Heterocycles derived from 5-(2-aminothiazol-4-yl)-8-hydroxyquinoline: Synthesis and antimicrobial activity

Article abstract of DOI:10.1002/jccs.200300154

5-(2-Aminothiazol-4-yl)-8-hydroxyquinoline 2 has been synthesized by treating thiourea with 5-chloroacetyl-8-hydroxyquinoline 1. The amine 2 was treated with aromatic aldehydes to furnish schiff bases 6a-c which on treatment with phenyl isothiocyanate gave the corresponding thiazolo-s-triazines 7a-c. Reaction of 2 with phenyl isothiocyanate gave the corresponding aminocarbothiamide derivative 8 which on reaction with malonic acid in acetyl chloride afforded thiobarbituric acid derivative 9. Coupling of 9 with diazonium salt gave the phenyl hydrazono derivative 10. However, reaction of 2 with carbon disulphide and methyl iodide afforded dithiocarbamidate 12 which on treatment with ethylenediamine, o-aminophenol and/or phenylene-diamine gave the aminoazolo derivatives 13-15, respectively. Other substituted fused thiazolopyrimidines 16-20 have been also prepared by the reaction of 2 with some selected dicarbonyl reagents. The characterisation of synthesized compounds has been done on the basis of elemental analysis, IR, ¹H-NMR and mass spectral data. All the newly synthesized compounds have been screened for their antimicrobial activities.

Full text of DOI:10.1002/jccs.200300154

Journal of the Chinese Chemical Society, 2003, 50, 1085-1092
1085
Heterocycles Derived from 5-(2-Aminothiazol-4-yl)-8-hydroxyquinoline:
Synthesis and Antimicrobial Activity
Shawkat A. Abdel-Mohsen
Department of Chemistry, Faculty of Science, Assiut University, Assiut, 71516, Egypt
5-(2-Aminothiazol-4-yl)-8-hydroxyquinoline 2 has been synthesized by treating thiourea with 5-chloro-
acetyl-8-hydroxyquinoline 1. The amine 2 was treated with aromatic aldehydes to furnish schiff bases 6a-c
which on treatment with phenyl isothiocyanate gave the corresponding thiazolo-s-triazines 7a-c. Reaction of
2 with phenyl isothiocyanate gave the corresponding aminocarbothiamide derivative 8 which on reaction with
malonic acid in acetyl chloride afforded thiobarbituric acid derivative 9. Coupling of 9 with diazonium salt
gave the phenyl hydrazono derivative 10. However, reaction of 2 with carbon disulphide and methyl iodide af-
forded dithiocarbamidate 12 which on treatment with ethylenediamine, o-aminophenol and/or phenylene-
diamine gave the aminoazolo derivatives 13-15, respectively. Other substituted fused thiazolopyrimidines
16-20 have been also prepared by the reaction of 2 with some selected dicarbonyl reagents. The characterisa-
tion of synthesized compounds has been done on the basis of elemental analysis, IR, 1H-NMR and mass spec-
tral data. All the newly synthesized compounds have been screened for their antimicrobial activities.
Keywords: 1,3-Thiazolo-8-quinolinol; Thiazolo[3,2-a]triazine; Thiazolylaminobenzazoles;
Thiazolo[3,2-a]pyrimidines antimicrobial activity.
INTRODUCTION
8-Quinolinol is widely used as a precursor for the syn-
wise, compound 2 was readily annelated to the corresponding
2-imino-3-phenacylthiazolo derivative 4 upon heating with
phenacyl bromide in dry benzene, whereas prolongued heat-
ing of 2 in anhydrous ethanol underwent cyclization reaction
to provide imidazothiazolo derivative 5. Both elemental and
spectroscopic data of componds 2-5 are consistent with the
assigned structure. Thus, as a representive example, the mass
spectrum of 2 revealed a molecular ion peak at m/z = 243 with
78% relative abundance corresponding to the molecular for-
mula C12H9N3OS. Its IR spectrum showed absorption peaks
at 3400-3300 cm-1 for NH2 function. The IR spectrum of com-
pound 4 showed absorption peak at 1690 cm-1 for CO func-
tion, whereas the absence of this peak in the spectrum of 5
supports its cyclic structure, Scheme I.
