Efficient PhB(OH)2-catalyzed one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones under solvent free conditions

Article abstract of DOI:10.1016/j.tet.2018.05.086

An efficient and practical one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones has been developed under solvent free-conditions using non-toxic and cheap phenylboronic acid as excellent catalyst. This strategy involves the sequential two-step Mannich/lactamization cascade reaction of inexpensive 2-formylbenzoic acid with primary amines and a wide variety of ketones, and an aldol/lactonization cascade reaction of 2-formylbenzoic acid with a broad range of ketones.

Full text of DOI:10.1016/j.tet.2018.05.086

Accepted Manuscript
Efficient PhB(OH) -catalyzed one-pot synthesis of 3-substituted isoindolin-1-ones and
2
isobenzofuran-1(3H)-ones under solvent free conditions
Angel Palillero-Cisneros, Mercedes Bedolla-Medrano, Mario Ordóñez
PII:
S0040-4020(18)30645-8
10.1016/j.tet.2018.05.086
TET 29593
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 March 2018
Revised Date: 27 May 2018
Accepted Date: 29 May 2018
Please cite this article as: Palillero-Cisneros A, Bedolla-Medrano M, Ordóñez M, Efficient PhB(OH) -
2
catalyzed one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones under
solvent free conditions, Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.086.
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ACCEPTED MANUSCRIPT
Graphical Abstract.
Efficient PhB(OH) -catalyzed one-pot synthesis of 3-
2
substituted isoindolin-1-ones and isobenzofuran-1(3H)-
ones under solvent-free conditions.
Angel Palillero-Cisneros, Mercedes Bedolla-Medrano and Mario Ordóñez*

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Efficient PhB(OH) -catalyzed one-pot synthesis of 3-substituted isoindolin-1-ones
2
and isobenzofuran-1(3H)-ones under solvent free conditions
Angel Palillero-Cisneros, Mercedes Bedolla-Medrano and Mario Ordóñez*
Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos. Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and practical one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-
1
(3H)-ones has been developed under solvent free-conditions using non-toxic and cheap
phenylboronic acid as excellent catalyst. This strategy involves the sequential two-step
Mannich/lactamization cascade reaction of inexpensive 2-formylbenzoic acid with primary amines and
a wide variety of ketones, and an aldol/lactonization cascade reaction of 2-formylbenzoic acid with a
broad range of ketones.
Available online
Keywords:
Phenylboronic acid
Mannich/lactamization
Aldol/lactonization
Isoindolin-1-ones
Isobenzofuran-1-ones
2009 Elsevier Ltd. All rights reserved.
1
. Introduction
Heterocyclic compounds like 2,3-disubstituted isoindolin-1-
ones are undoubtedly one of the most interesting compounds
since, they are present in a great number of natural products and
have attracted much attention in recent years because of their
wide range of biological activities. For example, the pagoclone 1
is a partial agonist at the benzodiazepine site of the GABA
A
1
receptor, which acts as an anxiolytic agent, is used in the
2
treatment of panic disorders, and also in the therapy for patients
3
who stutter, whereas that the 5ꞌ-hydroxy pagoclone 2 acts as an
4
anxiolytic agent. On the other hand, isobenzofuran-1(3H)-ones
represent also an important class of benzofurans, especially those
that possess an acyl group at the C-3 position of the lactone ring,
5
which exhibit a broad spectrum of pharmacological activities.
Due to the high potential of the 3-substituted isoindolin-1-
ones and isobenzofuran-1(3H)-ones, the synthesis of these
compounds has received considerable attention, and in the last
years significant progress has been made to develop more
efficient methods for their preparation. The methods for the
synthesis of 2,3-disubstituted isoindolin-1-ones include the
For example, the 3-acyl substituted isobenzofuran-1(3H)-one
type 3 acts as an anti-tuberculosis agent, has a potential anti-
nociceptive activity, cytotoxic activity against a panel of three
leukemia cancer cell lines, and as an anti-hypertensive and anti-
6
7
8
11
9
inflammatory agents. Additionally, the isobenzofuran-1(3H)-
ones are key intermediates in the synthesis of more complex
compounds with potential applications in the pharmaceutical
industry.
Mannich type reaction of N-acyliminium ions with the
12
13
appropriate enols or trimethylsilyl enol ethers with ylides, the
one-pot reaction of 2-formylbenzoic acid or its methyl ester with
amines and the corresponding enols or trimethylsilyl enol
10
14
ethers, the hydration of 3-alkynyl isoindolin-1-ones obtained by
15
alkynylation/lactamization of methyl 2-formylbenzoate, and the
*
Corresponding autor. Tel.: +52 7773297997; e-mail: palacios@uaem.mx
16
(http://www.ciq.uaem.mx/ nosotros/jose-mario-ordonez-palacios/)
reaction of o-alkynyl arylaldehydes with amines. On the other
hand, the 3-substituted isobenzofuran-1(3H)-ones have been
Supporting information for this article is given via a link at the end of the
document.
17
obtained by aldol/lactonization reaction, intramolecular oxa-

2
Tetrahedron
ACCEPTED MANUSCRIPT
18
Michael addition and by carbonylative cyclization of o-bromo-
Table 1. Optimization of Mannich/lactamization cascade reaction conditions
19
benzaldehyde. However, in spite of their potential utility,
these procedures suffer from one or more disadvantages such
as the use of strong, corrosive and harmful acids and bases, harsh
conditions or tedious multistep processes are necessary for its
purification.
Therefore, considering the high value of the 3-substituted
isoindolin-1-ones and isobenzofuran-1(3H)-ones, the growing
need to develop green synthetic methods in connection with our
current research interest in the synthesis of 2,3-disubstituted
a
Entry Catalyst
(mol%) Time (h)
Yield (%)
1
2
3
4
5
6
7
none
---
10
10
10
5
4.0
3.0
3.5
1.0
1.5
1.0
2.5
18
86
80
91
75
90
20
PTSA
isoindolin-1-ones and the exploration of phenylboronic acid
21
PPTS
[
PhB(OH) ] as a green catalyst in multi-component reactions,
2
PhB(OH)
PhB(OH)
PhB(OH)
PhB(OH)
2
2
2
2
herein we describe an efficient and practical method for the
synthesis of these compounds. Our synthetic strategy is based in
an one-pot Mannich/lactamization cascade reaction of 2-
formylbenzoic acid an essential reactant, which serves as
acceptor for the Mannich reaction and also as substrate for the
subsequent lactamization, with primary amines and a wide variety
of ketones catalyzed with PhB(OH)2 under solvent free-
conditions. Additionally, here we also describe an efficient and
practical method for the synthesis of 3-substituted benzofuran-
20
10
b
78
a
Isolated after chromatographic purification.
