Organocatalyzed Synthesis of Highly Functionalized Phthalimides via Diels-Alder Reaction Employing Two Dienophiles

Article abstract of DOI:10.1021/acs.joc.0c01991

An efficient and facile protocol for the synthesis of biologically and pharmaceutically important phthalimides is developed by l-proline-catalyzed reaction between two dienophiles of α,β-unsaturated aldehydes and maleimides. The reaction involves an efficient benzannulation that proceeds via a formal [4 + 2] cycloaddition of azadiene intermediates generated in situ from enals and N-substituted maleimides. This protocol provides a variety of functionalized phthalimide derivatives, including a potent COX-2 enzyme inhibitor.

Full text of DOI:10.1021/acs.joc.0c01991

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Article
Organocatalyzed Synthesis of Highly Functionalized Phthalimides
via Diels−Alder Reaction Employing Two Dienophiles
Muhammad Saeed Akhtar and Yong Rok Lee*
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ABSTRACT: An efficient and facile protocol for the synthesis of biologically
and pharmaceutically important phthalimides is developed by L-proline-
catalyzed reaction between two dienophiles of α,β-unsaturated aldehydes and
maleimides. The reaction involves an efficient benzannulation that proceeds
via a formal [4 + 2] cycloaddition of azadiene intermediates generated in situ
from enals and N-substituted maleimides. This protocol provides a variety of
functionalized phthalimide derivatives, including a potent COX-2 enzyme
inhibitor.
Scheme 1. (A) Commercial Medicines Bearing a Phthalimide
Moiety. (B) Reported Strategies for N-Substituted
Phthalimides
INTRODUCTION
■
The structural diversities and physicochemical properties of
nitrogen-containing heterocycles have received significant
attention as targets for medicinal chemistry over many years.1
Among these, phthalimides are important molecules used as
bioactive materials and pharmaceuticals.2 They are biologically
active; for instance, they have exhibited immunomodulatory,
anti-inflammatory, fungicidal, analgesic, antimicrobial, antitu-
mor, anxiolytic, anticonvulsant, antihistaminic, hypolipidemic,
herbicidal, and insecticidal activities.3 Some commercial drugs
containing phthalimide skeletons are used to treat rheumatoid
arthritis (Thalomid), multiple myeloma (Pomalyst), and
psoriasis (Otezla) (Scheme 1A).4 Furthermore, phthalimide
derivatives are widely exploited for the synthesis of valuable
materials for catalysts,5 dyes,6 polymers,7 and fluorescent
probes.8
The importance and utility of phthalimides have prompted
the development of various synthetic procedures. One common
approach to phthalimides involves the condensation of phthalic
acids or anhydrides with amines (Scheme 1B, path a).9 Other
approaches have also been reported, including a Ru-catalyzed
reaction of 1,2-benzenedimethanol with amines (Scheme 1B,
path b),10 a multicomponent reaction of arynes with isocyanides
and CO2 (Scheme 1B, path c),11 and a metal-catalyzed
cyclocarbonylation of aromatic amides (Scheme 1B, path d).12
Recently, prominent synthetic strategies for phthalimides
have involved transition-metal-catalyzed benzannulation reac-
tions. These strategies include Pd-catalyzed annulation of
vinylarenes with maleimides (Scheme 2A, path a)13 and Cu-
catalyzed cycloaddition of oximes with maleimides (Scheme 2A,
path b).14 However, more environmentally benign and atom-
economical protocols are still highly desired. Since Diels−Alder
reaction mostly requires electron-rich dienes, the dienamine
generated from the reaction of amines and α,β-unsaturated
Received: August 18, 2020
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© XXXX American Chemical Society
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A

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a
Scheme 2. Strategies for N-Substituted Phthalimides via
Benzannulation
Table 1. Optimization of the Reaction Conditions for 3a
catalyst
additive
(mol %)
yield
b
entry
1
(mol %)
solvent
toluene
condition
(%)
diethylamine
(20)
−
80 °C, 15 h
18
2
3
piperidine (20)
pyrrolidine
(20)
−
−
toluene
toluene
80 °C, 15 h
80 °C, 15 h
30
58
4
5
6
7
8
L-proline (20)
L-proline (20)
L-proline (20)
L-proline (20)
L-proline (20)
−
−
−
−
toluene
dioxane
THF
80 °C, 15 h
80 °C, 15 h
80 °C, 15 h
68
44
47
40
82
CH3CN 80 °C, 15 h
benzoic acid
(10)
acetic acid
(10)
pivalic acid
(10)
benzoic acid
(10)
benzoic acid
(20)
benzoic acid
(10)
benzoic acid
(10)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
80 °C, 10 h
80 °C, 12 h
80 °C, 12 h
80 °C, 12 h
80 °C, 12 h
9
L-proline (20)
L-proline (20)
L-proline (10)
L-proline (20)
L-proline (20)
L-proline (20)
52
43
63
81
79
64
10
11
12
13
14
aldehydes or ketones have a high tendency to undergo formal [4
+ 2] addition with dienophiles.15a,b Furthermore, dienamines
can also be employed as dienophiles in inverse-electron-demand
aza-Diels−Alder reactions.15c This motivated us to establish
effective methods for the synthesis of novel compounds based
on benzannulation via the Diels−Alder reaction. We have
reported a new methodology for anthraquinones and
tetracenediones by L-proline catalyzed [4 + 2] annulation of
α,β-unsaturated aldehydes with 1,4-naphthoquinones or 1,4-
anthracenediones (Scheme 2B).16 As part of continuing
research in this area, we describe herein the L-proline-catalyzed
benzannulation for diverse and multifunctionalized phthali-
mides via a Diels−Alder reaction employing two dienophiles,
instead of a diene and a dienophile (Scheme 2C). This
transformation enabled the transition-metal-free synthesis of
diverse phthalimides through an organocatalytic reaction
between maleimides and α,β-unsaturated aldehydes. In
addition, we also describe the possibility of the use of fumarates
or maleates and α,β-unsaturated aldehydes for phthalates
(Scheme 2C).
100 °C,
12 h
60 °C, 15 h
a
Reaction conditions: 3-methyl-2-butenal (1a, 1.4 mmol) and N-
b
phenylmaleimide (2a, 1.0 mmol) in solvent (5.0 mL). Isolated yield.
h). Switching the additive to acetic acid or pivalic acid led to 3a
being obtained in a lower yield (entries 9 and 10). Then the
amounts of catalyst and additive for the formation of 3a were
examined. The results revealed that decreasing the catalyst
loading to 10 mol % led to an inferior yield of 63% (entry 11).
Similarly, increasing the additive loading to 20 mol % did not
increase the yield (entry 12). Moreover, when the temperature
of the reaction was altered (100 or 60 °C), 3a was furnished in
inferior yields (entries 13 and 14). The structure of compound
1
3a was established through spectral data analysis. In the H
nuclear magnetic resonance (NMR) spectrum, the methyl group
on the benzene ring appeared as a singlet at δ 2.53 ppm, while
another singlet for an aromatic proton was observed at δ 7.73
ppm. Likewise, 13C NMR spectroscopy showed the expected
methyl carbon signal at δ 22.0 ppm and two amide carbonyl
carbon signals at δ 167.3 and 167.4 ppm.
Under the optimal conditions, the generality of the
benzannulation reaction was next investigated using different
α,β-unsaturated aldehydes, 1b−m (Scheme 3). Treatment of
crotonaldehyde (1b), trans-2-pentenal (1c), and trans-2-hexenal
(1d) with 2a resulted in products 3b−d in 73−85% yields.
Additional reactions featuring α,β-unsaturated aldehydes 1e−h,
all with long chains, proceeded smoothly with 2a and provided
expected products 3e−h in 74−83% yields. Further, the reaction
of citral (1i) with 2a gave 3i as the sole product in 71% yield
without the isolation of possible regioisomers generated through
RESULTS AND DISCUSSION
■
The reaction of 3-methyl-2-butenal (1a) and N-phenyl-
maleimide (2a) was investigated with several organocatalysts,
additives, and solvents to optimize the reaction conditions
(Table 1). Our initial attempt with diethylamine (20 mol %) as
the catalyst in toluene at 80 °C afforded compound 3a in 18%
yield (entry 1). Inspired by this result, we subsequently screened
other organocatalysts. Interestingly, when piperidine and
pyrrolidine were employed, product 3a was obtained in slightly
increased yields of 30% and 58%, respectively (entries 2 and 3).
Delightfully, with L-proline as the catalyst, 3a was produced in an
increased yield of 68% (entry 4). Further optimization for
product 3a was conducted by screening different solvents, for
instance, dioxane, tetrahydrofuran (THF), and acetonitrile, in
the presence of L-proline, but inferior yields of 3a were observed
(entries 5−7). Various additives, namely benzoic acid, acetic
acid, and pivalic acid (entries 8−10), were also screened.
