Synthesis of isoindolo[1,4]benzoxazinone and isoindolo[1,5]benzoxazepine: two new ring systems of pharmaceutical interest

Article abstract of DOI:10.1016/j.tet.2015.04.083

Abstract Two new ring systems, isoindolo[1,4]benzoxazinone and isoindolo[1,5]benzoxazepine, were conveniently synthesized through cyclization of suitably substituted isoindole derivatives. Some of the new compounds exhibited antiproliferative activity aga

Full text of DOI:10.1016/j.tet.2015.04.083

Tetrahedron xxx (2015) 1e7
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Tetrahedron
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Synthesis of isoindolo[1,4]benzoxazinone and isoindolo[1,5]
benzoxazepine: two new ring systems of pharmaceutical interest
Barbara Parrino, Cristina Ciancimino, Anna Carbone, Virginia Span oꢀ ,
*
Alessandra Montalbano, Paola Barraja, Girolamo Cirrincione , Patrizia Diana
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Universit aꢀ di Palermo, Via Archirafi 32, 90123 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new ring systems, isoindolo[1,4]benzoxazinone and isoindolo[1,5]benzoxazepine, were conve-
niently synthesized through cyclization of suitably substituted isoindole derivatives. Some of the new
compounds exhibited antiproliferative activity against a wide range of human tumor cell lines with GI50
Received 10 February 2015
Received in revised form 1 April 2015
Accepted 23 April 2015
Available online xxx
mean values at low micromolar level (3.72e5.13 mM).
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Isoindole
Isoindolo[1,4]benzoxazinone
Isoindolo[1,5]benzoxazepine
Antiproliferative activity
1
. Introduction
with GI50 values ranging from micromolar to nanomolar
31
concentrations.
Benzoxazine and benzoxazepine are heterocyclic compounds,
which have been used as intermediates in the synthesis of many
heterocyclic structures of biological interest.
The benzoxazine core occurs in different classes of compounds
that exhibit a wide range of pharmacological activities including
antibacterial, anti-inflammatory, cardiovascular, antidepressive,
and anticancer properties.
Also benzoxazepine derivatives arewell-knownpharmacophores
showing promising properties against various diseases such as an-
tipsychotic, central nervous system, and anti-cancer activities.
In this paper, continuing our studies on isoindole systems,32,33
we report the synthesis of derivatives of two new ring systems
isoindolo[1,4]benzoxazinone 5 and isoindolo[1,5]benzoxazepine
8e10 and the antiproliferative activity of some of them against
a wide range of human tumor cell lines at low micromolar level.
1
2
3
4
5
2. Results and discussion
6
7
8
Isoindolo[1,4]benzoxazinones
5
and isoindolo[1,5]benzox-
azepines 8e10 were synthesized from the key intermediates 2-(2-
hydroxyphenyl)-2H-isoindole-1-carbonitrile 3aec, prepared in
very good yields (94e100%) by Strecker like reaction between o-
phthaldialdehydes 1aec and 2-aminophenol 2 in the presence of
sodium hydrogen sulfite and potassium cyanide (Scheme 1).
The commercially unavailable 1,2-dicarbaldehydes 1b,c were
Variously substituted pyrrolo[1,5]benzoxazepines have shown
antiproliferative activity in a wide range of tumor cell lines at mi-
cromolar concentrations. They have been identified as novel
microtubule-targeting agents that possess the ability to potently to
induce cell cycle arrest and apoptosis against solid tumors and
9
hematological malignancies.
3
2,34
synthesized as previously reported.
In the course of our research on polycyclic nitrogen systems, we
1
0e20
The isoindolo[1,4]benzoxazinones 5aec were obtained in good
yields (68e79%) by refluxing the 2-(2-hydroxyphenyl)-2H-iso-
indole-1-carbonitrile intermediates 3aec in acetic acid through
a nucleophilic cyclization of the hydroxy group with the cyano
moiety, and subsequent in situ hydrolysis of the intermediates
have synthesized several ring systems bearing pyrrole,
indole,2
1e27
indazole,28,29 and isoindole, moieties with antitu-
30
mor activity.
We have reported the tetracyclic ring system isoindolo[2,1-a]
quinoxaline, which showed potent antiproliferative activity
4aec.
The isoindolo[1,5]benzoxazepine derivatives 8e10 were syn-
thesized starting from the 2-(2-hydroxyphenyl)-2H-isoindole-1-
carbonitriles 3aec, which were O-alkylated with ethyl bromo-
*
Corresponding author. Tel.: þ39 (0)91 6161606; e-mail address: girolamo.cir-
rincione@unipa.it (G. Cirrincione).
http://dx.doi.org/10.1016/j.tet.2015.04.083
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
B. Parrino et al. / Tetrahedron xxx (2015) 1e7
The acids thus obtained were reacted with thionyl chloride in
refluxing dichloromethane to generate the benzoxazepine nucleus
of derivatives 8aed, through intramolecular cyclization (65e74%).
The isoindolo[1,5]benzoxazepine derivatives 8aed were con-
veniently functionalized with acetyl chloride or ethyl iodide at
position 6 or 7 using an appropriate base. In particular, to obtain
derivatives 9aee, reactions were carried out in the presence of
triethylamine (50e95%) while sodium hydride was used for de-
rivatives 10aef (54e85%) (Scheme 1, Table 1).
Table 1
Isoindolo[1,5]benzoxazepines 8aed, 9aee, and 10aef
Compound
R1
R2
R3
Yield (%)
8
8
8
8
9
9
9
9
9
1
1
1
1
1
1
a
b
c
d
a
b
c
d
H
C
C
C
6
6
6
H
H
H
5
5
5
d
65
68
70
74
95
74
73
74
50
70
74
85
54
70
55
Me
OMe
H
d
d
p-Tolyl
d
H
C
C
C
6
H
6
H
6
H
5
5
5
MeCO
MeCO
MeCO
MeCO
Et
MeCO
MeCO
Et
Me
OMe
H
H
H
Me
H
Me
OMe
H
p-Tolyl
Scheme 1. Synthesis of isoindolo[1,4]benzoxazinones 5. Reagents and conditions: (i)
e
C
C
C
C
C
C
6
H
6
H
6
H
6
H
6
H
6
H
5
5
5
5
5
5
ꢁ
ꢁ
(
9
a) sodium hydrogen sulfite, water, 40 C, 30 min; (b) potassium cyanide, water, 40 C,
0 min (94e100%); (ii) acetic acid, reflux, 2 h; (iii) ice-water (68e79%).
0a
0b
0c
0d
0e
0f
Et
Et
Et
(
(
phenyl)acetate (11a) or ethyl bromo-(4-methylphenyl)acetate
11b), to give the corresponding esters 6aed (72e86%). The com-
p-Tolyl
mercially unavailable ethyl bromo-(4-methylphenyl)acetate 11b
was prepared starting from reaction of ethyl p-tolylacetate with N-
bromosuccinimide in carbon tetrachloride in the presence of 48%
HBr (75%).
All the synthesized compounds 5aec, 8aed, 9aee, and 10aef
Hydrolysis of the ester group of derivatives 6aed with 5%
aqueous sodium hydroxide solution in a mixture of ethanol/tetra-
hydrofuran, allowed the isolation of the corresponding acids 7aed
from good to high yields (86e95%) (Scheme 2).
were submitted to the National Cancer Institute (NCI; Bethesda
MD) and derivatives 8aec, 9e, and 10a,e,f were selected and pre-
ꢀ5
screened according to the NCI protocol at the 10 M dose on the
full panel of approximately 60 human cancer cell lines derived from
9
human cancer cell types that have been grouped in disease sub-
panels including leukemia, non-small-cell lung, colon, central
nervous system, melanoma, ovarian, renal, prostate, and breast
tumor cell lines. Compounds 8aec satisfied the criteria set by the
NCI for activity in this assay and were selected for further screen-
4
8
ings at five concentrations at 10-fold dilution (10 e10 M) on the
full panel.
The antitumor activity of compounds was given by three pa-
rameters for each cell line: GI50 (the molar concentration of the
compound that inhibits 50% net cell growth), TGI (the molar con-
centration of the compound leading to total inhibition of net cell
growth), and LC50 (the molar concentration of the compound that
induces 50% net cell death). The average values of mean graph
midpoint (MG_MID) were calculated for each of these parameters.
An evaluation of the data reported in Table 2 pointed out that
compounds 8a and 8c exhibited antiproliferative activity against
most of the human cell lines at micromolar GI50 values.
