Synthesis and antitubercular evaluation of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones

Article abstract of DOI:10.1016/j.bmcl.2011.05.054

A new class of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5-e] [1,3]oxazin-3(2H)-ones was synthesized in very good yields through polyphosphoric acid supported on silica (PPA-SiO₂) catalyzed one-pot three component condensation of 2-dibenzofuranol; aromatic aldehydes and acetamide or benzamide or urea under solvent free conditions. At 125 °C the reaction led to the formation of amidoalkyl dibenzofuranols 5a-k where as at 160 °C cyclization take place to give oxazin-3(2H)-one analogues 6a-e. Screening all the 16 compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) resulted 1-((4-chlorophenyl)(2- hydroxydibenzo[b,d]furanyl)methyl)urea 5h; 1-((4-bromophenyl)(2- hydroxydibenzo[b,d]furanyl)methyl)urea 5i; 1-phenyl-1H-benzo[2,3]benzo furo[4,5-e][1,3]oxazin-3(2H)-one 6a (MIC 3.13 μg/mL) and 1-(4-chlorophenyl)- 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-one 6b; 1-(4-bromophenyl)-1H- benzo[2,3]benzofuro [4,5-e][1,3]oxazin-3(2H)-one 6c (MIC 1.56 μg/mL) as most active antitubercular agents.

Full text of DOI:10.1016/j.bmcl.2011.05.054

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4316–4319
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Bioorganic & Medicinal Chemistry Letters
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Synthesis and antitubercular evaluation of amidoalkyl dibenzofuranols
and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones
Srinivas Kantevari a, , Thirumal Yempala a, Perumal Yogeeswari b, Dharmarajan Sriram b,
⇑
Balasubramanian Sridhar c
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500 078, India
c Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 February 2011
Revised 2 May 2011
Accepted 17 May 2011
Available online 27 May 2011
A new class of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones
was synthesized in very good yields through polyphosphoric acid supported on silica (PPA–SiO2) cata-
lyzed one-pot three component condensation of 2-dibenzofuranol; aromatic aldehydes and acetamide
or benzamide or urea under solvent free conditions. At 125 °C the reaction led to the formation of
amidoalkyl dibenzofuranols 5a–k where as at 160 °C cyclization take place to give oxazin-3(2H)-one
analogues 6a–e. Screening all the 16 compounds for in vitro antimycobacterial activity against Myco-
bacterium tuberculosis H37Rv (MTB) resulted 1-((4-chlorophenyl)(2-hydroxydibenzo[b,d]furanyl)me
thyl)urea 5h; 1-((4-bromophenyl)(2-hydroxydibenzo[b,d]furanyl)methyl)urea 5i; 1-phenyl-1H-benzo
Keywords:
Oxazin-3(2H)-ones
Amidoalkyl dibenzofuranols
Dibenzofuran
Antimycobacterial activity
Mycobacterium tuberculosis
[2,3]benzo furo[4,5-e][1,3]oxazin-3(2H)-one 6a (MIC 3.13
[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-one 6b; 1-(4-bromophenyl)-1H-benzo[2,3]benzofuro [4,5-e][1,
3]oxazin-3(2H)-one 6c (MIC 1.56 g/mL) as most active antitubercular agents.
Ó 2011 Elsevier Ltd. All rights reserved.
