Synthesis of benzodioxepanes

Article abstract of DOI:10.1016/j.tet.2012.05.063

Four benzodioxepanes 1a-1d were prepared from reaction of 4-methoxy-3-hydroxybenzaldehyde 4 via a series of reasonable transformations, including the regioselective PhBCl₂-mediated double allylation of 4, one-pot combination of ring-closing met

Full text of DOI:10.1016/j.tet.2012.05.063

Tetrahedron 68 (2012) 6224e6230
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of benzodioxepanes
*
Meng-Yang Chang , Ming-Hao Wu, Tein-Wei Lee
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Four benzodioxepanes 1ae1d were prepared from reaction of 4-methoxy-3-hydroxybenzaldehyde 4 via
a series of reasonable transformations, including the regioselective PhBCl2-mediated double allylation of
4, one-pot combination of ring-closing metathesis of skeleton 3 and BaeyereVilliger reaction, O-allyla-
tion of skeleton 2, Claisen rearrangement of skeleton 5, and one-pot combination of ring-closing me-
tathesis and hydrogenation.
Received 24 February 2012
Received in revised form 13 May 2012
Accepted 18 May 2012
Available online 26 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzodioxapane
ortho-Metalation
Ring-closing metathesis
BaeyereVilliger reaction
Claisen rearrangement
O-Allylation
1. Introduction
involvement of one methyl group, we think that the skeleton 1
should be carried out by the ring expansion of pyranobenzopyran
The pyranochromenes with polyoxygenated benzofused tri-
cyclic ring system, along with related structures (e.g., clusiaphe-
none, octandrenolone, flemiculosin) represent the structural motifs
of pyranobenzopyrans (Fig.1).1,2 The cyclic system incorporates two
rings connected by a fused ring that contains a benzene ring ad-
jacent to the ring junction. The skeleton is one of the important
classes of heterocycles with a wide range of biological and phar-
macological properties, and has attracted considerable interest in
organic and natural product syntheses.3 In order to extend this
tricyclic ring system from [6.6.6] to [7.6.7] ring size, the benzene
ring with two fused oxepanes is further studied. By the
skeleton with two geminal dimethyl groups. However, there is no
example for synthesizing the skeleton of 1,2,4-trioxygenated ben-
zodioxepanes 1.
In this article, we report a straightforward route for synthesizing
the novel skeleton 1 as shown in Scheme 1, whichconsists of a PhBCl2-
mediated double allylation of 4-methoxy-3-hydroxybenzaldehyde 4
with LDA, one-pot combination of ring-closing metathesis of diallyl
compound 3, followed by the BaeyereVilliger reaction of the resulting
benzoxpane, hydrogenation of skeleton 2, O-allylation, Claisen rear-
rangement, O-allylation of the resulting allyl product followed by one-
pot ring-closing metathesis and hydrogenation.
OMe
2
OH
O
OH
1
O
P
OMe
OMe
OH
R
1
R
2
O
O
hydrogenation, O-allylation,
O
O
O
O
4
O
R
1
R
1
R
2
Claisen reaction and
one-pot RCM/hydrogenation
= H, Me;
= H, Me;
= H, Me
R
3
O
R
R
R
pyranochromene P = Ph, clusiaphenone
P = Me, octandrenolone
P = (E)-CH=CHPh, flemiculosin
benzodioxepane 1
1
2
3
1
2
R
3
OMe
R
1
OMe
CHO
one-pot RCM/
Baeyer-Villiger reaction
Fig. 1. Structures of pyranochromenes and benzodioxepanes 1.
O
OH
double allylation
CHO
3
4
* Corresponding author. Tel.: þ886
7 3121101x2220; e-mail addresses:
mychang@kmu.edu.tw, mychang624@yahoo.com.tw (M.-Y. Chang).
Scheme 1. Retrosynthetic route of skeleton 1.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.063

M.-Y. Chang et al. / Tetrahedron 68 (2012) 6224e6230
6225
2. Results and discussion
Wang reported that a general synthesis of benzofused oxepane
via a sequential Claisen rearrangement and ring-closing metathesis
constituted the key route.4 Herein, a more convenient route for
synthesizing benzo[b]oxepane skeleton was the PhBCl2-mediated
double allylation of 4-methoxy-3-hydroxybenzaldehyde (4) with
LDA, as shown in Scheme 2. To initiate our work, the directed ortho-
metalation of 4 was further studied (Equation 1).5,6
The regioselective PhBCl2-mediated double allylation of 4 with
LDA (3.0 equiv) and allyl bromide provided intermediate A via the
possible boron complex chelated intermediate. Then, diallyl 3a
(72%) or 3b (47%) was the yield, respectively, obtained by treatment
of the resulting B with another allyl bromide. The LDA should ini-
tiate the generated A with the carbinolamine oxide state so that the
ortho C2-metalation can proceed.5h The C2-allylation was regiose-
lectively formed, and then intermediate B was further transformed
into skeleton 3 via the C3-O-allylation.
Fig. 2. X-Ray structure of 2c.
In another way, different additive could be employed as a che-
lating reagent for the double allylation of 4 with LDA (3.0 equiv) and
allyl bromide under -78 ꢀC condition, such as TMEDA5a,b or TMEDA/
Table 1
Double allylation of 4 with LDA and allyl bromidea
5g
MgBr2 as shown in Table 1. After screening four reaction condi-
Entry
Reagents (equiv), solvent, temp
Yieldb
tions, we found that PhBCl2 could provide a higher yield (72%) than
the others at ꢁ78 ꢀC (entries 1w3) in the synthesis of 3a.
1
2
3
4
TMEDA (1.0), THF, ꢁ78 ꢀC
12%
38%
40%
72%
TMEDA (1.0), MgBr2 (1.0), THF, ꢁ78 ꢀC
TMEDA (1.0), PhBCl2 (1.0), THF, ꢁ78 ꢀC
PhBCl2 (1.0), THF, ꢁ78 ꢀC
To construct the benzo[b]oxepane skeleton 5, 3a or 3b with the
diallyl group was first subjected to an intramolecular ring-closing
metathesis by using Grubbs second-generation catalyst in CH2Cl2
according to the reported condition.7 Next, the BaeyereVilliger
reaction of the resulting benzaldehyde bearing a seven-member
ring with K2CO3 and m-chloroperoxybenzoic acid (MCPBA) in
CH2Cl2 afforded 2a or 2b. Because CH2Cl2 could be used as the same
reaction solvent for ring-closing metathesis and BaeyereVilliger
reaction, a combination of the two steps was required.8 In com-
paring the two routes, we found that the one-pot reaction provided
a higher yield (58% for 2a; 49% for 2b) than did the two-step re-
action process (40% for 2a; 36% for 2b). Notably, the one-pot
a
The reactions were run on a 1.0 mmol scale with 4.
The product was >95% pure as determined by 1H NMR analysis.
b
methodology provided a rapid process to generate the ring sys-
tem of benzo[b]oxepene.
