Studies on thiazolopyridines. Part 3: Reactivity of thiazolo[3,2-a]-3-aza[1,8]naphthyridine towards some nucleophiles

Article abstract of DOI:10.1080/10426500307809

A variety of new thiazolo[3,2-a]pyridine derivatives 2a-h having 3-indolyl group were produced by refluxing 1a with different benzylidenemalononitrile derivatives. Reactivity of compound 4 toward some nitrogen nuclcophiles was investigated. Thus, the novel pyrazoles 6a,b were obtained when compound 4 was allowed to react with hydrazine and phenyl hydrazine in ethanol under reflux. On the other hand, pyrazolo[3′,4′:4,5]thiazolo[3,2-a]-3-aza[1,8]naphthyridine 8 was formed by condensation of compound 4 with benzoyl hydrazine. Finally, condensed heterocyclic compounds containing pyran rings 9 and 10 were obtained by treatment compound 4 with active ethylene compounds.

Full text of DOI:10.1080/10426500307809

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Studies on Thiazolopyridines. Part 3: Reactivity of
Thiazolo[3,2- a ]-3-aza[1,8]naphthyridine Towards
Some Nucleophiles
Gameel A. M. El-Hag Ali a
a Al-Azhar University, Cairo, Egypt
Published online: 27 Oct 2010.
To cite this article: Gameel A. M. El-Hag Ali (2003): Studies on Thiazolopyridines. Part 3: Reactivity of Thiazolo[3,2- a ]-3-
aza[1,8]naphthyridine Towards Some Nucleophiles, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:4, 711-720
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:711–720
C
Copyright 2003 Taylor & Francis
1042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390197922
STUDIES ON THIAZOLOPYRIDINES. PART 3:
REACTIVITY OF
THIAZOLO[3,2-a]-3-AZA[1,8]NAPHTHYRIDINE
TOWARDS SOME NUCLEOPHILES
Gameel A. M. El-Hag Ali
Al-Azhar University, Cairo, Egypt
(Received March 13, 2002; accepted May 14, 2002)
A variety of new thiazolo[3,2-a]pyridine derivatives 2a–h having
3-indolyl group were produced by refluxing 1a with different benzyl-
idenemalononitrile derivatives. Reactivity of compound 4 toward some
nitrogen nuclcophiles was investigated. Thus, the novel pyrazoles
6a,b were obtained when compound 4 was allowed to react with
hydrazine and phenyl hydrazine in ethanol under reflux. On the other
hand, pyrazolo[30,40:4,5]thiazolo[3,2-a]-3-aza[1,8]naphthyridine
8
was formed by condensation of compound 4 with benzoyl hydrazine.
Finally, condensed heterocyclic compounds containing pyran rings 9
and 10 were obtained by treatment compound 4 with active ethylene
compounds.
Keywords: Thiazolo[3,2-a]-3-aza[1,8]naphthyridine; thiazolo[3,2-
a]pyridine
Derivatives of thiazolo[3,2-a]pyridines are important as antimicrobial1
bactericide,2 coronary dialators, antihypertensive, and muscle
relaxants.3 It was reported that [1,8]naphthyridine derivatives are
useful as antihypertensive, diluritic, and antibacterial agents.4–6 On
the basis of the above facts, we report the synthesis of some novel
thiazolo[3,2-a]pyridines 2a–h to evaluate the antimicrobial properties
of them. Also, we investigated the reactivity of compound 4 towards
some nitrogen and carbon nucleophiles.
Address correspondence to Gameel A. M. El-Hag Ali, Chemistry Department, Fac-
ulty of Science, Al-Azhar University, Nasr City, PO Box 11884, Cairo, Egypt. E-mail:
m elgaby@hotmail.com
711

