An efficient one pot three component synthesis of N-(Methylene-4-oxo coumarinyl)anilines; their Z,E-isomeric product distribution determination from 1HNMR and their antibacterial studies

Article abstract of DOI:10.2174/157018012800389377

The new series of N-(methylene-4-oxo coumarinyl)anilines 1-13 was synthesised and screening of different solvents led to the discovery of high boiling alcohols as the suitable candidate for one pot efficient three component reaction. Particularly in 2-but

Full text of DOI:10.2174/157018012800389377

454
Letters in Drug Design & Discovery, 2012, 9, 454-458
An Efficient One Pot Three Component Synthesis of N-(Methylene-4-oxo
coumarinyl)anilines;
Their
Z,E-Isomeric
Product
Distribution
Determination From 1HNMR and their Antibacterial Studies
Abdul Rauf*,1, Hamish McNab2 and Ashfaq Mahmood Qureshi*,3
1Department of Chemistry, The Islamia University, Bahawalpur, 60000-Pakistan
2School of Chemistry, The University of Edinburgh, Joseph Black Building, The King’s Buildings, west Mains Road
Edinburgh, EH9 3JJ-UK
3Department of Chemistry, Bahauddin Zakariya University, Multan, 60800-Pakistan
Received December 09, 2011: Revised January 30, 2012: Accepted March 04, 2012
Abstract: The new series of N-(methylene-4-oxo coumarinyl)anilines 1-13 was synthesised and screening of different
solvents led to the discovery of high boiling alcohols as the suitable candidate for one pot efficient three component
reaction. Particularly in 2-butanol the product was precipitated out in excellent yields without the hassle of purification.
1
The product distribution of Z and E-isomers was established by HNMR. These compounds were screened for their in
vitro antibacterial activity against Escherichia Coli, Bacillus Subtilis, Shigella flexenari, Staphylococous aureus,
Pseudomonas aeruginosa and Salamonella typhi. Standard drug impenium was used as control.
Keywords: N-(methylene-4-oxo coumarinyl)anilines, Antibacterial, Escherichia Coli, Bacillus Subtilis, Shigella flexenari,
Staphylococous aureus, Pseudomonas aeruginosa and Salamonella typhi.
INTRODUCTION
antifungal and cytotoxic properties [6]. There biological
activity is resultant of the coumarin structural motif, which is
extensively employed as antimicrobial and anticoagulant [7,
8]. The reported proton NMR data of 1a-1c are remarkably
intriguing [2, 3] which prompted our interest in the synthesis
of a new series of N-(methylene-4-oxo coumarinyl)anilines
4. The chemical shifts and splitting pattern of ethylenic
proton and NH are revisited. The synthesis of new series of
N-(methylene-4-oxo coumarinyl)anilines were afforded and
their antibacterial activities were also studied.
Synthetic and naturally occurring coumarins (1,2-
benzopyrone) 1a and its derivatives are well known
cytotoxic agents [1]. Auraptene, a coumarin derivative,
which was isolated from citrus plant, has reportedly
exhibited anti-tumour and anti-carcinogenic biological
activities in rats and mice [2]. The synthesis of 3-
ureidomethylene coumarins 1b [3], N-(methylene-4-oxo
coumarinyl)carbamates 1c [4] and N-(methylene-4-oxo
coumarinyl)amino acids 1d [5] has been reported via three
component reaction from low to moderate yields (Fig. 1).
O
MATERIALS AND METHODS
General Procedure-Chemistry
CO2R
N
H
O
O
All reactions were carried out under a nitrogen
atmosphere unless otherwise stated. The reaction glassware
was flame dried as standard. TLC was performed using
Merck plastic/aluminium coated plates covered with a 0.2
O
O
1b
1a
O
R
O
mm of layer of silica gel 60 F254 Product spots were
.
visualised either by UV irradiation at 254 nm or by staining
with suitable stains followed by heat drying. Melting points
were determined on a Gallenkamp apparatus and were
N
COOH
N
H
H
O
O
1
O
O
uncorrected. HNMR spectra were recorded as solution in
1c
the d6-DMSO, using tetramethylsilane as internal standard.
