Synthesis of two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids

Article abstract of DOI:10.1021/jo050550l

Two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids, 6-hydroxy-3-methyl-8-(phenylethyl)-2,5-dihydro-1-benzoxepin-9-carboxylic acid (radulanin E) (1) and 9-hydroxy-3-methyl-2,5-dihydro-1-benzoxepin-7-carboxylic acid (2), were synthes

Full text of DOI:10.1021/jo050550l

Synthesis of Two Naturally Occurring
3-Methyl-2,5-dihydro-1-benzoxepin Carboxylic Acids
Seiji Yamaguchi,* Nao Tsuchida, Masahiro Miyazawa, and Yoshiro Hirai
Department of Chemistry, Faculty of Science, Toyama University, Gofuku, Toyama 930-8555, Japan
seiji@sci.toyama-u.ac.jp
Received March 18, 2005
Two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids, 6-hydroxy-3-methyl-
8-(phenylethyl)-2,5-dihydro-1-benzoxepin-9-carboxylic acid (radulanin E) (1) and 9-hydroxy-3-
methyl-2,5-dihydro-1-benzoxepin-7-carboxylic acid (2), were synthesized using Stille coupling
followed by Mitsunobu cyclization.
Many compounds having a 3-methyl-2,5-dihydro-1-
benzoxepin structure have been isolated from various
kinds of plants.1a-o As shown in Scheme 1, they might
be biogenetically derived from o-prenylphenols; an oxida-
tive seven-membered cyclization gives corresponding
3-methyl-2,5-dihydro-1-benzoxepins, while a similar five-
or six-membered cyclization gives corresponding 2-iso-
propenyl-2,3-dihydrobenzofurans or 2,2-dimethyl-2H-
chromenes.
Our recent interests have been focused on the effective
preparation of naturally occurring 3-methyl-2,5-dihydro-
1-benzoxepin derivatives. Now, in this paper, the first
syntheses of two naturally occurring 3-methyl-2,5-dihy-
dro-1-benzoxepin carboxylic acids, shown in Figure 1,
6-hydroxy-3-methyl-8-(phenylethyl)-2,5-dihydro-1-ben-
zoxepin-9-carboxylic acid (radulanin E) (1),1e,f isolated
from Radula sp. (Hepaticae), and 9-hydroxy-3-methyl-
2,5-dihydro-1-benzoxepin-7-carboxylic acid (2),1l isolated
from Hemizonia lobbii (Composiate), are described.
As shown in Scheme 2, only two procedures were
reported for the preparation of 3-methyl-2,5-dihydro-1-
benzoxepins; the first one was a ring-closing metathesis,
reported by Stefinovic et al.,2 and the other one was Stille
coupling of ortho-O-protected benzyl bromide with 3-(2-
tetrahydropyranyl)oxy-2-methyl-1(Z)-propenyltrimethyl-
stannane (3) following Mitsunobu seven-membered cy-
clization, as reported in our previous paper.3
Our previous studies4,5 on the Vilsmeier formylations
of 2-isopropenyl-2,3-dihydrobenzofurans show, as de-
picted in Scheme 3, that 2-isopropenyl-2,3-dihydroben-
zofuran and its 7-methoxy derivative gave the corre-
sponding 5-carbaldehydes, the 4-methoxy derivative gave
a mixture of 5-carbaldehyde and 7-carbaldehyde, and
2-isopropenyl-2,3-dihydrobenzofuran-5-carboxylic acid was
prepared by oxidation of the corresponding 5-carbalde-
hyde with Ag2O.
This implied a new approach for three naturally
occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic
acids, as shown in Scheme 4; radulanin E (1) and
radulanin H might be synthesized from 3-methyl-
6-(protected)oxy-8-(phenylethyl)-2,5-dihydro-1-benz-
oxepin (6) by Vilsmeier formylation followed by respective
oxidation via 9-carbaldehyde (4) and 7-carbaldehyde (5),
and 9-hydroxy-3-methyl-2,5-dihydro-1-benzoxepin-7-car-
* Corresponding author. Phone: +81-76-445-6617. Fax: +81-76-
445-6549.
(1) (a) Dean, F. M.; Taylor, D. A. H. J. Chem. Soc. C 1966, 114. (b)
MacCabe, P. H.; McCrindle, R.; Murray, D. H. J. Chem. Soc. C 1967,
145. (c) Dean, F. M.; Parton, B.; Somvichien, Taylor, D. A. H.
Tetrahedron Lett. 1967, 3459. (d) Eshlett, I. T.; Taylor, D. A. H. J.
