AgNO3Catalyzed Regio-Selective Synthesis of 3-Alkyl/Aryl-idene-3,4-dihydro-4-tosyl-2H-1,4-Benzoxazine: Novel Anti-Tubercular Scaffolds

Article abstract of DOI:10.1002/jhet.2472

A facile and efficient method for the construction of 3-alkyl/aryl substituted 1,4-benzoxazine and benzoxazepine via AgNO₃catalyzed cyclization of propargyloxy sulfonamides and their anti-tubercular activity against Mycobacterium tuberculosis H₃₇R_Vis described. This cyclization proceeds through 6-exo-dig manner to generate the products in moderate to good yields.

Full text of DOI:10.1002/jhet.2472

Month 2015
AgNO3 Catalyzed Regio-Selective Synthesis of 3-Alkyl/Aryl-idene-3,4-
dihydro-4-tosyl-2H-1,4-Benzoxazine: Novel Anti-Tubercular Scaffolds
a
a
b
a
a
*
*
Sivanandhan Karunanidhi, Rajshekhar Karpoormath, Milan Bera, Rajesh A. Rane, and Mahesh B. Palkar
aDepartment of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences,
University of KwaZulu-Natal, Durban, South Africa
bDepartment of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
*
E-mail: karpoormath@ukzn.ac.za; miluom@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received July 22, 2014
DOI 10.1002/jhet.2472
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A facile and efficient method for the construction of 3-alkyl/aryl substituted 1,4-benzoxazine and
benzoxazepine via AgNO3 catalyzed cyclization of propargyloxy sulfonamides and their anti-tubercular ac-
tivity against Mycobacterium tuberculosis H37RV is described. This cyclization proceeds through 6-exo-dig
manner to generate the products in moderate to good yields.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
methods suffered some limitations regarding generation
of molecular diversity [16–27]. Although there are many
reports about the synthesis of 2H-1,4-benzoxazines, only
few methods affords regio- and stereoselective 3-ylidene-
3,4-dihydro-2H-1,4-benzoxazines as biologically attractive
chiral analogs (upon asymmetric hydrogenation) and other
important building blocks [28–30]. Among all these re-
ports, the multi-step synthesis of these 3-ylidene substituted
3,4-dihydro-2H-1,4-benzoxazines were developed using
both palladium (Pd) and copper (Cu) catalysis. Synthesis
of the Z-isomers of title compound was demonstrated by
Kundu [28] et al., and followed by Zhou [29] et al., under
Pd and Cu-catalyzed multi-step procedure. Chowdhury
[30] et al. established E-isomers of 2H-1,4-benzoxazine un-
der Pd-catalyzed cyclization. In these reports, the authors
have described the synthesis of 2- or 3-arylidene substituted
3,4-dihydro-2H-1,4-benzoxazines derivatives. However, to
the best of our knowledge, there is no report on the general
synthesis of 3-alkylidene substituted 3,4-dihydro-2H-1,4-
benzoxazines derivatives. As a part of our ongoing research
interest toward the development of new methodologies to
construct various biologically active heterocycles, we
herein describe the synthesis of various substituted 3-
alkylidene-3,4-dihydro-2H-1,4-benzoxazines derivatives
(4a-4m) and their preliminary anti-tubercular activity
against Mycobacterium tuberculosis H37RV. During this
study, we found silver nitrate (AgNO3) to be the most
effective catalyst for cyclization (Scheme 1).
Organic compounds containing 1,4-benzoxazine deriva-
tives have attracted a great deal of attention in recent years,
both in chemical and medicinal research, which could be
attributed to their diverse pharmacological applications.
In particular, N and O-containing heterocycles such as
2H-1,4-benzoxazine and several of its derivatives display
a wide range of bio-activities like anticancer [1], anti-
tubercular [2,3], antihypertensive [4], antirheumatic [5],
serotonin-3(5-HT3) receptor antagonist [6], neuroprotective
antioxidant [7], and others [8,9]. In addition, levofloxacin,
containing 2,3-dihydro-1,4-benoxazine unit exhibits excellent
antimicrobial activity against Gram-positive and Gram-
negative bacteria [10]. In addition to this, the 3-substituted-
3,4-dihydro-2H-1,4-benzoxazines has been an integral part
of many important building blocks [11,12] used in the
synthesis of fascinating bioactive natural products [13] and
potent drugs [14] of therapeutic interests. Further, recently,
Li et al. [15] reported the synthesis and biological evaluation
of a novel series of 2-oxo-2H-1,4-benzoxazine derivatives as
a promising anti-tubercular agents through 1,4-dihydroxy-2-
naphthoyl-CoA (DHNA-CoA) synthase (MenB) enzyme
inhibition. Thus, the 1,4-benzoxazine represents a highly
privileged scaffold in the drug discovery process for the
development of potential anti-tubercular agents.
