Synthesis of novel indeno[1,2-c]isoquinoline derivatives

Article abstract of DOI:10.1080/00397910903009463

Indeno[1,2-c]isochromene was prepared using the readily obtainable starting materials via the condensation of dimethyl homophthalate with 3,4-dimethoxybenzaldehyde in the presence of sodium methoxide in absolute methanol followed by saponification and cyc

Full text of DOI:10.1080/00397910903009463

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Synthesis of Novel Indeno[1,2-
c]isoquinoline Derivatives
Mahmoud R. Mahmoud a , Manal M. El-Shahawi a , Eman A. A. El-
Bordany a & Fatma S. M. Abu El-Azm a
a Chemistry Department, Faculty of Science, Ain Shams University,
Abbassia, Cairo, Egypt
Version of record first published: 04 Feb 2010
To cite this article: Mahmoud R. Mahmoud, Manal M. El-Shahawi, Eman A. A. El-Bordany & Fatma
S. M. Abu El-Azm (2010): Synthesis of Novel Indeno[1,2-c]isoquinoline Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:5, 666-676
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Synthetic Communications1, 40: 666–676, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903009463
SYNTHESIS OF NOVEL INDENO[1,2-c]ISOQUINOLINE
DERIVATIVES
Mahmoud R. Mahmoud, Manal M. El-Shahawi,
Eman A. A. El-Bordany, and Fatma S. M. Abu El-Azm
Chemistry Department, Faculty of Science, Ain Shams University, Abbassia,
Cairo, Egypt
Indeno[1,2-c]isochromene was prepared using the readily obtainable starting materials via
the condensation of dimethyl homophthalate with 3,4-dimethoxybenzaldehyde in the pres-
ence of sodium methoxide in absolute methanol followed by saponification and cyclization
with concentrated sulfuric acid at 0ꢀC. The proclivity of cyclized product for undergoing
nucleophilic addition has been tested by reaction with nitrogen nucleophiles. Structural
1
13
assignments are based on spectroscopic data (infrared, H NMR, C NMR, and mass
spectra) and confirmed by the single-crystal x-ray molecular structure (2 and 3).
Keywords: Indeno[1,2-c]isochromene; isoquinoline derivatives; nitrogen nucleophiles
INTRODUCTION
Isoquinolinones[1] are important compounds from both synthetic and applied
points of view. Their structures are incorporated in several alkaloids[2] and other
pharmacologically important compounds.[3] In particular, 1,2-dihydroisoquinoline
derivatives[4] act as delivery systems that transport drugs through the otherwise
highly impermeable blood–brain barrier.[5] These compounds also exhibit sedative,[6]
antidepressant,[7] antitumor, and antimicrobial activities.[8] Isoquinolines are used in
the manufacture of dyes, paints, insecticides, antifungal agents; as a solvent for the
extraction of resins and terpenes; and as a corrosion inhibitor.[9,10]
Isoquinolinones have already been employed as useful intermediates in the syn-
thesis of indenoisoquinolines,[11] protoberberines,[12,13] and dibenzoquinolizines[13]
and are also of interest in medicinal chemistry.[14] Because of their biological and
pharmacological importance, several methods have been reported for the synthesis
of isoquinolinones. Most of these methods involve the use of either a preformed
isoquinoline or homophthalic acid, which is in turn obtained by a multistep
sequence.[15] Homophthalic acids are transformed into isoquinolinones via isocou-
marins,[16,17] isoquinolone-4-carboxylic acid,[15] or homophthalimide.[15f]
Received March 31, 2009.
Address correspondence to Mahmoud R. Mahmoud, Chemistry Department, Faculty of Science,
Ain Shams University, Abbassia 11566, Cairo, Egypt. E-mail: ftmsaber@yahoo.com
666

