A palladium-catalyzed facile and general method for the stereoselective synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines and their naphthoxazine analogues

Article abstract of DOI:10.1016/j.tet.2014.06.036

Palladium-catalyzed cyclocondensation of an aryl iodide with N-tosyl-2-(prop-2′-ynyloxy)aniline at room temperature is shown to constitute a convenient general method for the synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines in moderate to very good yields. The method could also be extended to the synthesis of (E)-3-arylidene-2H-naphth[1,2-b][1,4]oxazines. The regio- and stereo-selectivity of the process, short reaction time, operational simplicity, and use of inexpensive starting materials represent its attractive features.

Full text of DOI:10.1016/j.tet.2014.06.036

Tetrahedron 70 (2014) 5863e5871
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A palladium-catalyzed facile and general method for the
stereoselective synthesis of (E)-3-arylidene-3,4-dihydro-2H-
1,4-benzoxazines and their naphthoxazine analogues
*
Kaushik Brahma, Bimolendu Das, Chinmay Chowdhury
CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Palladium-catalyzed cyclocondensation of an aryl iodide with N-tosyl-2-(prop-20-ynyloxy)aniline at room
temperature is shown to constitute a convenient general method for the synthesis of (E)-3-arylidene-3,4-
dihydro-2H-1,4-benzoxazines in moderate to very good yields. The method could also be extended to
the synthesis of (E)-3-arylidene-2H-naphth[1,2-b][1,4]oxazines. The regio- and stereo-selectivity of the
process, short reaction time, operational simplicity, and use of inexpensive starting materials represent its
attractive features.
Article history:
Received 27 January 2014
Received in revised form 24 May 2014
Accepted 10 June 2014
Available online 19 June 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
1,4-Benzoxazine
1,4-Naphthoxazine
Palladium catalyst
Stereoselective
Cyclization
1. Introduction
Heterocycles having heteroatoms at 1,4-positions and fused to
a benzene ring are considered as important targets in medicinal
chemistry due to their wide range of biological and therapeutic
potentials. Among them, 2H-1,4-benzoxazines have been an integral
part of many naturally occurring and bioactive agents.1 In particular,
3-substituted-3,4-dihydro-2H-1,4-benzoxazine has attracted con-
siderable attention in recent times as it constitutes the structural
motif of potent drugs,2a,b and bioactive natural2c and synthetic2d,e
compounds, and acts as a valuable building block in the synthesis
of compounds of therapeutic interest.2f,g Besides, 2- and 3-ylidene-
1,4-benzoxazine derivatives have been shown to be important
pharmaceutical agents. For example, compound 1 (Fig.1) has proved
to be a potential agent for treating infections caused by Mycobac-
terium species,3a while naturally occurring compound 2, isolated
from a fermentation broth of Streptomyces sp., is identified as an
inhibitor of glutathione S-transferase, an enzyme implicated in drug
resistance in cancer chemotherapy.3b Besides, compound 3 pos-
sesses significant CNS depressing activity.3c Recently, Rh-catalyzed
asymmetric hydrogenation of the exocyclic double bond of (Z)-3-
(arylidene)-1,4-benzoxazines (4, R¼aryl group) has been shown
to provide an easy access to the corresponding saturated chiral
Fig. 1. Some biologically important 1,4-benzoxazine derivatives.
products4 (upto 98.6% ee), implying that 3-(or 2-)-ylidene-1,4-
benzoxazines 4 could be profitably used in the synthesis of bi-
ologically active scaffolds by functional group manipulation around
the exocyclic double bond.5
Emergence of such promising results has stimulated new in-
vestigations into the synthesis of 3-substituted-1,4-benzoxazines.
As a consequence, a number of both conventional6 and modern
synthetic methods7 have been developed for the synthesis of 3-
substituted-3,4-dihydro-2H-1,4-benzoxazines. But methods for
the synthesis of 3-ylidene-3,4-dihydro-1,4-benzoxazine 4 and its 2-
oxo derivatives have been limited in number.8,9 In particular, the
* Corresponding author. Tel.: þ91 33 2499 5862; fax: þ91 33 2473 0284; e-mail
address: chinmay@iicb.res.in (C. Chowdhury).
http://dx.doi.org/10.1016/j.tet.2014.06.036
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

5864
K. Brahma et al. / Tetrahedron 70 (2014) 5863e5871
report9 based on palladium-catalyzed reaction describes the syn-
thesis of the (Z)-isomers of compound 4 (R¼Aryl group) utilizing
a multi-step reaction sequence. On the other hand, syntheses of
(Z)-2-(arylidene)-1,4-benzoxazine, a regioisomer of 4, are accom-
plished using palladium10a and copper catalyst,10b though em-
ployment of gold catalysis10c affords such compound as a mixture
heating the reaction at 90 ꢀC for several hours (Table 1, entry 2).
Realizing that the formation of 4a is not occurring through the
acyclic intermediate 7 formed via Sonogashira’s pathway, we de-
cided to eliminate CuI from this reaction. Indeed, removal of CuI
along with the use of Et3N considerably suppressed the formation
of 7, but product 4a was still isolated with poor yield (Table 1, entry
3). Gratifyingly, replacing the base Et3N by a stronger one, viz.
K2CO3 led to the exclusive formation of 4a with 69% yield (Table 1,
entry 4). Next, we performed this reaction without PPh3, but the
yield of 4a (Table 1, entry 5) dropped significantly suggesting the
necessity of PPh3 in this reaction. In the subsequent experiments,
we screened few more palladium catalysts (Table 1, entries 6e8) to
improve the yield further, but none of them appeared to be superior
to Pd(OAc)2/PPh3. Among the solvents screened, DMF was found to
be the best. Thus, the reaction conditions of entry 4 of Table 1 were
considered to be optimal. However, when tosyl group of 5a was
replaced by H/Me/BOC and the resulting substrates were allowed to
react separately with phenyl iodide (6a) under the optimized re-
action conditions, these reactions did not furnish the correspond-
ing desired products even after extending the reaction time to 24 h.
In these cases, only C-phenylated products (at terminal acetylene
moiety) of the substrates were isolated in moderate yields
(20e40%) along with recovery of the starting material (10e30%).
Therefore, the N-tosylated acetylenic substrate like 5a was found to
be necessary for this reaction.
of (E)- and (Z)-stereoisomers. Surprisingly,
a stereoselective
method for the general synthesis of the (E)-isomers of both 2- and
3-arylidene-3,4-dihydro-1,4-benzoxazines is not known,11 which
prevents the exploration of their potential in industrial and aca-
demic research. Thus, development of a facile and general method
for stereoselective synthesis of these compounds remains an im-
portant challenge in organic synthesis.
With our recent success in palladium-catalyzed hetero-
annulations12 of suitably designed substrates leading to the syn-
thesis of various heterocycles including 1,2,3-triazolo-1,4-
benzoxazines,12f we became interested in the synthesis of the E-
isomers of 4 via one-pot palladium-catalyzed reactions. We envi-
sioned that a straightforward and stereoselective synthesis of (E)-3-
arylidene-1,4-benzoxazines 4 (R¼aryl, PG¼Ts) could be achieved by
performing the reaction between N-tosyl-2-(prop-20-ynyloxy)ani-
line 5a and aryl iodide 6 under appropriate catalyzed conditions.
