Novel one-step synthesis of 2-carbonyl/thiocarbonyl isoindolinones and mechanistic disclosure on the rearrangement reaction of o-phthalaldehyde with amide/thioamide analogs

Article abstract of DOI:10.1016/j.tet.2007.07.009

A rearrangement reaction of o-phthalaldehyde with urea/thiourea analogs or amides/thioamides under the catalysis of TMSCl (trimethylchlorosilane) is described, whereby a series of 2-carbonyl isoindolinones and 2-thiocarbonyl isoindolinones are afforded. T

Full text of DOI:10.1016/j.tet.2007.07.009

Tetrahedron 63 (2007) 9338–9344
Novel one-step synthesis of 2-carbonyl/thiocarbonyl isoindolinones
and mechanistic disclosure on the rearrangement reaction
of o-phthalaldehyde with amide/thioamide analogs
*
Jieping Wan, Bin Wu and Yuanjiang Pan
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
Received 10 May 2007; revised 4 July 2007; accepted 6 July 2007
Available online 30 July 2007
Abstract—A rearrangement reaction of o-phthalaldehyde with urea/thiourea analogs or amides/thioamides under the catalysis of TMSCl
(trimethylchlorosilane) is described, whereby a series of 2-carbonyl isoindolinones and 2-thiocarbonyl isoindolinones are afforded. This is
the first time that the N-carbonyl/thiocarbonyl isoindolinones are synthesized in a single step from o-phthalaldehyde. Similar reactions using
primary amines also proceed smoothly to give corresponding N-alkyl or N-aryl isoindolinones in this mild catalytic system. The mechanism of
this kind of rearrangement is discussed based on new evidences observed from the ESI-MS time-interval monitoring of the full reaction course
and deuterium exchange experiments.
Ó 2007 Elsevier Ltd. All rights reserved.
O
OH
N
OH
1. Introduction
R
N R
O
O
o-Phthalaldehyde is well-known as a versatile reactant due to
its special structure of two adjacent substituted formyl groups
inthebenzene ring.1 Numerousreactionsofo-phthalaldehyde
have been disclosed both on typical and atypical conversions,
and a variety of functional compounds including phthalide,2a
1-alkylthioisoindole,2b,c isoquinoline,2d benzo[b]fluoreno-
ne,2e benzotropone,2f etc. have been readily synthesized
through the condensation between proper nucleophiles and
o-phthalaldehyde. Among these reported reactions of
o-phthalaldehyde, thecondensationwithammoniaor primary
amines was given special attention due to the multifunction
of their products—phthalimidines 1 (2,3-dihydro-isoindol-
1-ones or isoindolinones, Scheme 1).3 The isoindolinone
skeleton is found in many naturally obtained compounds,4
and research on the isoindolinone ring system showed that
many compounds with this sub-unit exhibit attractive thera-
peuticalactivities.5 What ismore, the diverse biologicalactiv-
ities6 of isoindolinones were disclosed during the past
decades, and isoindolinones with proper structures could be
used as biochemical fluorescent markers as well as precursors
of electrically conductive polymers.7
OH
NHCOR
1
2
3
R= alkyl, aryl or amidocyangen
Scheme 1. Typical products from the literature reaction of o-phthalaldehyde
with amines/amides.
importance in the fields of biochemistry and synthetic study.
Primary research showed that compounds containing 2-car-
bonyl isoindolinone structure could inhibit the proteins
poly(ADP-ribose)polymerases (PARPs).8 Recently, a class
of isoindole-fused imidazoles which also contain 2-carbonyl
isoindolinone skeleton were reported having special fluo-
rescent properties as well as the ability to stain human
squamous epithelium cells.9 In addition, the 2-carbonyl
substituted isoindolinone structure frequently served as an
indispensable building block during the total synthesis of
some natural products.10 Furthermore, as substrates or key
intermediates, 2-carbonyl isoindolinone compounds were
also applied to prepare many other heterocycle-fused com-
pounds.11 Another significant application of 2-carbonyl iso-
indolinones is in the dynamic kinetic resolution research.12
After being substituted in the C-3 position with a hydroxy
group, the derivatives, namely N-acylhemiaminals obtained
as racemic substrates, were able to provide a single enantio-
mer with excellent stereoselectivity after acylation. The ob-
tained products could then be utilized for further chiral
synthesis,13 whereas identical conversion could not be
accomplished with 2-alkyl isoindolinone derivatives 1.12a
As derivatives of isoindolinone, 2-carbonyl isoindolinones
and 2-thiocarbonyl isoindolinones 4 also represent great
Keywords: 2-Carbonyl isoindolinone; 2-Thiocarbonyl isoindolinone; Rear-
rangement; Mechanism.
