Synthesis, reactions and antibacterial activity of 3-acetyl[1,2,4] triazolo[3,4-a]isoquinoline derivatives using chitosan as heterogeneous catalyst under microwave irradiation

Article abstract of DOI:10.1515/znb-2011-0313

3-Acetyl[1,2,4]triazolo[3,4-a]isoquinolines were prepared using chitosan as a catalyst. These compounds were used to prepare a novel series of enaminones 5, and their reactions with hydrazonoyl halides 1 and 11 gave triazoloisoquinolines 8 and 13, respectively, with a carbonylpyrazole side chain. Hydrazinolysis of 8 and 13 gave the pyrazolopyridazines 10 and pyrazolopyridazinones 14. Reaction of 5 with hydroximoyl halides 15 led to triazoloisoquinoline 16 with a carbonylisoxazole side chain. Antibacterial effects of compounds 8 and 10 were studied.

Full text of DOI:10.1515/znb-2011-0313

Synthesis, Reactions and Antibacterial Activity of
3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives using Chitosan
as Heterogeneous Catalyst under Microwave Irradiation
Hamdi M. Hassaneena, Huwaida M. E. Hassaneena, Yasmin Sh. Mohammeda,
Richard M. Pagnib
a Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
b Department of Chemistry, University of Tennessee, Knoxville, TN 37996, USA
Reprint requests to Prof. Hamdi M. Hassaneen. E-mail: Hamdi 251@yahoo.com
Z. Naturforsch. 2011, 66b, 299 – 310; received December 16, 2010
3-Acetyl[1,2,4]triazolo[3,4-a]isoquinolines were prepared using chitosan as a catalyst. These com-
pounds were used to prepare a novel series of enaminones 5, and their reactions with hydrazonoyl
halides 1 and 11 gave triazoloisoquinolines 8 and 13, respectively, with a carbonylpyrazole side chain.
Hydrazinolysis of 8 and 13 gave the pyrazolopyridazines 10 and pyrazolopyridazinones 14. Reaction
of 5 with hydroximoyl halides 15 led to triazoloisoquinoline 16 with a carbonylisoxazole side chain.
Antibacterial effects of compounds 8 and 10 were studied.
Key words: [1,2,4]Triazolo[3,4-a]isoquinoline, Enaminones, Hydrazinolysis,
Hydrazonoyl Chlorides, Cycloaddition Reaction, Chitosan, Hydroximoyl Chloride
Introduction
azoles 8 and 13, pyrazolopyridazines 10, pyrazolopyri-
dazinones 14, and carbonylisoxazoles 16. The antibac-
terial effects of compounds 8 and 10 were also exam-
ined.
Fused isoquinoline derivatives are a very interest-
ing class of compounds due to their significant phar-
macological and biological activities [1 – 7]. As a part
of our ongoing studies aimed at developing simple
and efficient syntheses of polyfunctional heteroaro-
matic compounds from readily obtained starting mate-
rials, we have previously reported the syntheses of tri-
azoloisoquinoline and pyrroloisoquinoline compounds
via the reaction of 3,4-dihydro-6,7-dimethoxyisoquin-
oline derivatives with hydrazonoyl halides in chlo-
roform in the presence of triethylamine or in pyri-
dine as catalyst and solvent [8 – 16]. The aim of the
present study has been to introduce a new synthetic
methodology by (1) replacing triethylamine in chloro-
form by the ecologically more acceptable catalyst chi-
tosan [17, 18], a naturally-occurring environmentally
friendly polymer that can be used as a heterogeneous
catalyst, thus affording a new environmentally benign
route to the above compounds, and (2) carrying out the
chitosan-catalyzed reactions under microwave irradia-
Results and Discussion
The starting material, 3,4-dihydro-6,7-dimethoxy-
isoquinoline (3), was prepared via ring closure of N-[2-
(3,4-dimethoxyphenyl)ethyl]formamide, prepared by
heating equimolar amounts of formic acid and 2-(3,4-
dimethoxyphenyl)ethylamine with POCl3 in CHCl3
according to the procedure of Bischler and Napieral-
sky [27].
Reaction of 2c, generated in situ by treatment of hy-
drazonoyl chloride 1c with chitosan [28] in ethanol,
with 3 under microwave irradiation for 10 min afforded
1
a single product, as evidenced by TLC and H NMR
analysis of the crude product mixture. The purified
product gave the correct elemental analysis and mass
spectrum for the cycloadduct 4c (Scheme 1).
As an example, the structure of 4c was confirmed by
tion to enhance reaction rates [19 – 26] for the synthe- NMR spectroscopy. The 1H NMR spectrum revealed a
sis of [1,2,4]triazolo[3,4-a]isoquinolines which were signal at δ = 2.42 ppm assignable to the protons of
found to be useful precursors for the synthesis of enam- the CH3CO group, in addition to protons of the iso-
inones 5. The latter compounds 5 were used to prepare quinoline and aromatic groups. Its 13C NMR spec-
conjugates of triazoloisoquinolines with carbonylpyr- trum afforded 18 signals, as expected. Similar reac-
c
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H. M. Hassaneen et al. · 3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives
1, 2, 4, 5
Ar
Ph
p-Tol
p-ClC6H4
a
b
c
Scheme 1. Synthesis of 3-acet-
yl[1,2,4]triazolo[3,4-a]isoquinol-
ines 5.
8
a
b
c
d
e
f
g
h
i
Ar / Arꢀ
Ph / Ph
Ph / p-Tol
Ph / p-ClC6H4
p-Tol / Ph
p-Tol / p-Tol
p-Tol / p-ClC6H4
p-ClC6H4 / Ph
p-ClC6H4 / p-Tol
p-ClC6H4 / p-ClC6H4
Scheme 2. Synthesis of pyraz-
oles 8.
tions afforded 4a and 4b. The required enaminones 5,
The isomeric structure 9 was excluded as follows:
which have not been reported hitherto, were prepared For example, in the pyrazole ring system C-4 is the
by refluxing 4 in dimethylformamide-dimethylacetal most electron rich carbon; thus, 4-H in 9 is expected
(DMFDMA) for 4 h. The structures of the enaminones to appear at high field of ca. δ = 6.31 ppm. On the
were confirmed by their elemental analyses and spec- other hand, 5-H in 8 is linked to the carbon atom at-
tral data (see Experimental Section). For example, the tached to a nitrogen atom, and thus is deshielded and
1H NMR spectrum of 5a showed two singlets at δ = will appear in the region δ = 7.5– 8.5 ppm [30– 32].
2.87 and 3.08 ppm characteristic for the -NMe2 group, The 1H NMR spectra of the isolated reaction products
two doublets at δ = 5.8 and 7.66 ppm with the coupling revealed, in each case, a singlet at δ = 8.5 ppm which
constant J = 13 Hz, assignable to the two olefinic pro- indicates the presence of the pyrazole 5-H rather than
tons. The value of the coupling constant is compatible 4-H. The 13C NMR spectra of all compounds were also
with the (E)-configuration [29] depicted in Scheme 1.
Reaction of enaminones 5 with hydrazonoyl
halides 1 in refluxing ethanol in the presence of chi-
tosan gave, in each case, one isolable product as evi-
denced by TLC analysis (Scheme 2). Both elemental
analyses and mass spectral data of the isolated prod-
ucts were consistent with either of two isomeric struc-
tures 8 or 9. Structure 8 was assigned to the compounds
based on careful analysis of the relevant 1H NMR
data.
in agreement with the proposed structures (see Experi-
mental Section).
The proposed mechanism leading to the products
starts with a regioselective 1,3-dipolar cycloaddition
of nitrilimines 2 to the carbon-carbon double bond of
the enaminones 5 to afford the cycloadducts 6 which
affords the pyrazole derivatives 8 via elimination of
dimethylamine.
In addition, the structure of compounds 8 was con-
firmed by their reactions with hydrazine hydrate. Thus,
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301
10 Ar / Arꢀ
10 Ar / Arꢀ
g
h
i
a
b
c
d
e
f
Ph / Ph
Ph / p-Tol
Ph / p-ClC6H4
p-Tol / Ph
p-Tol / p-Tol
p-Tol / p-ClC6H4
p-ClC6H4 / Ph
p-ClC6H4 / p-Tol
p-ClC6H4 / p-ClC6H4
Scheme 3. Synthesis of pyrazolopyridazines 10.
11, 12
Ar / Arꢀꢀ
Ph / Ph
Ph / p-Tol
Ph / p-ClC6H4
p-Tol / Ph
p-Tol / p-Tol
p-Tol / p-ClC6H4
p-ClC6H4 / Ph
p-ClC6H4 / p-Tol
p-ClC6H4 / p-ClC6H4
a
b
c
d
e
f
g
h
i
Scheme 4. Synthesis of pyr-
azolopyridazinones 14.
16 R / Ar
16 R / Ar
a
b
c
Ph / Ph
d
e
f
2-thienyl / Ph
Ph / p-Tol
Ph / p-ClC6H4
2-thienyl / p-Tol
2-thienyl / p-ClC6H4
R = Ph (15b) 2-thienyl (15b)
Scheme 5. Synthesis of isoxazoles 16.
refluxing of 8 with hydrazine hydrate in ethanol af- tures of the latter products 14 were confirmed on the
forded the pyrazolo[3,4-d]pyridazine derivatives 10 basis of elemental and spectral analyses. The IR spec-
(Scheme 3). The structure of the products, suggested tra of 14 showed bands at ν = 3159 and 1693 cm−1
,
by their preparative route and elemental analyses, was corresponding to NH and amide carbonyl groups, re-
further supported by their spectral properties. For ex- spectively, instead of the two carbonyl bands at ν =
ample, the IR spectra revealed the absence of carbonyl 1742 and 1641 cm−1 of 13.
