Reactions with hydrazonoyl halides 45: Synthesis of some new triazolino [4,3-a]pyrimidines, pyrazolo [3,4-d]pyridazines, isoxazolo[3,4-d]pyridazines, and thieno[2,3-b]pyridines

Article abstract of DOI:10.1080/00397910500330593

Triazolino[4,3-α]pyrimidines pyrazolo[3,4-d]pyridazines and isoxazolo[3,4-d] pyridazines were synthesized from hydrazonoyl halides. Also, 3-aminothieno[2,3-b] pyridines and pyrimidino[4′,5′:4,5]thieno[2,3- b]pyridines were synthesized from cynothioacetamide. Structures of the newly synthesized compounds were established on the basis of elemental analyses and spectral data. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500330593

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Reactions With Hydrazonoyl
Halides 45: Synthesis of Some
New Triazolino[4,3‐a]pyrimidines,
Pyrazolo[3,4‐d]pyridazines,
Isoxazolo[3,4‐d]pyridazines, and
Thieno[2,3‐b]pyridines
Abdou O. Abdelhamid a & Ali A. Al‐Atoom a
a Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Version of record first published: 21 Aug 2006
To cite this article: Abdou O. Abdelhamid & Ali A. Al‐Atoom (2006): Reactions With Hydrazonoyl Halides 45:
Synthesis of Some New Triazolino[4,3‐a]pyrimidines, Pyrazolo[3,4‐d]pyridazines, Isoxazolo[3,4‐d]pyridazines,
and Thieno[2,3‐b]pyridines, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:1, 97-110
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Synthetic Communicationsw, 36: 97–110, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500330593
Reactions With Hydrazonoyl Halides 45:
Synthesis of Some New Triazolino
[4,3-a]pyrimidines, Pyrazolo
[3,4-d]pyridazines, Isoxazolo[3,4-
d]pyridazines, and Thieno[2,3-b]pyridines
Abdou O. Abdelhamid and Ali A. Al-Atoom
Department of Chemistry, Faculty of Science, Cairo University, Giza,
Egypt
Abstract: Triazolino[4,3-a]pyrimidines pyrazolo[3,4-d]pyridazines and isoxazolo[3,4-d]
pyridazines were synthesized from hydrazonoyl halides. Also, 3-aminothieno[2,3-b]
pyridines and pyrimidino[40,50:4,5]thieno[2,3-b]pyridines were synthesized from
cynothioacetamide. Structures of the newly synthesized compounds were established
on the basis of elemental analyses and spectral data.
Keywords: Hydrazonoyl halides, isoxazolo[3,4-d]pyridazines, pyrazolo[3,4-d]pyrida-
zines, triazolino[4,3-a]pyrimidines, thieno[2,3-b]pyrimidines
INTRODUCTION
1,2,4-Triazolo[4,3-a]pyrimidines have been found to exhibit antiviral, anti-
fungal, antimicrobial, herbicidal, plant regulator, antitumor, antihypertensive,
cardiovascular, and anxiolytic activities.[1,2] Pyrazoles and annelated
pyrazoles have long been known to exhibit diverse biological activities.
Among these activities include their use as antipyretic,[3,4]analgesic,[4,5]
antitumor,[5] hypnotic,[6] fungicidal,[7] and herbicidal[8] agents. Oxazoles are
widely investigated for therapentic uses, especially as tranquilizing agents
Received in the UK May 10, 2005
Address correspondence to Abdou O. Abdelhamid, Department of Chemistry,
Faculty of Science, Cairo University, Giza, Egypt. E-mail: abdou_abdelhamid@
yahoo.com
97