Chem. Soc. C 1968, 481. (e) Asakawa, Y.; Kusube, E.; Takemoto, T.;
Suire, C. Phytochemistry 1978, 17, 2115. (f) Asakawa, Y.; Toyata, M.;
Takemoto, T. Phytochemistry 1978, 17, 2005. (g) Takasugi, M.; Nagao,
S.; Masamune, T.; Shirata, A.; Takahashi, K. Tetrahedron Lett. 1979,
4675. (h) Junior, P. Phytochemistry 1979, 18, 2051. (i) Epe, B.;
Oelbermann, U.; Mondon, A. Chem. Ber. 1981, 114, 757. (j) Asakawa,
Y.; Takeda, R.; Toyata, M.; Takemoto, T. Phytochemistry 1981, 20, 858.
(k) Asakawa, Y.; Takikawa, K.; Toyota, M.; Takemoto, T., Phytochem-
istry 1982, 21, 2481. (l) Breuer, M.; Leeder, G.; Proksch, P.; Budzik-
iewicz, H. Phytochemistry 1986, 25, 495. (m) McCormic, S.; Robson,
K.; Bohm, B. Phytochemistry 1986, 25, 1723. (n) Asakawa, Y.; Hash-
imoto, T.; Takikawa, K.; Tori, M.; Ogawa, S. Phytochemistry 1991, 30,
235. (o) Asakawa, Y.; Kondo, K.; Tori, M. Phytochemistry 1991, 30,
325.
(2) Stefinovic, M.; Snieckus, V. J. Org. Chem. 1998, 63, 2808.
(3) Yamaguchi, S.; Furihata, K.; Miyazawa, M.; Yokoyama, H.; Hirai,
Y. Tetrahedron Lett. 2000, 41, 4787.
(4) Yamaguchi, S.; Kondo, S.; Shimokawa, K.; Inoue, O.; Sannomiya,
M.; Kawase, Y. Bull. Chem. Soc. Jpn. 1982, 55, 2500.
(5) Yamaguchi, S.; Miyata, A.; Ueno, M.; Hase, T.; Yamamoto, K.;
Kawase, Y. Bull. Chem. Soc. Jpn. 1984, 57, 617.
10.1021/jo050550l CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/24/2005
J. Org. Chem. 2005, 70, 7505-7511
7505

Yamaguchi et al.
FIGURE 1. Natural 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids as the synthetic targets.
SCHEME 1. Biogenetic Oxidative Cyclization of o-Prenylphenols
SCHEME 2. Reported Preparative Procedures of 3-Methyl-2,5-dihydro-1-benzoxepins
SCHEME 3. Vilsmeier Formylation of Isopropenyldihydrobenzofurans
boxylic acid 2 might be synthesized from 3-methyl-9-
(protected)oxy-2,5-dihydro-1-benzoxepin (8) by Vilsmeier
formylation followed by oxidation via 7-carbaldehyde (7).
We already reported the preparation of 3-methyl-8-
(phenylethyl)-2,5-dihydro-1-benzoxepin-6-ol (radulanin
A)(6b) and its methoxy derivative (radulanin B) (6a).
According to the reported procedure, as shown in Scheme
5,3 6a and 6b were prepared from 2,6-dimethoxy-4-
(phenylethyl)benzaldehyde 9aa. The starting material
9aa was prepared from 1,3-dimethoxy-5-(phenylethyl)-
benzene by formylation by treatment with n-BuLi-DMF
(91%) and then converted to 9ab or 9bb by demethylation
with MgI2 or boron tribromide. 2-Methoxy-6-(methoxy-
methyloxy)-4-(phenylethyl)benzaldehyde 9ac and 2,6-bis-
(methoxymethyloxy)-4-(phenylethyl)benzaldehyde 9cc
were prepared by the respective MOM protection with
7506 J. Org. Chem., Vol. 70, No. 19, 2005

Two 3-Methyl-2,5-dihydro-1-benzoxepin Carboxylic Acids
SCHEME 4. Synthetic Strategy for 3-Methy-2,5-dihydro-1-benzoxepincarboxylic Acids via Vilsmeier
Formylation and Oxidation
SCHEME 5. Approach for Radulanin E (1) via 3-Methyl-8-(pheylethyl)-2,5-dihydro-1-benzoxepin-6-ol
Derivatives 6b,c and 4b
MOMCl-NaH. The benzaldehydes 9ac,cc, thus pre-
pared, were then converted to the corresponding benzyl
bromides 10ac,cc by reduction with NaBH4 or LiAlH4
followed by bromination with PBr3-pyridine. Stille cou-
pling of 10ac,cc with vinylstannane 3 using Pd2(dba)3-
Ph3As gave corresponding coupling products (11ac,cc),
which were converted to corresponding diol 12a or triol
12b by acidic deprotection. Mitsunobu cyclizations of
12a,b by treatment with Ph3P and DEAD gave the
corresponding benzoxepins, 6-methoxy-3-methyl-8-(phen-
ylethyl)-2,5-dihydro-1-benzoxepin (radulanin B) (6a) and
3-methyl-8-(phenylethyl)-2,5-dihydro-1-benzoxepin-6-ol
(radulanin A) (6b). Then, 6b was converted to the
corresponding MOMoxy derivative 6c.
