Application of the acetate of Baylis-Hillman adducts of salicylaldehydes in the synthesis of methyl 2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylates

Article abstract of DOI:10.1002/jhet.5570450622

(Chemical Equation Presented) A simple synthesis of several methyl 2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylates from Baylis-Hillman adducts of O-benzyl protected 2-hydroxybenzadehydes has been described through the acetylation, cyanation, debenzylation, as well as acid assisted Pinner cyclization.

Full text of DOI:10.1002/jhet.5570450622

Nov-Dec 2008
1701
Application of the Acetate of Baylis-Hillman Adducts of
Salicylaldehydes in the Synthesis of Methyl 2-Oxo-2,3-
dihydrobenzo[b]oxepine-4-carboxylates
Sang-Hyun Ahn, Hee Nam Lim and Kee-Jung Lee*
Organic Synthesis Laboratory, Department of Chemical Engineering
Hanyang University, Seoul 133-791, Korea
Fax +82(2)22984101; E-mail: leekj@hanyang.ac.kr
Received May 29, 2008
CO2Me
PTSA, toluene
reflux, 0.5-8 h
R1
CO2Me
R1
50-87%
OH CN
O
O
R2
R2
A simple synthesis of several methyl 2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylates from Baylis-
Hillman adducts of O-benzyl protected 2-hydroxybenzadehydes has been described through the
acetylation, cyanation, debenzylation, as well as acid assisted Pinner cyclization.
J. Heterocyclic Chem., 45, 1701 (2008).
The Baylis-Hillman (BH) reaction [1] has attracted the
aldehydes 8a-f with 3 equivalents of methyl acrylate and
triethanolamine in the presence of 1 equivalent of 1,4-
diazabicyclo[2,2,0]octane (DABCO) without solvent at
room temperature produced BH adducts, methyl 3-(2-
benzyloxy)phenyl-3-hydroxy-2-methylenepropanoates 9a-f
in 69-95% yields. The reaction of 9a-f with acetic
anhydride in the presence of a catalytic amount of 4-
(dimethylamino)pyridine(DMAP) in dichloromethane at
room temperature gave BH acetates 10a-f in 85-98%
yields. The cyanation reaction of the acetates 10a-f with
potassium cyanide [3,5] in dimethyl sulfoxide-water (3:1)
at room temperature occurred in an SN2´ fashion to give
attention of organic chemists in recent years as this
reaction provides synthetically useful multifunctional
molecules that have been successfully employed in the
synthesis of various heterocycles. During continued
efforts to develop Baylis-Hillman chemistry [2], we
recently reported [3] that methyl 2-amino-3H-1-
benzazepine-4-carboxylates 2 or methyl 2-(cyanomethyl)-
2,3-dihydro-1H-indole-2-carboxylates 3 were prepared
from the reaction of methyl 2-(cyanomethyl)-3-(2-
acylaminophenyl)propenoates 1, which were readily
obtained from BH adducts of N-protected 2-aminobenz-
aldehydes, with sodium methoxide in methanol as shown
in Scheme 1. We envisioned that we could synthesize
methyl 2-oxo-2,3-dihydrobenzo[b]-oxepine-4-carboxyl-
ates 5 or 2,3-dihydrobenzofurans 6 by the cyclization of
methyl 2-(cyanomethyl)-3-(2-hydroxyphenyl)propenoates
4 (Scheme 2).
Scheme 2
CO2Me
X
CO2Me
O
O
X
The Baylis-Hillman reactions of salicylaldehydes with
acrylic acid esters are well known [4] to afford a mixture
of coumarins and chromenes, directly. So, treatment of
several known O-benzyl protected 2-hydroxybenz-
5
6
OH CN
CO2Me
CN
4
X
O
Scheme 1
CO2Me
X
R=H
methyl 3-(2-benzyloxy)phenyl-2-(cyanomethyl)propenoates
11a-f (69-91%). In all cases, the stereoselectivity was found
to be 100% E-selectivity, as determined by 1H nmr analysis
of alkene and methylene protons by comparison with
literature values [3]. Debenzylation of 11a-f using boron
trifluoride etherate and dimethyl sulfide [6] in dichloro-
methane gave the required key intermediate methyl 3-(2-
hydroxyphenyl)-2-(cyanomethyl)propenoates 12a-f in 65-
84% yields. We investigated the intramolecular Pinner
cyclization reaction [7] using 12a-f with para-toluene-
CO2Me
X
N
NH2
NaOMe/MeOH
2
NH CN
O
R
X
CO2Me
R=Me or Et
1
N
CN
R
O
3

1702
S.-H. Ahn, H. N. Lim and K.-J. Lee
Vol 45
Scheme 3
O
O
OH
CH2=CHCO2Me
DABCO, (HOCH2CH2)3N
neat, r.t., 5 h-15 d
PhCH2Br, K2CO3
DMSO, 40 °C, 0.5 h
R1
R1
R1
CO2Me
H
H
OH
92%
OBn
69-95%
OBn
R2
R2
R2
8
7
9
OAc
Ac2O, DMAP
CH2Cl2, r.t., 20-60 min
KCN, DMSO-H2O (3:1)
r.t., 5-60 min
R1
CO2Me
R1
CO2Me
OBn CN
85-98%
69-91%
OBn
R2
R2
11
10
CO2Me
BF3•Et2O, CH3SCH3
CH2Cl2, r.t., 2-24 h
PTSA, toluene
reflux, 0.5-8 h
R1
R1
CO2Me
65-84%
50-87%
O
OH CN
O
R2
R2
13
12
b
7-13
a
c
d
e
f
R1
R2
H
H
H
OEt
Me
H
NO2
H
Cl
Cl
Br
H
sulfonic acid in toluene. After stirring the mixture at reflux
temperature for 0.5-8 hours, the desired methyl 2-oxo-2,3-
dihydrobenzo[b]oxepine-4-carboxylates 13a-f were
obtained in 50-87% yields. Electron-donating or electron-
withdrawing substituted compounds gave the corre-
sponding benzoxepines in reasonable yields (Scheme 3).
