Synthesis and characterization of new diiodocoumarin derivatives with promising antimicrobial activities

Article abstract of DOI:10.3762/bjoc.7.199

A series of 6,8-diiodocoumarin-3-N-carboxamides (4-11) were prepared. Treatment of ethyl 6,8-diiodocoumarin-3-carboxylate (1) with ethyl cyanoacetate/NH₄OAc gave ethyl 2-(3-carbamoyl-6,8-diiodocoumarin-4- yl)-2-cyanoacetate (12) and 2-amino-4-h

Full text of DOI:10.3762/bjoc.7.199

Synthesis and characterization of new
diiodocoumarin derivatives
with promising antimicrobial activities
Hany M. Mohamed1,2, Ashraf H. F. Abd EL-Wahab*1,3,
Ahmed M. EL-Agrody4, Ahmed H. Bedair1, Fathy A. Eid1,
Mostafa M. Khafagy1 and Kamal A. Abd-EL-Rehem1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1688–1696.
1Chemistry Department, Faculty of Science, Al-Azhar University, Nasr
City, Cairo 11884, Egypt, 2Chemistry Department, Faculty of
Medicine, Jazan University, 82621, Jazan, Saudi Arabia, 3Chemistry
Department, Faculty of Science, Jazan University, 2097, Jazan, Saudi
Arabia and 4Chemistry Department, Faculty of Science, King Khalid
University, 9004, Abha, Saudi Arabia
doi:10.3762/bjoc.7.199
Received: 24 September 2011
Accepted: 10 November 2011
Published: 19 December 2011
Associate Editor: M. P. Sibi
Email:
Ashraf H. F. Abd EL-Wahab* - ash_abdelwahab@hotmail.com.bn
© 2011 Mohamed et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
antimicrobial; 3,5-diiodosalicylaldehyde; diethyl malonate; ethyl
cyanoacetate; coumarins; Michael reaction
Abstract
A series of 6,8-diiodocoumarin-3-N-carboxamides (4–11) were prepared. Treatment of ethyl 6,8-diiodocoumarin-3-carboxylate (1)
with ethyl cyanoacetate/NH4OAc gave ethyl 2-(3-carbamoyl-6,8-diiodocoumarin-4-yl)-2-cyanoacetate (12) and 2-amino-4-
hydroxy-7,9-diiodocoumarino[3,4-c]pyridine-1-carbonitrile (13), and treatment with acetone in the presence of NH4OAc or methyl-
amine gave the ethyl 4-oxo-2,6-methano-2-methyl-3,4,5,6-tetrahydro-8,10-diiodobenzo[2,1-g]-2H-1,3-oxazocine-5-carboxylate
derivatives 14a,b. All compounds were evaluated for their antimicrobial activity and the compounds 12–14a,b exhibited a
pronounced effect on all tested microorganisms.
Introduction
Coumarins and their derivatives are biologically and pharma- reported to exhibit several biological activities, such as anti-
ceutically interesting compounds known for their use as addi- microbial, anticancer, antifungal, anti-HIV and antioxidant
tives in food, perfumes, cosmetics, pharmaceuticals, platelet properties [3-6], and they also served as versatile precursors for
aggregation and agrochemicals [1,2]. Coumarins have also been many organic transformations in the synthesis of a number of
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drug-like molecules [7,8]. Moreover, coumarin-based dyes and diiodocoumarin-3-carboxylate (1). Treatment of 1 with hot
pigments are organic fluorescent materials exhibiting unique ethanolic KOH (10%) followed by acidification with HCl gave
photochemical and photophysical properties, which render them the corresponding 6,8-diiodocoumarin-3-carboxylic acid (2),
useful in a variety of applications such as dye lasers, anion which on treatment with SOCl2 gave the 6,8-diiodocoumarin-3-
sensors, organic light-emitting diodes and solar cells [9,10]. carbonyl chloride (3). Treatment of 1 with piperidine in boiling
ethanol or with p-phenylenediamine in boiling AcOH afforded
Iodo-organic derivatives have been widely used as diagnostic- the 6,8-diiodocoumarin-3-carboxamide derivatives 4 and 5, res-
imaging drugs (such as diatrizoate meglumine, diatrizoic acid, pectively. Interaction of 3 with glycine in dry benzene under
iodipamide, iodixanol, iohexol, iomeprol and iopamidol) and as reflux gave the new 6,8-diiodocoumarin-3-N,N-dimethylcarbox-
amebicides [11,12]. The benzoxazocine derivatives have amide (7) instead of 6,8-diiodocoumarin-3-ylcarbonylglycine
received considerable attention due to their pharmacological (6). The formation of compound 7 suggests that two glycine
properties, such as their antidepressant, antithrombotic, anti- molecules react with 1 followed by the loss of ammonia and
psychotic (for the central nervous system, CNS) and anti-breast- decarboxylation, furnishing the observed product (Scheme 1).
cancer activities [13].
