A simple and efficient synthesis of isoindolinone derivatives based on reaction of ortho-lithiated aromatic imines with CO

Article abstract of DOI:10.1016/j.tet.2015.07.060

A simple and efficient one-pot synthesis of 2,3-disubstituted isoindolinones via the reaction of o-lithiated aromatic imines with carbon monoxide under one atmospheric pressure has been developed. Preliminary in vitro tests for fungicidal activity of thes

Full text of DOI:10.1016/j.tet.2015.07.060

Accepted Manuscript
A simple and efficient synthesis of isoindolinone derivatives based on reaction of
ortho-lithiated aromatic imines with CO
Hai-Jun Li, Yu-Qing Zhang, Liang-Fu Tang
PII:
S0040-4020(15)01119-9
10.1016/j.tet.2015.07.060
TET 27005
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 June 2015
Revised Date: 18 July 2015
Accepted Date: 22 July 2015
Please cite this article as: Li H-J, Zhang Y-Q, Tang L-F, A simple and efficient synthesis of isoindolinone
derivatives based on reaction of ortho-lithiated aromatic imines with CO, Tetrahedron (2015), doi:
10.1016/j.tet.2015.07.060.
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ACCEPTED MANUSCRIPT
Graphical Abstract
A simple and efficient synthesis of
Leave this area blank for abstract info.
isoindolinone derivatives based on reaction
of ortho-lithiated aromatic imines with CO
Hai-Jun Li, Yu-Qing Zhang and Liang-Fu Tang
Department of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, People’s Republic of China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A simple and efficient synthesis of isoindolinone derivatives based on reaction of
ortho-lithiated aromatic imines with CO
Hai-Jun Li, Yu-Qing Zhang and Liang-Fu Tang
Department of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient one-pot synthesis of 2,3-disubstituted isoindolinones via the reaction of
o-lithiated aromatic imines with carbon monoxide under one atmospheric pressure has been
developed. Preliminary in vitro tests for fungicidal activity of these isoindolinone derivatives
have been carried out, indicating that most of them exhibit good fungicidal activities.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Isoindolinone
Aromatic imine
Lithiation
Carbon monoxide
Fungicidal activity
reported to produce substituted isoindolinones,4,14 in most of
which o-lithiated benzamides were used as the nucleophiles. In
spite of all these achievements, the starting materials were not
readily available in many of above-mentioned methods, which
were usually obtained by multistep reactions. Consequently, the
development of new synthetic routes for isoindolinone
derivatives from simple and readily available starting materials is
highly desirable. Herein, we report a simple and efficient one pot
synthesis of isoindolinones via the reaction of o-lithiated
aromatic imines with carbon monoxide under one atmospheric
pressure.
1. Introduction
Isoindolinones have received extensive attention in recent
years because the isoindolinone skeleton presents in numerous
natural products and synthetic pharmaceuticals with a wide range
of biological activities.1 In view of crucial applications of
isoindolinone derivatives, their synthetic methodologies have
been widely investigated.2 A variety of methods for the synthesis
of isoindolinones have been developed in literatures, which
generally fall into two categories3 or are divided into eight
retrosynthetic cuts.4 In the first strategy, phthalimides5 or
phthalimidines6 are directly used as starting materials to prepared
isoindolinones especially 3-substituted derivatives. The second
approach is the construction of the lactam ring through various
cyclization reactions of functionalized aromatic compounds.
Despite many traditional annulative methods, such as the
amination reaction of o-halomethyl or o-acylbenzoate
derivatives,1 have been successfully applied to generate
isoindolinones and enriched the structural diversity as well as the
structure-activity relationship of isoindolinones, the development
of convenient and practical synthetic methods for these
compounds continues to remain an active area of research. Some
new approaches, such as the transition metal-catalyzed
carbonylation7 and C–H functionalization,8 Diels–Alder9 and
inverse-electron demand Diels–Alder10, aza-Wittig11 and radical
cyclization12 reactions as well as organocatalytic reactions13 have
been developed for the construction of the basic isoindolinone
2. Results and discussion
2.1. Reaction of o-lithiated aromatic imines with carbon
monoxide
skeleton. The o-lithiation/cyclization procedures have also been
———
Corresponding author. Tel.: +86-022-2350-2458; fax: +86-022-2350-2458; e-mail: lftang@nankai.edu.cn

2
Tetrahedron
Table 1
ACCEPTED MANUSCRIPT
Synthesis of substituted isoindolinones
Entry
1–7
R
R′
Isolated
yield (%)
66
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6
Et
Bun
Pri
Bun
57
78
59
31
88
57
63
70
57
66
74
85
63
70
64
55
64
64
74
79
70
69
70
59
But
Bun
cyclo-C6H11
2,6-Me2C6H3
Bun
Bun
Et
H
H
H
H
H
Me
Me
Me
Pri
But
9
cyclo-C6H11
2,6-Me2C6H3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Et
Pri
But
Scheme 1. Synthesis and reaction of o-lithiated aromatic imines
with carbon monoxide.
cyclo-C6H11
2,6-Me2C6H3
Me
Me
Et
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
4-MeC6H4CH2
4-MeC6H4CH2
4-MeC6H4CH2
4-MeC6H4CH2
4-MeC6H4CH2
C2H5O2CCH2
HOCH2
Pri
But
The metal-mediated synthesis of isoindolinones from
arylimines has been reported.15 Additionally, the reaction of
organolithium reagent with carbon monoxide is an important and
direct synthetic method for carbonyl compounds.16 The
construction of the isoindolinone skeleton through the imine
addition–cyclization sequence has been mentioned,14d but the
synthetic methodology for isoindolinones through o-lithiated
aromatic imines was not reported.14e,14f We found that in situ
treatment of o-lithiated aromatic imines prepared by the lithium-
halide exchange reactions with CO under one atmospheric
pressure at –78 oC and slow warming to room temperature
(Scheme 1) rendered 3-n-butyl substituted isoindolinones (1) in
moderate yields (Table 1, Entries 1–5). It should be pointed out
that significant amount of 2e was isolated in the synthetic process
of 1e (Entry 5). If aqueous acid was added to the reaction mixture
before elevating the temperature, compounds 2 were obtained
(Entries 6–10). In addition, when active alkyl halides, such as
CH3I, ArCH2Br and BrCH2CO2C2H5, were used as the
electrophiles, compounds 3–6 were obtained in moderate to good
yields (Entries 11–26). The steric hindrance of substituents of
imines has little effect on the reaction. The good yields were
obtained even for the bulky tert-butyl and 2,6-dimethylphenyl
groups. The low solubility and slow dissociation rate of
paraformaldehyde are possibly responsible for the low yield of 7
(Entry 27). Compounds 1b (41%) and 2b (14%) were also
isolated in this reaction.
cyclo-C6H11
2,6-Me2C6H3
Et
Pri
But
cyclo-C6H11
2,6-Me2C6H3
Pri
Pri
56
27
7
weak, as supported by the isolation of 2e in the synthetic process
of 1e. If more reactive alkyl halides compared to n-butyl bromide
were used as alkylation reagents, the n-butyl group would be
replaced, which was proved by the successful synthesis of
compounds 3–6. Compounds 2 were easily obtained by the
protonation of the enolate intermediate. Also as corroboration of
the mechanistic deduction, the treatment of the enolate
intermediate with I2 also led to the oxidative coupling product 8
in good yield.
