Vol.3, No.8, 651-660 (2011) Natural Science
http://dx.doi.org/10.4236/ns.2011.38089
Reactivity of 1-methylisoquinoline synthesis of
pyrazolyl triazoloisoquinoline and thiadiazolyl
isoquinoline derivatives
Hamdi Mahmoud Hassaneen*, Huwaida Mahmmed Elsayd Hassaneen,
Yasmin Shafie Mohammed
Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt; *Corresponding Author:
Received 18 May 2011; revised 10 June 2011; accepted 16 June 2011.
ABSTRACT
The reaction of 1-methylisoquinoline 1 with hy-
drazonoyl halides 2 in ethanol in the presence
of chitosan under microwave irradiation affords
triazoloisoquinoline 4. Product 4 reacts with
dimethylformamide-dimethylacetal to give ena-
minones 7 which react with hydrazonoyl halides
to give pyrazolyl triazoloisoquinoline 13. Also,
1-methylisoquinoline 1 reacts with arylisothio-
cyanate to give thioanilide 15 which reacts with
hydrazonoyl halides to give the corresponding
thiadiazolyl isoquinoline derivatives 20, 24.
Keywords: [1,2,4] Triazolo [3,4-a] Isoquinolines;
Enaminones; Hydrazonoyl Halides; Cycloaddition
Reactions; Chitosan; Thioanilides; [1,3,4]
Thiadiazolylisoquinoline Derivatives
1. INTRODUCTION
Within the class of fused isoquinoline with their car-
diovascular [1], anti-inflammatory [2], and antidepres-
sant activites [3], [1,2,4]triazolo [3,4-a]isoquinolines are
of considerable pharmaceutical and agricultural interest
[4-7]. Therefore, the synthesis of this ring system is an
attractive goal. We have previously reported the synthe-
ses of triazoloisoquinoline and fused isoquinoline com-
pounds via reaction of 3,4-dihydro-6,7-dimethoxyisoq-
uinoline derivatives with hydrazonoyl halides in chloro-
form in the presence of triethylamine or in pyridine as
catalyst and solvent [8-12]. The aim of the present study
is to introduce a new synthetic method by replacing
triethylamine in chloroform by the ecologically more
acceptable catalyst chitosan [13,14] and under micro-
wave irradiation to enhance reaction rates [15-19] for the
synthesis of [1,2,4]triazolo[3,4-a]isoquinolines which
were found to be useful precursors for the synthesis of
new enaminones 7. The latter compounds 7 were used to
prepare carbonylpyrazolyl triazoloisoquinoline deriva-
tives 13. Also, we synthesis thiadiazolyl isoquinoline
derivatives 20, 24 via a reaction of thioanilide 15 with
hydrazonoyl halides 16.
2. EXPERIMENTAL
The melting points were determined on a Stuart melt-
ing point apparatus and are uncorrected. The IR spectra
were recorded as KBr pellets using a FTIR unit Bruker-
vector 22 spectrophotometer. The 1H NMR and 13C
NMR spectra were recorded in CDCl3 and DMSO-d6 as
solvents at 300 MHz on Varian Gemini NMR spectro-
meter using TMS as internal standard. Chemical shifts
are reported in δ units (ppm). Mass spectra were meas-
ured on a Shimadzu GCMS-QP-1000 EX mass spec-
trometer at 70 eV. Microwave used was CEM Discover
labmateTM microwave apparatus (300 W with Chem-
DriverTM software). The elemental analyses were per-
formed at the Micro Analytical Center, Cairo University.
2.1. Synthesis of 1-(1-Aryl-8,9-Dimethoxy-
10b-Methyl-1,5,6,10b-Tetrahydro [1,2,4]
Triazolo [3,4-a]Isquinlin-3-yl)
Ethanone-4a-c
Chitosan (0.1 g) was added to a solution of hydrazo-
noyl chloride 2 (1 mmol) and 1-methyl-3,4-dihydro-6,
7-dimethoxyisoquinoline 1 (0.28 g, 1 mmol) in absolute
ethanol (5 mL) at room temperature. The reaction mixture
was irradiated 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 till pH became acidic and the solid was collected
and crystallized from suitable solvent. The compounds
prepared 4a-c with their physical data are listed in Tables
1 and 2.

H. M. Hassaneen et al. / Natural Science 3 (2011) 651-660 652
2.2. Synthesis of (E)-1-(1-Aryl-8,9-Dimethoxy-
10b-Methyl-1,5,6,10b-Tetrahydro [1,2,4]
Triazolo-[3,4-a]Isoquinolin-3-yl)-3-
Dimethylaminopropenone 7a-c
A mixture of 1-(1-aryl-8,9-dimethoxy-10b-methyl-1,
5,6,10b-tetra-hyd ro[1,2 ,4]triazolo[ 3,4-a]isoquinolin-3-yl)
ethanone 4 (5 mmoles) and DMF-DMA (3 mL) was re-
fluxed for 4 h. The solid that precipitated was collected
and crystallized from suitable solvent. The compounds
prepared 7 a-c with their physical data are listed in Tables
1 and 2.
2.3. Synthesis of Pyrazolyl
Triazoloisoquinoline Derivatives 13a-i
To a solution of the appropriate hydrazonoyl chloride 2,
8, 9 (1 mmol) and enaminones 7 (1 mmol) in absolute
ethanol (5 mL) was added chitosan (0.1 g) at room tem-
perature. The reaction mixture was irradiated under con-
stant 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 till pH became acidic
and the solid was collected and crystallized from suitable
solvent. The compounds prepared 13a-i with their
physical data are listed in Tables 1 and 2.