The structures of compounds 3–5 and 7 were confirmed by IR,
In view of the important biological properties of the 1H NMR, 13C NMR and MS. The IR spectra for compound 3
diiodocoumarin derivatives and iodo-organic compounds as showed 1774, 1718 cm−1 (2 CO); for compound 4 1713, 1631
medical agents, we planned to synthesize some new cm−1 (2 CO); for compound 5 1718 cm−1 (CO); and for com-
diiodocoumarin derivatives bearing side chains with different pound 7 1722, 1635 cm−1 (2 CO). 1H NMR for compounds 3–5
structures, as such derivatives could possess interesting and and 7 showed δ at 7.64–8.70 ppm (s, 1H, H-4), and 13C NMR
useful biological properties.
for compounds 3 and 5 showed δ at 143.2 and 147.2 ppm (C-4),
respectively. The mass spectra of compounds 3 and 7 showed
the corresponding molecular ion peaks at m/z 460 (M+, 2.6%)
Results and Discussion
Interaction of 3,5-diiodosalicylaldehyde with diethyl malonate and m/z 469 (M+, 18.5%). The fragmentation pattern of com-
according to the literature procedure [14,15] afforded ethyl 6,8- pounds 3 and 7 are illustrated in Scheme 2.
Scheme 1: Synthesis of 6,8-diiodocoumarin derivatives 1–7.
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Scheme 2: Proposed fragmentation pathways for the EI ions of the substituted 6,8-diiodocoumarins 3 and 7.
Reactions of 3 with 4-aminophenylethanol or p-aminophenol, or The structures of compounds 8–11 were established by IR,
with potentially bifunctional amino acids (anthranilic acid and 1H NMR, 13C NMR and MS. The IR spectra of compound 8
p-aminophenylacetic acid), was successful, and the corres- showed 3287 cm–1 (OH, NH) and 1719 cm–1 (CO) and for
ponding 6,8-diiodocoumarin-3-carboxamide derivatives 8–11 compound 9 3217 cm–1 (NH, OH) and 1720 cm–1 (CO).
were obtained (Scheme 3).
1H NMR for 8 showed δ at 3.01 (t, J = 7.0 Hz, 2H, Ar-CH2),
Scheme 3: Synthesis of 6,8-diiodocoumarin-3-N-carboxamide derivatives 8–11.
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Beilstein J. Org. Chem. 2011, 7, 1688–1696.
3.56 (s, 1H, OH), 3.83 (t, J = 7.0 Hz, 2H, CH2–OH), and 1643 cm–1 (CO), while the 1H NMR for compound 13 showed
10.49 ppm (s, 1H, NH), and for compound 11 at 3.55 (s, 2H, δ at 7.89 (brs, 2H, NH2), and 9.06 (brs, 1H, OH). The spectral
CH2), 8.71 (s, 1H, H-4), 10.10 (brs, 1H, NH), and 10.49 (s, 1H, data of compound 13 confirmed its enol structure.
OH). The 13C NMR for 11 showed δ at 160 (CO δ lactone),
163.4 (CONH), and 176.5 ppm (COOH). The mass spectra of Reaction of 1 with acetone in the presence of NH4OAc
compounds 8–11 provided additional evidence for the proposed or methylamine at room temperature for 7 days gave
structures.
1,3-oxazocine-5-carboxylate derivatives (14a,b) [16-18]
(Scheme 5). The formation of 14 indicates that the activated
As the C3–C4 olefinic bond in ethyl 6,8-diiodocoumarin-3- methylene compounds attack at the C3–C4 olefinic bond in 1
carboxylate (1) is activated by conjugation with electron-with- under Michael reaction conditions to yield a cyclic Michael
drawing carbonyl groups, the behavior of 1 towards activated adduct, which underwent hydrolysis by NH3 or MeNH2 and
methylene compounds under Michael reaction conditions was cyclization through the elimination of H2O (Scheme 5).
investigated. Thus, treatment of 1 with ethyl cyanoacetate/
NH4OAc in boiling ethanol afforded two reaction products. The The structure of compound 14a was established by 13C NMR,
insoluble reaction product was identified as ethyl 2-(3- which showed δ at 42.5 (CH2(c)), 168.4 cm–1 (CONH), and
carbamoyl-6,8-diiodocoumarin-4-yl)-2-cyanoacetate (12) and 170 cm–1 (CO). The structures of all newly synthesized com-
the soluble reaction product was identified as 2-amino-4- pounds were confirmed by IR, 1H NMR, 13C NMR and mass
hydroxy-7,9-diiodocoumarino[3,4-c]pyridine-1-carbonitrile spectrometry.
