Synthesis and antimicrobial activity of new benzofuranyl-1,3-benzoxazines and 1,3-benzoxazin-2-ones

Article abstract of DOI:10.1002/jhet.5570430226

New benzofuranyl-1,3-benzoxazines and 1,3-benzoxazin-2-ones are synthesized in which benzofuran is coupled with 1,3-benzoxazines and 1,3-benzoxazin-2-ones through -CONH- and -COCH₂- bridges, respectively. The antimicrobial activity of these com

Full text of DOI:10.1002/jhet.5570430226

Mar-Apr 2006
437
Synthesis and Antimicrobial Activity of New Benzofuranyl-1,3-
benzoxazines and 1,3-Benzoxazin-2-ones
Ravi K. Ujjinamatada*ꢀ, Raju S. Appala and Yankanagouda S. Agasimundin
Department of Chemistry, Gulbarga University, Gulbarga 585 106, India
ravikum@umbc.edu
Received August 22, 2005
New benzofuranyl-1,3-benzoxazines and 1,3-benzoxazin-2-ones are synthesized in which benzofuran is
coupled with 1,3-benzoxazines and 1,3-benzoxazin-2-ones through -CONH- and -COCH2- bridges,
respectively. The antimicrobial activity of these compounds is reported.
J. Heterocyclic Chem., 43, 437 (2006).
Introduction.
benzoxazines, and 1,3-benzoxazinones and in continuation
of our investigation on pharmacologically active benzo-
furan derivatives [12-14], it was thought of interest to
synthesize a new series of 2H-3-(benzofuran-2-carbox-
amidyl)-3,4-dihydro-1,3-benzoxazines 5a-c and 3-phenyl-
3,4-dihydro-4-(benzofuran-2-acetyl)-2H-1,3-benzoxazin-2-
ones 9a-c and to screen them for antimicrobial properties.
Among a wide variety of heterocycles that have been
explored for developing pharmaceutically important
molecules, benzofurans, 1,3-benzoxazines and 1,3-benz-
oxazinones have played an important role in medicinal
chemistry. Benzofuran derivatives have acquired a special
place in the heterocyclic field because of their broad
spectrum of biological activities [1]. Many 1,3-benzoxazine
derivatives are reported to possess antibacterial [2,3],
antifungal [4,5], analgesic [6], anti-inflammatory [6],
smooth muscle relaxant and spermicidal activities [7]. A
number of 1,3-benzoxazinone derivatives have been
synthesized and tested for their antimicrobial [8,9] and
analgesic properties [10]. Furthermore, few furodihydro-
benzoxazines have found the inhibitory effect on some of
the gram positive and gram negative bacteria and fungi
[11]. Prompted by the varied biological activities of 1,3-
Results and Discussion.
Benzofuran-2-carbohydrazide [15] 1 was used as a key
starting material for the synthesis of compounds 5a-c
(Scheme 1). First, benzofuran-2-carbohydrazide 1 was
reacted with salicylaldehyde 2a in ethanol in presence of
catalytic amount of hydrochloric acid to give 2-(benzofuran-
2-carboxamidylimino)methylphenol 3a. Then the reduction
of 3a using sodium borohydride in methanol gave 2-
(benzofuran-2-carboxamidylamino)methylphenol 4a. The
treatment of 4a with formaldehyde in ethanol underwent

438
R. K. Ujjinamatada, R. S. Appala and Y. S. Agasimundin
Vol 43
internal Mannich reaction to give 5a. Benzofuran-2-
carbohydrazide 1 was similarly reacted with 5-chloro and 5-
methyl salicyladehydes in ethanol to get 3b and 3c. The
resulting compounds 3b and 3c were reduced to 4b and 4c
using sodium borohydride and finally subjected to internal
Mannich reaction using formaldehyde to get 5b and 5c. The
structures of all the products were in good agreement with
spectral data and elemental analysis.
benzoxazines and 1,3-benzoxazin-2-ones through -CONH-
and -COCH2- bridges, respectively. These coupled hetero-
cycles demonstrated some promising antimicrobial activity.