Gratifyingly, with benzoic acid (10 mol %) as an additive, 3a was
obtained in an improved yield of 82% in short reaction time (10
1
the formation of other diene intermediates. The H NMR
spectrum of 3i showed an aromatic proton singlet at δ 7.75 ppm
and two aromatic doublets for the phthalimide moiety at δ 7.56
and 7.82 ppm. The reaction of 2-methyl-2-pentenal (1j) with 2a
afforded the desired product 3j in 72% yield. In addition,
reaction of (E)-2-phenyl-2-butenal (1k) with 2a afforded 3k in
B
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Scheme 3. Preparation of Phthalimides 3b−m from
Aldehydes 1b−m and 2a
Scheme 4. Preparation of Phthalimides 4a−r from 1a, 1b, and
N-Substituted Maleimides 2b−q
82% yield. Furthermore, the reactions of 3-phenyl-2-butenal
(1l) or (E)-4-phenylbut-2-enal (1m) having an aryl substituent
at β- or γ-position of the aldehyde with 2a were also successful
and afforded the desired products 3l and 3m in 73% and 83%
yields, respectively.
Scheme 5. Preparation of Phthalimides 5a−j from
Maleimides 2r−t Bearing Polyaromatics and
Heteroaromatics
Then we explored the synthesis of a variety of phthalimides
from N-substituted maleimides 2b−q bearing aryl, alkyl, allyl,
and benzyl groups using this protocol (Scheme 4). Reaction of
1a with N-substituted arylmaleimides 2b−d featuring electron-
donating or -withdrawing substituents led to products 4a−c in
86%, 78%, and 76% yields, respectively. The reactions of N-
substituted maleimides 2e−I containing acyclic or cyclic alkyl
groups proceeded smoothly to afford products 4d−h in 75−82%
yields. With N-allyl-substituted maleimide 2j, expected product
4i was obtained in 71% yield. The reaction of 1a with N-
benzylmaleimide 2k and N-benzylmaleimides 2l−n with
substituted benzene rings afforded expected products 4j−m in
76−86% yields. In addition, the reaction of 1a with N-(4-
acetylphenyl)maleimide (2o) afforded product 4n in 87% yield.
Notably, the reactions of 1a and 1b with (R)-(+)-N-(1-
phenylethyl)maleimide (2p) and (S)-(−)-N-(1-phenylethyl)-
maleimide (2q) produced chiral compounds 4o−r in 72−81%
yields.
To further examine the versatility of this protocol, we
investigated reactions with maleimides 2r−t bearing polyar-
omatic and heteroaromatic rings (Scheme 5). The reactions of
1a−c, 1e, 1f, and 1k with 2r provided products 5a−f in 71−85%
yields. The reaction between 1a and 2s bearing an N- pyrenyl
group afforded 5g in 83% yield. Reactions involving N-
heteroaromatic maleimides were also successful. Treatment of
1a, 1c, and 1d with N-(tetrahydrofurfuryl)maleimide (2t)
afforded 5h−j in 65−73% yields.
The significance of this efficient protocol was validated by the
synthesis of bioactive material 6, which has shown potent
activity (IC50 = 0.4 μM) as a COX-2 enzyme inhibitor (Scheme
6A).17 Cyclooxygenase (COX) is an enzyme that produces
prostaglandins, which are responsible for promoting pain,
inflammation, and fever. For another application of this
protocol, the synthesis of biphthalimides, which can be used
in various polymers, was then attempted using the correspond-
ing dimaleimides as starting materials (Scheme 6B). Notably,
the reactions of 2v and 2w with 1a provided desired products 7
and 8 in 83% and 77% yields, respectively.
To further validate the usefulness of this protocol, the reaction
of various electron-poor olefins such as alkyl fumarates/maleates
C
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Scheme 6. (A) Synthesis of Bioactive Material 6. (B)
Synthesis of Biphthalimides 7 and 8
Scheme 8. (A) Control Experiments. (B) Possible
Mechanistic Pathway for the Formation of 3a
or maleic anhydride with α,β-unsaturated aldehyde 1a was
examined (Scheme 7). Delightfully, the reactions of dimethyl or
Scheme 7. (A) Synthesis of Phthalates 9a and 9b from 1a and
Fumarates/Maleates 2x, 2y, and 2x′. (B) Reaction of 1a with
Maleic Anhydride (2z)
shown in Scheme 8B. Initially, in the presence of L-proline and
benzoic acid, α,β-unsaturated aldehyde 1a was converted into
iminium ion 11, which was then converted into azadiene
intermediate 12a via 12. The [4 + 2] cycloaddition of 12a with
2a gave Diels−Alder adduct 13, which subsequently underwent
elimination of L-proline to give intermediate 10. This
intermediate 10 was isolated in the control experiment, and
the regenerated L-proline was reused as a catalyst. Finally,
oxidative aromatization of intermediate 10 resulted in the
construction of 3a. In these reactions, the amines used as catalyst
were very week bases, so the reaction via the dienolate
generation followed by the [4 + 2] annulation was excluded.
CONCLUSION
■
In conclusion, we have reported an efficient, facile, and atom-
economical one-pot procedure for the synthesis of diverse and
functionalized phthalimides through a formal [4 + 2] cyclo-
addition using two dienophiles. A wide variety of N-substituted
maleimides and α,β-unsaturated aldehydes were compatible
with this transformation, providing an array of functionalized
phthalimides in good to excellent yields. The developed
methodology was successfully implemented for the synthesis
of a biologically attractive molecule that is a potent COX-2
enzyme inhibitor. Furthermore, this protocol also provided a
rapid synthetic route to phthalates by the reaction of fumarates
or maleates with α,β-unsaturated aldehydes.
diethyl fumarates (2x or 2y) with 1a were successful, and the
corresponding phthalates 9a and 9b were obtained in 65% and
68% yields, respectively. In addition, when dimethylmaleate
(2x′) was used as a substrate, the corresponding product 9a was
obtained in a slightly higher yield of 74% (Scheme 7A).
However, when maleic anhydride (2z) was employed, the
corresponding product 9c was not obtained and starting
materials were recovered (Scheme 7B).
In an attempt to investigate the reaction mechanism, control
experiments aimed at trapping the reaction intermediate
involved in the formation of 3a were carried out (Scheme
8A). Interestingly, when model substrate 1a was reacted with 2a
at a reduced temperature of 40 °C under a nitrogen atmosphere,
desired product 3a (8%) was obtained along with unaromatized
product 10 (76%). Further reaction of intermediate 10 under air
oxidation gave the desired product 3a in 84% yield. From these
experiments, we inferred that 10 is the probable intermediate for
the preparation of 3a. Compound 10 was also analyzed for
optical rotation and enantiomeric purity by using a chiral HPLC
column. However, the results revealed that 10 is a racemic
mixture (see Supporting Information, SI).
EXPERIMENTAL SECTION
■
All reagents and solvents were purchased at the highest commercial
quality and used without further purification. N-Substituted maleimides
and α,β-unsaturated aldehydes were purchased from Sigma-Aldrich,
TCI Chemicals, or Alfa Aesar. All the reactions were performed in oven-
dried glassware with magnetic stirring. Merck precoated silica gel plates
(Art. 5554) with a fluorescent indicator were used for analytical TLC
and were visualized with a UV lamp. Column chromatography was
performed using silica gel 9385 (Merck). H NMR and 13C NMR
1
spectra were recorded on a Varian VNS (600 and 150 MHz)
spectrometer or a Bruker DPX (300 and 75 MHz) spectrometer at
the core research center for natural products and medical materials of
Yeungnam University. The chemical shifts were described in parts per
On the basis of the control experiments and literature reports,
a possible mechanism for the synthesis of 3a was proposed as
D
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million (δ) relative to TMS (0 ppm) as an internal standard or relative
to the resonance of the residual protonated solvent (1H: CDCl3, δ =
7.24 ppm). 13C NMR spectra were referenced to the internal solvent
signals (13C: CDCl3, δ = 77.0 ppm). IR spectra were recorded on a
PerkinElmer Spectrum Two IR spectrometer. Melting points were
measured with a Fisher Johns melting point apparatus. The high-
resolution mass spectra (HRMS) were measured using a JEOL JMS-
700 mass spectrometer (magnetic sector-electric sector double focusing
mass analyzer) at the Korean Basic Science Institute. High performance
liquid chromatography (HPLC) was recorded on a Shimadzu
spectrometer (chiral column: CHIRALCELL OJ-H; solvent: hexane/
2-propanol = 99/1; flow rate: 1.0 mL/min; detection: at 254 nm).
Optical rotations were measured using a 2 mL cell with 100 mm path
length on Rudolph Research Analytical Autopol I automatic polar-
imeter and reported as follows: [α]25D (c: g/100 mL, in solvent).
General Procedure for the Synthesis of Phthalimides 3−6.
To a solution of α,β-unsaturated aldehydes 1 (1.4 mmol) and N-
substituted maleimide 2 (1.0 mmol) in toluene (5.0 mL) were added L-
proline (20 mol %) and benzoic acid (10 mol %). The mixture was
stirred and heated in an oil bath at 80 °C for 10−15 h. After completion
of the reaction as indicated by TLC, the reaction mixture was
evaporated in a rotary evaporator and the residue was purified on a silica
gel column chromatography using ethyl acetate/hexane (1:20) as
eluent to afford the desired product.