712
G. A. M. El-Hag Ali
RESULTS AND DISCUSSION
5-Amino-6,8-dicyano-7-(3-indolyl)-2-(3-indolylmethylidene)-3-oxothia-
zolo [3,2-a]pyridine 2a was produced by refluxing thiazolinone
derivative 1a with benzylidenemalononitrile of indol-3-carboxaldehyde
in ethanol and a catalytic amount of piperidine. The structure of
compound 2a was determined on the basis of elemental analyses and
spectral data. Its IR spectrum revealed the presence of bands at 3350,
1
1
1
3300, 3224 cm (NH2, NH), 2206 cm (C N), and 1689 cm (C O,
1
thiazolidinone), and HNMR spectrum in (CDCl3) displayed signal in
the region 4.40 assigned to pyridine-H and at 7.20 ppm (indole-H). In
the same manner a series of thiazolo[3,2-a]pyridines 2b–h were formed
SCHEME 1

Studies on Thiazolopyridines
713
as result of interaction of 1a with different arylidenemalononitries. In
addition, ternary condensation7 of 4-fluorobenzaldehyde malononitrile
and thioglycolic acid (2:2:1 molar ratio) in absolute ethanol catalyzed
by piperidine afforded the novel thiazolo[3,2-a]pyridine derivatives 3
in high yields (Scheme 1).
Thiazolo[3,2-a]-3-aza[1,8]naphthyridine 47 proved to be a key in-
termediate in the synthesis of novel heterocyclic derivatives and was
produced by heating compound 3 with formic acid. The reactivity of
compound 4 toward hydrazines as nitrogen nucleophiles was investi-
gated. Thus, when compound 4 was allowed to react with hydrazine
hydrate and phenyl hydrazine in absolute ethanol under reflux, the
novel pyrazoles 6a,b were obtained on the bases of analytical and spec-
tral data. Infrared spectra of compound 6a,b revealed the absence of
amino, cyano, and carbonyl functions. The 13C-NMR spectrum of com-
pounds 6a in CDCl3 exhibited the following signals: 165.82, 163.22,
160.82, 130.52, 130.43, 130.26, 116.08, 115.87, and 115.45 ppm. The
formation of 6a,b is assumed to proceed via the initial formation of
5 followed by ring fission8 to form 6 (Scheme 2). On the other hand,
SCHEME 2

714
G. A. M. El-Hag Ali
pyrazolo[30,40:4,5]thiazolo[3,2-a]-3-aza[1,8]naphthyridine 7 was ob-
tained when compound 4 was allowed to react with benzoyl hydrazine,
via the formation of 5 followed by elimination of water (Scheme 2).
The IR spectrum revealed the presence of amino, cyano, and carbonyl
functions.
This investigation was extended to include the reactivity of com-
pound 4 with some active methylene compounds as nucleophiles. Thus,
when compound 4 was refluxed with malononitrile (Scheme 3) in
the presence of an ethanol/ammonium acetate9 mixture pyrido[20, 30:
4,5]thiazolo[3,2-a]-3-aza[1,8] naphthyridine 8 was formed. The struc-
ture of 8 was confirmed by analytical and spectral data. The IR
spectrum exhibited bands at 3400, 3350, 3180 cm 1, which were as-
signed to NH2 and NH 2206 cm 1, (C N) and carbonyl function at
1666 cm 1(pyrimidinone). Its 1HNMR spectrum in DMSO-d6 displayed
a singlet at 4.91 (pyridine-H) and singlet at 10.82 (pyrimidine-H).
The reaction of 4 with malononitrile in ethanol/piperidine9 solu-
tion under reflux conditions gave pyrano[20,30: 4,5]thiazolo[3,2-a]-3-aza
[1,8]naphthyridine] 9. The elemental analyses and spectral data were
in agreement with structure 9.
SCHEME 3
Finally, when ethyl acetoacetate was allowed to react with com-
pound 4 two possible structures 10 and 11 were considered. Analyt-
ical and spectral data were consistent with the structure 10 and not
1
structure 11. The H-NMR spectrum [DMSO-d6] exhibited the pres-
ence of COCH3 (s) and absence of OC2H5 fragment (Scheme 4).

