Novel one-pot synthesis of 2-substituted 3-alkoxyisoindolin-1-imine derivatives from 2-cyanobenzaldehyde, amine, and alcohol

Article abstract of DOI:10.1055/s-0032-1317472

A novel, one-pot procedure has been developed for the synthesis of 2-substituted 3-alkoxyisoindolin-1-imine derivatives via three-component condensation of 2-cyanobenzaldehyde, amine, and alcohol. The efficient and convenient reaction conditions provide the corresponding products from various substrates in good yields (65-96%) catalyzed by acetic acid. The straightforward procedure is a valid contribution to methods for the synthesis of isoindolin-1-imine derivatives. Georg Thieme Verlag KG Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1317472

PAPER
▌3543
paper
Novel One-Pot Synthesis of 2-Substituted 3-Alkoxyisoindolin-1-imine
Derivatives from 2-Cyanobenzaldehyde, Amine, and Alcohol
One-Pot Synthesis of 2-Substituted 3-Alkoxyisoindolin-1-imines
Sida Shen,a Xingyu Xu,b Min Lei,*b Lihong Hu*a,b
a
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
b
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. of China
Fax +86(21)20231965; E-mail: mlei@mail.shcnc.ac.cn; E-mail: simmhulh@mail.shcnc.ac.cn
Received: 09.08.2012; Accepted after revision: 24.09.2012
hyde, an amine, and an alcohol catalyzed by acetic acid in
good yields and with wide scope (Scheme 1).
Abstract: A novel, one-pot procedure has been developed for the
synthesis of 2-substituted 3-alkoxyisoindolin-1-imine derivatives
via three-component condensation of 2-cyanobenzaldehyde, amine,
and alcohol. The efficient and convenient reaction conditions pro-
vide the corresponding products from various substrates in good
yields (65–96%) catalyzed by acetic acid. The straightforward pro-
cedure is a valid contribution to methods for the synthesis of isoin-
dolin-1-imine derivatives.
CHO
R1
R2NH2
R3OH
+
+
2
3
CN
1
OR3
AcOH (1.5 equiv)
65–80 °C, 10–60 min
Key words: 2-cyanobenzaldehyde, isoindolin-1-imine, multicom-
ponent reaction, 3-alkoxyisoindolin-1-imine
R1
N
R2
NH
4
In the last few years, considerable effort has been devoted
to the synthesis of isoindole analogues due to their signif-
icant biological activity,1 and also their presence in many
natural products.2 Among them, isoindolin-1-imines have
attracted much attention due to their significant therapeu-
tic and biological activity, such as NR2B-selective
NMDA receptor antagonists,3 the thrombin receptor
(PAR-1) inhibitors,4 and anti-proliferative effect.5 Meth-
ods for the synthesis of isoindolin-1-imine analogues are
based on condensation reactions from substrates that have
adjacent substituted formyl or cyano groups in the ben-
zene ring with suitable nucleophiles.3–6 Many of existing
methods suffer from certain limitations with respect to
yield, multistep strategies, or reaction condition. Due to
the potential biological activity of isoindolin-1-imine an-
alogues, great attention is still devoted to the development
of novel and simple methods for their synthesis.
Scheme 1 Synthesis of 2-substituted 3-alkoxyisoindolin-1-imines 4
Initially, the condensation reaction of 2-cyanobenzalde-
hyde (1a, 3 mmol), benzylamine (2a, 3 mmol), and etha-
nol (3a, 5 mL) was investigated in the presence of
different catalysts; the results are summarized in Table 1.
In this three-component reaction, the catalyst had a signif-
icant effect on the reaction time and the yield (Table 1).
The desired product 4a was afforded in poor yield (entry
1) under catalysis-free conditions, and was obtained in
moderate yields in the presence of 0.5 equivalents of a ba-
sic or acidic catalyst, such as triethylamine, 4-toluenesul-
fonic acid, L-proline, or sulfamic acid (entries 2–5). A
better result was obtained in the presence of acetic acid
(0.5 equiv), which afforded compound 4a in 83% yield
(entry 6). Subsequent experiments showed that increasing
the quantity of acetic acid from 0.3 to 1.5 equivalents not
only increased the yield of 4a from 74% to 95%, but also
decreased the reaction time from 60 minutes to 10 minutes
(entries 6–9). However, the yields did not improve when
a greater excess of acetic acid (2–5 equiv) was used in this
condensation reaction under the same conditions (entries
10, 11). Therefore, acetic acid (1.5 equiv) was sufficient
to catalyze this three-component reaction.
As a part of our continued efforts in the development of
novel, efficient, and green procedures for multicompo-
nent reactions (MCRs),7 we turned our attention to the
synthesis of isoindolin-1-imine derivatives by a multi-
component reaction. Notably, we investigated the reac-
tion of 2-cyanobenzaldehyde, an amine, and an alcohol,
and we found that a novel structure, an isoindolin-1-im-
ine, in which the amine and alcohol had formally inserted
into the C2 and C3 substituent, respectively, had been
formed. Given the novelty of this transformation, we pur-
sued a more detailed study of this reaction. Herein, we de-
scribe a novel, one-pot procedure for the synthesis of 2-
substituted 3-alkoxyisoindolin-1-imine derivatives via
three-component condensation of a 2-cyanobenzalde-
To demonstrate the scope and limitations of the proce-
dure, condensations of various 2-cyanobenzaldehydes 1,
amines 2, and alcohols 3 were carried out in the presence
of acetic acid (1.5 equiv) at 65–80 °C for 10–60 minutes,
and a series of 2-substituted 3-alkoxyisoindolin-1-imines
4 were synthesized (Table 2). The reaction scope of sub-
stituted aryl- and alkylamines was explored with 2-cyano-
benzaldehyde in ethanol or methanol. Benzyl- (entries 1–
3, 11–12), heterobenzyl- (entry 6), phenethyl- (entries 4,
5, 13), and alkylamines (entries 7–9, 14–16) provided
SYNTHESIS 2012, 44, 3543–3549
Advanced online publication: 16.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317472; Art ID: SS-2012-F0613-OP
© Georg Thieme Verlag Stuttgart · New York

