Synthesis and antimicrobial activity of a new class of methyleneamine- linked bis-heterocycles

Article abstract of DOI:10.1002/jhet.638

A new class of methyleneamine-linked bis-heterocycles that exhibit antimicrobial activity was synthesized. Bromination of 1 followed by condensation with thiourea gave 3. The reaction of 3 with propargyl bromide in dry toluene under inert atmosphere led to the formation of 4. Its subsequent reaction with different aromatic azides 5 using CuSO₄.5H ₂O-sodiumascorbate system in a 2:1 mixture of water and tert-butylalcohol yielded the title compounds 6a-j in good yields. The identities of these compounds were confirmed following elemental analysis, IR, ¹H, ¹³C NMR, and mass spectral studies. All the title compounds exhibited pronounced in vitro antibacterial and antifungal activities.

Full text of DOI:10.1002/jhet.638

September 2011
Synthesis and Antimicrobial Activity of a New Class of
Methyleneamine-Linked bis-Heterocycles
1175
A. Babul Reddy, R. V. Hymavathi, T. Chandrasekhar,
M. Naveen, and G. Narayana Swamy*
Department of Chemistry, Sri Krishnadevaraya University, Anantapur,
Andhra Pradesh 515055, India
*E-mail: narayanaswamy.golla@gmail.com
Received May 15, 2010
DOI 10.1002/jhet.638
Published online 9 June 2011 in Wiley Online Library (wileyonlinelibrary.com).
A new class of methyleneamine-linked bis-heterocycles that exhibit antimicrobial activity was synthe-
sized. Bromination of 1 followed by condensation with thiourea gave 3. The reaction of 3 with propar-
gyl bromide in dry toluene under inert atmosphere led to the formation of 4. Its subsequent reaction
with different aromatic azides 5 using CuSO4.5H2O-sodiumascorbate system in a 2:1 mixture of water
and tert-butylalcohol yielded the title compounds 6a–j in good yields. The identities of these com-
1
pounds were confirmed following elemental analysis, IR, H, 13C NMR, and mass spectral studies. All
the title compounds exhibited pronounced in vitro antibacterial and antifungal activities.
J. Heterocyclic Chem., 48, 1175 (2011).
INTRODUCTION
studied [7]. Hence, it is thought that a worthwhile pro-
gramme would be required to prepare molecules having
both triazole and thiazole rings through the most popular
method following 1,3-dipolar Huisgen cycloaddition
reaction of azides with alkynes [1a,8]. However, the
early Huisgen cycloaddition process needs a strong elec-
tron-withdrawing substituent either on azide or on
alkyne and was often conducted at high temperature for
a prolonged period of time and usually led to the isola-
tion of mixture of 1,4- and 1,5-disubstituted-1,2,3-tria-
zoles [1e,8]. The discovery that Cu(I) efficiently and
regiospecifically unites terminal alkynes and aromatic
azides, providing 1,4-disubstituted 1,2,3-triazoles under
mild condition, was a welcome advance [9]. There are
several reports in the literature for the synthesis of vari-
ous combinations of bis-heterocycles, but no reports are
available for the synthesis of bis-heterocycles encom-
passing 1,2,3-triazole and thiazole moieties. We, there-
The development of simple, facile, and efficient syn-
thetic methods for the synthesis of five-membered het-
erocycles from readily available reagents is one of the
major challenges in organic synthesis. Among five-
membered heterocycles, triazole and thiazole represent a
class of compounds of great importance in biological
chemistry. For instance, 1,2,3-triazole derivatives have
received much attention because of their wide range of
applications [1] as agents of anti-HIV [2], antimicrobial
[3], and b3-adrenergic antagonists [4]. Thiazole deriva-
tives are gaining interest in recent years due to their
broad spectrum of biological activities and molecules
containing thiazole ring system are extensively found in
the field of agrochemicals [5] in the synthesis of com-
mercial agricultural fungicides, trifluzamide, and etha-
boxam [6]. Because of their low toxicity, excellent bio-
logical activity as well as access of diverse derivatives,
this class of N-hetero cyclic derivatives is widely
fore, followed
a
convenient and regiocontrolled
C
V
2011 HeteroCorporation

1176
A. B. Reddy, R. V. Hymavathi, T. Chandrasekhar, M. Naveen, and G. N. Swamy
Vol 48
Table 1
Synthesis of methyleneamine-linked bis-heterocycles.
Entry
N-Substituted propargyl amine
Azide
bis-Heterocyclea
Reaction time (h)
23
Yield (%)
1
2
3
85b
78b
81b
26
24
4
21
87b
5
26
90b
(Continued)
Journal of Heterocyclic Chemistry
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September 2011
Synthesis and Antimicrobial Activity of a New Class
of Methyleneamine-Linked bis-Heterocycles
1177
Table 1
(Continued)
Entry
6
N-Substituted propargyl amine
Azide
bis-Heterocyclea
Reaction time (h)
28
Yield (%)
95b
7
23
89b
8
26
81b
9
32
78b
10
27
82b
a All products were characterized by IR, 1H, 13C NMR, and mass spectrometry.
b Yields obtained after recrystallization.
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DOI 10.1002/jhet

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A. B. Reddy, R. V. Hymavathi, T. Chandrasekhar, M. Naveen, and G. N. Swamy
Vol 48
mole) in acetic acid (15 mL) was added dropwise during 20
min. Stirring was continued for ꢃ24 h, the separated solid was
filtered and recrystallized from 95% ethanol to furnish 2 at an
yield 86%. To this intermediate 2 (4 g, 0.017mole) in ethanol
(30 mL), thiourea (2 g, 0.026 mole) was added and refluxed
for 8 h, and the reaction progress was monitored by TLC. The
solvent was evaporated under reduced pressure, and solid was
recrystallized from 95% ethanol to get sharp crystals of 3
(79%). To a solution of 3 (2 g, 0.0069 mole) in dry toluene
(10 mL), a cooled solution of propargyl bromide (0.99 g,
0.0083 mole) was added dropwise in the presence of K2CO3
(1.15 g, 0.0083 mole) under nitrogen atmosphere. The reaction
mixture was refluxed on water bath at 110ꢂC for 8 h, and the
reaction progress was monitored by TLC. The toluene and pro-
pargyl bromide were removed by distillation, and the residue
was washed with sodium bicarbonate (5% w/v) followed by
cold water. The crude product was dried and recrystallized
from 95% ethanol to get crystals of 4 (89%).
To a well-stirred solution of 4 (1 g, 0.003 mole), in 5 mL of
tertiary butanol and water mixture (1:1), copper sulphate
(0.004 mole), and sodium ascarbate (0.28 mole) were added.
After 15 min, aromatic azide 5 (0.055 mmole) was added to
the above reaction mixture and allowed to stir for 28–32 h.
The reaction progress was monitored by TLC. The resulting
mixture was diluted with water and extracted with ethyl ace-
tate (2 ꢄ 20 mL). The organic layer was dried over anhydrous
sodium sulphate and evaporated under reduced pressure to
afford a crude product, which on recrystallization using
EtOAc/hexane yielded crystalline solids 6a–j.
approach for the synthesis of new class of triazole-based
bis-heterocycles.
RESULTS AND DISCUSSION
Bromination of the ketone 1 followed by condensation
with thiourea in ethanol or methanol gave rise to the 4,5-
diaryl-2-aminothiazole derivative 3. Reaction of 3 with
propargyl bromide at room temperature under dry and
inert conditions in the presence of potassium carbonate
afforded the corresponding N-substituted propargyl
amines 4. Further reaction of 4 with different aromatic
azides 5 using CuSO4ꢀ5H2O-sodiumascorbate system in a
2:1 mixture of water and tert-butylalcohol led to the for-
mation of 6a–j in good yields. The reactions were moni-
tored by thin-layer chromatography. The chemical struc-
tures of 6a–j were confirmed by elemental analysis and
1
spectral data (IR, H, 13C NMR, and mass spectra).
Characteristic IR absorption bands were observed for
CAN, NAN, N¼¼N, C¼¼N, CAS, and NH at 1030–
1083, 1405–1476, 1537–1580, 1515–1689, 610–710, and
3248–3389 cmꢁ1, respectively [10]. The aromatic hydro-
gens resonated as multiplets at d 6.89–8.12. The forma-
tion of bis-heterocycles has been unequivocally estab-
lished through the characteristic chemical shift value of
the triazole proton (5-CH) at d ¼ 8.30–8.38 in contrast
to the appearance of 4-CH signal at d ¼7.50–7.75 in the
case of 1,5-disubstituted triazoles [10]. The yields were
higher when the azides contained electron-donating
groups (6d, 6e, and 6f; Table 1).
[4-(4-Chlorophenyl)-5-phenyl-thiazol-2-yl]-(1-phenyl-1H-[1,2,
3]triazol-4-ylmethyl)-amine (6a). M.p. 186–187ꢂC; 1H NMR
(DMSO-d6): d 8.32 (1H, s, CH), 7.96–6.98 (14H, m, Ar-H),
4.58 (2H, s, CH2), 4.21 (1H, brs, NH); 13C NMR data: 173.3,
158.1, 149.5, 137.3, 135.4, 133.1, 132.8, 129.4, 129.0, 128.5,
128.1, 127.0, 103.2, 53.6; IR (KBr) cmꢁ1: 3315, 2980, 2875,
2369, 1571, 1434, 1383, 1139, 1025, 868; LCMS m/z: 444
(Mþþ1); Anal. Calcd. for C24H18ClN5S: C, 64.93; H, 4.09; N,
15.79; S, 7.29. Found C, 64.87; H, 4.01; N, 15.72; S, 7.22.
[4-Phenyl-5-(4-chlorophenyl)-thiazol-2-yl]-(1-phenyl-1H-[1,
EXPERIMENTAL
All melting points were determined in open capillary tubes
on Mel-Temp apparatus (Laboratory Devices, Cambridge,
1
2,3]triazol-4-ylmethyl)-amine (6b). M.p. 202–203ꢂC; H NMR
MA), and are uncorrected. Infrared spectra (umax in cmꢁ1
)
(DMSO-d6): d 8.30 (1H, s, CH), 7.94–6.91 (14H, m, Ar-H),
4.52 (2H, s, CH2), 4.22 (1H, brs, NH); 13C NMR data: 173.5,
158.7, 149.1, 137.2, 135.6, 133.0, 132.2, 129.5, 129.0, 128.3,
128.1, 127.0, 103.2, 53.6; IR (KBr) cmꢁ1: 3325, 2986, 2871,
2363, 1579, 1437, 1385, 1142, 1026, 869; LCMS m/z: 444
(Mþþ1); Anal. Calcd. for C24H18ClN5S: C, 64.93; H, 4.09; N,
15.79; S, 7.29. Found C, 64.88; H, 4.04; N, 15.73; S, 7.26.
[4-(4-Bromophenyl)-5-phenyl-thiazol-2-yl]-(1-phenyl-1H-[1,2,
3]triazol-4-ylmethyl)-amine (6c). M.p. 231–233ꢂC; 1H NMR
(DMSO-d6): d 8.38 (1H, s, CH), 8.11–7.28 (14H, m, Ar-H),
4.43 (2H, s, CH2), 4.27 (1H, brs, NH); 13C NMR data: 176.9,
160.2, 153.5, 148.6, 143.1, 140.3, 137.5, 133.1, 132.0, 129.4,
129.0, 103.2, 52.3; IR (KBr) cmꢁ1: 3248, 2987, 2346, 1568,
1467, 1324, 1191, 1065, 976, 875; LCMS m/z: 487 (Mþ), 488
(Mþþ1); Anal. Calcd. for C24H18BrN5S: C, 59.02; H, 3.78; N,
14.34; S, 6.60. Found C, 59.02; H, 3.71; N, 14.28; S, 6.57.
[4-(4-Chlorophenyl)-5-phenyl-thiazol-2-yl]-(1-p-tolyl-1H-[1,2,
3]triazol-4-ylmethyl)-amine (6d). M.p. 191.5–193ꢂC; 1H NMR
(DMSO-d6): d 8.35 (1H, s, CH), 7.99–6.89 (13H, m, Ar-H),
4.51 (2H, s, CH2), 4.19 (1H, brs, NH), 2.73 (3H, s, CH3); 13C
NMR data: 175.1, 159.3, 153.8, 149.2, 144.2, 141.6, 137.0,
were recorded as KBr pellets on a Perkin-Elmer 283 double-
beam spectrophotometer. 1H and 13C NMR spectra were
recorded on ABX 400 MHz spectrophotometer operating at
400 MHz for 1H NMR, and 100 MHz for 13C NMR using
DMSO-d6 as solvent. The 1H and 13C NMR chemical shifts
were referenced to tetra methyl silane.
Typical experimental procedures.
Preparation of aromatic azides. Aromatic aniline (5 g,
0.0537 mole) dissolved in concentrated HCl or H2SO4 and
kept in ice bath at 0–5ꢂC. In another flask, NaNO2 (7.4 g,
0.1074 mole) was dissolved in water, cooled to 0ꢂC, and added
to aniline in acid at 0ꢂC that resulted change in color of the
reaction mixture. A mixture of NaN3 (13.9 g, 0.2148 mole)
and sodium acetate (44 g, 0.537 mole) in crushed ice at 0ꢂC
was added slowly to the above reaction mixture. The resulting
precipitate was filtered and dried.
[4-(4-Substitutedphenyl)-5-(4-substitutedphenyl)-thiazol-2-yl]-
(1-substitutedphenyl-1H-[1,2,3]triazol-4-ylmethyl)-amine 6a–
j. To a well-stirred solution of ketone 1 (8 g, 0.035 mole) in
acetic acid (70 mL), a solution of bromine (5.57 g, 0.035
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis and Antimicrobial Activity of a New Class
of Methyleneamine-Linked bis-Heterocycles
1179
Table 2
Antibacterial activity (MIC) of 6a–j.
Antibacterial activity (MIC, lg mLꢁ1
)
Compound
P. aeruginosa
S. aureus
E. coli
S. faecalis
P. acnes
6a
6b
6c
6d
6e
6f
6g
90
75
40
75
50
25
20
22
75
50
12
90
75
40
50
–
90
–
90
75
75
75
75
25
20
22
30
25
12
90
75
75
50
50
25
20
22
30
25
12
40
75
75
25
20
22
30
25
12
25
20
22
50
50
12
6h
6i
6j
Ciprofloxacin
MIC, minimum inhibition concentration.
132.7, 132.0, 129.5, 129.1, 104.8, 51.3, 22.9; IR (KBr) cmꢁ1
:
Calcd. for C24H17Cl2N5S: C, 60.25; H, 3.58; N, 14.64; S, 6.70.
Found C, 60.38; H, 3.52; N, 14.72; S, 6.76.
3389, 2976, 2391, 1515, 1409, 1312, 1176, 1034, 987, 799;
LCMS m/z: 458 (Mþþ1); Anal. Calcd. for C25H20ClN5S: C,
65.60; H, 4.43; N, 15.32; S, 7.01. Found C, 65.56; H, 4.40; N,
15.29; S, 7.00.
[4-(4-Chlorophenyl)-5-phenyl-thiazol-2-yl]-[1-(4-nitrophenyl)-
1H-[1,2,3]triazol-4-ylmethyl]-amine (6i). M.p. 212–213ꢂC; 1H
NMR (DMSO-d6): d 8.38 (1H, s, CH), 8.12–7.19 (13H, m, Ar-
H), 4.59 (2H, s, CH2), 4.27 (1H, brs, NH); 13C NMR data:
178.1, 162.3, 160.5, 158.3, 149.9, 138.0, 137.2, 136.5, 133.7,
129.0, 127.5, 124.6, 115.6, 54.9; IR (KBr) cmꢁ1: 3309, 2987,
2365, 1591, 1434, 1398, 1039, 982, 834; LCMS m/z: 489
(Mþþ1); Anal. Calcd. for C24H17Cl2N6O2S: C, 58.95; H, 3.50;
N, 17.19; S, 6.56. Found C, 58.95; H, 3.57; N, 17.32; S, 6.61.
[4-(4-Chlorophenyl)-5-phenyl-thiazol-2-yl]-[1-(2-nitrophenyl)-
1H-[1,2,3]triazol-4-ylmethyl]-amine (6j). M.p. 190–192ꢂC; 1H
NMR (DMSO-d6): d 8.32 (1H, s, CH), 8.03–7.38 (13H, m, Ar-
H), 4.62 (2H, s, CH2), 4.31 (1H, brs, NH); 13C NMR data:
178.4, 162.6, 161.0, 158.7, 149.8, 139.0, 137.2, 136.5, 133.3,
129.2, 127.7, 123.8, 114.6, 53.9; IR (KBr) cmꢁ1: 3312, 2994,
2363, 1590, 1431, 1389, 1037, 984, 839; LCMS m/z: 489
(Mþþ1); Anal. Calcd. for C24H17Cl2N6O2S: C, 58.95; H, 3.50;
N, 17.19; S, 6.56. Found C, 58.99; H, 3.58; N, 17.34; S, 6.69.
Antibacterial activity. Thiazole and triazole derivatives are
known to be potent antimicrobial agents [11–13]. The
[4-(4-Chlorophenyl)-5-phenyl-thiazol-2-yl]-(1-o-tolyl-1H-[1,2,
3]triazol-4-ylmethyl)-amine (6e). M.p. 170–172.5ꢂC; 1H NMR
(DMSO-d6): d 8.33 (1H, s, CH), 7.96–6.91 (13H, m, Ar-H),
4.52 (2H, s, CH2), 4.21 (1H, brs, NH), 2.71 (3H, s, CH3); 13C
NMR data: 174.9, 159.1, 153.6, 149.2, 144.6, 141.1, 137.5,
132.8, 132.2, 129.5, 129.2, 104.6, 51.1, 22.4; IR (KBr) cmꢁ1
:
3392, 2979, 2392, 1519, 1419, 1318, 1179, 1035, 988, 801;
LCMS m/z: 458 (Mþþ1); Anal. Calcd. for C25H20ClN5S: C,
65.60; H, 4.43; N, 15.32; S, 7.01. Found C, 65.58; H, 4.41; N,
15.28; S, 7.05.
[4-(4-Chlorophenyl)-5-phenyl-thiazol-2-yl]-[1-(4-methoxyphenyl)-
1H-[1,2,3]triazol-4-ylmethyl]-amine (6f). M.p. 139–141ꢂC; 1H
NMR (DMSO-d6): d 8.32 (1H, s, CH), 7.92–7.09 (13H, m, Ar-
H), 4.63 (2H, s, CH2), 4.21 (1H, brs, NH), 3.93 (3H, s,
OCH3); 13C NMR data: 174.2, 165.8, 151.0, 145.3, 136.5,
136.0, 130.7, 129.3, 128.6, 127.1, 114.8, 58.3, 52.9; IR (KBr)
cmꢁ1: 3298, 2985, 2843, 2371, 1579, 1489, 1388, 1071, 835;
LCMS m/z: 474 (Mþþ1); Anal. Calcd. for C25H20ClN5OS: C,
63.35; H, 4.23; N, 14.78; S, 6.77. Found C, 63.36; H, 4.21; N,
14.79; S, 6.70.
Table 3
[4-(4-Chlorophenyl)-5-phenyl-thiazol-2-yl]-[1-(4-chlorophenyl)-
1
Antifungal activity of 6a–j.
1H-[1,2,3]triazol-4-ylmethyl]-amine (6g). M.p. 271–271.5ꢂC; H
NMR (DMSO-d6): d 8.37 (1H, s, CH), 8.02–7.27 (13H, m, Ar-
H), 4.57 (2H, s, CH2), 4.17 (1H, brs, NH); 13C NMR data:
176.7, 162.8, 160.3, 157.0, 149.3, 138.9, 136.5, 133.1, 129.3,
128.5, 123.1, 114.6, 52.9; IR (KBr) cmꢁ1: 3318, 2935, 2341,
1581, 1478, 1368, 1011, 879; LCMS m/z: 479 (Mþþ1); Anal.
Calcd. for C24H17Cl2N5S: C, 60.25; H, 3.58; N, 14.64; S, 6.70.
Found C, 60.36; H, 3.50; N, 14.69; S, 6.73.
[4-(4-Chlorophenyl)-5-phenyl-thiazol-2-yl]-[1-(2-chlorophenyl)-
1H-[1,2,3]triazol-4-ylmethyl]-amine (6h). M.p. 168–169ꢂC; 1H
NMR (DMSO-d6): d 8.35 (1H, s, CH), 8.01–7.26 (13H, m, Ar-
H), 4.53 (2H, s, CH2), 4.19 (1H, brs, NH); 13C NMR data:
175.9, 162.9, 160.5, 157.6 , 149.1, 138.6, 135.8, 133.7, 129.6,
127.5, 124.1, 115.6, 52.7; IR (KBr) cmꢁ1: 3323, 2937, 2348,
1578, 1471, 1361, 1015, 882; LCMS m/z: 479 (Mþþ1); Anal.
Zone of inhibition (in mm)
Compound
C. albicans
A. niger
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
12
19
14
14
12
28
14
11
09
13
27
10
17
16
16
14
17
13
12
11
25
19
Clotrimazole (10 lg cupꢁ1
)
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DOI 10.1002/jhet

1180
A. B. Reddy, R. V. Hymavathi, T. Chandrasekhar, M. Naveen, and G. N. Swamy
Vol 48
Meldal, M. J Org Chem 2002, 67, 3057; (e) Kamijo, S.; Jin, T.; Huo,
Z.; Yamamoto, Y. J Org Chem 2004, 69, 2386.
compounds synthesized in the present study (6a through 6j)
were, therefore, screened for their antibacterial activity against
human pathogenic bacteria such as Pseudomonas aeruginosa,
Staphylococcus aureus, Escherichia coli, Streptococcus faeca-
lis, and Propionibacterium acnes. The minimum inhibition
concentration was determined using the dilution method [14].
DMF was used as a blank and Ciprofloxacin as standard, and
the results are presented in Table 2.
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Of the 10 compounds, 6f to 6h exhibited pronounced antibac-
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albicans and Aspergillus niger using fungicide Clotrimazole in
DMF as the standard [15]. All the compounds exhibited mod-
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the reference compound. Most of the compounds exerted high
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