* Corresponding author. Tel.: +86 571 8795 1264; fax: +86 571 8795 1629;
e-mail: cheyjpan@zju.edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.009

J. Wan et al. / Tetrahedron 63 (2007) 9338–9344
9339
Although primary amines were found to be capable of react-
ing with o-phthalaldehyde to give N-alkyl/aryl isoindol-
inones 1 under different conditions via a rearrangement
process,3 to our best knowledge, neither ureas/thioureas
nor amides/thioamides were ever reported to react with
o-phthalaldehyde following similar rearrangement route to
provide corresponding N-carbonyl/thiocarbonyl isoindoli-
nones 4 despite the fact that they identically contain the ami-
docyanogen group(s).1 Initial studies on the reaction of
o-phthalaldehyde with amides or urea/thiourea were carried
out by Reynolds and co-workers,14 and DoMinh’s group
published extended research later.15 In all these published
works, however, the products were just obtained as 2-car-
bonyl-1,3-dihydroxyisoindole 2 or phthalans 3 or sometimes
corresponding dimers,14c which were all long viewed as the
chemical foundation of a widely used medicinal method of
determining urea in blood or serum.16 No literature has
ever declared the products of type 4 whose formation in-
volves a further rearrangement step from those reactions.
The current ways of building 2-carbonyl isoindolinones
mainly rely on the additional N-acylation of a prepared iso-
indolinone,17,8,12 or the utilization of substrates with special
structure as well as the catalysis by noble metals18 or harsh
conditions.11e Given the desire to develop more practical and
diversified methodologies for the synthesis of 2-carbonyl/
thiocarbonyl isoindolinones, we report here a convenient,
mild, and atom-economical approach for the synthesis of
N-acyl isoindolinones.
exclusively with urea to furnish 1-oxo-1,3-dihydro-isoin-
dole-2-carboxylic acid amide 4a as the product. Subse-
quently, in order to achieve the optimal result of this newly
found reaction, different conditions were then examined
(Table 1). The results showed that this reaction was not sol-
vent-dependent as the product 4a was formed in good yields
both in polar and nonpolar solvents (entries 1–3). It is note-
worthy that this reaction was found to take place efficiently
in the ionic liquid [bmim]BF4 (1-butyl-3-methylimidazo-
lium tetrafluoroborate), and the product could be easily iso-
lated through extraction with ethyl acetate, the reactions
with urea/thiourea derivatives also proceeded smoothly in
[bmim]BF4. Unfortunately, when amides were subjected to
the reaction in place of ureas, poor results were observed,
which impelled us to further explore other effects in our pre-
viously adopted CH3CN/DMF system. We used different
Lewis and Bronsted acids as catalysts (entries 6–9), and
the results showed that the catalysis of TMSCl was crucial
to this reaction: the optimal catalytic amount of TMSCl
was finally established as 0.8 equiv mol (entries 5 and 11).
2.2. Rearrangement reaction of o-phthalaldehyde with
different ureas/thioureas/amides/thioamides
To examine the practical scope of the reaction, a class of
N-substituted ureas and thioureas were then subjected to
the reactions (Table 2). These reactions were carried out in
the aforementioned ionic liquid system (substrates 6a–f).
The result was that corresponding products were obtained
2. Results and discussion
Table 2. Reactions of different urea/thiourea and amide/thioamide analogs
with o-phthalaldehydea
2.1. Optimization of the rearrangement reaction
of o-phthalaldehyde with urea
O
X
CHO
CHO
TMSCl, rt. or 80 °C
N
R
This reaction was initially found during our study on the
TMSCl catalyzed reactions.19 When we adopted o-phthal-
aldehyde as one of the substrates, it was found to react
H2N
R
[bmim]BF4 or CH3CN/DMF
X
5
6
4
Substrate
R
X
Product
Yieldb (%)
6ac
6b
6c
6d
6e
6f
6g
6h
6i
NH2
O
O
O
O
S
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
85
83
88
76
75
67
70
81
86
73
67
90
83
78
75
87
86
88
90
—
Table 1. Optimization of the reaction conditions using o-phthalaldehyde
and ureaa
NHCH3
NHC2H5
NHPh
NHCH3
NHCH2CH]CH2
CH3
H
CH3
CH2Cl
CH2CN
(CH2)4CH3
CH(CH3)2
CH]CH2
CH2Ph
Ph
4-FPh
2,3-(CH3)2Ph
3,5-(OCH3)2Ph
NH2
O
CHO
CHO
O
catalyst
r t
N
NH2
S
S
H2N NH2
6a
O
5
4a
O
O
O
O
O
O
O
O
O
O
O
O
S
Entry
Solvent(s)
Catalyst
Yieldb (%)
6j
6k
6l
1
2
3
4
5
6
7
8
CH3CN
DMF
Benzene
[bmim]BF4
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
None
Messyb
81
76
85
87
0
25
0
6m
6n
6o
6pd
6q
6r
6s
CH3CN/DMFc
CH3CN/DMF
CH3CN/DMF
CH3CN/DMF
CH3CN/DMF
CH3CN/DMF
CH3CN/DMF
HCld
AlCl3
InCl3
TiCl4
TMSCl
9
10
Trace
Trace
85
6te
—
11e
a
Unless otherwise specified, the general conditions are 5 (1 mmol), 6
(1 mmol), TMSCl (0.8 mmol) mixed with 1.5 mL 2:1 CH3CN/DMF
under corresponding temperature and stirred for 7–12 h.