1
bands. The H NMR spectra yielded a signal for the
pyridazine methyl group at δ = 2.95 ppm; the acetyl
methyl signal in 8 occurred at δ = 2.27 ppm [33].
Next, hydrazonoyl chlorides 11 were treated with
enaminones 5 in ethanol in the presence of chitosan
to give the corresponding triazoloisoquinoline deriva-
tives 13. The structures of the products were estab-
lished on the basis of elemental analyses and spectral
data (IR, 1H and 13C NMR, mass spectra). For exam-
Stirring of equimolar amounts of enaminones 5 and
hydroximoyl chloride 15 in acetonitrile at r. t. gave, in
each case, one isolable product 16 (Scheme 5). The
structures of the products were established from their
elemental analyses and spectral data. For example,
compound 16a exhibits a molecular ion peak at m/z =
508 in its mass spectrum. Its IR spectrum showed
two carbonyl bands at ν = 1693 and 1647 cm−1. The
1H NMR and 13C NMR spectra confirmed the structure
of the cycloadduct 16a (see Experimental Section).
1
ple, the H NMR spectrum of 13a revealed a singlet
at δ = 8.5 ppm, assignable to the proton at position 5
of the pyrazole ring, a triplet at δ = 1.19 ppm and
a quartet at δ = 4.30 ppm, assignable to the protons
of ethoxycarbonyl group, in addition to the signals of
Biological screening
Eighteen compounds (8a – i and 10a – i) were as-
the isoquinoline moiety and the aromatic rings. The sayed for their antibacterial activities. It is clear from
structures of compounds 13 were further confirmed by the data in Table 1 that compounds with an unsub-
their conversion to pyrazolopyridazinones 14 upon re- stituted phenyl group in the triazoline moiety showed
action with hydrazine hydrate (Scheme 4). The struc- no antibacterial activities against the four pathogenic
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H. M. Hassaneen et al. · 3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives
Table 1. Antibacterial activity
of compounds 8a – i and 10a – i
using disc diffusion platesa.
Compound Bacillus subtilis Escherichia coli Neisseria gonorrhoeae Staphylococcus aureus
(G+)
I. Z.
(mm mg−1
(G−)
(G−)
(G+)
R. A.
I. Z.
R. A.
I. Z.
R. A.
(%)
100
I. Z.
R. A.
(%)
100
)
(%) (mm mg−1
)
(%) (mm mg−1
)
(mm mg−1
28
)
Tetracycline
32
100
30
100
0.0
0.0
0.0
46.7
50.0
40.0
0.0
40.0
33.3
36.7
33.3
0.0
29
(Standard)
8a
0.0
0.0
0.0
12
16
12
0.0
11
10
0.0
0.0
0.0
0.0
0.0
0.0
14
15
12
0.0
12
10
11
10
0.0
15
12
10
10
0.0
0.0
0.0
0.0
0.0
10
15
11
10
13
0.0
12
10
0.0
16
11
0.0
10
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
11
15
13
0.0
14
11
12
11
0.0
15
12
11
10
11
0.0
0.0
0.0
0.0
8b
8c
8d
37.5
50.0
37.5
0.0
34.4
31.3
40.6
0.0
34.5
51.7
37.9
34.5
44.9
0.0
41.4
34.5
0.0
55.2
37.9
0.0
34.5
0.0
39.3
53.6
46.4
0.0
50.0
39.3
42.9
39.3
0.0
53.6
42.9
39.3
35.7
39.3
0.0
8e
8f
8g
8h
8i
10a
10b
10c
10d
10e
10f
10g
10h
10i
13
0.0
0.0
15
11
10
0.0
10
10
0.0
46.9
34.4
31.3
0.0
31.3
31.3
50.0
40.0
33.3
33.3
0.0
a
G+ = gram positive; G− = gram
negative; I. Z. = inhibition zone;
R. A. = relative activity.
0.0
0.0
bacteria under test, irrespective of the substitution in Experimental Section
the phenyl group in the pyrazole ring (8a, 8b and 8c),
while compounds with phenyl groups substituted by
General
The melting points were determined on a Stuart melt-
ing point apparatus and are uncorrected. The IR spec-
tra were recorded as KBr pellets using an FTIR Bruker-
chlorine or methyl groups in the triazoline ring (8d –
8i) showed antibacterial activities. Compounds with
methyl groups showed higher activities against bacte-
ria (8d, 8e and 8f) than compounds with the chlorine
atom (8g, 8h and 8i). The most efficient compound in
series 8 was 8e which has two p-tolyl groups at posi-
tion 1 in both the triazoline and the pyrazole ring, with
relative activities compared to tetracycline of 50.0,
50.0, 51.7, and 53.6 %, respectively, in the four bac-
teria examined. Most of the pyrazolopyridazine com-
pounds 10 showed antibacterial activities against some
of the pathogenic bacteria. Compound 10c, for exam-
ple, exerted no antibacterial activity, while 10a, 10d
and 10e exerted antibacterial activities against the four
pathogenic bacteria examined. Compound 10d was the
most efficient one in series 10, with a relative ac-
tivity compared to tetracycline of 46.9, 50.0, 55.2,
and 53.6 %, respectively (Tables 1 and 2).
1
Vector 22 spectrophotometer. The H NMR and 13C NMR
spectra were recorded in CDCl3 and [D6]DMSO as sol-
vents at 300 MHz on a Varian Gemini NMR spectrom-
eter using TMS as internal standard. Chemical shifts are
reported in δ units (ppm). Mass spectra were measured
on a Shimadzu GMMS-QP-1000 EX mass spectrometer
at 70 eV. Microwave-assisted reactions were run in a CEM
Discover labmateTM microwave apparatus (300 W with
TM
CHEMDRIVER
software). The elemental analyses were
performed at the Microanalytical Center, Cairo University.
Compounds 1a – c [34], 11a, b [35], 11c [35, 36], 15a [37]
and 15b [38] had been prepared previously.
General procedure for the preparation of 1-aryl-3-acetyl-
8,9-dimethoxy[1,2,4]triazolo[3,4-a]1,5,6,10b-tetrahydro-
isoquinolines (4a – c)
To a solution of hydrazonoyl chloride 1 (1 mmol) and 3,4-
dihydro-6,7-dimethoxyisoquinoline (3) (0.28 g, 1 mmol) in
absolute ethanol (5 mL) was added chitosan (0.1 g) at r. t.
The reaction mixture was irradiated under constant pressure
(11.2 bar, 80 ◦C) for 10 min at a power of 300 W. The hot so-
lution was filtered to remove the chitosan. After cooling, di-
lute HCl was added to the solution until it became acidic. The
solid product was collected and crystallized from a suitable
Table 2. MIC values for two efficient antibacterial com-
poundsa.
Compound
8e
10d
Bacterial species
Bacillus subtilis
Neisseria gonorrhoeae
MIC value (µg mL−1
)
200
246
a
MIC values were determined for the highly efficient antibacterial
compounds using the most sensitive microorganisms.
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H. M. Hassaneen et al. · 3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives
303
solvent. The compounds prepared and their physical data are (E)-1-(8,9-Dimethoxy-1-(4-methylphenyl)-1,5,6,10b-tetra-
listed below.
hydro[1,2,4]triazolo[3,4-a]iso-quinolin-3-yl)-3-(dimethyl-
amino)propenone (5b)
1-Phenyl-3-acetyl-8,9-dimethoxy[1,2,4]triazolo[3,4-a]-
1,5,6,10b-tetrahydroisoquinoline (4a)
◦
Orange crystals, m. p. 158 C (ethanol), 80 % yield. – IR
(KBr): ν = 1635 (C=O) cm−1. – 1H NMR (CDCl3): δ =
2.27 (s, 3H), 2.70 (m, 1H), 2.84 (m, 1H), 2.87 (s, 3H), 3.04
(s, 3H), 3.64 (s, 3H), 3.79 (m, 1H), 3.82 (s, 3H), 4.01 (m,
1H), 5.80 (d, J = 13 Hz, 1H), 6.29 (s, 1H), 6.62 (s, 1H),
6.73 (s, 1H), 7.08 – 7.21 (m, 4H), 7.68 (d, J = 13 Hz, 1H). –
13C NMR (CDCl3): δ = 20.53, 28.06, 37.32, 42.09, 45.51,
55.84, 55.95, 78.31, 108.58, 111.07, 114.01, 125.90, 127.99,
129.13, 129.29, 129.54, 144.37, 147.64, 148.50, 151.20,
152.95, 178.88. – MS: m/z (%) = 420 (30) [M]+, 98 (100). –
Anal. for C24H28N4O3: calcd. C 68.55, H 6.71, N 13.32;
found C 68.31, H 7.02, N 13.64.
Yellow crystals, m. p. 130 ◦C (lit. [15]: 130 ◦C),
70 % yield.