INDENO[1,2-c]ISOQUINOLINE
667
DISCUSSION
3,4-Dimethoxybenzaldehyde was condensed with dimethyl homophthalate
in the presence of sodium methoxide in absolute methanol, which afforded the
Z-isomer 1. The preferential formation of the Z-isomer may be interpreted by
considering the stability of the final product. By constructing space models for these
isomers, it was found that the E-configuration is highly strained because of the steric
interference between the o-carbmethoxy phenyl and the bulky substituted aryl
group. Ample evidence for the Z-configuration of the half ester 1 is derived from
its conversion to the iso-chromene derivative 2 (Scheme 1).
(3R,4S)-Methyl-4-bromo-3-(2-bromo-4,5-dimethoxyphenyl)-1-oxo-3,4-dihydro-
1H-isochromene-4-carboxylate 2 was formed as the sole product in fairly good
yield via the stirring of compound 1 with a mixture of bromine and acetic acid
at room temperature for 1 h. The structure 2 was substantiated from the micro-
analytical and spectroscopic data beside the x-ray crystallographic analysis (Fig. 1).
This cyclization reaction can be envisioned by assuming that acid-catalyzed
electrophilic addition of bromine to the activated double bond took place, followed
by intramolecular 1,6-exo-tet cyclization (Scheme 2).
Esterification of 1 using absolute methanol in the presence of thionyl chloride
under reflux yielded the isomeric diester (E)-methyl 2-[3-(3,4-dimethoxyphenyl)-1-
methoxy-1-oxo-prop-2-en-2-yl]benzoate 3, which indicates the occurrence of cis=
trans-isomerization under acidic conditions (Scheme 1). The structure assigned for
the E-configuration of the diester 3 is established from analytical and spectral data.
Furthermore, x-ray crystallographic analysis (Fig. 2) confirms the proposed structure.
Adequate evidence for the Z-configuration of 1 is forthcoming from saponifi-
cation and cyclization of the corresponding diacid. Thus, mild saponification of 1 yields
the Z-dibasic acid 4. Cyclization of 4 using concentrated sulfuric acid at 0ꢀC afforded
9,10-dimethoxyindeno[1,2-c]isochromene-5,11(6aH, 11aH)dione 5 (Scheme 3).
Scheme 1. Lactonization and esterification of Z-half ester 1.

668
M. R. MAHMOUD ET AL.
Figure 1. Molecular structure of (3R,4S)-methyl-4-bromo-3-(2-bromo-4,5-dimethoxyphenyl)-1-oxo-3,4-
dihydro-1H-isochromene-4-carboxylate 2.
The synthetic route for the target compound 5 is shown in Scheme 4.
The indeno[1,2-c]isochromene 5 was used as the key starting material for syn-
thesis of indeno[1,2-c]isoquinoline derivatives.[11] Thus, refluxing 5 with hydrazine
Scheme 2. Acid-catalyzed electrophilic addition of bromine to 1 followed by intramolecular cyclization.

INDENO[1,2-c]ISOQUINOLINE
669
Figure 2. X-ray crystal structure of compound 3.
hydrate (80%) in dioxane afforded the (E)-6-amino-11-hydrazono-9,10-dimethoxy-
6,6a,11,11a-tetra-hydroindeno[1,2-c]isoquinolin-5-one 6 (Scheme 3).
Treatment of the ketolactone 5 with cyanoethanoic hydrazide in boiling
dioxane yielded the 2-cyano-N-(9,10-dimethoxy-5,11-dioxo-11,11a-dihydro-5H-
indeno[1,2-c]isoquinolin-6(6aH)-yl) acetamide 7 (Scheme 3).
[1,2,4]Triazolo[2,3-a]isoquinoline derivative 8 was obtained as the sole product
in fairly good yield upon treatment of compound 5 with semicarbazide hydrochloride
in refluxing pyridine (Scheme 3). The reaction involves nucleophilic ring opening via
nitrogen attack at the carbonyl group of the d-lactone (tetrahedral mechanism)
followed by 1,5-exo-trig cyclization with elimination of 2 mol water.
Refluxing the ketolactone 5 with benzylamine in pyridine afforded the
6-benzyl-9,10-dimethoxy-6,6a-dihydro-11aH-indeno[1,2-c]isoquinolin-5,11-dione
(Scheme 3).
9
However, fusion of 5 with an active methylene compound such as ethyl
cyanoacetate in the presence of anhydrous sodium acetate on an oil bath at
170ꢀC afforded (Z)-ethyl2-cyano-2-(9,10-dimethoxy-5-oxo-indeno[1,2-c]isochromene-
11(5H,6aH,11aH)ylidene)acetate 10 (Scheme 3).