Next we examined a reaction using 12a with sodium
methoxide in methanol. After stirring the mixture at reflux
temperature for 24 hours, the only product 3-cyanomethyl
coumarin 16 was obtained in a disappointing yield (36%)
along with the recovered starting compound 12a (25%).
When using excess base the increase of yield was
Scheme 4
NaOMe/MeOH
reflux, 24 h
CO2Me
OH CN
CO2Me
OH CN
CN
CO2Me
OH
12a
14
15
36%
CO2Me
CN
CN
O
O
O
6
16

Nov-Dec 2008
Synthesis of Methyl 2-Oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylates
1703
Methyl 3-(2-Benzyloxy-5-methyl)phenyl-3-hydroxy-2-methyl-
enepropanoate (9d). A mixture of 8d (2.26 g, 10 mmoles),
methyl acrylate (2.7 ml, 30 mmoles), DABCO (1.12 g, 10
mmoles), and triethanolamine (1.07 ml, 8 mmoles) was stirred at
room temperature for 15 days. The mixture was diluted with
water (20 ml) and extracted with dichloromethane (3 ꢀ 20 ml).
The combined organic layers were dried over anhydrous
magnesium sulfate and the solvent was evaporated in vacuo. The
resulting mixture was chromatographed on silica gel eluting
with hexane/ethyl acetate (3:1) to produce 9d (2.14 g, 69%) as a
white solid; mp 58.5 - 59.5 ꢀ; ir (potassium bromide): 3417,
1721 cm-1; 1H nmr (deuteriochloroform): ꢁ 2.29 (s, 3 H), 3.38 (d,
1 H, J = 6.3 Hz), 3.73 (s, 3 H), 5.06 (s, 2 H), 5.69 (s, 1 H), 5.91
(d, 1 H, J = 6.3 Hz), 6.29 (s, 1 H), 6.81-6.83 (m, 1 H), 7.02-7.05
(m, 1 H), 7.18-7.19 (m, 1 H), 7.31-7.45 (m, 5 H); 13C nmr
(deuteriochloroform): ꢀ 20.6, 51.9, 68.4, 70.3, 111.9, 125.9,
127.3, 127.9, 128.3, 128.5, 129.1, 130.3, 136.9, 141.3, 153.6,
167.1. Anal. Calcd. for C19H20O4: C, 73.06; H, 6.45. Found: C,
73.33; H, 6.24.
unsuccessful. Apparently under these reaction conditions,
base-promoted E/Z isomerization took place preferentially
to give 15, followed by subsequent formation of lactone
to produce coumarin 16. The possible dihydrobenzofuran
6 was not obtained (Scheme 4).
The selective synthesis of seven-membered ring
lactones, fused to an aromatic ring, is of considerable
interest due to their presence in biologically and
pharmacologically active compounds [8]. Several
approaches to such benzoxepines involve cyclization of
(E)-itaconic half-esters with sodium acetate in boiling
acetic anhydride [9], intramolecular cyclocarbonylation
of 2-allylphenols catalyzed by palladium complex [10],
allenyl alcohols catalyzed by a ruthenium complex [11],
cyclization of 2-iodobenzyl alcohols with propiolates
catalyzed by Ni(dppe)Br2 and zinc powder [12], the
rhodium-catalyzed carbon-carbon bond cleavage of cyclo-
butanone [13], and the ring closing methathesis reaction
of acrylic ester of 2-allylphenol [14].
In summary, a new method for the synthesis of methyl
2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylates from
Baylis-Hillman adducts of O-benzyl protected 2-hydroxy-
benzaldehydes has been developed through the
acetylation, cyanation, debenzylation, as well as acid
assisted cyclization.
Methyl 3-(2-Benzyloxy-5-nitro)phenyl-3-hydroxy-2-methyl-
enepropanoate (9e). A mixture of 8e (1.29 g, 5 mmoles),
methyl acrylate (1.35 ml, 15 mmoles), DABCO (0.56 g, 5
mmoles), and triethanolamine (0.53 ml, 4 mmoles) was stirred at
room temperature for 4 hours. The mixture was diluted with
water (10 ml) and extracted with dichloromethane (3 ꢀ 20 ml).
The combined organic layers were dried over anhydrous
magnesium sulfate and the solvent was evaporated in vacuo. The
resulting mixture was chromatographed on silica gel eluting
with hexane/ethyl acetate (3:1) to produce 9e (1.63 g, 95%) as a
white solid; mp 87.5-89 ꢀꢁꢂꢃꢄꢂ(potassium bromide): 3477, 1720
1
cm-1; H nmr (deuteriochloroform): ꢀ 3.41 (d, 1 H, J = 6.1 Hz),
EXPERIMENTAL
3.74 (s, 3 H), 5.18 (s, 2 H), 5.66 (s, 1 H), 5.93 (d, 1 H, J = 6.1
Hz), 6.32 (s, 1 H), 6.99 (d, 1 H, J = 9.2 Hz), 7.33-7.43 (m, 5 H),
Silica gel 60 (70-230 mesh ASTM) used for column
chromatography was supplied by E. Merck. Analytical thin layer
chromatography (TLC) was performed on Merck silica gel 60
F254 TLC plates. Melting points were measured by an
Electrothermal melting point apparatus and were uncorrected.
8.17 (dd, 1 H, J = 9.2 and 2.8 Hz), 8.39 (d, 1 H, J = 2.8 Hz); 13
C
nmr (deuteriochloroform): ꢀ 52.1, 67.5, 71.0, 111.4, 123.7,
125.1, 127.0, 127.4, 128.6, 128.8, 131.0, 135.2, 140.1, 141.7,
160.2, 166.7. Anal. Calcd. for C18H17NO6: C, 62.97; H, 4.99; N,
4.08. Found: C, 62.78; H, 4.76; N, 3.89.
Microanalysis was obtained using
a
Thermo Electron
Methyl 3-(2-Benzyloxy-3,5-dichloro)phenyl-3-hydroxy-2-
methylenepropanoate (9f). A mixture of 8f (1.41 g, 5 mmoles),
methyl acrylate (1.35 ml, 15 mmoles), DABCO (0.56 g, 5
mmoles), and triethanolamine (0.53 ml, 4 mmoles) was stirred at
room temperature for 6 hours. The mixture was diluted with
water (10 ml) and extracted with dichloromethane (3 ꢀ 20 ml).