The Vilsmeier formylation of the 6-methoxy derivative
(radulaninn B) 6a gave a 9:1 mixture of corresponding
9-carbaldehyde (4a) and 7-carbaldehyde (5a) in 40% yield
after being treated with N-methylformanilide and phos-
phoryl chloride at 90 °C for 1 h. In addition, the similar
Vilsmeier formylation of 6-MOMoxy derivative (6c) gave
a single formylated compound, 6-hydroxy-3-(phenylethyl)-
2.5-dihydro-1-benzoxepin-9-carbaldehyde (4b). The 9-car-
baldehyde 4b was then oxidized with Ag2O to give the
corresponding 9-carboxylic acid 1, which was identical
J. Org. Chem, Vol. 70, No. 19, 2005 7507

Yamaguchi et al.
SCHEME 6. Approach A for 9-Hydroxy-3-methyl-2,5-dihydro-1-benzoxepin-7-carboxylic Acid 2 via Vilsmeier
Formylation of 3-Methyl-9-(MOMoxy)-2,5-dihydro-1-benzoxepin 8c
SCHEME 7. New Plan (B) for Benzoxepin-7-carboxylic Acid 1 Using Halogen-Metal Exchange in
7-Bromo-3-methyl-9-(protected oxy)-2,5-dihydro-1-benzoxepin 19
SCHEME 8. Approach (B) for 7a or 2 via Halogen-Metal Exchange in
7-Bromo-9-methoxy-3-methyl-2,5-dihydro-1-benzoxepin 19a
with natural radulanin E.1e The Vilsmeier formylation
showed none of the formation of 7-carbaldehyde, and
another approach was required for natural radulanin H.
A similar approach for natural 9-hydroxy-3-methyl-2,5-
dihydro-1-benzoxepin-7-carboxylic acid 2 was planned as
shown in Scheme 5. 3-Methoxy-2-(methoxymethyloxy)-
benzaldehyde (14ac) was prepared by MOM protection
of commercially available o-vanilin (14ab) and 2,3-bis-
(methoxymethyloxy)benzaldehyde (14cc) was prepared
by MOM protection of catechol followed by formylation
by treatment with n-BuLi-DMF, and they were con-
verted to the corresponding benzyl bromide 15ac by
reduction with NaBH4 followed by bromination with
N-bromosuccimide-triphenyl phosphine. According to the
reported procedure,3 Stille coupling of 16ac,cc with
vinylstannane 3 using Pd2(dba)3-Ph3As effectively gave
the corresponding coupling products (17ac,cc); subse-
quent deprotection readily gave the corresponding diol
(18ab) and triol (18bb), and Mitsunobu cyclizations of
18ab,bb gave the corresponding 3-methyl-2,5-dihydro-
1-benzoxepins (8a,b). The 9-hydroxy derivative 8b was
converted to the corresponding 9-methoxy derivative 8a
or 9-methoxymethyloxy derivative 8c by treating it with
MeI-K2CO3 or MOMCl-NaH. However, both Vilsmeier
formylations of 8a,c were unsuccessful in all conditions
and showed recovery of 8a or deprotected 8b (from 8c).
It was very interesting that the seven-membered 9-meth-
oxy-3-methyl-2,5-dihydro-1-benzoxepin 8a showed the
different reactivity for Vilsmeier formylations from the
five-membered 2-isopropenyl-2,3-dihydrobenzofuran.
So, another new approach (B) for 2 was planned via
halogen-metal exchange of 7-bromo-3-methyl-9-(protect-
ed)oxy-2,5-dihydro-1-benzoxepins 19 and a subsequent
carboxylation or formylation, as shown in Scheme 7.
7508 J. Org. Chem., Vol. 70, No. 19, 2005

Two 3-Methyl-2,5-dihydro-1-benzoxepin Carboxylic Acids
SCHEME 9. Successful Approach (C) for Benzoxepin-7-carboxylic Acid 2 Using Halogen-Metal Exchange
in 5-Bromo-2,3-bis(methoxymethyloxy)benzyl Alcohol 21cc
As shown in Scheme 8, 7-bromo-9-methoxy-3-methyl-
2,5-dihydro-1-benzoxepin (19a) was prepared and sub-
jected to the conversion via halogen-metal exchange.