1-(4-Methylphenyl)-3-acetyl-8,9-dimethoxy[1,2,4]triazolo-
[3,4-a]1,5,6,10b-tetrahydroisoquinoline (4b)
Yellow crystals, m. p. 135 ◦C, (lit. [15]: 135 ◦C),
70 % yield.
1-(4-Chlorophenyl)-3-acetyl-8,9-dimethoxy[1,2,4]triazolo-
[3,4-a]1,5,6,10b-tetrahydroisoquinoline (4c)
Yellow crystals, m. p. 158 ◦C (acetonitrile), 73 % yield. –
IR (KBr): ν = 1674 (C=O) cm−1. – 1H NMR (CDCl3): δ =
2.42 (s, 3H), 2.75 (m, 1H), 2.82 (m, 1H), 3.60 (s, 3H), 3.82
(s, 3H), 3.87 (m, 2H), 6.41 (s, 1H), 6.60 (s, 1H), 6.65 (s, 1H),
7.10 – 7.25 (m, 4H). – 13C NMR (CDCl3): δ = 26.58, 27.84,
42.11, 55.86, 55.96, 77.92, 108.02, 111.26, 114.93, 125.42,
127.71, 127.92, 129.08, 143.12, 147.76, 148.79, 148.88,
190.01. – MS: m/z (%) = 387 (57) [M+2]+, 386 (10) [M+2–
H]+, 385 (100) [M]+. – Anal. for C20H20ClN3O3: calcd.
C 62.26, H 5.22, N 10.89; found C 62.41, H 5.10, N 10.66.
(E)-1-(8,9-Dimethoxy-1-(4-chlorophenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]iso-quinolin-3-yl)-3-(dimethyl-
amino)propenone (5c)
Orange crystals, m. p. 180 ◦C (acetonitrile), 79 % yield. –
IR (KBr): ν = 1643 (C=O) cm−1. – 1H NMR (CDCl3):
δ = 2.73 (m, 1H), 2.85 (m, 1H), 2.89 (s, 3H), 3.08 (s, 3H),
3.66 (s, 3H), 3.83 (s, 3H), 3.87 (m, 1H), 3.97 (m, 1H), 5.83
(d, J = 13 Hz, 1H), 6.27 (s, 1H), 6.64 (s, 1H), 6.67 (s,
1H),7.07 – 7.23 (m, 4H), 7.69 (d, J = 13 Hz, 1H). – 13C NMR
(CDCl3): δ = 28.04, 37.41, 42.08, 45.49, 55.90, 55.98, 77.69,
108.11, 111.14, 114.39, 124.34, 127.87, 128.79, 128.90,
129.09, 145.07, 147.77, 148.68, 151.60, 153.25, 178.61. –
MS: m/z (%) = 442 (20) [M+2]+, 441 (40) [M+2–H]+,
440 (94) [M]+, 439 (89) [M–H]+, 98 (100). – Anal. for
C23H25ClN4O3: calcd. C 62.65, H 5.72, Cl 8.04, N 12.71;
found C 62.41, H 5.51, Cl 8.30, N 12.63.
Preparation of (E)-1-(8,9-dimethoxy-1-aryl-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]-isoquinolin-3-yl)-3-(dimethyl-
amino)propenones (5a – c)
A mixture of a 1-aryl-3-acetyl-8,9-dimethoxy[1,2,4]triaz-
olo[3,4-a]1,5,6,10b-tetrahydroisoquinoline 4 (5 mmol) and
DMF-DMA (3 mL) was refluxed for 4 h. The solid that pre-
cipitated was collected and crystallized from a suitable sol-
vent. The compounds prepared with their physical data are
listed below.
Synthesis of 1-[4-(8,9-dimethoxy-1-aryl-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-
aryl-1H-pyrazol-3-yl]ethanones (8a – i)
To a solution of a hydrazonoyl chloride 1 (1 mmol) and
an enaminone 5 (1 mmol) in absolute ethanol (5 mL) was
added chitosan (0.1 g) at r. t. The reaction mi◦xture was irra-
diated under constant pressure (11.2 bar, 80 C) for 10 min
at a power of 300 W. The hot solution was filtered to remove
chitosan. After cooling, dilute HCl was added to the solution
until it became acidic. The solid was collected and crystal-
lized from a suitable solvent. The compounds prepared and
their physical data are listed below.
(E)-1-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(dimethylamino)-
propenone (5a)
◦
Orange crystals, m. p. 158 C (ethanol), 78 % yield. – IR
(KBr): ν = 1641 (C=O) cm−1. – 1H NMR (CDCl3): δ =
2.70 (m, 1H), 2.84 (m, 1H), 2.87 (s, 3H), 3.08 (s, 3H), 3.64
(s, 3H), 3.85 (s, 3H), 3.86 (m, 1H), 4.00 (m, 1H), 5.80 (d, J =
13 Hz, 1H), 6.34 (s, 1H), 6.64 (s, 1H), 6.75 (s, 1H), 6.87 –
7.31 (m, 5H), 7.66 (d, J = 13 Hz, 1H). – 13C NMR (CDCl3):
δ = 28.04, 37.30, 42.08, 45.50, 55.85, 55.97, 77.85, 108.44,
111.09, 113.59, 119.82, 125.90, 127.92, 129.04, 129.09,
146.41, 147.69, 148.56, 151.35, 153.16, 178.87. – MS: m/z
(%) = 406 (59) [M]+, 405 (100). – Anal. for C23H26N4O3:
calcd. C 67.96, H 6.45, N 13.78; found C 67.86, H 6.43,
N 14.03.
1-[4-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-3-carbonyl)-1-phenyl-1H-
pyrazol-3-yl]ethanone (8a)
◦
Orange crystals, m. p. 160 C (ethanol), 80 % yield. – IR
(KBr): ν = 1700 (C=O), 1646 (C=O) cm−1. – 1H NMR
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H. M. Hassaneen et al. · 3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives
(CDCl3): δ = 2.64 (s, 3H), 2.74 (m, 1H), 3.10 (m, 1H), 1H), 6.58 (s, 1H), 6.66 (s, 1H), 6.69 (s, 1H), 7.04 – 7.73 (m,
3.61 (s, 3H), 3.85 (m, 1H), 3.87 (s, 3H), 3.95 (m, 1H), 6.64 9H), 8.48 (s, 1H). – 13C NMR (CDCl3): δ = 20.55, 27.93,
(s, 1H), 6.70 (s, 1H), 6.71 (s, 1H), 6.96 – 7.77 (m, 10H), 28.17, 42.13, 55.84, 55.93, 78.98, 109.01, 111.53, 115.41,
8.52 (s, 1H). – 13C NMR (CDCl3): δ = 27.98, 28.25, 42.12, 119.85, 122.27, 127.55, 127.93, 128.58, 129.57, 129.66,
55.86, 55.95, 78.47, 108.56, 111.34, 114.75, 119.97, 121.18, 130.93, 131.40, 139.00, 141.96, 147.58, 148.85, 149.44,
122.18, 127.69, 128.06, 128.37, 129.21, 129.66, 131.57, 152.02, 177.10, 193.91. – MS: m/z (%) = 535 (64) [M]+,
139.02, 144.31, 147.61, 148.82, 149.68, 152.07, 177.26, 534 (100). – Anal. for C31H29N5O4: calcd. C 69.52, H 5.46,
194.01. – MS: m/z (%) = 521 (33) [M]+, 520 (77), 77 N 13.08; found C 69.33, H 5.21, N 13.31.
(100). – Anal. for C30H27N5O4: calcd. C 69.08, H 5.22,
N 13.43; found C 69.24, H 5.43, N 13.64.
1-[4-(8,9-Dimethoxy-1-(4-methylphenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]iso-quinoline-3-carbonyl)-1-
(4-methylphenyl)-1H-pyrazol-3-yl]ethanone (8e)
1-[4-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-
(4-methylphenyl)-1H-pyrazol-3-yl]ethanone (8b)
◦
Orange crystals, m. p. 158 C (ethanol), 76 % yield. – IR
(KBr): ν = 1701 (C=O), 1647 (C=O) cm−1. – 1H NMR
Orange crystals, m. p. 175 ◦C (dimethyl formamide), (CDCl3): δ = 2.30 (s, 3H), 2.41 (s, 3H), 2.63 (s, 3H), 2.70
78 % yield. – IR (KBr): ν = 1702 (C=O), 1644 (C=O) (m, 1H), 3.10 (m, 1H), 3.61 (s, 3H), 3.8 (m, 1H), 3.87 (s,
1
cm−1. – H NMR (CDCl3): δ = 2.41 (s, 3H), 2.63 (s, 3H), 3H), 4.20 (m, 1H), 6.60 (s, 1H), 6.68 (s, 1H), 6.70 (s, 1H),
2.74 (m, 1H), 3.10 (m, 1H), 3.60 (s, 3H), 3.85 (m, 1H), 3.87 7.08 – 7.63 (m, 8H), 8.46 (s, 1H). – 13C NMR (CDCl3):
(s, 3H), 4.20 (m, 1H), 6.63 (s, 1H), 6.69 (s, 1H), 6.71 (s, δ = 20.59, 20.98, 27.97, 28.24, 42.15, 55.82, 55.91, 78.98,
1H), 6.95 – 7.64 (m, 9H), 8.47 (s, 1H). – 13C NMR (CDCl3): 108.76, 111.31, 115.35, 119.85, 122.04, 127.53, 128.51,
δ = 20.98, 27.95, 28.24, 42.08, 55.83, 55.93, 78.40, 108.54, 129.67, 130.11, 130.93, 131.46, 136.75, 138.07, 142.02,
111.32, 114.69, 119.85, 121.11, 121.96, 127.70, 128.34, 147.50, 148.74, 149.49, 151.83, 177.16, 194.07. – MS: m/z
129.18, 130.13, 131.51, 136.73, 138.12, 144.31, 147.58, (%) = 549 (53) [M]+, 548 (100). – Anal. for C32H31N5O4:
148.79, 149.67, 151.86, 177.27, 194.03. – MS: m/z (%) = calcd. C 69.93, H 5.69, N 12.74; found C 69.62, H 5.41,
535 (58) [M]+, 534 (100). – Anal. for C31H29N5O4: calcd. N 12.98.