The goal was indeed realized as described in this paper.13
2. Results and discussion
In order to study the scope and generality of this transformation,
we performed the reaction of 5a with various iodides 6aek
(Table 2, entries 2e11) under optimized reaction conditions. A
range of functional groups both electron donating (e.g., OMe, Me)
and withdrawing (e.g., CO2Me, CF3, NO2) were found to be tolerated
under these reaction conditions. As can be seen from Table 2, aro-
matic iodides 6a,b without any functional group afforded the de-
sired products with very good yields (Table 2, entries 1 and 2).
Heteroaryl iodides 6cef were also found to be equally able to fur-
nish the desired products (Table 2, entries 3e6). To our disap-
pointment, however, when p-iodotoluene 6g was employed as the
coupling partner, the corresponding product 4g was obtained in
moderate yield (Table 2, entry 7). Nevertheless, replacing methyl
group of 6g by trifluoromethyl resulted in the improvement of the
corresponding product (Table 2, entry 8). Iodides 6i and 6j having
para-methoxy and carbomethoxy groups furnished the corre-
sponding products 4i (58%) and 4j (74%), respectively (Table 2,
entries 9 and 10). However, presence of both methyl and nitro
groups in the aryl iodide as in 6k afforded the product in moderate
yield (Table 2, entry 11). All the reactions were found to be very
clean in nature. Besides, no formation of any isomer of product 4
with (Z)-stereochemistry or of seven-membered ring product
formed via 7-endo-dig cyclization was observed in any case.
Next, we became interested to employ 5b as an acetylenic sub-
strate in this reaction in order to obtain the naphtho analogue of
product 4. To our gratification, 5b reacted successfully with phenyl
iodide (6a) under the optimized reaction conditions to yield the
targeted (E)-3-benzylidene-2H-naphth[1,2-b][1,4]oxazine 8a in 74%
yield (Table 2, entry 12). 3-Iodopyridine (6c) was also found to be
equally effective to produce the corresponding product 8b (Table 2,
entry 13). We then examined the effects of both electron donating
and withdrawing groups (EDGs and EWGs) on aryl iodides in this
reaction. Accordingly, when iodides containing EDG such as p-
methyl- and p-bromoiodobenzene (6g and 6l) were allowed to react
individually with acetylene 5b, moderate yields (54e57%) of the
corresponding products 8c and 8d were observed (Table 2, entries 14
and 15). On the other hand, with the electron-withdrawing nitro
group at the para-position of the aryl iodide, 6j provided the excel-
lent yield (83%) of the expected product 8e (Table 2, entry 16). To the
best of our knowledge, 3-arylidene-2H-naphth[1,2-b][1,4]benzox-
azines 8 are hitherto unknown heterocycles. It is worth mentioning
The starting substrates N-tosyl-2-(prop-20-ynyloxy)aniline 5a
and its naphthyl analogue 5b could easily be prepared using few
reaction steps starting from commercially available 2-nitrophenol
and 2-nitro-1-naphthol, respectively (see Supplementary data). In
view of the immense success of the ‘Sonogashira catalyst’ in various
heteroannulations, we were initially keen to employ Pd(PPh3)2Cl2/
CuI for the reaction between 5a and 6a; however, carrying out this
reaction at rt in the presence of K2CO3 as base furnished the desired
(E)-3-benzylidene-3,4-dihydro-1,4-benzoxazine (4a) with low
yield (14%) along with the C-phenylated internal alkyne 7 (35%).
This result prompted us to optimize the reaction conditions by
screening different reaction parameters such as catalyst, co-
catalyst, base, solvent, etc. and selected results are presented in
Table 1. To find out the best palladium catalyst, we then employed
Pd(OAc)2/PPh3 in place of Pd(PPh3)2Cl2, but this exclusively fur-
nished the alkyne 7, which could not be cyclized to 4a even after
Table 1
Optimization of the reaction conditions for the synthesis of 4aa,b
Entry
Catalyst
Co-catalyst
Base
Time (h)
Yield (%)
4a
7
1
2
3
4
Pd(PPh3)2Cl2
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2
Pd(PPh3)4
PdCl2/PPh3
Pd/C, PPh3
CuI
CuI
d
K2CO3
K2CO3
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
2
16
2
4
3
14
0
35
56
30
0
0
0
15
69
22
50
61
14
d
5
d
6
d
7c
8c
d
5
5
0
0
d
a
N-Tosyl-2-(prop-20-ynyloxy)aniline 5a (1.0 equiv), phenyl iodide 6a
(1.15 equiv), palladium catalyst (0.05 equiv), PPh3 (0.2 equiv), CuI (0.1 equiv, only for
entries 1 and 2), Bu4NBr (0.1 equiv), base (4.0 equiv) in anhydrous DMF at room
temp (except entries 7 and 8).
b
Room temp implies temperature between 35 ꢀC and 40 ꢀC.
Reaction mixture was heated to 80 ꢀC as no reaction took place at room
c
temperature.

K. Brahma et al. / Tetrahedron 70 (2014) 5863e5871
5865
Table 2
Synthesis of (E)-3-arylidine-3,4-dihydro-2H-1,4-benzoxazines (4) and their naphtho analogues 8a
Entry
1
Acetylene 5
Aryl iodide 6
Timeb (h)
2.0
Product
Yieldc (%)
69
71
2
3
4
5a
5a
5a
3.0
2.5
2.0
70
78
5
6
5a
5a
5.5
3.0
68
79
7
8
5a
5a
2.5
5.0
38
51
9
5a
5.0
58
74
10
11
5a
5a
3.5
2.5
55
(continued on next page)

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K. Brahma et al. / Tetrahedron 70 (2014) 5863e5871
Table 2 (continued )
Entry
Acetylene 5
Aryl iodide 6
Timeb (h)
Product
Yieldc (%)
12d
13d
14d
15d
6a
6c
6g
4.0
74
5b
5b
4.0
7.0
79
54
5b
5b
5.0
5.5
57
83
16d
a
Acetylene 5a/5b (0.5 mmol), iodide 6 (0.57 mmol), Pd(OAc)2 (0.025 mmol), PPh3 (0.1 mmol), K2CO3 (2.0 mmol), and n-Bu4NBr (0.05 mmol), in DMF (4 mL), at room
temperature.
b
c
Time indicating the completion of reaction as monitored through TLC.
Yields were calculated based on 5a/5b.
In contrast to entries 1e11, iodide 6 was applied in slight excess (1.5 equiv with respect to acetylene) to compensate for partial deiodination of 6 observed during the
d
reaction.
that (þ)-4-propyl-9-hydroxynaphthoxazine (PHNO), a new dop-
aminomimetic with selective D2 agonist properties, has been re-
ported to be useful in the treatment of Parkinson’s disease.14
The structures of the synthesized compounds, 3-arylidene de-
rivatives of 3,4-dihydro-2H-1,4-benzoxazines and naphth[1,2-b]
[1,4]oxazines (4 and 8) were unambiguously deduced by spectro-
scopic (1H, 13C and DEPT NMR experiments, IR, mass) and analytical
evidences. Notably, the chemical shifts of the olefinic proton in the
(Z)-isomers of 3-arylidene-1,4-benzoxazines 4 have been reported9
to lie in the range between 6 and 7 ppm. However, the olefinic
proton signals of our products (4, 8) appeared downfield
(dH>7 ppm), attributed to the deshielding effect of the tosyl group in
proximity, indicating the E-stereochemistry of the exocyclic double
3
bond. Besides, NOE experiments and JCH coupling constant values
between olefinic proton and methylenic carbon (OCH2) of the 1,4-
oxazine ring of the products provided additional support in favor
of E-stereochemistry. In literature,8a,9,15 3JCH values more than 7 Hz
were attributed to (E)-stereoisomers and less than 5 Hz to (Z)-iso-
mers. In the present case, 3JCH values of the products 4 and 8 were
between 7 and 9 Hz suggesting (E)-stereochemistry (see 13C NMR
data of 4a, 4d, 4i, 8a, 8c in experimental). Finally, single crystal X-ray
diffraction analysis of two representative products 4d and 8a con-
firmed the stereochemistry and structure simultaneously (Fig. 2).