(13), which probably formed as a result of amide formation,
dehydration and intramolecular cyclization (Scheme 4).
The inhibitory effects of the synthetic compounds against these
organisms are given in Table 1, Figure 1 and Figure 2. Among
The structures of compounds 12 and 13 were established by IR, the series tested, compounds 12–14a,b exhibited excellent
1H NMR, 13C NMR and MS. The IR spectra of compound 12 antibacterial activity, better than the standard ampicillin, against
showed 3309, 3277 cm–1 (NH2), 2206 cm–1 (CN), and two species of Gram-positive bacteria, Staphylococcus aureus
Scheme 4: Synthesis of ethyl cyanoacetate and pyridine derivatives 12 and 13.
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Scheme 5: Synthesis of 1,3-oxazocine derivatives 14a,b.
Table 1: Biological activity of the newly synthesized compounds.
Compound
no.a
Inhibition-zone diameter (mm/mg sample)
Gram-negative
Gram-positive
Staphylococcus
Fungi
Bacillus
cereus
Escherichia
Serratia
marcescens
(IMRU-70)
Aspergillus
fumigatus
Candida albicans
(MTCC-227)
aureus
coli
(NCTC-7447)
(ATCC-14579)
(NCTC-10410)
(MTCC-3008)
1
10
13
16
15
10
10
20
22
22
20
26
27
26
25
22
–
11
10
15
14
12
10
18
22
15
22
27
28
28
26
22
–
15
–
10
13
12
10
15
15
10
17
15
–
9
–
2
–
10
10
–
3
10
12
–
10
–
4
5
10
11
16
14
17
15
16
17
15
18
–
–
7
–
–
8
9
14
22
22
20
28
28
27
25
22
–
15
13
11
12
18
17
14
15
–
10
11
12
26
26
28
27
22
–
13
14a
14b
Ampicillin
Calforan
20
20
ac = 1 mg mL–1 in DMF.
(NCTC-7447), Bacillus cereus (ATCC-14579) and two Gram- against the tested organisms. Furthermore, compounds 1–8
negative bacteria, Escherichia coli (NCTC-10410) and Serratia showed moderate to weak activities against all the tested
marcescens (IMRU-70), while the same compounds showed bacteria and fungi, compared with the standards ampicillin and
moderate antifungal activity against the tested organisms. Com- calforan. In addition, compounds 2 and 5 in the series were
pounds 9–11 exhibited comparable activity to ampicillin against found to be inactive against Escherichia coli (NCTC-10410),
the tested bacteria and moderate to weak antifungal activity while compound 11 was inactive against Serratia marcescens
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Chemical shifts (δ) are related to that of the solvent. Mass
spectra were measured on a Shimadzu GMMS-QP-1000 EX
mass spectrometer at 70 eV. The elemental analyses were
performed at the Microanalytical Center, Cairo University,
Cairo (Egypt).
Ethyl 6,8-diiodocoumarin-3-carboxylate (1). Ethyl 6,8-
diiodocoumarin-3-carboxylate (1) was prepared by the inter-
action of 3,5-diiodosalicylaldehyde with diethyl malonate
according to the literature procedures [19-21].
6,8-Diiodocoumarin-3-carboxylic acid (2). A solution of com-
pound 1 (0.47 g, 10 mmol) in absolute ethanol (20 mL) was
mixed with ethanolic solution of KOH (10%), which was then
refluxed for 10 min. The reaction mixture was poured onto ice,
acidified with HCl and recrystallized from ethanol [22].
Figure 1: Graphical representation of the antibacterial activity of tested
compounds compared to ampicillin.
6,8-Diiodocoumarin-3-carbonyl chloride (3). Compound 2
(0.44 g, 10 mmol) was dissolved in dry benzene (40 mL), 2 mL
of thionyl chloride was added and the solution was refluxed for
1 h. A few drops of formic acid were added to eliminate the
unreacted thionyl chloride, and the solvent was removed under
reduced pressure. The solid obtained was recrystallized from
benzene. Yellow crystals: Yield 92%; mp 180 °C; Anal. calcd
for C10H3ClI2O3: C, 26.10; H, 0.65; found: C, 26.11; H, 0.67;
IR (KBr, cm–1): 3055 (C–H aromatic), 1774, 1718 (2 CO);
1H NMR (300 MHz, CDCl3, δ/ppm) 8.01 (d, J = 1.8 Hz, 1H,
Ar-H-7), 8.44 (d, J = 1.8 Hz, 1H, Ar-H-5), 8.58 (s, 1H, H-4);
13C NMR (75 MHz, CDCl3, δ/ppm) 86.0 (C-6), 89.1 (C-8),
118.6 (C-3), 120.3 (C-4a), 138.2 (C-5), 147.2 (C-4), 149.4
(C-7), 153.6 (C-8a), 155.0 (CO δ lactone), 162.9 (CO); MS m/z
(% relative intensity): 460 (M+, 2.6), 459 (M – 1, 30.4), 425
(83.4), 341 (19.3), 214 (10.9), 87 (100).