3544
S. Shen et al.
PAPER
Table 1 Catalyst Screening for the Synthesis of 4aa
31), and only the intermediate of the reaction between the
aldehyde group and benzylamine was obtained. The rea-
son for this result might be the reduction in the electron
density the cyano group as a result of the strong electron-
withdrawing effect of nitro group reducing the reactivity
of the cyano group.
OEt
N
CHO
catalyst
EtOH
+
+
BnNH2
Bn
reflux
CN
NH
1a
2a
3a
4a
The novel structures of 2-substituted 3-alkoxyisoindolin-
Entry
Catalyst (equiv)
Time (min)
Yieldb (%)
1
1-imines 4a–i,k–p,r–z,ac,ad were established from H,
13C and two-dimensional NMR spectral data, as illustrated
1
2
None
60
60
60
60
60
60
60
20
10
10
10
10
21
55
39
56
83
54
90
95
95
95
1
by the representative example 4a (Figure 1). In its H
Et3N (0.5)
NMR spectrum, H3 occurs as a singlet at δ = 5.83 that
shows (i) NOESY correlation with H8 (2 multiplets at δ =
3.16 and 2.97), with H9 [triplet at δ = 1.07 (t, J = 7.0 Hz)],
and with H10 [2 doublets at δ = 5.07 (d, J = 15.5 Hz) and
4.43 (d, J = 15.5 Hz)] (Figure 2), (ii) HMB correlation
contours with C10 (δ = 43.8), C8 (δ = 57.4), C4 (δ =
123.5), C7a (δ = 133.1), C3a (δ = 139.4), and C1 (δ =
162.9), respectively (Figure 3). The H10 protons exhibit
HMB correlations with δ = 88.0, 127.8, 137.4, 162.9, and
latter were assigned to C3, C12(16), C11, C1, respective-
ly. The H8 protons show HMB correlations with C3 (δ =
88.0) and C9 (δ = 15.0). The H7 proton occurs as a doublet
at δ = 7.71 (d, J = 6.0 Hz) which shows HMB correlation
contours with C6 (δ = 130.8) and C7a (δ = 139.4) (Figure
3).
3
PTSA (0.5)
L-proline (0.5)
sulfamic acid (0.5)
AcOH (0.5)
AcOH (0.3)
AcOH (1.0)
AcOH (1.5)
AcOH (2)
4
5
6
7
8
9
10
11
AcOH (5)
a Conditions: 2-cyanobenzaldehyde (1a, 3 mmol), BnNH2 (2a, 3
mmol), EtOH (3a, 5 mL), reflux.
7.31, t, J = 7.4 Hz
b Isolated yields.
H
128.4
12
7.25, t,
H
7.35, d,
7.71, d,
13
J = 7.4 Hz
14
J = 6.9 Hz
J = 6.H0 Hz
127.4
H
NH
15
127.8
7.31, t,
7.55, m
11
7
121.5
H
J = 7.4 Hz
good conversions, but aniline (entry 10) did not and only
the imine intermediate between aniline and 2-cyanobenz-
aldehyde was observed. Notably, benzyl- and phenethyl-
amines carrying either electron-withdrawing or electron-
donating groups reacted efficiently to give the corre-
sponding products without significant difference. Steric
bulk close to the alkylamine, such as isopropyl (entry 8),
cyclopropyl (entry 9), and cyclopentyl (entry 14), also ap-
peared to not to make a significant impact on the yields.
These conditions could be applied to 4-aminobutanoic
acid (entry 16) to provide good conversion, but not to 3-
(aminomethyl)pyridine (entry 17) under the same condi-
tions. Moreover, using other primary alcohols, including
butanol (entries 18–21) and benzyl alcohol (entries 22–
25), resulted in reactions that proceeded smoothly to give
the corresponding products in good yields (80–92%).