The reaction was carried out at 80 C.
b
o
With the optimized Mannich/lactamization reaction conditions
established above, later we turned our attention to investigate the
scope and versatility of this method in the synthesis of several
1
(3H)-ones via a PhB(OH) -catalyzed one-pot sequential
2
2
,3-disubstituted isoindolin-1-ones. Thus, the scope of this
aldol/lactonization reaction of 2-formylbenzoic acid with a great
number of ketones under solvent free-conditions.
sequential Mannich/lactamization reaction was first tested with 2-
formylbenzoic acid, benzylamine and a broad range of methyl
aryl ketones bearing para-electron donating as well as electron
withdrawing substituents. In all cases, the reaction proceeded
efficiently affording the 2,3-disubstituted isoindolin-1-ones 4b-g
in 63 to 91% yield. On the other hand, recognizing that a nitrogen
atom in the ketone might significantly influence the course of the
reaction by protonation or coordination with the phenylboronic
acid, we decided to evaluate the Mannich/lactamization reaction
using 4-acetylpyridine and 2-acetylpyrrole, which react very well
to give the desired 2,3-disubstituted isoindolin-1-ones 4h and 4i
in 74 and 60% yield, respectively, demonstrating that these
ketones tolerate very well these reaction conditions. We also
tested the reaction using dialkyl ketones as the 2-butanone, which
afforded the 2,3-disubstituted isoindolin-1-one 4j in 49% yield.
Finally, when the reaction was carried out using the 5,5-
dimethyl-1,3-cyclohexanedione (dimedone), furnished the 2,3-
disubstituted isoindolin-1-ones 4k in 83% yield (Scheme 1).
2
. Results and Discussion
For the synthesis of 2,3-disubstituted isoindolin-1-ones 4
through the Mannich/lactamization cascade reaction, we started
with the design and optimization conditions of the one-pot
reaction in the presence of some potential catalysts such as p-
toluenesulfonic acid (PTSA), pyridinium p-toluenesulfonate
(PPTS) and phenylboronic acid. For this purpose, the one-pot
reaction of 2-formylbenzoic acid, benzylamine and acetophenone
in 1:1:1 molar proportion was examined with detail in order to find
the most efficient reaction conditions. Under this context, initially
the 2-formylbenzoic acid was treated with benzylamine at room
temperature to obtain the corresponding imine, which was reacted
o
with acetophenone at 100 C under solvent and catalyst free-
conditions, obtaining the 2,3-disubstituted isoindolin-1-one 4a in
only 18% yield after 4.0 h (Table 1, entry 1). In the next
o
experiment, the imine was reacted with acetophenone at 100 C in
Then, to ensure the efficiency and generality of this sequential
Mannich/lactamization cascade reaction for the synthesis of 2,3-
disubstituted isoindolin-1-ones, a variety of primary amines
including p-methoxybenzylamine, cyclohexanemethylamine,
allylamine and 2,2-dimethoxyethylamine were tested using the
optimal conditions described above. For this purpose, we first
evaluated the one-pot reaction of 2-formylbenzoic acid and p-
methoxybenzylamine with acetophenone, p-methoxyacetophenone
and p-methylacetophenone. In all cases, the reaction proceeded
efficiently to give the 2,3-disubstituted isoindolin-1-ones 4l-n in
moderated to excellent yield (73-95%). However, when the p-
hydroxyacetophenone was reacted under the same conditions, the
isoindolin-1-one 4o was obtained in only 45% yield, whereas the
reaction with the acetylated p-hydroxyacetophenone derivative,
gave the isoindolin-1-one 4p in 65% yield. Again, the sequential
Mannich/lactamization cascade reaction with 4-acetylpyridine or
the presence of 10 mol% of PTSA or PPTS as catalyst, obtaining
the expected 2,3-disubstituted isoindolin-1-one 4a in 86% and
8
3
0% yield, respectively, after 3.0 and 3.5 h (Table 1, entries 2 and
). Later, we carried out the reaction of 2-formylbenzoic acid with
benzylamine followed by the treatment with acetophenone in the
presence of 10 mol% of PhB(OH) under solvent free-conditions
2
o
and at 100 C, obtaining 4a in 91% in only 1.0 h (Table 1, entry
4
). With these excellent results and in order to find the optimum
amount of PhB(OH) , the reaction was performed using 5 and 20
2
mol%, found that using 20 mol% of PhB(OH) the yield of the
2
desired 2,3-disubstituted isoindolin-1-one 4a did not improve, but
using 5 mol% of catalyst the yield decreased to 75% yield (Table
1
, entries 5 and 6). In addition, when the reaction was carried out
o
at 80 C, the yield of 4a also decreased to 78% and longer
reaction time was required (Table 1, entry 7). These results show
that all catalysts tested are excellent for the synthesis of the 2,3-
disubstituted isoindolin-1-one 4a through the one-pot reaction,
2-acetylpirrole, produced the 2,3-disubstituted isoindolin-1-ones
4
q and 4r in 80 and 88% yield, respectively. Finally, the one-pot
but we selected the PhB(OH) as the catalyst to continue this
2
reaction of 2-formylbenzoic acid with cyclohexanemethylamine,
allylamine or 2,2-dimethoxyethylamine and acetophenone under
the optimal conditions, afforded the desired 2,3-disubstituted
study under solvent free-conditions because it is easy access and
cheap.

o
isoindolin-1-ones 4s-u in moderated to excellent yields (63-91%)
entries 3). Further increase in the temperature at 145 C,
ACCEPTED MANUSCRIPT
(Scheme 2).
surprisingly the yield was lower (Table 2, entry 4). On the basis
of these results, we found that 135 C was the optimal
temperature for the synthesis of the isobenzofuran-1(3H)-one 5a
under solvent free-conditions. Additionally, under these reaction
o
O
O
H N Bn
2
PhB(OH)2
10 mol%
OH
H
+
N
Bn
O
100 oC, 1.0 h
O
R
conditions no decomposition of PhB(OH)
observed
2
to B(OH) was
3
R
.
O
R
R
4b-k
O
O
O
H N
R
2
PhB(OH)2
10 mol%
O
O
O
OH
H
+
N R
00 oC, 1.0 h
1
N
Bn
N
Bn
O
N
Bn
O
Me
O
O
O
Ar
Ar
4l-u
OMe
OMe
OMe
O
N
O
N
O
O
OMe
OH
Me
4
b; 90%
4c; 81%
4d; 91%
N
O
O
O
O
O
N
Bn
N
Bn
O
N
Bn
O
O
OMe
m; 95%
Me
4n; 73%
4l; 88%
4
OMe
OMe
OMe
NHAc
Cl
NO2
4
e; 80%
4f; 76%
4g; 63%
O
O
N
O
N
O
O
O
N
N
Bn
O
N
Bn
O
N
Bn
O
O
O
O
H
Me
N
4j; 49%
N
N
4
i; 60%
OH
OAc
4
h; 74%
4
o; 45%
4p; 65%
4q; 80%
O
OMe
N
Bn
O
O
O
N
O
N
HO
N
O
N
O
O
Me Me
k; 83%
4
H
Ph
Ph
4s; 63%
4t; 68%
Scheme 1. Synthesis of 2,3-disubstituted isoindolin-1-ones 4b-k
4
r; 88%
O
OMe
OMe
With the aim of demonstrate the potentiality of PhB(OH) acid
2
as an excellent catalyst toward the synthesis of 3-substituted
isobenzofuran-1(3H)-ones through the aldol/lactonization cascade
reaction under solvent free-conditions, we investigated the reaction
of 2-formylbenzoic acid with acetophenone as model reaction in
order to find the optimal reaction conditions. The results are
summarized in Table 2.
N
O
Ph
4
u; 91%
Scheme 2. Synthesis of 2,3-disubstituted isoindolin-1-ones 4l-u.
