A synthetic pathway to the 1,4-dihydro-2H-3-benzoxocine system from Morita-Baylis-Hillman cinnamyl alcohols with 2,5-dimethoxy-2,5-dihydrofuran via the Heck reaction

Article abstract of DOI:10.1055/s-0032-1317471

A new synthetic method for methyl 2-methoxy-1-(methoxycarbonylmethyl)-1,4- dihydro-2H-3-benzoxocine-5-carboxylates was developed using the Heck reaction between 2,5-dimethoxy-2,5-dihydrofuran and methyl 2-(hydroxymethyl)-3-(2- iodophenyl)propenoates as a

Full text of DOI:10.1055/s-0032-1317471

PAPER
▌3613
paper
A Synthetic Pathway to the 1,4-Dihydro-2H-3-benzoxocine System from
Morita–Baylis–Hillman Cinnamyl Alcohols with 2,5-Dimethoxy-2,5-dihydro-
furan via the Heck Reaction
1,4-Dihydro-2H-3-benzoxocine Derivatives
Sang-Hyun Ahn, Young Keun Kim, Jina Hyun, Kee-Jung Lee*
Organic Synthesis Laboratory, Department of Chemical Engineering, Hanyang University, Seoul 133-791, South Korea
Fax +82(2)22984101; E-mail: leekj@hanyang.ac.kr
Received: 10.08.2012; Accepted after revision: 24.09.2012
Pd(OAc)2
DIPEA, BTEAC
DMF, 70 °C
Abstract: A new synthetic method for methyl 2-methoxy-1-(meth-
oxycarbonylmethyl)-1,4-dihydro-2H-3-benzoxocine-5-carboxylates
was developed using the Heck reaction between 2,5-dimethoxy-2,5-
dihydrofuran and methyl 2-(hydroxymethyl)-3-(2-iodophenyl)pro-
penoates as a key step. The latter were readily obtained from the
Morita–Baylis–Hillman reaction of iodobenzaldehydes with methyl
acrylate through acetylation, rearrangement, and hydrolysis. The
methyl 2-methoxy-1-(methoxycarbonylmethyl)-1,4-dihydro-2H-3-
benzoxocine-5-carboxylates were converted into methyl 2-oxo-
1,2,5,11b-tetrahydro-3aH-furo[3,2-a][3]benzoxocine-6-carboxylates
on exposure to excess trifluoroacetic acid.
I
+
MeO
OMe
OMe
O
OH
CO2Me
OMe
O
O
OMe
OH
Key words: Morita–Baylis–Hillman, Heck reaction, 1,4-dihydro-
2H-3-benzoxocines, iodobenzaldehydes, 2,5-dimethoxy-2,5-dihy-
drofuran
CO2Me
BF3⋅OEt2, CH2Cl2
O
Scheme 1
Medium-sized oxacycles, oxocines, are an important
structural unit present in numerous biologically active
molecules.1 Among them, 3-benzoxocines are devoid of
any biological profile and only a few synthetic procedures
have been implemented. 3-Benzoxocines have been pre-
pared from 2-phenylethanol bearing bromoallenes in the
presence of a palladium(0) catalyst and alcohol,2 by flash
vacuum pyrolysis of 8-oxabenzo[c]tricyclo[5.1.0.02,6]oc-
tanes via ring expansion,3 and by a platinum-catalyzed
skeletal rearrangement of 2-epoxy-1-(siloxyalk-2-
ynyl)benzenes.4
Our synthesis began with the generation of methyl 2-(hy-
droxymethyl)-3-(2-iodophenyl)propenoates 5 as the start-
ing material following a previously reported procedure. In
the MBH reaction of iodobenzaldehydes 1 with methyl
acrylate, 1,4-diazabicyclo[2.2.2]octane (DABCO), and
triethanolamine without solvent, the MBH adducts 2 were
produced in 60–98% yield. Acetylation of the adducts 2
with acetic anhydride in the presence of a catalytic
amount of 4-(dimethylamino)pyridine in dichlorometh-
ane at room temperature gave the MBH acetates 3 in 88–
95% yield.9 In a DABCO-catalyzed rearrangement of al-
lylic esters 3 in tetrahydrofuran at reflux temperature,10
methyl 2-(acetoxymethyl)-3-(2-iodophenyl)propenoates
4 were obtained in 72–90% yield. Hydrolysis of the latter
with potassium carbonate in aqueous methanol11 at room
temperature gave the desired iodocinnamyl alcohols 5
(72–94% yield).
Ogasawara and co-workers have reported the expedient
synthesis of methyl benzofuran-3-acetate5 and indole-3-
acetic acid6 by employing the Heck reaction between 2-io-
dophenol or 2-iodoaniline derivatives and 2,5-dimethoxy-
2,5-dihydrofuran as the key step (Scheme 1).
The Morita–Baylis–Hillman (MBH) reaction7 has attract-
ed the attention of organic chemists in recent years. This
reaction provides synthetically useful, multifunctional
molecules that have been successfully employed in vari-
ous heterocycle syntheses. In efforts to expand MBH
chemistry,8 we have developed a method to synthesize the
3-benzoxocine derivatives 10 using the Heck reaction be-
tween the MBH cinnamyl alcohols 5 and 2,5-dimethoxy-
2,5-dihydrofuran (6), as shown in Scheme 2.
In the Heck reaction of the MBH cinnamyl alcohols 5 with
2,5-dimethoxy-2,5-dihydrofuran (6) in N,N-dimethylform-
amide containing N,N-diisopropylethylamine (DIPEA)
and benzyltriethylammonium chloride (BTEAC), in the
presence of a catalytic amount of palladium(II) acetate at
80 °C for 1–24 hours, methyl 2-methoxy-1-(methoxycar-
bonylmethyl)-1,4-dihydro-2H-3-benzoxocine-5-carbox-
ylates 10a–f were produced in 37–59% yield as single
diastereomers (Scheme 2 and Table 1); however, the di-
methoxy-substituted cinnamyl alcohol 5g did not react,
and unchanged 5g was recovered. The substituent group
at the 3-position seems to be important for the reactivity
SYNTHESIS 2012, 44, 3613–3622
Advanced online publication: 17.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317471; Art ID: SS-2012-F0656-OP
© Georg Thieme Verlag Stuttgart · New York

3614
S.-H. Ahn et al.
PAPER
H2C=CHCO2Me
DABCO, (HOCH2CH2)3N
r.t., 10–192 h
R1
OH
I
R1
O
I
Ac2O, DMAP
CH2Cl2, r.t., 20 min to 1 h
R2
R3
CO2Me
R2
R3
H
60–98%
88–95%
R4
R4
R1
2
1
OAc
R1
K2CO3, MeOH–H2O (3:1)
r.t., 20 min to 2 h
DABCO, THF
reflux, 2–7 d
R2
R3
CO2Me
R2
R3
CO2Me
OAc
72–90%
72–94%
I
I
R4
R1
R4
3
4
R1
2,5-dimethoxy-2,5-dihydrofuran (6)
Pd(OAc)2, DIPEA, BTEAC
DMF, 80 °C, 1–24 h
MeO
O
OMe
R2
R3
CO2Me
R2
R3
CO2Me
OH
6
PdI OH
I
R4
R4
R1
5
7
R1
R1
CO2Me
R2
R3
CO2Me
OH
6
R2
R3
CO2Me
OH
R2
R3
4
O
2
1
R4
37–59%
R4
R4
OMe
OMe
OMe
CO2Me
10
IPd
MeO
O
O
MeO
H
9
8
R1
H
F
R2
H
R3
H
R4
H
H
H
H
H
H
1, 2, 3, 4, 5, 10
a
b
c
d
e
f
H
H
H
H
H
H
H
Br
H
H
Cl
H
Me
OMe
H
H
OMe
OMe
g
Scheme 2
of the substrate due to steric factors. The formation of 3-
benzoxocines 10 might be explained by a typical Heck re-
action mechanism involving the oxidative addition of the
aryl iodide to give the arylpalladium iodide 7, then carbo-
metalation of the dihydrofuran 6 to give the 3-aryl-2,5-di-
methoxytetrahydrofuran-4-palladium iodide 8,12 and a
subsequent β-hydride syn elimination to give the dihydro-
furan 9. Then, acid-catalyzed (DIPEA·HI) transacetaliza-
tion and concomitant ring opening of 9 would produce the
3-benzoxocine 10.
Table 1 Preparation of 3-Benzoxocine Derivatives 10 and 14
10
Time (h) Yield (%) 14
Time (h) Yield (%)
10a
10b
10c
10d
10e
10f
3
6
41
59
37
43
43
42
14a
14b
14c
14d
14e
14f
24
72
24
48
24
24
69
68
70
76
63
61
23
24
2
Next, we examined the feasibility of 3-benzoxocines 10 as
a factor in the elimination of methanol for the preparation
of methyl 1-(methoxycarbonylmethyl)-4H-3-benzoxo-
cine-5-carboxylates 11 (Scheme 3). When 3-benzoxocine
10a was treated with boron trifluoride–diethyl ether com-
plex in dichloromethane,5 the elimination reaction did not
occur and unchanged starting material 10a was recovered.
On exposure to excess trifluoroacetic acid, the 3-benzoxo-
cines 10 were converted into methyl 2-oxo-1,2,5,11b-tet-
1
10g
24
0a
a Starting material 5g was recovered.
rahydro-3aH-furo[3,2-a][3]benzoxocine-6-carboxylates
14 as single products in 61–76% yield (Scheme 3 and
Table 1). The expected compounds 11 were not produced.