Antimicrobial Activity.
Compounds 5a-c and 9a-c were evaluated in vitro for
their antibacterial activity against E. coli, P. aeruginosa,
S. aureus and B. subtilis using dimethyl formamide
(DMF) as a solvent by cup-plate method [17]. All
compounds were dissolved in DMF for antimicrobial
activity. The activity was compared with Gentamycin and
Ciprofloxacin. The results are presented in Table 1.
Antifungal activity of compounds 5a-c and 9a-c were
evaluated against A. niger and C. albicans using dimethyl
formamide as a solvent by cup-plate method [17]. The
activity was compared with Griseofulvin and Fluconazole.
The results are presented in Table 2. The zone of
inhibition was measured after 24 h of incubation at 37 °C.
The zone of inhibition developed, if any, was then
accurately measured and recorded. Each zone of
inhibition recorded was average of six measurements.
Zone of inhibition for DMF was done separately and
found that there was no activity.
The above described approach was suitable for coupling
benzofuran with 1,3-benzoxazine moiety through -CONH-
bridge. An alternative approach which led to similar
coupling of these two heterocycles through –COCH2- bridge
instead of –CONH- is also successfully accomplished
(Scheme 2). This method required benzofuran analogues of
chalcone as the starting materials. Hence such chalcone
analogues 7a-c were prepared from 2-acetylbenzofuran [16]
and salicylaldehydes 2a-c under the conditions of Claisen-
Schmidt reaction. The structures of 3-(2-hydroxyphenyl)-1-
benzofuran-2yl-2-propen-1-ones 7a-c were confirmed by
spectroscopic data and elemental analysis. The chalcone
analogues 7a-c when reacted with phenylisocyante in
benzene and in presence of catalytic amount of potassium
hydroxide gave 3-phenyl-3,4-dihydro-4-(benzofuran-2-
acetyl)-2H-1,3-benzoxazin-2-ones 9a-c, presumably through
the intermediate open chain carbamate 8a-c. The structures
of the products 9a-c were inferred from elemental analysis
and spectral data. The IR spectra (potassium bromide) of 9a-
c which lack ꢀNH excluded the possible open chain
carbamate structures 8a-c. IR spectra of 9a-c contained two
distinct bands at 1666-1673 and 1718-1725 cm-1 region due
to ketonic and carbomoyloxy carbonyls, respectively. The
structures of all the products were in good agreement with
spectral data and elemental analysis.
Table 1
Antibacterial Activity (zone of inhibition in mm)
Compd.
R
E.coli
P. aeruginosa
S. aureus
B. subtilis
5a
5b
5c
9a
9b
9c
H
Cl
CH3
H
Cl
16
15
16
16
18
15
17
19
16
18
17
14
12
18
14
16
19
18
16
19
13
14
19
12
CH3
In summary, new benzofuranyl-1,3-benzoxazines 5a-c and
1,3-benzoxazin-2-ones 9a-c are synthesized in minimum
number of steps wherein benzofuran is coupled with 1,3-
Standards:
Gentamycin
Ciprofloxacin
20
28
23
26
22
24
22
32

Mar-Apr 2006
Synthesis and Antimicrobial Activity of New Benzofuranyl-1,3-benzoxazines
439
1
3423 (OH), 3326 (NH), 1664 (CO), 1618 (CN) cm-1; H nmr
(dimethylsulfoxide-d6): ꢁ 2.18 (s, 3H, CH3), 6.80-7.60 (m, 8H,
aromatic protons), 8.70, (s, 1H, CH), 9.40 (s, 1H, OH, deuterium
oxide-exchangeable), 10.40 (s, 1H, NH, deuterium oxide-
exchangeable); MS (EI, 70 eV): m/z 294.
Table 2
Antifungal Activity (zone of inhibition in mm)
Compd.