Initially, we carried out the reaction of 2-formylbenzoic acid
with acetophenone in the presence of 10 mol% of PhB(OH) at 100
C under solvent free-conditions, obtaining the 3-substituted
2
Once the optimal reaction conditions were established, in the
next step we investigated the scope of this process for the
synthesis of a variety of 3-substituted isobenzofuran-1(3H)-ones
from 2-formylbenzoic acid and several ketones. In this context,
the sequential aldol/lactonization cascade reaction was first tested
with 2-formylbenzoic acid and a broad range of methyl aryl
ketones bearing para-electron donating as well as electron
o
isobenzofuran-1(3H)-one 5a in 63% yield (Table 2, entry 1). In an
effort to increase the yield, we evaluated the influence of the
temperature. Thus, the reaction of 2-formylbenzoic acid with
o
acetophenone was performed at 125 C in the presence of 10 mol%
of PhB(OH) ; however, under these conditions, the yield of the
2
isobenzofuran-1(3H)-one 5a enhanced slightly (Table 2, entry 2).
withdrawing
substituents,
obtaining
the
3-substituted
o
Finally, when the reaction was carried out at 135 C in the
isobenzofuran-1(3H)-ones 5b-g in 56 to 75% yield. The 4-acetyl-
pyridine an acid sensitive ketone also reacted efficiently with 2-
formylbenzoic acid to give the desired isobenzofuran-1(3H)-one
presence of 10 mol% of PhB(OH) , the desired 3-substituted
2
isobenzofuran-1(3H)-one 5a was obtained in 80% yield (Table 2,

4
Tetrahedron
ACCEPTED MANUSCRIPT
5
h in 76% yield. When the 2-formylbenzoic acid was reacted
1(3H)-ones type 5, which by reaction with the amines, produced
the corresponding 3-substituted isoindolin-1-ones 4. However,
under our reaction conditions, initially the 2-formylbenzoic acid
was reacted with the primary amines at room temperature for 5.0
min, obtaining the corresponding protonated imine A, which was
observed by H NMR. Meanwhile, the phenylboronic acid
catalyzes the keto-enol tautomerization of the corresponding
ketone, that by nucleophilic attack to the protonated imine A,
produces the Mannich aduct B, which by ring closure
with 2-butanone, the 3-substituted isobenzofuran-1(3H)-one 5i was
also obtained in 81% yield. Finally, the reaction of 2-
formylbenzoic acid with 5,5-dimethyl-1,3-cyclohexanedione,
gave the 3-substituted isobenzofuran-1(3H)-one 5j in 95% yield
1
20c
(Scheme 3)
Table 2. Optimization of Aldol/lactonization cascade reaction conditions
O
O
PhB(OH)2
O
10 mol%
(lactamization) offers the 2,3-disubstituted isoindolin-1-one 4. In
OH
H
+
O
conditions
order to have more evidence of this mechanism, the progress of
Me
Ph
1
O
this reaction was followed by H NMR at 5, 15, 30, 45 and 60
O
min, and the isobenzofuran-1-one 5 was not observed. On the
other hand, the nucleophilic attack of the enol form to 2-
formylbenzoic acid, gives the β-hydroxy ketone C (aldol-
Ph
5
a
a
Entry
Conditions
Yield (%)
o
product),
which
through
intramolecular
esterification
1
2
3
4
100 C, 24.0 h
63
65
80
71
o
(lactonization), generates the isobenzofuran-1(3H)-one
5
125 C, 8.0 h
o
(Scheme 4).
135 C, 4.0 h
o
145 C, 4.0 h
O
O
a
Isolated after chromatographic purification.
O
H2N
R
OH
H
H
N
R
O
A
O
O
PhB(OH)2
O
OH
H
O
10 mol%
+
R
O
35 oC, 4-12 h
R'
R'
Me
PhB(OH)2
OH
1
R
O
O
Mannich
Aldol
R
R
5
b-j
O
O
O
O
O
O
O
O
O
O
O
OH
NH
OH
OH
R
O
O
R'
R'
OMe
b; 8.0 h, 75%
OH
5c; 9.0 h, 56%
Me
5d; 4.0 h, 67%
B
C
5
O
O
O
Lactamization
O
Lactonization
O
O
O
O
O
O
R'
O
O
O
H2N
R
N
R
O
R'
4
5
NHAc
Cl
NO2
5e; 6.0 h, 73%
5f; 12.0 h, 68%
5g; 12.0 h, 69%
Scheme 4. A proposed reaction pathway
O
O
O
3
. Conclusions
In summary, we have developed an efficient and practical
O
O
O
O
O
HO
O
method for the synthesis of 2,3-disubstituted isoindolin-1-ones
and 3-substituted isobenzofuran-1(3H)-ones through a sequential
Mannich/lactamization and aldol/lactonization cascade reaction,
respectively, both catalyzed by phenylboronic acid. Furthermore,
this method offers several significant advantages such allowing
the use of a wide variety of substrates, easy handling and no
workup was necessary, clean reaction profile, high atom-
economy and the products are obtained in good to high yields,
which makes it a useful and attractive method for the rapid and
efficient synthesis of 2,3-disubstituted isoindolin-1-ones and
isobenzofuran-1(3H)-ones. Additionally, we found that the
phenylboronic acid is an excellent catalyst for this process.
Me
5i; 10.0 h, 81%
Me Me
j; 4.0 h, 95%
N
5
5
h; 12.0 h, 76%
Scheme 3. Synthesis of 3-substituted isobenzofuran-1(3H)-ones 5b-j.
With these results, a plausible reaction pathway for the
formation of 3-substituted isoindolin-1-ones 4 and isobenzofuran-
(3H)-ones 5 is proposed in Scheme 4. Recently, Han et al.
proposed that in a multi-component reaction of 2-formylbenzoic
acid with a β-keto acids and primary amines catalyzed by a
quaternary ammonium salt, gave initially the isobenzofuran-
14a
1

4
4
. Experimental Section
1H, CH CO), 3.47 (dd, J = 17.5, 5.2 Hz, 1H, CH CO), 4.49 (AB
2 2
ACCEPTED MANUS
CRIPT
system, J = 15.4 Hz, 1H, CH Ph), 5.09 (AB system, J = 15.4 Hz,
2
.1 General Methods
1
7
7
H, CH Ph), 5.23 (dd, J = 7.4, 5.2 Hz, 1H, CHN), 7.17-7.27 (m,
H, Harom), 7.36-7.39 (m, 1H, Harom), 7.44-7.49 (m, 2H, Harom),
2
All commercial materials were used as received unless
.70 (AAꞌBBꞌ, J = 8.3 Hz, 2H, Harom), 7.89-7.91 (m, 1H, Harom).
otherwise noted. Flash chromatography was performed with 230-
00 mesh Silica Flash 60®. Thin layer chromatography was
1
3
C NMR (100 MHz, CDCl ) δ: 21.7, 42.0, 44.6, 56.0, 123.0,
3
4
1
23.9, 127.6, 128.0 (2C), 128.2 (2C), 128.5, 128.7 (2C), 129.4
performed on pre-coated TLC sheets of silica gel (60 F254, Merck)
and the plates were visualized with UV-light, iodine vapors and
submersion in a solution of ninhydrin or p-anisaldehyde. Melting
points were determined in a Fisher–Johns apparatus and are
uncorrected. NMR spectra were recorded on a Varian instrument
(
2C), 131.9, 133.8, 134.1 137.2, 144.7, 146.0, 168.4, 196.7.