The combined organic layers were dried over anhydrous
magnesium sulfate and the solvent was evaporated in vacuo. The
resulting mixture was chromatographed on silica gel eluting
with hexane/ethyl acetate (3:1) to produce 9f (1.74 g, 95%) as an
oil; ir (potassium bromide): 3431, 1716 cm-1; 1H nmr
(deuteriochloroform): ꢀ 2.79 (d, 1 H, J = 5.1 Hz), 3.72 (s, 3 H),
5.08 (two d, 2 H, J = 11.0 Hz), 5.76 (s, 1 H), 5.80 (d, 1 H, J =
Corporation Flash EA 1112 element analyzer. Infrared spectra
were recorded with a Nicolet Magna 550 FTIR spectrometer.
1
The H and 13C nmr spectra were measured on a Gemini 300
spectrometer using deuteriochloroform. All chemical shifts are
reported in parts per million relative to tetramethylsilane. The
coupling constants (J) are expressed in Hertz.
The known 2-benzyloxybenzaldehydes 8a [15], 8b [16], 8c
[17], 8d, 8e [18] and BH adducts 9a [19], 9b, 9c [20] were
prepared according to literature procedure.
2-(Benzyloxy)-3,5-dichlorobenzaldehyde (8f) [21].
A
mixture of 7f (3.82 g, 10 mmoles), benzyl bromide (1.31 ml, 11
mmoles), and potassium carbonate (1.52 g, 11 mmoles) in
dimethyl sulfoxide (10 ml) was stirred at 40 ꢀ for 30 minutes.
The mixture was diluted with water (20 ml) and extracted with
dichloromethane (3 ꢀ 20 ml). The combined organic layers were
dried over anhydrous magnesium sulfate and the solvent was
evaporated in vacuo. The resulting mixture was chromatographed
on silica gel eluting with hexane/ethyl acetate (3:1) to produce 8f
(2.59 g, 92%) as a white solid; mp: 81-83ꢀ; ir (potassium
5.1 Hz), 6.35 (s,
1 H), 7.27-7.48 (m, 7
H); 13C nmr
(deuteriochloroform): ꢀ 52.1, 67.2, 75.4, 126.6, 126.8, 128.4,
128.5, 128.6, 128.8, 129.9, 136.3, 138.1, 140.5, 151.0, 160.7,
166.4. Anal. Calcd. for C18H16Cl2O4: C, 58.87; H, 4.39. Found:
C, 58.65; H, 4.41.
Preparation of BH Acetates 10: General Procedure. Acetic
anhydride (1.42 ml, 15 mmoles) and 4-(dimethylamino)pyridine
(0.22 g, 2 mmoles) were added to a stirred solution of BH
adduct 9 (10 mmoles) in dichloromethane (15 ml) at room
temperature. After stirring for 20-60 minutes the reaction
mixture was diluted with saturated aqueous sodium bicarbonate
1
bromide): 1693 cm-1; H nmr (deuteriochloroform): ꢀ 5.14 (s, 2
H), 7.35-7.41 (m, 5 H), 7.67 (m, 2 H), 9.98 (s, 1 H); 13C nmr
(deuteriochloroform): ꢀ 77.7, 126.5, 128.9, 129.0, 129.2, 130.0,
130.6, 132.0, 134.8, 135.7, 155.9, 187.6. Anal. Calcd. for
C14H10Cl2O2: C, 59.81; H, 3.59. Found: C, 59.68; H, 3.82.

1704
S.-H. Ahn, H. N. Lim and K.-J. Lee
Vol 45
solution (10 ml) and extracted with dichloromethane (3 ꢀ 20
ml). The combined organic layers were dried over anhydrous
magnesium sulfate and the solvent was evaporated in vacuo. The
resulting mixture was chromatographed on silica gel eluting
with hexane/ethyl acetate (3:1) to produce 10 as an oil or solid.
The physical and spectral data of 10 prepared by this general
method follows.
Methyl 3-Acetoxy-3-(2-benzyloxy)phenyl-2-methylenepro-
panoate (10a). Reaction time: 20 minutes; oil; yield: 95%; ir
(neat): 1744, 1726 cm-1; 1H nmr (deuteriochloroform): ꢀ 2.08 (s,
3 H), 3.69 (s, 3 H), 5.11 (s, 2 H), 5.65 (s, 1 H), 6.40 (s, 1 H),
6.91-6.97 (m, 2 H), 7.14 (s, 1 H), 7.23-7.42 (m, 7 H); 13C nmr
(deuteriochloroform): ꢀ 21.0, 51.9, 68.2, 70.0, 112.2, 120.7,
126.4, 127.0, 127.3, 127.7, 128.4, 129.5, 136.9, 139.0, 155.8,
165.7, 169.4. Anal. Calcd. for C20H20O5: C, 70.57; H, 5.92.
Found: C, 70.39; H, 5.74.
