One pot synthesis of tetrahydroquinoline-5-thiones and evaluation of their antimicrobial activities

Article abstract of DOI:10.3184/030823408X314473

One-pot syntheses of various tetrahydroquinoline-5-thiones are reported. The antimicrobial activity of the obtained products against various types of bacteria was estimated.

Full text of DOI:10.3184/030823408X314473

JOURNAL OF CHEMICAL RESEARCH 2008
APRIL, 205–207
RESEARCH PAPER 205
One pot synthesis of tetrahydroquinoline-5-thiones and evaluation of
their antimicrobial activities
Aboul-Fetouh E. Mourada, Ashraf A. Alya*, Hassan H. Faragb, Mohamed F. Radwanc and
Eman A. Beshrc
aChemistry Department, Faculty of Science, El-Minia University, 61519-El-Minia, Egypt
bMedicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt
c Medicinal Chemistry Department, Faculty of Pharmacy, El-Minia University, 61519-El-Minia, Egypt
One-pot syntheses of various tetrahydroquinoline-5-thiones are reported. The antimicrobial activity of the obtained
products against various types of bacteria was estimated.
Keywords: dihydropyridines, tetrahydroquinoline-5-thiones, antimicrobial activity
The oxidation of 1,4-dihydropyridines (1,4-DHPs) to the
corresponding pyridines occurs initially during the first pass
metabolism in the liver.1 A variety of reagents has been
utilised for this oxidative conversion: nitric acid,2 manganese
dioxide–bentonite clay,3 chromium trioxide,4,5 potassium
permanganate,6 pyridinium chlorochromate,7 ceric ammonium
nitrate (CAN),8 clayfen,9 bismuth trinitrate,10 and ruthenium
trichloride.11 However, most of these reactions require an
extended period of time for completion, utilise strong oxidants
in large excess, and give only modest yields of the products.
Varma12 demonstrated that solid state oxidation of 1,4-
DHPs using elemental sulfur yields the dehydro derivatives,
whatever the 4-substituent is. Bagley reported that substituted
arene- or heteroarene-carbonitriles can be converted into the
corresponding thioamides, when treated with sodium sulfide
solution in methanol at reflux.13 Subsequently, we have applied
those conditions to 2-amino-4-aryl-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 1a–d, and we
described the results herein. We also tested the activity of the
obtained products as antimicrobial compounds. Having been
interested in the synthesis of pyridines that carry heterocyclic
substituents for some time,14 we now report the preparation of
tetrahydroquinoline-5-thiones by a novel, efficient and facile
procedure.
The formation of compounds 2a–d is emphasised by the
precedence of the activity of sulfur atom in the oxidation under
acidic conditions.15,16 The structures of 2a–d were confirmed
by spectroscopic data and elemental analyses. EI-MS gave
molecular ion peaks related to the molecular weight of the
suggested structures. The 1H NMR, 13C NMR andIR spectra of
2a–d generally were consistent with the suggested structures.
The IR spectra of 2a–d generally exhibited absorption bands at
n = 1200–1170 and 1322–1312 (C=S), 2220–2210 (CN), and
3240–3200 cm-1 (NH2). For example, in compound 2a these
appeared at ν = 1170, 1320, 2212, and 3240 cm-1 respectively.
1
In H NMR spectra, compounds 2a–d lack the characteristic
dihydropyridine- NH and 4-CH signals (d = 11.00–12.00 and
4.20–4.80 respectively)17 found in the starting materials 1a–d.
Three singlets were observed at d = 6.10–6.30 (broadened),
3.22–3.10, and 1.06–0.97 ppm corresponding to the NH2,
8-CH2 and CH3 protons, respectively. Distinctive d' values of
the 1H NMR spectrum of compound 2a are as shown in Fig. 1.
As an example, the 13C NMR spectrum of 2a (see also Fig. 1)
revealeddistinctivesignalsatd=182.0,164.0,160.0,143.0,128.0,
126.0 and 99.0 assignable to C-5, C-8a,Ar-C-4', C-2, C–4, C-4a
and C-3, respectively (Fig. 1). In the case of 2c, the 1H NMR
spectrum revealed the NH2-protons as a broad singlet at
d = 6.22 ppm, whereas the protons in the p-chlorophenyl ring
resonated as two double-doublets, each for two protons, at
d = 7.22 and 7.03 ppm (J = 8.0, 1.2 Hz). The 13C NMR
spectrum of 2c showed the thione group at d = 182.8 along
with C-4, C-2 and nitrile at d = 138.6, 126.8 and 113.5 ppm,
respectively. The carbon signals of all substitutes of
compounds 2a–d were completely recognised from their 13C
NMR spectra (see the Experimental). For example, compound
Results and discussion
The reaction of compounds 1a–d with sodium sulfide in
refluxing aqueous methanol (Scheme 1), followed by treatment
of the aqueous layer with a few drops of concentrated
hydrochloric acid (until pH=7), afforded the corresponding
tetrahydroquinoline-5-thiones 2a–d in good yields (Scheme 1).
O
Ar
S
Ar
1. MeOH, reflux
5-8 h
CN
CN
+
Na2S
2. HCl
N
H
1a-d
NH2
N
2a-d
NH2
O
Ar
CSNH2
NH2
Ar
Yield of 2 (%)
1-3
4-CH3O-C6H4-
4- CH3-C6H4-
4-Cl-C6H4-
C6H5
a
b
c
85
80
67
72
N
H
3a-d
d
Scheme 1 Synthesis of tetrahydrquinoline-5-thiones 2a–d.
* Correspondent. E-mail: ashrafaly63@yahoo.com.
PAPER: 08/5136

206 JOURNAL OF CHEMICAL RESEARCH 2008
d
( = 160.0)
(d
=130.4)
d
( = 3.90)
OMe
d
( = 53.8)
OMe
d
d
( =126.0)
( = 6.64)
= 7.60)
d
( =118.0)
d
d
( =182.0)
( =132.0)
d
(
d
(
= 99.0)
S
N
S
d
( = 48.8)
N
d
( = 3.20)
d
( =113.0)
H3C
N
NH2
d
(
= 0.97)
H3C
CH3
d
( =128.0)
d
N
NH2
( = 26.2)
CH3
d
( = 143.0)
(d
d
= 32.0)
d
( = 50.5)
( = 25.8)
d
(
= 1.06)
d
( = 6.10)
d
(
=164.0)
d
( = 2.42, 2.30)
Fig. 1 Disctinctive d’s values of compound 2a.
2b has carbon signals at d = 182.6 (C-5), 163.6 (C-8a), 142.0
(C-4), 134.0 (ArC-4'), 130.8 (2 ArCH, CH-2', -6'), 128.6
(ArC-1'), 127.6 (C-2), 126.8 (C-4a), 126.2 (2 ArCH,
CH-3', -5'), 113.4 (CN), 99.4 (C-3), 50.2 (C-7), 48.4 (C-6),
34.2 (CH3), 32.2 (C-8), 26.0 (CH3), 25.6 (CH3).
Table 1 Minimum inhibitory concentration of the tested
compounds 2a–d
Compound
Minimum inhibitory concentration in mg/ml
S. aureus B. subtillus E. coli K. pneumoniae
The synthesised compounds were tested for their
antibacterial activity by adopting (Cup–plate method)18,19 the
agar well diffusion technique. The following bacterial cultures
were used for anti-bacterial activity studies: Staphylococcus
aureus, Bacillus subtilis, Escherichia coli, and Klebsiella
pneumoniae. From Table 1 it is evident that the newly
synthesised compounds 2a–d have no antibacterial activity
against S. aureus and B. subtillus (Gram positive) while they
have antimicrobial activity against E.coli and K. pneumoniae
(Gram negative). Also, it was noted that compounds 2a–d
are more potent against E.coli and K. pneumoniae than the
standard drug Ciprofloxacin with MIC ranged from 6.25 to
12.5 and 6.25 to 20 µg/ml respectively. Compound 2a showed
more antimicrobial activity than 2b, 2c, or 2d, against either
E.coli or K. pneumoniae.
Ciprofloxacin
50
0
50
0
25
25
6.25
20
12.5
12.5
2a
2b
2c
2d
6.25
12.5
12.5
6.25
0
0
0
0
0
0
Synthesis of 2-amino-4-aryl-7,7-dimethyl-5-thioxo-5,6,7,8-tetrahydro-
quinoline-3-carbonitriles (2a–d)
General procedure
A mixture of 1a–d (1 mmol) and sodium sulfide (2.0 mmol, 0.16 g)
in methanol (50 ml) was heated at reflux for 5–8 h. The precipitate
formed was filtered off and a few drops of concentrated hydrochloric
acid were added to the clear solution till pH = 7. The solid material
formed was collected by filtration and purified by recrystallisation to
give products 2a–d.
In conclusion, we have developed simple, rapid and
practical method for sulfurisation and oxidation of 1,4-
dihydropyridinones to thienopyridines. Thienopyridines are
proved to be effective antimicrobial gram negative bacteria.
2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-thioxo-5,6,7,8-
tetrahydroquinoline-3-carbonitrile (2a): Pale orange crystals (0.29 g,
85%), m.p. 320–322°C (ethanol). 1H NMR: d = 7.60 (dd, 2 H, ArH,
J = 8.2, 1.2 Hz), 6.64 (dd, 2 H, ArH, J = 8.2, 1.2 Hz), 6.10 (br s,
2 H, NH2), 3.90 (s, 3 H, OCH3), 3.20 (s, 2 H, 6-CH2), 2.42 (d, 1
H, 8-H, J = 16.1 Hz), 2.30 (d, 1 H, 8'-H, J = 16.1 Hz), 1.06 (s, 3
H, CH3); 0.97 (s, 3 H, CH3). 13C NMR: d = 182.0 (C-5), 164.0 (C-
8a), 160.0 (ArC-4'), 143.0 (C-4), 132.0 (ArCH-2',6'), 130.4 (ArC-1'),
128.0 (C-2), 126.0 (C-4a), 118.0 (ArCH-3',5'), 113.0 (CN), 99.0
(C-3), 53.8 (OCH3), 50.5 (C-7), 48.8 (C-6), 32.0 (C-8), 26.2 (CH3),
25.8 (CH3). IR: n = 3240 (m, NH2), 3030-2980 (m, ArCH), 2970–
2765 (m, aliph-CH), 2212 (m, CN), 1610 (s, C=N), 1595 (m, C=C),
1320, 1170 (s, C=S). MS (70 eV), m/z (%) = 337 [M+] (100), 322
(18), 306 (36), 290 (28), 264 (18), 250 (30), 234 (16), 229 (28), 108
(60), 77 (34). Anal. Calcd. for C19H19N3OS (337.45): C, 67.63; H,
5.68; N, 12.45; S, 9.50. Found: C, 67.58; H, 5.64; N, 12.50; S, 9.59.
2-Amino-4-(4-methylphenyl)-7,7-dimethyl-5-thioxo-5,6,7,8-
tetrahydroquinoline-3-carbonitrile (2b): Yellow crystals (0.26 g,
80%), m.p. 311–313°C (acetone). 1H NMR: d = 7.50–7.28 (m,
4 H, ArH), 6.30 (br s, 2 H, NH2), 3.22 (s, 2 H, 6-CH2), 2.40 (d, 1 H,
8-H, J = 15.9 Hz), 2.34 (s, 3 H, CH3Ar), 2.30 (d, 1 H, 8'-H, J = 15.9
Hz), 1.10 (s, 3 H, CH3), 0.99 (s, 3 H, CH3). 13C NMR: d = 182.6
(C-5), 163.6 (C-8a), 142.0 (C-4), 134.0 (ArC-4'), 130.8 (ArCH-
2',6'), 128.6 (ArC-1'), 127.6 (C-2), 126.8 (C-4a), 126.2 (ArCH-3',-
5'), 113.4 (CN), 99.4 (C-3), 50.2 (C-7), 48.4 (C-6), 34.2 (CH3), 32.2
(C-8), 26.0 (CH3), 25.6 (CH3). IR (KBr): n = 3210 (m, NH2), 3050–
2990 (m, ArCH), 2972–2770 (m, aliph-CH), 2210 (m, CN), 1612
(s, C=N), 1560 (s, C=C), 1318, 1175 (s, C=S). MS (70 eV), m/z (%)
= 321 [M+] (100), 304 (32), 288 (32), 264 (22), 250 (28), 234 (20),
229 (30), 91 (56), 77 (30). Anal. Calcd for C19H19N3S (321.44): C,
70.99; H, 5.96; N, 13.07; S, 9.98. Found: C, 70.85; H, 5.90; N, 13.11;
S, 9.90.
Experimental
General
All melting points were recorded on a Gallenkamp apparatus. 1H NMR
(400.134 MHz) and 13C NMR (100.6 MHz) spectra were measured in
DMSO-d6, on a Bruker AM 400 spectrometer. Chemical shifts are
expressed in d, and coupling constants are expressed in Hz. Elemental
analyses were carried at the Cairo Microanalysis Centre of Ca
iro University. The IR spectra were run on a Shimadzu 470
spectrometer using KBr pellets; absorption frequencies are expressed
in cm-1. All the microorganisms used were obtained from the
laboratory stock of the Department of Microbiology; Faculty of
Pharmacy, El-Minia University. Ciprofloxacin was used as the
standard drug. Nutrient agar was poured onto the sterilised Petri dishes
(20–25 ml: each petri dish). The poured material was allowed to set
(1–1.5 h) and thereafter the ‘CUPS’ (10 mm diameter) was made by
punching into the agar surface with a sterile cork borer and scooping
out the punched part of the agar. Into these cups the test compound
solution was added via a sterile syringe. The plates were incubated
at 37oC for 48 h and the results were noted. A solvent control (DMF)
was also run. Further dilutions of the compounds and standard drug
in the test medium were prepared at the quantities of 400, 200, 100,
50, 25, 12.5, 6.25, 3.12, 1.56, 0.78 µg/ml. The minimum inhibitory
concentrations (MIC) were determined using the two-fold serial
dilution technique.19,20
Starting materials
Dihydropyridines 1a–d were prepared according to ref. 17.
PAPER: 08/5136

JOURNAL OF CHEMICAL RESEARCH 2008 207
2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-thioxo-5,6,7,8-
Received 5 March 2008; accepted 16 April 2008
Paper 08/5136 doi: 10.3184/030823408X314473
tetrahydroquinoline-3-carbonitrile (2c): Yellow crystals (0.23 g,
1
67%), m.p. 350–352°C (EtOH). H NMR: d = 7.22 (d, 2 H, ArH,
J = 8.0, 1.2 Hz), 7.03 (dd, 2 H, ArH, J = 8.0, 1.2 Hz), 6.22 (br s, 2 H,
NH2), 3.18 (s, 2 H, 6-CH2), 2.38 (d, 1 H, 8-H, J = 15.9 Hz), 2.20 (d,
1 H, 8'-H, J = 15.9 Hz), 1.20 (s, 3 H, CH3), 1.00 (s, 3 H, CH3). 13C
NMR: d = 182.8 (C-5), 166.2 (C-8a), 138.6 (C-4), 128.8 (ArC-1'),
128.0 (ArC-1'), 128.6 (C-4a) 126.8 (C-2), 126.1 (ArC-4'), 125.4
(ArCH,-3',5'), 123.2 (ArCH-2',6'), 113.5 (CN), 99.6 (C-3), 51.0 (C-7),
48.4 (C-6), 31.6 (C-8), 27.0 (CH3), 26.0 (CH3). IR (KBr): n = 3200
(m, NH2), 3040-2980 (ArCH), 2220 (m, CN), 1600 (s, C=N), 1587
(s, C=C), 1312, 1180 (m, C=S). MS (70 eV), m/z (%) = 341 [M+]
(100), 339 (34), 322 (18), 324 (14), 308 (40), 306 (36), 290 (28),
264 (18), 262 (24), 250 (30), 234 (16), 229 (28), 115 (52), 113 (60),
77 (34). Anal. Calcd for C18H16ClN3S (341.86): C, 63.24; H, 4.72;
Cl, 10.37; N, 12.29; S, 9.38. Found: C, 63.21; H, 4.69; Cl, 10.66; N,
12.32; S, 8.40.
2-Amino-4-phenyl-7,7-dimethyl-5-thioxo-5,6,7,8-tetrahydro-
quinoline-3-carbonitrile (2d): Yellow crystals (0.22 g, 72%), m.p.
330–332°C (acetone). 1H NMR: d = 7.40–7.00 (m, 5 H, Ar-H), 6.30
(br s, 2 H, NH2), 3.10 (s, 2 H, 6-CH2), 2.40 (d, 1 H, 8-H, J = 16.0
Hz), 2.20 (d, 1 H, 8'-H, J = 16.0 Hz), 1.10 (s, 3 H, CH3), 0.99 (s,
3 H, CH3). 13C NMR: d = 184.0 (C-5), 163.5 (C-8a), 144.0 (C-2),
139.6 (C-4), 134.8 (ArC-1'), 129.7 (C-4a), 128.6 (ArCH-3',5'), 127.2
(ArCH-2',6'), 126.2 (Arp-CH), 113.4 (CN), 98.2 (C-3), 51.4 (C-7),
50.0 (C-6), 32.4 (C-8), 26.8 (CH3), 26.0 (CH3). IR (KBr): n = 3228
(m, NH2), 3026–2968 (Ar-CH), 2218 (m, CN), 1612 (s, C=N), 1590
(s, C=C), 1322, 1170 (m, C=S). MS (70 eV), m/z (%) = 307 [M+]
(100), 290 (26), 262 (22), 248 (28), 234 (20), 229 (26), 77 (54). Anal.
Calcd. for C18H17N3S (307.41): C, 70.33; H, 5.57; N, 13.67; S, 10.43.
Found: C, 70.29; H, 5.50; N, 13.62; S, 10.40.
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PAPER: 08/5136