+
+
HRMS (FAB ): calcd. for C H NO [M+H] , m/z 356.1572;
found for [M+H] , m/z 356.1661.
24
22
2
+
4
.2.5. 2-Benzyl-3-(2-oxo-(4-N-acetylphenyl)ethyl)isoindolin-1-
1
1
1
(400 MHz for H) or a Bruker instrument (500 MHz for H) and
one (4e). White solid, 80% yield, M.p. = 92-94 °C. H NMR (500
MHz, CDCl ) δ: 1.86 (br, 1H, NH), 2.19 (s, 3H, CH ), 3.11 (dd, J
calibrated using the TMS and the residual solvent signal as
internal standards; chemical shifts (δ) are expressed in parts per
million (ppm) and coupling constants (J) in Hertz. High
resolution FAB mass spectra (HRMS) were obtained on a JEOL
MStation MS-700. The H and C NMR spectroscopic data for
3
3
=
17.2, 6.9 Hz, 1H, CH CO), 3.43 (dd, J = 17.2, 5.4 Hz, 1H,
2
CH CO), 4.52 (AB system, J = 15.4 Hz, 1H, CH Ph), 5.06 (AB
2
2
+
system, J = 15.4 Hz, 1H, CH Ph), 5.24 (dd, J = 6.9, 5.4 Hz, 1H,
2
1
13
CHN), 7.14-7.24 (m, 5H, Harom), 7.38 (d, J = 6.9 Hz, 1H, Harom),
12f
10d
18a
17i
10a
17b
10e
the compounds 4a, 5a, 5b,i, 5d,g, 5f, 5h
are identical with those described in the literature.
and 5j
7
.44-7.50 (m, 2H, Harom), 7.62 (d, J = 8.2 Hz, 2H, Harom), 7.73 (d,
13
J = 8.8 Hz, 2H, Harom), 7.88 (d, J = 7.5 Hz, 1H, Harom). C NMR
125 MHz, CDCl ) δ: 24.4, 41.6, 44.5, 56.1, 118.8, 118.9, 123.0,
(
3
4
4
.2. Experimental details and characterisation data
.2.1. Typical Procedure for the one-pot synthesis of 2,3-
1
1
23.7, 127.6, 127.8 (2C), 128.6, 128.7 (2C), 129.5 (2C), 131.5,
32.0, 136.6, 143.4, 143.5, 145.5, 168.8, 169.5, 195.8. HRMS
+
+
(
[
FAB ): calcd. for C H N O [M+H] , m/z 399.1630; found for
25 23 2 3
+
disubstituted isoindolin-1-ones derivatives 4a-u.
A mixture of 2-formylbenzoic acid (1 mmol) and amine (1
mmol) were stirred for 5.0 min at room temperature. After this
time the ketone compound (1.0 mmol) and PhB(OH) (0.1 mmol)
were added, and the reaction mixture was stirred at 100 C. The
progress of the reaction was checked by TLC. After completion
of the reaction, the mixture was cooled at room temperature and
the resulting crude product was purified by flash column
chromatography using hexane-AcOEt mixture as eluent, to give
the pure products 4a-u.
M+H] , m/z 399.1718.
4.2.6. 2-Benzyl-3-(2-oxo-(4-chlorophenyl)ethyl)isoindolin-1-one
1
2
(4f). White solid, 76% yield, M.p. = 150-152 °C. H NMR (500
o
MHz, CDCl ) δ: 3.11 (dd, J = 17.6, 6.9 Hz, 1H, CH CO), 3.43
3
2
(
dd, J = 17.6, 5.5 Hz, 1H, CH CO), 4.60 (AB system, J = 15.4
2
Hz, 1H, CH Ph), 4.99 (AB system, J = 15.4 Hz, 1H, CH Ph),
2
2
5
4
2
2
.22-5.25 (m, 1H, CHN), 7.13-7.18 (m, 1H, Harom), 7.19-7.25 (m,
H, Harom), 7.35-7.36 (m, 1H, Harom), 7.38 (AAꞌBBꞌ, J = 8.6 Hz,
H, Harom), 7.46-7.51 (m, 2H, Harom), 7.70 (AAꞌBBꞌ, J = 8.6 Hz,
13
H, Harom), 7.90-7.93 (m, 1H, Harom).
C NMR (125 MHz,
CDCl ) δ: 42.2, 44.8, 55.9, 122.8, 124.0, 127.6, 128.0 (2C),
4
.2.2.
2-Benzyl-3-(2-oxo-(4-methoxyphenyl)ethyl)isoindolin-1-
3
1
128.6, 128.8 (2C), 129.1 (2C), 129.5 (2C), 131.8, 131.9, 134.6,
one (4b). White solid, 90% yield, M.p. = 77-79 ºC. H NMR (400
MHz, CDCl ) δ: 3.09 (dd, J = 17.2, 7.4 Hz, 1H, CH CO), 3.43
+
1
37.1, 140.2, 145.7, 168.6, 195.9. HRMS (FAB ): calcd. for
3
2
+
+
C H O NCl [M+H] , m/z 376.1026; found for [M+H] , m/z
23
19
2
(dd, J = 17.2, 5.3 Hz, 1H, CH CO), 3.86 (s, 3H, CH O), 4.50 (AB
2
3
3
76.1107.
system, J = 15.4 Hz, 1H, CH Ph), 5.08 (AB system, J = 15.4 Hz,
1
J = 8.6 Hz, 2H, Harom), 7.10-7.29 (m, 5H, Harom), 7.35-7.39 (m,
2
H, CH Ph), 5.23 (dd, J = 7.4, 5.3 Hz, 1H, CHN), 6.88 (AAꞌBBꞌ,
4.2.7. 2-Benzyl-3-(2-oxo-(4-nitrophenyl)ethyl)isoindolin-1-one
2
1
(4g). White solid, 63% yield, M.p. = 158-160 ºC. H NMR (400
1
2
H, Harom), 7.44-7.51 (m, 2H, Harom), 7.78 (AAꞌBBꞌ, J = 8.6 Hz,
H, Harom), 7.85-7.95 (m, 1H, Harom). C NMR (100 MHz,
MHz, CDCl
(dd, J = 17.9, 5.9 Hz, 1H, CH
Hz, 1H, CH Ph), 4.87 (AB system, J = 15.5 Hz, 1H, CH
2
3
) δ: 3.19 (dd, J = 17.9, 6.3 Hz, 1H, CH
CO), 4.74 (AB system, J = 15.5
Ph),
2
CO), 3.48
13
2
CDCl ) δ: 41.7, 44.7, 55.6, 56.1, 113.9, 123.0, 123.9, 127.5,
2
3
1
1
28.0 (2C), 128.0, 128.7 (2C), 129.5, 130.5 (2C), 131.8, 131.9,
5.28 (dd, J = 6.3, 5.9 Hz, 1H, CHN), 7.05-7.25 (m, 5H, Harom),
7.34-7.42 (m, 1H, Harom), 7.45-7.57 (m, 2H, Harom), 7.86 (AAꞌBBꞌ,
+
37.2, 146.1, 164.0, 168.6, 195.5. HRMS (FAB ): calcd. for
+
+
C H NO [M+H] , m/z 372.1521; found for [M+H] , m/z
3
J = 10.2 Hz, 2H, Harom),
7.89-7.96 (m, 1H, Harom), 8.22 (AAꞌBBꞌ,
,
13
24
22
3
72.1589.
J = 10.2 Hz, 2H, Harom). C NMR (100 MHz, CDCl
3
) δ: 42.9,
5.1, 55.9, 122.6, 123.8 (2C), 124.1, 127.6, 127.9 (2C), 128.5,
28.7 (2C), 129.0 (2C), 131.8, 132.0, 136.8, 140.2, 145.2, 150.5,
68.2, 195.5. HRMS (FAB ): calcd. for C H N O [M+H] , m/z
87.1267; found for [M+H] , m/z 387.1392.
4
1
1
3
4
.2.3.
2-Benzyl-3-(2-oxo-(4-hydroxyphenyl)ethyl)isoindolin-1-
1
one (4c). White solid, 81% yield, M.p. = 184-186 ºC. H NMR
+
+
23
19
2
4
(400 MHz, CDCl ) δ: 2.10 (br, 1H, OH), 3.09 (dd, J = 17.2, 7.4
+
3
Hz, 1H, CH CO), 3.43 (dd, J = 17.2, 5.2 Hz, 1H, CH CO), 4.49
2
2
(AB system, J = 15.4 Hz, 1H, CH Ph), 5.08 (AB system, J = 15.4
4.2.8. 2-Benzyl-3-(2-oxo-2-(pyridin-4-yl)ethyl)isoindolin-1-one
2
1
Hz, 1H, CH Ph), 5.23 (dd, J = 7.4, 5.2 Hz, 1H, CHN), 6.84
(4h). Yellow solid, 74% yield, M.p. = 118-120 ºC. H NMR (500
2
(
AAꞌBBꞌ, J = 8.8 Hz, 2H, Harom), 7.16-7.22 (m, 2H, Harom), 7.22-
.24 (m, 3H, Harom), 7.37-7.39 (m, 1H, Harom), 7.44-7.51 (m, 2H,
Harom), 7.70 (AAꞌBBꞌ, J = 8.9 Hz, 2H, Harom), 7.88-7.90 (m, 1H,
MHz, CDCl
(dd, J = 18.0, 5.9 Hz, 1H, CH
Hz, 1H, CH Ph), 4.89 (AB system, J = 15.5 Hz, 1H, CH
3
) δ: 3.14 (dd, J = 18.0, 6.3 Hz, 1H, CH
CO), 4.71 (AB system, J = 15.5
Ph),
2
CO), 3.43
7
2
2
2
13
Harom). C NMR (100 MHz, CDCl ) δ: 41.4, 44.7, 56.5, 115.5,
1
1
HRMS (FAB ): calcd. for C H NO [M+H] , m/z 358.1365;
found for [M+H] , m/z 358.1442.
5.24-5.26 (m, 1H, CHN), 7.10-7.23 (m, 5H, Harom), 7.37 (d, J =
6.7, 1H, Hpy), 7.49-7.52 (m, 4H, Harom), 7.91 (d, J = 7.2, 1H, Hpy),
3
23.0, 123.9, 127.7, 128.0 (2C), 128.6, 128.8 (2C), 130.7 (2C),
30.9 131.5, 131.7, 132.1, 136.9, 146.1, 162.1, 169.2, 195.5.
13
8.74 (d, J = 5.3, 2H, Hpy). C NMR (125 MHz, CDCl ) δ: 42.6,
3
+
+
45.0, 55.8, 120.8 (2C), 122.6, 124.1, 127.6, 127.9 (2C), 128.8,
128.9 (2C), 131.8, 132.0, 137.0, 141.8, 145.3, 150.9 (2C), 168.6,
23
20
3
+
+
+
1
3
96.7. HRMS (FAB ): calcd. for C H N O [M+H] , m/z
22 19 2 2
+
4
.2.4. 2-Benzyl-3-(2-oxo-(4-methylphenyl)ethyl)isoindolin-1-one
43.1368; found for [M+H] , m/z 343.1458.
1
(4d). White solid, 91% yield, M.p. = 79-81 °C. H NMR (400
MHz, CDCl ) δ: 2.40 (s, 3H, CH ), 3.12 (dd, J = 17.5, 7.4 Hz,
4.2.9.
one (4i). Yellow solid, 60% yield, M.p. = 128-130 ºC. H NMR
2-Benzyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)isoindolin-1-
3
3
1

6
Tetrahedron
ACCEPTED MANUSCRIPT
(
3
1
400 MHz, CDCl ) δ: 3.01 (dd, J = 16.3, 7.3 Hz, 1H, CH CO),
(2C), 122.9, 123.8, 128.4, 129.3, 129.4 (2C), 129.5, 130.5 (2C),
+
3
2
.31 (dd, J = 16.3, 5.6 Hz, 1H, CH CO), 4.39 (AB system, J =
131.8, 131.9, 146.1, 159.0, 164.0, 168.5, 195.6. HRMS (FAB ):
+ +
2
5.3 Hz, 1H, CH Ph), 5.14 (dd, J = 7.3, 5.6 Hz, 1H, CHN), 5.18
calcd. for C H NO [M+H] , m/z 402.1627; found for [M+H] ,
25 24 4
2
(
AB system, J = 15.4 Hz, 1H, CH Ph), 6.22-6.24 (m, 1H, Hpyrrole),
m/z 402.1820.
2
6
.68-6.70 (m, 1H, Hpyrrole), 7.04-7.06 (m, 1H, Hpyrrole), 7.17-7.29
4
.2.14. 2-(4-Methoxybenzyl)-3-(2-oxo-(4-methylphenyl)ethyl)-
(m, 5H, Harom), 7.32-7.38 (m, 1H, Harom), 7.44-7.51 (m, 2H,
1
13
isoindolin-1-one (4n). Yellow oil, 73% yield. H NMR (500
MHz, CDCl ) δ: 2.24 (s, 3H, CH ), 2.95 (dd, J = 17.2, 7.1 Hz,
1
Harom), 7.87-7.97 (m, 1H, Harom), 9.75 (s, 1H, NHpyrrole). C NMR
100 MHz, CDCl ) δ: 41.2, 44.6, 56.1, 111.2, 117.2, 122.8,
3
3
(
1
1
3
H, CH CO), 3.28 (dd, J = 17.2, 5.5 Hz, 1H, CH CO), 3.55 (s,
2
2
24.0, 125.7, 127.6, 128.1 (2C), 128.5, 128.7 (2C), 129.0, 131.8,
+
3H, CH
3
O), 4.29 (AB system, J = 15.2 Hz, 1H, CH
PMP), 5.21-5.23 (m, 1H,
CHN), 6.58 (AAꞌBBꞌ, J = 8.7 Hz, 2H, Harom), 7.02 (AAꞌBBꞌ, J =
.7 Hz, 2H, Harom), 7.06 (AAꞌBBꞌ, J = 8.0 Hz, 2H, Harom), 7.20-
2
PMP), 4.84
31.9, 137.2, 145.7, 168.6, 186.6. HRMS (FAB ): calcd. for
+
+
(AB system, J = 15.2 Hz, 1H, CH
2
C H N O [M+H] , m/z 331.1368; found for [M+H] , m/z
3
21
19
2
2
31.1442.
8
4
4
0
.2.10. 2-Benzyl-3-(2-oxobutyl)isoindolin-1-one (4j). White solid,
7.23 (m, 1H, Harom), 7.27-7.34 (m, 2H, Harom), 7.55 (AAꞌBBꞌ, J =
8.0 Hz, 2H, Harom), 7.71-7.75 (m, 1H, Harom). C NMR (125 MHz,
1
13
9% yield, M.p. = 129-131 °C. H NMR (400 MHz, CDCl ) δ:
3
.96 (t, J = 7.3 Hz, 3H, CH ), 1.98 (dq, J = 18.1, 7.3 Hz, 1H,
CDCl ) δ: 21.7, 42.0, 44.1, 55.2, 55.9, 114.1 (2C), 122.9, 123.9,
3
3
CH ), 2.21 (dq, J = 18.1, 7.3 Hz, 1H, CH ), 2.66 (dd, J = 17.6, 6.2
128.3, 128.4 (2C), 129.3, 129.3, 129.4 (2C), 129.5, 131.8, 131.9,
2
2
+
Hz, 1H, CH CO), 2.84 (dd, J = 17.6, 6.2 Hz, 1H, CH CO), 4.64
133.9, 144.7, 146.0, 159.0, 168.5, 196.8. HRMS (FAB ): calcd
2
2
+
+
(
AB system, J = 15.4 Hz, 1H, CH Ph), 4.86 (AB system, J = 15.5
for C H NO [M+H] , m/z 386.1678; found for [M+H] , m/z
2
25 24 3
Hz, 1H, CH Ph), 5.07 (dd, J = 6.2 Hz, 1H, CHN), 7.17-7.40 (m,
386.1785.
2
6
H, Harom), 7.41-7.61 (m, 2H, Harom), 7.85-7.98 (m, 1H, Harom).
13
4.2.15. 2-(4-Methoxybenzyl)-3-(2-oxo-(4-hydroxyphenyl)ethyl)-
isoindolin-1-one (4o). Yellow oil, 45% yield. H NMR (400
C NMR (100 MHz, CDCl ) δ: 7.5, 36.5, 44.9, 45.7, 55.8, 122.4,
1
3
1
1
24.0, 127.6, 128.5 (2C), 128.6, 128.8 (2C), 131.9, 132.0, 137.4,
+
MHz, DMSO-d
(s, 3H, CH O), 3.69 (dd, J = 17.7, 5.2 Hz,1H, CH
system, J = 15.2 Hz, 1H, CH PMP), 4.94-5.02 (m, 2H, CH PMP
6
) δ: 3.30 (dd, J = 17.7, 7.3 Hz, 1H, CH
2
CO), 3.67
45.7, 168.8, 208.3. HRMS (FAB ): calcd. for C H NO
19
20
2
+
+
3
2
CO), 4.35 (AB
[
M+H] , m/z 294.1416; found for [M+H] , m/z 294.1510.
2
2
4
1
.2.11. 2-Benzyl-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-
-yl)isoindolin-1-one (4k). White solid, 83% yield, M.p. 220 °C
and CHN), 6.78-6.86 (m, 4H, Harom), 7.17 (AAꞌBBꞌ, J = 8.7 Hz,
=
2H, Harom), 7.44-7.56 (m, 3H, Harom), 7.70-7.76 (m, 1H, Harom),
1
13
H NMR (400 MHz, DMSO-d ) δ: 0.94 (s, 3H, CH ), 0.96 (s, 3H,
7.80 (AAꞌBBꞌ, J = 8.7 Hz, 2H, Harom). C NMR (100 MHz,
6
3
CH ), 1.90
(
d, J = 16.4 Hz, 1H, CH ), 1.98
(d, J = 16.4 Hz, 1H,
DMSO-d ) δ: 40.2, 42.6, 55.3, 55.9, 113.9 (2C), 115.2 (2C),
3
2
6
CH ), 2.21 (s, 2H, CH CO)
,
4.00 (AB system, J = 15.1 Hz, 1H,
122.8, 123.1, 127.8, 128.2, 129.0 (2C), 129.4, 130.7 (2C), 131.5,
2
2
+
CH Ph), 4.80 (AB system, J = 15.1 Hz, 1H, CH Ph), 5.69 (s, 1H,
131.7, 146.1, 158.4, 162.6, 167.3, 195.5. HRMS (FAB ): calcd.
2
2
+
+
CHN), 7.14-7.28 (m, 6H, Harom), 7.35-7.38 (m, 1H, H ), 7.41-
for C H NO [M+H] , m/z 388.1471; found for [M+H] , m/z
arom
24 22 4
13
7
.45 (m, 1H, Harom), 7.65 (d, J = 7.4 Hz, 1H, Harom). C NMR
388.1525.
(
1
1
100 MHz, DMSO-d ) δ: 27.5, 28.5, 31.4, 43.4, 46.8, 47.3, 54.3,
6
4
.2.16. 2-(4-Methoxybenzyl)-3-(2-oxo-(4-O-acetylphenyl)ethyl)-
1
06.0, 121.6, 122.3, 126.9, 127.2, 127.7 (2C), 128.3 (2C), 128.5,
+
isoindolin-1-one (4p). Yellow oil, 65% yield. H NMR (400
MHz, CDCl ) δ: 2.32 (s, 3H, CH ), 3.11 (dd, J = 17.6, 7.0 Hz,
H, CH CO), 3.45 (dd, J = 17.2, 5.5 Hz, 1H, CH CO), 3.71 (s,
28.7, 131.0, 132.5, 138.1, 147.3, 167.7. HRMS (FAB ): calcd.
+
+
3
3
for C H NO [M+H] , m/z 362.1678; found for [M+H] , m/z
3
23
24
3
1
3
2
2
62.1741.
H, CH O), 4.50 (AB system, J = 15.2 Hz, 1H, CH PMP), 4.96
3
2
4
.2.12. 2-(4-Methoxybenzyl)-3-(2-oxophenylethyl)isoindolin-1-
(AB system, J = 15.2 Hz, 1H, CH PMP), 5.23 (dd, J = 7.0, 5.5
2
1
one (4l). White solid, 88% yield, M.p. = 145-146 ºC. H NMR
Hz, 1H, CHN), 6.74 (AAꞌBBꞌ, J = 8.7 Hz, 2H, Harom), 7.14-7.20
(m, 4H, Harom), 7.33-7.40 (m, 1H, Harom), 7.43-7.50 (m, 2H,
Harom), 7.83 (AAꞌBBꞌ, J = 8.7 Hz, 2H, Harom), 7.87-7.92 (m, 1H,
(400 MHz, CDCl ) δ: 3.14 (dd, J = 17.6, 7.0 Hz, 1H, CH CO),
3
2
3
.49 (dd, J = 17.6, 5.4 Hz, 1H, CH CO), 3.71 (s, 3H, CH O), 4.48
2 3
13
(AB system, J = 15.2 Hz, 1H, CH PMP), 4.98 (AB system, J =
Harom). C NMR (100 MHz, CDCl ) δ: 21.2, 42.1, 44.2, 55.3,
2
3
1
5.2 Hz, 1H, CH PMP), 5.22-5.25 (m, 1H, CHN), 6.73 (AAꞌBBꞌ,
55.8, 114.1 (2C), 122.0 (2C), 122.8, 123.9, 128.5, 129.2 (2C),
129.4 (2C), 129.5, 129.8, 131.9, 133.9, 145.9, 154.8, 159.1,
2
J = 8.5 Hz, 2H, Harom), 7.18 (AAꞌBBꞌ, J = 8.5 Hz, 2H, Harom),
+
7
7
5
.31-7.64 (m, 6H, H ), 7.80 (d, J = 7.6 Hz, 2H, Harom), 7.85-
168.5, 168.8, 195.9. HRMS (FAB ): calcd. for C H NO
[M+H] , m/z 430.1576; found for [M+H] , m/z 430.1610.
arom
26 24
5
13
+
+
.99 (m, 1H, Harom). C NMR (100 MHz, CDCl ) δ: 42.2, 44.1,
3
5.3, 55.8, 114.1 (2C), 122.9, 123.9, 128.1 (2C), 128.5, 128.8
4
.2.17. 2-(4-Methoxybenzyl)-3-(2-oxo-2-(pyridin-4-yl)ethyl)-
(2C), 129.2, 129.4 (2C), 131.8, 132.0, 133.7, 136.2, 146.0, 159.0,
1
+
+
isoindolin-1-one (4q). Yellow oil, 80% yield. H NMR (500
MHz, CDCl ) δ: 3.13 (dd, J = 17.9, 5.7 Hz, 1H, CH CO), 3.43
dd, J = 17.8, 5.3 Hz, 1H, CH CO), 3.68 (s, 3H, CH O), 4.65 (AB
1
3
68.5, 197.2. HRMS (FAB ): calcd. for C H NO [M+H] , m/z
24 22 3
+
3
2
72.1521; found for [M+H] , m/z 372.1598.
(
2
3
4
.2.13. 2-(4-Methoxybenzyl)-3-(2-oxo-(4-methoxyphenyl)ethyl)-
system, J = 15.3 Hz, 1H, CH PMP), 4.81 (AB system, J = 15.2
2
1
isoindolin-1-one (4m). Yellow oil, 95% yield. H NMR (500
MHz, CDCl ) δ: 3.08 (dd, J = 17.2, 7.1 Hz, 1H, CH CO), 3.42
Hz, 1H, CH PMP), 5.22-5.26 (m, 1H, CHN), 6.69 (AAꞌBBꞌ, J =
2
7.9 Hz, 2H, Harom), 7.13 (AAꞌBBꞌ, J = 7.8 Hz, 2H, Harom), 7.36 (d,
3
2
(
3
dd, J = 17.2, 5.5 Hz, 1H, CH CO), 3.71 (s, 3H, CH O), 3.86 (s,
J = 5.9, 1H, H ), 7.47-7.52 (m, 4H, Harom) 7.91 (d, J = 6.1, 1H,
H ), 8.75 (d, J = 3.7, 2H, H ). C NMR (125 MHz, CDCl ) δ:
py py 3
2
3
py
13
H, CH O), 4.45 (AB system, J = 15.2 Hz, 1H, CH PMP), 4.99
3
2
(
AB system, J = 15.2 Hz, 1H, CH PMP), 5.21-5.23 (m, 1H,
42.6, 44.1, 55.2, 55.7, 114.2 (2C), 120.8 (2C), 122.5, 124.1,
128.7, 129.0 (2C), 129.3, 131.9, 132.0, 141.8, 145.4, 151.0 (2C),
2
CHN), 6.74 (AAꞌBBꞌ, J = 8.6 Hz, 2H, Harom), 6.89 (AAꞌBBꞌ, J =
+
8
7
8
.9 Hz, 2H, Harom), 7.18 (AAꞌBBꞌ, J = 8.6 Hz, 2H, Harom), 7.35-
.39 (m, 1H, Harom), 7.43-7.50 (m, 2H, Harom), 7.79 (AAꞌBBꞌ, J =
159.2, 168.5, 196.7. HRMS (FAB ): calcd. for C H N O
[M+H] , m/z 373.1474; found for [M+H] , m/z 373.1466.
23
21
2
3
+
+
13
.9 Hz, 2H, Harom), 7.86-7.92 (m, 1H, Harom). C NMR (125
4
.2.18. 2-(4-Methoxybenzyl)-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)-
MHz, CDCl ) δ: 41.7, 44.1, 55.2, 55.6, 56.0, 113.9 (2C), 114.1
1
3
isoindolin-1-one (4r). Yellow oil, 88% yield. H NMR (500

MHz, CDCl ) δ: 3.02 (dd, J = 16.3, 7.1 Hz, 1H, CH CO), 3.31
(500 MHz, CDCl ) δ: 2.60 (s, 1H, OH), 3.35 (dd, J = 17.3, 7.1
3
ACCE
2
PTED MANUSCRIPT
3
(
dd, J = 16.3, 5.7 Hz, 1H, CH CO), 3.73 (s, 3H, CH O), 4.33 (AB
Hz, 1H, CH CO), 3.70 (dd, J = 17.3, 6.0 Hz, 1H, CH CO), 6.16-
2
3
2
2
system, J = 15.3 Hz, 1H, CH PMP), 5.10 (AB system, J = 15.3
6.19 (m, 1H, CH-O), 6.88 (AAꞌBBꞌ, J = 8.8 Hz, 2H, Harom), 7.54-
7.58 (m, 2H, Harom), 7.70-7.66 (m, 1H, Harom), 7.86 (AAꞌBBꞌ, J =
8.8 Hz, 2H, Harom), 7.92 (d, J = 7.7 Hz, 1H, Harom). C NMR
2
Hz, 1H, CH PMP), 5.12 (dd, J = 7.1, 5.7 Hz, 1H, CHN), 6.21-
2
1
3
6
.23 (m, 1H, Hpyrrole), 6.70-6.71 (m, 1H, Hpyrrole), 6.76 (AAꞌBBꞌ, J
=
8.7 Hz, 2H, Harom), 7.05-7.06 (m, 1H, Hpyrrole), 7.18 (AAꞌBBꞌ, J
(125 MHz, CDCl ) δ: 43.1, 77.8, 115.6 (2C), 122.9, 125.7, 125.8,
3
=
8.7 Hz, 2H, Harom), 7.30-7.38 (m, 1H, Harom), 7.41-7.49 (m, 2H,
128.4, 129.5, 130.9 (2C), 134.5, 150.0, 162.5, 170.9, 194.7.
13
+
+
Harom), 7.82-7.93 (m, 1H, Harom), 10.06 (s, 1H, NHpyrrole).
NMR (125 MHz, CDCl ) δ: 41.1, 43.9, 55.3, 55.9, 111.1, 114.1
C
HRMS (FAB ): calcd. for C H O [M+H] , m/z 269.0736;
16 13 4
+
found for [M+H] , m/z 269.0849.
3
(
1
2C), 117.4, 122.7, 123.9, 126.0, 128.4, 129.2, 129.4 (2C), 131.6,
+
4.2.24. 3-(2-Oxo-(4-N-acetylphenyl)ethyl)isobenzofuran-1(3H)-
one (5e). White solid, 73% yield, M.p. = 187-189 ºC. H NMR
31.7, 131.9, 145.7, 159.0, 168.5, 186.7. HRMS (FAB ): calcd.
1
+
+
for C H N O [M+H] , m/z 361.1464; found for [M+H] , m/z
3
22
21
2
3
(
500 MHz, DMSO-d ) δ: 2.07 (s, 3H, CH ), 3.65 (dd, J = 17.8,
6
3
61.1565.
8
.0 Hz, 1H, CH CO), 3.74 (dd, J = 17.8, 8.0 Hz, 1H, CH CO),
2 2
4
.2.19. 2-Cyclohexylmethyl-3-(2-oxophenylethyl)isoindolin-1-one
6.08-6.11 (m, 1H, CH-O), 7.60 (t, J = 7.4 Hz, 1H, Harom), 7.70
(AAꞌBBꞌ, J = 8.8 Hz, 2H, Harom), 7.72 (s, 1H, Harom), 7.77 (t, J =
7.2 Hz, 1H, Harom), 7.84 (d, J = 7.6 Hz, 1H, Harom), 7.95 (AAꞌBBꞌ,
1
(4s). White solid, 63% yield, M.p. = 99-101 ºC. H NMR (400
MHz, CDCl ) δ: 0.83-1.32 (m, 4H, CH ), 1.45-1.88 (m, 6H,
CH ), 1.88-2.01 (m, 1H, CH), 2.90 (dd, J = 14.1, 5.4 Hz, 1H,
3
2
13
J = 8.8 Hz, 2H, Harom), 10.30 (s, 1H, NH). C NMR (125 MHz,
2
CH N), 3.21 (dd, J = 17.6, 7.6 Hz, 1H, CH CO), 3.54 (dd, J =
CDCl ) δ: 24.5, 42.4, 77.3, 118.2 (2C), 122.9, 124.9, 125.5,
2
2
3
1
7.6, 5.0 Hz, 1H, CH CO), 3.88 (dd, J = 14.1, 9.6 Hz, 1H,
129.3, 129.6 (2C), 130.8, 134.3, 144.0, 150.0, 169.1, 169.9,
2
+
+
CH N), 5.33 (dd, J = 7.6, 5.0 Hz, 1H, CHN), 7.35-7.55 (m, 5H,
Harom), 7.59-7.63 (m, 1H, Harom), 7.79-7.91 (m, 1H, Harom), 7.96
194.9. HRMS (FAB ): calcd. for C H NO [M+H] , m/z
18 16 4
+
2
310.1001; found for [M+H] , m/z 310.1102.
13
(d, J = 7.3 Hz, 2H, Harom). C NMR (100 MHz, CDCl ) δ: 25.7,
3
2
5.9, 26.4, 30.5, 31.2, 36.7, 41.9, 46.3, 55.8, 122.9, 123.8, 128.2
Acknowledgemets
(
1
3
2C), 128.5, 129.0 (2C), 131.6, 132.0, 133.9, 136.5, 145.8, 168.5,
+
+
97.6. HRMS (FAB ): calcd. for C H NO [M+H] , m/z
We gratefully acknowledge CONACyT of Mexico for
financial support via Projects 248868. APC thanks PRODEP for
the postdoctoral fellowship 103.5/16/14605 and MBM also
thanks CONACyT for the Graduate Scholarship 339697. We also
thank Victoria Labastida for her valuable technical support in
obtaining MS spectra.
2
3
26
2
+
48.1885; found for [M+H] , m/z 348.1897.
4
.2.20. 2-Propenyl-3-(2-oxophenylethyl)isoindolin-1-one (4t).
1
Yellow oil, 68% yield. H NMR (400 MHz, CDCl ) δ: 3.24 (dd, J
=
CH CO), 3.92 (dd, J = 15.9, 6.3 Hz, 1H, CH N), 4.52 (dd, J =
3
17.7, 7.5 Hz, 1H, CH CO), 3.59 (dd, J = 17.6, 5.4 Hz, 1H,
2
2
2
1
5.9, 5.2 Hz, 1H, CH N), 5.12-5.22 (m, 2H, CH =CH), 5.34 (dd,
Supplementary data
2
2
J = 7.5, 5.4 Hz, 1H, CHN), 5.79-5.89 (m, 1H, CH =CH), 7.38-
2
Supplementary data related to this article can be found online.
7
1
.54 (m, 5H, Harom), 7.58-7.62 (m, 1H, Harom), 7.85 (d, J = 7.3 Hz,
H, Harom), 7.95 (d, J = 7.4 Hz, 2H, Harom). C NMR (100 MHz,
13
CDCl ) δ: 42.0, 43.4, 55.9, 117.8, 122.9, 123.7, 128.1 (2C),
3
1
1
2
28.4, 128.8 (2C), 131.8, 133.1, 133.8, 136.4, 136.5, 145.9,
+
+
68.2, 197.2. HRMS (FAB ): calcd. for C H NO [M+H] , m/z
1
9
18
2
+
92.1259; found for [M+H] , m/z 292.1339.
4
.2.21. 2-(2,2-Dimethoxyethyl)-3-(2-oxophenylethyl)isoindolin-1-
1
one (4u). White solid, 91% yield, M.p. = 95-97 °C. H NMR (500
MHz, CDCl ) δ: 3.19 (dd, J = 17.6, 7.9 Hz, 1H, CH CO), 3.34 (s,
3
2
3
H, MeO), 3.36 (d, J = 14.5, 5.2 Hz, 1H, CH N), 3.39 (s, 3H,
2
MeO), 3.73 (dd, J = 17.6, 4.7 Hz, 1H, CH CO), 4.07 (dd, J =
2
1
4.5, 5.2 Hz, 1H, CH N), 4.63 (dd, J = 5.2 Hz, 1H, CH-O), 5.43
2
(dd, J = 7.9, 4.7 Hz, 1H, CHN), 7.43-7.51 (m, 5H, Harom), 7.58-
7
8
4
1
.61 (m, 1H, Harom), 7.85 (d, J = 7.3 Hz, 1H, Harom), 7.96 (d, J =
13
.3 Hz, 2H, Harom). C NMR (125 MHz, CDCl ) δ: 41.8 (CH N),
3
2
3.0, 54.6, 55.0, 57.0, 102.9, 123.0, 123.7, 128.2, 128.4 (2C),
28.8 (2C), 131.6, 131.9, 133.7, 136.6, 146.3, 168.8, 197.4.
+
+
HRMS (FAB ): calcd. for C H NO [M+H] , m/z 340.1471;
found for [M+H] , m/z 340.1556.
20
22
4
+
4
.2.22. Typical procedure for the one-pot synthesis of 3-
substituted isobenzofuran-1-ones 5a-j.
A mixture of 2-formylbenzoic acid (1 mmol) and ketone or
(1.0 mmol) was stirred for 5.0 min at room temperature, followed
by the addition of PhB(OH) (0.1 mmol). After this time, the
2
o
reaction mixture was stirred at 135 C for the appropriate time
and the progress of the reaction was checked by TLC. After
completion, the mixture was cooled at room temperature and the
crude product was purified by flash column chromatography
using hexane-AcOEt as eluent, to give the pure products 5a-j.
4
.2.23. 3-(2-Oxo-(4-hydroxyphenyl)ethyl)isobenzofuran-1(3H)-
1
one (5c). White solid, 56% yield, M.p. = 184-186 ºC. H NMR

8
Tetrahedron
ACCEPTED MANUSCRIPT
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