thesis of different heterocycles of biological interest.1-5 Het-
erocycles containing thiazole rings are associated with a par-
ticularly wide range of biological properties including anti-
protozoal6 and anticonvulsants7 activity, as well as a de-
pressant effect on the central nervous system,8 as anti-
helminthics,9 antidiabetics10 and as inhibitors of dihydro fo-
late.11 As an extension of our efforts towards the development
of convenient synthetic approaches for the synthesis of 5-
heterocyclo-8-hydroxyquinoline,12,13 we report herein a sim-
ple synthetic method for the synthesis of 5-(2-aminothiazol-
4-yl)-8-hydroxyquinoline (2) as a candidate for the synthesis
of some hitherto unreported polyfunctionally substituted
heterocycles and their fused derivatives.
Also treatment of 2 with some aromatic aldehydes gave
the corresponding 2-arylidene aminothiazolo derivatives
6a-c. Further reaction of 6a-c with phenylisothiocyanate in
refluxing toluene gave 5,6-disubstituted-thiazolo[3,2-a]-s-
triazine-4-thione derivatives 7a-c.14 Refluxing of 2 with
phenyl isothiocyanate in pyridine converted directly into 5-
[2-(N-phenyl-N-1,3-thiazol-2-yl)thiourea-4-yl]-8-hydroxy-
quinoline 8. The thiourea derivative 8 underwent intermolec-
ular cyclization by the reaction with malonic acid in the pres-
ence of acetyl chloride15 and furnished 3-N-phenylthiobar-
ituric acid-N-1,3-thiazolo derivative 9. The versatility of the
novel synthon 9 was proven by the following examples. 9 un-
derwent electrophilic substitution upon coupling with phen-
RESULTS AND DISCUSSION
It has been found that heating equimolar amounts of
5-chloroacetyl-8-hydroxyquinoline 1 and thiourea in ethanol
under reflux furnishes in high yield that which could be for-
mulated as 5-(2-aminothiazol-4-yl)-8-hydroxyquinoline 2.
The reaction of 2 with acetyl and/or benzoyl chloride in pres-
ence of dioxane at 50 °C afforded the expected 2-acetyl and
2-benzoylamino derivatives 3a and 3b, respectively. Like-

1086 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Abdel-Mohsen
Scheme I
yldiazonium chloride to yield the corresponding cyclic hy-
arylidenemalononitrile to give 4-amino-6-phenyl-thiazolo-
[3,2-a]pyrimidine-5-carbonitrile derivative 19, whose struc-
ture was assigned on the basis of analytical and spectral data.
The IR spectrum revealed absorption peaks at 3400, 3300
cm-1 for NH2 function and at 2220 cm-1 for CN function.
Finally, compound 2 is also capable of a similar con-
densation reaction with ethyl arylidenecyanoacetate to afford
6-phenyl-4-oxo-5H-6H-thiazolo[3,2-a]pyrimidine-5-carbo-
nitrile derivative 20, Scheme IV.
1
drazone-coupling product 10. H-NMR spectrum of com-
pound 10 revealed the presence of an D2O exchangeable sin-
glet at d = 11.30 ppm corresponding to the hydrazone NH
function. On the other hand, compound 9 reacted readily with
the appropriate aromatic aldehydes in refluxing EtOH con-
taining a catalytic amount of piperidine to yield exclusively
the corresponding arylidene derivatives 11a-c, Scheme II.
A number of thiazolylaminobenzoxazole, benzimida-
zole and imidazolidines are associated with antibacterial ac-
tivities.16 In view of this fact, we now report an interesting re-
action of 2-aminothiazolo derivative 2 with carbon disul-
phide and methyl iodide in the presence of conc. aq. NaOH,
leading to the formation of 5-[2-(N-dimethyldithiocarbami-
date-2-yl)-1,3-thiazol-4-yl]-8-hydroxyquinoline 12 which
on treatment with a bisnucleophile such as ethylenediamine,
o-aminophenol and o-phenylenediamine gave 5-[2-(amino-
imidazolidin-2-yl)-1,3-thiazol-4-yl]-8-hydroxyquinoline,
5-[2-(aminobenzoxazol-2-yl)-1,3-thiazol-4-yl]-8-hydroxy-
quinoline and 5-[2-(aminobenzimidazol-2-yl)-1,3-thiazol-
4-yl]-8-hydroxyquinoline 13-15, respectively, Scheme III.