lg/mL) and 1-(4-chlorophenyl)-1H-benzo
l
Tuberculosis (TB) is a chronic infectious disease of global influ-
ence caused mainly by Mycobacterium tuberculosis (MTB).1 Accord-
ing to world health organization (WHO) report, it claims over two
million lives each year and dwells hidden in as many as two billion
people. It is anticipated that in 2010 alone there will be 9.8 million
new cases, more than any other year in the history.2 By 2020, it is
estimated that one billion people will be new infected, over 125
million people will get sick and over 30 million will die of tubercu-
losis if control is not further strengthened.1–3 In addition, the TB
epidemic has been further fuelled by the emergence of its new vir-
ulent forms like multi drug resistant (MDR-TB) and extremely drug
resistant (XDR-TB).2 Among immuno-compromised individuals
such as those infected with HIV, on anti-tumor necrosis or with
diabetics, the resurgence of TB is alarming due to the development
of pathogenic synergy.1–4 Furthermore, it has been more than 40
years since a new tubercular drug discovered.4 The worsening
situation has prompted WHO to declare tuberculosis as a global
public health crisis. The challenge of meeting all these facts neces-
sitated an urgent need for development of fast acting new antitu-
bercular drugs with diverse and unique structural features.3,4
In recent years, the natural product inspired, structurally diverse
new molecules play a major role in drug discovery.5 The lichen
dibenzofuran derived secondary metabolite Usnic acid has been
shown to display an interesting biological activity.6 The new hybrid
heterocycles developed with dibenzofuran (CGS-35066 and CGS-
34043, Fig. 1) emerged as potent ECE-1 inhibitors.6e In the develop-
ment of antitubercular agents, benzofurobenzopyran analogues
were described to show very good in vitro as well in vivo antituber-
cular activity.7 We, therefore, envisaged that re-engineering ben-
zofurobenzopyran nucleus with 1,3-oxazinone unit of emerging
O
O
OH
O
O
OH
HO
O
O
O
Usnic acid
OCH3
Benzofurobenzopyran
O
O
H
O
O
P
N
N
N
N
H
N
H
P
COOMe
HO
HO
OH
OH
N
CGS-35066
CGS-34043
⇑
Corresponding author. Tel.: +91 4027191437; fax: +91 4027198933.
E-mail addresses: kantevari@gmail.com, kantevari@yahoo.com (S. Kantevari).
Figure 1. Bioactive hybrid heterocycles of dibenzofuran.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.054

S. Kantevari et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4316–4319
4317
Table 1
O
R1
F
O
Optimization of catalysts and reaction conditions
R
R
R
O
NH
N
N
H
N
O
CH3
OH
NH
CHO
OH
OH
O
CH3CONH2
Catalyst
Cl
Linezolid: R=CH3;
PNU100480: R= CH2SCH2
+
O
O
3
4b
Cl
O
5b
H
N
O
R
O
Entry
Catalyst
mol %
Time (h)
Yielda,b (%)
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
p-TSA
100
20
30
30
30
30
30
30
30
30
100
30
30
10
20
3.5
3.5
3.5
3.5
3.0
12.0
3.5
3.5
6.0
6.0
12.0
3.5
4.0
4.0
4.0
48
96
85
82
94
35
70
66
28
55
62
58
85
56
70
O
SnCl2Á2H2O
HClO4–SiO2
H2SO4–SiO2
PPA–SiO2
Antitubercular agent
Benzofurobenzopyran
O
NaHSO4–SiO2
Figure 2. Re-engineering antitubercular drugs Linezolid and PNU 100480 with
benzofurobenzopyran.
Montmorillonite-K10
Amberlyst-IR120-H+
CeCl3Á7H2O
CeCl3Á7H2O–NaI
TBAB
antitubercular drugs Linezolid and PNU-100480 (Fig. 2)4 could de-
liver scaffolds with diverse structural features and better antimyco-
bacterial activity. With our continued interest in developing new
antimycobacterial agents,8 we herein report an efficient synthesis
and evaluation of dibenzofuran derived hybrid heterocycles teth-
ered with amidoalcohols or fused with 1,3-oxazinone as novel anti-
tubercular agents. Synthesis of these amidoalkyl dibenzofuranols
5a–k were obtained in very good yields through polyphosphoric
acid supported on silica (PPA–SiO2)9 catalyzed one-pot, solvent free
condensation of 2-dibenzo furanol; aromatic aldehydes and acet-
amide or benzamide or urea at 125 °C. At 160 °C condensation with
urea proceeded to cyclization to give 1H-benzo[2,3]benzofuro[4,5-
e][1,3] oxazin-3(2H)-ones 6a–e. Among all new 16 compounds
screened for in vitro activity against M. tuberculosis H37Rv (MTB),
Dowex-H+
Polyphosphoric acid
PPA–SiO2
PPA–SiO2
a
Dibenzofuran-2-ol 3 (1 mmol), 4-chlorobenzaldehyde 4b (1 mmol), acetamide
(1 mmol) and catalyst were heated at 125 °C.