Methyl 3-Acetoxy-3-(2-benzyloxy-5-bromo)phenyl-2-methyl-
enepropanoate (10b). Reaction time: 30 minutes; oil; yield:
98%; ir (neat): 1747, 1728 cm-1; 1H nmr (deuteriochloroform): ꢀ
2.10 (s, 3 H), 3.70 (s, 3 H), 5.10 (s, 2 H), 5.67 (s, 1 H), 6.42 (s, 1
H), 6.78-6.80 (m, 1 H), 7.07 (s, 1 H), 7.29-7.39 (m, 7 H); 13C
nmr (deuteriochloroform): ꢀ 21.0, 52.0, 67.5, 70.3, 113.0, 114.0,
127.0, 127.8, 127.9, 128.5, 128.8, 130.5, 132.1, 136.3, 138.5,
154.8, 165.4, 169.3. Anal. Calcd. for C20H19BrO5: C, 57.29; H,
4.57. Found: C, 57.05; H, 4.39.
nmr (deuteriochloroform): ꢀ 20.9, 52.1, 67.7, 75.4, 126.8, 128.0,
128.3, 128.4, 128.5, 129.3, 129.7, 130.5, 134.7, 136.3, 138.2,
151.5, 165.1, 169.2. Anal. Calcd. for C20H18Cl2O5: C, 58.69; H,
4.43. Found: C, 58.72; H, 4.56.
Preparation of Methyl 3-(2-Benzyloxy)phenyl-2-(cyano-
methyl)propenoates 11: General Procedure. Potassium
cyanide (0.49 g, 7.5 mmoles) was added to a stirred solution of
BH acetate 10 in aqueous dimethyl sulfoxide (1:3, 10 ml) at
room temperature. After stirring for 5-60 minutes the reaction
mixture was diluted with water (10 ml) and extracted with
diethyl ether (3 ꢀ 10 ml). The combined organic layers were
dried over anhydrous magnesium sulfate and the solvent was
evaporated in vacuo. The resulting mixture was
chromatographed on silica gel eluting with hexane/ethyl acetate
(3:1) to produce 11 as an oil or solid.
The physical and spectral data of 11 prepared by this general
method follows.
Methyl (E)-3-(2-Benzyloxy)phenyl-2-(cyanomethyl)propen-
oate (11a). Reaction time: 1 hour; oil; yield: 77%; ir (neat):
1
2250, 1713 cm-1; H nmr (deuteriochloroform): ꢀ 3.46 (s, 2 H),
3.88 (s, 3 H), 5.16 (s, 2 H), 6.97-7.07 (m, 2 H), 7.31-7.39 (m, 7
H), 8.12 (s, 1 H); 13C nmr (deuteriochloroform): ꢀ 17.4, 52.6,
70.4, 112.8, 117.6, 121.1, 122.0, 123.3, 127.1, 128.1, 128.6,
129.8, 131.3, 136.4, 140.5, 156.6, 166.2. Anal. Calcd. for
C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C, 74.04; H,
5.38; N, 4.34.
Methyl 3-Acetoxy-3-(2-benzyloxy-3-ethoxy)phenyl-2-methyl-
enepropanoate (10c). Reaction time: 30 minutes; white solid;
yield: 85%; mp: 63-64.5 ꢀꢁꢂir (potassium bromide): 1745, 1727
Methyl (E)-3-(2-Benzyloxy-5-bromo)phenyl-2-(cyano-
methyl)propenoate (11b). Reaction time: 20 minutes; pale
yellow solid; yield: 85%; mp: 94-95ꢀ; ir (potassium bromide):
1
cm-1; H nmr (deuteriochloroform): ꢀ 1.46 (t, 3 H, J = 7.0 Hz),
1
2252, 1714 cm-1; H nmr (deuteriochloroform): ꢀ 3.43 (s, 2 H),
2.06 (s, 3 H), 3.68 (s, 3 H), 4.09 (q, 2 H, J = 7.0 Hz), 5.11 (s, 2
H), 5.59 (s, 1 H), 6.37 (s, 1 H), 6.87-7.07 (m, 3 H), 7.12 (s, 1 H),
7.28-7.54 (m, 5 H); 13C nmr (deuteriochloroform): ꢀ 14.9, 21.0,
51.9, 64.2, 68.3, 74.6, 113.5, 119.4, 124.0, 127.4, 127.8, 128.2,
128.3, 131.7, 137.7, 139.0, 145.9, 152.1, 165.6, 169.4. Anal.
Calcd. for C22H24O6: C, 68.74; H, 6.29. Found: C, 68.61; H,
6.06.
3.89 (s, 3 H), 5.14 (s, 2 H), 6.85-6.88 (m, 1 H), 7.30-7.45 (m, 7
H), 7.97 (s, 1 H); 13C nmr (deuteriochloroform): ꢀ 17.3, 52.8,
70.7, 113.2, 114.6, 117.1, 123.4, 125.2, 127.1, 128.2, 128.7,
132.1, 133.7, 135.8, 138.9, 155.5, 165.8. Anal. Calcd. for
C19H16BrNO3: C, 59.08; H, 4.18; N, 3.63. Found: C, 59.24; H,
3.91; N, 3.40.
Methyl 3-Acetoxy-3-(2-benzyloxy-5-methyl)phenyl-2-methyl-
enepropanoate (10d) Reaction time: 1 hour; oil; yield: 98%; ir
(dichloromethane): 1745, 1726 cm-1; 1H nmr (deuterio-
chloroform): ꢀ 2.09 (s, 3 H), 2.27 (s, 3 H), 3.69 (s, 3 H), 5.09 (s,
2 H), 5.67 (s, 1 H), 6.41 (s, 1 H), 6.80-6.83 (m, 1 H), 7.04-7.07
(m, 2 H), 7.13 (s, 1 H), 7.28-7.41 (m, 5 H); 13C nmr
(deuteriochloroform): ꢀ 20.6, 21.0, 51.9, 68.2, 70.1, 112.3,
126.1, 127.0, 127.1, 127.7, 128.3, 128.4, 129.9, 130.0, 137.1,
139.1, 153.8, 165.7, 169.5. Anal. Calcd. for C21H22O5: C, 71.17;
H, 6.26. Found: C, 71.32; H, 6.31.
Methyl (E)-3-(2-Benzyloxy-3-ethoxy)phenyl-2-(cyano-
methyl)propenoate (11c). Reaction time: 20 minutes; oil;
yield: 69%; ir (neat): 2250, 1712 cm-1; 1H nmr (deuterio-
chloroform): ꢀ 1.50 (t, 3 H, J = 7.0 Hz), 3.28 (s, 2 H), 3.86 (s, 3
H), 4.14 (q, 2 H, J = 7.0 Hz), 5.03 (s, 2 H), 6.82-7.24 (m, 3 H),
7.28-7.33 (m, 5 H), 7.85 (s, 1 H); 13C nmr (deuteriochloroform):
ꢀ 14.9, 17.2, 52.5, 64.4, 75.2, 114.9, 117.5, 120.8, 122.4, 124.5,
128.2, 128.3, 129.0, 136.8, 140.8, 145.8, 152.3, 166.0. Anal.
