85 (d,
J = 2.4 Hz, 2H), 7.71 (d, J = 2.4 Hz, 2H), 4.28ꢀ4.25 (m, 1H), 3.92 (dd, J = 10.0,7.2 Hz,
1H), 3.85ꢀ3.72 (m, 2H), 3.71ꢀ3.60 (m, 1H), 2.01ꢀ1.89(m, 2H), 1.85ꢀ1.58 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 168.4, 133.9, 132.1, 123.3, 76.2, 67.9, 41.8, 29.2, 25.3
ppm; IR (KBr) νmax 1711, 1584, 1387, 714 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for
C13H13NNaO3 [M+Na]+, 254.0788; found, 254.0792.
2-Phenylisoindoline-1,3-dione (3v)
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White solid (28 mg, 62 %), mp: 205.5ꢀ207.3 C; H NMR (400 MHz, CDCl3) δ
8.02ꢀ7.90 (m, 2H), 7.79ꢀ7.77 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.45ꢀ7.38 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.3, 134.4, 131.8, 129.1, 128.1, 126.6, 123.8 ppm; IR
(KBr) νmax 1764, 1243, 755 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C14H9NNaO2
[M+Na]+, 246.0525; found, 246.0520.
2-(p-Tolyl)isoindoline-1,3-dione (3w)
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White solid (37 mg, 78 %), mp: 203.9ꢀ205.3 C; H NMR (400 MHz, CDCl3) δ
7.97ꢀ7.90 (m, 2H), 7.80ꢀ7.74 (m, 2H), 7.30 (s, 4H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.4, 138.2, 134.3, 131.9, 129.8, 129.0, 126.5, 123.7, 21.2 ppm. IR (KBr)
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νmax 1716, 1383, 1108, 718 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C15H12NO2
[M+Na]+, 238.0863; found, 238.0863.
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2-(4-Isopropylphenyl)isoindoline-1,3-dione (3x)
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White solid (42 mg, 80 %), mp: 216.8ꢀ218.1 C; H NMR (400 MHz, CDCl3) δ
8.01ꢀ7.90 (m, 2H), 7.83ꢀ7.75 (m, 2H), 7.42ꢀ7.31 (m, 4H), 2.97 (dt, J = 13.8, 6.9 Hz,
1H), 1.28 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.5, 148.9, 134.3,
131.9, 129.2, 127.2, 126.4, 123.7, 33.9, 23.9 ppm. IR (KBr) νmax 1706, 1110, 882, 746
cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C17H15NNaO2 [M+Na]+, 288.0992; found,
288.0995.
2-(4-Phenoxyphenyl)isoindoline-1,3-dione (3y)
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White solid (35 mg, 55 %), mp: 153.1ꢀ154.8 C; H NMR (400 MHz, CDCl3) δ
8.02ꢀ7.92 (m, 2H), 7.86ꢀ7.76 (m, 2H), 7.40 (t, J = 8.0 Hz, 4H), 7.20ꢀ7.09 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 167.4, 157.2, 156.5, 134.4, 131.8, 129.9, 128.1, 126.4,
123.9, 123.8, 119.5, 118.8 ppm. IR (KBr) νmax 1711, 1590, 1291, 748 cmꢀ1; HRMS
(ESIꢀTOF) m/z: calcd for C20H13NNaO3 [M+Na]+, 338.0789; found, 338.0788.
2-(4-Fluorophenyl)isoindoline-1,3-dione (3z)
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White solid (22 mg, 45 %), mp: 178.0ꢀ179.4 C; H NMR (400 MHz, CDCl3) δ
7.97ꢀ7.94 (m, 2H), 7.85ꢀ7.76 (m, 2H), 7.46ꢀ7.37 (m, 2H), 7.20 (t, J = 8.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 167.2, 134.5, 131.7, 128.4, 128.3, 123.8, 116.2, 116.0
ppm. IR (KBr) νmax 1715, 1113, 885, 755 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for
C14H8FNNaO2 [M+Na]+, 264.0431; found, 264.0431.
2-(4-Chlorophenyl)isoindoline-1,3-dione (3aa)
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White solid (28 mg, 55 %), mp: 179.4ꢀ181.5 C; H NMR (400 MHz, CDCl3) δ
7.97ꢀ7.95 (m, 2H), 7.83ꢀ7.78 (m, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 167.0, 134.6, 133.8, 131.7, 130.2, 129.3, 127.7,
123.9 ppm. IR (KBr) νmax 1714, 1495, 1120, 822, 754 cmꢀ1; HRMS (ESIꢀTOF) m/z:
calcd for C14H9ClNO2 [M+H]+, 258.0319; found, 258.0316.