When the alcohol was changed to the secondary alcohol
propan-2-ol (entry 26), the yields decreased even with a
prolonged reactive time. In addition, the corresponding
product could not be obtained in the reaction with the ter-
tiary alcohol tert-butyl alcohol (entry 27) or phenol (entry
28). To further investigate the effects of substituted 2-cy-
anobenzaldehydes for this multicomponent condensation,
the reaction of the 2-cyanobenzaldehydes including elec-
tron-withdrawing or electron-donating groups was carried
out. Thus reaction of 2-cyano-3-methoxybenzaldehyde
(1b, entries 29, 30) gave the products in excellent yields,
but 2-cyano-4-nitrobenzaldehyde (1c) did not give the
isoindol-1-imine product under these conditions (entry
1
137.4
128.4
127.8
H
7a
6
162.9
16
139.4
10
130.8
H 7.35, d, J = 6.9 Hz
N
43.9
123.5 3a
2
129.3
5
H
88.0
4.43, d, J = 15.5 Hz
5.07, d,
J = 15.5 Hz
3
H
H
4
133.1
7.50, m
O
57.4
5.83, H
7.45, m
H
s, H-3
8
H
9CH3
1.07, t,
J = 7.0 Hz
2.97, mH
15.0
3.16, m
Figure 1 1 H and 13C NMR assignments for compound 4a
14
13
12
NH
15
7
4
1
11
10
7a
3a
6
5
16
N
2
3
O
H
8
9
Figure 2 Important NOESY correlations for compound 4a
To further investigate the mechanism of the acetic acid
catalyzed condensation, several reactions were carried out
under the conditions of Scheme 2. Firstly, the condensa-
tion of 2-cyanobenzaldehyde (1a) and benzylamine (2a)
was carried out in water in the presence of acetic acid (1.5
equiv) at 100 °C for one hour, and the tautomerism prod-
ucts 2-[(benzylamino)(hydroxy)methyl]benzonitrile (5a)
and 2-benzyl-3-iminoisoindolin-1-ol (6a) were obtained
in 30% and 70% yields, respectively. Subsequent experi-
ments showed that 2-benzyl-3-methoxyisoindolin-1-im-
ine (4k) also could be synthesized in high yield, but longer
Synthesis 2012, 44, 3543–3549
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 2-Substituted 3-Alkoxyisoindolin-1-imines
3545
Table 2 Synthesis of 2-Substituted 3-Alkoxyisoindolin-1-imines 4 Catalyzed by Acetic Acida
Entry
R1
R2
R3
Temp (°C) Time (min) Product
Yieldb (%)
1
2
H
Bn
Et
80
80
80
80
80
80
80
80
80
80
65
65
65
65
65
65
65
80
80
80
80
80
80
80
80
80
80
80
80
80
80
10
10
10
10
10
10
10
10
10
60
10
10
10
10
10
10
60
30
30
30
30
45
30
30
30
60
60
60
10
10
20
4a
4b
4c
95
91
94
94
90
89
93
85
90
H
4-MeOC6H4CH2
Et
3
H
4-ClC6H4CH2
Et
4
H
4-FC6H4(CH2)2
Et
4d
4e
5
H
3,4-(MeO)2C6H3(CH2)2
Et
6
H
2-furylmethyl
Et
4f
7
H
Pr
Et
4g
4h
4i
8
H
i-Pr
Et
9
H
cyclopropyl
Et
c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
H
Ph
Et
4j
–
H
Bn
Me
Me
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bn
Bn
Bn
Bn
i-Pr
t-Bu
Ph
Et
4k
4l
95
91
87
91
94
85
trace
90
92
91
88
84
87
80
81
65
H
4-ClC6H4CH2
H
3,4-(MeO)2C6H3(CH2)2
4m
4n
4o
4p
4q
4r
H
cyclopentyl
H
Bu
H
(CH2)3CO2H
H
3-pyridyl
H
Bn
H
Bu
4s
H
4-FC6H4CH2
4t
H
3,4-(MeO)2C6H3(CH2)2
4u
4v
4w
4x
4y
4z
H
i-Bu
H
cyclopropyl
H
Bn
H
4-FC6H4(CH2)2
H
Bn
Bn
Bn
Bn
Pr
c
H
4aa
4ab
4ac
4ad
4ae
–
c
H
–
3-OMed
3-OMed
96
95
Et
e
c
4-NO2
Bn
Et
–
a Conditions: 2-cyanobenzaldehyde 1 (3 mmol), amine 2 (3 mmol), alcohol 3 (5 mL), AcOH (4.5 mmol).
b Isolated yields.
c Not detected by LC-MS.
d Substrate was 2-cyano-3-methoxybenzaldehyde (1b), product contained a 5-methoxy group.
e Substrate was 2-cyano-4-nitrobenzaldehyde (1c).
time, via condensation from the mixture of 5a and 6a with product 6a did not afford product 4k immediately might
methanol 3b, which was carried out in the presence of be the reason for the longer time for the reaction from 5a
acetic acid at 65 °C for 12 hours. That major tautomerism and 6a, and perhaps the structure 5a was the primary in-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3543–3549

3546
S. Shen et al.
PAPER
OH
CN
OH
N
CHO
H2O, AcOH
100 °C, 1 h
NH2
+
N
H
CN
NH
1a
2a
5a (30%)
6a (70%)
MeO
MeOH (3b), AcOH
65 °C, 10 min
MeOH (3b), AcOH
65 °C, 12 h
N
NH
4k (95%)
Scheme 2
condensation reaction of 2-cyanobenzaldehyde 1, amine
2, and alcohol 3 catalyzed by acetic acid. A variety of sub-
strates can participate in the process with good yields.
Therefore, our method is a valid contribution to the meth-
odology for the synthesis of isoindolin-1-imine deriva-
tives.
13
14
15
12
H
7
NH
1
11
16
6
7a
3a
N
10
2
5
3
4
O
8
H
9
Reagents and all solvents were analytically pure grade and were
used without further purification. Column chromatography was per-
formed using silica gel (200–300 mesh). TLC was performed on
GF254 silica gel plates (Yantai Huiyou Inc., China). Melting points
Figure 3 Key HMBC correlations for compound 4a
were determined with a WRS-1B apparatus. 1H (400 MHz) and 13
C
termediate of the condensation for the synthesis of 4k
from 2-cyanobenzaldehyde (1a), benzylamine (2a), and
methanol (3b). The transformation from relatively stable
structure 6a to the reactive intermediate 5a might take a
long time.