Isolated yields.
For substrates 6a–f, the ionic liquid [bmim]BF4 was used as medium.
For substrates 6p–s, a reflux temperature is necessary for satisfactory
results, while all other reactions were observed under room temperature.
No target product was observed.
a
Unless otherwise specified, the general reaction conditions are 5
(1 mmol), 6a (1 mmol) mixed and stirred for 7 h in 1.5 mL solvent(s) in
the presence of 0.8 mmol catalyst.
b
c
d
b
c
d
e
Isolated yields.
V
Concentrated hydrochloric acid: 37%.
CH CN=VDMF ¼ 2:1.
3
e
TMSCl: 1.6 mmol for testing the effect of catalyst’s amount.

9340
J. Wan et al. / Tetrahedron 63 (2007) 9338–9344
in good yields. Furthermore, in order to clearly characterize
the products 4a–f, the ESI-MS2 fragmentation experiments
To broaden the scope of this TMSCl catalyzed system,
we turned our attention to the reactions between primary
amines and o-phthalaldehyde. Since reactions of this kind
were widely studied for their values both in synthetic and
medicinal researches, it was our goal as well to achieve
this conversion using this newly developed methodology
and thereby provide a general guideline for both the prepa-
ration of 2-carbonyl/thiocarbonyl and 2-alkyl/aryl isoindol-
inones. The easily available reagents phenylamine and
isopropylamine were selected as representatives of aryl-
amine and alkylamine, respectively, and both substrates pro-
ceeded well to the anticipated products in good yields
(Scheme 3).
1
were applied besides the conventional H, 13C NMR, and
HRMS analyses since there may exist possible isomers 7
or 8 that could not be excluded by the 1H and 13C NMR spec-
tra (Scheme 2). Main fragmentations (ESI-MS2 fragmenta-
tion spectra are available in Supplementary data) of these
compounds were then found to follow the general route dis-
played in Scheme 2 (the broken line in 4a–f), from which we
could confirm the structure of products as 4a–f. The X-ray
crystal diffraction of 4c (Fig. 1) provided further evidence
for this conclusion.20 Meanwhile, the failure of the reaction
with thiourea was somewhat unexpected. It merely led to
a messy mixture without the target product (TLC and ESI)
despite our effort. Notwithstanding this, an N-substituted
electron-donating group promoted the reaction of thiourea
(6e–f).
O
CHO
CH3CN/DMF
TMSCl, rt
8h
H2N R
R
N
R
CHO
5
yield
O
O
9a: Ph
b: i-Pr
O
10a 80%
b 72%
R
NH
N
N
N
NH
X
X
R
Scheme 3. Reactions of o-phthalaldehyde with primary amines.
NH
X
R
4a-f
8
7
All products 4a–s, 10a and b were characterized with 1H and
13C NMR, HRMS, ESI-MS, and IR analyses, additional
characterizations of 4a–f were carried out as previously
described. Products 4b–e, 4h, 4j–o as well as 4q–s were
obtained as new compounds.
R=substitution groups of 6a-f; X= O or S
Scheme 2. Structure and main ESI-MS2 fragmention of 4a–f as well as pos-
sible isomers.
The results achieved from substrates 6a–f prompted us to
further investigate the reactions using amides/thioamides as
substitution of ureas/thioureas. As mentioned above, when
the amides were subjected to the ionic liquid [bmim]BF4
for similar reaction, poor results were observed, which di-
rected us back to the protocol of CH3CN/DMF system. First,
a class of aliphatic amides were used as substrates; as ex-
pected, corresponding 2-carbonyl/thiocarbonyl isoindol-
inones were obtained in good to excellent yields under
room temperature (6g–o). In continuation of these experi-
mental results, we further investigated the reactions with ar-
omatic amides instead of aliphatic ones since previous work
had claimed that the steric effect of aromatic amides gave
different results from those of aliphatic amides.15a To our
delight, several benzamides tested all selectively led to corre-
sponding 2-carbonyl isoindolinones as the main products
(6p–s) without unexpected exception. What was different
was that the reactions of (substituted) benzamides required
refluxing temperature in order to achieve satisfactory yields.
This discrepancy may be ascribed to the steric effect.
