Synthesis of 3-alkylideneisoindolinones and isoindolones by a Horner-Wadsworth-Emmons reaction

Article abstract of DOI:10.1007/s00706-013-1146-9

A series of 3-alkylideneisoindolinones was prepared by a Horner-Wadsworth-Emmons (HWE) reaction of aromatic aldehydes with N-(ω-hydroxyalkyl)-substituted 3-phosphoisoindolin-1-ones, obtained in one-pot synthesis from 2-formylbenzoic acid. Additionally, the intramolecular HWE reaction of the N-(ω-formylalkyl)-substituted phosphoisoindolin-1-ones afforded the corresponding isoindolone derivatives. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1146-9

Monatsh Chem
DOI 10.1007/s00706-013-1146-9
ORIGINAL PAPER
Synthesis of 3-alkylideneisoindolinones and isoindolones
by a Horner–Wadsworth–Emmons reaction
´
Miguel Angel Reyes-Gonzalez Angel Zamudio-Medina
´
•
•
´
Oscar Abelardo Ramırez-Marroquın
•
´
´
´
Mario Ordon˜ez
Received: 26 November 2013 / Accepted: 26 December 2013
Ó Springer-Verlag Wien 2014
Abstract A series of 3-alkylideneisoindolinones was
prepared by a Horner–Wadsworth–Emmons (HWE) reac-
tion of aromatic aldehydes with N-(x-hydroxyalkyl)-
substituted 3-phosphoisoindolin-1-ones, obtained in one-
pot synthesis from 2-formylbenzoic acid. Additionally, the
intramolecular HWE reaction of the N-(x-formylalkyl)-
substituted phosphoisoindolin-1-ones afforded the corre-
sponding isoindolone derivatives.
preparation of tricyclic isoindolin-1-ones of type 3 (R = H)
has been seldom studied, and only the radical cyclization
cascadeof ynamides [25, 26] andcyclizationofN-(iodoalkyl)
cyclic imides with SmI2 [27] have been reported.
Recently, we reported a practical synthesis of N-
substituted isoindolin-1-ones [28] and 3-(arylmethyl-
ene)isoindolin-1-ones under mild reaction conditions [29].
As part of our interest in the development of practical and
efficient synthesis methods in an environmentally friendly
manner, we herein report an alternative simple route for the
synthesis of N-(x-hydroxyalkyl)-substituted 3-(arylmeth-
ylene)isoindolin-1-ones 7 and 8 and tricyclic compounds
type 3 from easily obtained dimethyl isoindolin-1-one-3-
ylphosphonates. The process involves a ‘one-pot’ three-
component reaction of 2-formylbenzoic acid [30] with the
appropriate amino alcohol and dimethyl phosphite, fol-
lowed by an intermolecular HWE reaction. Otherwise,
subsequent oxidation of the hydroxy moiety, and finally an
intramolecular HWE reaction provides the respective tri-
cyclic compounds.
Keywords Phosphonates Á Three-component reaction Á
Wittig reaction Á Heterocycles
Introduction
In recent years, the 3-methyleneisoindolin-1-ones and their
derivatives have been the subject of growing interest because
they are present in numerous natural products or are designed
aspharmaceutical compounds witha wide range ofbiological
activities. For example, AKS 186 was found to inhibit
vasoconstriction induced by a thromboxane A2 analog [1, 2],
whereas the derivatives 1 [3] and 2 [4–6] are useful inter-
mediates in the synthesis of important heterocyclic
compounds, and the isoindolin-1-ones of type 3 have attrac-
tedinterestinthefield ofmedicinal chemistry [7–10](Fig. 1).
Other isoindolin-1-ones have also shown a remarkably wide
array of biological activities [11–15]. Due to the biological
importance of 3-methyleneisoindolin-1-ones, several meth-
ods for their synthesis have been developed [16–24], but the
Results and discussion
For the synthesis of the target compounds 3, 7, and 8, our
strategy started with the preparation of dimethyl isoindolin-
1-one-3-ylphosphonates 6a–6d, which were obtained in
good yields by means of a ‘one-pot’ three-component
reaction of 2-formylbenzoic acid (4) with the correspond-
ing amino alcohol 5 and dimethyl phosphite in methanol
under microwave irradiation in an open flask (55 °C/
180 W, 10 min) [28]. Remarkably, this process did not
need any catalyst (Scheme 1).
´
´
´
M. A. Reyes-Gonzalez Á A. Zamudio-Medina Á
´
´
´
O. A. Ramırez-Marroquın Á M. Ordon˜ez (&)
´
´
Centro de Investigaciones Quımicas, Universidad Autonoma del
Estado de Morelos, Cuernavaca, Mexico
e-mail: palacios@uaem.mx
With the isoindolin-1-one-3-phosphonates 6a and 6b in
hand, we focused our attention on the intermolecular HWE
123

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M. A. Reyes-Gonzalez et al.
´
Table 1 Synthesis of 3-(arylmethylene)isoindolin-1-ones 7a–7e and
8a–8e
OH
OH
O
N
O
N
( )n
( )n
1. n-BuLi
THF, -78 °C
2. ArCHO
H
P(OMe)2
O
Ar
6a; n = 0
6b; n = 1
7a-7e; n = 0
8a-8e; n = 1
Entry Product
Yield/% Ratio (E):(Z)
1
2
3
4
5
6
7
8
9
10
7a, n = 0, Ar = C6H5
85
95
92
81
83:17
20:80
19:81
67:33
57:43
79:21
83:17
77:23
87:13
75:25
7b, n = 0, Ar = 4-MeOC6H4
7c, n = 0, Ar = 4-ClC6H4
7d, n = 0, Ar = 3,4-(MeO)2C6H3
7e, n = 0, Ar = 3,4-(OCH2O)C6H3 80
8a, n = 1, Ar = C6H5
86
88
91
92
8b, n = 1, Ar = 4-MeOC6H4
8c, n = 1, Ar = 4-ClC6H4
8d, n = 1, Ar = 3,4-(MeO)2C6H3
Fig. 1 Structure of biologically active 3-isoindolin-1-ones
8e, n = 1, Ar = 3,4-(OCH2O)C6H3 95
Scheme 1
The stereochemistry assignment in the compounds 7a–
7e and 8a–8e was performed based on our previously
reported results [29]. Additionally, 2-D NOESY spectra
and X-ray crystallographic analysis of compound 7c per-
mitted us to unambiguously assign it as the (Z)-isomer
(Fig. 2).