In particular, 2c could be isolated with 16% yield by treatment of
2b with the one-pot reaction condition (Equation 2). The structure
of tricyclic compound 2c was determined using single-crystal X-ray
analysis (Fig. 2).9 For the one-pot reaction condition of 2a, the
isolation of the epoxide product was not observed. It was believed
OMe
OMe
3
OMe
R
OMe
1
O
O
then
3
OH
O
Br
LDA, PhBCl ,
2
(1.0 eq)
(1.0 eq)
Grubbs II
CH Cl
K CO , MCPBA
2
R
R
1
1
R
1
2
then
Br
2
2
CHO
4
CHO
CHO
OH
2a, R = H (58%)
3a, R = H
1
1
3b, R = Me
2b, R = Me (49%)
1
1
OMe
OMe
O
O
O
H , Pd/C, EtOAc
2
K CO , acetone
2 3
decalin
R
R
1
1
Br
R
2
then
OH
R
2
5a, R = H (92%)
6a, R = R = H (93%)
1
1
2
5b, R = Me (68%)
6b, R = Me, R = H (95%)
1
1
2
6c, R = H, R = Me (89%)
1
2
OMe
O
OMe
OMe
O
Grubbs II,
O
O
K CO , acetone
Pd/C, CH Cl ,
2
3
2
2
R
1
R
1
R
1
R
2
R
R
2
2
R
3
then
then H
2
OH
7a, R = R = H (77%)
Br
O
R
R
3
1
2
3
7b, R = H, R = Me (65%)
1
2
8a, R = R = R = H (94%)
8b, R = R = H, R = Me (88%)
1a, R = R = R = H (82%)
1 2 3
1
2
3
7c, R = Me, R = H (74%)
1
2
1b, R = R = H, R = Me (76%) X-Ray
1
3
2
1 3 2
8c, R = Me, R = R = H (89%)
1c, R = Me, R = R = H (80%)
1 2 3
1
2
3
8d, R = R = Me, R = H (82%)
1d, R = R = Me, R = H (78%)
1
3
2
1 3 2
Scheme 2. Synthesis of benzodioxepanes 1.

6226
M.-Y. Chang et al. / Tetrahedron 68 (2012) 6224e6230
activated carbon; hydrogen was then added into the mixture. By
this addition sequence, 1ae1d were synthesized via the one-pot
combination reaction of ring-closing metathesis and hydrogena-
tion. The structure of 1b was constructed using single-crystal X-ray
analysis (Fig. 3).9 Compound 1d was isolated in two inseparable
isomers.
OMe
OMe
one-pot RCM and
Baeyer-Villiger reaction
O
O
Me
Me
O
3b
+
OH
OH
2b (49%)
2c (16%) X-Ray
hydrogenation
OMe
O
OMe
OH
Me
Me
+
Me
OH
5b (68%)
OH
5c (20%)
Fig. 3. X-Ray structure of 1b.
Equation 2. Reactions of 3b.
OMe
OMe
O
Given the above results, we envisioned that 1e should be pre-
pared by this three-step route as shown in Scheme 3. According to
the protocol, diallyl 8e was produced via the reaction sequence of
O-allylation of 2a (86%), Claisen rearrangement of 6d (58%) and O-
allylation of 7d (80%). Generally, the overall three-step yield of 8e
was poorer than 8ae8d; however, attempts to generate 1e failed
under the ring-closing metathesis reaction conditions.11 Among the
complex mixture, de-O-allyl skeleton 8f with the E/Z isomerized
compounds were isolated in a 56% yield.12 After changing the re-
action temperature and solvent, the complex mixture was still
isolated. This study showed that the olefinic motif of 2a should be
a key factor affecting the reactivity of ring-closing metathesis of 8e.
OH
Ph
Br
O
B
PhBCl ,
2
N(i-Pr)
2
Li
LDA
H
O
(i-Pr) N
O
2
Li
4
A
OMe
3
OMe
3
R
1
R
1
O
Ph
B
Br
2
N(i-Pr)
2
2
CHO
(i-Pr) N
O
2
3a, R = H
3b, R = Me
1
1
Li
B
Equation 1. Possible intermediates A and B.
OMe
OMe
OMe
O
O
O
K CO ,
2
3
decalin
that the difference between 2a and 2b should be the methyl group,
providing a stabilizing factor for the formation of epoxide. After the
adjusting reaction temperature and equivalents of K2CO3 and
MCPBA, the ratio value (2b/2c¼3/1) was similar. Then, when 2a or
2b was treated with hydrogen in the presence of a catalytic amount
of 10% palladium on activated carbon in ethyl acetate, 5a or 5b was
isolated with 92% or 68% yield, respectively. Under the hydroge-
nation condition, 5c with resorcin motif could be generated with
20% yield. Therefore, the ring-opening of oxepane was achieved via
the allylic hydrogenation.
allylBr
OH
O
OH
7d (58%)
6d (86%)
2a
OMe
O
OMe
O
OMe
O
K CO
2
3
Grubbs cat.
allylBr
O
OH
O
Based on the above results, we attempted to prepare another
oxepane fused ring. O-Allylation of 5a or 5b with the combination of
K2CO3 and allyl bromide (R2¼H, for 5a and 5b) or crotyl bromide
(R2¼Me, for 5b) afforded 6a (93%), 6b (95%) or 6c (89%). Furthermore,
compounds 7ae7c were isolated in moderate yields with a range of
180e200 ꢀC (by decalin) under the Claisen condition.10 Notably,
when reaction time was changed to 2 h or 6 h, the ratio value of
starting materials and rearranged compounds was isolated in nearly
3/1 (6a/7a, 6b/7b, and 6c/7c) or 1/3 (6a/7a, 6b/7b, and 6c/7c) without
the formation of side products, respectively. By adjusting heating
time (10 h), skeleton 7 could be obtained in sole isomer.
O-Allylation of 7a, 7b or 7c with the combination of K2CO3 and
allyl bromide (R3¼H, for 7a and 7c) or crotyl bromide (R3¼Me, for
7b and 7d) afforded 8a (94%), 8b (88%), 8c (89%) or 8d (82%).
Skeleton 8 was provided in modest total yield of three-steps via the
reaction sequence of O-allylation, Claisen rearrangement and O-
allylation. Finally, 1ae1d were accomplished by the one-pot re-
action of 8ae8d first treated with Grubbs second-generation cat-
alyst in the presence of a catalytic amount of 10% palladium on
8e (80%)
8f (56%)
1e (no detected)
Scheme 3. Reactions of 2a with the three-step route.
Two 3,4- and 2,4-dihydroxybenzaldehyde 9a and 9b were cho-
sen as the reasonable starting materials to examine the posited
hypothesis. As shown in Scheme 4 or Scheme 5,10a or 10b with four
allyl groups was formed with 38% or 46% yields, respectively, via the
facile three-step route: (i) O-allylation of 9a or 9b; (ii) Claisen
rearrangement of the resulting product; and (iii) the repeated O-
allylation. Furthermore, when treatment of skeleton 10 included
reactions with Grubbs first- or second-generation catalyst, the
complex mixture was isolated; the desired cyclized 11a or 11b was
not yielded during the procedure. Attempts to synthesize skeleton
11 failed due to the competitive metathesis of terminal olefin on the
skeleton 10. By the similar reactivity, there is no ring-closing me-
tathesis happening for compound 10a or 10b under the reduction
condition. The major byproduct 12a or 12b was isolated with a 48%

M.-Y. Chang et al. / Tetrahedron 68 (2012) 6224e6230
6227
FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were
carried out with Heraeus Vario III-NCSH, Heraeus CHNeOSeRapid
Analyzer or Elementar Vario EL III.
OH
O
1) K CO , allylBr
2
3
OH
O
2) decalin, reflux
Grubbs cat.
3) K CO , allylBr
2
3
(38% of three-step)
4.2. A representative procedure of skeleton 3 is as follows
CHO
9a
CHO
10a
LDA (1.0 M, 3.0 mmol, 3 mL) was added to a solution of 4
(1.0 mmol) in THF (20 mL) at ꢁ78 ꢀC. The reaction mixture was
stirred at ꢁ78 ꢀC for 10 min PhBCl2 (160 mg, 1.0 mmol) was added
to the reaction mixture at ꢁ78 ꢀC. The reaction mixture was stirred
at ꢁ78 ꢀC for 10 min. Allyl bromide (121 mg, 1.0 mmol) was added
to the reaction mixture at ꢁ78 ꢀC. The reaction mixture was stirred
at ꢁ78 ꢀC for 1 h. Allyl bromide (121 mg, 1.0 mmol) or crotyl bro-
mide (80%, 168 mg, 1.0 mmol) was added to the reaction mixture at
ꢁ78 ꢀC. The reaction mixture was stirred at ꢁ78 ꢀC for 1 h. The
reaction mixture was slowly warmed to rt. The reaction mixture
was stirred at rt for 1 h. Saturated NaHCO3 (aq) (2ꢂ5 mL) was added
to the reaction mixture and the residue was extracted with ethyl
acetate (3ꢂ30 mL). The combined organic layers were washed with
brine, dried, filtered, and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexanes/ethyl
acetate¼10/1e6/1) afforded skeleton 3.
