Synthesis of benzo[b][1,4]oxazin-3(4H)-ones via smiles rearrangement for antimicrobial activity

Article abstract of DOI:10.1007/s00044-010-9360-z

The benzo[b][1,4]oxazin-3(4H)-one derivatives, 1a-p, carrying F, Br, and Cl on the benzene ring, or benzyl, cyclohexyl, n-hexyl, and tetrafuryl methylene groups attached to nitrogen atom were synthesized via Smiles rearrangement and assayed in vitro for their antimicrobial activity against Gram-positive, Gram-negative bacteria, and fungi. The antimicrobial activity of the benzo[b][1,4]oxazin-3(4H)-ones showed, on the whole, potency toward all the tested Gram-positive and Gramnegative microorganism (MIC ranging from 16 to 64 lg/ ml), whereas weak effectiveness was exhibited against fungi. Data obtained suggest that fluorine atom in the compounds, 1c, 1f, 1i plays an important role in enhancing the antimicrobial properties of this class of compounds. These observations provide some predictions to design further antimicrobial active compounds prior to their synthesis according to molecular modeling studies.

Full text of DOI:10.1007/s00044-010-9360-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:670–677
DOI 10.1007/s00044-010-9360-z
ORIGINAL RESEARCH
Synthesis of benzo[b][1,4]oxazin-3(4H)-ones via smiles
rearrangement for antimicrobial activity
•
•
•
Liang Fang Hua Zuo Zhu-Bo Li Xiao-Yan He
•
•
Li-Ying Wang Xiao Tian Bao-Xiang Zhao
•
•
•
Jun-Ying Miao Dong-Soo Shin
Received: 20 October 2009 / Accepted: 3 May 2010 / Published online: 5 June 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The benzo[b][1,4]oxazin-3(4H)-one deriva-
tives, 1a–p, carrying F, Br, and Cl on the benzene ring, or
benzyl, cyclohexyl, n-hexyl, and tetrafuryl methylene
groups attached to nitrogen atom were synthesized via
Smiles rearrangement and assayed in vitro for their anti-
microbial activity against Gram-positive, Gram-negative
bacteria, and fungi. The antimicrobial activity of the
benzo[b][1,4]oxazin-3(4H)-ones showed, on the whole,
potency toward all the tested Gram-positive and Gram-
negative microorganism (MIC ranging from 16 to 64 lg/
ml), whereas weak effectiveness was exhibited against
fungi. Data obtained suggest that fluorine atom in the
compounds, 1c, 1f, 1i plays an important role in enhancing
the antimicrobial properties of this class of compounds.
These observations provide some predictions to design
further antimicrobial active compounds prior to their syn-
thesis according to molecular modeling studies.
Keywords Antimicrobial activity ꢀ
Benzo[b][1,4]oxazin-3(4H)-one ꢀ Smiles rearrangement ꢀ
Synthesis
Introduction
The treatment of infectious diseases still remains an
important and challenging problem because of a combi-
nation of factors including emerging infectious diseases
and the increasing number of multi-drug resistance against
man-made antibiotics in human pathogens (Tenover and
McDonald, 2005; Roberts, 2004; Muroi et al. 2004). A
potential approach to overcome the resistance problem is to
design innovative agents with a different mode of action so
that no cross resistance with the present therapeuticals can
occur.
1,4-Oxazinones derivatives represent one of the most
active classes of compounds possessing a wide spectrum of
biological activity, including antiulcer (Katsura et al.
1991), antihypertensive (Kajino et al. 1991), antifungal
(Fringuelli et al. 2002; Macchiarulo et al. 2002), anticancer
(Nair et al. 1983), anti-inflammatory (Wahidulla and
Bhattacharjee, 2001; Lanni et al. 2007), antithromobotic
(Buckman et al. 1998), antipsychotics (Smid et al. 2005),
and other activities (Anderluh et al. 2005; Caliendo et al.