R
A. niger
C. albicans
5a
5b
5c
9a
9b
9c
H
Cl
CH3
H
Cl
CH3
12
13
-
10
13
11
14
13
14
-
12
-
Anal. Calcd. for C17H14N2O3: C, 69.38; H, 3.52; N, 9.52 %.
Found: C, 69.54; H, 4.66; N, 9.48.
Preparation of Compounds 4a-c.
General Procedure.
Sodium borohydride (0.3 g, 0.088 mol) was added to a
solution of 2-(benzofuran-2-carboxamidylimino)methylphenols
3a-c (0.005 mol) in methanol (20 mL) and the reaction mixture
was stirred for 30 minutes. Then it was poured into cold water
(50 mL). The product, which separated as a solid, was collected
by filtration after washing with water and crystallized from
proper solvent.
Standards:
Griseofulvin
Fluconazole
16
18
18
21
EXPERIMENTAL
Melting points were determined in open capillary tubes and
are uncorrected. IR spectra (potassium bromide) were recorded
on Perkin Elmer FTIR 1615 double beam spectrophotometer
2-(Benzofuran-2-carboxamidylamino)methylphenol (4a).
This compound was obtained in 90 % yield; white crystals
from ethanol; mp 175-177 °C; ir (potassium bromide): 3390
(OH), 3225 (NH), 3120 (NH), 1645 (CO) cm-1; 1H nmr
(dimethyl sulfoxide-d6): ꢁ 4.03 (s, 2H, CH2), 5.7 (s, 1H, OH,
deuterium oxide-exchangeable), 6.75-7.78 (m, 9H, aromatic
protons), and 9.69 (s, 1H, NH, deuterium oxide-exchangeable),
10.45 (s, 1H, NH, deuterium oxide-exchangeable), ; MS (EI, 70
eV): m/z 282.
1
(ꢀmax in cm-1), H nmr spectra were recorded at 300 MHz (on a
Bruker AM-300) instrument using dimethyl sulfoxide-d6 as a
solvent (chemical shifts in ꢁ, ppm downfield from TMS as
internal reference), and mass spectra on a Varian MAT CH-5
and CH-7 instruments at 70 eV.
Preparation of Compounds 3a-c.
General Procedure.
Anal. Calcd. for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92 %.
Found: C, 67.90; H, 5.18; N, 10.11.
Benzofuran-2-carbohydrazide 1 (1.76 g, 0.01 mol) and
salicylaldehyde/5-substituted salicylaldehyde (0.01 mol) were
refluxed in ethanol (50 mL) containing two drops of
concentrated hydrochloric acid for 45 minutes. Crystalline solid
which separated on cooling was collected and crystallized from
the suitable solvent.
2-(Benzofuran-2-carboxamidylamino)-5-chloro-methylphenol (4b).
This compound was obtained in 91 % yield; white crystals
from ethanol; mp 293-295 °C; ir (potassium bromide): 3405
(OH), 3227 (NH), 3175 (NH), 1643 (CO) cm-1; 1H nmr
(dimethyl sulfoxide-d6): ꢁ 4.25 (s, 2H, CH2), 6.79-7.89 (m,
8H, aromatic protons), 8.94 (s, 1H, OH, deuterium oxide-
exchangeable), 9.94 (s, 1H, NH, deuterium oxide-exchange-
able), 11. 12 (s, 1H, NH, deuterium oxide-exchangeable);
MS (EI, 70 eV): m/z 316, 318.
2-(Benzofuran-2-carboxamidylimino)methylphenol (3a).
This compound was obtained in 87 % yield; pale yellow
crystals from ethanol; mp 218-220 °C; ir (potassium bromide):
3400 (OH), 3250 (NH), 1660 (CO), 1625 (CN) cm-1; 1H nmr
(dimethyl sulfoxide-d6): ꢁ 6.87-7.80 (m, 9H, aromatic protons),
8.75 (s, 1H, CH), 11.22 (s, 1H, OH, deuterium oxide-exchange-
able), 12.48 (s, 1H, NH, deuterium oxide-exchangeable); MS
(EI, 70 eV): m/z 280.