(100 MHz) NMR, NOESY, HSQC, HMBC spectra were recorded
on Bruker AMX 400 spectrometer in the solvent indicated. HRMS
(ESI) were determined on a Micromass Q-Tif Global mass spec-
trometer and MS (ESI)were obtained on a Bruker Esquire 3000 Plus
spectrometer.
Thus, on the basis of the obtained results, a plausible
mechanism can reasonably be proposed for the series of 2-
substituted 3-alkoxyisoindolin-1-imines (Scheme 3). Af-
ter the nucleophilic addition of amine 2 to the 2-cyano-
2-Substituted 3-Alkoxyisoindolin-1-imines 4; General Proce-
dure
To a stirred soln of 2-cyanobenzaldehyde (1, 3 mmol) in alcohol 3
(5 mL) were added AcOH (4.5 mmol) and amine 2 (3 mmol). The
mixture was stirred at 65–80 °C for 10–60 min. After completion of
the reaction, the mixture was concentrated under reduced pressure.
The crude product was purified by chromatography (silica gel,
CH2Cl2–MeOH, 100:1 to 50:1) to afford compound 4.
benzaldehyde 1, adduct
5 gives unstable imine
intermediate 7 by dehydration and protonation under acid-
ic condition. Subsequent nucleophilic addition of alcohol
3 to 7 affords 8. Finally, cyclization of 8 in the presence
of acetic acid gives the title isoindolin-1-imines 4.
2-Benzyl-3-ethoxyisoindolin-1-imine (4a)
Yellow gum; yield: 760 mg (95%).
In conclusion, we have developed an efficient and conve-
nient method for the preparation of 2-substituted 3-alk-
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 6.0 Hz, 1 H), 7.55–
7.43 (m, 3 H), 7.35 (d, J = 6.9 Hz, 2 H), 7.31 (t, J = 7.4 Hz, 2 H),
7.25 (t, J = 7.4 Hz, 1 H), 5.83 (s, 1 H), 5.07 (d, J = 15.5 Hz, 1 H),
4.43 (d, J = 15.5 Hz, 1 H), 3.21–3.13 (m, 1 H), 3.00–2.93 (m, 1 H),
1.07 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.9, 139.4, 137.4, 133.1, 130.8,
129.3, 128.4 (2 C), 127.8 (2 C), 127.2, 123.5, 121.5, 88.0, 57.4,
43.9, 15.0.
oxyisoindolin-1-imines
4
via the three-component
OH
R2
– H2O
N
CHO
AcOH
R1
R2NH2
H
+
R1
H+
CN
MS (ESI): m/z = 267.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H19N2O: 267.1492; found:
N
1
2
5
••
R3OH
3
267.1494.
OR3
OR3
R2
AcOH
3-Ethoxy-2-(4-methoxybenzyl)isoindolin-1-imine (4b)
Yellow gum; yield: 810 mg (91%).
R2
N
N
H
R1
H
R1
R1
N
R2
1H NMR (400 MHz, CDCl3): δ = 7.76–7.57 (m, 1 H), 7.53–7.41 (m,
3 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.83 (d, J = 6.4 Hz, 2 H), 5.80 (s, 1
H), 5.02 (d, J = 15.2 Hz, 1 H), 4.33 (d, J = 15.2 Hz, 1 H), 3.76 (s, 3
H), 3.20–3.13 (m, 1 H), 2.99–2.92 (m, 1 H), 1.07 (t, J = 7.0 Hz, 3 H).
N
N
NH
7
8
4
Scheme 3 Possible mechanism for the formation of compound 4
Synthesis 2012, 44, 3543–3549
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 2-Substituted 3-Alkoxyisoindolin-1-imines
3547
13C NMR (100 MHz, CDCl3): δ = 162.8, 158.8, 139.4, 133.0, 130.9,
129.6, 129.4 (3 C), 123.4, 121.6, 113.9 (2 C), 87.9, 57.5, 55.2, 43.4,
15.1.
3.12 (dq, J = 9.1, 7.1 Hz, 1 H), 2.89 (dq, J = 9.1, 7.0 Hz, 1 H), 1.80–
1.58 (m, 2 H), 1.09 (t, J = 7.1 Hz, 3 H), 0.96 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.6, 139.0, 133.3, 130.5, 129.1,
123.1, 121.2, 88.3, 56.6, 42.1, 20.7, 14.8, 11.4.
MS (ESI): m/z = 297.5 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2O2: 297.1598; found:
MS (ESI): m/z = 219.7 [M + H]+.
297.1601.
HRMS (ESI): m/z [M + H]+ calcd for C13H19N2O: 219.1492; found:
219.1493.
2-(4-Chlorobenzyl)-3-ethoxyisoindolin-1-imine (4c)
Yellow gum; yield: 845 mg (94%).
3-Ethoxy-2-isopropylisoindolin-1-imine (4h)
Yellow gum; yield: 556 mg (85%).