b
Isolated yields.
of catalyst. Investigation of the reaction temperature indicated that
125 °C is most favorable for the formation of amidoalkyl dibenzo-
furanol 5b. The choice of PPA–SiO2 for further study is due to its
heterogeneous, reusable nature with good acidic dehydrating
properties and easy reaction work-up conditions. Having success
with the reaction, the other aromatic aldehydes 4a–e and 2-dib-
enzofuranol 3 and acetamide/benzamide/urea were heated at
125 °C in the presence of 30 mol % of PPA–SiO2 catalyst (Scheme
2, Table 2). All the products 5a–k obtained in excellent yields
(75–94%) were fully characterized by 1H and 13C NMR, IR and mass
(EI, ESI and HRMS) spectral data.11
Encouraged by these results, we extended the protocol to the
synthesis of oxazinone ring system (Scheme 3) with enhanced liph-
ophilic nature. Condensation of 3 with aromatic aldehyde 4a–e and
urea in the presence of 30 mol % PPA–SiO2 at elevated temperature
(160 °C) gave 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-
ones 6a–e in very good yields (Table 3). The products 6a–e was fully
characterized by 1H and 13C NMR, IR and mass (ESI and HRMS) spec-
tral data.11 The single crystal X-ray diffraction studies of 6d unam-
biguously confirmed the regioselectivity of the structure (Fig. 3).12
The antimycobacterial activity of the synthesized amidoalkyl
dibenzofuranols 5a–k and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxa-
zin-3(2H)-ones 6a–e has been screened against M. tuberculosis
H37Rv (MTB) by agar dilution method for the determination of
MIC in triplicates. The minimum inhibitory concentration (MIC)
is defined as the minimum concentration of compound required
to completely inhibit the bacterial growth. The MIC values of 5a–
5h, 5i, 6a (MIC 3.13
to be most active agents.
lg/mL) and 6b, 6c (MIC 1.56 lg/mL) are found
2-Dibenzofuranol (3), being versatile substrate in the synthesis
of heterocyclic compounds, was chosen as starting material for the
synthesis of amidoalkyl dibenzofuranols 5a–k and 1H-
benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones 6a–e. It was
prepared from dibenzofuran 1 according to the literature proce-
dure7,10 through a reaction sequence; Friedel–Craft acylation,
Baeyer–Villiger oxidation and ester hydrolysis in very good overall
yield (Scheme 1). It was fully characterized by 1H and 13C NMR, IR
and mass spectral data.11
In continuation of our recent work,8,10 initially, efforts were fo-
cused on the one-pot three component reaction of 2-dibenzofura-
nol 3 with 4-chlorobenzaldehyde 4b and acetamide in the presence
of various Lewis and protic acid catalysts in solvent and solvent
free conditions. Out of all the catalysts and reaction conditions
examined (Table 1), the reaction was efficient with 20 mol % tin(II)
chloride dehydrate (SnCl2. 2H2O) at 125 °C under solvent free con-
ditions (Table 1, entry 2) to give amidoalkyl dibenzofuranol 5b in
96% yield. Among the heterogeneous protic acid catalysts exam-
ined polyphosphoric acid supported on silica (30 mol %) under sol-
vent free condition was found to be equally efficient as tin(II)
chloride to give the corresponding amidoalkyl dibenzofuranol 5b
in 94% yield. Furthermore no product was detected in the absence
O
i) mCPBA,TFA, CH2Cl2,
RT, 3 days
OH
CH3
CH3COCl
ii) NaOCH3, 1N HCl,
1h, RT,
CHCl3, 2h, RT,
O
1
O
3
95%
O
2
82%
Scheme 1. Synthesis of 2-dibenzofuranol.