670
M. R. MAHMOUD ET AL.
Scheme 3. Reactions of indeno[1,2-c]isochromene 5 with nitrogen and carbon nucleophiles.
EXPERIMENTAL
All melting points were taken on a Griffin and Geory melting-point apparatus
and are uncorrected. Infrared (IR) spectra were recorded on a Pye Unicam SP 1200
1
spectrophotometer using the KBr wafer technique. H NMR spectra were determ-
ined on a Varian Gemini 300-MHz instrument using tetramethylsilane (TMS) as
internal standard (chemical shifts in d). 13C NMR spectra were measured on a Jeol
75-MHz instrument. Electron impact–mass spectrometry (EI-MS) was measured on a
Schimadzu GC-MS, QP 1000 EX instrument operating at 70 eV. Elemental analyses

INDENO[1,2-c]ISOQUINOLINE
671
Scheme 4. Cyclization of the dibasic acid 4 using conc. H2SO4 at 0ꢀC.
were carried out at the Microanalytical Unit, Faculty of Science, Ain Shams
University using a Perkin-Elmer 2400 CHN elemental analyzer, and satisfactory
analytical data (ꢁ0.4) were obtained for all compounds. The homogeneity of the
synthesized compounds was controlled by thin-layer chromatography (TLC) using
TLC aluminum sheets with silica gel F254 (Merck).
(Z)-2-(3-(3,4-Dimethoxyphenyl)-1-methoxy-1-oxoprop-
2-en-2-yl)benzoic Acid 1
A mixture of dimethyl homophthalate (2.08 g, 0.01 mol) and 3,4-dimethoxy-
benzaldehyde (1.66 g, 0.01 mol) was stirred in absolute methanol (50 ml) in the pres-
ence of sodium methoxide (0.5 g Na in 50 ml MeOH). The whole mixture was stirred
at room temperature for 1 h (TLC). The precipitated solid was filtered off, dissolved
in cold water, and acidified with cold, dilute hydrochloric acid. The deposited solid
was filtered off, washed several times with cold water, dried, and then recrystallized
from ethanol to give 1 as white crystals; mp 177–179ꢀC, yield 90%. IR (n): br
3396–2436 cmꢂ1 (acidic OH group), 1722 cmꢂ1 (C Oa,b-unsaturated ester), 1685 cmꢂ1
=
=
(C Oaromatic acid). MS: 342 (100), 265 (34.1), 151 (38.8), 91 (3.0), 65 (7.5). Anal.
calcd. for C19H18O6 (342.35): C, 66.6; H, 5.3. Found: C, 66.3; H, 5.4.
(3R,4S)-Methyl-4-bromo-3-(2-bromo-4,5-dimethoxyphenyl)-
1-oxo-3,4-dihydro-1H-iso-chromene-4-carboxylate 2
Bromine (3 ml in 15 ml AcOH) was added dropwise to a solution of the half
ester 1 (3.42 g, 0.01 mol) in acetic acid (30 ml) with stirring at room temperature
for 1 h. The whole mixture was then kept at room temperature overnight. The reac-
tion mixture was then diluted with cold water. The precipitated solid was filtered off,
dried, and then recrystallized from benzene to give 2 as buff crystals; mp 182–184ꢀC,
yield 89%. IR (n): 1748 cmꢂ1 (C Od-lactone), 1739 cmꢂ1 (C Oester). 1H NMR (CDCl3)
d 8.5–7.2 (m, 6Harom.), 6.58 (s, 1H, C3-H), 4.14 (s, 6H, Ar-OMe), 4.09 (s, 3H,
=
=

