An efficient synthesis of novel dibenzo-fused nine-membered oxacycles using a sequential Baylis-Hillman reaction and radical cyclization

Article abstract of DOI:10.1055/s-2007-1000827

A short and high yield synthetic route to novel dibenz[b,g]oxonins, one of which has been characterized by X-ray crystallography, has been developed based on a sequential Baylis-Hillman reaction and radical cyclization. The regioselective radical cyclization followed a 9-endo-trig pathway. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000827

94
PAPER
An Efficient Synthesis of Novel Dibenzo-Fused Nine-Membered Oxacycles
Using a Sequential Baylis–Hillman Reaction and Radical Cyclization
Synthesis of
N
o
i
vel
D
ib
r
enzo-Fu
t
sed N
i
h
ne-Membere
a
d Oxacycles Pada Majhi,a Arpita Neogi,a Soumen Ghosh,b Alok Kumar Mukherjee,b Madeleine Helliwell,c
Partha Chattopadhyay*a
a
Division of Chemistry, Indian Institute of Chemical Biology, Kolkata 700 032, India
Fax +91(33)24735197; E-mail: partha@iicb.res.in
Department of Physics, Jadavpur University, Kolkata 700 032, India
Department of Chemistry, University of Manchester, Manchester, M13 9PL, UK
b
c
Received 5 September 2007; revised 24 September 2007
closure by 1,4-addition, leading to the formation of the de-
Abstract: A short and high yield synthetic route to novel
dibenz[b,g]oxonins, one of which has been characterized by X-ray
crystallography, has been developed based on a sequential Baylis–
Hillman reaction and radical cyclization. The regioselective radical
cyclization followed a 9-endo-trig pathway.
sired ring system.8 We were particularly interested in uti-
lizing the Baylis–Hillman reaction, which is an atom-
economical C–C bond-forming reaction, which gives rise
to densely functionalized adducts9 that have been used as
starting materials for the regioselective preparation of
many heterocyclic compounds.9,10 Thus, starting from the
benzyloxy derivatives of substituted salicylaldehyde, suit-
able alkene substrates for the cyclization could become
accessible by the application of the Baylis–Hillman reac-
tion. In this communication we report a short and conve-
nient procedure for the synthesis of dibenz[b,g]oxonins
using this approach. This appears to be the first example
of the synthesis of this novel system utilizing the above
methodology.
Key words: dibenz[b,g]oxonin, radical cyclization, Baylis–Hill-
man reaction, medium-ring heterocycle, regioselective
The abundance of dibenzannulated medium-ring deriva-
tives in natural products,1 coupled with their pronounced
activity as strong central nervous system suppressants2
and application as cardioselective muscarinic antagonists3
continue to ensure that they are important synthetic tar-
gets. Although several approaches to the synthesis of
dibenzofused seven- and eight-membered-ring com-
pounds using ring-closing metathesis, palladium-induced
cyclization, or other methods have been reported in the lit-
erature, applications of these methodologies to the prepa-
ration of nine- and ten-membered-ring compounds are
scarce.4 Nine-membered dibenzoheterocycles are struc-
tural fragments of many biologically important natural
products5 and still continue to draw attention from syn-
thetic organic chemists. A few classical methods for the
synthesis of dibenzoxonins and azonines have been
reported6 but the yields are poor. Attempts4g to prepare
linearly fused dibenzoxonins using the Heck reaction
have, so far, failed. Thus, the development of a suitable
procedure for the synthesis of this ring system remains
challenging.
The starting materials 2a–h were prepared in 88–96%
yield by benzylation of commercially available salicyl-
aldehydes 1a–c (1.0 equiv) with substituted 2-bromo- or
2-iodobenzyl bromides (1.2 equiv) using potassium car-
bonate (5 equiv) in acetone (Table 1).
Subsequent Baylis–Hillman reactions of the aldehydes 2
were carried out with a variety of activated alkenes, which
showed that acrylonitrile was clearly superior to other ac-
tivated alkenes such as methyl or ethyl acrylate with re-
spect to the yield of 3 (Table 2, entries 9 and 10). The
reactions were thereafter performed with acrylonitrile in
the presence of 100 mol% of 1,4-diazabicyclo[2.2.2]oc-
tane. The use of a lesser amount of 1,4-diazabicyc-
lo[2.2.2]octane reduced the yield of the adducts 3. After
conducting the experiments with different solvent sys-
tems, viz. dioxane (no reaction), dioxane–water (10%
yield), and tetrahydrofuran–water (no reaction), the yield
was optimum using neat acrylonitrile. Usual workup and
chromatographic purification afforded the Baylis–Hill-
man adducts 3a–h in 70–82% yield (Table 2) together
with traces of unreacted aldehydes. Substrates 2f–h bear-
ing electron-donating groups (t-Bu or OMe) needed a
longer reaction time compared to the aldehydes 2a–e.