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 6.6 Hz, 1 H), 7.57–
7.36 (m, 3 H), 6.10 (s, 1 H), 4.41 (dt, J = 13.7, 6.8 Hz, 1 H), 3.25
(dq, J = 14.5, 7.1 Hz, 1 H), 2.87 (dq, J = 14.5, 7.1 Hz, 1 H), 1.40 (d,
J = 2.0 Hz, 3 H), 1.39 (d, J = 2.0 Hz, 3 H), 1.09 (t, J = 7.0 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.69–7.67 (m, 1 H), 7.58–7.42 (m,
3 H), 7.42–7.13 (m, 4 H), 5.81 (s, 1 H), 5.02 (d, J = 15.5 Hz, 1 H),
4.41 (d, J = 15.5 Hz, 1 H), 3.16–3.10 (m, 1 H), 2.98–2.93 (m, 1 H),
1.06 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.0, 139.3, 136.1, 133.0, 132.7,
131.0, 129.4 (3 C), 128.6 (2 C), 123.6, 121.5, 88.1, 57.5, 43.4, 15.0.
MS (ESI): m/z = 301.6 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 162.9, 139.4, 133.4, 130.8, 129.3,
123.3, 121.4, 87.1, 56.4, 44.1, 21.1, 19.5, 14.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H18ClN2O: 301.1102;
MS (ESI): m/z = 219.7 [M + H]+.
found: 301.1105.
HRMS (ESI): m/z [M + H]+ calcd for C13H19N2O: 219.1492; found:
219.1490.
3-Ethoxy-2-(4-fluorophenethyl)isoindolin-1-imine (4d)
Yellow gum; yield: 840 mg (94%).
2-Cyclopropyl-3-ethoxyisoindolin-1-imine (4i)
Yellow gum; yield: 583 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 6.9 Hz, 1 H), 7.54–
7.36 (m, 3 H), 5.79 (s, 1 H), 3.19–3.13 (m, 1 H), 3.03–2.97 (m, 1 H),
2.53–2.50 (m, 1 H), 1.09 (t, J = 7.1 Hz, 3 H), 0.98–0.85 (m, 3 H),
0.72–0.68 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.3, 139.6, 134.2, 130.9, 129.5,
123.1, 122.1, 89.6, 57.8, 22.8, 15.1, 5.4, 5.2.
MS (ESI): m/z = 217.4 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O: 217.1335; found:
1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 6.2 Hz, 1 H), 7.49–
7.46 (m, 3 H), 7.23–7.19 (m, 2 H), 6.96–6.92 (m, 2 H), 5.66 (s, 1 H),
3.95–3.88 (m, 1 H), 3.58–3.50 (m, 1 H), 3.11–2.86 (m, 4 H), 1.07 (t,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.7, 162.73 and 160.30 (1JCF
=
243.0 Hz), 139.2, 134.85 and 134.82 (4JCF = 3.0 Hz), 133.1, 130.8,
130.22 and 130.15 (3JCF = 7.0 Hz) (2 C), 129.3, 123.4, 121.2, 115.37
and 115.16 (2JCF = 21.0 Hz) (2 C), 88.7, 57.0, 42.1, 32.9, 15.1.
MS (ESI): m/z = 299.5 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H20FN2O: 299.1554;
217.1337.
found: 299.1558.
2-Benzyl-3-methoxyisoindolin-1-imine (4k)
2-(3,4-Dimethoxyphenethyl)-3-ethoxyisoindolin-1-imine (4e)
Yellow gum; yield: 718 mg (95%).
Yellow gum; yield: 918 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 5.9 Hz, 1 H), 7.51–
7.45 (m, 3 H), 7.39–7.20 (m, 5 H), 5.84 (s, 1 H), 5.12 (d, J = 15.4
Hz, 1 H), 4.37 (d, J = 15.4 Hz, 1 H), 2.87 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.8, 138.5, 137.1, 133.1, 130.8,
129.3, 128.4 (2 C), 127.8 (2 C), 127.1, 123.4, 121.4, 87.9, 48.8,
43.6.
MS (ESI): m/z = 253.4 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H17N2O: 253.1335; found:
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 6.3 Hz, 1 H), 7.55–
7.41 (m, 3 H), 6.85–6.74 (m, 3 H), 5.63 (s, 1 H), 3.98–3.93 (m, 1 H),
3.84 (s, 3 H), 3.75 (s, 3 H), 3.58–3.50 (m, 1 H), 3.16–2.83 (m, 4 H),
1.08 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.7, 148.8, 147.5, 139.3, 133.2,
131.7, 130.8, 129.3, 123.4, 121.2, 120.7, 111.9, 111.2, 88.8, 57.1,
55.8, 55.7, 42.1, 33.1, 15.1.
MS (ESI): m/z = 341.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H25N2O3: 341.1860; found:
253.1339.
341.1862.
2-(4-Chlorobenzyl)-3-methoxyisoindolin-1-imine (4l)
White solid; yield: 780 mg (91%).
3-Ethoxy-2-(furan-2-ylmethyl)isoindolin-1-imine (4f)
Yellow gum; yield: 680 mg (89%).
1H NMR (400 MHz, DMSO-d6): δ = 8.48 (d, J = 8.0 Hz, 1 H), 7.88–
7.72 (m, 3 H), 7.47 (s, 4 H), 6.16 (s, 1 H), 5.27 (d, J = 16.1 Hz, 1 H),
4.77 (d, J = 16.1 Hz, 1 H), 2.94 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 161.4, 140.4, 134.8, 134.0,
133.1, 131.2, 130.6 (2 C), 129.2 (2 C), 128.6, 125.2, 124.7, 91.5,
51.8, 45.3.