672
M. R. MAHMOUD ET AL.
COOMe). MS: 500 (28.1), 420 (10.2), 333 (8.8), 256 (100). Anal. calcd. for
C19H16Br2O6 (500.14): C, 45.6; H, 3.2; Br, 31.9. Found: C, 45.4; H, 3.1; Br, 31.6.
Single-Crystal X-Ray Diffraction Analysis of C19H16O6Br2
Intensities were collected on the Kappa CCD Enraf-Nonius FR 590 diffracto-
meter[18] using the x-2h scan technique. C19H16O6Br2 crystallized in space group
˚
˚
˚
P21=C with a ¼ 20.1043 (7) A, b ¼ 8.7046 (2) A, c ¼ 11.0497 (3) A, and b ¼ 97.0923
(11)ꢀ, V ¼ 1918.90 (10) Aꢂ3, Z ¼ 4. Of the 9619 unique reflections measured (Mo
Ka radiation), 2273 were considered observed [I > 3r (I)]. The final refinement resi-
duals were R ¼ 0.068 (on F) and wR2 ¼ 0.144 (on F2). The data was solved using SIR
92.[19] The radiation type is a graphite monochromatized[20] Mo Ka (k ¼ 0.71073 A)
˚
˚
operated at 50 kV and 20 mA. The data was refined using Maxus.
(E)-Methyl-2-(3-(3,4-dimethoxyphenyl)-1-methoxy-1-oxoprop-
2-en-2-yl)benzoate 3
SOCl2 (7 ml) was added dropwise with stirring to a solution of the half ester 1
(3.42 g, 0.01 mol) in absolute methanol (50 ml) at room temperature for 0.5 h. The
whole mixture was then refluxed on a water bath for 8 h. The excess methanol was
distilled off, and the reaction product then poured on sodium carbonate solution.
The deposited solid was filtered off, dried, and recrystallized from ethanol to give
ꢂ1
1
3 as colorless crystals; mp 110–112ꢀC, yield 86%. IR (n): 1720 cm (C Oester). H
NMR (CDCl3) d 8.1–6.7 (m, 7Harom.), 6.2 (s, 1H, olefinic), 3.8 (s, 6H, Ar-OMe),
3.7 (s, 3H, COOMe), 3.36 (s, 3H, Ar-COOMe). MS: 356 (68.5), 297 (20.5), 151
(27.4), 79 (19.2), 59 (100). Anal. calcd. for C20H20O6 (356.37): C, 67.4; H, 5.6. Found:
C, 67.1; H, 5.3.
=
Single-Crystal X-Ray Diffraction Analysis of C20H20O6
Intensities were collected on the Kappa CCD Enraf-Nonius FR 590 diffracto-
meter[18] using the x-2h scan technique. C20H20O6 crystallized in space group P21
ꢀ
˚
˚
˚
with a ¼ 7.8839 (4) A, b ¼ 8.1087 (4) A, c ¼ 14.4840 (10) A, and b ¼ 97.447 (2) . Of
the 2917 unique reflections measured (Mo Ka radiation), 844 were considered
observed [I > 3r (I)]. The final refinement residuals were R ¼ 0.041 (on F) and
wR2 ¼ 0.084 (on F2). The data was solved using SIR 92.[19] The radiation type is a
graphite monochromatized[20] Mo Ka (k ¼ 0.71073 A) operated at 50 kV and
˚
˚
20 mA. The data was refined using Maxus.
(Z)-2-(1-Carboxy-2-(3,4-dimethoxyphenyl)vinyl)benzoic Acid 4
The half-ester 1 (3.42 g, 0.01 mol) was heated under reflux with 10% sodium
hydroxide (30 ml) for 1 h (TLC). The reaction mixture was allowed to cool and then
acidified with cold dilute hydrochloric acid. The deposited solid was filtered off,
washed several times with cold water, dried, and then recrystallized from ethanꢂo1l
to give 4 as white crystals; mp 193–195ꢀC, yield 84%. IR (n): br 3500–3100 cm
=
(acidic OH group), 1678 (C Oa,b-unsaturated acid). MS: 328 (61.3), 310 (23.2), 282

