Catalyst-Free Synthesis of 3-(2-Quinolinemethylene)-Substituted Isoindolinones in Water

Article abstract of DOI:10.1055/s-0037-1609491

A facile and environmentally benign approach toward the synthesis of novel 3-alkyl-substituted isoindolinones by three-component reactions of 2-formylbenzoic acids, primary amines and 2-methylazaarenes in water under catalyst- and additive-free conditions is described. This protocol features the direct construction of multiple C-N and C-C bonds via a tandem Mannich-type reaction and intramolecular cyclization in a one-pot fashion, affording the desired 3-(2-quinolinemethylene)-substituted isoindolinones in high to excellent yields.

Full text of DOI:10.1055/s-0037-1609491

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
Y. Tian et al.
Paper
Synthesis
Catalyst-Free Synthesis of 3-(2-Quinolinemethylene)-Substituted
Isoindolinones in Water
Youping Tian
O
O
Jialin Sun
H2O
OH
R1
N
R2
N
R1
+
R2NH2
+
R3
Kaihua Zhang
Gaoqiang Li
Feng Xu*
reflux
CHO
N
R3
25 examples
43–92% yield
Key Laboratory of Macromolecular Science of Shaanxi Province,
School of Chemistry and Chemical Engineering, Shaanxi Normal
University, Xi’an, Shaanxi 710062, P. R. of China
fengxu@snnu.edu.cn
Received: 05.11.2017
Accepted after revision: 05.03.2018
Published online: 28.03.2018
environmentally friendly protocols for the synthesis of iso-
indolinones is still a significant challenge and highly desir-
able.
DOI: 10.1055/s-0037-1609491; Art ID: ss-2017-h0716-op
O
Abstract A facile and environmentally benign approach toward the
synthesis of novel 3-alkyl-substituted isoindolinones by three-compo-
nent reactions of 2-formylbenzoic acids, primary amines and 2-methyl-
azaarenes in water under catalyst- and additive-free conditions is de-
scribed. This protocol features the direct construction of multiple C–N
and C–C bonds via a tandem Mannich-type reaction and intramolecular
cyclization in a one-pot fashion, affording the desired 3-(2-quino-
linemethylene)-substituted isoindolinones in high to excellent yields.
O
N
R2
R1
H
N
N
N
Cl
Ph
GlyT1 inhibitors
O
pagoclone
CYp11B1/2 inhibitors
Key words multicomponent reactions, isoindolines, catalyst-free,
Mannich-type reaction, cyclization
O
O
O
NH
H
3-Substituted isoindolinones and their derivatives are
ubiquitous in a number of naturally occurring compounds
and biologically active drug molecules such as glycine
transporter 1 (GlyT1) inhibitors,1 lennoxamine,2 pagoclone3
and (S)-PD 1729384 (Figure 1). These compounds with an
isoindolinone scaffold have been shown to possess a broad
range of pharmacological properties such as antihyperten-
sive,5 antipsychotic,6 anti-inflammatory,7 anesthetic,8 anti-
ulcer,4,9 vasodilatory,10 antiviral,11 and antileukemic12 activ-
ities. Due to their wide spectrum of biological activity, sev-
eral synthetic routes for the preparation of these
compounds have been established over the past three de-
cades. Traditional methods for the synthesis of isoindoli-
nones include the Diels–Alder approach,13 Heck cycliza-
tion,14 Wittig reaction,15 monoreduction of phthalimid-
es,15c,16 transition-metal-catalyzed17 and Lewis acid
catalyzed18 approaches and radical cyclization.19 However,
these methods are generally associated with several draw-
backs such as multistep procedures, operational complexity
and the use of noble transition-metal catalysts, large
amounts of reducing agents or toxic and inflammable sol-
vents. Therefore, the development of simple, efficient and
N
N
N
O
lennoxamine
(S)-PD 172938
Figure 1 Biologically active N-substituted isoindolinones
Recently, catalyst-free methods for the synthesis of 3-
substituted isoindolinones through the cyclization reaction
of 2-formylbenzoic acid and primary amines with nucleo-
philes such as indoles,20a 4-hydroxycoumarin,20b trialkyl
phosphates,20c pyrazolone20d and 1,3-diones20e–g have at-
tracted much attention. In these developed approaches, the
acidic proton of 2-formylbenzoic acid plays an important
role in promoting the reaction process for it generally facili-
tates the protonation of the formed imine in the reaction.
However, most of the above-mentioned catalyst-free proto-
cols were confined to the synthesis of 3-heteroaryl-substi-
tuted isoindolinones, and methods for the efficient synthe-
ses of 3-alkyl-substituted isoindolinones remain scarce.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
Y. Tian et al.
Paper
Synthesis
Quinolines and their derivatives are valuable com-
pounds in both medicinal and agricultural chemistry, and
are widely found in biologically important natural prod-
ucts.21 The direct benzylic C–H bond functionalization of
azaarenes22 such as 2-methylpyridine and 2-methylquino-
line with various electrophiles possessing C=O,23 C=C,24
C=N,25 and N=N26 bonds has been realized by catalysis with
Lewis/Brønsted acids or transition metals. Grigg17a reported
that the palladium-catalyzed carbonylation–amination–Mi-
chael addition reaction of 1-iodo-2-alkenylbenzene with
amines afforded various isoindolinones in good yields
(Scheme 1, a). In 2010, Huang et al. developed a palladium-
catalyzed benzylic addition of 2-methylazaarenes to N-sul-
fonyl aldimines in THF, which could be used to access 3-(2-
pyridinemethylene)-substituted isoindolinones.25a In the
same year, a Lewis acid approach involving the Sc(OTf)3-
catalyzed C–H functionalization of 2-methylazaarenes for
the synthesis of 3-(2-pyridinemethylene)-substituted iso-
indolinones was also reported by Huang (Scheme 1, b).18a
However, these two methods require pre-synthesized
imines as substrates, which somewhat limit their applica-
tion.
without an additional catalyst, a process which was called
‘self-activation’ and promoted the transformation in a more
efficient way. To the best of our knowledge, the C(sp3)–H
bond functionalization of azaarenes with in situ generated
iminium compounds for synthesis of 3-substituted isoin-
dolinones with azaarene motifs in the absence of a catalyst
in aqueous medium has not been realized. As part of our
continuous endeavors on the development of environmen-
tally friendly methods for the synthesis of value-added en-
tities from multicomponent reactions, we report herein an
unprecedented synthesis of 3-(2-quinolinemethylene)-sub-
stituted isoindolinones derivatives using water as the reac-
tion medium under catalyst-free conditions (Scheme 1, c).
To test the possibility of the above hypothesis, phthal-
aldehydic acid (1a) (1.2 mmol), benzylamine (2a) (1 mmol),
and 2-methylquinoline (3a) (1 mmol) were selected as sub-
strates in a model reaction to prepare the desired 3-(2-
quinolinemethylene)-substituted isoindolinone 4aaa. To
our delight, when the reaction was carried out without any
catalyst under solvent-free conditions at 110 °C, the desired
product 4aaa was smoothly isolated in 50% yield (Table 1,
entry 1). Encouraged by this result, we further evaluated
the influence of different reaction parameters on the model
reaction.
Ronald Grigg et al.17a
As shown in Table 1, common organic solvents, such as
DMF, toluene, 1,4-dioxane, THF, EtOH, DMSO and MeCN
were applied to promote the model reaction. Unfortunately,
lower isolated yields of 4aaa were obtained when the reac-
tion was performed in these solvents (Table 1, entries 2–8).
In recent decades, the use of water as a reaction medium
instead of hazardous organic solvents to promote organic
transformations has attracted much attention, because wa-
ter is a readily available, cheap, safe and environmentally
benign solvent. Therefore, the model reaction was next per-
formed in water at reflux under catalyst-free conditions.
Surprisingly, the reaction was complete in a shorter time of
12 hours and produced the desired compound 4aaa in a
greatly improved yield of 92% (Table 1, entry 9). Thus it was
clear that water was the best reaction solvent for the cur-
rent transformation.