4318
S. Kantevari et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4316–4319
R1
O
CHO
R
OH
NH
O
PPA-SiO2
125 oC
OH
+
+
R1
NH2
R1= CH3, Ph, NH2
4d:
O
3
R
4a-e
O
5a-h
4a:
4b:
4c:
R=H; R=Cl; R=Br;
4e: R= 3,4,5-trimethoxy
R=OCH3
Scheme 2. Synthesis of amidoalkyldibenzofuran-2-ols 5a–k.
H
N
O
O
R
CHO
OH
PPA-SiO2
160 o
O
+
+
C
H2N
NH2
O
3
R
4a-e
O
6a-e
Scheme 3. PPA–SiO2 catalyzed synthesis of 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones 6a–e.
Table 2
Physical data and antitubercular evaluation of 5a–k against M. tuberculosis H37RV
Entry
Aldehyde
Amide/urea
Reaction time
Product
Yielda (%)
Mp (°C)
Log P/C Log Pb
MIC (lg/mL)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4e
4b
4e
4b
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
PhCONH2
PhCONH2
NH2CONH2
NH2CONH2
NH2CONH2
NH2CONH2
—
3.0
3.0
3.0
4.0
4.0
2.5
4.0
3.0
3.0
3.5
4.0
—
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
—
—
—
82
94
90
88
78
88
75
85
84
80
76
—
220–221
218
208
192
183
210–212
124
68
82
76
161
—
—
3.00/3.525
3.56/4.238
3.83/4.388
2.87/3.444
2.62/2.825
5.46/6.117
4.52/4.704
3.23/4.022
3.50/4.172
2.55/3.228
2.29/2.609
—
6.25
6.25
6.25
6.25
12.5
12.5
12.5
3.13
3.13
6.25
12.5
0.1
4c
4d
4e
Isoniazid
Ethambutol
Pyrazinamide
—
—
—
—
—
—
—
—
3.13
50.0
—
a
Isolated yields.
Calculated using Chemdraw Ultra 12.0.
b
k and 6a–e along with the standard drugs for comparison are fur-
nished in Tables 2 and 3. Sixteen new compounds screened have
showed in vitro activity against MTB with MIC ranging from 1.56
to 12.5
pounds 5a–d and 5j inhibited MTB with MIC of 6.25
two compounds 5h and 5i inhibited MTB with MIC 3.13
In case of oxazinone analogues 6a–e, two compounds 6b and 6c
inhibited MTB with MIC 1.56 g/mL. When compared to one of
the first line anti-TB drug ethambutol (MIC 3.13 g/mL), three
l
g/mL. Among amidoalkyl dibenzofuranols, five com-
g/mL and
g/mL.
l
l
l
l
compounds 5h, 5i and 6a are found to be equally active as etham-
butol and two compounds 6b and 6c are more active than etham-
butol. When compared to pyrazinamide (MIC 50.8 lg/mL), all the
16 compounds were found to be more potent, though all the com-
pounds were less potent than another anti-TB drug isoniazid.
Structural correlations of the new compounds with respect to
their antitubercular activity reveal that oxazinone analogues 6a–
e are better placed to show potent activity by two folds than the
corresponding amidoalkyl dibenzofuranols (e.g., Table 2, entries 8
and 9; Table 3, entries 2 and 3). Among the amidoalkyl dibenzofur-
anols 5a–k, compounds derived with urea are more active than the
respective acetamide and benzamide derivatives (Table 2, entries
2, 6 and 8). In oxazinone analogues chloro (6b) and bromo (6c)
derivatives are more active than the unsubtituted (6a) or methoxy
compounds (6d–e). All these results reveal that moderate
Figure 3. ORTEP representation of 6d with thermal displacement ellipsoids drawn
at the 30% probability.