The isoindolo[1,2-d][1,5]benzoxazepine derivative 8a proved
the most active in terms either of GI50 (MG_MID¼3.72
mM) and
percentage of sensitive cell lines out of the total number of cell lines
investigated (100%). Moreover for compound 8a positive TGI and
LC50 values were observed with respect to a good number of cell
lines (95% and 59%, respectively).
Derivative 8a was shown to be selective with respect to the
breast cancer subpanel having all the subpanel cell lines GI50 in the
range 2.78e3.80 mM (see Table 1 of Supplementary data).
Scheme 2. Synthesis of isoindolo[1,5]benzoxazepines 8e10. Reagents and conditions:
(
i) (a) sodium hydride, tetrahydrofuran, rt, 1 h; (b) ethyl bromo-(phenyl)acetate (11a)
or ethyl bromo-(4-methylphenyl)acetate (11b), reflux, 4e24 h (72e86%); (ii) 5% so-
dium hydroxide, ethanol/tetrahydrofuran, rt, 15 min (86e95%); (iii) thionyl chloride,
dichloromethane, reflux, 30e90 min (65e74%); (iv) (a) triethylamine, dichloromethane
or dimethylformamide, rt, 1 h; (b) acetyl chloride (for 9aed) or ethyl iodide (for 9e), rt,
3. Conclusion
In this paper we have conveniently synthesized derivatives of
two new ring systems isoindolo[1,4]benzoxazinone 5 and isoindolo
[1,5]benzoxazepines 8e10. The novel compounds were examined
1.5e24 h (50e95%); (v) (a) sodium hydride, tetrahydrofuran or dimethylformamide, rt,
1
h; (b) acetyl chloride (for 10a,b), ethyl iodide (for 10cef), rt, 1e24 h (54e85%).
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B. Parrino et al. / Tetrahedron xxx (2015) 1e7
3
Table 2
4.2.1. 2-(2-Hydroxyphenyl)-2H-isoindole-1-carbonitrile (3a). White
a
Overview of the in vitro antitumor screening results for isoindolo[1,5]benzox-
azepines 8aec
ꢁ
ꢀ1 1
;
solid; mp 143 C; yield 100%; IR: 3299 (OH), 2256 (CN) cm
NMR (CDCl , 200 MHz),
(ppm): 7.17e7.35 (6H, m, 6ꢃAreH),
7.68e7.74 (2H, m, 2ꢃAreH), 7.91 (1H, br s, OH), 8.27 (1H, d,
H
3
d
GI50
(
m
M)b
13
Compound
Nc
Nd
Range
MG_MIDe
J¼8.4 Hz, AreH); C NMR (CDCl
07.8 (CH), 115.4 (CH), 117.6 (CH), 120.0 (CH), 120.9 (CH), 122.4 (C),
123.7 (CH), 123.9 (CH), 125.6 (CH), 126.2 (C), 126.5 (C), 127.6 (CH),
3
, 50.3 MHz), d (ppm): 107.6 (C),
1
8a
8b
8c
58
58
57
58
14
38
1.84e15.5
1.61e5.55
1.46e91.0
3.72
4.68
5.13
144.2 (C), 152.1 (C). Found: C, 76.82; H, 4.25; N, 11.69. C15
9
H NO
TGI (
m
M)f
requires C, 76.91; H, 4.30; N, 11.96%.
Compound
Nc
Ng
Range
MG_MID
4
.2.2. 2-(2-Hydroxyphenyl)-5,6-dimethyl-2H-isoindole-1-
8
8
8
a
b
c
58
58
57
55
1
11
3.87e49.7
5.76
3.32e68.6
16.6
87.1
67.6
ꢁ
carbonitrile (3b). White needles; mp 146e148 C; yield 94%; IR:
ꢀ
1 1
3301 (OH), 2256 (CN) cm
2.36 (3H, s, CH ), 2.40 (3H, s, CH
s, AreH), 7.68 (1H, d, J¼7.3 Hz, AreH), 7.76 (1H, s, AreH), 8.28 (1H,
;
H NMR (CDCl
3
, 200 MHz), d (ppm):
LC50
(m
M)h
3
3
), 7.24 (4H, m, 4ꢃAreH), 7.44 (1H,
Nc
Ni
Compound
Range
MG_MID
13
br s, OH); C NMR (CDCl
3
, 50.3 MHz), (ppm): 20.7 (CH ), 20.9
d
3
8a
8b
8c
58
58
57
34
d
1
8.08e99.7
d
74.1
>100
>100
(CH ), 107.0 (CH), 115.3 (CH), 117.4 (CH), 118.8 (CH), 119.6 (CH), 119.7
3
87.8
(C), 122.7 (C), 123.6 (CH), 125.8 (C), 126.0 (C), 127.1 (CH), 134.0 (C),
136.2 (C), 141.0 (C), 144.0 (C). Found: C, 77.95; H, 5.12; N, 10.79.
a
Data obtained from the NCI in vitro disease-oriented human tumor cell line
screen.
C
17
H13NO requires C, 77.84; H, 5.38; N, 10.68%.
b
GI50: concentration (molar) that inhibit 50% net cell growth.
Number of cell lines investigated.
Number of cell lines giving positive GI50 values.
MG_MID: mean graph midpoint; this is the arithmetic mean value for all tested
c
4
.2.3. 2-(2-Hydroxyphenyl)-5,6-dimethoxy-2H-isoindole-1-
d
e
ꢁ
carbonitrile (3c). White solid; mp 131e133 C; yield 100%; IR: 3410
ꢀ
1 1
(OH), 2257 (CN) cm
;
H NMR (CDCl
3
, 200 MHz), d (ppm): 3.84
cancer cell lines. If the indicated effect was not attainable under the concentration
range used, the highest tested concentration was used for the calculation.
(3H, s, OCH
3
), 3.86 (3H, s, OCH ), 7.02 (1H, s, AreH), 7.19e7.41 (3H,
3
f
TGI: concentration (molar) that inhibit total net cell growth.
Number of cell lines giving positive TGI values.
LC50: concentration (molar) that induces 50% net cell death.
Number of cell lines giving positive LC50 values.
m, 3ꢃAreH), 7.53 (1H, s, AreH), 8.10e8.15 (1H, m, AreH), 8.33 (1H,
g
13
s, AreH), 10.39 (1H, br s, OH); C NMR (CDCl
55.3 (CH ), 55.5 (CH ), 93.4 (C), 95.5 (CH), 99.1 (CH), 116.1 (CH),
16.8 (CH),118.8 (C),119.2 (CH),125.5 (C),126.9 (CH),127.4 (C),127.9
CH), 148.0 (C), 148.9 (C), 150.9 (C), 152.2 (C). Found: C, 69.56; H,
3
, 50.3 MHz), d (ppm):
h
i
3
3
1
(
4
.68; N, 9.37. C17
3
H13NO requires C, 69.38; H, 4.79; N, 9.52%.
in their cytotoxic action against the NCI panel of about 60 human
cancer cell lines. Some of them showed antiproliferative activity
against a wide range of human tumor cell lines with GI50 mean
values at low micromolar level.
4.3. General procedure for the synthesis of 6H-isoindolo[1,2-
c][1,4]benzoxazin-6-ones 5aec
A solution of the intermediates 3aec (0.9 mmol) in acetic acid
2 mL) was heated under reflux for 2 h. After cooling, the mixture
was poured onto ice and the resulting precipitate filtered off and
purified by chromatography using dichloromethane as eluant.
4
4
. Experimental section
(
.1. Reagents and techniques
Anhydrous organic solvents were prepared by the appropriate
4
.3.1. 6H-Isoindolo[1,2-c][1,4]benzoxazin-6-one (5a). White solid;
procedures prior to use. The other organic solvents were reagent
grade and used as received. Analytical TLC was performed on
Merck Kieselgel 60-F254 plates. Column chromatography was
performed with Merck silica gel 230e400 mesh ASTM or with
a B u€ chi Sepacor chromatography module (prepacked cartridge
system). All melting points were taken on a B u€ chi B 540 melting
ꢁ
ꢀ1 1
mp 213e214 C; yield 79%; IR: 1710 (CO) cm
;
H NMR (CDCl
3
,
2
2
00 MHz),
ꢃAreH), 8.10 (1H, s, AreH), 8.34 (1H, dd, J¼0.9, 8.4 Hz, AreH);
, 50.3 MHz), (ppm): 106.2 (C), 110.1 (CH), 115.4 (CH),
18.7 (CH), 120.2 (CH), 120.6 (CH), 122.1 (C), 124.6 (CH), 124.7 (CH),
26.6 (C), 127.0 (CH), 128.2 (CH), 129.0 (C), 144.3 (C), 153.4 (C).
d
(ppm): 7.29e7.50 (5H, m, 5ꢃAreH), 7.76e7.85 (2H, m,
13
C
NMR (CDCl
1
1
3
d
point apparatus; IR spectra were determined in bromoform with
Found: C, 76.85; H, 3.62; N, 5.63. C15
N, 5.95%.