Compounds 1–7 have been characterized by 1H and 13C NMR
spectra, while the new compounds have been also characterized
by IR and HRMS. Additionally, the structures of 1b and 4c have
been confirmed by X-ray single-crystal diffraction, which are
shown in Supporting information.
2.2. Possible formation pathway of 1–7
The formation of 1 is very interesting since no extra
electrophiles were introduced and all organic components
emerged in products. The plausible pathway for the formation of
isoindolinone derivatives is depicted in Scheme 2. Initially,
reaction of aryl lithium with CO gave the corresponding acyl
lithium (A),17 which resonated to nitrogen anion (B) through
conjugated double bonds. A polarity reversal took place in this
process, namely the nucleophilic carbon (acyl anion) changing to
the electrophilic carbon (ketene). Subsequently, the nitrogen
anion attacked the ketene carbonyl to form the key enolate (C),
which has a carbanion resonance form (D). The alkylation
reaction of the enolate intermediate with n-butyl bromide formed
in the lithium-halide exchange reaction yielded compound 1. The
nucleophility of the enolate intermediate to n-butyl bromide is
Scheme 2. Possible pathway for the formation of isoindolinones.
2.3. Fungicidal activity
Preliminary in vitro tests for fungicidal activity of all
compounds have been carried out by the fungi growth inhibition
method.18 The data are summarized in Table 2, which indicate
that most of compounds exhibit good fungicidal activities. All of
2-cyclohexyl isoindolinone derivatives (1d–5d) have high
activities to Cercospora rachidicola. The steric factor of 2-
substituents of isoindolinones has little effect on the fungicidal

3
ACCEPTED MANUSCRIPT
Table 2
Antifungal activity of 1–27 (Percent inhibition)a
Comp.
Cercospora
beticola
Cercospora
rachidicola
Alternaria
solani
Botrytis
cinerea
Gibberella
zeae
Macrophoma
kuwatsukai
Sclerotinia
sclerotiorum
Valsa
mali
Thanatephorus
cucumeris
(Frank) Domk
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6
7
0.0
21.7
4.4
26.1
17.4
4.4
17.4
8.7
0.0
11.1
0.0
6.5
0.0
9.7
25.8
0.0
6.5
16.1
16.1
29.0
6.5
17.7
67.7
17.7
55.9
11.8
35.3
17.7
23.5
5.9
14.7
11.8
8.8
2.9
8.8
11.8
76.5
72.1
85.3
73.5
73.5
73.5
23.5
50.0
64.7
91.2
55.9
29.4
75.0
21.0
17.7
11.3
32.3
24.2
25.8
25.8
33.9
25.8
82.3
14.5
25.8
25.8
33.9
27.4
24.2
24.2
24.2
28.8
30.3
16.7
36.4
36.4
57.6
34.9
15.2
24.2
91.2
17.9
0.0
23.4
34.0
23.4
55.3
12.8
70.2
19.2
34.0
23.4
21.3
2.1
46.8
40.4
19.2
27.7
80.9
68.1
63.8
53.2
58.5
83.0
80.9
66.0
61.7
66.0
34.0
25.5
88.1
0.0
30.8
15.4
69.2
7.7
45.8
37.5
41.7
29.2
16.7
20.8
0.0
25.0
12.5
12.5
20.8
37.5
54.2
12.5
64.7
23.5
23.5
29.4
23.5
29.4
23.5
23.5
5.9
33.3
22.2
11.1
16.7
11.1
16.7
27.8
61.1
16.7
11.1
16.7
38.9
55.6
38.2
44.1
44.1
64.7
64.7
44.1
47.1
52.9
55.9
47.1
17.7
17.7
46.9
16.1
76.8
21.4
10.7
32.1
0.0
19.6
16.1
3.6
7.7
23.1
23.1
61.5
38.5
15.4
30.8
15.4
46.2
53.9
65.4
38.5
53.9
53.9
46.2
46.2
38.5
38.5
53.9
61.5
15.4
15.4
55.6
17.4
4.4
4.4
9.7
13.1
13.0
13.0
30.4
45.8
47.9
41.7
45.8
35.4
45.8
54.2
33.3
33.3
33.3
25.0
33.3
80.8
16.1
48.4
6.5
26.8
44.6
8.9
100.0
38.2
79.4
67.7
61.8
76.5
58.8
73.5
52.9
70.6
73.5
47.1
11.8
71.4
23.2
29.0
68.4
65.8
52.6
63.2
57.9
60.5
56.6
59.2
63.2
26.3
39.5
100.0
17.7
5.9
0.0
Positive
84.1
controlb
a Concentration: 50 µg/mL in DMF.
b Positive control: azoxystrobin
activity. For example, compounds 2e–5e display good activities
to Alternaria solani. Moreover, the inhibition percentage of 3e in
vitro for Botrytis cinerea and 5e for Gibberella zeae is
approximate to 100% and 91.2%, respectively, and significantly
higher than that of other compounds. In addition, it seems that
the 3-benzyl isoindolinones are more active than other
derivatives, supported by the higher inhibition percentage of 4
and 5 against the tested fungi than that of 1–3, demonstrating that
the aryl groups may strongly affect the fungicidal activity
possibly through the π-π stacking interactions with the enzymes,
similar to those findings reported in the antibacterial activity of
isoindolinones.1e
by the condensation reaction of o-bromobenzaldehyde with the
corresponding amine according to the published methods.19
3.2. Typical procedure for the synthesis of 1
A hexane solution of n-BuLi (1.6 M, 1.25 mL, 2 mmol) was
added to the solution of imine (2 mmol) in THF (35 mL) at −78
°C under an argon atmosphere. After the resulting mixture was
stirred for 30 min, CO was bubbled into the solution. The CO
atmosphere was kept with a balloon at the exit. The reaction
mixture was continuously stirred at low temperature for 1 h,
allowed to reach room temperature slowly and stirred overnight.