98
A. O. Abdelhamid and A. A. Al-Atoom
and central nervous system (CNS) regulants and are reported to have bacterio-
static, bactericidal, and fungicidal activities.[9] Moreover thienopyridines are
of special importance because of their reported biological activities.[10]
Also, hydrazonoyl halides have been widely used for the synthesis of
heterocyclic compounds.[11–16] We report herein the synthesis of some
new triazolino[4,3-a]pyridazines pyrazolo[3,4-d]pyridazines, isoxazolo[3,4-
d] pyridazines, and thieno[2,3-b]pyrimidines.
RESULTS AND DISCUSSION
Treatment of ethyl 4-methyl-6-[2-(thienyl)]-2-thioxo-1,3,6-trihydropyrim-
idine-5-carboxylate (1a) with C-methoxy-N-phenylhydrazonoyl chloride
(2a) and triethylamine in boiling chloroform under reflux gave the 1,2,4-
triazolo[4,3-a]pyrimidine-5-carboxylates 5a. 1H NMR spectrum of 5a
showed signals at d ¼ 1.25 (t, 3H, CH2CH3), 2.52 (s, 3H, CH3), 3.94
(s, 3H, OCH3), 4.12 (q, 2H, CH2CH3), 6.83 (s, 1H, CH), and 7.07–8.21
(m, 8H, ArH). Its IR spectrum revealed bands at n ¼ 1735 and 1689 cm21
(CO).
Thus, treatment of ethyl 6-methyl-4-(2-thienyl)-2-methylthio-3,4-dihydro-
pyrimidine-5-carboxylate (6a) with 2a in boiling ethanolic sodium ethoxide
solution gave products identical with 5a.
The formation of 5 can be explained by 1,3-dipolar cycloaddition of
nitrile imide 6 (generated in situ from hydrazonoyl halides 2 with triethyl-
amine or sodium ethoxide) to the C55S of 1a to give intermediate 3, with
ring opening and ring closure to afford 5 by elimination of hydrogen sulfide
(Scheme 1).
Similarly, treatment of the appropriate hydrazonoyl halides 2b–f with 1a
(or treatment of 2a–g with 1b) in boiling chloroform containing triethylamine
gave 1,2,4-triazolo[4,3-a]pyrimidine-5-carboxylate derivatives 5b–f and 9a–g,
respectively.
By analogy, the appropriate hydrazonoyl halides 2a–g (or 2a–e) reacted
with each of 2-methylthio-4-oxo-6-(2-thienyl)-3-hydropyrimidine-5-carbo-
nitrile (10) or 2-methylthio-4-oxo-6-phenyl-3-hydropyrimidine-5-carbonitrile
(11) in boiling ethanolic sodium ethoxide solution under reflux to give 1,2,4-
triazolino[4,3-a]pyrimidine derivatives 12a–g and 13a–f, respectively
(Scheme 2).
Treatment of C-methoxycarbonyl-N-phenylhydrazonoyl chloride (2a)
with 3-(dimethylamino)-1-(2-thienyl)prop-2-en-1-one (15) and triethylamine
in boiling tolune under reflux afforded methyl 1-phenyl-4-(2-thienylcarbo-
nyl)pyrazole-3-carboxylate (16a) (Scheme 3). 1H NMR spectrum of 16a
showed signals at d ¼ 3.69 (s, 3H, OCH3), 7.44–7.88 (m, 8H, ArHs), and
8.24 (s, 1H, pyrazole C-5). Similarly, the appropriate hydrazonoyl halides
2b–g reacted with 15 to give 1-phenyl-3-substituted 4-(2-thienylcarbonyl)-
pyrazoles 16b–g, respectively.

Hydrazonoyl Halides
99
Scheme 1.
Treatment of 16a with hydrazine hydrate in boiling ethanol afforded one
isolable product according to TLC, formulated as 2-phenyl-4-(2-thienyl)-
6-hydropyrazolo[3,4-d]pyridazin-7-one (17a). Structure of 17a was eluci-
dated by elemental analysis, spectral data, and alternative synthesis.
1H NMR spectrum of 17a showed signals at d ¼ 7.33–7.62 (m, 8 H, ArHs),
8.23 (s, 1H, pyrazole C-5), and 11.12 (s, br., 1H, NH). Thus, treatment of
either 16b or 16c with boiling ethanol gave a product identical in all
respects (mp, mixed mp, and spectra) to 17a. Also, pyrazolo[3,4-d]pyridazines
17b–e were obtained from the appropriate pyrazoles 11d–g with hydrazine
hydrate in boiling ethanol under reflux (Scheme 3).
Treatment of the appropriate hydroximoyl chlorides 18a–f with 15 in toluene
at room temperature in presence of triethylamine gave 4,5-diacylisoxazoles