Representative 1 mmol Scale Procedure for the Synthesis of
Phthalimide 3a. To a solution of 3-methyl-2-butenal 1a (1.4 mmol,
118 mg) and N-phenylmaleimide 2a (1.0 mmol, 173 mg) in toluene
(5.0 mL) were added L-proline (20 mol %, 23 mg) and benzoic acid (10
mol %, 11 mg). The mixture was stirred and heated in an oil bath at 80
°C for 10 h. After completion of the reaction as indicated by TLC, the
reaction mixture was evaporated in a rotary evaporator and the residue
was purified on a silica gel column chromatography using ethyl acetate/
hexane (1:20) as eluent to afford the desired product 3a (185 mg) in
82% yield as a yellow solid.
Procedure for Synthesis of Phthalimides 7 and 8. To a solution
of α,β-unsaturated aldehyde 1 (2.8 mmol) and N-substituted
dimaleimide 2 (1.0 mmol) in toluene (5.0 mL) were added L-proline
(20 mol %) and benzoic acid (10 mol %). The mixture was stirred and
heated in an oil bath at 80 °C for 10−15 h. After completion of the
reaction as indicated by TLC, the reaction mixture was evaporated in a
rotary evaporator and the residue was purified on a silica gel column
chromatography using ethyl acetate/hexane (1:20) as eluent to afford
the desired product.
General Procedure for Synthesis of Products 9a−c. To a
solution of α,β-unsaturated aldehyde 1a (1.4 mmol) and alkyl
fumarate/maleate 9 (1.0 mmol) in toluene (5.0 mL) were added L-
proline (20 mol %) and benzoic acid (10 mol %). The reaction was
carried out in an oil bath at 110 °C under nitrogen atmosphere. The
mixture was stirred for 36 h. After complete disappearance of starting
material 1a as indicated by TLC, the reaction mixture was evaporated in
a rotary evaporator and the residue was purified on a silica gel column
chromatography using ethyl acetate/hexane (1:20) as eluent to afford
the desired product.
123.6, 22.0; IR (neat) 3019, 2970, 1738, 1440, 1370, 1217, 1094, 1061
cm−1; HRMS (EI) m/z: [M+] Calcd for C15H11NO2 237.0790; found
237.0792.
2-Phenylisoindoline-1,3-dione (3b). Yield 73% (163 mg) as a white
solid: mp 207−209 °C; purification by column chromatography
(EtOAc/n-hexane = 1:20). 1H NMR (600 MHz, CDCl3) δ 7.94 (2H,
dd, J = 5.4, 3.0 Hz), 7.77 (2H, dd, J = 5.4, 3.0 Hz), 7.49 (2H, t, J = 7.8
Hz), 7.43 (2H, d, J = 7.7 Hz,), 7.39 (1H, t, J = 7.5 Hz); 13C{1H} NMR
(150 MHz, CDCl3) δ 167.2, 134.3, 131.7, 131.6, 129.1, 128.0, 126.5,
123.7; IR (neat) 3054, 1776, 1704, 1494, 1380, 1217, 1113 cm−1;
HRMS (EI) m/z: [M+] Calcd for C14H9NO2 223.0633; found
223.0635.
4-Methyl-2-phenylisoindoline-1,3-dione (3c). Yield 85% (201 mg)
as a white solid: mp 142−144 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.76 (1H, d, J = 7.4 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.51−7.47
(3H, m), 7.42 (2H, d, J = 7.8 Hz), 7.38 (1H, t, J = 7.4 Hz), 2.73 (3H, s);
13C{1H} NMR (150 MHz, CDCl3) δ 167.9, 167.2, 138.4, 136.6, 133.8,
132.1, 131.7, 128.9, 128.3, 127.9, 126.5, 121.3, 17.6; IR (neat) 3070,
3025, 2959, 1717, 1495, 1374, 1202, 1105 cm−1; HRMS (EI) m/z:
[M+] Calcd for C15H11NO2 237.0790; found 237.0793.
4-Ethyl-2-phenylisoindoline-1,3-dione (3d). Yield 81% (203 mg)
as a white solid: mp 107−109 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.77 (1H, d, J = 7.2 Hz), 7.64 (1H, t, J = 7.6 Hz), 7.55 (1H, d,
J = 7.7 Hz), 7.49−7.46 (2H, m), 7.43−7.42 (2H, m), 7.37 (1H, t, J = 7.3
Hz), 3.16 (2H, q, J = 7.6 Hz), 1.31 (3H, t, J = 7.6 Hz); 13C{1H} NMR
(150 MHz, CDCl3) δ 167.7, 167.2, 144.8, 135.1, 134.0, 132.3, 131.7,
128.9, 127.8, 127.7, 126.5, 121.3, 24.5, 14.8; IR (neat) 2971, 1705,
1592, 1488, 1377, 1230, 1100 cm−1; HRMS (EI) m/z: [M+] Calcd for
C16H13NO2 251.0946; found 251.0943.
2-Phenyl-4-propylisoindoline-1,3-dione (3e). Yield 82% (218 mg)
as a yellow solid: mp 96−98 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.77 (1H, d, J = 7.2 Hz), 7.64 (1H, t, J = 7.5 Hz), 7.53 (1H, d,
J = 7.7 Hz), 7.49−7.47 (2H, m), 7.43−7.41 (2H, m), 7.38 (1H, t, J = 7.3
Hz), 3.10 (2H, t, J = 7.2 Hz), 1.74−1.68 (2H, m), 0.99 (3H, t, J = 7.2
Hz); 13C{1H} NMR (150 MHz, CDCl3) δ 167.8, 167.2, 143.4, 135.9,
133.8, 132.3, 131.7, 128.9, 127.9, 127.9, 126.6, 121.4, 33.3, 24.0, 13.9;
IR (neat) 3016, 2967, 1739, 1495, 1373, 1219, 1105 cm−1; HRMS (EI)
m/z: [M+] Calcd for C17H15NO2 265.1103; found 265.1104.
4-Butyl-2-phenylisoindoline-1,3-dione (3f). Yield 83% (279 mg) as
a yellow solid: mp 70−72 °C; purification by column chromatography
(EtOAc/n-hexane = 1:20). 1H NMR (600 MHz, CDCl3) δ 7.77 (1H, d,
J = 7.3 Hz), 7.64 (1H, t, J = 7.5 Hz), 7.53 (1H, d, J = 7.7 Hz), 7.48 (2H,
t, J = 7.7 Hz), 7.42 (2H, d, J = 7.9 Hz), 7.38 (1H, t, J = 7.4 Hz), 3.12
(2H, t, J = 7.8 Hz), 1.68−1.63 (2H, m), 1.44−1.38 (2H, m), 0.94 (3H, t,
J = 7.4 Hz); 13C{1H} NMR (150 MHz, CDCl3) δ 167.8, 167.2, 143.7,
135.8, 133.9, 132.3, 131.7, 129.0, 127.9, 127.9, 126.6, 121.4, 33.0, 31.1,
22.5, 13.8; IR (neat) 3019, 2957, 1739, 1449, 1372, 1215, 1105 cm−1;
HRMS (EI) m/z: [M+] Calcd for C18H17NO2 279.1259; found
279.1257.
4-Pentyl-2-phenylisoindoline-1,3-dione (3g). Yield 76% (224 mg)
as a brown solid: mp 53−55 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.77 (1H, d, J = 7.2 Hz), 7.63 (1H, t, J = 7.6 Hz), 7.53 (1H, d,
J = 7.7 Hz), 7.49−7.47 (2H, m), 7.42−7.41 (2H, m), 7.38 (1H, t, J = 7.4
Hz), 3.11 (2H, t, J = 7.8 Hz), 1.70−1.65 (2H, m), 1.39−1.32 (4H, m),
0.88 (3H, t, J = 7.0 Hz); 13C{1H} NMR (150 MHz, CDCl3) δ 167.8,
167.2, 143.7, 135.8, 133.9, 132.3, 131.6, 128.9, 127.9, 127.8, 126.6,
121.37, 31.6, 31.4, 30.6, 22.4, 13.9; IR (neat) 2924, 2854, 1738, 1705,
1495, 1376, 1225, 1105 cm−1; HRMS (EI) m/z: [M+] Calcd for
C19H19NO2 293.1416; found 293.1417.
Procedure for Synthesis of Compound 10. To a solution of α,β-
unsaturated aldehyde 1a (1.4 mmol) and N-substituted maleimide 2a
(1.0 mmol) in toluene (5.0 mL) were added L-proline or pyrrolidine
(20 mol %) and benzoic acid (10 mol %). The reaction was carried out
in an oil bath at 40 °C under nitrogen atmosphere. The mixture was
stirred for 10 h. After complete disappearance of starting material 1a as
indicated by TLC, the reaction mixture was evaporated in a rotary
evaporator and the residue was purified on a silica gel column
chromatography using ethyl acetate/hexane (1:20) as eluent to afford
the desired product 10.