2002). They are also widely used as photochromic com-
pounds (Christie et al. 1995; Sun et al. 1997) and some
possess herbicidal activity (Huang et al. 2005).
L. Fang
Department of Oncology, The Ninth People’s Hospital
of Chongqing, Chongqing 400700, China
H. Zuo (&) ꢀ Z.-B. Li ꢀ X.-Y. He ꢀ L.-Y. Wang ꢀ X. Tian
College of Pharmaceutical Sciences, Southwest University,
Chongqing 400715, China
e-mail: zuohua@swu.edu.cn
B.-X. Zhao ꢀ J.-Y. Miao
As part of our ongoing studies in developing new
methodology and novel compounds (Ma et al. 2004; Cho
et al. 2003; Cho et al. 2004; Shin and Park 2007; Zuo et al.
2008) for diverse activities, we herein report the synthesis
of a new class of structurally novel benzo[b][1,4]oxazin-
3(4H)-one derivatives. The structural variations were
Institutes of Organic Chemistry and Developmental Biology,
Shandong University, Jinan 250100, China
D.-S. Shin (&)
Department of Chemistry, Changwon National University,
Changwon, GN 641-733, South Korea
e-mail: dsshin@changwon.ac.kr
123

Med Chem Res (2011) 20:670–677
671
selected by introducing, at different positions of F, Cl, and
Br to benzene moiety, different alkyl or aryl substituents at
N-position.
acetonitrile to afford acetamide, 4. The synthesis of acet-
amide, 3 was easily achieved by reacting of amine, 5,
chloroacetyl chloride and K2CO3, in a molar ratio of 1: 1.2:
1.5 in anhydrous acetonitrile. Cyclization of substituted
acetamide, 4 by treating it with cesium carbonate in
anhydrous DMF gave substituted benzo[b][1,4]oxazin-
3(4H)-ones in good yield.
The benzo[b][1,4]oxazin-3(4H)-ones (16 samples) were
synthesized by three-step reaction via Smiles rearrange-
ment, different from all the existing methods, and this
protocol allows the generation of large combinatorial
chemical libraries of benzo[b][1,4]oxazin-3(4H)-ones. All
the compounds were tested in vitro antimicrobial properties
against Gram-positive, Gram-negative bacteria, and fungi
and exhibited moderate to excellent activity.
1
The structure of compound 4 was confirmed by IR, H
NMR, 13C NMR, and GC-MS. The broad peak in 1H NMR
of substituted benzo[b][1,4]oxazin-3(4H)-one, 4 disap-
1
peared in H NMR proton spectrum of 1, which indicated
the cyclization of 4. The evidence was further confirmed by
the disappearance of N–H stretching in IR spectrum of
product 1. The spectral data of 1a—p were in accordance
with the reported data by one-pot protocol (Zuo et al.
2008). Furthermore, the single-crystal structure analysis of
compound 1 m showed the right approach of Smiles
rearrangement (Fig. 1).
Materials and methods
Synthesis
We herein used three-step reaction procedure under con-
ventional condition (Scheme 1), different from the one-pot
protocol reported earlier by us (Zuo et al. 2008). Therefore,
the intermediates were separated and characterized, and the
proposed Smiles rearrangement mechanism was verified by
the evidence presented in this study. The synthetic proce-
dures were carried out by refluxing substituted 2-chloro-
phenol (2) with equal equivalent of the acetamide, 3
and 1.2 equivalent of potassium carbonate, in anhydrous
General procedure for the synthesis of N-substituted-2-
chloroacetamide (4)
The solution of substituted 2-chlorophenol (2) (1.0 mmol),
N-substituted-2-chloroacetamide,
3 (1.0 mmol), K2CO3
(1.2 mmol) and CH3CN (20 ml) was refluxed. After com-
pletion of the reaction (monitored by TLC), the solution was
cooled; the solvent was evaporated under reduced pressure.