2.4. Synthesis of Thiadiazolyl Isoquinoline
Derivatives 20a-j and 24a-g
Equimolar quantities of thioanilides 15 and the appro-
priate hydrazonoyl halides were dissolved in absolute
ethanol (5 mL) in the presence of chitosan (0.1 g) at
room temperature. The reaction mixture was irradiated
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 till pH
became acidic and the solid was collected and crystal-
lized from suitable solvent to give the corresponding 1,
3,4-thiadiazoles. The compounds prepared 20a-j and
24a-g with their physical data are listed in Tables 1 and
2.
3. RESULTS AND DISCUSSION
The reaction of hydrazonoyl halides 2 with 1-methyl-
3, 4-dihydro-6, 7-dimethoxyisoquinoline 1 which has ac-
tive group at C-1 was studied.
The capacity of this dipolarophile 1 to behave as cy-
clic ketimine 1 A or as a secondary enamine 1B has been
discussed by many investigators [20,21]. Our aim point
of interest whether addition of nitrilimines 3 occurred on
the C = N double bond of ketimine structure 1 A or
enamine double bond of 1 B (Figure 1). Thus, reaction
of 1 with nitrilimines 3, generated in situ by treatment of
hydrazonoyl chlorides 2 with chitosan [22] in ethanol
under microwave irradiation, gave products whose ele-
mental analyses were compatible with triazole deriva-
tives 4, spyropyrazolines 5 or triazine derivatives 6. The
structures 5 and 6 were discarded on the basis of 1H
NMR evidences. For example, structure 5 will reveal
two singlet signals assignable to CH2 and NH protons,
while the other isomeric structure 6 is expected to reveal
doublet and triplet assignable to C1-CH2 and C11b-CH
protons. Such signals were absent in the 1H NMR spec-
tra of the isolated products from reaction of 2 with 1.
Instead of these signals, the 1H NMR spectra of the latter
products showed one singlet signal at δ 2.08 ppm. The
presence of such signal is compatible with the assigned
structure 4. Indeed the proton resonance of the moiety
-N = C(CH3)- appears in the 1H NMR spectra of the di-
polarophile 1 at δ 2.3 ppm [23]. This resonance was
shifted to higher field in the 1H NMR spectra (2.08 ppm)
of the cycloadducts 4 indicating the conversion of such
moiety to the saturated moiety -N-C(CH3)- due to
cycloaddition. Based on these findings the products iso-
lated from the reaction mixture were assigned structure 4
(Figure 1).
Refluxing of 4a with DMFDMA for 4 h afforded a
compound 7a which analyzed correctly for C24H28N4O3
(Figure 2). Similarly compounds 4b, c were also pre0
pared by reaction of the corresponding 3-acetylisoquino-
line derivatives with DMFDMA. The structures of the
products 7 were fully established on the basis of spectral
(MS, IR, 1H NMR and 13C NMR) and elemental analy-
ses. For example, the 1H NMR spectrum of 7a showed
two singlet signals at δ 2.96 and 3.72 ppm characteristic
for -N(Me)2 group, two doublet signals at δ about 5.75
and 7.64 ppm with coupling constant J = 13 Hz assign-
able to the two olefinic protons. The value of coupling
constant is compatible with the E-configuration [24] de-
picted in Figure 2. Also its 13C NMR spectrum showed
two signals at δ 37.31 and 45.48 ppm assignable to
-N(Me)2 group [25], in addition to the signals of other
carbon atoms.
Reaction of enaminones 7 with nitrilimines 10, gener-
ated in situ by the action of chitosan on the correspond-
ing α-ketohydrazonoyl halides 2, 8, 9 in refluxed ethanol
gave, in each case, one isolable product as evidenced by
TLC analysis and 1H NMR spectra of the crude reaction
mixture (Figure 3).
All the isolated cycloadducts gave satisfactory ele-
mental analyses and mass spectral data which were con-
sistent with either one of the two isomeric structures 13
or 14. Structure 14 was ruled out on the basis of 1H
NMR spectra. For example, in the pyrazole ring system
C (4) is the most electron rich carbon, thus, H (4) in is
expected to appear at higher field at δ 6.31 ppm. On the

H. M. Hassaneen et al. / Natural Science 3 (2011) 651-660
653653
Table 1. Characterization data of the synthesized compounds.