In accord to the well known cyclocondensation of 2-
aminothiazoles with b-bifunctional reagents to yield thia-
zolo[3,2-a] pyrimidines.17 Thus, by a simple fusion of com-
pound 2 with ethylacetoacetate, ethylcyanoacetate and di-
ethylmalonate gave 6-methyl-4-oxo-thiazolo[3,2-a]pyrimi-
dine, 6-amino-4-oxo-thiazolo[3,2-a]pyrimidine and 4,6-di-
oxo-5H-thiazolo[3,2-a]pyrimidine derivatives 16-18, re-
spectively. Compound 2 also was subjected to the reaction
with arylidene compounds. It was found that 2 reacts with
ANTIMICROBIAL ACTIVITY
All of the prepared compounds were evaluated in vitro
for their antifungal activity against A. niger and C. albicans
and antibacterial activity against B. subtilis and E. coli and
using DMF as solvent at 100 hg/mL concentation by cup-
plate method.18
(i) Antifungal Activity
The results obtained revealed that when the 5-(2-Ami-
nothiazol-4-yl)-8-hydroxyquinoline (2) is substituted with a
benzoyl group (c.f. 3b, R=Ph), it is most active against A.
niger. But compound 3a which has an acetyl group (R=CH3)
is less active. Compounds 5 and 6 have no significant anti-
fungal activity. A comparison of the antifungal activity of the
arylidenethiazolo derivatives 6a-c indicated that p-chloro-
phenyl group 6b induces more fungitoxicity against C. albi-
cans than other substitutents 6a and 6c.
It was noted that amongst s-triazine compounds 7a-c,

Heterocycles Derived from 5-Thiazolo-8-quinolinol
J. Chin. Chem. Soc., Vol. 50, No. 5, 2003 1087
Scheme II
only 7c (R=p-NO2C6H4) is more active against A. niger. A
comparison of the antifungal activity data of compounds
8-11a-c clearly indicates that the thiobarbituric acid deriva-
tive 9 and its coupling products 10 and 11b are more active
against both of the fungi species than its parent thioureas de-
rivative 8. This may be attributed to the more planar and com-
pact structure19 and also with the earlier observation that the
combination of C=O and C=S functions sometimes works
better than either alone.20
antibacterial activity, 2-aminothiazolo; thiobarbituric acid
and thiazolobenzimidazolo derivatives 2, 9 and 15, respec-
tively, revealed strongest activity against B. subtilis only the
aminothiazolopyrimidine derivative 17 exhibited good activ-
ity against E. coli. Other compounds possessed mild to mod-
erate activity against the investigated bacteria species.
EXPERIMENTAL
(ii) Antibacterial Activity
Melting points are uncorrected; IR spectra (KBr): Pye-
1
Amongst the synthesized compounds 2-20 screened for
Unicam infrared spectrophotometer; H-NMR spectra were

1088 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Abdel-Mohsen
Scheme III
Scheme IV

Heterocycles Derived from 5-Thiazolo-8-quinolinol
J. Chin. Chem. Soc., Vol. 50, No. 5, 2003 1089
recorded on a 90 MHZ Varian NMR spectrophotometer
(DMSO-d6), TMS as internal standard, chemical shifts in
ppm; Mass spectra; JEOL-JMS 600 spectrometer; elemental
analyses were accomplished at the microanalytical labora-
tory of the Chemistry Department at Assiut University. 5-
Chloroacetyl-8-hydroxyquinoline (1) was prepared accord-
ing to the literature.21
cm-1; 1H-NMR: d 9.2 (s, 1H, NH), 8.9-7.5 (m, 12H, arom.pro-
tons), 5.2 (s, 2H, CH2-COPh).
5-(6-Phenylthiazolo[3,2-a]imidazol-3-yl)-8-hydroxyquino-
line (5)
A mixture of 2 (0.01 mol) and phenacyl bromide (0.01
mol) in anhydrous ethanol (30 mL) was boiled under reflux
for 7 h. The reaction mixture was cooled, then poured into
cold H2O. The solid product which precipitated was collected
by filtration, washed with water, dried and crystallized from
EtOH. Yield 66%; m.p.: 266 °C; C20H13N3OS (343.15); calc.:
C 69.97, H 3.79, N 12.24, S 9.32; found: C 69.92, H 3.75, N
12.22, S 9.31; IR: 3100 (CH arom.), 1620 (N= CH) cm-1;
1H-NMR: d 8.9-7.3 (m, 13H, arom.protons).