Inspired by these results, we turned our attention to the
synthesis of tricyclic compounds 10b–10d, which were
obtained through an intramolecular HWE reaction with the
aldehydes 9b–9d. Thus, in order to obtain the starting
aldehydes, initially the isoindolin-1-one-3-phosphonates 6
were treated with pyridinium chlorochromate (PCC) in
dichloromethane at room temperature, obtaining the cor-
responding aldehydes 9 in low yield and unidentified
products. In order to improve the chemical yield, we suc-
cessfully attempted the oxidation using the Dess–Martin
periodinane (DMP). In this context, 6b was reacted with
DMP in dry dichloromethane at room temperature obtain-
ing the aldehyde 9b in 89 % yield. Under the identical
conditions, the oxidation of the alcohols 6c and 6d afforded
the corresponding aldehydes 9c and 9d in 89 and 88 %
yield, respectively. The compound 9b was not stable when
it was purified through flash column chromatography, and
for that reason the crude product was directly used in the
next step. With the aldehydes 9b–9d in hand, we carried
out the intramolecular HWE reaction using the same pro-
tocol described above. Thus, the reaction of aldehyde 9b
with n-BuLi solution in dry THF at -78 °C gave the
reaction with several aromatic aldehydes in order to obtain
the desired 3-(arylmethylene)isoindolin-1-ones 7a–7e and
8a–8e, using the protocol that we have already reported
[29]. Thus, treatment of the isoindolin-1-one-3-phospho-
nates 6a and 6b with n-BuLi in dry THF at -78 °C
followed by the addition of the corresponding aromatic
aldehyde afforded the 3-(arylmethylene)isoindolin-1-ones
7a–7e and 8a–8e in good yield and with moderate to good
(E):(Z) selectivity. The results are summarized in Table 1.
It is worth mentioning that for this process it was not
necessary to protect the OH moiety of substrates, nor to use
an excess of n-BuLi.
123

Synthesis of 3-alkylideneisoindolinones and isoindolones
Fig. 2 The X-ray crystal
structure for (Z)-7c
Scheme 2
desired tricyclic compound 10b in 26 % yield and other
unidentified products. In order to use a less nucleophilic
base that only abstracts the a-phosphonate hydrogen, the
reaction of the aldehyde 9b was performed using potassium
bis(trimethylsilyl)amide (KHMDS) in dry THF at -78 °C,
obtaining in this case 10b in 30 % yield, whereas the
treatment of 9c with KHMDS in dry THF at -78 °C pro-
vided the tricyclic compound 10c in 75 %. However, the
reaction of 9d afforded only unstable products. In an effort
to improve the chemical yield of the HWE reaction and to
implement easier handling reaction conditions, we carried
out the intramolecular HWE reaction of 9b–9d using
K2CO3 [31] as base in acetonitrile at reflux, obtaining the
desired tricyclic compounds 10b and 10c in quantitative
yield (Scheme 2).
Conclusions
In conclusion, we report an efficient procedure for the
synthesis of N-(x-hydroxyalkyl)-substituted 3-(arylmeth-
ylene)isoindolin-1-ones by means of a HWE reaction
between dimethyl isoindolin-1-one-3-ylphosphonates and
aromatic aldehydes without previous protection of the OH
moiety. This process expands the synthesis utility of
dimethyl isoindolin-1-one-3-ylphosphonates, and could be
applied to the preparation of biologically active com-
pounds, such as the dehydrolennoxamine derivatives.
Additionally, we report the utility of dimethyl isoindolin-1-
one-3-ylphosphonates in the synthesis of tricyclic com-
pounds by means of an oxidation followed by an
intramolecular HWE reaction under easy handling, metal-
free conditions, and excellent chemical yields. The main
advantage of this protocol is the easy access to the required
dimethyl isoindolin-1-one-3-ylphosphonates, which are
obtained on a large scale in only one step under microwave
irradiation in open flask and catalyst-free conditions.
Experimental
All commercial materials were used as received from
commercial sources without further purification. Melting
points were registered in a Fisher-Johns apparatus. Flash
chromatography was performed using 230–400 mesh Silica
Flash 60Ò silica gel. Thin layer chromatography was per-
formed with pre-coated TLC sheets of silica gel (60F254,
Merck). NMR spectra were recorded in a Varian System
123

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M. A. Reyes-Gonzalez et al.
´
instrument (400 MHz for 1H, and 100 MHz for 13C) and in
a Mercury instrument (81 MHz for 31P), and calibrated
with CDCl3 as the solvent and TMS as the internal standard
signal. Chemical shifts (d) are reported in parts per million.
Multiplicities are recorded as: s = singlet, d = doublet,
t = triplet, dd = doublet of doublets, td = triplet of dou-
blets, bs = broad singlet, q = quartet, and m = multiplet.
Coupling constants (J) are given in Hz. High resolution
FAB? and CI? mass spectra (HRMS) were obtained in a
JEOL HRMStation JHRMS-700. The X-ray was obtained
in an APEX-Bruker at 173(2) K. Spectroscopic data for
6a–6c [29], 10b, and 10c [25–27] were identical to those
reported in the literature.
were dried over Na2SO4, filtered, and evaporated under
1
reduced pressure. The crude product was analyzed by H
NMR and then purified by flash chromatography
AcOEt:hexanes (2:1), obtaining the corresponding 3-benzy-
lideneisoindolin-1-ones 7a–7e and 8a–8e.