5-Methyl-2-phenylisoindoline-1,3-dione (3a). Yield 82% (195 mg)
as a yellow solid: mp 196−198 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.81 (1H, d, J = 7.6 Hz), 7.74 (1H, s), 7.56 (1H, d, J = 7.6
Hz), 7.48 (2H, t, J = 7.8 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.38 (1H, t, J =
7.4 Hz), 2.53 (3H, s); 13C{1H} NMR (150 MHz, CDCl3) δ 167.4,
167.3, 145.7, 134.9, 132.1, 131.7, 129.1, 129.0, 127.9, 126.5, 124.2,
4-Hexyl-2-phenylisoindoline-1,3-dione (3h). Yield 74% (227 mg)
as a yellow solid: mp 75−77 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (300 MHz,
CDCl3) δ 7.76 (1H, d, J = 7.3 Hz), 7.63 (1H, t, J = 7.5 Hz), 7.53−7.35
(6H, m), 3.11 (2H, t, J = 7.9 Hz), 1.71−1.61 (2H, m), 1.41−1.27 (6H,
m), 0.86 (3H t, J = 6.9 Hz); 13C{1H} NMR (75 MHz, CDCl3) δ 167.7,
167.2, 143.7, 135.8, 133.8, 132.2, 131.6, 128.9, 127.8, 127.7, 126.5,
E
https://dx.doi.org/10.1021/acs.joc.0c01991
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
121.3, 31.5, 31.4, 30.9, 29.1, 22.5, 14.0; IR (neat) 2952, 2922, 2848,
1742, 1707, 1499, 1382, 1205, 1113 cm−1; HRMS (EI) m/z: [M+]
Calcd for C20H21NO2 307.1572; found 307.1570.
5-Methyl-2-(2,4,6-trichlorophenyl)isoindoline-1,3-dione (4c).
Yield 76% (260 mg) as a yellow solid: mp 179−181 °C; purification
by column chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600
MHz, CDCl3) δ 7.83 (1H, d, J = 7.7 Hz), 7.76 (1H, s), 7.59 (1H, d, J =
7.6 Hz), 7.47 (2H, s), 2.53 (3H, s); 13C{1H} NMR (150 MHz, CDCl3)
δ 165.6, 165.4, 146.1, 136.3, 136.1, 135.2, 132.0, 129.0, 128.6, 127.1,
124.6, 124.0, 22.0; IR (neat) 3099, 2924, 1778, 1722, 1464, 1358, 1234,
1078 cm−1; HRMS (EI) m/z: [M+] Calcd for C15H8Cl3NO2 338.9621;
found 338.9622.
2,5-Dimethylisoindoline-1,3-dione (4d). Yield 78% (136 mg) as a
yellow solid: mp 127−129 °C; purification by column chromatography
(EtOAc/n-hexane = 1:20). 1H NMR (600 MHz, CDCl3) δ 7.67 (1H, d,
J = 7.6 Hz), 7.59 (1H, s), 7.45 (1H, d, J = 7.5 Hz), 3.12 (3H, s), 2.46
(3H, s); 13C{1H} NMR (150 MHz, CDCl3) δ 168.5, 145.02, 134.2,
134.2, 132.5, 129.5, 123.6, 123.0, 23.8, 21.9; IR (neat) 3019, 2969,
2949, 1740, 1433, 1372, 1218, 1101 cm−1; HRMS (EI) m/z: [M+]
Calcd for C10H9NO2 175.0633; found 175.0632.
2-Ethyl-5-methylisoindoline-1,3-dione (4e). Yield 81% (153 mg)
as a brown solid: mp 73−75 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.67 (1H, d, J = 7.6 Hz), 7.59 (1H, s), 7.45 (1H, d, J = 7.5
Hz), 3.68 (2H, q, J = 7.2 Hz), 2.46 (3H, s), 1.23 (3H, t, J = 7.2 Hz);
13C{1H} NMR (150 MHz, CDCl3) δ 168.3, 168.2, 144.9, 134.2, 132.6,
129.6, 123.6, 122.9, 32.7, 21.9, 13.8; IR (neat) 2987, 2944, 1739, 1711,
1438, 1371, 1208, 1095, 1035 cm−1; HRMS (EI) m/z: [M+] Calcd for
C11H11NO2 189.0790; found 189.0792.
5-Methyl-2-propylisoindoline-1,3-dione (4f). Yield 75% (152 mg)
as a white solid: mp 53−55 °C; purification by column chromatography
(EtOAc/n-hexane = 1:20). 1H NMR (600 MHz, CDCl3) δ 7.67 (1H, d,
J = 7.6 Hz), 7.60 (1H, s), 7.45 (1H, d, J = 7.5 Hz), 3.59 (2H, t, J = 7.3
Hz), 2.47 (3H, s), 1.69−1.63 (2H, m), 0.90 (3H, t, J = 7.4 Hz) 13C{1H}
NMR (150 MHz, CDCl3) δ 168.6, 168.5, 145.0, 134.3, 132.4, 129.5,
123.6, 123.0, 39.4, 21.9, 21.8, 11.2; IR (neat) 2966, 2924, 1734, 1437,
1367, 1217, 1095, 1040 cm−1; HRMS (EI) m/z: [M+] Calcd for
C12H13NO2 203.0946; found 203.0948.
2-(Tert-butyl)-5-methylisoindoline-1,3-dione (4g). Yield 82% (178
mg) as a yellow solid: mp 74−76 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.60 (1H, d, J = 7.6 Hz), 7.52 (1H, s), 7.42 (1H, d, J = 7.5
Hz), 2.45 (3H, s), 1.65 (9H, s); 13C{1H} NMR (150 MHz, CDCl3) δ
169.78, 169.7, 144.7, 134.1, 132.5, 129.5, 122.9, 122.4, 57.6, 29.0, 21.9;
IR (neat) 3003, 2970, 2940, 1740, 1455, 1364, 1213, 1097 cm−1;
HRMS (EI) m/z: [M+] Calcd for C13H15NO2 217.1103; found
217.1101.
2-Cyclohexyl-5-methylisoindoline-1,3-dione (4h). Yield 78% (190
mg) as a white solid: mp 155−157 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (300 MHz,
CDCl3) δ 7.65 (1H, d, J = 7.6 Hz), 7.57 (1H, s), 7.44 (1H, d, J = 7.6
Hz), 4.10−4.00 (1H, m), 2.46 (3H, s), 2.22−2.10 (2H, m), 1.85−1.81
(2H, m), 1.71−1.64 (3H, m), 1.41−1.21 (3H, m); 13C{1H} NMR (75
MHz, CDCl3) δ 168.6, 168.5, 144.8, 134.2, 132.4, 129.4, 123.4, 122.8,
50.7, 29.8, 26.0, 25.1, 21.9.; IR (neat) 3022, 2930, 2860, 1739, 1432,
1367, 1215, 1087 cm−1; HRMS (EI) m/z: [M+] Calcd for C15H17NO2
243.1259; found 243.1263.
2-Allyl-5-methylisoindoline-1,3-dione (4i). Yield 71% (143 mg) as
a white solid: mp 64−66 °C; purification by column chromatography
(EtOAc/n-hexane = 1:20). 1H NMR (600 MHz, CDCl3) δ 7.69 (1H, d,
J = 7.4 Hz), 7.61 (1H, s), 7.47 (1H, d, J = 7.6 Hz), 5.87−5.81 (1H, m),
5.20 (1H, d, J = 17.1 Hz), 5.15 (1H, d, J = 10.2 Hz), 4.24 (2H, d, J = 5.5
Hz), 2.47 (3H, s); 13C{1H} NMR (150 MHz, CDCl3) δ 168.0, 167.9,
145.1, 134.4, 132.4, 131.6, 129.4, 123.7, 123.1, 117.4, 39.9, 21.9; IR
(neat) 3022, 2923, 1740, 1707, 1428, 1373, 1218, 1105 cm−1 HRMS
(EI) m/z: [M+] Calcd for C12H11NO2 201.0790; found 201.0788.
2-Benzyl-5-methylisoindoline-1,3-dione (4j). Yield 86% (217 mg)
as a yellow solid: mp 123−125 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.71 (1H, d, J = 7.6 Hz), 7.63 (1H, s), 7.48 (1H, d, J = 7.6
Hz), 7.42 (2H, d, J = 7.6 Hz), 7.31 (2H, t, J = 7.5 Hz), 7.25 (1H, t, J =
7.3 Hz), 4.83 (2H, s), 2.49 (3H, s); 13C{1H} NMR (150 MHz, CDCl3)
δ 168.1, 168.0, 145.1, 136.4, 134.4, 132.4, 129.4, 128.5, 128.5, 127.6,
5-(4-Methylpent-3-en-1-yl)-2-phenylisoindoline-1,3-dione (3i).