9
H NO requires C, 76.59; H, 3.86;
1
13
a Shimadzu FT/IR 8400S spectrophotometer; H and C NMR
spectra were measured in DMSO-d or CDCl (Me Si as internal
reference), at 200 and 50.3 MHz, using a Bruker AC-E series
00 MHz spectrometer. Elemental analyses (C, H, N) were within
6
3
4
4
.3.2. 8,9-Dimethyl-6H-isoindolo[1,2-c][1,4]benzoxazin-6-one
2
ꢁ
ꢀ1
(
5b). White solid; mp 244e246 C; yield 68%; IR: 1717 (CO) cm
;
ꢂ0.4% of the theoretical values and were performed with a VARIO
1
H NMR (CDCl
CH
), 7.27e7.46 (3H, m, 3ꢃAreH), 7.49 (1H, s, AreH), 7.74e7.78 (1H,
m, AreH), 7.92 (1H, s, AreH), 8.06 (1H, s, AreH); C NMR (CDCl
50.3 MHz), (ppm): 20.7 (CH ), 20.9 (CH ), 110.3 (CH), 115.2 (CH),
118.6 (CH), 119.1 (CH), 119.5 (CH), 122.3 (C), 124.5 (CH), 124.6 (C),
26.0 (C), 127.7 (CH), 128.6 (C), 134.8 (C), 137.7 (C), 137.8 (C), 144.2
3 3
, 200 MHz), d (ppm): 2.37 (3H, s, CH ), 2.40 (3H, s,
EL III elemental analyzer.
3
13
3
,
4
.2. General procedure for the synthesis of 2-(2-
hydroxyphenyl)-2H-isoindole-1-carbonitriles 3aec
d
3
3
1
To a solution of sodium hydrogen sulfite (0.71 g, 4.0 mmol) in
water (18 mL), the suitable o-phthalaldehyde 1aec (4.0 mmol) was
added. The mixture was stirred until the solid was dissolved, and
the 2-aminophenol 2 (0.44 g, 4.0 mmol) was added. The reaction
(C). Found: C, 77.85; H, 4.62; N, 5.63. C17
4.98; N, 5.32%.
2
H13NO requires C, 77.55; H,
4.3.3. 8,9-Dimethoxy-6H-isoindolo[1,2-c][1,4]benzoxazin-6-one
ꢁ
ꢁ
ꢀ1 1
mixture was heated on a steam bath for 30 min at 40 C, then
(5c). White solid; mp 212 C; yield 70%; IR: 1710 (CO) cm
NMR (CDCl , 200 MHz), (ppm): 3.87 (3H, s, OCH ), 3.90 (3H, s,
OCH
), 7.18 (1H, s, AreH), 7.39e7.50 (4H, m, 4ꢃAreH), 8.34 (1H, dd,
J¼1.8, 6.1 Hz, AreH), 8.63 (1H, s, AreH); C NMR (CDCl
; H
potassium cyanide (0.81 g, 12.0 mmol) in water (5 mL) was added,
and the mixture was heated for an additional 90 min. The solid
formed was filtered and recrystallized from ethanol.
3
d
3
3
13
3
, 50.3 MHz),
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4
B. Parrino et al. / Tetrahedron xxx (2015) 1e7
d
(ppm): 55.4 (2ꢃOCH
16.1 (CH), 117.8 (CH), 121.5 (C), 122.2 (C), 124.5 (C), 124.8 (CH), 127.4
CH), 143.2 (C), 149.1 (C), 151.6 (C), 152.8 (C). Found: C, 69.36; H,
3
), 97.5 (CH), 99.0 (CH), 104.5 (C), 112.7 (CH),
NMR (CDCl
(3H, s, OCH
3
, 200 MHz),
d
(ppm): 1.14 (3H, t, J¼7.1 Hz, CH
3
), 3.94
2
), 5.61
1
(
4
3
), 3.99 (3H, s, OCH
3
), 4.13 (2H, q, J¼7.1 Hz, CH
(1H, s, CH), 6.94 (2H, d, J¼6.2 Hz, 2ꢃAreH), 7.04 (1H, dd, J¼1.1,
8.2 Hz, AreH), 7.16 (1H, td, J¼1.1, 8.2 Hz, AreH), 7.26e7.29 (5H, m,
4
.68; N, 4.57. C17H13NO requires C, 69.15; H, 4.44; N, 4.74%.
1
3
5
ꢃAreH), 7.35e7.48 (2H, m, 2ꢃAreH), 7.52 (1H, br s, AreH);
C
),
4
.4. Synthesis of ethyl bromo(4-methylphenyl)acetate 11b
NMR (CDCl
1.8 (CH
3 3 3 3
, 50.3 MHz), d (ppm): 13.9 (CH ), 55.9 (CH ), 56.1 (CH
6
2
), 79.4 (CH), 94.4 (C), 98.4 (CH), 100.0 (CH), 114.9 (CH),
To a solution of ethyl p-tolylacetate (2.00 g, 11.0 mmol) in carbon
115.0 (C), 119.4 (C), 120.8 (CH), 122.4 (CH), 126.7 (2ꢃCH), 128.3 (CH),
128.4 (C), 128.5 (C), 128.7 (2ꢃCH), 129.0 (CH), 130.3 (CH), 134.5 (C),
148.7 (C), 151.1 (C), 151.5 (C), 169.2 (C). Found: C, 71.38; H, 5.18; N,
tetrachloride (29 mL), N-bromosuccinimide (2.00 g, 11.0 mmol) and
a catalytic amount of 48% aqueous HBr solution were added. The
mixture was stirred at reflux for 26 h. After cooling, the excess of N-
bromosuccinimide was removed by filtration. The solvent was
evaporated under reduced pressure and the crude product was
purified by chromatography using dichloromethane as eluant.
24 2 5
6.02. C27H N O requires C, 71.04; H, 5.30; N, 6.14%.
4.5.4. Ethyl [2-(1-cyano-2H-isoindol-2-yl)phenoxy](4-methylphenyl)
acetate (6d). White solid; the mixture was refluxed for 24 h; mp
ꢀ
1
1
ꢁ
ꢀ1
1
Orange oil; yield 75%; IR: 1743 (CO) cm
00 MHz), ), 2.30 (3H, s, CH
(ppm): 1.13 (3H, t, J¼7.0 Hz, CH
), 5.87 (1H, s, CH), 7.20 (2H, d, J¼7.5 Hz,
;
H NMR (CDCl
3
,
101e102 C; yield 80%; IR: 2200 (CN), 1729 (CO) cm
(CDCl , 200 MHz), ), 2.26 (3H, s,
(ppm): 1.10 (3H, t, J¼7.1 Hz, CH
CH ), 5.58 (1H, s, CH), 7.00e7.29 (7H, m,
), 4.11 (2H, q, J¼7.1 Hz, CH
7ꢃAreH), 7.35e7.53 (3H, m, 3ꢃAreH), 7.63e7.73 (3H, m, 3ꢃAreH);
; H NMR
2
(
2
5
d
3
3
), 4.18
3
d
3
2H, q, J¼7.0 Hz, CH
2
3
2
1
3
ꢃAreH), 7.45 (2H, d, J¼7.5 Hz, 2ꢃAreH); C NMR (CDCl
3
,
13
0.3 MHz), (ppm): 13.8 (CH ), 20.7 (CH ), 62.1 (CH ), 128.5
d
3
3
2
C NMR (CDCl
(CH ), 79.7 (CH), 100.2 (C), 115.2 (CH), 118.5 (CH), 121.0 (CH), 121.7
(CH), 122.5 (CH), 123.0 (CH), 124.3 (C), 125.7 (CH), 126.9 (2ꢃCH),
27.4 (C), 128.5 (CH), 129.2 (C), 129.5 (2ꢃCH), 130.8 (CH), 131.7 (C),
132.0 (C), 139.0 (C), 151.9 (C), 169.3 (C). Found: C, 76.35; H, 5.15; N,
6.76. C26 requires C, 76.08; H, 5.40; N, 6.82%.
3 3 3
, 50.3 MHz), d (ppm): 14.0 (CH ), 21.2 (CH ), 61.8
(
2ꢃCH), 129.3 (2ꢃCH), 132.3 (C), 138.7 (C), 139.6 (CH), 168.0 (C).
2
Found: C, 51.60; H, 4.98. C11 13BrO requires C, 51.38; H, 5.10%.