Based on known palladium chemistry and control experiments,
a plausible reaction mechanism is proposed (Scheme 1). Oxidative
addition of aryl iodide 6 to Pd(0), formed in situ16a from Pd(OAc)2
and PPh3, produces the species ArPd(II)I (A). This subsequently
Fig. 2. ORTEP representations of products 4d and 8a.

K. Brahma et al. / Tetrahedron 70 (2014) 5863e5871
5867
Table 3
Reactions of 5a with aryl and vinyl bromide/chloride/triflate 9a
Entry
1
RX (9)
Time (h)
6
Product
Product
4 (% yield)b
10 (% yield)b
4a (0%)
4a (0%)
4a (0%)
10 (40%)
2
3
12
5
10 (42%)
10 (55%)
Scheme 1. Possible reaction mechanism.
activates the triple bond of the acetylenic moiety to undergo
intramolecular nucleophilic attack16b,c by the neighboring nitrogen
atom (N-Ts) to generate the vinylic palladium intermediate species
C via trans-aminopalladation.16d,e Finally, reductive elimination16f
from intermediate C might result in the formation of the product
(4/8) ensuring E-stereochemistry and regeneration of Pd(0) to
make the catalytic cycle active. Possibly, tetrabutylammonium
bromide (Bu4NBr) is participating in halogen exchange reaction17
with intermediate species A leading to the formation of the more
reactive species RPd(II)Br for expediting the process, while also
performing the role of phase-transfer catalyst in order to facilitate
the reaction by increasing the amount of base in the reaction sys-
tem. This hypothesis was tested by performing control experi-
ments. Accordingly, in two separate experiments (Scheme 2),
acetylene 5a was allowed to react with phenyl iodide 6a in DMF at
room temperature for 20 h in the presence of Pd(OAc)2 (5 mol %),
PPh3 (20 mol %), and K2CO3; either Bu4NI was used in place of
Bu4NBr or no ammonium salt used. Surprisingly, both the reactions
were found to be incomplete. However, the reaction involving
Bu4NI led to the isolation of the cyclized product 4a with 47% yield
along with the recovery of acetylenic substrate 5a (24%). In the
other reaction, the product 4a was isolated with 41% yield while the
acetylenic substrate 5a remained unreacted to the extent of 26%.
These experiments pointed out the importance of Bu4NBr in this
reaction.18
4
5
6
7
12
6
4l (0%)
10 (37%)
10 (20%)
10 (27%)
10 (25%)
4m (32%)
4n (50%)
4n (0%)
12
11
8
12
4o (73%)
10 (0%)
a
Reaction conditions: 5a (0.5 mmol), substrate
9
(0.57 mmol), Pd(OAc)2
(0.028 mmol), PPh3 (0.11 mmol), K2CO3 (2.0 mmol), and n-Bu4NBr (0.057 mmol), in
DMF (4 mL) at room temperature.
b
Yields were calculated based on 5a.
bromide with 5a under the optimized reaction conditions. Sur-
prisingly, there was no sign of the formation of the expected
product 4a in TLC; instead a slower moving spot was found to be
developed during the course of the reaction. The spectral analysis of
this purified product (40% yield) indicated the formation of the bis-
heteroannulated product 10 (Table 3, entry 1). This structural
conclusion was further confirmed by X-ray diffraction analysis (for
ORTEP diagram, see Fig. 3). Formation of the product 10 can be
attributed to the synthesis of the dimer of the acetylenic substrate
Scheme 2. Control experiments to establish the role of Bu4NBr.
After successful demonstration of the reaction of 5a with vari-
ous aryl iodides 6, we planned to extend the scope of this reaction
further by employing internal alkynes or aryl bromide/chloride/
triflate (or corresponding vinyl analogue). Our initial attempts to
employ the internal alkyne 7 as substrate in the reactions with
different aryl iodides turned out to be unfruitful, suggesting pos-
sible steric hindrance induced by substitution on the alkyne moiety
(see mechanism of Scheme 1). Thereafter, we studied the reactions
of 5a with other halides/triflates in place of aryl iodide 6 as de-
scribed in Table 3. We initially studied the reaction of phenyl
Fig. 3. ORTEP representation of product 10.

5868
K. Brahma et al. / Tetrahedron 70 (2014) 5863e5871
5a followed by intramolecular cyclization. However, the sub-
sequent employment of the phenyl chloride (9b) and triflates (9c
and 9d) in this reaction led to the observations of the same product
10 in moderate yields (Table 3, entries 2e4). We then focused our
attention on the reactivity of vinyl iodide/bromide/chloride/triflate
(entries 5e8 of Table 3). On the other hand, employment of vinyl
iodide (9e) resulted in a mixture of expected product 4m (32%) and
the side product 10 (20%) (Table 3, entry 5). Next, though the use of
4. Experimental section
4.1. General
Reagents were purchased from commercial sources and used
without further purifications. Reactions were performed under ar-
gon atmosphere. Thin layer chromatography (TLC) was performed
on silica gel 60 F254 aluminum sheets [Merck, Germany] and visu-
alization of the developed chromatogram was achieved by UV ab-
sorbance. Column chromatography was carried out on Merck silica
gel (100e200 mesh). Solvents were purified using standard means.
1H and 13C NMR spectra were recorded with Bruker-300 or 600 MHz
NMR spectrometers. IR spectra were recorded with a JASCO FT/IR-
4200 infrared spectrometer either neat or as KBr plates; only ma-
jor peaks were reported in cmꢁ1. Melting points were determined
on a microscopic apparatus and were uncorrected. Mass spectra
were recorded by JEOL MS 700 mass spectrometer or Q-TOF-Micro
mass spectrometer operating in electron spray ionization (ESI) or
fast atom bombardment (FAB) mode. Elemental analyses were
performed on an automated carbon, hydrogen, nitrogen, and sulfur
analyzer at IICB, Kolkata. Crystallographic data were obtained with
a Bruker Kappa Apex 2 instrument.
b
-bromostyrene (9f) in this reaction increased the yield of the de-
sired product 4n to the extent of 50%, the reaction was found to be
somewhat slower (Table 3, entry 6); in contrast, -chlorostyrene
b
(9g) did not afford any targeted product 4 except the side product
10 in low yield (25%). Pleasingly, vinyl triflate 9h furnished the
desired product 4o (73%) exclusively with complete suppression of
the side product 10.