The solvent was removed under reduced pressure, and the residue
was purified by column chromatography on silica with ethyl
acetate/petroleum ether (V/V = 1:5) as the eluent to give the
product.
In summary, a simple and efficient one pot synthesis of
isoindolinones from the readily available starting materials has
been developed. Preliminary in vitro tests for fungicidal activity
of these isoindolinone derivatives indicate that most of them
exhibit good fungicidal activities.
3.2.1. 2-Ethyl-3-n-butylisoindolin-1-one (1a). Yellow oil; 1H
NMR δ 0.80 (t, J = 7.3 Hz, 3H), 0.86−1.08 (m, 2H), 1.21−1.27
(m, 5H), 1.88−2.05 (m, 2H), 3.19 (qd, J = 7.1 Hz, J = 14.2 Hz,
1H), 4.04 (qd, J = 7.4 Hz, J = 14.6 Hz, 1H), 4.63 (dd, J = 3.5 Hz,
J = 5.2 Hz,1H), 7.41−7.45 (m, 2H), 7.52 (dt, J = 1.1 Hz, J = 7.4
Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H); 13C NMR δ 13.7, 13.9, 22.6,
24.4, 30.2, 34.6, 58.7, 122.0, 123.4, 127.9, 131.2, 132.9, 145.2,
3. Experimental
3.1. General
All reactions were carried out under an argon atmosphere.
Solvents were dried by standard methods and freshly distilled
prior to use. NMR (1H and 13C) were recorded on a Bruker 400
spectrometer using CDCl3 as the solvent, and the chemical shifts
were reported in ppm with respect to the reference (internal
168.3; IR (νC O) 1682 cm−1; HRMS (ESI) calcd for C14H20NO
=
[M+H]+: 218.1545, found: 218.1541.
3.2.2. 2-Isopropyl-3-n-butylisoindolin-1-one (1b). Yellow solid;
mp: 47−49 oC; 1H NMR δ 0.82 (t, J = 7.3 Hz, 3H), 1.02−1.31 (m,
4H), 1.42 (d, J = 6.9 Hz, 3H), 1.47 (d, J = 7.0 Hz, 3H), 1.92−2.10
(m, 2H), 4.32 (sept., J = 6.9 Hz, 1H), 4.69 (dd, J = 3.3 Hz, J =
5.2 Hz, 1H), 7.38 (dd, J = 0.7 Hz, J = 7.5 Hz, 1H), 7.43 (t, J = 7.3
Hz, 1H), 7.52 (dt, J = 1.2 Hz, J = 7.4 Hz, 1H), 7.81 (d, J = 7.5 Hz,
1H); 13C NMR δ 13.9, 20.3, 21.2, 22.7, 24.2, 32.0, 44.9, 59.5,
1
SiMe4 for H and 13C NMR spectra). IR spectroscopic data were
obtained from a Tensor 27 spectrometer as KBr pellets. HR mass
spectra were obtained on a Varian QFT-ESI spectrometer.
Melting points were measured with an X-4 digital micro melting-
point apparatus and were uncorrected. The imines were prepared

4
Tetrahedron
1.70–1.77 (m, 1H), 1.85–1.91 (m, 4H), 4.23–4.32 (m, 1H), 4.37
121.8, 123.3, 127.9, 131.1, 133.2, 145.4, 168.7; IR (ν ) 1678
=
ACCEPTED MANUSCRIPT
C O
cm−1; HRMS (ESI) calcd for C15H22NO [M+H]+: 232.1701, found:
232.1701.
(s, 2H), 7.45–7.48 (m, 2H), 7.51–7.55 (m, 1H), 7.86–7.88 (m,
1H); 13C NMR δ 25.5, 25.6, 31.5, 46.0, 50.5, 122.7, 123.6, 127.9,
131.0, 133.4, 141.3, 167.9.
1
3.2.3. 2-tert-Butyl-3-n-butylisoindolin-1-one (1c). Yellow oil; H
3.3.5. 2-(2,6-Dimethylphenyl)isoindolin-1-one (2e).22 White solid;
mp: 113−115 oC; 1H NMR δ 2.22 (s, 6H), 4.63 (s, 2H), 7.18–7.19
(m, 2H), 7.23–7.25 (m, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.64 (dt, J =
1.2 Hz, J = 7.5 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H); 13C NMR δ
18.0, 51.2, 122.9, 124.4, 128.3, 128.5, 128.6, 131.7, 132.4, 135.5,
136.8, 141.7, 167.8.
NMR δ 0.79 (t, J = 7.2 Hz, 3H), 1.09−1.26 (m, 4H), 1.60 (s, 9H),
1.94−2.06 (m, 2H), 4.80 (dd, J = 2.7 Hz, J = 5.6 Hz, 1H), 7.33 (d,
J = 8.0 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.48 (dt, J = 1.2 Hz, J =
7.4 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H); 13C NMR δ 13.9, 22.6, 24.3,
28.6, 34.9, 55.1, 60.2, 121.4, 123.0, 127.7, 131.0, 133.8, 145.9,
169.4; IR (νC O) 1683 cm−1; HRMS (ESI) calcd for C16H24NO
=
[M+H]+: 246.1858, found: 246.1857.
3.4. Typical procedure for the synthesis of 3–6
3.2.4. 2-Cyclohexyl-3-n-butylisoindolin-1-one (1d). Yellow oil;
1H NMR δ 0.80 (t, J = 7.3 Hz, 3H), 1.08−1.28 (m, 4H),
1.35−1.47 (m, 2H), 1.71−2.17 (m, 10H), 3.91 (tt, J = 3.7 Hz, J =
12.1 Hz, 1H), 4.68−4.70 (m, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.42
(t, J = 7.4 Hz, 1H), 7.51 (dt, J = 1.0 Hz, J = 7.4 Hz, 1H), 7.81 (d,
J = 7.5 Hz, 1H); 13C NMR δ 13.9, 22.7, 24.1, 25.6, 26.1, 26.3,
30.7, 31.4, 32.1, 53.3, 59.6, 121.7, 123.3, 127.8, 131.1, 133.2,
A hexane solution of n-BuLi (1.6 M, 1.25 mL, 2 mmol) was
added to the solution of imine (2 mmol) in THF (35 mL) at −78
°C under an argon atmosphere. After the resulting mixture was
stirred for 30 min, CO was bubbled into the solution. The CO
atmosphere was kept with a balloon at the exit. The reaction
mixture was stirred at low temperature for 1 h, R′X (2 mmol) was
added dropwise. The resulting mixture was continuously stirred
at low temperature for 1 h, allowed to reach room temperature
slowly and stirred overnight. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography on silica with ethyl acetate/petroleum ether (V/V
= 1:5) as the eluent to give the product.