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2-(4-Bromophenyl)isoindoline-1,3-dione (3ab)
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White solid (45 mg, 75 %), mp: 196.3ꢀ198.4 C; H NMR (400 MHz, CDCl3) δ
7.99ꢀ7.92 (m, 2H), 7.83ꢀ7.77 (m, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 166.9, 134.6, 132.3, 131.6, 130.8, 127.9, 123.9,
121.8 ppm. IR (KBr) νmax 1712, 1392, 1119, 884, 712 cmꢀ1; MS (EI) m/z 104, 151,
178, 257, 301.
2-(Naphthalen-1-yl)isoindoline-1,3-dione (3ac)
Brown solid (41 mg, 76 %), mp: 180.4ꢀ181.7 oC; 1H NMR (400 MHz, CDCl3) δ 8.23
(d, J = 8.4, 1H), 8.09 (d, J = 8.4, 1H), 8.02 (d, J = 7.2, 1H), 7.92 (d, J = 8.0, 1H), 7.87
(d, J = 8.4, 1H), 7.78ꢀ7.74 (m, 2H), 7.70 (t, J = 7.2, 2H), 7.65 (t, J = 7.6 1H), 6.83 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 166.0, 162.8, 139.8, 137.4, 137.2, 133.9, 131.6,
131.4, 129.9, 128.4, 127.6, 127.2, 126.9, 125.9, 125.1, 124.4, 124.3, 114.3, 86.4 ppm;
IR (KBr) νmax 1727, 1409, 1373, 1009, 757 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for
C18H11NNaO2 [M+Na]+, 296.0682; found, 296.0679.
2-Phenyl-1H-benzo[e]isoindole-1,3(2H)-dione (3ad)
Yellow solid (39 mg, 72%), mp: 166.3ꢀ167.0 oC; 1H NMR (400 MHz, CDCl3) δ 9.00
(d, J = 8.0 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.96 (dd, J = 16.4, 8.0 Hz, 2H), 7.74 (d,
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J = 7.2 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.51ꢀ7.48 (m, 4H), 7.41 (s, 1H); C NMR
(100 MHz, CDCl3) δ 168.5, 167.8, 136.8, 135.4, 131.8, 131.1, 129.7, 129.1, 128.9,
128.8, 128.2, 127.9, 127.0, 126.7, 125.1, 118.7 ppm; IR (KBr) νmax 1714, 1376, 1099,
756 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C18H11NNaO2 [M+Na]+, 296.0682; found,
296.0681.
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2-Benzylisoindoline-1,3-dione (3ae)
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Yellow solid (32 mg, 68%), mp: 105.6ꢀ107.4 C; H NMR (400 MHz, CDCl3) δ
7.88ꢀ7.78 (m, 2H), 7.69 (d, J = 2.5 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.33ꢀ7.25 (m,
3H), 4.84 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 168.1, 136.4, 134.0, 132.1, 128.7,
128.6, 127.8, 123.4, 41.6 ppm; IR (KBr) νmax 1712, 1390, 1343, 943, 754 cmꢀ1;
HRMS (ESIꢀTOF) m/z: calcd for C15H11NNaO2 [M+Na]+, 260.0682; found,
260.0684.
2-(Hydroxymethyl)-N-phenylbenzamide (4a)
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White solid (0.44 g, 89 %), mp: 134.1ꢀ135.7 C; H NMR (400 MHz, CDCl3) δ 8.43
(s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.54ꢀ7.49 (m, 1H),
7.44ꢀ7.37 (m, 4H), 7.18 (t, J = 7.4 Hz, 1H), 5.35 (s, 1H), 4.71 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 167.8, 139.2, 137.9, 136.1, 131.5, 131.0, 129.1, 128.5, 128.4, 124.8,
120.4, 64.6 ppm; IR (KBr) νmax 3063, 2925, 1594, 1542, 1323, 1009, 753 cmꢀ1;
HRMS (ESIꢀTOF) m/z: calcd for C14H13NNaO2 [M+Na]+, 250.0838; found,
250.0842.