As a part of our longstanding interest in the synthesis of
medium-ring heterocycles1e we planned to synthesize
dibenzofused nine-membered-ring compounds by using
intramolecular radical cyclization. We had earlier report-
ed the successful preparation of benzannulated seven- and
eight-membered oxacycles through radical cyclization of
unsaturated alkenes,7 however, this method did not work
for the synthesis of nine-membered-ring compounds. We
reasoned that the presence of an electron-withdrawing
group conjugated to the alkene bond might help the ring
Intramolecular radical cyclizations were carried out by
dropwise addition of a benzene solution of tributyltin hy-
dride (1.5 equiv) and AIBN (5 mol%) to a refluxing ben-
zene solution of the alkenes 3a–h under a nitrogen
atmosphere. After separation of the tin compounds11 from
the reaction mixture, acetylation of the product followed
SYNTHESIS 2008, No. 1, pp 0094–0100
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Advanced online publication: 07.12.2007
DOI: 10.1055/s-2007-1000827; Art ID: P10407SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Novel Dibenzo-Fused Nine-Membered Oxacycles
95
Table 1 Alkylation of Salicylaldehyde Derivatives 1a–c
R5
X
Br
R4
CHO
R1
R2
R3
1a–c
CHO
OH
R1
R2
X
R5
R4
K2CO3, acetone
reflux, 3 h
O
R3
2a–h
Entry
Substrate
Product
2a
R1
H
R2
H
R3
H
R4
R5
X
Yielda (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1c
H
H
Br
Br
Br
Br
I
93
91
88
89
93
95
96
91
2b
H
H
H
OMe
OMe
OCH2O
H
H
2c
H
H
H
OMe
2d
H
H
H
2e
H
H
H
H
H
H
H
2f
t-Bu
H
t-Bu
H
H
H
Br
Br
I
2g
OMe
OMe
H
2h
H
H
H
a Yield of isolated product after silica gel chromatography.
by chromatography furnished the targeted tricyclic ethers
4a–e as the only isolable products in very good yields
(Table 3). The reaction is diastereospecific since we did
not encounter any other stereoisomer either by NMR anal-
ysis of the crude acetate mixture of the compounds or
upon purification by flash chromatography. No cyclized
product was obtained using the substrate 3f (Table 3, en-
try 6); instead we obtained a mixture of intractable prod-
ucts.
Table 2 Preparation of Baylis–Hillman Adducts 3a–ja
R
R
HO
R1
R2
X
R5
R4
2a–h
DABCO (100 mol%)
O
R3
3a–i
a–h R = CN; R1–R5 as in Table 1
i
j
R = CO2Me; R1 = R2 = R3 = R4 = R5 = H
R = CO2Et; R1 = R2 = R3 = R4 = R5 = H
Table 3 Synthesis of Dibenzannulated Ethers 4a–ea
AcO
CN
Entry
Substrate
2a
Time (h)
14
Product
3a
Yieldb (%)
R1
a. Bu3SnH, AIBN
1
2
81
74
76
74
82
72
76
77
09
3a–h
b. Ac2O, Py
R2
O
R5
2b
14
3b
3c
R3
R4
4a–e
3
2c
14
Entry
Substrate
Product
4a
Yieldb (%)
4
2d
14
3d
3e
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
76
76
70
70
83
5
2e
14
4b
6
2f
20
3f
4c
7
2g
26
3g
4d
8
2h
26
3h
3i
4a
9
2a
40
c
–
–
c
10
2a
40
3j
–
3g
3h
4e
74
79
a All reactions were performed at r.t.
b Yield of isolated product after silica gel chromatography.
c No reaction.
4e
a Bu3SnH was added very slowly over 3 h.
b Yield of isolated product after silica gel chromatography.
c No cyclized product.
Synthesis 2008, No. 1, 94–100 © Thieme Stuttgart · New York

96
T. P. Majhi et al.
PAPER
2-(2-Bromobenzyloxy)benzaldehyde (2a)
White crystalline solid; yield: 93%; mp 92 °C.
their poorly resolved spectra apparently arising due to the IR (KBr): 3067, 2860, 1680 cm–1.
The stereochemistry of most of the oxonin derivatives
could not be established by 1H NMR spectroscopy due to
conformational mobility of the nine-membered ring.12
However, the relative stereochemistry of 4b could be un-
equivocally determined by single crystal X-ray analysis13
(Figure 1), which clearly showed a synclinal orientation
of the acetoxy and cyanide groups about the C12–C13
bond. The conformation of the oxonin ring can be de-
scribed approximately as twist-boat. The stereochemistry
of the other products was assigned by analogy.
1H NMR (300 MHz, CDCl3): d = 5.26 (s, 2 H), 7.07 (t, J = 7.0 Hz,
2 H), 7.23 (m, 1 H), 7.36 (t, J = 7.4 Hz, 1 H), 7.58 (m, 3 H), 7.87 (d,
J = 7.6 Hz, 1 H), 10.59 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 69.7, 112.9, 121.1, 122.2, 125.0,
127.5, 128.5, 128.7, 129.5, 132.6, 135.2, 135.8, 160.4, 189.3.
MS (ESI+): m/z = 313, 315 (M + Na+, for 79Br, 81Br).
Anal. Calcd for C14H11BrO2: C, 57.76; H, 3.81. Found: C, 57.56; H,
3.69.
2-(2-Bromo-5-methoxybenzyloxy)benzaldehyde (2b)
White crystalline solid; yield: 91%; mp 90 °C.