5-(2-Aminothiazol-4-yl)-8-hydroxyquinoline (2)
A mixture of 5-chloroacetyl-8-hydroxyquinoline 1
(0.05 mol) and thiourea (0.05 mol) in absolute ethanol (100
mL) was refluxed for 5 h. The reaction mixture was concen-
trated, cooled and neutralized with sodium acetate solution
(6%). The precipitated solid was filtered off, washed with
water, dried and recrystallized from benzene. Yield 75%;
m.p. 270-2 °C; C12H9N3OS (243.12); calc.: C 59.25, H 3.70,
N 17.28, S 13.16; found: C 58.94, H 3.69, N 17.25, S 13.14;
IR: 3400-3300 (NH2), 3100 (CH, thiazole ring), 1620 (C=N)
cm-1; 1H-NMR: d 8.7-7.4 (m, 7H, arom.protons), 6.5 (s, 2H,
NH2, exchangeable); MS: m/z = 243 (M+, 78%).
5-(2-Arylideneaminothiazol-4-yl)-8-hydroxyquinoline
(6a-c; general procedure)
To a solution of 2 (0.01 mol) in DMF (30 mL) contain-
ing a catalytic amount of piperidine (3 drops), the appropriate
aromatic aldehyde (0.01 mol) was added. The reaction mix-
ture was heated under reflux for 5 h, poured into an ice/H2O
mixture (30 mL), and neutralized with dilute HCl. The solid
product was filtered off and crystallized from an appropriate
solvent.
5-(2-Acetyl(benzoyl)aminothiazol-4-yl)-8-hydroxyquinoline
(3a,b; general procedure)
A mixture of 2 (0.05 mol) and acetyl and/or benzoyl
chloride (0.1 mol) in dioxane (10 mL) was heated at 50 °C for
2 h. The reaction mixture was allowed to cool to room tem-
perature then poured into a solution of K2CO3 with continu-
ous stirring for ½ h. The solid so obtained was collected by
filtration, dried and crystallized from EtOH.
6a (Ar=Ph): Yield 70%; m.p.: 180 °C; (ethanol)
C19H13N3OS (331.11); calc.: C 68.88, H 3.92, N 12.68, S
9.66; found: C 68.82, H 3.91, N 12.65, S 9.63; IR: 3010 (CH
arom); 1645 (N=CH thiazole ring) cm-1; 1H-NMR: d 6.8-9.2
(m, 13H, arom.protons and N=CH).
3a (R=CH3): Yield 93%; m.p.: 310 °C; C14H11N3O2S
(285.31); calc.: C 58.94, H 3.85, N 15.08; S 11.22; found: C
58.92, H 3.83, N 14.98, S 11.18; IR: 3300 (NH); 1690 (CO)
6b (Ar=(p)-ClC6H4): Yield 68%; m.p.: 175 °C; (di-
oxane) C19H12N3OSCl (365.08); calc.: C 62.28, H 3.28, N
11.49, S 8.75, Cl 9.71; found: C 62.22, H 3.25, N 11.44, S
8.74, Cl 9.68; IR: 3010 (CH arom); 1645 (N=CH thiazole
1
cm-1; H-NMR: d 10.15 (s, 1H, NH), 8.8-7.4 (m, 7H, arom.
1
protons), 2.25 (s, 3H, COCH3).
ring) cm-1; H-NMR: d 9.2-6.8 (m, 12H, arom.protons and
3b (R=Ph): Yield 88%; m.p.: 302 °C; C19H13N3O2S
(347.06); calc.: C 65.57, H 3.74, N 12.10, S 9.22; found: C
65.51, H 3.71, N 12.08, S 9.20; IR: 3250 (NH); 1690 (CO)
cm-1; 1H-NMR: d 10.20 (s, 1H, NH), 8.9-7.4 (m, 7H, arom.
protons); MS: m/z = 347 (M+, 22.8 %).
N=CH). MS: m/z = 365 (M+, 23.6 %).
6c (Ar=(p)-NO2C6H4): Yield 69%; m.p.: 195 °C; (EtOH)
C19H12N4O3S (376.21); calc.: C 60.63, H 2.92, N 14.89, S
8.77; found: C 60.59, H 2.90, N 14.87, S 8.73; IR: 3010 (CH
1
arom); 1645 (N=CH thiazole ring), 1525 (NO2) cm-1; H-
NMR: d 9.3-6.7 (m, 12H, arom.protons and N=CH).