100
A. O. Abdelhamid and A. A. Al-Atoom
Scheme 2.
19a–f, respectively. Compounds 19a–f were converted to isoxazolo[3,4-d]
pyridazines 20a–f, respectively (Scheme 3).
Treatment of 15 with cyanothioacetamide in boiling pyridine (or in
ethanol containing catalytic amount of piperidine) under reflux gave
2-sulfanyl-6-(2-thienyl)pyridine-3-carbonitrile (21) in
a
good yield.
Structure 21 was elucidated by elemental analysis, spectra, and chemical
transformation. Thus, 21 reacted with ethyl chloroacetate in N,N-dimethyl-
formamide containing potassium hydroxide to afford the product correspond-
ing to addition and dehydrochlorination reactions.
The IR spectrum of this product showed bands corresponding to CN and
ester-CO groups. Its 1H NMR spectrum revealed the signals at d ¼ 1.23 (t, 3H,
CH2CH3), 4.09 (s, 2H, SCH2), 4.19 (q, 2H, CH3CH2), and 7.47–8.04 (m, 5H,
ArHs). Based on the these data, these reaction products could be formulated as
ethyl 2-(3-cyano-6-(2-thienyl)-2-pyridylthio) acetate (22a). Further confir-
mation of the structure of 22a arose from their cyclization in boiling
ethanol containing a catalytic amount of piperidine to give the corresponding
ethyl 3-aminothieno[2,3-b]pyridine-2-carboxyylate 23a (Scheme 1). The IR
spectrum of 23a showed no band of the CN function but the bands at 3420,
3301 (NH2 group). 1H NMR spectrum of 23a revealed an absence of
signals of the –SCH2– group and the presence of the NH2 protons. These
findings proved that the CN and the –SCH22 groups were both involved in
the cyclization step leading to 23a.
Also, 21 reacted with chloroacetone in N,N-dimethylformamide containing
potassium hydroxide to afford 2-(2-oxopropylthio)-6-(2-thienyl)pyridine-3-car-
bonitrile (22b). The reaction seemed to proceed through dehydrochlorination to
give the 22b, which underwent cyclization via addition of the –SCH2–

Hydrazonoyl Halides
101
Scheme 3.
hydrogens to the nitrile function to give 1-(3-amino-6-(2-thienyl)thiopheno
1
[2,3-b]pyridine-2-yl)ethan-1-one (23b). H NMR of 23b showed signals at
d ¼ 2.39 (s, 3H), 4.05 (s, 2H), and 7.14–7.78 (m, 5H).
Similarly, compound 21 reacted with each of chloroacetonitrile or iodo-
methane in N,N-dimethylformamide containing potassium hydroxide and
afforded 2-(cyanomethylthio)-6-(2-thienyl)pyridine-3-carbonitrile (22c) and
2-methylthio-6-(2-thienyl)pyridine-3-carbonitrile
(22d),
respectively.
Compound 22c was converted to 3-amino-6-(2-thienyl)thieno[2,3-b]
pyridine-2-carbonitrile (23c) by boiling in ethanol containing catalytic
amounts of piperidine (Scheme 4).

102
A. O. Abdelhamid and A. A. Al-Atoom
Scheme 4.
Compound 23c reacted with each of formic acid or formamide to give the cor-
responding 7-(2-thienyl)-3-hydropyrimidino[40,50:4,5]thieno[2,3-b]pyridine-4-
one (24a) and 7-(2-thienyl)pyrimidino[40,50:4,5]thieno[2,3-b]pyridine-4-ylamine
(24b), respectively (Scheme 4). Structures 24a and 24b were established on the
basis of spectral data and elemental analysis. Thus, IR spectrum of 24a revealed
a band at 1654 (C55O). IR spectrum of 24b revealed bands at 3471, 3317 (NH2).
EXPERIMENTAL
All melting points were determined on an electrothermal apparatus and are
uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201
PC spectrophotometer. 1H NMR spectra were recorded in CDCl3 and
(CD3)2SO solutions on a Varian Gemini 300-MHz spectrometer, and
chemical shifts are expressed in d units using TMS as an internal reference.
Elemental analyses were carried out at the Microanalytical Center of the
Cairo University. 2-Bromoacetylthiopene,[17] hydrazonoyl halides[18–24] 2a–g,
and hydroximoyl chorides[25–28] 18a–e were prepared as previously reported.