Studies on Thiazolopyridines
715
SCHEME 4
Antimicrobial Activity
Antimicrobial activity of the compounds 2a, 2b, 2e, 2g, 2h, 6a, 9, and
10, were tested in vitro against Staphylococcus aureus (ATCC-6538),
Bacillus cereus (NRRL-B-569), Serratia marcesens (IMRU-70), proteus
merabitis (NTC-289), and Aspergillus ochraceus Wilhelm (AUCC-230).
The tested compounds were dissolved in DMF at a concentration of
250 mg/ml by the agar diffusion technique.10 Ampicillin (25 g) and
mycostatine (25 g) were used as refrences for the antibacterial and an-
tifungal activities. The inhibition zones (in mm) were measured after

716
G. A. M. El-Hag Ali
TABLE I Antimicrobial Activity of Some Synthesized Compounds
Aspergillus
ochraceus
Wilhelm
Staphylococcus
aureus
Bacillus
cereus
Serritia
marcesens
Proteus
merabitis
Compd.
(ATCC-6538-P) (NRRL-B-569) (IMRU-70) (NTC-289) (AUCC-230)
2a
2b
2e
2g
2h
6a
9
10
++
+++
++
++
+++
+
+
+++
++
++
+++
+
R
++
R
+++
++
+++
++
+++
++
+++
+++
+
++
+
++
+
+
+
++
++
++
+
+
++
++
++
++
+
Standard
++++
++++
++++
++++
++++
R = resistance.
+ = less active.
++ = moderate active.
+++ = highly active.
++++ = very highly active.
Standard for gram positive and gram negative (Ampicillin) and (mycostatin) for fungi.
24 h incubation, and the results were represented in Table I. Many
of the synthesized compounds exhibited various antimicrobial activity
towards all the microorganisms used with their minimal inhibitory con-
centration (MIC).
EXPERIMENTAL
All melting points are uncorrected (Sturart Scientific Co., UK). IR
spectra were measured as KBr pellets on a Shimadzu IR 200 spec-
trophotometer. 1H-NMR spectra were recorded in deutrated DMSO-d6
at 200 MHz on a Varian Gemini NMR spectrometer using tetramethyl-
silane as an internal reference. Elemental analyses were carried out at
the Microanalytical Center of Cairo University. The characteristic data
for prepared compounds are given in Table II. The spectral data are
collected in Table I.
5-Arylmethylidene-3-oxo-2-cyanomethyl-4,5 dihydro-
thiazoline (1a,b)
A mixture of aromatic aldehyde (0.01 mmol), malononitrile (0.01 mmol),
and thioglycollic acid (0.01 mmol) in absolute ethanol (20 mL) was
refluxed for 2 h in the presence of piperidine (0.5 mL). The reaction