MS (ESI): m/z = 287.4 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H16ClN2O: 287.0946;
1H NMR (400 MHz, CDCl3): δ = 7.68 (dd, J = 6.4, 1.7 Hz, 1 H),
7.55–7.42 (m, 3 H), 7.37–7.33 (m, 1 H), 6.37–6.26 (m, 2 H), 5.94
(s, 1 H), 4.95 (d, J = 15.9 Hz, 1 H), 4.48 (d, J = 15.9 Hz, 1 H), 3.17
(dq, J = 9.1, 7.1 Hz, 1 H), 2.97 (dq, J = 9.1, 7.1 Hz, 1 H), 1.10 (t, J =
7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.5, 150.8, 142.2, 139.3, 132.9,
130.9, 129.4, 123.5, 121.6, 110.3, 108.0, 88.4, 57.4, 37.1, 15.1.
MS (ESI): m/z = 257.4 [M + H]+.
found: 287.0947.
HRMS (ESI): m/z [M + H]+ calcd for C15H17N2O2: 257.1285; found:
257.1283.
2-(3,4-Dimethoxyphenethyl)-3-methoxyisoindolin-1-imine (4m)
Yellow gum; yield: 850 mg (87%).
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 7.1 Hz, 1 H), 7.56–
7.40 (m, 3 H), 6.85–6.72 (m, 3 H), 5.63 (s, 1 H), 4.00–3.93 (m, 1 H),
3.84 (s, 3 H), 3.77 (s, 3 H), 3.57–3.48 (m, 1 H), 3.06–2.90 (m, 2 H),
2.81 (s, 3 H).
3-Ethoxy-2-propylisoindolin-1-imine (4g)
Yellow gum; yield: 608 mg (93%).
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 6.7 Hz, 1 H), 7.54–
7.40 (m, 3 H), 5.91 (s, 1 H), 3.63–3.56 (m, 1 H), 3.33–3.25 (m, 1 H),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3543–3549

3548
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PAPER
13C NMR (100 MHz, CDCl3): δ = 162.8, 148.8, 147.5, 138.6, 133.4,
131.7, 130.8, 129.4, 123.5, 121.3, 120.6, 111.9, 111.2, 89.0, 55.8,
55.7, 48.7, 42.1, 33.1.
MS (ESI): m/z = 327.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H23N2O3: 327.1703; found:
13C NMR (100 MHz, CDCl3): δ = 162.8, 139.4, 133.5, 130.8, 129.4,
123.4, 121.6, 88.5, 61.2, 40.4, 31.7, 29.7, 20.4, 19.3, 13.9, 13.8.
MS (ESI): m/z = 261.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H25N2O: 261.1961; found:
261.1963.
327.1705.
3-Butoxy-2-(4-fluorobenzyl)isoindolin-1-imine (4t)
Yellow gum; yield: 852 mg (91%).
2-Cyclopentyl-3-methoxyisoindolin-1-imine (4n)
Yellow gum; yield: 628 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 6.8 Hz, 1 H), 7.58–
7.41 (m, 3 H), 6.10 (s, 1 H), 4.41–4.35 (m, 1 H), 2.87 (s, 3 H), 2.15–
1.63 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 163.5, 138.8, 133.7, 130.7, 129.3,
123.2, 121.2, 87.9, 54.4, 48.1, 29.5, 28.2, 23.4, 23.2.
MS (ESI): m/z = 231.7 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H19N2O: 231.1492; found:
1H NMR (400 MHz, CDCl3): δ = 7.69 (s, 1 H), 7.60–7.44 (m, 3 H),
7.44–7.30 (m, 2 H), 6.99 (t, J = 8.6 Hz, 2 H), 5.81 (s, 1 H), 5.05 (d,
J = 14.7 Hz, 1 H), 4.38 (d, J = 15.6 Hz, 1 H), 3.11–3.06 (m, 1 H),
2.89–2.84 (m, 1 H), 1.46–1.36 (m, 2 H), 1.32–1.23 (m, 2 H), 0.84 (t,
J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.25 and 160.81 (1JCF = 244.0
Hz), 162.9, 139.3, 133.20 and 133.18 (4JCF = 2.0 Hz), 132.8, 131.0,
129.76 and 129.68 (3JCF = 8.0 Hz) (2 C), 129.4, 123.6, 121.5, 115.46
and 115.24 (2JCF = 22.0 Hz) (2 C), 87.9, 61.7, 43.3, 31.6, 19.3, 13.8.
231.1493.
MS (ESI): m/z = 313.4 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H22FN2O: 313.1711;
found: 313.1713.
2-Butyl-3-methoxyisoindolin-1-imine (4o)
Yellow gum; yield: 615 mg (94%).
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 7.4 Hz, 1 H), 7.58–
7.40 (m, 3 H), 5.93 (s, 1 H), 3.70–3.62 (m, 1 H), 3.34–3.27 (m, 1 H),
2.83 (s, 3 H), 1.75–1.58 (m, 2 H), 1.48–1.33 (m, 2 H), 0.95 (t, J =
7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.9, 138.7, 133.8, 130.8, 129.5,
123.5, 121.5, 88.8, 48.6, 40.4, 29.7, 20.4, 13.9.
MS (ESI): m/z = 219.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H19N2O: 219.1492; found:
3-Butoxy-2-(3,4-dimethoxyphenethyl)isoindolin-1-imine (4u)
Yellow solid; yield: 971 mg (88%).