3-Benzylidene-2-(2-hydroxyethyl)isoindolin-1-one
(7a, C17H15NO2)
Yield: 237 mg (85 %), (E):(Z) isomer ratio 83:17. After
chromatographic separation, the (E)-isomer was obtained
1
as a white solid; m.p.: 111–113 °C; H NMR (400 MHz,
CDCl3): d = 2.75 (bs, 1H, OH), 3.47 (t, J = 5.6 Hz, 2H,
CH2N), 3.80 (t, J = 6.0 Hz, 2H, CH2OH), 6.82 (s, 1H,
CH), 7.31–7.35 (m, 3H, Harom), 7.38–7.42 (m, 2H, Harom),
7.49 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H, Harom), 7.60 (ddd,
J = 7.6, 7.6, 1.2 Hz, 1H, Harom), 7.74 (d, J = 8.0 Hz, 1H,
Dimethyl [2-(5-hydroxypentyl)-3-oxoisoindolin-1-yl]-
phosphonate (6d, C15H22NO5P)
To a solution of 1.0 g 2-formylbenzoic acid (6.7 mmol) in
10 cm3 methanol was added 686 mg 5-amino-1-pentanol
(6.7 mmol). The reaction mixture was irradiated in a CEM
microwave at 55 °C and 180 W for 5 min. After this time,
880 mg dimethyl phosphite (0.7 cm3, 8.0 mmol) was
added and the reaction mixture was irradiated again at
55 °C, 180 W for 5 min. The crude product was purified by
flash column chromatography (AcOEt 100 % and then
acetone 100 %), obtaining 2.02 g (93 %) of 6d as a
colorless liquid. 1H NMR (400 MHz, CDCl3):
d = 1.34–1.45 (m, 2H), 1.55-1.81 (m, 4H), 3.52–3.64 (m,
1H), 3.58 (d, J = 10.8 Hz, 3H, (CH3O)2P), 3.66–3.77 (m,
2H), 3.73 (d, J = 10.8 Hz, 3H, (CH3O)2P), 4.06–4.14 (m,
1H), 4.47 (bs, 1H, OH), 4.94 (d, J = 13.6 Hz, 1H,
CHP(OCH3)2), 7.53 (t, J = 7.6 Hz, 1H, Harom), 7.59
(ddd, J = 7.6, 7.6, 1.2 Hz, 1H, Harom), 7.74 (ddd,
J = 7.6, 7.2, 0.8 Hz, 1H, Harom), 7.86 (d, J = 8.4 Hz,
1H, Harom) ppm; 13C NMR (100 MHz, CDCl3): d = 18.2,
22.8, 27.3, 36.9, 48.9 (d, J = 7.6 Hz, (CH3O)2P), 49.0 (d,
J = 7.6 Hz, (CH3O)2P), 52.9 (d, J = 154.5 Hz,
CHP(OCH3)2), 57.5, 119.1, 119.5, 124.2, 126.9, 127.3,
133.4, 164.1 ppm; 31P NMR (81 MHz, CDCl3):
d = 20.25 ppm; HRMS [CI?]: m/z calculated for
C15H23NO5P [M ? H]? 328.1200, found 328.1289.
H
arom), 7.82 (d, J = 7.2 Hz, 1H, Harom) ppm; 13C NMR
(100 MHz, CDCl3): d = 44.8, 61.2, 106.9, 119.3, 123.3,
127.8, 128.3, 129.1, 129.5, 132.1, 133.9, 134.6, 135.1,
138.4, 170.4 ppm; HRMS [CI?]: m/z calculated for
C17H16NO2 [M ? H]? 266.1103, found 266.1171.
3-(4-Methoxybenzylidene)-2-(2-hydroxyethyl)isoindolin-1-
one (7b, C18H17NO3)
Yield: 294 mg (95 %), (E):(Z) isomer ratio 20:80. After
chromatographic separation, the (Z)-isomer was obtained
1
as a white solid; m.p.: 157–159 °C; H NMR (400 MHz,
CDCl3): d = 2.95 (bs, 1H, OH), 3.49–3.51 (m, 2H, CH2N),
3.84 (s, 3H, CH3O), 3.85 (t, J = 5.2 Hz, 2H, CH2O), 6.78
(s, 1H, CH), 6.92 (AA’BB’, J = 8.6 Hz, 2H, Harom), 7.25
(AA’BB’, J = 8.6 Hz, 2H, Harom), 7.48 (dd, J = 7.6,
7.6 Hz, 1H, Harom), 7.59 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H,
H
arom), 7.73 (d, J = 7.6 Hz, 1H, Harom), 7.82 (d,
J = 7.6 Hz, 1H, Harom) ppm; 13C NMR (100 MHz,
CDCl3): d = 45.0, 55.5, 61.3, 107.5, 114.0, 119.5, 123.4,
126.7, 128.0, 129.1, 130.9, 132.3, 134.6, 138.6, 159.4,
170.8 ppm; HRMS [CI?]: m/z calculated for C18H18NO3
[M ? H]? 296.1208, found 296.1275.