C 69.52, H 5.46, N 13.08; found C 69.80, H 5.64, N 13.31.
1-[4-(8,9-Dimethoxy-1-(4-methylphenyl)-1,5,6,10b-tetra-
1-[4-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-
(4-chlorophenyl)-1H-pyrazol-3-yl]ethanone (8c)
hydro[1,2,4]triazolo[3,4-a]iso-quinoline-3-carbonyl)-1-
(4-chlorophenyl)-1H-pyrazol-3-yl]ethanone (8f)
◦
Orange crystals, m. p. 188 C (ethanol), 77 % yield. – IR
Orange crystals, m. p. 196 ◦C (acetonitrile), 75 % yield. – (KBr): ν = 1705 (C=O), 1647 (C=O) cm−1. – 1H NMR
1
IR (KBr): ν = 1702 (C=O), 1645 (C=O) cm−1. – H NMR (CDCl3): δ = 2.30 (s, 3H), 2.62 (s, 3H), 2.75 (m, 1H), 3.10
(CDCl3): δ = 2.61 (s, 3H), 2.74 (m, 1H), 3.04 (m, 1H), (m, 1H), 3.60 (s, 3H), 3.86 (m, 1H), 3.87 (s, 3H), 4.20 (m,
3.58 (s, 3H), 3.80 (m, 1H), 3.86 (s, 3H), 4.16 (m, 1H), 1H), 6.61 (s, 1H), 6.66 (s, 1H), 6.68 (s, 1H), 7.05 – 7.71 (m,
6.63 (s, 1H), 6.65 (s, 1H), 6.68 (s, 1H), 6.92 – 7.71 (m, 8H), 8.46 (s, 1H). – 13C NMR (CDCl3): δ = 20.60, 27.94,
9H), 8.47 (s, 1H). – 13C NMR (CDCl3): δ = 27.91, 28.22, 28.24, 42.14, 55.81, 55.90, 79.07, 108.75, 111.32, 115.45,
42.07, 55.82, 55.92, 78.47, 108.53, 111.34, 114.77, 121.02, 121.02, 122.48, 127.38, 128.50, 129.70, 129.75, 131.12,
121.24, 122.39, 127.56, 128.33, 129.20, 129.75, 131.33, 131.29, 133.70, 137.50, 141.85, 147.49, 148.76, 149.40,
133.70, 137.47, 144.14, 147.57, 148.80, 149.58, 152.15, 152.15, 176.90, 193.87. – MS: m/z (%) = 571 (16) [M+2]+,
177.03, 193.80. – MS: m/z (%) = 557 (18) [M+2]+, 556 (42) 570 (79) [M+2–H]+, 569 (82) [M]+, 568 (100) [M–H]+. –
[M+2–H]+, 555 (53) [M]+, 554 (100) [M–H]+. – Anal. for Anal. for C31H28ClN5O4: calcd. C 65.32, H 4.95, Cl 6.22,
C30H26ClN5O4: calcd. C 64.80, H 4.71, Cl 6.38, N 12.60; N 12.29; found C 65.22, H 4.87, Cl 6.18, N 12.46.
found C 64.60, H 4.52, Cl 6.21, N 12.44.
1-[4-(8,9-Dimethoxy-1-(4-chlorophenyl)-1,5,6,10b-tetra-
1-[4-(8,9-Dimethoxy-1-(4-methylphenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]iso-quinoline-3-carbonyl)-1-
phenyl-1H-pyrazol-3-yl]ethanone (8d)
hydro[1,2,4]triazolo[3,4-a]iso-quinoline-3-carbonyl)-1-
phenyl-1H-pyrazol-3-yl]ethanone (8g)
◦
Orange crystals, m. p. 145 C (ethanol), 76 % yield. – IR
◦
Orange crystals, m. p. 124 C (ethanol), 80 % yield. – IR (KBr): ν = 1705 (C=O), 1647 (C=O) cm−1. – 1H NMR
(KBr): ν = 1705 (C=O), 1639 (C=O) cm−1. – 1H NMR (CDCl3): δ = 2.61 (s, 3H), 2.76 (m, 1H), 3.04 (m, 1H), 3.63
(CDCl3): δ = 2.27 (s, 3H), 2.61 (s, 3H), 2.70 (m, 1H), 3.10 (s, 3H), 3.85 (s, 3H), 3.89 (m, 1H), 4.09 (m, 1H), 6.52 (s,
(m, 1H), 3.57 (s, 3H), 3.80 (m, 1H), 3.83 (s, 3H), 4.20 (m, 1H), 6.63 (s, 1H), 6.70 (s, 1H), 7.04 – 7.75 (m, 9H), 8.48
Unauthenticated
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H. M. Hassaneen et al. · 3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives
305
(s, 1H). – 13C NMR (CDCl3): δ = 27.97, 28.14, 42.08, collected, washed with water, and crystallized from dimethyl
55.93, 55.95, 78.25, 108.24, 111.39, 115.38, 119.88, 122.08, formamide. The compounds prepared and their physical data
125.76, 127.51, 128.10, 128.27, 129.09, 129.65, 131.46, are listed below.
138.89, 143.09, 147.69, 148.92, 149.99, 151.98, 177.35,
8,9-Dimethoxy-3-(7-methyl-2-phenyl-2H-pyrazolo[3,4-d]-
pyridazin-4-yl)-1-phenyl-1,5,6,10b-tetra-hydro[1,2,4]triaz-
olo[3,4-a]isoquinoline (10a)
193.87. – MS: m/z (%) = 557 (14) [M+2]+, 556 (45) [M+2–
H]+, 555 (39) [M]+, 554 (71) [M–H]+, 287 (100). – Anal.
for C30H26ClN5O4: calcd. C 64.80, H 4.71, Cl 6.38, N 12.60;
found C 65.05, H 5.01, Cl 6.21, N 12.96.
◦
Red crystals, m. p. 230 C, 89 % yield. – IR (KBr): no
C=O bands. – 1H NMR (DMSO): δ = 2.64 (s, 3H), 2.74 (m,
1H), 3.10 (m, 1H), 3.61 (s, 3H), 3.85 (m, 1H), 3.87 (s, 3H),
3.95 (m, 1H), 6.64 (s, 1H), 6.70 (s, 1H), 6.71 (s, 1H), 6.96 –
7.77 (m, 10H), 8.52 (s, 1H). – 13C NMR (DMSO): δ = 18.09,
28.36, 43.19, 55.79, 55.87, 78.72, 108.31, 111.92, 114.25,
120.07, 121.36, 122.64, 125.78, 127.63, 128.26, 128.84,
129.50, 129.28, 131.76, 139.13, 144.52, 145.12, 147.27,
148.92, 149.85, 152.90. – MS: m/z (%) = 517 (100) [M]+,
516 (80). – Anal. for C30H27N7O2: calcd. C 69.62, H 5.26,
N 18.94; found C 69.41, H 5.51, N 18.71.
1-[4-(8,9-Dimethoxy-1-(4-chlorophenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]iso-quinoline-3-carbonyl)-1-
(4-methylphenyl)-1H-pyrazol-3-yl]ethanone (8h)
Orange crystals, m. p. 192 ◦C (acetonitrile), 80 % yield. –
1
IR (KBr): ν = 1701 (C=O), 1651 (C=O) cm−1. – H NMR
(CDCl3): δ = 2.41 (s, 3H), 2.61 (s, 3H), 2.76 (m, 1H), 3.06
(m, 1H), 3.65 (s, 3H), 3.85 (m, 1H), 3.87 (s, 3H), 4.10 (m,
1H), 6.53 (s, 1H), 6.64 (s, 1H), 6.71 (s, 1H), 7.05 – 7.63 (m,
8H), 8.44 (s, 1H). – 13C NMR (CDCl3): δ = 20.97, 27.97,
28.12, 42.06, 55.91, 55.93, 78.22, 108.22, 111.35, 115.34,
8,9-Dimethoxy-3-(7-methyl-2-(4-methylphenyl)-2H-pyraz-
119.81, 121.88, 125.71, 127.53, 128.24, 129.07, 130.12, olo[3,4-d]pyridazin-4-yl)-1-phenyl-1,5,6,10b-tetrahydro-
131.39, 136.64, 138.18, 143.13, 147.67, 148.89, 149.99, [1,2,4]triazolo[3,4-a]isoquinoline (10b)
151.81, 177.37, 193.88. – MS: m/z (%) = 571 (24) [M+2]+,
Red crystals, m. p. 220 ◦C, 87 % yield. – IR (KBr):
570 (46) [M+2–H]+, 569 (78) [M]+, 568 (100) [M–H]+, 227
no C=O bands. – 1H NMR (DMSO): δ = 2.49 (s, 3H),
(80). – Anal. for C31H28ClN5O4: calcd. C 65.32, H 4.95,
Cl 6.22, N 12.29; found C 65.22, H 4.61, Cl 6.13, N 12.14.