3.4.1. 2-Ethyl-3-methylisoindolin-1-one (3a).23 Pale yellow oil;
1H NMR δ 1.25 (t, J = 7.2 Hz, 3H), 1.48 (d, J = 6.7 Hz, 3H), 3.32
(dq, J = 7.1 Hz, J = 14.2 Hz, 1H), 3.98 (dq, J = 7.4 Hz, J = 14.6
Hz, 1H), 4.58 (q, J = 6.7 Hz, 1H), 7.44 (dd, J = 7.3 Hz, J = 13.2
Hz, 2H), 7.54 (td, J = 1.0 Hz, J = 7.4 Hz, 1H), 7.83 (d, J = 7.5
Hz, 1H); 13C NMR δ 13.8, 18.2, 34.6, 55.2, 121.9, 123.5, 128.1,
131.3, 132.1, 146.9, 167.8.
145.5, 168.7; IR (νC O) 1684 cm−1; HRMS (ESI) calcd for
=
C18H25NNaO [M+Na]+: 294.1834, found: 294.1830.
3.2.5. 2-(2,6-Dimethylphenyl)-3-n-butylisoindolin-1-one (1e).
1
Yellow oil; H NMR δ 0.84 (t, J = 7.2 Hz, 3H), 1.22−1.34 (m,
3H), 1.41−1.53 (m, 1H), 1.65−1.74 (m, 1H), 1.78−1.86 (m, 1H),
2.17 (s, 3H), 2.31 (s, 3H), 4.85 (dd, J = 5.5 Hz, J = 7.3 Hz, 1H),
7.14−7.25 (m, 3H), 7.52−7.64 (m, 3H), 7.99 (d, J = 7.5 Hz, 1H);
13C NMR δ 13.9, 18.4, 18.9, 22.8, 28.2, 32.9, 62.4, 122.9, 124.3,
128.2, (2C), 128.7, 128.9, 131.6, 131.8, 134.9, 136.1, 138.1,
146.6, 167.4; IR (νC O) 1694 cm−1; HRMS (ESI) calcd for
=
C20H23NNaO [M+Na]+: 316.1677, found: 316.1667.
3.3. Typical procedure for the synthesis of 2
3.4.2. 2-Isopropyl-3-methylisoindolin-1-one (3b).23b Pale yellow
oil; 1H NMR δ 1.41 (d, J = 6.9 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H),
1.54 (d, J = 6.7 Hz, 3H), 4.35–4.44 (m, 1H), 4.63 (q, J = 6.6 Hz,
1H), 7.38 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.52 (t, J =
7.4 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H); 13C NMR δ 20.4, 20.6, 21.8,
44.4, 55.4, 121.7, 123.3, 128.0, 131.2, 132.3, 147.1, 168.0.
3.4.3. 2-tert-Butyl-3-methylisoindolin-1-one (3c).24 Pale yellow
oil; 1H NMR δ 1.56 (d, J = 6.4 Hz, 3H), 1.61 (s, 9H), 4.76 (q, J =
6.4 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H),
7.49 (td, J = 1.1 Hz, J = 7.5 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H);
13C NMR δ 23.9, 28.8, 55.0, 56.4, 121.4, 123.2, 127.8, 131.1,
132.9, 147.5, 168.7.
A hexane solution of n-BuLi (1.6 M, 1.25 mL, 2 mmol) was
added to the solution of imine (2 mmol) in THF (35 mL) at −78
°C under an argon atmosphere. After the resulting mixture was
stirred for 30 min, CO was bubbled into the solution. The CO
atmosphere was kept with a balloon at the exit. The reaction
mixture was stirred at low temperature for 1 h, hydrochloric acid
(1.0 M, 2 mL, 2 mmol) was slowly added dropwise. Then, the
reaction mixture was allowed to reach room temperature slowly.
The solvent was removed under reduced pressure, and the residue
was purified by column chromatography on silica with ethyl
acetate/petroleum ether (V/V = 1:5) as the eluent to give the
product.
3.3.1. 2-Ethylisoindolin-1-one (2a).5b Yellow oil; 1H NMR δ 1.24
(t, J = 7.3 Hz, 3H), 3.64 (q, J = 7.3 Hz, 2H), 4.35 (s, 2H), 7.39–
7.43 (m, 2H), 7.47–7.51 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H); 13C
NMR δ 13.6, 37.0, 49.3, 122.7, 123.5, 127.9, 131.1, 133.0, 141.1,
168.2.
3.3.2. 2-Isopropylisoindolin-1-one (2b).5b White solid; mp:
82−84 oC; 1H NMR δ 1.31 (d, J = 6.8 Hz, 6H), 4.36 (s, 2H), 4.70
(sept., J = 6.8 Hz, 1H), 7.42–7.51 (m, 2H), 7.50–7.59 (m, 1H),
7.86 (d, J = 8.2 Hz, 1H); 13C NMR δ 20.9, 42.6, 45.0, 122.7,
123.6, 128.0, 131.0, 133.4, 141.2, 167.8; HRMS (ESI) calcd for
C11H14NO [M+H]+: 176.1075, found: 176.1072.
3.4.4. 2-Cyclohexyl-3-methylisoindolin-1-one (3d). Pale yellow
oil; H NMR δ 1.19–1.30 (m, 1H), 1.39–1.48 (m, 1H), 1.55 (d, J
1
= 6.7 Hz, 3H), 1.72–1.96 (m, 8H), 3.92–4.01 (m, 1H); 4.64 (q, J
= 6.5 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H),
7.53 (t, J = 7.2 Hz, 1H), 7.83 (d, J = 7.4 Hz, 1H); 13C NMR δ
20.8, 25.6, 26.1, 26.2, 30.9, 31.9, 52.9, 55.6, 121.7, 123.4, 127.9,
131.2, 132.3, 147.2, 168.0; IR (νC O) 1683 cm−1; HRMS (ESI)
=
calcd for C15H19NNaO [M+Na]+: 252.1364, found: 252.1358.