H
2
1
4
2
.5. General procedure for the synthesis of ethyl [2-(1-cyano-
H-isoindol-2-yl)phenoxy]acetate compounds 6aed
22 2 3
H N O
To a solution of suitable isoindoles 3aec (4.0 mmol) in tetra-
hydrofuran (20 mL), sodium hydride (4.0 mmol) was added. The
mixture was stirred at room temperature for 1 h, then ethyl bromo-
4.6. General procedure for the synthesis of [2-(1-cyano-2H-
isoindol-2-yl)phenoxy]acetic acids 7aed
(
(
4
phenyl)acetate 11a or ethyl bromo-(4-methylphenyl)acetate 11b
4.0 mmol) was added. The mixture was stirred under reflux for
e24 h. After cooling, the solvent was evaporated at reduced
To a solution of derivatives 6aed (25.0 mmol) in a mixture of
tetrahydrofuran and ethanol (1:1) (30 mL) a 5% aqueous sodium
hydroxide solution (25 mL) was added dropwise. The reaction
mixture was stirred for 15 min at room temperature. The solvent
was evaporated under reduced pressure, the remaining aqueous
layer was acidified with 6 N hydrochloric acid and extracted with
pressure and the crude was purified by chromatography using
dichloromethane as eluant.
4
.5.1. Ethyl [2-(1-cyano-2H-isoindol-2-yl)phenoxy](phenyl) acetate
2 4
ethyl acetate. The organic layer was dried with Na SO and evap-
orated. The product obtained was recrystallized from ethanol.
ꢁ
(6a). White solid; the mixture was refluxed for 7 h; mp 99e100 C;
ꢀ1
1
yield 86%; IR: 2200 (CN), 1746 (CO) cm
;
H NMR (CDCl
), 4.12 (2H, q, J¼7.1 Hz,
), 5.65 (1H, s, CH), 7.04e7.18 (3H, m, 3ꢃAreH), 7.22e7.32 (6H,
m, 6ꢃAreH), 7.45 (1H, dd, J¼1.7, 7.9 Hz, AreH), 7.52 (1H, dd, J¼1.7,
3
,
2
CH
00 MHz),
d
(ppm): 1.12 (3H, t, J¼7.1 Hz, CH
3
4.6.1. [2-(1-Cyano-2H-isoindol-2-yl)phenoxy](phenyl)acetic
acid
ꢁ
2
(7a). White solid; mp 182e183 C; yield 90%; IR: 3566 (OH), 2211
ꢀ1 1
6
(CN), 1733 (CO) cm ; H NMR (DMSO-d , 200 MHz), d (ppm): 6.05
13
7
5
.9 Hz, AreH), 7.68e7.74 (3H, m, 3ꢃAreH); C NMR (CDCl
3
,
(1H, s, CH), 7.14e7.35 (9H, m, 9ꢃAreH), 7.53e7.67 (3H, m, 3ꢃAreH),
0.3 MHz), (ppm): 13.9 (CH ), 61.9 (CH ), 79.3 (CH), 95.1 (C), 114.5
d
3
2
7.84 (1H, d, J¼8.5 Hz, AreH), 8.05 (1H, d, J¼0.7 Hz, AreH),13.35 (1H,
13
(
(
(
(
C), 114.7 (CH), 118.2 (CH), 120.9 (CH), 121.7 (CH), 122.4 (CH), 122.9
CH), 124.1 (C), 125.7 (CH), 126.7 (2ꢃCH), 128.1 (C), 128.3 (CH), 128.7
2ꢃCH), 129.0 (CH), 130.7 (CH), 131.9 (C), 134.3 (C), 151.4 (C), 169.1
6
br s, OH); C NMR (DMSO-d , 50.3 MHz), d (ppm): 77.7 (CH), 94.1
(C), 114.1 (C), 114.7 (CH), 117.4 (CH), 121.6 (CH), 121.8 (CH), 122.7
(CH), 123.0 (CH), 123.6 (C), 126.0 (CH), 126.9 (2ꢃCH), 127.1 (C), 128.4
(2ꢃCH), 128.5 (CH), 128.8 (CH), 131.0 (CH), 131.1 (C), 134.4 (C), 151.3
20 2 3
C). Found: C, 75.58; H, 4.88; N, 6.84. C25H N O requires C, 75.74;
H, 5.08; N, 7.07%.
16 2 3
(C), 170.2 (C). Found: C, 74.90; H, 4.65; N, 7.45. C23H N O requires
C, 74.99; H, 4.38; N, 7.60%.
4.5.2. Ethyl
[2-(1-cyano-5,6-dimethyl-2H-isoindol-2-yl)phenox-
y](phenyl)acetate (6b). White solid; the mixture was refluxed for
4.6.2. [2-(1-Cyano-5,6-dimethyl-2H-isoindol-2-yl)phenoxy](phenyl)
ꢁ
ꢀ1
1
ꢁ
4
h; mp 131ee133 C; yield 72%; IR: 2196 (CN), 1746 (CO) cm ; H
NMR (CDCl , 200 MHz), ), 2.36
(ppm): 1.13 (3H, t, J¼7.1 Hz, CH
3H, s, CH ), 2.40 (3H, s, CH ), 5.63 (1H, s,
acetic acid (7b). White solid; mp 212e213 C; yield 95%; IR: 3557
ꢀ
1 1
3
d
3
(OH), 2203 (CN), 1728 (CO) cm
;
H NMR (DMSO-d
6
, 200 MHz),
(
3
3
), 4.13 (2H, q, J¼7.1 Hz, CH
2
d
(ppm): 2.33 (3H, s, CH ), 2.37 (3H, s, CH
3
3
), 6.04 (1H, s, CH), 7.21
CH), 7.04 (1H, dd, J¼1.1, 8.3 Hz, AreH), 7.16 (1H, td, J¼1.2, 7.7 Hz,
AreH), 7.24e7.33 (5H, m, 5ꢃAreH), 7.36e7.52 (4H, m, 4ꢃAreH),
(1H, td, J¼0.9, 7.5 Hz, AreH), 7.25e7.36 (6H, m, 6ꢃAreH), 7.42 (1H,
br s, AreH), 7.51e7.61 (3H, m, 3ꢃAreH), 7.87 (1H, br s, AreH), 13.36
.58 (1H, br s, AreH); 13C NMR (CDCl
d
(ppm): 13.9
(1H, br s, OH); C NMR (DMSO-d
13
, 50.3 MHz),
d
(ppm): 20.1 (CH
),
7
3
, 50.3 MHz),
6
3
(
(
(
CH
3
), 20.6 (CH
3
), 20.9 (CH
3
), 61.9 (CH
2
), 79.3 (CH), 99.9 (C), 114.7
3
20.4 (CH ), 77.6 (CH), 92.9 (C), 114.4 (C), 114.6 (CH), 116.2 (CH), 119.9
CH), 115.0 (C), 117.1 (CH), 119.5 (CH), 120.8 (CH), 122.3 (CH), 123.6
(CH), 121.7 (CH), 121.8 (CH), 123.0 (C), 126.9 (2ꢃCH), 127.2 (C), 128.3
(CH), 128.5 (2ꢃCH), 128.7 (CH), 130.7 (C), 130.8 (CH), 132.3 (C), 135.4
(C), 136.1 (C), 151.2 (C), 170.2 (C). Found: C, 75.66; H, 4.85; N, 7.35.
C), 126.7 (2ꢃCH), 128.3 (C), 128.4 (CH), 128.7 (2ꢃCH), 129.0 (CH),
1
30.4 (CH), 131.6 (C), 132.8 (C), 134.4 (C), 136.2 (C), 151.4 (C), 169.1
(
C). Found: C, 76.58; H, 5.85; N, 6.32. C27
H N
24 2
O
3
requires C, 76.39;
25 20 2 3
C H N O requires C, 75.74; H, 5.08; N, 7.07%.
H, 5.70; N, 6.60%.