2.3. Mechanistic study and discussion
Our studies on the mechanism of these reactions were
designed on the basis of related mechanistic research on
previously developed reactions of primary amines with
o-phthalaldehyde. According to currently available publica-
tions,21 the main controversies about this rearrangement
focus on the intermediates formed during the reaction pro-
cess. Intermediate 11 (Scheme 4, path 1) was regarded as
the key structure for the formation of the products in the clas-
ꢀ
sical proposal, while Alajarın and co-workers recently pro-
posed a [1,5]-H sigmatropic rearrangement route based on
computational study as well as correlative literature in which
the intermediate 13 was believed to play crucial role in pro-
viding the final products (Scheme 4, path 2).21
In our experiments, however, amides/thioamides (or ureas/
thioureas) substituted primary amines, which made us be-
lieve that similar intermediates (Scheme 5) 16 and 21
(R¼CH3, X¼O) have the stability to be detected by ESI-
MS if formed during the reaction course. Thus, we selected
the reaction of acetamide with o-phthalaldehyde as the
model to monitor the intermediates with ESI-MS during
the reaction process with a time-interval of 15 min. To our
delight, the existence of 16 (R¼CH3, X¼O, see Supplemen-
tary data for details) was successfully detected22 during the
reaction, and the ESI-MS signal disappeared following com-
pletion of the reaction. On the other hand, characteristic
fragmentation signals supporting intermediate 21 were not
observed under the same condition (path 2a).
Afterward, we deliberately applied a deuterium reagent
CH3OD as commutative reagent in order to probe the exact
route of the rearrangement. When CH3OD was added as
Figure 1. X-ray crystal structure of 4c.

J. Wan et al. / Tetrahedron 63 (2007) 9338–9344
9341
O
OH
N
OH
-H2O
path 1
N
R
N
R
R
10
CHO
CHO
OH
12
H2N
R
11
O
O
O
5
H
H
path 2
-H2O
[1,5]-H
H
N
N
N
R
R
R
15
14
13
R= alkyl or aryl
Scheme 4.
OCH3
extra additive to the typical reaction system, the deuterium
substituted product 20 was obtained in 28.57% yield based
on the HRMS analysis, further characterization of ESI-
OH
N
O
O
CH3OD
N
1
MS2 fragmentation (Fig. 2) and H as well as 13C NMR
OCH3
OH
(see Supplementary data) confirmed the structure of 20. It
is interesting that when CH3OD was used as the single solvent
for the same reaction, the formation of both 4i and 20 was re-
markably prevented (TLC and ESI-MS), instead, characteris-
tic signals matching the alternative product 22 (Scheme 6)
were observed in ESI-MS.23 Moreover, the reaction outlined
in Scheme 6 supported 16 as the main intermediates. There-
fore, we reasonably proposed path 1a (Scheme 5) as the
general mechanism of this rearrangement condensation. Con-
sequently, the obtained deuterium substituted product 20 re-
vealed that the electron transfer (path 1a1) which led to an
intermediate 19 was the main cause which led to the rear-
ranged products in our experiments, while the other proposed
route path la2 is not favored based on our experiment. Further
investigation on this topic is currently in progress in our
group.
16i
22
Scheme 6.
3. Conclusion
We developed a new type of TMSCl catalyzed reaction of
o-phthalaldehyde with acylamide/thioamide or urea/thio-
urea compounds, in which 2-carbonyl/thiocarbonyl iso-
indolinones were readily formed through a rearrangement
process. This marks the first time that this conversion is
reported. The said catalytic system developed was proven
to have general compatibility and efficiency both with the re-
action of newly found amides/thioamides and those of the
previously reported primary amines. In addition, as mecha-
nisms of this kind are presently controversial, new evidences
H
O
HO
OH
path 1a
X
R
2
path 1a
R
1,3-hydride shift
H+
R
N
N
N
-H2O
X
OH
X
16
4
18
-H2O
path 1a
1
X
O
CHO
CHO
O
OH
NH2
R
R
R
O
R
CH3OD
N
N
electron transfer
N
X
H
N
X
X
path 2a
D
H
5
R
20
19
X=O or S; R=alkyl, aryl or amidocyanogen
-H2O
17
21
X
not detected by ESI-MS
Scheme 5. Mechanistic display of TMSCl catalyzed rearrangement reactions of o-phthalaldehyde with carbonyl/thiocarbonyl substrates.
Intens.
based on the ESI-MS combined with deuterium exchange
experiments were provided to describe the course of the
rearrangement.
+MS2(176.8), 0.0-0.1min (#1-#3)
134.9
x104
3
98.9
O
N
2
1
0
O
H
4. Experimental
4.1. General
D
116.8
120
176.8
60
80
100
140
160
180 m/z
All chemicals were obtained from commercial suppliers
and used without further purification. Anhydrous conditions
Figure 2. ESI-MS fragmentation of deuterium substituted product 20.

9342
J. Wan et al. / Tetrahedron 63 (2007) 9338–9344
are not required for the reaction. Melting points were deter-
d 169.7, 150.5, 141.3, 137.7, 134.2, 131.2, 129.3, 128.9,
125.1, 124.3, 123.6, 120.3, 48.8; IR (KBr, cmꢂ1): 3448,
2931, 1711, 1604, 1559, 1498, 1441, 738; HRMS: calcd
for C15H12N2O2Na (M+Na)+: 275.0791; found: 275.0785.
1
mined using XT-4 apparatus and were not corrected. H
and 13C NMR spectra were recorded on Bruker AVANCE
DMX-500 spectrometer at 500 MHz and 125 MHz in
CDCl3, respectively. Chemical shifts are reported in parts
per million (d), relative to the internal standard of tetrame-
4.2.5. 1-Oxo-1,3-dihydro-isoindole-2-carbothioic acid
1
1
thylsilane (TMS). H and 13C NMR spectra were acquired
methylamide (4e). Yellow crystals, mp: 139–142 ꢁC; H
under standard conditions (5 mm QNP probe). Mass spectra
were performed on a Bruker Esquire 3000plus mass spec-
trometer (Bruker–Franzen Analytik GmbH Breman,
Germany) equipped with ESI interface and ion trap analyzer.
HRMS were obtained on a Bruker 7-tesla FT-ICR MS equip-
ped with an electrospray source (Billelica, MA, USA).
NMR (500 MHz, CDCl3): d 12.83 (1H, s), 7.47–8.02 (4H,
m), 5.54 (2H, s), 3.26 (3H, d, J¼4 Hz); 13C NMR
(125 MHz, CDCl3): d 194.8, 181.5, 141.1, 139.1, 133.8,
129.0, 126.7, 122.1, 61.7, 32.5; IR (KBr, cmꢂ1): 3210,
2964, 1710, 1666, 1591, 1557, 1477, 1464, 736; HRMS:
calcd for C10H10N2OSNa (M+Na)+: 229.0406; found:
229.0404.
4.2. General procedure for the TMSCl catalyzed reac-
tions between ureas/thioureas and o-phthalaldehyde
4.2.6. 1-Oxo-1,3-dihydro-isoindole-2-carbothioic acid
allylamide (4f). Yellow crystals, mp: 134–136 ꢁC; 1H
NMR (500 MHz, CDCl3): d 13.02 (1H, s), 7.51–8.07 (4H,
m), 5.98–6.04 (1H, m), 5.58 (2H, s), 5.43 (1H, d,
J¼16.5 Hz), 5.28 (1H, J¼11.5 Hz), 4.44 (2H, t,
J1,2¼4.5 Hz, J3,2¼5 Hz); 13C NMR (125 MHz, CDCl3):
d 195.1, 180.7, 141.3, 139.2, 133.9, 132.0, 129.1, 126.8,
122.2, 118.1, 61.9, 49.0; IR (KBr, cmꢂ1): 3282,
2913, 1710, 1619, 1533, 1469, 1427, 986, 920, 734;
HRMS: calcd for C12H12N2OSNa (M+Na)+: 255.0563;
found: 255.0562.
o-Phthalaldehyde (1 mmol) and ureas/thioureas (1 mmol)
were placed in a flame-dried round-bottomed flask, 1.5 mL
of ionic liquid [bmim]BF4 was used as reaction medium,
0.8 mmol TMSCl was added, and the mixture was stirred
for 7–9 h at room temperature. The completion of reactions
was determined by TLC. The mixture was extracted with
(3ꢀ10 mL) acetate ester. The combined organic layer was
evaporated in vacuum, and the residue was obtained as ana-
lytically pure product. An additional recrystallization with
ethanol was carried out when necessary. Compound 4f was
isolated by silica gel chromatography with the elution of
mixed ethyl acetate and petroleum ether (VEA/VPE¼1:3).
4.3. Typical procedure for TMSCl catalyzed reactions of
o-phthalaldehyde and aliphatic amides
4.2.1. 1-Oxo-1,3-dihydro-isoindole-2-carboxylic acid
Reactions in this section were performed under the same
general conditions as those of the reaction of ureas/thio-
1
amide (4a). Colorless crystals, mp: 191–193 ꢁC; H NMR
(500 MHz, CDCl3): d 7.96 (1H, s), 7.66–7.82 (3H, m),
7.60 (1H, s), 7.54–7.57 (1H, m), 4.78 (2H, s); 13C NMR
(125 MHz, CDCl3): d 169.3, 153.4, 141.3, 134.0, 131.0,
128.7, 125.0, 123.5, 48.4; IR (KBr, cmꢂ1): 3371, 3228,
2917, 1739, 1719, 1670, 1586, 1473, 750; HRMS: calcd
for C9H8N2O2Na (M+Na)+: 199.0478; found: 199.0476.
ureas, but the mixed solvents of CH3CN/DMF ðVCH CN
=
3
VDMF ¼ 2:1Þ were used as media in place of ionic liquid
and stirred for 10–12 h for completion of reactions. The iso-
lation of products was generally accomplished by silica gel
column chromatography with elution of mixed ethyl acetate
and petroleum ether (VEA/VPE¼1:3).
4.2.2. 1-Oxo-1,3-dihydro-isoindole-2-carboxylic acid
4.3.1. 2-Thioacetyl-2,3-dihydro-isoindol-1-one (4g).
Brown crystals, mp: 168–170 ꢁC; 1H NMR (500 MHz,
CDCl3): d 7.50–8.11 (4H, m), 5.08 (2H, s), 2.98 (3H, s);
13C NMR (125 MHz, CDCl3): d 198.0, 172.5, 141.4,
139.1, 133.8, 129.0, 127.1, 122.6, 55.7, 28.1; IR (KBr,
cmꢂ1): 2926, 1698, 1603, 1423, 724; HRMS: calcd for
C10H9NOSNa (M+Na)+: 214.0295; found: 214.0297.
1
methylamide (4b). Yellow crystals, mp: 153–155 ꢁC; H
NMR (500 MHz, CDCl3): d 8.47 (1H, s), 7.50–7.89 (4H,
m), 4.84 (2H, s), 2.98 (3H, d, J¼5.0 Hz); 13C NMR
(125 MHz, CDCl3): d 169.5, 153.8, 141.4, 133.8, 131.4,
128.7, 124.9, 123.5, 48.8, 26.7; IR (KBr, cmꢂ1): 3317,
2942, 2865, 1704, 1682, 1583, 1551, 1469, 749; HRMS:
calcd for C10H10N2O2Na (M+Na)+: 213.0643; found:
213.0628.
4.3.2. 1-Oxo-1,3-dihydro-isoindole-2-carbaldehyde (4h).
1
Colorless crystals, mp: 157–159 ꢁC; H NMR (500 MHz,
4.2.3. 1-Oxo-1,3-dihydro-isoindole-2-carboxylic acid
CDCl3): d 9.29 (1H, s), 7.51–7.94 (4H, m), 4.73 (2H, s);
13C NMR (125 MHz, CDCl3): d 168.9, 160.3, 142.2,
134.9, 130.2, 129.1, 125.4, 124.0, 45.7; IR (KBr, cmꢂ1):
2921, 1731, 1697, 1613, 1469, 1438, 737; HRMS: calcd
for C9H7NO2Na (M+Na)+: 184.0369; found: 184.0368.
1
ethylamide (4c). Colorless crystals, mp: 108–109 ꢁC; H
NMR (500 MHz, CDCl3): d 8.55 (1H, s), 7.52–7.90 (4H,
m), 4.86 (2H, s), 3.45 (2H, q, J1,2¼7.0 Hz, J3,2¼6.2 Hz),
1.26 (3H, t, J2,1¼7.0 Hz); 13C NMR (125 MHz, CDCl3):
d 169.6, 153.2, 141.4, 133.8, 131.6, 128.7, 124.9, 123.6,
48.8, 35.1, 15.3; IR (KBr, cmꢂ1): 3325, 2968, 2930, 2872,
1716, 1677, 1603, 1540, 1467, 731; HRMS: calcd for
C11H12N2O2Na (M+Na)+: 227.0791; found: 227.0784.
4.3.3. 2-Acetyl-2,3-dihydro-isoindol-1-one (4i). Colorless
1
crystals, mp: 144–146 ꢁC; H NMR (500 MHz, CDCl3):
d 7.51–7.92 (4H, m), 4.81 (2H, s), 2.68 (3H, s); 13C NMR
(125 MHz, CDCl3): d 171.4, 168.0, 141.3, 134.3, 131.5,
128.9, 125.4, 123.7, 48.3, 25.0; IR (KBr, cmꢂ1): 2934,
2860, 1731, 1686, 1612, 1472, 1431, 1381, 744; HRMS:
calcd for C10H9NO2Na (M+Na)+: 198.0525; found:
198.0521.
4.2.4. 1-Oxo-1,3-dihydro-isoindole-2-carboxylic acid
phenylamide (4d). Colorless crystals, mp: 181–183 ꢁC;
1H NMR (500 MHz, CDCl3): d 10.68 (1H, s), 7.05–7.88
(9H, m), 4.86 (2H, s); 13C NMR (125 MHz, CDCl3):

J. Wan et al. / Tetrahedron 63 (2007) 9338–9344
9343
4.3.4. 2-(2-Chloro-acetyl)-2,3-dihydro-isoindol-1-one
(4j). To obtain this product, the rest of the components and
catalyst must be mixed and stirred under room temperature
for 5 min before adding the substrate 2-chloro-acetamide.
Yellow crystals, mp: 135–136 ꢁC; 1H NMR (500 MHz,
CDCl3): d 7.54–7.94 (4H, m), 4.91 (2H, s), 4.88 (2H, s);
13C NMR (125 MHz, CDCl3): d 168.0, 167.2, 141.7,
134.8, 131.5, 129.1, 125.7, 123.8, 48.6, 45.2; IR (KBr,
cmꢂ1): 2955, 1721, 1613, 1464, 1450, 1403, 744; HRMS:
calcd for C10H8ClNO2Na (M+Na)+: 232.0136; found:
232.0134.
temperature was required for all benzamide reactions carried
out in our laboratory.
4.4.1. 2-Benzoyl-2,3-dihydro-isoindol-1-one (4p). Color-
less crystals, mp: 137–140 ꢁC; 1H NMR (500 MHz,
CDCl3): d 7.45–7.88 (9H, m), 5.05 (2H, s); 13C NMR
(125 MHz, CDCl3): d 170.6, 167.1, 141.6, 134.7, 134.4,
132.0, 131.3, 129.0, 128.9, 128.0, 125.5, 123.7, 49.0; IR
(KBr, cmꢂ1): 2946, 1732, 1671, 1616, 1599, 1496, 1470,
1441, 733; HRMS: calcd for C15H11NO2Na (M+Na)+:
260.0682; found: 260.0675.
4.3.5. 3-Oxo-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propio-
4.4.2. 2-(4-Fluoro-benzoyl)-2,3-dihydro-isoindol-1-one
(4q). Colorless crystals, mp: 148–150 ꢁC; 1H NMR
1
nitrile (4k). Colorless crystals, mp: 214–216 ꢁC; H NMR
(500 MHz, CDCl3): d 7.55–8.00 (4H, m), 4.90 (2H, s),
4.31 (2H, s); 13C NMR (125 MHz, CDCl3): d 168.0, 162.6,
141.4, 135.3, 130.2, 129.4, 125.9, 123.9, 113.5, 48.6, 28.4;
IR (KBr, cmꢂ1): 2959, 2252, 1731, 1704, 1614, 1464,
1453, 1382, 741; HRMS: calcd for C11H8N2O2Na
(M+Na)+: 223.0478; found: 223.0476.
(500 MHz, CDCl3): d 7.13–7.90 (8H, m), 5.06 (2H, s); 13
C
NMR (125 MHz, CDCl3): d 169.5, 167.2, 141.6, 134.5,
131.9, 131.8, 131.2, 129.0, 125.6, 123.7, 115.3, 115.1,
49.1; IR (KBr, cmꢂ1): 2947, 1719, 1671, 1603, 1509,
1448, 737; HRMS: calcd for C15H10FNO2Na (M+Na)+:
278.0588; found: 278.0581.
4.3.6. 2-Hexanoyl-2,3-dihydro-isoindol-1-one (4l). Color-
4.4.3. 2-(2,3-Dimethyl-benzoyl)-2,3-dihydro-isoindol-1-
one (4r). Colorless crystals, mp: 144–146 ꢁC; 1H NMR
(500 MHz, CDCl3): d 7.49–7.84 (4H, m), 7.12–7.29 (3H,
m), 5.05 (2H, s), 2.34 (3H, s), 2.24 (3H, s); 13C NMR
(125 MHz, CDCl3): d 171.2, 166.6, 141.5, 137.4, 136.6,
134.5, 133.2, 131.5, 131.3, 129.0, 125.7, 125.6, 124.1,
123.8, 48.5, 20.3, 16.6; IR (KBr, cmꢂ1): 2955, 2860, 1749,
1672, 1615, 1493, 1468, 1441, 1375, 743; HRMS: calcd
for C17H15NO2Na (M+Na)+: 288.0995; found: 288.0986.
1
less crystals, mp: 79–81 ꢁC; H NMR (500 MHz, CDCl3):
d 7.50–7.92 (4H, m), 4.82 (2H, s), 3.10 (2H, t, J¼7.5 Hz),
1.73–7.76 (2H, m, J¼7.5 Hz), 1.38–1.42 (4H, m), 0.92
(3H, t, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3): d 174.7,
167.8, 141.4, 134.2, 131.7, 128.8, 125.4, 123.6, 48.4, 37.1,
31.6, 24.3, 22.7, 14.2; IR (KBr, cmꢂ1): 2954, 2929, 2848,
1713, 1695, 1615, 1467, 1440, 740; HRMS: calcd for
C14H17NO2Na (M+Na)+: 254.1151; found: 254.1145.
4.3.7. 2-Isobutyryl-2,3-dihydro-isoindol-1-one (4m). Col-
orless crystals, mp: 84–87 ꢁC; 1H NMR (500 MHz, CDCl3):
d 7.48–7.91 (4H, m), 4.81 (2H, s), 3.95 (1H, m), 1.25 (6H, d,
J¼6.5 Hz); 13C NMR (125 MHz, CDCl3): d 178.8, 167.5,
141.4, 134.2, 131.7, 128.8, 125.4, 123.6, 48.8, 34.2, 19.0;
IR (KBr, cmꢂ1): 2981, 2963, 2935, 2870, 1716, 1696,
1611, 1467, 1446, 1388, 734; HRMS: calcd for
C12H13NO2Na (M+Na)+: 226.0838; found: 226.0834.
