Synthesis, Characterization, Crystal Structure and Biological Study of Carboxamides Obtained from 2-Aminothiazole Derivatives

Article abstract of DOI:10.1007/s10870-019-00800-w

Abstract: Two series of novel thiazolylcarboxamide derivatives were synthesized by the reaction of ethyl 2-amino-4-methylthiazole-5-carboxylate or 1-(2-amino-4-methylthiazol-5-yl)ethan-1-one with four substituted carbonyl chlorides at 0?°C in excellent yi

Full text of DOI:10.1007/s10870-019-00800-w

Journal of Chemical Crystallography
https://doi.org/10.1007/s10870-019-00800-w
ORIGINAL PAPER
Synthesis, Characterization, Crystal Structure and Biological Study
of Carboxamides Obtained from 2‑Aminothiazole Derivatives
Sachin S. Wazalwar1 · Anita R. Banpurkar1 · Franc Perdih2
Received: 24 January 2019 / Accepted: 18 July 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Two series of novel thiazolylcarboxamide derivatives were synthesized by the reaction of ethyl 2-amino-4-methylthiazole-
5-carboxylate or 1-(2-amino-4-methylthiazol-5-yl)ethan-1-one with four substituted carbonyl chlorides at 0 °C in excellent
yield. All products were characterized by FTIR, 1H NMR spectroscopy and mass spectrometry. Crystal structures of four
compounds were studied by X-ray analysis. All the synthesized compounds were screened against Escherichia coli, Pseu-
domonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes for antibacterial activity and against Candida
albicans, Aspergillusniger and Aspergillus clavatus for antifungal activity.
Graphic Abstract
Present study describes the biological activity and crystal structure study of carboxamides obtained from 2-aminothaizol
derivatives. Owing to the insolubility of these amides in single volatile solvent, crystals were grown in a mixture of solvents.
Keywords Thiazolylcarboxamides · Aminothiazole · Carbonyl chloride · Amidation · Antibacterial and antifungal activity ·
Single crystal X-ray study
Introduction
inhibitor from the group of non-steroidal anti-infammatory
drugs (NSAID) [1–4] and thiazotropsin A is binding to the
minor groove of duplex DNA [5, 6]. Sulfur and nitrogen
containing 1,3-thiazoles are very important class of hetero-
cyclic compounds [7, 8]. They are well known for their bio-
logical activities [9–12]. Structures are shown in Scheme 1.
Ethyl 2-amino-4-methylthiazole-5-carboxylate and its 2-sub-
stituted derivatives are building blocks in organic synthe-
sis in making biologically and medicinally useful moieties
[13, 14]. Also 1-(2-amino-4-methylthiazol-5-yl)ethan-1-
one is used as an intermediate for synthesis of 4-methyl-
5-formylthiazole, a key intermediate for cefditoren pivoxil
[15–17]. Derivatives of ethyl 2-amino-4-methylthiazole-
5-carboxylate have been reported to have shown signifcant
The amides of 2-aminothiazoles are pharmaceutically
very important from drug discovery point of view and are
found in many important disease-intervening substances.
For example, meloxicam is a selective cyclooxygenase-2
* Sachin S. Wazalwar
sacheein@gmail.com
1
Department of Applied Chemistry, Rajiv Gandhi College
of Engineering, Research & Technology, Chandrapur,
MS 442403, India
2
Faculty of Chemistry and Chemical Technology, University
of Ljubljana, 1000 Ljubljana, Slovenia
Vol.:(0123456789)
1 3

Journal of Chemical Crystallography
three protons at 2.37–2.40 ppm for thiazolylmethyl group. A
singlet showing two protons around 7.68 ppm reveals –NH2
group of aminothiazole which confrms the structure of 1
and 2 (Scheme 2).
Synthesized compounds 4a–d and 5a–d show character-
1
istic H NMR singlet around 12.60–13.00 ppm attributed
to –NH group. A triplet in the range of 1.20–1.30 ppm is
attributed to O–CH2–CH3 group of 4a–d while a singlet
around 2.32 ppm for three protons is attributed CO–CH3
group of 5a–d. The IR spectrum of compounds 4a–d
show one υ(C=O) absorption band in the range of 1643 to
1687 cm−1 range and another υ(C=O) absorption band in
the range of 1511 to 1533 cm−1 range. Similarly compounds
5a–d show υ(C=O) absorption band at 1662 cm−1 and
1599 cm−1. Strong absorption band at 1643 to 1687 cm−1
for 4a–d and at 1662 cm−1 for 5a–d may be attributed to the
carbonyl group of amide. Absorption due to υ(C=N) band
in the region 1500–1600 cm−1 and υ(–NH) stretching band
around 3200 cm−1 is observed which confrm the formation
of desired products.