In recent reports,19 2,3-dihydro-1,4-benzodioxepins linked with
uracil or its 5-fluoro derivative showed good antiproliferative ac-
tivity against human breast cancer cell lines (MCF-7). With our in-
terest on uracil derivatives,20 we decided to apply this methodology
for the preparation of novel uracil derivatives with possible bi-
ological activities. Indeed, the synthesis of novel 5-substituted N,N-
dimethyluracil derivative 4f could easily be accomplished adopting
our reaction protocol (Table 2, entry 6). In addition, one of the
synthesized products 4e (Table 2, entry 5), a 2,4-dimethoxy py-
rimidine derivative, could easily be demethylated by treating with
trimethylsilyl chloride and sodium iodide at rt leading to the for-
mation of a novel uracil derivative 11 (Scheme 3). The cytotoxicity
assays of the synthesized compounds including uracil derivatives 4f
and 11 in various cancer cell lines are under investigation.
4.2. General procedure for the synthesis of (E)-3-arylidene-4-
tosyl-3,4-dihydro-2H-1,4-benzoxazines (4) and -naphth[1,2-b]
[1,4]oxazines (8)
A mixture of Pd(OAc)2 (4 mg, 5 mol %) and PPh3 (20 mg,
20 mol %) in dry DMF (2 mL) was stirred for 10 min under argon
atmosphere. Aryl iodide 6 (0.382 mmol, 1.15 equiv with respect to
acetylene 5a), K2CO3 (183 mg, 1.33 mmol), and n-Bu4NBr (11 mg,
0.033 mmol) were added to it successively. The resulting reaction
mixture was allowed to stir for another 10 min. A solution of
acetylenic substrate 5a (0.332 mmol) in dry DMF (2 mL) was added
drop wise to the reaction mixture. The whole reaction mixture was
then allowed to stir at room temperature under argon atmosphere.
After completion of the reaction (monitored by TLC), the solvent
was removed under reduced pressure and the crude mixture was
poured into water (20 mL). The aqueous layer was extracted with
ethyl acetate (20 mLꢂ3). The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The resulting crude residue was purified through
column chromatography over silica gel (100e200 mesh) using
ethyl acetate/petroleum ether as eluent to obtain the product 4.
The same procedure was adopted for the synthesis of the
naphtho analogues 8 using 5b as acetylenic substrate. Here, the
only difference was that aryl iodide (6) was used in slight excess
(1.5 equiv with respect to acetylene 5b instead of 1.15 equiv) as
partial deiodination was observed during the course of reaction.
The reaction procedure for the synthesis of the products re-
ported in Table 3 was similar to that of acetylenic substrate 5a and
aryl iodide 6 as described above. The only difference was that aryl
bromide/chloride/triflate or corresponding vinyl analogue was
used in place of aryl iodide (6).
Scheme 3. Synthesis of 5-substituted uracil derivative 11.
Since N-unsubstituted 1,4-benzoxazines are biologically impor-
tant,2e,3a,b,21 we also attempted N-deprotection reactions of 4a at
different temperature (ꢁ78 ꢀC to ꢁ30 ꢀC) using the known reagent
sodium naphthalenide.12d Unfortunately, the desired product was
not obtained despite repeated attempts. Instead, 1,4-benzoxazine-
3-one (12) was isolated with up to 50% yield. Efforts are currently
underway to establish the appropriate protocol for deprotection.
3. Conclusions
In conclusion, we have developed a palladium-catalyzed effi-
cient and general method for the stereoselective synthesis of (E)-3-
arylidene-3,4-dihydro-2H-1,4-benzoxazines (4) and their naph-
thoxazine derivatives 8. The reaction provides moderate to very
good yield of the products at room temperature within few hours
and tolerates various functional groups. The use of the inexpensive
starting materials, short reaction time period, regio- and stereo-
selectivity, and operational simplicity make the process attractive.
The scope and limitation of this reaction protocol have been ex-
amined by employing aryl bromide/chloride/triflate and their cor-
responding vinyl analogues. The method can also be applied to the
synthesis of uracil derivatives of biological interest. Besides, the (E)-
stereochemistry of the exocyclic double bond in the products (4, 8,
and 10) was firmly established by spectroscopic data and X-ray
diffraction analysis.22 The synthetic utility of the exocyclic double
bond4,5,8b is likely to be explored further for the generation of
scaffolds based on diversity oriented synthesis. The work in this
direction is currently under progress.
4.3. Spectral data of (E)-3-arylidene-4-tosyl-3,4-dihydro-2H-
1,4-benzoxazines (4) and naphth[1,2-b][1,4]oxazines (8)
4.3.1. (E)-3-Benzylidene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazine
(4a). Yield: 69%; yellowish white solid, Rf (30% EtOAc/petroleum
ether) 0.65, mp 128e130 ꢀC; IR (KBr): 3026, 1590, 1361, 1169 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): dH 2.42 (s, 3H), 4.19 (s, 2H), 6.75 (d,
J¼8.1 Hz,1H), 7.01 (t, J¼7.2 Hz,1H), 7.08e7.15 (m, 3H), 7.23e7.26 (m,
3H), 7.32e7.39 (m, 3H), 7.50 (d, J¼7.5 Hz, 2H), 7.85 (d, J¼7.8 Hz, 1H);
13C NMR (CDCl3, 75 MHz): dC 21.6, 61.7 (3JCH¼8.1 Hz), 116.9, 121.1,
125.0, 126.1, 126.8, 127.8, 128.2, 128.6, 128.9, 129.7, 132.2, 134.2,

K. Brahma et al. / Tetrahedron 70 (2014) 5863e5871
5869
134.6, 144.5, 147.2; HRMS (EIþ): calcd for C22H19NO3S ([M]þ)
377.1085, found 377.1088.
21.3, 21.6, 61.7, 116.9, 121.0, 125.1, 126.1, 126.8, 127.8, 127.9, 128.9,
129.3, 129.7, 131.3, 132.3, 134.6, 138.2, 144.5, 147.2; ESI-MS: m/z
414.23 [MþNa]þ. Anal. Calcd for C23H21NO3S: C, 70.56; H, 5.41; N,
3.58. Found: C, 70.60; H, 5.45; N, 3.53.
4.3.2. (E)-3-[(Naphthalen-1-yl)methylidene]-4-tosyl-3,4-dihydro-2H-
1,4-benzoxazine (4b). Yield: 71%; white solid, Rf (30% EtOAc/petro-
leum ether) 0.42, mp 154e156 ꢀC; IR (KBr): 3056, 1591, 1360,
1165 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.39 (s, 3H), 4.05 (s, 2H),
6.78 (d, J¼8.1 Hz, 1H), 7.04 (t, J¼7.5 Hz, 1H), 7.13 (t, J¼7.5 Hz, 1H),
7.18e7.26 (m, 3H), 7.45 (t, J¼7.5 Hz, 1H), 7.53e7.61 (m, 4H), 7.75 (s,
1H), 7.86 (t, J¼9.1 Hz, 2H), 7.96 (d, J¼7.8 Hz, 1H), 8.10 (d, J¼7.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz): dC 21.6, 62.0, 117.1, 121.2, 124.93,
124.99, 125.2, 125.9, 126.36, 126.44, 126.72, 126.75, 127.7, 128.4,
128.8,129.8, 130.0, 130.6,131.4,131.8,133.4,134.5,144.6,147.3; HRMS
(ESIþ): calcd for C26H21NNaO3S ([MþNa]þ) 450.1139, found 450.1175.
4.3.8. (E)-3-(4-Trifluoromethylbenzylidene)-4-tosyl-3,4-dihydro-2H-
1,4-benzoxazine (4h). Yield: 51%; white solid, Rf (40% EtOAc/petro-
leum ether) 0.67, mp 138e140 ꢀC; IR (KBr): 1592, 1359, 1171 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): dH 2.42 (s, 3H), 4.17 (s, 2H), 6.77 (br d,
J¼7.8 Hz, 1H), 7.02 (t, J¼7.3 Hz, 1H), 7.12 (app t, J¼7.3 Hz, 1H),
7.24e7.27 (m, 5H), 7.49 (d, J¼8.1 Hz, 2H), 7.64 (d, J¼7.8 Hz, 2H), 7.85
(br d, J¼8.1 Hz, 1H); 13C NMR (CDCl3, 150 MHz): dC 21.6, 61.9, 117.0,
121.4, 123.9 (q, J¼270 Hz), 125.0, 125.6 (q, J¼3.7 Hz), 126.1, 127.0,
127.7, 129.2, 129.81, 130.07, 130.08 (q, J¼32.6 Hz), 130.8, 134.5, 137.9,
144.8, 147.2; HRMS (ESIþ): calcd for C23H18F3NNaO3S ([MþNa]þ)
468.0857, found 468.0890.
4.3.3. (E)-3-[(Pyridin-3-yl)methylidene]-4-tosyl-3,4-dihydro-2H-1,4-
benzoxazine (4c). Yield: 70%; yellow solid, Rf (60% EtOAc/petroleum
ether) 0.42, mp 124e125 ꢀC; IR (KBr): 1597, 1362, 1168 cmꢁ1
;
1H
4.3.9. (E)-3-(4-Methoxybenzylidene)-4-tosyl-3,4-dihydro-2H-1,4-
NMR (CDCl3, 300 MHz): dH 2.42 (s, 3H), 4.16 (s, 2H), 6.77 (d, J¼7.8 Hz,
1H), 7.03 (t, J¼7.5 Hz, 1H), 7.12 (t, J¼7.5 Hz, 1H), 7.21e7.27 (m, 2H),
7.33 (t, J¼6.1 Hz, 1H), 7.48e7.50 (m, 4H), 7.86 (d, J¼8.1 Hz, 1H), 8.39
(s, 1H), 8.55e8.57 (m, 1H); 13C NMR (CDCl3, 75 MHz): dC 21.6, 61.5,
116.9, 121.3, 123.5, 124.8, 126.0, 126.9, 127.6, 129.8, 130.3, 130.8, 134.2,
136.2, 144.8, 147.0, 148.9, 149.2; HRMS (EIþ): calcd for C21H18N2O3S
([M]þ) 378.1038, found 378.1036.
benzoxazine (4i). Yield: 58%; white solid, Rf (30% EtOAc/petroleum
ether) 0.45, mp 136e138 ꢀC; IR (KBr): 2923, 1603, 1354, 1168 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): dH 2.41 (s, 3H), 3.82 (s, 3H), 4.19 (s, 2H),
6.74 (d, J¼7.8 Hz, 1H), 6.89 (d, J¼8.1 Hz, 2H), 6.99 (t, J¼7.1 Hz, 1H),
7.06e7.12 (m, 3H), 7.19e7.25 (m, 3H), 7.49 (d, J¼7.8 Hz, 2H), 7.83 (d,
J¼8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz): dC 21.6, 55.3, 61.8
(3JCH¼7.9 Hz), 114.1, 116.9,121.0, 125.2, 126.1, 126.6, 126.8, 127.1, 127.8,
129.8, 130.4, 132.0, 134.7, 144.5, 147.2, 159.6; HRMS (EIþ): calcd for
4.3.4. (E)-3-[(Thiophen-2-yl)methylidene]-4-tosyl-3,4-dihydro-2H-
1,4-benzoxazine (4d). Yield: 78%; yellow solid, Rf (30% EtOAc/petro-
leum ether) 0.41, mp 110e112 ꢀC; IR (KBr): 3064, 1584, 1360,
1164 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.40 (s, 3H), 4.44 (s, 2H),
6.77 (d, J¼8.1 Hz, 1H), 6.99e7.15 (m, 4H), 7.20 (d, J¼7.8 Hz, 2H),
7.26e7.28 (m, 1H), 7.37 (d, J¼4.5 Hz, 1H), 7.43 (d, J¼8.1 Hz, 2H), 7.76
(d, J¼8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz): dC 21.6, 63.7
(3JCH¼8.4 Hz), 116.9, 121.4, 123.3, 125.8, 126.6, 127.2, 127.3, 127.58,
127.62, 129.60, 129.64, 134.5, 136.3, 144.5, 148.2; HRMS (EIþ): calcd
for C20H17NO3S2 ([M]þ) 383.0649, found 383.0650.
C
23H21NO4S ([M]þ) 407.1191, found 407.1189.
4.3.10. (E)-3-(2-Carbomethoxybenzylidene)-4-tosyl-3,4-dihydro-2H-
1,4-benzoxazine(4j). Yield: 74%; greenish yellow solid, Rf (30% EtOAc/
petroleum ether) 0.25, mp 140e141 ꢀC; IR (KBr): 2956, 1712, 1591,
1360, 1171 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.41 (s, 3H), 3.92 (s,
3H), 3.96 (s, 2H), 6.71e6.76 (m,1H), 6.98e7.12 (m, 3H), 7.24e7.26 (m,
2H), 7.42 (t, J¼7.4 Hz, 1H), 7.49e7.56 (m, 3H), 7.68 (s, 1H), 7.90 (d,
J¼8.1 Hz, 1H), 8.04 (d, J¼7.5 Hz, 1H); 13C NMR (CDCl3, 150 MHz): dC
21.6, 52.4, 61.5, 116.1, 116.9, 121.0, 124.9, 126.0, 126.6, 127.8, 128.0,
128.4, 129.8, 130.6, 131.1, 132.2, 132.9, 134.8, 135.3, 144.5, 146.9, 167.0;
ESI-MS: m/z 457.92 [MþNa]þ. Anal. Calcd for C24H21NO5S: C, 66.19;
H, 4.86; N, 3.22. Found: C, 66.16; H, 4.83; N, 3.17.
4.3.5. (E)-3-[(2,4-Dimethoxypyrimidin-5-yl)methylidene]-4-tosyl-3,4-
dihydro-2H-1,4-benzoxazine (4e). Yield: 68%; brown solid, Rf (40%
EtOAc/petroleum ether) 0.37, mp 142e143 ꢀC; IR (KBr): 2955, 1596,
1392, 1170 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.42 (s, 3H), 4.02 (s,
6H), 4.04 (s, 2H), 6.75 (dd, J¼1.1, 8.0 Hz, 1H), 6.98e7.03 (m, 2H), 7.10
(td, J¼1.2, 7.7 Hz, 1H), 7.24e7.27 (m, 2H), 7.49 (d, J¼8.1 Hz, 2H),
7.83e7.86 (m, 2H); 13C NMR (CDCl3, 75 MHz): dC 21.6, 54.3, 55.0, 61.3,
109.7,116.9,121.1,122.6,124.7,125.98,126.8,127.8,129.3,129.7,134.4,
144.7, 146.8, 157.4, 165.1, 168.5; HRMS (ESIþ): calcd for
4.3.11. (E)-3-(2-Methyl-4-nitrobenzylidene)-4-tosyl-3,4-dihydro-2H-
1,4-benzoxazine (4k). Yield: 55%; light yellow solid, Rf (40% EtOAc/
petroleum ether) 0.64, mp 120e121 ꢀC; IR (KBr): 3064, 1591, 1520,
1349, 1169 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.41 (s, 3H), 2.46 (s,
3H), 4.01 (s, 2H), 6.78 (d, J¼7.8 Hz, 1H), 7.04 (t, J¼7.2 Hz, 1H), 7.12 (d,
J¼8.1 Hz, 2H), 7.24e7.26 (m, 3H), 7.48 (d, J¼8.1 Hz, 2H), 7.91 (d,
J¼8.1 Hz, 1H), 8.05 (d, J¼8.1 Hz, 1H), 8.10 (s, 1H); 13C NMR (CDCl3,
75 MHz): dC 20.1, 21.6, 61.6, 117.1, 121.0,121.4, 124.7,124.9, 125.7,126.9,
127.5, 128.8, 129.5, 129.8, 131.3, 134.3, 139.2, 140.1, 144.9, 147.0, 147.4;
HRMS (EIþ): calcd for C23H20N2O5S ([M]þ) 436.1092, found 436.1091.
C
22H21N3NaO5S ([MþNa]þ) 462.1099, found 462.1119.
4.3.6. (E)-3-[(N,N0-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-
5-yl)methylidene]-4-tosyl-3,4-dihydro-2H-1,4-benzoxazine
(4f). Yield: 79%; light yellow solid, Rf (40% EtOAc/petroleum ether)
0.15, mp 143e145 ꢀC; IR (KBr): 3046, 1710, 1657, 1592, 1353,
1169 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.40 (s, 3H), 3.38 (s, 3H),
3.44 (s, 3H), 4.14 (s, 2H), 6.72e6.74 (m, 2H), 6.98 (t, J¼7.4 Hz, 1H),
7.08e7.11 (m, 2H), 7.23e7.26 (m, 2H), 7.53 (d, J¼7.8 Hz, 2H), 7.81 (d,
J¼7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): dC 21.6, 28.3, 37.3, 62.7,
107.9, 116.9, 121.0, 122.2, 124.8, 125.6, 126.8, 127.8, 129.7, 130.0, 134.3,
142.5, 144.6, 147.1, 151.0, 161.4; HRMS (ESIþ): calcd for
4.3.12. (E)-3-Allylidene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazine
(4m). Yield: 32%; gum, Rf (30% EtOAc/petroleum ether) 0.57; IR
(KBr): 2984, 1652, 1593, 1489, 1361, 1299, 1254, 1167 cmꢁ1; 1H NMR
(CDCl3, 300 MHz): dH 2.39 (s, 3H), 4.12 (s, 2H), 5.35 (d, J¼10.2 Hz,1H),
5.51 (d, J¼16.8 Hz, 1H), 6.33e6.45 (m, 1H), 6.69e6.77 (m, 2H),
6.95e7.01 (m, 1H), 7.09 (td, J¼1.3, 7.6 Hz, 1H), 7.20 (d, J¼8.1 Hz, 2H),
7.41 (d, J¼8.1 Hz, 2H), 7.80 (dd, J¼1.5, 8.1 Hz, 1H); 13C NMR (CDCl3,
75 MHz): dC 21.6, 61.6, 116.9, 121.2, 122.8, 126.0, 126.8, 127.0, 128.2,
129.6, 130.9, 134.5, 144.4, 147.4; HRMS (FABþ): calcd for C18H18NO3S
([MþH]þ) 328.1007, found 328.1012.
C
22H21N3NaO5S ([MþNa]þ) 462.1099, found 462.1079.
4.3.7. (E)-3-(4-Methylbenzylidene)-4-tosyl-3,4-dihydro-2H-1,4-
benzoxazine (4g). Yield: 38%; white solid, Rf (30% EtOAc/petroleum
ether) 0.56, mp 132e134 ꢀC; IR (KBr): 3031, 1590, 1358, 1163 cmꢁ1
;
4.3.13. (E)-3-((E)-3-Phenylallylidene)-4-tosyl-3,4-dihydro-2H-1,4-
benzoxazine (4n). Yield: 50%; white solid, Rf (30% EtOAc/petroleum
ether) 0.59, mp 110e112 ꢀC; IR (KBr): 3029, 2922, 1594, 1488, 1455,
1358, 1298, 1247, 1166 cmꢁ1; 1H NMR (CDCl3, 600 MHz): dH 2.39 (s,
1H NMR (CDCl3, 300 MHz): dH 2.36 (s, 3H), 2.42 (s, 3H), 4.19 (s, 2H),
6.75 (d, J¼7.8 Hz, 1H), 6.98e7.12 (m, 4H), 7.17e7.26 (m, 5H), 7.49 (d,
J¼8.1 Hz, 2H), 7.84 (d, J¼7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): dC

5870
K. Brahma et al. / Tetrahedron 70 (2014) 5863e5871
3H), 4.21 (s, 2H), 6.74e6.79 (m, 2H), 6.82 (d, J¼15.0 Hz, 1H), 6.88 (d,
J¼10.8 Hz, 1H), 6.98e7.01 (m, 1H), 7.08e7.11 (m, 1H), 7.20 (d,
J¼7.8 Hz, 2H), 7.26e7.29 (m, 1H), 7.33e7.35 (m, 2H), 7.43 (br d,
J¼8.4 Hz, 4H), 7.84 (dd, J¼1.5, 8.4 Hz, 1H); 13C NMR (CDCl3,
150 MHz): dC 21.6, 62.8117.0, 121.2, 121.3, 125.3, 126.0, 126.7, 126.8,
127.6, 127.7, 128.5, 128.8, 129.7, 130.9, 134.6, 136.4, 137.4, 144.5,
147.4; HRMS (EIþ): calcd for C24H21NO3S ([M]þ) 403.1242, found
403.1243.
81Br. Anal. Calcd for C26H20BrNO3S: C, 61.66; H, 3.98; N, 2.77. Found:
C, 61.59; H, 3.94; N, 2.80.
4.3.19. (E)-3-(4-Nitrobenzylidene)-4-tosyl-3,4-dihydro-2H-naphth
[1,2-b][1,4]oxazine (8e). Yield: 83%; light yellow solid, Rf (30%
EtOAc/petroleum ether) 0.59, mp 156e157 ꢀC; IR (KBr): 2924, 1597,
1349, 1167 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.40 (s, 3H), 4.33 (s,
2H), 7.22e7.26 (m, 2H), 7.34e7.39 (m, 3H), 7.42e7.51 (m, 5H), 7.80
(d, J¼7.8 Hz, 1H), 7.93e8.02 (m, 2H), 8.27 (d, J¼8.4 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): dC 21.6, 61.7, 119.4, 120.8, 121.3, 123.9, 124.1, 124.6,
125.8, 126.4, 127.5, 127.8, 129.5, 129.7, 129.9, 131.6, 132.3, 133.9,
140.9, 141.8, 144.9, 147.3; ESI-MS: m/z 495.20 [MþNa]þ. Anal. Calcd
for C26H20N2O5S: C, 66.09; H, 4.27; N, 5.93. Found: C, 66.04; H, 4.23;
N, 5.97.
4.3.14. (E)-3-((3,4-Dihydronaphthalen-1-yl)methylene)-4-tosyl-3,4-
dihydro-2H-1,4-benzoxazine (4o). Yield: 73%; white solid, Rf (30%
EtOAc/petroleum ether) 0.59, mp 112e114 ꢀC; IR (KBr): 1590, 1488,
1356, 1299, 1261, 1166 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.39 (br
s, 5H), 2.81(t, J¼7.9 Hz, 2H), 4.08 (s, 2H), 5.83 (br s, 1H), 6.75 (d,
J¼7.8 Hz, 1H), 7.00e7.03 (m, 2H), 7.08e7.25 (m, 7H), 7.49 (d,
J¼7.8 Hz, 2H), 7.89 (d, J¼7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): dC
21.6, 23.3, 27.6, 61.8, 117.1, 121.0, 124.5, 125.0, 126.7, 126.8, 127.7,
127.8, 129.6, 129.7, 129.8, 131.0, 132.5, 133.7, 134.7, 135.7, 144.5,
147.2; HRMS (FABþ): calcd for C26H24NO3S ([MþH]þ) 430.1476,
found 430.1456.
4.3.20. (1E,2E)-1,2-Bis(4-tosyl-2H-benzo[b][1,4]oxazin-3(4H)-yli-
dene)ethane (10). Yield: 20e55% (see Table 3 in text); colorless
crystalline solid, Rf (30% EtOAc/petroleum ether) 0.58, mp
172e174 ꢀC; IR (KBr): 1625, 1592, 1488, 1357, 1298, 1251, 1169 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): dH 2.40 (s, 6H), 4.27 (s, 4H), 6.70 (s, 2H),
6.79 (dd, J¼1.0, 7.8 Hz, 2H), 6.99e7.04 (m, 2H), 7.10e7.16 (m, 2H),
7.21 (d, J¼8.1 Hz, 4H), 7.39 (d, J¼8.1 Hz, 4H), 7.78 (dd, J¼1.3, 8.4 Hz,
2H); 13C NMR (CDCl3, 75 MHz): dC 21.6, 62.5,117.1,121.6,121.7,125.2,
126.1, 127.2, 127.6, 129.7, 132.1, 134.2, 144.8, 148.0; HRMS (ESIþ):
calcd for C32H28N2NaO6S2 ([MþNa]þ) 623.1286 found 623.1293.
4.3.15. (E)-3-Benzylidene-4-tosyl-3,4-dihydro-2H-naphth[1,2-b][1,4]
oxazine (8a). Yield: 74%; brown solid, Rf (30% EtOAc/petroleum
ether) 0.42, mp 152e154 ꢀC; IR (KBr): 3050, 1595, 1357, 1171 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): dH 2.41 (s, 3H), 4.32 (s, 2H), 7.16e7.27
(m, 4H), 7.34e7.54 (m, 9H), 7.79 (d, J¼7.8 Hz, 1H), 7.95 (d, J¼7.8 Hz,
1H), 8.01 (d, J¼9.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz): dC 21.6, 61.5
(3JCH¼7.8 Hz), 119.4, 120.3, 121.4, 124.5, 124.7, 125.6, 126.2, 127.4,
127.9, 128.3, 128.6, 129.0, 129.8, 132.2, 132.5, 134.1, 134.3, 141.7,
144.6; HRMS (ESIþ): calcd for C26H21NNaO3S ([MþNa]þ) 450.1139
found 450.1157.
4.4. Synthesis of (E)-3-[(20,40-dioxo-10,20,30,40-tetrahydropyr-
imidine-5-yl)methylidene]-4-tosyl-3,4-dihydro-2H-1,4-
benzoxazine (11)
To a well-stirred solution of compound 4e (90 mg, 0.20 mmol) in
anhydrous acetonitrile were added anhydrous sodium iodide
(92 mg, 0.61 mmol) and trimethylsilyl chloride (0.76 mL, 0.61 mmol)
successively. The resulting solution was then allowed to stir at room
temperature for 18 h under argon atmosphere. After removing the
solvent under reduced pressure, the residue was poured into water
(10 mL) and extracted with ethyl acetate (3ꢂ12 mL). The combined
ethyl acetate extracts were washed with saturated sodium meta-
bisulphite solution (8 mL) and water (8 mL), respectively. Solvent
was dried over anhydrous sodium sulfate and concentrated in
vacuo. The resulting residue was purified through silica gel
(100e200 mesh) chromatography using 2% methanol in chloroform
as eluent to obtain the titled compound 11 as a light yellow solid
(72 mg, yield 86%); Rf (100% EtOAc) 0.50, mp>300 ꢀC; IR (KBr): 2924,
4.3.16. (E)-3-[(Pyridin-3-yl)methylidene]-4-tosyl-3,4-dihydro-2H-
naphth[1,2-b][1,4]oxazine (8b). Yield: 79%; brown solid, Rf (40%
EtOAc/petroleum ether) 0.22, mp 119e121 ꢀC; IR (KBr): 1594, 1465,
1406, 1359, 1273, 1168, 1095 cmꢁ1 1H NMR (CDCl3, 300 MHz): dH
;
2.40 (s, 3H), 4.29 (s, 2H), 7.23e7.29 (m, 3H), 7.33e7.37 (m, 1H),
7.39e7.55 (m, 6H), 7.79 (d, J¼7.8 Hz, 1H), 7.94 (d, J¼7.8 Hz, 1H), 8.01
(d, J¼9.0 Hz, 1H), 8.42 (br s, 1H), 8.58 (d, J¼4.5 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): dC 21.6, 61.2, 119.2, 120.6, 121.3, 123.5, 124.2, 124.6,
125.7, 126.3, 127.4, 127.8, 128.2, 129.9, 130.3, 130.4, 132.2, 133.8,
136.4, 141.6, 144.8, 149.0, 149.2; ESI-MS: m/z 451.28 [MþNa]þ. Anal.
Calcd for C25H20N2O3S: C, 70.07; H, 4.70; N, 6.54. Found: C, 70.04; H,
4.75; N, 6.51.
1689, 1591, 1473, 1437, 1408, 1315, 1267 cmꢁ1 1H NMR (DMSO-d6,
;
4.3.17. (E)-3-(4-Methylbenzylidene)-4-tosyl-3,4-dihydro-2H-naphth
[1,2-b][1,4]oxazine (8c). Yield: 54%; white solid, Rf (30% EtOAc/pe-
troleum ether) 0.44, mp 148e149 ꢀC; IR (KBr): 1594, 1467, 1408,
300 MHz): dH 2.37 (s, 3H), 4.23 (s, 2H), 6.62 (s, 1H), 6.77 (d, J¼7.8 Hz,
1H), 7.00 (t, J¼7.4 Hz,1H), 7.12 (t, J¼7.5 Hz,1H), 7.36 (d, J¼7.5 Hz, 2H),
7.45e7.49 (m, 3H), 7.66 (d, J¼7.8 Hz, 1H), 11.26 (s, 1H), 11.36 (s, 1H);
13C NMR (DMSO-d6, 75 MHz): dC 21.1, 62.2, 106.4, 116.9, 120.9, 123.0,
124.6, 125.2, 127.1, 127.4, 127.7, 130.0, 133.7, 142.1, 144.7, 147.0, 150.9,
162.8; ESI-MS: m/z 433.79 [MþNa]þ. Anal. Calcd for C20H17N3SO5: C,
58.38; H, 4.16; N. 10.21. Found: C, 58.43; H, 4.13, N. 10.17.
1358, 1269, 1162, 1095, 1045, 802, 669 cmꢁ1 1H NMR (CDCl3,
;
300 MHz): dH 2.38 (s, 3H), 2.39 (s, 3H), 4.32 (s, 2H), 7.06 (d, J¼7.5 Hz,
2H), 7.14e7.26 (m, 4H), 7.31 (s, 1H), 7.38e7.52 (m, 5H), 7.78 (d,
J¼7.5 Hz, 1H), 7.93e8.02 (m, 2H); 13C NMR (CDCl3, 75 MHz): dC 21.3,
21.6, 61.5 (3JCH¼7.8 Hz), 119.5, 120.2, 121.4, 124.5, 124.7, 125.5, 126.1,
127.4, 127.6, 127.9, 128.9, 129.3, 129.8, 131.3, 132.2, 132.5, 134.2,
138.3, 141.8, 144.5; HRMS (ESIþ): calcd for C27H23NNaO3S
([MþNa]þ) 464.1296, found 464.1271.
4.5. Synthesis of 2H-benzo[b][1,4]oxazin-3(4H)-one (12)
Sodium (73.1 mg, 3.18 mmol) was added to a solution of naph-
thalene (448 mg, 3.50 mmol) in dry THF (5 mL). After stirring for 2 h
at room temperature, a greenish solution was appeared. To a well-
stirred solution of tosylated compound 4a (60 mg, 0.159 mmol) in
dry THF (3 mL) at ꢁ65 ꢀC was added the aforesaid greenish solution
drop wise and the whole reaction mixture was allowed to stir
at ꢁ65 ꢀC for 20 min. After consumption of the starting materials
(TLC), the reaction mixture was quenched with 2e3 drops of water
and extracted with ethyl acetate (3ꢂ10 mL). The organic extracts
were dried over anhydrous sodium sulfate and concentrated in
vacuo. The resulting residue was purified through silica gel
4.3.18. (E)-3-(4-Bromobenzylidene)-4-tosyl-3,4-dihydro-2H-naphth
[1,2-b][1,4]oxazine (8d). Yield: 57%; white solid, Rf (30% EtOAc/pe-
troleum ether) 0.37, mp 182e184 ꢀC; IR (KBr): 1587, 1355,
1162 cmꢁ1; 1H NMR (CDCl3, 300 MHz): dH 2.40 (s, 3H), 4.29 (s, 2H),
7.04 (d, J¼8.1 Hz, 2H), 7.20e7.26 (m, 3H), 7.36e7.54 (m, 7H), 7.79 (d,
J¼7.8 Hz, 1H), 7.94 (d, J¼8.1 Hz, 1H), 7.99 (d, J¼9.0 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): dC 21.6, 61.5, 119.4, 120.5, 121.3, 122.5, 124.3, 124.7,
125.6, 126.2,127.4, 127.9, 129.1, 129.8, 130.5,131.1, 131.9, 132.2,133.2,
134.1, 141.7, 144.7; ESI-MS: m/z 528.18, 530.18 [MþNa]þ for 79Br,

K. Brahma et al. / Tetrahedron 70 (2014) 5863e5871
5871
1996, 37, 9317; (e) Majumder, K. C.; Ray, K.; Ponra, S. Tetrahedron Lett. 2010, 51,
5437.
(100e200 mesh) column chromatography using 20% ethyl acetate
in petroleum ether as eluent to obtain the titled compound 12 as
a light brown solid (11.8 mg, yield 50%); Rf (30% EtOAc/petroleum
ether) 0.21, mp 152e154 ꢀC (reported23 mp 171e173 ꢀC); 1H NMR
(CDCl3, 300 MHz): dH 4.62 (s, 2H), 6.79e6.82 (m, 1H), 6.95e6.98 (m,
3H), 8.39 (br s, 1H); 13C NMR (CDCl3, 75 MHz): dC 67.3, 115.9, 116.9,
122.7, 124.3, 126.0, 143.7, 165.7; MS (EIþ): m/z 149 [M]þ.
7. (a) For a review, see: Achari, B.; Mandal, S. B.; Dutta, P. K.; Chowdhury, C. Synlett
2004, 2449; for examples see: (b) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Lett.
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Acknowledgements
9. For a palladium-catalyzed synthesis of 4, see: Kundu, N. G.; Chaudhuri, G.;
Upadhyay, A. J. Org. Chem. 2001, 66, 20 see also Ref. 4.
K.B. and B.D. thank Council of Scientific and Industrial Research,
New Delhi for their fellowship. Financial support from CSIR net-
work project (CSC 0108) is gratefully acknowledged.
10. (a) Chaudhuri, G.; Chowdhury, C.; Kundu, N. G. Synlett 1998, 1273; (b) Xu, X.;
Liang, L.; Liu, J.; Yang, J.; Mai, L.; Li, Y. Tetrahedron Lett. 2009, 50, 57; (c) Manzo,
A. M.; Perboni, A.; Broggini, G.; Rigamonti, M. Synthesis 2011, 127.
11. To the best of our knowledge, only one example of (E)-3-ylidene-1,4-benzox-
azine was reported during the synthesis of other heterocycles; see Ref. 8a.
12. (a) Das, B.; Kundu, P.; Chowdhury, C. Org. Biomol. Chem. 2014, 12, 741; (b)
Brahma, K.; Achari, B.; Chowdhury, C. Synthesis 2013, 45, 545; (c) Chowdhury,
C.; Das, B.; Mukherjee, S.; Achari, B. J. Org. Chem. 2012, 77, 5108; (d) Chowdhury,
C.; Mukherjee, S.; Chakraborty, B.; Achari, B. Org. Biomol. Chem. 2011, 9, 5856;
(e) Brahma, K.; Sasmal, A. K.; Chowdhury, C. Org. Biomol. Chem. 2011, 9, 8422; (f)
Chowdhury, C.; Sasmal, A. K.; Dutta, P. K. Tetrahedron Lett. 2009, 50, 2678.
13. For a preliminary communication, see: Chowdhury, C.; Brahma, K.; Mukherjee,
S.; Sasmal, A. K. Tetrahedron Lett. 2010, 51, 2859.
Supplementary data
X-ray crystallographic data of 4d, 8a and 10, and characteriza-
tion data of 5a and 5b are included. Copies of 1H, 13C NMR spectra of
compounds 5a,b, 4, 8, 10, 11, and 12 are also incorporated. Sup-
plementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2014.06.036.
14. Jones, J. H.; Anderson, P. S.; Baldwin, J. J.; Clineschmidt, B. V.; McClure, D. E.;
Lundell, G. F.; Randall, W. C.; Martin, G. E.; Williams, M.; Hirshfield, J. M.; Smith,
G.; Lumma, P. K. J. Med. Chem. 1984, 27, 1607.
15. Voegeli, U.; von Philipsborn, W. Org. Magn. Reson. 1975, 7, 617.
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