Owing to their medicinal importance, several synthetic
strategies/methods for 3,4-dihydro-1,4 benzoxazines have
been reported over the past few decades. However, these
© 2015 HeteroCorporation

S. Karunanidhi, R. Karpoormath, M. Bera, R. A. Rane, and M. B. Palkar
Vol 000
Table 1
Intra-molecular heterocyclization of 3a with various metal salts.
Scheme 1. Cyclization of propargyloxy sulfonamides using silver nitrate
(AgNO3). [Color figure can be viewed in the online issue, which is avail-
able at wileyonlinelibrary.com.]
Entry
Metal salts (5 mol%)
Time (h)
Yieldb(%)
1
2
3
4
5
6
7
8
9
CuI
CuCl2
Cu(OTf)2
AgNO3
Sc(OTf)3
HgCl2
ZnCl2
AlCl3
BF3.Et2O
10
10
10
10
10
10
10
10
10
64
58
61
85
NRc
NR
55
RESULTS AND DISCUSSION
NR
NR
All propargyloxy amine substrates (3a-3m) were synthe-
sized by modifying the reported procedure (Scheme 2). The
treatment of o-nitrophenol derivatives and o-nitrobenzyl
alcohol with alkyl or aryl substituted propargyl bromide
in the presence of K2CO3 in acetone or acetonitrile afforded
1a-1f in 75–85% yield. The intermediate nitro derivatives
1e-1f were reduced with iron powder in acetic acid to give
corresponding aniline derivatives 2e-2f in 75–93% yield.
The amine functional group in compounds 2e-2f were
protected with protecting groups such as tosyl chloride,
phenyl sulfonyl chloride, mesyl chloride, and so on in
dichloromethane to construct respective propargyloxy
sulfonamides (3a-3m) with 80–90% yield.
aReaction condition: 3a (0.5 mM), metal salts (5 mol%), K2CO3 (1 mM),
MeCN (3 mL).
bIsolated yield.
cNR = No reaction.
conditions (entry 4, Table 1). Further, the cyclization was
also performed with some other Lewis acidic metal salts
like Sc(OTf)3, HgCl2, AlCl3, and BF3.Et2O; but in all these
cases, we have not observed any desired product formation
(Vide TLC, entries 5,6,8, and 9, Table 1). Notably, the
catalytic activity of ZnCl2 toward this cyclization was
reduced under similar conditions, and desired product 4a
was isolated with 55% yield (entry 7, Table 1).
The effect of various solvents such as dichloroethane
(45%), toluene (39%), and THF (28%) on the yield of
reaction was studied under same reaction condition, and
it was observed that acetonitrile was found to give the
highest yield. Thus, the optimal reaction condition
developed so far include stirring of the substrates with
5 mol% of AgNO3, 2 equiv of K2CO3 in acetonitrile under
refluxing condition for 12h. It is worth mentioning here
that this type of cyclization have been developed with
costly reagents like CuI/TBAB combination and catalytic
Pd source [28–30]. But in the case of our reaction, only cat-
alytic amount of AgNO3 was sufficient for that cyclization.
With optimal reaction condition in hand, we next turned
our attention to explore the scope and generality of this
cyclization protocol with the substrates 3a-3m that
afforded desire products 4a-4m with high yields (Table 2).
To assess the impact of different structural motifs on the re-
action, we studied this reaction by varying alkyl or phenyl
group attached to the acetylenic linkage and by changing
the various protecting group at the amine center, which
were found to be tolerant to the reaction conditions. In
this series, we initially investigated the cyclization of
propargyloxy amine derivatives (3a-3c, when R=H) having
different protecting group such as tosyl (SO2-p-Me-C6H4),
phenylsulfonyl (SO2-Ph) and mesyl (SO2-Me) in presence
of 5mol% AgNO3 that provided the desired products 4a-4c
To construct the target molecules, we evaluated the
catalytic role of various metal salts toward intra-molecular
cyclization of 3a-3m. Intra-molecular cyclization of 3a
with different catalyst loading in presence of base under
reflux condition was used as a model reaction (Table 1).