5-Bromo-3-methoxy-2-(methoxymethyloxy)benzalde-
hyde (20ac) was prepared from 2-hydroxy-5-bromo-3-
methoxybenzaldehyde (20ab), prepared by bromination
of o-vanilin 14ab,6 and then converted to the correspond-
ing benzyl bromide (22ac) by reduction with NaBH4
giving (21ac), followed by bromination with NBS-PPh3.
Stille coupling of 22ac with vinylstannane 3 gave the
corresponding coupling product 23ac, which was then
converted to the corresponding 7-bromo-9-methoxyben-
zoxepin (19a) by acidic deprotection with HCl-MeOH,
giving 24ab followed by Mitsunobu cyclization with
Ph3P-DEAD. Metalation of 19a was unsuccessful in all
procedures (with alkyllithiums or Grignard reagents) and
only showed recovery of 19a. Thus, the conversion from
7-bromo-9-(methoxymethyloxy)-3-methyl-2,5-dihydro-1-
benzoxepin (19c) to the corresponding 7-carbaldehyde 7c
or 2 would likely be fruitless.
At last, we found a new successful approach (C) for
9-hydroxy-3-methyl-2,5-dihydro-1-benzoxepin-7-carboxy-
lic acid 2, as shown in Scheme 9. This approach used the
halogen-metal exchange in bromo benzyl alcohol (21cc),
which was prepared from 5-bromo-3-hydroxy-2-methoxy-
benzaldehyde (20ab) in three steps: (1) demethylation
with BBr3 (92%) giving 20bb, (2) MOM protection with
MOMCl-NaH (73%), giving 5-bromo-2,3-bis(methoxym-
ethyloxy)benzaldehyde (20cc), and (3) reduction with
NaBH4. The halogen-metal exchange in 21cc was ef-
fective using metalation by treatment with n-BuLi fol-
lowed by formylation by treatment with DMF to give
5-formyl-2,3-bis(methoxymethyloxy)benzyl alcohol (25cc).
The formyl benzyl alcohol 25cc was then converted to
the corresponding benzyl bromide (26cc) by bromination
with NBS-Ph3P. Stille coupling of 26cc with vinylstan-
nane 3 using Pd2(dba)3-Ph3As gave the corresponding
coupling product (27cc), which was then converted to the
corresponding diol (28bb) by deprotection with HCl-
MeOH. Mitsunobu cyclization of 28bb gave 9-hydroxy-
3-methyl-2,5-dihydro-1-benzoxepin-7-carbaldehyde (7b),
and the oxidation of 7b with Ag2O gave 9-hydroxy-3-
methyl-2,5-dihydro-1-benzoxepin-7-carboxylic acid 2, which
was identical with natural acid in all spectral data.1l
Experimental Section
Methods and Materials. All reactions requiring anhydrous
conditions were conducted in well dried glassware under an
argon atmosphere. Solvents were distilled immediately before
use: THF and Et2O from Na/benzophenone; benzene, pyridine,
and DMF from calcium hydride (DMF; under reduced pres-
sure); and MeOH from Mg(OMe)2. CH2Cl2, was distilled first
from P2O5 and then from CaH2. Organic solutions were
concentrated by a rotary evaporator below 45 °C in vacuo.
Analytical TLC was carried out using 0.25 mm Merck silica
gel plates (60F-254) using UV light as plates, and column
chromatography was performed with 230-400 mesh Merck
silica gel 60 for flash chromatography. Melting points were
taken on a micro melting point apparatus and are uncorrected.
IR spectra were obtained in liquid films or KBr disks on an
1
FT/IR spectrometer, and H NMR spectra were obtained in a
CDCl3 solution on a 400 MHz spectrometer. 1H NMR data are
reported in parts per million (δ) downfield from internal TMS;
coupling constants are given in hertz. Elemental analyses were
determined on a micro CHN analyzer. Mass spectra were
recorded under electron ionization (EI) conditions on a mass
spectrometer.
General Method for Stille Coupling.3 Under an argon
atmosphere, Pd2(dba)3-CHCl3 (53 mg, 0.054 mmol) and tri-
phenylarsine (126 mg, 0.41 mmol) were added to dry deoxy-
genated DME (3 mL), and the suspension was stirred at room
temperature for 15 min. A solution of benzyl bromide 16ac,cc,
22ac, or 26cc (1.00 mmol) and vinylstannane 3 (366 mg, 1.15
mmol) in dry deoxygenated DME (7 mL) was added to the
suspension, and the mixture was heated at 85 °C for 24 h.
After cooling, the mixture was diluted with diethyl ether and
filtered through a thin pad of anhydrous magnesium sulfate.
The ethereal filtrate was washed with a 10% aqueous potas-
sium fluoride solution, a saturated aqueous ammonium chlo-
ride solution, and brine, dried over anhydrous magnesium
sulfate, and concentrated in vacuo. The residue was purified
on a silica gel column, eluted with 10% ethyl acetate in hexane,
to give a corresponding coupled product 17ac,cc, 23ac, or
27cc. The yields of the Stille coupling are summarized in Table
1.
(6) Ruppe, E.; Linck, K. Arch. Pharm. 1915, 253, 33. Davies, W. J.
Chem. Soc. 1923, 123, 1580.
J. Org. Chem, Vol. 70, No. 19, 2005 7509

Yamaguchi et al.
TABLE 1. Stille Coupling of Benzyl Bromides 11ac,cc,
16ac,cc, 22ac, and 26cc with Vinylsatnanne 3a
TABLE 2. Mitsunobu Cyclization of Diols 13ab, 18ab,
and 24ab or Triols 13bb, 18bb, and 28bba
benzyl bromide
coupling product (yield)
substrate
reaction time
benzoxepin (yield)
11ac
11cc
16ac
16cc
22ac
26cc
12ac (53%)3
12cc (56%)3
17ac (62%)
17cc (93%)
23ac (58%)
27cc (99%)
13ab
13bb
18ab
18bb
24ab
28bb
15 min
30 min
2 h
6a (82%)3
6b (91%)3
8a (93%)
8b (54%)
19a (54%)
7b (87%)
1.5 h
1.5 h
30 min
a Conditions: benzyl bromide (1 mol), vinylstannane 3 (1.2 mol),
Pd2(dba)3 (5 mol %), ph3As (40 mol %); reaction time, 24 h; reaction
temp, 85 °C.
a Conditions: substrate (1 mol), Ph3P (2 mol), DEAD (2 mol);
reaction temp, rt.
(s, 2H), 4.04 (s, 2H), 4.61 (br s, 1H), 5.32 (t, J ) 7.0 Hz, 1H),
7.42 (br, 1H), 8.28 (br, 1H), 9.41 (br s, 1H), 9.43 (br s, 1H),
9.86 (s, 1H), 9.88 (br s, 1H), 9.90 (br s, 1H); MS m/z 204 (M+),
189 (M+ - H2O - CH3). Anal. Calcd for C12H14O4‚1/4H2O: C,
63.57; H, 6.46. Found: C, 63.81; H, 6.39.
1
17ac: 73%; pale yellow oil; H NMR δ 1.53-1.76 (m, 6H),
1.82 (br s, 3H), 3.54 (br t, J ) 7.4 Hz, 2H), 3.59 (s, 3H), 3.84
(s, 3H), 3.90 (dt, J ) Hz, 2H), 4.22 (d, J ) 11.7 Hz, 1H), 4.23
(d, J ) 11.7 Hz, 1H), 4.64 (t, J ) 4.0 Hz, 1H), 5.10 (s, 2H),
5.56 (t, J ) 7.4 Hz, 1H), 6.79 (d, J ) 7.7 Hz, 2H), 7.01 (t, J )
7.7 Hz, 1H). Anal. Calcd for C19H28O5: C, 67.83; H, 8.39.
Found: C, 67.57; H, 8.29.
General Method for Mitsunobu Cyclization.3 Mit-
sunobu cyclizations of diol 13ab and triol 13bb giving radu-
lanin A (6b) and radulanin B (6a) were already reported in
our previous paper.3 Diols 18ab, 24ab or triols 18bb, 28bb
were subjected to the similar Mitsunobu cyclizations, according
1
17cc: 93%; pale yellow oil; H NMR δ 1.55-1.76 (m, 6H),
1.82 (br s, 3H), 3.50-3.52 (m, 2H), 3.50 (s, 3H), 3.59 (s, 3H),
3.45-3.56 (m, 1H), 3.86-3.92 (m, 1H), 4.18-4.25 (m, 2H), 4.63
(t, J ) 3.2 Hz, 1H), 5.11 (s, 2H), 5.18 (s, 2H), 5.54 (t, J ) 7.3
Hz, 1H), 6.83 (dd, J ) 2.3 and 7.1 Hz, 1H), 6.95-7.01 (m, 2H).
Anal. Calcd for C20H30O6: C, 65.55; H, 8.25. Found: C, 65.27;
H, 8.23.
3
to the reported procedure.
Under an argon atmosphere, to a solution of diols 18ab,
24ab or triols 18bb, 28bb (0.500 mmol) and triphenylphos-
phine (285 mg, 1.09 mmol) in dry THF (3 mL) at room
temperature was added a 40% DEAD toluene solution (461
mg, 1.06 mmol) in dry THF (2.5 mL), and the mixture was
stirred for 1.5 h. The mixture was diluted with water and
extracted with diethyl ether. The organic layer was washed
with brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was purified on a silica
gel column, eluted with 10% ethyl acetate in hexane, to give
the corresponding 3-methyl-2,5-dihydro-1-benzoxepin 8a,b,
19a, or 7b. The yields in the Mitsunobu cyclization are
summarized in Table 2.
1
23ac: 58%; pale yellow oil; H NMR δ 1.55-1.76 (m, 6H),
1.82 (br s, 3H), 3.50-3.52 (m, 2H), 3.56 (s, 3H), 3.81 (s, 3H),
3.45-3.56 (m, 1H), 3.86-3.92 (m, 1H), 4.18 (br s, 2H), 4.62 (t,
J ) 3.1 Hz, 1H), 5.05 (s, 2H), 5.48 (t, J ) 7.3 Hz, 1H), 6.88 (d,
J ) 2.2 Hz, 1H), 6.92 (d, J ) 2.2 Hz, 1H). Anal. Calcd for
C19H27O5Br: C, 54.94; H, 6.55. Found: C, 54.81; H, 6.33.
27cc: 99%; yellow oil; IR ν 1697 cm-1; 1H NMR δ 1.52-1.81
(m, 6H), 1.85 (br s, 3H), 3.50-3.52 (m, 2H), 3.51 (s, 3H), 3.59
(s, 3H), 3.45-3.56 (m, 1H), 3.86-3.92 (m, 1H), 4.10-4.15 (m,
2H), 4.64 (t, J ) 3.8 Hz, 1H), 5.23 (s, 2H), 5.25 (s, 2H), 5.55 (t,
J ) 7.4 Hz, 1H), 7.59 (d, J ) 2.0 Hz, 1H), 7.64 (d, J ) 2.0 Hz,
1H), 9.86 (s, 1H). Anal. Calcd for C21H30O7‚1/2H2O: C, 62.51;
H, 7.76. Found: C, 62.53; H, 7.69.
6a: 93%; colorless oil; 1H NMR δ 1.52 (br s, 3H), 3.36 (br d,
J ) 3.9 Hz, 2H), 4.45 (br s, 2H), 5.61-5.65 (br t, J ) 3.9 Hz,
1H), 5.72 (s, 1H), 6.59-6.61 (m, 1H), 6.83-6.92 (m, 2H); MS
m/z 190 (M+), 175 (M+ - CH3). The sample was identical with
that prepared from 6b by methylation using methyl iodide-
potassium carbonate (69%).
General Method for Acidic Deprotection. Under an
argon atmosphere, to a solution of 17ac,cc, 23ac, or 27cc in
methanol was added a catalytic amount of concentrated
hydrochloric acid, and the mixture was refluxed for 30 min.
After cooling, the mixture was concentrated in vacuo, and the
mixture was treated with a saturated aqueous sodium hydro-
gencarbonate solution and extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo. The residue
was purified on a silica gel column, eluted with 50% ethyl
acetate in hexane, to give the corresponding deprotected diols
18ab, 24ab or triols 18bb, 28bb.
6b: 54%; pale yellow oil; IR ν 3424 cm-1; 1H NMR δ 1.57 (br
s, 3H), 3.40 (br d, J ) 3.9, 2H), 4.45 (br s, 2H), 5.61-5.65 (m,
1H), 5.72 (s, 1H), 6.59-6.61 (m, 1H), 6.83-6.92 (m, 2H); MS
m/z 176 (M+).
19a: 54%; red crystals; mp 68-70 °C (recrystallized from
hexane); 1H NMR δ 1.52 (br s, 3H), 3.34 (br d, J ) 3.9 Hz,
2H), 3.85 (s, 3H), 4.40 (br s, 2H), 5.50-5.66 (br t, J ) 3.9 Hz,
1H), 6.84 (d, J ) 2.1 Hz, 1H), 6.93 (d, J ) 2.1 Hz, 1H); MS m/z
270 and 268 (M+). Anal. Calcd for C12H13O2Br: C, 53.55; H,
4.87. Found: C, 53.65; H, 5.00.
18ab: 80%; pale yellow oil; IR ν 3420 cm-1; 1H NMR δ 1.85
(br s, 3H), 3.46 (d, J ) 7.7 Hz, 2H), 3.91 (s, 3H), 4.27 (br s,
2H), 5.45 (t, J ) 7.7 Hz, 1H), 6.77 (m, 2H), 6.83 (t, J ) 7.7 Hz,
2H); MS m/z 208 (M+). Anal. Calcd for C12H16O3: C, 69.21; H,
7.74. Found: C, 69.13; H, 7.63.
7b: 87%; colorless needles; mp 100-101 °C (recrystallized
from cyclohexane-diethyl ether); IR ν 3367, 1691 cm-1 1H
;
NMR δ 1.64 (br s, 3H), 3.45 (br d, J ) 3.9 Hz, 2H), 4.55 (br s,
2H), 5.60-5.80 (br t, J ) 3.9 Hz, 1H), 5.86 (s, 1H), 7.17 (d, J
) 2.1 Hz, 1H), 7.35 (d, J ) 2.1 Hz, 1H), 9.84 (s, 1H); MS m/z
204 (M+), 189 (M+ - CH3). Anal. Calcd for C12H12O3: C, 70.57;
H, 5.92. Found: C, 70.68; H, 6.03.
18bb: 87%; pale yellow oil; IR ν 3381 cm-1; 1H NMR δ 1.80
(br s, 3H), 2.51 (br s, 1H), 3.43 (d, J ) 8.1 Hz, 2H), 4.32 (br s,
2H), 5.44 (t, J ) 8.1 Hz, 1H), 5.80 (br s, 1H), 6.66 (dd, J ) 7.3
and 2.0 Hz, 1H), 6.72-6.79 (m, 2H), 7.60 (br s, 1H); MS m/z
194 (M+). Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found:
C, 68.27; H, 7.29.
MOM Protection of 6b, 8b. Under an argon atmosphere,
a solution of 6b or 8b (0.15 mmol) in dry THF (5 mL) was
carefully treated with a suspension of 60% oily sodium hydride
(33 mg, 1.4 mmol) in dry THF (3 mL) at room temperature,
and the mixture was stirred at room temperature for 30 min.
Chloromethyl methyl ether (3.9 mL, 40 mmol) was added
dropwise to the mixture, and the mixture was stirred at room
temperature for 2 h. The mixture was treated with cold water
and extracted with ethyl acetate. The organic layer was
washed with a 5% aqueous sodium hydroxide solution and
brine, dried over anhydrous magnesium sulfate, and concen-
trated in vacuo. The residue was purified on a silica gel
24ab: 87%; orange crystals, mp 105-107 °C; IR ν 3438, 3266
cm-1; 1H NMR δ 1.82 (br s, 3H), 3.38 (d, J ) 7.8 Hz, 2H), 3.78
(s, 3H), 4.23 (br s, 2H), 5.39 (t, J ) 7.8 Hz, 1H), 6.85 (d, J )
2.8 Hz, 1H), 6.88 (d, J ) 2.8 Hz, 1H); MS m/z 286 and 288
(M+). Anal. Calcd for C12H15O3Br: C, 50.19; H, 5.27. Found:
C, 50.26; H, 5.32.
28bb: 92%; yellow crystals, mp 164-166 °C (recrystallized
from ethanol); IR ν 3456 cm-1; 1H NMR δ 1.74 (br s, 3H), 3.32
7510 J. Org. Chem., Vol. 70, No. 19, 2005

Two 3-Methyl-2,5-dihydro-1-benzoxepin Carboxylic Acids
column, eluted with 5% ethyl acetate in hexane, to give the
corresponding MOM ether 6c or 8c.
(s, 1H), 6.53 (s, 1H), 7.17-7.22 (m, 3H), 7.27-7.31 (m, 2H),
8.48 (s, 1H).
6c: 35%; yellow oil; 1H NMR δ 1.53 (br s, 3H), 2.82-2.92
(m, 4H), 3.45 (br d, J ) 3.8 Hz, 2H), 3.48 (s, 3H), 4.40 (br s,
2H), 5.12 (s, 2H), 5.16 (br t, J ) 3.8 Hz, 1H), 6.37 (d, J ) 1.2
Hz, 1H), 6.68 (d, J ) 1.2 Hz, 1H), 7.18-7.23 (m, 3H), 7.26-
7.30 (m, 2H).
General Method for Oxidation with Ag2O.4 Fresh silver
oxide was prepared by treating a solution of silver nitrate (34
mg, 0.20 mmol) with 1 M aqueous sodium hydroxide solution
(0.40 mL), and the suspension was stirred at room temperature
for 30 min. A solution of carbaldehyde 4b or 7b (0.100 mmol)
in a 1 M sodium hydroxide aqueous solution was added to the
suspension of silver oxide, and the mixture was refluxed gently
for 30 min. After cooling, the mixture was filtered to remove
metallic Ag, and the aqueous alkaline filtrate was washed once
with diethyl ether, acidified with 10% hydrochloric acid, and
extracted with diethyl ether. The organic layer was washed
with brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was purified on a silica
gel column, eluted with 30% ethyl acetate in hexane, to give a
corresponding carboxylic acid 1 or 2.
8c: 86%; pale pink oil; 1H NMR δ 1.52 (br s, 3H), 3.36 (br d,
J ) 3.8 Hz, 2H), 3.86 (s, 3H), 4.43 (br s, 2H), 5.60 (br t, J )
3.8 Hz, 1H), 6.93-7.02 (m, 3H), 10.37 (s, 1H).
Vilsmeier Formylation of 6a,c.4,5 Under an argon atmo-
sphere, N-methylformanilide (98 mg, 0.73 mmol) was treated
with phosphoryl chloride (80 mg, 0.53 mmol), and the mixture
was heated at 90 °C for 20 min. A solution of benzoxepin 6a,c
(0.01 mmol) in N-methylformanilide (1.5 mL) was added to
the mixture, and the mixture was heated at the same tem-
perature for 40 min. After cooling, the mixture was poured on
a saturated aqueous sodium hydrogencarbonate solution and
extracted with diethyl ether. The organic layer was washed
with brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was purified on a silica
gel column, eluted with 5% ethyl acetate in hexane, to give a
mixture of 9-carbaldehyde 4a and 7-carbaldehyde 5a (from 6a)
or a pure 9-carbaldehyde 4b (from 6c). The ratio of 4a and 5a
1
1: 50%; IR ν 3411, 1665 cm-1; H NMR δ 1.55 (br s, 3H),
2.78-2.90 (br d, J ) 7.0 Hz, 2H), 3.38-3.49 (m, 2H), 4.42 (br
s, 2H), 5.58-5.64 (br t, J ) 7.0 Hz, 1H), 6.38 (s, 1H), 6.53 (s,
1H), 7.17-7.22 (m, 3H), 7.27-7.31 (m, 2H), 8.48 (s, 1H). The
spectral data were identical with those of natural radulanin
H, obtained from Radula species.1k
2: 63%; yellow crystals; IR ν 3500-2500, 1695 cm-1 1H
;
1
was determined from the H NMR spectrum of the mixture.
4a: 36% determined by 1H NMR; yellow oil; IR ν 1678 cm-1
;
NMR (DMSO-d6) δ 1.51 (br s, 3H), 3.33 (br d, J ) 7.3 Hz, 2H),
4.35 (br s, 2H), 5.56-5.62 (br t, J ) 7.3 Hz, 1H), 7.17 (d, J )
2.1 Hz, 1H), 7.30 (d, J ) 2.1 Hz, 1H), 8.30 (s, 1H), 9.44 (s,
1H); MS m/z 220 (M+), 1695 (M+ - CH3). The spectral data
were identical with those of natural 9-hydroxy-3-methyl-2,5-
dihydro-1-benzoxepin-7-carboxylic acid, obtained from Hemi-
zonia lobbii.1l
1H NMR δ 1.55 (br s, 3H), 2.85 (dd, J ) 5.9 and 7.8 Hz, 2H),
3.27 (dd, J ) 5.9 and 7.8 Hz, 2H), 3.42-3.43 (br d, J ) 3.9 Hz,
2H), 3.77 (s, 3H), 4.51 (br s, 2H), 5.58-5.64 (br t, J ) 3.9 Hz,
1H), 6.36 (s, 1H), 7.17-7.22 (m, 3H), 7.27-7.31 (m, 2H), 10.49
(s, 1H).
6-Methoxy-3-methy-8-(phenylethyl)-2,5-dihydro-1-ben-
zoxepin-7-carbaldehyde 5a: 4% determined by 1H NMR;
1
yellow oil; IR ν 3367, 1691 cm-1; H NMR δ 1.55 (br s, 3H),
Supporting Information Available: Preparative proce-
dures and spectral data of benzaldehydes 9ac,cc, 14ac,cc, and
20ac,cc, benzyl alcohols 10ac,cc, 15ac,cc, 21ac,cc, and 25cc,
and benzyl bromides 11ac,cc, 16ac,cc, 22ac, and 26cc. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2.91 (br d, J ) 3.9 Hz, 2H), 3.20 (m, 2H), 3.42-3.43 (m, 2H),
3.80 (s, 3H), 4.51 (br s, 2H), 5.58-5.64 (br t, J ) 3.9 Hz, 1H),
6.11 (s, 1H), 7.17-7.12 (m, 3H), 7.27-7.31 (m, 2H), 10.36 (s,
1H).
4b: 50% from 6c; yellow oil; IR ν 3411, 1665 cm-1; 1H NMR
δ 1.55 (br s, 3H), 2.78-2.90 (br d, J ) 3.9 Hz, 2H), 3.38-3.49
(m, 2H), 4.42 (br s, 2H), 5.58-5.64 (br t, J ) 3.9 Hz, 1H), 6.38
JO050550L
J. Org. Chem, Vol. 70, No. 19, 2005 7511