Synthesis 2012, 44, 3613–3622
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,4-Dihydro-2H-3-benzoxocine Derivatives
3615
R1
R1
CO2Me
CO2Me
BF3⋅OEt2, CH2Cl2
r.t. to reflux, 48 h
R2
R3
R2
R3
O
O
R4
R4
OMe
CO2Me
10
CO2Me
11
CF3CO2H
CH2Cl2
r.t., 24–72 h
R1
CO2Me
R1
CO2Me
R1
CO2Me
6
R2
R2
R3
–
R2
R3
CF3CO2
4
or MeOH
O+
O
O
R3
1
2
61–76%
R4
R4
R4
O
O
1'
O
+OMe
O
MeO
12
13
14
R1
H
F
R2
H
R3
R4
H
H
H
H
H
H
10, 14
a
b
c
d
e
f
H
H
H
Cl
H
H
H
H
H
H
H
Br
H
Me
OMe
Scheme 3
The pathway is presumed to be initiated by the acid- the methine proton at C2 at δ = 5.24 as a doublet (J = 7.4
mediated elimination of methanol generating the oxonium Hz), and the methine proton at C6 at δ = 8.00 as a singlet.
ion 12, followed by attack of the ester carbonyl oxygen to The methylene protons at C4 were found at δ = 3.77–3.82
give 13, and subsequent demethylation by nucleophilic at- as a multiplet and 4.90 as a doublet (J = 14.4 Hz), each for
tack of a trifluoroacetate ion or methanol to give the lac- a single proton. The methylene protons of the lactone
tone 14.
were observed at δ = 2.84 (J = 17.3, 8.4 Hz) and 3.21
(J = 17.3, 13.2 Hz), each as a doublet of a doublet. Only a
single methyl signal was found at δ = 3.88, as a singlet.
The structure of 14a was also confirmed by HMQC and
DEPT experiments. The two methylene protons of the lac-
tone correlated with carbon atoms at δ = 33.2 and the C4
methylene protons correlated with carbon atoms at
δ = 60.7. The three methine protons at C1, C2, and C6 were
correlated with carbon atoms at δ = 45.0, 106.0, and
141.3, respectively.
The structures of the 3-benzoxocine derivatives 10 and 14
were elucidated by H and 13C NMR spectroscopy.13 In
1
the 1H NMR spectrum of 10a, the characteristic chemical
shift of the methine proton at C1 was at δ = 3.71–3.76 as a
multiplet, and the methine proton at C2 was observed at
δ = 4.21 as a doublet (J = 9.4 Hz). The methine proton at
C6 was found at δ = 7.76 as a singlet. The methylene pro-
tons at C4 were observed at δ = 4.41 as a doublet (J = 19.0
Hz) and 4.90 as a doublet of a doublet (J = 19.0, 1.8 Hz),
and the methylene protons of the acetate at C1 appeared at Next, in order to determine the stereochemistry of 10 and
δ = 2.75 and 2.92, each as a doublet of a doublet (J = 15.9, 14, NOE experiments were conducted on 10a and 14a. Ir-
7.6 Hz). The proton signals for the three methoxy groups radiation of the signal for C1H (δ = 3.71–3.76) in 10a led
appeared as three singlets at δ = 3.35, 3.61, and 3.82. The to NOE enhancement of the signal for C2H (0.58%) and ir-
13C NMR spectrum of 10a showed two ester carbonyl car- radiation of the signal for C2H (δ = 4.21) led to NOE en-
bon signals at δ = 166.6 and 172.4, and three methoxy car- hancement of the signal for C1H (0.41%). Small NOE
bon signals at δ = 51.7, 52.0, and 55.5. The structure of enhancements might suggest that 10a is a trans-com-
10a was confirmed by HMQC and DEPT experiments. pound, but the stereochemistry is uncertain.14 In the case
Methylene protons correlated with carbon atoms at of 14a, as shown in Figure 1, irradiation of the signal for
δ = 34.6 for acetate at C1 and with carbon atoms at C1H (δ = 3.69–3.75) led to NOE enhancement of the sig-
δ = 59.4 for C4. The three methine protons at C1, C2, and nals for C1′Ha (δ = 2.84, 2.03%) and C2H (0.58%), and no
C6 were correlated with carbon atoms at δ = 41.2, 104.6, enhancement of the signal for C1′Hb (δ = 3.21, 0%). Irra-
and 137.4, respectively.
In contrast, in the 1H NMR spectrum of 14a, the methine
proton at C1 was observed at δ = 3.69–3.75 as a multiplet,
diation of the signal for C2H (δ = 5.24) led to NOE en-
hancement of the signals for C1′Hb (0.70%) and C1H
(0.86%), and no enhancement of the signal for C1′Ha (0%).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3613–3622

3616
S.-H. Ahn et al.
PAPER
2-Iodobenzaldehyde (1a) and 2-fluoro-6-iodobenzaldehyde (1b)
were purchased from Aldrich. The known iodobenzaldehydes 1c,15a
1d–f,15b and 1g,15c MBH adduct 2a,9a and MBH acetate 3a9b were
prepared according to the literature procedures. Petroleum ether
(PE) refers to the fraction boiling at 30–60 °C.
These results suggest that 14a is presumably a trans-com-
pound.14
C1-H irradiation
C2-H irradiation
CO2Me
CO2Me
6
6
Morita–Baylis–Hillman Adducts 2; General Procedure
A mixture of the iodobenzaldehyde 1 (10 mmol), methyl acrylate
(2.70 mL, 30 mmol), DABCO (1.12 g, 10 mmol), and triethanol-
amine (1.19 g, 8 mmol) was stirred at r.t. for 10–192 h. Then, the
mixture was diluted with H2O (20 mL) and extracted with CH2Cl2
(3 × 30 mL). The combined organic layers were dried (MgSO4) and
the solvent was evaporated under reduced pressure. The resulting
mixture was chromatographed on silica gel (hexane–EtOAc, 3:1) to
provide 2.
4
4
0.86%
0.58%
O
O
1
2
1
2
H
H
H
H
1'
1'
0%
O
O
Hb
Hb
Ha
Ha
O
O
0%
2.03%
0.70%
Methyl 3-(2-Fluoro-6-iodophenyl)-3-hydroxy-2-methylenepro-
panoate (2b)
Reaction time: 10 h; yield: 3.29 g (98%); yellow oil.
Figure 1
IR (CH2Cl2): 3435, 1720, 1664, 1631, 1595, 1566, 1449 cm–1.
To introduce more diversity in the products, we tested our
strategy by investigating the Heck reaction of the bromo-
substituted MBH cinnamyl alcohol 15 (Figure 2), instead
of the iodocinnamyl alcohol 5a, and found that the reac-
tion did not occur. In addition, we examined the Heck re-
action of the MBH iodocinnamyl alcohol 16 derived from
methyl vinyl ketone; however, the reaction yielded a very
1H NMR (CDCl3): δ = 3.12 (dd, J = 6.7, 2.6 Hz, 1 H, OH), 3.76 (s,
3 H, OCH3), 5.81 (s, 1 H, CH), 5.96 (dd, J = 6.7, 1.8 Hz, 1 H, CH),
6.40 (s, 1 H, CH), 6.94–7.09 (m, 2 Harom), 7.67–7.70 (m, 1 Harom).
13C NMR (CDCl3): δ = 52.1, 75.8, 100.0, 116.9 (d, J = 23.1 Hz),
126.2, 130.5 (d, J = 12.8 Hz), 130.9 (d, J = 9.4 Hz), 135.9 (d,
J = 3.1 Hz), 139.5, 160.6 (d, J = 253.8 Hz), 166.4.
EIMS: m/z (%) = 336 (1) [M+], 249 (36), 209 (100), 177 (60), 149
complex mixture of products that could not be purified, (16), 123 (47), 101 (20), 87 (62).
indicating a limitation of the method. Other typical Heck
reaction conditions were also unsuccessful.
Anal. Calcd for C11H10FIO3: C, 39.31; H, 3.00. Found: C, 39.14; H,
3.19.
Methyl 3-(5-Bromo-2-iodophenyl)-3-hydroxy-2-methylenepro-
panoate (2c)
CO2Me
OH
COMe
OH
Reaction time: 17 h; yield: 3.85 g (97%); colorless oil.
Br
15
I
IR (CH2Cl2): 3436, 1720, 1630, 1439 cm–1.
16
1H NMR (CDCl3): δ = 3.24 (d, J = 4.1 Hz, 1 H, OH), 3.82 (s, 3 H,
OCH3), 5.53 (s, 1 H, CH), 5.73 (d, J = 4.1 Hz, 1 H, CH), 6.38 (s, 1
H, CH), 7.16 (dd, J = 8.5, 2.6 Hz, 1 Harom), 7.66 (d, J = 2.6 Hz, 1
Harom), 7.68 (d, J = 8.5 Hz, 1 Harom).
Figure 2
In summary, a new method for the synthesis of methyl 2-
methoxy-1-(methoxycarbonylmethyl)-1,4-dihydro-2H-3-
benzoxocine-5-carboxylates from the MBH adducts of io-
dobenzaldehydes was developed through a process of
acetylation, rearrangement, hydrolysis, and palladium-
catalyzed Heck reaction with 2,5-dimethoxy-2,5-dihydro-
furan. Lactonization of the 2-methoxy-1-(methoxycar-
bonylmethyl)-1,4-dihydro-2H-3-benzoxocine derivatives
occurred to yield methyl 2-oxo-1,2,5,11b-tetrahydro-
3aH-furo[3,2-a][3]benzoxocine-6-carboxylates on expo-
sure to excess trifluoroacetic acid.
13C NMR (CDCl3): δ = 52.3, 75.4, 96.7, 123.1, 127.7, 131.3, 132.7,
140.1, 140.6, 144.8, 166.8.
EIMS: m/z (%) = 397 (1), 395 (1) [M+], 311 (13), 309 (11), 271
(91), 269 (100), 239 (14), 237 (14), 185 (33), 183 (37), 158 (51),
156 (33), 131 (27), 115 (26), 102 (43).
Anal. Calcd for C11H10BrIO3: C, 33.28; H, 2.54. Found: C, 33.06;
H, 2.38.
Methyl 3-(4-Chloro-2-iodophenyl)-3-hydroxy-2-methylenepro-
panoate (2d)
Reaction time: 17 h; yield: 3.25 g (92%); colorless oil.
IR (CH2Cl2): 3432, 1722, 1630, 1577, 1553, 1463, 1438 cm–1.
