Synthesis of functionalized 1-benzoxepins by tandem ring-opening/ cyclocondensation of 3-bromoisoxazoles

Article abstract of DOI:10.1055/s-2004-837216

A series of functionalized 1-benzoxepins were synthesized by way of a tandem ring-opening/cyclocondensation of aldehyde-containing 3-bromoisoxazoles.

Full text of DOI:10.1055/s-2004-837216

LETTER
259
Synthesis of Functionalized 1-Benzoxepins by Tandem Ring-Opening/Cyclo-
condensation of 3-Bromoisoxazoles
F
unctionalized 1-Benz
a
oxepins rtin G. Kociolek,* Nicholas G. Straub, Jolene V. Schuster
Penn State Erie, The Behrend College, School of Science, Erie, PA 16563, USA
Fax +1(814)8986213; E-mail: mgk5@psu.edu
Received 15 October 2004
bonyl or ferrous chloride tetrahydrate (Scheme 1).5 These
Abstract: A series of functionalized 1-benzoxepins were synthe-
sized by way of a tandem ring-opening/cyclocondensation of alde-
hyde-containing 3-bromoisoxazoles.
isoxazoles can be synthesized in good yields from the
corresponding alkynes 4 and dibromoformaldoxime and
have shown stability to a variety of reagents, making them
versatile synthetic intermediates.6
Key words: benzoxepin, isoxazoles, reductive ring-opening, fer-
rous chloride, cyclocondensation
O
O
R
i
ii
N
R
H
CN
The construction of heterocycles occupies a central place
in the synthesis of biologically interesting natural and un-
natural products. In particular, interest in the synthesis of
seven-membered oxacycles has steadily increased, in part
due to their occurrence in a variety of natural and unnatu-
ral biologically active compounds.1 An array of different
methods have been employed for synthesis of this class
heterocycles, these include reactions driven by anions,
cations, radicals as well as metal-mediated ring-closures.2
Of particular interest in our group are a number of bio-
logically active compounds containing the seven-mem-
bered 2,3,4,5-tetrahydro-1-benzoxepin (1) ring skeleton.
These natural products include pterulone (2) and related
compounds,3 which demonstrate antifungal and ubiqui-
none oxidoreductase inhibiting properties, as well as heli-
annuol C (3) (Figure 1).4 Herein, we would like to report
our initial investigations into the synthesis of the 1-benz-
oxepin ring system by way of a tandem ring-opening/
cyclocondensation of 3-bromoisoxazoles.
R
Br
4
6
5
Scheme 1 Reagents and conditions: i) Br2CNOH, NaHCO3,
CH2Cl2, r.t.; ii) FeCl2·4H2O, MeCN, r.t.
b-Cyanoketones have been shown to be useful synthetic
precursors, as they readily undergo a variety of conden-
sation reactions. With both our ring-opening and the reac-
tivity of b-cyanoketones in mind, we envisioned the
possibility of a tandem ring-opening/cyclocondensation
sequence as shown in Figure 2. Ring-opening of the bro-
moisoxazole derivative 7, substituted with a carbonyl
tether, would initially give the b-ketonitrile 8. This b-ke-
tonitrile could then undergo an intramolecular condensa-
tion to give hydroxyketone 9, which would readily
undergo dehydration to give the cyclic unsaturated cyano-
ketone 10. Unsaturated cyanoketones of this type have
been shown to be versatile synthetic intermediates, as they
readily undergo [4+2] cycloadditions7 and Michael addi-
tion/oxidative cyclization.8
Recently, we demonstrated that 3-bromoisoxazoles 5 can
be reductively opened to give b-ketonitriles 6 in good to
moderate yields by treatment with molybdenum hexacar-
OH
CN
O
O
N
CN
O
O
O
Br
8
7
H
O
H
H
1
O
O
O
CN
CN
OH
HO
Cl
OH
H
H3C
O
O
H
9
2
3
10
Figure 1 2,3,4,5-Tetrahydro-1-benzoxepin (1) and related natural
products, pterlulone (2) and heliannuol C (3).
Figure 2 Tandem ring-opening/cyclocondensation sequence.
The use of intramolecular condensations of activated
methylene compounds to construct carbocycles and
heterocycles has been previously reported. The ozonoly-
sis of unsaturated ketonitriles have been shown to give
SYNLETT 2005, No. 2, pp 0259–0262
Advanced online publication: 17.12.2004
DOI: 10.1055/s-2004-837216; Art ID: S10204ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
2.
2
0
0
5