The (E)-isomer was obtained as a yellow solid; m.p.:
1
131–134 °C; H NMR (400 MHz, CDCl3): d = 2.90 (bs,
1H, OH), 3.88 (s, 3H, CH3O), 3.97 (t, J = 5.6 Hz, 2H,
CH2N), 4.09 (t, J = 5.6 Hz, 2H, CH2OH), 6.61 (s, 1H,
CH), 6.96 (d, J = 8.8 Hz, 2H, Harom,), 7.31–7.39 (m, 4H,
General procedure for the synthesis
of 3-benzylideneisoindolinones 7a–7e and 8a–8e
H
arom), 7.42 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H, Harom), 7.83 (d,
A solution of n-BuLi (1.0 equiv) was added dropwise to a
stirred solution of the isoindolin-1-one-3-ylphosphonates 6
(1.0 equiv) in 15 cm3 THF at -78 °C under nitrogen. The
solution was stirred for 15 min at this temperature, followed
by the addition of the corresponding aldehyde (1.0 equiv).
The reaction mixture was stirred at -78 °C for 15 min, and at
room temperature for 1 h. The reaction mixture was quen-
ched by the addition of saturated solution of NH4Cl and
extracted with AcOEt (2 9 20 cm3). The organic extracts
J = 7.2 Hz, 1H, Harom) ppm; 13C NMR (100 MHz,
CDCl3): d = 42.8, 55.6, 61.5, 111.1, 114.4, 123.3, 123.6,
127.3, 129.4, 130.1, 131.0, 131.9, 134.3, 135.4, 159.6,
168.0 ppm; HRMS [CI?]: m/z calculated for C18H18NO3
[M ? H]? 296.1208, found 296.1278.
3-(4-Chlorobenzylidene)-2-(2-hydroxyethyl)isoindolin-1-
one (7c, C17H14ClNO2)
Yield: 263 mg (92 %), (E):(Z) isomer ratio 19:81. After
chromatographic separation, the (Z)-isomer was obtained
123

Synthesis of 3-alkylideneisoindolinones and isoindolones
1
as a yellow solid; m.p.: 139–141 °C; H NMR (400 MHz,
Harom), 7.34* (dd, J = 7.6, 7.6, 1.2 Hz, 1H, Harom),
7.39–7.43* (m, 2H, Harom), 7.48 (ddd, J = 7.6, 7.6,
1.2 Hz, 1H, Harom), 7.59 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H,
CDCl3): d = 2.73 (bs, 1H, OH), 3.49 (t, J = 5.6 Hz, 2H,
CH2N), 3.81 (t, J = 5.6 Hz, 2H, CH2OH), 6.72 (s, 1H,
CH), 7.27 (AA’BB’, J = 8.0 Hz, 2H, Harom), 7.37
(AA’BB’, J = 8.0 Hz, 2H, Harom), 7.49 (ddd, J = 7.6,
7.6, 1.2 Hz, 1H, Harom), 7.61 (ddd, J = 7.6, 7.6, 1.2 Hz,
1H, Harom), 7.73 (d, J = 7.6 Hz, 1H, Harom), 7.82 (d,
J = 7.6 Hz, 1H, Harom) ppm; 13C NMR (100 MHz,
CDCl3): d = 44.9, 61.1, 105.7, 119.6, 123.6, 128.1,
128.8, 129.5, 131.0, 132.5, 133.2, 134.0, 135.6, 138.4,
170.6 ppm; HRMS [CI?]: m/z calculated for C17H15ClNO2
[M ? H]? 300.0713, found 300.0793.
H
arom), 7.72 (d, J = 8 Hz, 1H, Harom), 7.82 (dd, J = 7.2,
7.2 Hz, 1H, Harom) ppm; 13C NMR (100 MHz, CDCl3):
d = 29.3*, 29.6, 42.5*, 44.9, 61.1*, 61.3, 101.2*, 101.3,
106.8*, 108.2, 108.6*, 109.6, 109.7, 110.5*, 119.2,
123.1*,123.2, 127.9*, 128.1, 128.6*, 128.9, 129.1,
130.0*, 131.6*, 132.0, 134.9, 135.1*, 136.4*, 138.4,
147.3, 147.4*, 147.7, 147.9*, 167.6*, 170.4 ppm (asterik
denotes minor isomer); HRMS [CI?]: m/z calculated for
C18H16NO4 [M ? H]? 310.1000, found 310.1069.
Summary of the crystallographic data (CCDC 978159):
˚
triclinic, space group P-1, a = 7.2380(10) A,
3-Benzylidene-2-(3-hydroxypropyl)isoindolin-1-one
(8a, C18H17NO2)
˚
b = 8.6727(12) A, c = 11.7007(17) A, V = 705.17(17)
˚
Yield: 240 mg (86 %), (E):(Z) isomer ratio 79:21; yellow
solid; m.p.: 96–98 °C; 1H NMR (400 MHz, CDCl3):
d = 1.33* (quint, J = 6.4 Hz, 2H, CH2CH2N), 1.94 (quint,
J = 6.4 Hz, 2H, CH2CH2N), 3.20* (bs, 1H, OH), 3.26* (t,
J = 5.6 Hz, 2H, CH2N), 3.62 (t, J = 5.6 Hz, 2H, CH2N),
3.75 (bs, 1H, OH), 3.80* (t, J = 6.4 Hz, 2H, CH2OH), 4.07
(t, J = 6.4 Hz, 2H, CH2OH), 6.63 (s, 1H, CH), 6.85* (s,
1H, CH), 7.30-7.46 (m, 8H, Harom), 7.51* (ddd, J = 7.2,
7.2 Hz, 1H, Harom), 7.62* (ddd, J = 7.6, 7.6, 1.2 Hz, 1H,
3
3
˚
A , Z = 2, Dc = 1.412 Mg/m , 6,697 reflections collected,
2,487 unique (Rint = 0.0516), data/parameters: 2,487/1/
191; final R indices R1 = 0.0484, wR2 = 0.1240, R indices
(all data): R1 = 0.0516, wR2 = 0.1266, goodness-of-fit:
1.106.