1H NMR (CDCl3): δ = 3.27 (d, J = 4.1 Hz, 1 H, OH), 3.79 (s, 3 H,
OCH3), 5.55 (s, 1 H, CH), 5.74 (d, J = 4.1 Hz, 1 H, CH), 6.36 (s, 1
H, CH), 7.37 (dd, J = 8.5, 2.1 Hz, 1 Harom), 7.43 (d, J = 8.5 Hz, 1
Silica gel 60 (70–230 mesh ASTM) used for column chromatogra-
phy was supplied by E. Merck. Analytical TLC was carried out on
Merck silica gel 60 F254 TLC plates. Melting points were deter-
mined using an electrothermal melting point apparatus and are un-
corrected. Elemental analyses were obtained using a Thermo
Electron Corporation Flash EA 1112 instrument. Low-resolution
mass spectra were recorded on a PerkinElmer Clarus 600 mass
spectrometer at 70 eV. IR spectra were recorded on a Nicolet Magna
550 FTIR spectrometer. 1H and 13C NMR spectra were measured on
a Varian 300 spectrometer using CDCl3. HMQC, DEPT, and NOE
spectra were measured on a Varian 600 spectrometer. All chemical
shifts are reported in ppm relative to TMS. Coupling constants (J)
are expressed in Hz.
Harom), 7.84 (d, J = 2.1 Hz, 1 Harom).
13C NMR (CDCl3): δ = 52.2, 75.3, 98.8, 127.4, 128.7, 128.8, 134.2,
138.6, 140.4, 141.4, 166.8.
EIMS: m/z (%) = 353 (2), 351 (5) [M+], 267 (23), 265 (33), 227
(33), 225 (100), 195 (25), 193 (70), 167 (8), 165 (23), 141 (25), 139
(74), 131 (17), 115 (20), 112 (60), 102 (24).
Anal. Calcd for C11H10ClIO3: C, 37.47; H, 2.86. Found: C, 37.18; H,
2.99.
Synthesis 2012, 44, 3613–3622
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,4-Dihydro-2H-3-benzoxocine Derivatives
3617
Methyl 3-Hydroxy-3-(2-iodo-5-methylphenyl)-2-methylenepro-
panoate (2e)
Hz), 136.0 (d, J = 3.4 Hz), 136.3, 160.9 (d, J = 256.4 Hz), 165.2,
169.2.
EIMS: m/z (%) = 378 (1) [M+], 303 (11), 251 (68), 209 (38), 177
(73), 149 (15), 133 (42), 43 (100).
Reaction time: 61 h; yield: 3.15 g (95%); colorless oil.
IR (CH2Cl2): 3434, 1723, 1630, 1464, 1438 cm–1.
1H NMR (CDCl3): δ = 2.31 (s, 3 H, CH3), 3.14 (d, J = 4.1 Hz, 1 H,
OH), 3.80 (s, 3 H, OCH3), 5.55 (s, 1 H, CH), 5.77 (d, J = 4.1 Hz, 1
H, CH), 6.36 (s, 1 H, CH), 6.84 (dd, J = 7.9, 2.1 Hz, 1 Harom), 7.31
(d, J = 2.1 Hz, 1 Harom), 7.69 (d, J = 7.9 Hz, 1 Harom).
13C NMR (CDCl3): δ = 21.1, 52.2, 75.8, 95.0, 127.3, 128.8, 130.7,
138.6, 139.2, 140.8, 142.3, 167.0.
Anal. Calcd for C13H12FIO4: C, 41.29; H, 3.20. Found: C, 41.42; H,
3.48.
Methyl 3-Acetoxy-3-(5-bromo-2-iodophenyl)-2-methylenepro-
panoate (3c)
Reaction time: 20 min; yield: 3.99 g (91%); white solid; mp 84–
86 °C (Et2O–PE).
EIMS: m/z (%) = 332 (1) [M+], 245 (13), 205 (100), 173 (18), 145
(23), 119 (52), 105 (11).
IR (KBr): 1748, 1727, 1634, 1439, 1371 cm–1.
1H NMR (CDCl3): δ = 2.15 (s, 3 H, CH3), 3.78 (s, 3 H, OCH3), 5.64
(s, 1 H, CH), 6.52 (s, 1 H, CH), 6.76 (s, 1 H, CH), 7.17 (dd, J = 8.5,
2.4 Hz, 1 Harom), 7.40 (d, J = 2.4 Hz, 1 Harom), 7.72 (d, J = 8.5 Hz, 1
Anal. Calcd for C12H13IO3: C, 43.39; H, 3.95. Found: C, 43.06; H,
3.79.
H
arom).
Methyl 3-Hydroxy-3-(2-iodo-5-methoxyphenyl)-2-methylene-
propanoate (2f)
13C NMR (CDCl3): δ = 20.8, 52.3, 76.2, 97.4, 122.8, 128.5, 131.3,
133.1, 137.7, 141.1, 142.2, 165.1, 169.1.
Reaction time: 49 h; yield: 2.89 g (83%); colorless oil.
IR (CH2Cl2): 3445, 1720, 1630, 1589, 1568, 1466 cm–1.
EIMS: m/z (%) = 313 (14), 311 (20), 271 (11), 269 (11), 190 (40),
1H NMR (CDCl3): δ = 3.30 (d, J = 4.1 Hz, 1 H, OH), 3.79 (s, 3 H,
OCH3), 3.80 (s, 3 H, OCH3), 5.52 (s, 1 H, CH), 5.74 (d, J = 4.1 Hz,
1 H, CH), 6.35 (s, 1 H, CH), 6.62 (dd, J = 8.5, 3.2 Hz, 1 Harom), 7.10
(d, J = 3.2 Hz, 1 Harom), 7.68 (d, J = 8.5 Hz, 1 Harom).
158 (17), 114 (13), 43 (100).
Anal. Calcd for C13H12BrIO4: C, 35.56; H, 2.75. Found: C, 35.30;
H, 2.98.
Methyl 3-Acetoxy-3-(4-chloro-2-iodophenyl)-2-methylenepro-
panoate (3d)
Reaction time: 30 min; yield: 3.74 g (95%); white solid; mp 67–
69 °C (Et2O–PE).
13C NMR (CDCl3): δ = 52.2, 55.4, 75.6, 87.2, 113.8, 115.9, 127.4,
139.8, 140.6, 143.7, 160.1, 167.0.
EIMS: m/z (%) = 348 (7) [M+], 261 (5), 221 (100), 189 (10), 161
(34), 145 (12), 135 (51), 121 (25), 108 (19).
IR (KBr): 1748, 1726, 1636, 1578, 1464, 1438 cm–1.
Anal. Calcd for C12H13IO4: C, 41.40; H, 3.76. Found: C, 41.26; H,
3.52.
1H NMR (CDCl3): δ = 2.13 (s, 3 H, CH3), 3.76 (s, 3 H, OCH3), 5.64
(s, 1 H, CH), 6.50 (s, 1 H, CH), 6.77 (s, 1 H, CH), 7.22 (d, J = 8.2
Hz, 1 Harom), 7.34 (dd, J = 8.2, 2.1 Hz, 1 Harom), 7.88 (d, J = 2.1 Hz,
1 Harom).
13C NMR (CDCl3): δ = 20.8, 52.2, 76.0, 99.4, 128.1, 128.5, 128.9,
134.8, 137.9, 138.7, 139.2, 165.1, 169.0.
EIMS: m/z (%) = 394 (1) [M+], 269 (11), 267 (38), 225 (22), 195
(11), 193 (32), 167 (6), 165 (16), 151 (6), 149 (20), 113 (33), 43
(100).
Methyl 3-Hydroxy-3-(2-iodo-3,4-dimethoxyphenyl)-2-methyl-
enepropanoate (2g)
Reaction time: 192 h; yield: 2.27 g (60%); white solid; mp 114–
115 °C (Et2O–PE).
IR (KBr): 3461, 1720, 1630, 1586, 1480 cm–1.
1H NMR (CDCl3): δ = 3.07 (d, J = 4.4 Hz, 1 H, OH), 3.78 (s, 3 H,
OCH3), 3.84 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 5.61 (s, 1 H, CH),
5.84 (d, J = 4.4 Hz, 1 H, CH), 6.36 (s, 1 H, CH), 6.92 (d, J = 8.5 Hz,
1 Harom), 7.20 (d, J = 8.5 Hz, 1 Harom).
13C NMR (CDCl3): δ = 52.1, 56.0, 60.3, 75.6, 98.4, 112.3, 123.5,
127.0, 135.8, 141.1, 148.6, 152.2, 167.0.
Anal. Calcd for C13H12ClIO4: C, 39.57; H, 3.07. Found: C, 39.32; H,
2.95.
Methyl 3-Acetoxy-3-(2-iodo-5-methylphenyl)-2-methylenepro-
panoate (3e)
Reaction time: 30 min; yield: 3.48 g (93%); white solid; mp 65–
67 °C (Et2O–PE).
EIMS: m/z (%) = 378 (10) [M+], 291 (13), 251 (26), 219 (53), 191
(20), 175 (13), 165 (100), 151 (59), 138 (28), 113 (76).
Anal. Calcd for C13H15IO5: C, 41.29; H, 4.00. Found: C, 41.45; H,
4.14.
IR (KBr): 1746, 1726, 1633, 1466, 1437 cm–1.
1H NMR (CDCl3): δ = 2.13 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 3.76
(s, 3 H, OCH3), 5.61 (s, 1 H, CH), 6.49 (s, 1 H, CH), 6.80 (s, 1 H,
CH), 6.85 (dd, J = 8.0, 2.1 Hz, 1 Harom), 7.09 (d, J = 2.1 Hz, 1 Harom),
7.73 (d, J = 8.0 Hz, 1 Harom).
13C NMR (CDCl3): δ = 20.9, 21.1, 52.2, 76.5, 95.5, 127.8, 129.0,
131.1, 138.3, 138.4, 139.5, 139.6, 165.4, 169.2.
Morita–Baylis–Hillman Acetates 3; General Procedure
Ac2O (1.53 g, 15 mmol) was added to a stirred soln of the MBH ad-
duct 2 (10 mmol) and DMAP (0.34 g, 3 mmol) in CH2Cl2 (20 mL)
at r.t. The reaction mixture was stirred at r.t. for 20 min to 1 h, then
diluted with H2O (5 mL) and extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were dried (MgSO4) and the solvent
was evaporated under reduced pressure. The resulting mixture was
chromatographed on silica gel (hexane–EtOAc, 3:1) to provide 3.
EIMS: m/z (%) = 374 (1) [M+], 247 (73), 245 (27), 205 (67), 173
(53), 145 (66), 129 (36), 119 (14), 115 (19), 43 (100).
Anal. Calcd for C14H15IO4: C, 44.94; H, 4.04. Found: C, 44.76; H,
3.88.
Methyl 3-Acetoxy-3-(2-fluoro-6-iodophenyl)-2-methylenepro-
panoate (3b)
Reaction time: 1 h; yield: 3.44 g (91%); yellow oil.
Methyl 3-Acetoxy-3-(2-iodo-5-methoxyphenyl)-2-methylene-
propanoate (3f)
Reaction time: 30 min; yield: 3.43 g (88%); white solid; mp 92–
94 °C (Et2O–PE).
IR (KBr): 1747, 1726, 1635, 1591, 1569, 1468 cm–1.
1H NMR (CDCl3): δ = 2.13 (s, 3 H, CH3), 3.77 (s, 3 H, OCH3), 3.78
IR (CH2Cl2): 1751, 1728, 1636, 1596, 1567, 1451 cm–1.
1H NMR (CDCl3): δ = 2.13 (s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 5.80
(s, 1 H, CH), 6.49 (s, 1 H, CH), 6.95–7.08 (m, CH and 2 Harom),
7.68–7.71 (m, 1 Harom).
13C NMR (CDCl3): δ = 20.7, 52.0, 75.4, 100.2 (d, J = 3.4 Hz), 116.7
(d, J = 22.8 Hz), 127.4, 127.5 (d, J = 12.8 Hz), 131.3 (d, J = 9.1
(s, 3 H, OCH3), 5.59 (s, 1 H, CH), 6.48 (s, 1 H, CH), 6.63 (dd,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3613–3622

3618
S.-H. Ahn et al.
PAPER
IR (CH2Cl2): 1744, 1723, 1636, 1567, 1540, 1449, 1433 cm–1.
1H NMR (CDCl3): δ = 2.09 (s, 3 H, CH3), 3.88 (s, 3 H, OCH3), 4.77
(s, 2 H, CH2), 7.20 (dd, J = 8.5, 2.4 Hz, 1 Harom), 7.42 (d, J = 2.4 Hz,
1 Harom), 7.74 (d, J = 8.5 Hz, 1 Harom), 7.77 (s, 1 H, CH).
J = 8.8, 2.9 Hz, 1 Harom), 6.77 (s, 1 H, CH), 6.88 (d, J = 2.9 Hz, 1
Harom), 7.73 (d, J = 8.8 Hz, 1 Harom).
13C NMR (CDCl3): δ = 20.9, 52.2, 55.3, 76.5, 87.7, 115.0, 115.3,
128.2, 138.2, 140.3, 141.0, 159.9, 165.3, 169.1.
EIMS: m/z (%) = 390 (3) [M+], 263 (58), 221 (67), 189 (34), 161
(100), 145 (30), 135 (15), 115 (17), 43 (93).
13C NMR (CDCl3): δ = 20.8, 52.5, 58.9, 96.7, 122.4, 128.9, 132.4,
133.4, 140.3, 140.4, 146.7, 166.2, 170.3.
Anal. Calcd for C14H15IO5: C, 43.10; H, 3.87. Found: C, 42.66; H,
4.18.
EIMS: m/z (%) = 313 (24), 311 (27), 239 (9), 237 (10), 190 (50),
158 (18), 114 (15), 43 (100).
Anal. Calcd for C13H12BrIO4: C, 35.56; H, 2.75. Found: C, 35.34;
H, 2.59.
Methyl 3-Acetoxy-3-(2-iodo-3,4-dimethoxyphenyl)-2-methyl-
enepropanoate (3g)
Reaction time: 40 min; yield: 3.99 g (95%); white solid; mp 88–
90 °C (Et2O–PE).
IR (KBr): 1746, 1725, 1635, 1586, 1481 cm–1.
Methyl (E)-2-(Acetoxymethyl)-3-(4-chloro-2-iodophenyl)pro-
penoate (4d)
Reaction time: 7 d; yield: 1.56 g (79%); yellow oil.
1H NMR (CDCl3): δ = 2.12 (s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 3.84
(s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 5.62 (s, 1 H, CH), 6.47 (s, 1 H,
CH), 6.85 (s, 1 H, CH), 6.87 (d, J = 8.5 Hz, 1 Harom), 7.02 (d, J = 8.5
Hz, 1 Harom).
13C NMR (CDCl3): δ = 20.9, 52.1, 56.0, 60.3, 76.7, 98.9, 112.0,
123.9, 127.5, 132.8, 138.7, 149.0, 152.6, 165.4, 169.2.
EIMS: m/z (%) = 420 (5) [M+], 293 (23), 251 (45), 233 (25), 219
(46), 205 (16), 191 (27), 175 (21), 165 (14), 131 (20), 113 (51), 43
(100).
IR (CH2Cl2): 1738, 1723, 1638, 1574, 1545, 1460, 1436 cm–1.
1H NMR (CDCl3): δ = 2.07 (s, 3 H, CH3), 3.88 (s, 3 H, OCH3), 4.78
(s, 2 H, CH2), 7.20 (d, J = 8.2 Hz, 1 Harom), 7.38 (dd, J = 8.2, 2.1 Hz,
1 Harom), 7.80 (s, 1 H, CH), 7.91 (d, J = 2.1 Hz, 1 Harom).
13C NMR (CDCl3): δ = 20.9, 52.5, 59.0, 99.2, 128.4, 128.5, 130.1,
135.4, 136.8, 138.6, 146.9, 166.4, 170.4.
EIMS: m/z (%) = 269 (13), 267 (41), 227 (7), 225 (23), 195 (14),
193 (41), 167 (7), 165 (20), 149 (14), 43 (100).
Anal. Calcd for C13H12ClIO4: C, 39.57; H, 3.07. Found: C, 39.38; H,
2.88.
Anal. Calcd for C15H17IO6: C, 42.88; H, 4.08. Found: C, 42.50; H,
3.72.
Methyl (E)-2-(Acetoxymethyl)-3-(2-iodo-5-methylphenyl)pro-
Morita–Baylis–Hillman Cinnamyl Acetates 4; General Proce-
dure
penoate (4e)
Reaction time: 7 d; yield: 1.66 g (89%); white solid; mp 79–80 °C
(Et2O–PE).
IR (KBr): 1741, 1720, 1635, 1459, 1435 cm–1.
1H NMR (CDCl3): δ = 2.07 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 3.88
(s, 3 H, OCH3), 4.80 (s, 2 H, CH2), 6.90 (dd, J = 8.2, 2.1 Hz, 1
A mixture of the MBH acetate 3 (5 mmol) and DABCO (0.14 g,
1.25 mmol) in THF (20 mL) was stirred at reflux temperature for 2–
7 d. Then, the mixture was diluted with H2O (20 mL) and extracted
with CH2Cl2 (3 × 30 mL). The combined organic layers were dried
(MgSO4) and the solvent was evaporated under reduced pressure.
The resulting mixture was chromatographed on silica gel (hexane–
EtOAc, 3:1) to yield 4.
Harom), 7.06 (d, J = 2.1 Hz, 1 Harom), 7.76 (d, J = 8.2 Hz, 1 Harom),
7.85 (s, 1 H, CH).
13C NMR (CDCl3): δ = 20.9, 21.0, 52.4, 59.3, 94.9, 127.8, 130.4,
131.5, 138.1, 138.2, 138.9, 148.3, 166.7, 170.5.
Methyl (E)-2-(Acetoxymethyl)-3-(2-iodophenyl)propenoate
(4a)9b
Reaction time: 2 d; yield: 1.62 g (90%); white solid; mp 65–66 °C
(Et2O–PE).
IR (KBr): 1743, 1704, 1638, 1580, 1557 cm–1.
1H NMR (CDCl3): δ = 2.06 (s, 3 H, CH3), 3.88 (s, 3 H, OCH3), 4.80
(s, 2 H, CH2), 7.04–7.41 (m, 3 Harom), 7.87 (s, 1 H, CH), 7.89–7.92
(m, 1 Harom).
EIMS: m/z (%) = 374 (1) [M+], 299 (5), 247 (100), 205 (30), 173
(66), 145 (74), 128 (30), 115 (41), 43 (96).
Anal. Calcd for C14H15IO4: C, 44.94; H, 4.04. Found: C, 44.78; H,
4.19.
Methyl (E)-2-(Acetoxymethyl)-3-(2-iodo-5-methoxyphe-
nyl)propenoate (4f)
Reaction time: 4 d; yield: 1.62 g (83%); pale yellow solid; mp 97–
99 °C (Et2O–PE).
13C NMR (CDCl3): δ = 20.8, 52.4, 59.2, 99.1, 128.0, 128.2, 129.5,
130.4, 138.4, 139.2, 148.0, 166.6, 170.4.
IR (KBr): 1738, 1720, 1636, 1585, 1563, 1462 cm–1.
1H NMR (CDCl3): δ = 2.07 (s, 3 H, CH3), 3.78 (s, 3 H, OCH3), 3.88
(s, 3 H, OCH3), 4.82 (s, 2 H, CH2), 6.67 (dd, J = 8.5, 2.9 Hz, 1
Methyl (E)-2-(Acetoxymethyl)-3-(2-fluoro-6-iodophenyl)pro-
penoate (4b)
Reaction time: 3 d; yield: 1.36 g (72%); yellow oil.