3.4.5. 2-(2,6-Dimethylphenyl)-3-methylisoindolin-1-one (3e). Red
solid; mp: 141–143 oC; 1H NMR δ 1.43 (d, J = 6.8 Hz, 3H), 2.19
(s, 3H), 2.28 (m, 3H), 4.94 (q, J = 6.8 Hz, 1H), 7.16–7.26 (m,
3H), 7.54 (dd, J = 7.7 Hz, J = 16.1 Hz, 2H), 7.65 (dt, J = 0.9 Hz,
J = 7.5 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H); 13C NMR δ 18.1, 18.3,
18.8, 58.1, 122.1, 124.3, 128.3, 128.4, 128.7, 128.8, 131.6, 131.8,
134.3, 136.4, 138.1, 147.4, 167.3; IR (νC=O) 1695 cm−1; HRMS
(ESI) calcd for C17H17NNaO [M+Na]+: 274.1208, found:
274.1204.
3.3.3. 2-tert-Butylisoindolin-1-one (2c).20 White solid; mp: 52−54
1
oC; H NMR δ 1.59 (s, 9H), 4.48 (s, 2H), 7.44 (dd, J = 7.4 Hz, J
= 12.7 Hz, 2H), 7.52 (dt, J = 3.7 Hz, J = 7.4 Hz, 1H), 7.81 (d, J =
7.5 Hz, 1H); 13C NMR δ 28.1, 48.5, 54.4, 122.3, 123.2, 127.9,
130.9, 134.5, 140.7, 168.9; HRMS (ESI) calcd for C12H16NO
[M+H]+: 190.1232, found: 190.1229.
3.4.6. 3-Benzyl-2-ethylisoindolin-1-one (4a). Yellow oil; 1H
NMR δ 1.29 (t, J = 7.2 Hz, 3H), 2.83 (dd, J = 8.2 Hz, J = 13.8 Hz,
3.3.4. 2-Cyclohexylisoindolin-1-one (2d).21 White solid; mp:
97−99 C; H NMR δ 1.15–1.26 (m, 1H), 1.45–1.52 (m, 4H),
o
1

5
1H), 3.32 (qd, J = 7.1 Hz, J = 14.1 Hz, 1H), 3.43 (dd, J = 4.7 Hz,
J = 13.8 Hz, 1H), 4.14 (qd, J = 7.3 Hz, J = 14.6 Hz, 1H), 4.83 (dd,
J = 4.7 Hz, J = 8.1 Hz, 1H), 6.91 (dd, J = 2.5 Hz, J = 5.6 Hz, 1H),
7.09–7.13 (m, 2H), 7.26–7.31 (m, 3H), 7.38–7.44 (m, 2H), 7.78–
7.81 (m, 1H); 13C NMR δ 13.7, 35.0, 38.4, 59.7, 122.9, 123.5,
127.0, 128.1, 128.5, 129.5, 130.8, 132.5, 136.0, 144.8, 168.1; IR
(νC=O) 1685 cm−1; HRMS (ESI) calcd for C17H17NNaO [M+Na]+:
274.1208, found: 274.1200.
7.57 (t, J = 7.4 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H); 13C NMR δ
ACCEPTED MANUSCRIPT
20.5, 21.1, 21.4, 40.0, 45.6, 61.1, 123.1, 123.2, 128.0, 129.3,
129.4, 130.5, 132.9, 133.5, 136.7, 145.2, 168.4; IR (νC=O) 1683
cm−1; HRMS (ESI) calcd for C19H21NNaO [M+Na]+: 302.1521,
found: 302.1519.
3.4.13. 2-tert-Butyl-3-(p-methylbenzyl)isoindolin-1-one (5c). Pale
yellow solid; mp: 86–88 oC; 1H NMR δ 1.71 (s, 9H), 2.34 (s, 3H),
2.41 (dd, J = 9.9 Hz, J = 13.5 Hz, 1H), 3.74 (dd, J = 3.0 Hz, J =
13.5 Hz, 1H), 4.90 (dd, J = 3.2 Hz, J = 9.8 Hz, 1H), 6.51 (d, J =
7.5 Hz, 1H), 6.94 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H),
7.25 (dt, J = 1.0 Hz, J = 7.5 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H),
7.73 (d, J = 7.5 Hz, 1H); 13C NMR δ 21.1, 28.8, 42.4, 55.2, 61.5,
122.7, 123.1, 127.8, 129.2, 129.4, 130.2, 132.3, 133.5, 136.6,
145.4, 169.0; IR (νC=O) 1668 cm−1; HRMS (ESI) calcd for
C20H23NNaO [M+Na]+: 316.1677, found: 316.1670.
3.4.7. 3-Benzyl-2-isopropylisoindolin-1-one (4b). Pale yellow
solid; mp: 84–86 oC; 1H NMR δ 1.51 (d, J = 6.8 Hz, 3H), 1.60 (d,
J = 7.0 Hz, 3H), 2.62 (dd, J = 9.8 Hz, J = 13.5 Hz, 1H), 3.65 (dd,
J = 4.4 Hz, J = 13.5 Hz, 1H), 4.23–4.35 (m, 1H), 4.81 (dd, J =
4.4 Hz, J = 9.8 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 6.5
Hz, 2H), 7.28–7.42 (m, 5H), 7.80 (d, J = 7.5 Hz, 1H); 13C NMR δ
20.5, 21.5, 40.4, 45.6, 61.0, 123.1, 123.2, 127.1, 128.1, 128.6,
129.6, 130.6, 132.9, 136.7, 145.0, 168.4; IR (νC=O) 1685 cm−1;
HRMS (ESI) calcd for C18H20NO [M+H]+: 266.1545, found:
266.1543.
3.4.14. 2-Cyclohexyl-3-(p-methylbenzyl)isoindolin-1-one (5d).
o
1
Pale yellow solid; mp: 94–96 C; H NMR δ 1.23–1.41 (m, 3H),
1.69–1.98 (m, 6H), 2.14–2.23 (m, 1H), 2.36 (s, 3H), 2.55 (dd, J =
9.7 Hz, J = 13.5 Hz, 1H), 3.59 (dd, J = 4.3 Hz, J = 13.6 Hz, 1H),
3.78–3.86 (m, 1H), 4.76 (dd, J = 4.4 Hz, J = 9.6 Hz, 1H), 6.58 (d,
J = 7.6 Hz, 1H), 7.04 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 7.8 Hz,
2H), 7.26–7.30 (m, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.77 (d, J = 7.5
Hz, 1H); 13C NMR δ 21.1, 25.6, 26.2, 26.3, 30.8, 31.4, 40.1, 54.1,
61.1, 123.1, 123.2, 128.0, 129.3, 129.4, 130.5, 132.9, 133.6,
136.6, 145.2, 168.4; IR (νC=O) 1669 cm−1; HRMS (ESI) calcd for
C22H25NNaO [M+Na]+: 342.1834, found: 342.1831.