OH
OH
O
O
CHO
CHO
11a (no detected)
12a (48%)
Scheme 4. Reactions of 9a.
OH
O
1) K CO , allylBr
2
3
2) decalin, reflux
Grubbs cat.
3) K CO , allylBr
2
3
OH
O
(46% of three-step)
CHO
CHO
9b
10b
4.2.1. 2-Allyl-3-allyloxy-4-methoxy-benzaldehyde (3a). Yield¼72%
OH
O
(167 mg); Colorless oil; 1H NMR (200 MHz, CDCl3):
d 10.07 (s, 1H),
7.66 (d, J¼8.4 Hz, 1H), 6.92 (d, J¼8.4 Hz, 1H), 6.19e5.92 (m, 2H),
5.41e5.20 (m, 2H), 5.09e4.85 (m, 2H), 4.49e4.45 (m, 2H), 3.94 (s,
3H), 3.90e3.86 (m, 2H). Compound 3a is a known compound and the
1H NMR analytical data are consistent with those in the literature.13
OH
O
CHO
CHO
12b (40%)
11b (no detected)
Scheme 5. Reactions of 9b.
4.2.2. 2-Allyl-4-methoxy-3-(2-methyl-allyloxy)-benzaldehyde
(3b). Yield¼47% (116 mg); Colorless oil; 1H NMR (200 MHz, CDCl3):
or 40% yield.12 With the experimental results, we envisioned that
the adjacent terminal tetra-allyl groups could be not cyclized to the
benzodioxepane skeleton; therefore, the rapid synthetic route for
establishing the benzodioxepane skeleton could be not resulted.
d
10.07 (s, 1H), 7.66 (d, J¼8.6 Hz, 1H), 6.93 (d, J¼8.6 Hz, 1H),
6.17e5.95 (m, 1H), 5.14 (s, 1H), 5.02e4.88 (m, 3H), 4.34 (s, 2H), 3.93
(s, 3H), 3.90e3.87 (m, 2H), 1.88 (s, 3H). Compound 3b is a known
compound and the 1H NMR analytical data are consistent with
those in the literature.13
3. Conclusion
4.3. A representative procedure of skeleton 2 is as follows
We have successfully presented the ortho-metalative mediated
double allylation reaction of 4 with PhBCl2 for producing diallyl
skeleton 3. Four benzodioxepanes 1ae1d were prepared from the
novel one-pot combination of ring-closing metathesis of skeleton 3
followed by BaeyereVilliger reaction, hydrogenation of skeleton 2,
O-allylation, Claisen rearrangement of skeleton 6, and one-pot
combination of ring-closing metathesis and hydrogenation. Fur-
ther studies on the PhBCl2-mediated double allylation are actively
underway in laboratories.
Grubbs second catalyst (24 mg, 2.8% mmol) was added to a so-
lution of skeleton 3 (1.0 mmol) in CH2Cl2 (10 mL) at rt for 1 h. Then,
K2CO3 (276 mg, 2.0 mmol) was added into the reaction mixture. The
reaction mixture stirred for 15 min m-chloroperoxybenzoic acid
(MCPBA, 230 mg, 75%, 1.0 mmol) was added into the reaction
mixture. The reaction mixture was stirred for 10 h. Saturated
NaHCO3 (aq) (2ꢂ10 mL) was added to the reaction mixture and the
residue was extracted with CH2Cl2 (3ꢂ30 mL). The combined or-
ganic layers were washed with brine, dried, filtered, and evapo-
rated to afford crude product under reduced pressure. Purification
on silica gel (hexanes/ethyl acetate¼6/1e3/1) afforded skeleton 2.
4. Experimental section
4.1. General
4.3.1. 9-Methoxy-2,5-dihydrobenzo[b]oxepin-6-ol (2a). Yield¼58%
(112 mg); Colorless solid; mp¼163e164 ꢀC (recrystallized from
hexanes and ethyl acetate); HRMS (ESI, Mþþ1) calcd for C11H13O3
All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous MgSO4 before concentration in vacuo. Melting points
were determined with a SMP3 melting apparatus. 1H and 13C NMR
spectra were recorded on a Varian INOVA-400 spectrometer oper-
193.0865, found 193.0866; 1H NMR (400 MHz, CDCl3):
d 6.65 (d,
J¼8.8 Hz,1H), 6.50 (d, J¼8.8 Hz,1H), 5.85 (ddt, J¼1.6, 4.5, 7.6 Hz,1H),
5.50e5.45 (m, 1H), 4.63 (s, 1H), 4.60 (dt, J¼2.0, 4.8 Hz, 2H), 3.81 (s,
3H), 3.53 (ddd, J¼2.0, 4.0, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
148.3, 146.5, 145.9, 127.8, 125.5, 125.4, 110.6, 110.5, 70.6, 56.5, 22.9;
Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.92; H, 6.50.
ating at 200/400 and at 100 MHz, respectively. Chemical shifts (d)
are reported in parts per million (ppm) and the coupling constants
(J) are given in Hertz. High resolution mass spectra (HRMS) were
measured with a mass spectrometer Finnigan/Thermo Quest MAT
95XL. X-ray crystal structures were obtained with an Enraf-Nonius
4.3.2. 9-Methoxy-3-methyl-2,5-dihydrobenzo[b]oxepin-6-ol
(2b). Yield¼49% (101 mg); Colorless solid; mp¼107e108 ꢀC
(recrystallized from hexanes and ethyl acetate); HRMS (ESI, Mþþ1)
calcd for C12H15O3 207.1021, found 207.1030; 1H NMR (400 MHz,

6228
M.-Y. Chang et al. / Tetrahedron 68 (2012) 6224e6230
CDCl3):
d
6.65 (d, J¼8.8 Hz, 1H), 6.50 (d, J¼8.8 Hz, 1H), 5.60 (ddt,
stirred at rt for 10 min. Different bromide (1.5 mmol) was added to
the reaction mixture at rt. The reaction mixture was stirred at reflux
for 10 h. The reaction was traced by TLC until skeleton 5 was con-
sumed. The reaction mixture was cooled to rt, concentrated, and
partitioned with ethyl acetate (3ꢂ30 mL) and water. The combined
organic layers were washed with brine, dried, filtered, and evapo-
rated to afford crude product under reduced pressure. Purification
on silica gel (hexanes/ethyl acetate¼10/1e8/1) afforded skeleton 6.
J¼1.6, 4.5, 7.6 Hz, 1H), 4.75 (s, 1H), 4.44 (s, 2H), 3.81 (s, 3H), 3.44 dd,
(J¼1.6, 4.0 Hz, 2H), 1.52 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 147.9,
146.4, 145.8, 134.3, 125.8, 120.2, 110.6, 110.4, 73.4, 56.5, 22.0, 19.9;
Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 70.10; H, 7.07.