Hydrazonoyl Halides
103
1,2,4-Triazilino[4,3-a]pyrimidines 5a–f, 9a–g, 12b–g, and 13b–e
Method A: An equimolar amount of each of the appropriate hydrazonoyl
halides 2a–g, the appropriate 6a, 6b, 10, or 11, and sodium ethoxide
(5 mmol) in ethanol (20 mL) was refluxed for 3 h. The reaction mixture was
cooled, and the resulting solid was collected and crystallized from ethanol
to give (5a–f, 9a–g, 12b–g, and 13a–e (Tables 1 and 2).
Method B: A mixture of the appropriate hydrazonoyl halides 2a–g
(5 mmol) and the appropriate pyrimidin-2-thione 1a or 1b (1.38 g, 5 mmol)
in chloroform (20 mL) containing triethylamine [0.5 g (0.75 mL), 5 mmol]
was refluxed for 10 h. Chloroform was evaporated under reduced pressure,
and the residue solid was crystallized from ethanol to give products
identical in all respects (mp, mixed mp, and spectra) with corresponding
products obtained by method A.
Ethyl 6-Methyl-4-(2-thienyl)-2-methylthio-3,4-dihydropyrimidine-
5-carboxylate (6a) and Ethyl 6-Methyl-2-methylthio-4-phenyl-
3,4-dihydropyrimidine-5-carboxylate (6b)
Equimolar amounts of the appropriate pyrimidine-2-thione derivatives 1a and
1b and sodium methoxide (5 mmol) in methanol (20 mL) were stirred for 3 h.
Iodomethane (0.72 g, 5 mmol) was added with stirring; after 2 h the resulting
solid was collected and recrystallized from the proper solvent to give 6a and
6b, respectively (Tables 1 and 2).
3-(Dimethylamino)-1-(2-thienyl)prop-2-en-1-one (15)
Equimolar amounts of 2-acetylthiophene (14) and dimethylformamide-
dimethylacetal (50 mmol each) were refluxed in dry xylene (40 mL) for 4 h.
The hot solution was evaporated to its half volume and then cooled. The
resulting solid was collected and crystallized to give 15 (Tables 1 and 2).
3-Acyl-1-phenyl-4-(2-thienoyl)pyrazoles 16a–g
Equimolar amounts of each of 3-(dimethylamino)-1-(2-thienyl)prop-2-en-
1-one (15) and the appropriate hydrazonoyl halides 2a–g (5 mmol) were
refluxed in dry toluene containing triethylamine for 3 h. The hot solution
was filtered off, and the filtrate was evaporated and triturated with
petroleum ether (40–608C). The resulting solid was collected and recrystal-
lized from ethanol to give 16a–g, respectively (Tables 1 and 2).

104
Table 1. Characterization data of the newly synthesized compounds
% Analyses calcd., found
A. O. Abdelhamid and A. A. Al-Atoom
Compd. Mp (8C)
Yield (%), Mol. Formula,
color Mol. wt
no.
solvent
C
H
N
S
5a
125–27
EtOH
55
Brown
65
C21H20N4O4S 59.42 4.75 13.20
424.48 59.58 4.63 13.36
C22H22N4O4S 60.26 5.06 12.78
438.51 60.00 4.92 12.65
C26H23N5O3S 64.31 4.77 14.42
64.48 4.88 14.51
C21H20N4O3S 61.75 4.94 13.72
408.48 61.84 5.03 13.83
C26H22N4O3S 66.37 4.71 11.91
66.22 4.85 12.00
7.55
7.39
7.31
7.43
6.60
6.71
7.85
7.94
6.81
6.73
5b
5c
160–61
EtOH
Brown
55
109–10
EtOH
Deep brown 485.57
5d
5e
194–96
EtOH
75
Pale olive
50
145–46
EtOH
Deep brown 470.55
5f
176–78
EtOH
62
Brown
67
C24H20N4O3S2 60.49 4.23 11.76 13.46
476.58 60.65 4.10 11.82 13.33
C13H16N2O2S2 52.68 5.44
296.41 52.78 5.31
6a
125–26
Pet.ether
159–60
EtOH
9.45 21.63
9.56 21.69
Pale olive
72
6b
9a
C14H16N2O2S 60.85 5.84 10.14 11.60
Colorless
68
276.36
C22H20N4O4
404.43
61.04 5.72 10.26 11.43
65.34 4.98 13.85
65.50 5.00 14.02
66.02 5.30 13.39
66.19 5.47 13.22
69.66 4.98 15.04
69.60 4.82 14.91
68.03 5.19 14.42
67.90 4.98 14.63
71.99 4.92 12.44
72.00 5.00 12.27
160–61
EtOH
Yellow
70
9b
9c
161–62
EtOH
C23H22N4O4
418.46
Yellow
81
212–13
EtOH
C27H23N5O3
465.52
Yellow
72
9d
9e
204–205
EtOH
C22H20N4O3
388.43
C27H22N4O3
Yellow
75
148–49
EtOH
Pale brown 450.51
78
9f
190–92
EtOH
C25H20N4O3S 65.77 4.42 12.27
7.02
6.90
Brown
73
456.53
C31H24N4O3
500.56
65.69 4.40 12.34
74.38 4.83 11.19
74.30 4.66 10.95
9g
153–54
EtOH
Red
80
12b
12c
12d
12e
12f
12g
213–15
AcOH
322–24
DMF
C19H13N5O3S 58.30 3.35 17.89
58.51 3.41 17.97
C23H14N6O2S 63.00 3.22 19.17
Pale orange 438.47 62.91 3.40 19.00
74 C18H11N5O2S 59.82 3.07 19.38
Pale brown 361.38 60.00 3.25 19.49
82 C23H13N5O2S 65.24 3.09 16.54
Pale brown 423.46 65.06 3.22 16.64
8.19
8.36
7.31
7.39
8.78
8.67
7.57
7.38
Pale brown 391.41
70
237–39
AcOH
219–21
AcOH
174–77
DMF
55
Yellow
60
C21H11N5O2S2 58.73 2.58 16.31 14.93
429.48 58.91 2.73 16.23 15.08
C27H15N5O2S 68.49 3.19 14.79 6.77
249–50
(continued)