4
.6.3. [2-(1-Cyano-5,6-dimethoxy-2H-isoindol-2-yl)phenox-
ꢁ
4.5.3. Ethyl
[2-(1-cyano-5,6-dimethoxy-2H-isoindol-2-yl)phenox-
y](phenyl)acetic acid (7c). White solid; mp 215e217 C; yield 86%;
IR: 3020 (OH), 2207 (CN), 1733 (CO) cm
ꢀ1
1
y](phenyl)acetate (6c). White solid; the mixture was refluxed for
;
H NMR (DMSO-d
6
,
ꢁ
ꢀ1 1
6
h; mp 114e116 C; yield 78%; IR: 2256 (CN), 1731 (CO) cm ; H
200 MHz), (ppm): 3.83 (3H, s, OCH ), 3.88 (3H, s, OCH
d
3
3
), 6.03 (1H,
Please cite this article in press as: Parrino, B.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.083

B. Parrino et al. / Tetrahedron xxx (2015) 1e7
5
s, CH), 6.92 (1H, s, AreH), 7.15 (1H, s, AreH), 7.20e7.38 (7H, m,
ꢃAreH), 7.54e7.57 (2H, m, 2ꢃAreH), 7.78 (1H, s, AreH),13.30 (1H,
AreH), 7.81e7.86 (1H, m, AreH); 13C NMR (CDCl
3
(ppm): 56.2 (CH ), 56.3 (CH ), 92.2 (CH), 96.1 (CH), 98.9 (C), 99.6
(CH), 113.4 (C), 124.3 (CH), 125.3 (CH), 125.5 (C), 126.1 (C), 126.3
(CH), 128.2 (2ꢃCH), 128.3 (C), 128.7 (2ꢃCH), 129.1 (CH), 130.1 (CH),
131.7 (C), 136.1 (C), 149.8 (C), 152.0 (C), 153.0 (C), 190.3 (C). Found: C,
3
, 50.3 MHz),
7
d
3
13
br s, OH); C NMR (DMSO-d
CH ), 77.6 (CH), 93.2 (C), 95.5 (CH), 99.1 (CH), 114.6 (CH), 118.8 (C),
21.7 (CH), 126.6 (CH), 126.9 (2ꢃCH), 127.4 (C), 127.6 (C), 128.1 (C),
28.3 (CH),128.5 (2ꢃCH),128.7 (CH),130.6 (CH),135.4 (C),148.2 (C),
6
, 50.3 MHz),
d
(ppm): 55.4 (CH
3
), 55.5
(
3
1
1
73.26; H, 4.58; N, 6.58. C25
6.83%.
18 2 4
H N O requires C, 73.16; H, 4.42; N,
151.1 (C), 151.3 (C), 170.2 (C). Found: C, 69.89; H, 4.52; N, 6.36.
C
25 20 2 5
H N O requires C, 70.08; H, 4.71; N, 6.54%.
4
.7.4. 6-(4-Methylphenyl)-7-oxo-6,7-dihydroisoindolo[1,2-d][1,5]
4
.6.4. [2-(1-Cyano-2H-isoindol-2-yl)phenoxy](4-methylphenyl)ace-
benzoxazepine-12-carbonitrile (8d). Yellow needles; the mixture
was refluxed for 1.5 h; mp 180e181 C; yield 74%; IR: 2255 (CN),
ꢁ
ꢁ
tic acid (7d). White solid; mp 200e202 C; yield 90%; IR: 3021
ꢀ
1
1
ꢀ1 1
(
OH), 2204 (CN), 1751 (CO) cm
;
H NMR (DMSO-d
), 5.98 (1H, s, CH), 7.05e7.36 (8H, m,
ꢃAreH), 7.52e7.67 (3H, m, 3ꢃAreH), 7.83 (1H, d, J¼8.5 Hz, AreH),
6
, 200 MHz),
1653 (CO) cm ; H NMR (CDCl
CH
), 5.63 (1H, s, CH), 7.14e7.26 (4H, m, 4ꢃAreH), 7.40e7.45 (4H,
m, 4ꢃAreH), 7.83e7.92 (2H, m, 2ꢃAreH), 8.21e8.25 (2H, m,
3
, 200 MHz), d (ppm): 2.35 (3H, s,
d
(ppm): 2.23 (3H, s, CH
3
3
8
8
5
13
13
.03 (1H, s, AreH), 12.84 (1H, br s, OH); C NMR (DMSO-d
6
,
2ꢃAreH); C NMR (CDCl
3 3
, 50.3 MHz), d (ppm): 21.3 (CH ), 92.9
0.3 MHz), (ppm): 20.6 (CH ), 77.6 (CH), 94.1 (C), 114.0 (C), 114.7
d
3
(CH), 113.0 (C), 118.4 (CH), 122.0 (CH), 124.6 (CH), 125.7 (CH), 126.4
(CH), 127.0 (C), 127.1 (C), 127.4 (CH), 128.1 (2ꢃCH), 128.2 (CH), 128.6
(C), 129.4 (2ꢃCH), 130.9 (CH), 131.5 (C), 131.7 (C), 132.3 (C), 133.1 (C),
(
(
(
CH), 117.4 (CH), 121.5 (CH), 121.6 (CH), 121.7 (CH), 122.7 (CH), 122.9
CH), 123.5 (C), 125.9 (C), 126.9 (2ꢃCH), 127.1 (C), 128.3 (CH), 129.0
2ꢃCH), 131.0 (CH), 132.4 (C), 138.2 (C), 151.3 (C), 170.3 (C). Found: C,
164.5 (C), 191.0 (C). Found: C, 79.01; H, 4.12; N, 7.90. C24
16 2 2
H N O
7
18 2 3
5.26; H, 4.50; N, 7.25. C24H N O requires C, 75.38; H, 4.74; N,
requires C, 79.11; H, 4.43; N, 7.69%.
7.33%.
4.8. General procedure for the synthesis of 12-cyano-iso-
4
.7. General procedure for the synthesis of 7-oxo-6,7-
indolo[1,2-d][1,5]benzoxazepin-7-yl acetate compounds 9aed
dihydroisoindolo[1,2-d][1,5]benzoxazepine-12-carbonitriles
aed
8
To a solution of derivatives 8aed (0.6 mmol) in dichloro-
methane (5 mL), triethylamine was added (0.16 mL, 1.2 mmol) and
the mixture was stirred for 1 h at room temperature. Then acetyl
chloride (1.2 mmol) was added and the mixture was maintained
under stirring at room temperature for 5e24 h. The mixture was
poured onto ice and extracted with ethyl acetate. The organic phase
was concentrated and the crude purified by chromatography using
dichloromethane as eluant.
To a suspension of derivatives 7aed (1.4 mmol) in dichloro-
methane (30 mL), thionyl chloride (0.3 mL, 4.2 mmol) was added
and the reaction mixture was refluxed for 30e90 min. After cooling,
the mixture was basified with a 5% aqueous sodium hydroxide
solution and extracted with dichloromethane. The solvent was
evaporated under reduced pressure and the crude was purified by
chromatography using dichloromethane as eluant.
4.8.1. 12-Cyano-6-phenylisoindolo[1,2-d][1,5]benzoxazepin-7-yl ace-
4
.7.1. 7-Oxo-6-phenyl-6,7-dihydroisoindolo[1,2-d][1,5]benzox-
tate (9a). Yellow needles; the mixture was stirred at room tem-
ꢁ
azepine-12-carbonitrile (8a). Yellow solid; the mixture was
refluxed for 1 h; mp 153e154 C; Yield 65%; IR: 2256 (CN), 1652
perature for 5 h; mp 212ee213 C; yield 95%; IR: 2196 (CN), 1765
ꢁ
ꢀ1 1
(CO) cm ; H NMR (CDCl
3
, 200 MHz),
d
(ppm): 2.39 (3H, s, CH
3
),
ꢀ1 1
(
CO) cm
3
; H NMR (CDCl , 200 MHz), d (ppm): 5.66 (1H, s, CH),
7.30e7.63 (8H, m, 8ꢃAreH), 7.77e7.95 (4H, m, 4ꢃAreH), 8.05e8.10
13
7.23e7.48 (10H, m, 10ꢃAreH), 7.82e7.94 (2H, m, 2ꢃAreH),
8
3 3
(1H, m, AreH); C NMR (CDCl , 50.3 MHz), d (ppm): 20.5 (CH
),
13
.18e8.25 (1H, m, AreH); C NMR (CDCl
3
, 50.3 MHz),
d
(ppm): 92.9
94.1 (C), 113.9 (C), 117.9 (CH), 120.4 (CH), 122.2 (CH), 122.4 (C), 124.2
(C), 125.1 (CH), 125.8 (CH), 126.9 (2ꢃCH), 127.0 (CH), 127.4 (CH),
129.1 (2ꢃCH), 129.9 (C), 130.1 (CH), 130.8 (C), 131.2 (CH), 131.6 (C),
131.7 (C), 149.3 (C), 153.8 (C), 169.0 (C). Found: C, 76.68; H, 4.01; N,
(
(
1
CH), 99.4 (C), 113.0 (C), 118.4 (CH), 121.9 (CH), 124.5 (CH), 125.7
CH), 126.5 (CH), 126.9 (C), 127.4 (CH), 128.1 (2ꢃCH), 128.2 (CH),
28.6 (C), 128.7 (2ꢃCH), 129.2 (CH), 130.9 (CH), 131.4 (C), 131.7 (C),
1
35.9 (C), 149.9 (C), 190.7 (C). Found: C, 78.66; H, 4.17; N, 7.82.