% Analyses calcd., found
Compd. no. Mp (˚C),
solvent
Yield (%),
color Mol. Formula
C H N Cl S
4a 162
EtOH
72
Yellow C21H23N3O3 69.02
68.83
6.34
6.13
11.50
11.67
4b 142
EtOH
73
Yellow C22H25N3O3 69.64
69.45
6.64
6.58
11.07
11.25
4c 154
EtOH
73
Yellow C21H22ClN3O3 63.08
62.93
5.55
5.75
10.51
10.66
8.87
8.63
7a 192
CH3CN
80
Yellow C24H28N4O3 68.55 68.40
6.71
6.92
13.32
13.04
7b 186
CH3CN
79
Yellow C25H30N4O3 69.10 68.87
6.96
7.03
12.89
13.06
7c 212
DMF
78
Orange C24H27ClN4O3 63.36
63.11
5.98
6.01
12.31
12.02
7.79
7.53
13a 210
CH3CN
75
Yellow C31H29N5O4 69.52 69.31
5.46
5.18
13.08
12.96
13b 170
EtOH
78
Yellow C32H31N5O4 69.93
69.72
5.69
5.77
12.74
12.91
13c 164
EtOH
76
Yellow C31H28ClN5O4 65.32
65.05
4.95
5.11
12.29
12.38
6.22
6.16
13d 150
EtOH
75
Yellow C32H31N5O5 67.95
67.68
5.52
5.46
12.38
12.41
13e 174
EtOH
73
Yellow C33H33N5O5 68.38 68.15
5.74
5.94
12.08
11.93
13f 158
EtOH
76
Yellow C32H30ClN5O5 64.05
63.87
5.04
5.31
11.67
11.83
5.91
6.12
13g 95
EtOH
72
Orange C36H31N5O4 72.35
72.51
5.23
5.42
11.72
11.47
13h 180
CH3CN
73
Orange C37H33N5O4 72.65 72.54
5.44
5.41
11.45
11.26
13i 90
EtOH
72
Orange C36H30ClN5O4 68.40
68.25
4.78
4.91
11.08
10.86
5.61
5.68
20a 174 - 175
CH3CN
81
Yellow C24H25N3O4S 63.85 63.92
5.58
5.62
9.31
9.61 7.09 6.92
20b 208 - 210
DMF
81
Yellow C23H22ClN3O4S 58.54
58.35
4.70
4.85
8.90
9.14
7.51
7.32
6.78
6.70
20c 201 - 202
DMF
82
Yellow C22H21N3O4S 62.41 62.53
5.00
4.89
9.92
9.68 7.56 7.59
20d 210 - 211
DMF
81
Yellow C23H23N3O4S 63.15
62.96
5.30
5.45
9.61
9.64 7.32 7.49
20e 210 - 220
DMF
79
Yellow C22H20ClN3O4S 57.71
57.57
4.40
4.32
9. 18
8.88
7.74
7.45
6.99
7.18
20f 266 -268
DMF
80
Yellow C26H22N4O4S 64.19
64.34
4.56
4.27
11.52
11.80 6.58 6.74
20g 279 - 280
DMF
79
Yellow C27H24N4O4S 64.79
64.99
4.83
5.07
11.19
10.88 6.39 6.26
20h 276 - 278
DMF
82
Orange C26H21ClN4O4S 59.95
60.22
4.06
3.89
10.76
10.53
6.81
7.04
6.14
6.07

H. M. Hassaneen et al. / Natural Science 3 (2011) 651-660 654
20i 270 - 272
DMF
80
Yellow C24H20N4O4S2 58.54
58.58
4.09
4.25
11.38
11.17 13.00 13.23
20j 278 - 280
DMF
81
Yellow C24H20N4O5S 60.50
60.42
4.23
3.98
11.76
11.63 6.72 6.81
24a 240 - 242
DMF
81
Yellow C23H23N3O3S 65.55
65.32
5.50
5.57
9.97
10.21 7.59 7.74
24b 228 - 230
DMF
78
Orange C22H20ClN3O3S 59.80
60.01
4.56
4.63
9.51
9.59
8.02
7.96
7.24
7.01
24c 200 - 201
DMF
84
Brown C28H25N3O3S 69.55
69.64
5.21
4.93
8.69
8.44 6.62 6.68
24d 179 - 181
DMF
82
Red C27H22ClN3O3S 64.35 64.42
4.40
4.72
8.34
8.48
7.04
6.83
6.35
6.57
24e 210-211
DMF
79
Yellow C27H24N4O3S 66.93 67.11
4.99
5.07
11.56
11.31 6.60 6.53
24f 170 - 172
DMF
80
Yellow C28H26N4O3S 67.46
67.26
5.26
4.95
11.24
11.13 6.42 6.51
24g 219 - 220
CH3CN
83
Yellow C27H23ClN4O3S 62.49
62.57
4.47
4.15
10.80
10.88
6.84
6.62
6.17
5.93
Figure 1. Synthesis of 3-acetyl-10b-methyl [1,2,4] triazolo [3,4-a] isoquinolines 4.
Figure 2. Synthesis of enaminones 7.

H. M. Hassaneen et al. / Natural Science 3 (2011) 651-660
655655
Table 2. Spectra of the synthesized compounds.
Compd. no. Spectral data (IR, 1H NMR, 13C NMR and MS)
4a
IR (KBr) ν 1670 (C=O) cm–1; 1H NMR (CDCl3) δ 2.08 (s, 3H), 2.37 (m, 1H), 2.38 (s, 3H), 2.80 (m, 1H), 3.18 (s, 3H), 3.2 (m,
1H), 3.73 (s, 3H), 4.60 (m, 1H), 5.85 (s, 1H), 6.40 (s, 1H), 7.13 - 7.28 (m, 5H) ppm; 13C NMR (CDCl3) δ 26.21, 27.32, 29.24,
40.22, 54.9, 55.35, 90.09, 109.20, 111.04, 123.94, 125.09, 127.16, 127.69, 128.70, 143.19, 146.04, 147.75, 147.97, 189.88 ppm;
MS, m/z (%): 365 (M+, 10.9), 334 (100.0), 103 (22.0), 90 (38.4), 76 (30.8).