IR (CH2Cl2): 1724, 1651, 1594, 1560, 1452, 1437 cm–1.
Harom), 6.86 (d, J = 2.9 Hz, 1 Harom), 7.74 (d, J = 8.5 Hz, 1 Harom),
7.84 (s, 1 H, CH).
13C NMR (CDCl3): δ = 20.9, 52.5, 55.3, 59.3, 87.4, 115.5, 116.7,
128.0, 139.0, 139.7, 148.2, 159.7, 166.6, 170.4.
1H NMR (CDCl3): δ = 1.93 (s, 3 H, CH3), 3.89 (s, 3 H, OCH3), 4.74
(s, 2 H, CH2), 7.06–7.16 (m, 2 Harom), 7.48 (s, 1 H, CH), 7.68–7.71
(m, 1 Harom).
13C NMR (CDCl3): δ = 20.6, 52.5, 59.8, 98.8, 115.7 (d, J = 22.5
Hz), 127.0, 131.3 (d, J = 12.8 Hz), 131.5, 134.6, 139.5, 158.2 (d,
J = 252.7 Hz), 165.9, 170.4.
EIMS: m/z (%) = 390 (1) [M+], 263 (91), 221 (20), 189 (44), 161
(100), 145 (16), 133 (11), 115 (14), 102 (22), 43 (84).
Anal. Calcd for C14H15IO5: C, 43.10; H, 3.87. Found: C, 42.82; H,
3.68.
EIMS: m/z (%) = 335 (2), 251 (57), 209 (22), 177 (60), 148 (24),
133 (25), 120 (15), 101 (12), 43 (100).
Methyl (E)-2-(Acetoxymethyl)-3-(2-iodo-3,4-dimethoxyphe-
nyl)propenoate (4g)
Reaction time: 2 d; yield: 1.70 g (81%); white solid; mp 82–83 °C
(Et2O–PE).
Anal. Calcd for C13H12FIO4: C, 41.29; H, 3.20. Found: C, 41.14; H,
3.04.
Methyl (E)-2-(Acetoxymethyl)-3-(5-bromo-2-iodophenyl)pro-
penoate (4c)
Reaction time: 7 d; yield: 1.94 g (88%); yellow oil.
IR (KBr): 1740, 1718, 1633, 1582, 1481, 1434 cm–1.
Synthesis 2012, 44, 3613–3622
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,4-Dihydro-2H-3-benzoxocine Derivatives
3619
1H NMR (CDCl3): δ = 2.10 (s, 3 H, CH3), 3.85 (s, 3 H, OCH3), 3.87
(s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 4.82 (s, 2 H, CH2), 6.92 (d,
J = 8.5 Hz, 1 Harom), 7.05 (d, J = 8.5 Hz, 1 Harom), 7.91 (s, 1 H, CH).
EIMS: m/z (%) = 271 (95), 269 (100), 239 (9), 237 (10), 211 (16),
209 (18), 182 (11), 180 (10), 131 (45), 102 (62).
Anal. Calcd for C11H10BrIO3: C, 33.28; H, 2.54. Found: C, 33.55;
H, 2.71.
13C NMR (CDCl3): δ = 20.9, 52.3, 56.0, 59.5, 60.3, 98.4, 112.0,
125.6, 126.4, 131.1, 148.4 (2 peaks), 152.8, 166.9, 170.6.
Methyl (E)-3-(4-Chloro-2-iodophenyl)-2-(hydroxymethyl)pro-
penoate (5d)
Reaction time: 20 min; yield: 835 mg (79%); white solid; mp 119–
120 °C (Et2O–PE).
EIMS: m/z (%) = 420 (2) [M+], 293 (92), 233 (10), 219 (80), 203
(22), 191 (62), 187 (15), 175 (18), 160 (10), 145 (13), 131 (21), 115
(14), 102 (11), 43 (100).
IR (KBr): 3476, 1707, 1631, 1573, 1464, 1434 cm–1.
Anal. Calcd for C15H17IO6: C, 42.88; H, 4.08. Found: C, 42.69; H,
3.87.
1H NMR (CDCl3): δ = 2.56 (br s, 1 H, OH), 3.90 (s, 3 H, OCH3),
4.31 (s, 2 H, CH2), 7.38–7.39 (m, 2 Harom), 7.67 (s, 1 H, CH), 7.90–
7.91 (m, 1 Harom).
Morita–Baylis–Hillman Cinnamyl Alcohols 5; General Proce-
dure
A mixture of the MBH cinnamyl acetate 4 (3 mmol) and K2CO3
(0.62 g, 4.5 mmol) in H2O–MeOH (1:3, 12 mL) was stirred at r.t. for
20 min to 2 h. Then, the mixture was diluted with H2O (20 mL) and
extracted with CH2Cl2 (3 × 30 mL). The combined organic layers
were dried (MgSO4) and the solvent was evaporated under reduced
pressure. The resulting mixture was chromatographed on silica gel
(hexane–EtOAc, 3:1) to yield 5.
13C NMR (CDCl3): δ = 52.5, 58.0, 99.4, 128.5, 130.8, 132.1, 135.3,
137.0, 138.6, 144.1, 167.7.
EIMS: m/z (%) = 227 (32), 225 (100), 195 (4), 193 (11), 167 (7),
165 (22), 138 (7), 136 (16), 131 (30), 101 (21).
Anal. Calcd for C11H10ClIO3: C, 37.47; H, 2.86. Found: C, 37.22; H,
2.59.
Methyl (E)-2-(Hydroxymethyl)-3-(2-iodophenyl)propenoate
Methyl (E)-2-(Hydroxymethyl)-3-(2-iodo-5-methylphenyl)pro-
(5a)
penoate (5e)
Reaction time: 30 min; yield: 897 mg (94%); white solid; mp 90–
91 °C (Et2O–PE).
IR (KBr): 3494, 1704, 1627, 1580, 1557, 1463 cm–1.
Reaction time: 1 h; yield: 717 mg (72%); white solid; mp 54–56 °C
(Et2O–PE).
IR (KBr): 3439, 1711, 1633, 1459, 1435 cm–1.
1H NMR (CDCl3): δ = 2.64 (t, J = 6.7 Hz, 1 H, OH), 3.90 (s, 3 H,
OCH3), 4.34 (d, J = 6.7 Hz, 2 H, CH2), 7.03–7.09 (m, 1 Harom), 7.38–
7.45 (m, 2 Harom), 7.73 (s, 1 H, CH), 7.89–7.92 (m, 1 Harom).
13C NMR (CDCl3): δ = 52.4, 58.1, 99.3, 128.2, 130.2, 130.3, 131.6,
138.5, 139.1, 145.2, 167.9.
1H NMR (CDCl3): δ = 2.33 (s, 3 H, CH3), 2.68 (t, J = 6.7 Hz, 1 H,
OH), 3.89 (s, 3 H, OCH3), 4.35 (d, J = 6.7 Hz, 2 H, CH2), 6.88 (dd,
J = 7.9, 1.8 Hz, 1 Harom), 7.23 (d, J = 1.8 Hz, 1 Harom), 7.72 (s, 1 H,
CH), 7.75 (d, J = 7.9 Hz, 1 Harom).
13C NMR (CDCl3): δ = 21.1, 52.4, 58.1, 95.2, 130.8, 131.4, 131.5,
138.2, 138.3, 138.8, 145.2, 168.0.
EIMS: m/z (%) = 191 (100), 159 (9), 147 (7), 131 (30), 115 (12),
EIMS: m/z (%) = 332 (1) [M+], 205 (100), 161 (17), 145 (26), 131
103 (24).
(13), 115 (41).
Anal. Calcd for C11H11IO3: C, 41.53; H, 3.49. Found: C, 41.25; H,
3.21.
Anal. Calcd for C12H13IO3: C, 43.39; H, 3.95. Found: C, 43.18; H,
4.07.
Methyl (E)-3-(2-Fluoro-6-iodophenyl)-2-(hydroxymethyl)pro-
penoate (5b)
Reaction time: 30 min; yield: 766 mg (76%); white solid; mp 58–
59 °C (Et2O–PE).
Methyl (E)-2-(Hydroxymethyl)-3-(2-iodo-5-methoxyphe-
nyl)propenoate (5f)
Reaction time: 2 h; yield: 825 mg (79%); white solid; mp 123–
125 °C (Et2O–PE).
IR (KBr): 3499, 1691, 1629, 1584, 1564, 1463, 1433 cm–1.
1H NMR (CDCl3): δ = 2.55 (br s, 1 H, OH), 3.81 (s, 3 H, OCH3),
3.90 (s, 3 H, OCH3), 4.36 (s, 2 H, CH2), 6.67 (dd, J = 8.8, 2.9 Hz, 1
IR (KBr): 3427, 1715, 1647, 1594, 1560, 1451, 1437 cm–1.
1H NMR (CDCl3): δ = 2.65 (t, J = 7.0 Hz, 1 H, OH), 3.91 (s, 3 H,
OCH3), 4.23 (dd, J = 7.0, 1.8 Hz, 2 H, CH2), 7.04–7.17 (m, 2 Harom),
7.34 (s, 1 H, CH), 7.69–7.72 (m, 1 Harom).
13C NMR (CDCl3): δ = 52.4, 59.2, 99.3, 115.7 (d, J = 23.4 Hz),
126.9 (d, J = 17.4 Hz), 131.5 (d, J = 8.8 Hz), 134.5, 134.8 (d,
J = 3.4 Hz), 136.8, 158.3 (d, J = 251.8 Hz), 167.1.
H
arom), 7.05 (d, J = 2.9 Hz, 1 Harom), 7.70 (s, 1 H, CH), 7.74 (d,
J = 8.8 Hz, 1 Harom).
13C NMR (CDCl3): δ = 52.4, 55.5, 58.1, 87.6, 115.8, 116.9, 131.8,
139.2, 139.6, 145.2, 159.7, 167.9.
EIMS: m/z (%) = 209 (100), 177 (11), 165 (4), 149 (34), 133 (10),
EIMS: m/z (%) = 348 (5) [M+], 221 (100), 206 (10), 189 (23), 177
120 (20), 101 (25).