3-(3,4-Dimethoxybenzylidene)-2-(2-hydroxyethyl)-
isoindolin-1-one (7d, C19H19NO4)
Yield: 275 mg (81 %), (E):(Z) isomer ratio 67:33; yellow
solid; m.p.: 86–88 °C; 1H NMR (400 MHz, CDCl3):
d = 2.93* (bs, 1H, OH), 3.08 (bs, 1H, OH), 3.55* (t,
J = 5.2 Hz, 2H, CH2N), 3.86 (s, 3H, CH3O), 3.89* (t,
J = 5.6 Hz, 2H, CH2OH), 3.90* (s, 3H, CH3O), 3.92* (s,
3H, CH3O), 3.95 (s, 3H, CH3O), 3.97 (t, J = 6 Hz, 2H,
CH2N), 4.08 (t, J = 6 Hz, 2H, CH2OH), 6.64 (s, 1H, CH),
6.79* (s, 1H, CH), 6.86* (s, 1H, Harom), 6.89-6.92 (m, 1H,
H
H
arom), 7.76* (d, J = 8 Hz, 1H, Harom), 7.82–7.86* (m, 1H,
arom), 7.84 (d, J = 7.6 Hz, 1H, Harom) ppm; 13C NMR
(100 MHz, CDCl3): d = 30.7, 31.0*, 35.6, 37.5*, 58.4,
58.6*, 107.5*, 111.1, 119.3*, 123.2, 123.3*, 127.8*, 128.0,
128.2, 128.7, 129.1, 129.3, 129.4*, 129.5, 129.8, 131.7,
132.1, 132.2*, 134.1*, 135.0, 135.9*, 167.2*, 167.8,
171.0* ppm (asterik denotes minor isomer); HRMS
[CI?]: m/z calculated for C18H18NO2 [M ? H]?
280.1259, found 280.1338.
H
arom), 6.95 (d, J = 8.4 Hz, 1H, Harom), 7.01 (d, J = 8 Hz,
1H, Harom), 7.33 (t, J = 8 Hz, 1H, Harom), 7.41 (t,
J = 7.6 Hz, 2H, Harom), 7.48* (t, J = 7.6 Hz, 1H, Harom),
7.60* (t, J = 8 Hz, 1H, Harom), 7.74* (d, J = 7.6 Hz, 1H,
3-(4-Methoxybenzylidene)-2-(3-hydroxypropyl)isoindolin-
1-one (8b, C19H19NO3)
Yield: 639 mg (88 %), (E):(Z) isomer ratio 83:17. After
H
arom), 7.83 (t, J = 7.6 Hz, 1H, Harom) ppm; 13C NMR
(100 MHz, CDCl3): d = 42.6, 45.1*, 56.1, 61.1, 61.5*,
107.5*, 111.1*, 111.2, 111.4, 112.6*, 112.7, 119.4*, 122.3,
122.4*, 123.3, 123.4, 123.5*, 127.0*, 127.5, 128.0*, 129.2,
129.4, 130.1*, 131.7, 132.3*, 134.7*, 135.3, 136.2, 138.6*,
148.9, 149.0, 149.1, 167.8, 170.8* ppm (asterik denotes
minor isomer); HRMS [CI?]: m/z calculated for
C19H20NO4 [M ? H]? 326.1300, found 326.1380.
chromatographic separation, the (E)-isomer was obtained
1
as a white solid; m.p.: 134–136 °C; H NMR (400 MHz,
CDCl3): d = 1.36 (quint, J = 6.0 Hz, 2H, CH2CH2N),
2.89 (bs, 1H, OH), 3.27 (t, J = 6.0 Hz, 2H, CH2N), 3.85 (s,
3H, CH3O), 3.86 (t, J = 6.4 Hz, 2H, CH2OH), 6.80 (s, 1H,
CH), 6.93 (AA’BB’, J = 8.2 Hz, 2H, Harom), 7.27
(AA’BB’, J = 8.2 Hz, 2H, Harom), 7.49 (ddd, J = 7.6,
7.6, 0.8 Hz, 1H, Harom), 7.60 (ddd, J = 7.6, 7.6, 0.8 Hz,
1H, Harom), 7.74 (d, J = 7.6 Hz, 1H, Harom), 7.84 (d,
J = 7.6 Hz, 1H, Harom) ppm; 13C NMR (100 MHz,
CDCl3): d = 31.0, 37.4, 55.3, 58.5, 107.6, 113.7, 119.3,
123.3, 126.5, 127.8, 128.9, 130.7, 132.1, 134.1, 138.3,
159.2, 169.7 ppm; HRMS [CI?]: m/z calculated for
C19H20NO3 [M ? H]? 310.1365, found 310.1447.
3-[(Benzo[d][1, 3]dioxol-5-yl)methylene]-2-
(2-hydroxyethyl)isoindolin-1-one (7e, C18H15NO4)
Yield: 165 mg (80 %), (E):(Z) isomer ratio 57:43; yellow
solid; m.p.: 142–144 °C; 1H NMR (400 MHz, CDCl3):
d = 2.83 (bs, 1H, OH), 2.92* (bs, 1H, OH), 3.56* (m, 2H,
CH2N), 3.89 (t, J = 5.6 Hz, 2H, CH2N), 3.95* (t,
J = 4.8 Hz, 2H, CH2OH), 4.06 (t, J = 5.6 Hz, 2H,
CH2OH), 6.01 (s, 2H, OCH2O), 6.03* (s, 2H, OCH2O),
6.56* (s, 1H, CH), 6.71 (s, 1H, CH), 6.78–6.93 (m, 3H,
The (Z)-isomer was obtained as a yellow solid; m.p.:
1
95–98 °C; H NMR (400 MHz, CDCl3): d = 1.90 (quint,
123

´
M. A. Reyes-Gonzalez et al.
´
denotes minor isomer); HRMS [CI?]: m/z calculated for
C20H22NO4 [M ? H]? 340.1471, found 340.1559.