The residue was poured into water and pH adjusted to 6–7 and
Scheme 1 Reagents and
condition: (a) K2CO3,
anhydrous MeCN, reflux; (b)
Cs2CO3, anhydrous DMF,
reflux; and (c) ClCOCH2Cl,
K2CO3, anhydrous MeCN; 0°C,
r.t.
Fig. 1 The single-crystal
structure of 1 m
123

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Med Chem Res (2011) 20:670–677
Strains
extracted with ethyl acetate. The organic layer was washed
with brine and dried over anhydrous MgSO4. Removal of
solvent afforded the corresponding N-substituted-2-chlor-
oacetamide, 4.
Gram-positive bacteria were Staphylococcus aureus ATCC
25923; and Bacillus subtilis ATCC 6633, and Gram-neg-
ative bacteria were Escherichia coli ATCC 25922; Proteus
vulgaris (ATCC 6896); and Pseudomonas aeruginosa
ATCC 27853. Fungi were Candida albicans ATCC 76615;
and Aspergillus flavus ATCC 10124.
Spectral data of the selected product N-cyclohexyl-2-
(2,3-dichlorophenoxy) acetamide (4n): White solid, mp
163-164°C; IR (KBr) m/cm-1: 3280, 3083, 2978, 2931,
2858, 1655, 1579, 1557, 1459, 1445, 1386, 1300, 1268,
1
1250, 1118, 1101, 971, 954, 883, 860, 768, 702, 637; H
NMR (400 MHz, CDCl3) d 1.23–1.31 (m, 3H), 1.37–1.47
(m, 2H), 1.60–1.64 (m, 1H), 1.70–1.76 (m, 2H), 1.92–1.96
(m, 2H), 3.85–3.94 (m, 1H), 4.51 (s, 2H), 6.75 (br, 1H),
6.81 (dd, J = 6.8, 2.0 Hz, 1H), 7.15–7.27 (m, 2H); 13C
NMR (100 MHz, CDCl3) d 24.6, 25.5, 32.9, 47.8, 68.3,
111.7, 122.0, 123.7, 127.8, 134.1, 154.1, 166.1; MS (EI) m/
z: 267 (M ? , 100%), 220 (17), 184 (40), 175 (15), 140
(15), 83 (26), 55 (17).
MIC tests
The microorganisms originated from the American Type
Culture Collection (ATCC). The antimicrobial activity
was assayed in vitro by the twofold broth dilution tech-
nique (Ericcsson and Sherris, 1971; Stalons and Thorns-
berry et al. 1975) against Gram-positive bacteria
(Staphylococcus aureus ATCC 25923 and Bacillus sub-
tilis ATCC 6633), Gram-negative bacteria (Escherichia
coli ATCC 25922, Proteus vulgaris ATCC 6896, and
Pseudomonas aeruginosa ATCC 27853), and fungi
(Candida albicans ATCC 76615 and Aspergillus aflavus
ATCC 10124). The minimal inhibitory concentrations
(MIC, lg/ml) were defined as the lowest concentrations of
compound that completely inhibited the growth of each
strain.
General procedure for the synthesis of benzo[b][1,4]
oxazin-3(4H)-ones (1)
The reaction mixture of appropriate N-substituted-2-
chloroacetamide, 4 (1.0 mmol) and Cs2CO3 (1.2 mmol)
was refluxed in dry DMF (10 ml). After the completion of
the reaction (monitored by TLC), the DMF was removed
under vacuum. Water (20 ml) was added to the residue.
The aqueous solution was extracted by ethyl acetate
(4 9 30 ml), and the combined organic layers were dried
over anhydrous MgSO4. The solvent was removed under
vacuum to obtain the crude product which was purified by
column chromatography (silica gel) to afford the desired
pure compound.
Ampicillin, streptomycin, ceftazidime, and clotrima-
zole were used as reference antibacterial and antifungal
substances. Test compounds were dissolved in distilled
dimethylsulfoxide and then were plated in 96-well mi-
croplates. Each tested compound (1024 lg/ml in DMSO)
was transferred to each microplate well, to be diluted in
100 ll of broth and 100 ll of inocula (Broth Agar
Medium for all Gram-positive and Gram-negative bac-
teria and Sabouraud Liquid Medium for fungi) to obtain
final concentrations at 512, 256, 128, 64, 32, 16, 8, 4, 2,
1 lg/ml. Dimethylsulfoxide never exceeded 1% v/v.
The amount of inocula was 5.009 105 bacteria/ml and
1.009 104 fungi/ml. After incubation at 37°C for 24 h
(bacteria) and at 30°C for 48 h (fungi), the last tube
remaining clear with no growth of microorganism was
recorded to represent MIC. The MICs were read
after incubation at 37°C for 24 h (bacteria) and at 30°C
for 48 h (fungi). Growth controls consisting of media
and media with 1% v/v dimethylsulfoxide were
employed.
Spectral data of the selected product 8-chloro-4-cyclo-
hexyl-2H-benzo[b] [1,4] oxazin-3(4H)-one (1n): Light
pink solid, mp 74–76°C; IR (KBr) m/cm-1: 3002, 2924,
2854, 1679, 1594, 1467, 1451, 1444, 1409, 1361, 1336,
1282, 1258, 1149, 1086, 1041, 984, 859, 768, 732, 704,
1
642; H NMR (400 MHz, CDCl3) d 1.22–1.43 (m, 3H),
1.71 (t, 1H), 1.79–1.91 (m, 4H), 2.30–2.40 (m, 2H), 4.10–
4.18 (m, 1H), 4.56 (s, 2H), 6.95 (t, J = 8.0 Hz, 1H), 7.06–
7.09 (m, 2H); 13C NMR (100 MHz, CDCl3) d 25.3, 26.4,
29.4, 57.5, 68.9, 114.8, 122.6, 122.7, 124.7, 131.3, 142.8,
165.7; MS (EI) m/z: 265 (M?, 23%), 183 (100), 154 (45),
55 (14), 44 (10).
Antimicrobial susceptibility test
The minimal bactericidal concentrations (MBC, lg/ml)
were measured by subculturing 100 ll of each sample
remaining clear in tubes containing 1 ml of fresh medium.
The tubes were then incubated at 37°C for 24 h. All the
experiments were performed in duplicate and repeated
three times.
Test compounds
Test compounds 1a–p were synthesized according to the
above procedure
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Med Chem Res (2011) 20:670–677
673
Table 1 Antimicrobial activity of 1a–p expressed as MIC (lg/ml)
Entry
Product
Microorganismsa
Gram-positive
Gram-negative
Fungia
CA
SA
64
BS
EC
64
PV
PA
16
AF
1
32
32
32
64
64
32
32
64
128
128
256
256
128
2
3
4
32
64
64
32
16
32
16
16
32
128
128
128
c
5
32
32
16
32
16
256
–
6
16
32
16
16
16
256
64
7
8
32
32
32
32
32
32
16
16
32
32
512
128
–
–
123

674
Med Chem Res (2011) 20:670–677
Table 1 continued
Entry
Product
Microorganismsa
Gram-positive
Gram-negative
Fungia
SA
32
BS
EC
16
PV
PA
CA
128
AF
9
32
16
128
128
10
11
12
32
32
32
32
32
32
32
32
64
128
128
256
256
32
32
64
–
32
16
128
–
13
14
64
64
64
32
32
32
16
32
16
16
128
128
–
256
15
16
64
32
32
128
128
32
16
128
64
32
32
32
128
64
123

Med Chem Res (2011) 20:670–677
675
Table 1 continued
Entry
Product
Microorganismsa
Gram-positive
SA
Gram-negative
EC
Fungia
CA
BS
PV
PA
AF
17
18
19
20
a
Ampicillin
2
2
1
16
4
16
4
128
2
–
–
–
2
–
–
–
2
Streptomycin
Ceftazidime
Clotrimazole
32
2
4
4
4
128
512
512
512
512
512
Gram-positive bacteria: SA, Staphylococcus aureus ATCC 25923; BS, Bacillus subtilis ATCC 6633 and Gram-negative bacteria: EC,
Escherichia coli ATCC 25922; PV, Proteus vulgaris (ATCC 6896); and PA, Pseudomonas aeruginosa ATCC 27853
b
Fungi: CA Candida albicans ATCC 76615; and AF Aspergillus flavus ATCC 10124
c
Not tested. Compounds resulted inactive against the fungi
reference drugs ampicillin, streptomycin, ceftazidime, and
clotrimazole, and the minimal inhibitory concentrations
that inhibited the growth of the tested microorganisms
(MIC) were detected.
All the compounds displayed good inhibition of the
growth of Gram-positive and Gram-negative bacteria,
including Staphylococcus aureus, Bacillus subtilis, Esche-
richia coli, Proteus vulgaris, and Pseudomonas aeruginosa.
Most compounds exhibited MIC values in the range of 16–
64 lg/ml, and the MIC values are represented in Table 1
and Fig. 1. All of the benzo[b][1,4]oxazin-3(4H)-ones
exhibit activity lower than those of the reference drugs
Fig. 2 MIC values (lg/mL) of benzo[b][1,4]oxazinones, 1a–p
against bacteria
ampicillin, streptomycin, ceftazidime, and clotrimazole.
The data of average MIC values against Gram-positive and
Gram-negative bacteria reported in Figs. 2, 3 indicate that
the antibacterial activity against Gram-positive bacteria is
weaker than Gram-negative bacteria. It is noteworthy that,
among the benzo[b][1,4]oxazin-3(4H)-one derivatives the
inhibitory effect appears to be dependent on the substitution
at the benzene ring. The compounds containing fluorine
atom possess stronger antimicrobial activity than the com-
pounds holding either chlorine or bromine atom at the
benzene ring (1c, 1f, 1i). It means the introduction of a
fluorine atom enhancing the activity against Gram-positive
and Gram-negative bacteria. Moreover, the position of the
substituent exerts, in general, a certain effect on the activity
against all the microorganisms. For instance, the introduc-
tion of a chlorine atom in the substances 1a–p at 7,8-posi-
tion at the benzene ring, respectively, shows higher
antibacterial activity in respect of substances holding
chlorine atom at 6-position of ring. On the other hand, with
regard to the influence of substitutions on the nitrogen atom
of the benzo[b] [1,4]oxazin-3(4H)-one ring, neither alkyl
nor aryl substitution significantly affects the antibacterial
activity, while the increase of methylene number attached to
benzene group contributes to the activity (1a and 1 m). It is
also interesting to point out that benzyl, cyclohexyl, and n-
hexyl moieties on N-atom attribute to slightly higher
Fig. 3 Average MIC values (lg/ml) of [1,4]oxazinones, 1a–p against
bacteria
Results and discussion
The benzo[b][1,4]oxazin-3(4H)-ones, 1 were assayed in
vitro for their antimicrobial activity against a panel of
selected Gram-positive, Gram-negative bacteria, and fungi
shown in Table 1, in comparison with those of the
123

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attached to nitrogen atom were synthesized via Smiles
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activity against Gram-positive, Gram-negative bacteria,
and fungi. The method presents an efficient protocol for
synthesizing benzo[b][1,4]oxazin-3(4H)-ones, and its
antimicrobial activity showed, on the whole, very good
potency toward a wide spectrum of Gram-positive and
Gram-negative microorganism (MIC ranging from 16 to
64 lg/ml), whereas weak effectiveness was exhibited
against fungi. Data obtained suggest that fluorine atom in
the compounds, 1c, 1f, 1i plays an important role in
enhancing the antimicrobial properties of this class of
compounds. The good properties of this new class of
antibacterial substances deserve further investigation to
clarify the mode of action at molecular level, responsible
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