We were able to obtain crystals suitable for X-ray struc-
tural analysis of 4b and 5b–d (Fig. 1). Crystallographic
data is listed in Table 1. Compounds 4b and 5b, difer-
ing only in the substituent on position 5 of the thiazol
ring (ethoxycarbonyl vs. acetyl group), both crystallize in
monoclinic C2/c space group with very similar cell param-
eters. Although compound 5d is a close analogue of 5b,
it crystallizes in monoclinic P21/c space group suggesting
diferent packing mode. Compound 5c crystallizes in tri-
clinic P–1 space group. X-ray crystal structures of studied
compounds show that all the bond lengths are within nor-
mal ranges [19]. All analyzed molecules are nearly planar
with the dihedral angle between thiazole ring and thiophene
(4b, 5b), phenyl (5c) and furan (5d) ring (Fig. 1) is in the
range of 5.02(9)–9.36(14)°. The ethoxycarbonyl group
in 4b and acetyl group in 5b–d are almost coplanar with
the thiazole ring showing dihedral angles in the range of
7.43(15)–10.87(6)°.
Scheme 1 Structures of drugs showing presence of 2-aminothiazole
amide linkage
antileukemic activity on various human cells and exhibited
a promising antineoplastic potential [13]. Amidation of
2-aminothiazol is of great interest to the researchers due to
the weak nucleophilicity of the amino group. 2-benzamido-
4-methylthiazole-5-carboxylic acid derivatives were stud-
ied as potential xanthine oxidase inhibitors and free radical
scavengers [18].
Supramolecular structures of studied compounds have
a common motif with a hydrogen-bonded chain formed
through the N2–H2···O1 bonding between the amide NH
group as a hydrogen-bond donor and the carbonyl O atom
of ethoxycarbonyl substituent in 4b and acetyl substituent in
5b–d as a hydrogen-bond acceptor supported by a C–H···O1
hydrogen bond forming a R21(7) ring motif [20] (Table 2,
Figs. 2, 3, 4).
Result and Discussion
Supramolecular structures are achieved through C–H···π
and π···π interactions. In 4b, a stack of chains is formed due
to π···π interactions between thiazole rings of two adjacent
molecules with centroid-to-centroid distance of 3.9177(11)
Å, and dihedral angle between the rings of 7.53(7)°, and
also by C–H···π interactions between the methyl group or
the methylene hydrogen atom of the ethyl group and the
The starting compounds 1 and 2 were synthesized and
characterized by FTIR and 1H NMR spectroscopy. The IR
spectrum of 1 and 2 shows characteristic υ(–NH) absorption
band in the region 3260–3300 cm−1 and υ(–CO–) absorp-
1
tion band in the region 1662 cm−1. The H NMR spectra
of 1 and 2 in DMSO exhibit characteristic singlet showing
1 3

Journal of Chemical Crystallography
Scheme 2 Synthesis of thiazolylcarboxamides of 4a–d and 5a–d
Fig. 1 Molecular structures and atom numbering schemes for 4b and 5b–d. Probability ellipsoids are drawn at the 50% level
thiophene ring (Fig. 2a–d). The presence of acetyl group
in 5b at the position 5 of the thiazole ring in comparison
to the ethyl carboxylato group in 4b doesn’t alter the chain
formation via N2–H2···O1 and C–H···O1 hydrogen bond-
ing (Figs. 2a and 3a). However, it has a signifcant infu-
ence on the supramolecular structure even though both
compounds 4b and 5b crystallize in monoclinic C2/c space
group. Contrary to 4b with stacks of chains, in 5b C–H···π
and π···π interactions connect only two adjacent mole-
cules via π···π interaction between two thiazole rings with
centroid-to-centroid distance of 4.1453(9) Å and ring slip-
page of 2.174 Å, and C–H···π interactions between methyl
hydrogen of acetyl group and the thiophene ring (Table 3,
Figs. 2 and 3).