Calcd. for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C,
71.53; H, 5.85; N, 3.70.
Methyl 3-Acetoxy-3-(2-benzyloxy-5-nitro)phenyl-2-methyl-
enepropanoate (10e). Reaction time: 30 minutes; white solid;
yield: 91%; mp: 80-82.5 ꢀ; ir (potassium bromide): 1747, 1727
cm-1; 1H nmr (deuteriochloroform): ꢀ 2.13 (s, 3 H), 3.70 (s, 3 H),
5.23 (s, 2 H), 5.73 (s, 1 H), 6.47 (s, 1 H), 6.98-7.01 (m, 1 H),
7.08 (s, 1 H), 7.32-7.40 (m, 5 H), 8.17-8.22 (m, 2 H); 13C nmr
(deuteriochloroform): ꢀ 20.9, 52.1, 67.3, 70.9, 111.8, 123.8,
125.7, 127.1, 128.0, 128.3, 128.4, 128.7, 135.2, 137.9, 141.4,
160.5, 165.2, 169.3. Anal. Calcd. for C20H19NO7: C, 62.33; H,
4.97; N, 3.63. Found: C, 62.11; H, 4.88; N, 3.42.
Methyl (E)-3-(2-Benzyloxy-5-methyl)phenyl-2-(cyano-
methyl)propenoate (11d). Reaction time: 30 minutes; white
solid; yield: 89%; mp: 79-81ꢀ; ir (potassium bromide): 2250,
1713 cm-1; 1H nmr (deuteriochloroform): ꢀ 2.32 (s, 3 H), 3.46 (s,
2 H), 3.88 (s, 3 H), 5.12 (s, 2 H), 6.86-6.89 (m, 1 H), 7.11-7.16
(m, 2 H), 7.31-7.41 (m, 5 H), 8.09 (s, 1 H); 13C nmr
(deuteriochloroform): ꢀ 17.4, 20.5, 52.6, 70.5, 112.9, 117.7,
121.8, 123.1, 127.1, 128.0, 128.6, 130.2, 130.5, 131.7, 136.6,
140.7, 154.5, 166.2. Anal. Calcd. for C20H19NO3: C, 74.75; H,
5.96; N, 4.36. Found: C, 74.52; H, 5.85; N, 4.18.
Methyl 3-Acetoxy-3-(2-benzyloxy-3,5-dichloro)phenyl-2-
methylenepropanoate (10f). Reaction time: 30 minutes; oil;
Methyl (E)-3-(2-Benzyloxy-5-nitro)phenyl-2-(cyanomethyl)-
propenoate (11e). Reaction time: 5 minutes; white solid; yield:
91%; mp: 113-115 ꢀ; ir (potassium bromide): 2253, 1714 cm-1;
1H nmr (deuteriochloroform): ꢀ 3.47 (s, 2 H), 3.91 (s, 3 H), 5.29
(s, 2 H), 7.07-7.10 (m, 1 H), 7.39-7.44 (m, 5 H), 7.99 (s, 1 H),
8.18-8.19 (m, 1 H), 8.24-8.28 (m, 1 H); 13C nmr (deuterio-
1
yield: 90%; ir (potassium bromide): 1748, 1728 cm-1; H nmr
(deuteriochloroform): ꢀ 2.10 (s, 3 H), 3.70 (s, 3 H), 5.11 (two d,
2 H, J = 13.4 Hz), 5.64 (s, 1 H), 6.42 (s, 1 H), 7.04 (s, 1 H),
7.20-7.21 (m, 1 H), 7.32-7.42 (m, 4 H), 7.52-7.55 (m, 2 H); 13C

Nov-Dec 2008
Synthesis of Methyl 2-Oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylates
1705
chloroform): ꢀ 17.2, 52.9, 71.3, 112.5, 116.5, 123.8, 124.8,
125.4, 126.9, 127.1, 128.7, 128.9, 134.8, 137.8, 141.3, 161.0,
165.5. Anal. Calcd. for C19H16N2O5: C, 64.77; H, 4.58; N, 7.95.
Found: C, 64.59; H, 4.72; N, 7.69.
20.5, 52.7, 116.1, 117.6, 120.7, 122.2, 130.1, 130.2, 132.0,
140.5, 151.7, 166.5. Anal. Calcd. for C13H13NO3: C, 67.52; H,
5.67; N, 6.06. Found: C, 67.35; H, 5.46; N, 5.79.
Methyl (E)-2-Cyanomethyl-3-(2-hydroxy-5-nitro)phenyl-
propenoate (12e). Reaction time: 10 hours; pale yellow solid;
yield: 76%; mp: 169-172 ꢀ;ꢁ ir (potassium bromide): 3221,
Methyl (E)-3-(2-Benzyloxy-3,5-dichloro)phenyl-2-(cyano-
methyl)propenoate (11f). Reaction time: 15 minutes; oil; yield:
71%; ir (potassium bromide): 2252, 1718 cm-1; 1H nmr
(deuteriochloroform): ꢀ 3.25 (s, 2 H), 3.87 (s, 3 H), 4.96 (s, 2
H), 7.12 (d, 1 H, J = 2.5 Hz), 7.28-7.36 (m, 5 H), 7.49 (d, 1 H, J
= 2.5 Hz), 7.63 (s, 1 H); 13C nmr (deuteriochloroform): ꢀ 17.1,
52.8, 76.3, 116.5, 124.6, 127.6, 128.5, 128.8, 129.2, 130.0,
130.1, 131.2, 131.5, 135.4, 138.2, 151.3, 165.3. Anal. Calcd. for
C19H15Cl2NO3: C, 60.65; H, 4.02; N, 3.72. Found: C, 60.42; H,
4.15; N, 3.50.