IR (KBr): 3048, 2864, 1683 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.80 (s, 3 H), 5.20 (s, 2 H), 6.77
(dd, J = 2.7, 8.6 Hz, 1 H), 7.07 (m, 2 H), 7.15 (s, 1 H), 7.49 (d,
J = 8.8 Hz, 1 H), 7.56 (m, 1 H), 7.89 (d, J = 6.5 Hz, 1 H), 10.59 (s,
1 H).
13C NMR (150 MHz, CDCl3): d = 55.5, 69.8, 112.2, 113.1, 114.4,
115.1, 121.3, 125.2, 129.0, 133.3, 136.0, 136.3, 159.2, 160.5, 189.6.
MS (ESI+): m/z = 343, 345 (M + Na+, for 79Br, 81Br).
Anal. Calcd for C15H13BrO3: C, 56.10; H, 4.08. Found: C, 56.16; H,
4.17.
2-(2-Bromo-4,5-dimethoxybenzyloxy)benzaldehyde (2c)
Figure 1 ORTEP diagram of 4b with atom-numbering scheme
White solid; yield: 88%; mp 118 °C.
IR (KBr): 3067, 2871, 1687 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H), 3.89 (s, 3 H), 5.19
(s, 2 H), 7.08 (m, 4 H), 7.57 (m, 1 H), 7.86 (m, 1 H), 10.54 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 56.1, 56.2, 69.9, 111.8, 112.7,
113.2, 115.4, 121.2, 125.2, 127.2, 129.1, 135.9, 148.6, 149.4, 160.6,
189.6.
These studies showed that the cyclization preferred the 9-
endo-trig pathway in agreement with the general trend ob-
served in the radical cyclization of medium and large
rings, where endo-cyclization modes are favored,14 and
also due to the presence of the electron-withdrawing
group conjugated to the alkene bond.
MS (ESI+): m/z = 373, 375 (M + Na+, for 79Br, 81Br).
In summary, we have established a straightforward three-
step synthetic route to dibenzofused nine-membered oxa-
cycles using sequential Baylis–Hillman reaction and rad-
ical cyclization on salicylaldehyde derivatives. This
finding opens up the possibility of obtaining synthetically
challenging nine-membered dibenzoheterocycles incor-
porating nitrogen or sulfur heteroatom using the above
methodology.
Anal. Calcd for C16H15BrO4: C, 54.72; H, 4.31. Found: C, 54.61; H,
4.30.
2-[2-Bromo-4,5-(methylenedioxy)benzyloxy]benzaldehyde (2d)
White crystalline solid; yield: 89%; mp 134 °C.
IR (KBr): 3083, 2848, 1686 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.16 (s, 2 H), 6.00 (s, 2 H), 7.05
(m, 4 H), 7.55 (m, 1 H), 7.87 (m, 1 H), 10.55 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 69.8, 101.1, 108.6, 112.7, 113.0,
1H and 13C NMR spectra were recorded in a Bruker AM 300L or
Bruker Avance 600 MHz spectrometer using CDCl3 as solvent and
TMS as internal standard. Mass spectra were obtained using either
Jeol AX-500 or Micromass Q-Tofmicro spectrometers. IR spectra
were obtained using a Jasco FT/IR Model 410. TLC was performed
on pre-coated plates (0.25 mm, silica gel 60 F254). Column chroma-
tography and flash chromatography were carried out using commer-
cial grade silica gel (60–120 mesh or 230–400 mesh). Petroleum
ether (PE) used was the fraction with boiling range 60–80 °C.
121.1, 125.1, 128.3, 128.6, 135.8, 147.6, 148.2, 160.5, 189.4.
MS (ESI+): m/z = 357, 359 (M + Na+, for 79Br, 81Br).
Anal. Calcd for C15H11BrO4: C, 53.76; H, 3.31. Found: C, 53.63; H,
3.39.
2-(2-Iodobenzyloxy)benzaldehyde (2e)
White solid; yield: 93%; mp 82 °C.
IR (KBr): 3055, 2879, 1681 cm–1.
2-(Benzyloxy)benzaldehydes 2a–h; General Procedure
To a soln of 2-hydroxybenzaldehyde or its substituted analogues (1
mmol) in acetone, substituted 2-bromo- or 2-iodobenzyl bromide
(1.2 mmol) and anhyd K2CO3 (5 mmol) were added and the mixture
was heated at reflux for 3 h (TLC). After cooling K2CO3 was re-
moved by filtration and the filtrate was evaporated. Chromatogra-
phy (silica gel, CH2Cl2–PE) yielded 2a–h.
1H NMR (300 MHz, CDCl3): d = 5.16 (s, 2 H), 7.07 (m, 3 H), 7.40
(t, J = 7.6 Hz, 1 H), 7.56 (m, 2 H), 7.88 (m, 2 H), 10.59 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 74.1, 112.9, 121.1, 124.9, 127.5,
128.4, 128.5, 129.5, 129.7, 135.8, 138.0, 139.2, 160.4, 189.3.
MS (ESI+): m/z = 361 (M + Na+).
Anal. Calcd for C14H11IO2: C, 49.73; H, 3.28. Found: C, 49.62; H,
3.39.
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Synthesis of Novel Dibenzo-Fused Nine-Membered Oxacycles
97
2-(2-Bromobenzyloxy)-4,5-di-tert-butylbenzaldehyde (2f)
MS (ESI+): m/z = 366, 368 (M + Na+, for 79Br, 81Br).
White solid; yield: 95%; mp 152 °C.