J = 6.0 Hz, 2H, CH2CH2N), 3.58 (t, J = 6.0 Hz, 2H,
CH2N), 3.85 (s, 3H, CH3O), 4.02 (t, J = 6.0 Hz, 2H,
CH2OH), 6.55 (s, 1H, CH), 6.94 (AA’BB’, J = 8.8 Hz,
2H, Harom), 7.29-7.41 (m, 5H, Harom), 7.80 (d, J = 7.6 Hz,
1H, Harom) ppm; 13C NMR (100 MHz, CDCl3): d = 30.9,
35.8, 55.5, 58.6, 111.4, 114.3, 123.3, 123.4, 127.1, 129.3,
130.0, 131.0, 131.8, 135.3, 135.5, 159.5, 168.0 ppm;
HRMS [CI?]: m/z calculated for C19H20NO3 [M ? H]?
310.1365, found 310.1447.
3-[(Benzo[d][1,3]dioxol-6-yl)methylene]-2-
(3-hydroxypropyl)isoindolin-1-one (8e, C19H17NO4)
Yield: 719 mg (95 %), (E):(Z) isomer ratio 75:25. After
chromatographic separation, the (E)-isomer was obtained
1
as a yellow solid; m.p.: 99–102 °C; H NMR (400 MHz,
CDCl3): d = 1.93 (quint, J = 6.0 Hz, 2H, CH2OH), 2.16
(bs, 1H, OH), 3.61 (t, J = 5.6 Hz, 2H, CH2N), 4.04 (t,
J = 6.4 Hz, 2H, CH2CH2N), 6.04 (s, 2H, OCH2O), 6.53 (s,
1H, CH), 6.86-6.94 (m, 3H, Harom), 7.35–7.46 (m, 3H,
3-(4-Chlorobenzylidene)-2-(3-hydroxypropyl)isoindolin-1-
one (8c, C18H16ClNO2)
H
H
arom), 7.42–7.46 (m, 2H, Harom), 7.83 (d, J = 7.6 Hz, 1H,
arom) ppm; 13C NMR (100 MHz, CDCl3): d = 30.7, 35.6,
Yield: 669 mg (91 %), (E):(Z) isomer ratio 77:23; white
solid; m.p.: 76–80 °C; 1H NMR (400 MHz, CDCl3):
d = 1.35* (quint, J = 6 Hz, 2H, CH2CH2N), 1.91 (quint,
J = 6.0 Hz, 2H, CH2CH2N), 2.63* (bs, 1H, OH), 2.85 (bs,
1H, OH), 3.29* (t, J = 6 Hz, 2H, CH2N), 3.59 (t,
J = 5.6 Hz, 2H, CH2N), 3.81* (t, J = 6 Hz, 2H, CH2OH),
4.02 (t, J = 6 Hz, 2H, CH2OH), 6.51 (s, 1H, CH), 6.74* (s,
1H, CH), 6.81* (AA’BB’, J = 8.4 Hz, 2H, Harom), 7.07*
(AA’BB’, J = 8.4 Hz, 2H, Harom), 7.27–7.43 (m, 7H,
58.4, 101.3, 108.6, 109.7, 111.0, 123.2, 123.3 (2), 128.4,
129.3, 129.8, 131.7, 134.9, 135.7, 147.4, 147.9, 167.7 ppm;
HRMS [CI?]: m/z calculated for C19H18NO4 [M ? H]?
324.1158, found 324.1242.
The (Z)-isomer was obtained as a yellow solid; m.p.:
119–121 °C; 1H NMR (400 MHz, CDCl3): d = 1.42
(quint, J = 5.6 Hz, 2H, CH2OH), 2.90 (bs, 1H, OH), 3.31
(t, J = 5.6 Hz, 2H, CH2N), 3.89 (t, J = 6.0 Hz, 2H,
CH2CH2N), 6.02 (s, 2H, OCH2O), 6.74 (s, 1H, CH), 6.80-
6.86 (m, 3H, Harom), 7.49 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H,
H
arom), 7.62* (ddd, J = 7.6, 7.6, 0.8 Hz, 1H, Harom), 7.74*
(d, J = 7.6 Hz, 1H, Harom), 7.81 (d, J = 7.2 Hz, 1H,
arom), 7.84* (d, J = 7.6 Hz, 1H, Harom) ppm; 13C NMR
H
(100 MHz, CDCl3): d = 30.9, 35.7*, 35.9, 37.4*, 58.4*,
58.7, 105.9*, 109.7, 119.4*, 123.1*, 123.3, 123.5, 128.5*,
129.2, 129.3*, 129.6*, 129.8, 130.1, 130.9*, 131.1, 131.7*,
132.0, 132.3*, 133.0*, 133.6, 134.1, 134.8*, 135.0, 136.6,
138.1*, 167.8*, 167.9 ppm (asterik denotes minor isomer);
HRMS [CI?]: m/z calculated for C18H17ClNO2 [M ? H]?
314.0870, found 314.0949.
H
arom), 7.60 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H, Harom), 7.72 (d,
J = 7.6 Hz, 1H, Harom), 7.84 (d, J = 7.6 Hz, 1H, Harom
)
ppm; 13C NMR (100 MHz, CDCl3): d = 31.1, 37.4, 58.6,
101.3, 107.3, 108.1, 109.7, 119.3, 123.2, 123.3, 127.8,
128.0, 129.0, 132.1, 134.4, 138.2, 147.3, 147.5, 169.8 ppm;
HRMS [CI?]: m/z calculated for C19H18NO4 [M ? H]?
324.1158, found 324.1242.