Preparation of Methyl (E)-2-Cyanomethyl-3-(2-hydroxy-
phenyl)propenoates 12 : General procedure. To a stirred
solution of 11 (1 mmole) in anhydrous dichloromethane (10 ml)
was added boron trifluoride etherate (1.23 ml, 10 mmoles) and
dimethyl sulfide (4.44 ml, 60 mmoles) at room temperature.
After stirring for 2-24 hours under nitrogen atmosphere, the
mixture was diluted with aqueous ammonium hydroxide (0.1 M,
20 ml) and extracted with dichloromethane (3 ꢀ 30 ml). The
combined organic layers were dried over anhydrous magnesium
sulfate and the solvent was evaporated in vacuo. The resulting
mixture was chromatographed on silica gel eluting with
hexane/ethyl acetate (3:1) to produce 12 as a solid.
1
2266, 1705 cm-1; H nmr (dimethyl sulfoxide-d6): ꢀ 3.64 (s, 2
H), 3.84 (s, 3 H), 7.10-7.13 (m, 1 H), 7.86 (s, 1 H), 8.16-8.23
(m, 2 H), 11.88 (br s, 1 H); 13C nmr (dimethyl sulfoxide-d6): ꢀ
16.9, 52.7, 116.2, 117.8, 121.1, 123.8, 125.9, 127.0, 137.2,
139.4, 161.9, 165.6. Anal. Calcd. for C12H10N2O5: C, 54.97; H,
3.84; N, 10.68. Found: C, 54.72; H, 3.79; N, 10.43.
Methyl (E)-2-Cyanomethyl-3-(3,5-dichloro-2-hydroxy)-
phenylpropenoate (12f). Reaction time: 4 hours; white solid;
yield: 73%; mp: 129-132 ꢀ;ꢁ ir (potassium bromide): 3280,
1
2272, 1720 cm-1; H nmr (deuteriochloroform): ꢀ 3.44 (s, 2 H),
3.91 (s, 3 H), 5.95 (s, 1 H), 7.18 (d, 1 H, J = 2.4 Hz), 7.42 (d, 1
H, J = 2.4 Hz), 7.88 (s, 1 H); 13C nmr (deuteriochloroform): ꢀ
17.5, 52.9, 116.7, 121.4, 123.0, 124.8, 125.8, 128.2, 129.8,
137.5, 148.0, 165.5. Anal. Calcd. for C12H9Cl2NO3: C, 50.38; H,
3.17; N, 4.90. Found: C, 50.15; H, 3.06; N, 4.69.
Preparation of Methyl 2-Oxo-2,3-dihydrobenzo[b]-
oxepine-4-carboxylates 13: General Procedure. A stirred
solution of 12 (1 mmole) and para-toluenesulfonic acid
monohydrate (0.38 g, 2 mmoles) in toluene (5 ml) was heated at
reflux temperature for 0.5-8 hours. After cooling to room
temperature, the mixture was diluted with saturated aqueous
sodium bicarbonate solution (5 ml) and extrated with
dichloromethane (3 ꢀ 10 ml). The combined organic layers were
dried over anhydrous magnesium sulfate and the solvent was
evaporated in vacuo. The resulting mixture was chromato-
graphed on silica gel eluting with hexane/ethyl acetate (3:1) to
produce 13 as a solid.
The physical and spectral data of 12 prepared by this general
method follows.
Methyl (E)-2-Cyanomethyl-3-(2-hydroxyphenyl)propen-
oate (12a). Reaction time: 5 hours; white solid; yield: 68%; mp:
101-103.5 ꢀ; ir (potassium bromide): 3334, 2257, 1707 cm-1;
1H nmr (deuteriochloroform): ꢀ 3.47 (s, 2 H), 3.90 (s, 3 H), 6.27
(s, 1 H), 6.88-7.02 (m, 2 H), 7.24-7.31 (m, 2 H), 8.04 (s, 1 H);
13C nmr (deuteriochloroform): ꢀ 17.5, 52.8, 116.2, 117.6, 120.8,
120.9, 122.1, 129.9, 131.4, 140.5, 154.1, 166.5. Anal. Calcd. for
C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.11; H,
4.88; N, 6.29.
The physical and spectral data of 13 prepared by this general
method follows.
Methyl 2-Oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylate
(13a). Reaction time: 2 hours; white solid; yield: 78%; mp: 84.5-
86.5 ꢀ; ir (potassium bromide): 1770, 1699 cm-1; 1H nmr
(deuteriochloroform): ꢀ 3.45 (s, 2 H), 3.89 (s, 3 H), 7.27-7.52
(m, 4 H), 7.89 (s, 1 H); 13C nmr (deuteriochloroform): ꢀ 33.2,
52.7, 121.4, 124.8, 125.1, 125.6, 130.9, 131.4, 137.7, 150.7,
165.0, 167.7. Anal. Calcd. for C12H10O4: C, 66.05; H, 4.62.
Found: C, 65.87; H, 4.48.
Methyl 7-Bromo-2-oxo-2,3-dihydrobenzo[b]oxepine-4-
carboxylate (13b). Reaction time: 1 hour; white solid; yield:
76%; mp: 112-114 ꢀ;ꢁir (potassium bromide): 1771, 1714 cm-1;
1H nmr (deuteriochloroform): ꢀ 3.45 (s, 2 H), 3.89 (s, 3 H),
7.16-7.19 (m, 1 H), 7.57-7.60 (m, 2 H), 7.80 (s, 1 H); 13C nmr
(deuteriochloroform): ꢀ 33.2, 52.9, 117.9, 123.3, 126.1, 127.4,
133.2, 134.2, 136.3, 149.7, 164.6, 166.9. Anal. Calcd. for
C12H9BrO4: C, 48.51; H, 3.05. Found: C, 48.39; H, 2.89.