1H NMR (400 MHz, CDCl3): δ = 7.90 (dd, J = 6.1, 1.7 Hz, 1 H),
7.59–7.51 (m, 2 H), 7.44 (dd, J = 6.2, 1.9 Hz, 1 H), 6.85–6.67 (m, 3
H), 5.59 (s, 1 H), 4.08–4.02 (m, 1 H), 3.83 (s, 3 H), 3.76 (s, 3 H),
3.60–3.53 (m, 1 H), 3.14–2.90 (m, 3 H), 2.85–2.79 (m, 1 H), 1.52–
1.36 (m, 2 H), 1.32–1.23 (m, 2 H), 0.83 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.0, 148.9, 147.6, 139.5, 131.8,
131.6, 131.0, 129.9, 123.4, 122.7, 120.7, 111.9, 111.2, 89.5, 61.9,
55.8, 55.7, 42.5, 32.9, 31.5, 19.2, 13.7.
219.1593.
4-(1-Imino-3-methoxyisoindolin-2-yl)butanoic Acid (4p)
White solid; yield: 632 mg (85%).
MS (ESI): m/z = 369.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H29N2O3: 369.2173; found:
369.2175.
1H NMR (400 MHz, CD3OD): δ = 8.14 (dd, J = 7.6, 1.0 Hz, 1 H),
7.87 (td, J = 7.6, 1.0 Hz, 1 H), 7.80–7.68 (m, 2 H), 6.28 (s, 1 H),
3.92–3.63 (m, 2 H), 3.07 (s, 3 H), 2.41–2.24 (m, 2 H), 2.11–1.97 (m,
2 H).
13C NMR (100 MHz, CD3OD): δ = 179.5, 162.1, 140.4, 134.1,
130.6, 128.3, 124.1, 123.2, 92.2, 50.3, 41.9, 33.4, 23.5.
MS (ESI): m/z = 249.4 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O3: 249.1234; found:
3-(Benzyloxy)-2-isobutylisoindolin-1-imine (4v)
Yellow gum; yield: 750 mg (84%).
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 4.3 Hz, 1 H), 7.61–
7.49 (m, 3 H), 7.36–7.17 (m, 5 H), 6.11 (s, 1 H), 4.08 (d, J = 11.1
Hz, 1 H), 3.88 (d, J = 11.1 Hz, 1 H), 3.58 (dd, J = 14.0, 7.9 Hz, 1
H), 3.16 (dd, J = 14.0, 7.9 Hz, 1 H), 2.24–2.17 (m, 1 H), 1.00 (d, J =
6.6 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H).
249.1235.
13C NMR (100 MHz, CDCl3): δ = 163.1, 138.9, 137.5, 133.5, 130.9,
129.6, 128.3 (2 C), 127.7 (2 C), 127.7, 123.5, 121.7, 89.00, 63.8,
47.7, 27.3, 20.5, 20.3.
MS (ESI): m/z = 295.7 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H23N2O: 295.1805; found:
2-Benzyl-3-butoxyisoindolin-1-imine (4r)
Yellow solid; yield: 794 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 5.7, 2.3 Hz, 1 H),
7.60–7.41 (m, 3 H), 7.41–7.17 (m, 5 H), 5.84 (s, 1 H), 5.13 (d, J =
15.5 Hz, 1 H), 4.42 (d, J = 15.5 Hz, 1 H), 3.20–3.02 (m, 1 H), 2.90
(dd, J = 11.0, 4.5 Hz, 1 H), 1.53–1.37 (m, 2 H), 1.34–1.24 (m, 2 H),
0.85 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.6, 139.6, 136.8, 132.4, 131.3,
129.6, 128.6 (2 C), 128.0 (2 C), 127.4, 123.4, 122.2, 88.2, 61.9,
44.1, 31.6, 19.3, 13.8.
295.1808.
3-(Benzyloxy)-2-cyclopropylisoindolin-1-imine (4w)
Yellow gum; yield: 725 mg (87%).
1H NMR (400 MHz, CDCl3): δ = 7.90 (dd, J = 5.3, 2.9 Hz, 1 H),
7.67–7.40 (m, 3 H), 7.40–6.96 (m, 5 H), 6.00 (s, 1 H), 4.22 (d, J =
11.4 Hz, 1 H), 4.05 (d, J = 11.4 Hz, 1 H), 2.79–2.44 (m, 1 H), 1.05–
0.74 (m, 4 H).
MS (ESI): m/z = 295.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H23N2O: 295.1805; found:
13C NMR (100 MHz, CDCl3): δ = 163.3, 139.3, 137.6, 134.2, 131.1,
129.7, 128.3 (2 C), 127.6, 127.5 (2 C), 123.3, 122.3, 89.6, 64.5,
23.0, 5.6, 5.3.
MS (ESI): m/z = 279.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O: 279.1492; found:
295.1808.
3-Butoxy-2-butylisoindolin-1-imine (4s)
Yellow gum; yield: 717 mg (92%).
1H NMR (400 MHz, CDCl3): δ = 7.69 (dd, J = 6.0, 2.0 Hz, 1 H),
7.53–7.40 (m, 3 H), 5.93 (s, 1 H), 3.66 (dd, J = 14.8, 7.5 Hz, 1 H),
3.36–3.23 (m, 1 H), 3.07 (dt, J = 9.1, 6.5 Hz, 1 H), 2.82 (dt, J = 9.1,
6.6 Hz, 1 H), 1.73–1.59 (m, 2 H), 1.54–1.20 (m, 6 H), 0.95 (t, J =
7.4 Hz, 3 H), 0.84 (t, J = 7.3 Hz, 3 H).
279.1490.