Yield 71% (216 mg) as a yellow solid: mp 149−151 °C; purification
by column chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600
MHz, CDCl3) δ 7.83 (1H, d, J = 7.6 Hz), 7.76 (1H, s), 7.56 (1H, d, J =
7.6 Hz), 7.49 (2H, t, J = 7.7 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.38 (1H t, J =
7.4 Hz), 5.12 (1H, t, J = 7.3 Hz), 2.80 (2H, t, J = 7.6 Hz), 2.35 (2H, q, J
= 7.5 Hz), 1.67 (3H, s), 1.54 (3H, s); 13C{1H} NMR (150 MHz,
CDCl3) δ 167.5, 167.3, 150.2, 134.5, 133.3, 132.0, 131.8, 129.3, 129.0,
127.9, 126.5, 123.6, 123.6, 122.3, 36.4, 29.5, 25.6, 17.7; IR (neat) 3019,
2970, 2253, 1735, 1697, 1583, 1497, 1373, 1205, 1120 cm−1; HRMS
(EI) m/z: [M+] Calcd for C20H19NO2 305.1416; found 305.1419.
4,6-Dimethyl-2-phenylisoindoline-1,3-dione (3j). Yield 72% (182
mg) as a white solid: mp 115−117 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.56 (1H, s), 7.47 (2H, t, J = 7.8 Hz), 7.41 (2H, d, J = 7.8 Hz),
7.36 (1H, t, J = 7.4 Hz), 7.30 (1H, s), 2.67 (3H, s), 2.46 (3H, s);
13C{1H} NMR (150 MHz, CDCl3) δ 167.9, 167.4, 145.0, 138.2, 137.1,
132.5, 131.8, 128.9, 127.8, 126.5, 125.8, 121.9, 21.8, 17.6; IR (neat)
3019, 2969, 1739, 1500, 1371, 1213, 1104 cm−1; HRMS (EI) m/z:
[M+] Calcd for C16H13NO2 251.0946; found 251.0945.
2,5-Diphenylisoindoline-1,3-dione (3k). Yield 82% (245 mg) as a
brown solid: mp 186−188 °C; purification by column chromatography
(EtOAc/n-hexane = 1:20). 1H NMR (300 MHz, CDCl3) δ 8.16 (1H,
s), 7.99 (2H, t, J = 8.4 Hz), 7.66 (2H, d, J = 7.2 Hz), 7.53−7.37 (8H, m);
13C{1H} NMR (75 MHz, CDCl3) δ 167.2, 167.1, 147.8, 138.9, 132.9,
132.5, 131.6, 130.0, 129.2, 129.1, 128.9, 128.1, 127.3, 126.5, 124.2,
122.2; IR (neat) 3016, 2969, 1738, 1427, 1371, 1215, 1098 cm−1;
HRMS (EI) m/z: [M+] Calcd for C20H13NO2 299.0946; found
299.0946.
2,5-Diphenylisoindoline-1,3-dione (3l). Yield 73% (218 mg) as a
yellow solid: mp 185−187 °C; purification by column chromatography
(EtOAc/n-hexane = 1:20). 1H NMR (600 MHz, CDCl3) δ 8.16 (1H,
s), 8.00−7.96 (2H, m), 7.66 (2H, d, J = 7.5 Hz), 7.51 (4H, t, J = 7.1 Hz),
7.45−7.43 (3H, m), 7.40 (1H, t, J = 7.4 Hz); 13C{1H} NMR (150 MHz,
CDCl3) δ 167.2, 167.1, 147.8, 138.9, 132.9, 132.6, 131.7, 130.1, 129.2,
129.1, 128.9, 128.1, 127.3, 126.5, 124.2, 122.3; IR (neat) 3062, 1700,
1491, 1372, 1094, 857 cm−1; HRMS (EI) m/z: [M+] Calcd for
C20H13NO2 299.0946; found 299.0947.
2,4-Diphenylisoindoline-1,3-dione (3m). Yield 83% (248 mg) as a
white solid: mp 152−154 °C; purification by column chromatography
(EtOAc/n-hexane = 1:20). 1H NMR (600 MHz, CDCl3) δ 7.95 (1H, d,
J = 7.4 Hz), 7.80 (1H, t, J = 7.6 Hz), 7.71 (1H, d, J = 7.7 Hz), 7.58 (2H,
d, J = 7.9 Hz), 7.48−7.43 (5H, m), 7.41 (2H, d, J = 7.8 Hz), 7.36 (1H, t,
J = 7.3 Hz); 13C{1H} NMR (150 MHz, CDCl3) δ 166.9, 166.8, 141.5,
136.4, 136.0, 134.1, 132.8, 131.6, 129.4, 128.9, 128.7, 128.0, 128.0,
127.0, 126.6, 122.6; IR (neat) 3030, 1714, 1498, 1366, 1102, 742 cm−1;
HRMS (EI) m/z: [M+] Calcd for C20H13NO2 299.0946; found
299.0949.
5-Methyl-2-(p-tolyl)isoindoline-1,3-dione (4a). Yield 86% (217
mg) as a yellow solid: mp 185−187 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.79 (1H, d, J = 7.6 Hz), 7.71 (1H, s), 7.54 (1H, d, J = 7.6
Hz), 7.28 (4H, s), 2.52 (3H, s), 2.38 (3H, s); 13C{1H} NMR (150
MHz, CDCl3) δ 167.5, 167.3, 145.5, 137.9, 134.7, 132.1, 129.6, 129.1,
129.0, 126.3, 124.0, 123.5, 21.9, 21.1; IR (neat) 3038, 2917, 1774, 1699,
1513, 1375, 1233, 1085 cm−1; HRMS (EI) m/z: [M+] Calcd for
C16H13NO2 251.0946; found 251.0943.
2-(4-Bromophenyl)-5-methylisoindoline-1,3-dione (4b). Yield
78% (245 mg) as a yellow solid: mp 203−205 °C; purification by
1
column chromatography (EtOAc/n-hexane = 1:20). H NMR (300
MHz, CDCl3) δ 7.81 (1H, d, J = 7.7 Hz), 7.73 (1H, s), 7.61−7.55 (3H,
m), 7.35−7.31 (2H, m), 2.53 (3H, s); 13C{1H} NMR (75 MHz,
CDCl3) δ 167.0, 166.9, 145.9, 135.1, 132.2, 131.9, 130.7, 128.9, 127.9,
124.3, 123.7, 121.6, 22.1; IR (neat) 3019, 2970, 1739, 1446, 1369,
1217, 1087 cm−1; HRMS (EI) m/z: [M+] Calcd for C15H10BrNO2
314.9895; found 314.9895.
F
https://dx.doi.org/10.1021/acs.joc.0c01991
J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
123.8, 123.1, 41.4, 21.9; IR (neat) 3019, 2969, 2940, 1739, 1427, 1371,
1217, 1102 cm−1; HRMS (EI) m/z: [M+] Calcd for C16H13NO2
251.0946; found 251.0947.
7.2 Hz), 5.53 (1H, q, J = 7.3 Hz), 2.46 (3H, s), 1.90 (3H, d, J = 7.2 Hz);
13C{1H} NMR (150 MHz, CDCl3) δ 168.2, 168.1, 145.0, 140.3, 134.3,
132.3, 129.3, 128.3, 127.5, 127.3, 123.6, 123.0, 49.4, 21.9, 17.5; IR
(neat) 2975, 2924, 1739, 1707, 1452, 1371, 1214, 1150, 1026 cm−1;
HRMS (EI) m/z: [M+] Calcd for C17H15NO2 265.1103; found
265.1103.
5-Methyl-2-(3-methylbenzyl)isoindoline-1,3-dione (4k). Yield
79% (210 mg) as a yellow solid: mp 110−113 °C; purification by
1
column chromatography (EtOAc/n-hexane = 1:20). H NMR (600
MHz, CDCl3) δ 7.69 (1H, d, J = 7.5 Hz), 7.62 (1H, s), 7.46 (1H, d, J =
7.5 Hz), 7.20 (2H, d, J = 6.6 Hz), 7.17 (1H, t, J = 7.8 Hz), 7.05 (1H, d, J
= 7.3 Hz), 4.77 (2H, s), 2.47 (3H, s), 2.30 (3H, s); 13C{1H} NMR (150
MHz, CDCl3) δ 168.2, 168.1, 145.1, 138.2, 136.3, 134.4, 132.5, 129.5,
129.1, 128.4, 128.4, 125.5, 123.8, 123.1, 41.4, 21.9, 21.3; IR (neat)
3022, 2925, 1769, 1690, 1425, 1389, 1103 cm−1; HRMS (EI) m/z:
[M+] Calcd for C17H15NO2 265.1103; found 265.1105.
5-Methyl-2-(4-methylbenzyl)isoindoline-1,3-dione (4l). Yield 83%
(219 mg) as a yellow solid: mp 105−107 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (300 MHz,
CDCl3) δ 7.68 (1H, d, J = 7.6 Hz), 7.60 (1H, s), 7.45 (1H, d, J = 7.6
Hz), 7.31 (2H, d, J = 7.8 Hz), 7.09 (2H, d, J = 7.8 Hz), 4.77 (2H, s), 2.46
(3H, s), 2.28 (3H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 168.1, 168.0,
145.0, 137.3, 134.3, 133.4, 132.4, 129.4, 129.2, 128.4, 123.7, 123.0, 41.7,
21.9, 21.0; IR (neat) 3017, 2968, 1739, 1428, 1370, 1218, 1101 cm−1;
HRMS (EI) m/z: [M+] Calcd for C17H15NO2 265.1103; found
265.1101.
