A convenient synthesis and antimicrobial activity of functionalized 1,2,4-triazoles and 3-amino-alkyltetraazabicyclo[3.3.0]octan-8-ones

Article abstract of DOI:10.14233/ajchem.2013.15183

5-Amino-1,2,4-triazole derivatives and their bicyclic system were synthesized in moderate to good yields from the corresponding a-aminoesters, hydrazine or methylhydrazine and the starting material dimethyl N-cyanodithioiminocarbonate. Many target compounds were obtained. But, in cases when the bicyclic system is not formed, 5-amino-1,2,4-triazoles are usually formed. Structures of the prepared compounds were elucidated on the basis of their spectral data and their antifungal and antibacterial activities were also evaluated.

Full text of DOI:10.14233/ajchem.2013.15183

Asian Journal of Chemistry; Vol. 27, No. 11 (2015), 4081-4084
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.19092
One Pot Synthesis and Antimicrobial Activity of Substituted 2-Aminothiazoles
ABDULLAH SULAIMAN AL-AYED
Department of Chemistry, College of Sciences and Arts at Al-Rass, Qassim University, P.O. Box 53, Kingdom of Saudi Arabia
Corresponding author: Fax: +966 3 63339351; Tel: +966 505142736; E-mail: asaaied@qu.edu.sa
Received: 9 February 2015;
Accepted: 20 March 2015;
Published online: 16 July 2015;
AJC-17407
In this work, we described a preparation of substituted 2-aminothiazoles by two different methods using a one-pot procedure and starting
from methoxymethylene-3-aryl-thiourea (2). The synthesized 2-aminothiazoles (5a-h) were characterized on the basis of elemental analysis
and their spectral (IR, 1H NMR and 13C NMR) data and evaluated their biological activities. The majority of compounds were found to
exhibit significant antimicrobial activity.
Keywords: Methoxymethylene-3-aryl-thiourea, 2-Aminothiazoles, Antimicrobial activity.
heterocyclic five-membered12-14, we designed and synthesized
novel substituted 2-aminothiazole as possible antibacterial
INTRODUCTION
The growing interest in bioactive substituted thiazoles
agents.
has led to an increasing demand for efficient syntheses of this
class of heterocyclic compounds. A large number of research
EXPERIMENTAL
articles have been published during the last few years about
the synthesis and pharmacological applications of thiazole
derivatives. They have attracted widespread attention due to
their diverse biological activities.As medicines, many of them
display including anti-HIV1, anti-inflammatory2, tubercular
activities3, hypertension4, anticancer5, anticonvulsant6, anti-
bacterial and antifungal7,8. Particularly, the 2-aminothiazole
moiety, proven its value in medicinal that has been successfully
applied in dopamine agonists, such as mirapexin, the widely
used anti-parkinsonian agent9 and multi-targeted protein
tyrosine kinase inhibitor with potential antineoplastic activity
(Masitinib)10 and in agrochemicals fields such as herbicide
antidotes11 (Scheme-I).
Melting points were taken with a Kofler hot staged
apparatus and are uncorrected. All reactions were monitored
by thin layer chromatography (TLC). IR spectra were deter-
mined with a Perkin Elmer 1600 series FTIR spectrometer.
Elemental analyses were determined using an elementar vario
El III ElementalAnalyzer. 1H NMR and 13C NMR spectra were
recorded on aVarian Unity spectrometer at 300 MHz using TMS
as an internal standard. The bacterial strains and Aspergillus
niger fungus were obtained from the Centre of the agro food
of Tunis (Tunisia).
Synthesis of methoxymethylene-3-aryl-thiourea (2):
Isothiocyanate was mixed in a 1:1 ratio with the desired imidic
acid methyl ester (1) in dry ether. The reaction mixture was
stirred at room temperature for about 2-3 h. The formed solid
was separated by filtration and the precipitates were washed
with dry ether and then recrystallized from absolute ethanol.
Encouraged by the biological activities of derivatives
mentioned above and as a part of the ongoing work of our
team on the synthesis and reactivity of biologically active
CF3
H
N
O
S
O
S
S
N
S
N
N
N
H
N
H
N
N
H
N
NH2
Cl
N
N
CF3
Mirapexin
anti-Parkinsonian agent
Masitinib
tyrosine kinase inhibitor targeting KIT
Herbicide antidotes
Scheme-I: Drug candidates with 2-aminothiazole moiety

4082 Al-Ayed
Asian J. Chem.