3.88 (m, 1H), 3.95 (s, 3H), 4.18 (m, 1H), 6.70 (s, 1H),
2.58 (s, 3H), 2.72 (m, 1H), 3.19 (m, 1H), 3.71 (s, 3H),
6.78 (s, 1H), 6.82 (s, 1H), 7.02 – 8.07 (m, 9H), 9.27 (s,
1H). – 13C NMR (DMSO): δ = 19.01, 21.10, 28.34, 43.21,
1-[4-(8,9-Dimethoxy-1-(4-chlorophenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]iso-quinoline-3-carbonyl)-1-
(4-chlorophenyl)-1H-pyrazol-3-yl]ethanone (8i)
55.73, 55.95, 78.76, 108.69, 111.42, 114.63, 119.86, 121.31,
121.70, 125.58, 127.34, 128.51, 129.27, 130.03, 131.19,
136.58, 137.99, 139.73, 144.18, 147.43, 148.97, 149.21,
153.92. – MS: m/z (%) = 531 (69) [M]+, 530 (100), 91 (97),
77 (81). – Anal. for C31H29N7O2: calcd. C 70.04, H 5.50,
N 18.44; found C 70.31, H 5.32, N 18.11.
Orange crystals, m. p. 200 ◦C (acetonitrile), 79 % yield. –
1
IR (KBr): ν = 1705 (C=O), 1651 (C=O) cm−1. – H NMR
(CDCl3): δ = 2.61 (s, 3H), 2.76 (m, 1H), 3.04 (m, 1H), 3.64
(s, 3H), 3.84 (m, 1H), 3.87 (s, 3H), 4.07 (m, 1H), 6.53 (s,
1H), 6.62 (s, 1H), 6.70 (s, 1H), 7.04 – 7.71 (m, 8H), 8.45
(s, 1H). – 13C NMR (CDCl3): δ = 27.94, 28.14, 42.05,
55.88, 55.92, 78.27, 108.07, 111.26, 115.36, 120.99, 122.28,
125.83, 127.37, 128.19, 129.10, 129.77, 131.27, 133.79,
137.36, 142.96, 147.61, 148.85, 149.91, 152.08, 177.14,
193.74. – MS: m/z (%) = 593 (3) [M+4]+, 592 (25) [M+4–
H]+, 591 (28) [M+2]+, 590 (74) [M+2–H]+, 589 (72) [M]+,
588 (100) [M–H]+, 587 (96). – Anal. for C30H25Cl2N5O4:
calcd. C 61.02, H 4.27, Cl 12.01, N 11.86; found C 61.31,
H 4.48, Cl 11.81, N 11.91.
8,9-Dimethoxy-3-(7-methyl-2-(4-chlorophenyl)-2H-pyraz-
olo[3,4-d]pyridazin-4-yl)-1-phenyl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinoline (10c)
◦
Red crystals, m. p. 238 C, 89 % yield. – IR (KBr): no
C=O bands. – 1H NMR (DMSO): δ = 2.50 (s, 3H), 2.75
(m, 1H), 3.04 (m, 1H), 3.53 (s, 3H), 3.72 (s, 3H), 3.92 (m,
1H), 4.55 (m, 1H), 6.77 (s, 1H), 6.79 (s, 1H), 6.81 (s, 1H),
7.31 – 8.24 (m, 9H), 9.33 (s, 1H). – MS: m/z (%) = 553 (26)
[M+2]+, 552 (51) [M+2–H]+, 551 (65) [M]+, 550 (95) [M–
H]+, 77 (100). – Anal. for C30H26ClN7O2: calcd. C 65.27,
H 4.75, Cl 6.42, N 17.76; found C 65.11, H 4.62, Cl 6.40,
N 17.71.
Synthesis of 8,9-dimethoxy-3-(7-methyl-2-phenyl-2H-pyr-
azolo[3,4-d]pyridazin-4-yl)-1-phenyl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinolines (10a – i)
8,9-Dimethoxy-3-(7-methyl-2-phenyl-2H-pyrazolo[3,4-d]-
pyridazin-4-yl)-1-(4-methylphenyl)-1,5,6, 10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinoline (10d)
A 3-acetyl-4-carbonylpyrazole derivative 8 (5 mmol) in
ethanol (30 mL) and hydrazine hydrate 99 % (0.7 mL,
10 mmol) were refluxed for 4 h, during which time the corre-
◦
Red crystals, m. p. 232 C, 88 % yield. – IR (KBr): no
sponding pyrazolopyridazine 10 precipitated. The solid was C=O bands. – 1H NMR (DMSO): δ = 2.26 (s, 3H), 2.51 (s,
Unauthenticated
Download Date | 5/24/16 12:27 PM

306
H. M. Hassaneen et al. · 3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives
3H), 2.73 (m, 1H), 3.04 (m, 1H), 3.53 (s, 3H), 3.71 (s, 3H), 552 (12) [M+2–H]+, 551 (17) [M]+, 550 (55) [M–H]+, 279
3.90 (m, 1H), 4.50 (m, 1H), 6.38 (s, 1H), 6.75 (s, 1H), 6.79 (s, (100). – Anal. for C30H26ClN7O2: calcd. C 65.27, H 4.75,
1H), 7.13 – 8.22 (m, 9H), 9.31 (s, 1H). – 13C NMR (DMSO): Cl 6.42, N 17.76; found C 65.01, H 4.32, Cl 6.11, N 17.42.
δ = 18.78, 20.67, 28.23, 42.93, 55.74, 56.12, 78.63, 108.91,
111.72, 114.95, 120.41, 122.36, 125.86, 127.79, 127.98,
128.24, 129.47, 129.63, 130.84, 131.07, 139.06, 141.96,
144.46, 147.85, 148.44, 149.83, 153.91. – MS: m/z (%) =
531 (62) [M]+, 367 (100). – Anal. for C31H29N7O2: calcd.
C 70.04, H 5.50, N 18.44; found C 70.10, H 5.32, N 18.33.
8,9-Dimethoxy-3-(7-methyl-2-(4-methylphenyl)-2H-pyraz-
olo[3,4-d]pyridazin-4-yl)-1-(4-chlorophenyl)-1,5,6,10b-
tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline (10h)
Red crystals, m. p. 232 ◦C, 89 % yield. –
IR (KBr): no C=O bands. – 1H NMR (DMSO): δ = 2.49
(s, 3H), 2.52 (s, 3H), 2.79 (m, 1H), 3.13 (m, 1H), 3.56 (s,
3H), 3.71 (s, 3H), 3.91 (m, 1H), 4.12 (m, 1H), 6.72 (s,
1H), 6.78 (s, 1H), 6.81 (s, 1H), 7.33 – 8.09 (m, 8H), 9.30
(s, 1H). – 13C NMR (DMSO): δ = 19.03, 20.83, 28.12,
42.34, 55.98, 56.00, 78.76, 108.58, 112.43, 115.81, 119.44,
122.03, 125.34, 127.11, 128.35, 128.61, 129.26, 130.99,
131.33, 136.51, 138.42, 143.57, 145.04, 147.45, 148.98,
150.07, 152.98. – MS: m/z (%) = 567 (39) [M+2]+, 566 (58)
[M+2–H]+, 565 (86) [M]+, 564 (100) [M–H]+. – Anal. for
C31H28ClN7O2: calcd. C 65.78, H 4.99, Cl 6.26, N 17.32;
found C 65.39, H 4.81, Cl 6.20, N 17.31.
8,9-Dimethoxy-3-(7-methyl-2-(4-methylphenyl)-2H-pyraz-
olo[3,4-d]pyridazin-4-yl)-1-(4-methylphenyl)-1,5,6,10b-
tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline (10e)
◦
Red crystals, m. p. 228 C, 88 % yield. – IR (KBr): no
C=O bands. – 1H NMR (DMSO): δ = 2.29 (s, 3H), 2.38 (s,
3H), 2.57 (s, 3H), 2.78 (m, 1H), 3.26 (m, 1H), 3.69 (s, 3H),
3.88 (m, 1H), 3.96 (s, 3H), 4.21 (m, 1H), 6.67 (s, 1H), 6.70
(s, 1H), 6.73 (s, 1H), 7.02 – 8.12 (m, 8H), 9.26 (s, 1H). –
13C NMR (DMSO): δ = 18.29, 20.49, 21.73, 28.54, 42.97,
56.14, 56.56, 78.89, 108.76, 111.57, 115.68, 120.65, 122.73,
125.78, 127.54, 128.15, 129.44, 130.96, 131.23, 132.90,
136.75, 137.76, 142.92, 145.68, 147.25, 148.94, 149.50,
153.67. – MS: m/z (%) = 545 (66) [M]+, 544 (100). – Anal.
for C32H31N7O2: calcd. C 70.44, H 5.73, N 17.97; found
C 70.31, H 5.92, N 18.20.