3.4.8. 3-Benzyl-2-tert-butylisoindolin-1-one (4c). White solid; mp:
1
90–92 oC; H NMR δ 1.74 (s, 9H), 2.44–2.50 (m, 1H), 3.82 (d, J
= 13.4 Hz, 1H), 4.95 (d, J = 9.8 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H),
7.08 (d, J = 6.1 Hz, 2H), 7.25–7.39 (m, 5H), 7.75 (d, J = 7.5 Hz,
1H); 13C NMR δ 28.8, 42.9, 55.3, 61.4, 122.6, 123.1, 127.1, 127.9,
128.5, 129.6, 130.2, 133.3, 136.7, 145.2, 169.0; IR (νC=O) 1683
cm−1; HRMS (ESI) calcd for C19H21NNaO [M+Na]+: 302.1521,
found: 302.1518.
3.4.9. 3-Benzyl-2-cyclohexylisoindolin-1-one (4d). Pale yellow
solid; mp: 96–98 oC; 1H NMR δ 1.26–1.45 (m, 3H), 1.72–2.01 (m,
6H), 2.17–2.25 (m, 1H), 2.63 (dd, J = 9.6 Hz, J = 13.5 Hz, 1H),
3.65 (dd, J = 4.5 Hz, J = 13.5 Hz, 1H), 3.79–3.88 (m, 1H), 4.82
(dd, J = 4.5 Hz, J = 9.6 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 7.19 (d,
J = 6.5 Hz, 2H), 7.28–7.41 (m, 5H), 7.80 (d, J = 7.5 Hz, 1H); 13C
NMR δ 25.6, 26.2, 26.3, 30.8, 31.4, 40.6, 54.1, 61.1, 123.0, 123.3,
127.1, 128.0, 128.6, 129.6, 130.5, 132.9, 136.8, 145.1, 168.4; IR
(νC=O) 1683 cm−1; HRMS (ESI) calcd for C21H23NNaO [M+Na]+:
328.1677, found: 328.1673.
3.4.15. 2-(2,6-Dimethylphenyl)-3-(p-methylbenzyl)isoindolin-1-
one (5e). Pale yellow solid; mp: 115–117 oC; 1H NMR δ 2.23 (s,
3H), 2.32 (s, 3H), 2.36 (s, 3H), 2.58 (dd, J = 11.2 Hz, J = 13.0 Hz,
1H), 3.19 (dd, J = 4.0 Hz, J = 13.1 Hz, 1H), 5.04 (dd, J = 4.1 Hz,
J = 11.0 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 7.9 Hz,
2H), 7.13 (d, J = 7.8 Hz, 2H), 7.17–7.26 (m, 3H), 7.38 (dt, J =
1.0 Hz, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5
Hz, 1H); 13C NMR δ 18.5, 19.0, 21.1, 38.5, 63.4, 123.5, 124.2,
128.3, 128.4, 128.9, 129.0, 129.4, 129.4, 131.2, 131.7, 133.8,
134.2, 136.3, 136.6, 138.1, 145.8, 167.1; IR (νC=O) 1701 cm−1;
HRMS (ESI) calcd for C24H23NNaO [M+Na]+: 364.1677, found:
364.1665.
3.4.10. 3-Benzyl-2-(2,6-dimethylphenyl)isoindolin-1-one (4e).
Pale yellow solid; mp: 104–106 oC; 1H NMR δ 2.26 (s, 3H), 2.35
(s, 3H), 2.67 (dd, J = 11.0 Hz, J = 13.1 Hz, 1H), 3.26 (dd, J = 4.2
Hz, J = 13.1 Hz, 1H), 5.10 (dd, J = 4.2 Hz, J = 10.9 Hz, 1H),
6.68 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 6.7 Hz, 2H), 7.20–7.36 (m,
6H), 7.41 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.99 (d, J =
7.5 Hz, 1H); 13C NMR δ 18.6, 19.0, 39.0, 63.4, 123.4, 124.2,
127.1, 128.4, 128.5, 128.7, 128.9, 129.0, 129.5, 131.3, 131.6,
134.2, 136.3, 136.9, 138.1, 145.7, 167.1; IR (νC=O) 1699 cm−1;
HRMS (ESI) calcd for C23H21NNaO [M+Na]+: 350.1521, found:
350.1514.
3.4.16. 2-Isopropyl-3-ethylcarboxylmethylisoindolin-1-one (6).
1
Yellow oil; H NMR δ 1.23 (t, J = 7.1 Hz, 3H), 1.43 (d, J = 6.9
Hz, 3H), 1.48 (d, J = 7.0 Hz, 3H), 2.60 (dd, J = 8.3 Hz, J = 16.0
Hz, 1H), 3.07 (dd, J = 4.1 Hz, J = 16.0 Hz, 1H), 4.11–4.28 (m,
3H), 4.98 (dd, J = 4.1 Hz, J = 8.2 Hz, 1H), 7.39–7.52 (m, 3H),
7.80 (d, J = 7.4 Hz, 1H); 13C NMR δ 14.1, 20.4, 21.1, 39.0, 45.3,
56.4, 61.0, 122.2, 123.4, 128.4, 131.4, 132.7, 145.1, 168.3, 170.3;
IR (νC=O) 1689 and 1732 cm−1; HRMS (ESI) calcd for C15H21NO3
[M+H]+: 262.1443, found: 262.1444.
3.4.11. 2-Ethyl-3-(p-methylbenzyl)isoindolin-1-one (5a). Pale
yellow oil; 1H NMR δ 1.28 (t, J = 7.2 Hz, 3H), 2.33 (s, 3H), 2.78
(dd, J = 8.1 Hz, J = 13.8 Hz, 1H), 3.27–3.40 (m, 2H), 4.12 (qd, J
= 7.4 Hz, J = 14.6 Hz, 1H), 4.79 (dd, J = 4.6 Hz, J = 8.1 Hz, 1H),
6.94 (dd, J = 3.9 Hz, J = 4.7 Hz, 1H), 6.97 (d, J = 7.9 Hz, 2H),
7.08 (d, J = 7.8 Hz, 2H), 7.39–7.41 (m, 2H), 7.79 (dd, J = 2.9 Hz,
J = 5.7 Hz, 1H); 13C NMR δ 13.7, 21.1, 35.0, 38.0, 59.8, 123.0,
123.4, 128.1, 129.2, 129.3, 130.8, 132.5, 132.9, 136.5, 145.0,
168.0; IR (νC=O) 1689 cm−1; HRMS (ESI) calcd for C18H19NNaO
[M+Na]+: 288.1364, found: 288.1357.