Anal. Calcd. for C16H13ClN2O3: C, 60.67; H, 4.14; N, 8.84 %.
Found: C, 60.78; H, 4.25; N, 8.67.
2-(Benzofuran-2-carboxamidylamino)-5-methyl-methylphenol (4c).
This compound was obtained in 89 % yield; white crystals
from ethanol; mp 246-248 °C; ir (potassium bromide): 3418
(OH), 3310 (NH), 3187 (NH), 1651(CO) cm-1; 1H nmr (dimethyl
sulfoxide-d6): ꢁ 2.05 (s, 3H, CH3), 4.17 (s, 2H, CH2), 6.58-7.15
(m, 8H, aromatic protons), 7.49 (s, 1H, OH, deuterium oxide-
exchangeable), 7.73 (s, 1H, NH, deuterium oxide-exchange-
able), 8.89 (s, 1H, NH, deuterium oxide-exchangeable); MS (EI,
70 eV): m/z 296.
Anal. Calcd. for C16H12N2O3: C, 68.56; H, 4.32; N, 9.99 %.
Found: C, 68.43; H, 4.58; N, 10.06.
2-(Benzofuran-2-carboxamidylimino)-5-chloro-methylphenol (3b).
This compound was obtained in 91 % yield; pale yellow
crystals from ethanol; mp 293-295 °C; ir (potassium bromide):
1
3416 (OH), 3273 (NH), 1662 (CO), 1621 (CN) cm-1; H nmr
(dimethyl sulfoxide-d6): ꢁ 6.93-7.78 (m, 8H, aromatic protons),
8.48 (s, 1H, CH), 10.05 (s, 1H, OH, deuterium oxide-exchange-
able), 11.23 (s, 1H, NH, deuterium oxide-exchangeable); MS
(EI, 70 eV): m/z 314, 316.
Anal. Calcd. for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45 %.
Found: C, 68.76; H, 5.67; N, 9.13.
Preparation of Compounds 5a-c.
Anal. Calcd. for C16H11ClN2O3: C, 61.06; H, 3.52; N, 8.90 %.
Found: C, 61.27; H, 3.43; N, 8.95.
General Procedure.
Compounds 4a-c (0.002 mol) and formalin (1 mL, 37%) were
refluxed in ethanol (15 mL) for five hours. The reaction mixture
was poured onto ice cold water (50 mL) and the product that
separated was collected and crystallized from suitable solvent.
2-(Benzofuran-2-carboxamidylimino)-5-methyl-methylphenol (3c).
This compound was obtained in 89 % yield; pale yellow
crystals from ethanol; mp 246-248 °C; ir (potassium bromide):

440
R. K. Ujjinamatada, R. S. Appala and Y. S. Agasimundin
Vol 43
2H-3-(Benzofuran-2-carboxamidyl)-3,4-dihydro-1,3-benz-
oxazine (5a).
1H, OH, deuterium oxide-exchangeable), 6.80-8.15 (m, 10H,
-COCH=CH- and aromatic protons); MS (EI, 70 eV): m/z 298, 300.
Anal. Calcd. for C17H11ClO3: C, 68.35; H, 3.71 %. Found: C,
68.11; H, 3.96.
This compound was obtained in 77 % yield; white tiny
crystals from ethanol; mp 156-158 °C; ir (potassium bromide):
1660 (CO), 1150 (C-O-C) cm-1; 1H nmr (dimethyl sulfoxide-d6):
ꢀ 4.45 (s, 2H, N-CH2-C), 5.16 (N-CH2-O), 8.43 (s, 1H, NH,
deuterium oxide-exchangeable), 6.95-7.75 (m, 9H, aromatic
protons); MS (EI, 70 eV): m/z 294.