1-(Methoxy-phenyl-methylene)-3-phenyl-thiourea (2a):
added dropwise under nitrogen atmosphere with stirring at
room temperature a solution of methoxymethylene-3-aryl-
thiourea (2) (10 mmol) in THF (20 mL). After stirring for 1 h,
Br-CH2-EWG (10 mmol) dissolved in THF (30 mL) was added.
The reaction mixture was stirred for a period of 12 h and
hydrolyzed with water (10 mL). The organic layer was
extracted zith chloroform, dried over MgSO4 and concentrated
under reduced pressure to give the corresponding 2-amino-
thiazole 5 witch was purified by recrystallization from ethanol.
4-Phenyl-2-phenylamino-thiazole-5-carboxylic acid
Yield 90 %; m.p. 124-126 °C; 1H NMR (CDCl3): δ 8.87 (br. s,
1H), 7.47-7.28 (m, 10 H), 3.85 (s, 3H); 13C NMR (CDCl3): δ
181.4, 167.1, 137.8-122.6 (Carom), 47.2. IR (KBr, νmax, cm-1)
3207, 1658, 1550, 1448, 1340, 1315, 1296, 1054.
1-(4-Chloro-phenyl)-3-(methoxy-phenyl-methylene)-
thiourea (2b):Yield 73 %; m.p. 136-138 °C; 1H NMR (CDCl3):
δ 9.06 (br. s, 1H), 7.45-7.39 (m, 5 H), 7.27-7.18 (m, 4 H),
3.85 (s, 3H); 13C NMR (CDCl3): δ 180.7, 166.9, 134.7-126.8
(Carom), 49.1. FT-IR (KBr, νmax, cm-1) 3202, 1654, 1552, 1448,
1351, 1319, 1283, 1089.
1
ethyl ester (5a): Yield 82 %; m.p. 142-144 °C; H NMR
1-Benzyl-3-(methoxy-phenyl-methylene)thiourea (2c):
Yield 81 %; m.p. 106-108 °C; 1H NMR (CDCl3): δ 7.85 (br. s,
1H), 7.52-7.37 (m, 5 H), 7.21-7.13 (m, 5 H), 3.92(s, 2H) 3.81
(s, 3H); 13C NMR (CDCl3): δ 181.2, 167.4, 141.3-127.1 (Carom),
53.8, 47.2. FT-IR (KBr, νmax, cm-1) 3197, 1656, 1554, 1447,
1351, 1310, 1282, 1056.
(CDCl3): δ 9.67 (br. s, 1H), 7.54-7.22 (m, 10 H), 4.23 (q, 2H,
13
J = 7.6 Hz), 1.18 (t, 3H, J = 7.6 Hz); C NMR (CDCl3): δ
168.4, 161.5, 158.5, 140.3, 133.7-121.6 (Carom), 60.5, 14.2;
FT-IR (CHCl3, νmax, cm-1) 3389, 1709, 1602, 1537, 1442, 1294.
Anal. calcd. (%) for C17H14N2O2S: C, 65.79; H, 4.55; N, 9.03.
Found (%): C, 65.58; H, 4.76; N, 9.19.
1-(1-Methoxy-2-phenyl-ethylidene)-3-phenyl-thiourea
(2d):Yield 62 %; m.p. 114-116 °C; 1H NMR (CDCl3): δ 8.76
(br. s, 1H), 7.47-7.36 (m, 10 H), 3.13 (s, 2H), 3.85 (s, 3H); 13C
NMR (CDCl3): δ 179.5, 167.1, 137.2-125.1 (Carom), 48.4, 32.8.
FT-IR (KBr, νmax, cm-1) 3217, 1657, 1548, 1439, 1349, 1308,
1282, 1062.
Synthesis of methoxymethylene-isothiourea (3): To a
suspension of 20 mmol of sodium hydride in 50 mL of dry
THF, 10 mmol of methoxymethylene-3-aryl-thiourea (2) was
added at room temperature under nitrogen atmosphere. After
stirring for 1 h, 10 mmol of methyl iodide in 20 mL of THF
was added. The mixture was stirred for an additional 18 h. Then,
the solution was quenched by distilled water. The extraction
was carried out with ether. After the usual work up, the solvent
was evaporated under reduced pressure was either dried under
vacuum (3c-d) or treated with pentane and recrystallized from
methanol (3a-b).
Phenyl-(4-phenyl-2-phenylamino-thiazol-5-yl)-
1
methanone (5b): Yield 78 %; m.p.136-138 °C; H NMR
13
(CDCl3): δ 9.52 (br. s, 1H), 7.75-7.18 (m, 15 H); C NMR
(CDCl3): δ 186.3, 163.4, 145.5, 141.1, 137.3-120.5 (Carom);
FT-IR (KBr, νmax, cm-1) 3393, 1693, 1598, 1538, 1444, 1302.
Anal. calcd. (%) for C22H16N2OS: C, 74.13; H, 4.52; N, 7.86.
Found (%): C, 73.91; H, 4.74; N, 8.03.
2-(4-Chloro-phenylamino)-4-phenyl-thiazole-5-
carboxylic acid ethyl ester (5c):Yield 73 %; m.p. 160-162 °C;
1H NMR (DMSO-d6): δ 8.47 (br. s, 1H), 7.45-7.22 (m, 9 H),
4.19 (q, 2H, J = 7.6 Hz), 1.22 (t, 3H, J = 7.6 Hz); 13C NMR
(DMSO-d6): δ 168.4, 160.4, 157.0, 141.2, 135.3-122.1 (Carom),
59.9, 14.8; FT-IR (KBr, νmax, cm-1) 3398, 1697, 1692, 1590,
1532, 1466, 832, 764. Anal. calcd. (%) for C17H13ClN2O2S: C,
59.21; H, 3.80; N, 8.12. Found (%): C, 59.47; H, 4.07; N,
4.32.
2-Benzylamino-4-phenyl-thiazole-5-carboxylic acid
1
1-(Methoxy-phenyl-methylene)-2-methyl-3-phenyl-
ethyl ester (5d): Yield 76 %; m.p. 160-162 °C; H NMR
1
isothiourea (3a): Yield 76 %; m.p. 52-54 °C; H NMR
(CDCl3): δ 9.18 (br. s, 1H), 7.42-7.17 (m, 10 H), 4.51 (s, 2 H),
4.23 (q, 2H, J = 7.6 Hz), 1.19 (t, 3H, J = 7.6 Hz); 13C NMR
(CDCl3): δ 168.5, 162.0, 158.1, 139.8, 134.5-121.4 (Carom),
60.2, 49.3, 14.6; FT-IR (KBr, νmax, cm-1) 3396, 1696, 1594,
1528, 1485. Anal. calcd. (%) for C18H16N2O2S: C, 66.64; H,
4.97; N, 8.64. Found (%): C, 66.42; H, 4.15; N, 8.83.
(CDCl3): δ 7.43-7.37 (m, 10 H), 3.76 (s, 3H), 2.55 (s, 3H); 13C
NMR (CDCl3): δ 166.4, 165.7, 137.2-123.5 (Carom), 46.8, 15.27.
FT-IR (KBr, νmax, cm-1) 1653, 1645, 1550, 1340, 1327.
1-(4-Chloro-phenyl)-3-(methoxy-phenyl-methylene)-2-
methyl-isothiourea (3b):Yield 64 %; m.p. 94-96 °C. 1H NMR
(CDCl3): δ 7.29-7.42 (m, 10 H), 3.81 (s, 3H), 2.58 (s, 3H); 13C
NMR (CDCl3): δ 166.7, 165.2, 142.7-124.2 (Carom), 47.3, 14.9.
FT-IR (KBr, νmax, cm-1) 1650, 1648, 1552, 1357, 1331.
1-Benzyl-3-(methoxy-phenyl-methylene)-2-methyl-
isothiourea (3c):Yield 67 %; An oil. 1H NMR (CDCl3): 7.09-
7.22 (m, 5 H), 7.35-7.48 (m, 5 H), 3.87(s, 2H), 3.73 (s, 3H);
2.49 (s, 3H); 13C NMR (CDCl3): δ 165.8, 163.4, 136.5-125.7
(Carom), 51.3, 47.8, 15.3. FT-IR (CHCl3, νmax, cm-1) 1652, 1643,
1554, 1351, 1310, 816, 768.
4-Benzyl-2-phenylamino-thiazole-5-carboxylic acid
1
ethyl ester (5e): Yield 81 %; m.p. 160-162 °C; H NMR
(CDCl3): δ 8.13 (br. s, 1H), 7.38-7.21 (m, 10 H), 4.57 (s, 2 H),
4.21 (q, 2H, J = 7.6 Hz), 1.23 (t, 3H, J = 7.6 Hz); 13C NMR
(CDCl3): δ 168.3, 161.8, 156.3, 139.4, 136.2-121.4 (Carom),
60.6, 36.0, 14.5; FT-IR (KBr, νmax, cm-1) 3406, 1703, 1602,
1531, 1476. Anal. calcd. (%) for C18H16N2O2S: C, 66.64; H,
4.97; N, 8.64. Found (%): C, 66.47; H, 4.12; N, 8.56.
4-Phenyl-2-phenylamino-thiazole-5-carbonitrile (5f):
Yield 88 %; m.p. 150-152 °C; 1H NMR (DMSO-d6): δ 10.53
(br. s, 1H), 7.53-7.18 (m, 10 H); 13C NMR (DMSO-d6): δ 160.1,
1-(1-Methoxy-2-phenyl-ethylidene)-2-methyl-3-phenyl-
1
isothiourea (3d): Yield 73 %; An oil; H NMR (CDCl3): δ
7.42-7.47 (m, 10 H), 3.82 (s, 3H), 3.13 (s, 2H), 2.61 (s, 3H);
13C NMR (CDCl3): δ 165.8, 162.7, 138.4-123.6 (Carom), 51.4,
33.7, 13.9. FT-IR (KBr, νmax, cm-1) 1653, 1647, 1531, 1349,
1308.
151.5, 139.2, 133.8-120.5 (Carom), 114.2; FT-IR (KBr, νmax,
cm-1) 3395, 2224, 1605, 1538, 1481. Anal. calcd. (%) for
C16H11N3S: C, 69.29; H, 4.00; N, 15.15. Found (%): C, 69.45;
H, 3.88; N, 14.97.
Synthesis of 2-aminothiazole 5 (methodA): To a suspen-
sion of 20 mmol of sodium hydride in 50 mL of dry THF was
(4-Chloro-pheny)-1-(4-phenyl-2-phenylamino-thiazol-
5-yl)-methanone (5g):Yield 72 %; m.p. 142-144 °C; 1H NMR

Vol. 27, No. 11 (2015)
One Pot Synthesis and Antimicrobial Activity of Substituted 2-Aminothiazoles 4083
(DMSO-d6): δ 9.47 (br. s, 1H), 7.63-7.21 (m, 14 H); 13C NMR
(DMSO-d6): δ 189.7, 162.1, 147.2, 140.5, 138.1-121.3 (Carom);
FT-IR (KBr, νmax, cm-1) 3393, 1696, 1602, 1537, 1463, 835,
762.Anal. calcd. (%) for C22H15ClN2OS: C, 67.60; H, 3.87; N,
7.17. Found (%): C, 67.73; H, 4.03; N, 7.04.
The literature shows that the schemeA and C are the most
commonly used and known the Hantzsch reaction15. We show
in the present research article that the pattern B is very conve-
nient way allowing access to this type of compound. The
synthetic pathways depicted in Schemes II and III outlines,
the chemistry of the present study. Our synthesis began with
the starting material methoxymethylene-3-aryl-thiourea (2),
which are easily prepared in good yield following the reaction
of imidic acid methyl ester (1) with isothiocyanate (Scheme-II).
4-Benzyl-2-phenylamino-thiazole-5-carbonitrile (5h):
1
Yield 62 %; m.p. 114-116 °C; H NMR (DMSO-d6): δ 9.03
(br. s, 1H), 7.37-7.23 (m, 10 H), 4.53 (s, 2 H); 13C NMR
(DMSO-d6): δ 159.8, 149.3, 139.7, 134.0-121.2 (Carom), 114.1,
35.2; FT-IR (KBr, νmax, cm-1) 3397, 2225, 1601, 1539, 1485.
Anal. calcd. (%) for C17H13N3S: C, 70.08; H, 4.50; N, 14.42.
Found (%): C, 70.23; H, 4.38; N, 14.57.
O
S
O
N
Ether
r.t.
R2
R2
C
+
R1
N
N
S
R1
NH
H
RESULTS AND DISCUSSION
2
1
To access the thiazole ring, three reaction schemes (A, B
and C) are possible.
Compounds 2, 3
2a, 3a
R1
R2
Ph
4-Cl-Ph
Ph-CH2-
Yield (%)
90, 76
73, 64
81, 67
62, 73
Ph
Ph
Ph
2b, 3b
2c, 3c
2d, 3d
N
N
C
C
C
C
C
N
C
Ph-CH2-
Ph
C
C
Scheme-II
S
S
S
Compounds 2 behave as 1,3-bielectrophilic reagents.
However, in certain conditions, the thioamide function they
can be in equilibrium with its tautomeric form thioimidic acid.
B
A
C
O
S
O
SMe
N
NaH , THF
00C
+
MeI
R
2
R
2
R
1
N
N
R
N
1
H
3
2
1/ Na2S, 9H2O
NaH
X
method B
method A
EWG
EWG
O
S Na
O
S
N
,
MeS Na
2/ X-CH2-EWG
3/ NaH
R
2
R
2
R
N
N
1
R
1
N
3'
4
S
NH
EWG
NaH
R
2
THF
N
R
1
5
X = Cl, Br
R = Ph, Ph-CH -
R = Ph, 4-Cl-Ph , Ph-CH -
1
2
2
2
EWG = CN, CO Et , Ph-CO- , 4-Cl-Ph-CO-
2
Compounds 5
R1
Ph
Ph
Ph
Ph
R2
Ph
Ph
EWG
CO2Et
Ph-CO
CO2Et
CO2Et
CO2Et
CN
Yield* (%)
5a
5b
5c
5d
5e
5f
82
78
73
76
81
88
72
62
4-Cl-Ph
Ph-CH2-
Ph
Ph-CH2-
Ph
Ph
Ph-CH2-
Ph
Ph
Ph
5g
5h
4-Cl-Ph-CO
CN
*Yield calculated using method A.
Scheme-III

4084 Al-Ayed
Asian J. Chem.
TABLE-1
O
S
O
SH
ANTIMICROBIAL SCREENING RESULTS
R2
R2
R1
N
N
H
R1
N
N
OF 2-AMINOTHIAZOLES (5a-h)
Diameter of growth inhibition zone (mm)
Thioamide form
Thioamidic acid form
Compd.
Antibacterial activity
Antifungal activity
P. aeruginosa
E. coli
9
17
12
-
S. aureus
A. niger
13
9
17
15
13
-
8
5
24
-
Thus, these compounds are transformed into 1,4-electro-
philic-nucleophilic reagents. This equilibrium has been
exploited by many researchers to synthesize a wide range of
sulfur heterocycles16-18. The first test performed on the methyl
iodide in the presence of sodium hydride as a base was succe-
ssful. We isolated after hydrolysis, the corresponding product
and thus verified the existence of the thioimidic thioamide-
acid equilibrium in such compounds.
This success has lead us to believe that the introduction
of a relatively active methylene promote cyclization to thiazole.
By increasing the mobility of hydrogen in the α-position with
respect to sulfur using alkyl halides activated by electron-
withdrawing groups, we finally got the expected 2-aminothiazoles
(5) (methodA) via the non-isolated intermediates 4 with yields
ranging from 62 to 88 %. We operated in the presence of a double
amount of sodium hydride (Scheme-II).
The methoxymethylene-isothiourea (3) can be engaged
in a one-pot three-step procedure (method B) and sodium
sulfide was added to form the thiolate (3') that reacted with
activated halides and finally, cyclization was completed by
reacting intermediate 4 with sodium hydride (Scheme-II). It
is noted that the best yields were obtained in this procedure
by using 2 equivalents of activated halides. This can be explained
by considering that the activated halide reacts first with sodium
methylthiolate, which is more nucleophilic than the inter-
mediate formed thiolate (3'). It is noted that the yields obtained
by this method are low and vary from 20 to 30 %.
5a
5b
5c
5d
5e
5f
5g
12
11
9
5
8
12
13
11
-
11
13
11
9
-
8
11
12
-
5
19
16
18
-
5h
Griseofulvin
Ampicillin
15
22
19
attached to the thiazole nucleus has no significant influence
on the antimicrobial activity.
Conclusion
A one-pot procedure was developed to prepare substituted
2-aminothiazoles using two different methods starting from
methoxymethylene-3-aryl-thiourea. All the synthesized
thiazoles have been tested for in vitro antimicrobial activities.
The antimicrobial activity is closely related to electron-attached
group in position 5 of the thiazole ring. The thiazole 5f (EWG
= CN) showed potent antibacterial activity and 5c (EWG =
CO2Et) showed potent antifungal activity.
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