(S)-4-Methyl-2-(1-phenylethyl)isoindoline-1,3-dione (4r). Yield
75% (199 mg) as a Brown sticky liquid: purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.55 (1H, d, J = 7.3 Hz), 7.45−7.42 (3H, m), 7.34 (1H, d, J =
7.7 Hz), 7.25 (2H, t, J = 7.6 Hz), 7.18 (1H, t, J = 7.4 Hz), 5.48 (1H, q, J
= 7.3 Hz), 2.59 (3H, s), 1.84 (3H, d, J = 7.3 Hz); 13C{1H} NMR (150
MHz, CDCl3) δ 168.9, 168.1, 140.4, 137.8, 136.2, 133.3, 132.3, 128.5,
128.41, 127.5, 127.4, 120.7, 49.3, 17.4, 17.4; IR (neat) 2978, 2932,
1751, 1703, 1452, 1364, 1332, 1213, 1146, 1028 cm−1; HRMS (EI) m/
z: [M+] Calcd for C17H15NO2 265.1103; found 256.1104.
5-Methyl-2-(naphthalen-1-yl)isoindoline-1,3-dione (5a). Yield
85% (245 mg) as a brown solid: mp 188−190 °C; purification by
1
column chromatography (EtOAc/n-hexane = 1:20). H NMR (300
MHz, CDCl3) δ 7.98−7.91 (2H, m), 7.87 (1H, d, J = 7.6 Hz), 7.80 (1H,
s), 7.64−7.54 (3H, m), 7.52−7.45 (3H, m), 2.53 (3H, s); 13C{1H}
NMR (75 MHz, CDCl3) δ 167.9, 167.7, 145.7, 134.9, 134.3, 132.2,
130.2, 129.7, 129.2, 128.4, 128.2, 126.9, 126.8, 126.4, 125.3, 124.3,
123.7, 122.3, 21.9; IR (neat) 3060, 1767, 1706, 1401, 1363, 1233, 1090
cm−1; HRMS (EI) m/z: [M+] Calcd for C19H13NO2 287.0946; found
287.0949.
2-(2-Methoxybenzyl)-5-methylisoindoline-1,3-dione (4m). Yield
76% (215 mg) as a yellow solid: mp 155−157 °C; purification by
1
column chromatography (EtOAc/n-hexane = 1:20). H NMR (600
MHz, CDCl3) δ 7.71 (1H, d, J = 7.6 Hz), 7.63 (1H, s), 7.48 (1H, d, J =
7.6 Hz), 7.20 (1H, t, J = 7.8 Hz), 7.12 (1H, d, J = 7.5 Hz), 6.85−6.83
(2H, m), 4.87 (2H, s), 3.83 (3H, s), 2.48 (3H, s); 13C{1H} NMR (150
MHz, CDCl3) δ 168.2, 168.1, 157.0, 145.0, 134.3, 132.5, 129.5, 128.6,
128.2, 124.2, 123.7, 123.1, 120.3, 110.3, 55.3, 36.7, 21.9; IR (neat)
3016, 2930, 1765, 1704, 1492, 1428, 1391, 1243, 1107, 1018 cm−1;
HRMS (EI) m/z: [M+] Calcd for C17H15NO3 281.1052; found
281.1055.
2-(Naphthalen-1-yl)isoindoline-1,3-dione (5b). Yield 72% (198
mg) as a white solid: mp 185−187 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 8.00−7.92 (3H, m), 7.94 (1H, d, J = 8.1 Hz), 7.81−7.80 (2H,
m), 7.62−7.57(2H, m), 7.53−7.45 (3H, m); 13C{1H} NMR (150
MHz, CDCl3) δ 167.7, 134.4, 134.4, 131.9, 130.2, 129.8, 128.5, 128.1,
127.0, 126.9, 126.4, 125.3, 123.8, 122.3; IR (neat) 3064, 1776, 1708,
1464, 1399, 1371, 1227, 1176, 1105 cm−1; HRMS (EI) m/z: [M+]
Calcd for C18H11NO2 273.0790; found 273.0791.
2-(2-Methoxybenzyl)-5-methylisoindoline-1,3-dione (4n). Yield
87% (243 mg) as a white solid: mp 205−207 °C; purification by
4-Methyl-2-(naphthalen-1-yl)isoindoline-1,3-dione (5c). Yield
79% (226 mg) as a yellow solid: mp 155−157 °C; purification by
1
column chromatography (EtOAc/n-hexane = 1:20). H NMR (600
1
MHz, CDCl3) δ 8.06 (2H, d, J = 8.5 Hz), 7.81 (1H, d, J = 7.6 Hz), 7.74
(1H, s), 7.59−7.56 (3H, m), 2.61 (3H, s), 2.53 (3H, s); 13C{1H} NMR
(150 MHz, CDCl3) δ 197.0, 166.9, 166.7, 146.1, 136.0, 135.8, 135.2,
131.8, 129.0, 128.9, 125.9, 124.3 123.83, 26.6, 22.0; IR (neat) 3010,
2930, 1733, 1367, 1218, 1084, 831, 734 cm−1; HRMS (EI) m/z: [M+]
Calcd for C17H13NO3 279.0895; found 279.0898.
(R)-5-Methyl-2-(1-phenylethyl)isoindoline-1,3-dione (4o). Yield
81% (215 mg) as a yellow solid: mp 85−87 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.65 (1H, d, J = 7.5 Hz), 7.57 (1H, s), 7.47 (2H, d, J = 7.7
Hz), 7.45 (1H, d, J = 7.6 Hz), 7.30 (2H, t, J = 7.5 Hz), 7.23 (1H, t, J =
7.2 Hz), 5.53 (1H, q, J = 7.3 Hz), 2.46 (3H, s), 1.90 (3H, d, J = 7.2 Hz);
13C{1H} NMR (150 MHz, CDCl3) δ 168.3, 168.2, 145.1, 140.4, 134.3,
132.3, 129.3, 128.4, 127.5, 127.3, 123.6, 123.0, 49.4, 21.9, 17.5; IR
(neat) 2921, 2854, 1765, 1697, 1451, 1376, 1353, 1260, 1149, 1025
cm−1; HRMS (EI) m/z: [M+] Calcd for C17H15NO2 265.1103; found
265.1100.
column chromatography (EtOAc/n-hexane = 1:20). H NMR (300
MHz, CDCl3) δ 7.98−7.91 (2H, m), 7.83 (1H, d, J = 7.3 Hz), 7.69−
7.60 (2H, m), 7.56 (2H, dd, J = 7.9, 3.1 Hz), 7.52−7.48 (2H, m), 7.45
(1H, d, J = 7.2 Hz), 2.76 (3H, s); 13C{1H} NMR (75 MHz, CDCl3) δ
168.5, 167.8, 138.6, 136.8, 134.4, 133.9, 132.4, 130.3, 129.7, 128.6,
128.5, 128.3, 127.0, 126.9, 126.4, 125.3, 122.4, 121.5, 17.7; IR (neat)
3064, 1707, 1399, 1366, 1098 cm−1; HRMS (EI) m/z: [M+] Calcd for
C19H13NO2 287.0946; found 287.0944.
2-(Naphthalen-1-yl)-4-propylisoindoline-1,3-dione (5d). Yield
75% (237 mg) as a brown solid: mp 78−80 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.97 (1H, d, J = 8.3 Hz), 7.93 (1H, d, J = 8.0 Hz), 7.84 (1H, d,
J = 7.3 Hz), 7.68 (1H, t, J = 7.6 Hz), 7.64 (1H, d, J = 8.1 Hz), 7.59−7.57
(2H, m), 7.53−7.47 (2H, m), 7.46 (1H, d, J = 7.2 Hz), 3.18−3.08 (2H,
m), 1.78−1.71 (2H, m), 1.01 (3H, t, J = 7.4 Hz); 13C{1H} NMR (150
MHz, CDCl3) δ 168.3, 167.7, 143.6, 135.9, 134.3, 133.9, 132.5, 130.3,
129.7, 128.5, 128.3, 128.2, 127.0, 126.9, 126.4, 125.3, 122.4, 121.5, 33.3,
24.1, 13.9; IR (neat) 2959, 2927, 2863, 1768, 1706, 1463, 1400, 1368,
1237, 1097 cm−1; HRMS (EI) m/z: [M+] Calcd for C21H17NO2
315.1259; found 315.1262.