2,3-Dihydrophthalazine-1,4-dione (4b)
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White solid (0.34 g, 95%), mp: >300 oC; 1H NMR (400 MHz, DMSOꢀd6) δ 8.18ꢀ7.97
(m, 2H), 7.85ꢀ7.72 (m, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 156.5, 131.6, 128.6,
125.4 ppm; IR (KBr) νmax 3080, 1713, 1584, 1368, 9401, 755 cmꢀ1; HRMS (ESIꢀTOF)
m/z: calcd for C8H6N2NaO2 [M+Na]+, 185.0321; found, 185.0319.
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N1-Cyclopentyl-N2-phenylphthalamide (4c)
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White solid (0.54 g, 79 %), mp: 204.1ꢀ206.2 C; H NMR (400 MHz, CDCl3) δ 9.18
(s, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.49 (s, 3H), 7.35 (t, J = 7.4
Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 6.42 (s, 1H), 4.31 (dd, J = 13.2, 6.8 Hz, 1H),
1.96ꢀ1.94 (m, 2H), 1.58ꢀ1.56 (m, 4H), 1.41ꢀ1.40 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 169.6, 166.6, 138.1, 134.6, 130.6, 130.3, 129.4, 129.0, 127.9, 124.6, 120.1,
52.1, 33.0, 23.7 ppm; IR (KBr) νmax 3067, 1743, 1589, 1546, 941, 755 cmꢀ1; HRMS
(ESIꢀTOF) m/z: calcd for C19H21N2O2 [M+H]+, 309.1598; found, 309.1594.
3-Hydroxy-2-phenyl-3-(trifluoromethyl)isoindolin-1-one (4d)
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White solid (0.58 g, 89 %), mp: 189.8ꢀ191.0 C; H NMR (400 MHz, CDCl3) δ 7.72
(d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.4Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.40ꢀ7.35 (m,
1H), 7.32 (t, J = 7.4 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 5.64
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 167.6, 140.4, 133.9, 133.2, 131.1, 131.0,
129.1, 128.6, 128.4, 124.0, 123.8, 121.2, 89.9, 89.4, 89.1, 88.6 ppm; IR (KBr) νmax
3072, 1702, 1593, 1368, 1182, 953, 696 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for
C15H11F3NO2 [M+H]+, 294.0736; found, 294.0735.
2-(tert-Butyl)-5-(dimethylamino)isoindoline-1,3-dione (4e)
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Fluorescence yellow solid (39 mg, 80 %), mp: 109.4ꢀ110.6 C; H NMR (400 MHz,
CDCl3) δ 7.57 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 18.9 Hz, 1H), 6.79 (t, J = 9.3 Hz, 1H),
3.09 (s, 6H), 1.67 (s, 9H); 13C NMR (100MHz, CDCl3) δ 170.4, 170.2, 154.2, 134.7,
124.1, 118.5, 115.0, 104.9, 57.3, 40.6, 29.2 ppm; IR (KBr) νmax 1700, 1320, 753 cmꢀ1;
HRMS (ESIꢀTOF) m/z: calcd for C14H18N2NaO2 [M+Na]+, 269.1260; found,
269.1267.
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2-Cyclopentyl-5-(dimethylamino)isoindoline-1,3-dione (4f)
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Fluorescence yellow solid (33 mg, 65 %), mp: 87.1ꢀ88.1 C; H NMR (400 MHz,
CDCl3) δ 7.61 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.62ꢀ4.52 (m,
1H), 3.10 (s, 6H), 2.08ꢀ2.05 (m, 2H), 1.97ꢀ1.86 (m, 4H), 1.62ꢀ1.61 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 169.3, 169.0, 154.3, 134.8, 124.5, 118.0, 114.5, 105.5, 50.7, 40.5,
29.6, 25.0. IR (KBr) νmax 1699, 1368, 1078, 750 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd
for C15H19N2O2 [M+H]+, 259.1444; found, 259.1441.
5-Methyl-2-(3,4,5-trimethoxyphenyl)isoindoline-1,3-dione (I)
White solid (51 mg, 78 %), mp: 214.4ꢀ216.0 C; 1H NMR (400 MHz, CDCl3) δ 7.82
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(d, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 6.65 (s, 2H), 3.88 (d, J =
3.8 Hz, 9H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6, 167.5, 153.4, 145.9,
137.9, 135.0, 132.1, 129.1, 127.3, 124.2, 123.7, 104.5, 60.9, 56.2, 22.1 ppm. IR (KBr)
νmax 1704, 1598, 1131, 742 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C18H17NNaO5
[M+Na]+, 350.0991; found, 350.0999.