Figure 2: Graphical representation of antifungal activity of tested com-
pounds, compared to calforan.
(IMRU-70). An investigation of the structure–activity relation-
ship (SAR) revealed that the activity is considerably affected by 6,8-Diiodo-3-(piperidine-1-carbonyl)coumarin (4). A solu-
the presence of the diiodocoumarino[3,4-c]pyridine, 2-methyl- tion of compound 1 (0.47 g, 10 mmol) in absolute ethanol
8,10-diiodobenzo[2,1-g]-2H-1,3-oxazocine, diiodocoumarin-3- (30 mL) was refluxed with piperidine (0.9 g, 10 mmol) for 1 h.
carboxamide or 2,3-dimethyl-8,10-diiodobenzo[2,1-g]-2H-1,3- After cooling, the solid formed was filtered off, washed with
oxazocine, and slightly decreases with the presence of different ethanol and dried under vacuum. The solid obtained was re-
amide groups at position C-3 of the diiodocoumarin moiety or crystallized from benzene. Colorless crystals: Yield 80%; mp
with the presence of ester, acid or acid chloride at position C-3 230 °C; Anal. calcd for C15H13I2NO3: C, 35.37; H, 2.55; N,
of the diiodocoumarin moiety.
2.75; found: C, 35.36; H, 2.53; N, 2.76; IR (KBr, cm–1): 3040
(C–H aromatic), 2935, 2854 (C–H aliphatic), 1713, 1631 (CO);
1H NMR (300 MHz, CDCl3, δ/ppm) 1.59, 1.67, 3.29, 3.69 (m,
10H, (CH2)5), 7.64 (s, 1H, H-4), 7.78 (d, J = 2.1 Hz, 1H, Ar-H-
Experimental
General methods
Melting points were determined on a Stuart melting point appa- 7), 8.28 (d, J = 2.1 Hz, 1H, Ar-H-5); 13C NMR (75 MHz,
ratus and are uncorrected; IR spectra were recorded in KBr on a CDCl3, δ/ppm) 24.30, 25.40, 48.03 (CH2 piperidine), 86.0
FT-IR 5300 spectrometer and Perkin Elmer spectrum RXIFT- (C-8), 89.1 (C-6), 118.6 (C-3), 120.3 (C-4a), 138.2 (C-5), 147.2
IR system (ν, cm−1). The 1H NMR spectra at 300 MHz and (C-4), 149.4 (C-7), 153.6 (C-8a), 155.0 (CO δ lactone), 162.9
13C NMR spectra at 75 MHz were recorded in CDCl3 or (CO-amide); MS m/z (% relative intensity): 509 (M+, 0.3), 424
DMSO-d6 on a Varian Mercury VX-300 NMR spectrometer. (3.4), 341 (2.7), 214 (1.5), 84 (100).