The cyclization reaction in presence of different copper-
salts such as CuI, CuCl2, and Cu(OTf)2 provided the
desired heterocycle 4a in moderate yields (entries 1, 2,
and 3, Table 1). Replacement of copper-salts with AgNO3
improved the yield up to 85% under similar reaction
Scheme 2. Preparation of propargyloxy sulfonamides. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
AgNO3 catalyzed regio-selective synthesis of 2H-1,4-benzoxazine
Table 2
Substrate scope for cyclization protocol.
Entry
Compound
R
R1
PG
n
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
CH3
CH3
CH3
C2H5
C2H5
C2H5
H
H
H
H
H
H
H
H
H
p-CH3C6H4SO2
C6H5SO2
CH3SO2
p-CH3C6H4SO2
C6H5SO2
CH3SO2
p-CH3C6H4SO2
C6H5SO2
CH3SO2
p-CH3C6H4SO2
C6H5SO2
p-CH3C6H4SO2
p-CH3C6H4SO2
0
0
0
0
0
0
0
0
0
0
0
0
1
10
10
12
12
12
12
12
12
12
12
12
12
12
85
85
70
64
72
75
62
64
60
72
71
76
75
9
H
10
11
12
13
4j
4k
4l
CH3
CH3
H
H
C6H5
H
4m
H
product 4l in 76% yield (entry 12). Finally, we moved to syn-
thesize the 6/7 fused ring using this reaction protocol. Here, it
revealed that substrate 3m underwent intra-molecular
cyclization that afforded the corresponding exo-cyclic 6/7
fused ring product in 75% yield (entry 13). All the products
Scheme 3. Proposed reaction mechanism. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
1
in this series were characterized by H, 13C, distortionless
enhancement by polarization transfer (DEPT) NMR, and
HRMS spectra.
Condition: substrate (1mM), K2CO3 (2mM), AgNO3
(5 mol%), MeCN (3 mL), 90°C, and 10–12h; all are iso-
lated yield.
Based on the results described previously, a plausible
reaction mechanism was depicted as shown in Scheme 3. At
first, the triple bond of the propargyloxy amine substrates co-
ordinates to the AgNO3 and form the intermediate 5. Assisted
by a base, the ring closing event from 5 may follow 6-exo-dig
pathway, and subsequent protodemetalation would afford the
desired exo-cyclic product and regenerate the catalyst
Considering the bio-potential of benzoxazine motif, we
evaluated our synthesized compounds for their anti-
tubercular activity using Resazurin Microtiter (REMA)
assay and the results are presented in Table 3. The bioactiv-
ity data clearly indicates that these novel bezoxazine com-
pounds have quite decent prospective to be further
developed into potential anti-tubercular drug. Among the
series tested, compounds 4a, 4j, and 4k (<15 μg/mL)
displayed moderate inhibitory activity against M. tubercu-
losis H37RV. However, the other compounds were found
to be less active. The brief SAR studies revealed that the
presence of p-methyl benzene sulfonyl group contributed
for anti-tubercular activity to a greater extent. Further in-
vestigation into enhancing the anti-tubercular potential of
these classes of molecules is in progress at our laboratory.
in high yields (entries 1, 2, and 3). Next, we examined this
protocol by introducing the methyl group attached to the
acetylenic linkage of propargyloxy sulfonamide derivatives
(3d-3f, when R = Me) that afforded the corresponding
exo-cyclic products 4d-4f in excellent yields (entries 4,
5, and 6). Similarly, ethyl substituted internal alkynoxy sul-
fonamide substrates 3g-3i gave the corresponding exo-cyclic
products 4g-4i in moderate to good yields (entries 7, 8, and
9). Later, we turned our attention to substituted propargylic
group as a reaction partner. Notably methyl-substituted
compounds 3j and 3k could afford the cyclization products
4j and 4k in 72% and 71%, respectively (entry 10 and 11).
Similarly, phenyl group attached to the internal alkynic linkage
of substrate 3l proceeded through cyclization to give the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Karunanidhi, R. Karpoormath, M. Bera, R. A. Rane, and M. B. Palkar
Vol 000
Table 3
Antimicrobial activity of benzoxazine moieties against Mycobacterium tuberclosis H37RV.