4.3.3. 6-Methoxy-8a-methyl-1a,2,8,8a-tetrahydro-1,7-dioxabenzo[a]
cyclopropa[d]cyclohepten-3-ol (2c). Yield¼16% (36 mg); Colorless
solid; mp¼155e156 ꢀC (recrystallized from hexanes and ethyl ac-
etate); HRMS (ESI, Mþþ1) calcd for C12H15O4 223.0970, found
4.5.1. 6-Allyloxy-9-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepine
(6a). Yield¼93% (218 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd
for C14H19O3 235.1334, found 235.1341; 1H NMR (400 MHz, CDCl3):
223.0972; 1H NMR (400 MHz, CDCl3):
d
6.65 (d, J¼8.8 Hz, 1H), 6.51
(d, J¼8.8 Hz, 1H), 4.89 (br s, 1H), 4.40 (d, J¼14.0 Hz, 1H), 3.97 (d,
J¼14.0 Hz, 1H), 3.79 (s, 3H), 3.49 (dd, J¼5.2, 15.2 Hz, 1H), 3.26 (t,
J¼5.2 Hz, 1H), 3.17 (dd, J¼5.2, 15.2 Hz, 1H), 1.21 (s, 3H); 13C NMR
d
6.67 (d, J¼9.2 Hz, 1H), 6.53 (d, J¼8.4 Hz, 1H), 6.06 (ddd, J¼5.2, 10.4,
17.2 Hz, 1H), 5.39 (dq, J¼1.6, 17.2 Hz, 1H), 5.26 (dq, J¼1.6, 10.4 Hz,
1H), 4.45 (dt, J¼2.4, 5.2 Hz, 2H), 4.06 (t, J¼5.2 Hz, 2H), 3.81 (s, 3H),
2.93 (t, J¼2.0 Hz, 2H), 1.98 (dt, J¼6.0, 12.0 Hz, 2H), 1.70 (dt, J¼6.0,
(100 MHz, CDCl3): d 147.7, 146.8, 145.9, 120.5, 111.0, 110.8, 71.1, 60.8,
59.7, 56.5, 24.0, 20.7; Anal. Calcd for C12H14O4: C, 64.85; H, 6.35.
Found: C, 65.04; H, 6.67. Single-crystal X-ray diagram: crystal of 2c
was grown by slow diffusion of ethyl acetate into a solution of 2c in
CH2Cl2 to yield colorless prism. The compound crystallizes in the
12.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 150.8,150.4, 146.4, 133.9,
126.9, 117.0, 109.7, 107.6, 73.6, 70.4, 56.5, 32.4, 25.3, 24.5.
ꢀ
monoclinic crystal system, space group P 1 21/n 1, a¼9.3065(6) A,
4.5.2. 6-But-2-enyloxy-9-methoxy-2,3,4,5-tetrahydrobenzo[b]ox-
epine (6b). Yield¼95% (236 mg); Colorless oil; HRMS (ESI, Mþþ1)
calcd for C15H21O3 249.1491, found 249.1489; 1H NMR (400 MHz,
3
ꢀ
ꢀ
ꢀ
b¼9.8913(6) A, c¼11.2771(6) A, V¼1028.82(11) A , Z¼4,
dcalcd¼1.435 g/cm3, F(000)¼472, 2
q
range 2.67e26.45ꢀ, R indices
(all data) R1¼0.0589, wR2¼0.1693.
CDCl3):
d
6.66 (d, J¼8.8 Hz,1H), 6.54 (d, J¼8.8 Hz,1H), 5.85e5.78 (m,
1H), 5.75e5.68 (m, 1H), 4.37 (dt, J¼1.6, 6.0 Hz, 2H), 4.05 (t, J¼5.6 Hz,
2H), 3.80 (s, 3H), 2.91 (dt, J¼2.4, 6.0 Hz, 2H), 1.98 (dt, J¼6.0, 11.6 Hz,
2H), 1.75 (d, J¼7.2 Hz, 3H), 1.72 (dt, J¼6.0, 11.6 Hz, 2H); 13C NMR
4.4. A representative procedure of skeleton 5 is as follows
Palladium on activated carbon (10%, 5 mg) was added to a so-
lution of skeleton 3 (1.0 mmol) in ethyl acetate (20 mL) at rt. Then
hydrogen was bubbled into the mixture for 10 min, and stirring
occurred at rt for 20 h. The reaction mixture was filtered and
evaporated to yield crude product. Purification on silica gel (hex-
anes/ethyl acetate¼6/1e3/1) afforded skeleton 5.
(100 MHz, CDCl3): d 150.5, 146.3, 129.6, 128.0, 126.7, 109.6, 107.8,
107.6, 73.6, 70.5, 56.5, 32.4, 25.3, 24.5, 17.9.
4.5.3. 6-Allyloxy-9-methoxy-3-methyl-2,3,4,5-tetrahydrobenzo[b]ox-
epine (6c). Yield¼89% (221 mg); Colorless oil; HRMS (ESI, Mþþ1)
calcd for C15H21O3 249.1491, found 249.1495; 1H NMR (400 MHz,
CDCl3):
d
6.66 (d, J¼8.8 Hz, 1H), 6.53 (d, J¼8.8 Hz, 1H), 6.10e6.01 (m,
4.4.1. 9-Methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin-6-ol (5a). Yield¼92%
(179 mg); Colorless solid; mp¼113e114 ꢀC (recrystallized from hex-
anes and ethyl acetate); HRMS (ESI, Mþþ1) calcd for C11H15O3
1H), 5.42e5.36 (m, 1H), 5.27e5.24 (m, 1H), 4.45 (dt, J¼1.6, 5.2 Hz, 2H),
4.26 (ddd, J¼1.2, 4.0, 12.0 Hz, 1H), 3.80 (s, 3H), 3.41 (dd, J¼9.6, 12.0 Hz,
1H), 3.19 (ddd, J¼1.6, 7.6, 14.4 Hz, 1H), 2.63 (ddt, J¼1.6,11.2,13.6 Hz,1H),
2.20e2.12 (m,1H),1.98e1.91 (m,1H),1.23 (ddd, J¼1.6,11.2,13.6 Hz,1H),
195.1021, found 195.1028; 1H NMR (400 MHz, CDCl3):
d 6.62 (d,
J¼8.8 Hz,1H), 6.45 (d, J¼8.8 Hz,1H), 4.57 (s,1H), 4.06 (t, J¼5.2 Hz, 2H),
0.92 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 150.6,150.3,146.3,
3.80 (s, 3H), 2.87 (dt, J¼3.6, 6.0 Hz, 2H), 1.99 (dt, J¼5.6, 11.6 Hz, 2H),
133.8, 126.6, 117.0, 109.6, 107.5, 78.7, 70.3, 56.5, 36.5, 33.3, 22.5, 17.3.
1.73 (dt, J¼5.6, 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 151.0, 147.1,
146.1, 124.2, 110.5, 109.5, 73.7, 56.8, 32.3, 25.2, 24.8; Anal. Calcd for
C11H14O3: C, 68.02; H, 7.27. Found: C, 68.22; H, 7.53.
4.6. A representative procedure of skeleton 7 is as follows
Decalin (8 mL) was added to a solution of skeleton 6 (0.7 mmol)
at rt. The reaction mixture was stirred at reflux for 10 h. The re-
action was traced by TLC until skeleton 6 was consumed. The re-
action mixture was cooled to rt. Decalin was evaporated to afford
crude product under reduced pressure. Purification on silica gel
(hexanes/ethyl acetate¼8/1e4/1) afforded skeleton 7.
4.4.2. 9-Methoxy-3-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-6-ol
(5b). Yield¼68% (141 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd for
C12H17O3 209.1178, found 209.1182; 1H NMR (400 MHz, CDCl3):
d
6.59 (d, J¼8.4 Hz, 1H), 6.46 (d, J¼8.4 Hz, 1H), 5.72 (br s, 1H), 4.26
(ddd, J¼1.2, 4.0,12.0 Hz,1H), 3.77 (s, 3H), 3.39 (dd, J¼9.6,12.0 Hz,1H),
3.09 (ddd, J¼1.6, 7.6, 14.4 Hz, 1H), 2.62 (ddd, J¼1.6, 11.6, 13.2 Hz, 1H),
2.20e2.10 (m, 1H), 1.96e1.90 (m, 1H), 1.22 (ddd, J¼1.6, 11.6, 13.2 Hz,
4.6.1. 7-Allyl-9-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepin-6-ol
(7a). Yield¼77% (126 mg); Colorless solid; mp¼114e115 ꢀC
(recrystallized from hexanes and ethyl acetate); HRMS (ESI, Mþþ1)
calcd for C14H19O3 235.1334, found 235.1339; 1H NMR (400 MHz,
1H), 0.89 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 150.5,147.4,
145.5, 124.2, 110.4, 109.6, 78.7, 56.7, 36.5, 33.2, 22.7, 17.2.
4. 4. 3. 4-Methoxy-2-(3-methylbutyl)benzene-1, 3-dio l
(5c). Yield¼20% (42 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd for
C12H19O3 211.1334, found 211.1338; 1H NMR (400 MHz, CDCl3):
CDCl3):
d
6.52 (s, 1H), 6.00 (ddt, J¼6.4, 10.4, 16.8 Hz, 1H), 5.20 (dq,
J¼1.6, 16.8 Hz, 1H), 5.19 (dq, J¼1.6, 10.4 Hz, 1H), 4.70 (br s, 1H), 4.04
(t, J¼5.6 Hz, 2H), 3.80 (s, 3H), 3.36 (d, J¼6.4 Hz, 2H), 2.88 (t,
J¼5.6 Hz, 2H), 1.98 (dt, J¼5.6, 11.6 Hz, 2H), 1.71 (dt, J¼5.6, 11.6 Hz,
d
6.58 (d, J¼8.8 Hz, 1H), 6.28 (d, J¼8.8 Hz, 1H), 5.75 (s, 1H), 4.67 (s,
1H), 3.82 (s, 3H), 2.66 (dt, J¼5.6, 8.0 Hz, 2H), 1.63 (dt, J¼6.8, 13.6 Hz,
2H); 13C NMR (100 MHz, CDCl3):
d
149.6, 145.6 (2ꢂ), 136.5, 125.0,
1H), 1.45 (ddt, J¼5.6, 10.8, 13.6 Hz, 2H), 0.96 (d, J¼6.8 Hz, 6H); 13C
119.1, 116.8, 112.0, 73.7, 56.8, 36.1, 32.4, 25.3, 24.8.
NMR (100 MHz, CDCl3):
d 148.4, 144.4, 140.8, 116.4, 108.3, 105.1,
56.5, 38.1, 28.2, 22.5 (2ꢂ), 21.5.
4.6.2. 9-Methoxy-7-(1-methyl-allyl)-2,3,4,5-tetrahydrobenzo[b]ox-
epin-6-ol (7b). Yield¼65% (113 mg); Colorless oil; HRMS (ESI,
Mþþ1) calcd for C15H21O3 249.1491, found 249.1497; 1H NMR
4.5. A representative procedure of skeleton 6 is as follows
(400 MHz, CDCl3):
d
6.55 (s, 1H), 6.05 (ddd, J¼5.6, 10.0, 17.2 Hz, 1H),
K2CO3 (280 mg, 2.0 mmol) was added to a solution of skeleton 5
(1.0 mmol) in acetone (30 mL) at rt. The reaction mixture was
5.23 (dt, J¼1.6, 17.2 Hz, 1H), 5.21 (dt, J¼1.6, 10.0 Hz, 1H), 4.89 (s, 1H),
4.04 (ddt, J¼5.2, 12.0, 16.8 Hz, 2H), 3.81 (s, 3H), 3.57 (dt, J¼1.6,

M.-Y. Chang et al. / Tetrahedron 68 (2012) 6224e6230
6229
7.2 Hz, 1H), 2.88 (ddt, J¼3.2, 7.2, 9.6 Hz, 2H), 1.97 (dt, J¼5.6, 11.2 Hz,
2H), 1.77e1.65 (m, 2H), 1.40 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
(ESI, Mþþ1) calcd for C18H25O3 289.1804, found 289.1807; 1H NMR
(400 MHz, CDCl3):
d
6.57 (s, 1H), 6.07 (ddd, J¼5.6, 10.0, 17.2 Hz, 1H),
CDCl3):
d
149.4, 145.6, 145.2, 142.5, 125.1, 124.2, 114.8, 109.9, 73.6,
5.95 (ddd, J¼6.8, 10.8, 17.2 Hz, 1H), 5.41 (dq, J¼1.6, 17.2 Hz, 1H), 5.26
(dq, J¼1.6, 10.8 Hz, 1H), 5.08 (dq, J¼2.0, 17.2 Hz, 1H), 5.07 (dq, J¼2.0,
10.0 Hz, 1H), 4.25 (ddd, J¼1.6, 4.0, 12.0 Hz, 1H), 4.21 (dt, J¼1.2,
5.2 Hz, 2H), 3.81 (s, 3H), 3.40 (dt, J¼1.2, 6.8 Hz, 2H), 3.34 (dd, J¼2.0,
11.6 Hz, 1H), 3.07 (ddd, J¼1.6, 7.6, 14.4 Hz, 1H), 2.67 (dt, J¼1.6,
11.2 Hz, 1H), 2.20e2.12 (m, 1H), 1.99e1.93 (m, 1H), 1.20 (dt, J¼1.2,
12.0 Hz, 1H), 0.91 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
56.9, 38.8, 32.3, 25.3, 24.8, 18.5.
4.6.3. 7-Allyl-9-methoxy-3-methyl-2,3,4,5-tetrahydrobenzo[b]ox-
epin-6-ol (7c). Yield¼74% (128 mg); Colorless oil; HRMS (ESI,
Mþþ1) calcd for C15H21O3 249.1491, found 249.1493; 1H NMR
(400 MHz, CDCl3):
d
6.51 (s, 1H), 6.01 (ddd, J¼5.6, 10.0, 17.2 Hz, 1H),
5.20 (dt, J¼1.6, 17.2 Hz, 1H), 5.19 (dt, J¼1.6, 10.0 Hz, 1H), 4.72 (br s,
1H), 4.25 (ddd, J¼1.2, 4.0, 12.0 Hz, 1H), 3.79 (s, 3H), 3.41 (dd, J¼8.4,
14.0 Hz, 1H), 3.36 (dd, J¼6.4, 10.4 Hz, 2H), 3.09 (ddd, J¼1.6, 7.6,
14.4 Hz, 1H), 2.64 (ddd, J¼1.6, 11.2, 13.6 Hz, 1H), 2.19e2.11 (m, 1H),
1.98e1.91 (m, 1H), 1.24 (ddd, J¼1.6, 11.2, 13.6 Hz, 1H), 0.91 (d,
d 148.5, 148.1, 148.0, 137.4, 133.9, 130.7, 127.6, 117.2, 115.7, 110.9, 78.7,
75.2, 56.2, 36.7, 34.2, 33.8, 23.8, 17.2.
4.7.4. 7-Allyl-9-methoxy-3-methyl-6-(2-methyl-allyloxy)-2,3,4,5-
tetrahydrobenzo[b]oxepine (8d). Yield¼82% (124 mg); Colorless oil;
HRMS (ESI, Mþþ1) calcd for C19H27O3 303.1960, found 303.1967; 1H
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 149.4, 145.5, 145.4,
NMR (400 MHz, CDCl3):
d
6.57 (s, 1H), 5.97 (ddd, J¼6.8,10.4,16.8 Hz,
136.5, 124.8, 119.1, 126.8, 111.9, 78.8, 56.8, 36.6, 36.1, 33.3, 22.8, 17.3.