4b
IR (KBr) ν 1662 (C=O) cm–1; 1H NMR (CDCl3) δ 2.05 (s, 3H), 2.29 (s, 3H), 2.34 (m, 1H), 2.38 (s, 3H), 2.84 (m, 1H), 3.14 (m,
1H), 3.23 (s, 3H), 3.75 (s, 3H), 4.65 (m, 1H), 5.79 (s, 1H), 6.41 (s, 1H), 7.09 - 7.12 (m, 4H) ppm; 13C NMR (CDCl3) δ 20.61,
26.24, 27.40, 29.20, 40.35, 54.76, 55.40, 90.21, 109.45, 111.02, 124.39, 127.11, 127.86, 129.28, 135.16, 140.60, 145.96, 147.68,
147.95, 189.92 ppm; MS, m/z (%): 364 (M+-15, 100.0), 104 (33.4), 90 (20.2).
4c
IR (KBr) ν 1666 (C=O) cm–1; 1H NMR (CDCl3) δ 2.03 (s, 3H), 2.35 (m, 1H), 2.39 (s, 3H), 2.83 (m, 1H), 3.13 (m, 1H), 3.27 (s,
3H), 3.74 (s, 3H), 4.60 (m, 1H), 5.86 (s, 1H), 6.41 (s, 1H), 7.14-7.25 (m, 4H) ppm; 13C NMR (CDCl3) δ 26.51, 27.70, 29.17,
40.61, 55.17, 55.63, 90.24, 109.39, 111.42, 125.16, 127.13, 128.17, 128.93, 130.49, 142.18, 146.44, 148.29, 148.40, 190.13 ppm;
MS, m/z (%): 399 (M+, 1.8), 384 (M+-15, 100.0), 90 (8.6).
7a
IR (KBr) ν 1642 (C=O) cm–1; 1H NMR (CDCl3) δ 2.04 (s, 3H), 2.38 (m, 1H), 2.80 (s, 3H), 2.88 (m, 1H), 2.96 (s, 3H), 3.16 (s,
3H), 3.19 (m, 1H), 3.72 (s, 3H), 4.80 (m, 1H), 5.75 (d, 1H), 5.89 (s, 1H), 6.38 (s, 1H), 7.04 - 7.24 (m, 5H), 7.64 (d, 1H) ppm; 13C
NMR (CDCl3) δ 27.85, 29.10, 37.31, 40.42, 45.48, 54.95, 55.37, 88.63, 93.13, 109.52, 110.93, 123.80, 124.29, 128.02, 128.04,
128.50, 144.36, 145.88, 147.67, 150.13, 152.23, 179.19 ppm; MS, m/z (%): 420 (M+, 3.2), 405 (M+-15, 87.9), 322 (11.0), 98
(100.0).
7b
IR (KBr) ν 1640 (C=O) cm–1; 1H NMR (CDCl3) δ 1.99 (s, 3H), 2.26 (s, 3H), 2.35 (m, 1H), 2.80 (s, 3H), 2.87 (m, 1H), 2.95 (s,
3H), 3.16 (m, 1H), 3.20 (s, 3H), 3.71 (s, 3H), 4.80 (m, 1H), 5.74 (d, 1H), 5.81 (s, 1H), 6.37 (s, 1H), 7.01-7.10 (m, 4H), 7.63 (d,
1H) ppm; 13C NMR (CDCl3) δ 20.77, 28.10, 29.25, 37.38, 42.71, 45.49, 54.96, 55.58, 88.96, 93.40, 109.94, 111.08, 124.49,
128.13, 128.38, 129.25, 134.42, 141.99, 145.97, 147.82, 150.18, 152.37, 179.46 ppm; MS, m/z (%): 434 (M+, 2.0), 419 (M+-15,
46.7), 336 (10.5), 98 (100.0).
7c
IR (KBr) ν 1640 (C=O) cm–1; 1H NMR (CDCl3) δ 1.98 (s, 3H), 2.37 (m, 1H), 2.79 (s, 3H), 2.87 (m, 1H), 2.94 (s, 3H), 3.15 (m,
1H), 3.28 (s, 3H), 3.71 (s, 3H), 4.67 (m, 1H), 5.75 (d, 1H), 5.90 (s, 1H), 6.38 (s, 1H), 7.13-7.19 (m, 4H), 7.63 (d, 1H) ppm; 13C
NMR (CDCl3) δ 28.17, 28.99, 37.42, 40.77, 44.98, 55.18, 55.61, 88.71, 93.22, 109.68, 111.30, 124.97, 127.99, 128.48, 128.67,
129.48, 143.35, 146.25, 148.08, 150.81, 152.68, 179.17 ppm; MS, m/z (%): 454 (M+, 1.9), 439 (M+-15, 29.2), 285 (31.5), 98
(100.0).
13a
IR (KBr) ν 1692 (C=O), 1645 (C=O) cm–1; 1H NMR (CDCl3) δ 2.13 (s, 3H), 2.52 (m, 1H), 2.63 (s, 3H), 3.24 (s, 3H), 3.38 (m,
1H), 3.41 (m, 1H), 3.81 (s, 3H), 4.79 (m, 1H), 5.87 (s, 1H), 6.53 (s, 1H), 7.15 - 7.68 (m, 10H), 8.33 (s, 1H) ppm; 13C NMR
(CDCl3) δ 27.93, 28.12, 29.65, 40.92, 55.23, 55.64, 90.27, 109.58, 111.46, 119.85, 122.74, 124.95, 125.70, 127.27, 127.88,
128.77, 128.91, 129.54, 131.01, 138.98, 143.35, 146.17, 148.24, 149.04, 151.56, 178.11, 193.99 ppm; MS, m/z (%): 535 (M+,
1.8), 520 (M+-15, 100.0), 303 (21.1), 213 (13.9), 77 (33.8).