Studies on Thiazolopyridines
717
TABLE II Spectra Data of the Synthesized Compounds
1
Compd.
IR
(cm
)
1H-NMR (ppm, DMSO-d6)
max
1a
2200 (C N) , 1710 (C O)
2200 (C N), 1719 (C O)
4.62 (s, 2H,CH2), 6.05 (s, 1H, indole-H),
7.20–759 (m, 5H, Ar H + methine-H),
12.16 (broad, 1H, NH)
1b
2a
4.72 (s, 2H,CH2), 7.12–7.85 (m, 5H,
Ar H + methine-H)
3350, 3300 (NH2), 3224 (NH)
2206 (C N), 1689 (C O)
4.40 (s, 1H, Pyridine-H), 7.20 (s, 1H,
indole-H), 7.47–8.09 (m, 9H, Ar.H +
methine-H), 8.56 (s, 2H, NH2), 8.64,
9.26 (broad, 2H, 2NH)
2b
2c
3400, 3325 (NH2), 3286 (NH),
2206 (C N), 1712 (C O)
4.47 (s, 1H, pyridine-H), 6.62 (s, 1H,
indole-H), 7.10–7.79 (m, 9H, Ar H +
methine-H), 8.10 (broad, 2H, NH2),
9.3 (1H, broad, NH)
4.46 (s, pyridine-H), 6.61 (s, 1H, indole-H),
7.22–7.94 (m, 9H, Ar H + methine-H),
7.78 (broad, 2H, NH2), 8.21 ( broad, 1H,
NH)
3425, 3379 (NH2), 3286 (NH)
2206 (C N), 1712 (C O)
2d
2e
3379, 3278 (NH2), 3201 (NH),
2198 (C N), 1720 (C O)
4.24 (s, 1H pyridine-H), 6.00 (s,1H,
indole-H), 7.14–7.84 (m, 9H, Ar H +
methine-H), 8.22 (broad 2H, NH2), 8.54
(broad, 1H, 1H, NH), 9.09 (broad, 1H,
OH)
2f
3310, 3286 (NH2), 3224 (NH),
2214 (C N), 1712 (C O)
3379, 3287 (NH2), 3221 (NH),
2183 (C N), 1705 (C O)
2g
4.77 (s, 1H pyridine-H), 6.05 (s, 1H,
indole-H), 7.27–8.01 (m, 12H, Ar H +
methine-H), 8.17 (s, 2H, NH2), 11.17
(broad, 1H, NH)
6a
6b
7
3201 (board, NH + OH)
7.26 (s, 1H pyrazole-H), 7.26–7.84 (m, 5H,
Ar H + NH) 8.62 (s, 1H, OH)
7.06–7.65 (m, 10-H, Ar H + CH), 12.65
(broad, 1H, OH)
4.63 (s, 1H, pyridine-H), 7.14–7.74 (m,
14-H, ArH + CH), 10.82 (s, 1H,
pyrimidine-H), 11.60, 12.13 (broad, 2H,
2NH)
3155 (OH), 1674 (C O)
3224 (NH), 1705 (C O) 3409
(OH)
8
9
3350, 3400 (NH2), 3186 (NH),
2206 (C O)
4.91 (s, 1H, pyridine-H), 5.24 (broad, 2H,
NH2), 6.92–7.73 (m, 8H, Ar H), 10.82
(s, 1H, pyrimdine-H), 11.61 (broad, 1H,
NH).
4.31 (s, 1H, pyridine-H), 4.93 (s, 1H,
pyran-H), 5.26 (broad, 2H, NH2),
6.88–7.72 (m, 8H, Ar H), 7.96 (S, 1H,
pyrimidine-H), 11.92 (broad, 1H, NH)
2.4 (s, 3H, CH3), 4.31 (s, H, pyridine-H),
7.16–7.74 (m, 8H, Ar H), 10,82 (s, 1H,
pyrimidine-H), 12.01 (broad, 1H, NH)
3350, 3300 (NH2), 3209 (NH),
2214 (C N), 1665 (C O)
10
3201 (NH), 2214 (C N), 1666
(C O)

718
G. A. M. El-Hag Ali
TABLE III Physical and Analytical Data of the Synthesized Compounds
Calculated/Found (%)
Solvent
cryst.
Mol. formula
(m.wt)
Compd. Yield (%)
m.p ( C)
162–63
C
H
N
1a
1b
2a
2b
2c
2d
2e
2f
2g
2h
6a
6b
7
80
77
74
83
70
81
71
69
65
68
78
69
66
76
63
61
DMF/E
DMF
DMF/E
DMF/E
DMF/E
DMF/E
DMF/E
DMF/E
DMF/E
DMF/E
B1/E
C14H9N3OS
(267)
C12H7FN2OS
(246)
C26H16N6OS
(460)
62.92
62.81
58.53
58.40
67.82
67.84
65.60
65.61
63.22
63.30
57.60
57.57
65.90
65.92
64.23
64.22
71.33
71.34
71.33
71.22
60.67
60.60
70.86
70.80
63.82
63.81
61.29
61.30
60.93
60.94
61.36
61.42
3.37
3.30
2.84
2.89
3.47
3.48
3.18
3.19
3.07
2.97
2.80
2.86
3.43
3.48
3.64
3.62
3.60
3.63
3.60
3.63
3.93
3.92
4.33
4.20
3.19
3.20
2.55
2.57
2.73
2.72
2.65
2.60
15.73
15.82
11.38
11.42
18.26
18.27
15.94
15.92
15.36
15.30
14.00
14.12
16.00
15.90
14.98
14.95
14.86
14.82
14.86
15.01
15.73
15.80
11.07
11.12
14.89
14.87
19.25
19.23
16.40
16.41
10.60
10.80
170–71
106–08
116–17
273–75
255–57
141–42
124–26
240–42
242–44
168–70
283–85
C
24H14FN5OS
(439)
C24H14ClN5OS
(455.5)
C24H14BrN5OS
(500)
C24H15N5O2S
(437)
C
25H17N5O3S
(467)
C
28H17N5OS
(471)
C28H17N5OS
(471)
C9H7FN2O
(178)
E/B
C
15H11FN2O
(254)
E/B
179–180 C30H18F2N6O2S
(564)
8
B
166–68
200–02
140–41
C
26H13F2N7OS
(509)
9
B
C
26H14F2N6O2S
(512)
C27H14F2N4O4S
(528)
10
B
E: ethanol; b: benzene; and DMF = dimethylformamide.
mixture was poured into ice/HCl. The obtained product was recrystal-
lized to give 1a,b, Table III.
2-Arylmethylidene-5-amino-6,8-dicyano-7-aryl-7H-2,3-
dihydro-3-oxo-thiazolo [3,2-a] pyridine (2a–h)
A mixture of (1a, or 1b, 0.01 mmol), and arylidenemalononitrile (0.01
mmol) was refluxed for 2 h in absolute ethanol (20 ml) in the prescence