1H), 5.15 (br s, 1H), 5.08 (dq, J¼2.0, 16.8 Hz, 1H), 5.07 (dq, J¼2.0,
16.8 Hz, 1H), 4.98 (s, 1H), 4.25 (ddd, J¼1.2, 3.6, 11.6 Hz, 1H), 4.07 (s,
2H), 3.81 (s, 3H), 3.39 (d, J¼6.0 Hz, 2H), 3.34 (dd, J¼2.0, 11.6 Hz, 1H),
3.07 (ddd, J¼1.6, 7.6, 14.4 Hz, 1H), 2.67 (dt, J¼1.6, 11.6 Hz, 1H),
2.21e2.13 (m, 1H), 1.99e1.93 (m, 1H), 1.87 (s, 3H), 1.21 (dt, J¼6.0,
11.6 Hz, 1H), 0.91 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
4.6.4. 7-Allyl-9-methoxy-2,5-dihydrobenzo[b]oxepin-6-ol
(7d). Yield¼58% (94 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd for
C14H17O3 233.1178, found 233.1182; 1H NMR (400 MHz, CDCl3):
d
6.56 (s, 1H), 6.05e5.95 (m, 1H), 5.84 (ddd, J¼5.6, 10.0, 17.2 Hz, 1H),
5.47 (ddq, J¼2.8, 4.4, 11.6 Hz, 1H), 5.20 (dt, J¼1.6, 17.2 Hz, 1H), 5.19
(dt, J¼1.6, 10.0 Hz, 1H), 4.70 (s, 1H), 4.59 (dt, J¼2.4, 4.8 Hz, 2H), 3.81
(s, 3H), 3.54 (ddd, J¼2.0, 4.0, 6.4 Hz, 2H), 3.37 (dt, J¼1.6, 6.4 Hz, 2H);
d
148.5, 148.0 (2ꢂ), 141.5, 137.5, 130.7, 127.6, 115.7, 112.2, 110.9, 78.7,
77.9, 56.2, 36.8, 34.1, 33.9, 23.7, 19.7, 17.2.
13C NMR (100 MHz, CDCl3):
d 146.9, 146.1, 144.5, 136.3, 127.8, 126.2,
4.7.5. 7-Allyl-6-allyloxy-9-methoxy-2,5-dihydrobenzo[b]oxepine
(8e). Yield¼80% (109 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd
for C17H21O3 273.1491, found 273.1495; 1H NMR (400 MHz, CDCl3):
125.6, 120.2, 117.0, 112.0, 70.6, 56.5, 36.2, 22.9.
4.7. A representative procedure of skeleton 8 is as follows
d
6.61 (s, 1H), 6.12e6.91 (m, 2H), 5.84 (ddd, J¼5.6, 10.8, 17.2 Hz, 1H),
5.47e5.38 (m, 2H), 5.26 (dq, J¼1.6, 12.0 Hz, 1H), 5.09 (dq, J¼1.6,
16.8 Hz,1H), 5.08 (dq, J¼1.6,10.8 Hz,1H), 4.58 (dt, J¼2.4, 5.2 Hz, 2H),
4.19 (dt, J¼1.2, 5.2 Hz, 2H), 3.83 (s, 3H), 3.51 (ddt, J¼2.0, 4.0, 7.6 Hz,
K2CO3 (140 mg, 1.0 mmol) was added to a solution of skeleton 7
(0.5 mmol) in acetone (20 mL) at rt. The reaction mixture was
stirred at rt for 10 min. Different bromide (0.8 mmol) was added to
the reaction mixture at rt. The reaction mixture was stirred at reflux
for 10 h. The reaction was traced by TLC until skeleton 7 was con-
sumed. The reaction mixture was cooled to rt, concentrated, and
partitioned with ethyl acetate (3ꢂ30 mL) and water. The combined
organic layers were washed with brine, dried, filtered, and evapo-
rated to afford crude product under reduced pressure. Purification
on silica gel (hexanes/ethyl acetate¼10/1e8/1) afforded skeleton 8.
2H), 3.38 (d, J¼6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 148.7,
146.9, 145.9, 137.3, 133.8, 131.8, 128.7, 128.1, 125.4, 117.3, 115.8, 111.2,
75.2, 70.6, 56.1, 34.2, 23.7.
4.8. A representative procedure of skeleton 1 is as follows
Grubbs second catalyst (24 mg, 2.8% mmol) and palladium on
activated carbon (10%,15 mg) were added to a solution of skeleton 8
(0.3 mmol) in CH2Cl2 (10 mL) at rt for 1 h. Then hydrogen was
bubbled into the mixture for 10 min, and stirring occurred at rt for
20 h. The reaction mixture was filtered and evaporated to yield
crude product. Purification on silica gel (hexanes/ethyl acetate¼6/
1e3/1) afforded skeleton 1.
4.7.1. 7-Allyl-6-allyloxy-9-methoxy-2,3,4,5-tetrahydrobenzo[b]ox-
epine (8a). Yield¼94% (129 mg); Colorless oil; HRMS (ESI, Mþþ1)
calcd for C17H23O3 275.1647, found 275.1655; 1H NMR (400 MHz,
CDCl3):
d
6.57 (s, 1H), 6.07 (ddd, J¼5.6, 10.0, 17.2 Hz, 1H), 5.97 (ddd,
J¼6.8, 10.8, 17.2 Hz, 1H), 5.41 (dq, J¼1.6, 17.2 Hz, 1H), 5.26 (dq, J¼1.6,
10.8 Hz, 1H), 5.18 (dq, J¼2.0, 17.2 Hz, 1H), 5.17 (dq, J¼2.0, 10.0 Hz,
1H), 4.20 (dt, J¼1.6, 5.2 Hz, 2H), 4.02 (t, J¼5.2 Hz, 2H), 3.81 (s, 3H),
3.38 (dt, J¼1.2, 6.8 Hz, 2H), 2.88 (t, J¼5.6 Hz, 2H), 1.98 (dt, J¼6.0,
11.6 Hz, 2H), 1.70 (dt, J¼6.0, 11.6 Hz, 2H); 13C NMR (100 MHz,
4.8.1. 7-Methoxy-2,3,4,5,9,10,11,12-octahydro-1,8-dioxabenzo[1,2;
3,4]dicycloheptene (1a). Yield¼82% (61 mg); Colorless oil; HRMS
(ESI, Mþþ1) calcd for C15H21O3 249.1491, found 249.1488; 1H NMR
(400 MHz, CDCl3):
d
6.52 (s, 1H), 4.01 (t, J¼5.2 Hz, 2H), 3.89 (t,
CDCl3):
d
148.7, 148.2 (2ꢂ), 148.1, 137.5, 133.9, 127.6, 117.2, 115.7,
J¼5.2 Hz, 2H), 3.80 (s, 3H), 2.91 (t, J¼5.6 Hz, 2H), 2.75 (dd, J¼4.4,
111.1, 75.2, 73.7, 56.3, 34.2, 32.5, 25.8, 25.8.