4.4.4. 2-(3,5-Dimethoxy-benzoyl)-2,3-dihydro-isoindol-1-
one (4s). White solid, mp: 141–143 ꢁC; 1H NMR (500 MHz,
CDCl3): d 7.51–7.89 (4H, m), 6.64 (1H, t), 6.81 (2H, d), 5.04
(2H, s), 3.83 (6H, s); 13C NMR (125 MHz, CDCl3): d 170.4,
166.9, 160.5, 141.6, 136.6, 134.4, 131.3, 129.0, 125.7, 123.7,
106.7, 104.3, 55.8, 49.1; IR (KBr, cmꢂ1): 2972, 2947, 2847,
1749, 1671, 1604, 1496, 1454, 1426, 1372, 1293, 746;
HRMS: calcd for C17H15NO4Na (M+Na)+: 320.0893;
found: 320.0883.
4.3.8. 2-Acryloyl-2,3-dihydro-isoindol-1-one (4n). White
solid, mp: 114–115 ꢁC; 1H NMR (500 MHz, CDCl3):
d 7.51–7.93 (5H, m), 6.62–6.66 (1H, m), 5.95–5.97 (1H,
m), 4.90 (2H, s); 13C NMR (125 MHz, CDCl3): d 167.9,
166.2, 141.6, 134.4, 131.6, 131.4, 130.0, 128.9, 125.6,
123.7, 48.6; IR (KBr, cmꢂ1): 2918, 2852, 1732, 1672,
1614, 1473, 1446, 1411, 896, 735; HRMS: calcd for
C11H9NO2Na (M+Na)+: 210.0525; found: 210.0520.
4.5. Preparation of 10a and 10b
The preparation process followed the general conditions for
4f–o.
4.5.1. 2-Phenyl-2,3-dihydro-isoindol-1-one (10a). Color-
less crystals, mp: 164–167 ꢁC; 1H NMR (500 MHz,
CDCl3): d 7.16–7.93 (9H, m), 4.83 (2H, s); 13C NMR
(125 MHz, CDCl3): d 167.8, 140.3, 139.7, 133.4, 132.2,
129.3, 128.5, 124.6, 124.3, 122.8, 120.0, 50.9; IR (KBr,
cmꢂ1): 3026, 2922, 2851, 1686, 1595, 1501, 1465, 1440,
732; HRMS: calcd for C14H11NONa (M+Na)+: 232.0733;
found: 232.0726.
4.3.9. 2-Phenylacetyl-2,3-dihydro-isoindol-1-one (4o).
1
Colorless crystals, mp: 139–140 ꢁC; H NMR (500 MHz,
CDCl3): d 7.20–7.88 (9H, m), 4.78 (2H, s), 4.42 (2H, s);
13C NMR (125 MHz, CDCl3): d 172.3, 167.8, 141.5,
134.4, 131.6, 130.0, 128.9, 128.8, 127.3, 125.6, 123.7,
48.7, 43.1; IR (KBr, cmꢂ1): 2923, 2851, 1719, 1705, 1619,
1498, 1462, 1446, 735; HRMS: calcd for C16H13NO2Na
(M+Na)+: 274.0838; found: 274.0835.
4.5.2. 2-Isopropyl-2,3-dihydro-isoindol-1-one (10b). Col-
orless crystals, mp: 82–84 ꢁC; 1H NMR (500 MHz,
CDCl3): d 7.41–7.83 (4H, m), 4.67 (1H, m, J1,2¼7 Hz),
4.33 (2H, s), 1.28 (6H, d, J2,1¼7 Hz); 13C NMR (125 MHz,
CDCl3): d 168.0, 141.4, 133.6, 131.2, 128.1, 123.4, 122.9,
45.2, 42.8, 21.0; IR (KBr, cmꢂ1): 2975, 2929, 2864, 1672,
1591, 1471, 1461, 1411, 1386, 740; HRMS: calcd for
C11H13NONa (M+Na)+: 198.0889; found: 198.0884.
4.4. Representative procedure for the TMSCl catalyzed
reactions of o-phthalaldehyde and benzamides
Identical conditions adopted as in the above aliphatic am-
ides’reactions caused ideal results in this section, but a reflux

9344
J. Wan et al. / Tetrahedron 63 (2007) 9338–9344
10. (a) Kobayashi, Y.; Fujimoto, T.; Fukuyama, T. J. Am. Chem.
Acknowledgements
Soc. 1999, 121, 6501–6502; (b) Santos, M. M.; Lobo, A.;
Prabhakar, S.; Marques, M. M. Tetrahedron Lett. 2004, 45,
2347–2349.
We thank National Natural Science Foundation of China
(Grant no. 20472073) for financial support.
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Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.07.009.
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ꢀ
ꢀ
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22. The exact structure was established through the in situ fragmen-
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observed in ESI-MS, isolation of pure compound wasn’t
successful due to the instability of 22.
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€
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