INDENO[1,2-c]ISOQUINOLINE
673
(16.0), 122 (6.1), 77 (52.5), 51 (100). Anal. calcd. for C18H16O6 (328.32): C, 65.8; H,
4.9. Found: C, 65.7; H, 5.1.
9,10-Dimethoxyindeno[1,2-c]isochromene-5,11(6aH,11aH)-dione 5
The acid 4 (3.28 g, 0.01 mol) was stirred at 0ꢀC with concentrated sulfuric acid
(30 ml) for 30 min, then left overnight in refrigerator. The reaction mixture was
poured onto ice-cold water, and the deposited solid was filtered off, washed several
times with cold water, dried, and recrystallized from benzene to give 5 as pale yellow
crystals; mp 186–188ꢀC, yield 65%. IR (n): 1737 cm (C Od-lactone), 1710 cmꢂ1
ꢂ1
=
ketone). 1H NMR (CDCl3) d 8.15–7.20 (m, 6Harom.),
=
(C Osaturated
five-membered
6.26–6.24 (d, 1H, C6a-H, J ¼ 6.9 Hz), 4.17–4.15 (d, 1H, C11a-H, J ¼ 6.9 Hz), 3.92
(s, 6H, 2OMe). MS: 310 (100), 282 (39.5), 251 (99.1). Anal. calcd. for C18H14O5
(310.30): C, 69.6; H, 4.5. Found: C, 69.3; H, 4.5.
(E)-6-Amino-11-hydrazono-9,10-dimethoxy-6,6a,11,11a-
tetrahydroindeno[1,2-c]isoquinolin-5-one 6
A mixture of 5 (3.1 g, 0.01 mol) and hydrazine hydrate (1 ml, 0.02 mol) in 20 ml
dioxane was refluxed for 6 h (TLC). After evaporation of solvent, the colorless solid
product was collected by filtration and recrystallized from dioxane to ꢂg1ive 6 as
colorless crystals; mp 226–228ꢀC, yield 75%. IR (n): br. 3316, 3284 cm (NH2),
1649 cmꢂ1 (C Ocyclic amide). MS: 338 (42.8), 307 (100). Anal. calcd. for C18H18N4O3
=
(338.36): C, 63.9; H, 5.3; N, 16.5. Found: C, 63.8; H, 5.2; N, 16.2.
2-Cyano-N-(9,10-dimethoxy-5,11-dioxo-11,11a-dihydro-5H-
indeno[1,2-c]isoquinolin-6(6aH)-yl)acetamide 7
A mixture of 5 (3.1 g, 0.01 mol) and cyanoethanoic hydrazide (1 g, 0.01 mol) in
20 ml dioxane was refluxed for 6 h (TLC). After evaporation of solvent, a yellow
solid product was separated, collected by filtration, and recrystallized from dioxane
to give 7 as yellow crystals; mp 254–256ꢀC, yield 77%. IR (n): 3285 cmꢂ1 (NH),
=
2253 (w) cmꢂ1 (CꢃN), 1709 cmꢂ1 (C Osaturated
ketone), 1666 cmꢂ1
five-membered
(C Ocyclic amide). 1H NMR (DMSO-d6) d 10.7 (s, 1H, NH, exchangeable with
=
D2O), 7.9–7.2 (m, 6Harom.), 5.57–5.55 (d, 1H, C11-H, J ¼ 6 Hz), 4.59–4.57 (d, 1H,
11a-H, J ¼ 6 Hz), 4.03 (d,d, 2H, CH2), 3.82 (s, 6H, 2OMe). MS: 323 ([Mþ
.
C
.
=
–CH2 ¼ C O, ꢂCN , 28.4), 307 (100), 293 (22.5), 264 (17.5), 165 (23.5), 77 (21.6).
Anal. calcd. for C21H17N3O5 (391.38): C, 64.4; H, 4.4; N, 10.73. Found: C, 64.1;
H, 4.3; N, 10.4.
[1,2,4]Triazolo[2,3-a]isoquinoline Derivative 8
A mixture of 5 (3.1 g, 0.01 mol) and semicarbazide hydrochloride (1.11 g,
0.01 mol) in 20 ml pyridine was refluxed for 6 h (TLC). After evaporation of solvent,
a buff solid product was deposited, collected by filtration, dried, and recrystallized
from ethanol=dioxane to give 8 as buff crystals; mp > 330ꢀC, yield 80%. IR
=
(n): 3432 cmꢂ1 (NH), 1707 cmꢂ1 (C Osaturated
ketone), 1682 cmꢂ1
five-membered