3-(3,4-Dimethoxybenzylidene)-2-(3-hydroxypropyl)-
isoindolin-1-one (8d, C20H21NO4)
General procedure for the synthesis of aldehydes 9b-9d
Yield: 732 mg (92 %), (E):(Z) isomers ratio 87:13; yellow
oil; 1H NMR (400 MHz, CDCl3): d = 1.41 (quint,
J = 6.0 Hz, 2H, CH2CH2N), 1.95* (quint, J = 6 Hz, 2H,
CH2CH2N), 2.14 (bs, 1H, OH), 3.30 (t, J = 6.0 Hz, 2H,
CH2N), 3.62* (t, J = 6.0 Hz, 2H, CH2N), 3.87* (s, 3H,
CH3O), 3.87–3.91 (m, 2H, CH2OH), 3.90 (s, 3H, CH3O),
3.93 (s, 3H, CH3O), 3.96* (s, 3H, CH3O), 4.06* (t,
J = 5.6 Hz, 2H, CH2OH), 6.60* (s, 1H, CH), 6.82 (s, 1H,
CH), 6.87–6.97 (m, 4H, Harom), 7.03* (d, J = 8.0 Hz, 1H,
A
solution of the hydroxyphosphonates 6b–6d
(1.67 mmol) in 10 cm3 dry dichloromethane was added to
a stirred solution of Dess–Martin-Periodinane reagent (1.5
equiv), and the reaction mixture was stirred at room tem-
perature overnight. The solvent was then removed under
reduced pressure, and the crude product was purified by
flash chromatography (AcOEt:acetone 50:50), yielding the
desired aldehydes 9b–9d. Aldehyde 9c was unstable.
H
arom), 7.35* (ddd, J = 8.0, 8.0, 1.2 Hz, 1H, Harom),
7.42–7.46* (m, 2H, Harom), 7.50 (dd, J = 7.6, 7.6 Hz, 1H,
arom), 7.61 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H, Harom), 7.75 (d,
J = 8.0 Hz, 1H, Harom), 7.84* (d, J = 8.0 Hz, 1H, Harom
Dimethyl 2-(2-formylethyl)-3-oxoisoindolin-1-
ylphosphonate (9b, C13H16NO5P)
H
Yield: 443 mg (89 %) as a white solid; m.p.: 103–105 °C;
1H NMR (400 MHz, CDCl3): d = 2.77 (dddd, J = 18.4,
6.0, 6.0, 1.6 Hz, 1H, CH2CHO), 3.08 (dddd, J = 18.4, 6.8,
6.8, 1.2 Hz, 1H, CH2CHO), 3.52 (d, J = 10.8 Hz, 3H,
(CH3O)2P), 3.72 (d, J = 10.8 Hz, 3H, (CH3O)2P), 3.98
(ddd, J = 14.4, 6.0, 6.0 Hz, 1H, CH2N), 4.12 (ddd,
J = 14.4, 6.0, 6.0 Hz, 1H, CH2N), 5.01 (d, J = 13.2 Hz,
1H, CHP(OCH3)2), 7.47 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H,
)
ppm; 13C NMR (100 MHz, CDCl3): d = 30.8*, 31.3,
35.7*, 37.6, 55.9, 55.96*, 55.99*, 56.0, 58.6*, 58.7, 107.2,
110.9*, 111.1, 111.5*, 112.8*, 112.9, 119.1, 122.1*, 122.2,
123.14*, 123.2, 123.21*, 127.0, 127.4*, 127.9, 128.9*,
129.1*, 129.9, 131.5*, 131.9, 134.2, 135.1*, 135.6*, 138.3,
148.8, 148.9, 149.1*, 149.2*, 167.6*, 169.6 ppm (asterik
123

Synthesis of 3-alkylideneisoindolinones and isoindolones
Harom), 7.54 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H, Harom),
7.68–7.71 (m, 1H, Harom), 7.79 (d, J = 1.2 Hz, 1H, Harom),
9.75 (t, J = 1.2 Hz, 1H, CHO) ppm; 13C NMR (100 MHz,
CDCl3): d = 36.3, 42.4, 53.6 (d, J = 7.6 Hz, (CH3O)2P),
53.7 (d, J = 7.6 Hz, (CH3O)2P), 57.8 (d, J = 153.7 Hz,
CHP(OCH3)2), 123.7, 124.3, 128.9, 131.7, 131.8, 138.5,
168.8, 200.2 ppm; 31P NMR (81 MHz, CDCl3):
d = 18.4 ppm; HRMS [CI?]: m/z calculated for
C13H17NO5P [M ? H]? 298.0800, found 298.0836.
References
1. Kato Y, Takemoto M, Achiwa K (1993) Chem Pharm Bull
41:2003
2. Kato Y, Ebiike H, Achiwa K, Ashizawa N, Kurihara T, Kobay-
ashi F (1990) Chem Pharm Bull 38:2060
3. Bianchi G, Chiarini M, Marinelli F, Rossi L, Arcadi A (2010)
Adv Synth Catal 352:136
4. Sahakitpichan P, Ruchirawat S (2004) Tetrahedron 60:4169
5. Kim G, Kim JH, Kim W-J, Kim YA (2003) Tetrahedron Lett
44:8207
6. Ishibashi H, Kawanami H, Ikeda M (1997) J Chem Soc Perkin
Trans 1:817
Dimethyl 2-(4-formylbutyl)-3-oxoisoindolin-1-
ylphosphonate (9d, C15H20NO5P)
7. Guervenou J, Gourves J-P, Couthon H, Corbel B, Sturtz G,
Kervarec N (2000) Phosphorus. Sulfur Silicon Relat Elem
156:107
8. Gourves J-P, Couthon H, Sturtz G (1999) Eur J Org Chem 3489
9. Griesbeck AG, Henz A, Kramer W, Lex J, Nerowski F,
Yield: 631 mg (88 %) as a colorless oil; 1H NMR (400 MHz,
CDCl3): d = 1.58–1.78 (m, 4H), 2.49–2.54 (m, 2H),
3.55–3.62 (m, 4H), 3.75 (d, J = 10.8 Hz, 3H, (CH3O)2P),
4.10–4.13 (m, 1H), 4.94 (d, J = 13.6 Hz, 1H, CHP(OCH3)2),
7.51–7.55 (m, 1H), 7.57–7.61 (m, 1H), 7.75–7.77 (m, 1H),
7.86–7.88 (m, 1H), 9.76 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3): d = 19.1, 27.2, 41.3, 43.1, 53.6 (d, J = 5.9 Hz,
(CH3O)2P), 53.7 (d, J = 7.3 Hz, (CH3O)2P), 56.9 (d,
J = 155.2 Hz, CHP(OCH3)2), 123.8, 124.3, 128.9, 131.5,
132.1, 138.2, 168.7, 201.6 ppm; 31P NMR(81 MHz, CDCl3):
d = 18.3 ppm; HRMS [CI?]: m/z calculated for
C15H21NO5P [M ? H]? 326.1100, found 326.1141.