IR (KBr): 2958, 2865, 1685 cm–1.
Anal. Calcd for C17H14BrNO2: C, 59.32; H, 4.10; N, 4.07. Found: C,
59.22; H, 4.13; N, 4.17.
1H NMR (300 MHz, CDCl3): d = 1.35 (s, 9 H), 1.44 (s, 9 H), 5.08
(s, 2 H), 7.23 (m, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.57 (d, J = 7.9 Hz,
1 H), 7.68 (d, J = 1.8 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.84 (d,
J = 7.6 Hz, 1 H), 10.25 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 30.9, 31.1, 34.7, 35.3, 79.2,
120.9, 124.1, 127.5, 127.7, 129.0, 129.2, 130.9, 132.4, 136.1, 143.0,
146.8, 159.3, 190.2.
2-{[2-(2-Bromo-5-methoxybenzyloxy)phenyl]hydroxymeth-
yl}acrylonitrile (3b)
Thick colorless oil; yield: 74%.
IR (neat): 3458, 3072, 2938, 2839, 2228, 1905, 1599 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.05 (s, 1 H), 3.78 (s, 3 H), 5.13
(s, 2 H), 5.61 (s, 1 H), 6.00 (s, 2 H), 6.77 (dd, J = 2.4, 8.5 Hz, 1 H),
6.94–7.07 (br, 3 H), 7.33 (m, 1 H), 7.40 (d, J = 7.4 Hz, 1 H), 7.84
(d, J = 8.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 55.5, 69.9, 70.3, 112.1, 112.7,
115.0, 115.3, 117.2, 121.7, 125.5, 127.3, 128.0, 129.9, 130.1, 133.5,
136.6, 155.4, 159.2.
MS (ESI+): m/z = 425, 427 (M + Na+ for 79Br, 81Br).
Anal. Calcd for C22H27BrO2: C, 65.51; H, 6.75. Found: C, 65.39; H,
6.67.
2-(2-Bromobenzyloxy)-3-methoxybenzaldehyde (2g)
White crystalline solid; yield: 96%; mp 86 °C.
MS (ESI+): m/z = 396, 398 (M + Na+, for 79Br, 81Br).
IR (KBr): 3088, 2874, 1692 cm–1.
Anal. Calcd for C18H16BrNO3: C, 57.77; H, 4.31; N, 3.74. Found: C,
57.65; H, 4.19; N, 3.82.
1H NMR (300 MHz, CDCl3): d = 3.94 (s, 3 H), 5.28 (s, 2 H), 7.19
(m, 3 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.41 (m, 1 H), 7.56 (m, 2 H),
10.32 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.9, 75.0, 117.9, 118.8, 123.3,
124.3, 127.4, 129.7, 130.0, 130.2, 132.6, 135.9, 150.7, 152.8, 190.0.
2-{[2-(2-Bromo-4,5-dimethoxybenzyloxy)phenyl]hydroxymeth-
yl}acrylonitrile (3c)
White solid; yield: 76%; mp 149 °C.
IR (KBr): 3487, 2939, 2227, 1599 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.06 (s, 3 H), 3.89 (s, 3 H), 5.11
(s, 2 H), 5.57 (s, 1 H), 5.97 (s, 1 H), 5.98 (s, 1 H), 6.96–7.07 (br, 4
H), 7.32–7.39 (m, 2 H).
MS (ESI+): m/z = 343, 345 (M + Na+, for 79Br, 81Br).
Anal. Calcd for C15H13BrO3: C, 56.10; H, 4.08. Found: C, 56.22; H,
3.98.
13C NMR (150 MHz, CDCl3): d = 56.1, 56.2, 69.9, 70.6, 112.1,
112.4, 113.4, 115.5, 117.2, 121.6, 125.5, 127.1, 127.2, 128.1, 129.8,
130.1, 148.6, 149.6, 155.6.
2-(2-Iodobenzyloxy)-3-methoxybenzaldehyde (2h)
White solid; yield: 91%; mp 99 °C.
IR (KBr): 3068, 2858, 1694 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.94 (s, 3 H), 5.23 (s, 2 H), 7.04
(dt, J = 1.6, 7.5 Hz, 1 H), 7.18 (m, 2 H), 7.40 (m, 2 H), 7.51 (dd,
J = 1.5, 7.6 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 10.31 (s, 1 H).
MS (ESI+): m/z = 426, 428 (M + Na+, for 79Br, 81Br).
Anal. Calcd for C19H18BrNO4: C, 56.45; H, 4.49; N, 3.46. Found: C,
56.64; H, 4.38; N, 3.52.
13C NMR (75 MHz, CDCl3): d = 56.0, 79.4, 98.5, 117.9, 118.9,
2-({2-[2-Bromo-4,5-(methylenedioxy)benzyloxy]phenyl}hy-
droxymethyl)acrylonitrile (3d)
Thick colorless oil; yield: 74%.
IR (neat): 3479, 2936, 2223, 1608 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.07 (s, 2 H), 5.57 (d, J = 6.2 Hz,
124.3, 128.3, 129.7, 129.8, 130.2, 139.1, 139.3, 150.7, 152.8, 190.1.
MS (ESI+): m/z = 391 (M + Na+).
Anal. Calcd for C15H13IO3: C, 48.93; H, 3.56. Found: C, 48.83; H,
3.43.