Hydrazonoyl Halides
105
Table 1. Continued
% Analyses calcd., found
Compd. Mp (8C)
Yield (%), Mol. Formula,
color Mol. wt
no.
solvent
C
H
N
S
AcOH
Perpel
76
473.52
68.35 3.34 14.87
65.45 3.92 18.17
65.23 4.00 18.02
69.44 3.73 19.43
69.58 3.87 19.31
67.60 3.69 19.71
67.71 3.78 19.57
71.93 3.62 16.78
72.04 3.80 16.85
6.66
13b
13c
13d
13e
15
234–35
AcOH
228–30
AcOH
205–207
AcOH
202–204
EtOH
C21H15N5O3
385.39
C25H16N6O2
Yellow
70
Pale yellow 432.45
60
C20H13N5O2
355.36
Yellow
72
C25H15N5O2
417.43
C9H11NOS
Yellow
70
147–49
EtOH
59.64 6.12
59.80 6.00
7.73 17.69
7.90 17.52
8.97 10.36
9.13 10.20
Pale yellow 181.25
16a
16b
16c
16d
16e
16f
123–24
EtOH
52
Colorless
65
C16H12N2O3S 61.53 3.87
312.35 61.67 3.89
C17H14N2O3S 62.56 4.32
62.66 4.15
105–106
EtOH
8.58
8.39
9.82
9.66
8.59
8.77
Pale yellow 326.38
187–89
EtOH
70
Yellow
75
C21H15N3O2S 67.54 4.05 11.25
373.44 67.55 4.20 11.40
C16H12N2O2S 64.85 4.08
153–56
EtOH
9.45 10.82
9.32 11.00
Yellow
296.35
C21H14N2O2S 70.37 3.94
358.40 70.54 3.79
C19H12N2O2S2 62.62 3.32
62.53 3.18
C25H16N2O2S 73.51 3.95
Pale orange 408.48 73.30 4.11
64.70 3.90
174–75
EtOH
66
7.82
7.68
8.95
8.81
Orange
72
190–92
AcOH
170–72
AcOH
286–87
EtOH
7.69 17.60
7.55 17.48
Pale orange 364.45
63
16g
17a
17b
17c
17d
17e
19a
19b
19c
6.86
7.03
7.85
7.72
78
Yellow
60
C15H10N4OS
294.34
61.21 3.42 19.04 10.89
61.00 3.60 18.89 10.75
65.73 4.14 19.17 10.97
65.90 3.98 19.35 11.13
233–35
EtOH
C16H12N4S
292.36
Yellow
55
300–303
AcOH
318–20
AcOH
263–64
AcOH
74.76
C21H14N4S
354.53
71.17 3.98 15.80
71.26 4.08 15.63
9.04
8.84
Yellow
70
C19H12N4S2
360.46
63.31 3.36 15.54 17.79
63.17 3.25 15.68 17.84
Yellow
63
C25H16N4S
404.50
74.23 4.00 13.85
73.99 3.86 13.96
7.92
8.07
Yellow
70
C15H9NO3S
283.31
63.59 3.02
63.42 3.36
64.65 3.73
64.53 3.62
57.14 2.58
56.97 2.47
4.94 11.32
4.79 11.23
4.71 10.79
4.58 10.68
5.13 11.73
5.28 11.83
EtOH
89–91
EtOH
Colorless
68
C16H11NO3S
297.27
C13H7NO4S
Colorless
50
80–82
EtOH
Pale brown 273.27
(continued)