6.8 Hz, 2H), 1.99e1.91 (m, 4H), 1.71e1.64 (m, 4H); 13C NMR
(100 MHz, CDCl3):
56.4, 34.4, 32.6, 32.6, 26.5, 25.7, 25.2; Anal. Calcd for C15H20O3: C,
72.55; H, 8.12. Found: C, 72.30; H, 8.41.
d 151.3, 148.2, 147.1, 131.0, 129.7, 111.2, 73.7, 73.5,
4.7.2. 6-Allyloxy-9-methoxy-7-(1-methylallyl)-2,3,4,5-tetrahy-
drobenzo[b]oxepine (8b). Yield¼88% (127 mg); Colorless oil; HRMS
(ESI, Mþþ1) calcd for C18H25O3 289.1804, found 289.1800; 1H NMR
(400 MHz, CDCl3):
d
6.55 (s, 1H), 6.09 (ddd, J¼5.2, 10.0, 16.8 Hz, 1H),
4.8.2. 7-Methoxy-5-methyl-2,3,4,5,9,10,11,12-octahydro-1,8-
dioxabenzo[1,2; 3,4]dicycloheptene (1b). Yield¼76% (60 mg); Col-
orless solid; mp¼104e105 ꢀC (recrystallized from hexanes and
ethyl acetate); HRMS (ESI, Mþþ1) calcd for C16H23O3 263.1647,
6.01 (ddd, J¼6.0, 10.4, 17.2 Hz, 1H), 5.42 (dq, J¼1.6, 17.2 Hz, 1H), 5.26
(dq, J¼1.6, 10.4 Hz, 1H), 5.04 (dt, J¼1.6, 10.0 Hz, 1H), 5.03 (dt, J¼1.6,
6.8 Hz, 1H), 4.24e4.18 (m, 2H), 4.03 (dd, J¼4.4, 9.2 Hz, 2H), 3.88
(ddt, J¼1.2, 2.8, 8.4 Hz, 1H), 3.81 (s, 3H), 2.88 (t, J¼5.6 Hz, 2H), 1.98
(dt, J¼6.4, 11.6 Hz, 2H), 1.74e1.68 (m, 2H), 1.31 (d, J¼7.2 Hz, 3H); 13C
found 263.1650; 1H NMR (400 MHz, CDCl3):
d 6.56 (s, 1H), 4.06 (dt,
J¼5.2, 12.0 Hz, 1H), 3.99 (dt, J¼5.2, 12.0 Hz, 1H), 3.93e3.84 (m, 2H),
3.83 (s, 3H), 3.04 (dt, J¼2.0, 7.2 Hz, 1H), 2.91 (dd, J¼7.2, 11.2 Hz, 2H),
2.08e1.85 (m, 4H), 1.82e1.53 (m, 4H), 1.34 (d, J¼6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3):
d 148.5, 148.3, 147.5, 143.3, 133.8, 133.2,
130.6, 117.1, 112.9, 108.7, 75.6, 73.6, 56.3, 35.6, 32.5, 25.9, 25.8, 20.7.
4.7.3. 7-Allyl-6-allyloxy-9-methoxy-3-methyl-2,3,4,5-tetrahy-
NMR (100 MHz, CDCl3): d 150.6, 148.0, 147.2, 134.8, 129.9, 109.2,
drobenzo[b]oxepine (8c). Yield¼89% (128 mg); Colorless oil; HRMS
73.7, 73.1, 56.5, 37.2, 33.4, 32.5, 29.1, 25.7, 25.1, 19.5; Anal. Calcd for

6230
M.-Y. Chang et al. / Tetrahedron 68 (2012) 6224e6230
C16H22O3: C, 73.25; H, 8.45. Found: C, 73.60; H, 8.76. Single-crystal
X-ray diagram: crystal of 1b was grown by slow diffusion of ethyl
acetate into a solution of 1b in CH2Cl2 to yield colorless prism. The
compound crystallizes in the monoclinic crystal system, space
C
d
19H23O3 299.1647, found 299.1642; 1H NMR (400 MHz, CDCl3):
10.25 (s, 1H), 7.63 (s, 1H), 6.13e5.91 (m, 4H), 5.43 (dq, J¼1.6,
17.2 Hz, 2H), 5.30 (dq, J¼1.6, 17.2 Hz, 2H), 5.15e4.98 (m, 4H), 4.48
(dt, J¼1.2, 5.6 Hz, 2H), 4.37 (dt, J¼1.2, 16.8 Hz, 2H), 3.47 (dt, J¼2.0,
5.6 Hz, 2H), 3.41 (d, J¼6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
ꢀ
ꢀ
ꢀ
group P2(1)/c 1, a¼10.1627(8) A, b¼17.1270(13) A, c¼8.8092(7) A,
3
V¼1405.89(19) A , Z¼4, dcalcd¼1.239 g/cm3, F(000)¼568, 2
q
range
d 189.6, 161.9, 160.3, 136.6, 136.2, 133.1, 132.7, 130.4, 128.8, 128.1,
ꢀ
2.19e27.50ꢀ, R indices (all data) R1¼0.1001, wR2¼0.1882.
126.1, 118.4, 117.6, 116.7, 115.5, 77.8, 74.7, 33.8, 28.8.
4.8.3. 7-Methoxy-10-methyl-2,3,4,5,9,10,11,12-octahydro-1,8-
dioxabenzo[1,2; 3,4]dicycloheptene (1c). Yield¼80% (63 mg); Col-
orless oil; HRMS (ESI, Mþþ1) calcd for C16H23O3 263.1647, found
Acknowledgements
The authors would like to thank the National Science Council
of the Republic of China for its financial support (NSC 99-2113-M-
037-006-MY3). We also thank Prof. Victor Snieckus (Department
of Chemistry, Queen’s University, Canada) for the helpful
suggestion in the PhBCl2-mediated reaction mechanism of 4
with LDA.
263.1654; 1H NMR (400 MHz, CDCl3):
d
6.52 (s,1H), 4.23 (ddd, J¼1.2,
3.6, 11.6 Hz, 1H), 3.98e3.91 (m, 1H), 3.87e3.81 (m, 1H), 3.80 (s, 3H),
3.35 (dd, J¼9.6, 11.6 Hz, 1H), 3.17 (ddd, J¼1.6, 7.6, 14.4 Hz, 1H), 2.75
(ddt, J¼2.0, 5.2, 10.4 Hz, 2H), 2.62 (dt, J¼2.0, 11.6 Hz, 1H), 2.17e2.09
(m, 1H), 1.94 (dt, J¼2.0, 6.0 Hz, 2H), 1.97e1.89 (m, 1H), 1.75e1.62 (m,
2H), 1.19 (ddd, J¼1.6, 6.4, 11.6 Hz, 1H), 0.89 (d, J¼6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 151.2,148.0,146.9,130.9,129.5,111.0, 78.8,
Supplementary data
73.5, 56.3, 36.7, 34.4, 33.7, 32.6, 26.5, 23.1, 17.3.
Scanned photocopies of 1H and 13C NMR (CDCl3) spectral data
were supported. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.tet.2012.05.063.
4.8.4. 7-Methoxy-3,10-dimethyl-2,3,4,5,9,10,11,12-octahydro-1,8-
dioxabenzo[1,2; 3,4]dicycloheptene (1d). Inseparated mixture;
Yield¼78% (65 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd for
C17H25O3 277.1804, found 277.1808; 1H NMR (400 MHz, CDCl3):
References and notes
d
6.51 (s, 1H), 4.27e4.12 (m, 2H), 3.80 (s, 3H), 3.42e3.28 (m, 1H),
3.23e3.11 (m, 2H), 2.89e2.81 (m 1H), 2.66e2.57 (m, 2H), 2.17e2.05
(m, 2H), 1.95e1.87 (m, 2H), 1.26e1.12 (m, 2H), 0.92e0.86 (m, 6H).
1. (a) Ellis, G. P. Chromenes, Chromanones, and Chromones. The Chemistry of Het-
erocyclic Compounds; Wiley: New York, NY, 1977; vol. 31, p 11; (b) Hepworth, J.
In; Katrizky, A. R., Rees, C. W., Eds. Comprehensive Heterocyclic Chemistry;
Pergamon: Oxford, UK, 1984; vol. 3, p 737.
4.9. A representative procedure of skeleton 10 is as follows
2. (a) Davis, M.; Pettett, M. Aust. J. Chem. 1979, 32, 369; (b) Rustaiyan, A.; Naza-
rians, L.; Bohlmann, F. Phytochemistry 1980, 19, 1254; (c) Kamperdick, C.; Van,
N. H.; Sung, T. V.; Adam, G. Phytochemistry 1997, 45, 1049; (d) Muyard, F.;
Bissoue, A. N.; Bevalot, F.; Tillequin, F.; Cabalion, P.; Vaquette, J. Phytochemistry
1996, 42, 1175; (e) Lee, Y. R.; Li, X. Bull. Korean Chem. Soc. 2007, 28, 1739.
3. (a) McKee, T.; Fuller, R. W.; Covington, C. D.; Cardellina, J. H., II; Gulakowski,
R. J.; Krepps, B. L.; McMahon, J. B.; Boyd, M. R. J. Nat. Prod. 1996, 59, 754; (b)
Galinis, D. L.; Fuller, R. W.; McKee, T. C.; Cardellina, J. H., II; Gulakowski, R. J.;
McMahon, J. B.; Boyd, M. R. J. Med. Chem. 1996, 39, 4507; (c) Cardellina, J. H.;
Bokesch, H. R.; McKee, T. C.; Boyd, M. R. Bioorg. Med. Chem. Lett. 1995, 5,
1011.
4. Tsai, J.-C.; Li, S.-R.; Chen, L.-Y.; Chen, P. Y.; Jhong, J. Y.; Shu, C.-J.; Lo, Y.-F.; Lin, C.-
N.; Wang, E.-C. J. Chin. Chem. Soc. 2008, 55, 1317 and cited references therein.
5. (a) De Silva, S. O.; Watanabe, M.; Snieckus, V. J. Org. Chem. 1979, 44, 4802; (b)
Shih, T. L.; Wyvratt, M. J.; Mrozik, H. J. Org. Chem. 1987, 52, 2029; (c) Snieckus, V.
Chem. Rev. 1990, 90, 879; (d) Rauer, W.; Schleyer, P. V. R. J. Am. Chem. Soc. 1989,
111, 7191; (e) Stefinovic, M.; Snieckus, V. J. Org. Chem. 1998, 63, 2808; (f) Lane,
C.; Snieckus, V. Synlett 2000, 1294; (g) Sibi, M. P.; Chattopadhyay, S.; Dank-
wardt, J. W.; Snieckus, V. J. Am. Chem. Soc. 1985, 107, 6312; (h) Comins, D. L.
Synlett 1992, 615; (i) Le Fur, N.; Mojovic, L.; Ple, N.; Turck, A.; Reboul, V.;
Metzner, P. J. Org. Chem. 2006, 71, 2609; (j) Alessi, M.; Larkin, A. L.; Ogilvie, K. A.;
Green, L. A.; Lai, S.; Lopez, S.; Snieckus, V. J. Org. Chem. 2007, 72, 1588; (k)
Chang, M.-Y.; Lee, N.-C. Synlett 2012, 867.
K2CO3 (140 mg, 1.0 mmol) was added to a solution of skeleton 9
(0.3 mmol) in acetone (10 mL) at rt. The reaction mixture was
stirred at rt for 10 min. Allyl bromide (0.8 mmol) was added to the
reaction mixture at rt. The reaction mixture was stirred at reflux for
10 h. The reaction mixture was cooled to rt, concentrated, and
partitioned with ethyl acetate (3ꢂ30 mL) and water. The combined
organic layers were washed with brine, dried, filtered, and evapo-
rated to afford crude product under reduced pressure. Decalin
(2 mL) was added to a solution of the resulting crude product at rt.
The reaction mixture was stirred at reflux for 10 h. The reaction
mixture was cooled to rt. Decalin was evaporated to afford crude
product under reduced pressure. K2CO3 (140 mg, 1.0 mmol) was
added to a solution of resulting crude product in acetone (10 mL) at
rt. The reaction mixture was stirred at rt for 10 min. Allyl bromide
(0.8 mmol) was added to the reaction mixture at rt. The reaction
mixture was stirred at reflux for 10 h. The reaction mixture was
cooled to rt, concentrated, and partitioned with ethyl acetate
(3ꢂ30 mL) and water. The combined organic layers were washed
with brine, dried, filtered, and evaporated to afford crude product
under reduced pressure. Purification on silica gel (hexanes/ethyl
acetate¼8/1e4/1) afforded skeleton 10.
6. The authors thank one reviewer for the helpful suggestion in the PhBCl2-me-
diated allylation.
7. For reviews on the ring-closing metathesis reaction, see: (a) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446; (b) Schmalz, H. G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1833; (c) Schuster, M.; Blechert, S. Angew. Chem.,
Int. Ed. 1997, 36, 2036; (d) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 1.,
371; (e) Philips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75; (f) Pandit, U. K.;
Overkleeft, H. S.; Borer, B. C.; Bieraugel, H. Eur. J. Org. Chem. 1999, 5, 959; (g)
Wright, D. L. Curr. Org. Chem. 1999, 3, 75; (h) Maier, M. E. Angew. Chem., Int. Ed.
2000, 39, 2073; (i) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 9, 3693; (j)
Cossy, J. Chem. Rec. 2005, 5, 70.
4.9.1. 2,5-Diallyl-3,4-bisallyloxybenzaldehyde (10a). Yield of three-
step¼38% (34 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd for
C19H23O3 299.1647, found 299.1650; 1H NMR (400 MHz, CDCl3):
8. (a) Kato, H.; Ishigame, T.; Oshima, N.; Hoshiya, N.; Shimawaki, K.; Arisawa, M.;
Shuto, S. Adv. Synth. Catal. 2011, 353, 2676; (b) Tietze, L. F. Chem. Rev. 1996, 96,
195.
d
10.11 (s, 1H), 7.50 (s, 1H), 6.12e5.91 (m, 4H), 5.40 (dq, J¼1.6,
17.2 Hz, 1H), 5.38 (dq, J¼2.0, 16.8 Hz, 1H), 5.25 (dq, J¼1.6, 10.4 Hz,
2H), 5.10 (dq, J¼1.6, 10.4 Hz, 1H), 5.07 (dq, J¼1.6, 10.4 Hz, 1H), 5.03
(dq, J¼1.6, 10.0 Hz, 1H), 4.91 (dq, J¼1.6, 17.2 Hz, 1H), 4.58 (dt, J¼1.2,
5.6 Hz, 2H), 4.46 (dt, J¼1.2, 16.8 Hz, 2H), 3.84 (dt, J¼2.0, 5.6 Hz, 2H),
9. CCDC 865591 (1b) and 867570 (2c) contain the supplementary crystallographic
data for this paper. This data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: 44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
10. For reviews on the Claisen rearrangement, see: (a) Castro, A. M. Chem. Rev.
2004, 104, 2939; (b) Nubbemeyer, U. Synthesis 2003, 961; (c) Hiersemann, M.;
Abraham, L. Eur. J. Org. Chem. 2002, 1461; (d) Chai, Y.; Hong, S.; Lindsay, H. A.;
MaFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905.
3.43 (d, J¼6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 191.2, 155.1,
150.4, 137.2,136.2,135.2,133.6,133.6,133.2,130.3,128.3,118.0,117.7,
116.4, 115.7, 73.9, 73.7, 34.0, 28.7.
11. Chattopadhyay, S. K.; Biswas, T.; Maity, S. Synlett 2006, 2211.
12. Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127,
17160.
4.9.2. 3,5-Diallyl-2,4-bisallyloxybenzaldehyde (10b). Yield of three-
step¼46% (41 mg); Colorless oil; HRMS (ESI, Mþþ1) calcd for
13. Wang, E. C.; Wang, C. C.; Hsu, M. K.; Huang, K. S. Heterocycles 2002, 57, 2021.