8,9-Dimethoxy-3-(7-methyl-2-(4-chlorophenyl)-2H-pyraz-
olo[3,4-d]pyridazin-4-yl)-1-(4-chlorophenyl)-1,5,6,10b-
tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline (10i)
◦
Red crystals, m. p. 244 C, 86 % yield. – IR (KBr): no
C=O bands. – 1H NMR (DMSO): δ = 2.53 (s, 3H), 2.86
(m, 1H), 3.29 (m, 1H), 3.76 (s, 3H), 3.98 (m, 1H), 4.12 (s,
3H), 4.26 (m, 1H), 6.72 (s, 1H), 6.78 (s, 1H), 6.82 (s, 1H),
7.34 – 8.29 (m, 8H), 9.28 (s, 1H). – MS: m/z (%) = 589 (25)
[M+4]+, 588 (37) [M+4–H]+, 587 (27) [M+2]+, 586 (67)
[M+2–H]+, 585 (67) [M]+, 584 (100) [M–H]+. – Anal. for
C30H25Cl2N7O2: calcd. C 61.44, H 4.30, Cl 12.09, N 16.72;
found C 61.62, H 4.41, Cl 12.30, N 16.52.
8,9-Dimethoxy-3-(7-methyl-2-(4-chlorophenyl)-2H-pyraz-
olo[3,4-d]pyridazin-4-yl)-1-(4-methylphenyl)-1,5,6,10b-
tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline (10f)
◦
Red crystals, m. p. 239 C, 87 % yield. – IR (KBr): no
C=O bands. – 1H NMR (DMSO): δ = 2.30 (s, 3H), 2.54 (s,
3H), 2.83 (m, 1H), 3.19 (m, 1H), 3.72 (s, 3H), 3.87 (m, 1H),
3.91 (s, 3H), 4.25 (m, 1H), 6.37 (s, 1H), 6.58 (s, 1H), 6.62
(s, 1H), 7.02 – 8.29 (m, 8H), 9.26 (s, 1H). – MS: m/z (%) =
567 (16) [M+2]+, 566 (38) [M+2–H]+, 565 (53) [M]+, 564
(100) [M–H]+. – Anal. for C31H28ClN7O2: calcd. C 65.78,
H 4.99, Cl 6.26, N 17.32; found C 65.51, H 5.21, Cl 6.11,
N 17.63.
Synthesis of ethyl 4-(8,9-dimethoxy-1-aryl-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-
aryl-1H-pyrazole-3-carboxylates (13a – e)
These compounds were prepared as described above for
the synthesis of 8 using hydrazonoyl halides 11 (1 mmol) in
place of 1. The products were crystallized from ethanol. The
compounds prepared and their physical data are listed below.
8,9-Dimethoxy-3-(7-methyl-2-phenyl-2H-pyrazolo[3,4-d]-
pyridazin-4-yl)-1-(4-chlorophenyl)-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinoline (10g)
Ethyl 4-(8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-phenyl-
1H-pyrazole-3-carboxylate (13a)
◦
Red crystals, m. p. 237 C, 86 % yield. – IR (KBr): no
C=O bands. – 1H NMR (CDCl3): δ = 2.85 (m, 1H), 2.95 (m,
1H), 3.02 (s, 3H), 3.74 (s, 3H), 3.86 (s, 3H), 4.20 (m, 1H),
4.50 (m, 1H), 6.47 (s, 1H), 6.69 (s, 1H), 6.79 (s, 1H), 7.16 –
◦
Orange crystals, m. p. 128 C, 73 % yield. – IR (KBr):
7.97 (m, 9H), 9.01 (s, 1H). – 13C NMR (CDCl3): δ = 18.52, ν = 1739 (C=O), 1639 (C=O) cm−1. – 1H NMR (CDCl3):
28.04, 43.45, 55.61, 56.03, 78.38, 108.15, 111.22, 114.43, δ = 1.19 (t, 3H), 2.74 (m, 1H), 3.00 (m, 1H), 3.59 (s, 3H),
121.76, 122.01, 125.81, 125.98, 128.19, 128.71, 129.14, 3.86 (s, 3H), 3.88 (m, 1H), 4.11 (m, 1H), 4.30 (q, 2H), 6.65
129.44, 129.80, 130.53, 139.65, 144.07, 145.45, 147.95, (s, 1H), 6.69 (s, 1H), 6.72 (s, 1H), 6.95 – 7.77 (m, 10H),
148.91, 149.99, 153.86. – MS: m/z (%) = 553 (5) [M+2]+, 8.54 (s, 1H). – 13C NMR (CDCl3): δ = 13.88, 27.89, 41.95,
Unauthenticated
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307
55.81, 55.95, 61.65, 78.00, 108.36, 111.25, 114.34, 120.13, 129.73, 130.78, 131.21, 138.91, 141.79, 147.60, 148.78,
121.06, 122.71, 127.86, 128.06, 129.03, 129.22, 129.52, 149.03, 173.67, 176.21. – MS: m/z (%) = 565 (44) [M]+, 564
131.24, 138.87, 144.05, 145.92, 147.65, 148.81, 149.22, (100), 563 (99). – Anal. for C32H31N5O5: calcd. C 67.95,
162.54, 176.33. – MS: m/z (%) = 551 (56) [M]+, 550 (100), H 5.52, N 12.38; found C 67.61, H 5.32, N 12.61.
77 (88). – Anal. for C31H29N5O5: calcd. C 67.50, H 5.30,
Ethyl 4-(8,9-dimethoxy-1-(4-chlorophenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-
N 12.70; found C 67.41, H 5.50, N 12.51.
phenyl-1H-pyrazole-3-carboxylate (13e)
Ethyl 4-(8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-(4-meth-
ylphenyl)-1H-pyrazole-3-carboxylate (13b)
Orange crystals, m. p. 118 ◦C, 72 % yield. – IR (KBr): ν =
1
1743 (C=O), 1643 (C=O) cm−1. – H NMR (CDCl3): δ =
1.16 (t, 3H), 2.74 (m, 1H), 3.00 (m, 1H), 3.62 (s, 3H), 3.85
Orange crystals, m. p. 134 ◦C, 74 % yield. – IR (KBr): ν =
(s, 3H), 3.90 (m, 1H), 4.15 (m, 1H), 4.30 (q, 2H), 6.27 (s,
1671 (C=O), 1634 (C=O) cm−1. – 1H NMR (CDCl3): δ =
1H), 6.55 (s, 1H), 6.60 (s, 1H), 6.64 – 7.75 (m, 9H), 8.50 (s,
1H). – 13C NMR (CDCl3): δ = 13.87, 27.93, 41.95, 55.92,
1.15 (t, 3H), 2.34 (s, 3H), 2.70 (m, 1H), 3.00 (m, 1H), 3.55 (s,
3H), 3.82 (s, 3H), 3.85 (m, 1H), 4.08 (q, 2H), 4.30 (m, 1H),
55.99, 61.69, 77.87, 108.10, 111.34, 114.41, 120.11, 122.63,
6.61 (s, 1H), 6.65 (s, 1H), 6.69 (s, 1H), 6.91 – 7.60 (m, 9H),
124.39, 127.87, 128.06, 128.91, 129.15, 129.56, 131.21,
8.46 (s, 1H). – 13C NMR (CDCl3): δ = 13.88, 20.95, 27.85,
138.80, 145.09, 145.93, 147.76, 148.95, 149.54, 162.40,
176.41. – MS: m/z (%) = 587 (30) [M+2]+, 586 (57) [M+2–
H]+, 585 (100) [M]+. – Anal. for C31H28ClN5O5: calcd.
C 63.53, H 4.82, Cl 6.05, N 11.95; found C 63.82, H 4.66,
Cl 6.30, N 11.80.
41.91, 55.79, 55.95, 61.60, 77.92, 108.39, 111.30, 114.33,
119.95, 121.02, 122.54, 127.87, 128.14, 129.04, 129.22,
130.03, 131.12, 138.09, 144.00, 145.68, 147.61, 148.79,
149.22, 162.53, 176.36. – MS: m/z (%) = 565 (58) [M]+,
564 (100). – Anal. for C32H31N5O5: calcd. C 67.95, H 5.52,
N 12.38; found C 67.84, H 5.76, N 12.67.
Synthesis of 4-(8,9-dimethoxy-1-aryl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-2-aryl-2,6-dihydro-
pyrazolo[3,4-d]pyridazin-7-ones (14a – e)
Ethyl 4-(8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-(4-chloro-
phenyl)-1H-pyrazole-3-carboxylate (13c)
These compounds were prepared as described above for
the synthesis of 10 using the 3-ethoxy-4-carbonylpyrazole
derivatives 13 instead of the 3-acetyl-4-carbonylpyrazole
derivatives 8. The products were crystallized from dimethyl
formamide. The compounds prepared and their physical data
are listed below.