The spectra were recorded at 500 MHz (Burker AM 500)
and 400 MHz (Burker AM 400) spectrometers. The chemical
shift values were measured in part per million (ppm),
coupling constants J, were measured in Hz. Mass spectra
were recorded on a micromass analytical machine, using
either chemical ionisation (CI) or electron ionisation (EI).
The mass of the fragment is given followed by the relative %
in brackets.
1d
Fig. (1). Some important coumarins derivatives.
Previously, we have synthesised N-(methylene-4-oxo
coumarinyl)sulfonamides and reported their antibacterial,
*Address correspondence to this author at the Department of Chemistry,
The Islamia University, Bahawalpur, 60000-Pakistan; Tel: 0092629250473;
E-mail: lecorganic@yahoo.com, shamashfaq@yahoo.com
1875-628X/12 $58.00+.00
© 2012 Bentham Science Publishers

An Efficient One Pot Three Component Synthesis
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5 455
NH2
R
H
OH
O
O
H
O
O
O
N
O
R
R
N
H
H
+
Triethyl formate
2-butanol
O
O
Reflux
Z-Isomer
E-Isomer
Scheme 1.
RESULTS AND DISCUSSION
Screening of the Solvents
An equimolar ratio of 4-Hydroxy coumarin and
substituted anilines in the presence of triethylorthoformate
(1.5eq) gave Z and E-isomers of N-(methylene-4-oxo
coumarinyl)anilines in excellent yields (Scheme 1).
The commercially available aromatic amines were
condensed with 4-hydroxycoumarin in the presence of
triethylorthoformate and N-(methylene-4-oxo coumarinyl)
aromatics via three component reaction under reflux.
Reported methods afforded low yields after tedious
separation, therefore screening of the solvents was done,
which could address these two issues i.e. low yield and
tedious separation. The results are tabulated in Table 2.
The Z and E-isomeric ratio was determined by intrinsic
analysis of the 1HNMR data; NH proton splits into two non-
isochronous doublets, the one low field doublet is assigned
to the Z-isomer NH which is deshielded as compared to E-
isomer’s NH. Indeed this effect is due to the +M
(Mesomeric) effect of lactone which is favouring stronger
hydrogen bonding in case of Z-isomer. The ethylenic proton
generally showed a second order splitting but in case of 7
and 12 it is first order, splitting into two characteristic
doublets. At these instances the doublet due to ethylenic
proton of E-isomer is found to be lowfield revealing the
same Z to E-isomeric product distribution as NH proton
suggested. On the basis of these grounds the Z and E-
isomeric product distribution was determined and presented
in Table 1.
Table 2. Solvent Screening
MeOH
% yields
EtOH
% yields
2-Propanol
% yields
2-Butanol
% yields
Compounds
1
2
7
5-7
0
24
21
16
16.5
22
17
24
16
19
21
24
11
13
37
39
32
43
45
43
46
53
52
38
31
38
41
92
88
92
90
87
83
82
88
90
88
92
85
80
3
4
0
5
11
8
16
17
8
Table 1. Z and E Isomeric Distribution
10
0
Compounds
Z-Isomer %
E-Isomer %
1
2
73
71
62
65
66
57
64
73
43
50
61
62
68
27
29
38
35
34
43
36
27
57
50
39
38
32
9
12
8
10
11
12
13
3
7
4
5
5
0
6
7
The reactions carried out in methanol, ethanol and 2-
propanol and products collected were impure and yields
were low. The introduction of 2-butanol resulted in high
yields and purity. These results can be explained on the basis
of the comparison of the boiling points of these solvents; 2-
butanol is high boiling solvent in comparison to methanol,
ethanol and 2-propanol. The activation energy required for
the completion of this three component reaction is
sufficiently available if the reaction is performed in the high
boiling solvent, whereas in the low boiling solvents small
number of molecules can acquire this energy and low yields
and unreacted reactants are observed. Although, increase in
the reaction time in low boiling solvents can enhance the
yields to some extent but still the purification issues prevail.