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N-(4-Acetamidophenyl)-6,8-diiodocoumarin-3-carboxamide NH), 3049 (Ar-H), 2958, 2928 (aliphatic-H), 1719 (CO);
(5). A solution of compound 1 (0.47 g, 10 mmol) in glacial 1H NMR (300 MHz, DMSO-d6, δ/ppm) 3.01 (t, J = 7.0 Hz, 2H,
acetic acid (30 mL) was refluxed with p-phenylenediamine Ar-CH2), 3.56 (s, 1H, OH), 3.83 (t, J = 7.0 Hz, 2H, CH2-OH),
(1.10 g, 10 mmol) for 2 h. After cooling, the solid formed was 7.29, 7.63 (2d, J = 8.2 Hz, 4H, AB-q, Ar-H), 8.37 (d, J = 2.0
filtered off, washed with ethanol, dried under vacuum and re- Hz, 1H, H-7), 8.46 (d, J = 2.0 Hz, 1H, H-5), 8.71 (s, 1H, H-4),
crystallized from benzene. Colorless crystals: Yield 87%; mp 10.49 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6, δ/ppm) 38.4
319 °C; Anal. calcd for C18H12I2N2O4: C, 37.64; H, 2.90; N, (Ar-CH2), 62.2 (CH2-OH), 111.2, 114.0 (C-6,8), 114.5, 119.8
4.88; found: C, 37.65; H, 2.92; N, 4.90; IR (KBr, cm–1): 3285 (C-3',2',5',6'), 129.3, 132.1 (C-5,7), 135.4, 135.9, 136.0
(NH), 1718 (CO); 1H NMR (300 MHz, DMSO-d6, δ/ppm) 2.40 (C-3,1',4'), 148.3 (C-4), 156.4, 159.9 (C4a,8a), 161.4 (CO δ
(s, 3H, CH3), 7.28, 7.66 (2d, 4H, J = 8.4 Hz, AB-q, Ar-H), 8.37 lactone), 163.9 (CO-amide); MS m/z (% relative intensity): 561
(d , J = 1.8 Hz, 1H, Ar-H-7), 8.46 (d , J = 1.8 Hz, 1H, Ar-H-5), (M+, 0), 543 (M – H2O, 3), 530 (67), 425 (M – NH-C6H4-
8.70 (s, 1H, H-4), 8.90 (s, 1H, CH3CONH), 10.12 (brs, 1H, CH2CH2OH, 100), 341 (6), 107 (36), 128 (23), 127 (14), 87
NH); 13C NMR (75 MHz, DMSO-d6, δ/ppm) 23.1 (CH3), 89.0 (36).
(C-6), 90.1 (C-8), 121.5, 128.0 (C-2', 3', 5', 6'), 114.3, 133.5,
135.6 (C-3, 1', 4'), 125.3 (C-4a), 136.2 (C-5), 143.2 (C-4), 146.4 N-(4-Hydroxyphenyl)-6,8-diiodocoumarin-3-carboxamide
(C-7), 148.6 (C-8a), 160 (CO δ lactone), 163.7 (CO-amide), (9). Yellow crystal: Yield 85%; mp 303 °C; Anal. calcd for
170.0 (COCH3); MS m/z (% relative intensity): 574 (M+, 3), C16H9I2NO4: C, 36.03; H, 1.69; N, 2.63; found: C, 36.05; H,
532 (M – CH2=C=O, 38.7), 424 (18.2), 341 (33.8), 298 (6.5), 1.68; N, 2.63; IR (KBr, cm–1): 3217 (NH, OH), 1720 (CO);
171 (9.3), 107 (100).
1H NMR (300 MHz, DMSO-d6, δ/ppm) 7.25–7.85 (m, 4H,
Ar-H), 8.35 (d, J = 1.8 Hz, 1H, Ar-H-7), 8.43 (d, J = 1.8 Hz,
6,8-Diiodocoumarin-3-N,N-dimethylcarboxamide (7). A 1H, Ar-H-5), 8.70 (s, 1H, H-4), 10.12 (brs, 1H, OH), 11.9 (brs,
solution of compound 3 (0.46 g, 1 mmol) in dry benzene 1H, NH); 13C NMR (75 MHz, DMSO-d6, δ/ppm) 89.5 (C-6),
(50 mL) was refluxed with glycine (0.75 g, 10 mmol) for 2 h. 92.0 (C-8), 130.5, 124.4, 134.3, 121.5 (C-3',4',5',6'), 114.3,
After cooling, the solid formed was filtered off, washed with 140.8, 116.0 (C-3,1',2'), 125.5 (C-4a), 134.2 (C-5), 139.5 (C-4),
ethanol, dried under vacuum, and recrystallized from dioxane. 144.5 (C-7), 146.6 (C-8a), 160 (CO δ lactone), 163.2 (CONH),
Colorless crystals: Yield 83%; mp 302 °C; Anal. calcd for 170 (COOH); MS m/z (% relative intensity): 533 (M+, 45), 425
C12H9I2NO3: C, 30.70; H, 1.92; N, 2.98; found: C, 30.72; H, (M+ – NH-C6H4-OH, 100), 341 (16), 214 (10), 171 (17), 87
1.94; N, 3.00; IR (KBr, cm–1): 2931 (C–H aliphatic), 1722 and (63).
1635 (CO); 1H NMR (300 MHz, DMSO-d6, δ/ppm) 2.93 (s,
3H, N-CH3), 2.97 (s, 3H, N-CH3), 8.02 (s, 1H, H-4), 8.13 (d, J 2-(6,8-Diiodocoumarin-3-carboxamido)benzoic acid (10).