(R)-4-Methyl-2-(1-phenylethyl)isoindoline-1,3-dione (4p). Yield
72% (191 mg) as a white solid: mp 112−114 °C; purification by
1
column chromatography (EtOAc/n-hexane = 1:20). H NMR (600
MHz, CDCl3) δ 7.61 (1H, d, J = 7.3 Hz), 7.51−7.49 (3H, m), 7.39 (1H,
d, J = 7.7 Hz), 7.31 (2H, t, J = 7.6 Hz), 7.24 (1H, t, J = 7.3 Hz), 5.55
(1H, q, J = 7.3 Hz), 2.65 (3H, s), 1.91 (3H, d, J = 7.3 Hz); 13C{1H}
NMR (150 MHz, CDCl3) δ 168.9, 168.1, 140.3, 137.7, 136.2, 133.3,
132.3, 128.5, 128.3, 127.5, 127.3, 120.7, 49.2, 17.4, 17.4; IR (neat)
2924, 2851, 1766, 1705, 1454, 1383, 1333, 1213, 1147, 1048 cm−1;
HRMS (EI) m/z: [M+] Calcd for C17H15NO2 265.1103; found
265.1103.
(S)-5-Methyl-2-(1-phenylethyl)isoindoline-1,3-dione (4q). Yield
79% (210 mg) as a white solid: mp 91−93 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3)) δ 7.65 (1H, d, J = 7.6 Hz), 7.57 (1H, s), 7.48 (2H, d, J = 7.8
Hz), 7.44 (1H, d, J = 7.6 Hz), 7.30 (2H, t, J = 7.5 Hz), 7.23 (1H, t, J =
4-Butyl-2-(naphthalen-1-yl)isoindoline-1,3-dione (5e). Yield 71%
(234 mg) as brown solid: mp 70−72 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.97 (1H, d, J = 8.3 Hz), 7.93 (1H, d, J = 7.9 Hz), 7.84 (1H, d,
J = 7.3 Hz), 7.68 (1H, t, J = 7.6 Hz), 7.64 (1H, d, J = 8.0 Hz), 7.59−7.57
(2H, m), 7.53−7.48 (2H, m), 7.46 (1H, d, J = 7.2 Hz), 3.21−3.16 (1H,
m), 3.14−3.10 (1H, m), 1.72−1.67 (2H, m), 1.46−1.40 (2H, m), 0.95
(3H, t, J = 7.3 Hz); 13C{1H} NMR (150 MHz, CDCl3) δ 168.3, 167.7,
143.9, 135.9, 134.4, 133.9, 132.5, 130.3, 129.7, 128.5, 128.3, 128.1,
127.0, 126.9, 126.4, 125.3, 122.4, 121.5, 33.0, 31.1, 22.5, 13.8; IR (neat)
2956, 2924, 2862, 1771, 1709, 1465, 1403, 1371, 1232, 1109 cm−1;
HRMS (EI) m/z: [M+] Calcd for C22H19NO2 329.1416; found
329.1418.
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2-(Naphthalen-1-yl)-5-phenylisoindoline-1,3-dione (5f). Yield
84% (293 mg) as white solid: mp 171−173 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 8.23 (1H, s), 8.06−8.01 (2H, m), 7.99 (1H, d, J = 8.3 Hz),
7.95 (1H, d, J = 8.0 Hz), 7.69 (2H, d, J = 7.6 Hz), 7.66 (1H, d, J = 8.2
Hz), 7.60 (1H, t, J = 7.8 Hz), 7.54−7.45 (6H, m); 13C{1H} NMR (150
MHz, CDCl3) δ 167.7, 167.6, 147.9, 138.9, 134.4, 132.9, 132.8, 130.3,
130.2, 129.9, 129.2, 128.9, 128.5, 128.2, 127.3, 127.0, 126.9, 126.5,
125.3, 124.3, 122.4, 122.4; IR (neat) 3052, 2924, 1769, 1705, 1509,
1463, 139, 1364, 1229, 1095 cm−1; HRMS (EI) m/z: [M+] Calcd for
C24H15NO2 349.1103; found 349.1105.
5-Methyl-2-(pyren-1-yl)isoindoline-1,3-dione (5g). Yield 83% (301
mg) as a yellow solid: mp 255−257 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 8.28 (1H, d, J = 8.0 Hz), 8.23 (1H, d, J = 7.6 Hz), 8.19 (1H, d,
J = 7.5 Hz), 8.14−8.08 (3H, m), 8.03 (1H, t, J = 7.6 Hz), 7.92 (2H, dd, J
= 7.8, 3.0 Hz), 7.84 (1H, s), 7.83 (1H, d, J = 9.1 Hz), 7.63 (1H, d, J = 7.6
Hz), 2.58 (3H, s); 13C{1H} NMR (150 MHz, CDCl3) δ 168.2, 168.0,
145.9, 135.0, 132.5, 131.9, 131.0, 130.7, 129.5, 128.8, 128.4, 128.3,
127.1, 126.3, 126.3, 125.9, 125.7, 125.3, 125.2, 125.0, 124.4, 124.4,
123.8, 121.7, 22.1; IR (neat) 3041, 2959, 1770, 1705, 1436, 1369, 1235,
1086 cm−1; HRMS (EI) m/z: [M+] Calcd for C25H15NO2 361.1103;
found 361.1103.
5-Methyl-2-((tetrahydrofuran-2-yl)methyl)isoindoline-1,3-dione
(5h). Yield 73% (179 mg) as a brown solid: mp 82−84 °C; purification
by column chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600
MHz, CDCl3) δ 7.68 (1H, d, J = 7.6 Hz), 7.60 (1H, s), 7.45 (1H, d, J =
7.6 Hz), 4.23−4.19 (1H, m), 3.87 (1H, q, J = 7.8 Hz), 3.76−3.68 (2H,
m), 3.60 (1H, dd, J = 13.8, 4.9 Hz), 2.46 (3H, s), 1.99−1.89 (2H, m),
1.88−1.80 (1H, m), 1.65−1.59 (1H, m); 13C{1H} NMR (150 MHz,
CDCl3) δ 168.5, 168.3, 145.0, 134.3, 132.4, 129.4, 123.7, 123.1, 76.1,
67.8, 41.6, 29.1, 25.2, 21.9; IR (neat) 2968, 2925, 2867, 1742, 1720,
1430, 1378, 1218, 1091, 1044 cm−1; HRMS (EI) m/z: [M+] Calcd for
C14H15NO3 245.1052; found 245.1048.
CDCl3) δ 7.81 (2H, d, J = 7.6 Hz), 7.73 (2H, s), 7.66 (1H, s), 7.60 (1H,
t, J = 7.8 Hz), 7.56 (2H, d, J = 7.6 Hz), 7.50 (2H, d, J = 7.7 Hz), 2.53
(6H, s); 13C{1H} NMR (150 MHz, CDCl3) δ 167.0, 166.9, 145.9,
135.1, 132.4, 131.9, 129.3, 129.0, 125.2, 124.3, 123.7, 22.0; IR (neat)
3010, 2841, 1732, 1637, 1218, 1084, 831 cm−1; HRMS (EI) m/z: [M+]
Calcd for C24H16N2O4 396.1110; found 396.1107.
2,2′-(Methylenebis(4,1-phenylene))bis(5-methylisoindoline-1,3-
dione) (8). Yield 77% (374 mg) as a brown solid: mp 260−262 °C;
purification by column chromatography (EtOAc/n-hexane = 1:20). 1H
NMR (600 MHz, CDCl3) δ 7.80 (2H, d, J = 7.6 Hz), 7.73 (2H, s), 7.54
(2H, d, J = 7.6 Hz), 7.36−7.31 (8H, m), 4.06 (2H, s), 2.52 (6H, s);
13C{1H} NMR (150 MHz, CDCl3) δ 167.4, 167.3, 145.6, 140.3, 134.8,
132.1, 129.9, 129.6, 129.6, 129.14, 126.5, 124.1, 123.6, 41.1, 22.0; IR
(neat) 3011, 1728, 1365, 1217, 1080, 782 cm−1; HRMS (EI) m/z: [M+]
Calcd for C31H22N2O4 486.1580; found 486.1577.
Dimethyl 4-Methyl Phthalate (9a). Yield 65% (135 mg) from 2x
and 74% (154 mg) from 2x’ as a colorless oil: purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (300 MHz,
CDCl3) δ 7.64 (1H, d, J = 7.9 Hz), 7.44 (1H, s), 7.29 (1H, dd, J = 7.9,
1.7 Hz), 3.87 (3H, s), 3.85 (3H, s), 2.38 (3H, s); 13C{1H} NMR (75
MHz, CDCl3) δ 168.6, 167.6, 142.0, 132.6, 131.3, 129.1, 129.1, 128.2,
52.5, 52.4, 21.2; IR (neat) 2951, 1723, 1436, 1199, 1124, 966, 774
cm−1; HRMS (EI) m/z: [M+] Calcd for C11H12O4 208.0736; found
208.0735.
Diethyl 4-Methyl Phthalate (9b). Yield 68% (161 mg) as a colorless
oil: purification by column chromatography (EtOAc/n-hexane = 1:20).