The chain formation in 5c is further enhanced by a
C12–H12···O2 hydrogen-bond between the phenyl moi-
ety and the carbonyl O atom of the amide group forming
a R22(12) ring motif, while in 5d the chain formation is
enhanced by a C9–H9···S1 hydrogen-bonding between the
furanyl moiety and the thiazole S atom forming a R21(5) ring
1 3

Journal of Chemical Crystallography
Table 1 Crystallographic data
for 4b and 5b–d
Compound code
4b
5b
5c
5d
CCDC number
Molecular formula
Molecular weight
Crystal system
Space group
a (Å)
b (Å)
c (Å)
α (°)
β (°)
1826821
C12H12N2O3S2
296.36
Monoclinic
C2/c
13.7498 (8)
8.0735 (4)
23.7840 (11)
90
96.347 (5)
90
1826822
C11H10N2O2S2
266.33
Monoclinic
C2/c
13.5566 (6)
8.1496 (4)
21.432 (9)
90
95.793 (4)
90
1826823
C14H14N2O3S
290.33
Triclinic
P–1
7.9860 (5)
8.2593 (5)
11.0646 (6)
74.674 (5)
81.594 (5)
77.941 (5)
2
1826824
C11H10N2O3S
250.27
Monoclinic
P21/c
7.5438 (14)
20.7257 (14)
7.9241 (9)
90
115.377 (18)
90
γ (°)
Z
8
8
4
V (Å3)
2624.1 (2)
1.500
0.410
2355.83 (19)
1.502
0.442
685.11 (7)
1.407
0.245
1119.4 (3)
1.485
0.286
Dcalc (g cm−3
)
μ (mm−1
F(000)
)
1232
1104
304
520
Refections collected
Independent refections
Rint
7757
3023
0.0203
6700
2703
0.0182
6024
3151
0.0206
7110
2564
0.0320
Parameters
174
156
184
156
R1, wR2 [I>2σ(I)]a
R1, wR2 (all data)a
GOFb
0.0512, 0.1419
0.0563, 0.1473
1.094
0.0348, 0.0953
0.0403, 0.0993
1.060
0.0438, 0.1048
0.0649, 0.1171
1.049
0.0442, 0.0442
0.0442, 0.1151
1.038
Δρmin, Δρmax (e Å−3
)
− 0.229, 1.329
− 0.275, 0.316
− 0.175, 0.254
− 0.239, 0.233
aR=∑||Fo| − |Fc||/∑|Fo|; wR2 ={∑[w(Fo2 − F2c)2]/∑[w(F2o)2]}1/2. S={∑[(Fo2 − F2c)2]/(n/p)}1/2 where n is
the number of refections and p is the total number of parameters refned
b
motif. Additionally, two adjacent chains in 5c and 5d are
connected into a belt in a antiparallel and parallel fashion
(Fig. 4), respectively, via hydrogen-bonding through the
centrosymmetric C10–H10···O3 hydrogen-bond between the
phenyl moiety and the methoxy group of the adjacent mol-
ecule with a R22(8) ring motif (in 5c), and via hydrogen-bond-
ing through the C11–H11···O2 hydrogen-bonding between
the furanyl moiety and the carbonyl O atom of the amide
group with a R33(16) ring motif (in 5d) (Table 2, Fig. 4).
The alteration of thiophene group in 5b with a methoxy-
phenyl (5c) and furanyl (5d) groups enables the belt forma-
tion (Fig. 4). It also changes the mode of π···π interactions. In
5c, two adjacent molecules form π···π interactions between a
thiazole and phenyl rings in a head-to-tail orientation with
centroid-to-centroid distance of 3.8621(11) Å, and dihedral
angle between the rings of 5.02(9)° (Table 3). Such dimeric
units are connected into a pillar through the C4–H4A···π
interactions between the methyl substituent and phenyl ring
leading to a stack of belts (Fig. 5).
with centroid-to-centroid distance of 4.0513(15) Å and with
slightly smaller ring slippage of 1.970 Å in comparison to
5b (2.174 Å) (Table 3). Due to smaller slippage the forma-
tion of additional π···π interaction is enabled between the
thiazole and furan ring with centroid-to-centroid distance
of 4.1617(16) Å, and dihedral angle between the rings of
9.36(14)°. Thus, the pillar structure is formed leading to a
stack of belts (Fig. 6).