Compound
R
R1
PG
n
MIC (μg/mL)
4a
4b
4c
4d
4e
4f
4 g
4 h
4i
4j
4 k
4 l
4 m
Isoniazid
H
H
H
CH3
CH3
CH3
C2H5
C2H5
C2H5
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
H
-
p-CH3C6H4SO2
C6H5SO2
CH3SO2
p-CH3C6H4SO2
C6H5SO2
CH3SO2
p-CH3C6H4SO2
C6H5SO2
CH3SO2
p-CH3C6H4SO2
C6H5SO2
p-CH3C6H4SO2
p-CH3C6H4SO2
—
0
0
0
0
0
0
0
0
0
0
0
0
1
<15
ND
250
<250
250
<250
ND
ND
<250
<15
<15
ND
250
0.40
H
C6H5
H
-
—
(3 mL) was added with silver nitrate (0.05 mM), anhydrous
potassium carbonate (2 mM). The mixture was refluxed under
nitrogen atmosphere for 10–12 h. After the completion of the
reaction (monitored by TLC), the crude was extracted with di-
chloromethane, washed with water, dried over anhydrous Na2SO4
and concentrated under vaccuo. The residue was purified by col-
umn to afford the compound.
CONCLUSION
In conclusion, we have achieved an efficient and
straightforward method for the construction of alkyl/aryl
substituted 1,4-benzoxazine via AgNO3 catalyzed cycliza-
tion protocol. The procedure reported here is more eco-
nomic than earlier reported methods. We have described
the applicability of this method for the synthesis of 6/7
fused ring system. Moderate activity for compounds 4a,
4j, and 4k (<15 μg/mL), against M. tuberculosis H37RV,
was observed. Moreover, exo-cyclic double bond incorpo-
rated into the final compounds after cyclization can be fur-
ther exploited for functionalization to improve the activity
profile of these compounds.
3-Methylene-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
(4a). The product was obtained as a white solid (0.26g, 85%); mp
154–156°C, Rf 0.61 (hexane/ethyl acetate 96:04 v/v). 1H NMR
(400 MHz, CDCl3): δ = 2.39 (s, 3H), 3.95 (s, 2H), 5.25 (s, 1H),
5.68 (s, 1H), 6.76–6.78 (m, 1H), 6.97–7.01 (m, 1H), 7.09–7.11
(m, 1H), 7.19–7.21 (d, J = 8.2 Hz, 2H), 7.43–7.45 (d,
J = 8.2 Hz, 2H), 7.83–7.86 (m, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.6, 66.3, 114.0, 117.0, 121.3, 124.81, 125.7,
126.6, 127.7, 129.6, 134.3, 135.6, 147.4, and 147.5 ppm.
HRMS (ESI): m/z calcd for C16H15NO3S [M + H]+ 302.0806;
found 302.0801.
EXPERIMENTAL
3-Methylene-4-(Phenylsulfonyl)-3,4-dihydro-2H-
benzo[b][1,4]oxazine (4b). The product was obtained as a white
solid (0.24 g, 85%); mp 142–145°C, Rf 0.60 (hexane/ethyl acetate
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded
on BRUKER-AC 400 MHz spectrometer (Bruker Corporation,
Fällanden, Switzerland). Chemical shifts are reported in ppm
from tetramethylsilane with the solvent resonance as the internal
standard. The solvent peak of CDCl3 (deuterochloroform) were
resonating at δ 7.24 ppm (1H NMR) and δ 77.0 ppm (13C
NMR), respectively. The NMR data was reported as follows:
chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, br = broad, m = multiplet), integration, and coupling
constant (Hz).
All reactions were carried out under nitrogen atmosphere in
flame-dried glassware using Schlenk techniques. Chromato-
graphic purifications were done with either 60–120 or 100–200
mesh silica gel (SRL). For reaction monitoring, precoated silica
gel 60 F254 TLC sheets (Merck) were used. Dichloroethane was
dried and distilled prior to use.
1
96:04 v/v). H NMR (400 MHz, CDCl3): δ = 3.94 (s, 2H), 5.25
(s, 1H), 5.69 (s, 1H), 6.75–6.78 (m, 1H), 6.97–7.01 (m, 1H),
7.07–7.11 (m, 1H), 7.42–7.43 (t, J = 8.3 Hz, 2H), 7.51–7.59 (m,
3H), 7.83–7.85 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 66.4, 113.9, 117.1, 121.4, 124.7, 125.7, 126.8, 127.7,
129.0, 133.5, 135.6, 137.2, and 147.6 ppm. HRMS (ESI): m/z
calcd for C15H13NO3S [M + H]+ 288.0616; found 288.1034
(Accounts for 13 protons).
