Practical synthesis of 3-(2-arylethylidene)isoindolin-1-ones (analogues of AKS-182) and 3-(2-arylethylidene)isobenzofuran-1(3H)-ones

Article abstract of DOI:10.1016/j.tet.2019.130838

A simple and practical method is reported for the synthesis of 3-(2-arylethylidene)isoindolin-1-ones and 3-(2-arylethylidene)isobenzofuran-1(3H)-ones, proceeding with good to excellent yields and (E:Z) selectivity. This methodology involves the sequential reduction-dehydration reaction of readily obtained 3-(2-oxo-2-arylethyl)isoindolin-1-ones and 3-(2-oxo-2-arylethyl)isobenzofuran-1(3H)-ones followed by a base-catalyzed double bond isomerization with K₂CO₃ in acetonitrile. The development of a concise synthesis of AKS-182 has been achieved using this methodology.

Full text of DOI:10.1016/j.tet.2019.130838

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Practical synthesis of 3-(2-arylethylidene)isoindolin-1-ones (analogues of AKS-182)
and 3-(2-arylethylidene)isobenzofuran-1(3H)-ones
Mario Ordóñez, Angel Palillero-Cisneros, Victoria Labastida-Galván, Joel Luis Terán-
Vázquez
PII:
S0040-4020(19)31246-3
https://doi.org/10.1016/j.tet.2019.130838
TET 130838
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 August 2019
Revised Date: 22 November 2019
Accepted Date: 26 November 2019
Please cite this article as: Ordóñez M, Palillero-Cisneros A, Labastida-Galván V, Terán-Vázquez
JL, Practical synthesis of 3-(2-arylethylidene)isoindolin-1-ones (analogues of AKS-182) and 3-
(2-arylethylidene)isobenzofuran-1(3H)-ones, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.130838.
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Graphical Abstract.
Practical synthesis of 3-(2-arylethylidene)isoindolin-1-
ones (analogues of AKS-182) and 3-(2-arylethylidene)-
isobenzofuran-1(3H)-ones
Mario Ordóñez*, Angel Palillero-Cisneros, Victoria Labastida-Galván and Joel Luis Terán-Vázquez

Tetrahedron
journal homepage: www.elsevier.com
Practical synthesis of 3-(2-arylethylidene)isoindolin-1-ones (analogues of AKS-182)
and 3-(2-arylethylidene)isobenzofuran-1(3H)-ones
Mario Ordóñez*a, Angel Palillero-Cisnerosa, Victoria Labastida-Galvána and Joel Luis Terán-Vázquezb
aCentro de Investigaciones Químicas−IICBA, Universidad Autónoma del Estado de Morelos. Av. Universidad 1001, 62209 Cuernavaca, Morelos,
Mexico.
bCentro de Química−Instituto de Ciencias Edificio IC9 Benemérita Universidad Autónoma de Puebla Complejo de Ciencias, C.U.,72570 Puebla,
Pue. (México)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and practical method is reported for the synthesis of 3-(2-aryl-ethylidene)isoindolin-1-ones
and 3-(2-arylethylidene)isobenzofuran-1(3H)-ones, proceeding with good to excellent yields and
(E:Z) selectivity. This methodology involves the sequential reduction-dehydration reaction of readily
obtained 3-(2-oxo-2-arylethyl)isoindolin-1-ones and 3-(2-oxo-2-arylethyl)isobenzofuran-1(3H)-ones
followed by a base-catalyzed double bond isomerization with K2CO3 in acetonitrile. The development
of a concise synthesis of AKS-182 has been achieved using this methodology.
Available online
We dedicate this paper to Professor Stephen Davies
in recognition of his contributions to stereoselective
synthesis
©2019 Elsevier Ltd. All rights reserved
Keywords:
AKS-182 analogues
.
3-(Arylethylidene)isoindolin-1-ones
3-(Arylethylidene)isobenzofuran-1(3H)-ones
Reduction-dehydration
Base-catalyzed double bond isomerization
1. Introduction
phenylethyl-idene)isoindolin-1-ones AKS-186, AKS-182 and 4a,
only three methods have been reported in the literature; (a) the
The 3-substituted isoindolin-1-ones are important compounds
in organic and medicinal chemistry. They are present in
numerous bioactive natural products and are also key
intermediates in the preparation of numerous functionalized
derivatives. For example, the 3-(2-phenylethylidene)isoindolin-1-
one derivatives AKS-186 and AKS-182 inhibit vasoconstriction
induced by thromboxane A2 (TXA2).1 Additionally,
isobenzofuran-1(3H)-ones (also known as phthalides) such as (Z)-
3-butylideneisobenzofuran-1(3H)-one [(Z)-butylidenephthalide]
Wittig-Horner reaction of 3-diphenylphosphynylisoindolin-1-one 1
with phenyl-acetaldehyde,3 (b) the nucleophilic addition of
phenethylmagnesium bromide to phthalimide 2 followed by
dehydration,1 and (c) the photodecarboxylative cyclization
reaction of phthalimide derivative 3 with the potassium salt of 3-
phenylpropanoic acid4 (Scheme 1).
and
(Z)-3-iso-butylideneisobenzo-furan-1(3H)-one
[(Z)-iso-
butylidenephthalide], have been found in natural products
exhibiting several pharmacological activities and are also
versatile building blocks2 (Fig. 1).
Despite the high pharmacological potential of 3-(2-arylethyl-
idene)isoindolin-1-ones and 3-(2-arylethylidene)isobenzofuran-
1(3H)-ones, the synthesis of these compounds have not been
widely explored. Specifically, for the synthesis of 3-(2-
* Corresponding autor. Tel.: +52 7773297997; e-mail: palacios@uaem.mx
(http://www.ciq.uaem.mx/ nosotros/jose-mario-ordonez-palacios/)
Supporting information for this article is given via a link at the end of the
document.

2
Tetrahedron
Figure 1. Structures of AKS-182, AKS-186 and representative
butylidenephthalides.
Scheme 1. Synthesis of 3-(2-phenylethylidene)isoindolin-1-ones.
Scheme 2. Synthesis of 3-(2-phenylethylidene)isobenzofuran-1(3H)-one 6a.
In a similar way, only two methods have been reported for
the synthesis of 3-(2-phenylethylidene)isobenzofuran-1(3H)-one
6a: (a) the copper-catalyzed coupling reaction of 2-iodobenzoic
acid with benzylacetylene,5 and (b) the cyclocarbonylation
reaction of 2-triflyloxyacetophenone derivative 5 with carbon
monoxide catalyzed by palladium(II) acetate and 1,3-
bis(diphenylphosphino)-propane (dppp)6 (Scheme 2).
Scheme 3. Synthesis of 3-(2-oxo-2-arylethyl)isoindolin-1-ones 7a-h.
With the required 3-(2-oxo-2-arylethyl)isoindolin-1-ones 7a-
h in hand, we turned our attention to the sequential reduction-
dehydration reaction to obtain the corresponding 3-
styrylisoindolin-1-ones 9a-h. Chemoselective reduction of the
ketone group in 3-(2-oxo-2-phenylethyl)isoindolin-1-one 7a with
sodium borohydride in a tetrahydrofuran-methanol solution at 0
oC, gave 2-benzyl-3-(2-hydroxy-2-phenylethyl)isoindolin-1-one
8a, which without further purification was reacted with 20 mol%
Due to the high pharmacological potential of 3-(2-aryl-
ethylidene)isoindolin-1-ones and 3-(2-arylethylidene)isobenzo-
furan-1(3H)-ones, and in connection with our current research
interest in the synthesis of 2,3-disubstituted isoindolin-1-ones,7
herein we describe a practical method for the synthesis of these
compounds. Our synthetic strategy involves the sequential
reduction-dehydration reaction of 3-(2-oxo-2-arylethyl)isoindol-
in-1-ones and 3-(2-oxo-2-arylethyl)isobenzofuran-1(3H)-ones
followed by double bond isomerization with K2CO3 in
acetonitrile.
BF3 OEt2 in dichloromethane at room temperature, giving (E)-2-
•
benzyl-3-styrylisoindolin-1-one 9a in 60% yield after 4.0 h
(Table 1, entry 1). In order to improve the yield, the dehydration
reaction of 8a was carried out with 20 mol% p-toluenesulfonic
acid (PTSA) in dichloromethane at room temperature, to give the
target compound 9a in 62% yield after 8.0 h (Table 1, entry 2).8
In the next experiment, compound 8a was reacted with PTSA in
2. Results and Discussion
For the synthesis of 3-(2-arylethylidene)isoindolin-1-ones 4a-
g, AKS-182 and 3-(2-arylethylidene)isobenzofuran-1(3H)-ones
6a-c, our strategy began with the preparation of 3-(2-oxo-2-
arylethyl)isoindolin-1-ones 7a-h and 3-(2-oxo-2-arylethyl)iso
benzofuran-1(3H)-ones 11a-c, which were obtained via the
PhB(OH)2-catalyzed Mannich-lactamization sequence reaction of
2-formylbenzoic acid with benzylamine or p-methoxybenzyl-
amine and aryl methyl ketones, and by the one-pot aldol-
lactonization cascade reaction of 2-formylbenzoic acid with aryl
methyl ketones under solvent free-conditions, according to our
recent publication (Scheme 3).7a
o
benzene at 50 C, to obtain the desired (E)-3-styrylisoindolin-1-
one 9a in 80% yield after 12.0 h (Table 1, entry 3). In order to find
the optimum temperature, the reaction of 8a was performed with
o
PTSA in benzene at 100 C; under these conditions the yield of
the desired (E)-3-styrylisoindolin-1-one 9a increased to 85%
(Table 1, entry 4). The dehydration reaction of 8a with PTSA in
o
toluene at 105 C, gave (E)-3-styrylisoindolin-1-one 9a in 88%
yield in only 4.0 h (Table 1, entry 5). Finally, when the
dehydration reaction of 8a was carried with 10 mol% PTSA in

o
toluene at 105 C, the target compound 9a was obtained in 85%
When 3-(2-oxo-2-arylethyl)isoindolin-1-ones containing an
OH group in the para-position were used, protection was
necessary. Thus, the reaction of 3-(2-oxo-2-arylethyl)isoindolin-
1-ones 7g,h with anhydride acetic in dichloromethane at room
temperature, produced the acetylated products 10a,b in excellent
yields, which upon reduction with NaBH4 in a tetrahydrofuran-
methanol mixture at 0 oC followed by dehydration with 20 mol%
yield but a longer reaction time was required (Table 1, entry 6).
Table 1. Optimization for the synthesis of (E)-2-benzyl-3-styrylisoindolin-1-
one 9a.
o
PTSA in toluene at 105 C, provided the (E)-3-styrylisoindolin-1-
one derivatives 9g,h in 81% and 77% yield, respectively (Scheme
5).
Entry Catalyst
Solvent
Conditions
Yield 9a (%)a
1
2
3
4
5
6
BF3.OEt2 CH2Cl2 25 oC, 4.0 h
60
62
80
85
88
85
PTSA
PPTS
PTSA
PTSA
PTSAb
CH2Cl2 25 oC, 8.0 h
PhH
50 oC, 12.0 h
100 oC, 8.0 h
105 oC, 4.0 h
105 oC, 7.0 h
PhH
PhMe
PhMe
a Isolated yield after chromatographic purification.
b 10 mol% of PTSA was used.
With the optimized sequential reduction-dehydration reaction
conditions established (Table 1), the scope and generality of this
method for the synthesis of several (E)-3-styrylisoindolin-1-ones
derivatives was investigated. Thus, the sequential reduction-
dehydration reaction was tested with 2-benzyl-3-(2-oxo-2-
arylethyl)isoindolin-1-ones 7b,c and 2-p-methoxybenzyl-3-(2-
oxo-2-arylethyl)isoindolin-1-ones 7d-f, containing methylene
aryl ketones bearing para-electron donating substituents. In all
cases, the reaction proceeded efficiently affording the target (E)-
3-styryl-isoindolin-1-one derivatives 9b-f in 72-92% yield
(Scheme 4).
Scheme 5. Synthesis of (E)-3-styrylisoindolin-1-one derivatives 9g,h.
With the optimized sequential reduction-dehydration reaction
conditions in hand for the preparation of (E)-3-styrylisoindolin-1-
ones 9a-h, we next investigated the scope and potential of this
method for the synthesis of (E)-3-styrylisobenzofuran-1(3H)-
ones. For this purpose, we carried out the reduction of 3-(2-oxo-
2-arylethyl)isobenzofuran-1(3H)-ones 11a-c with NaBH4 in a
tetrahydrofuran-methanol mixture at 0 oC followed by the
o
dehydration reaction with 20 mol% PTSA in toluene at 105 C,
obtaining the corresponding (E)-3-styrylisobenzofuran-1(3H)-
one derivatives 12a-c in 72-80% yield (Scheme 6).10
Scheme 4. Scope of the synthesis of (E)-3-styrylisoindolin-1-ones 9b-f.9
Scheme 6. Synthesis of (E)-3-styrylisobenzofuran-1(3H)-ones 12a-d.

4
Tetrahedron
In order to obtain the target compound AKS-182 and
double bound isomerization in (E)-3-styrylisoindolin-1-ones and
(E)-3-styrylisobenzofuran-1(3H)-ones using K2CO3 as a base, is
an excellent method for the preparation of several 3-(2-aryl-
ethylydene)isoindolin-1-ones, AKS-182 analogues and 3-(2-
arylethylydene)isobenzofuran-1(3H)-ones in good yield and
(E:Z) selectivity.
analogues, we next investigated the possibility to induce double
bond isomerization in (E)-3-styrylisoindolin-1-ones 9a-h. To
prove the viability of double bond isomerization, we first
examined the reaction of (E)-3-styrylisoindolin-1-one 9a with
strong bases such as n-BuLi, sec-BuLi, t-BuOK and NaH in dry
tetrahydrofuran at different temperatures; however, after several
attempts, the desired product was not obtained (Table 2, entries
1-6). However, the reaction of (E)-3-styrylisoindolin-1-one 9a
with K2CO3 in acetonitrile at reflux, produced the desired 2-
benzyl-3-(2-phenylethylydene)isoindolin-1-one 4a in 84% yield
with a 86:14 (E:Z) selectivity, which was determined directly
from the 1H NMR spectra of the crude reaction mixture (Table 2,
entry 7). Other bases such as DBU, Et3N and K2CO3/DBU did
not give satisfactory results.
Table 2. Optimization for the synthesis of (E/Z)-2-benzyl-3-(2-phenyl-
ethylydene)isoindolin-1-one 4a.
Entry
Base/Solvent
Temp./Time
Yield 4a
(E:Z) ratio
(%)a
1
2
3
4
5
6
6
7
n-BuLi/THF
n-BuLi/THF
s-BuLi/THF
s-BuLi/THF
t-BuOK/THF
NaH/THF
-78 oC, 1.0 h
0 oC, 1.0 h
-78 oC, 3.0 h
0 oC, 1.0 h
25 oC, 1.0 h
25 oC, 3.0 h
70 oC, 1.0 h
-
-
-
-
-
-
-
-
-
-
-
-
-
NaH/THF
K2CO3/MeCN 70 oC, 6.0 h
-
84
86:14
a Isolated yield after chromatographic purification.
The stereochemistry assignment for (E)-4a was assigned by
1H NMR spectroscopy according to our recently published
results,7b,11 and confirmed by comparison with spectroscopic data
reported in the literature.1,3,4 Additionally, X-ray crystallographic
analysis permitted us to unambiguously assign it as the (E)-
isomer.12
After optimization of the experimental conditions for the
double bond isomerization in (E)-3-styrylisoindolin-1-one 9a, we
extended this protocol to (E)-3-styrylisoindolin-1-ones 9b-h,
obtaining our target 3-(2-arylethylydene)-isoindolin-1-ones 4b-g
and AKS-182 in 55-80% yield and good (E:Z) selectivity, with
the E isomer as the major product (Scheme 7).
Scheme 7. Synthesis of 3-(2-arylethylydene)isoindolin-1-ones 4b-g and
AKS-182.
4. Experimental Section
4.1 General Methods
Finally, the double bond isomerization in (E)-3-styryl-
isobenzo-furan-1(3H)-ones 12a-c with K2CO3 CH3CN at reflux,
gave the target compounds 3-(2-arylethylydene)isobenzofuran-
1(3H)-ones 6a-c in 64-80% and very good (Z:E) selectivity, with
the Z isomer as the major product (Scheme 8).13,14
All commercial materials were used as received unless
otherwise noted. Flash chromatography was performed with 230-
400 mesh Silica Flash 60®. Thin layer chromatography was
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 para-anisaldehyde.
Melting points were determined in a Fisher–Johns apparatus and
are uncorrected. NMR spectra were recorded on a Varian
3. Conclusion
In summary, we have developed an efficient and practical
method for the synthesis of (E)-3-styrylisoindolin-1-ones and
(E)-3-styrylisobenzofuran-1(3H)-ones through
a
sequential
reduction-dehydration reaction. Additionally, we found that the
1
instrument (400 MHz for H) or a Bruker instrument (500 MHz

1
for H) and calibrated using the TMS and the residual solvent
7.46-7.52 (m, 2H, Harom), 7.78-8.01 (m, 1H, Harom). 13C NMR
(125 MHz, CDCl3) δ: 44.2 (CH2), 62.7 (CH3), 123.3, 124.0,
126.5, 127.6, 128.0 (2C), 128.5 (2C), 128.8, 128.9 (2C), 131.9,
134.3 82C), 134.6, 137.4, 144.4, 168.2 (C=O). HRMS (FAB+):
calcd. for C24H22NO [M+H]+, m/z 341.1701; found for [M+H]+,
m/z 341.1720.
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.
4.2.4. (E)-2-(4-Methoxybenzyl)-3-styrylisoindolin-1-one (9d).
1
Yellow oil, 72% yield. H NMR (500 MHz, CDCl3) δ: 3.78 (s,
3H, CH3O), 4.16 (AB system, J = 14.8 Hz, 1H, CH2), 4.89 (d, J =
9.3 Hz, 1H, CHN), 5.26 (AB system, J = 14.8 Hz, 1H, CH2), 5.81
(dd, J = 15.7, 9.3 Hz, 1H, CH=CH), 6.77 (d, J = 15.7 Hz, 1H,
CH=CH), 6.84 (AAꞌBBꞌ, J = 8.7 Hz, 2H, Harom), 7.23 (AAꞌBBꞌ, J
= 8.7 Hz, 2H, Harom), 7.29-7.40 (m, 6H, Harom), 7.46-7.53 (m, 2H,
H
arom), 7.89-7.92 (m, 1H, Harom). 13C NMR (125 MHz, CDCl3) δ:
43.6 (CH2), 55.4 (CH3O), 62.7 (CHN), 114.16 (2C), 123.3, 123.8,
125.7 (2C), 126.8, 128.5, 128.6, 128.8 (2C), 129.5 (2C), 130.0,
131.8, 132.0, 135.8, 135.9, 144.6, 159.0, 168.1 (C=O). HRMS
(FAB+): calcd. for C24H22NO2 [M+H]+, m/z 356.1651; found for
[M+H]+, m/z 356.1676.
4.2.5. (E)-2-(4-Methoxybenzyl)-3-(4-methoxystyryl)isoindolin-1-
1
one (9e). Yellow oil, 75% yield. H NMR (500 MHz, CDCl3) δ:
3.77 (s, 3H, CH3O), 3.81 (s, 3H, CH3O), 4.16 (AB system, J =
14.8 Hz, 1H, CH2), 4.86 (d, J = 9.2 Hz, 1H, CHN), 5.24 (AB
system, J = 14.8 Hz, 1H, CH2), 5.64 (dd, J = 15.7, 9.2 Hz, 1H,
CH=CH), 6.70 (d, J = 15.7 Hz, 1H, CH=CH), 6.83 (AAꞌBBꞌ, J =
8.7 Hz, 2H, Harom), 6.88 (AAꞌBBꞌ, J = 8.8 Hz, 2H, Harom), 7.22
(AAꞌBBꞌ, J = 8.6 Hz, 2H, Harom), 7.31 (AAꞌBBꞌ, J = 8.7 Hz, 2H,
Harom), 7.33-7.35 (m, 1H, Harom), 7.44-7.52 (m, 2H, Harom) 7.88-
7.89 (m, 1H, Harom). 13C NMR (125 MHz, CDCl3) δ: 43.5 (CH2),
55.4 (2 CH3O), 62.7 (CHN), 114.1 (2C), 114.2 (2C), 123.3,
123.4, 123.7, 128.0 (2C), 128.5, 128.8, 129.6, 129.8 (2C), 131.7,
131.9, 135.4, 144.8, 159.0, 159.8, 168.0 (C=O). HRMS (FAB+):
calcd. for C25H24NO3 [M+H]+, m/z 386.1756; found for [M+H]+,
m/z 386.1734.
Scheme 8. Synthesis of 3-(2-arylethylydene)isobenzofuran-1(3H)-ones 6a-c.
4.2. Experimental details and characterization data
4.2.1. Typical procedure for the synthesis of (E)-3-styrylisoindolin-
1-ones derivatives (9a-h) and (E)-3-styrylisobenzofuran-1(3H)-
ones (12a-c). To a solution of 3-(2-oxo-2-arylethyl)isoindolin-1-
ones 7a-h (1 mmol) or 3-(2-oxo-2-arylethyl)isobenzofuran-
1(3H)-ones 11a-c in tetrahydrofuran-methanol (7:3) (10 mL),
o
was added NaBH4 (1.2 mmol) and stirred for 20 min at 0 C.
After completion of the reaction, the mixture was warmed to
room temperature and quenched with NH4Cl solution, stirred for
5 min at room temperature and extracted with ethyl acetate (3 x
10 mL). The combined organic layers were washed with water
(20 mL), dried over anhydrous Na2SO4 and evaporated in vacuo.
PTSA (0.2 mmol) was added to the crude product in toluene (15
4.2.6. (E)-2-(4-Methoxybenzyl)-3-(4-methylstyryl)isoindolin-1-one
1
(9f). Yellow oil, 77% yield. H NMR (500 MHz, CDCl3) δ: 2.36
(s, 3H, CH3), 3.78 (s, 3H, CH3O), 4.15 (AB system, J = 14.8 Hz,
1H, CH2), 4.87 (d, J = 9.3 Hz, 1H, CHN), 5.26 (AB system, J =
14.8 Hz, 1H, CH2), 5.74 (dd, J = 15.7, 9.3 Hz, 1H, CH=CH), 6.74
(d, J = 15.7 Hz, 1H, CH=CH), 6.84 (AAꞌBBꞌ, J = 8.7 Hz, 2H,
Harom), 7.16 (AAꞌBBꞌ, J = 7.9 Hz, 2H, Harom), 7.22 (AAꞌBBꞌ, J =
8.7 Hz, 2H, Harom), 7.28 (AAꞌBBꞌ, J = 8.1 Hz, 2H, Harom), 7.33
(AAꞌBBꞌ, J = 8.1 Hz, 2H, Harom), 7.46-7.53 (m, 1H, Harom) 7.88-
7.90 (m, 1H, Harom). 13C NMR (125 MHz, CDCl3) δ: 21.2 (CH3),
43.5 (CH2), 55.4 (CH3O), 62.9 (CHN), 113.9 (2C), 123.3, 123.8,
124.5, 126.7 (2C), 128.6, 129.5 (2C), 129.6, 129.9 (2C), 131.7,
133.0, 135.9, 138.6, 144.5, 159.0, 158.6, 167.9 (C=O). HRMS
(FAB+): calcd. for C25H24NO2 [M+H]+, m/z 370.1807; found for
[M+H]+, m/z 370.1810.
o
mL) and stirred at 105 C. After completion of the reaction, the
mixture was cooled to room temperature, the solvent was
evaporated and the resulting crude product was purified by flash
column chromatography using hexane-ethyl acetate mixture as
eluent, to give the pure products 9a-h and 12a-c. The 1H and 13
C
NMR spectroscopic data for the compounds 9a9b, 12a10 and
12c10a are identical with those described in the literature.
4.2.2. (E)-2-Benzyl-3-(4-methoxystyryl)isoindolin-1-one (9b).
1
Yellow oil, 88% yield. H NMR (400 MHz, CDCl3) δ: 3.82 (s,
3H, CH3O), 4.21 (AB system, J = 14.9 Hz, 1H, CH2), 4.87 (d, J =
9.2 Hz, 1H, CHN), 5.31 (AB system, J = 14.9 Hz, 1H, CH2), 5.65
(dd, J = 15.7, 9.2 Hz, 1H, CH=CH), 6.70 (d, J = 15.7 Hz, 1H,
CH=CH), 6.87 (AAꞌBBꞌ, J = 8.8 Hz, 2H, Harom), 7.17-7.38 (m,
8H, Harom), 7.38-7.55 (m, 2H, Harom), 7.87-8.00 (m, 1H, Harom).
13C NMR (100 MHz, CDCl3) δ: 44.1 (CH2), 55.4 (CH3O), 63.0
(CHN), 114.3 (2C), 123.2, 123.3, 123.8, 127.5, 128.0 (2C), 128.5
(2C), 128.6 (2C), 128.8 (2C), 131.7, 131.9, 135.5, 137.5, 144.9,
159.9, 168.1 (C=O). HRMS (FAB+): calcd. for C24H22NO2
[M+H]+, m/z 356.1651; found for [M+H]+, m/z 356.1620.
4.2.7. (E)-2-Benzyl-3-(4-hydroxystyryl)isoindolin-1-one (9g).
White oil, 81% yield. 1H NMR (500 MHz, CDCl3) δ: 1.45 (s, 1H,
OH), 4.23 (AB system, J = 14.9 Hz, 1H, CH2), 4.89 (d, J = 9.2
Hz, 1H, CHN), 5.31 (AB system, J = 14.9 Hz, 1H, CH2), 5.60
(dd, J = 15.7, 9.3 Hz, 1H, CH=CH), 6.69 (d, J = 15.6 Hz, 1H,
CH=CH), 6.86 (AAꞌBBꞌ, J = 8.6 Hz, 2H, Harom), 7.23 (AAꞌBBꞌ, J
= 8.6 Hz, 2H, Harom), 7.25-7.34 (m, 6H, Harom), 7.46-7.54 (m, 2H,
Harom), 7.90-7.93 (m, 1H, Harom). 13C NMR (125 MHz, CDCl3) δ:
44.2 (CH2), 63.2 (CHN), 115.8, 115.9 122.1, 123.3, 123.9, 127.7,
127.9, 128.2 (2C), 128.5 (2C), 128.7, 128.8 (2C), 131.6, 132.0,
136.1, 137.2, 144.9, 157.2, 168.6 (C=O). HRMS (FAB+): calcd.
for C23H20NO2 [M+H]+, m/z 342.1494; found for [M+H]+, m/z
342.1469.
4.2.3. (E)-2-Benzyl-3-(4-methylstyryl)isoindolin-1-one (9c).
1
Yellow oil, 92% yield. H NMR (500 MHz, CDCl3) δ: 2.36 (s,
3H, CH3), 4.21 (AB system, J = 14.9 Hz, 1H, CH2), 4.89 (d, J =
9.3 Hz, 1H, CHN), 5.32 (AB system, J = 14.8 Hz, 1H, CH2), 5.75
(dd, J = 15.6, 9.3 Hz, 1H, CH=CH), 6.73 (d, J = 15.6 Hz, 1H,
CH=CH), 7.14-7.16 (m, 2H, Harom), 7.25-7.33 (m, 8H, Harom),

6
Tetrahedron
4.2.8. (E)-2-(4-Methoxybenzyl)-3-(4-hydroxystyryl)isoindolin-1-
one (9h). Yellow oil, 77% yield. H NMR (500 MHz, CDCl3) δ:
H
H
arom), 7.63 (d, J = 7.7 Hz, 1H, Harom), 7.91 (d, J = 7.5 Hz, 1H,
arom). 13C NMR (100 MHz, CDCl3) δ: 29.7 (CH2CH), 41.6
1
1.93 (s, 1H, OH), 3.77 (s, 3H, CH3O), 4.17 (AB system, J = 14.6
Hz, 1H, CH2), 4.88 (d, J = 9.1 Hz, 1H, CHN), 5.26 (AB system, J
= 14.6 Hz, 1H, CH2), 5.60 (dd, J = 15.5, 9.1 Hz, 1H, CH=CH),
6.70 (d, J = 15.5 Hz, 1H, CH=CH), 6.82-6.91 (m, 4H, Harom),
7.02-7.37 (m, 5H, Harom), 7.37-7.56 (m, 2H, Harom), 7.89-7.93 (m,
1H, Harom). 13C NMR (125 MHz, CDCl3) δ: 43.6 (CH2), 55.0
(CH3O), 62.9 (CHN), 114.2 (2C), 115.9 (2C), 122.1, 123.8,
127.8, 128.1, 128.28 (2C), 128.7, 129.3, 129.9 (2C), 130.0,
131.6, 132.0, 136.0, 144.8, 157.0, 168.2 (C=O). HRMS (FAB+):
calcd. for C24H21NO3 [M+H]+, m/z 372.1600; found for [M+H]+,
m/z 372.1611.
(CH2Ph), 55.3 (CH3O), 114.0 (CHCH2), 123.3, 123.4, 123.7,
126.9, 127.8, 128.5 (2C), 128.6 128.7 (2C), 128.7, 128.9 (2C),
129.1, 132.1, 132.2, 134.0 (2C), 136.3, 168.1 (C=O). HRMS
(FAB+): calcd. for C24H22NO2 [M+H]+, m/z 356.1651; found for
[M+H]+, m/z 356.1593.
4.2.13. (E)-2-Benzyl-3-[2-(4-methylphenyl)ethylidene]isoindolin-1-
one (4c). White solid, Mp: 130-132 ºC, 65% yield. 1H NMR (500
MHz, CDCl3) δ: 2.29 (s, 3H, CH3), 3.88 (d, J = 7.9 Hz, 2H,
CH2CH), 5.00 (s, 2H, NCH2Ph), 5.56 (t, J = 7.9 Hz, 1H,
CHCH2), 6.97 (AAꞌBBꞌ, J = 7.8 Hz, 2H, Harom), 7.05 (AAꞌBBꞌ, J
= 7.6 Hz, 2H, Harom), 7.12-7.35 (m, 5H, Harom), 7.48 (t, J = 7.4
Hz, 1H, Harom), 7.55 (t, J = 7.5 Hz, 1H, Harom), 7.82 (d, J = 7.5
Hz, 1H, Harom), 7.94 (d, J = 7.5 Hz, 1H, Harom). 13C NMR (125
MHz, CDCl3) δ: 21.0 (CH3), 32.7 (CH2CH), 43.0 (NCH2Ph),
111.8 (CHCH2), 123.3, 123.7, 127.0 (2C), 127.3, 128.0 (2C),
128.7 (2C), 128.9, 129.3 (2C), 132.1, 134.0, 135.3, 135.4, 136.0,
136.4, 137.0, 166.6 (C=O). HRMS (FAB+): calcd. for C24H22NO
[M+H]+, m/z 340.1701; found for [M+H]+, m/z 340.1680.
4.2.9. (E)-3-(4-Methoxystyryl)isobenzofuran-1(3H)-one (12b).
1
Yellow oil, 72% yield. H NMR (500 MHz, CDCl3) δ: 3.82 (s,
3H, CH3O), 5.95-6.02 (m, 2H, CH-O and CH=CH), 6.82-6.88
(m, 2H, CH=CH and Harom), 6.87 (AAꞌBBꞌ, J = 8.8 Hz, 2H,
Harom), 7.35 (AAꞌBBꞌ, J = 8.6 Hz, 2H, Harom), 7.46 (d, J = 7.7 Hz,
1H, Harom), 7.56 (t, J = 7.5 Hz, 1H, Harom), 7.69 (t, J = 7.5 Hz, 1H,
Harom), 7.94 (d, J = 7.7 Hz, 1H, Harom). 13C NMR (125 MHz,
CDCl3) δ: 55.5 (CH3O), 82.6 (CH-O), 114.2 (2C), 121.5, 122.8,
125.8, 125.9 (2C), 128.1, 128.3, 129.5, 134.3, 135.1, 149.1,
160.1, 170.5 (C=O). HRMS (FAB+): calcd. for C17H14O3
[M+H]+, m/z 267.1021; found for [M+H]+, m/z 267.1003.
4.2.14. (E)-2-Benzyl-3-[2-(4-hydroxyphenyl)ethylidene]isoindolin-1-
1
one (4d). White oil, 72% yield, (E/Z) 90:10 ratio. H NMR (500
MHz, DMSO-d6) δ: 3.83 (d, J = 8.1 Hz, 2H, CH2CH), 5.01 (s,
2H, NCH2Ph), 5.22* (s, 2H, NCH2Ph), 5.69 (t, J = 7.9 Hz, 1H,
CHCH2), 5.89* (t, J = 7.9 Hz, 1H, CHCH2), 6.63 (d, J = 8.6 Hz,
2H, Harom), 7.72* (d, J = 8.6 Hz, 2H, Harom), 6.91 (d, J = 8.6 Hz,
2H, Harom), 7.14* (d, J = 7.2 Hz, 1H, Harom), 7.20 (d, J = 6.9 Hz,
2H, Harom), 7.21-7.26 (m, 1H, Harom), 7.28-7.32 (m, 2H, Harom),
7.55* (t, J = 7.8 Hz, 1H, Harom), 7.60 (t, J = 7.8 Hz, 1H, Harom),
7.63* (t, J = 7.8 Hz, 1H, Harom), 7.69 (t, J = 7.8 Hz, 1H, Harom),
7.81* (d, J = 6.7 Hz, 1H, Harom), 7.87 (d, J = 6.7 Hz, 1H, Harom),
7.92* (d, J = 7.9 Hz, 1H, Harom), 8.02 (d, J = 7.9 Hz, 1H, Harom),
9.29 (s, 1H, OH). 13C NMR (125 MHz, DMSO-d6) δ: 31.2
(CH2CH), 42.2 (CH2Ph), 112.6 (CHCH2), 115.3, 123.1, 123.8,
125.6, 126.8 (2C), 127.3, 128.7 (2C), 129.1 (2C), 129.3, 129.7,
129.8, 132.7, 134.0, 134.9, 137.2, 155.7, 165.6 (C=O). HRMS
(FAB+): calcd. for C23H20NO2 [M+H]+, m/z 342.1494; found for
[M+H]+, m/z 342.1484.
4.2.10. Typical Procedure for the synthesis of (E:Z)-3-(2-aryl-
ethylydene)isoindolin-1-ones (4a-g), AKS-182 and (E:Z)-3-(2-
arylethylydene)isobenzofuran-1(3H)-ones (6a-c). To a solution of
the corresponding 3-styrylisoindolin-1-one or 3-styrylisobenzo-
furan-1(3H)-one (1 mmol) in CH3CN (5 mL), K2CO3 (1 mmol)
was added, stirred for 5.0 min at room temperature and then at 80
oC. After completion of the reaction, the mixture was cooled to
room temperature then water (5 mL) and ethyl acetate (5 mL x 3)
were added. The aqueous layer was extracted with ethyl acetate
(5 mL x 3) and the combined organic layers were washed with
water and brine, dried over anhydrous Na2SO4 and evaporated in
vacuo. The resulting crude product was purified by flash column
chromatography using hexane-ethyl acetate mixture as eluent, to
give (E:Z)-3-(2-arylethylydene)isoindolin-1-ones 4a-g and (E:Z)-
3-(2-arylethylydene)isobenzofuran-1(3H)-ones 6a-c. The E:Z
1
4.2.15. (E)-2-(4-Methoxybenzyl)-3-[2-(4-methoxyphenyl)ethylidene]-
ratio was determined by H-NMR spectroscopy for the crude
1
product. The H and 13C NMR spectroscopic data for AKS-182
isoindolin-1-one (4e). Yellow solid, Mp: 119-121 ºC, 80% yield,
1
are identical with those described in the literature.1a,3
(E/Z) 85:15 ratio. H NMR asterisk denotes minor isomer (500
MHz, CDCl3) δ: 3.56* (s, 3H, CH3O), 3.57* (s, 3H, CH3O), 3.74
(s, 3H, CH3O), 3.75 (s, 3H, CH3O), 3.86 (d, J = 7.9 Hz, 2H,
CH2CH), 4.95 (s, 2H, NCH2Ph), 5.18* (s, 1 H, NCH2Ph), 5.57 (t,
J = 7.9 Hz, 1H, CHCH2), 5.70* (t, J = 8.1 Hz, 1H, CHCH2), 6.79
(d, J = 7.8 Hz, 2H, Harom), 6.80 (d, J = 7.8, Hz, 2H, Harom), 6.83*
(d, J = 8.3 Hz, 1H, Harom), 6.88* (d, J = 8.3 Hz, 1H, Harom), 7.02
(d, J = 8.5 Hz, 2H, Harom), 7.07* (d, J = 8.5 Hz, 1H, Harom), 7.15
(d, J = 8.5 Hz, 2H, Harom), 7.43-7.61* (m, 1H, Harom), 7.81 (d, J =
7.7 Hz, 1H, Harom), 7.88* (d, J = 8.5 Hz, 1H, Harom) 7.94 (d, J =
7.7 Hz, 1H, Harom). NMR 13C asterisk denotes minor isomer (125
MHz, CDCl3) δ: 31.6* (CH2CH), 32.3 (CH2CH), 42.4 (CH2Ph),
44.1* (CH2Ph), 55.2 (CH3O, 2C), 55.3* (CH3O), 107.7*
(CHCH2), 111.8 (CHCH2), 114.0, 114.14, 114.2*, 119.1, 123.3,
123.6, 127.0, 127.8, 127.9, 128.3, 128.5, 128.8, 129.1, 129.2,
129.6, 129.8, 130.5, 131.5, 131.9 (2C), 132.0, 134.0, 135.1,
135.4, 138.1, 158.2 (2C), 158.8, 166.5 (C=O), 168.3* (C=O).
HRMS (FAB+): calcd. for C24H22NO2 [M+H]+, m/z 386.1756;
found for [M+H]+, m/z 386.1728.
4.2.11. (E)-2-Benzyl-3-(2-phenylethylidene)isoindolin-1-one (4a).
White solid, Mp: 102-104 ºC, 84% yield. H NMR (400 MHz,
1
CDCl3) δ: 3.93 (d, J = 7.9 Hz, 2H, CH2CH), 5.02 (s, 2H,
NCH2Ph), 5.56 (t, J = 7.9 Hz, 1H, CHCH2), 7.03-7.14 (m, 2H,
Harom), 7.14-7.35 (m, 8H, Harom), 7.41-7.63 (m, 2H, Harom), 7.84
(d, J = 7.7 Hz, 1H, Harom), 7.96 (d, J = 7.4 Hz, 1H, Harom 13C
NMR (100 MHz, CDCl3) δ: 33.2 (CH2CH), 43.0 (CH2Ph), 111.3
(CHCH2), 123.3 (2C), 123.8 (2C), 126.9, 127.0 (2C), 127.3,
128.2 (2C), 128.7 (3C), 129.0, 130.9, 132.1, 135.5, 137.0, 139.9,
166.9 (C=O). HRMS (FAB+): calcd. for C23H20NO [M+H]+, m/z
326.1545; found for [M+H]+, m/z 326.1516.
4.2.12. (E)-2-Benzyl-3-[2-(4-methoxyphenyl)ethylidene]isoindolin-
1
1-one (4b). Yellow solid, Mp: 60-62 ºC, 68% yield. H NMR
(400 MHz, CDCl3) δ: 3.55 (d, J = 8.0 Hz, 2H, CH2CH), 3.77 (s,
3H, CH3O), 5.27 (s, 2H, NCH2Ph), 5.72 (t, J = 8.0 Hz, 1H,
CHCH2), 6.78 (AAꞌBBꞌ, J = 8.4 Hz, 2H, Harom), 6.85 (AAꞌBBꞌ, J
= 8.4 Hz, 2H, Harom) 7.16 (d, J = 7.5 Hz, 2H, Harom), 7.23-7.34 (m,
3H, Harom), 7.49 (t, J = 7.5 Hz, 1H, Harom), 7.57 (t, J = 7.5 Hz, 1H,

4.2.16. (E)-2-(4-Methoxybenzyl)-3-[2-(4-methylphenyl)ethylidene]-
isoindolin-1-one (4f). White solid, Mp: 73-75 ºC, 68% yield. H
167.2 (C=O). HRMS (FAB+): calcd. for C17H15O2 [M+H]+, m/z
251.1072; found for [M+H]+, m/z 251.1086.
1
NMR (500 MHz, CDCl3) δ: 2.31 (s, 3H, CH3), 3.77 (s, 3H,
CH3O), 3.91 (d, J = 7.9 Hz, 2H, CH2CH), 4.96 (s, 2H, NCH2Ph),
5.59 (t, J = 7.9 Hz, 1H, CHCH2), 6.82 (AAꞌBBꞌ, J = 8.7 Hz, 2H,
Acknowledgements
H
arom), 7.01 (AA'BB', J = 8.0 Hz, 2H, Harom), 7.07 (AA'BB', J =
The authors thank the CONACYT of Mexico, for their financial
support via project 286614, and S. Bernes for the measurement of
crystal structures.
7.9 Hz, 2H, Harom), 7.16 (AAꞌBBꞌ, J = 8.7 Hz, 2H, Harom), 7.50 (d,
J = 7.6 Hz, 1H, Harom), 7.56 (d, J = 7.6 Hz, 1H, Harom), 7.84 (d, J
= 7.7 Hz, 1H, Harom), 7.95 (d, J = 7.7 Hz, 1H, Harom). 13C NMR
(125 MHz, CDCl3) δ: 21.0 (CH3), 32.8 (CH2CH), 42.5 (CH2Ph),
55.4 (CH3O), 111.8 (CHCH2), 114.1, 123.4, 123.8, 128.1, 128.4
(2C), 128.9, 129.2, 129.4 (2C), 130.2, 130.6, 132.1, 134.0, 135.4,
135.6, 136.1, 136.5, 158.9, 166.6 (C=O). HRMS (FAB+): calcd.
for C25H23NO2 [M+H]+, m/z 370.1807; found for [M+H]+, m/z
370.1810.
Supplementary data
Supplementary data related to this article can be found online.
References and notes
1. (a) Kato, Y.; Takemoto, M.; Achiwa, K. Chem. Pharm. Bull. 1999, 47,
529–535; (b) Kato, Y.; Takemoto, M.; Achiwa, K. Chem. Pharm. Bull.
1993, 41, 2003–2006; (b) Kato, Y.; Ebiike, H.; Achiwa, K.; Ashizawa,
N.; Kurihara, T.; Kobayashi, F. Chem. Pharm. Bull. 1990, 38, 2060–
2062.
4.2.17. (E)-2-(4-Methoxybenzyl)-3-[2-(4-hydroxyphenyl)ethylidene]-
isoindolin-1-one (4g). Yellow solid, Mp: 160-162 ºC, 65% yield.
1H NMR (500 MHz, CDCl3) δ: 1.69 (s, 1H, OH), 3.77 (s, 3H,
CH3O), 3.87 (d, J = 7.9 Hz, 2H, CH2CH), 4.97 (s, 2H, NCH2Ph),
5.58 (t, J = 7.9 Hz, 1H, CHCH2), 6.74 (AAꞌBBꞌ, J = 8.5 Hz, 2H,
Harom), 6.81 (AAꞌBBꞌ, J = 8.5 Hz, 2H, Harom), 6.96 (AAꞌBBꞌ, J =
8.4 Hz, 2H, Harom), 7.16 (AAꞌBBꞌ, J = 8.5 Hz, 2H, Harom), 7.51 (t,
J = 7.5 Hz, 1H, Harom), 7.57 (t, J = 7.5 Hz, 1H, Harom), 7.84 (d, J =
7.5 Hz, 1H, Harom), 7.96 (d, J = 7.5 Hz, 1H, Harom). 13C NMR (125
MHz, CDCl3) δ: 31.9 (CH2CH), 42.3 (CH2Ph), 55.2 (CH3O),
114.1 (CHCH2), 114.2, 115.5, 115.8, 122.9 (2C), 123.5 (2C),
128.6 (2C), 129.0 (2C), 129.2 (2C), 129.3 (2C), 132.0 (2C),
135.0, 158.7, 166.4 (C=O). HRMS (FAB+): calcd. for C24H22NO3
[M+H]+, m/z 372.1600; found for [M+H]+, m/z 372.1574.
2. (a) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213–6284;
(b) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891–900; (c) Ljn, G.;
Chan, S. S.-K.; Chung, H.-S.; Li, S.-L. Stud. Nat. Prod. Chem. 2005, 32,
611–669.
3. Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron 1997, 53, 10313–
10330.
4. (a) Josland, S.; Mumtaz, S.; Oelgemöller, M. Chem. Eng. Technol. 2016,
39, 81–87; (b) Hatoum, F.; Engler, J.; Zelme, C.; Wißen, J.; Motti, C. A.;
Lex, J.; Oelgemöller, M. Tetrahedron Lett. 2012, 53, 5573–5577.
5. Kumar, M. R.; Irudayanathan, F. M.; Moon, J. H.; Lee, S. Adv. Synth.
Catal. 2013, 355, 3221–3230.
6. (a) Ciattini, P. G.; Mastropietro, G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1993, 34, 3763–3166; (b) Ortar, G.; Schiano, A.; Moriello, A. S.;
Morera, E.; Nalli, M.; Di Marzo, V.; De Petrocellis, L. Bioorg. Med.
Chem. Lett. 2013, 23, 5614–5618.
4.2.18. (Z)-3-(2-Phenylethylydene)isobenzofuran-1(3H)-one (6a).
White soli, Mp: 89-91 oC, 80% yield. 1H NMR (500 MHz,
CDCl3) δ: 3.81 (d, J = 7.9 Hz, 2H, CH2CH), 5.78 (t, J = 7.9 Hz,
1H, CHCH2), 7.20-7.25 (m, 1H, Harom), 7.26-7.34 (m, 4H, Harom),
7.51 (t, J = 7.8 Hz, 1H, Harom), 7.61 (d, J = 7.8 Hz, 1H, Harom),
7. (a) Palillero-Cisneros, A.; Bedolla-Medrano, M.; Ordóñez, M.