3.5. Synthesis of 7
A hexane solution of n-BuLi (1.6 M, 1.25 mL, 2 mmol) was
added to the solution of (N-isopropyl)-o-bromobenzylideneamine
(0.45 g, 2 mmol) in THF (35 mL) at −78 °C under an argon
atmosphere. After the resulting mixture was stirred for 30 min,
CO was bubbled into the solution. The CO atmosphere was kept
with a balloon at the exit. The reaction mixture was stirred at low
temperature for 1 h, paraformaldehyde (0.12 g, 4 mmol) was
added. The resulting mixture was continuously stirred at low
temperature for 1 h, allowed to reach room temperature slowly
and stirred overnight. The reaction mixture was quenched with 1
M HCl (2 mL, 2 mmol). The solvent was removed under reduced
pressure, and the residue was purified by column
chromatography on silica with ethyl acetate/petroleum ether (V/V
= 1:4) as the eluent to give the product as colorless oils. Yield
3.4.12. 2-Isopropyl-3-(p-methylbenzyl)isoindolin-1-one (5b). Pale
1
yellow oil; H NMR δ 1.68 (d, J = 6.8 Hz, 3H), 1.76 (d, J = 7.0
Hz, 3H), 2.56 (s, 3H), 2.75 (dd, J = 9.8 Hz, J = 13.5 Hz, 1H),
3.77 (dd, J = 4.3 Hz, J = 13.5 Hz, 1H), 4.40–4.52 (m, 1H), 4.95
(dd, J = 4.3 Hz, J = 9.8 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.23 (d,
J = 7.9 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.46–7.51 (m, 1H),
1
0.11 g (27%); H NMR δ 1.37 (d, J = 6.8 Hz, 3H), 1.41 (d, J =

6
Tetrahedron
ACCEPTED MANUSCRIPT
Othman, M. Tetrahedron Lett. 2013, 54, 5227–5231; (c) Ukhin, L. Y.;
7.0 Hz, 3H), 3.72 (s, br, 1H), 3.84 (dd, 1H, J = 5.4 Hz, J = 11.2
Akopova, A. R.; Bicherov, A. V.; Kuzmina, L. G.; Morkovnik, A. S.;
Borodkin, G. S. Tetrahedron Lett. 2011, 52, 5444–5447; (d) Yu, X.;
Wang, Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C. Eur. J. Org. Chem. 2011,
3060–3066; (e) Zhou, Y.; Qian, L.; Zhang, W. Synlett. 2009, 843–847.
7. (a) Han, C.; Shen, Y.; Lu, P.; Wang, Y. Chin. J. Chem. 2013, 31, 182–186.
(b) Marosvölgyi-Haskó, D.; Takács, A.; Riedl, Z.; Kollár, L. Tetrahedron
2011, 67, 1036–1040; (c) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N.
J. Am. Chem. Soc. 2009, 131, 6898–6899; (d) Grigg, R.; Sridharan, V.;
Shah, M.; Mutton, S.; Kilner, C.; MacPherson, D.; Milner, P. J. Org.
Chem. 2008, 73, 8352–8356; (e) Orito, K.; Miyazawa, M.; Nakamura, T.;
Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.;
Yamazaki, T.; Tokuda, M. J. Org. Chem. 2006, 71, 5951–5958.
8. (a) Ma, W.; Ackermann, L. ACS Catal. 2015, 5, 2822−2825; (b)
Manoharan, R.; Jeganmohan, M. Chem. Commun. 2015, 51, 2929−2932;
(c) Reddy, M. C.; Jeganmohan, M. Org. Lett. 2014, 16, 4866−4869; (d)
Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135,
5364−5367; (e) Yu, Q.; Zhang, N.; Huang, J.; Lu, S.; Zhu, Y.; Yu, X.;
Zhao, K. Chem. Eur. J. 2013, 19, 11184–11188; (f) Zhang, M. J. Chem.
Res. 2013, 606–610; (g) Zhu, C.; Falck, J. R. Tetrahedron 2012, 68,
9192−9199; (h) Li, D. D.; Yuan, T. T.; Wang, G. W. Chem. Commun.
2011, 47, 12789–12791; (i) Shacklady-McAtee, D. M.; Dasgupta, S.;
Watson, M. P. Org. Lett. 2011, 13, 3490−3493; (j) Wang, F.; Song, G.; Li,
X. Org. Lett. 2010, 12, 5430−5433.
Hz, 1H), 4.09 (dd, 1H, J = 4.0 Hz, J = 11.1 Hz, 1H), 4.34 (sept., J
= 6.9 Hz, 1H), 4.63 (t, J = 4.5 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H),
7.46 (t, J = 7.4 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5
Hz, 1H); 13C NMR δ 20.2, 21.3, 45.2, 61.5, 63.6, 122.8, 123.2,
128.3, 131.3, 132.9, 143.8, 169.1; IR (νOH) 3369 and (νC=O) 1666
cm−1; HRMS (ESI) calcd for C12H17NO2 [M+H]+: 206.1181,
found: 206.1180.
3.6. Synthesis of 8
A hexane solution of n-BuLi (1.6 M, 1.25 mL, 2 mmol) was
added to the solution of (N-tert-butyl)-o-bromobenzylideneamine
(0.48 g, 2 mmol) in THF (35 mL) at −78 °C under an argon
atmosphere. The resulting mixture was stirred for 30 min, CO
was bubbled into the solution. The CO atmosphere was kept with
a balloon at the exit. After the reaction mixture was stirred at low
temperature for 1 h, I2 (0.51 g, 2 mmol) was added, and the low
temperature bath was removed immediately. The reaction
mixture was continuously stirred overnight at the ambient
temperature. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography on silica
with ethyl acetate/petroleum ether (V/V = 1:4) as the eluent to
give known 3,3′-bis(2-tert-butylisoindol-1-one) (8).20a Yield 56%.