1 H), 5.99 (m, 4 H), 6.94 (m, 2 H), 7.07 (m, 2 H), 7.30–7.41 (br, 2
H).
13C NMR (150 MHz, CDCl3): d = 69.9, 70.5, 102.0, 109.5, 112.1,
112.9, 113.8, 117.2, 121.7, 125.5, 127.3, 128.1, 128.4, 129.9, 130.1,
147.6, 148.5, 155.5.
1-(2-Benzyloxyphenyl)prop-2-en-1-ols 3a–i; General Procedure
To the crude aldehyde 2a–h (1 equiv), DABCO (100 mol%), and
acrylonitrile (or methyl acrylate or ethyl acrylate) were added and
the mixture was stirred at r.t. for 14–16 h. On completion of the re-
action (TLC), the mixture was extracted with CH2Cl2 (3 × 15 mL).
The combined extracts were washed with H2O, dried (Na2SO4), and
concentrated under reduced pressure to afford a residue, which was
purified by flash chromatography [silica gel, 230–400 mesh,
CH2Cl2–PE] to furnish the corresponding Baylis–Hillman adducts
3a–h.
MS (ESI+): m/z = 410, 412 (M + Na+, for 79Br, 81Br).
Anal. Calcd for C18H14BrNO4: C, 55.69; H, 3.63; N, 3.61. Found: C,
55.64; H, 3.58; N, 3.52.
2-{Hydroxy[2-(2-iodobenzyloxy)phenyl]methyl}acrylonitrile
(3e)
2-{[2-(2-Bromobenzyloxy)phenyl]hydroxymethyl}acrylonitrile
(3a)
Thick colorless oil; yield: 81%.
Thick colorless oil; yield: 82%.
IR (neat): 3471, 2946, 2228, 1593 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.09 (s, 1 H), 5.11 (s, 2 H), 5.66
(d, J = 5.6 Hz, 1 H), 5.95 (s, 1 H), 6.97 (s, 1 H), 6.95 (d, J = 8.2 Hz,
1 H), 7.03 (m, 2 H), 7.34 (m, 4 H), 7.88 (d, J = 7.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 70.2, 74.2, 97.8, 112.1, 117.2,
121.7, 125.4, 127.3, 128.0, 128.5, 129.1, 130.0, 130.1, 138.3, 139.5,
155.4.
IR (neat): 3453, 3067, 2929, 2226, 1915, 1663, 1601 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.05 (d, J = 6.4 Hz, 1 H), 5.17 (s,
2 H), 5.60 (d, J = 6.4 Hz, 1 H), 5.97 (d, J = 5.8 Hz, 2 H), 6.97 (d,
J = 8.2 Hz, 1 H), 7.05 (t, J = 7.5 Hz, 1 H), 7.24 (m, 1 H), 7.31–7.43
(br, 4 H), 7.61 (d, J = 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 69.7, 111.9, 117.1, 121.5, 122.6,
125.4, 127.3, 127.6, 127.7, 129.3, 129.7, 129.8, 130.0, 132.7, 135.3,
155.2.
MS (ESI+): m/z = 414, 416 (M + Na+, for 79Br, 81Br).
Synthesis 2008, No. 1, 94–100 © Thieme Stuttgart · New York

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T. P. Majhi et al.
PAPER
Anal. Calcd for C17H14INO2: C, 52.19; H, 3.61; N, 3.58. Found: C,
52.24; H, 3.68; N, 3.71.
Radical Cyclization; General Procedure
To a gently refluxing (400-W lamp) soln of the alkene 3a–h (1
mmol) and AIBN (2.5 mol%) in anhyd benzene (120 mL) under N2
was added a soln of Bu3SnH (1.5 mmol) and AIBN (2.5 mol%) in
anhyd benzene (150 mL) slowly over a period of 3 h. On completion
of the addition, the mixture was heated at reflux for a further 3 h.
The solvent was removed under vacuum. The residue was dissolved
in Et2O (100 mL) and stirred vigorously for 10 h with sat. aq KF (75
mL). The white precipitate was filtered off and washed with Et2O.
After separation of the ether layer, the aqueous layer was extracted
with Et2O (6 × 25 mL). The combined organic layers were washed
with H2O (3 × 30 mL), dried (Na2SO4), and evaporated under re-
duced pressure to give a thick oil. This was dissolved in anhyd py-
ridine (2 mL) and freshly distilled Ac2O (0.2 mL) was added with
stirring at 0 °C. The stirring was continued at r.t. for 8 h. On com-
pletion of the reaction (TLC), the mixture was poured into crushed
ice and extracted with CH2Cl2. The crude acetate was purified by
flash chromatography [silica gel, 30–40% CH2Cl2–petroleum ether
(bp 60–80 °C)] to furnish 4a–e.
2-{[2-(2-Bromobenzyloxy)-4,5-di-tert-butylphenyl]hydroxy-
methyl}acrylonitrile (3f)
Thick colorless oil; yield: 72%.
IR (neat): 3476, 2941, 2221, 1585 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 9 H), 1.42 (s, 9 H), 5.05
(q-like, 2 H), 5.59 (s, 1 H), 5.95 (s, 1 H), 6.04 (m, 2 H), 7.24 (m, 1
H), 7.35 (s, 1 H), 7.44 (m, 2 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.83 (d,
J = 7.6 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 31.3, 31.4, 34.8, 35.6, 68.7, 76.1,
117.1, 120.6, 123.0, 125.7, 126.3, 127.4, 127.7, 128.9, 130.2, 132.3,
133.5, 136.7, 142.7, 147.3, 153.3.