Orange crystals, m. p. 150 ◦C, 73 % yield. – IR (KBr): ν =
1743 (C=O), 1637 (C=O) cm−1. – 1H NMR (CDCl3): δ =
1.19 (t, 3H), 2.74 (m, 1H), 3.00 (m, 1H), 3.59 (s, 3H), 3.87
(s, 3H), 3.90 (m, 1H), 4.10 (q, 2H), 4.30 (m, 1H), 6.67 (s,
1H), 6.69 (s, 1H), 6.72 (s, 1H), 6.96 – 7.72 (m, 9H), 8.51
(s, 1H). – 13C NMR (CDCl3): δ = 13.87, 27.89, 41.96,
55.82, 55.97, 61.76, 78.08, 108.36, 111.26, 114.40, 121.19,
121.25, 122.98, 125.72, 127.79, 128.10, 129.26, 129.70,
131.09, 137.39, 143.98, 146.13, 147.68, 148.85, 149.18,
162.30, 176.16. – MS: m/z (%) = 587 (29) [M+2]+, 586 (46)
[M+2–H]+, 585 (63) [M]+, 584 (100) [M–H]+. – Anal. for
C31H28ClN5O5: calcd. C 63.53, H 4.82, N 11.95, Cl 6.05;
found C 63.73, H 5.09, N 12.22, Cl 5.91.
4-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinolin-3-yl)-2-phenyl-2,6-dihydro-
pyrazolo[3,4-d]pyridazin-7-one (14a)
Orange crystals, m. p. 260 ◦C, 83 % yield. – IR (KBr): ν =
3159 (NH), 1693 (C=O) cm−1. – 1H NMR (DMSO): δ =
2.77 (m, 1H), 2.85 (m, 1H), 3.72 (s, 3H), 3.78 (s, 3H), 3.83
(m, 1H), 4.24 (m, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 6.79 (s, 1H),
6.86 – 8.10 (m, 10H), 9.13 (s, 1H), 12.71 (s, 1H). – 13C NMR
(DMSO): δ = 26.70, 42.29, 55.44, 55.54, 76.90, 109.10,
111.81, 113.40, 117.44, 119.36, 120.46, 120.97, 126.61,
128.17, 128.35, 128.75, 129.62, 132.35, 138.90, 142.20,
145.95, 147.23, 147.84, 148.51, 155.77. – MS: m/z (%) =
519 (46) [M]+, 518 (85), 91 (100). – Anal. for C29H25N7O3:
calcd. C 67.04, H 4.85, N 18.87; found C 67.30, H 4.61,
N 18.50.
Ethyl 4-(8,9-dimethoxy-1-(4-methylphenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-1-
phenyl-1H-pyrazole-3-carboxylate (13d)
Orange crystals, m. p. 118 ◦C, 75 % yield. – IR (KBr): ν =
1743 (C=O), 1635 (C=O) cm−1. – 1H NMR (CDCl3): δ =
1.20 (t, 3H), 2.30 (s, 3H), 2.76 (m, 1H), 2.96 (m, 1H), 3.60 (s,
3H), 3.86 (s, 3H), 4.00 (m, 1H), 4.12 (q, 2H), 4.34 (m, 1H),
6.63 (s, 1H), 6.68 (s, 1H), 6.71 (s, 1H), 7.11 – 7.76 (m, 9H),
8.53 (s, 1H). – 13C NMR (CDCl3): δ = 13.90, 20.58, 27.92,
41.99, 55.83, 55.95, 61.64, 78.46, 108.56, 111.25, 114.78,
4-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro[1,2,4]tri-
azolo[3,4-a]isoquinolin-3-yl)-2-(4-methylphenyl)-2,6-di-
hydropyrazolo[3,4-d]pyridazin-7-one (14b)
Orange crystals, m. p. 230 ◦C, 84 % yield. – IR (KBr): ν =
120.14, 122.80, 125.76, 127.80, 128.03, 128.24, 129.52, 3200 (NH), 1681 (C=O) cm−1. – 1H NMR (DMSO): δ =
Unauthenticated
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308
H. M. Hassaneen et al. · 3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives
2.37 (s, 3H), 2.73 (m, 1H), 2.84 (m, 1H), 3.52 (s, 3H), 3.71 7.32 – 8.09 (m, 9H), 9.12 (s, 1H), 12.74 (s, 1H). – 13C NMR
(s, 3H), 3.79 (m, 1H), 4.21 (m, 1H), 6.63 (s, 1H), 6.72 (s, (DMSO): δ = 26.77, 42.40, 55.52, 55.60, 76.80, 108.74,
1H), 6.77 (s, 1H), 6.86 – 7.95 (m, 9H), 9.05 (s, 1H), 12.79 111.82, 114.74, 117.48, 120.63, 120.67, 120.71, 126.76,
(s, 1H). – 13C NMR (DMSO): δ = 20.52, 26.73, 42.33, 128.14, 128.18, 128.86, 129.74, 132.25, 138.95, 142.25,
55.43, 55.55, 76.93, 108.96, 111.74, 113.40, 117.42, 119.41, 144.90, 147.32, 148.39, 148.59, 155.90. – MS: m/z (%) =
120.54, 120.57, 126.45, 128.17, 128.38, 129.08, 130.08, 555 (22) [M+2]+, 554 (59) [M+2–H]+, 553 (55) [M]+, 552
132.37, 138.57, 142.26, 145.97, 146.03, 147.22, 148.48, (98) [M–H]+, 125 (100). – Anal. for C29H24ClN7O3: calcd.
155.85. – MS: m/z (%) = 533 (37) [M]+, 532 (87), 91 C 62.87, H 4.37, Cl 6.40, N 17.70; found C 62.53, H 4.51,
(100). – Anal. for C30H27N7O3: calcd. C 67.53, H 5.10, Cl 6.61, N 17.71.
N 18.38; found C 67.61, H 4.90, N 18.71.
Synthesis of [4-(8,9-dimethoxy-1-aryl-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-
isoxazol-3-yl]arylmethanones (16a – f)
4-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro[1,2,4]tri-
azolo[3,4-a]isoquinolin-3-yl)-2-(4-chlorophenyl)-2,6-di-
hydropyrazolo[3,4-d]pyridazin-7-one (14c)
A mixture of equimolar amounts of the appropriate enam-
inone 5 and hydroximoyl chloride 15 (5 mmol each) was
stirred for 3 h, during which the compounds dissolved, and
the corresponding adduct 16 was precipitated. The solid was
collected and crystallized from acetonitrile. The compounds
prepared and their physical data are listed below.
Brown crystals, m. p. 243 ◦C, 85 % yield. – IR (KBr): ν =
3166 (NH), 1685 (C=O) cm−1. – 1H NMR (DMSO): δ =
2.76 (m, 1H), 2.85 (m, 1H), 3.54 (s, 3H), 3.78 (s, 3H), 3.81
(m, 1H), 4.29 (m, 1H), 6.62 (s, 1H), 6.75 (s, 1H), 6.78 (s, 1H),
6.82 – 8.11 (m, 9H), 9.11 (s, 1H), 12.71 (s, 1H). – 13C NMR
(DMSO): δ = 26.71, 42.32, 55.47, 55.54, 76.93, 109.20,
111.92, 113.78, 117.46, 119.46, 120.42, 120.89, 126.63,
128.27, 128.60, 128.81, 129.63, 132.38, 138.92, 142.34,
146.02, 146.98, 147.81, 148.59, 155.74. – MS: m/z (%) =
555 (20) [M+2]+, 554 (24) [M+2–H]+, 553 (66) [M]+, 552
(53) [M–H]+, 91 (100). – Anal. for C29H24ClN7O3: calcd.
C 62.87, H 4.37, Cl 6.40, N 17.70; found C 62.71, H 4.22,
Cl 6.33, N 17.92.
[4-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro[1,2,4]tri-
azolo[3,4-a]isoquinoline-3-carbonyl)isoxazol-3-yl]phenyl-
methanone (16a)
Orange crystals, m. p. 154 ◦C, 75 % yield. – IR (KBr): ν =
1
1693 (C=O), 1647 (C=O) cm−1. – H NMR (CDCl3): δ =
2.69 (m, 1H), 2.83 (m, 1H), 3.57 (s, 3H), 3.75 (m, 1H), 3.86
(s, 3H), 3.99 (m, 1H), 6.63 (s, 1H), 6.65 (s, 1H), 6.71 (s, 1H),
6.99 – 7.94 (m, 10H), 9.39 (s, 1H). – 13C NMR (CDCl3): δ =
27.72, 41.89, 55.80, 55.98, 78.31, 108.28, 111.31, 114.78,
120.10, 121.68, 127.21, 128.01, 128.68, 129.32, 129.91,
134.34, 135.66, 143.43, 147.66, 148.08, 148.94, 159.57,
162.51, 173.45, 186.33. – MS: m/z (%) = 508 (11) [M]+,
104 (100). – Anal. for C29H24N4O5: calcd. C 68.49, H 4.76,
N 11.02; found C 68.41, H 4.82, N 11.21.
4-(8,9-Dimethoxy-1-(4-methylphenyl)-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-2-phenyl-2,6-di-
hydropyrazolo[3,4-d]pyridazin-7-one (14d)
Orange crystals, m. p. 230 ◦C, 85 % yield. – IR (KBr): ν =
3352 (NH), 1712 (C=O) cm−1. – 1H NMR (DMSO): δ =
2.33 (s, 3H), 2.81 (m, 1H), 2.96 (m, 1H), 3.72 (s, 3H), 3.90
(s, 3H), 3.98 (m, 1H), 4.19 (m, 1H), 6.69 (s, 1H), 6.71 (s,
1H), 6.81 (s, 1H), 6.85 – 7.95 (m, 9H), 8.96 (s, 1H), 12.76
(s, 1H). – 13C NMR (DMSO): δ = 20.52, 26.74, 42.37, [4-(8,9-Dimethoxy-1-(4-methylphenyl)-1,5,6,10b-tetra-
55.43, 55.56, 76.95, 109.00, 111.79, 113.42, 117.39, 119.45, hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-
120.50, 120.59, 126.46, 128.27, 128.39, 129.09, 130.12, isoxazol-3-yl]phenylmethanone (16b)
132.33, 138.61, 142.29, 145.99, 146.05, 147.18, 148.41,
◦
155.83. – MS: m/z (%) = 533 (18) [M]+, 532 (35), 77
(100). – Anal. for C30H27N7O3: calcd. C 67.53, H 5.10,
N 18.38; found C 67.41, H 4.90, N 18.31.