The NMR spectra showed the presence of two stereoisomers (syn
and anti in ca. 1:1 ratio), led by the steric repulsion between
bulky tert-butyl groups as well as tert-butyl groups and benzene
ring.20a These two isomers were isolated by their different
solubility in ethyl acetate/hexane (V/V = 1:5). The syn isomer
was soluble while the anti isomer was insoluble. Data of syn-8:
mp: 215–217 oC; 1H NMR δ 1.83 (s, 18H), 5.37 (s, 2H), 7.11 (t, J
= 7.5 Hz, 2H), 7.20 (t, J = 7.0 Hz, 2H), 7.36 (d, J = 7.6 Hz, 4H);
13C NMR δ 29.4, 56.1, 62.6, 122.4, 122.7, 128.2, 130.9, 134.0,
140.0, 170.6; IR (νC=O) 1680 cm−1. Data of anti-8: mp: 225–227
9. (a) Ball, M.; Boyd, A.; Churchill, G.; Cuthbert, M.; Drew, M.; Fielding, M.;
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8409; (b) Corona, D.; Díaza, E.; Guzmán, A.; Jankowski, C. K.
Spectrochim. Acta, Part A 2005, 61, 2788–2795.
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2658; (b) Marion, F.; Coulomb, J.; Servais, A.; Courillon, C.; Fensterbank,
L.; Malacria, M. Tetrahedron 2006, 62, 3856–3871; (c) Shen, L.; Hsung,
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oC; H NMR δ 1.11 (s, 9H), 1.78 (s, 9H), 5.23 (s, 1H), 5.56 (s,
1
1H), 6.07 (s, 1H), 7.27–7.90 (m, 8H); 13C NMR δ 28.6, 29.1, 55.1,
57.2, 63.6, 66.0, 122.0, 122.6, 123.4, 123.6, 128.8, 129.3, 131.8,
132.3, 133.2, 134.2, 141.2, 144.2, 169.8, 171.5; IR (νC=O) 1682
cm−1. HRMS (ESI) calcd for C24H29N2O2 [M+H]+: 377.2229,
found: 377.2227.
Acknowledgments
This work is supported by the National Natural Science
Foundation of China (No. 21372124).
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7
Supplementary Material
free of charge from The Cambridge Crystallographic Data
ACCEPTED MANUSCRIPT
Centre via www.ccdc.cam.ac.uk/data_request/cif. Crystal
structure determinations of 1b and 4c and their molecular
structures along with their data are provided.
CCDC 1407659 and 1407660 contain the supplementary
crystallographic data for this paper. These data can be obtained

ACCEPTED MANUSCRIPT
Supporting Information
A simple and efficient synthesis of isoindolinone derivatives based on reaction
of ortho-lithiated aromatic imines with CO
Hai-Jun Li, Yu-Qing Zhang and Liang-Fu Tang
Department of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
Crystal structure determinations
Crystals of 1b and 4c suitable for X-ray analyses were obtained by slow diffusion of hexane into
their CH2Cl2 solutions at –18 oC. All intensity data were collected on a Rigaku Saturn CCD detector
for 1b as well as SuperNova Eos detector for 4c using graphite monochromated Mo-Kα radiation
(λ = 0.71073 Å). Semi-empirical absorption corrections were applied using the Crystalclear
program.1 The structures were solved by direct methods and difference Fourier map using SHELXS
of the SHELXTL package and refined with SHELXL2 by full-matrix least-squares on F2. All
non-hydrogen atoms were refined anisotropically. Hydrogen atoms were added geometrically and
refined with riding model position parameters. A summary of the fundamental crystal data for 1b
and 4c is listed in Table S1.
References
1. CrystalStructure 3.7.0 and Crystalclear 1.36: Crystal Structure Analysis Package, Rigaku and
Rigaku/MSC (2000–2005), TX.
2. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.
Corresponding author. Tel.: +86-022-2350-2458; fax: +86-022-2350-2458; e-mail: lftang@nankai.edu.cn
1

ACCEPTED MANUSCRIPT
Table S1
Crystal data and refinement parameters for complexes 1b and 4c
Complex
1b
4c
Formula
C15H21NO
231.33
0.20×0.18×0.12 0.18×0.12×0.08
Monoclinic
P21/n
9.5272(19)
9.804(2)
14.277(3)
90
C19H21NO
279.37
Formula weight
Crystal size (mm)
Crystal system
Space group
a (Å)
Monoclinic
P21/n
9.2123(7)
8.7120(7)
19.1984(15)
90
b (Å)
c (Å)
α
β
γ
(o)
(o)
(o)
99.26(3)
90
94.503(7)
90
T (K)
113(2)
1316.2(5)
4
1.167
504
0.072
2.53–27.87
13213
133(1)
1536.1(2)
4
V (Å) 3
Z
Dc (g.cm-3)
F(000)
1.208
600
0.074
µ
θ
(mm-1)
Range (o)
3.16–25.01
5190
No. of measured reflections
No. of unique reflections (Rint)
No. of observed reflections with (I>2
No. of parameters
3136 (0.0469)
2201
(I))
2693 (0.0279)
2216
194
σ
158
GOF
1.019
1.082
Residuals R, Rw
0.0442, 0.0996 0.0394, 0.0942
2

ACCEPTED MANUSCRIPT
Fig.1. The molecular structure of 1b. The thermal ellipsoids are drawn at the 30% probability level.
Selected bond distances (Å) and angles (o): C(1)–O(1) 1.235(1), C(1)–N(1) 1.370(2), C(8)–N(1)
1.478(2), C(8)–C(9) 1.538(2) Å; C(1)–N(1)–C(8) 112.8(1), C(8)–N(1)–C(13) 124.6(1),
O(1)–C(1)–N(1) 125.9(1), O(1)–C(1)–C(2) 127.3(1), N(1)–C(1)–C(2) 106.8(1), N(1)–C(13)–C(15)
113.9(1), C(14)–C(13)–C(15) 112.0(1)o.
Fig.2. The molecular structure of 4c. The thermal ellipsoids are drawn at the 30% probability level.
Selected bond distances (Å) and angles (o): C(8)–O(1) 1.225(2), C(8)–N(1) 1.364(2), C(1)–N(1)
1.475(2), C(1)–C(9) 1.543(2) Å; C(1)–N(1)–C(8) 112.0(1), C(1)–N(1)–C(16) 124.7(1),
C(1)–C(9)–C(10) 111.5(1), O(1)–C(8)–N(1) 126.7(1), N(1)–C(8)–C(7) 106.9(1), N(1)–C(1)–C(9)
113.3(1), N(1)–C(1)–C(2) 102.3(1), N(1)–C(16)–C(17) 110.2(1), C(17)–C(16)–C(19) 106.8(1)o.
The End
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