MS (ESI+): m/z = 478, 480 (M + Na+, for 79Br, 81Br).
Anal. Calcd for C25H30BrNO2: C, 65.79; H, 6.63; N, 3.07. Found: C,
65.64; H, 6.68; N, 3.11.
2-{[2-(2-Bromobenzyloxy)-3-methoxyphenyl]hydroxymeth-
yl}acrylonitrile (3g)
Thick colorless oil; yield: 76%.
13-Acetoxy-6,11,12,13-tetrahydrodibenzo[b,g]oxonin-12-car-
bonitrile (4a)
White solid; yield: 76%; mp 174 °C.
IR (neat): 3468, 2952, 2221, 1606 cm–1.
IR (KBr): 3065, 2897, 2242, 1738, 1602 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.91 (s, 3 H), 5.16 (m, 2 H), 5.55
(d, J = 5.4 Hz, 1 H), 5.94 (s, 2 H), 6.97 (m, 2 H), 7.16 (m, 1 H), 7.21
(m, 1 H), 7.35 (m, 1 H), 7.49 (dd, J = 1.2, 7.5 Hz, 1 H), 7.61 (dd,
J = 1.2, 8.7 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.11 (s, 3 H), 2.54 (d, J = 14.2 Hz,
1 H), 3.12 (br, 1 H), 3.58 (br, 1 H), 4.87 (d, J = 12.3 Hz, 1 H), 5.34
(m, 1 H), 6.12 (d, J = 11.1 Hz, 1 H), 7.13 (m, 2 H), 7.30 (m, 5 H),
7.56 (d, J = 7.7 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 55.9, 74.0, 75.3, 113.0, 118.8,
119.3, 123.5, 124.9, 125.1, 127.7, 129.6, 130.0, 130.5, 131.4, 132.9,
136.7, 145.1, 152.4.
13C NMR (150 MHz, CDCl3): d = 21.0, 30.8, 40.3, 68.6, 118.9,
120.7, 124.6, 125.1, 127.1, 127.8, 129.2, 129.4, 130.4, 130.5, 132.0,
136.1, 168.8, 169.2.
MS (ESI+): m/z = 396, 398 (M + Na+, for 79Br, 81Br).
MS (ESI+): m/z = 330 (M + Na+).
Anal. Calcd for C18H16BrNO2: C, 57.77; H, 4.31; N, 3.74. Found: C,
57.59; H, 4.43; N, 3.75.
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.58. Found: C,
74.12; H, 5.51; N, 4.47.
2-{[2-(2-Iodobenzyloxy)-3-methoxyphenyl]hydroxymeth-
yl}acrylonitrile (3h)
Thick colorless oil; yield: 77%.
13-Acetoxy-8-methoxy-6,11,12,13-tetrahydrodibenzo[b,g]oxo-
nin-12-carbonitrile (4b)
White crystalline solid; yield: 76%; mp 216 °C.
IR (neat): 3487, 2933, 2231, 1599 cm–1.
IR (KBr): 3077, 2835, 2241, 1738, 1611 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.77 (br s, 1 H), 3.89 (s, 3 H), 5.08
(d, J = 12.2 Hz, 1 H), 5.16 (d, J = 12.2 Hz, 1 H), 5.55 (d, J = 4.3 Hz,
1 H), 5.94 (s, 2 H), 6.98 (m, 3 H), 7.13 (t, J = 7.9 Hz, 1 H), 7.38 (t,
J = 7.6 Hz, 1 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.11 (s, 3 H), 2.33–2.46 (br, 1 H),
3.05 (s, 1 H), 3.53 (s, 1 H), 3.83 (s, 3 H), 4.82 (br, 1 H), 5.28 (d,
J = 9.4 Hz, 1 H), 6.11 (d, J = 11.0 Hz, 1 H), 6.87 (br, 2 H), 7.30 (m,
4 H), 7.61 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 55.9, 69.6, 78.4, 98.0, 113.0,
117.1, 119.3, 124.9, 125.6, 128.4, 129.4, 129.7, 130.1, 132.9, 139.3,
139.8, 144.9, 152.4.
13C NMR (150 MHz, CDCl3): d = 21.0, 32.2, 40.5, 55.3, 66.8,
113.9, 114.7, 116.2, 116.6, 118.8, 120.8, 124.6, 127.2, 128.0, 130.6,
131.6, 133.2, 137.5, 158.9, 169.4.
MS (ESI+): m/z = 444, 446 (M + Na+, for 79Br, 81Br).
MS (ESI+): m/z = 360 (M + Na+).
Anal. Calcd for C18H16INO3: C, 51.32; H, 3.83; N, 3.33. Found: C,
51.37; H, 3.88; N, 3.25.
Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found: C,
71.12; H, 5.56; N, 4.17.
Methyl 2-{[2-(2-Bromobenzyloxy)phenyl]hydroxymethyl}acry-
late (3i)
Thick yellow oil; yield: 9%.
13-Acetoxy-8,9-dimethoxy-6,11,12,13-tetrahydrodiben-
zo[b,g]oxonin-12-carbonitrile (4c)
White solid; yield: 70%; mp 198 °C.
1H NMR (300 MHz, CDCl3): d = 3.73 (s, 3 H), 5.15 (s, 2 H), 5.72
(s, 1 H), 6.00 (d, J = 4.5 Hz, 1 H), 6.31 (s, 1 H), 6.86 (m, 3 H), 7.00
(t, J = 7.2 Hz, 1 H), 7.31 (m, 2 H), 7.44 (m, 1 H), 7.57 (d, J = 7.8
Hz, 1 H).
IR (KBr): 2956, 2835, 2243, 1743, 1604 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.11 (s, 3 H), 2.43 (br, 1 H), 2.96
(br, 1 H), 3.53 (s, 1 H), 3.90 (s, 3 H), 3.91 (s, 3 H), 4.75 (br, 1 H),
5.29 (br, 1 H), 6.04 (d, J = 11.4 Hz, 1 H), 6.48 (m, 2 H), 7.16 (m, 2
H), 7.42 (m, 1 H), 7.66 (s, 1 H).
MS (ESI+): m/z = 399, 401 (M + Na+, for 79Br, 81Br).
13C NMR (150 MHz, CDCl3): d = 21.0, 32.8, 40.5, 46.0, 46.1, 66.9,
68.4, 113.7, 113.9, 121.3, 124.8, 125.1, 127.2, 128.3, 130.5, 130.9,
147.9, 149.0, 149.5, 168.8, 169.4.
Anal. Calcd for C18H17BrO4: C, 57.31; H, 4.54. Found: C, 57.20; H,
4.32.
MS (ESI+): m/z = 390 (M + Na+).
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PAPER
Synthesis of Novel Dibenzo-Fused Nine-Membered Oxacycles
99
Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76; N, 3.81. Found: C,
68.34; H, 5.59; N, 3.77.
(4) For the synthesis of dibenzo heterocycles incorporating
seven-, eight-, and ten-membered rings, see: (a) Denieul,
M.-P.; Laursen, B.; Hazell, R.; Skrydstrup, T. J. Org. Chem.
2000, 65, 6052. (b) Margolis, B. J.; Swidorsky, J. J.; Rogers,
B. N. J. Org. Chem. 2003, 68, 644. (c) Beccalli, E. M.;
Broggini, G.; Paladino, G.; Zoni, C. Tetrahedron 2005, 61,
61. (d) Carril, M.; SanMartin, R.; Churruca, F.; Tellitu, I.;
Domínguez, E. Org. Lett. 2005, 7, 4785. (e)Yu, H.;Richey,
R. N.; Carson, M. W.; Coghlan, M. J. Org. Lett. 2006, 8,
1685. (f) Ouyang, X.; Kiselyov, A. S. Tetrahedron Lett.
1999, 40, 5827. (g) Arnold, L. A.; Luo, W.; Guy, R. K. Org.
Lett. 2004, 6, 3006. (h) Tocco, G.; Begala, M.; Delogu, G.;
Picciau, C.; Podda, G. Tetrahedron Lett. 2004, 45, 6909.
(i) Lu, S.-M.; Alper, H. J. Am. Chem. Soc. 2005, 127,
14776. (j) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E.
Org. Lett. 2005, 7, 2723. (k) Arnold, L.; Guy, R. K. Bioorg.
Med. Chem. Lett. 2006, 16, 5360. (l) Boyer, F.-D.; Hanna, I.
Org. Lett. 2007, 9, 715. (m) Furneaux, R. H.; Gainsford, G.
J.; Mason, J. M. J. Org. Chem. 2004, 69, 7665. (n) Wang,
E.-C.; Lin, Y.-L.; Chen, H.-M.; Lee, S.-R.; Kabuto, C.;
Takeuchi, Y. Heterocycles 2006, 68, 125.
13-Acetoxy-8,9-(methylenedioxy)-6,11,12,13-tetrahydrodiben-
zo[b,g]oxonin-12-carbonitrile (4d)
White crystalline solid; yield: 70%; mp 184 °C.
IR (KBr): 2896, 2244, 1744, 1603 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.12 (s, 3 H), 2.47 (d, J = 13.8 Hz,
1 H), 2.95 (dd, J = 14.4, 5.4 Hz, 1 H), 3.16 (ddd, J = 2.7, 5.4, 11.4
Hz, 1 H), 4.72 (d, J = 12.3 Hz, 1 H), 5.24 (d, J = 12.3 Hz, 1 H), 5.99
(s, 2 H), 6.10 (d, J = 11.1 Hz, 1 H), 6.78 (s, 1 H), 7.03 (s, 1 H), 7.12
(m, 2 H), 7.33 (m, 2 H).
13C NMR (150 MHz, CDCl3): d = 20.8, 31.0, 40.4, 68.5, 101.5,
110.8, 111.8, 118.5, 121.0, 124.7, 125.2, 128.0 129.5, 130.4, 130.7,
146.9, 148.1, 168.8.
MS (ESI+): m/z = 374 (M + Na+).
Anal. Calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99. Found: C,
68.22; H, 4.92; N, 4.06.
13-Acetoxy-4-methoxy-6,11,12,13-tetrahydrodibenzo[b,g]oxo-
nin-12-carbonitrile (4e)
White solid; yield: 74%; mp 176 °C.
IR (KBr): 2924, 2840, 2242, 1742, 1586 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.10 (s, 3 H), 2.53 (br, 1 H), 3.06
(br, 1 H), 3.58 (br, 1 H), 3.93 (s, 3 H), 4.76 (s, 1 H), 5.32 (d, J = 12.4
Hz, 1 H), 6.08 (br, 1 H), 7.06–7.55 (br, 7 H).
13C NMR (150 MHz, CDCl3): d = 21.0, 32.8, 40.2, 55.8, 55.9, 67.0,
112.5, 118.5, 124.8, 125.1, 127.8, 129.2, 129.4, 130.7, 130.8, 151.9,
152.1, 168.8, 169.4.
(5) (a) Uprety, H.; Bhakuni, D. S. Tetrahedron Lett. 1975, 16,
1201. (b) Brandt, S.; Marfat, A.; Helquist, P. Tetrahedron
Lett. 1979, 20, 2193. (c) Theuns, H. G.; Lenting, H. B. N.;
Salemink, C. A.; Tanaka, H.; Shibata, M.; Ito, K.; Lousberg,
R. J. J. C. Phytochemistry 1984, 23, 1157. (d) Bremner, J.
B.; Jaturonrusmee, W.; Engelhardt, L. M.; White, A. H.
Tetrahedron Lett. 1989, 30, 3213.
(6) For the synthesis of dibenzoxonins and azonins see:
(a) Elliott, I. W.; Sloan, M. J.; Tate, E. Tetrahedron 1996, 52,
8063. (b) Pala, G.; Crescenzi, E.; Bietti, G. Tetrahedron
1970, 26, 5789. (c) Kano, S.; Ogawa, T.; Yokomatsu, T.;
Komiyama, E.; Shibuya, S. Tetrahedron Lett. 1974, 15,
1063.
MS (ESI+): m/z = 360 (M + Na+).
Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found: C,
71.32; H, 5.58; N, 4.11.
(7) For our efforts in the synthesis of medium-ring heterocycles
using regioselective radical cyclization see:
(a) Chattopadhyay, P.; Mukherjee, M.; Ghosh, S. Chem.
Commun. 1997, 2139. (b) Nandi, A.; Mukhopadhyay, R.;
Chattopadhyay, P. J. Chem. Soc., Perkin Trans. 1 2001,
3346. (c) Nandi, A.; Chattopadhyay, P. Tetrahedron Lett.
2002, 43, 5977. (d) Neogi, A.; Majhi, T. P.; Ghoshal, N.;
Chattopadhyay, P. Tetrahedron 2005, 61, 9368.
Acknowledgement
We are grateful to Dr. B. Achari of our department for helpful sug-
gestions and CSIR for the award of Senior Research Fellowships (to
A.N. and T.M.). S.G. acknowledges Jadavpur University and the
government of West Bengal, India for a research fellowship.
(8) (a) Gibson, S. E.; Guillo, N.; Tozer, M. J. Chem. Commun.
1997, 637. (b) Neogi, A.; Majhi, T. P.; Ghosh, S.;
Mukherjee, A. K.; Chattopadhyay, P. Tetrahedron 2006, 62,
12003.
References
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Bastida, J. E.; Codina, C.; Campbell, W. E.; Mathee, S.
Phytochemistry 1995, 40, 307. (e) For our recent review on
the synthesis of benzannulated medium-ring heterocycles,
see: Majhi, T. P.; Achari, B.; Chattopadhyay, P.
Heterocycles 2007, 71, 1011.
(2) (a) Lehner, H.; Gauch, R.; Michaelis, W. Arzneim.-Forsch.
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(13) Crystal data of 4b: C20H19NO4, MW = 337.4, monoclinic,
space group = P21/n, a = 8.186 (5), b = 7.703 (5), c = 26.301
(5) Å, b = 98.59 (1)°, V = 1639.8 (1) Å3, z = 4,
F(000) = 712, T = 100 (2) K, m (MoKa) = 0.096 mm–1. A
total 3353 unique reflections were measured (qmax = 26.48°)
on a CCD area detector using graphite monochromatized
(3) Schmidt, G. US 3,406,168, 1968; Chem. Abstr. 1969, 70,
87866d.
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100
T. P. Majhi et al.
PAPER
GOF = 0.817 for all 3353 observed data. R1 = 0.0439 for
MoKa radiation (l = 0.71073 Å). The structure was solved
by direct methods with SHELXS-97 (Sheldrick, 1997) and
refined by full-matrix least-squares method on F2 using
SHELXL-97 (Sheldrick, 1997). The non-hydrogen atoms
were refined anisotropically and the hydrogen atoms located
from the difference Fourier maps were allowed to ride on
their parent atoms. Final R1 = 0.0878, wR2 = 0.0816 and
1918 data [Fo > 4s(Fo)]. CCDC 649417.
(14) As predicted by MO calculations and experimentally
corroborated by Beckwith and others (a) Beckwith, A. L. J.;
Schiesser, C. H. Tetrahedron 1985, 41, 3925. (b) Porter, N.
A.; Chang, V. H. T. J. Am. Chem. Soc. 1987, 109, 4976.
Synthesis 2008, No. 1, 94–100 © Thieme Stuttgart · New York