106
A. O. Abdelhamid and A. A. Al-Atoom
Table 1. Continued
% Analyses calcd., found
Compd. Mp (8C)
Yield (%), Mol. Formula,
color
no.
solvent
Mol. wt
C
H
N
S
19d
103–105
EtOH
80
Yellow
60
C13H7NO3S2
289.33
53.97 2.44
54.14 2.31
68.46 3.33
68.35 3.50
68.46 3.33
68.26 3.17
4.84 22.16
4.67 22.00
19e
19f
20a
133–35
EtOH
C19H11NO3S
333.37
4.20
4.37
4.20
4.11
9.62
9.77
9.62
9.51
Brown
70
105–107
EtOH
C19H11NO3S
333.37
Yellow
85
150–52
EtOH
C15H9N3OS
279.32
64.50 3.25 15.04 11.48
64.37 3.12 15.20 11.62
Yellowish
brown
71
20b
20c
20d
20e
20f
21
85–87
EtOH
C16H11N3OS
293.35
65.51 3.78 14.32 10.93
65.38 3.61 14.25 11.05
57.98 2.62 15.60 11.91
57.83 2.74 15.51 11.86
54.72 2.47 14.73 22.47
54.60 2.33 14.81 22.58
Yellow
55
110–12
EtOH
C13H7N3O2S
269.28
Brown
85
228–30
AcOH
59–61
EtOH
C13H7N3OS2
285.35
Yellow
55
C19H11N3OS
329.38
69.28 3.37 12.76
69.13 3.25 12.71
69.28 3.37 12.76
69.33 3.43 12.65
9.73
9.87
9.73
9.78
Yellow
63
188–90
EtOH
C19H11N3OS
329.38
C10H6N2S2
Olive
75
233–35
AcOH
134–36
EtOH
55.02 2.77 12.83 29.38
54.85 2.61 12.75 29.47
Pale brown 218.30
65
Pale brown 304.39
22a
22b
22c
22d
23a
C14H12N2O2S2 55.25 3.97
9.20 21.07
8.99 20.84
55.36 4.14
132–34
EtOH
73
Pale brown 274.37
C13H10N2OS2 56.91 3.67 10.21 23.37
57.02 3.56 10.03 23.49
56.01 2.74 16.33 24.92
56.05 3.77 16.38 25.14
56.87 3.47 12.06 27.60
56.94 3.29 11.91 27.51
184–85
EtOH
60
Brown
70
C12H7N3S2
257.34
C11H8N2S2
119–20
EtOH
Pale orange 232.33
55
254–56
AcOH
C14H12N2O2S2 55.25 3.97
55.36 4.14
9.20 21.07
8.99 20.84
Yellowish
brown
62
304.39
23b
23c
225–27
EtOH
C13H10N2OS2 56.91 3.67 10.21 23.37
Orange
70
274.37
C12H7N3S2
257.34
56.74 3.51 10.11 23.20
56.01 2.74 16.33 24.92
56.05 3.77 16.38 25.14
275–76
AcOH
Yellowish
brown
62
24a
24b
,340
DMF
,310
DMF
C13H7N3OS2
285.35
54.72 2.47 14.73 22.47
54.60 2.36 14.68 22.50
54.91 2.84 19.70 22.55
55.08 2.78 19.62 22.63
Yellow
60
Brown
C13H8N4S2
284.36