The high boiling solvent and 2-butanol in comparison to
methanol, ethanol and 2-propanol are efficiently taking the
reaction to completion and above all the desired product is
8
9
10
11
12
13
The product distribution of the Z and E-isomer clearly
depicted that Z-isomer is more favoured. This is quite
reasonable as in Z-isomeric substrates the N-substituted
phenyl ring is away having less steric interactions. In case of
9 and 12, the presence of carboxylic acid group at para
position tends to favour the formation of E-isomer.

456 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5
Rauf et al.
Table 3. Compounds Synthesised 1-23
F
F
F
O
O
O
O
O
N
H
N
H
N
H
O
O
O
O
1
3
2
H3C
CH3
Br
Br
O
O
O
O
O
N
H
N
H
CH3
Br
N
H
O
O
4
5
O
O
6
COOH
O
O
O
O
N
N
COOH
N
H
H
H
COOH
O
O
O
O
O
9
7
8
NO2
COOH
OH
OH
O
O
O
O
N
H
N
H
COOH
N
H
O
O
O
O
COOH
11
10
O
12
NO2
COOH
O
N
H
O
O
13
highly pure as it is completely insoluble in 2-butanol. These
two factors i.e. high boiling point and very low solubility for
the targeted compounds make 2-butanol a stand out choice
for this multicomponent reaction.
dd, J 13.1 and 15.7, =CHNH ), 7.99 (1H, m, ArH), 7.91 (1H,
m, ArH), 7.73 (1H, m, ArH), 7.44 (2H, m, ArH), 7.35 (3H,
m, ArH); m/z (CI) 283(MH+, 2%), 282(15), 172(42), 166(2),
148(8), 121(16), 91(5), 84(62), 66(100), 57(21), 55(17).
3-[(3-Fluoro-phenylamino)-methylene]-chroman-2,4-dione
2
General Procedure for the Preparation of Compounds 1-
13
δH(500 MHz; CDCl3) 13.40 (0.71H, d, J 13.6, NH, Z-
isomer ), 11.82 (0.29H, d, J 14.6, NH, E-isomer), 8.90 (1H,
dd, J 13.6 and 13.2, =CHNH), 7.98 (1H, dd, J 7.6 and 1.3
ArH), 7.69 (2H, m, ArH), 7.51 (2H, m, ArH), 7.35 (2H, m,
ArH), 7.15 (1H, m, ArH); m/z (EI) 284.2(M+, 16),
283.1(76), 254.1(5), 221.1(4), 173.0(100), 162.1(10),
149.1(27) , 135.1(18), 121(25), 108(7), 95.1(6), 83(10),
71.1(14), 57.1(22), 46.1(100)45.1(13.5), 40.3(2).
To a stirred solution of 4-hydroxycoumarin (1.62 g,
0.01mole) and triethylorthoformate (2.25 g, 0.015mole) in n-
butanol (30 mL) was added the respective amines
(0.01mole). The mixture was refluxed for 3 h. The
precipitates formed during refluxing were collected by
suction filtration. Washing with hot ethanol, TLC afforded
pure products in excellent yield (Table 3).
3-[(2-Fluoro-phenylamino)-methylene]-chroman-2,4-dione
1
3-[(4-Fluoro-phenylamino)-methylene]-chroman-2,4-dione
3
δH(500 MHz; CDCl3) 13.80 (0.77 H, d, J 13.1, NH, Z-
isomer), 11.96 (0.23 H, d, J 14.2, NH, E-isomer), 8.99 (1H,
δH(400 MHz; CDCl3) 13.42 (0.62 H, d, J 13.8, NH, Z-
isomer), 11.85 (0.38 H, d, J 14.8, NH, E-isomer), 8.82 (1H,

An Efficient One Pot Three Component Synthesis
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5 457
dd, J 14.6 and 13.8, =CHNH), 7.96 (1H, d, J 7.8, ArH ),7.71
(3H, m, ArH) 7.33(4H, m, ArH); m/z (EI) 284 (M+, 13),
283(72), 254.1(5), 207(3), 173(100), 162(10), 149(9),
139(28), 135(22), 121(30), 111(38), 95(16), 84(22), 71(13),
57(21), 46(80).