7.25. C25
16 2 3
H N O requires C, 76.52; H, 4.11; N, 7.14%.
C
H
23 14
N
2
O
2
requires C, 78.84; H, 4.03; N, 8.00%.
4.8.2. 12-Cyano-9,10-dimethyl-6-phenylisoindolo[1,2-d][1,5]benzox-
4
.7.2. 9,10-Dimethyl-7-oxo-6-phenyl-6,7-dihydroisoindolo[1,2-d]
azepin-7-yl acetate (9b). Yellow needles; the mixture was stirred at
ꢁ
[1,5]benzoxazepine-12-carbonitrile (8b). Yellow solid; the mixture
room temperature for 24 h; mp 248e249 C; yield 74%; IR: 2256
ꢁ
ꢀ1 1
was refluxed for 1 h; mp 224e225 C; Yield 68%; IR: 2228 (CN),
(CN),1775 (CO) cm ; H NMR (CDCl
s, CH ), 2.38 (3H, s, CH ), 2.39 (3H, s, CH
8ꢃAreH), 7.87e7.92 (3H, m, 3ꢃAreH); C NMR (CDCl
(ppm): 20.2 (CH ), 20.3 (CH ), 20.5 (CH ), 93.0 (C), 99.5 (CH), 114.2
3
, 200 MHz),
), 7.49e7.64 (8H, m,
, 50.3 MHz),
d (ppm): 2.37 (3H,
ꢀ1 1
1
660 (CO) cm ; H NMR (CDCl
CH ), 2.41 (3H, s, CH ), 5.60 (1H, s, CH), 7.19e7.24 (1H, m, AreH),
.34e7.40 (7H, m, 7ꢃAreH), 7.58 (1H, br s, AreH), 7.85e7.89 (1H, m,
3
, 200 MHz),
d
(ppm): 2.36 (3H, s,
3
3
3
13
3
3
3
7
d
3
3
3
13
AreH), 8.02 (1H, br s, AreH); C NMR (CDCl
3
, 50.3 MHz),
d
(ppm):
(C),116.6 (CH), 118.8 (CH),121.8 (C), 122.1 (CH),123.2 (C), 125.6 (CH),
126.8 (2ꢃCH), 126.9 (C), 129.0 (2ꢃCH), 129.9 (CH), 130.1 (C), 130.9
(CH), 131.2 (C), 131.8 (C), 135.2 (C), 138.0 (C), 148.7 (C), 153.6 (C),
2
0.7 (CH ), 20.8 (CH ), 92.9 (CH), 100.2 (C), 113.3 (C), 117.5 (CH),
3
3
1
21.0 (CH), 124.5 (CH), 125.8 (CH), 126.4 (CH), 128.3 (2ꢃCH), 128.5
(
C), 128.6 (C), 128.7 (2ꢃCH), 129.1 (CH), 130.5 (CH), 131.5 (C), 132.0
20 2 3
168.9 (C). Found: C, 76.92; H, 4.67; N, 6.54. C27H N O requires C,
(
C), 136.4 (C), 138.1 (C), 139.2 (C), 150.2 (C), 190.4 (C). Found: C,
77.13; H, 4.79; N, 6.66%.
7
18 2 2
9.20; H, 4.56; N, 7.25. C25H N O requires C, 79.35; H, 4.79; N,
7.40%.
4.8.3. 12-Cyano-9,10-dimethoxy-6-phenylisoindolo[1,2-d][1,5]ben-
zoxazepin-7-yl-acetate (9c). Yellow needles; the mixture was stir-
ꢁ
4
.7.3. 9,10-Dimethoxy-7-oxo-6-phenyl-6,7-dihydroisoindolo[1,2-d]
red at room temperature for 24 h; mp 247e248 C; yield 73%; IR:
ꢀ
1 1
[1,5]benzoxazepine-12-carbonitrile (8c). Yellow needles; the mix-
2256 (CN), 1768 (CO) cm
2.29 (3H, s, CH ), 3.93 (3H, s, OCH
AreH), 7.05 (1H, s, AreH), 7.29e7.47 (6H, m, 6ꢃAreH), 7.78e7.81
;
H NMR (CDCl
3
, 200 MHz),
d (ppm):
ꢁ
ture was refluxed for 30 min; mp 195e197 C; yield 70%; IR: 2256
3
3
), 4.00 (3H, s, OCH
3
), 6.98 (1H, s,
ꢀ1 1
(
CN),1658 (CO) cm ; H NMR (CDCl
s, OCH ), 4.02 (3H, s, OCH ), 5.60 (1H, s, CH), 7.04 (1H, s, AreH),
.19e7.24 (1H, m, AreH), 7.34e7.41 (7H, m, 7ꢃAreH), 7.57 (1H, s,
3
, 200 MHz), d (ppm): 3.95 (3H,
13
3
3
(2H, m, 2ꢃAreH), 7.89e7.94 (1H, m, AreH); C NMR (CDCl
3
,
7
50.3 MHz), (ppm): 20.7 (CH ), 55.9 (CH ), 56.2 (CH ), 94.0 (C), 96.4
d
3
3
3
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6
B. Parrino et al. / Tetrahedron xxx (2015) 1e7
(
1
(
CH), 98.1 (CH), 115.1 (C), 118.4 (C), 122.0 (CH), 123.5 (C), 125.3 (CH),
26.4 (CH), 127.1 (2ꢃCH), 128.6 (2ꢃCH), 129.3 (C), 129.5 (CH), 129.6
CH), 131.0 (C), 131.9 (C), 132.2 (C), 149.4 (C), 149.6 (C), 151.7 (C),
76.34; H, 4.05; N, 7.40. C25
7.14%.
16 2 3
H N O requires C, 76.52; H, 4.11; N,
153.9 (C), 168.3 (C). Found: C, 71.85; H, 4.63; N, 6.44. C27
H
20
N
2
O
5
4.10.2. 6-Acetyl-9,10-dimethyl-7-oxo-6-phenyl-6,7-dihydroisoindolo
requires C, 71.67; H, 4.46; N, 6.19%.
[1,2-d][1,5]benzoxazepine-12-carbonitrile (10b). Yellow needles; the
mixture was stirred at room temperature for 1 h; mp 97e99 C;
ꢁ
ꢀ
1 1
4
.8.4. 12-Cyano-6-(4-methylphenyl)isoindolo[1,2-d][1,5]benzox-
yield 74%; IR: 2215 (CN),1771 (CO),1630 (CO) cm ; H NMR (CDCl
200 MHz), (ppm): 1.95 (3H, s, CH ), 2.29 (3H, s, CH ), 2.38 (3H, s,
CH
), 7.32 (1H, d, J¼8.1 Hz, AreH), 7.40e7.49 (2H, m, 2ꢃAreH),
7.55e7.63 (3H, m, 3ꢃAreH), 7.69 (1H, s, AreH), 7.74e7.89 (4H, m,
3
,
azepin-7-yl-acetate (9d). Yellow/orange needles; the mixture was
stirred at room temperature for 24 h; mp 239 C; yield 74%; IR:
d
3
3
ꢁ
3
ꢀ
1 1
2
2
7
(
(
1
1
1
196 (CN), 1763 (CO) cm
.28 (3H, s, CH ), 2.42 (3H, s, CH
.68e7.83 (4H, m, 4ꢃAreH), 7.94e7.99 (1H, m, AreH); C NMR
CDCl , 50.3 MHz), (ppm): 20.8 (CH ), 21.5 (CH ), 94.5 (C), 100.1
C),114.7 (C),118.5 (CH),120.4 (CH),122.1 (CH),122.9 (C),124.4 (CH),
24.9 (C), 125.7 (CH), 126.5 (CH), 126.7 (CH), 127.1 (2ꢃCH), 129.0 (C),
29.4 (2ꢃCH), 130.2 (CH), 130.8 (C), 132.6 (C), 140.1 (C), 150.4 (C),
54.5 (C), 168.6 (C). Found: C, 77.05; H, 4.23; N, 6.96. C26
requires C, 76.83; H, 4.46; N, 6.89%.