Hydrazonoyl Halides
107
Table 2. Spectra of some newly synthesized compounds
Comp.
no.
Spectral data
5a
1H NMR: 1.22 (t, 3H), 2.54 (s, 3H), 4.03 (s, 3H, OCH3), 4.15(q, 2H), 6.87
(s, 1H) and 7.22–8.18 (m, 8H). IR: 3090 (CH), 1733, 1690 (CO), and 1606
(C55C).
5b
5c
1H NMR: 1.23 (t, 3H), 1.45 (t, 3H), 2.54 (s, 3H), 4.17 (q, 2H), 4.50 (q, 2H),
and 6.84–8.19 (m, 9H). IR: 3093 (CH), 1729, 1691 (CO), and 1606
(C55C).
1H NMR: 1.20 (t, 3H), 2.57 (s, 3H), 4.14 (q, 2H), 6.86–8.16(m, 14H) and
8.63 (s, br., NH). IR: 3390, 3259 (NH), 3062 (CH), 1685 (CO), and 1600
(C55C).
5d
5e
5f
IR: 3107 (CH), 1730, 1696 (CO), and 1599 (C55C).
IR: 3070 (CH), 1691, 1654 (CO), and 1606 (C55C).
IR: 3070 (CH), 1689 (CO) and 1608 (C55C).
1H NMR: 1.26 (t, 3H), 2.29 (s, 3H, SCH3), 2.46 (s, 3H), 4.16 (q, 2H), 5.95
(s, br., NH), and 6.88–7.15 (m, 4H). IR: 3313 (NH), 3074 (CH) and 1651
(CO).
6a
6b
1H NMR: 2.39 (s, 3H), 2.46 (s, 3H, SCH3), 3.63 (s, 3H, OCH3), 5.71 (s, br.,
NH), 6.58 (s, 1H), and 7.20–7.30 (m, 5H). IR: 3320 (NH), 3081 (CH) and
1653 (CO).
9a
9b
9c
1H NMR: 2.51 (s, 3H), 3.64 (s, 3H, OCH3), 3.93 s, 3H, OCH3), 8.85 (s, 1H)
and 7.22–8.20 (m, 10H). IR: 1712 (CO), and 1604 (C55C).
1H NMR: 1.36 (t, 3H), 2.51 (s, 3H, CH3), 3.64 (s, 3H, OCH3), 4.39 (q,2H),
6.86 (s, 1H), 7.21–8.21 (m, 10H). IR: 1728 (CO) and 1604 (C55C).
1H NMR: 2.54 (s, 3H), 3.63 (s, 3H, OCH3), 7.07 (s, 1H), 7.15–8.20
(m, 15H), and 8.36 (s, br., NH). IR: 3240 (NH), 1705, 1666 (CO), and
1612 (C55C).
9d
9e
1H NMR: 1.58 (s, 3H), 2.54 (s, 3H), 3.63 (s, 3H, OCH3), 6.87 (s, 1H), and
7.21–8.23 (m, 10H). IR: 1697 (CO), and 1604 (C55C).
1H NMR: 2.57 (s, 3H), 3.64 (s, 3H, OCH3), 7.02 (s, 1H), and 7.15–8.24
(m, 15H) IR: 1697, 1658 (CO), and 1612 (C55C).
9f
1H NMR: 2.35 (s, 3H), 3.64 (s, 3H, OCH3), 7.03 (s, 1H), and 7.13–8.29
(m, 13H). IR: 2923 (CH), 1697 (CO), and 1612 (C55C).
1H NMR: 2.58 (s, 3H), 3.64 (s, 3H, OCH3), 7.04 (s, 1H) and 7.08–8.62
(m, 17 H). IR: 1697 (CO) and 1604 (C55C).
9g
12b
13b
1H NMR: 1.49 (t, 3H), 4.59 (q, 2H), and 7.19–8.51 (m, 8H). IR: 3097 (CH),
2214 (CN), 1697 (CO) and 1604 (C55C).
1H NMR: 1.50 (t, 3H), 4.64 (q, 2H), and 7.26–8.15 (m, 10H). IR: 3068 (CH),
2225 (CN), 1713 (CO), and 1596 (C55C).
13c
13d
13e
16a
IR: 3379 (NH), 2214 (CN), 1670 (CO), and 1562 (C55C).
IR: 3062 (CH), 2218 (CN), 1692 (CO), and 1598 (C55C).
IR: 2214 (CN), 1689 (CO), and 1604 (C55C).
IR: 3082 (CH), 1720, 1635 (COs), and 1542 (C55C).
(continued)