= 2.1 Hz, 1H, Ar-H-7), 8.38 (d, J = 2.1 Hz, 1H, Ar-H-5); MS Yellow crystals: Yield 91%; mp 315 °C; Anal. calcd for
m/z (% relative intensity): 469 (M+, 18.5), 425 (83.4), 397 C17H9I2NO5: C, 36.37; H, 1.60; N, 2.50; found: C, 36.39; H,
(16.1), 341 (19.3) and 72 (100).
36.39; N, 2.52; IR (KBr, cm–1): 3271 (OH, NH), 3055 (Ar-H),
1751, 1651 (CO, CONH); 1H NMR (300 MHz, DMSO-d6, δ/
ppm) 7.27, 7.64 (2d, J = 8.4 Hz, 4H, AB-q, Ar-H), 8.38 (d, J =
1.8 Hz, 1H, Ar-H-7), 8.47 (d, J = 1.8 Hz, 1H, Ar-H-5), 8.71 (s,
1H, H-4), 10.10 (brs, 1H, NH), 10.49 (s, 1H, OH); 13C NMR
(75 MHz, DMSO-d6, δ/ppm) 90.0 (C-6), 92.1 (C-8), 123.0,
130.0 (C-2',3',5',6'), 114.3, 135.0, 130.5 (C-3,1',4'), 125.5
(C-4a), 133.2 (C-5), 138.5 (C-4), 144.2 (C-7), 146.1 (C-8a), 160
(CO δ lactone), 163.4 (CO-amide), 176.5 (COOH); MS m/z (%
relative intensity): 561 (M+, 7.1), 560 (M – 1, 40.8), 517 (M+ –
CO2, 2.7), 516 (M – CO2H, 24.5), 425 (M – NHC6H4-2-CO2H,
11.5), 424 (100), 341 (17), 171 (14.5) and 87 (58.2).
General procedure for the synthesis of 6,8-
diiodocoumarin-3-carboxamide derivatives
8–11
To a well-stirred solution of 3 (0.46 g, 1 mmol) in dry
dichloromethane (DCM) containing a few drops of triethyl-
amine (TEA) an equivalent amount of an ambient nucleophile
[4-aminophenylethanol, p-aminophenol, anthranilic acid and
p-aminophenylacetic acid (1.2 mmol)] was added. The reaction
mixture was stirred at room temperature under dry conditions
for 3 h. DCM was removed under reduced pressure until
dryness, the obtained solid was then washed with 10% HCl and
the remaining solid recrystallized from dioxane.
2-(4-(6,8-Diiodocoumarin-3-carboxamido)phenyl)acetic acid
(11). Yellow crystals: Yield 93%; mp 285 °C; Anal. calcd for
N-(4-(2-Hydroxyethyl)phenyl)-6,8-diiodocoumarin-3- C18H11I2NO5: C, 37.57; H, 1.91; N, 2.44; found: C, 37.59; H,
carboxamide (8). Yellow crystals: Yield 87%; mp 291 °C; 1.92; N, 2.46; IR (KBr, cm–1): 3286 (OH, NH), 3047 (Ar-H),
Anal. calcd for C18H13I2NO4: C, 38.51; H, 2.32; N, 2.50; 2916 (aliphatic-H), 1720 (CO); 1H NMR (300 MHz, DMSO-d6,
found: C, 38.52; H, 2.34; N, 2.51; IR (KBr, cm–1): 3287 (OH, δ/ppm) 3.55 (s, 2H, CH2), 7.27, 7.64 (2d, J = 8.4 Hz, 4H, AB-q,
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Ar-H), 8.38 (d, J = 1.8 Hz, 1H, Ar-H-7), 8.47 (d, J = 1.8 Hz, rated under reduced pressure, and the products were identified
1H, Ar-H-5), 8.71 (s, 1H, H-4), 10.10 (brs, 1H, NH), 10.49 (s, as compounds 14a and 14b. The crude products were crystal-
1H, OH); 13C NMR (75 MHz, DMSO-d6, δ/ppm) 90.0 (C-6), lized from benzene.
92.1 (C-8), 123.0, 130.0 (C2',3',5',6'), 114.3, 135.0, 130.5
(C-3,1',4'), 125.5 (C-4a), 133.2 (C-5), 138.5 (C-4), 144.2 (C-7), Ethyl 4-oxo-2,6-methano-2-methyl-3,4,5,6-tetrahydro-8,10-
146.1 (C-8a), 160 (CO δ lactone), 163.4 (CO-amide), 176.5 diiodobenzo[2,1-g]-2H-1,3-oxazocine-5-carboxylate (14a).
(COOH); MS m/z (% relative intensity): 575 (M+, 12.4), 574 Colorless: Yield 72%; mp 222 °C; Anal. calcd for
(M – 1, 68.9), 531 (M – CO2, 7.3), 425 (M – NH-C6H4-4- C15H15I2NO4: C, 34.16; H, 2.85; N, 2.66; found: C, 34.18; H,
CH2COOH, 13.5), 424 (100), 341 (18.9), 171 (27.2), 106 (94.6) 2.87; N, 2.68; IR (KBr, cm–1): 3217 (NH), 2977 (aliphatic-H),
and 87 (59.5).
1728, 1689 (CO); 1H NMR (300 MHz, DMSO-d6, δ/ppm) 0.87
(t, J = 6.9 Hz, 3H, CH3 (e)), 1.64–1.95 (m, 5H, CH2(c),
CH3(f)), 3.80 (q, J = 4.5 Hz, 2H, CH2 (d)), 3.72–3.97 (m, 2H,
H(a) + H(b)), 7.16 (d, J = 1.8 Hz, 1H, Ar-H-9), 7.92 (d, J = 2.1
Hz, 1H, Ar-H-7), 8.88 (brs, 1H, NH); 13C NMR (75 MHz,
DMSO-d6, δ/ppm) 14.1 (CH3(e)), 24.7 (CH3(f)), 42.5 (CH2(c)),
56.0, 57.3 (CH(a)-CH(b)), 61.2 (CH2(d)), 130, 138, 141.9, 154
(C-2,3,5), 87.1, 87.5 (C-4,6),168.4 (CONH), 170 (CO); MS m/z
(% relative intensity): 527 (M+, 4.3) 454 (M – CO2C2H5, 42.5),
182 (100), 136 (44.8), 57 (13.4).
General procedure for the synthesis of ethyl
cyanoacetate and pyridine derivatives 12
and 13
Ethanolic solution of ethyl 6,8-diiodocoumarin-3-carboxylate
(1) (0.47 g, 10 mmol, 30 mL) was refluxed with ethyl cyano-
acetate (1.13 g, 10 mmol) for 6 h. The solid precipitated was
filtered off while hot, washed with ethanol and dried under
vacuum, and was identified as compound 12. The filtrate evapo-
rated under reduced pressure to produce a solid identified as
compound 13. Compound 12 crystallized from dioxane,
whereas compound 13 crystallized from chloroform.
Ethyl 3-methyl-4-oxo-2,6-methano-2,3-dimethyl-3,4,5,6-
tetrahydro-8,10-diiodobenzo[2,1-g]-2H-1,3-oxazocine-5-
carboxylate (14b). Colorless: Yield 70%; mp 198 °C; Anal.
Ethyl 2-(3-carbamoyl-6,8-diiodocoumarin-4-yl)-2-cyano- calcd for C16H17I2NO4: C, 35.50; H, 3.14; N, 2.59; found: C,
acetate (12). Pale yellow crystal: Yield 82%; mp 310 °C; Anal. 35.51; H, 3.16; N, 2.61; IR (KBr, cm–1): 3051 (Ar-H), 2985.6
calcd for C15H10I2N2O5: C, 32.62; H, 1.81; N, 5.07; found: C, (aliphatic-H), 1735, 1651 (CO); 1H NMR (300 MHz, DMSO-
32.64; H, 1.79; N, 5.05; IR (KBr, cm–1): 3309, 3277 (NH2), d6, δ/ppm) 1.23 (t, J = 7.2 Hz, 3H, CH3(e)), 1.78 (s, 3H,
2206 (CN), 1643 (CO); 1H NMR (300 MHz, CDCl3, δ/ppm) CH3(f)), 2.83 (s, 3H, NCH3), 2.38–2.42 (m, 2H, CH2(b)),
1.50 (t, J = 7.2 Hz, 3H, CH3), 4.44 (q, J = 7.2 Hz, 2H, CH2), 3.4–3.57 (m, 2H, H(a) + H(b)), 4.18 (q, J = 7.2 Hz, 2H,
5.05 (s, 1H, CH), 8.00 (d, J = 1.8 Hz, 1H, Ar-H-7), 8.40 (d, J = CH2(d)), 7.66 (d, 1H, Ar-H-9), 7.95 (d, J = 1.8 Hz, 1H, Ar-H-
1.8 Hz, 1H, Ar-H-5), 8.70 (brs, 2H, NH2, exchangeable with 7); MS m/z (% relative intensity): 541 (M+, 3.4), 196 (59.2),
D2O); MS m/z (% relative intensity): 552 (M+, 2), 388 (8.0), 150 (27.6), 56 (100).
313 (30.0), 264 (4.0), 236 (35.0).