;
H NMR (CDCl
3
, 200 MHz), d (ppm):
), 7.15e7.46 (7H, m, 7ꢃAreH),
13
3
3
4ꢃAreH); C NMR (CDCl
3 3
, 50.3 MHz), d (ppm): 19.8 (CH ), 19.9
(CH ), 20.8 (CH ), 99.5 (C), 105.3 (C), 111.4 (C), 117.8 (CH), 118.6 (CH),
1
3
3
3
3
d
3
3
122.0 (C), 123.4 (CH), 126.7 (CH), 127.5 (C), 128.7 (CH), 128.9 (C),
129.3 (2ꢃCH), 129.5 (C), 129.6 (2ꢃCH), 131.7 (CH), 135.5 (CH), 137.7
(C), 139.6 (C), 145.6 (C), 167.3 (C), 182.0 (C), 192.2 (C). Found: C,
77.35; H, 4.58; N, 6.40. C27
6.66%.
20 2 3
H N O requires C, 77.13; H, 4.79; N,
18 2 3
H N O
4
6
.11. General procedure for the synthesis of 6-ethyl-7-oxo-
,7-dihydroisoindolo[1,2-d][1,5]benzoxazepine-12-
4
.9. Synthesis of 7-ethoxy-6-phenylisoindolo[1,2-d][1,5]ben-
carbonitriles 10cef
zoxazepine-12-carbonitrile 9e
To a solution of compounds 8cef (0.6 mmol) in dime-
thylformamide (3 mL), sodium hydride (14.4 mg, 0.6 mmol) was
added and the mixture was stirred for 1 h at room temperature.
Then, ethyl iodide (0.05 mL, 0.6 mmol) was added and the mixture
was stirred at room temperature for 1e3 h. The mixture was poured
onto ice and extracted with ethyl acetate. The organic phase was
concentrated and the crude purified by chromatography using
dichloromethane as eluant.
To a solution of 8a (0.6 mmol) in dimethylformamide (3 mL),
triethylamine (0.6 mmol) was added and the mixture was stirred
for 1 h at room temperature. Then, ethyl iodide (0.05 mL, 0.6 mmol)
was added and the mixture was stirred at room temperature for
1.5 h. The mixture was poured onto ice, the resulting precipitate
was filtered off, and purified by chromatography with dichloro-
methane as eluant.
ꢁ
ꢀ1
Yellow needles; mp 220e221 C; yield 50%; IR: 2256 (CN) cm
H NMR (CDCl , 200 MHz), ), 4.25
(ppm): 1.19 (3H, t, J¼7.1 Hz, CH
2H, q, J¼7.1 Hz, CH ), 7.26e7.37 (4H, m, 4ꢃAreH), 7.45e7.76 (8H,
m, 8ꢃAreH), 8.13e8.18 (1H, m, AreH); C NMR (CDCl
(ppm): 14.0 (CH ), 60.9 (CH ), 100.0 (C), 118.5 (CH), 119.1 (C), 122.0
;
1
3
d
3
4
.11.1. 6-Ethyl-7-oxo-6-phenyl-6,7-dihydroisoindolo[1,2-d][1,5]ben-
(
2
zoxazepine-12-carbonitrile (10c). Yellow solid; the mixture was
13
3
, 50.3 MHz),
ꢁ
stirred at room temperature for 3 h; mp 99e100 C; yield 85%; IR:
d
3
2
ꢀ1 1
2
213 (CN), 1747 (CO) cm ; H NMR (CDCl
), 4.23 (2H, q, J¼7.1 Hz, CH
ꢃAreH), 7.56e7.81 (7H, m, 7ꢃAreH), 7.88 (1H, dd, J¼1.5, 7.7 Hz,
3
, 200 MHz),
d (ppm): 1.13
(
(
1
CH), 123.4 (CH), 123.5 (C), 126.2 (CH), 126.4 (CH), 126.6 (CH), 127.2
(
4
3H, t, J¼7.1 Hz, CH
3
2
), 7.33e7.44 (4H, m,
C), 127.3 (C), 128.2 (C), 128.3 (CH), 128.5 (2ꢃCH), 130.0 (2ꢃCH),
30.1 (C), 130.5 (C), 131.1 (CH), 133.8 (CH), 146.2 (C), 163.2 (C).
13
AreH), 8.04e8.09 (1H, m, AreH); C NMR (CDCl
3
, 50.3 MHz),
18 2 2
Found: C, 79.54; H, 4.53; N, 7.08. C25H N O requires C, 79.35; H,
d
(ppm): 13.7 (CH ), 60.7 (CH ), 99.5 (CH), 101.8 (C), 112.0 (C), 118.2
3
2
4
.79; N, 7.40%.
(
(
CH), 118.6 (C), 121.4 (CH), 123.5 (CH), 126.3 (C), 126.7 (CH), 126.8
CH), 127.4 (C), 128.5 (2ꢃCH), 128.9 (CH), 129.2 (2ꢃCH), 129.3 (C),
4
6
.10. General procedure for the synthesis of 6-acetyl-7-oxo-
,7-dihydroisoindolo[1,2-d][1,5]benzoxazepine-12-
130.3 (C), 131.3 (CH), 134.3 (CH), 145.6 (C), 158.6 (C), 162.7 (C).
Found: C, 79.54; H, 4.53; N, 7.08. C25
4.79; N, 7.40%.
18 2 2
H N O requires C, 79.35; H,
carbonitriles 10a,b
To a solution of derivatives 8a,b (1.0 mmol) in tetrahydrofu-
ran (23 mL), sodium hydride (24 mg, 1.0 mmol) was added and
the reaction mixture was stirred for 1 h at room temperature.
Acetyl chloride (78.5 mg, 1.0 mol) was added and the reaction
mixture was stirred at room temperature for 1e24 h. The solvent
was evaporated under reduced pressure and the residue was
dissolved in dichloromethane, washed with a saturated solution
4.11.2. 6-Ethyl-9,10-dimethyl-7-oxo-6-phenyl-6,7-dihydroisoindolo
[1,2-d][1,5]benzoxazepine-12-carbonitrile (10d). Yellow solid; the
ꢁ
mixture was stirred at room temperature for 1 h; mp 116e118 C;
ꢀ1
1
yield 54%; IR: 2211 (CN), 1746 (CO) cm
200 MHz),
(ppm): 1.16 (3H, t, J¼7.1 Hz, CH
4.23 (2H, q, J¼7.1 Hz, CH ), 7.30 (2H, t, J¼7.8 Hz, 2ꢃAreH), 7.45e7.64
(6H, m, 6ꢃAreH), 7.74e7.79 (2H, m, 2ꢃAreH), 7.90 (1H, br s, AreH);
;
H NMR (CDCl
3
,
d
3
), 2.37 (6H, s, 2ꢃCH
3
),
2
13
of ammonium chloride, dried (Na
2
SO
4
), and evaporated. The
C NMR (CDCl
(CH ), 60.7 (CH
(CH), 123.4 (CH), 126.2 (CH), 127.0 (C), 128.3 (C), 128.4 (CH), 128.5
2ꢃCH), 129.8 (C), 130.0 (2ꢃCH), 130.7 (C), 130.8 (CH), 133.7 (CH),
137.0 (C), 137.1 (C), 146.3 (C), 159.6 (C), 163.2 (C). Found: C, 79.96; H,
5.63; N, 6.55. C27 requires C, 79.78; H, 5.46; N, 6.89%.
3
, 50.3 MHz),
3 3
d (ppm): 14.0 (CH ), 20.7 (CH ), 20.9
crude was purified by chromatography with dichloromethane as
eluant.