S. Kantevari et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4316–4319
4319
Table 3
Physical data and antitubercular evaluation of 6a–e against M. tuberculosis H37RV
Entry
Aldehyde 4
R
Product 6
Yielda (%)
Mp ( °C)
Log P/C Log Pb
MIC (lg/mL)
1
2
3
4
5
4a
4b
4c
4d
4e
H
Cl
Br
OCH3
6a
6b
6c
6d
6e
85
90
90
81
76
126
130
192
189
167
3.61/4.489
4.16/5.202
4.43/5.352
3.48/4.408
3.23/3.789
3.13
1.56
1.56
6.25
12.5
3,4,5-Tri OCH3
a
Isolated yields.
Calculated using Chemdraw Ultra 12.0
b
4. (a) Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. Nature 2011, 469,
483; (b) Ginsberg, A. M.; Spigelman, M. Nat. Med. 2007, 13, 290; (c) Check, E.
Nat. Med. 2007, 13, 266.
5. (a) Kumar, A.; Srivastava, S.; Gupta, G.; Chaturvedi, V.; Sinha, S.; Srivastava, R.
ACS Comb. Sci. 2011, 13, 65; (b) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew.
Chem., Int. Ed. 2003, 42, 3996.
liphophilic nature is needed for amidoalkyl dibenzofuranols to be
active against M. tuberculosis H37Rv (MTB) and cyclized oxazinone
analogues are structurally better correlates with liphophilic nature
and showed better activity.
In conclusion we have synthesized a new class of amidoalkyl
dibenzofuranols 5a–k and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxa-
zin-3(2H)-ones 6a–e through polyphosphoric acid supported on
silica (PPA–SiO2) catalyzed one-pot three component condensation
of 2-dibenzofuranol; aromatic aldehydes and acetamide or benz-
amide or urea under solvent free conditions in very good yields.
At 160 °C condensation with urea proceeded to cyclization to give
1H-benzo[2,3] benzofuro[4,5-e][1,3] oxazin-3(2H)-ones 6a–e.
Screening all these new derivatives against M. tuberculosis H37Rv
(MTB) resulted amidoalkyl dibenzofuranols 5h, 5i, 6a (MIC
6. (a) Stoll, A. Experientia 1947, 3, 11; (b) Klosa, J. Pharmazie 1953, 8, 435; (c)
Müller, K. Appl. Microbiol. Biotechnol. 2001, 56, 9; (d) Ingólfsdóttir, K.; Chung, G.
A. C.; Skúlason, V. G.; Gissurarson, S. R.; Vihelmdóttir, M. Eur. J. Pharm. Sci. 1998,
6, 141; (e) Lombaert, S. D.; Blanchard, L.; Stamford, L. B.; Tan, J.; Wallace, E. M.;
Satoh, Y.; Fitt, J.; Hoyer, D.; Simonsbergen, D.; Moliterni, J.; Marcopoulos, N.;
Savage, P.; Chou, M.; Trapani, A. J.; Jeng, A. Y. J. Med. Chem. 2000, 43, 488.
7. (a) Khouri, T. I.; Gaslonde, T.; Prado, S.; Saint-Joanis, B.; Bardoud, F.;
Amanatiadou, E. P.; Vizirianakis, I. S.; Kordulakova, J.; Jackson, M.; Brosch, R.;
Janin, Y. L.; Daffé, M.; Tillequin, F.; Michel, S. Eur. J. Med. Chem. 2010, 45, 5833;
(b) Prado, S.; Ledeit, H.; Michel, S.; Koch, M.; Darbord, J. C.; Cole, S. T.; Tillequin,
F.; Brodin, P. Bioorg. Med. Chem. 2006, 14, 5423; (c) Prado, S.; Janin, Y. L.; Saint-
Joanis, B.; Brodin, P.; Michel, S.; Koch, M.; Cole, S. T.; Tillequin, F.; Bost, P. E.
Bioorg. Med. Chem. 2007, 15, 2177.
3.13 lg/mL) and oxazin-3(2H)-ones 6b and 6c (MIC 1.56 lg/mL)
as most potent antitubercular agents.
8. (a) Kantevari, S.; Patpi, S. R.; Sridhar, B.; Yogeeswari, P.; Sriram, D. Bioorg. Med.
Chem. Lett. 2011, 14, 1214; (b) Sriram, D.; Yogeeswari, P.; Dinakaran, M.;
Banerjee, D.; Bhat, P.; Gadhwal, S. Eur. J. Med. Chem. 2010, 45, 120; (c)
Manikannan, R.; Muthusubramanian, S.; Yogeeswari, P.; Sriram, D. Bioorg. Med.
Chem. Lett. 2010, 20, 3352.
Acknowledgments
9. Kantevari, S.; Bantu, R.; Nagarapu, L. J. Mol. Catal. A: Chem. 2007, 269, 53.
10. (a) Kantevari, S.; Yampala, T.; Vuppalapati, S. N. V. Synthesis 2010, 959; (b)
Kantevari, S.; Putapatri, S. R. Synlett 2010, 2251; (c) Kantevari, S.; Addala, D.;
Sridhar, B. Synthesis 2010, 3745.
Authors are thankful to Dr. J. S. Yadav, Director and
Dr. V. V. N. Reddy, Head, Organic Chemistry Division-II, IICT,
Hyderabad for their continuous support, encouragement and
financial assistance from MLP projects. T.Y. is thankful to CSIR
for fellowship (SRF).
11. Representative
furanyl)methyl]urea (5h). Light yellow solid; mp 68 °C. IR (KBr): 3384, 3063,
2922, 2852, 1701, 1638, 1590, 1461, 1431, 1216, 1154, 1092 cmÀ1 1H NMR
spectral
data:
[(4-Chlorophenyl)(2-hydroxydibenzo
.
(300 MHz, DMSO-d6): d = 9.32 (s, 1H), 8.15 (d, J = 6.9 Hz, 1H), 7.75 (s, 1H), 7.50
(d, J = 8.1 Hz, 1H), 7.40 (t, 1H), 7.32–7.10 (m, 7H), 7.0 (d, J = 8.6 Hz, 1H), 5.55 (s,
2H). HRMS (ESI): m/z calcd for: C20H15O3N2ClNa [(M+Na)+]: 389.0668; found:
389.0685. [(4-Bromophenyl)(2-hydroxydibenzofuranyl)methyl] urea (5i)
White solid; mp 82 °C. IR (KBr): 3374, 2923, 2853, 1647, 1597, 1528, 1454,
Supplementary data
1429, 1369, 1219, 1181, 1076 cmÀ1 1H NMR (300 MHz, DMSO-d6): d = 9.50 (s,
.
Supplementary data (complete experimental procedures and
copies of 1H, 13C NMR and mass (HRMS) spectra of compounds
5c,d, and 6c,d CCDC 823486 (for 6d) contain the crystallographic
data and can be obtained free of charge from the Cambridge Crys-
tallographic Data centre via http://www.ccdc.cam.ac.uk/data_re-
quest/cif) associated with this article can be found, in the online
version, at doi:10.1016/j.bmcl.2011.05.054.
1H), 8.20 (br, 1H), 7.6 (d, J = 8.1 Hz, 1H), 7.5–7.23 (m, 5H), 7.20 (d, J = 8.3 Hz,
2H), 7.0 (s, 3H), 5.80 (s, 2H).13C NMR (75 MHz, DMSO-d6): d = 158.4, 156.1,
151.2, 149.2, 142.7, 130.8, 129.0, 128.0,127.2, 121.8, 122.7, 122.4, 122.1, 119.2,
116.0, 111.7, 110.8, 49.3. HRMS (ESI): m/z calcd for C20H15O3N2BrNa [(M+Na)+]:
433.0163; found: 433.0152. 1-(4-chlorophenyl)-1H-benzo[2,3]benzofuro[4,5-
e][1,3]oxazin-3(2H)-one (6b) White solid; mp 130 °C. IR (KBr): 3252, 2923,
1728, 1431, 1386, 1216, 1163, 1090 cmÀ1 1H NMR (300 MHz, DMSO-d6):
.
d = 8.75 (s, 1H), 7.60 (m, 3H), 7.43 (t, 1H), 7.25–7.36 (m, 5H), 7.2 (t, 1H), 6.2 (s,
1H). HRMS (ESI): m/z calcd for C20H12O3NClNa [(M+Na)+]: 372.0403; found:
372.0399.
1-(4-bromophenyl)-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-
References and notes
3(2H)-one (6c) White solid; mp 192 °C. IR (KBr): 3259, 29225, 1729, 1433,
1217, 1082, 1003 cmÀ1 1H NMR (500 MHz, DMSO-d6): d = 8.7 (s, 1H), 7.5–7.6
.
1. (a) Russell, D. G.; Barry, C. E.; Flynn, J. L. Science 2010, 328, 852; (b) Russell, D. G.
Nat. Rev. Microbiol. 2007, 5, 39; (c) Kaufmann, S. H. E.; McMichael, A. J. Nat. Med.
2005, 11, 578; (d) Manabe1, Y. C.; Bishai1, W. R. Nat. Med. 2000, 6, 1327.
2. (a) World Health Organization. Multidrug and Extensive Drug Resistant
Tuberculosis: 2010 Global Report on Surveillance and Response, 2010.; (b)
(m, 3H), 7.48–7.4 (m, 3H), 7.30–7.15 (m, 4H), 6.14 (s, 1H). 13C NMR (75 MHz,
CDCl3+ DMSO-d6): d = 156.0, 151.7, 49.4, 45.4, 139.3, 131.3, 131.2, 128.2, 126.9,
122.2, 121.8, 121.5, 121.3, 115.2, 113.4, 111.5, 111.1, 53.5. MS (EI): m/z for
C
20H12O3NBr: 393 [M+], 395 [(M+2)+].
12. Crystal data: C21H15NO4, M = 345.34, triclinic, space group P1;, a = 8.3749(10) Å,
b = 9.9268(12) Å, c = 11.6531(14) Å, = 112.558 (2)°, b = 92.821(2) °,
100.038(2)° V = 873.77 (18) Å3, Z = 2, Dcalcd = 1.313 mg mÀ3
T = 294(2) K,
= 0.092 mmÀ1
F(0 0 0) = 360, k = 0.71073 Å. Data collection yielded 8350
Global tuberculosis control:
a short update to the 2009 report <http://
a
c =
www.who.int/tb/publications/global_report/2009/update/en/index.html>.
3. (a) Nikalie, A. G.; Mudassar, P. Asian J. Biol. Sci. 2011, 4, 101; (b) Sacchettini, J. C.;
Rubin, E. J.; Freundlich, J. S. Nat. Rev. Microbiol. 2008, 6, 41; (c) Showalter, H. D.
H.; Denny, W. A. Tuberculosis 2008, 88, S3–S17; (d) Duncan, K.; Barry, C. E., III
Curr. Opin. Microbiol. 2004, 7, 460; (e) Muddassar, M.; Jang, J. W.; Gon, H. S.;
Cho, Y. S.; Kim, E. E.; Keum, K. C.; Oh, T.; Cho, S.-N.; Pae, A. N. Bioorg. Med. Chem.
2010, 18, 6914.
,
l
,
reflections resulting in 3059 unique, averaged reflections, 2632 with I >2(I).
Full-matrix least-squares refinement led to a final R = 0.0393, wR = 0.1048 and
GOF = 1.042. Intensity data were measured on Bruker Smart Apex with CCD
area detector.