Orange crystals, m. p. 150 C, 80 % yield. – IR (KBr):
ν = 1689 (C=O), 1651 (C=O) cm−1. – 1H NMR (CDCl3):
δ = 2.33 (s, 3H), 2.64 (m, 1H), 2.81 (m, 1H), 3.64 (s,
3H), 3.68 (m, 1H), 3.86 (s, 3H), 4.02 (m, 1H), 6.62 (s,
1H), 6.63 (s, 1H), 6.70 (s, 1H), 7.04 – 7.94 (m, 9H), 9.37
(s, 1H). – 13C NMR (CDCl3): δ = 20.64, 27.80, 41.99,
56.98, 56.07, 78.19, 107.82, 111.10, 115.40, 120.62, 126.01,
127.56, 127.65, 128.23, 129.92, 129.99, 134.58, 135.20,
4-(8,9-Dimethoxy-1-(4-chlorophenyl)-1,5,6,10b-tetrahydro-
[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-2-phenyl-2,6-di-
hydropyrazolo[3,4-d]pyridazin-7-one (14e)
Orange crystals, m. p. 234 ◦C, 84 % yield. – IR (KBr): ν = 142.12, 147.14, 148.64, 149.68, 159.51, 162.54, 173.11,
3228 (NH), 1685 (C=O) cm−1. – 1H NMR (DMSO): δ = 187.01. – MS: m/z (%) = 522 (6) [M]+, 104 (100). – Anal.
2.74 (m, 1H), 2.85 (m, 1H), 3.56 (s, 3H), 3.72 (s, 3H), 3.81 for C30H26N4O5: calcd. C 68.95, H 5.02, N 10.72; found
(m, 1H), 4.19 (m, 1H), 6.63 (s, 1H), 6.68 (s, 1H), 6.79 (s, 1H), C 68.72, H 5.31, N 10.41.
Unauthenticated
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309
[4-(8,9-Dimethoxy-1-(4-chlorophenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-
isoxazol-3-yl]phenylmethanone (16c)
177.56. – MS: m/z (%) = 528 (3) [M]+, 111 (100). – Anal.
for C28H24N4O5S: calcd. C 63.63, H 4.58, N 10.60, S 6.05;
found C 63.42, H 4.56, N 10.34, S 5.83.
Yellow crystals, m. p. 162 ◦C, 77 % yield. – IR (KBr): ν =
1693 (C=O), 1651 (C=O) cm−1. – 1H NMR (CDCl3): δ =
2.71 (m, 1H), 2.80 (m, 1H), 3.62 (s, 3H), 3.78 (m, 1H), 3.87
(s, 3H), 3.92 (m, 1H), 6.54 (s, 1H), 6.56 (s, 1H), 6.66 (s, 1H),
7.00 – 7.93 (m, 9H), 9.36 (s, 1H). – 13C NMR (CDCl3): δ =
27.78, 41.91, 55.92, 56.01, 78.13, 107.97, 111.37, 115.42,
120.07, 126.36, 127.07, 127.94, 128.69, 129.23, 129.90,
134.40, 135.59, 142.22, 147.78, 148.40, 149.08, 159.51,
162.50, 173.57, 186.17. – MS: m/z (%) = 544 (2) [M+2]+,
543 (3) [M+2–H]+, 542 (11) [M]+, 541 (9) [M–H]+, 105
(89), 51 (100). – Anal. for C29H23ClN4O5: calcd. C 64.15,
H 4.27, Cl 6.53, N 10.32; found C 64.16, H 4.41, Cl 6.43,
N 10.11.
[4-(8,9-Dimethoxy-1-(4-chlorophenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-
isoxazol-3-yl](2-thienyl)methanone (16f)
Yellow crystals, m. p. 158 ◦C, 80 % yield. – IR (KBr): ν =
1
1674 (C=O), 1651 (C=O) cm−1. – H NMR (CDCl3): δ =
2.72 (m, 1H), 2.90 (m, 1H), 3.62 (s, 3H), 3.80 (m, 1H), 3.87
(s, 3H), 3.97 (m, 1H), 6.57 (s, 1H), 6.68 (s, 1H), 6.70 (s, 1H),
6.88 – 7.83 (m, 7H), 9.27 (s, 1H). – 13C NMR (CDCl3): δ =
27.85, 42.01, 55.78, 55.93, 78.25, 108.01, 111.01, 115.42,
119.82, 121.58, 127.01, 128.03, 128.49, 129.18, 131.45,
136.59, 141.03, 142.63, 147.51, 148.03, 148.91, 159.16,
162.40, 173.29, 177.57. – MS: m/z (%) = 550 (6) [M+2]+,
549 (10) [M+2–H]+, 548 (15) [M]+, 547 (7) [M–H]+, 111
(100). – Anal. for C27H21ClN4O5S: calcd. C 59.08, H 3.86,
Cl 6.46, N 10.21, S 5.83; found C 59.33, H 3.99, Cl 6.31,
N 10.50, S 5.72.
[4-(8,9-Dimethoxy-1-phenyl-1,5,6,10b-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-3-carbonyl)isoxazol-3-yl]-
(2-thienyl)methanone (16d)
Orange crystals, m. p. 164 ◦C, 78 % yield. – IR (KBr): ν =
1674 (C=O), 1647 (C=O), 1596 (C=C) cm−1. – 1H NMR
(CDCl3): δ = 2.72 (m, 1H), 2.89 (m, 1H), 3.56 (s, 3H),
3.78 (m, 1H), 3.86 (s, 3H), 4.04 (m, 1H), 6.64 (s, 1H), 6.66
(s, 1H), 6.70 (s, 1H), 6.95 – 7.81 (m, 8H), 9.30 (s, 1H). –
13C NMR (CDCl3): δ = 27.75, 41.94, 55.78, 55.95, 78.41,
108.30, 111.32, 114.78, 119.76, 121.59, 127.14, 128.08,
128.44, 129.25, 130.46, 136.51, 142.61, 143.36, 147.60,
148.21, 148.91, 159.14, 162.42, 173.50, 177.56. – MS: m/z
(%) = 514 (9) [M]+, 111 (100). – Anal. for C27H22N4O5S:
calcd. C 63.03, H 4.31, N 10.89, S 6.22; found C 63.21,
H 4.60, N 10.61, S 6.12.
Antibacterial activity
The antibacterial activities of the compounds were as-
sayed according to Bauer [39]. 100 µL of the bacterial spore
suspensions was spread onto plates containing Mueller-
Hinton agar. The disc diffusion method for bacteria was used
to study the sensitivity of the pathogenic bacterial species to
the tested compounds. Plates inoculated with Staphylococ-
cus aureus Gram (+), Bacillus subtilis Gram (+), Escherichia
coli Gram (–) and◦Neisseria gonorrhoeae Gram (–) were in-
cubated at 35 2 C for 24 h; the diameter of the inhibition
zones was then measured. Standard discs of tetracycline and
DMSO discs were used as positive and negative controls, re-
spectively [40].
The minimum inhibitory concentration (MIC) of the most
potent antibacterial compounds was determined by the broth
microdilution method by a whole-cell assay in 96-well mi-
crotitre format [41]. Bacterial cell suspensions with an initial
cell optical density at 600 nm (OD600) of 0.001 in nutrient
broth (DIFCO) medium were inoculated with serial bi-fold
dilutions (0 – 280 µg mL−1) of the tested compound. The
growth was measured by OD600 after 48 h. The MIC is de-
fined as the least concentration of the antibacterial compound
that completely inhibits the growth of a particular bacterial
species under standardized in vitro conditions.
[4-(8,9-Dimethoxy-1-(4-methylphenyl)-1,5,6,10b-tetra-
hydro[1,2,4]triazolo[3,4-a]isoquinoline-3-carbonyl)-
isoxazol-3-yl](2-thienyl)methanone (16e)
◦
Orange crystals, m. p. 152 C, 78 % yield. – IR (KBr):
ν = 1674 (C=O), 1651 (C=O) cm−1. – 1H NMR (CDCl3):
δ = 2.31 (s, 3H), 2.71 (m, 1H), 2.95 (m, 1H), 3.52 (s,
3H), 3.72 (m, 1H), 3.86 (s, 3H), 4.07 (m, 1H), 6.61 (s,
1H), 6.64 (s, 1H), 6.68 (s, 1H), 7.00 – 7.80 (m, 7H), 9.28
(s, 1H). – 13C NMR (CDCl3): δ = 20.63, 27.75, 41.97,
55.78, 55.94, 78.90, 108.51, 111.32, 115.30, 119.81, 121.59,
127.00, 128.24, 128.43, 129.76, 131.45, 136.49, 141.02,
142.63, 147.52, 148.02, 148.86, 159.15, 162.35, 173.28,
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