3-Methylene-4-(Methylsulfonyl)-3,4-dihydro-2H-
benzo[b][1,4]oxazine (4c). The product was obtained as a white
solid (0.16 g, 70%); mp 130–133°C, Rf 0.55 (hexane/ethyl acetate
1
96:04 v/v). H NMR (400 MHz, CDCl3): δ = 2.93 (s, 3H), 4.62
(s, 2H), 5.13–5.14 (d, J = 0.8 Hz, 2H), 5.53 (s, 1H), 6.92–7.00
(m, 2H), 7.59–7.62 (m, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 37.3, 69.0, 109.5, 117.5, 122.1, 125.2, 125.9,
General procedure for the preparation of benzoxazine: To
the stirred solution of sulfonamides (1 mM) in dry acetonitrile
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
AgNO3 catalyzed regio-selective synthesis of 2H-1,4-benzoxazine
127.0, 136.9, and 148.9 ppm. HRMS (ESI): m/z calcd for
5.82–5.86 (t, J = 7.2 Hz, 1H), 6.89–6.96 (m, 2H), 7.09–7.13 (m,
1H), 7.16–7.67 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 12.99, 21.8, 38.6, 67.7, 117.6, 121.2, 124.1, 125.3, 126.5,
126.9, 136.2, and 147.1 ppm. HRMS (ESI): m/z calcd. for C12
H15NO3S [M + H]+ 254.0851; found 254.0857.
C10H11NO3S [M + H]+ 226.0538; found 226.0541.
(Z)-3-Ethylidene-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
(4d). The product was obtained as a white solid (0.20 g, 64%); mp
148–152°C, Rf 0.59 (hexane/ethyl acetate 97:03 v/v). 1H NMR
(400 MHz, CDCl3,): δ = 2.39 (s, 3H), 2.86 (s, 3H), 3.84–3.89 (m,
1H), 4.91–4.94 (d, J= 12.9 Hz, 1H), 6.71–6.72 (m, 1H), 6.95–6.70
(m, 1H), 7.09–7.13 (m, 1H), 7.18–7.20 (d, J= 8.1 Hz, 2H), 7.26 (s,
1H), 7.35–7.39 (d, J= 8.3 Hz, 2H), 7.73–7.75 (m, 1H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.6, 30.9, 70.1, 105.9, 117.1, 121.3,
125.4, 126.2, 127.6, 127.8, 129.7, 130.2, 134.4, 144.7, and
148.5 ppm. HRMS (ESI): m/z calcd for C17H17NO3S [M+Na]+
338.0827; found 338.0830.
2-Methyl-3-Methylene-4-tosyl-3,4-dihydro-2H-
benzo[b][1,4]oxazine (4j). The product was obtained as a white
solid (0.23 g, 72%); mp 102–104°C, Rf 0.59 (hexane/ethyl acetate
96:04 v/v). 1H NMR (400 MHz, CDCl3): δ = 1.28–1.29 (d,
J = 6.3 Hz, 3H), 2.36 (s, 3H), 3.69–3.73 (m, 1H), 5.28 (s, 1H),
5.68 (s, 1H), 6.72–6.74 (m, 1H), 6.93–6.97 (m, 1H), 7.03–7.07
(m, 1H), 7.71–7.19 (d, J = 8.12 Hz, 2H), 7.42–7.44 (d, J = 8.3 Hz,
2H), 7.79–7.81 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 18.2, 21.6, 70.1, 112.9, 117.0, 121.1, 124.9, 125.2, 126.5,
127.7, 129.6, 134.7, 139.7, 147.3, and 147.3 ppm. HRMS (ESI):
m/z calcd for C17H17NO3S [M+ H]+ 316.1007; found 316.1009.
(Z)-3-Ethylidene-4-(Phenylsulfonyl)-3,4-dihydro-
2H-benzo[b][1,4]oxazine (4e). The product was obtained as a
white solid (0.21 g, 72%); mp 136–138°C, Rf 0.61 (hexane/ethyl
acetate 98:02 v/v). 1H NMR (400MHz, CDCl3): δ = 2.87–2.87 (d,
J = 1.8 Hz, 3H), 3.86–3.90 (m, 1H), 4.89–4.93 (d, J = 13.1Hz,
1H), 6.71–6.73 (m, 1H), 6.97–7.01 (m, 1H), 7.10–7.14 (m, 1H),
7.25 (s, 1H), 7.41–7.43 (t, J = 7.5 Hz, 2H), 7.51–7.52 (d,
J = 7.3 Hz, 2H), 7.55–7.59 (t, J = 7.4 Hz, 1H), 7.73–7.75 (m, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 22.3, 30.9, 70.4,
105.8, 117.2, 121.4, 126.3, 127.8, 127.8, 129.1, 133.7, 137.2, and
148.7 ppm. HRMS (ESI): m/z calcd for C16H15NO3S [M+ H]+
302.0806; found 302.0812.
2-Methyl-3-Methylene-4-(Phenylsulfonyl)-3,4-dihydro-2H-
benzo[b][1,4]oxazine (4k). The product was obtained as a white
solid (0.20 g, 71%); mp 98–100°C, Rf 0.61 (hexane/ethyl acetate
96:04 v/v). 1H NMR (400 MHz, CDCl3): δ =1.27–1.28 (d,
J= 6.2 Hz, 3H), 3.67–3.70 (m, 1H), 5.28 (s, 1H), 5.69 (s, 1H), 6.72–
6.75 (m, 1H), 6.94–9.98 (m, 1H), 7.04–7.09 (m,1H), 7.43–7.42 (t,
J= 7.4 Hz, 2H), 7.53–7.57 (m, 3H), 7.79–7.85 (m, 1H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 18.2, 70.3, 112.8, 117.1, 121.2, 124.8,
125.2, 126.6, 127.6, 128.9, 133.4, 137.6, 138.8, and 147.4 ppm.
HRMS (ESI): m/z calcd for C16H15NO3S [M+H]+ 302.0851; found
302.0862.
(Z)-3-Ethylidene-4-(Methylsulfonyl)-3,4-dihydro-
2H-benzo[b][1,4]oxazine (4f).
The product was obtained as a
white solid (0.18 g, 75%); mp 118–120°C, Rf 0.56 (hexane/ethyl
acetate 96:04 v/v). 1H NMR (400 MHz, CDCl3): δ =1.18–1.21 (s,
3H), 2.82 (s, 3H), 4.73–4.78 (m, 1H), 5.12–5.15 (d, J= 13.7 Hz, 1H),
6.98–9.66 (m, 2H), 7.10–7.14 (m, 1H), 7.19 (s, 1H), 7.47–7.49 (m, 1H)
ppm. 13C NMR (100MHz, CDCl3): δ = 29.7, 30.5, 38.2, 72.6, 103.1,
117.8, 122.3, 125.6, 126.7, 128.1, and 130.2 ppm. HRMS (ESI): m/z
calcd for C11 H13NO3S [M+Na]+ 261.0650; found 261.0612.
(Z)-3-Benzylidene-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
(4l). The product was obtained as a white solid(0.27 g, 76%); mp
179–182°C, Rf 0.45 (hexane/ethyl acetate 96:04 v/v). 1H NMR
(400 MHz, CDCl3): δ = 2.36 (s, 3H), 4.01–4.03 (d, J= 11.4 Hz, 1H),
6.6 (s, 1H), 6.99–7.02 (m, 1H), 7.03–7.16 (m, 3H), 7.28–7.75 (m,
5H), 7.90–7.93 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.6, 67.6, 117.2, 120.9, 124.8, 125.8, 127.2, 127.3, 128.3, 128.8,
129.6, 129.9, 131.3, 133.8, 134.7, 144.5, and 147.8 ppm. HRMS
(ESI): m/z calcd C22H19NO3S [M+Na]+ 400.0983; found 400.1623.
(Z)-3-Propylidene-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
(4g). The product was obtained as a white solid (0.20 g, 62%); mp
121–124°C, Rf 0.59 (hexane/ethyl acetate 96:04 v/v). 1H NMR
(400 MHz, CDCl3): δ =0.94–0.98 (t, J= 7.5 Hz, 3 H), 2.29 (s, 3 H),
3.57 (s, 1 H), 4.09 (s, 1 H), 6.63–6.65 (m, 1 H), 6.85–6.89 (m, 1 H),
6.97–7.02 (m, 1 H), 7.09–7.11 (d, J= 8.1 Hz, 2 H), 7.32–7.33 (d,
J=8.3Hz, 2H), 7.76–7.78 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.0, 21.8, 29.7, 66.4, 117.1, 120.0, 125.0, 125.8, 126.8,
126.9, 127.7, 129.7, 134.9, 136.9, 142.4, 147.4 ppm. HRMS (ESI):
m/z calcd for C18H19NO3S [M+H]+ 330.1164; found 330.1161.
(Z)-4-(Phenylsulfonyl)-3-Propylidene-3,4-dihydro-2H-benzo[b]
[1,4]oxazine (4h). The product was obtained as a white solid
(0.20 g, 64%); mp 95–98°C, Rf 0.58 (hexane/ethyl acetate
2-Methylene-1-tosyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine
(4m). 3The product was obtained as a pale yellow solid (0.24 g,
1
75%); mp 165–167°C Rf 0.45 (hexane/ethyl acetate 96:04 v/v). H
NMR (400 MHz, CDCl3): δ = 2.42 (s, 3H), 4.19 (s, 2H), 4.43 (s, 2H),
5.30 (s, 1H), 5.43 (s, 1H), 7.11–7.12 (d, J= 7.4 Hz, 1H), 7.22–7.25 (t,
J= 7.7 Hz, 3H), 7.30–7.34 (m, 1H), 7.53–7.55 (d, J=7.9Hz, 1H),
7.60–7.62 (d, J= 8.3 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.5, 72.3, 72.9, 118.7, 127.7, 127.8, 128.5, 128.9, 129.1, 128.5,
136.1, 137.2, 138.7, 143.1, and 143.9 ppm. HRMS (ESI): m/z calcd
for C17H17NO3S [M+Na]+ 338.0827; found 338.0822.
96:04 v/v). 1H NMR (400 MHz, CDCl3)
: δ = 1.02–1.06
Anti-tubercular Activity. The anti-tubercular activity of the
compounds, against M. tuberculosis H37RV, was performed
using REMA assay [31]. Isoniazid was used as reference drug
in the study. Homogenous mycobacterial (H37RV) culture
suspension was seeded in microtitre plates at density of 105
cells per well in 100 μL of the Middlebrook 7H9 broth (Difco
laboratories, Detroit, MI, USA), and the test compounds were
serially diluted directly on the plate. The control received
equivalent amount of DMSO. The plates were incubated at 37°
C for 7 days. Freshly prepared resazurin dye (0.02%) was
added and plates were again incubated for 48 h. MIC is the
lowest concentration at which complete inhibition was
observed and was determined by visual inspection (color
change from blue to pink).
(t, J = 7.5 Hz, 3H), 2.48–2.51 (t, J = 7.9 Hz, 3H), 3.62 (s, 1H),
4.17 (s, 1H), 5.78–5.81 (t, J = 7.2 Hz, 1H), 6.70–6.72 (m, 1H),
6.93–6.97 (m, 1H), 7.06–7.10 (m, 1H), 7.37–7.41 (m, 2H),
7.55–7.56 (t, J = 7.6 Hz, 2H), 7.84–7.86 (m, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.1, 21.8, 66.4, 117.2, 120.7, 124.9,
125.7, 126.8, 126.9, 127.7, 129.1, 134.5, 130.0, 137.7, and
147.4 ppm. HRMS (ESI): m/z calcd for C17H17NO3S [M + H]+
316.1120; found 316.1119 (Accounts for 17 protons).
(Z)-4-(Methylsulfonyl)-3-Propylidene-3,4-dihydro-2H-benzo[b]
[1,4]oxazine (4i). The product was obtained as a white solid
(0.15 g, 60%); mp 90–92°C, Rf 0.59 (hexane/ethyl acetate
96:04 v/v). 1H NMR (400 MHz, CDCl3): δ = 1.00–1.04 (t,
J = 7.5 Hz, 3H), 2.35–2.43 (m, 2H), 2.91 (s, 3H), 4.62 (s, 2H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Karunanidhi, R. Karpoormath, M. Bera, R. A. Rane, and M. B. Palkar
Vol 000
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Acknowledgments. All the authors of this manuscript acknowledge
College of Health Sciences, University of KwaZulu-Natal,
Durban, South Africa for their support in the form of fellowship
and funding. We thank Dilip Jagjivan for his assistance with
NMR experiments.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet