Synthesis of Biologically Active [4-(4-Bromophenyl)-2-thiazolyl]hydrazones and their D-Galactose Derivatives

Article abstract of DOI:10.1002/cjoc.201090118

Benzaldehyde [4-(4-bromophenyl)thiazol-2-yl]hydrazones 5a-5d were prepared by reacting the thiosemicarbazones 2a-2d with 2,4'-dibromoacetophenone (1) in absolute ethanol. Acetylation of 5a and 5b with Ac₂O/Py at room temperature gave the N-acetyl derivatives 6a and 6b. 4-Methyl-2-pentanone/cyclopentanone [4-(4-bromophenyl) thiazol-2-yl]hydrazones (8a) and (8b) were similarly obtained from the reaction of 1 with the thiosemicarbazones 7a and 7b, respectively. Cyclization of D-galactose thiosemicarbazone (9) and its tautomers 10 and 11 with 1 afforded an equilibrium mixture of the acyclic 2-thiazolylhydrazone 12, together with its respective cyclic galactosyl derivatives 13 and 14, whose structures were studied by using ¹H and ¹³C NMR spectra. The antimicrobial activity of the synthesized thiazole derivatives was evaluated in vitro by using an agar diffusion technique, and some of these compounds showed potential activity against Candida albicans.

Full text of DOI:10.1002/cjoc.201090118

FULL PAPER
Synthesis of Biologically Active [4-(4-Bromophenyl)-2-thia-
zolyl]hydrazones and their D-Galactose Derivatives
Ramadan, El Sayed*
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Benzaldehyde [4-(4-bromophenyl)thiazol-2-yl]hydrazones 5a— 5d were prepared by reacting the thiosemi-
carbazones 2a— 2d with 2,4'-dibromoacetophenone (1) in absolute ethanol. Acetylation of 5a and 5b with Ac2O/Py
at room temperature gave the N-acetyl derivatives 6a and 6b. 4-Methyl-2-pentanone/cyclopentanone [4-(4-bromo-
phenyl)thiazol-2-yl]hydrazones (8a) and (8b) were similarly obtained from the reaction of 1 with the thiosemicar-
bazones 7a and 7b, respectively. Cyclization of D-galactose thiosemicarbazone (9) and its tautomers 10 and 11 with
1 afforded an equilibrium mixture of the acyclic 2-thiazolylhydrazone 12, together with its respective cyclic galac-
tosyl derivatives 13 and 14, whose structures were studied by using 1H and 13C NMR spectra. The antimicrobial ac-
tivity of the synthesized thiazole derivatives was evaluated in vitro by using an agar diffusion technique, and some
of these compounds showed potential activity against Candida albicans.
Keywords thiazole, thiosemicarbazone, D-galactose, 2,4'-dibromoacetophenone
－1
Introduction
3227.65—3395.45 cm corresponding to the NH group,
－1
in addition to bands in 1556.45—1606.59 cm due to
the C＝N and C＝C stretching vibrations. The 1H NMR
spectrum of 5a showed a singlet at δ 12.17 due to the
NH group and a singlet at δ 8.00 corresponding to the
azomethine proton (CH＝N), while the aromatic and
thiazole protons appeared in the region of δ 7.33—7.78.
Compound 5b showed the presence of a singlet at δ
12.58 corresponding to the NH proton, a singlet at δ
7.43 to the C-5 proton of the thiazole ring, and a singlet
at δ 8.06 to the azomethine (CH＝N) proton. The aro-
matic protons appeared as four doublets in the region of
δ 7.56—8.22 with J＝8.4 Hz due to ortho H, H cou-
Thiazole ring is known to be present as a part of
many natural products, which exhibited antibiotic and
antifungal activities.1-4 Natural products having thiazole
rings isolated from marine species showed antineoplas-
tic and cytotoxic properties.5 Cyclopeptides containing
thiazole and dihydrothiazole rings also have cytotoxic
activity.6-9 Moreover, a number of 2-thiazolylhydr-
azones have shown mitochondrial monoamine oxidase
inhibitory (MAOI) activity,10 antibacterial activities
against S. aureus and P. aeruginosa,11 and antifungal
activities against C. albicans and C. krusei.12 Therefore,
we report herein the synthesis and antimicrobial activity
of novel [4-(4-bromophenyl)-2-thiazolyl]hydrazones
and their D-galactose derivatives.
1
pling. The H NMR spectra of 5c and 5d showed a
similar pattern (experimental part).
The mechanism of the formation of thiazole ring
may begin with direct substitution of the bromine atom
in 1 by the sulphur atom of the arylmethylidene thio-
semicarbazones 2 to give the intermediate 3,13 which
underwent a nucleophilic attack of the nitrogen atom to
the carbonyl carbon atom giving 4, subsequent dehydra-
tion of the intermediate 4 afforded the thiazole deriva-
tives 5 (Scheme 1).
Results and disscussion
In the present work, benzaldehyde [4-(4-bromo-
phenyl)thiazol-2-yl]hydrazones 5a—5d were prepared
in 78%—86% yields by the cyclocondensation of the
respective arylmethylidene thiosemicarbazones 2a—2d
with 2,4'-dibromoacetophenone (1) in refluxing absolute
ethanol containing a few drops of N,N-dimethylform-
amide. The starting materials 2a—2d were synthesized
by condensing benzaldehyde, 4-nitrobenzaldehyde, 4-
methobxybenzaldehyde and 2-chlorobenzaldehyde with
thiosemicarbazide in ethanol in the presence of a cata-
lytic amount of glacial acetic acid. The IR spectra of
compounds 5a—5d showed absorption bands in
Acetylation of the hydrazones 5a and 5b was carried
out with acetic anhydride in pyridine at room tempera-
ture to give the N-acetyl derivatives 6a and 6b, respec-
tively, whos－e IR spectra showed bands at 1685.67 and
1
1693.38 cm due to the C＝O stretching vibration of
N-COCH3 group, which was also confirmed by the
presence of sharp singlets at δ 2.48 and 2.54 corre-
*
E-mail: alsramadan@hotmail.com; elsayedramadan2008@yahoo.com
Received August 10, 2009; revised October 19, 2009; accepted November 18, 2009.
594
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 594— 600

Synthesis of [4-(4-Bromophenyl)-2-thiazolyl]hydrazones and their Derivatives
Scheme 1 Synthesis of 2-thiazolyhydrazones and their N-acetyl derivatives
1
sponding to its methyl protons in their 1H NMR spectra.
Condensation of 4-methyl-2-pentanone with thio-
semicarbazide in ethanol and a few drops of glacial ace-
tic acid gave a mixture of (E) and (Z)-4-methyl-
2-pentylidene aminothiourea of thiosemicarbazone (7a)
pounds were identified by studying their FT-IR, H
NMR and mass spectra (Experimental part).
It was reported that sugar hydrazones and thiosemi-
carbazones may exist in solution as an equilibrium
mixture of acyclic and cyclic glycosyl tautomers.15-19
Therefore, when D-galactose was condensed with thio-
semicarbazide in ethanol and a few drops of glacial ace-
tic acid an equilibrium mixture of 9, 10 and 11 was
given. The IR spectrum of －the product showed an ab-
sorption band at 1620.09 cm 1 corresponding to the C＝
N group of 9, while the presence of bands at 1060.78
1
in a ratio of 9∶1 as indicated from its H NMR spec-
trum, which showed the presence of two doublets at δ
0.81, 0.83 (two CH3 groups), two singlets at δ 1.83, 1.85
(CH3), a multiplet in δ 1.87—1.92 (CH), two doublets at
δ 2.04, 2.25 (CH2), two singlets at δ 7.41, 7.52 (D2O-
exchangeable, NH), two singlets at δ 7.94, 7.99 (D2O-
exchangeable, NH) and two singlets at δ 9.86, 9.99
(D2O-exchangeable, SH). Its reaction with 1 in absolute
ethanol and a few drops of N,N-dimethylformamide
gave 4-methyl-2-pentanone [4-(4-bromophenyl)thiazol-
2-yl]hydrazone (8a) in a good yield.
－1
－1
cm (C—O—C, C—N stretching) and 867.91 cm
(anomeric C—H deformation) proved the existence of
the anomers 10 and 11.20,21
Sugar hydrazones containing a thiazole ring have not
been reported yet. Therefore, cyclocondensation of the
mixture of 9, 10 and 11 with 1 in absolute ethanol gave
the acyclic 2-thiazolylhydrazone 12, together with its
respective cyclic galactosyl derivatives 13 and 14. Their
It was reported that cyclopentylidene aminothiourea
of thiosemicarbazone (7b) reacted with 1 in isopropyl
alcohol to give cyclopentanone [4-(4-bromophenyl)-
thiazol-2-yl]hydrazone (8b) in 66% yield.14 However,
when the reaction was conducted in absolute ethanol
instead of isopropyl alcohol the yield of 8b was im-
proved to 79%. Therefore, absolute ethanol proved to be
the best solvent for our purpose. The synthesized com-
structures were confirmed by both H and 13C NMR
1
spectra, and the interpretation of these spectra was es-
tablished by H, 13C HMQC NMR experiment, which
1
helped the assignment of both proton and carbon signals
(Scheme 2).
Chin. J. Chem. 2010, 28, 594— 600
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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595

Ramadan
FULL PAPER
Scheme 2 Synthesis of D-galactohydrazonothiazole derivatives
The 13C NMR spectra of 12, 13 and 14 showed sig-
nals between δc 61.15—79.61 for the sugar carbons be-
sides signals at δc 149.45, 91.13 and a weak signal at δc
84.29 due to the C-1 of the sugar part of 12, 13 and 14.
The presence of 13 in the pyranosyl form was deduced
by comparing its 13C NMR spectrum with those of α-
and β-D-galactopyranose 15 and 16,22-24 and 1-(1β-D-
galactopyranosyl)-2-isonicotinoylhydrazine (17).25
of 13 was also based on the value of J1,2＝8.4 Hz, de-
1
duced from its H NMR spectrum, confirming a trans
relationship of H-1 with H-2. The aromatic and thiazole
carbons were resonated in the range of δc
104.46—175.28.
Table 1 13C NMR chemical shifts (δc) of the D-galactose de-
rivatives 13, 15— 17
Substitution of the hydroxyl group at C-1 of 16 with
the hydrazine residue causes a shift for all carbon sig-
nals of 13, but with a small effect on the magnitude of
chemical shifts of C-3 and C-5 because they have the
same stereochemical relationship to the anomeric C-1,
consequently C-3 and C-5 can be identified at δc 72.81
and 77.00, respectively. The C-5 in 13 resonated at al-
most a similar chemical shift to that of 17, while C-6
appeared in the highest field at δc 61.15. The lower field
signal of the two remaining signals at δc 69.44 was as-
signed to C-2, while the higher field signal at δc 68.73
was attributed to C-4. The chemical shift of the ano-
meric carbon of 13 can not be compared with those of
C-1 of 15 and 16 because it appeared at δc 91.13, but it
is very close to that of 17 confirming its β-configuration
(Table 1). The assignment of the anomeric configuration
δc
Compd.
C-1
C-2
C-3
C-4
C-5
C-6
15
93.20 70.20 69.40 70.20 71.20 62.10[22]
93.11 69.18 70.01 70.14 71.30 62.00[23]
93.10 69.10 69.80 70.20 71.20 61.90[24]
97.50 73.00 73.80 69.70 75.90 61.90[22]
97.28 72.72 73.63 69.58 75.96 61.81[23]
97.30 72.70 73.60 69.60 75.70 61.70[24]
91.83 68.75 73.61 68.38 76.58 60.55[25]
91.13 69.44 72.81 68.73 77.00 61.15
16
17
13
The 1H NMR spectrum of the equilibrium mixture of
12, 13 and 14 in DMSO-d6 containing D2O showed the
presence of two doublets at δ 7.53 and 7.69 with J＝8.4,
596
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 594— 600

Synthesis of [4-(4-Bromophenyl)-2-thiazolyl]hydrazones and their Derivatives
8.4 Hz corresponding to the aromatic protons, in addi-
tion to three singlets at δ 7.19, 7.21 and 7.59 due to the
thiazole protons. The NH protons appeared as broad
singlets at δ 10.42 and 11.97 (D2O-exchangeable). The
H-1 of 12 appeared as a doublet at δ 7.40 (J＝6.85 Hz),
which correlated with C-1 at δc 149.45, while the dou-
blet of H-1 of 13 resonated at δ 3.86 (J1,2＝8.4 Hz),
which correlated with C-1 at δc 91.13. The remainder
proton signals of 12, 13 and 14 appeared in the region of
δ 3.30—4.43, but their assignment was not possible be-
cause they were overlapped with each other and with
the solvent.
Table 2 Antimicrobial activity of the synthesized compounds
Compd.
C. albicans S. aureus E. coli P. aeruginosa
IZ MIC MBC
IZ
IZ
IZ
5a
5b
5c
5d
6a
6b
8a
8b
13 —
12 —
—
—
—
—
—
—
—
—
—
—
—
30
30
—
—
—
—
—
—
—
—
—
—
—
26
—
—
—
—
—
—
—
—
10
—
—
—
30
—
12 —
500
12 —
500
16 31
500
15 250
500
19 31
250
19 31
500
12, 13, 14
DMSO
Clotrimazole 40 —
Imipenam
Ampicillin
25 31
—
Antimicrobial activity
12 250
—
The results of the antimicrobial studies presented in
Table 2 revealed that compounds 6a, 6b, 8a, 8b, 12, 13
and 14 showed antimicrobial activity against the fungus
Candida albicans with growth inhibition zones (IZ) in
the range of 15—25 mm, minimal inhibition concentra-
tion (MIC) within 31—250 µg/mL and minimal bacteri-
cidal concentration (MBC) of 250—500 µg/mL.
— —
— —
IZ: growth inhibition zones (mm); MIC: minimum inhibitory
concentration (µg/mL); MBC: minimum bactericidal concentra-
tion (µg/mL); — No inhibition zone.
13C NMR spectra were recorded on a JEOL JNM
ECA-500 MHz spectrometer (Japan). Chemical shifts (δ)
are relative to TMS as an internal standard, and cou-
pling-constant values J are given in Hz. Microanalyses
for C, H and N were performed on an Elementar-Vario
EL Ш Element analyzer (Germany) in Cairo Univeristy.
Antimicrobial tests were measured at Pharmaceutical
Microbiology Department, Faculty of Pharmacy, Alex-
andria Univeristy.
However, they were inactive against Staphylococcus
aureus, Escherichia coli and Pseudomonas aeruginosa
except the hydrazone 8b which showed low activity
against P. aeruginosa (IZ＝10) compared to the refer-
ence imipenam (IZ＝30). The hydrazones 5a—5d were
inactive against C. albicans while the N-acetyl deriva-
tives 6a (IZ＝16) and 6b (IZ＝15) showed activity to
some extent. The most active compounds against C.
albicans were the thiazoles 8a (IZ＝19), 8b (IZ＝19)
and the equilibrium mixture of the D-galactose deriva-
tives 12, 13 and 14 (IZ＝25). It is clear that in deriva-
tives of the [4-(4-bromophenyl)-2-thiazolyl]hydrazone
series, the higher activity against C. albicans is present
in those derivatives having a sugar hydrazone moiety in
the 2-position of the thiazole nucleus. On the other hand,
the 2-alkylidene and cyclo-alkylidene derivatives 8a and
8b showed a moderate activity. The presence of various
arylmethylidenehydrazino groups in the 2-position, to-
gether with a 4-BrC6H4 in the 4-position of thiazole ring
caused a marked drop in activity against C. albicans.
However, the N-acetyl derivatives 6a and 6b showed
low activity.
Arylmethylidene/alkylidene
(2a— 2d, 7a, 7b)
thiosemicarbazones
Thiosemicarbazide (1.82 g, 20 mmol) in water (60
mL) and glacial acetic acid (1.0 mL) was warmed on a
steam bath to a clear solution, and added to an aldehyde
or ketone solution (20 mmol) in absolute ethanol (50
mL). The mixture was boiled gently for 2 h on the steam
bath and the product that separated out on cooling was
filtered, and recrystallized from EtOH.
4-Benzylidene thiosemicarbazide (2a) 3.22 g
(90%), m.p. 158—160 ℃ (Lit.26 159—160 ℃).
4-(4-Nitrobenzylidene) thiosemicarbazide (2b)
4.12 g (92%), m.p. 254—255 ℃ (Lit.26 255 ℃).
4-(4-Methoxybenzylidene) thiosemicarbazide (2c)
3.68 g (88%), m.p. 176—178 ℃ (Lit.26 177—178 ℃).
4-(2-Chlorobenzylidene) thiosemicarbazide (2d)
3.63 g (85%), m.p. 222—224 ℃ (Lit.26 223 ℃).
4-(4-Methyl-2-pentylidene) thiosemicarbazide (7a)
Experimental
Melting points were determined with a Mel-Temp
apparatus and are uncorrected. Mass spectra were re-
corded using an Electron Impact (EI) mode on a
GCMS-14A Shimadzu Gas Chromatograph-MS appa-
ratus (Japan) and Shimadzu GCMS-QP2010 Plus spec-
trometer (Japan) operating at an electron ionizing en-
ergy of 70 eV. TLC was performed on Baker-Flex silica
gel 1B-F plates using ethyl acetate-petroleum ether (V∶
V＝4∶1) and ethyl acetate-methanol (V∶V＝2∶1) as
eluents; the compounds were detected by UV light ab-
sorption. IR spectra were measured on a Shimadzu
1
2.90 g (83.7%), m.p. 79—81 ℃; H NMR (DMSO-d6)
δ: 0.81, 0.83 [2d, J＝6.9, 6.9 Hz, 6H, (CH3)2CH], 1.83
(s, 2.7H, CH3), 1.85 (s, 0.3H, CH3), 1.87—1.92 [m, 1H,
CH(CH3)2], 2.04 (d, J＝7.65 Hz, 1.8H, CH2CH), 2.25
(d, J＝7.65 Hz, 0.2H, CH2CH), 7.41 (s, 0.9H, D2O-ex-
changeable, NH), 7.52 (s, 0.1H, D2O-exchangeable,
NH), 7.94, 7.99 (2s, 1H, D2O-exchangeable, NH), 9.86
(s, 0.9H, D2O-exchangeable, SH), 9.99 (s, 0.1H,
D2O-exchangeable, SH); IR (KBr) ν: 3398.34, 3238.26,
1
FT-IR 8400 S spectrophotometer (Japan). H NMR and
Chin. J. Chem. 2010, 28, 594— 600
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Ramadan
FULL PAPER
3157.25, 1604.66, 1255.57 cm － 1. Anal. calcd for
C7H15N3S: C 48.52, H 8.73, N 24.25; found C 48.24, H
8.61, N 24.09.
N'-[4-(4-Bromophenyl)thiazol-2-yl]-N-(2-chloro-
benzylidene)hydrazine (5d)
3.30 g (84%), m.p.
1
198—200 ℃; H NMR (DMSO-d6) δ: 7.36, 7.38 (2dd,
J＝8.4, 8.4, 7.65, 7.65 Hz, 2H, Ar-H), 7.40 (s, 1H, thi-
azole-H), 7.47 (dd, J＝6.85, 1.5 Hz, 1H), 7.57 (d, J＝
8.4 Hz, 2H, Ar-H), 7.77 (d, J＝8.4 Hz, 2H, Ar-H), 7.89
(dd, J＝7.65, 2.3 Hz, 1H, Ar-H), 8.36 (s, 1H, ＝CH),
12.51 (s, 1H, D2O-exchangeable, NH); IR (KBr) ν:
4-Cyclopentylidene thiosemicarbazide (7b) 2.55
g (81%), m.p. 152—154 ℃ (Lit.26 153—154 ℃).
Aldehyde/ketone
[4-(4-bromophenyl)thiazol-2-yl]-
hydrazone (5a—5d, 8a, 8b)
＋
－1
To a suspension of compounds 2a—2d, 7a or 7b (10
mmol) in absolute ethanol (25 mL) and DMF (0.5 mL),
was added the solution of 1 (2.78 g, 10 mmol) in abso-
lute ethanol (25 mL). The mixture was heated under
reflux for 3 h on a water bath. The product that sepa-
rated out on cooling was collected by filtration and
recrystallized from EtOH/DMF.
3395.45, 1603.70 cm ; MS m/z (%): 395.05 (M ＋4,
7.99), 393.05 (M＋＋2, 27.71), 391.05 (M＋, 20.54),
256.95 (12.28), 256.00 (100.00), 255.05 (15.31), 254.00
(97.88), 213.95 (17.99), 211.95 (18.05), 184.00 (4.91),
182.00 (5.96), 176.05 (5.20), 175.10 (14.99), 174.10
(90.16), 173.15 (8.68), 148.10 (5.29), 147.10 (12.91),
146.10 (13.71), 134.05 (5.28), 133.05 (9.28), 120.05
(7.26), 111.00 (11.39), 103.05 (9.95), 102.05 (19.78),
89.05 (19.24), 76.00 (9.78), 75.00 (24.41), 74.05 (5.85),
63.00 (6.18), 51.00 (7.87), 50.00 (9.12).
N-Benzylidene-N'-[4-(4-bromophenyl)thiazol-2-
yl]hydrazine (5a) 2.79 g (78%), m.p. 196—198 ℃;
1H NMR (DMSO-d6) δ: 7.33—7.41 (m, 4H, Ar-H, thi-
azole-H), 7.57 (d, J＝8.4 Hz, 2H, Ar-H), 7.63 (d, J＝6.9
Hz, 2H, Ar-H), 7.78 (d, J＝8.4 Hz, 2H, Ar-H), 8.00 (s,
1H, ＝CH), 12.17 (s, 1H, D2O-exchangeable, NH); IR
N'-[4-(4-Bromophenyl)thiazol-2-yl]-N-(4-methyl-
2-pentylidene)hydrazine (8a) 2.82 g (80%), m.p.
180—182 ℃; 1H NMR (DMSO-d6) δ: 0.85 [d, J＝6.85
Hz, 6H, (CH3)2CH], 1.86 (s, 3H, CH3), 1.89—1.93 [m,
1H, CH(CH3)2], 2.07 (d, J＝6.9 Hz, 2H, CH2CH), 7.28
(s, 1H, thiazole-H), 7.56 (d, J＝8.4 Hz, 2H, Ar-H), 7.75
(d, J＝8.4 Hz, 2H, Ar-H), 10.73 (s, 1H, D2O-exchange-
－1
(KBr) ν: 3296.12, 156＋2.23 cm ; MS m/z (%): 359
(M＋＋2, 12.6), 357 (M , 18.2), 256 (47.0), 254 (47.5),
214 (11.2), 212 (9.5), 175 (11.6), 174 (100), 104 (16.2),
103 (28.6), 102 (14.3), 90 (10.6), 89 (27.8), 77 (75.6),
76 (15.3), 75 (18.6), 63 (19.8), 52 (12.4), 51 (63.4).
Anal. calcd for C16H12BrN3S: C 53.64, H 3.38, N 11.73;
found C 53.48, H 3.03, N 11.50.
－1
able, NH); IR (KBr) ν: 3056.96, 1602.74 cm ; MS m/z
(%): 353 (M＋＋2, 21.7), 351 (M＋, 11.6), 296 (15.7),
294 (37.9), 269 (14.6), 267 (7.6), 256 (11.1), 254 (9.6),
214 (7.1), 212 (5.6), 175 (9.6), 174 (38.4), 134 (12.6),
133 (8.6), 103 (17.2), 102 (9.1), 101 (8.1), 89 (8.1), 84
(22.7), 82 (40.9), 81 (22.7), 80 (31.3), 75 (17.2), 57
(100), 56 (11.6), 55 (13.6), 51 (18.2).
N'-[4-(4-Bromophenyl)thiazol-2-yl]-N-(4-nitroben-
zylidene)hydrazine (5b) 3.47 g (86%), m.p. 270—
1
272 ℃; H NMR (DMSO-d6) δ: 7.43 (s, 1H, thia-
zole-H), 7.56 (d, J＝8.4 Hz, 2H, Ar-H), 7.77 (d, J＝8.4
Hz, 2H, Ar-H), 7.84 (d, J＝8.4 Hz, 2H, Ar-H), 8.06 (s,
1H, ＝CH), 8.22 (d, J＝8.4 Hz, 2H, Ar-H), 12.58 (s,
1H, D2O-exchangeable, NH); IR (KBr) ν: 3292.26,
N'-[4-(4-Bromophenyl)thiazol-2-yl]-N-cyclopentyl-
idenehydrazine (8b) 2.66 g (79%), m.p. 214—216
℃ (Lit.14 213—215 ℃); H NMR (DMSO-d6) δ: 1.65
1
－1
＋
1556.45 cm ; MS m/z (%): 404 (M ＋2, 13.3), 402
(M＋, 14.8), 256 (42.6), 254 (39.9), 214 (11.3), 212
(13.7), 174 (100), 127 (71.2), 102 (13.0), 101 (3.9), 89
(19.4), 76 (33.1), 75 (20.7), 63 (17.3), 56 (69.8). Anal.
calcd for C16H11BrN4O2S: C 47.66, H 2.75, N 13.89;
found C 47.46, H 2.47, N 13.74.
(quintet, J＝6.9 Hz, 2H, CH2CH2CH2CH2), 1.73 (quin-
tet, J＝6.9 Hz, 2H, CH2CH2CH2CH2), 2.32 (t, J＝6.85
Hz, 4H, CH2CH2CH2CH2), 7.28 (s, 1H, thiazole-H),
7.56 (d, J＝8.4 Hz, 2H, Ar-H), 7.75 (d, J＝8.4 Hz, 2H,
Ar-H), 10.70 (s, 1H, D2O-exchangeable, NH); IR (KBr)
－1
ν: 3182.33, 1627.81, 1560.30 cm ; MS m/z (%): 337
(M＋＋2, 14.3), 335 (M＋, 21.9), 308 (12.4), 306 (20.0),
256 (11.1), 254 (17.8), 214 (7.9), 212 (7.3), 175 (14.3),
174 (100), 133 (12.1), 132 (14.0), 103 (13.7), 102 (13.7),
89 (29.5), 83 (33.7), 82 (65.7), 81 (18.1), 80 (40.6), 79
(14.3), 76 (17.8), 75 (14.9), 74 (10.5), 63 (14.3), 55
(63.2), 54 (52.4), 51 (13.7).
N'-[4-(4-Bromophenyl)thiazol-2-yl]-N-(4-methoxy-
benzylidene)hydrazine (5c)
3.18 g (82%), m.p.
1
208—210 ℃; H NMR (DMSO-d6) δ: 3.74 (s, 3H,
CH3O), 6.96 (d, J＝8.4 Hz, 2H, Ar-H), 7.33 (s, 1H, thi-
azole-H), 7.55, 7.57 (2d, J＝8.4, 9.15 Hz, 4H, Ar-H),
7.75 (d, J＝8.4 Hz, 2H, Ar-H), 7.98 (s, 1H, ＝CH),
11.96 (s, 1H, D2O-exchangeable, NH); IR (KBr) ν:
＋
－1
Aldhyde-N"-acetyl-N"-[4-(4-bromophenyl)thiazol-2-
3227.65, 1606.59 cm ; MS m/z (%): 389.10 (M ＋2,
22.60), 387.10 (M＋ , 22.14), 258.00 (4.83), 256.95
(12.42), 256.00 (100.00), 255.05 (15.33), 254.00 (98.28),
213.95 (16.76), 211.95 (16.76), 184.00 (4.49), 182.00
(5.72), 175.05 (9.76), 174.05 (43.06), 173.15 (5.75),
148.10 (4.85), 147.10 (7.50), 146.10 (8.68), 134.10
(21.83), 133.10 (12.41), 120.10 (9.18), 107.05 (7.08),
103.05 (7.08), 102.05 (4.96), 92.05 (17.84), 91.05 (9.14),
77.05 (24.76), 76.05 (6.90), 75.00 (5.14), 64.05 (9.81),
63.05 (8.24), 51.00 (6.75), 50.05 (4.61).
yl]hydrazone 6a, 6b
A cold solution of 5a or 5b (1.5 mmol) in dry pyri-
dine (5.0 mL) was treated with acetic anhydride (5.0 mL)
and the mixture was kept for 24 h at room temperature.
It was poured onto crushed ice and the product was fil-
tered off, washed with water, dried and recrystallized
from EtOH.
N"-Aceto-N'-benzylidene-N"-[4-(4-bromophenyl)-
thiazol-2-yl]hydrazine (6a) 0.45 g (75%), m.p. 174—
598
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 594— 600

Synthesis of [4-(4-Bromophenyl)-2-thiazolyl]hydrazones and their Derivatives
－1
176 ℃; 1H NMR (DMSO-d6) δ: 2.48 (s, 3H, N-
COCH3), 7.47—7.51 (m, 3H, Ar-H), 7.61 (d, J＝8.4 Hz,
2H, Ar-H), 7.80—7.83 (m, 4H, Ar-H), 8.11 (s, 1H, thi-
azole-H), 8.76 (s, 1－H, ＝CH); IR (KBr) ν＋: 1685.67,
IR (KBr) ν: 3334.69, 1620.09 cm . Anal. calcd for
C15H18BrN3O5S: C 41.68, H 4.20, N 9.72; found C
41.79, H 4.47, N 9.63.
1
Antimicrobial testing
1602.74, 1529.45 cm ; MS m/z (%): 401 (M ＋2, 9.4),
399 (M＋, 10.6), 360 (11.7), 359 (54.8), 358 (23.8), 357
(66.7), 356 (9.2), 256 (37.3), 254 (29.2), 214 (12.4), 212
(11.5), 175 (10.8), 174 (69.4), 134 (11.9), 133 (10.3),
104 (33.0), 103 (37.8), 102 (8.8), 101 (10.1), 90 (100),
89 (76.0), 78 (16.2), 77 (93.0), 76 (40.0), 75 (26.3), 63
(33.3), 52 (16.6), 51 (91.7), 50 (36.0). Anal. calcd for
C18H14BrN3OS: C 54.01, H 3.53, N 10.50; found C
53.72, H 3.09, N 10.43.
The tested compounds were evaluated by an agar
diffusion technique,27 using a 1 g/L solution in DMSO.
The test strains and strain numbers were C. albicans
(ATCC 2091), S. aureus (ATCC 6538P), E. coli (ATCC
8739) and P. aeruginosa (ATCC 9027). Each tested
organism was subcultured in 3 mL of sterile nutrient
broth and incubated for 18 h at 37 ℃. Aspetically 0.4
mL was taken by a glass pipette from the resultant mi-
crobial growth onto 40 mL of warm agar in one sterile
flask for each organism. The seeded agar was poured
onto sterile Petri dishes (15 cm in diameter) onto a level
surface to obtain a layer of about 4 mm thickness and
the plates were then left to solidify. Cups of 8 mm in
diameter were made by a cork borer, each was then
filled with 65 µL of the compound at different concen-
trations and one cup filled by solvent as control. The
plates were then incubated at 37 ℃ for 24 h. The di-
ameter of each resultant inhibition zone (IZ) was accu-
rately measured in three different directions and its av-
erage was calculated. DMSO as a blank showed no
growth inhibition zones against S. aureus, E. coli and P.
aeruginosa, while against C. albicans it showed inhibi-
tion zone of 12 mm. The minimal inhibitory concentra-
tion (MIC) and minimal bactericidal concentration
(MBC) of the tested compounds were measured using a
broth dilution method.28 Reference standards were
clotrimazole (0.01 g/mL) for C. albicans, ampicillin (10
mcg/disc) for S. aureus and imipenam (10 mcg/disc) for
E. coli, P. aeruginosa and S. aureus.
N"-Aceto-N"-[4-(4-bromophenyl)thiazol-2-yl]-N'-
(4-nitrobenzylidene)hydrazine (6b) 0.53 g (79%),
m.p. 260—262 ℃; 1H NMR (DMSO-d6) δ: 2.54 (s, 3H,
N-COCH3), 7.62 (d, J＝8.4 Hz, 2H, Ar-H), 7.86 (d, J＝
8.4 Hz, 2H, Ar-H), 8.07 (d, J＝8.4 Hz, 2H, Ar-H), 8.27
(d, J＝8.4 Hz, 2H, Ar-H), 8.28 (s, 1H, thiazole-H), 8.73
(s, －1H, ＝CH); IR (KBr) ν:＋1693.38, 1579.59, 1515.94
＋
1
cm ; MS m/z (%): 446 (M ＋2, 11.0), 444 (M , 7.5),
404 (55.9), 402 (55.9), 256 (16.7), 254 (26.7), 214 (9.6),
212 (13.9), 175 (14.6), 174 (87.9), 103 (34.5), 102
(16.7), 101 (16.0), 90 (15.7), 89 (79.7), 77 (15.7), 76
(100), 75 (63.3), 74 (27.4), 63 (54.8), 51 (39.1). Anal.
calcd for C18H13BrN4O3S: C 48.55, H 2.94, N 12.58;
found C 48.53, H 3.24, N 12.54.
D-Galactose thiosemicarbazones 9, 10 and 11
A solution of D-galactose (3.60 g, 20 mmol) in water
(5.0 mL) was treated with a solution of thiosemicarba-
zide (1.82 g, 20 mmol) in ethanol (50 mL) and glacial
acetic acid (1.0 mL). The mixture was heated under re-
flux for 2 h on a water bath. The product that separated
out on cooling was filtered and recrystallized from
EtOH; 4.15 g (82%), m.p. 154—156 ℃; IR (KBr) ν:
3369.41, 3211.26, 1620.09, 1261.30, 1060.78, 867.91
References
－1
1
Todorova, A. K.; Juettner, F.; Linden, A.; Pluess, T.; von
Philipsborn, W. J. Org. Chem. 1995, 60, 7891.
Moody, C. J.; Bagley, M. C. Synlett 1996, 1171.
Toogood, P. L.; Hollenbeck, J. J.; Lam, H. M.; Li, L. Bioorg.
Med. Chem. Lett. 1996, 6, 1543.
Martin, B. J.; Clough, J. M.; Pattenden, G.; Waldron, I. R.
Tetrahedron Lett. 1993, 34, 5151.
Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473.
Pettit, G. R.; Kamano, Y.; Brown, P.; Gust, D.; Inoue, M.;
Herald, C. L. J. Am. Chem. Soc. 1982, 104, 905.
Wipf, P. Chem. Rev. 1995, 95, 2115.
Hamada, Y.; Kohda, K.; Shioiri, T. Tetrahedron Lett. 1984,
25, 5303.
Bertram, A.; Blake, A. J.; Gonzalez-Lopez de Turiso, F.;
Hannam, J. S.; Jolliffe, K. A.; Pattenden, G.; Skae, M. Tet-
rahedron 2003, 59, 6979.
cm . Anal. calcd for C7H15N3O5S: C 33.19, H 5.97, N
16.59; found C 32.95, H 5.66, N 16.29.
2
3
D-Galactose [4-(4-bromophenyl)thiazol-2-yl]hydra-
zone (12), 1-[4-(4-bromophenyl)thiazol-2-yl]-2-(β-D-
galactopyranosyl)hydrazine (13) and 1-[4-(4-bromo-
phenyl)thiazol-2-yl]-2-(α or β-D-galactofuranosyl)-
hydrazine (14)
4
5
6
To a suspension of compounds 9, 10 and 11 (2.53 g,
10 mmol) in absolute ethanol (25 mL) was added the
solution of 1 (2.78 g, 10 mmol) in absolute ethanol (25
mL). The mixture was heated under reflux for 3 h on a
water bath. The product that separated out on cooling
was recrystallized from EtOH. 3.36 g (77.8%), m.p.
165—168 ℃; 1H NMR (DMSO-d6＋D2O) δ: 3.86 (d,
J1,2＝8.4 Hz, H-1β pyranosyl), 7.19, 7.21, 7.59 (3s, thi-
azole-H), 7.40 (d, J＝6.85 Hz, H-1 acyclic), 7.53 (d, J＝
8.4 Hz, Ar-H), 7.69 (d, J＝8.4 Hz, Ar-H), 10.42, 11.97
(2brs, D2O-exchangeable, NH); 13C NMR (DMSO-d6)
δc: 61.15, 62.28, 63.49, 68.47, 68.73, 69.44, 70.15,
70.62, 72.81, 72.93, 74.42, 77.00, 79.61, 84.29, 91.13,
149.45 (sugar-C), 104.46—175.28 (Ar-C, thiazole-C);
7
8
9
10 Mazzone, G.; Pignatello, R.; Panico, A.; Mazzone, S.; Pug-
lisi, G.; Pennis, G.; Raciti, G.; Mazzone, P.; Matera, M.
Pharmazie 1992, 47, 902.
11 Holla, B. S.; Malini, K. V.; Rao, B. S.; Sarojini, B. K.;
Kumari, N. S. Eur. J. Med. Chem. 2003, 38, 313.
Chin. J. Chem. 2010, 28, 594— 600
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
599

Ramadan
FULL PAPER
12 Maccioni, E.; Cardia, M. C.; Bonsignore, L.; Plumitallo, A.;
Pellerano, M. L.; De Logu, A. II Farmaco 2002, 57, 809.
13 Babadjamian, A.; Gallo, R.; Metzger, J.; Chanon, M. J.
Heterocycl. Chem. 1976, 13(6), 1205.
14 Chimenti, F.; Bizzarri, B.; Maccioni, E.; Secci, D.; Bolasco,
A.; Fioravanti, R.; Chimenti, P.; Granese, A.; Carradori, S.;
Rivanera, D.; Lilli, D.; Zicari, A.; Distinto, S. Bioorg. Med.
Chem. Lett. 2007, 17(16), 4635.
1984, 135(1), 13.
20 Barker, S. A.; Bourne, E. J.; Stephens, R.; Whiffen, D. H. J.
Chem. Soc. 1954, 3468.
21 Holker, J. R. Chem. Ind. (London) 1964, (13), 546.
22 Laffite, C.; Nguyen Phuoc Du, A. M.; Winternitz, F.; Wylde,
R. Carbohydr. Res. 1978, 67(1), 105.
23 Archbald, P. J.; Fenn, M. D.; Roy, A. B. Carbohydr. Res.
1981, 93(2), 177.
15 Takeda, Y. Carbohydr. Res. 1979, 77(1), 9.
16 Williams, J. M. Carbohydr. Res. 1983, 117, 89.
17 Kett, W. C.; Batley, M.; Redmond, J. W. Carbohydr. Res.
1997, 299(3), 129.
24 Szurmai, Z.; Liptak, A. Carbohydr. Res. 1982, 107(1), 33.
25 Bailey, K.; Butterfield, A. G. Can. J. Chem. 1981, 59, 641.
26 Sah, P. P. T.; Daniels, T. C. Rev. Trav. Chim. 1950, 69,
1545.
18 El Ashry, E. S. H.; Awad, L. F.; Abdul Ghani, M.; Atta, A. I.
ARKIVOC 2005, XV, 97.
19 Chavis, C.; De Gourcy, C.; Imbach, J.-L. Carbohydr. Res.
27 Jain, S. R.; Kar, A. Planta Med. 1971, 20(2), 118.
28 Ericsson, H. M.; Sherris, J. C. Acta Pathol. Microbiol.
Scand B. Microbiol. Immunol. 1971, 217(Suppl.), 1.
(E0908101 Pan, B.; Dong, H.)
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 594— 600