Tetrahedron 2018, 74, 4174–4181; (b) Reyes-González, M. A.; Zamudio-
Medina, A.; Ordóñez, M. Tetrahedron Lett. 2012, 53, 5756–5758; (c)
Ordóñez, M.; Tibhe, G. D.; Zamudio-Medina, A.; Viveros-Ceballos, J. L.
Synthesis 2012, 569–574; (d) Viveros-Ceballos, J. L.; Cativiela, C.;
Ordóñez, M. Tetrahedron: Asymmetry 2011, 22, 1479–1484.
8. For the dehydration of alcohols derived from isoindolin-1-ones, see:
Dhanasekaran, S.; Kayet, A.; Suneja, A.; Bisai, V.; Singh, V. K. Org.
Lett. 2015, 17, 2780−2783.
7.66 (t, J = 7.8 Hz, 1H, Harom), 7.90 (d, J = 7.8 Hz, 1H, Harom). 13
C
NMR (125 MHz, CDCl3) δ: 32.1 (CH2CH), 107.8, 119.9, 124.7,
125.4, 126.6, 128.7 (2C), 128.8 (2C), 129.7, 134.4, 139.3, 139.5,
145.8, 167.1 (C=O). HRMS (FAB+): calcd. for C16H13O2
[M+H]+, m/z 237.0916; found for [M+H]+, m/z 237.0918.
4.2.19. (Z:E)-3-[2-(4-Metoxyphenyl)ethylydene]isobenzofuran-
1(3H)-one (6b). Yellow oil, 80% yield, (Z/E) 95:05 ratio. 1H MR
asterisk denotes minor isomer (500 MHz, CDCl3) δ: 3.76 (d, J =
7.9 Hz, 2H, CH2CH), 3.79 (s, 3H, CH3O), 3.88* (d, J = 8.4 Hz,
2H, CH2CH), 5.76 (t, J = 7.9 Hz, 1H, CHCH2), 6.03* (t, J = 7.9
Hz, 1H, CHCH2), 6.86 (AAꞌBBꞌ, J = 8.7, Hz, 2H, Harom), 7.15*
(AAꞌBBꞌ, J = 8.7 Hz, 2H, Harom), 7.20 (AAꞌBBꞌ, J = 8.7 Hz, 2H,
Harom), 7.48* (d, J = 7.5 Hz, 1H, Harom), 7.53 (d, J = 7.5 Hz, 1H,
Harom), 7.59* (d, J = 7.8 Hz, 1H, Harom), 7.62 (d, J = 7.8 Hz, 1H,
Harom), 7.67 (t, J = 7.8, 1H, Harom), 7.91 (d, J = 7.8 Hz, H, Harom).
13C NMR (125 MHz, CDCl3) δ: 31.3 (CH2CH), 55.4 (CH3O),
108.3, 113.9, 114.2, 119.9, 124.6, 125.4, 129.4, 129.7 (2C),
131.3, 134.4, 139.6, 145.6, 158.3, 167.2 (C=O). HRMS (FAB+):
calcd. for C17H15O3 [M+H]+, m/z 267.1021; found for [M+H]+,
m/z 267.1005.
9. (a) Qi, C.; Gandon, V.; Lebœuf, D. Adv. Synth. Catal. 2017, 359, 2671–
2675; (b) Lu, N.; Wang, L.; Li, Z.; Zhang, W. Beilstein J. Org. Chem.
2012, 8, 192–200.
10. For the synthesis of the (E)-3-styrylisobenzofuran-1(3H)-one 12a, see:
(a) Krätzschmar, F.; Kaßel, M.; Delony, D.; Breder, A. Chem. Eur. J.
2015, 21,7030–7034; (b) Shashikumar, N. D.; Krishnamurthy, G.;
Bhojyanaik, H. S. J. Heterocyclic Chem. 2014, 51, E354–E357; (c) Lv,
G.; Huang, G.; Zhang, G.; Pan, C.; Chen, F.; Cheng, J, Tetrahedron
2011, 67, 4879-4886; (d) Ye, Z.; Lv, G.; Wang, W.; Zhang, M.; Cheng,
J. Angew. Chem. Int. Ed. 2010, 49, 3671–3674; (e) Ye, Z.; Qian, P.; Lv,
G.; Luo, F.; Cheng, J. J. Org. Chem. 2010, 75, 6043–6045; (f) Chang,
H.-T.; Jeganmohan, M.; Cheng, C.-H. Chem. Eur. J. 2007, 13, 4356–
4363; (g) Mali, R. S.; Massey, A. P. Synth. Commun. 1997, 27, 1049–
1057.
4.2.20.
(Z)-3-[2-(4-Mehylphenyl)ethylydene]isobenzofuran-
11. Reyes-González, M. Á.; Zamudio-Medina, Á.; Ramírez-Marroquín, O.
A.; Ordóñez, M. Monatsh. Chem. 2014, 145, 1001–1007.
1(3H)-one (6c). Yellow oil, 70% yield. 1H NMR (500 MHz,
CDCl3) δ: 2.32 (s, 3H, CH3), 3.78 (d, J = 7.9 Hz, 2H, CH2CH),
5.77 (t, J = 7.9 Hz, 1H, CHCH2), 7.13 (AAꞌBBꞌ, J = 7.9, Hz, 2H,
Harom), 7.18 (AAꞌBBꞌ, J = 8.0, Hz, 2H, Harom), 7.52 (t, J = 7.8 Hz,
1H, Harom), 7.61 (d, J = 7.8 Hz, 1H, Harom), 7.67 (t, J = 7.8 Hz,
1H, Harom), 7.91 (d, J = 7.8 Hz, 1H, Harom). 13C NMR (125 MHz,
CDCl3) δ: 21.7 (CH3), 31.7 (CH2CH), 108.2, 119.9, 124.7, 125.4,
128.6 (2C), 128.7, 129.5, 129.7 (2C), 134.4, 136.2, 136.3, 145.7,
12. CCDC 1961555 [for (E)-4a]; CCDC 1961556 [for (E)-4e] contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
13. For the synthesis of (Z)-3-(2-phenylethylidene)isobenzofuran-1(3H)-one
6a, see: references 5a and 6b.

8
Tetrahedron
14. CCDC 1961557 [for (E)-6a] contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.

Universidad Autónoma del Estado de Morelos
Centro de Investigaciones Químicas
October 29th, 2019
Practical synthesis of 3-(2-aryl-ethylidene)isoindolin-1-ones and 3-(2-arylethylidene)isobenzofuran-
1(3H)-ones.
Concise synthesis of AKS-182
Sequential reduction-dehydration reaction
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: