Synthesis, characterization and biological studies of Bis{μ-2,2'-[N,N'- diylbis (nitrilomethylidyne)]diphenolato}dicobalt(II) using triple component solvent system

Article abstract of DOI:10.14233/ajchem.2013.13374

The crystal structure of compound [Co₂(C₁₄H ₁₂N₂O₂)₂] showed dimeric complex. Two nitrogen atoms and two oxygen atoms of the [N,Nbis( salicylidine)diamine] formed distorted square pyramidal geometry in the region of Co(II) and one oxygen atom from each ligand acting as bridge between two ligand molecules which are distorted in parallel path among each other. The titled complex showed amorphous crystalline structure in toluene solvent but to get more clear X-ray crystallographic data three component solvent system (ethanol, toluene, ethyl acetate) was used. The ligand was synthesized and characterized by FTIR, Mass spectrometry, NMR while the titled complex was characterized by FTIR and X-ray crystallography. The ligand and complex were screened for their antibacterial activity against bacterial species Escheria coli, Staphylococcus aureus and Bacillus subtilis and antifungal activity against A. flavus, A. alternate and A. niger. The activity data shows that the metal complex has more antibacterial and antifungal activities than the synthesized ligand against bacterial strains.

Full text of DOI:10.14233/ajchem.2013.13374

Asian Journal of Chemistry; Vol. 27, No. 8 (2015), 2823-2826
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18094
MicrowaveAssisted Gould-Jacobs Reaction for Synthesis of 3-Acetyl-4-hydroxyquinoline Derivatives
1
1,2
1
1
ASHHAR UZ ZAMAN , MISBAHUL AIN KHAN , MUNAWAR ALI MUNAWAR , MUHAMMAD MAKSHOOF ATHAR ,
3,*
1
1,4
MUHAMMAD PERVAIZ , ANSAR PERVAIZ and AYAZ MAHMOOD
1
2
3
4
Institute of Chemistry, University of the Punjab, Lahore, Pakistan
Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
Department of Chemistry, Government College University, Lahore, Pakistan
Schazoo Laboratories (Pvt.) Ltd, Lahore, Pakistan
*
Corresponding author: Tel/Fax: +92 42 37164058; E-mail: mpbhatti786@gmail.com
Received: 28 May 2014; Accepted: 4 August 2014; Published online: 27 April 2015;
AJC-17140
Different types of quinoline derivatives have been synthesized by microwave irradiation and reaction yields were compared with reported
classical methodology. The emphasis on this research project was to reduce reaction times and enhance the yields of the title compounds
especially by using readily available materials including aryl amines. The key intermediate formed by condensation of microwave assisted
multicomponent reaction under solvent free conditions was further cyclized through a heat mediated Gould-Jacobs cyclization reaction to
get substituted quinolines.A study was also made to establish one pot synthesis of quinoline derivatives in order to eliminate the purification/
drying step to get key intermediate but the product yields were found to be very poor than those in the classical methodology. The
synthesized compounds were characterized and identified, using different spectroscopic tools i.e., FT-IR, mass spectrometry, elemental
1
analysis and H NMR.
Keywords: Microwave irradiation, Substituted quinolines, Gould-Jacobs reaction.
INTRODUCTION
EXPERIMENTAL
An important class of broad-spectrum antibiotics is based
Analytical reagent grade chemicals and solvents including
aryl amines, ethyl acetoacetate, triethyl orthoformate, N,N-
dimethylformamide, toluene, acetic acid, ethanol, methanol,
ethyl acetate, n-hexane and petroleum ether (40-60) ºC were
purchased fromAcross Organics, Sigma-Aldrich and Lab Scan
and were used without any further purification. Melting points
were taken by electro thermal open capillary method and are
uncorrected. Microwave synthesis was preformed using a
conventional (unmodified) domestic MW oven. NMR spectra
were measured on a (Jeol JNM-ECA300) 300 MHz spectro-
meter. Chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane (TMS). Electron ionization
technique was used on Perkin Elmer Clarus 680 GC-MS
instrument at 70 eV for the mass spectra. Perkin Elmer FTIR
1
-3
on quinoline molecules that were traditionally obtained
by refluxing an aniline and diethyl ethoxymethylenemalo-
4
nate for several hours often in low yield . In classical work,
reactions were carried out at reflux temperature for several
hours and cyclization was performed in different high boiling
liquids such as diphenyl ether, paraffin oil, high boiling
mineral oils etc. resulting in low yields and other side
reactions such as decomposition. Heating the reaction mixture
by microwaves to temperatures above the boiling points, with
or without solvents, improves the yields and shortens the
5
reaction time dramatically . Gould-Jacobs reaction was
6
reported in 1939 to prepare 4-quinolone derivatives .Although,
a number of reactions have been reported with different
modification in the Gould-Jacobs reaction but in every
reported work ethoxymethylenemalonate was used as a star-
1
5,16
was used for IR spectra
.
General procedure for the preparation of β-anilino-
acrylic ester (2a-f) (intermediate) through microwave irra-
diation: Equimolar (10 mmol) quantities of ethyl acetoacetate,
triethyl orthoformate and aryl amine 1 were mixed and
microwave irradiated without solvent for two minutes at 120 ºC
and cooled. Crystals formed upon cooling, strained, washed
5
,7
ting material . The preparation of these ethoxymethyl-
enemalonates is a tedious job and its stability for long time is
8
-13
another problem as well as a risk factor for maintaining the
smooth production of such a pharmacologically important
intermediate.

2
824 Ashhar uz Zaman et al.
Asian J. Chem.
with pet. ether (40-60 °C), dried and recrystallized from ethanol
to get key intermediates (2a-f) as shown in Scheme-I, Table-1.
microwave irradiation at 250 ºC for 10-15 min, cooled to room
temperature and diluted with n-hexane, filtered, dried and
recrystallized from N,N-dimethyl formamide (DMF) to afford
(3a-f) as shown in Scheme-I, Table-1.
4
4
R
CH
3
R
3
3
R
EtO C
2
R
R
EtO
EtO
O
OEt
3
-Acetyl-4-hydroxy-7-chloroquinoline (3a): Solid, m.p.
O
MW
+
OEt + O
-1
2
30 ºC, IR (KBr, νmax, cm ): 3073.8 (OH, Str, H-bonded),
1665.85, 1609.39 (C=O, Str), 1352.85, 1303.87 and 1200.14
2
2
H
2min
R
N
H
NH
2
1
1
2
CH3
R
R
+
+
(
OH, Bend) EIMS: m/z: 221M ; 223M +2, 206, 178, 150, 138,
1
1
1
0
-
1
123. H NMR (300MHz, DMSO-d
.16 (d, J = 8.62Hz, 1H, ArH), 7.61 (s, 1H, ArH), 7.33 (d, J =
8.64 Hz, 1H, ArH), 2.56 (s, 3H, AcCH ). Anal. calcd. (%) for
6
): δ ppm 8.54 (s, 1H,ArH),
5
m
in
8
4
1
R
R
OH
O
3
3
2
R
R
C
11
H
8
NO
Found (%): C, 56.25; H, 3.62; Cl, 15.93; N, 6.29.
-Acetyl-4-hydroxy-5-chloroquinoline (3aa): Solid,
2
Cl (221.64): C, 59.61; H, 3.64; Cl, 16.00; N, 6.32.
CH
3
N
3
-1
m.p. 243 ºC, IR (KBr, νmax, cm ): 3073.0 (OH, Str, H-bonded),
3
1
671.48, 1608.24 (C=O, Str), 1350.12, 1303.33 and 1197.71
Scheme-I
1
(
OH, Bend). H NMR (300 MHz, DMSO-d
1H, ArH), 8.16 (d, 1H, ArH), 7.53 (t, 1H, ArH), 7.31 (d, 1H,
ArH), 2.56 (s, 3H, AcCH ).
3-Acetyl-4-hydroxy-8-methoxyquinoline (3b): Solid,
6
): δ ppm 8.41 (s,
Ethyl-2-{[(3-chlorophenyl)amino]methylidene}-3-
oxobutanoate (2a): White crystals, m.p. 87 ºC, IR (KBr, νmax
,
3
-
1
cm ): 2923.0 (NH, Str), 1706.4 (C=O, Str, Ester), 1637.3
C=O, Str, Ac), 1597.5 (NH, bend), 795.1 and 762.9 (C-Cl,
Str). Anal. calcd. (%) for C13 Cl (267.7): C, 58.33; H,
.27; Cl, 13.24; N, 5.23. Found (%): C, 57.98; H, 5.24; Cl,
-1
(
m.p. 244 ºC, IR (KBr, νmax, cm ): 3054.68 (OH, Str, H-bonded),
1659.75, 1615.30 (C=O, Str), 1361.14, 1274.21 and 1195.4
(OH, Bend) EIMS: m/z: 217M , 202, 174, 143, 115, 100. H
NMR (300MHz, CDCl ): δ ppm 9.225 (s, 1H, ArOH), 8.540
H14NO
3
+
1
5
1
3.16; N, 5.21.
3
Ethyl-2-{[(2-methoxyphenyl)amino]methylidene}-3-
(s, 1H, ArH), 7.984 (d, J = 8.4 Hz, 1H, ArH), 7.337 (t, J = 8.1
Hz, 1H, ArH), 7.0875 (d, J = 7.5 Hz, 1H, ArH), 3.999 (s, 3H,
oxobutanoate (2b): White crystals, m.p. 108 ºC, IR (KBr,
-1
ν
max, cm ): 2923.0 (NH, Str), 1696.8 (C=O, Str, Ester), 1629.6
C=O, Str, Ac), 1596.3 (NH, Bend). Anal. calcd. (%) for
(263.29): C, 63.86; H, 6.51; N, 5.32. Found (%):
ArOCH
3
), 2.786 (s, 3H, AcCH
(217.22): C, 66.35; H, 5.10; N, 6.45. Found (%):
C, 66.96; H, 5.07; N, 6.41.
3-Acetyl-4-hydroxy-8-methylquinoline (3c): Solid, m.p.
3
). Anal. calcd. (%) for
(
C
12
H11NO
3
C
14
H17NO
4
C, 63.48; H, 6.47; N, 5.29.
-1
Ethyl-2-{[(2-methylphenyl)amino]methylidene}-3-
266 ºC, IR (KBr, νmax, cm ): 3198.5 (OH, Str, H-bonded),
1671.50, 1615.1 (C=O, Str), 1342.40, 1280.50 and 1190.50
oxobutanoate (2c): White crystals, m.p. 154 ºC, IR (KBr, νmax
,
-
1
+
cm ): 3018.19 (NH, Str), 1720.0 (C=O, Str, Ester), 1660.45
C=O, Str, Ac), 1580.1 (NH, Bend). Anal. calcd. (%) for
(247.29): C, 68.00; H, 6.93; N, 5.66. Found (%):
(OH, Bend) EIMS: m/z: 201M , 186, 158, 143, 115, 103, 91.
1
(
C
H NMR (300 MHz, DMSO-d ): δ ppm 8.47 (s, 1H, ArH),
6
8.07 (d, J = 7.2Hz, 1H, ArH), 7.47 (d, J = 8.1 Hz, 1H, ArH),
7.23 (t, J = 7.5, 1H, ArH), 2.59 (s, 3H, ArCH ), 2.50 (s, 3H,
AcCH ). Anal. calcd. (%) for C12 (201.22): C, 71.63;
14
H17NO
3
C, 67.69; H, 6.92; N, 5.64.
3
Ethyl-2-{[(4-bromophenyl)amino]methylidene}-3-
oxobutanoate (2d): White crystals, m.p. 162 ºCC, IR (KBr,
3
H11NO
2
H, 5.51; N, 6.96. Found (%): C, 71.21; H, 5.48; N, 6.92.
-1
ν
(
max, cm ): 3301.9 (NH, Str), 1725.4 (C=O, Str, Ester), 1629.3
C=O, Str, Ac), 1593.1 (NH, Bend), 568.53 (C-Br, Str). Anal.
calcd. (%) for C13 Br (312.16): C, 50.02; H, 4.52; Br,
5.60; N, 4.49. Found (%): C, 49.95%; H, 4.51; Br, 25.54; N,
.47.
Ethyl-2-{[(3-methoxyphenyl)amino]methylidene}-3-
oxobutanoate (2e): White crystals, m.p. 92 ºC, IR (KBr, νmax
3-Acetyl-4-hydroxy-6-bromoquinoline (3d): Solid,
-1
m.p. 286 ºC, IR (KBr, νmax, cm ): 3090.7 (OH, Str, H-bonded),
H14NO
3
1644.58, 1611.52 (C=O, Str), 1341.46, 1300.41 and 1206.39
+
+2
2
4
(OH, Bend) EIMS: m/z: 265M , 267M , 251, 223, 144, 116,
1
101. H NMR (DMSO-d
1H, ArH), 7.81 (d, J = 8.7 Hz, 1H, ArH), 7.57 (d, J = 8.8 Hz,
1H, ArH), 2.50 (s, 3H, AcCH ). Anal. calcd. (%) for
NO Br (266.09): C, 49.65; H, 3.03; Br, 30.03; N, 5.26.
6
): δ ppm 8.56 (s, 1H, ArH), 8.29 (s,
,
3
-
1
cm ): 3031.9 (NH, Str), 1699.56 (C=O, Str, Ester), 1635.68
C=O, Str, Ac), 1608.28 (NH, Bend). Anal. calcd. (%) for
(263.29): C, 63.86; H, 6.51; N, 5.32. Found (%):
C
11
H
8
2
(
C
Found (%): C, 49.34; H, 3.00; Br, 29.85; N, 5.23.
3-Acetyl-4-hydroxy-7-methoxyquinoline (3e): Solid,
14
H17NO
4
-1
C, 63.58; H, 6.49; N, 5.30.
m.p. 258 ºC, IR (KBr, νmax, cm ): 3118.12 (OH, Str, H-bonded),
Ethyl-2-{[(4-nitrophenyl)amino]methylidene}-3-
oxobutanoate (2f): Yellow crystals, m.p. 210 ºC, IR (KBr,
1662.74, 1625.83 (C=O, Str), 1355.28, 1303.66 and 1199.10
+
(OH, Bend) EIMS: m/z: 217M , 202, 174, 159, 143, 115, 100.
-1
1
ν
(
max, cm ): 2925.2 (NH, Str), 1710.9 (C=O, Str, Ester), 1688.8
C=O, Str, Ac), 1587.9 (NH, Bend), 1477.5 & 1358.0 (Arom.
NO , Str). Anal. calcd. (%) for C13 (278.26): C, 56.11;
H NMR (DMSO-d ): δ ppm 8.45 (s, 1H, ArH), 8.12 (d, J =
6
8.6 Hz, 1H, ArH), 7.04 (d, J = 7.8 Hz, 1H, ArH), 7.02 (s, 1H,
ArH), 3.87 (s, 3H, ArOCH ), 2.51 (s, 3H, AcH). Anal. calcd.
(%) for C12 (217.22): C, 66.35; H, 5.10; N, 6.45. Found
2
H
14
N
2
O
5
3
H, 5.07%; N, 10.07. Found (%): C, 56.01; H, 5.02; N, 10.03.
General procedure of cyclization to synthesize quino-
lines through microwave assisted Gould-Jacobs reaction:
Dried intermediates (2a-f) obtained were cyclized with four
times amounts by volume diphenyl ether as solvent by
H11NO
3
(%): C, 65.96; H, 5.08; N, 6.43.
3-Acetyl-4-hydroxy-6-nitroquinoline (3f): Solid, m.p.
-1
296 ºC, IR (KBr, νmax, cm ): 3088.0 (OH, Str, H-bonded),
1665.80, 1575.2 (C=O, Str), 1502.6 (Ar- NO ,), 1338.10 (Ar-
2

Vol. 27, No. 8 (2015)
Microwave Assisted Gould-Jacobs Reaction for Synthesis of 3-Acetyl-4-hydroxyquinoline Derivatives 2825
TABLE-1
COMPARATIVE STUDY OF MICROWAVE ASSISTED GOULD-JACOBS REACTION WITH OLD CLASSICAL
METHODOLOGY FOR THE SYNTHESIS OF 3-ACETYL-4-HYDROXY QUINOLINE DERIVATIVES
Entry
Aryl amine
Reaction time (min)
Yield (%)
Reaction time (h) Yield (%)
Product
CH3
NH2
EtO C
2
O
2
a
2
91
16
16
67
64
Cl
N
H
Cl
CH3
NH2
O
EtO2C
O
2b
CH3
2
94
N
H
O
H3C
CH3
NH2
EtO C
2
CH3
O
2
c
2
2
2
91
90
96
16
16
16
60
52
61
N
CH3
H
NH2
CH3
Br
EtO C
2
O
2d
N
H
Br
NH2
CH3
EtO C
2
O
2e
H C
3
O
O
-
N
H
CH3
NH2
O
CH3
+
N
EtO2C
O
O
2
f
2
92
59
68
16
0.5
0.5
45
39
51
N
H
+
N
-
O
O
CH3
OH
O
EtO C
2
O
CH3
3a
10
12
Cl
N
H
Cl
N
CH3
OH
O
EtO2C
O
CH3
3b
N
H
N
O
O
H3C
H3C
CH3
OH
O
EtO C
2
O
CH3
3
c
10
15
10
72
65
74
0.5
0.5
0.5
49
38
49
N
N
CH3
H
CH3
CH3
OH
O
Br
EtO C
2
O
Br
CH3
3d
N
H
N
CH3
OH
O
EtO C
2
O
CH3
3e
H3C
O
N
H
H3C
O
N

2
826 Ashhar uz Zaman et al.
Asian J. Chem.
-
O
CH3
-
O
OH
O
+
N
EtO2C
+
N
O
O
3f
15
59
0.5
33
O
CH3
N
H
N
+
NO
2
), 1287.20 and 1201.65 (OH, Bend) EIMS: m/z: 232M ,
using suitable acetoacetate esters and aryl amines (1) to get
the desired quinoline derivatives. An attempt to carry one pot
reaction for 3 resulted in low yields accompanied by extensive
decomposition and charring.
1
2
1
7
17, 189, 143, 115, 100. H NMR (DMSO-d
H, ArH), 8.71 (s, 1H, ArH), 8.37 (d, J = 8.1 Hz, 1H, ArH),
.91 (d, J = 7.8 Hz, 1H, ArH), 2.50 (s, 3H, AcCH ). Anal.
(232.19): C, 56.90; H, 3.47; N, 12.06.
6
): δ ppm 8.68 (s,
3
calcd. (%) for C11
Found (%): C, 56.56; H, 3.45; N, 12.01.
H N O
8 2 4
Conclusion
The study showed enhanced and efficient synthesis of
important broad spectrum antibiotic intermediate 3-acetyl-4-
hydroxyquinoline derivatives by using microwave irradiation
with reduced reaction times in good yields using readily
available starting materials excluding ethoxymethylene
derivatives. The study also supersedes the old wet classical
methodologies by microwave assisted multi component one
pot synthesis. Further, this study also shows some limitations
in the said reaction for the cyclization of the molecule at
possible positions (as in case of meta-substituted aryl amines)
and also explores the effect of solvent in the last step.
RESULTS AND DISCUSSION
In this work, we describe a highly efficient multi-compo-
nent microwave assisted Gould-Jacobs reaction for the synthesis
of 3-acetyl-4-hydroxyquinoline derivatives using readily
available staring materials in good yield. The yield of key inter-
mediate (2) was always excellent i.e. more than 90 %. The
first step to get key intermediate (2), was achieved by Michael
addition/elimination mechanism and have been reported by
using traditional wet classical synthesis with ethoxymethylene-
malonate by refluxing in ethanol for over night or by using a
1
4
base such as potassium hydroxide . By replacing the old
methodology with microwave we have developed a new avenue
in such addition/elimination reactions with much shorter
reaction time and another step towards green chemistry. This
step is solvent free and also an example of one pot multi compo-
nent reaction eliminating the use of ethoxymethylenemalonate.
The second step to cyclize the key intermediate (2) espe-
cially by Gould-Jacobs reaction, is an electrophilic aromatic
substitution reaction to afford the quinoline derivatives as
shown in Table-1. This step was performed by using diphenyl
ether as a solvent with four times dilution by weight to the
reactants to be cyclized. Purification procedures were simple
because cyclized products were precipitated out by the addition
of n-hexane and further recrystallized to get the pure quinoline
derivatives. However it is interesting to note that only meta-
substituted aryl amine produced two isomers instead of one
product. The product 3a, which should be 7-chloro derivative,
gave a mixture of 7-chloro and 5-chloro products with 8.7 %
of 5-chloro derivatives only. However in case of 3e, which
should be a mixture of 5 and 7-methoxy, products was always
a pure 7-methoxy derivative. This could be attributed to the
steric hindrance of the bulky methoxy group causes hindrance
in aromatic substitution reaction. This abnormality was
confirmed by NMR spectroscopic tool. The effect of solvent
to the cyclization position was also investigated and found
that by changing solvent from diphenyl ether to paraffin liquid
the ratio of the 5 and 7-chloro isomers was inverted.
ACKNOWLEDGEMENTS
The authors thank Dr. Muhammad Wakeel Ahsan, Chief
Executive of Bhatti Scientifics Lahore, Pakistan and Mr. Basar-
uz-Zaman Managing Director of Zeta Chemical Company
Lahore, Pakistan for support in research work.
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1
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13
ration . This work could be advantageously manipulated by