3
2
), 101.6 (C), 112.6 (C), 117.3 (CH), 118.2 (C), 120.7
(
4.10.1. 6-Acetyl-7-oxo-6-phenyl-6,7-dihydroisoindolo[1,2-d][1,5]ben-
zoxazepine-12-carbonitrile (10a). Yellow solid; the mixture was
22 2 2
H N O
ꢁ
stirred at room temperature for 24 h; mp 126e128 C; yield 70%;
ꢀ
1
1
IR: 2256 (CN), 1775 (CO), 1635 (CO) cm
00 MHz), (ppm): 2.02 (3H, s, CH
), 7.24e7.68 (9H, m, 9ꢃAreH),
.81e7.93 (4H, m, 4ꢃAreH); C NMR (CDCl , 50.3 MHz), (ppm):
0.4 (CH ), 106.2 (C), 111.3 (C), 119.2 (CH), 120.8 (CH), 123.5 (CH),
23.9 (C), 126.6 (CH), 126.9 (CH), 128.4 (CH), 128.6 (CH), 128.7 (C),
28.9 (2ꢃCH), 129.5 (C), 130.0 (2ꢃCH), 130.1 (C), 131.6 (CH), 132.3
C), 135.0 (CH), 145.8 (C), 167.3 (C), 182.3 (C), 191.8 (C). Found: C,
;
H NMR (CDCl
3
,
4.11.3. 6-Ethyl-9,10-dimethoxy-7-oxo-6-phenyl-6,7-dihydroisoindolo
[1,2-d][1,5]benzoxazepine-12-carbonitrile (10e). Yellow needles; the
2
7
d
3
13
ꢁ
3
d
mixture was stirred at room temperature for 1 h; mp 119e120 C;
ꢀ
1
1
2
3
yield 70%; IR: 2211 (CN), 1681 (CO) cm
200 MHz), (ppm): 1.17e1.24 (5H, m, CH3, CH
2ꢃCH ), 6.58e7.11 (3H, m, 3ꢃAreH), 7.18e7.79 (8H, m, 8ꢃAreH);
C NMR (CDCl , 50.3 MHz), (ppm): 14.5 (CH ), 56.2 (CH ), 56.3
;
H NMR (CDCl
3
,
1
1
(
d
2
), 4.01 (6H, s,
3
13
3
d
3
3
Please cite this article in press as: Parrino, B.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.083

B. Parrino et al. / Tetrahedron xxx (2015) 1e7
7
(
(
(
(
CH
3
), 64.0 (CH
2
), 96.8 (CH), 100.1 (C), 100.2 (CH), 112.3 (CH), 112.4
9. Lennon, J. C.; Bright, S. A.; Carroll, E.; Butini, S.; Campiani, G.; O’Meara, A.;
Williams, D. C.; Zisterer, D. M. Biochem. Pharmacol. 2014, 87, 611.
C), 120.2 (CH), 124.7 (C), 125.6 (C), 126.2 (C), 128.4 (2ꢃCH), 129.4
2ꢃCH), 130.1 (CH), 130.9 (C), 132.0 (CH), 132.6 (C), 134.3 (CH), 151.4
C), 152.9 (C), 154.3 (C), 184.2 (C), 191.6 (C). Found: C, 74.18; H, 5.26;
1
0. Barraja, P.; Diana, P.; Lauria, A.; Montalbano, A.; Almerico, A. M.; Dattolo, G.;
Cirrincione, G.; Viola, G.; Dall’Acqua, F. Bioorg. Med. Chem. Lett. 2003, 13, 2809.
11. Barraja, P.; Caracausi, L.; Diana, P.; Carbone, A.; Montalbano, A.; Cirrincione, G.;
Brun, P.; Pal uꢀ , G.; Castagliuolo, I.; Dall’Acqua, F.; Vedaldi, D.; Salvador, A. Bioorg.
N, 6.76. C27
22 2 4
H N O requires C, 73.96; H, 5.06; N, 6.39%.
Med. Chem. 2010, 18, 4830.
12. Barraja, P.; Caracausi, L.; Diana, P.; Montalbano, A.; Carbone, A.; Salvador, A.;
4
.11.4. 6-Ethyl-6-(4-methylphenyl)-7-oxo-6,7-dihydroisoindolo[1,2-
Brun, P.; Castagliuolo, I.; Tisi, S.; Dall’Acqua, F.; Vedaldi, D.; Cirrincione, G.
ChemMedChem 2011, 6, 1238.
d][1,5]benzoxazepine-12-carbonitrile (10f). The mixture was stirred
at room temperature for 1 h; orange oil; Yield 55%; IR: 2213 (CN),
1
3. Barraja, P.; Diana, P.; Span oꢀ , V.; Montalbano, A.; Carbone, A.; Parrino, B.; Cir-
rincione, G. Tetrahedron 2012, 68, 5087.
14. Carbone, A.; Parrino, B.; Barraja, P.; Span oꢀ , V.; Cirrincione, G.; Diana, P.; Maier,
A.; Kelter, G.; Fiebig, H.-H. Mar. Drugs 2013, 11, 643.
5. Barraja, P.; Span oꢀ , V.; Diana, P.; Carbone, A.; Cirrincione, G. Tetrahedron Lett.
ꢀ
1 1
1740 (CO) cm
;
H NMR (CDCl
3
, 200 MHz),
d
(ppm): 1.18 (3H, t,
), 7.08 (2H,
J¼7.1 Hz, CH
3
), 2.33 (3H, s, CH
3
), 4.25 (2H, q, J¼7.1 Hz, CH
2
1
d, J¼8.0 Hz, 2ꢃAreH), 7.30e7.35 (2H, m, 2ꢃAreH), 7.46e7.76 (7H,
2009, 50, 5389.
13
m, 7ꢃAreH), 8.14e8.19 (1H, m, AreH); C NMR (CDCl
3
, 50.3 MHz),
16. Barraja, P.; Diana, P.; Montalbano, A.; Carbone, A.; Viola, G.; Basso, G.; Salvador,
A.; Vedaldi, D.; Dall’Acqua, F.; Cirrincione, G. Bioorg. Med. Chem. 2011, 19, 2326.
7. Montalbano, A.; Parrino, B.; Diana, P.; Barraja, P.; Carbone, A.; Spano, V.; Cir-
rincione, G. Tetrahedron 2013, 69, 2550.
18. Span oꢀ , V.; Montalbano, A.; Carbone, A.; Parrino, B.; Diana, P.; Cirrincione, G.;
Castagliuolo, I.; Brun, P.; Issinger, O.-G.; Tisi, S.; Primac, I.; Vedaldi, D.; Salvador,
A.; Barraja, P. Eur. J. Med. Chem. 2014, 74, 340.
9. Carbone, A.; Parrino, B.; Di Vita, G.; Attanzio, A.; Span oꢀ , V.; Montalbano, A.;
d
(ppm): 14.0 (CH ), 21.7 (CH ), 60.9 (CH ), 102.6 (C), 112.3 (C), 118.5
3
3
2
1
(
(
1
CH), 119.1 (C), 122.0 (CH), 123.5 (CH), 125.4 (C), 126.1 (CH), 126.4
CH), 126.5 (CH), 127.3 (C), 128.2 (CH), 129.2 (2ꢃCH), 130.0 (2ꢃCH),
30.1 (C), 130.5 (C), 131.0 (CH), 144.7 (C), 146.3 (C), 159.4 (C), 163.2
(
20 2 2
C). Found: C, 79.85; H, 4.83; N, 7.48. C26H N O requires C, 79.57;
1
H, 5.14; N, 7.14%.
Barraja, P.; Tesoriere, L.; Livrea, M. A.; Diana, P.; Cirrincione, G. Mar. Drugs 2015,
3, 460.
1
2
0. Parrino, B.; Carbone, A.; Muscarella, M.; Spano, V.; Montalbano, A.; Barraja, P.;
Salvador, A.; Vedaldi, D.; Cirrincione, G.; Diana, P. J. Med. Chem. 2014, 57, 9495.
Acknowledgements
21. Diana, P.; Stagno, A.; Barraja, P.; Carbone, A.; Parrino, B.; Dall’Acqua, F.; Vedaldi,
D.; Salvador, A.; Brun, P.; Castagliuolo, I.; Issinger, O. G.; Cirrincione, G. Chem-
MedChem 2011, 6, 1291.
2. Diana, P.; Stagno, A.; Barraja, P.; Montalbano, A.; Carbone, A.; Parrino, B.;
Cirrincione, G. Tetrahedron 2011, 67, 3374.
3. Barraja, P.; Caracausi, L.; Diana, P.; Span oꢀ , V.; Montalbano, A.; Carbone, A.;
This work was financially supported by Ministero dell’Istruzione
dell’Universit ꢀa e della Ricerca (MIUR).
2
2
2
2
Supplementary data
Parrino, B.; Cirrincione, G. ChemMedChem 2012, 7, 1901.
4. Diana, P.; Carbone, A.; Barraja, P.; Montalbano, A.; Parrino, B.; Lopergolo, A.;
Pennati, M.; Zaffaroni, N.; Cirrincione, G. ChemMedChem 2011, 6, 1300.
5. Carbone, A.; Pennati, M.; Parrino, B.; Lopergolo, A.; Barraja, P.; Montalbano, A.;
Span oꢀ , V.; Sbarra, S.; Doldi, V.; De Cesare, M.; Cirrincione, G.; Diana, P.;
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.04.083.
Zaffaroni, N. J. Med. Chem. 2013, 56, 7060.
2
6. Carbone, A.; Pennati, M.; Barraja, P.; Montalbano, A.; Parrino, B.; Span oꢀ , V.;
Lopergolo, A.; Sbarra, S.; Doldi, V.; Zaffaroni, N.; Cirrincione, G.; Diana, P. Curr.
Med. Chem. 2014, 21, 1654.
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Please cite this article in press as: Parrino, B.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.083