¨
Oelgemoller M, Peters K, Peters E-M (1997) Helv Chim Acta
80:912
10. Yoon UC, Kim DU, Lee CW, Choi YS, Lee Y-J, Ammon HL,
Mariano PS (1995) J Am Chem Soc 117:2698
11. Gandhi VB, Luo Y, Liu X, Shi Y, Klinghofer V, Johnson EF,
Park C, Giranda VL, Penning TD, Zhu GD (2010) Bioorg Med
Chem Lett 20:1023
12. Jagtap PG, Southan GJ, Baloglu E, Ram S, Mabley JG, Marton A,
´
Salzman A, Szabo C (2004) Bioorg Med Chem Lett 14:81
13. Cappelli A, Gallelli A, Braile C, Anzini M, Vomero S, Mennuni
L, Makovec F, Menziani MC, De Benedetti PG, Donati A, Giorgi
G (2012) Bioorg Med Chem 10:2681
¨
14. Cid HMB, Trankle C, Baumann K, Pick R, Mies-Klomfass E,
General procedure for the synthesis of isoindolones
Kostenis E, Mohr K, Holzgrabe U (2000) J Med Chem 43:2155
15. Zhuang Z-P, Kung M-P, Mu M, Kung HF (1998) J Med Chem
41:157
10b–10d
16. Moreau A, Couture A, Deniau E, Grandclaudon P (2004) J Org
Chem 69:4527
17. Couture A, Deniau E, Grandclaudon P (1997) Tetrahedron
53:10313
18. Zhang L, Zhang Y, Wang X, Shen J (2013) Molecules 18:654
19. Ju J, Qi C, Zheng L, Hua R (2013) Tetrahedron Lett 54:5159 and
references therein
20. Duncanson P, Cgeong Y-K, Motevalli M, Griffiths DV (2012)
Org Biomol Chem 10:4266
Method A: a solution of KHMDS in toluene (0.5 M, 2
equiv) was added dropwise to a stirred solution of the
corresponding aldehydes 9b–9d (1.0 equiv) in 15 cm3 THF
at -78 °C under nitrogen. The reaction mixture was stirred
for 15 min and then warmed at room temperature over a
period of 1 h. The reaction mixture was quenched by the
addition of saturated solution of NH4Cl and extracted with
AcOEt (2 9 20 cm3). The organic extracts were dried over
Na2SO4, filtered, and evaporated under reduced pressure.
´
´
21. Pace V, Martınez F, Nova CI, Fernandez M, Siniestra JV,
´
Alcantara AR (2009) Tetrahedron Lett 50:3050
22. Crawford LA, Clemence NC, McNab H, Tyas RG (2008) Org
Biomol Chem 6:2334
1
The crude product was analyzed by H NMR and then
purified by flash column chromatography (AcOEt:hexanes
2:1), yielding the corresponding tricyclic compounds 10b–
10d. Compound 10d was unstable.
´
´
´ ´
23. Garcıa A, Rodrıguez D, Castedo L, Saa C, Domınguez D (2001)
Tetrahedron Lett 42:1903
24. Pigeon P, Decroix D (1998) Synth Commun 28:2507
25. Marion F, Coulomb J, Servais A, Courillon C, Fensterbank L,
Malacria M (2006) Tetrahedron 62:3856
26. Marion F, Courillon C, Malacria M (2003) Org Lett 5:5095
27. Ha D-C, Yun C-S, Yu E (1996) Tetrahedron Lett 37:2577
Method B [31]: to a solution of the corresponding
aldehydes 9b–9d (1.0 equiv) in 10 cm3 acetonitrile was
added K2CO3 (1.5 equiv), and the reaction mixture was
heated at 85 °C for 2.5 h. The reaction mixture was filtered
and the solvent was evaporated under reduced pressure
until complete dryness, yielding the corresponding tricyclic
compounds 10b and 10c in 98 % yield. Spectroscopic data
were identical to those reported in Refs. [25–27].
´
28. Ordon˜ez M, Tibhe GD, Zamudio-Medina A, Viveros-Ceballos JL
(2012) Synthesis 44:569
´
´
29. Reyes-Gonzalez MA, Zamudio-Medina A, Ordon˜ez M (2012)
Tetrahedron Lett 53:5756
30. Viveros-Ceballos JL, Cativiela C, Ordon˜ez M (2011) Tetrahedron
Asymmetry 22:1479
´
31. Modica E, Compostella F, Colombo D, Franchini L, Cavalliari
M, Mori L, De Libero G, Panza L, Ronchetti F (2006) Org Lett
8:3255
Acknowledgments The authors thank CONACYT of Mexico for
´
financial support via project 181816. We thank V. Labastida-Galvan
for the determination of mass spectra. MARG and OARM also thank
the CONACYT for Graduate Scholarships.
123