The evaluation of the reaction temperature was next
carried out. When the reaction temperature was slightly
lowered to 80 °C, compound 4aaa was isolated in a sharply
decreased yield of 60%, even on lengthening the reaction
time to 24 hours (Table 1, entry 10). Therefore, heating at
reflux temperature was the best choice for the protocol in
water.
N
Pd(0) (5mol%)
N
+
+
CO
RNH2
Cs2CO3, toluene, 90 °C
I
N
R
O
Hanmin Huang et al.25a,18a
Ts
N
Pd(OAc)2 (5 mol%)
Phen (5 mol%)
N
NTs
+
OMe
Ts
THF, 120 °C
N
O
O
N
N
Sc(OTf)3 (10 mol%)
THF, 120 °C
NTs
+
OMe
N
O
O
this work
O
R1
N
R2
O
H2O
+
R3
R2 NH2
OH
+
R1
N
reflux
N
CHO
R3
Scheme 1 Background to the research and the method described in
this work
When the amount of benzylamine (2a) was increased to
2 equivalents, the yield of product 4aaa decreased sharply
to 50% (Table 1, entry 11), which demonstrated that an ex-
cess of acid was essential to the formation of the isoindoli-
none. Furthermore, the effect of additional acids was exam-
ined. When 10 mol% of additional acids such as AcOH, PTSA
and L-proline were added to the reaction system, the corre-
In 2014, Xiao’s group reported a benzylic C–H bond
nucleophilic addition between azaarenes and coumarin-3-
carboxylic acids.24d,e It was found that the introduction of a
carboxylic group to the substrate activated 2-alkyl-
azaarenes as a Brønsted acid and accelerated the reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
Y. Tian et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditionsa
means of simple coupling strategies and the like. Sterically
demanding aryl-alkylamines also served as very good can-
didates in this transformation. The steric effects seemed to
have no obvious influence on the formation of the desired
isoindolinones, which were obtained in high yields (Table 2,
entries 4 and 8). A heteroaryl-alkylamine, furfurylamine,
also successfully afforded the corresponding isoindolinone
4aia in 82% yield. Phenyl-ethylamine and phenyl-propyl-
amine showed similar reactivities to that of benzylamine
and produced the corresponding products in excellent
yields (Table 2, entries 10 and 11). Alkylamines such as n-
BuNH2, 1-octylamine, 1-dodecylamine and n-PrNH2
showed excellent reactivity in this one-pot, three-compo-
nent reaction, producing the corresponding products 4ala–
aoa in good yields (Table 2, entries 12–15).
O
O
OH
NH2
+
+
N
N
CHO
1a
N
2a
3a
4aaa
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
2
–
110
24
20
20
20
20
20
20
20
12
24
18
18
18
18
50
20
30
20
42
40
46
40
92
60
50
62
51
48
DMF
110
3
toluene
1,4-dioxane
THF
110
4
reflux
reflux
reflux
110
5
6
EtOH
DMSO
MeCN
H2O
Table 2 Scope of the Aminesa
7
8
reflux
reflux
80
O
O
9
R
H2O
OH
N
10
11c
12d
13e
14f
H2O
R
NH2
+
+
reflux
CHO
N
2a–r
N
H2O
reflux
reflux
reflux
reflux
1a
3a
H2O
4aaa–ara
H2O
Entry
R
Product
Yield (%)b
H2O
1
2
C6H5CH2
4aaa
4aba
4aca
4ada
4aea
4afa
4aga
4aha
4aia
4aja
4aka
4ala
4ama
4ana
4aoa
–
92
83
86
80
88
89
88
83
82
92
90
83
86
84
60
0
a Reaction conditions: phthalaldehydic acid (1a) (1.2 mmol), benzylamine
(2a) (1.0 mmol), 2-methylquinoline (3a) (1 mmol), solvent (3 mL).
b Yield of isolated product.
4-ClC6H4CH2
4-FC6H4CH2
c Benzylamine (2a) (2 mmol) was used.
3
d
L-proline (10 mol%) was used.
e PTSA (10 mol%) was used.
f AcOH (10 mol%) was used.
4
2-ClC6H4CH2
3,4-Cl2C6H3CH2
4-MeC6H4CH2
4-MeOC6H4CH2
5
6
7
sponding isoindolinone 4aaa was obtained in reduced
yields of 62%, 51% and 48%, respectively (Table 1, entries
12–14). Therefore, the optimum reaction conditions are as
follows: benzylamine (2a) (1 mmol), 2-methylquinoline
(3a) (1 mmol) and 1.2 equivalents of phthalaldehydic acid
(1a) in water at reflux for 12 hours (Table 1, entry 9).
8
2,4-(MeO)2C6H3CH2
furfuryl
9
10
11
12
13
14
15
16
17c
18
19
20
2-phenylethyl
4-phenylbutyl
1-butyl
With optimized reaction conditions in hand, we next in-
vestigated the scope of the amines 2a–r in one-pot, three-
component reactions with 2-methylquinoline (3a) and
phthalaldehydic acid (1a). As shown in Table 2, various pri-
mary amines including aryl-alkylamines, heteroaryl-alkyl-
amines, arylamines and alkylamines were selected to un-
dergo the transformation under catalyst-free conditions in
water. Aryl-alkylamines bearing both electron-withdraw-
ing groups (Table 2, entries 2–5) and electron-donating
groups (Table 2, entries 6–8) on the phenyl ring all smooth-
ly provided the corresponding products 4aba–aja in good to
excellent yields (80–92%). It was noteworthy that aryl-al-
kylamines with halo substituents on the phenyl ring were
well tolerated under the conditions of this protocol (Table 2,
entries 2–5), which should permit further derivatization by
1-octyl
1-dodecyl
n-Pr
t-Bu
H
–
0
C6H5
4apa
4aqa
4ara
40
30
70
4-ClC6H4
4-MeC6H4
a Reaction conditions: 1a (1.2 mmol, 1.2 equiv), 2a–r (1.0 mmol), 3a (1
mmol), H2O (3 mL), reflux, 12 h.
b Yield of isolated product.
c Ammonium hydroxide (28%, 4 mL) was used as the ammonia gas precur-
sor and the reaction was carried out at 80 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
Y. Tian et al.
Paper
Synthesis
However, sterically hindered tert-butylamine was com-
pletely ineffective in this transformation and no desired
product was obtained (Table 2, entry 16). Furthermore,
when ammonium hydroxide was used as the ammonia gas
precursor to undergo the transformation, unfortunately, no
desired product was formed (Table 2, entry 17).
For the aromatic amines, decreased yields of isoindoli-
nones were observed (Table 2, entries 18–20), which was
mainly caused by the weak nucleophilicity of the aryl-
amine. The structure of compound 4ara was confirmed un-
ambiguously by single-crystal X-ray analysis (Figure 2).
To further investigate the generality of this one-pot,
three-component reaction, various substituted 2-methyl-
quinolines were selected and the results are shown in
Scheme 2. 2-Methylquinolines with different substituents
such as 8-chloro, 8-methoxy, 6-methyl, 6-chloro, 6-bromo
and 6-methoxy all smoothly afforded the corresponding
products in moderate to good yields. Additionally, 2-ethyl-
quinoline and 1-methylisoquinoline were examined and
successfully gave the corresponding products 4aah and
Figure 2 X-ray crystal structure of compound 4ara (CCDC 1546209)
4aai in 89% and 85% yields, respectively. When 4-cyanoph-
thalaldehydic acid (1b) was utilized to evaluate the poten-
tial of this protocol, the desired isoindolinone 4baa was
successfully obtained in 43% yield. However, when 4-methyl-
quinoline, 2-methylpyridine and 2,6-lutidine were used in-
O
O
H2O
OH
R1
N
NH2
R3
+
R1
+
reflux
N
CHO
1a,b
2a
3a–i
N
4aaa–baa
R3
O
N
O
N
O
O
N
N
Cl
N
N
N
N
Cl
4aaa, 92%
4aab, 50%
4aac, 64%
4aad, 70%
O
O
N
O
N
O
N
N
O
N
N
N
N
Br
O
4aae, 80%
4aaf, 65%
4aag, 68%
4aah, 89%
O
N
O
N
O
O
N
N
NC
N
N
R4
N
N
0%
4baa, 43%
4aai, 85%
R4 = H or Me, 0%
Scheme 2 Scope of the phthalaldehydic acids and azaarenes. Reagents and conditions: 1a,b (1.2 mmol), 2a (1 mmol), 3a–i (1 mmol), H2O (3 mL),
reflux, 12 h. Yields are those of isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

E
Y. Tian et al.
Paper
Synthesis
stead of 2-methylquinoline, no desired product was detect-
ed, with the reason possibly being due to the electronic ef-
fect of the methyl group on the pyridyl ring.25e
O
O
O
H2O
OH
(a)
+
reflux
N
N
CHO
1a
To further demonstrate the potential utility of this pro-
tocol, a gram-scale synthesis of 2-benzyl-3-(quinolin-2-yl-
methyl)isoindolin-1-one (4aaa) was next carried out
(Scheme 3). When a mixture of phthalaldehydic acid (1a)
(1.8 g, 12 mmol), benzylamine (2a) (10 mmol) and 2-methyl-
quinoline (3a) (10 mmol) was selected to perform the isoin-
dolinone synthesis in water without any catalyst, an 89%
yield of 2-benzyl-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4aaa) was obtained. No obvious decrease of the reaction
efficiency was observed. This is very meaningful for poten-
tial large-scale applications of this methodology.
3a
B (86%)
O
O
O
(b)
N
B
+
H2O
reflux
N
NH2
N
4aaa (88%)
2a
O
O
N
H2O
NH2
OH
+
(c)
reflux
NH
O
O
CHO
1a
2a
H2O
OH
NH2
5
(92%)
N
+
+
O
reflux
CHO
1a
(1.8 g, 12 mmol) (10 mmol)
N
OH
2a
3a
O
N
(10 mmol)
O
4aaa
N
CHO
NH2
(3.24 g)
89%
1a
CH2Cl2
r.t.
OH
(d)
+
O
Scheme 3 Gram-scale synthesis of 4aaa
HN
D
C
To provide insight into the reaction mechanism, several
control experiments were conducted (Scheme 4). When
phthalaldehydic acid (1a) and 2-methylquinoline (3a) were
subjected to the optimized reaction conditions for 6 hours,
product B was isolated in 86% yield (Scheme 4, eq. a). When
a mixture of compound B and benzylamine (2a) was sub-
jected to the optimized reaction conditions for 5 hours,
product 4aaa was generated in 88% yield (Scheme 4, eq. b).
The intermediate 5 was isolated in 92% yield from the reac-
tion mixture of 1a and 2a under the optimized conditions
after 8 hours (Scheme 4, eq. c). These results validated that
the imine C might be formed as the key intermediate of this
conversion. To prove this hypothesis, phthalaldehydic acid
(1a) and benzylamine (2a) were mixed in CH2Cl2 at room
temperature for 12 hours until the imine C27 was complete-
ly formed (Scheme 4, eq. d), which was monitored by TLC
analysis. Next, the reaction mixture was concentrated un-
der reduced pressure, after which 2-methylquinoline (3a)
was added to the residue to perform the transformation un-
der the optimized conditions and smoothly afford product
4aaa in 90% yield (Scheme 4, eq. e). Unfortunately, we failed
to isolate the imine C, which might be caused by an equilib-
rium between the imine C and 3-(benzylamino)isobenzo-
furan-1(3H)-one (D).27a,b However, when benzylamine (2a)
was changed to phenylamine (2p) to perform the same pro-
cedure, we successfully isolated 3-(phenylamino)isobenzo-
furan-1(3H)-one (2pD) in 92% yield, the special stability of
which can be explained by the p-π conjugation effect
(Scheme 4, eq. f).27c Compound 2pD was next utilized to re-
act with 2-methylquinoline (3a) under the standard reac-
tion conditions, with the product 4apa being smoothly ob-
2a
O
O
H2O
OH
(e)
+
N
N
reflux
N
C
3a
O
N
4aaa (90%)
OH
O
CHO
O
O
1a
CH2Cl2
r.t.
OH
N
+
(f)
NH2
HN
2pD (92%)
2pC
2p
O
O
O
H2O
reflux
(g)
+
N
N
HN
3a
N
2pD
4apa (50%)
O
O
O
CHO
H2O
reflux
1a'
+
(h)
N
N
3a
NH2
N
2a
4aaa (20%)
Scheme 4 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
Y. Tian et al.
Paper
Synthesis
tained in 50% yield (Scheme 4, eq. g). However, product
4aaa was obtained in only 20% yield when methyl 2-form-
ylbenzoate (1a′) was tested with benzylamine (2a) and 2-
methylquinoline (3a) under the optimized conditions
(Scheme 4, eq. h). This suggested that phthalaldehydic acid,
as a Brønsted acid, played a key role in the functionalization
of the methyl group of 2-methylquinoline (3a).
On the basis of the experiments described above and
previous reports,20a,g,23k,24d,28a a plausible reaction mecha-
nism concerning two possible reaction pathways for the
formation of 2-benzyl-3-(quinolin-2-ylmethyl)isoindolin-
1-one (4aaa) is depicted in Scheme 5. In path a, 2-meth-
ylquinoline (3a) firstly isomerized into the enamine inter-
mediate 3a′ with the aid of acid.28b The intermediate 3a′
then nucleophilically attacks phthalaldehydic acid (1a),
producing compound A, which was further dehydrated to
give intermediate B. The intermediate B next reacts with
benzylamine (2a) to provide the final product 4aaa. In path
b, the nucleophilic addition of benzylamine (2a) on phthal-
aldehydic acid (1a) first generates imine C, which may part-
ly isomerize into intermediate D. The reaction of the imine
C and intermediate 3a′ affords the Mannich product E,
which is subsequently dehydrated to produce the desired
product 4aaa.
meaningful for future applications. Further studies to ex-
tend this method to the synthesis of other isoindolinone
derivatives are in progress in our laboratory.
Reagents and solvents were obtained commercially and were used
without further purification. All the reactions were carried out under
air. Products were purified by flash chromatography with Qingdao
Make Silica Gel Dryer Co., Ltd. silica gel (300–400 mesh). Melting
points were obtained using a BeijingTech X-5 instrument apparatus.
1H NMR and 13C NMR spectra were recorded on Bruker 300 M and
Bruker 400 M spectrometers at ambient temperature with CDCl3 as
the solvent and TMS as the internal standard. High-resolution mass
analyses were performed on a Bruker Esquire 6000 (ESI-ION Trap)
mass spectrometer.
Substituted Isoindolinones; General Procedure
A mixture of phthalaldehydic acid (1a) or 4-cyanophthalaldehydic
acid (1b) (1.2 mmol), amine 2 (1 mmol), and 2-methylquinoline 3a (1
mmol) was stirred in H2O (3 mL) at reflux temperature until the reac-
tion was complete (TLC analysis). The mixture was allowed to cool to
room temperature and a solution of saturated NaHCO3 (5 mL) was
added. The resulting mixture was extracted with EtOAc (3 × 10 mL).
The combined organic layers were dried over anhydrous MgSO4 and
concentrated to give a residue that was purified by column chroma-
tography (EtOAc/petroleum ether, 1:5 to 1:2).
In conclusion, we have developed a highly efficient and
environmentally friendly method for the preparation of 3-
alkyl-substituted isoindolinones in water under catalyst-
free conditions. The developed protocol provides a straight-
forward synthetic method for the construction of 3-subsi-
tuted isoindolinones in good to excellent yields without us-
ing precious transition-metal catalysts. Importantly, this re-
action could be readily scaled up to gram scale and no
obviously decreased yield was observed, which is very
2-Benzyl-3-(quinolin-2-ylmethyl)isoindolin-1-one (4aaa)
Yellow oil; yield: 334.9 mg (92%).
1H NMR (300 MHz, CDCl3): δ = 7.99 (d, J = 8.5 Hz, 1 H), 7.93 (d, J = 8.4
Hz, 1 H), 7.86–7.83 (m, 1 H), 7.76–7.65 (m, 2 H), 7.49 (t, J = 7.4 Hz, 1
H), 7.40–7.35 (m, 2 H), 7.25–7.12 (m, 5 H), 7.07–7.04 (m, 1 H), 6.90 (d,
J = 8.4 Hz, 1 H), 5.26 (d, J = 15.3 Hz, 1 H), 5.20 (t, J = 6.2 Hz, 1 H), 4.40
(d, J = 15.3 Hz, 1 H), 3.54 (dd, J = 14.5, 5.5 Hz, 1 H), 3.31 (dd, J = 14.4,
6.9 Hz, 1 H).
O
COOH
CHO
COOH
path a
O
••
NH2CH2Ph
OH
2a
NHCH2Ph
1a
D
N
H
N
A
O
3a'
H
H
O
H
– H2O
N
NCH2Ph
N
H
3a'
3a
C
O
O
O
O
••
OH
H2N CH2Ph
NCH2Ph
N
NHCH2Ph
2a
aminolysis
N
N
– H2O
B
E
4aaa
Scheme 5 Proposed reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
Y. Tian et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3): δ = 168.6, 157.2, 147.8, 145.6, 137.3,
136.3, 132.0, 131.4, 129.7, 129.0, 128.6, 128.3, 127.9, 127.6, 127.4,
127.0, 126.4, 123.8, 122.8, 121.9, 58.8, 44.5, 41.7.
HRMS (ESI): m/z [M + H]+ calcd for C25H21N2O: 365.1648; found:
365.1649.
1H NMR (400 MHz, CDCl3): δ = 7.99–7.94 (m, 2 H), 7.86–7.83 (m, 1 H),
7.78–7.68 (m, 2 H), 7.53–7.49 (m, 1 H), 7.45 -7.42 (m, 2 H), 7.19–7.17
(m, 2 H), 7.03 (d, J = 2.0 Hz, 1 H), 6.94–6.89 (m, 2 H), 5.33 (t, J = 6.2
Hz,1 H), 5.03 (d, J = 15.6 Hz, 1 H), 4.33 (d, J = 15.6 Hz, 1 H), 3.38 (dd, J =
6.2, 3.0 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 168.7, 156.9, 147.7, 145.6, 137.7,
136.5, 132.4, 131.7, 131.5, 131.2, 130.4, 129.9, 129.5, 128.8, 128.4,
127.7, 127.1, 126.9, 126.4, 123.8, 122.7, 121.8, 58.8, 43.7, 42.1.
2-(4-Chlorobenzyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4aba)
HRMS (ESI): m/z [M + H]+ calcd for C25H1935Cl2N2O: 433.0869; found:
Yellow oil; yield: 330.2 mg (83%).
433.0869.
1H NMR (400 MHz, CDCl3): δ = 7.96 (t, J = 9.0 Hz, 2 H), 7.86–7.83 (m, 1
H), 7.77–7.75 (m, 1 H), 7.71–7.68 (m, 1 H), 7.53–7.49 (m, 1 H), 7.42–
7.40 (m, 2 H), 7.14–7.09 (m, 3 H), 7.00 (d, J = 8.2 Hz, 2 H), 6.92 (d, J =
8.3 Hz, 1 H), 5.25 (t, J = 6.2 Hz, 1 H), 5.14 (d, J = 15.4 Hz, 1 H), 4.35 (d,
J = 15.4 Hz, 1 H), 3.46 (dd, J = 14.6, 5.8 Hz, 1 H), 3.33 (dd, J = 14.6, 6.6
Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.6, 157.0, 147.8, 145.5, 136.4,
135.8, 133.1, 131.7, 131.5, 129.8, 129.2, 128.9, 128.6, 128.3, 127.6,
126.9, 126.4, 123.8, 122.7, 121.9, 58.8, 44.0, 41.9.
2-(4-Methylbenzyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4afa)
Yellow oil; yield: 336.4 mg (89%).
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 8.1
Hz, 1 H), 7.85–7.83 (m, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.68–7.64 (m, 1
H), 7.48–7.45 (m, 1 H), 7.39–7.32 (m, 2 H), 7.07–7.00 (m, 5 H), 6.90 (d,
J = 8.4 Hz, 1 H), 5.26 (d, J = 15.2 Hz, 1 H), 5.18 (t, J = 6.0 Hz, 1 H), 4.36
(d, J = 15.2 Hz, 1 H), 3.54 (dd, J = 14.4, 5.3 Hz, 1 H), 3.28 (dd, J = 14.3,
7.1 Hz, 1 H), 2.26 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.4, 157.1, 147.8, 145.5, 137.0,
136.3, 134.2, 132.0, 131.3, 129.6, 129.2, 129.0, 128.2, 127.9, 127.6,
126.9, 126.3, 123.7, 122.8, 121.9, 58.6, 44.1, 41.5, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C25H2035ClN2O: 399.1259; found:
399.1254.
2-(4-Fluorobenzyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4aca)
HRMS (ESI): m/z [M + H]+ calcd for C26H23N2O: 379.1805; found:
Yellow oil; yield: 328.5 mg (86%).
379.1806.
1H NMR (400 MHz, CDCl3): δ = 7.99 (t, J = 8.8 Hz, 2 H), 7.86–7.84 (m, 1
H), 7.78 (d, J = 8.1 Hz, 1 H), 7.73–7.69 (m, 1 H), 7.54–7.50 (m, 1 H),
7.44–7.41 (m, 2 H), 7.12–7.05 (m, 3 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.90–
6.85 (m, 2 H), 5.25 (t, J = 6.2 Hz, 1 H), 5.18 (d, J = 15.3 Hz, 1 H), 4.35 (d,
J = 15.3 Hz, 1 H), 3.50 (dd, J = 14.5, 5.9 Hz, 1 H), 3.35 (dd, J = 14.5, 6.6
Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.5, 162.1 (d, J = 246.6 Hz), 157.1,
147.8, 145.5, 136.4, 133.1 (d, J = 3.2 Hz), 131.5, 129.7, 129.5 (d, J = 8.5
Hz), 128.9, 128.3, 127.6, 126.9, 126.4, 123.8, 122.7, 121.9, 115.3 (d, J =
21.6 Hz), 58.7, 43.8, 41.8.
2-(4-Methoxybenzyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4aga)
Yellow oil; yield: 346.7 mg (88%).
1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 8.4 Hz, 1 H), 7.94 (d, J = 8.2
Hz, 1 H), 7.84–7.82 (m, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.68 (t, J = 7.6 Hz,
1 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.40–7.34 (m, 2 H), 7.09–7.03 (m, 3 H),
6.92 (d, J = 8.7 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 2 H), 5.24–5.16 (m, 2 H),
4.32 (d, J = 15.0 Hz, 1 H), 3.72 (d, J = 2.1 Hz, 3 H), 3.55 (dd, J = 14.3, 5.4
Hz, 1 H), 3.31 (dd, J = 14.3, 7.1 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.4, 158.9, 157.2, 147.8, 145.5,
136.3, 131.3, 129.6, 129.4, 129.2, 129.0, 128.2, 127.6, 126.9, 126.3,
123.6, 122.8, 121.9, 113.9, 58.6, 55.2, 43.8, 41.5.
HRMS (ESI): m/z [M + H]+ calcd for C25H20FN2O: 383.1554; found:
383.1548.
2-(2-Chlorobenzyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4ada)
HRMS (ESI): m/z [M + Na]+ calcd for C26H22N2NaO2: 417.1573; found:
417.1571.
Yellow oil; yield: 318.4 mg (80%).
1H NMR (400 MHz, CDCl3): δ = 7.93 (t, J = 8.6 Hz, 2 H), 7.86–7.84 (m, 1
H), 7.73 (d, J = 8.2 Hz, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 1
H), 7.41–7.39 (m, 2 H), 7.27–7.24 (m, 2 H), 7.16–7.14 (m, 2 H), 7.07–
7.05 (m, 1 H), 6.91 (d, J = 8.7 Hz, 1 H), 5.31 (t, J = 6.2 Hz, 1 H), 5.20 (d,
J = 16.2 Hz, 1 H), 4.74 (d, J = 16.2 Hz, 1 H), 3.59 (dd, J = 14.5, 5.3 Hz, 1
H), 3.33 (dd, J = 14.5, 7.2 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.7, 156.8, 147.8, 145.5, 136.2,
134.7, 131.7, 131.5, 129.5, 129.4, 129.3, 129.0, 128.6, 128.2, 127.5,
127.0, 126.9, 126.3, 123.7, 122.9, 121.7, 59.1, 42.1, 41.5.
2-(2,4-Dimethoxybenzyl)-3-(quinolin-2-ylmethyl)isoindolin-1-
one (4aha)
Yellow oil; yield: 351.9 mg (83%).
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.4 Hz, 1 H), 7.90 (d, J = 8.5
Hz, 1 H), 7.80–7.77 (m, 1 H), 7.70 (dd, J = 8.1, 1.4 Hz, 1 H), 7.64–7.60
(m, 1 H), 7.45–7.41 (m, 1 H), 7.33–7.24 (m, 2 H), 7.18 (d, J = 8.0 Hz, 1
H), 6.94–6.92 (m, 2 H), 6.37–6.34 (m, 2 H), 5.23 (dd, J = 7.7, 4.8 Hz, 1
H), 5.10 (d, J = 15.2 Hz, 1 H), 4.53 (d, J = 15.2 Hz, 1 H), 3.72–3.68 (m, 4
H), 3.58 (s, 3 H), 3.21 (dd, J = 14.3, 7.8 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C25H2035ClN2O: 399.1259; found:
399.1262.
13C NMR (101 MHz, CDCl3): δ = 168.4, 160.3, 158.1, 157.4, 147.7,
145.7, 136.0, 132.1, 131.0, 130.5, 129.4, 129.0, 127.9, 127.5, 126.8,
126.1, 123.4, 122.8, 121.9, 117.8, 104.3, 98.2, 58.9, 55.2, 55.1, 41.1,
38.4.
2-(3,4-Dichlorobenzyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4aea)
HRMS (ESI): m/z [M + H]+ calcd for C27H25N2O3: 425.1860; found:
Yellow oil; yield: 380.1 mg (88%).
425.1850.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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Y. Tian et al.
Paper
Synthesis
2-(Furan-2-ylmethyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4aia)
2-Octyl-3-(quinolin-2-ylmethyl)isoindolin-1-one (4ama)
Yellow oil; yield: 332.1 mg (86%).
Yellow oil; yield: 290.3 mg (82%).
1H NMR (400 MHz, CDCl3): δ = 8.05 (t, J = 9.3 Hz, 2 H), 7.78–7.76 (m, 2
H), 7.71 (t, J = 7.6 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.37–7.30 (m, 2 H),
7.06 (d, J = 8.3 Hz, 1 H), 6.98 (d, J = 7.3 Hz, 1 H), 5.38 (t, J = 6.5 Hz, 1 H),
3.99–3.92 (m, 1 H), 3.56 (dd, J = 14.4, 5.7 Hz, 1 H), 3.21 (dd, J = 14.4,
7.3 Hz, 1 H), 3.12–3.05 (m, 1 H), 1.62–1.54 (m, 2 H), 1.24–1.15 (m, 10
H), 0.82 (t, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.2, 157.6, 147.8, 145.4, 136.6,
132.4, 131.1, 129.9, 129.0, 128.2, 127.8, 127.0, 126.5, 123.6, 122.8,
122.3, 58.8, 41.9, 40.6, 31.8, 29.3, 29.3, 28.4, 27.0, 22.7, 14.2.
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 8.4
Hz, 1 H), 7.80–7.74 (m, 2 H), 7.69 (t, J = 7.7 Hz, 1 H), 7.50 (t, J = 7.5 Hz,
1 H), 7.39–7.37 (m, 2 H), 7.30 (s, 1 H), 7.09–7.07 (m, 1 H), 6.96 (d, J =
8.3 Hz, 1 H), 6.28–6.27 (m, 1 H), 6.20 (d, J = 3.3 Hz, 1 H), 5.30–5.15 (m,
2 H), 4.51 (d, J = 16.0 Hz, 1 H), 3.67 (dd, J = 14.3, 4.9 Hz, 1 H), 3.38 (dd,
J = 14.3, 7.3 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.1, 157.0, 150.6, 147.8, 145.3,
142.3, 136.2, 131.9, 131.4, 129.6, 129.0, 128.2, 127.6, 126.9, 126.3,
123.7, 122.7, 121.8, 110.4, 108.3, 59.0, 41.2, 37.3.
HRMS (ESI): m/z [M + H]+ calcd for C26H31N2O: 387.2431; found:
387.2413.
HRMS (ESI): m/z [M + H]+ calcd for C23H19N2O2: 355.1441; found:
355.1429.
2-Dodecyl-3-(quinolin-2-ylmethyl)isoindolin-1-one (4ana)
2-Phenethyl-3-(quinolin-2-ylmethyl)isoindolin-1-one (4aja)
Yellow oil; yield: 371.4 mg (84%).
Yellow oil; yield: 347.8 mg (92%).
1H NMR (400 MHz, CDCl3): δ = 8.06 (dd, J = 8.3, 4.3 Hz, 2 H), 7.82–7.79
(m, 2 H), 7.75–7.71 (m, 1 H), 7.56–7.52 (m, 1 H), 7.45–7.33 (m, 2 H),
7.10 (d, J = 8.2 Hz, 1 H), 7.00 (d, J = 7.2 Hz, 1 H), 5.48–5.35 (m, 1 H),
4.06–3.87 (m, 1 H), 3.60 (dd, J = 14.4, 5.7 Hz, 1 H), 3.26 (q, J = 7.7 Hz, 1
H), 3.15–3.09 (m, 1 H), 1.29–1.14 (m, 20 H), 0.87 (t, J = 7.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.1, 147.8, 145.4, 136.4, 132.3,
131.0, 129.7, 128.9, 128.0, 127.6, 126.3, 123.4, 122.6, 122.1, 58.7, 41.7,
40.5, 31.8, 29.59, 29.55, 29.48, 29.44, 29.3, 29.2, 28.2, 26.8, 22.6, 14.1.
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 8.3 Hz, 1 H), 8.04 (d, J = 8.2
Hz, 1 H), 7.85–7.81 (m, 2 H), 7.77–7.73 (m, 1 H), 7.58–7.54 (m, 1 H),
7.43–7.38 (m, 2 H), 7.21–7.15 (m, 3 H), 7.08–7.03 (m, 4 H), 5.33 (t, J =
6.3 Hz, 1 H), 4.26–4.19 (m, 1 H), 3.49 (dd, J = 14.5, 5.8 Hz, 1 H), 3.45–
3.22 (m, 2 H), 3.00–2.96 (m, 1 H), 2.92–2.85 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.3, 157.4, 147.9, 145.5, 138.8,
136.5, 132.2, 131.2, 129.8, 129.0, 128.7, 128.4, 128.1, 127.7, 127.0,
126.4, 126.3, 123.5, 122.6, 122.0, 59.2, 42.5, 41.9, 34.6.
HRMS (ESI): m/z [M + H]+ calcd for C30H39N2O: 443.3057; found:
443.3059.
HRMS (ESI): m/z [M + H]+ calcd for C26H22N2O: 379.1805; found:
379.1805.
2-Propyl-3-(quinolin-2-ylmethyl)isoindolin-1-one (4aoa)
2-(4-Phenylbutyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4aka)
Yellow oil; yield: 189.7 mg (60%).
1H NMR (400 MHz, CDCl3): δ = 8.06 (t, J = 8.8 Hz, 2 H), 7.81 (d, J = 7.2
Hz, 2 H), 7.75–7.70 (m, 1 H), 7.56–7.51 (m, 1 H), 7.41–7.33 (m, 2 H),
7.10–7.07 (m, 1 H), 6.96 (d, J = 7.4 Hz, 1 H), 5.42–5.38 (m, 1 H), 4.00–
3.95 (m, 1 H), 3.67–3.56 (m, 1 H), 3.25–3.12 (m, 2 H), 1.79–1.56 (m, 2
H), 0.85 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.3, 157.5, 148.0, 145.4, 136.6,
132.4, 131.1, 129.9, 129.0, 128.2, 127.8, 127.0, 126.5, 123.6, 122.8,
122.3, 58.7, 42.1, 41.8, 21.7, 11.4.
Yellow oil; yield: 365.4 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 8.6 Hz, 1 H), 8.05 (d, J = 8.5
Hz, 1 H), 7.85–7.81 (m, 2 H), 7.77–7.73 (m, 1 H), 7.56 (t, J = 7.4 Hz, 1
H), 7.44–7.37 (m, 2 H), 7.28–7.24 (m, 2 H), 7.19–7.03 (m, 5 H), 5.40 (t,
J = 6.4 Hz, 1 H), 4.08–4.00 (m, 1 H), 3.59–3.51 (m, 1 H), 3.27 (dd, J =
14.5, 7.3 Hz, 1 H), 3.21–3.14 (m, 1 H), 2.59–2.54 (m, 2 H), 1.74–1.50
(m, 4 H).
13C NMR (101 MHz, CDCl3): δ = 168.2, 157.4, 147.8, 145.4, 142.1,
136.4, 132.3, 131.1, 129.8, 129.0, 128.4, 128.3, 128.1, 127.7, 127.0,
126.4, 125.7, 123.5, 122.7, 122.1, 58.6, 41.8, 40.2, 35.4, 28.6, 27.8.
HRMS (ESI): m/z [M + H]+ calcd for C21H21N2O: 317.1648; found:
317.1635.
HRMS (ESI): m/z [M + H]+ calcd for C28H27N2O: 407.2118; found:
407.2121.
2-Phenyl-3-(quinolin-2-ylmethyl)isoindolin-1-one (4apa)
White solid; yield: 140.0 mg (40%); mp 157–159 °C.
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8.5 Hz, 1 H), 7.98 (d, J = 8.4
Hz, 1 H), 7.90 (d, J = 7.4 Hz, 1 H), 7.86–7.70 (m, 4 H), 7.54 (t, J = 7.5 Hz,
1 H), 7.47–7.37 (m, 4 H), 7.19 (t, J = 7.4 Hz, 1 H), 7.03 (t, J = 8.6 Hz, 2
H), 6.13 (dd, J = 8.7, 4.3 Hz, 1 H), 3.68 (dd, J = 14.6, 4.3 Hz, 1 H), 3.11
(dd, J = 14.6, 8.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 167.2, 157.6, 147.9, 145.1, 137.2,
136.3, 131.1, 131.9, 129.7, 129.2, 129.1, 128.5, 127.7, 127.0, 126.4,
125.4, 124.1, 123.6, 123.1, 122.4, 60.2, 41.8.
2-Butyl-3-(quinolin-2-ylmethyl)isoindolin-1-one (4ala)
White solid; yield: 273.9 mg (83%); mp 117–119 °C.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 8.3
Hz, 1 H), 7.78–7.74 (m, 2 H), 7.68 (t, J = 7.5 Hz, 1 H), 7.48 (t, J = 7.5 Hz,
1 H), 7.36–7.31 (m, 2 H), 7.04 (d, J = 8.3 Hz, 1 H), 6.97–6.95 (m, 1 H),
5.39 (dd, J = 7.4, 5.6 Hz, 1 H), 4.01–3.94 (m, 1 H), 3.58 (dd, J = 14.4, 5.5
Hz, 1 H), 3.22–3.08 (m, 2 H), 1.64–1.52 (m, 2 H), 1.27–1.15 (m, 2 H),
0.81 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.1, 157.4, 147.8, 145.4, 136.4,
132.3, 131.0, 129.7, 128.9, 128.1, 127.6, 126.3, 123.4, 122.7, 122.1,
58.6, 41.7, 40.2, 30.3, 20.0, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C24H19N2O: 351.1492; found:
351.1488.
2-(4-Chlorophenyl)-3-(quinolin-2-ylmethyl)isoindolin-1-one
(4aqa)
HRMS (ESI): m/z [M + H]+ calcd for C22H23N2O: 331.1805; found:
331.1796.
White solid; yield: 115.2 mg (30%), mp 160–162 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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Y. Tian et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5
Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.80 (d, J = 8.2 Hz, 1 H), 7.77–7.73 (m,
1 H), 7.67–7.63 (m, 2 H), 7.57–7.53 (m, 1 H), 7.47–7.40 (m, 2 H), 7.34–
7.32 (m, 2 H), 7.07 (d, J = 7.2 Hz, 1 H), 6.99 (d, J = 8.3 Hz, 1 H), 6.08 (dd,
J = 8.5, 4.4 Hz, 1 H), 3.63 (d, J = 14.0 Hz, 1 H), 3.16–3.10 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 167.1, 157.3, 147.9, 145.0, 136.4,
135.9, 132.1, 130.6, 129.9, 129.2, 129.1, 128.7, 127.7, 127.0, 126.5,
124.53, 124.52, 124.2, 123.1, 122.4, 60.2, 41.7.
H), 6.92 (d, J = 8.4 Hz, 1 H), 5.27 (d, J = 15.3 Hz, 1 H), 5.19 (t, J = 6.0 Hz,
1 H), 4.41 (d, J = 15.4 Hz, 1 H), 3.54 (dd, J = 14.5, 5.4 Hz, 1 H), 3.34 (dd,
J = 14.5, 6.8 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.6, 157.5, 146.2, 145.4, 137.3,
135.4, 132.1, 131.5, 130.8, 130.7, 128.7, 128.4, 128.0, 127.6, 127.5,
126.3, 124.0, 122.8, 122.7, 58.7, 44.6, 41.5.
HRMS (ESI): m/z [M + H]+ calcd for C25H2035ClN2O: 399.1259; found:
399.1262.
HRMS (ESI): m/z [M + H]+ calcd for C24H1835ClN2O: 385.1102; found:
385.1104.
2-Benzyl-3-[(6-bromoquinolin-2-yl)methyl]isoindolin-1-one
(4aae)
3-(Quinolin-2-ylmethyl)-2-(p-tolyl)isoindolin-1-one (4ara)
Yellow oil; yield: 353.6 mg (80%).
White solid; yield: 254.8 mg (70%); mp 168–170 °C.
1H NMR (400 MHz, CDCl3): δ = 7.89–7.72 (m, 5 H), 7.40 (s, 2 H), 7.26–
7.06 (m, 6 H), 6.92–6.89 (m, 1 H), 5.27–5.17 (m, 2 H), 4.40 (d, J = 15.5
Hz, 1 H), 3.50 (d, J = 14.5 Hz, 1 H), 3.31 (d, J = 14.2 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.6, 157.7, 146.4, 145.3, 137.3,
135.3, 133.2, 132.1, 131.5, 130.9, 129.7, 128.7, 128.4, 128.1, 127.9,
127.5, 123.9, 122.8, 122.7, 58.7, 44.6, 41.5.
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 9.6 Hz, 1 H), 7.98 (d, J = 8.3
Hz, 1 H), 7.89 (d, J = 9.0 Hz, 1 H), 7.79 (d, J = 8.9 Hz, 1 H), 7.75–7.71 (m,
1 H), 7.58–7.51 (m, 3 H), 7.45–7.36 (m, 2 H), 7.20 (d, J = 8.2 Hz, 2 H),
7.02 (d, J = 9.3 Hz, 2 H), 6.05 (dd, J = 8.8, 4.3 Hz, 1 H), 3.67 (dd, J = 14.6,
4.3 Hz, 1 H), 3.08 (dd, J = 14.4, 8.8 Hz, 1 H), 2.33 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 167.1, 157.6, 147.9, 145.1, 136.3,
135.3, 134.5, 132.2, 131.7, 129.8, 129.7, 129.1, 128.4, 127.7, 127.0,
126.4, 124.1, 123.7, 123.1, 122.4, 60.4, 41.8, 21.1.
HRMS (ESI): m/z [M + Na]+ calcd for C25H1979BrN2NaO: 465.0573;
found: 465.0579.
HRMS (ESI): m/z [M + H]+ calcd for C25H21N2O: 365.1648; found:
365.1649.
2-Benzyl-3-[(6-methoxyquinolin-2-yl)methyl]isoindolin-1-one
(4aaf)
White solid; yield: 256.2 mg (65%); mp 148–150 °C.
2-Benzyl-3-[(8-chloroquinolin-2-yl)methyl]isoindolin-1-one
(4aab)
1H NMR (400 MHz, CDCl3): δ = 7.89–7.83 (m, 3 H), 7.42–7.35 (m, 3 H),
7.24–7.21 (m, 3 H), 7.13 (dd, J = 6.8, 2.7 Hz, 2 H), 7.05–7.03 (m, 2 H),
6.89 (d, J = 8.1 Hz, 1 H), 5.27 (d, J = 15.3 Hz, 1 H), 5.17 (t, J = 6.4 Hz, 1
H), 4.37 (d, J = 15.6 Hz, 1 H), 3.92 (s, 3 H), 3.52 (dd, J = 14.3, 5.5 Hz, 1
H), 3.28 (dd, J = 14.3, 7.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.6, 157.7, 145.6, 137.4, 135.1,
132.1, 131.4, 131.3, 130.5, 128.7, 128.3, 128.0, 127.4, 123.9, 122.9,
122.4, 122.2, 105.1, 58.9, 55.6, 44.6, 41.6.
Yellow oil; yield: 199.1 mg (50%).
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 8.6 Hz, 1 H), 7.77 (t, J = 6.8
Hz, 2 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.46–7.34 (m, 4 H), 7.28–7.25 (m, 1
H), 7.21–7.26 (m, 4 H), 6.86 (d, J = 8.8 Hz, 1 H), 5.27–5.23 (m, 2 H),
4.59 (d, J = 15.2 Hz, 1 H), 3.56–3.44 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 168.6, 157.7, 145.4, 143.9, 137.4,
136.7, 132.1, 131.6, 129.8, 128.7, 128.6, 128.4, 128.2, 128.1, 127.5,
126.8, 126.3, 123.8, 122.9, 122.7, 58.8, 44.7, 41.2.
HRMS (ESI): m/z [M + H]+ calcd for C26H23N2O2: 395.1754; found:
395.1759.
HRMS (ESI): m/z [M + H]+ calcd for C25H2035ClN2O: 399.1259; found:
399.1258.
2-Benzyl-3-[(8-methoxyquinolin-2-yl)methyl]isoindolin-1-one
(4aag)
2-Benzyl-3-[(6-methylquinolin-2-yl)methyl]isoindolin-1-one
(4aac)
White solid; yield: 268.0 mg (68%); mp 147–149 °C.
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.4 Hz, 1 H), 7.85–7.83 (m, 1
H), 7.47–7.42 (m, 3 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.23–7.20 (m, 3 H),
7.17–7.15 (m, 2 H), 7.12–7.10 (m, 1 H), 7.07 (d, J = 7.8 Hz, 1 H), 6.93
(d, J = 8.4 Hz, 1 H), 5.24–5.19 (m, 2 H), 4.39 (d, J = 15.4 Hz, 1 H), 4.06 (s,
3 H), 3.59 (dd, J = 14.3, 5.8 Hz, 1 H), 3.47 (dd, J = 14.3, 6.8 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.7, 156.1, 155.2, 145.5, 139.8,
137.4, 136.4, 132.1, 131.5, 128.6, 128.3, 128.2, 128.0, 127.4, 126.6,
123.9, 122.9, 122.5, 119.5, 108.2, 59.1, 56.3, 44.6, 42.1.
Yellow oil; yield: 241.9 mg (64%).
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.9 Hz, 1 H), 7.83 (d, J = 8.1
Hz, 2 H), 7.51–7.48 (m, 2 H), 7.37–7.31 (m, 2 H), 7.21–7.11 (m, 5 H),
7.01 (d, J = 6.7 Hz, 1 H), 6.85 (d, J = 8.5 Hz, 1 H), 5.24 (d, J = 15.3 Hz, 1
H), 5.17 (t, J = 6.4 Hz, 1 H), 4.38 (d, J = 15.4 Hz, 1 H), 3.49 (dd, J = 14.4,
5.7 Hz, 1 H), 3.25 (dd, J = 14.3, 6.9 Hz, 1 H), 2.48 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.7, 156.2, 146.4, 145.6, 137.4,
136.3, 135.9, 132.1, 131.4, 128.7, 128.6, 128.3, 128.0, 127.5, 127.1,
126.5, 123.9, 123.4, 122.9, 122.0, 58.9, 44.6, 41.6, 21.6.
HRMS (ESI): m/z [M + Na]+ calcd for C26H22N2NaO2: 417.1573; found:
417.1575.
HRMS (ESI): m/z [M + Na]+ calcd for C26H22N2NaO: 401.1624; found:
401.1631.
2-Benzyl-3-[1-(quinolin-2-yl)ethyl]isoindolin-1-one (4aah)
White solid; yield: 344.4 mg (89%); mp 214–216 °C.
2-Benzyl-3-[(6-chloroquinolin-2-yl)methyl]isoindolin-1-one
(4aad)
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8.6 Hz, 1 H), 8.04 (d, J = 9.5
Hz, 1 H), 7.87 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.74–7.70 (m, 1 H),
7.57–7.52 (m, 1 H), 7.42–7.28 (m, 6 H), 7.23–7.19 (m, 2 H), 6.48–6.42
(m, 1 H), 5.45 (d, J = 15.2 Hz, 1 H), 5.32 (d, J = 8.0 Hz, 1 H), 4.40 (d, J =
15.2 Hz, 1 H), 3.92 (d, J = 9.8 Hz, 1 H), 0.97 (d, J = 9.3 Hz, 3 H).
Yellow oil; yield: 278.7 mg (70%).
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 9.0 Hz, 1 H), 7.88–7.83 (m, 2
H), 7.75 (d, J = 2.3 Hz, 1 H), 7.64 (dd, J = 9.0, 2.3 Hz, 1 H), 7.45–7.40 (m,
2 H), 7.25–7.22 (m, 3 H), 7.14 (dd, J = 6.8, 2.8 Hz, 2 H), 7.09–7.07 (m, 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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Y. Tian et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3): δ = 169.0, 161.4, 147.8, 143.2, 137.3,
136.5, 133.0, 131.0, 129.7, 129.5, 128.9, 128.5, 128.2, 127.7, 127.6,
127.0, 126.5, 123.8, 123.7, 120.4, 63.2, 44.3, 41.2, 10.8.
(3) Stuk, T. L.; Assink, B. K.; Bates, R. C.; Erdman, D. T.; Fedij, V.;
Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Process
Res. Dev. 2003, 7, 851.
(4) Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow,
D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.;
Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett. 1998, 8, 1499.
(5) Ferland, J. M.; Demerson, C. A.; Humber, L. G. Can. J. Chem. 1985,
63, 361.
(6) (a) Linden, M.; Hadler, D.; Hofmann, S. Hum. Psychopharmacol.
