Novel synthesis of (E)-3-arylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)- ones using Baylis-Hillman derivatives via reductive cyclization

Article abstract of DOI:10.1080/00397910802519166

A simple synthesis of novel (E)-3-arylidene-2,3-dihydrobenzo[b][1,4] oxazepin-4(5H)-ones from bromides of the Baylis - Hillman adducts using Fe/AcOH for the in situ reduction of nitro group, into an amino group, followed by the cyclization as a key step,

Full text of DOI:10.1080/00397910802519166

Synthetic Communications1, 39: 1290–1298, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802519166
Novel Synthesis of (E)-3-Arylidene-2,3-
dihydrobenzo[b][1,4]oxazepin-4(5H)-ones
Using Baylis–Hillman Derivatives via
Reductive Cyclization
Manickam Bakthadoss and Gandhi Murugan
Department of Organic Chemistry, University of Madras, Guindy Campus,
Chennai, India
Abstract: A simple synthesis of novel (E)-3-arylidene-2,3-dihydrobenzo[b][1,4]-
oxazepin-4(5H)-ones from bromides of the Baylis–Hillman adducts using Fe=
AcOH for the in situ reduction of nitro group, into an amino group, followed
by the cyclization as a key step, has been described.
Keywords: Baylis–Hillman reaction, benzoxazepinones, Fe=AcOH, 4-methyl
2-nitrophenol, 2-nitrophenol
INTRODUCTION
Benzoxazepinone moiety is an integral part of many biologically
important molecules that exhibit a range of biological activity such as
antidepressant activity,[1] HIV reverse transcriptase inhibition,[2] anti-
inflammatory activity,[3] and so forth. It is also utilized as a multi-
drug-resistance modulating agent,[4] and central nervous system agents.[5]
Because the compounds that have a benzoxazepinone moiety possess var-
ious important biological properties, development of simple procedure
for making these compounds is an important and interesting endeavor
in the field of synthetic organic chemistry and pharmaceutical chemistry.
Received June 25, 2008.
Address correspondence to Manickam Bakthadoss, Department of Organic
Chemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu,
India. E-mail: bhakthadoss@yahoo.com
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(E)-3-Arylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-ones
1291
In continuation of our interest in the field of Baylis–Hillman chem-
istry,[6–8] we herein report the first synthetic route for the synthesis of
seven membered benzoxazepinones from the Baylis–Hillman bromides
involving a substitution, in situ reduction, and cyclization reaction sequ-
ence as shown in the retrosynthetic strategy described in Scheme 1.
During the past few years, the Baylis–Hillman reaction has become
increasingly important because it provides multifunctionalized molecu-
les whose applications in synthetic organic chemistry have been well
documented in the literature.[9–16] The Baylis–Hillman adducts are also
utilized very well as building blocks for many natural products and
biologically active molecules.[9–10,14,17–20]
RESULTS AND DISCUSSION
To the best of our knowledge, there is no report available for the synthesis
(E)-3-arylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-ones even though
there are reports known for the synthesis of dibenzoxazepinones.[21,22]
We envisaged that the aryloxy compounds derived from Baylis–Hillman
bromides (1) can be easily converted into the desired (E)-3-arylidene-2,3-
dihydrobenzo[b][1,4]oxazepin-4(5H)-ones via the construction of C-O and
C-N bonds involving Fe=AcOH for the in situ reduction of the nitro group
into an amino group followed by the cyclization as a key step.
To execute our idea, we first selected methyl (2Z)-2-(bromomethyl)-
3-phenylprop-2-enoate (1a)[6] derived from the Baylis–Hillman adduct
and treated with 2-nitrophenol (2) in the presence of K2CO3 in acetoni-
trile at room temperature, which provided the required (2E)-methyl-
2-[(2-nitrophenoxy)methyl]-3-phenylacrylate (3a). A precursor for the
synthesis of (E)-3-benzylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-
ones. After obtaining the precursor (3a) in excellent yield (95%), we
Scheme 1. Retro synthetic strategy for the synthesis of benzoxazepinone frame-
works.

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M. Bakthadoss and G. Murugan
Scheme 2. Synthesis of (E)-3-arylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-
ones.
planned to carry out the conversion of nitro functionality into the amino
group, followed by the cyclization of amino group with ester moiety
intramolecularly, which would provide the desired benzoxazepinone
derivative (4a) in a single step. Accordingly, we treated the (2E)-methyl-
2-[(2-nitrophenoxy)methyl]-3-phenylacrylate (3a) with Fe=AcOH under
reflux conditions (2 h), which successfully provided the desired (E)-3-
benzylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (4a) in a single
operation with 60% yield (Scheme 2, Table 1).
Encouraged by this result, we prepared a variety of (2E)-methyl-2-
[(2-nitroaryloxy)methyl]-3-arylacrylates (3b–h) and successfully converted
them into the corresponding (E)-3-arylidene-2,3-dihydrobenzo[b][1,4]-
oxazepin-4(5H)-ones (4b–h) in 56–65% yields (Scheme 2). The results
are summarized in Table 1.
To extend the generality of this methodology, we also treated various
bromo compounds (1a–h) derived from the Baylis–Hillman adducts with
Table 1. Synthesis of (E)-3-arylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-ones
Allyl
bromide
Yield
Intermediatea,b (%)b
Yield
Mp
R
Producta,b
(%)b (0 ꢀC)
1a
1b
1c
1d
1e
1f
H
4-Me
4-OMe
3,4-Dimethoxy
2-CI
3a
3b
3c
3d
3e
3f
95
90
92
85
91
90
93
94
4a
4b
4c
4d
4e
4f
60 171–173
65 195–197
58 176–177
60 198–200
62 141–143
58 177–179
56 178–180
60 177–188
3-CI
4-CI
4-F
1g
1h
3g
3h
4g
4h
1
aAll the products gave satisfactory IR, H NMR (300, 400 MHz), 13C NMR
(75, 100 MHz), and mass spectraldata and elemental analyses.
bYields of the pure products (3a–h, 4a–h) obtained after column
chromatography.

(E)-3-Arylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-ones
1293
Scheme 3. Synthesis of (E)-3-arylidene-2,3-dihydro-7-methylbenzo[b][1,4]oxaze-
pin-4(5H)-ones.
4-methyl-2-nitrophenol (5) in the presence of K2CO3 in acetonitrile as
solvent under room temperature, which led to the required precursors
(2E)-methyl-2-[(4-methyl-2-nitroaryloxy)methyl]-3-arylacrylates (6a-h) in
excellent yields (85–95%) (Scheme 3). The precursors (6a–h) then were
Successfully converted into corresponding (E)-3-arylidene-2, 3-dihydro-
7-methylbenzo[b][1,4]oxazepin-4(5H)-ones (7a–h) in 62–71% yields
(Scheme 3). The results are summarized in Table 2.
CONCLUSION
In conclusion, we have successfully developed for the first time a simple
and novel protocol for facile transformation of Baylis–Hillman bro-
mides into an interesting class of heterocyclic frameworks containing
an important benzoxazepinone moiety via a reductive cyclization, thus
Table 2. Synthesis of (E)-3-arylidene-2,3-dihydro-7-methylbenzo[b][1,4]oxazepin-
4(5H)-ones
Ally
bromide
Yield
Intermediatea,b (%)b
Yield Mp
(%)b (0 ꢀC)
R
Producta,b
1a
1b
1c
1d
1e
1f
H
4-Me
4-OMe
3,4-Dimethoxy
2-CI
6a
6b
6c
6d
6e
6f
95
91
92
88
93
85
91
90
7a
7b
7c
7d
7e
7f
62 151–153
63 179–181
62 169–170
71 162–163
65 175–177
67 191–192
64 197–198
63 157–159
3-CI
4-CI
4-F
1g
1h
6g
6h
7g
7h
1
aAll the products gave satisfactory IR, H NMR (300, 400 MHz), 13C NMR
(75, 100 MHz), and mass spectraldata and elemental analyses.
bYields of the pure product (6a–h, 7a–h) obtained after column chromatography.

1294
M. Bakthadoss and G. Murugan
demonstrating the synthetic potential of the Baylis–Hillman adducts in
organic chemistry.
EXPERIMENTAL
General Methods
All melting points are uncorrected. Infrared (IR) spectra were recorded
on a Shimadzu Fourier transform infrared (FT-IR) 8000 instrument.
NMR spectra were recorded in CDCl3 by using tetramethyl silane (TMS)
as an internal standard on Bruker 300 and Varian 400 instruments. Mass
spectra were recorded on a Jeol DX-303 instrument. Column chromato-
graphy was performed on silica gel (100–200 mesh). All reactions were
monitored by thin-layer chromotography (TLC) using glass plates coated
with Acme silica gel (GF-254).
Typical Procedure for the Synthesis of Compound 3/6
A mixture of 2-nitrophenol=4-methyl 2-nitrophenol (4 mmol), trisub-
stituted allyl bromide (1) (4 mmol), and K2CO3 (4 mmol) in acetonitrile
(15 mL) was stirred at room temperature for 1 h. After the completion of
the reaction as indicated by TLC, the reaction mixture was concentrated.
The resulting crude mass was diluted with water (30 mL) and extracted
with ethyl acetate (3ꢁ30 mL). The combined organic layer obtained
was washed with brine (2ꢁ30 mL) and dried over anhydrous Na2SO4.
The organic layer was concentrated and purified by column chromato-
graphy on silica gel (Acme 100-200 mesh) using ethyl acetate–hexanes
(1:9) to afford the pure product 3=6 in very good yield as mentioned in
Tables 1 and 2.
Typical Procedure for the Synthesis of 4/7
A mixture of compound 3=6 (2 mmol) and iron powder (12 mmol) in
acetic acid (10 mL) was refluxed for 2 h. After the completion of the
reaction as indicated by TLC, the reaction mixture was filtered
through celite and concentrated under reduced pressure. The resulting
crude mass was diluted with water (20 mL) and extracted with ethyl
acetate (3ꢁ20 mL). The combined organic layer obtained was washed
with brine (2ꢁ20 mL) and dried over anhydrous Na2SO4. The organic
layer was concentrated and purified by column chromatography on

(E)-3-Arylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-ones
1295
silica gel (Acme 100–200 mesh) using ethyl acetate–hexanes (2:8) to
afford the pure final product 4=7 in good yield as mentioned in
Tables 1 and 2.
Spectral Data for Selected Compounds
(E)-Methyl 2-[(2-Nitrophenoxy)methyl]-3-phenylacrylate (3a)
Yield: (95%); mp 88–90 ꢀC (white solid). IR (KBr, cmꢂ1); 1731, 1645,
1
1523, 1353. H NMR (CDCl3): d ¼ 3.86 (s, 3H); 4.99 (s, 2H); 7.04–7.85
(m, 9H); 8.09 (s, 1H). 13C NMR (CDCl3): d ¼ 52.38, 64.87, 115.97,
120.96, 125.48, 126.24, 128.78, 129.72, 129.81, 133.96, 134.19, 140.67,
146.67, 151.92, 167.33. MS m=z 314 (Mþ þ 1). Anal. calcd. for
C17H15NO5: C, 65.52; H, 4.83; N, 4.47. Found: C, 65.46; H, 4.78;
N, 4.55.
(E)-3-Benzylidene-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (4a)
Yield: (60%); mp 171–173 ꢀC (pale yellow solid). IR (KBr, cmꢂ1): 3168,
1
1670, 1627. H NMR (CDCl3): d ¼ 4.90 (s, 2H); 6.98–7.98 (m, 9H); 8.01
(s, 1H); 9.45 (br s, 1H). 13C NMR (CDCl3): d ¼ 66.23, 120.83, 121.08,
123.51, 124.31, 128.65, 128.78, 129.11, 129.58, 130.32, 134.48, 141.40,
149.23, 169.79. MS m=z 252 (Mþ þ 1). Anal. calcd. for C16H13NO2: C,
76.48; H, 5.21; N, 5.57. Found: C, 76.50; H, 5.23; N, 5.60.
(E)-Methyl 2-[(4-Methyl-2-nitrophenoxy)methyl]-3-phenylacrylate (6a)
Yield: (95%); mp 92–94 ꢀC (white soild). IR (KBr, cmꢂ1): 1717, 1628,
1
1578, 1344. H NMR (CDCl3): d ¼ 2.33 (s, 3H); 3.84 (s, 3H); 4.95 (s,
2H); 7.09–7.62 (m, 8H); 8.07 (s, 1H). 13C NMR (CDCl3): d ¼ 20.23,
52.34, 65.10, 116.26, 125.55, 126.44, 128.75, 129.75, 131.08, 134.21,
134.58, 140.37, 146.49, 149.84, 167.38. MS m=z 328 (Mþ þ 1). Anal.
calcd. for C18H17NO5: C, 66.05; H, 5.23; N, 4.28. Found: C, 66.15; H,
5.30; N, 4.35.
(E)-3-Benzylidene-2,3-dihydro-7-methylbenzo[b][1,4]oxazepin-4(5H)-one
(7a)
Yield: (62%); mp 151–153 ꢀC (yellow solid). IR (KBr, cmꢂ1): 3205, 1661,
1
1626. H NMR (CDCl3): d ¼ 2.30 (s, 3H); 4.90 (s, 2H); 6.78–7.43 (m,

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M. Bakthadoss and G. Murugan
8H); 7.95 (s, 1H); 8.75 (br s, 1H). 13C NMR (CDCl3): d ¼ 20.59,
66.66, 120.66, 121.08, 125.05, 128.20, 128.63, 129.07, 129.58, 130.44,
133.23, 134.52, 141.23, 147.19, 169.43. MS m=z 266 (Mþ þ 1). Anal.
calcd. for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 76.78; H,
5.61; N, 5.40.
ACKNOWLEDGMENTS
We thank Department of Science and Technology (DST) (New Delhi) for
the financial support under the fast-track scheme. We also thank DST-
Fund for Improvement of Science & Technology (FIST) for the funding
program at the Department of Organic Chemistry, University of Madras,
Chennai.
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