A new route for the synthesis of 4-arylacetamido-2-aminothiazoles and their biological evaluation

Article abstract of DOI:10.1515/znb-2015-0013

A series of 4-arylacetamido-2-amino- and 2-arylamino-1,3-thiazoles (4a-o) were synthesized in a single step in high yields from ?-bromoacetoacetanilides and thiourea/phenyl thioureas and were characterized by spectral and analytical methods. The compounds were evaluated for their in vitro antibacterial antifungal and antioxidant activities. In vitro antimicrobial evaluation of these compounds indicated their specificity towards Gram-positive species. p-Tolyl and m-chlorophenyl substituents on the arylamino moiety (compounds 4b and 4g) exhibited the lowest minimum inhibitory concentration values. The other compounds exhibited promising antimicrobial and moderate antioxidant activity.

Full text of DOI:10.1515/znb-2015-0013

Z. Naturforsch. 2015; 70(7)b: 483–489
Madhura V., Hrishikesh M. Revankar and Manohar V. Kulkarni*
A new route for the synthesis of 4-arylacetamido-
2-aminothiazoles and their biological evaluation
Abstract:
A series of 4-arylacetamido-2-amino- and with a methoxyimino function at C-4 forms part of cefo-
2-arylamino-1,3-thiazoles (4a–o) were synthesized in a taxime [13]. 2-Aminothiazole-4-carboxylates and carbox-
single step in high yields from ω-bromoacetoacetanilides amides have been reported to exhibit potent antimicrobial
and thiourea/phenyl thioureas and were characterized by activity (Fig. 1) [14].
spectral and analytical methods. The compounds were
It is also pertinent to mention that the amides reported
evaluated for their in vitro antibacterial antifungal and in the literature were prepared by the two-step route [12]
antioxidant activities. In vitro antimicrobial evaluation involving the synthesis of thiazole esters or acids 5 fol-
of these compounds indicated their specificity towards lowed by amidation. In the present paper, we describe
Gram-positive species. p-Tolyl and m-chlorophenyl sub-
a single-step synthesis of 4-arylacetamido-2-amino-
stituents on the arylamino moiety (compounds 4b and 1,3-thiazoles by the reaction of ω-bromoacetoacetanilide
4g) exhibited the lowest minimum inhibitory concentra- and thioureas through route B (Fig. 2). Retrosynthetic
tion values. The other compounds exhibited promising analysis (Fig. 2) shows that the target molecules can be
antimicrobial and moderate antioxidant activity.
obtained by a two-step route (A) through intermediate
2-amino-1,3-thiazole-4-acetic acid esters 5, which have
Keywords: antimicrobial activity; antioxidant; 4-arylacet- been reported earlier in the literature [5, 6, 12]. A similar
amido-2-amino-1,3-thiazole;
phenyl thiourea.
ω-bromoacetoacetanilide; method has been reported, where morpholine derivatives
of 1,3-thiazole were synthesized and found to function as
ion channel modulators [15]. This route requires amida-
tion of the intermediate esters 5. The steps involved in the
DOI 10.1515/znb-2015-0013
Received January 15, 2015; accepted February 6, 2015
synthesis are outlined in Scheme 1.
2 Results and discussion
ω-Bromoacetoacetanilides 2 were prepared by the bromi-
1 Introduction
The 1,3-thiazole nucleus has been a seat of diverse bio- nation of acetoacetanilides 1 [16] and were refluxed with
logical activities through its innumerable derivatives equimolar quantities of phenyl thioureas 3 [17] in ethanol
[1–4]. 2,4- and 2,5-disubstituted thiazoles have exhibited to obtain the target compounds in a single step. Suffi-
promising anti-inflammatory, analgesic and antipyretic ciently pure compounds were obtained in good yields and
activities [5–9]. Cystothiazoles isolated from the Cys- the structures were confirmed by spectral methods.
tobacter fuscus have been reported for their selective,
As a typical case, compound 4b (R ꢀ=ꢀ 4-CH3, R′ ꢀ=ꢀ H)
broad-spectrum antifungal activity without affecting the gave an IR spectrum which exhibited NH–Ar stretching
bacterial growth [10]. Arylamides from 2-amino-1,3-thi- frequency at 3299 cm , amide NH at 3392 cm−1 and amide
−1
azoles have been reported as antiviral agents [11]. The carbonyl at 1665 cm . In the 1H NMR spectrum, singlets at
−1
introduction of a phenoxypropanolamine side chain in δ ꢀ=ꢀ 2.20, 3.59 and 6.68 ppm were assigned to 4-CH3, CH2
2-amino-1,3-thiazole-4-acetic acid has resulted in selective protons and thiazole 5-H, respectively. Aminothiazole
β3-adrenergic receptor agonists [12]. 2-Amino-1,3-thiazole NH appeared at 10.01 ppm and amide NH at 10.12 ppm.
In the 13C NMR spectrum of 4b, the two upfield signals at
δ ꢀ=ꢀ 20.29 and 30.63 ppm were assigned to CH3 and CH2
*Corresponding author: Manohar V. Kulkarni, Department of
carbons, respectively. Two low-intensity downfield signals
Chemistry, Karnatak University, Pavate Nagar, Dharwad, 580-003,
at 163.36 and 167.83 ppm were due to carbonyl and azome-
thine carbon, respectively. Aromatic carbons resonated in
the expected range between 103.86 ppm and 146.02 ppm.
India, e-mail: manohar274@gmail.com
Madhura V. and Hrishikesh M. Revankar: Department of Chemistry,
Karnatak University, Pavate Nagar, Dharwad, 580-003, India
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484ꢀ
ꢀMadhura V. et al.: Synthesis of 4-arylacetamido-2-aminothiazoles and their biological evaluation
O
O
N
O
R
N
S
O
O
N
NHR
R
N
S
N
S
Cl
β3-adrenergic receptor agonists
Anti-viral
Anti-inflammatory
Fig. 1:ꢁStructurally related biologically active thiazoles.
−1
S. aureus (MIC 3.25 μg mL ). The presence of a free –NH2
2.1 Biological evaluation
group without any substitution on the aryl(acetamide)
All synthesized compounds were screened for in vitro ring (compound 4a) was found to give the least active
−1
antibacterial, antifungal and antioxidant activities.
compound (MIC ꢀ=ꢀ 12.5 μg mL ) against S. aureus, but the
presence of Cl at position C-3 or C-4 of the aryl(acetamide)
ring may be the reason for better activity (4h and 4j) with
MIC ꢀ=ꢀ 1.6 μg mL . The presence of the chloro group at
the ortho-position of the aryl amino moiety makes it the
−1
2.1.1 Antibacterial activity
All the synthesized compounds were evaluated for their least active one amongst the synthesized compounds with
−1
antibacterial activity against (i) Gram-positive bacteria, MIC ꢀ=ꢀ 12.5 μg mL .
Enterococcus faecalis (ATCC 35550) and Staphylococcus
aureus (ATCC 12598), and (ii) Gram-negative bacteria,
Klebsiella pneumoniae (ATCC 29665) and Escherichia coli 2.1.2 Antifungal activity
(ATCC 25922). The compounds showed very good antibac-
terial activity especially against Gram-positive species All the synthesized title compounds were screened for
(Table 1). Some of the compounds (4b, 4d, 4f, 4g, 4m, their antifungal activity against Candida albicans (ATCC
4n, 4o) were found to be more potent than standard cip- 2091) and Aspergillus niger (ATCC 9029). The antifungal
rofloxacin against S. aureus, and almost all compounds data (Table 1) revealed that all the synthesized compounds
−1
were found to be more potent (0.2–0.8 μg mL ) than the irrespective of the substituent present showed very
standard ciprofloxacin against E. faecalis. Compounds good antifungal activity against C. albicans and A. niger
−1
were inactive against Gram-negative bacteria. Compound with MIC values between 0.2 and 1.6 μg mL compared
−1
4f showed a minimum inhibitory concentration (MIC) of to standard fluconazole (MIC values 16 and 8 μg mL ).
−1
12.5 μg mL , while the rest of the compounds showed MIC Compounds 4d, 4g, 4l, 4n (against C. albicans) and com-
−1
values of 100 μg mL .
pounds 4a–4e, 4g, 4i, 4j, 4n (against A. niger) showed
−1
The absence of any substitutions on both the aryl highest activity with an MIC of 0.2 μg mL .
rings makes compound 4e totally inactive, but the intro-
duction of –Cl at the meta-position of the aryl-acetamide
moiety activates compound 4k to some extent against
S
H
H
N
N
CH3
Br
H2N
NH R
R′
R′
O
O
O
O
Ar HN
O
3
H
2
A
NH2
1
N
B
N
S
Ethanol
Reflux
H
Ar
R
N
R
O
N
H
S
Br
O
B
H
4
2
3
R
N
N
A
NH
R′
O
S
4a−4o
R′O
O
H
3C
Cl
Cl
NH2
R′O
N
S
H
Ar NH2
N
R
Cl
R
CH3 ,
=
,
,
,
R
,
H,
O
N
S
Cl
O
H
R′ = H, 2-CH3, 3-Cl, 4-Cl
6
5
Fig. 2:ꢁRetrosynthetic analysis of N-phenyl-2-(2-(arylamino)-1,3-thi-
azol-4-yl)acetamide.
Scheme 1:ꢁSynthesis of substituted 4-arylacetamido 2-amino-
1,3-thiazoles 4a–4o.
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Madhura V. et al.: Synthesis of 4-arylacetamido-2-aminothiazoles and their biological evaluationꢀ
ꢀ485
−1
Table 1:ꢁResults of biological evaluation of compounds 4a–4o (MICs in μg mL ).
Compoundꢃ
R
ꢃ
R′
ꢀ
ꢀ
ꢀ
Antibacterialꢀ
Antifungal
ꢀ
Gram-positiveꢀ
Gram-negative
ꢀ
S. aureusꢀ
E. faecalis
E. coliꢀ
K. pneumoniae
C. albicansꢀ
A. niger
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
H
ꢃ
H
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
12.5ꢃ
0.2ꢃ
0.2ꢃ
0.2ꢃ
0.2ꢃ
0.8ꢃ
1.6ꢃ
0.2ꢃ
0.2ꢃ
0.2ꢃ
0.4ꢃ
0.4ꢃ
0.2ꢃ
0.2ꢃ
0.8ꢃ
0.8ꢃ
0.8ꢃ
100ꢃ
100ꢃ
100ꢃ
100ꢃ
–ꢃ
12.5ꢃ
50ꢃ
50ꢃ
100ꢃ
100ꢃ
100ꢃ
–ꢃ
–ꢃ
100ꢃ
100ꢃ
100ꢃ
100ꢃ
100ꢃ
100ꢃ
–ꢃ
100ꢃ
100ꢃ
100ꢃ
100ꢃ
100ꢃ
25ꢃ
0.4ꢃ
0.4ꢃ
0.8ꢃ
0.2ꢃ
0.8ꢃ
0.8ꢃ
0.2ꢃ
1.6ꢃ
0.4ꢃ
0.8ꢃ
0.4ꢃ
0.2ꢃ
0.2ꢃ
0.2ꢃ
0.4ꢃ
0.2
0.2
0.2
0.2
0.2
0.4
0.2
0.4
0.2
0.2
0.4
0.4
0.4
0.2
0.8
4-CH3C6H4ꢃ
H
2-ClC6H4
ꢃ
H
12.5ꢃ
0.2ꢃ
2-CH3C6H4ꢃ
H
C6H5
ꢃ
ꢃ
ꢃ
ꢃ
H
–ꢃ
4-ClC6H4
3-ClC6H4
H
H
0.2ꢃ
H
0.2ꢃ
4-Cl
4-Cl
3-Cl
3-Cl
3-Cl
3-Cl
1.6ꢃ
4-CH3C6H4ꢃ
H
C6H5
4-ClC6H4
4-CH3C6H4ꢃ
C6H5
4-CH3C6H4ꢃ
3.125ꢃ
1.6ꢃ
ꢃ
ꢃ
ꢃ
3.125ꢃ
1.6ꢃ
100ꢃ
100ꢃ
100ꢃ
–ꢃ
0.4ꢃ
ꢃ
2-CH3ꢃ
2-CH3ꢃ
0.2ꢃ
0.2ꢃ
Ciprofloxacin
Fluconazole
ꢃ
ꢃ
2ꢃ
2ꢃ
2ꢃ
2ꢃ
–ꢃ
–
–ꢃ
–ꢃ
–ꢃ
–ꢃ
16ꢃ
8
2.1.3 Antioxidant activity
can be obtained by linear regression of plots, where the
abscissa represents the concentration of the tested com-
Compounds 4a–4o were tested for antioxidant property pounds and the ordinate the average percent of scaveng-
with 1,1-diphenylpicrylhydrazyl (DPPH). Hydrogen or ing capacity.
electron donation ability of the compounds was measured
Compounds show moderate antioxidant properties
from the bleaching of the purple colored methanolic solu- (Table 2). Compound 4i shows maximum activity amongst
tion of 2,2-diphenyl-1-picrylhydrazyl (DPPH) [18, 19]. The the synthesized compounds. Substituents on the aromatic
spectrophotometric assay uses the stable radical DPPH as ring attached to amide NH do not make much contribution
a reagent. One milliliter of various concentrations of the to the activity, whereas a phenyl ring attached to amino
−1
test compounds (150, 200, 250 and 300 mg mL ) in metha- nitrogen of the aminothiazole moiety has a greater contri-
nol was added to 4 mL of 0.004 % (w/v) methanol solution bution. The absence of the phenyl ring renders the com-
of DPPH. After a 30-min incubation period at room tem- pounds least active. Compounds 4a, 4h, 4j did not show
−1
perature, the absorbance was read against blank at 517 any scavenging activity even at 300 μg mL . Further, sub-
nm. The percent of inhibition (I %) of free radical produc- stituents on the phenyl ring contribute to the activity. A
tion from DPPH was calculated by the following equation, methyl group at para-position (4c, 4b, 4o, 4m) and Cl at
ortho-position (4c) favors scavenging activity, whereas the
I0 = ( Acontrol -Asample ) / Acontrol × 100,
presence of a methyl group (4d) at ortho-position and Cl
where Acontrol is the absorbance of the control reaction at meta-position (4g) inhibits the scavenging activity to
(containing all reagents except the test compound) and some extent.
A
sample is the absorbance of the test compound. Tests were
carried out in triplicate.
3 Experimental section
2.2 IC50 values
Melting points were determined in open capillaries and
are uncorrected. IR spectra (KBr disk) were recorded on a
The 50 % inhibitory concentration value (IC50) is indi- Nicolet-5700 FT-IR spectrophotometer. 1H NMR spectra were
cated as the effective concentration of the sample that is recorded on Bruker 300 MHz and 400 MHz spectrometers
required to scavenge 50 % of the DPPH free radicals which using CDCl3 and [D6]DMSO as solvents and tetramethylsilane
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ꢀMadhura V. et al.: Synthesis of 4-arylacetamido-2-aminothiazoles and their biological evaluation
486ꢀ
Table 2:ꢁResults of antioxidant activity for compounds 4a–4o.
Compound
ꢀ
R
ꢀ
R′
ꢀ
300 (μg mL−1)ꢀ
250 (μg mL−1)ꢀ
200 (μg mL−1)ꢀ
150 (μg mL−1)ꢀ
IC50 (μg mL−1)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
H
ꢃ
H
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
–ꢃ
70.00ꢃ
58.63ꢃ
46.18ꢃ
54.98ꢃ
51.46ꢃ
28.30ꢃ
–ꢃ
–ꢃ
64.65ꢃ
49.00ꢃ
35.95ꢃ
48.53ꢃ
45.36ꢃ
22.00ꢃ
–ꢃ
–ꢃ
46.09ꢃ
46.90ꢃ
35.72ꢃ
45.25ꢃ
43.96ꢃ
20.64ꢃ
–ꢃ
–ꢃ
36.31ꢃ
40.71ꢃ
35.25ꢃ
36.45ꢃ
37.74ꢃ
17.79ꢃ
–ꢃ
–
207.41
237.20
402.00
258.03
288.58
655.00
–
4-CH3C6H4ꢃ
H
2-ClC6H4
ꢃ
H
2-CH3C6H4ꢃ
H
C6H5
ꢃ
ꢃ
ꢃ
ꢃ
H
4-ClC6H4
3-ClC6H4
H
H
H
4-Cl
4-Cl
3-Cl
3-Cl
3-Cl
3-Cl
4-CH3C6H4ꢃ
H
C6H5
4-ClC6H4
66.50ꢃ
–ꢃ
60.32ꢃ
–ꢃ
52.03ꢃ
–ꢃ
44.99ꢃ
–ꢃ
184.89
–
ꢃ
ꢃ
ꢃ
49.69ꢃ
51.78ꢃ
62.04ꢃ
45.12ꢃ
58.87ꢃ
–ꢃ
48.45ꢃ
45.56ꢃ
34.07ꢃ
38.19ꢃ
36.66ꢃ
–ꢃ
35.28ꢃ
34.96ꢃ
30.08ꢃ
32.90ꢃ
33.25ꢃ
–ꢃ
33.12ꢃ
33.24ꢃ
25.49ꢃ
25.14ꢃ
31.49ꢃ
–ꢃ
293.36
291.06
278.45
338.00
283.21
20.23
4-CH3C6H4ꢃ
C6H5
4-CH3C6H4ꢃ
ꢃ
2-CH3ꢃ
2-CH3ꢃ
–
Ascorbic acidꢃ
–
ꢃ
ꢃ
(TMS) as an internal standard. The chemical shifts are
expressed in δ (ppm). Mass spectra were recorded on a Shi-
madzu GCMS-QP2010S instrument. Elemental analysis was
carried out using a Hereaus CHN rapid analyzer. The purity
3.3 Synthesis of N-phenyl-2-(2-(phenylamino)-
1,3-thiazol-4-yl)acetamide/2-(2-aminothi-
azol-4-yl)-N-phenylacetamide (3)
of the compounds was checked by thin layer chromatog- A mixture of 0.01 mol of substituted ω-bromoaceto-
raphy (TLC). All the chemicals used were purchased from acetanilide and 0.01 mol of urea/substituted phenyl
Sigma-Aldrich, Bangalore, Karnatak, India.
thiourea was refluxed in ethanol on a water bath for 4 h;
the reaction mixture was concentrated and poured into
crushed ice and neutralized with few drops of liquor
ammonia. The separated solid was washed thoroughly
with water and dried to get analytically pure 3.
3.1 Synthesis of (substituted phenyl)
thioureas [17]
To a cold methanolic solution of the appropriate aniline
(0.25 mol) were added conc. HCl (20 mL) and potassium 3.4 2-(2-Amino-1,3-thiazol-4-yl)-N-
thiocyanate (0.30 mol). The mixture was shaken well and
phenylacetamide (4a)
heated over a steam bath for 3 h. The potassium chloride
that separated was filtered out; the filtrate concentrated Off-white solid. Yield: 70 %; m.p.: 160–61 °C. – FT-IR (KBr,
−1
to a small volume to separate the phenyl thiourea. It was cm ): υ ꢀ=ꢀ 1672 (Cꢀ=ꢀO), 3407 (amide N–H), 3276 (asymmet-
1
collected by filtration after cooling and purified by crystal- ric), 3188 (symmetric) (NH2). – H NMR (300 MHz, [D6]
lization from methanol or rectified ethanol.
DMSO, 25 °C, TMS): δ ꢀ=ꢀ 3.47 (s, 2H, –CH2), 6.31 (s, 1H, thia-
zole H), 6.90 (s, 2H, NH2, D2O-exchangeable), 7.03 (m, 1H,
Ar-H), 7.29 (m, 2H, Ar-H), 7.60 (d, J ꢀ=ꢀ 7.5 Hz, 2H, Ar-H),
10.07 (s, 1H, amide NH, D2O-exchangeable). – MS: m/z
3.2 Synthesis of ω-bromoacetoacetanilides
+
(%) ꢀ=ꢀ 233 (1) [M] . – C11H11N3OS (233.06): calcd. C 56.63 H
[16]
4.75, N 18.01, S 13.74; found C 56.67, H 4.73, N 18.05, S 13.70.
A solution of 0.022 mol of substituted acetoacetanilide in
12 mL of glacial acetic acid was treated dropwise with a
solution of bromine (0.022 mol) in 17 mL of glacial acetic 3.5 2-(2-(p-Toluidino)-4,5-dihydro-1,3-
acid containing a small crystal of iodine, over a period of
thiazol-4-yl)-N-phenylacetamide (4b)
1 h at room temperature. The mixture was stirred further for
3 h and poured into water to give ω-bromoacetoacetanilide Off-white solid. Yield: 80 %; m.p.: 175–76 °C. – FT-IR (KBr,
which was crystallized from ethanol.
cm ): υ ꢀ=ꢀ 1665 (Cꢀ=ꢀO), 3392 (amide N–H), 3299 (NH). – 1H
−1
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NMR (300 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 2.20 (s, 3H, Hz, 1H, Ar-H), 7.03 (t, J ꢀ=ꢀ 7.2 Hz, 1H, Ar-H), 7.22–7.31 (m,
CH3), 3.59 (s, 2H, –CH2), 6.68 (s, 1H, thiazole H), 7.02 (t, 4H, Ar-H), 7.57–7.61 (m, 4H, Ar-H), 10.01 (s, 1H, NH, D2O-
J ꢀ=ꢀ 8.3 Hz, 3H, Ar-H), 7.28 (t, J ꢀ=ꢀ 8.0 Hz, 2H, Ar-H), 7.45 (d, exchangeable), 10.12 (s, 1H, amide NH, D2O-exchangea-
+
J ꢀ=ꢀ 8.2, 2H, Ar-H), 7.58 (d, J ꢀ=ꢀ 8.2 Hz, 2H, Ar-H), 10.01 (s, ble). – MS: m/z (%) ꢀ=ꢀ 309 (16) [M] . – C17H15N3OS (309.09):
1H, NH, D2O-exchangeable), 10.12 (s, 1H, amide NH, D2O- calcd. C 66.00, H 4.89, N 13.58, S 10.36; found C 66.02, H
exchangeable). – 13C NMR (100 MHz, [D6]DMSO): δ ꢀ=ꢀ 20.29 4.85, N 13.63, S 10.40.
(CH3), 30.63 (CH2), 103.86 (thiazole C-5), 116.93, 119.03,
123.12, 128.65, 129.22, 129.92, 138.78, 139.18, 146.02 (Ar-C),
163.36 (Cꢀ=ꢀO), 167.83 (thiazole C-2). – MS: m/z (%) ꢀ=ꢀ 323 (6)
3.9 2-(2-(4-Chlorophenylamino)-1,3-
+
[M] . – C18H17N3OS (323.11): calcd. C 66.85, H 5.30, N 12.99, S
thiazol-4-yl)-N-phenylacetamide (4f)
9.91; found C 66.88, H 5.36, N 12.94, S 9.88.
Light brown solid. Yield: 80 %; m.p.: 183–84 °C. – FT-IR
−1
(KBr, cm ): υ ꢀ=ꢀ 1662 (Cꢀ=ꢀO), 3373 (amide N–H), 3251 (NH).
3.6 2-(2-(2-Chlorophenylamino)-1,3-
thiazol-4-yl)-N-phenylacetamide (4c)
1
– H NMR (300 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 3.58 (s,
2H, –CH2), 6.72 (s, 1H, thiazole H), 7.02 (t, J ꢀ=ꢀ 6.0 Hz, 1H,
Ar-H), 7.28 (t, J ꢀ=ꢀ 9.0 Hz, 4H, Ar-H), 7.61 (t, J ꢀ=ꢀ 9.0 Hz, 4H,
Ar-H), 10.13 (s, 1H, NH, D2O-exchangeable), 10.29 (s, 1H,
amide NH, D2O-exchangeable). – MS: m/z (%) ꢀ=ꢀ 343 (9)
Off-white solid. Yield: 65 %; m.p.: 114–15 °C. – FT-IR (KBr,
−1
cm ): υ ꢀ=ꢀ 1664 (Cꢀ=ꢀO), 3381 (amide N–H), 3261 (NH). – 1H
NMR (300 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 3.59 (s, 2H,
–CH2), 6.68 (s, 1H, thiazole H), 7.00 (q, J ꢀ=ꢀ 8.1 Hz, 2H, Ar-H),
7.20 (t, J ꢀ=ꢀ 8.1 Hz, 1H, Ar-H), 7.28 (t, J ꢀ=ꢀ 7.5 Hz, 2H, Ar-H), 7.42
(d, J ꢀ=ꢀ 8.0 Hz, 1H, Ar-H), 7.57 (d, J ꢀ=ꢀ 8.1 Hz, 2H, Ar-H), 8.25
(d, J ꢀ=ꢀ 7.5 Hz, 1H, Ar-H), 9.55 (s, 1H, NH, D2O-exchangea-
ble), 10.11 (s, 1H, amide NH, D2O-exchangeable). – MS: m/z
+
+
[M] , 345 (3) [M+2] . – C17H14ClN3OS (343.05): calcd. C 59.38,
H 4.10, N 12.22, S 9.33; found C 59.35, H 4.14, Cl 10.31, N
12.18, S 9.30.
+
+
(%) ꢀ=ꢀ 343 (10) [M] , 345 (3) [M+2] . – C17H14ClN3OS (343.05): 3.10 2-(2-(3-Chlorophenylamino)-1,3-
calcd. C 59.38, H 4.10, N 12.22, S 9.33; found C 59.43, H 4.13,
N 12.15, S 9.29.
thiazol-4-yl)-N-phenylacetamide (4g)
Off-white solid. Yield: 65 %; m.p.: 110–11 °C. – FT-IR (KBr,
−1
1
cm ): υ ꢀ=ꢀ 1665 (Cꢀ=ꢀO), 3265 (amide N–H), 3189 (NH). – H
NMR (300 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 3.63 (s, 2H,
–CH2), 6.70 (s, 1H, thiazole H), 6.92 (d, J ꢀ=ꢀ 7.3 Hz, 1H,
Ar-H), 7.04 (d, J ꢀ=ꢀ 7.3 Hz, 1H, Ar-H), 7.27 (t, J ꢀ=ꢀ 9.0 Hz, 3H,
3.7 2-(2-(o-Toluidino)-1,3-thiazol-4-yl)-N-
phenylacetamide (4d)
Light yellow solid. Yield: 75 %; m.p.: 155–56 °C. – FT-IR Ar-H), 7.40 (d, J ꢀ=ꢀ 7.3 Hz, 1H, Ar-H), 7.60 (d, J ꢀ=ꢀ 9.0 Hz, 2H,
−1
(KBr, cm ): υ ꢀ=ꢀ 1663 (Cꢀ=ꢀO), 3410 (amide N–H), 3297 (NH). Ar-H),7.85 (s, 1H, Ar-H), 10.15 (s, 1H, NH, D2O-exchangea-
1
– H NMR (300 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 2.21 (s, ble), 10.37 (s, 1H, amide NH, D2O-exchangeable). – MS: m/z
+
+
3H, CH3), 3.56 (s, 2H, –CH2), 6.68 (s, 1H, thiazole H), 6.98 (%) ꢀ=ꢀ 343 (9) [M] , 345 (3) [M+2] . – C17H14ClN3OS (343.05):
(m, 2H, Ar-H), 7.13 (m, 2H, Ar-H), 7.25 (t, J ꢀ=ꢀ 7.5 Hz, 2H, calcd. C 59.38, H 4.10, N 12.22, S 9.33; found C 59.41, H 4.09,
Ar-H), 7.56 (d, J ꢀ=ꢀ 7.8 Hz, 2H, Ar-H), 7.77 (d, J ꢀ=ꢀ 7.8 Hz, 1H, N 12.15, S 9.28.
Ar-H), 9.22 (s, 1H, NH, D2O-exchangeable), 10.10 (s, 1H,
amide NH, D2O-exchangeable). – MS: m/z (%) ꢀ=ꢀ 323 (18)
+
[M] . – C18H17N3OS (323.11): calcd. C 66.85, H 5.30, N 12.99, S 3.11 2-(2-Amino-1,3-thiazol-4-yl)-N-
9.91; found C 66.87, H 5.33, N 12.96, S 9.93.
(4-chlorophenyl)acetamide (4h)
Light brown solid. Yield: 65 %; m.p.: 152–53 °C. – FT-IR
−1
3.8 N-Phenyl-2-(2-(phenylamino)-1,3-
thiazol-4-yl)acetamide (4e)
(KBr, cm ): υ ꢀ=ꢀ 1663 (Cꢀ=ꢀO), 3293 (amide N–H), 3178 (asym-
metric), 3139 (symmetric) (NH2). – 1H NMR (300 MHz, [D6]
DMSO, 25 °C, TMS): δ ꢀ=ꢀ 3.43 (s, 2H, –CH2), 6.28 (s, 1H,
Light brown solid. Yield: 70 %; m.p.: 142–43 °C. – FT-IR thiazole H), 6.89 (s, 2H, NH2, D2O-exchangeable), 7.32 (d,
−1
(KBr, cm ): υ ꢀ=ꢀ 1665 (Cꢀ=ꢀO), 3425 (amide N–H), 3298 J ꢀ=ꢀ 7.0 Hz, 2H, Ar-H), 7.61 (d, J ꢀ=ꢀ 7.0 Hz, 2H, Ar-H), 10.21 (s,
1
(NH). – H NMR (400 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 1H, amide NH, D2O-exchangeable). – MS: m/z (%) ꢀ=ꢀ 267
+
+
3.63 (s, 2H, –CH2), 6.62 (s, 1H, thiazole H), 6.90 (t, J ꢀ=ꢀ 7.2 (8) [M] , 269 (2.5) [M+2] . – C11H10ClN3OS (267.02): calcd.
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C 49.35, H 3.76, N 15.69, S 11.98; found C 49.38, H 3.72, N (343.05): calcd. C 59.38, H 4.10, N 12.22, S 9.33; found C
15.72, S 12.02.
59.42, H 4.05, N 12.20, S 9.29.
3.12 2-(2-(p-Toluidino)-1,3-thiazol-4-yl)-N-
(4-chlorophenyl)acetamide (4i)
3.15 N-(3-Chlorophenyl)-2-(2-(4-
chlorophenylamino)-1,3-thiazol-4-yl)
acetamide (4l)
Off-white solid. Yield: 60 %; m.p.: 174–75 °C. – FT-IR (KBr,
1
cm– ): υ ꢀ=ꢀ 1668 (Cꢀ=ꢀO), 3405 (amide N–H), 3295 (NH). – 1H Off-white solid. Yield: 75 %; m.p.: 144–45 °C. – FT-IR
−1
NMR (300 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 2.18 (s, 3H, (KBr, cm ): υ ꢀ=ꢀ 1664 (Cꢀ=ꢀO), 3261 (amide N–H), 3192
1
–CH3), 4.22 (s, 2H, –CH2), 6.56 (s, 1H, thiazole H), 7.02 (d, (NH). – H NMR (300 MHz, CDCl3, 25 °C, TMS): δ ꢀ=ꢀ 3.69
J ꢀ=ꢀ 7.1 Hz, 2H, Ar-H), 7.33 (d, J ꢀ=ꢀ 7.3 Hz, 2H, Ar-H), 7.40 (d, (s, 2H, –CH2), 6.41 (s, 1H, thiazole H), 7.04 (d, J ꢀ=ꢀ 7.4 Hz,
J ꢀ=ꢀ 7.1 Hz, 2H, Ar-H), 7.59 (d, J ꢀ=ꢀ 7.3 Hz, 2H, Ar-H), 9.99 (s, 1H, Ar-H), 7.16–7.37 (m, 6H, Ar-H), 7.55 (s, 1H, Ar-H), 9.33
1H, NH, D2O-exchangeable), 10.28 (s, 1H, amide NH, D2O- (s, 1H, NH, D2O-exchangeable), 10.09 (s, 1H, amide NH,
+
exchangeable). – 13C NMR (100 MHz, [D6]DMSO): δ ꢀ=ꢀ 14.06 D2O-exchangeable). – MS: m/z (%) ꢀ=ꢀ 377 (10) [M] , 379 (7)
+
+
(CH3), 36.99 (CH2), 103.94 (thiazole C-5), 116.93, 120.55, [M+2] , 381 (1.5) [M+4] . – C17H13Cl2N3OS (377.02): calcd. C
126.67, 128.57, 129.22, 129.94, 138.13, 138.76, 145.80 (Ar-C), 53.98, H 3.46, N 11.11, S, 8.48; found C 54.01, H 3.50, N 11.06,
163.38 (Cꢀ=ꢀO), 168.02 (thiazole C-2). – MS: m/z (%) ꢀ=ꢀ 357 S 8.44.
+
+
(18) [M] , 359 (6) [M+2] . – C18H16ClN3OS (357.07): calcd. C
60.41, H 4.51, N 11.74, S 8.96; found C 60.47, H 4.54, N 11.70,
S 8.99.
3.16 2-(2-(p-Toluidino)-1,3-thiazol-4-yl)-N-
(3-chlorophenyl)acetamide (4m)
3.13 2-(2-Amino-1,3-thiazol-4-yl)-N-
(3-chlorophenyl)acetamide (4j)
Off-white solid. Yield: 75 %; m.p.: 150–51 °C. – FT-IR (KBr,
−1
cm ): υ ꢀ=ꢀ 1665 (Cꢀ=ꢀO), 3253 (amide N–H), 3188 (NH). – 1H
NMR (300 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 2.35 (s, 3H,
Off-white solid. Yield: 70 %; m.p.: 191–92 °C. – FT-IR (KBr, –CH3), 3.67 (s, 2H, –CH2), 6.38 (s, 1H, thiazole H), 7.03 (d, J ꢀ=ꢀ
−1
cm ): υ ꢀ=ꢀ 1661 (Cꢀ=ꢀO), 3285 (amide N–H), 3186 (asym- 8.4 Hz, 1H, Ar-H), 7.18–7.31 (m, 5H, Ar-H), 7.38 (d, J ꢀ=ꢀ 8.1 Hz,
metric), 3118 (symmetric) (NH2). – 1H NMR (300 MHz, [D6] 1H, Ar-H), 7.52 (s, 1H, Ar-H), 9.49 (s, 1H, NH D2O-exchange-
DMSO, 25 °C, TMS): δ ꢀ=ꢀ 4.41 (s, 2H, –CH2), 6.29 (s, 1H, able), 10.15 (s, 1H, amide NH, D2O-exchangeable). – MS:
+
+
thiazole H), 6.85 (s, 2H, NH2, D2O-exchangeable), 7.06 (d, m/z (%) ꢀ=ꢀ 357 (15) [M] , 359 (5) [M+2] . – C18H16ClN3OS
J ꢀ=ꢀ 7.5 Hz, 1H, Ar-H), 7.29 (t, J ꢀ=ꢀ 7.9 Hz, 1H, Ar-H), 7.39 (d, (357.07): calcd. C 60.41, H 4.51, N 11.74, S 8.96; found C
J ꢀ=ꢀ 7.9 Hz, 1H, Ar-H), 7,75 (s, 1H, Ar-H), 10.29 (s, 1H, amide 60.45, H 4.49, N 11.77, S 9.00.
NH, D2O-exchangeable). – 13C NMR (100 MHz, [D6]DMSO):
δ ꢀ=ꢀ 39.74 (CH2), 102.73 (thiazole C-5), 117.32, 117.85, 118.40,
122.78, 123.09, 130.43, 133.01, 140.62, 145.39 (Ar-C), 168.24 3.17 2-(2-(Phenylamino)-1,3-thiazol-4-yl)-N-
+
(Cꢀ=ꢀO), 168.40 (thiazole C-2). – MS: m/z (%) ꢀ=ꢀ 267 (6) [M] ,
o-tolylacetamide (4n)
+
269 (2) [M+2] . – C11H10ClN3OS (267.02): calcd. C 49.35, H
3.76, N 15.69, S 11.98; found C 49.31, H 3.78, N 15.65, S 11.95. Off-white solid. Yield: 74 %; m.p.: 135–36 °C. – FT-IR (KBr,
−1
cm ): υ ꢀ=ꢀ 1655 (Cꢀ=ꢀO), 3263 (amide N–H), 3198 (NH). – 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ ꢀ=ꢀ 2.12 (s, 3H, –CH3),
3.14 N-(3-Chlorophenyl)-2-(2-(phenylamino)- 3.74 (s, 2H, –CH2), 6.44 (s, 1H, thiazole H), 7.02 (d, J ꢀ=ꢀ 7.4
Hz, 1H, Ar-H), 7.09–7.31 (m, 7H, Ar-H), 7.97 (d, J ꢀ=ꢀ 7.6 Hz,
1H, Ar-H), 8.90 (s, 1H, NH, D2O-exchangeable), 9.53 (s, 1H,
1,3-thiazol-4-yl)acetamide (4k)
Off-white solid. Yield: 65 %; m.p.: 138–40 °C. – FT-IR (KBr, amide NH, D2O-exchangeable). – 13C NMR (100 MHz, [D6]
−1
1
cm ): υ ꢀ=ꢀ 1659 (Cꢀ=ꢀO), 3275 (amide N–H), 3191 (NH). – H DMSO): δ ꢀ=ꢀ 17.85 (CH3), 40.33 (CH2), 104.97 (thiazole C-5),
NMR (300 MHz, CDCl3, 25 °C, TMS): δ ꢀ=ꢀ 3.69 (s, 2H, –CH2), 118.66, 122.09, 123.60, 124.52, 126.66, 128.15, 129.52, 130.28,
6.43 (s, 1H, thiazole H), 7.04 (d, J ꢀ=ꢀ 7.8 Hz, 2H, Ar-H), 7.15– 136.18, 139.80, 145.56 (Ar-C), 165.83 (Cꢀ=ꢀO), 167.38 (thiazole
+
7.42 (m, 6H, Ar-H), 7.56 (s, 1H, Ar-H), 9.41 (s, 1H, NH, D2O- C-2). – MS: m/z (%) ꢀ=ꢀ 323 (10) [M] . – C18H17N3OS (323.11):
exchangeable), 10.11 (s, 1H, amide NH, D2O-exchangeable). calcd. C 66.85, H 5.30, N 12.99, S 9.91; found C 66.81, H 5.33,
+
+
– MS: m/z (%) ꢀ=ꢀ 343 (9) [M] , 345 (3) [M+2] . – C17H14ClN3OS N 13.02, S 9.86.
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ꢀ489
modifying the substituents. In preliminary screenings,
the synthesized compounds were found to exhibit potent
antibacterial activity against Gram-positive bacteria S.
3.18 2-(2-(p-Toluidino)-1,3-thiazol-4-yl)-N-o-
tolylacetamide (4o)
Off-white solid. Yield: 72 %; m.p.: 134–35 °C. – FT-IR (KBr, aureus and E. faecalis and antifungal activity against A.
cm ): υ ꢀ=ꢀ 1664 (Cꢀ=ꢀO), 3263 (amide N–H), 3188 (NH). – 1H niger and C. albicans.
−1
NMR (400 MHz, [D6]DMSO, 25 °C, TMS): δ ꢀ=ꢀ 2.17 (s, 3H,
–CH3), 2.23 (s, 3H, –CH3), 3.64 (s, 2H, –CH2), 6.62 (s, 1H,
thiazole H), 7.03–7.19 (m, 5H, Ar-H), 7.46–7.52 (m, 3H, Ar-H),
References
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9.38 (s, 1H, NH, D2O-exchangeable), 10.02 (s, 1H, amide
+
NH, D2O-exchangeable). – MS: m/z (%) ꢀ=ꢀ 337 (10) [M] . –
C19H19N3OS (337.12): calcd. C 67.63, H 5.68, N 12.45, S 9.50;
found C 67.68, H 5.66, N 12.41, S 9.53.
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We have established a direct route for the synthesis of
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