NH, E-isomer), 8.95 (1H, dd, J 14.2 and 13.6, =CHNH),
7.99 (2H, dd, J 8.4 and 1.7, ArH ), 7.76 (2H, dd, J 8.7 and
1.9, ArH), 7.69 (1H, m, ArH ), 7.36 (3H, m, ArH ); m/z (CI)
309(MH+, 10), 308(58), 188(11), 172(100), 161(14), 143(8),
120(40), 91(14), 89(7), 65(20).
3-[(2,4,6-Trimethyl-phenylamino)-methylene]-chroman-
2,4-dione 4
4-[(2, 4-Dioxo-chroman-3-ylidenemethyl)-amino]-2-
hydroxy-benzoic acid 10
δH(400 MHz; CDCl3) 12.51 (0.65H, d, J 14.4, NH, Z-
isomer), 11.12 (0.35H, d, J, NH, E-isomer ), 8.32 (1H, d, J
14.3, =CHNH), 7.96 (1H, dd, J 7.7 and 7.6, ArH), 7.69 (1H,
t, ArH), 7.33 (2H, m, ArH), 7.01 (2H, s,) 2.26 (3H, s, CH3 ),
2.24 (3H, s, CH3 ), 2.20 (3H, s, CH3 ); m/z (EI+) 430(M+,
1), 307(60), 306(100), 305(96), 292(30), 278(9), 213(55),
187(44), 173(32), 158(560, 145(65), 131(24), 121(60),
105(16), 83(45), 46(100).
δH(400 MHz; CDCl3) 13.27 (0.50H, d, J 13.64, NH, Z-
isomer), 11.74 (0.50H, d, J 14.5, NH, E-isomer), 8.89 (1H,
dd, J 13.5 and 13.3, =CHNH), 7.97 (1H, m, ArH ), 7.84 (1H,
d, J 8.5, ArH), 7.70 (1H, m, ArH ), 7.36 (1H, d, J 7.24, ArH
) 7.32 (1H, d, J 8.2, ArH) 7.20 (3H, m, ArH ) 3.35 (1H,
broad s, OH); m/z (EI) 589(M+, 4) 325(53), 280(20),
281(92), 264(14), 204(11), 187(16), 173(100), 160(21),
121(84), 120(38), 94(27), 65(16), 46(70).
3-[(2,4,6-Tribromo-phenylamino)-methylene]-chroman-
2,4-dione 5
5-[(2, 4-Dioxo-chroman-3-ylidenemethyl)-amino]-2-
hydroxy-benzoic acid 11
δH(400 MHz; CDCl3) 12.79 (0.66H, d, J 13.4, NH, Z-
isomer), 11.43 (0.34H, d, J 14.5, NH, E-isomer), 8.57 (1H,
dd, J 14.6 and 12.1, =CHNH), 8.11 (2H, s, ArH ), 7.96 (1H,
dd, J 8.8 and 1.1, ArH), 7.71 (1H, m, ArH ), 7.36 (2H, m,
ArH ); m/z (EI) 500(M+, 11), 423(93), 421(100), 420(94),
354(7), 301(12), 273(7), 231(6), 188(5), 173(49), 134(3),
121(45), 92(11), 65(8).
δH(400 MHz; CDCl3) 13.38 (0.61H, d, J 13.9, NH, Z-
isomer), 11.28 (0.39H, d, J 14.9, NH, E-isomer), 8.7 (1H,
dd, J 14.1 and 13.8, =CHNH), 7.96 (2H, m, ArH ), 7.82 (1H,
ddd, J 8.9, 8.5 and 2.7, ArH), 7.67 (1H, m, ArH ), 7.34 (1H,
d, J 7.4, ArH ) 7.30 (1H, d, J 8.3 ArH ) 7.04 ( 1H d, J 8.9,
ArH) 3.40 (1H, broad s, OH); m/z (EI) 324(M+, 12),
325(64), 307(90), 281(63), 187(13), 173(100), 153(9),
121(6), 120(22), 93(18), 65(13), 46(32).
3-(Naphthalen-2-ylaminomethylene)-chroman-2,4-dione 6
2-[(2,4-Dioxo-chroman-3-ylidenemethyl)-amino]-4-nitro-
benzoic acid 12
δH(400 MHz; CDCl3) 14.46 (0.57H, d, J 12.6, NH, Z-
isomer), 12.54 (0.43H, d, J 14.3, NH, E-isomer), 9.03 (1H,
dd, J 14.3 and 12.5, =CHNH), 7.98 (2H, s, ArH ), 7.96 (1H,
dd, J 8.8 and 1.1, ArH), 7.71 (1H, m, ArH ), 7.36 (2H, m,
ArH ), 7.28 (4H, m, ArH ), 7.11(1H, s, ArH) ; m/z (EI)
314.9(M+, 100), 313.9(89), 298(6), 286(5), 270.1(5),
195(12), 194(35), 173(62), 167.1(39), 154.1(22), 139(14),
127(20), 121(40), 115(16), 94(17), 78(99), 63(99), 46.1(86)
δH(400 MHz; CDCl3) 14.40 (0.62H, d, J 13.2, NH, Z-
isomer), 13.53 (0.38H, d, J 14.1, NH, E-isomer), 9.02 (1H,
dd, J 14.1 and 12.9, =CHNH), 8.68 (1H, m, ArH ), 8.23 (1H,
dd, J 8.6 and 8.6, ArH), 8.11 (1H, m, ArH), 7.96 (1H, m,
ArH) 7.71 (1H, m, ArH) 7.34 (2H, m, ArH) 3.31 (1H, broad
s, COOH); m/z (EI) 332(M+, 5), 310(40), 281(9), 182(18),
173(99), 164(31), 121(48), 120(31), 92(19), 61(11), 63(12),
46(100).
2-[(2, 4-Dioxo-chroman-3-ylidenemethyl)-amino]-benzoic
acid 7
4-[(2,4-Dioxo-chroman-3-ylidenemethyl)-amino]-2-nitro-
benzoic acid 13
δH(400 MHz; CDCl3) 14.44 (0.64H, d, J 13.7, NH, Z-
isomer), 13.57 (0.36H, d, J 14.5, NH, E-isomer), 8.97 (1H,
dd, J 14.5 and 13.7, =CHNH), 8.03 (1H, d, J 7.7, ArH ),
7.95 (2H, m, ArH), 7.71 (2H, m, ArH), 7.40 (1H, m, ArH )
7.33 (2H, m, ArH ); m/z (EI) 581(M+, 1), 308(7), 265(21),
264(100), 247(18), 221(8), 187(16), 171(23), 172(99),
162(18), 144(23), 121(81), 120(65), 92(43), 77.1(25),
65(23), 63(16), 46(100).
δH(400 MHz; CDCl3) 13.32 (0.68H, d, J 13.5, NH, Z-
isomer), 11.90 (0.32H, d, J 14.4, NH, E-isomer), 8.96 (1H,
dd, J 14.3 and 13.5, =CHNH), 8.11 (2H, m, ArH ), 7.98 (2H,
m, ArH), 7.72 (1H, m, ArH), 7.34 (2H, m, ArH) 3.4 (1H,
broad s, COOH); m/z (EI) 438(M+, 4), 310(82), 309(100),
263(16), 189(26), 173(74), 172(99), 162(38), 120(99),
119(91), 92(48), 64(31), 53(29), 46(99).
3-[(2,4-Dioxo-chroman-3-ylidenemethyl)-amino]-benzoic
acid 8
In-vitro antibacterial activities were analysed at HEJ
Research Institute of Chemistry, International Centre for
Chemical Sciences, University of Karachi, Pakistan.