1H NMR (300 MHz, CDCl3) δ 7.64 (1H, d, J = 7.8 Hz), 7.44 (1H, s),
7.29 (1H, dd, J = 7.8, 1.7 Hz), 4.37−4.28 (4H, m), 2.38 (3H, s), 1.33
(6H, td, J = 7.2, 2.7 Hz); 13C{1H} NMR (75 MHz, CDCl3) δ 168.2,
167.2, 141.8, 132.9, 131.2, 129.1, 129.0, 128.6, 61.5, 61.3, 21.2, 14.0,
14.0; IR (neat) 2951, 1723, 1435, 1279, 1199, 1124, 966, 774 cm−1;
HRMS (EI) m/z: [M+] Calcd for C13H16O4 236.1049; found 236.1046.
(S)-5-Methyl-2-phenyl-3a,4-dihydro-1H-isoindole-1,3(2H)-dione
(10). Yield 76% (182 mg) as a white solid: mp 135−137 °C; purification
by column chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600
MHz, CDCl3) δ 7.45 (2H, t, J = 7.8 Hz), 7.36 (1H, t, J = 7.4 Hz), 7.33
(2H, d, J = 7.8 Hz), 6.97−6.96 (1H, m), 6.05−6.04 (1H, m), 3.62−3.57
(1H, m), 2.66 (1H, dd, J = 17.4, 8.8 Hz), 2.37 (1H, t, J = 17.8 Hz), 1.98
(3H, s); 13C{1H} NMR (150 MHz, CDCl3) δ 175.1, 166.8, 145.1,
132.0, 129.2, 129.0, 128.3, 126.4, 122.6, 120.6, 38.6, 28.9, 23.8; IR
(neat) 3025, 2959, 2939, 1737, 1435, 1371, 1218, 1097 cm−1; HRMS
(EI) m/z: [M+] Calcd for C15H13NO2 239.0946; found 239.0944.
4-Methyl-2-((tetrahydrofuran-2-yl)methyl)isoindoline-1,3-dione
(5i). Yield 65% (159 mg) as a white solid: mp 55−57 °C; purification by
1
column chromatography (EtOAc/n-hexane = 1:20). H NMR (600
MHz, CDCl3) δ 7.64 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.5 Hz), 7.41
(1H, d, J = 7.6 Hz), 4.25−4.21 (1H, m), 3.89 (1H, q, J = 7.2 Hz), 3.77−
3.70 (2H, m), 3.61 (1H, dd, J = 13.9, 4.8 Hz), 2.67 (3H, s), 2.01−1.91
(2H, m), 1.89−1.83 (1H, m), 1.67−1.61 (1H, m); 13C{1H} NMR (150
MHz, CDCl3) δ 169.1, 168.4, 137.8, 136.2, 133.3, 132.4, 128.7, 120.8,
76.1, 67.8, 41.5, 29.1, 25.2, 17.5; IR (neat) 2970, 2927, 2870, 1703,
1428, 1387, 1228, 1050 cm−1; HRMS (EI) m/z: [M+] Calcd for
C14H15NO3 245.1052; found 245.1049.
4-Ethyl-2-((tetrahydrofuran-2-yl)methyl)isoindoline-1,3-dione
(5j). Yield 69% (160 mg) as a brown liquid: purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
CDCl3) δ 7.63 (1H, d, J = 7.3 Hz), 7.54 (1H, t, J = 7.5 Hz), 7.45 (1H, d,
J = 7.7 Hz), 4.24−4.20 (1H, m), 3.88 (1H, q, J = 7.3 Hz), 3.76−3.69
(2H, m), 3.59 (1H, dd, J = 13.7, 4.8 Hz), 3.13−3.03 (2H, m, J = 7.2 Hz),
2.00−1.90 (2H, m), 1.88−1.82 (1H, m), 1.66−1.60 (1H, m), 1.25 (3H,
t, J = 7.5 Hz); 13C{1H} NMR (150 MHz, CDCl3) δ 168.8, 168.3, 144.2,
134.5, 133.6, 132.5, 128.0, 120.8, 76.1, 67.8, 41.5, 29.1, 25.2, 24.3, 14.8;
IR (neat) 2969, 2943, 2873, 1766, 1704, 1427, 1390, 1172, 1052 cm−1;
HRMS (EI) m/z: [M+] Calcd for C15H17NO3 259.1208; found
259.1206.
5-Methyl-2-(3,4,5-trimethoxyphenyl)isoindoline-1,3-dione (6).
Yield 73% (239 mg) as a white solid: mp 214−216 °C; purification
by column chromatography (EtOAc/n-hexane = 1:20). 1H NMR (300
MHz, CDCl3) δ 7.79 (1H, d, J = 7.6 Hz), 7.71 (1H, s), 7.55 (1H, d, J =
7.7 Hz), 6.61 (2H, s), 3.85 (9H, d, J = 2.7 Hz), 2.52 (3H, s); 13C{1H}
NMR (75 MHz, CDCl3) δ 167.5, 167.4, 153.3, 145.8, 137.7, 134.9,
131.9, 128.9, 127.2, 124.1, 123.5, 104.3, 60.8, 56.1, 22.0; IR (neat)
2924, 2841, 1700, 1597, 1508, 1417, 1303, 1234, 1127, 1001 cm−1;
HRMS (EI) m/z: [M+] Calcd for C18H17NO5 327.1107; found
327.1104.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01991.
1
Copies of H NMR and 13C NMR spectra, polarimetry,
and HPLC analysis (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3a−m, 4a−r, 5a−j, 6−8, 9a,b, and 10 (ZIP)
AUTHOR INFORMATION
■
Corresponding Author
Yong Rok Lee − School of Chemical Engineering, Yeungnam
University, Gyeongsan 38541, Republic of Korea; orcid.org/
0000-0002-4048-8341; Phone: +82-53-810-2529;
Email: yrlee@yu.ac.kr; Fax: +82-53-810-4631
Author
Muhammad Saeed Akhtar − School of Chemical Engineering,
Yeungnam University, Gyeongsan 38541, Republic of Korea;
orcid.org/0000-0002-5486-4408
2,2′-(1,3-Phenylene)bis(5-methylisoindoline-1,3-dione) (7). Yield
83% (329 mg) as a white solid: mp 277−279 °C; purification by column
chromatography (EtOAc/n-hexane = 1:20). 1H NMR (600 MHz,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01991
H
https://dx.doi.org/10.1021/acs.joc.0c01991
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Article
D.; Kircik, L. Oral Apremilast for the Treatment of Plaque Psoriasis. J.
Clin. Aesthet. Dermatol. 2016, 9, 43−48.
Notes
The authors declare no competing financial interest.
(5) (a) Recupero, F.; Punta, C. Free Radical Functionalization of
Organic Compounds Catalyzed by N-Hydroxyphthalimide. Chem. Rev.
2007, 107, 3800−3842. (b) Simon, L.; Muniz, F. M.; Saez, S.; Raposo,
C.; Moran, J. R. Enzyme Mimics for Michael Additions with Novel
Proton Transport Groups. Eur. J. Org. Chem. 2008, 14, 2397−2403.
(6) (a) Chapran, M.; Lytvyn, R.; Begel, C.; Wiosna-Salyga, G.;
Ulanski, J.; Vasylieva, M.; Volyniuk, D.; Data, P.; Grazulevicius, J. V.
High-triplet-level Phthalimide Based Acceptors for Exciplexes with
Multicolor Emission. Dyes Pigm. 2019, 162, 872−882. (b) Zhan, Y.;
Zhao, X.; Wang, W. Synthesis of Phthalimide Disperse Dyes and Study
on the Interaction Energy. Dyes Pigm. 2017, 146, 240−250. (c) Koh, J.;
Kim, J. Synthesis of Phthalimide-Based Alkali-Dischargeable Azo
Disperse Dyes and Analysis of their Alkali-Hydrolysis Mechanism. Dyes
Pigm. 1998, 37, 265−272. (d) Zhao, X. Study on the Hydrolysis
Performance of Phthalimide Disperse Dyes. Dyes Pigm. 2019, 163,
600−606.
(7) (a) Guo, X. G.; Kim, F. S.; Jenekhe, S. A.; Watson, M. D.
Phthalimide-Based Polymers for High Performance Organic Thin-Film
Transistors. J. Am. Chem. Soc. 2009, 131, 7206−7207. (b) Sinkeldam, R.
W.; van Houtem, M.; Pieterse, K.; Vekemans, J.; Meijer, E. W. Chiral
Poly(ureidophthalimide) Foldamers in Water. Chem. - Eur. J. 2006, 12,
6129−6137. (c) Huang, J.; Wang, X.; Zhan, C.; Zhao, Y.; Sun, Y.; Pei,
Q.; Liu, Y.; Yao, J. Wide Band Gap Copolymers Based on Phthalimide:
Synthesis, Characterization, and Photovoltaic Properties with 3.70%
ACKNOWLEDGMENTS
■
This work was supported by the National Research foundation
of Korea (NRF) grant funded by the Korea government (MSIT)
(2018R1A2B2004432). This research was supported by the
Nano Material Technology Development Program of the
Korean National Research foundation (NRF) funded by the
Korean Ministry of Education, Science, and Technology
(2012M3A7B4049675).
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