Studies on Thiazolopyridines
719
of piperidine (0.5 ml). The solid product was collected by filteration and
recrystallized to give (2a–h) (Table III).
5-Hydroxy-3-(4-fluorophenyl)-pyrazoles (6a,b)
A solution of 4 (0.01 mmol) and hydrazine hydrate (0.012 mmol) or
phenyl hydrazine (0.01 mmol) in absolute ethanol (30 ml) was heated
under reflux conditions for 1 h. The reaction mixture was cooled and
solid product was collected to give 6 (Table III).
5,8-Bis(4-fluorophenyl)-5,8,9-trihydro
3,9-dimino-10-benzoyl-6-cyano pyrazolo[3‘,4‘:4,5]-
thiazolo[3,2-a]-3-aza[1,8]naphthridine (7)
To a solution of 4 (0.0 mmol) in absolute ethanol (30 ml) and benzoyl
hydrazine was refluxed for 3 h and the reaction mixture was cooled the
obtained solid was recrystallized to give 8 (Table III).
5,8-Bis(4-fluorophenyl)-6,9-dicyano-10-amino-3-imino-
3,5-dihydro-4-oxo-pyrido[2‘,3‘:4,5]thiazolo-
[3,2-a]-3-aza [1,8]naphthyridine (8)
A mixture of 4 (0.01 mmol) and malononitrile (0.01 mmol) in 20 ml
ethanol was refluxed for 8 h in the presence of ammonium acetate
(2 gm). The solvent was evaporated in vacuo and the solid formed was
collected by filtration to give 8 (Table III).
5,8,-Bis(4-fluorophenyl)-6,9-dicyano-10-amino-3-imino-
3,5-dihydro-4-oxo-pyrano[2‘,3‘:4,5]thiazolo[3,2-a]
3-aza[1,8]naphthyridine (9)
A mixture of 4 (0.0 mmol), malononitrile (0.0 mmol) and piperidine
(0.5 ml) in ethanol (20 ml) was refluxed for 3 h. The obtained product
was recrystallized to give 9 (Table III).
5,8 Bis-(4-fluorophenyl)-9-acetyl-4,10-dioxo-3-imino-
3,5-dihydro-6 cyano-pyrano[2‘,3‘,4,5]thiazolo[3,2-a]-
3-aza[1,8]naphthyridine (11)
A mixture of 4 (0.01 mmol) and ethyl acetoactate (0.01 mmol) in ab-
solute ethanol (20 ml) was refluxed for 2 h in the presence of triethy-
lamine (0.5 ml) The obtained solid product was recrystallized to give 10
(Table III).

720
G. A. M. El-Hag Ali
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