674
M. R. MAHMOUD ET AL.
(C Ocyclic imide), 1662 cmꢂ1 (C N). MS: 349 (43.1), 323 (58.5), 50 (100). Anal. calcd.
for C19H15N3O4 (349.34): C, 65.3; H, 4.3; N, 12.0. Found: C, 65.1; H, 4.3; N, 11.7.
=
=
6-Benzyl-9,10-dimethoxy-6,6a-dihydro-11aH-Indeno[1,2-
c]isoquinoline-5,11-dione 9
A mixture of 5 (3.1 g, 0.01 mol) and benzylamine (1 ml, 0.01 mole) in 15 ml pyri-
dine was refluxed for 3 h (TLC). The reaction mixture was allowed to cool and acidi-
fied with cold dilute hydrochloric acid. The precipitate was collected by filtration and
recrystallized from ethanol to give 9 as pink crystals; mp 169–171ꢀC, yield 60%. IR
(n): 1707 cmꢂ1 (C Osaturated
ketone), 1657 cmꢂ1 (C Ocyclic amide). 1H
=
=
five-membered
NMR (CDCl3) d 8.20–6.71 (m, 11Harom.), 5.55–5.50 (d, 1H, C6a-H, J ¼ 15 Hz),
4.87–4.82 (d, 1H, C11a-H, J ¼ 15 Hz), 4.22 (s, 2H, CH2), 3.85 (s, 6H, 2OMe). 13C
NMR (CDCl3) d (ppm): 198.71 (C11), 163.08 (C5), 155.77 (C10), 150.71 (C9),
147.63 (C1a), 137.15 (C4a), 133.35 ( C01, benzyl ring), 132.36 (C7a), 129.16 (C2),
128.99 (C1), 128.22 (C03, benzyl ring), 127.89 (C20 , benzyl ring), 127.82 (C4), 127.35
(C3), 127.18 (C04, benzyl ring), 126.01 (C10a), 106.44 (C7), 104.48 (C8), 57.16 (C11a),
56.31 (OCH3), 56.10 (OCH3), 51.85 (C6a), 50.64 (NCH2). MS: 399 (13.3), 308
(24.4), 294 (40.1), 106 (58.4), 91 (100), 65 (38.6). Anal. calcd. for C25H21NO4
(399.44): C, 75.2; H, 5.3; N, 3.5. Found: C, 75.1; H, 5.4; N, 3.2.
(Z)-Ethyl-2-cyano-2-(9,10-dimethoxy-5-oxoindeno[1,2-c]isochromen-
11(5H,6aH,11aH)ylidene)acetate 10
A mixture of 5 (3.1 g, 0.01 mol), ethyl cyanoacetate (1.13 ml, 0.01 mol), and
fused sodium acetate (0.82 g, 0.01 mol) was fused in an oil bath at 170ꢀC for
15 min. The crude product was stirred with water for 15 min, filtered, dried, and then
recrystallized from ethanol=dioxane to give 10 as white crystals; mp 204–207ꢀC,
yield 50%. IR (n): 2249 cmꢂ1 (CꢃN), 1742 cmꢂ1 (C Od-lactone), 1702 cmꢂ1
=
=
(C Oa,b-unsaturated ester). MS: 405 (11.2), 293 (100). Anal. calcd. for C23H19NO6
(405.40): C, 68.1; H, 4.7; N, 3.4. Found: C, 67.8; H, 5.1; N, 3.4.
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