(19), 161 (37), 133 (12), 118 (16), 102 (13).
Anal. Calcd for C11H10FIO3: C, 39.31; H, 3.00. Found: C, 39.13; H,
2.79.
Anal. Calcd for C12H13IO4: C, 41.40; H, 3.76. Found: C, 41.23; H,
3.55.
Methyl (E)-3-(5-Bromo-2-iodophenyl)-2-(hydroxymethyl)pro-
penoate (5c)
Reaction time: 20 min; yield: 1.12 g (94%); white solid; mp 76–
78 °C (Et2O–PE).
IR (KBr): 3418, 1711, 1634, 1567, 1539, 1448 cm–1.
1H NMR (CDCl3): δ = 2.56 (t, J = 6.7 Hz, 1 H, OH), 3.90 (s, 3 H,
OCH3), 4.33 (d, J = 6.7 Hz, 2 H, CH2), 7.20 (dd, J = 8.5, 2.4 Hz, 1
Methyl (E)-2-(Hydroxymethyl)-3-(2-iodo-3,4-dimethoxyphe-
nyl)propenoate (5g)
Reaction time: 30 min; yield: 930 mg (82%); white solid; mp 101–
103 °C (Et2O–PE).
IR (KBr): 3481, 1694, 1624, 1579, 1480 cm–1.
1H NMR (CDCl3): δ = 2.62 (t, J = 6.7 Hz, 1 H, OH), 3.85 (s, 3 H,
OCH3), 3.88 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 4.36 (d, J = 6.7
Hz, 2 H, CH2), 6.93 (d, J = 8.5 Hz, 1 Harom), 7.25 (d, J = 8.5 Hz, 1
Harom), 7.75 (s, 1 H, CH).
Harom), 7.56 (d, J = 2.4 Hz, 1 Harom), 7.62 (s, 1 H, CH), 7.74 (d,
J = 8.5 Hz, 1 Harom).
13C NMR (CDCl3): δ = 52.5, 57.9, 97.2, 122.5, 132.6, 132.7, 133.3,
140.4 (2 peaks), 143.6, 167.5.
13C NMR (CDCl3): δ = 52.2, 56.0, 58.2, 60.3, 98.4, 112.1, 126.3,
130.4, 131.4, 145.4, 149.0, 152.7, 168.2.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3613–3622

3620
S.-H. Ahn et al.
PAPER
EIMS: m/z (%) = 378 (2) [M+], 251 (100), 221 (12), 207 (12), 191
(17).
13C NMR (CDCl3): δ = 34.3, 41.0, 51.8, 52.2, 55.6, 59.3, 104.2,
120.6, 126.3, 131.6, 133.0, 133.1, 135.7, 136.9, 137.7, 166.2, 172.1.
Anal. Calcd for C13H15IO5: C, 41.29; H, 4.00. Found: C, 41.17; H,
3.94.
EIMS: m/z (%) = 336 (5), 334 (5), 308 (10), 306 (9), 267 (49), 265
(51), 235 (25), 233 (25), 221 (21), 219 (17), 207 (35), 155 (11), 142
(100), 115 (46).
Methyl 2-Methoxy-1-(methoxycarbonylmethyl)-1,4-dihydro-
2H-3-benzoxocine-5-carboxylates 10; General Procedure
A mixture of the MBH cinnamyl alcohol 5 (1 mmol), 2,5-dimeth-
oxy-2,5-dihydrofuran (6; 0.24 mL, 2 mmol), DIPEA (0.53 mL, 3
mmol), BTEAC (0.23 g, 1 mmol), and Pd(OAc)2 (7 mg, 3 mol%) in
DMF (10 mL) was stirred at 80 °C for 1–24 h under nitrogen atmo-
sphere. Then, the mixture was diluted with H2O (20 mL) and ex-
tracted with Et2O (3 × 30 mL). The combined organic layers were
dried (MgSO4) and the solvent was evaporated under reduced pres-
sure. The resulting mixture was chromatographed on silica gel
(hexane–EtOAc, 3:1) to provide 10.
Anal. Calcd for C17H19BrO6: C, 51.14; H, 4.80. Found: C, 50.92; H,
4.64.
Methyl 9-Chloro-2-methoxy-1-(methoxycarbonylmethyl)-1,4-
dihydro-2H-3-benzoxocine-5-carboxylate (10d)
Reaction time: 24 h; yield: 152 mg (43%); white solid; mp 101–
102 °C (Et2O–PE).
IR (KBr): 1738, 1710, 1645, 1590, 1436, 1251 cm–1.
1H NMR (CDCl3): δ = 2.70 (dd, J = 15.8, 7.6 Hz, 1 H, C1CH2), 2.91
(dd, J = 15.8, 7.0 Hz, 1 H, C1CH2), 3.36 (s, 3 H, OCH3), 3.63 (s, 3
H, OCH3), 3.66–3.75 (m, 1 H, C1H), 3.82 (s, 3 H, OCH3), 4.21 (d,
J = 9.7 Hz, 1 H, C2H), 4.40 (d, J = 19.4 Hz, 1 H, C4H), 4.88 (dd,
J = 19.1, 1.5 Hz, 1 H, C4H), 7.15 (s, 1 Harom), 7.25 (s, 2 Harom), 7.69
(s, 1 H, C6H).
13C NMR (CDCl3): δ = 34.3, 41.2, 51.8, 52.1, 55.5, 59.4, 104.2,
125.1, 127.0, 131.8, 132.1, 134.1, 134.7, 136.2, 140.0, 166.4, 172.0.
EIMS: m/z (%) = 354 (1) [M+], 263 (10), 230 (11), 223 (32), 221
(100), 203 (14), 191 (25), 189 (74), 175 (47), 162 (23), 149 (16),
142 (60), 127 (25), 115 (33).
Methyl 2-Methoxy-1-(methoxycarbonylmethyl)-1,4-dihydro-
2H-3-benzoxocine-5-carboxylate (10a)
Reaction time: 3 h; yield: 131 mg (41%); white solid; mp 94–95 °C
(Et2O–PE).
IR (KBr): 1738, 1706, 1644, 1436, 1251 cm–1.
1H NMR (CDCl3): δ = 2.75 (dd, J = 15.9, 7.6 Hz, 1 H, C1CH2), 2.92
(dd, J = 15.9, 7.6 Hz, 1 H, C1CH2), 3.35 (s, 3 H, OCH3), 3.61 (s, 3
H, OCH3), 3.71–3.76 (m, 1 H, C1H), 3.82 (s, 3 H, OCH3), 4.21 (d,
J = 9.4 Hz, 1 H, C2H), 4.41 (d, J = 19.0 Hz, 1 H, C4H), 4.90 (dd,
J = 19.0, 1.8 Hz, 1 H, C4H), 7.18–7.32 (m, 4 Harom), 7.76 (s, 1 H,
C6H).
Anal. Calcd for C17H19ClO6: C, 57.55; H, 5.40. Found: C, 57.69; H,
5.57.
13C NMR (CDCl3): δ = 34.6, 41.2, 51.7, 52.0, 55.5, 59.4, 104.6,
124.7, 126.8, 128.9, 130.6, 131.5, 135.5, 137.4, 138.0, 166.6, 172.4.
EIMS: m/z (%) = 320 (1) [M+], 187 (100), 155 (80), 143 (38), 141
(64), 128 (58), 115 (42).
Methyl 2-Methoxy-1-(methoxycarbonylmethyl)-8-methyl-1,4-
dihydro-2H-3-benzoxocine-5-carboxylate (10e)
Reaction time: 2 h; yield: 144 mg (43%); white solid; mp 119–
121 °C (Et2O–PE).
IR (KBr): 1739, 1705, 1643, 1506, 1435, 1254 cm–1.
Anal. Calcd for C17H20O6: C, 63.74; H, 6.29. Found: C, 63.45; H,
6.11.
1H NMR (CDCl3): δ = 2.32 (s, 3 H, CH3), 2.72 (dd, J = 15.8, 7.9 Hz,
1 H, C1CH2), 2.91 (dd, J = 15.8, 7.0 Hz, 1 H, C1CH2), 3.35 (s, 3 H,
OCH3), 3.60 (s, 3 H, OCH3), 3.64–3.72 (m, 1 H, C1H), 3.81 (s, 3 H,
OCH3), 4.18 (d, J = 9.4 Hz, 1 H, C2H), 4.39 (d, J = 18.8 Hz, 1 H,
C4H), 4.88 (dd, J = 18.8, 1.6 Hz, 1 H, C4H), 7.05–7.13 (m, 3 Harom),
7.73 (s, 1 H, C6H).
Methyl 7-Fluoro-2-methoxy-1-(methoxycarbonylmethyl)-1,4-
dihydro-2H-3-benzoxocine-5-carboxylate (10b)
Reaction time: 6 h; yield: 199 mg (59%); colorless oil.
IR (CH2Cl2): 1738, 1710, 1649, 1611, 1573, 1454, 1436, 1257 cm–1.
1H NMR (CDCl3): δ = 2.74 (dd, J = 15.8, 7.6 Hz, 1 H, C1CH2), 2.93
(dd, J = 15.8, 7.6 Hz, 1 H, C1CH2), 3.36 (s, 3 H, OCH3), 3.61 (s, 3
H, OCH3), 3.62–3.71 (m, 1 H, C1H), 3.83 (s, 3 H, OCH3), 4.18 (d,
J = 9.7 Hz, 1 H, C2H), 4.43 (d, J = 19.1 Hz, 1 H, C4H), 4.91 (dd,
J = 19.1, 2.3 Hz, 1 H, C4H), 6.96–7.03 (m, 2 Harom), 7.26–7.33 (m,
1 Harom), 7.81 (d, J = 2.1 Hz, 1 H, C6H).
13C NMR (CDCl3): δ = 34.6, 41.3, 51.8, 52.1, 55.5, 59.4, 104.2,
113.9 (d, J = 22.0 Hz), 120.1, 123.8, 129.5, 130.0 (d, J = 8.8 Hz),
133.3, 140.4, 160.6 (d, J = 249.3 Hz), 166.1, 172.2.
13C NMR (CDCl3): δ = 20.8, 34.6, 40.9, 51.7, 52.0, 55.4, 55.5, 59.4,
104.8, 124.6, 129.7, 131.3, 135.0, 135.3, 136.4, 137.6, 166.7, 172.5.
EIMS: m/z (%) = 334 (1) [M+], 201 (100), 183 (10), 169 (96), 155
(41), 142 (54), 128 (21), 115 (23).
Anal. Calcd for C18H22O6: C, 64.66; H, 6.63. Found: C, 64.47; H,
6.48.
Methyl 2,8-Dimethoxy-1-(methoxycarbonylmethyl)-1,4-di-
hydro-2H-3-benzoxocine-5-carboxylate (10f)
Reaction time: 1 h; yield: 147 mg (42%); white solid; mp 38–40 °C
(Et2O–PE).
EIMS: m/z (%) = 338 (1) [M+], 278 (10), 247 (10), 215 (10), 205
(100), 187 (15), 173 (80), 161 (41), 159 (64), 146 (64), 133 (39).
IR (KBr): 1737, 1706, 1646, 1605, 1574, 1506, 1436, 1238 cm–1.
Anal. Calcd for C17H19FO6: C, 60.35; H, 5.66. Found: C, 60.12; H,
5.38.
1H NMR (CDCl3): δ = 2.71 (dd, J = 15.8, 8.1 Hz, 1 H, C1CH2), 2.90
(dd, J = 15.8, 7.6 Hz, 1 H, C1CH2), 3.35 (s, 3 H, OCH3), 3.60–3.69
(m, 1 H, C1H), 3.61 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.82 (s, 3
H, OCH3), 4.16 (d, J = 9.4 Hz, 1 H, C2H), 4.39 (d, J = 19.0 Hz, 1 H,
C4H), 4.89 (d, J = 19.0 Hz, 1 H, C4H), 6.84–6.86 (m, 2 Harom), 7.08–
7.11 (m, 1 Harom), 7.71 (s, 1 H, C6H).
13C NMR (CDCl3): δ = 34.7, 40.6, 51.7, 52.1, 55.3, 55.5, 59.3,
104.8, 114.8, 115.2, 125.8, 130.1, 131.8, 136.6, 137.2, 158.0, 166.6,
172.4.
Methyl 8-Bromo-2-methoxy-1-(methoxycarbonylmethyl)-1,4-
dihydro-2H-3-benzoxocine-5-carboxylate (10c)
Reaction time: 23 h; yield: 148 mg (37%); white solid; mp 124–
125 °C (Et2O–PE).
IR (KBr): 1737, 1707, 1646, 1488, 1435, 1251 cm–1.
1H NMR (CDCl3): δ = 2.71 (dd, J = 15.8, 8.4 Hz, 1 H, C1CH2), 2.92
(dd, J = 15.8, 6.7 Hz, 1 H, C1CH2), 3.56 (s, 3 H, OCH3), 3.61 (s, 3
H, OCH3), 3.63–3.70 (m, 1 H, C1H), 3.82 (s, 3 H, OCH3), 4.17 (d,
J = 9.4 Hz, 1 H, C2H), 4.40 (d, J = 19.1 Hz, 1 H, C4H), 4.89 (dd,
J = 19.1, 2.1 Hz, 1 H, C4H), 7.04–7.07 (m, 1 Harom), 7.41–7.46 (m,
2 Harom), 7.66 (s, 1 H, C6H).
EIMS: m/z (%) = 350 (1) [M+], 259 (15), 227 (11), 216 (100), 199
(12), 185 (51), 171 (35), 158 (56), 141 (11), 128 (28), 115 (25).
Anal. Calcd for C18H22O7: C, 61.71; H, 6.33. Found: C, 61.42; H,
6.21.
Synthesis 2012, 44, 3613–3622
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,4-Dihydro-2H-3-benzoxocine Derivatives
3621
Methyl 2-Oxo-1,2,5,11b-tetrahydro-3aH-furo[3,2-a][3]ben-
zoxocine-6-carboxylates 14; General Procedure
Methyl 10-Chloro-2-oxo-1,2,5,11b-tetrahydro-3aH-furo[3,2-
a][3]benzoxocine-6-carboxylate (14d)
Reaction time: 48 h; yield: 234 mg (76%); white solid; mp 151–
153 °C (Et2O–PE).
A mixture of the 3-benzoxocine 10 (1 mmol) and TFA (1.53 mL, 20
mmol) in CH2Cl2 was stirred at r.t. for 24–72 h. Then, the mixture
was diluted with H2O (20 mL) and extracted with CH2Cl2 (3 × 30
mL). The combined organic layers were dried (MgSO4) and the sol-
vent was evaporated under reduced pressure. The resulting mixture
was chromatographed on silica gel (hexane–EtOAc, 3:1) to provide
14.
IR (KBr): 1797, 1713, 1636, 1592, 1488, 1435, 1256 cm–1.
1H NMR (CDCl3): δ = 2.86 (dd, J = 17.3, 8.5 Hz, 1 H, C1CH2), 3.14
(dd, J = 17.3, 12.9 Hz, 1 H, C1CH2), 3.66–3.75 (m, 1 H, C1H), 3.78–
3.83 (m, 1 H, C4H), 3.88 (s, 3 H, OCH3), 4.90 (d, J = 14.7 Hz, 1 H,
C4H), 5.23 (d, J = 7.3 Hz, 1 H, C2H), 7.32–7.39 (m, 3 Harom), 7.92
(s, 1 H, C6H).
13C NMR (CDCl3): δ = 33.2, 44.8, 52.7, 60.8, 105.6, 125.5, 128.1,
131.0, 131.8, 133.7, 135.0, 136.1, 139.9, 166.3, 171.0.
EIMS: m/z (%) = 308 (1) [M+], 278 (5), 276 (16), 248 (12), 234
(29), 230 (16), 207 (10), 202 (38), 189 (16), 176 (47), 174 (100),
162 (22), 149 (24), 141 (64), 127 (35), 115 (62).
Methyl 2-Oxo-1,2,5,11b-tetrahydro-3aH-furo[3,2-a][3]ben-
zoxocine-6-carboxylate (14a)
Reaction time: 24 h; yield: 189 mg (69%); white solid; mp 125–
126 °C (Et2O–PE).
IR (KBr): 1794, 1713, 1634, 1256 cm–1.
1H NMR (CDCl3): δ = 2.84 (dd, J = 17.3, 8.4 Hz, 1 H, C1CH2), 3.21
(dd, J = 17.3, 13.2 Hz, 1 H, C1CH2), 3.69–3.75 (m, 1 H, C1H), 3.77–
3.82 (m, 1 H, C4H), 3.88 (s, 3 H, OCH3), 4.90 (d, J = 14.4 Hz, 1 H,
C4H), 5.24 (d, J = 7.4 Hz, 1 H, C2H), 7.38–7.50 (m, 4 Harom), 8.00
(s, 1 H, C6H).
13C NMR (CDCl3): δ = 33.2, 45.0, 52.6, 60.7, 106.0, 125.0, 127.7,
129.9, 130.3, 130.5, 133.1, 135.3, 141.3, 166.5, 171.6.
Anal. Calcd for C15H13ClO5: C, 58.36; H, 4.24. Found: C, 58.59; H,
4.55.
Methyl 9-Methyl-2-oxo-1,2,5,11b-tetrahydro-3aH-furo[3,2-
a][3]benzoxocine-6-carboxylate (14e)
Reaction time: 24 h; yield: 181 mg (63%); white solid; mp 134–
135 °C (Et2O–PE).
EIMS: m/z (%) = 274 (1) [M+], 200 (33), 168 (30), 140 (100), 128
(46), 115 (49).
IR (KBr): 1796, 1714, 1633, 1435, 1251 cm–1.
1H NMR (CDCl3): δ = 2.39 (s, 3 H, CH3), 2.81 (dd, J = 17.3, 8.6 Hz,
1 H, C1CH2), 3.17 (dd, J = 17.3, 13.0 Hz, 1 H, C1CH2), 3.61–3.71
(m, 1 H, C1H), 3.73–3.82 (m, 1 H, C4H), 3.88 (s, 3 H, OCH3), 4.89
(d, J = 14.4 Hz, 1 H, C4H), 5.20 (d, J = 7.3 Hz, 1 H, C2H), 7.19–7.29
(m, 3 Harom), 7.96 (s, 1 H, C6H).
13C NMR (CDCl3): δ = 20.9, 33.3, 44.8, 52.6, 60.8, 106.1, 124.9,
130.1, 130.4, 130.7 (2), 135.1, 137.6, 141.6, 166.6, 171.7.
Anal. Calcd for C15H14O5: C, 65.69; H, 5.15. Found: C, 65.58; H,
5.01.
Methyl 8-Fluoro-2-oxo-1,2,5,11b-tetrahydro-3aH-furo[3,2-
a][3]benzoxocine-6-carboxylate (14b)
Reaction time: 72 h; yield: 199 mg (68%); white solid; mp 160–
161 °C (Et2O–PE).
IR (KBr): 1796, 1715, 1640, 1612, 1571, 1456, 1259 cm–1.
EIMS: m/z (%) = 288 (1) [M+], 228 (10), 214 (48), 182 (18), 169
(18), 154 (100), 142 (50), 128 (40), 115 (43).
1H NMR (CDCl3): δ = 2.86 (dd, J = 17.3, 8.6 Hz, 1 H, C1CH2), 3.19
(dd, J = 17.3, 12.9 Hz, 1 H, C1CH2), 3.61–3.71 (m, 1 H, C1H), 3.79–
3.86 (m, 1 H, C4H), 3.89 (s, 3 H, OCH3), 4.94 (d, J = 14.7 Hz, 1 H,
C4H), 5.21 (d, J = 7.3 Hz, 1 H, C2H), 7.10–7.23 (m, 2 Harom), 7.45–
7.53 (m, 1 Harom), 8.00 (s, 1 H, C6H).
13C NMR (CDCl3): δ = 33.3, 44.9, 52.7, 60.9, 105.8, 115.0 (d,
J = 21.7 Hz), 120.6, 123.4, 123.6, 131.5 (d, J = 10.0 Hz), 132.0,
135.6, 160.9 (d, J = 252.1 Hz), 166.0, 171.3.
Anal. Calcd for C16H16O5: C, 66.66; H, 5.59. Found: C, 66.43; H,
5.31.
Methyl 9-Methoxy-2-oxo-1,2,5,11b-tetrahydro-3aH-furo[3,2-
a][3]benzoxocine-6-carboxylate (14f)
Reaction time: 24 h; yield: 185 mg (61%); white solid; mp 193–
194 °C (Et2O–PE).
IR (KBr): 1795, 1713, 1636, 1605, 1502, 1254 cm–1.
EIMS: m/z (%) = 292 (1) [M+], 218 (19), 186 (35), 173 (8), 158
1H NMR (CDCl3): δ = 2.81 (dd, J = 17.3, 8.5 Hz, 1 H, C1CH2), 3.15
(dd, J = 17.3, 13.2 Hz, 1 H, C1CH2), 3.59–3.68 (m, 1 H, C1H), 3.74–
3.81 (m, 1 H, C4H), 3.84 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 4.89
(d, J = 14.4 Hz, 1 H, C4H), 5.25 (d, J = 7.3 Hz, 1 H, C2H), 6.88 (d,
J = 2.6 Hz, 1 Harom), 7.01 (dd, J = 8.8, 2.6 Hz, 1 Harom), 7.31 (d,
J = 8.5 Hz, 1 Harom), 7.94 (s, 1 H, C6H).
13C NMR (CDCl3): δ = 33.4, 44.5, 52.6, 55.4, 60.7, 106.2, 114.8,
115.8, 125.1, 126.3, 130.7, 136.4, 141.2, 158.6, 166.5, 171.7.
EIMS: m/z (%) = 304 (3) [M+], 230 (53), 204 (13), 199 (26), 185
(17), 171 (100), 158 (45), 145 (22), 141 (15), 128 (46), 115 (44).
(100), 146 (38), 133 (39).
Anal. Calcd for C15H13FO5: C, 61.64; H, 4.48. Found: C, 61.37; H,
4.28.
Methyl 9-Bromo-2-oxo-1,2,5,11b-tetrahydro-3aH-furo[3,2-
a][3]benzoxocine-6-carboxylate (14c)
Reaction time: 24 h; yield: 247 mg (70%); white solid; mp 171–
172 °C (Et2O–PE).
IR (KBr): 1795, 1713, 1635, 1435, 1256 cm–1.
1H NMR (CDCl3): δ = 2.85 (dd, J = 17.3, 8.5 Hz, 1 H, C1CH2), 3.15
(dd, J = 17.3, 13.0 Hz, 1 H, C1CH2), 3.62–3.72 (m, 1 H, C1H), 3.78–
3.83 (m, 1 H, C4H), 3.88 (s, 3 H, OCH3), 4.90 (d, J = 14.7 Hz, 1 H,
C4H), 5.19 (d, J = 7.3 Hz, 1 H, C2H), 7.30 (s, 1 Harom), 7.54–7.62 (m,
2 Harom), 7.89 (s, 1 H, C6H).
Anal. Calcd for C16H16O6: C, 63.15; H, 5.30. Found: C, 63.27; H,
5.53.
13C NMR (CDCl3): δ = 33.2, 44.6, 52.7, 60.7, 105.8, 121.6, 126.6,
131.7, 132.1, 132.8, 133.0, 137.2, 139.4, 166.1, 171.2.
Acknowledgment
This work was supported in part by the Brain Korea 21 program,
Republic of Korea.
EIMS: m/z (%) = 354 (1), 352 (1) [M+], 294 (9), 292 (10), 280 (29),
278 (30), 250 (10), 248 (28), 220 (66), 218 (56), 208 (11), 206 (10),
199 (21), 195 (10), 168 (10), 155 (11), 145 (14), 141 (95), 139 (58),
128 (57), 115 (100).
References
Anal. Calcd for C15H13BrO5: C, 51.01; H, 3.71. Found: C, 49.76; H,
3.61.
(1) For reviews of medium-ring cyclic ethers, see: (a) Elliott, M.
C. Contemp. Org. Synth. 1994, 1, 457. (b) Moody, C. J.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3613–3622

3622
S.-H. Ahn et al.
PAPER
Davies, M. J. In Studies in Natural Products Chemistry; Vol.
10; Atta-Ur-Rahman, Ed.; Elsevier: New York, 1992, 201.
(2) (a) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.;
Tanaka, T. Heterocycles 2003, 61, 65. (b) Ohno, H.;
Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J. Am.
Chem. Soc. 2004, 126, 8744.
(3) Kurita, J.; Aruga, T.; Tsuchiya, T. Heterocycles 1990, 31,
1769.
(4) Chaudhuri, R.; Das, A.; Liao, H.-Y.; Liu, R.-S. Chem.
Commun. 2010, 46, 4601.
S.; Lee, K.-J. J. Heterocycl. Chem. 2006, 43, 1721. (e) Ji, S.-
H.; Hong, W. P.; Ko, S. H.; Lee, K.-J. J. Heterocycl. Chem.
2006, 43, 799. (f) Lim, H. N.; Ji, S.-H.; Lee, K.-J. Synthesis
2007, 2454. (g) Song, Y. S.; Lee, K.-J. Synthesis 2007, 3037.
(h) Lim, H. N.; Song, Y. S.; Lee, K.-J. Synthesis 2007, 3376.
(i) Jeon, K. J.; Lee, K.-J. J. Heterocycl. Chem. 2008, 45, 615.
(j) Park, S. P.; Song, Y. S.; Lee, K.-J. Tetrahedron 2009, 65,
4703. (k) Han, E.-G.; Kim, H. J.; Lee, K.-J. Tetrahedron
2009, 65, 9616. (l) Park, S. P.; Ahn, S.-H.; Lee, K.-J.
Tetrahedron 2010, 66, 3490. (m) Ahn, S.-H.; Jang, S. S.;
Han, E.-G.; Lee, K.-J. Synthesis 2011, 377.
(5) Samizu, K.; Ogasawara, K. Heterocycles 1994, 38, 1745.
(6) (a) Samizu, K.; Ogasawara, K. Synlett 1994, 499.
(b) Sakagami, H.; Ogasawara, K. Heterocycles 1999, 51,
1131.
(9) (a) Park, J. B.; Ko, S. H.; Hong, W. P.; Lee, K.-J. Bull.
Korean Chem. Soc. 2004, 25, 927. (b) Park, J. B.; Ko, S. H.;
Kim, B. G.; Hong, W. P.; Lee, K.-J. Bull. Korean Chem. Soc.
2004, 25, 27.
(10) Mason, P. H.; Emslie, N. D. Tetrahedron 1994, 50, 12001.
(11) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem.
Soc. 2004, 25, 413.
(12) Palladium is very sensitive to steric effects and generally
forms less hindered complexes where possible. Thus,
coordination of the palladium(II) intermediate occurs at the
face of the dimethoxydihydrofuran anti to the methoxy
group.
(7) For reviews of the Morita–Baylis–Hillman reaction, see:
(a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653. (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001. (c) Ciganek, E. Org. React.
1997, 51, 201. (d) Langer, P. Angew. Chem. Int. Ed. 2000,
39, 3049. (e) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811. (f) Kataoka, T.; Kinoshita, H.
Eur. J. Org. Chem. 2005, 45. (g) Basavaiah, D.; Rao, K. V.;
Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581. (h) Singh, V.;
Batra, S. Tetrahedron 2008, 64, 4511. (i) Declerck, V.;
Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1.
(j) Gowrisankar, S.; Lee, H. S.; Kim, S. H.; Lee, K. Y.; Kim,
J. N. Tetrahedron 2009, 65, 8769. (k) Ma, G.-N.; Jiang, J.-J.;
Shi, M.; Wei, Y. Chem. Commun. 2009, 5496. (l) Basavaiah,
D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447.
(m) Zhong, W.; Liu, Y.; Wang, G.; Hong, L.; Chen, Y.;
Chen, X.; Zheng, Y.; Zhang, W.; Ma, Y.; Shen, Y.; Yao, Y.
Org. Prep. Proced. Int. 2011, 43, 1.
(13) The NMR numbering systems used for compounds 10 and
14 are shown in Schemes 2 and 3.
(14) Hartree–Fock 3-21G calculation data using Spartan are as
follows: (a) cis-10a: dihedral angle = 76.80°, J1,2 = 2.34 Hz;
trans-10a: dihedral angle = 50.21°, J1,2 = 6.84 Hz; cis-14a:
dihedral angle = 38.19°, J1,2 = 8.70 Hz; trans-14a: dihedral
angle = 154.14°, J1,2 = 7.26 Hz. (b) Observed J values: 10a:
J1,2 = 9.4 Hz; 14a: J1,2 = 7.4 Hz.
(15) (a) Zhou, N.; Wang, L.; Thompson, D. W.; Zhao, Y. Org.
Lett. 2008, 10, 3001. (b) Akgün, E.; Glinski, M. B.; Dhawan,
K. L.; Durst, T. J. Org. Chem. 1981, 46, 2730. (c) Dong, L.-
C.; Crowe, M.; West, J.; Ammann, J. R. Tetrahedron Lett.
2004, 45, 2731.
(8) For our recent examples, see: (a) Hong, W. P.; Lim, H. N.;
Park, H. W.; Lee, K.-J. Bull. Korean Chem. Soc. 2005, 26,
655. (b) Hong, W. P.; Lee, K.-J. Synthesis 2005, 33.
(c) Hong, W. P.; Lee, K.-J. Synthesis 2006, 963. (d) Song, Y.
Synthesis 2012, 44, 3613–3622
© Georg Thieme Verlag Stuttgart · New York