3-(2-Hydroxy-5-methylphenyl)-1-benzofuran-2yl-2-propen-1-
one (7c).
This compound was obtained in 89 % yield; yellow silky
crystals from aqueous ethanol; mp 182-185d °C; ir (potassium
bromide): 3425 (OH), 1651 (CO) cm-1; 1H nmr (deuterio-
chloroform): ꢀ 2.20 (s, 3H, CH3), 6.10 (s, 1H, OH, deuterium
oxide-exchangeable), 6.70-8.10 (m, 10H, -COCH=CH- and
aromatic protons); MS (EI, 70 eV): m/z 278.
Anal. Calcd. for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52 %.
Found: C, 69.55; H, 4.83; N, 9.28.
2H-3-(Benzofuran-2-carboxamidyl)-6-chloro-3,4-dihydro-1,3-
benzoxazine (5b).
Anal. Calcd. for C18H14O3: C, 77.68; H, 5.07 %. Found: C,
77.49; H, 5.26.
This compound was obtained in 81 % yield; white tiny
crystals from ethanol; mp 197-199 °C; ir (potassium bromide):
1667 (CO), 1155 (C-O-C) cm-1; 1H nmr (dimethyl sulfoxide-d6):
ꢀ 4.40 (s, 2H, N-CH2-C), 5.10 (N-CH2-O), 8.40 (s, 1H, NH,
deuterium oxide-exchangeable), 6.80-7.70 (m, 8H, aromatic
protons); MS (EI, 70 eV): m/z 328, 330.
Preparation of Compounds 9a-c.
General Procedure.
A mixture of chalcone derivatives 7a-c (0.001 mol) and
phenylisocyanate (0.0015 mol) in anhydrous benzene (15 mL)
containing a catalytic amount of potassium hydroxide (10 mg) was
refluxed for 30 minutes and the reaction mixture was allowed to
cool. The solid that separated was collected by filtration, washed
with pet ether and crystallized from suitable solvent.
Anal. Calcd. for C17H13ClN2O3: C, 62.11; H, 3.99; N, 8.52 %.
Found: C, 62.45; H, 4.18; N, 8.43.
2H-3-(Benzofuran-2-carboxamidyl)-6-methyl-3,4-dihydro-1,3-
benzoxazine (5c).
This compound was obtained in 79 % yield; white tiny
crystals from ethanol; mp 185-187 °C; ir (potassium bromide):
1670 (CO), 1147 (C-O-C) cm-1; 1H nmr (dimethyl sulfoxide-d6):
ꢀ 2.10 (s, 3H, CH3), 4.30 (s, 2H, N-CH2-C), 5.30 (N-CH2-O),
6.95-7.70 (m, 8H, aromatic protons), 8.40 (s, 1H, NH, deuterium
oxide-exchangeable); MS (EI, 70 eV): m/z 308.
3-Phenyl-3,4-dihydro-4-(benzofuran-2-acetyl)-2H-1,3-benzoxa-
zin-2-one (9a).
This compound was obtained in 78 % yield; red crystals from
benzene-pet ether; mp 224-227 °C; ir (potassium bromide):
1
1720 (COO), 1670 (CO) cm-1; H nmr (deuteriochloroform): ꢀ
Anal. Calcd. for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09 %.
Found: C, 70.43; H, 5.44; N, 9.17.
3.40 (d, J = 6.3 Hz, 2H, CH2), 5.50 (t, J = 5.9 Hz, 1H, CH), 6.80-
7.70 (m, 14H, aromatic protons); MS (EI, 70 eV): m/z 383.
Anal.Calcd. for C24H17NO4: C, 75.19; H, 4.47; N, 3.65 %.
Found: C, 75.40; H, 4.38; N, 3.37.
Preparation of Compounds 7a-c.
General Procedure.
6-Chloro-3-phenyl-3,4-dihydro-4-(benzofuran-2-acetyl)-2H-1,3-
benzoxazin-2-one (9b).