13b
IR (KBr) ν 1694 (C=O), 1645 (C=O) cm–1; 1H NMR (CDCl3) δ 2.10 (s, 3H), 2.31 (s, 3H), 2.52 (m, 1H), 2.63 (s, 3H), 3.26 (s, 3H),
3.30 (m, 1H), 3.34 (m, 1H), 3.83 (s, 3H), 4.80 (m, 1H), 5.82 (s, 1H), 6.54 (s, 1H), 7.01 - 7.69 (m, 9H), 8.34 (s, 1H) ppm; 13C
NMR (CDCl3) δ 20.85, 27.97, 28.14, 29.59, 40.97, 55.04, 55.63, 90.32, 109.75, 111.38, 119.89, 122.77, 125.34, 127.20, 127.87,
128.86, 129.43, 129.54, 131.04, 135.78, 139.02, 140.71, 146.05, 148.17, 148.86, 151.60, 178.01, 194.10 ppm; MS, m/z (%): 549
(M+, 1.1), 534 (M+-15, 100.0), 317 (13.2), 213 (23.9), 91 (11.8).
13c
IR (KBr) ν 1692 (C=O), 1650 (C=O) cm–1; 1H NMR (CDCl3) δ 2.08 (s, 3H), 2.52 (m, 1H), 2.62 (s, 3H), 3.31 (m, 1H), 3.33 (m,
1H), 3.35 (s, 3H), 3.82 (s, 3H), 4.78 (m, 1H), 5.90 (s, 1H), 6.55 (s, 1H), 7.06 - 7.69 (m, 9H), 8.32 (s, 1H) ppm; MS, m/z (%): 581
(M+, 1.0), 557 (17.1), 556 (46.1), 555 (45.9), 554 (100.0), 337 (15.0), 213 (43.8), 98 (13.6).
13d
IR (KBr) ν 1728 (C=O), 1635 (C=O) cm–1; 1H NMR (CDCl3) δ 1.31 (t, 3H), 2.17 (s, 3H), 2.45 (m, 1H), 3.20 (m, 1H), 3.24 (s,
3H), 3.30 (m, 1H), 3.80 (s, 3H), 4.36 (q, 2H), 4.81 (m, 1H), 5.95 (s, 1H), 6.50 (s, 1H), 7.16-7.69 (m, 10H), 8.44 (s, 1H) ppm; 13C
NMR (CDCl3) δ 14.13, 27.82, 29.57, 40.66, 55.22, 55.69, 61.52, 90.21, 109.37, 111.37, 120.17, 123.14, 124.02, 125.36, 127.64,
127.94, 128.27, 129.01, 129.46, 131.10, 138.94, 144.05, 145.92, 147.65, 148.81, 149.22, 162.54, 176.33 ppm; MS, m/z (%): 550
(M+-15, 100.0), 474 (30.1), 103 (45.1), 76 (82.4), 56 (47.6).
13e
IR (KBr) ν 1720 (C=O), 1639 (C=O) cm–1; 1H NMR (CDCl3) δ 1.32 (t, 3H), 2.12 (s, 3H), 2.30 (s, 3H), 2.49 (m, 1H), 3.18 (m,
1H), 3.25 (s, 3H), 3.13 (m, 1H), 3.79 (s, 3H), 4.36 (q, 2H), 4.77 (m, 1H), 5.88 (s, 1H), 6.48 (s, 1H), 7.10 - 7.67(m, 9H), 8.43 (s,
3H) ppm;

H. M. Hassaneen et al. / Natural Science 3 (2011) 651-660 656
13f
IR (KBr) ν 1720 (C=O), 1639 (C=O) cm–1; 1H NMR (CDCl3) δ 1.31 (t, 3H), 2.12 (s, 3H), 2.46 (m, 1H), 3.09 (m, 1H), 3.18 (m,
1H), 3.35 (s, 3H), 3.79 (s, 3H), 4.39 (q, 2H), 4.72 (m, 1H), 5.98 (s, 1H), 6.51 (s, 1H), 7.15 - 7.71 (m, 9H), 8.42 (s, 1H) ppm; MS,
m/z (%): 584 (M+-15, 100.0), 148 (21.1), 127 (22.1), 103 (61.5), 76 (67.1).
13g
IR (KBr) ν 1675 (C=O), 1631 (C=O) cm–1; 1H NMR (CDCl3) δ 2.10 (s, 3H), 2.44 (m, 1H), 3.21 (s, 3H), 3.24 (m, 1H), 3.28 (m,
1H), 3.82 (s, 3H), 4.77 (m, 1H), 5.83 (s, 1H), 6.51 (s, 1H), 7.02-8.04 (m, 15H), 8.61 (s, 1H) ppm; 13C NMR (CDCl3) δ 27.75,
29.40, 40.52, 55.06, 55.59, 89.90, 109.26, 111.36, 119.79, 123.67, 124.39, 125.29, 127.28, 127.72, 128.19, 128.33, 128.73,
129.43, 130.15, 130.86, 133.13, 136.51, 138.88, 143.03, 146.07, 148.12, 148.54, 152.01, 176.64, 189.11 ppm; MS, m/z (%): 582
(M+-15, 100.0), 104 (81.6), 76 (94.3).
13h
IR (KBr) ν 1678 (C=O), 1624 (C=O) cm–1; 1H NMR (CDCl3) δ 2.07 (s, 3H), 2.29 (s, 3H), 2.44 (m, 1H), 3.20 (m, 1H), 3.23 (s,
3H), 3.28 (m, 1H), 3.83 (s, 3H), 4.78 (m, 1H), 5.79 (s, 1H), 6.51 (s, 1H), 6.90 - 8.04 (m, 14H), 8.62 (s, 1H) ppm; 13C NMR
(CDCl3) δ 20.78, 27.83, 29.39, 40.65, 54.95, 55.66, 90.03, 109.51, 111.34, 119.89, 123.72, 124.83, 127.26, 127.75, 128.25,
128.51, 129.33, 129.48, 130.21, 130.97, 133.15, 135.41, 136.61, 139.00, 140.51, 146.02, 148.13, 148.40, 152.10, 176.55, 189.29
ppm; MS, m/z (%): 611 (M+, 1.1), 596 (M+-15, 100.0), 324 (49.7), 104 (21.7), 76 (25.7).
13i
IR (KBr) ν 1678 (C=O), 1639 (C=O) cm–1; 1H NMR (CDCl3) δ 2.04 (s, 3H), 2.50 (m, 1H), 3.20 (m, 1H), 3.30 (s, 3H), 3.36 (m,
1H), 3.83 (s, 3H), 4.79 (m, 1H), 5.83 (s, 1H), 6.53 (s, 1H), 6.87 - 8.03 (m, 14H), 8.57 (s, 1H) ppm; MS, m/z (%): 632 (M+, 2.9),
617 (M+-15, 100.0), 275 (21.8), 104 (59.2), 76 (44.3).
20a
IR (KBr) ν 1732 (C=O) cm–1; 1H NMR (CDCl3) δ 1.41 (t, 3H), 2.43 (s, 3H), 2.66 (t, 2H), 3.79 (s, 3H), 3.84 (t, 2H), 3.88 (s, 3H),
4.44 (q, 2H), 6.22 (s, 1H), 6.69 (s, 1H), 6.81 (s, 1H), 7.30 - 7.48 (m, 4H) ppm; 13C NMR (CDCl3) δ 14.18, 21.14, 26.92, 45.84,
55.81, 56.43, 62.19, 85.56, 108.46, 110.49, 122.59, 125.39, 130.06, 131.78, 136.88, 138.71, 143.14, 147.37, 149.93, 150.56,
157.96, 160.06 ppm; MS, m/z (%): 451 (M+, 8.9), 293 (100.0), 91 (18.3).
20b
IR (KBr) ν 1734 (C=O) cm–1; 1H NMR (CDCl3) δ 1.43 (t, 3H), 2.65 (t, 2H), 3.78 (s, 3H), 3.84 (t, 2H), 3.88 (s, 3H), 4.46 (q, 2H),
6.20 (s, 1H), 6.67 (s, 1H), 6.78 (s, 1H), 7.31 - 7.52 (m, 4H) ppm; MS, m/z (%):473 (M+ + 2, 3.5), 471 (M+, 10.1), 293 (100.0), 91
(18.9).
20c
IR (KBr) ν 1708 (C=O) cm–1; 1H NMR (CDCl3) δ 2.66 (t, 2H), 3.79 (s, 3H), 3.84 (t, 2H), 3.88 (s, 3H), 3.96 (s, 3H), 6.23 (s, 1H),
6.69 (s, 1H), 6.81 (s, 1H), 7.31 - 7.48 (m, 5H) ppm; 13C NMR (CDCl3) δ 27.00, 45.79, 52.86, 55.83, 56.45, 85.82, 108.41, 110.66,
121.58, 125.01, 130.22, 131.90, 136.85, 138.88, 142.83, 147.58, 149.67, 150.70, 158.01, 160.64 ppm; MS, m/z (%): 423 (M+,
8.9), 293 (100.0), 91 (21.4).
20d
IR (KBr) ν 1705 (C=O) cm–1; 1H NMR (CDCl3) δ 2.43 (s, 3H), 2.66 (t, 2H), 3.79 (s, 3H), 3.84 (t, 2H), 3.88 (s, 3H), 3.96 (s, 3H),
6.23 (s, 1H), 6.69 (s, 1H), 6.81 (s, 1H), 7.31 - 7.48 (m, 4H) ppm; 13C NMR (CDCl3) δ 21.15, 26.92, 45.78, 52.86, 55.82, 56.44,
85.68, 108.47, 110.51, 122.54, 125.36, 130.10, 131.79, 136.83, 138.78, 142.83, 147.39, 149.86, 150.61, 157.92, 160.51 ppm; MS,
m/z (%): 437 (M+, 9.3), 293 (100.0), 91 (20.3).
20e IR (KBr) ν 1704 (C=O) cm–1; 1H NMR (CDCl3) δ 2.62 (t, 2H), 3.75 (s, 3H), 3.84 (t, 2H), 3.88 (s, 3H), 3.95 (s, 3H), 6.21 (s, 1H),
6.75 (s, 1H), 7.01 (s, 1H), 7.25 - 7.49 (m, 4H) ppm; MS, m/z (%): 459 (M+ + 2, 4.1), 457 (M+, 10.2), 293 (100.0), 91 (20.9).
20f
1H NMR (CDCl3) δ 2.90 (t, 2H), 3.86 (s, 3H), 3.98 (s, 3H), 4.09 (t, 2H), 6.62 (s, 1H), 7.07 - 8.11 (m, 11H) ppm; 13C NMR
(CDCl3) δ 26.16, 47.94, 56.01, 56.16, 86.68, 107.02, 111.55, 116.32, 123.02, 125.85, 127.32, 127.64, 128.66, 129.68, 141.00,
141.42, 142.82, 144.47, 148.48, 151.12, 161.81, 168.40 ppm; MS, m/z (%): 486 (M+, 8.2), 324 (100.0).
20g
1H NMR (CDCl3) δ 2.35 (s, 3H), 2.89 (t, 2H), 3.88 (s, 3H), 4.00 (s, 3H), 4.08 (t, 2H), 6.57 (s, 1H), 7.07-8.07 (m, 10H) ppm; 13C
NMR (CDCl3) δ 21.43, 26.16, 47.84, 55.96, 56.15, 86.65, 107.06, 111.44, 116.32, 123.06, 125.84, 127.30, 127.59, 128.86,
129.68, 140.95, 141.41, 142.82, 144.38, 148.34, 151.06, 161.80, 168.39 ppm; MS, m/z (%): 500 (M+, 6.7), 324 (100.0).
20h
1H NMR (CDCl3) δ 2.91 (t, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 4.01 (t, 2H), 6.59 (s, 1H), 7.07 - 8.10 (m, 10H) ppm; MS, m/z (%):
522 (M+ + 2, 3.9), 520 (M+, 9.6), 324 (100.0).
20i
1H NMR (DMSO-d6) δ 2.82 (t, 2H), 3.75 (s, 3H), 3.90 (s, 3H), 4.12 (t, 2H), 6.75 (s, 1H), 7.12 - 8.07 (m, 9H) ppm; 13C NMR
(DMSO-d6) δ 25.54, 47.01, 55.51, 55.86, 108.17, 111.12, 111.64, 111.82, 112.78, 116.30, 122.70, 125.61, 129.04, 130.01, 139.98,
144.92, 146.08, 147.80, 150.67, 151.12, 161.21, 161.54 ppm; MS, m/z (%): 492 (M+, 7.9), 324 (100.0), 127 (22.1), 73 (25.0).
20j
1H NMR (DMSO-d6) δ 2.82 (t, 2H), 3.75 (s, 3H), 3.90 (s, 3H), 4.13 (t, 2H), 6.68 (s, 1H), 6.76-8.08 (m, 9H) ppm; 13C NMR
(DMSO-d6) δ 25.54, 46.92, 55.51, 55.86, 108.19, 111.12, 111.63, 111.84, 112.78, 116.19, 122.70, 125.67, 129.05, 130.01, 140.01,
144.96, 146.07, 147.80, 150.68, 151.06, 157.46, 161.10 ppm; MS, m/z (%): 476 (M+, 10.6), 324 (100.0).
24a IR (KBr) ν 1647 (C=O) cm–1; 1H NMR (DMSO-d6) δ 2.40 (s, 3H), 2.48 (s, 3H), 2.71 (t, 2H), 3.79 (s, 3H), 3.92 (t, 2H), 3.98 (s,
3H), 6.24 (s, 1H), 6.82 (s, 1H), 6.88 (s, 1H), 7.42 - 7.93 (m, 4H) ppm; MS, m/z (%): 421 (M+, 10.4), 293 (100.0), 91 (19.1).
24b IR (KBr) ν 1649 (C=O) cm–1; 1H NMR (DMSO-d6) δ 2.42 (s, 3H), 2.68 (t, 2H), 3.78 (s, 3H), 3.90 (t, 2H), 3.95 (s, 3H), 6.24 (s,
1H), 6.83 (s, 1H), 6.88 (s, 1H), 7.48 - 7.91 (m, 4H) ppm; MS, m/z (%): 443 (M+ + 2, 5.1), 441(M+, 12.8), 293 (100.0), 91 (22.9).

H. M. Hassaneen et al. / Natural Science 3 (2011) 651-660
657657
24c
IR (KBr) ν 1616 (C=O) cm–1; 1H NMR (CDCl3) δ 2.47 (s, 3H), 2.68 (t, 2H), 3.81 (s, 3H), 3.87 (t, 2H), 3.90 (s, 3H), 6.32 (s, 1H),
6.71 (s, 1H), 6.84 (s, 1H), 7.36-8.30 (m, 9H) ppm; 13C NMR (CDCl3) δ 21.26, 26.95, 46.00, 55.92, 56.53, 86.65, 108.62, 110.62,
122.67, 125.29, 126.01, 128.25, 130.25, 130.26, 131.98, 133.14, 135.55, 137.11, 138.89, 147.46, 150.72, 151.28, 158.22, 184.25
ppm; MS, m/z (%): 483 (M+, 6.7), 293 (100.0), 91 (16.8), 105 (66.8).
24d IR (KBr) ν 1616 (C=O) cm–1; 1H NMR (CDCl3) δ 2.67 (t, 2H), 3.79 (s, 3H), 3.87 (t, 2H), 3.91 (s, 3H), 6.34 (s, 1H), 6.70 (s, 1H),
6.84 (s, 1H), 7.35 - 8.32 (m, 9H) ppm; MS, m/z (%): 505 (M+ + 2, 3.9), 503(M+, 9.5), 293 (100.0), 91 (17.2), 105 (67.8).
24e IR (KBr) ν 1672 (C=O), 3385 (NH) cm–1; 1H NMR (CDCl3) δ 2.68 (t, 2H), 3.81 (s, 3H), 3.83 (t, 2H), 3.91 (s, 3H), 6.29 (s, 1H),
6.63 - 8.70 (m, 12H), 11.75 (s, 1H) ppm; MS, m/z (%): 484 (M+, 7.6), 293 (100.0).
24f IR (KBr) ν 1670 (C=O), 3386 (NH) cm–1; 1H NMR (CDCl3) δ 2.47 (s, 3H), 2.68 (t, 2H), 3.80 (s, 3H), 3.85 (t, 2H), 3.89 (s, 3H),
6.22 (s, 1H), 6.66-8.65 (m, 11H), 11.73 (s, 1H) ppm; MS, m/z (%): 498 (M+, 9.5), 293 (100.0).
24g IR (KBr) ν 1670 (C=O), 3388 (NH) cm–1; 1H NMR (CDCl3) δ 2.66 (t, 2H), 3.81 (s, 3H), 3.83 (t, 2H), 3.89 (s, 3H), 6.32 (s, 1H),
6.66 - 8.66 (m, 11H), 11.74 (s, 1H) ppm; MS, m/z (%): 520 (M+ + 2, 2.7), 518 (M+, 8.3), 293 (100.0).
Figure 3. Synthesis of pyrazoles 13.
other hand, H (5) is linked to the carbon attached to ni-
trogen atom and thus it’s deshielded to appear in the
region δ 7.5 - 8.5 ppm [26-28]. The 1H NMR spectra of
isolated reaction products revealed, in each case, a
singlet signal at δ 8.5 ppm which indicates the presence
of the pyrazole H (5) rather than H (4) in the structure of
the isolated products.
The proposed mechanism leading to the formation of
the latter product suggested that the studied reaction
starts with regioselective 1, 3-dipolar cycloaddition of
nitrilimines 10 to C=C of the enaminones 7 to afford the
cycloadducts 11 which gave the pyrazole derivatives 13

H. M. Hassaneen et al. / Natural Science 3 (2011) 651-660 658
via elimination of dimethylamine and the other isomer
14 resulting from 12 was discarded (Figure 3).
Treatment of thioanilide [9] 15a with hydrazonoyl
halides 16 in refluxing ethanol in the presence of chito-
san under microwave irradiation for 10 min yielded only
one isolable product 20 as indicated by TLC and 1H
NMR of the crude reaction product (Figure 4).
The structure of the products was inferred from their
elemental analyses, spectral data and by their alternative
synthesis. Thus reaction of 15b with 16 gave products
identical in all respects (mp, IR, 1H NMR, MS) with
products 20 which formed by the reaction of 15a with 16,
respectively (Figure 4). For example, the 1H NMR of
20a showed triplet and quartet signals at δ 1.41 and at δ
4.44 ppm respectively, assignable to the ethoxycarbonyl
group, and a singlet signal at δ 6.81 ppm assignable to
methylidene proton in addition to the signals of the iso-
quinoline moiety. Its IR spectrum showed the character-
istic ester carbonyl absorption band at 1732 cm–1.
Two possible structures 20 and 21 can be suggested
for the products resulting from the reaction of 15 with
hydrazonoyl halides 16 or nitrilimine 17. Structure 21
was ruled out because the reaction product was recov-
ered unchanged after treatment with mercuric oxide in
boiling acetic acid.
To account for the formation of 20, two possible
pathways are proposed. In the first way (path A), the
reaction led to the formation of thiohydrazones 18 fol-
lowed by elimination of arylamine to give 20. The sec-
ond path (path B), nitrilimines 17 cycloadded to the C =
S double bond to give the intermediate 19 which upon
elimination of arylamine led to 20.
To study the effect of the carbonyl group on the reac-
tivity of the hydrazonoyl halides, we investigated the
reaction of α-ketohydrazonoyl halides 2, 9, 22 with
thioanilides 15. Thus treatment of 15a or 15b with hy-
drazonoyl halides 2, 9, 22 in refluxing ethanol in the
presence of chitosan under microwave irradiation for 10
min gave the corresponding thiadiazole derivatives 24
(Figure 5).
The structures of the products 24 were supported by
their elemental analyses and spectral data. The other
possible structures 25 and 26 were excluded on the basis
of elemental analysis and spectral data. For example,
their IR spectra lacked the carbonyl absorption band
while such band is present in the spectra of the product
Figure 4. Synthesis of [1,3,4]thiadiazolyl isoquinolines 20.

H. M. Hassaneen et al. / Natural Science 3 (2011) 651-660
659659
Figure 5. Synthesis of [1,3,4]thiadiazolyl isoquinolines 24.
24. The structure of the latter products proved that the
carbonyl group has no effect on the course of this reac-
tion.
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