2-(2,6-Diisopropylphenyl)isoindoline-1,3-dione (II)
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White solid (28 mg, 45 %), mp: 169.8ꢀ172.4 C; 1H NMR (400 MHz, CDCl3) δ 7.97
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(d, J = 7.8 Hz, 2H), 2.72ꢀ2.66 (m, 2H), 1.17 (d, J = 6.8 Hz, 12H); 13C NMR (100
MHz, CDCl3) δ 168.3, 147.3, 134.3, 132.0, 130.2, 126.9, 124.0, 123.9, 29.4, 24.0 ppm;
IR (KBr) νmax 1712, 1587, 1369, 756 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for
C20H21NNaO2 [M+Na]+, 330.1464; found, 330.1469.
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2-(2,2-Diethoxyethyl)isoindoline-1,3-dione (precursor of III)
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Yellow oil (36 mg, 68 %): H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.4 Hz, 2H),
7.72 (d, J = 2.5 Hz, 2H), 4.89 (t, J = 4.8 Hz, 1H), 3.83 (d, J = 5.2 Hz, 2H), 3.78ꢀ3.69
(m, 2H), 3.59ꢀ3.50 (m, 2H), 1.16 (t, J = 6.8 Hz, 6H);13C NMR (100 MHz, CDCl3) δ
168.1, 134.0, 132.1, 123.3, 98.5, 61.8, 39.8, 15.2 ppm; IR (KBr) νmax 1714, 1388,
1019, 716 cmꢀ1; HRMS (ESIꢀTOF) m/z: calcd for C14H17NNaO4 [M+Na]+, 286.1050;
found, 286.1051.
Methyl 2-(1,3-Dioxo-2-phenylisoindolin-4-yl)acetate (precursor of IV)
White solid (32 mg, 55 %), mp: 98.3ꢀ99.7 oC; 1H NMR (400 MHz, CDCl3) δ 7.90 (d,
J = 7.2 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz,
2H), 7.47ꢀ7.33 (m, 3H), 4.22 (s, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.8, 167.6, 167.0, 136.7, 134.3, 133.6, 132.4, 131.6, 129.1, 128.1, 126.6, 122.9,
52.3, 36.2 ppm; IR (KBr) νmax 1714, 1585, 1377, 754 cmꢀ1; HRMS (ESIꢀTOF) m/z:
calcd for C17H13NNaO4 [M+Na]+, 318.0737; found, 318.0741.
N-(2-Butyl-1,3-dioxoisoindolin-5-yl)-4-methylbenzenesulfonamide (V)
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White solid (22 mg, 29 %), mp: 147.5ꢀ149.1 C; H NMR (400 MHz, CDCl3) δ
7.79ꢀ7.78(m, 4H), 7.37ꢀ7.33 (m, 4H), 3.68 (t, J = 7.2 Hz, 2H), 2.47 (s, 3H), 1.70ꢀ1.61
(m, 2H), 1.38 (dt, J = 15.0, 7.4 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.2, 166.9, 145.7, 139.6, 137.3, 136.0, 133.2, 133.1, 129.9, 128.6, 126.3,
123.8, 38.1, 30.5, 21.7, 20.1, 13.6; IR (KBr) νmax 1715, 1382, 1170, 932, 665, 551
cmꢀ1; MS (EI) m/z 91, 155, 174, 217, 329, 372.
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Acknowledgements
The authors thank the National Key Research and Development Program of China
(2016YFA0602900), the National Natural Science Foundation of China
(21420102003 and 21672072), and the Fundamental Research Funds for the Central
Universities (2015ZY001 and 2017ZD062) for financial support.
Supporting Information
1H and 13C NMR spectra of all synthesized compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
1. (a) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744; (b) Gao, K.; Yoshikai,
N. Acc. Chem. Res. 2014, 47, 1208; (c) Ackermann, L. Acc. Chem. Res. 2014, 47,
281.
2. (a) Li, S.; Chen, G.; Feng, C.ꢀG.; Gong, W.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2014, 136,
5267.; (b) Kong, W. J.; Liu, Y.ꢀJ.; Xu, H.; Chen, Y.ꢀQ.; Dai, H.ꢀX.; Yu, J.ꢀQ. J. Am.
Chem. Soc. 2016, 138, 2146; (c) Zhang, F.ꢀL.; Hong, K.; Li, T.ꢀJ.; Park, H.; Yu,
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