1997, 12, 445. (b) Zhuang, Z. P.; Kung, M. P.; Mu, M.; Kung, H. F.
J. Med. Chem. 1998, 41, 157.
(7) (a) Takahashi, I.; Hirano, E.; Kawakami, T.; Kitajima, H. Hetero-
cycles 1996, 43, 2343. (b) Lawrence, N. J.; Liddle, J.; Bushell, S.
M.; Jackson, D. A. J. Org. Chem. 2002, 67, 457.
(8) Laboratori Baldacci, S. P. A. Japanese Patent 5,946,268, 1984;
Chem. Abstr. 1984, 101, 54922.
(9) Lippmann, W. US Patent 4267189, 1981; Chem. Abstr. 1981, 95,
61988m
(10) Achinami, K.; Ashizawa, N.; Kobayasui, F. Japanese Patent
03,133,955, 1991; Chem. Abstr. 1991, 115, 255977j
(11) (a) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.;
Kingsbury, W. D. J. Org. Chem. 1994, 59, 2623. (b) De Clercq, E.
J. Med. Chem. 1995, 38, 2491.
(12) (a) Taylor, E. C.; Zhou, P.; Jennings, L. D.; Mao, Z.; Hu, B.; Jun, J. G.
Tetrahedron Lett. 1997, 38, 521. (b) Riedinger, C.; Endicott, J. A.;
Kemp, S. J.; Smyth, L. A.; Watson, A.; Valeur, E.; Golding, B. T.;
Griffin, R. J.; Hardcastle, I. R.; Noble, M. E.; McDonnell, J. M.
J. Am. Chem. Soc. 2008, 130, 16038.
HRMS (ESI): m/z [M + Na]+ calcd for C26H22N2NaO: 401.1624; found:
401.1631.
2-Benzyl-3-(isoquinolin-1-ylmethyl)isoindolin-1-one (4aai)
White solid; yield: 309.4 mg (85%); mp 125–127 °C.
1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 5.7 Hz, 1 H), 7.90 (d, J = 7.3
Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.71 (d, J = 8.6 Hz, 1 H), 7.66–7.60 (m,
2 H), 7.42 (q, J = 8.2 Hz, 2 H), 7.31 (t, J = 8.0 Hz, 1 H), 7.21–7.15 (m, 3
H), 7.08–7.06 (m, 2 H), 6.81 (d, J = 7.6 Hz, 1 H), 5.40 (t, J = 6.4 Hz, 1 H),
5.24 (d, J = 15.4 Hz, 1 H), 4.30 (d, J = 15.4 Hz, 1 H), 3.88 (dd, J = 14.9, 6.1
Hz, 1 H), 3.41 (dd, J = 14.9, 7.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.8, 157.1, 146.0, 141.7, 137.3,
136.3, 131.9, 131.4, 130.2, 128.7, 128.3, 127.9, 127.6, 127.5, 124.6,
123.9, 123.1, 120.3, 58.6, 44.8, 38.3.
HRMS (ESI): m/z [M + H]+ calcd for C25H21N2O: 365.1648; found:
365.1659.
2-Benzyl-1-oxo-3-(quinolin-2-ylmethyl)isoindoline-5-carboni-
trile (4baa)
White solid; yield: 167.3 mg (43%); mp 140–142 °C.
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.2 Hz, 1 H), 7.99–7.93 (m, 2
H), 7.81 (d, J = 8.2 Hz, 1 H), 7.75–7.71 (m, 2 H), 7.57–7.53 (m, 1 H),
7.43 (s, 1 H), 7.27–7.25 (m, 3 H), 7.18–7.16 (m, 2 H), 6.98 (d, J = 8.8 Hz,
1 H), 5.35–5.27 (m, 2 H), 4.45 (d, J = 15.1 Hz, 1 H), 3.60 (dd, J = 14.8,
5.0 Hz, 1 H), 3.24 (dd, J = 14.8, 7.4 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 166.7, 156.1, 147.8, 146.2, 136.8,
136.6, 136.0, 132.4, 130.1, 129.1, 128.9, 128.1, 127.9, 127.8, 127.2,
127.0, 126.8, 124.7, 121.7, 118.4, 114.8, 58.7, 44.9, 40.9.
(13) For selected recent examples, see: (a) Gutierrez, A. J.; Shea, K. J.;
Svoboda, J. J. J. Org. Chem. 1989, 54, 4335. (b) Huang, X.; Xu, J.
J. Org. Chem. 2009, 74, 8859.
(14) Selected examples: (a) Grigg, R.; Dorrity, M. J. R.; Malone, J. F.;
Mongkolaus-Savaratana, T.; Norbert, W. D. J. A.; Sridharan, V.
Tetrahedron Lett. 1990, 31, 3075. (b) Couty, S.; Liégault, B.;
Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511.
HRMS (ESI): m/z [M + Na]+ calcd for C26H19N3NaO: 412.1420; found:
412.1419.
(15) Selected examples: (a) Epsztajn, J.; Grzelak, R.; Jóźwiak, A. Syn-
thesis 1996, 1212. (b) Aubert, T.; Farnier, M.; Guilard, R. Can. J.
Chem. 1990, 68, 842. (c) Mamidyala, S. K.; Cooper, M. A. Chem.
Commun. 2013, 49, 8407.
Funding Information
(16) Selected examples: (a) Luzzio, F. A.; Zacherl, D. P. Tetrahedron
Lett. 1998, 39, 2285. (b) Das, S.; Addis, D.; Knopke, L. R.;
Bentrup, U.; Junge, K.; Brukner, A.; Beller, M. Angew. Chem. Int.
Ed. 2011, 50, 9180. (c) Shi, L. Y.; Hu, L.; Wang, J.; Cao, X.; Gu, H.
Org. Lett. 2012, 14, 1876. (d) Cabrero-Antonino, J. R.; Sorribes, I.;
Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2016, 55, 387.
(e) Cabrero-Antonino, J. R.; Adam, R.; Papa, V.; Holsten, M.;
Junge, K.; Beller, M. Chem. Sci. 2017, 8, 5536.
(17) Selected examples: (a) Grigg, R.; Gai, X.; Sridharan, V.; Zhang, L.;
Khamnaen, T.; Rajviroongit, S.; Collard, S.; Keep, A. Can. J. Chem.
2005, 83, 990. (b) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G.
C.; Booker-Milburn, K. I. Org. Lett. 2011, 13, 5326. (c) Li, D. D.;
Yuan, T. T.; Wang, G. W. Chem. Commun. 2011, 47, 12789.
(d) Sun, L. X.; Zeng, T.; Jiang, D.; Dai, L. Y.; Li, C. J. Can. J. Chem.
2011, 90, 92. (e) Bisai, V.; Suneja, A.; Singh, V. K. Angew. Chem.
Int. Ed. 2014, 53, 10737. (f) Reddy, M. C.; Jeganmohan, M. Org.
Lett. 2014, 16, 4866. (g) Xia, C.; White, A. J. P.; Hii, K. K. M. J. Org.
Chem. 2016, 81, 7931. (h) Zhang, Y.; Wang, D.; Cui, S. Org. Lett.
2015, 17, 2494. (i) Nozawa-Kumada, K.; Kadokawa, J.;
Kameyama, T.; Kondo, Y. Org. Lett. 2015, 17, 4479. (j) Jiménez,
J.; Kim, B. S.; Walsh, P. J. Adv. Synth. Catal. 2016, 358, 2829.
(k) Dutta, M.; Mandal, S.; Peguand, R.; Pratihar, S. J. Org. Chem.
2017, 82, 2193. (l) Liu, L.; Qiang, J.; Bai, S. H.; Sung, H. L.; Miao, C.
B.; Li, J. Adv. Synth. Catal. 2017, 359, 1283.
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (Nos. 21572123, 21172138 and 21302117),
the Fundamental Research Funds for the Central Universities
(GK201601003 and GK201603047) and the Distinguished Doctoral
Research Funds from Shaanxi Normal University (S2011YB04).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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Paper
Synthesis
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