Synthesis 2012, 44, 3543–3549
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 2-Substituted 3-Alkoxyisoindolin-1-imines
3549
2-Benzyl-3-(benzyloxy)isoindolin-1-imine (4x)
Yellow gum; yield: 787 mg (80%).
3.25 (m, 1 H), 2.97–2.89 (m, 1 H), 2.97–2.89 (m, 1 H), 1.76–1.65
(m, 2 H), 1.11 (t, J = 7.1 Hz, 3 H), 0.97 (t, J = 7.4 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.77 (dd, J = 5.1, 3.5 Hz, 1 H),
7.57–7.42 (m, 3 H), 7.39–7.22 (m, 8 H), 7.23–7.13 (m, 2 H), 6.00
(s, 1 H), 5.10 (d, J = 15.5 Hz, 1 H), 4.45 (d, J = 15.5 Hz, 1 H), 4.15
(d, J = 11.2 Hz, 1 H), 3.97 (d, J = 11.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.1, 139.2, 137.6, 137.3, 133.2,
131.2, 129.7, 128.7 (2 C), 128.4 (2 C), 128.1 (2 C), 127.8 (2 C),
127.7, 127.4, 123.8, 121.8, 88.3, 64.3, 44.2.
13C NMR (100 MHz, CDCl3): δ = 162.7, 162.2, 141.3, 126.1, 122.8,
115.7, 108.1, 88.3, 56.7, 55.6, 42.4, 21.0, 15.1, 11.5.
MS (ESI): m/z = 249.5 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H21N2O2: 249.1598; found:
249.1601.
MS (ESI): m/z = 329.3 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H21N2O: 329.1648; found:
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (grants 30925040, 81102329), the Chinese National
Science & Technology Major Project ‘Key New Drug Creation and
Manufacturing Program’ (grant 2011ZX09307-002-03), and the
Science Foundation of Shanghai (grant 12XD14057).
329.1650.
3-(Benzyloxy)-2-(4-fluorophenethyl)isoindolin-1-imine (4y)
Yellow gum; yield: 875 mg (81%).
1H NMR (400 MHz, CDCl3): δ = 7.74 (dt, J = 7.3, 3.2 Hz, 1 H),
7.59–7.42 (m, 3 H), 7.35–7.14 (m, 7 H), 7.05–6.85 (m, 2 H), 5.81
(s, 1 H), 4.09 (d, J = 11.2 Hz, 1 H), 3.98 (ddd, J = 14.2, 8.8, 5.3 Hz,
1 H), 3.90 (d, J = 11.2 Hz, 1 H), 3.58 (ddd, J = 14.2, 8.8, 5.3 Hz, 1
H), 3.16–2.89 (m, 2 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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13C NMR (100 MHz, CDCl3): δ = 162.73 and 160.30 (1JCF = 243.0
Hz), 162.7, 138.8, 137.5, 134.71 and 134.68 (4JCF = 3.0 Hz), 133.1,
131.1, 130.23 and 130.16 (3JCF = 7.0 Hz) (2 C), 129.6, 128.4 (2 C),
127.7 (3 C), 123.6, 121.5, 115.38 and 115.17 (2JCF = 21.0 Hz) (2 C),
88.8, 63.9, 42.2, 32.8.
MS (ESI): m/z = 361.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C23H22FN2O: 361.1711;
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2-Benzyl-3-isopropoxyisoindolin-1-imine (4z)
Yellow gum; yield: 546 mg (65%).
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1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 5.0 Hz, 1 H), 7.54–
7.45 (m, 3 H), 7.34–7.20 (m, 5 H), 5.78 (s, 1 H), 5.16 (d, J = 15.8
Hz, 1 H), 4.42 (d, J = 15.8 Hz, 1 H), 3.62 (dt, J = 12.3, 6.1 Hz, 1 H),
1.19 (d, J = 6.1 Hz, 3 H), 1.02 (d, J = 6.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.8, 140.5, 137.4, 132.7, 130.9,
129.3, 128.6 (2 C), 127.7 (2 C), 127.2, 123.7, 121.6, 87.9, 67.9,
43.9, 23.8, 23.5.
MS (ESI): m/z = 281.5 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2O: 281.1648; found:
281.1651.
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2-Benzyl-3-ethoxy-5-methoxyisoindolin-1-imine (4ac)
Yellow gum; yield: 852 mg (96%).
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.4 Hz, 1 H), 7.31–
7.25 (m, 5 H), 7.01 (dd, J = 8.4, 2.3 Hz, 1 H), 6.97 (d, J = 2.3 Hz, 1
H), 5.78 (s, 1 H), 5.04 (d, J = 16.1 Hz, 1 H), 4.40 (d, J = 15.5 Hz, 1
H), 3.86 (s, 3 H), 3.21–3.13 (m, 1 H), 3.01–2.94 (m, 1 H), 1.07 (t,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.9, 162.4, 141.5, 137.6, 128.6
(2 C), 127.9 (2 C), 127.2, 125.7, 122.9, 115.8, 108.3, 87.9, 57.4,
55.7, 44.1, 15.1.
MS (ESI): m/z = 297.5 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2O2: 297.1598; found:
297.1601.
3-Ethoxy-5-methoxy-2-propylisoindolin-1-imine (4ad)
Yellow gum; yield: 706 mg (95%).
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.9 Hz, 1 H), 7.01–
6.98 (m, 2 H), 5.87 (s, 1 H), 3.87 (s, 3 H), 3.62–3.55 (m, 1 H), 3.32–
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3543–3549