δH(400 MHz; CDCl3) 13.40 (0.73H, d, J 13.7, NH, Z-
isomer), 13.2 (1H, broad s, COOH), 11.89 (0.27H, d, J 14.7,
NH, E-isomer), 8.89 (1H, m, =CHNH), 8.10 (1H, d, J 9.32,
ArH ), 7.98 (1H, d, J 7.7, ArH), 7.91 (1H, m, ArH), 7.86
(1H, d, J 7.6, ArH ) 7.70(1H, m, ArH) 7.95(1H, m, ArH)
7.35(2H, m, ArH) ;m/z (CI) 308.9(MH+,61) 309.9(10),
279.9(2), 263.8(3), 188(15), 173.9(11)., 172.9(100), 161(15),
148.9(8), 120.9(40), 91.9(16), 65(24).
Antibacterial Bioassay
The compounds 1-13 were studied in vitro for
Escherichia Coli, Bacillius Subtilis, Shigella flexenari,
Staphylococous aureus, Pseudomonas aeruginosa and
Salamonella typhi and standard drug impenium was used as
control. The method employed was agar well diffusion
method [9, 10]. Using a sterile borer wells (6 mm diameter)
were dug in bacterial inoculation was done on the nutrient
agar (~ 104-106 CFU/ml). The concentration of sample
4-[(2,4-Dioxo-chroman-3-ylidenemethyl)-amino]-benzoic
acid 9
δH(400 MHz; CDCl3) 13.42 (0.43H, d, J 13.6, NH, Z-
isomer), 13.07(1H, broad s, COOH)11.87 (0.57H, d, J 14.5,

458 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 5
Rauf et al.
Table 4. Antibacterial Activity of the Synthesised Compounds Against Various Micro-Organisms
Compd No
Escherichia Coli
Bacillius Subtilis
Shigella flexenari Staphylococus aureus Pseudomonasa eruginosa
Salamonella typhi
1
-
14
-
-
-
-
-
-
-
14
10
10
10
10
-
-
10
-
2
3
-
-
-
4
-
-
-
-
-
5
-
-
-
-
-
6
-
-
-
-
10
-
7
8
-
17
-
-
-
-
-
-
-
-
08
-
9
-
12
-
-
-
-
10-13
-
-
-
-
-
30
32
26
32
24
25
Impenium
Std Drug
employed to the wells is 1mg/mL of DMSO. The control
wells were supplemented with DMSO (1 mL) and standard
drug ‘Impenium’ (10 µg/well). These samples were
incubated at 37°C for 24-48hrs. The zone inhibition in mm
was recorded, DMSO did not show any activity against any
organism included in this study. The biological activities are
presented in Table 4.
ACKNOWLEDGEMENTS
One of the authors (A. Rauf) wishes to thank the Higher
Education Commission of Pakistan for Postdoctoral
fellowship award that made this research possible.
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position made the substrate biologically potent. The sample
10-13 did not show any activity which emphasizes that
future work should consider the SAR (structure activity
relationship) of the substituents on these substrates.
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[4]
[5]
[6]
CONCLUSION
Various novel N-(methylene-4-oxo coumarinyl)anilines
were synthesized in excellent yield using an efficient one pot
multicomponent reaction. The methodology was scrutinised
for the best solvent to increase yield and avail hassle free
separation and 2-butanol was the appropriate solvent for this
reaction in comparison to low boiling solvent.
[7]
N-(methylene-4-oxo coumarinyl)anilines derivatives
exhibited intriguing 1HNMR; which was employed to
determine E/Z product distribution among the synthesised
compounds. All the synthesised compounds, when screened
against 6 different microorganisms, exhibited moderate to no
inhibition; which enlightens that halogens and carboxylic
acids substituents are potent pharmacophore against these
microorganisms.
[8]
[9]
[10]
Qureshi, A.M., Qadir, M., Rauf, A., Idrees, M., Mumtaz, S.,
Najam-ul-Haq, M., Aziz-ur-rehman, Ismail, M., Athar, M.,
Khushal, R., Riaz, S., Bokhari, H. Antimicrobial efficacy of metal-
barbiturate conjugates against pathogenic strains of Escherichia
coli and Staphylococcus aureus, Lett. Drug. Dis & Des, 2011, 8,
10, 980-987.
CONFLICT OF INTEREST
None declared.