260
M. G. Kociolek et al.
LETTER
a-cyanoalkenones, by way of the aldehyde intermediate.9 Attempts to apply this tandem reaction sequence to a
Similarly, the titanium-mediated intramolecular conden- ketone derivative 15a, as well as compounds with longer
sation between b-ketoesters and acetals has been report- tethers, 15b and 15c, proved unsuccessful. In the case of
ed.10
15a, the isoxazole opened cleanly giving ketonitrile 16a
in 70% yield, however, the condensation failed to take
place under the reaction conditions. In the case of 15b and
15c, a mixture of products was formed, NMR analysis in-
dicated the presence of the ketonitriles 16b or 16c, but
none of the expected eight- or nine-membered cyclic
ethers were observed (Scheme 3).
With our interest in the benzoxepin ring system in mind,
we investigated the application of this tandem methodol-
ogy to their synthesis. The synthesis of the desired 3-bro-
moisoxazole precursors was accomplished in two steps
from the appropriately substituted salicylaldehydes. Ini-
tially, salicylaldehyde (11) was alkylated with a propargyl
tosylate followed by reaction of resulting alkyne 12 with
dibromoformaldoxime to give the desired 3-bromoisox-
azole 13 in 86% yield. The tandem ring-opening/cyclo-
condensation sequence was then facilitated by treatment
of the isoxazoles with ferrous chloride tetrahydrate to give
4-cyano-1-benzoxepin-3(2H)-one (14) in 76% yield
(Scheme 2). Attempts to facilitate this tandem reaction
with Mo(CO)6, produced a mixture of products, the major
being the ring-opened b-ketonitrile, with no evidence for
the 1-benzoxepin.
O
O
i
R
R
X
O
CN
O
N
O
n
15
16
O
Br
a R = CH3; n = 1
b R = H; n = 2
c R = H; n = 3
Scheme 3 Reagents and conditions: i) FeCl2·4H2O, MeCN, r.t.
O
O
In conclusion, we have demonstrated the facile synthesis
of the 2,3-dihydroxy-1-benzoxepin ring system from sali-
cylaldehyde derivatives, by way of a novel tandem ring-
opening/cyclocondensation of 3-bromoisoxazoles. The
versatility of this method is demonstrated by the synthesis
of a number of substituted benzoxepin derivatives. The
high degree of functionality in this unsaturated cyano-
ketone ring makes these compounds ideal precursors to
highly functionalized benzoxepins. In addition, this short
synthetic sequence has the advantage of starting with
readily available salicylaldehyde derivatives. Further in-
vestigations will focus on the application of this method-
ology to natural products containing this ring system as
well as applying it to carbocycles and other heterocyclic
ring systems.
H
i
H
OH
O
ii
12
11
O
CN
H
iii
O
O
O
N
O
14
13
Br
Scheme 2 Reagents and conditions: i) propargyl tosylate, K2CO3,
DMF, r.t.; ii) Br2CNOH, K2CO3, CH2Cl2, r.t.; iii) FeCl2·4H2O,
MeCN, r.t.
A series of bromoisoxazole precursors were synthesized
as described above starting with substituted salicylalde-
hydes and the appropriate propargyl tosylates.11 With the
exception of 12b, the propargyl ethers 12a–f have been
previously reported.12 The compounds were then subject-
ed to the ring-opening conditions with ferrous chloride,
the results of which are shown in Table 1.13 All the
bromoisoxazoles and 1-benzoxepins gave satisfactory IR,
1H NMR and elemental analysis.
Acknowledgment
Thanks to Penn State Erie, The Behrend College and the School of
Science for start-up funds for MGK as well as undergraduate re-
search fellowships for both NGS and JVS.
References
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yields.
Synlett 2005, No. 2, 259–262 © Thieme Stuttgart · New York

LETTER
Functionalized 1-Benzoxepins
261
Table 1 Synthesis of 3-Bromoisoxazoles 13 and Substituted Benzoxepins 14
Entry
Bromoisoxazole 13/Benzoxepin 14
Yield of 13 (%)
Yield of 14 (%)
a
86
76
O
CN
H
O
O
O
N
O
Br
b
c
83
85
67
82
O
O
O
O
CN
H
O
O
N
O
Br
O
O
CN
H
O
O
N
O
Br
d
e
f
78
82
79
70
70
65
O
CN
Br
Br
H
O
O
O
N
O
Br
O
CN
H
O
O
O
O
N
O
Br
CN
H
O
O
O
N
O
Br
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Synlett 2005, No. 2, 259–262 © Thieme Stuttgart · New York

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M. G. Kociolek et al.
LETTER
Sugai, T.; Nishiyama, S. Synlett 2003, 411. (k) Macias, F.
A.; Chinchilla, D.; Molinillo, J. M. G.; Marin, D.; Varela, R.
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54.24; H, 3.03; N, 4.22. Found: C, 53.96; H, 3.15; N, 4.19.
Compound 13d: white solid; mp 119–120 °C. IR (KBr):
3146, 1687, 1589 cm–1. 1H NMR (400 MHz, CDCl3):
d = 10.38 (s, 1 H), 7.95 (d, J = 2.3 Hz, 1 H), 7.66 (dd,
J = 2.3, 9.2 Hz, 1 H), 6.92 (d, J = 2.3 Hz, 1 H), 6.48 (s, 1 H),
5.27 (s, 2 H). Anal. Calcd for C11H7Br2NO3: C, 36.60; H,
1.95; N, 3.88. Found: C, 36.72; H, 2.03; N, 3.88.
Compound 13e: colorless oil. IR (KBr): 3129, 1687, 1598
cm–1. 1H NMR (400 MHz, CDCl3): d = 10.49 (s, 1 H), 7.93–
6.90 (m, 4 H), 6.36 (s, 1 H), 5.62 (q, J = 6.7 Hz, 1 H), 1.78
(d, J = 6.7 Hz, 3 H). Anal. Calcd for C12H10BrNO3: C, 48.67;
H, 3.40; N, 4.73. Found: C, 48.74; H, 3.50; N, 4.75.
Compound 13f: Colorless oil. IR (KBr): 3126, 1686, 1597
cm–1. 1H NMR (400 MHz, CDCl3): d = 10.44 (s, 1 H), 7.92–
6.98 (m, 4 H), 6.42 (s, 1 H), 1.82 (s, 6 H). Anal. Calcd for
C13H12BrNO3: C, 50.34; H, 3.90; N, 4.52. Found: C, 50.16;
H, 4.16; N, 4.77.
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(13) Typical Procedure:
(11) Typical Procedure:
Propargyl tosylate (2.10 g, 10 mmol) and salicylaldehyde
(11, 1.05 g, 10 mmol) were dissolved in dry DMF (15 mL)
at r.t. K2CO3 (2.76 g, 20 mmol) was added and the reaction
stirred at r.t. for 18 h. The reaction was poured into H2O (50
mL) and extracted with Et2O (3 × 25 mL). The combined
ether layers were dried (MgSO4) and evaporated giving
propargyl ether 12a as a white solid (1.36 g, 85%), which
gave satisfactory 1H NMR data and was used without further
purification.
Bromoisoxazole 13 (0.28 g, 1 mmol) was dissolved in
MeCN (25 mL). Nitrogen was bubbled through the solution
for 15 min after which FeCl2·4H2O (0.50 g, 2.5 mmol) was
added and stirred at r.t. under nitrogen for 18 h. The reaction
was then filtered through Celite and evaporated; the residue
was purified by column chromatography (silica gel;
hexanes–EtOAc) to give 14 as a yellow solid (0.14 g, 76%).
Compound 14a: yellow solid; mp 162–163 °C. IR (KBr):
2227, 1676, 1603, 1559 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.98 (s, 1 H), 7.15–7.60 (m, 4 H), 4.64 (s, 2 H). Anal.
Calcd for C11H7NO2: C, 71.35; H, 3.81; N, 7.56. Found: C,
71.63; H, 3.92; N, 7.49.
Compound 14b: yellow solid; mp 186–187 °C. IR (KBr):
2225, 1677, 1601, 1565 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.99–8.25 (m, 3 H), 7.31 (d, J = 9.2 Hz, 1 H), 4.71 (s, 1
H), 2.63 (s, 3 H). Anal. Calcd for C13H9NO3: C, 68.72; H,
3.99; N, 6.16. Found: C, 68.60; H, 4.18; N, 6.14.
Compound 12b previously unreported: 1H NMR (400 MHz,
CDCl3): d = 10.51 (s, 1 H), 8.43 (d, J = 2.2 Hz, 1 H), 8.25
(dd, J = 2.2, 9.1 Hz, 1 H), 7.21 (d, J = 9.1 Hz, 1 H), 4.92 (d,
J = 2.1 Hz, 2 H), 2.60 (m, 4 H).
Compound 12a (1.36 g, 8.5 mmol) was dissolved in CH2Cl2
(20 mL) and K2CO3 (42.5 mmol) was added.
Dibromoformaldoxime (1.72 g, 8.5 mmol) dissolved in
CH2Cl2 (30 mL) was added dropwise over 20 h via syringe
pump. The reaction was poured into 1 M HCl (100 mL) and
the layers separated. The aqueous layer was extracted with
additional CH2Cl2 (50 mL) and the combined organic layers
dried (Na2SO4) and evaporated leaving a yellow oil which
was purified by column chromatography (silica gel;
hexanes–EtOAc) giving 13a as a light yellow solid (2.06 g,
86% yield).
Compound 14c: yellow solid; mp 150 °C (sub). IR (KBr):
2224, 1679, 1616, 1591, 1554 cm–1. 1H NMR (400 MHz,
CDCl3): d = 8.62 (s, 1 H), 7.26–8.13 (m, 6 H), 4.71 (s, 2 H).
Anal. Calcd for C15H9NO2: C, 76.59; H, 3.86; N, 5.95.
Found: C, 76.17; H, 4.07; N, 6.02.
Compound 13a: light yellow solid; mp 95–96 °C. IR (KBr):
3139, 1688, 1597 cm–1. 1H NMR (400 MHz, CDCl3):
d = 10.44 (s, 1 H), 7.92–6.97 (m, 4 H), 6.53 (s, 1 H), 5.30 (s,
2 H). Anal. Calcd for C11H8BrNO3: C, 46.84; H, 2.86; N,
4.97. Found: C, 46.95; H, 2.99; N, 4.89.
Compound 14d: yellow solid; mp 120–122 °C. IR (KBr):
2225, 1682, 1599, 1550 cm–1. 1H NMR (400 MHz, CD3CN):
d = 7.75 (s, 1 H), 7.34–7.53 (m, 2 H), 6.89 (d, J = 9.1 Hz, 1
H), 4.41 (s, 2 H). Anal. Calcd for C11H6BrNO2: C, 50.03; H,
2.29; N, 5.30. Found: C, 49.71; H, 2.41; N, 5.23.
Compound 13b: white solid; mp 144–145 °C. IR (KBr):
3138, 1692, 1669, 1594 cm–1. 1H NMR (400 MHz, CDCl3):
d = 10.47 (s, 1 H), 8.43 (d, J = 2.2 Hz, 1 H), 8.25 (dd,
J = 2.2, 9.1 Hz, 1 H), 7.21 (d, J = 9.1 Hz, 1 H), 6.55 (s, 1 H),
5.40 (s, 2 H), 2.61 (s, 3 H). Anal. Calcd for C13H10BrNO4: C,
48.17; H, 3.11; N, 4.32. Found: C, 47.90; H, 3.20; N, 4.34.
Compound 13c: white solid; mp 147–149 °C. IR (KBr):
3153, 1665, 1619, 1592 cm–1. 1H NMR (400 MHz, CDCl3):
d = 10.80 (s, 1 H), 9.25–9.09 (m, 1 H), 8.19–7.28 (m, 5 H),
6.64 (s, 1 H), 5.41 (s, 2 H). Anal. Calcd for C15H10BrNO3: C,
Compound 14e: yellow solid; mp 130–131 °C. IR (KBr):
2226, 1687, 1604, 1560 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.85 (s, 1 H), 7.15–7.60 (m, 4 H), 4.45 (q, J = 6.7 Hz, 1
H), 1.56 (d, J = 6.7 Hz, 3 H). Anal. Calcd for C12H9NO2: C,
72.35; H, 4.55; N, 7.03. Found: C, 71.98; H, 4.61; N, 6.95.
Compound 14f: yellow solid; mp 105–106 °C. IR (KBr):
2228, 1674, 1604, 1563 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.84 (s, 1 H), 7.08–7.61 (m, 4 H), 1.42 (s, 6 H). Anal.
Calcd for C13H11NO2: C, 73.22; H, 5.20; N, 6.57. Found: C,
73.10; H, 5.21; N, 6.53.
Synlett 2005, No. 2, 259–262 © Thieme Stuttgart · New York