Methyl (E)-3-(5-Bromo-2-hydroxy)phenyl-2-(cyanomethyl)-
propenoate (12b). Reaction time: 12 hours; white solid; yield:
83%; mp: 150-152 ꢀ;ꢁ ir (potassium bromide): 3396, 2254,
1
1692 cm-1; H nmr (dimethyl sulfoxide-d6): ꢀ 3.59 (s, 2 H), 3.82
(s, 3 H), 6.90-6.93 (m, 1 H), 7.40-7.46 (m, 2 H), 7.82 (s, 1 H),
10.59 (br s, 1 H); 13C nmr (dimethyl sulfoxide-d6): ꢀ 16.9, 52.6,
110.1, 117.9, 118.0, 122.5, 122.7, 131.7, 133.7, 137.9, 155.2,
165.8. Anal. Calcd. for C12H10BrNO3: C, 48.67; H, 3.40; N, 4.73.
Found: C, 48.62; H, 3.43; N, 4.65.
Methyl (E)-2-Cyanomethyl-3-(3-ethoxy-2-hydroxy)phenyl-
propenoate (12c). Reaction time: 2 hours; white solid; yield:
65%; mp: 148.5-150 ꢀ; ꢂꢃꢁ (potassium bromide): 3356, 2254,
1
1720 cm-1; H nmr (deuteriochloroform): ꢀ 1.48 (t, 3 H, J = 7.0
Hz), 3.48 (s, 2 H), 3.89 (s, 3 H), 4.15 (q, 2 H, J = 7.0 Hz), 6.11
(s, 1 H), 6.86-6.91 (m, 3 H), 8.03 (s, 1 H); 13C nmr
(deuteriochloroform): ꢀ 14.8, 17.6, 52.6, 64.8, 112.6, 117.6,
120.0, 121.3, 122.4, 128.7, 139.4, 144.2, 146.0, 166.2. Anal.
Calcd. for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C,
64.13; H, 5.55; N, 5.12.
Methyl (E)-2-Cyanomethyl-3-(2-hydroxy-5-methyl)phenyl-
propenoate (12d). Reaction time: 10 hours; white solid; yield:
75%; mp: 113.5-115 ꢀ; ir (potassium bromide): 3380, 2256,
1710 cm-1; 1H nmr (deuteriochloroform): ꢀ 2.30 (s, 3 H), 3.46 (s,
2 H), 3.89 (s, 3 H), 6.00 (s, 1 H), 6.76-6.80 (m, 1 H), 7.03-7.09
(m, 2 H), 8.00 (s, 1 H); 13C nmr (deuteriochloroform): ꢀ 17.6,
Methyl
9-Ethoxy-2-oxo-2,3-dihydrobenzo[b]oxepine-4-
carboxylate (13c). Reaction time: 8 hours; pale yellow solid;
yield: 61%; mp: 88-90 ꢀ;ꢁ ir (potassium bromide): 1767, 1713
1
cm-1; H nmr (deuteriochloroform): ꢀ 1.48 (t, 3 H, J = 7.0 Hz),
3.44 (s, 2 H), 3.88 (s, 3 H), 4.13 (q, 2 H, J = 7.0 Hz), 6.90-7.05 (m,
2 H), 7.17-7.22 (m, 1 H), 7.86 (s, 1 H); 13C nmr (deuterio-
chloroform): ꢀ 14.7, 33.5, 52.7, 64.9, 114.6, 121.7, 125.1, 125.3,
126.9, 137.8, 140.5, 150.1, 165.0, 167.7. Anal. Calcd. for
C14H14O5: C, 64.12; H, 5.38. Found: C, 63.90; H, 5.41.
Methyl 7-Methyl-2-oxo-2,3-dihydrobenzo[b]oxepine-4-
carboxylate (13d). Reaction time: 30 minutes; pale yellow

1706
S.-H. Ahn, H. N. Lim and K.-J. Lee
Vol 45
2003, 103, 811. [f] Kataoka, T.; Kinoshita, H. Eur. J. Org. Chem. 2005,
45. [g] Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511.
[2a] Song, Y. S.; Lee, C. H.; Lee, K.-J. J. Heterocycl. Chem. 2003,
40, 939. [b] Lee, C. H.; Song, Y. S.; Cho, H. I.; Yang, J. W.; Lee, K.-J. J.
Heterocycl. Chem. 2003, 40, 1103. [c] Ko, S. H.; Lee, K.-J. J. Heterocycl.
Chem. 2004, 41, 613. [d] Lee, C. H.; Lee, K.-J. Synthesis 2004, 1941. [e]
Hong, W. P.; Lee, K.-J. Synthesis 2005, 33. [f] Hong, W. P.; Lee, K.-J.
Synthesis 2006, 963. [g] Yi, H.-W.; Park, H. W.; Song, Y. S.; Lee, K.-J.
Synthesis 2006, 1953. [h] Lim, H. N.; Ji, S.-H; Lee, K.-J. Synthesis 2007,
2454. [i] Song, Y. S.; Lee, K.-J. Synthesis 2007, 3037. [j] Cha, M. J.; Song,
Y. S.; Han, E.-G.; Lee, K.-J. J. Heterocycl. Chem. 2008, 45, 235. [k] Jeon,
K. J.; Lee, K.-J. J. Heterocycl. Chem. 2008, 45, 615.
[3] Lim, H. N.; Song, Y. S.; Lee, K.-J. Synthesis 2007, 3376.
[4a] Kaye, P. T.; Nocanda, X. W. J. Chem. Soc., Perkin Trans 1,
2000, 1331. [b] Kaye, P. T.; Robinson, R. S. S. Afr. J. Chem. 1998, 51,
47. [c] Kaye, P. T.; Robinson, R. S. Synth. Commun. 1996, 26, 2085.
[5a] Singh, V.; Pathak, R.; Batra, S. Catal. Commun. 2007, 8,
2054 [b] Yadav, J. S.; Gupta, M. K.; Pandey, S. K.; Reddy, B. V. S.;
Sarma, A. V. S. Tetrahedron Lett. 2005, 46, 655. [c] Hong, W. P.; Lim,
H. N.; Park, H. W.; Lee, K.-J. Bull. Korean Chem. Soc. 2005, 26, 655.
[6a] Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J. Org. Chem.