It can be also observed in the studied structures that het-
eroatoms N and S of the thiazole ring are not involved as
hydrogen bond acceptors with the only exception of com-
pound 5d where sulfur atom S1 is involved in bifurcated
hydrogen bonding of the C9–H9 moiety. Heteroatoms in
thiofuran and furan (5b and 5d, respectively) are also not
involved as hydrogen bond acceptors. As revealed by a
search of the Cambridge Structural Database (CSD, Ver-
sion 5.40, plus updates [21]), 7 entries were found with
the thiazole moiety possessing amido group at the posi-
tion 2 and keto or alkoxycarbonyl group at the position 5.
In 6 out of 7 entries the alkoxycarbonyl group (–COOR,
R=Me, Et, tBu) is present and only one entry possesses the
keto group at the position 5. In all those 7 entries hydrogen
bonding motifs are diferent than in 4b and 5b–d. Similar
In 5d, π···π stacking interactions through two differ-
ent interactions of the aromatic rings are present. Two
adjacent molecules connect in a similar fashion as in 5b
through the π···π interaction between two thiazole rings
1 3

Journal of Chemical Crystallography
Table 2 Hydrogen bond
geometry of 4b and 5b–d
D–H···A
D–H (Å)
H···A (Å)
D···A (Å)
D–H···A (°)
Symmetry code
4b
N2–H2···O1
C4–H4C···O2
C10–H10···O1
C4–H4A···Cg2
C6–H6A···Cg2
5b
0.86
0.96
0.93
0.96
0.97
2.15
2.35
2.33
2.97
2.94
3.003 (2)
2.938 (3)
3.230 (3)
3.801 (3)
3.678 (3)
170.4
119.3
161.4
146
x, y+1, z
x, y, z
x, y+1, z
− x+½, y−½, − z+½
− x+1, y−1, − z+½
133
N2–H2···O1
C9–H9···O1
C6–H6B···Cg2
5c
N2–H2···O1
C10–H10···O3
C12–H12···O2
C13–H13···O1
C4–H4A···Cg2
5d
0.86
0.93
0.96
2.02
2.27
2.94
2.8755 (18)
3.139 (2)
3.593 (2)
172.7
156.0
127
x−½,y−½, z
x−½,y−½, z
− x+1, − y+1, − z+1
0.86
0.93
0.93
0.93
0.96
2.13
2.58
2.57
2.37
2.86
2.981 (2)
3.508 (2)
3.481 (2)
3.287 (2)
3.607 (3)
169.3
174.4
167.6
170
x−1, y, z
− x, − y+1, − z+2
x−1, y, z
x−1, y, z
− x+1, − y, − z+1
135
N2–H2···O1
C9–H9···S1
C9–H9···O1
C11–H11···O2
0.86
0.93
0.93
0.93
2.05
2.84
2.29
2.48
2.901 (2)
3.551 (2)
3.132 (3)
3.400 (3)
171.6
133.8
149.8
169.1
x, y, z−1
x, y, z−1
x, y, z−1
x, − y+½, z−½
Cg2 is S2/C9–12 (for 4b), S2/C8–111 (for 5b) and C8–C13 (for 5c) ring centroid
Fig. 2 a Chain formation in 4b generated by N2–H2···O1 and C10–
H10···O1 hydrogen bonding. Hydrogen-bonding is indicated by blue
dashed lines. b C4–H4A···π, C6–H6A···π and π···π interactions. Inter-
actions are indicated by black dashed lines. c Stacking of chains into
a stack due to C–H···π and π···π interactions. d Packing of stacks;
adjacent stacks are shown in green color (Color fgure online)
Fig. 3 a Chain formation in 5b generated by N2–H2···O1 and C9–
H9···O1 hydrogen bonding. Hydrogen-bonding is indicated by blue
dashed lines. b C6–H6B···π and π···π interactions between two adja-
cent molecules. Interactions are indicated by black dashed lines. c
Packing of chains (arbitrary colors) (Color fgure online)
hydrogen-bonded chain formation through the N–H···O
bonding between the amide NH group and the carbonyl O
atom of ethoxycarbonyl or acetyl substituent as in 4b and
5b–d can be observed in only one entry; however, zig-zag
chains are formed (Chandra L, 2011 CSD communication,
1 3

Journal of Chemical Crystallography
Fig. 4 Belt formation in 5c and 5d generated by N2–H2···O1 and C–H···O1 hydrogen bonding and by C12–H12···O2 and C10–H10···O3 (in 5c)
and by C9–H9···S1 and C11–H11···O2 (in 5d). Hydrogen-bonding is indicated by blue dashed lines (Color fgure online)
Private communication). In two entries chains are formed
by N–H···O bonding, however, not with oxygen atom of
alkoxycarbonyl or acetyl group as in 4b and 5b–d [22, 23].
In three entries nitrogen atom of the thiazole ring is involved
in hydrogen bonding forming centrosymmetric hydrogen-
bonded dimers through N–H···N(thiazole) [24, 25] or chains
through N–H···N(thiazole) and N–H···O(amide) interactions
[26]. In one entry compound crystallizes as a hydrate lead-
ing to very diferent hydrogen bonding motif (Borges F,
Gomes LR, Low JN, 2017, CSD communication, Private
communication).
aureus and S. pyogenus as bacterial strain and C. albicans,
A. niger and A. clavatus as fungal strain. It was found that
all synthesized thiazolylcarboxamides 4a–d and 5a–d show
activity against S. aureus close to standard ampicillin with
4b and 5a–b being more active than ampicillin. Activity of
compound 4b against E.coli and S. pyogenus was found to be
close to activity of standard drugs like ampicillin, chloram-
phenicol, ciprofoxacin and activity against P. aeruginosa
and S. aureus was found to be close to values of chloram-
phenicol and ampicillin, respectively. Compounds 4c and
5b show the activity against E. coli and S. aureus similar
to ampicillin. 5d was found to be active against E. coli, S.
aureus and S. pyogenus similar as ampicillin (Table 4).
All synthesized compounds were screened for antibacte-
rial and antifungal activity against E. coli, P. aeruginosa, S.
1 3

Journal of Chemical Crystallography
Table 3 Geometrical parameters
(Å, °) for π···π stacking
CgI···CgJ
CgI···CgJ
α
β
CgI-Perp
Ring slippage Symmetry code
interactions in 4b and 5b–d
4b
Cg1···Cg1 3.9177 (11) 7.53 (7)
27.81 3.4652 (8)
–
− x+1, y, − z+½
5b
Cg1···Cg1 4.1453 (9)
5c
Cg1···Cg2 3.8621 (11) 5.02 (9)
5d
Cg1···Cg1 4.0513 (15)
0
31.64 − 3.5292 (6) 2.174
− x+1, − y+1, − z+1
− x+1, − y+1, − z+1
26.01 3.5249 (7)
29.09 3.5404 (10)
–
0
1.970
–
− x+1, − y+1, − z+1
− x, − y+1, − z
Cg1···Cg2 4.1617 (16) 9.36 (14) 31.48 − 3.6910 (9)
CgI···CgJ, α, β and CgI-Perp are, respectively, the centroid-to-centroid distance between rings I and J, the
inter-ring dihedral angle, slip angle and the perpendicular distance of CgI from ring J. Cg1 is S1/C1/N1/
C2–C3 and Cg2 is C8–C13 (for 5c) and O3/C8–C11(for 5d) ring centroids, respectively
Fig. 5 a C4–H4A···π and π···π interactions in 5c. Interactions are
indicated by black dashed lines. b Packing of hydrogen-bonded belts
(arbitrary colors) (Color fgure online)
Fig. 6 a π···π stacking interactions in 5d. Interactions are indicated
by black dashed lines. b Packing of hydrogen-bonded belts (arbitrary
colors) (Color fgure online)
Conclusions
Compounds 4a, 4b and 5c were found to be active against
fungal strain C. albicans similar to griseofulvin, whereas 4d
and 5a were found to be more active than griseofulvin. Com-
pound 5d shows activity against C. albicans similar to nystatin
and griseofulvin (Table 5).
Thiazolylcarboxamide derivatives were synthesized by the
reaction of ethyl 2-amino-4-methylthiazole-5-carboxylate
or 1-(2-amino-4-methylthiazol-5-yl)ethan-1-one with four
1 3

Journal of Chemical Crystallography
Table 4 Antibacterial activity
of 4a–d and 5a–d along with
standard drugs
Minimal inhibition concentration (μg/mL)
S. no.
Code given
E. coli
(MTCC443)
P. aeruginosa
(MTCC1688)
S. aureus
(MTCC96)
S. pyogenus
(MTCC442)
1
2
3
4
5
6
7
8
4a
50
25
100
50
250
100
250
250
62.5
125
250
250
0.25
250
50
125
50
4b
4c
100
250
250
100
250
100
0.05
100
50
125
100
500
250
125
62.5
1
–
50
25
10
500
250
125
125
250
100
0.5
100
50
4d
5a
5b
5c
5d
9
Gentamycin
Ampicillin
Chloramphenicol
Ciprofoxacin
Norfoxain
10
11
12
13
25
10
50
10
50
10
Table 5 Antifungal activity of 4a–d and 5a–d along with standard
activity only against C. albicans. Compounds 4d and 5a
have higher activity towards C. albicans as compared to
griseofulvin. Compounds 5a, 5b and 5c show activity
equivalent to griseofulvin against C. albicans, while 5d
shows activity higher than griseofulvin and equivalent to
nystatin against C. albicans.
drugs
Minimal inhibition concentration (μg/mL)
S. no. Code given
C. albicans
A. niger
A. clavatus
(MTCC227) (MTCC282) (MTCC1323)
1
2
3
4
5
6
7
8
9
4a
500
500
1000
250
250
> 1000
500
100
> 1000
1000
> 1000
500
1000
500
1000
500
100
> 1000
500
> 1000
500
500
500
1000
500
100
4b
4c
Experimental
4d
5a
Materials and Method
5b
5c
All the starting materials and solvents (ethyl acetoacetate,
acetylacetone, thiourea, N-bromosuccinimide, 2-chloroben-
zoic acid, thiophene-2-carboxylic acid, 4-methoxybenzoic
acid, furoic acid, pyridine, thionyl chloride, tetrahydro-
furan) were purchased from commercial sources and were
used without further purifcation. Melting points were deter-
mined in open capillaries using Electro thermal melting
point apparatus and are uncorrected. Infrared (FTIR) spectra
(4000–600 cm−1) of the samples were recorded using a Per-
kin–Elmer Spectrum 100, equipped with a Specac Golden
5d
Nystatin
100
10
Griseofulvin 500
100
100
substituted carbonyl chlorides in pyridine as a solvent at
0–5 °C in excellent yield. Single-crystal X-ray structures
of 4b and 5b–d were determined. Owing to the insolu-
bility of synthesized amides it was difcult to obtain the
crystals using any volatile solvent alone. But this was
overcome by use of a mixture of solvents. This method
resulted in good quality crystals of amides. It helped in
revealing structural features of this class of compounds.
Compounds form hydrogen-bonded chains (4b, 5b) and
belts (5c, d) and are further connected through C–H···π
and/or π···π interactions. Compound 4b shows antibacte-
rial activity comparable to ciprofoxacin on E. coli. 4b also
shows higher antibacterial activity than chloramphenicol
in case of E. coli and it shows activity equivalent to chlo-
ramphenicol in case of P. aerugenosa, S. aureus and S.
pyogenus. All compounds show considerable antifungal
1
Gate Diamond ATR as a solid sample support. H NMR
spectra were recorded with a Bruker Avance III 500 NMR
spectrometer with TMS as internal reference. MS spectra
were recorded with an Agilent 6624 Accurate Mass TOF
LC/MS instrument (ESI ionization).
Experimental Procedure
Synthesis
Synthesis of Ethyl 2‑Amino‑4‑methylthiazole‑5‑carboxy‑
late(1) and 1‑(2‑Amino‑4‑methylthiazol‑5‑yl)ethan‑1‑one
1 3

Journal of Chemical Crystallography
(2) Compounds 1 and 2 were synthesized according to the
(s, 1H, NH). IR (cm−1): 3160 (NH), 1687 (C=O), 1533
(C=O), 1377 (C=C), 1273 (C–O).
earlier reported procedure [27] (Scheme2).
General Procedure for Amidation of 1 and 2 Substituted
carbonyl chlorides (3a–d) were prepared by the reaction
of substituted carboxylic acid (50 mmol) and thionyl chlo-
ride (5.5 mL, 75 mmol) at about 50 °C. 3a–d was added to
cooled mixture of 50.0 mmol of 1 or 2 in pyridine (10 mL)
respectively with continuous stirring for about 10 min at
0-5 °C to give dark yellow precipitate of corresponding
carboxamides 4a–d and 5a–d respectively (Scheme 2). The
product obtained was fltered and washed with dilute solu-
tion of sodium bicarbonate to remove unreacted carboxylic
acid if any. It was then washed with water and dried. The
compounds obtained were recrystallized using hot ethyl
acetate [28].
Ethyl
4‑Methyl‑2‑(thiophene‑2‑carboxamido)thia‑
zole‑5‑carboxylate (4b) Yield: 76%, pale yellow solid,
melting point: 218 °C Solubility: ethyl acetate. MS
(ESI+) m/z: 297 (MH+), HRMS: calcd. for C12H13N2O3S2:
297.0362. Found: 297.0372.1H NMR (500 MHz, DMSO,
δ ppm): 1.29 (t, 3H, OCH2CH3), 2.59 (s, 3H, thiazole-
4-CH3), 4.26(q, 2H, OCH2CH3), 7.26 (t, 1H, thiophene),
8.01 (s, 1H, thiophene), 8.27(s, 1H, thiophene),13.11(s,
1H, NH). IR (cm−1): 3273 (NH), 1643 (C=O), 1511
(C=O), 1413 (C=C), 1278 (C–O).
Ethyl 2‑(4‑methoxybenzamido)‑4‑methylthiazole‑5‑car‑
boxylate (4c) Yield-73%, pale yellow solid, melting
point: 160 °C, Solubility: ethyl acetate. MS (ESI+) m/z:
321 (MH+), HRMS: calcd. for C15H17N2O4S: 321.0904.
Found: 321.0913.1H NMR (500 MHz, DMSO, δ ppm):
1.29 (t, 3H, OCH2CH3), 2.60 (s, 3H, thiazole-4-CH3),
3.82 (s, 3H, ArOCH3), 4.26 (q, 2H, OCH2CH3), 7.01 (d,
2H, Ar) 7.89 (d, 2H, Ar–H), 12.64 (s, 1H, NH).IR (cm−1):
2984 (NH), 1674 (C=O), 1517 (C=O), 1423 (C=C), 1294
(C–O).
Crystal Growth Using Combination of Three Solvents
It was observed that the compounds 4a–d and 5a–d were
insoluble in ethanol, chloroform as well as ethyl acetate
at room temperature. Crystals of 4b and 5b–d suitable for
single-crystal x-ray analysis were obtained by adding about
1 g of compound in a mixture of ethanol, chloroform and
ethyl acetate (1:1:1 v/v) 3 mL each. The mixture was heated
slowly in water bath till complete dissolution of the com-
pound, and allowed for slow evaporation in a dark chamber
for about 6–8 days.
Ethyl 2‑(Furan‑2‑carboxamido)‑4‑methylthiazole‑5‑carbox‑
ylate (4d) Yield-71%, pale yellow solid, melting point:
215 °C, Solubility: ethyl acetate. MS (ESI+) m/z: 281
(MH+), HRMS: calcd. for C12H13N2O4S: 281.0591. Found:
1
281.0595. H NMR (500 MHz, DMSO, δ ppm): 1.29 (t,
3H, OCH2CH3), 2.58 (s, 3H, thiazole-4-CH3), 4.26 (q, 2H,
OCH2CH3), 6.75-6.76 (m, 1H, furanyl), 7.72 (s, 1H, fura-
nyl), 8.64 (s, 1H, furanyl), 12.99 (s, 1H, NH). IR (cm−1):
3266 (NH), 1652 (C=O), 1517 (C=O), 1470 (C=C), 1275
(C–O).
Spectral and Physical Data
Ethyl 2‑Amino‑4‑methylthiazole‑5‑carboxylate (1) Yield-
83%, pale yellow solid, melting point: 178–179 °C, Solubil-
ity: Ethanol, 1H NMR (DMSO, 500 MHz, δ ppm): 1.22 (t,
3H, OCH2CH3), 2.37 (s, 3H, thiazole-4-CH3), 4.14 (q, 2H,
OCH2CH3), 7.68 (s, 2H, –NH2).IR (cm−1): 3362 (amine),
2984 (alkyl C–H), 1662 (C=O), 1501 (CH=N), 1366 (C=C).
N‑(5‑Acetyl‑4‑methylthiazol‑2‑yl)‑2‑chlorobenzamide
(5a) Yield-76%, pale yellow solid, melting point: 185 °C,
Solubility: ethyl acetate. MS (ESI+) m/z: 295 (MH+),
HRMS: calcd. forC13H12ClN2O2S: 295.0303. Found:
1‑(2‑Amino‑4‑methylthiazol‑5‑yl)ethan‑1‑one (2) Yield-
85%, pale yellow solid, melting point: 230 °C, Solubility:
Ethanol, 1H NMR (DMSO, 500 MHz, δ ppm): 2.31 (s, 3H,
COCH3), 2.40 (s, 3H, thiazole-4-CH3), 7.79 (s, 2H, –NH2).
IR (cm−1): 3264 (amine), 2989 (alkyl), 1662 (C=O), 1491
(CH=N), 1304 (C=C).
1
295.0297. H NMR (500 MHz, DMSO, δ ppm): 2.32 (s,
3H, COCH3), 2.59 (s, 3H, thiazol-4-CH3), 7.47–7.67 (m,
4H, –Ar), 13.07 (s, 1H, NH). IR (cm−1): 3253 (NH), 1662
(C=O), 1599 (C=O), 1496 (C=C), 1309 (C–O).
N‑(5‑Acetyl‑4‑methylthiazol‑2‑yl)thiophene‑2‑carboxamide
(5b) Yield-74%, pale yellow solid. melting point: 195 °C,
Solubility: ethyl acetate. MS (ESI+) m/z: 267 (MH+),
HRMS: calcd. for C11H11N2O2S2: 267.0256. Found:
Ethyl 2‑(2‑Chlorobenzamido)‑4‑methylthiazole‑5‑carbox‑
ylate (4a) Yield-74%, pale yellow solid, melting point:
140 °C, Solubility: ethyl acetate. MS (ESI+) m/z: 325
(MH+). HRMS: calcd. for C14H14ClN2O3S: 325.0408.
1
267.0252. H NMR (500 MHz, DMSO, δ ppm): 2.32 (s,
1
3H, COCH3), 2.61 (s, 3H, thiazol-4-CH3), 7.26–8.26 (m,
3H, thiophene), 13.10 (s, 1H, NH). IR (cm−1): 3264 (NH),
1662 (C=O), 1599 (C=O), 1491 (C=C), 1309 (C–O).
Found: 325.0416. H NMR (500 MHz, DMSO, δ ppm):
1.30 (t, 3H, OCH2CH3), 2.58 (s, 3H, thiazole–4–CH3),
4.27 (q, 2H, OCH2CH3), 7.78–7.43 (m, 4H, –Ar), 13.09
1 3

Journal of Chemical Crystallography
N‑(5‑Acetyl‑4‑methylthiazol‑2‑yl)‑4‑methoxybenzamide
(5c) Yield-72%, pale yellow solid. melting point: 175 °C,
Solubility: ethyl acetate. MS (ESI+) m/z: 291 (MH+),
HRMS: calcd for C14H15N2O3S: 291.0798. Found:
proposed by the clinical and laboratory standard institute
[32–36].
Acknowledgements The authors are thankful to Microcare Labora-
tory and Tuberculosis Research Centre, Surat, India for providing
antibacterial and antifungal activity. Financial support from the Slo-
venian Research Agency (ARRS) through project P1-0175 is gratefully
acknowledged. We thank the EN-FIST Centre of Excellence, Ljubljana,
Slovenia, for using SuperNova difractometer.
1
291.0792. H NMR (500 MHz, DMSO, δ ppm): 2.32 (s,
3H, COCH3), 2.61 (s, 3H, thiazol-4-CH3), 3.85 (s, 3H,
–OCH3) 7.08 (d, 2H, –Ar),8.12 (d, 2H, –Ar), 12.82 (s, 1H,
NH). IR (cm−1): 3264 (NH), 1662 (C=O), 1599 (C=O),
1496 (C=C), 1247(C–O).
N‑(5‑Acetyl‑4‑methylthiazol‑2‑yl)furan‑2‑carboxamide
(5d) Yield-70%, pale yellow solid melting point: 190 °C,
Solubility: ethyl acetate. MS (ESI+) m/z: 251 (MH+),
HRMS: calcd for C11H11N2O3S: 251.0485. Found:
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