5-(2-Imino-3-phenacylthiazol-4-yl)-8-hydroxyquinoline (4)
To a solution of 2 (0.01 mol) in dry benzene, phenacyl
bromide (0.01 mol) was added. The reaction mixture was
heated under reflux for 5 hr. and then evaporated in vacuo.
The remaining product was triturated with EtOH, and the
formed solid product was collected by filtration and recrys-
tallized from DMF. Yield 68%; m.p.: 243 °C; C20H15N3O2S
(361.12); calc.: C 66.48, H 4.15, N 11.63; S 8.86; found: C
66.42, H 4.11, N 11.60, S 8.83; IR: 3300 (NH); 1690 (CO)
5-(5,6-Disubstituted-thiazolo[3,2-a]-s-triazine-4-thiones-3-
yl)-8-hydroxyquinoline (7a-c; general procedure)
An equimolar mixture of 6a-c (0.01 mol) and phenyl
isothiocyanat in toluene was refluxed for 4-6 h. The solvent
was distilled off, the residue washed with a small amount of
ethanol followed by water and the product recrystallized
from EtOH as yellowish crystals.
7a (Ar=Ph): Yield 65%; m.p.: 325 °C; C26H18N4OS2

1090 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Abdel-Mohsen
(466.24); calc.: C 66.95, H 3.86, N 12.01, S 13.73; found: C
66.91, H 3.82, N 11.98, S 13.71; IR: 3050 (CH arom); 1500
(C=S) cm-1; 1H-NMR: d 9.1-7.2 (m, 17H, arom.protons), 6.45
(s, 1H, H-7 pyrimidinethione).
line (0.05 mol) in concentrated HCl (10 mL) at 0-5 °C under
stirring] was added dropwise while cooling at 0-5 °C and stir-
ring. The reaction mixture was left at room temperature for 2
h. The solid product thus obtained was collected by filtration
and crystallized from dioxane. Yield 64%; m.p. 220-2 °C;
C28H18N6O3S2 (550.12); calc.: C 61.09, H 3.27, N 15.27, S
11.63; found: C 60.97, H 3.24, N 15.25, S 11.62; IR: 3350
7b (Ar=(p)-ClC6H4): Yield 63%; m.p.: 298 °C;
C26H17N4OS2Cl (501.05); calc.: C 62.21, H 3.38, N 11.16, S
12.76, Cl 7.07; found: C 62.19, H 3.35, N 11.15, S 12.73, Cl
1
1
6.99; IR: 3050 (CH arom); 1500 (C=S) cm-1; H-NMR: d
(NH), 3010 (CH arom), 1695 (C=O), 1360 (C=S) cm-1; H-
9.1-7.2 (m, 16H, arom.protons), 6.50 (s, 1H, H-7 pyrimidine-
thione); MS: m/z = 501 (M+, 18.5 %).
NMR: d 11.30 (s, 1H, NH), 8.9-7.4 (m, 17H, arom.protons).
7c (Ar=(p)-NO2C6H4): Yield 62%; m.p.: >330 °C;
C26H17N5O3S2 (511.13); calc.: C 61.05, H 3.32, N 13.69, S
12.52; found: C 60.98, H 3.30, N 13.65, S 12.51; IR: 3150
(CH arom), 1520 (C=S), 1170 (NO2) cm-1; 1H-NMR: d 9.0-
7.3 (m, 16H, arom.protons), 6.70 (s, 1H, H-7 pyrimidine-
thione).
5-(3-N-Phenylthiobarituric acid-5-benzal-N-1-thiazol-4-
yl)-8-hydroxyquinoline (11a-c; general procedure)
Equimolar amounts of 9 and the appropriate aromatic
aldehydes (0.01 mol) in absolute ethanol (30 mL) containing
a catalytic amount of piperidine (0.5 mL) were heated under
reflux for 6 h. and then evaporated in vacuo. The remaining
product was triturated with diethyl ether, and the formed
solid was collected by filtration and recrystallized from
EtOH.
5-[2-(N-phenyl-N-1,3-thiazol-2-yl)thiourea-4-yl]-8-hydro-
xyquinoline (8)
To a solution of 2 (0.01 mol) in pyridine (20 mL) was
added phenyl isothiocyanate (0.01 mol) and the reaction mix-
ture refluxed for 6 h. It was then cooled and the solvent re-
moved in vacuo. The resulting residue was triturated with
water and the solid obtained was recrystallized from aq. etha-
nol. Yield 66%; m.p. 235 °C; C19H14N4OS2 (378.11); calc.: C
60.31, H 3.70, N 14.81, S 16.93; found: C 60.28, H 3.68, N
14.80, S 16.91; IR: 3280-3200 (Sec NH), 3050 (CH arom),
11a (Ar=Ph): Yield 69%; m.p. 201-3 °C; C29H18N4O3S2
(470.10); calc.: C 74.04, H 3.82, N 11.91, S 13.61; found: C
73.98, H 3.81, N 11.89, S 13.58; IR: 3060 (CH arom), 1695
1
(C=O), 1640 (C=C), 1360 (C=S) cm-1; H-NMR: d 8.9-7.4
(m, 17H, arom.protons), 6.99 (s, 1H, CH=C).
11b (Ar=(p)-ClC6H4): Yield 61%; m.p. >320 °C;
C29H17N4O3S2Cl (504.51); calc.: C 68.97, H 3.36, N 11.10, S
12.67, Cl 7.03 ; found: C 68.95, H 3.34, N 10.98, S 12.63, Cl
7.01; IR: 3050 (CH arom), 1695 (C=O), 1640 (C=C), 1340
(C=S) cm-1; 1H-NMR: d 9.1-7.4 (m, 16H, arom.protons), 6.95
(s, 1H, CH=C).
1
1590 (C=N), 1360-1340 (C=S) cm-1; H-NMR: d 9.6-10.4
(br. s, 2H, 2NH), 8.9-7.4 (m, 12H, arom.protons).
5-(3-N-Phenylthiobarituric acid-N-1-thiazol-4-yl)-8-
hydroxyquinoline (9)
11c (Ar=(p)-NO2C6H4): Yield 63%; m.p. 248 °C;
C29H17N5O5S2 (579.06); calc.: C 60.10, H 2.93, N 12.08, S
11.05; found: C 60.07, H 2.91, N 11.99, S 11.01; IR: 3050
(CH arom), 1695 (C=O), 1640 (C=C), 1250 (C=S) cm-1; 1H-
NMR: d 9.1-7.4 (m, 16H, arom.protons), 7.15 (s, 1H, CH=C).
A mixture of 8 (0.013 mol), malonic acid (0.013 mol)
and acetyl chloride (3 mL) was warmed at 80 °C for 1 h. The
temperature was raised to 130 °C for an additional 3 h. The
contents were then poured onto crushed ice, cooled to 10 °C,
pH adjusted to 9-10 with 10 M NaOH, and the resulting solid
was crystallized from DMF. Yield 71%; m.p. 250-2 °C;
C22H14N4O3S2 (446.15); calc.: C 59.19, H 3.13, N 12.55, S
14.34; found: C 59.17, H 3.11, N 12.51, S 14.31; IR: 3010
(CH arom), 2990 (CH aliph), 1695 (C=O), 1360-1340 (C=S)
cm-1; 1H-NMR: d 9.1-7.4 (m, 12H, arom.protons), 3.7 (s, 2H,
CH2 thiobarbituric acid).
5-[2-(N-Dimethyldithiocarbamidate-2-yl)-1,3-thiazol-4-yl]-
8-hydroxyquinoline (12)
To a well-stirred cold solution of 2 (0.05 mol) in DMF
(20 mL), were added 20M aq. NaOH (4 mL), carbon disul-
phide (7.5 mL, 0.1 mol), and methyl iodide (0.05 mol) in se-
quence at an interval of 30 min. and stirring was continued for
3 h. The mixture was then poured in cold water and the result-
ing solid was washed with water and recrystallized from aq.
ethanol. Yield 63%; m.p. 190-2 °C; C17H17N3OS3 (375.31);
calc.: C 54.40, H 4.53, N 11.20, S 25.60; found: C 54.38, H
4.51, N 11.18, S 25.57; IR: 3050 (CH arom), 2985 (CH aliph),
1640 (C=N) cm-1; 1H-NMR: d 8.9-7.4 (m, 7H, arom.protons),
2.65 (s, 6H, 2 SCH3); MS: m/z = 375 (M+, 17.4 %).
5-(3-N-Phenylthiobarituric acid-5-phenylhydrazono-N-1-
thiazol-4-yl)-8-hydroxyquinoline (10)
To a stirred solution of 9 (0.05 mol) in ethanol (50 mL)
containing NaOAc (4 g), phenyldiazonium chloride (0.05
mol) [prepared by addition of NaNO2 (0.05 mol) to pure ani-

Heterocycles Derived from 5-Thiazolo-8-quinolinol
J. Chin. Chem. Soc., Vol. 50, No. 5, 2003 1091
5-[2-(Aminoimidazolidin-2-yl)-1,3-thiazol-4-yl]-8-hydro-
xyquinoline (13)
tion and recrystallized from dioxane.
To a solution of ethylenediamine (0.08 mol) in DMF
(15 mL). A solution of 12 (0.04 mol) in DMF (15 mL) was
added with stirring at room temperature. The reaction mix-
ture was maintained at 100 °C for 6 h, cooled and then ice-
cold water was added; the resulting solid was washed with
water, dried and recrystallized from EtOH. Yield 59%; m.p.
216-18 °C; C15H13N5OS (311.21); calc.: C 57.87, H 4.18, N
22.50, S 10.27; found: C 57.85, H 4.15, N 22.48, S 10.24; IR:
3380-3300 (NH), 3050 (CH arom), 2990 (CH aliph), 1640
(C=N) cm-1; 1H-NMR: d 9.1 (s, 1H, cylic NH, exchangeable
with D2O), 8.9-7.4 (m, 7H, arom.protons), 5.9 (s, 1H, acylic
NH), 2.75 (t, 2H, methylene protons), 2.4 (t, 2H, methylene
protons).
5-[6-Methyl-4-oxo-thiazol[3,2-a]pyrimidines-3-yl)-8-hy-
droxyquinoline (16)
Yield 63%; m.p. 226 °C; C16H11N3O2S (309.2); calc.: C
62.13, H 3.55, N 13.59, S 10.35; found: C 62.11, H 3.53, N
13.57, S 10.33; IR: 3050 (CH arom), 2985 (CH, aliph), 1690
1
(C=O), 1650 (C=C), 1580 (C=N) cm-1; H-NMR: d 8.8-7.3
(m, 8H, arom.protons), 2.9 (s, 3H, CH3).
5-[6-Amino-4-oxo-thiazol[3,2-a]pyrimidines-3-yl)-8-hydro-
xyquinoline (17)
Yield 55%; m.p. 311-12 °C; C15H10N4O2S (310.3);
calc.: C 58.06, H 3.22, N 18.06, S 10.32; found: C 58.01, H
3.20, N 18.03, S 10.31; IR: 3400-3300 (NH2), 3010 (CH
1
arom), 1695 (C=O), 1640 (C=C), 1580 (C=N) cm-1; H-
5-[2-(Aminobenzoxazol(benzimidazol)-2-yl)-1,3-thiazol-4-
yl]-8-hydroxyquinoline (14-15; general procedure)
To a solution of o-aminophenol and/or o-phenylenedi-
amine (0.04 mol) in DMF (20 mL) was added a solution of 12
(0.04 mol) in DMF (20 mL) with vigorous stirring at room
temperature and the mixture was refluxed for 8 h. The mix-
ture was then poured on crushed ice and the resulting solid
was dried and recrystallized from EtOH.
NMR: d 8.8-7.3 (m, 8H, arom.protons), 3.86 (s, 2H, NH2).
5-[4,6-Dioxo-5H-thiazolo[3,2-a]pyrimidines-3-yl)-8-hydro-
xyquinoline (18)
Yield 45%; m.p. 277 °C; C15H9N3O3S (311.2); calc.: C
57.87, H 2.89, N 13.50, S 10.28; found: C 57.85, H 2.87, N
13.48, S 10.26; IR: 3050 (CH arom), 2995 (CH, aliph), 1700
1
(C=O), 1640 (C=C), 1600 (C=N) cm-1; H-NMR: d 8.9-7.4
(m, 7H, arom.protons), 4.50 (s, 2H, CH2 pyrimidine).
5-[2-(Aminobenzoxazol-2-yl)-1,3-thiazol-4-yl]-8-hydroxy-
quinoline (14)
5-[4-Amino-6-phenyl-thiazolo[3,2-a]pyrimidine-5-carbo-
nitrile-3-yl)-8-hydroxyquinoline (19)
Yield 66%; m.p. 178-9 °C; C19H12N4O2S (360.09);
calc.: C 63.33, H 3.33, N 15.55, S 8.88; found: C 63.31, H
3.30, N 15.52, S 8.86; IR: 3400-3350 (NH), 3050 (CH arom),
To a solution of 2 (0.01 mol) in DMF (25 mL) contain-
ing triethylamine (0.5 mL), benzalmalononitrile (0.01 mol)
was added. The reaction mixture was heated under reflux for
5 h. then evaporated in vacuo. The remaining product was
triturated with ethanol, and the formed solid product was col-
lected by filtration and recrystallized from dioxane. Yield
69%; m.p. 306 °C; C22H15N5OS (397.3); calc.: C 66.49, H
3.77, N 17.63, S 8.06; found: C 66.45, H 3.74, N 17.61, S
8.01; IR: 3400-3350 (NH2), 3050 (CH arom), 2240 (CN),
1
1640 (C=N) cm-1; H-NMR: d 8.9-7.4 (m, 11H, arom.pro-
tons), 5.7 (s, 1H, acylic NH).
5-[2-(Aminobenzimidazol-2-yl)-1,3-thiazol-4-yl]-8-hydro-
xyquinoline (15)
Yield 51%; m.p. 188 °C; C19H13N5OS (359.3); calc.: C
63.78, H 3.62, N 19.49, S 8.91; found: C 63.75, H 3.61, N
19.47, S 8.89; IR: 3350-3300 (NH), 3050 (CH arom), 1630
(C=N) cm-1; 1H-NMR: d 9.3 (s, 1H, cylic NH, exchangeable
with D2O), 8.9-7.3 (m, 11H, arom.protons), 6.1 (s, 1H, acylic
NH).
1
1620 (C=N) cm-1; H-NMR: d 8.9-7.4 (m, 13H, arom.pro-
tons), 3.95 (s, 2H, NH2).
5-[6-Phenyl-4-(5H,6H)oxo-thiazolo[3,2-a]pyrimidine-5-
carbonitrile-3-yl)-8-hydroxyquinoline (20)
5-[6-Substituted-thiozol[3,2-a]pyrimidines-3-yl)-8-hydro-
xyquinoline (16-18; general procedure)
A mixture of 2 (0.01 mol) and ethyl a-cyanocinnamate
(0.01 mol) in ethanol (25 mL), containing piperidine (0.5
mL) was refluxed for 3 h. The reaction mixture was then
cooled and poured over an ice-HCl mixture. The solid formed
was collected by filtration, washed with water and crystal-
lized from EtOH-DMF. Yield 53%; m.p. 243-5 °C;
C22H14N4O2S (398.12); calc.: C 66.33, H 3.51, N 14.07, S
A mixture of 2 (0.01 mol) and dicarbonyl compounds
such as ethylacetoacetate, ethyl-cyanoacetate and/or diethyl-
malonate (0.01 mol) was heated at 180 °C in an oil bath for 3
h. The hot reaction mixture was allowed to cool; it was tritu-
rated with ethanol. The solid product was collected by suc-

1092 J. Chin. Chem. Soc., Vol. 50, No. 5, 2003
Abdel-Mohsen
9. Robins, R. K.; Hitchings, G. H. J. Am. Chem. Soc. 1958, 80,
3449.
10. Raeymakers, A. H. M.; Alleuigin, F. T. N.; Vandenherk, J.;
Domoen, P. J. A.; Ottenwert, T. T. T.; Janssen, P. A. J. J. Med.
Chem. 1966, 9, 545.
8.04; found: C 66.32, H 3.49, N 14.03, S 8.02; IR: 3050 (CH
arom), 2220 (CN), 1695 (C=O), 1620 (C=N) cm-1; 1H-NMR:
d 8.9-7.4 (m, 14H, arom.protons). MS, m/z = 398 (M+, 14.65).
11. Hurbert, B. S.; Perone, R.; Hermann, T. A.; Hitchings, G. H.
J. Med. Chem. 1968, 11, 711.
Received December 9, 2002.
12. Khalil, Z. H.; Yanni, A. S.; Gaber, A. M.; Abdel-Mohsen, Sh.
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