108
A. O. Abdelhamid and A. A. Al-Atoom
Table 2. Continued
Comp.
no.
Spectral data
16b
1H NMR: 1.16 (t, 3H), 4.24 (q, 2H), 7.10–7.77 (m, 8H), and 8.25 (s, 1H, C-3
pyrazole). IR: 3066 (CH), 1724 (CO), and 1596 (C55C).
IR: 3394 (NH), 3112 (CH), 1689, 1635 (COs), and 1593 (C55C).
IR: 3097 (CH), 1693 (CO), and 1596 (C55C).
16c
16d
16e
16f
IR: 3074 (CH), 1662 (CO), and 1593 (C55C).
IR: 3085 (CH), 1689, 1643 (CO), and 1608 (C55C).
IR: 3051 (CH), 1662 (CO), and 1608 (C55C).
IR: 3348 (NH), 1678 (CO), and 1593 (C55C).
1H NMR 2.42 (s, 3H), 7.10–7.98 (m, 7H), and 8.99 (s, 1H). IR: 3097 (CH),
1677 (CO), and 1612 (C55C).
16g
17a
19b
21
22a
IR: 3079 (CH), 2218 (CN), and 1585 (C55C).
1H NMR: 1.26 (t, 3H), 4.04 (s, 2H, SCH2), 4.19 (q, 2H), and 7.11–7.76
(m, 5H). IR: 3078 (CH), 2214 (CN), 1735 (CO), and 1566 (C55C).
1H NMR: 2.38 (s, 3H), 4.10 (s, 2H, SCH2), and 7.13–7.79 (m, 5H). IR: 3093
(CH), 2214 (CN), 1652 (CO), and 1566 (C55C).
22b
22c
22d
IR: 3105 (CH), 2217 (CN), and 1568 (C55C).
1H NMR: 2.70 (s, 3H), and 7.12–7.78 (m, 5H). IR: 3055 (CH), 2218 (CN),
and 1573 (C55C).
23a
23b
23c
1H NMR: 1.31 (t, 3H), 4.27 (q, 2H), and 7.20–8.58 (m, 7H). IR: 3420, 3301
(NH2), 3097 (CH), and 1612 (C55C).
1H NMR: 2.52 (s, 3H), and 7.22–8.62 (m, 7H). IR: 3398, 3282 (NH2), 3058
(CH), 1701 (CO), and 1612 (C55C).
IR: 3453, 3349 (NH2), 3077 (CH), 2194 (CN), and 1572 (C55C).
2-Phenyl-4-(2-thienyl)-7-substituted 6-Hydropyrazolo[3,4-d]
pyridazines 17a–e and 6-(2-Thienyl)-3-substituted Isoxazolo[4,3-d]
pyridazins 20a–f
An appropriate amount of 16a–g or 19a–f (0.5 g) and hydrazine hydrate
(1 mL) in ethanol (15 mL) were refluxed for 1 h. The resulting solid was
collected and recrystallized from DMF (or EtOH) to give the corresponding
pyrazolo[3,4-d]pyridazines 17a–e and isoxazolo[3,4-d]pyridaziines 20a–f
(Tables 1 and 2).
3-Acyl-6-(2-thienyl)isoxazoles 19a–f
Triethylamine [0.5g (0.75 mL), 5 mmol] was added dropwise to equimolar
amounts of 15 and the appropriate hydroximoyl chloride 18a–f (5 mmol each)
in dry toluene (20 mL) with stirring. Stirred was continued for 10h. The
reaction mixture was filtered off, and the filtrate was evaporated and triturated

Hydrazonoyl Halides
109
with petroleum ether (40–608C). The resulting solid was collected and recrystal-
lized from proper solvent to give 19a–f, respectively (Tables 1 and 2).
6-(2-Thienyl)-2-thioxohydropyridine-3-carbonitrile (21)
Method A: A mixture of 15 (1.8 g, 10 mmol) and cyanothioacetamide
(1 g, 10 mmol) was refluxed in pyridine (25 mL) for 5 h, and then poured
onto ice-cold water and neutralized with 10% hydrochloric acid. The
resulting solid was collected and recrystallized from ethanol to give 21
(Tables 1 and 2).
Method B: A mixture of 15 (1.8 g, 10 mmol), cyanothioacetamide (1 g,
10 mmol), and piperidine (0.5 mL) was refluxed in ethanol (20 mL) for 3 h,
and then poured onto ice-cold water and neutralized with hydrochloric acid
(3 drops). The resulting solid was collected and recrystallized from ethanol
to product identical in all respects (mp, mixed mp, and spectra) with sample
obtained in method A.
Thieno[2,3-b]pyridines 23a–c
A mixture of 6-(2-thienyl)-2-thioxohydropyridine-3-carbonitrile (21) (1.1 g,
5 mmol) and potassium hydroxide (0.28 g, 5 mmol) in N,N-dimethylforma-
mide (15 mL) was stirred at room temperature for 6 h. An appropriate
amount of ethyl chloroacetate, chloroacetone, chloroacetonitrile, or iodo-
methane (5 mmol) was added to the solution with stirring. The resulting
solid was collected and recrystallized from ethanol to afford 22a–d, respect-
ively (Tables 1 and 2). An appropriate amount of 22a–c (0.5 g) was refluxed in
ethanol (15 mL) containing piperidine (3 drops) for 2 h. The solid formed
while boiling was collected and recrystallized from AcOH to give 23a–c,
respectively (Tables 1 and 2).
Hydropyrimidino[40,50:4,5]thieno[2,3-b]pyridine-4-one (24a)
A mixture of 23c (1.2 g, 5 mmol) and formic acid (5 mL) in N,N-dimethyl-
formamide (10 mL) was refluxed for 5 h. The reaction mixture was poured
onto crushed ice (20 g). The resulting solid was collected and recrystallized
from DMF to give 24a (Tables 1 and 2).
Pyrimidino[40,50:4,5]thieno[2,3-b]pyridine-4-ylamine (24b)
A mixture of 23c (1 g) and formamide (5 mL) in N,N-dimethylformamide
(10 mL) was refluxed for 5 h. The reaction mixture was poured onto crushed

110
A. O. Abdelhamid and A. A. Al-Atoom
ice (20 g). The resulting solid was collected and recrystallized from DMF to
give 24b (Tables 1 and 2).
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