A solution of 2-acetylbenzofuran 6 (1.60 g, 0.01 mol) and
salicylaldehyde/5-substituted salicylaldehyde (0.01 mol) in ethanol
(25 mL) at ice cold temperature, was treated with aqueous solution
of sodium hydroxide (70 %, 5 mL) in portions with constant
stirring. The reaction mixture was further stirred for two hours at
the same temperature and left overnight at room temperature. It
was then poured into cold water (100 mL) and carefully acidified to
pH 6.5 with 2 N hydrochloric acid. The separated solid was
collected and crystallized from suitable solvent.
This compound was obtained in 75 % yield; brown crystals
from ethyl acetate-pet ether; mp 218-220 °C; ir (potassium
1
bromide): 1725 (COO), 1666 (CO) cm-1; H nmr (deuterio-
chloroform): ꢀ 3.54 (d, J = 6.4 Hz, 2H, CH2), 5.48 (t, J = 5.7 Hz,
1H, CH), 6.70-7.68 (m, 13H, aromatic protons); MS (EI, 70
eV): m/z 417, 419.
Anal. Calcd. for C24H16ClNO4: C, 68.99; H, 3.86; N, 3.35 %.
Found: C, 68.91; H, 3.94; N, 3.29.
3-(2-Hydroxyphenyl)-1-benzofuran-2yl-2-propen-1-one (7a).
6-Methyl-3-phenyl-3,4-dihydro-4-(benzofuran-2-acetyl)-2H-1,3-
benzoxazin-2-one (9c).
This compound was obtained in 92 % yield; yellow silky
crystals from aqueous ethanol; mp 178-181d °C; ir (potassium
bromide): 3425 (OH), 1640 (CO) cm-1; 1H nmr (deuterio-
chloroform): ꢀ 10.10 (s, 1H, OH, deuterium oxide-exchange-
able), 6.90-8.05 (m, 11H,-COCH=CH- and aromatic protons);
MS (EI, 70 eV): m/z 264.
This compound was obtained in 72 % yield; brown crystals
from ethyl acetate-pet ether; mp 230-232 °C; ir (potassium
1
bromide): 1718 (COO), 1673 (CO) cm-1; H nmr (deuterio-
chloroform): ꢀ 2.10 (s, 1H, CH3), 3.48 (d, J = 6.3 Hz, 2H, CH2),
5.50 (t, J = 5.9 Hz, 1H, CH), 6.80-7.70 (m, 13H, aromatic
protons); MS (EI, 70 eV): m/z 397
Anal. Calcd. for C17H12O3: C, 72.26; H, 4.58 %. Found: C,
72.02; H, 4.35.
Anal. Calcd. for C25H19NO4: C, 75.55; H, 4.82; N, 3.35 %.
Found: C, 68.91; H, 3.94; N, 3.29.
3-(5-Chloro-2-hydroxyphenyl)-1-benzofuran-2yl-2-propen-1-
one (7b).
Acknowledgement.
This compound was obtained in 91 % yield; yellow silky crystals
from aqueous ethanol; mp 196-199d°C; ir (potassium bromide): 3410
The authors are thankful to the Head, RSIC, Indian
Institute of Technology, Mumbai and Director, Indian
1
(OH), 1646 (CO) cm-1; H nmr (deuteriochloroform): ꢀ 6.23 (s,

Mar-Apr 2006
Synthesis and Antimicrobial Activity of New Benzofuranyl-1,3-benzoxazines
441
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data. Authors are also grateful to Dr. Rama Bhimaiah,
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(1993).
Department of Pharmcology, Mahadevappa
Medical College, Gulbarga for antimicrobial screening.
Rampure
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ꢀ
Present address of corresponding author: Department of
Chemistry and Biochemistry, University of Maryland Baltimore County,
1000 Hilltop Circle, Baltimore, MD 21250, USA. E-mail: ravikum@
umbc.edu; Fax: 410-455-2608.
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