Antimicrobial assays
2-Amino-4-hydroxy-7,9-diiodocoumarino[3,4-c]pyridine-1- The newly synthesized compounds were screened for their anti-
carbonitrile (13). Pale yellow crystals: Yield 84%; mp 340 °C; microbial activities in vitro against two species of Gram-posi-
Anal. calcd for C13H5I2N3O3: C, 30.90; H, 0.99; N, 8.32; found tive bacteria, namely Staphylococcus aureus (NCTC-7447),
C, 30.92; H, 1.00; N, 8.34; IR (KBr, cm-1): 3374 (OH), 3277, Bacillus cereus (ATCC-14579), and two Gram-negative
3228 (NH2), 2207 (CN), 1707, 1662 (CO); 1H NMR (300 MHz, bacteria, namely Escherichia coli (NCTC-10410), Serratia
CDCl3, δ/pm) 9.06 (brs, 1H, OH, exchangeable with D2O), 8.20 marcescens (IMRU-70); and against two species of fungi,
(s, 1H, H-8), 7.97 (s, 1H, H-10), 7.89 (brs, 2H, NH2, exchange- namely Aspergillus fumigatus (MTCC-3008) and Candida albi-
able with D2O); MS m/z (% relative intensity): 505 (M+, 100), cans (MTCC-227). The tested microorganisms were obtained
477 (M – CO, 18.9), 397 (20.8), 341 (18.9), 171 (25.2), 106 from the Regional Center for Mycology & Biotechnology
(32.6) and 87 (35.5).
(RCMP), Al-Azhar University.
General procedure for the synthesis of 1,3-
oxazocine-5-carboxylate derivatives 14a,b
The activities of these compounds were tested by using the disc-
diffusion method [23] for bacteria and the paper-disk-diffusion
A mixture of compound 1 (2.35 g, 5 mmol), acetone (30 mL) method [24] for fungi. The area of zone inhibition was
and (a) ammonium acetate (0.4 g, 5 mmol) or (b) methylamine measured with ampicillin (30 µg mL−1) as the standard anti-
(0.16 g, 5 mmol) was stirred at room temperature for 7 days. In biotic reference for antibacterial activity, and calforan
both cases a colorless solid formed after the solvent had evapo- (30 µg mL−1) was used as a reference antifungal activity. The
1695

Beilstein J. Org. Chem. 2011, 7, 1688–1696.
17.Koelsch, C. F.; Freerks, M. C. J. Org. Chem. 1953, 18, 1538–1545.
doi:10.1021/jo50017a013
tested compounds were dissolved in N,N-dimethylformamide
(DMF) to give a solution of 1 mg mL−1. The inhibition zones
(diameter of the hole) were measured in millimeters (6 mm) at
the end of an incubation period of 48 h at 28 °C; N,N-dimethyl-
formamide showed no inhibition zone.
18.Bedair, A. H.; Aly, F. M.; El-Agrody, A. M.; El-Assy, R. K. M.
Acta Pharm. 1986, 36, 363–369.
19.Kadnikov, D. V.; Larock, R. C. J. Organomet. Chem. 2003, 687,
425–435. doi:10.1016/S0022-328X(03)00786-1
20.Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001,
42, 9285–9287. doi:10.1016/S0040-4039(01)02041-X
21.Yavari, I.; Adib, M.; Hojabri, L. Tetrahedron 2002, 58, 6895–6899.
doi:10.1016/S0040-4020(02)00758-5
Conclusion
It was interesting to note that four of the new compounds (12,
13 and 14a,b) were found to have an antimicrobial activity
greater than that of the standard antibiotic ampicillin or the stan-
dard antifungal claforan, while compounds 1–11 were either
inactive or only weakly active against the tested microorgan-
isms. The presence of fused diiodocoumarino[3,4-c]pyridine
and diiodobenzo[2,1-g]-2H-1,3-oxazocine nucleus increased the
antimicrobial activity, whereas the presence of diiodocoumarin-
3-carboxamides decreased the antimicrobial activity.
22.Creaven, B. S.; Egan, D. A.; Kavanagh, K.; McCann, M.; Noble, A.;
Thati, B.; Walsh, M. Inorg. Chim. Acta 2006, 359, 3976–3984.
doi:10.1016/j.ica.2006.04.006
23.European Committee for Antimicrobial Susceptibility Testing (EUCAST)
of the European Society of Clinical Microbiology and Infectious
Diseases (ESCMID). Clin. Microbiol. Infect. 2000, 6, 509–515.
24.National Committee for Clinical Laboratory Standards. Methods for
dilution antimicrobial susceptibility tests for bacteria that grow
aerobically, 5th ed; Approved Standard M7-A5.Wayne, PA: NCCLS,
2000.
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