1979, 44, 1661. [b] Williard, P. G.; Fryhle, C. B. Tetrahedron. Lett.
1980, 21, 3731.
[7a] Pinner, A.; Klein, F. Ber. 1877, 10, 1889. [b] Pinner, A.;
Klein, F. Ber. 1878, 11, 1475. [c] Aplander, K.; Hidestål, O.;
Katebzadeh, K.; Lindström, U. M. Green Chem. 2006, 8, 22. [d] Kwok,
R.; Wolff, M. E. J. Org. Chem. 1963, 28, 423.
[8a] Engler, A.; Anke, T.; Sterner, O. J. Antibiot. 1997, 50, 330.
[b] Ishikawa, N. K.; Yamaji, K.; Tahara, S.; Fukushi, Y.; Takahasio, K.
Phytochemistry 2000, 54. 777. [c] Marriott, K.-S.; Anderson, M.;
Jackson, Y. A. Heterocycles 2001, 55, 91; [d] Tersawa, K.; Hosoya, H.;
Sugita, Y.; Yokoe, I.; Sakagami, H. Anticancer Res. 2000, 20, 2951.
[9] Rizzacasa, M. A.; Sargent, M. V. Aust. J. Chem. 1987, 40,
1737.
[10] Ali, B. E.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am. Chem.
Soc. 1996, 118, 4264.
[11] Yoneda, E.; Zhang, S. W.; Onitsuka, K.; Takahashi, S.
Tetrahedron Lett. 2001, 42, 5459.
[12] Rayabarapu, D. K.; Cheng, C.-H. J. Am. Chem. Soc. 2002,
124, 5630.
[13a] Murakami, M.; Tsuruta, T.; Ito, Y. Angew. Chem. Int. Ed.
2000, 39, 2484. [b] Matsuda, T.; Shigeno, M.; Murakami, M. J. Am.
Chem. Soc. 2007, 129, 12086.
[14] Fꢁrstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.;
Nolan, S.P. J. Org. Chem. 2000, 65, 2204.
[15] Thomas, D. H.; Gregory, P. R. J. Org. Chem. 1979, 44, 12,
2004.
[16] Rainford, L. C.; Tanzer, L. K. J. Org. Chem. 1941, 6, 722.
[17] Profit, E. J. Prakt. Chem. 1957, 5, 175. Chem. Abstr. 1958,
52, 10940d.
solid; yield: 87%; mp: 103-104.5 ꢀ;ꢁ ir (potassium bromide):
1
1761, 1716 cm-1; H nmr (deuteriochloroform): ꢀ 2.39 (s, 3 H),
3.43 (s, 2 H), 3.88 (s, 3 H), 7.16-7.29 (m, 3 H), 7.84 (s, 1 H); 13
C
nmr (deuteriochloroform): ꢀ 20.6, 33.2, 52.7, 121.2, 124.6,
125.3, 130.9, 132.2, 134.8, 137.8, 148.8, 165.1, 167.9. Anal.
Calcd. for C13H12O4: C, 67.23; H, 5.21. Found: C, 67.05; H,
5.18.
Methyl 7-Nitro-2-oxo-2,3-dihydrobenzo[b]oxepine-4-carbox-
ylate (13e). Reaction time: 1 hour; white solid; yield: 50%; mp:
1
149-152 ꢀ;ꢁ ir (potassium bromide): 1783, 1716cm-1; H nmr
(deuteriochloroform): ꢀ 3.51 (s, 2 H), 3.92 (s, 3 H), 7.43-7.46
(m, 1 H), 7.93 (s, 1 H), 8.32-8.39 (m, 2 H); 13C nmr
(deuteriochloroform): ꢀ 33.4, 53.1, 122.9, 126.0, 126.2, 126.7,
127.2, 135.8, 144.3, 154.2, 164.3, 165.4. Anal. Calcd. for
C12H9NO6: C, 54.76; H, 3.45; N, 5.32. Found: C, 54.51; H, 3.22;
N, 5.49.
Methyl 7,9-Dichloro-2-oxo-2,3-dihydrobenzo[b]oxepine-4-
carboxylate (13f). Reaction time: 1 hour; white solid; yield:
63%; mp: 139-142 ꢀ; ir (potassium bromide): 1786, 1717cm-1;
1H nmr (deuteriochloroform): ꢀ 3.46 (s, 2 H), 3.90 (s, 3 H), 7.33
(d, 1 H, J = 2.4 Hz), 7.58 (d, 1 H, J = 2.4 Hz), 7.79 (s, 1 H); 13C
nmr (deuteriochloroform): ꢀ 33.3, 53.0, 127.0, 127.7, 128.2,
128.5, 130.3, 131.5, 135.8, 145.0, 164.4, 166.0. Anal. Calcd. for
C12H8Cl2O4: C, 50.20; H, 2.81. Found: C, 50.02; H, 2.64.
3-Cyanomethylcoumarin (16). To a stirred solution of 12a
(0.22 g, 1 mmole) in methanol (3 ml) was added sodium
methoxide (0.065 g, 1.2 mmoles) and refluxed for 24 hours. The
reaction mixture was neutralized with 5% aqueous hydrochloric
acid solution (5 ml) and extracted with dichloromethane (3 ꢀ 20
ml). The combined organic layers were dried over anhydrous
magnesium sulfate and the solvent was evaporated in vacuo. The
resulting mixture was chromatographed on silica gel eluting
with hexane/ethyl acetate (3:1) to produce 16 as a yellow solid
after crystallization with cold methanol, along with the recovery
of starting compound 12a (25%); mp: 166-168 ꢀ; ir (potassium
bromide): 2260, 1715 cm-1; 1H nmr (deuteriochloroform): ꢀ 3.71
(d, 2 H, J = 1.5 Hz), 7.32-7.39 (m, 2 H), 7.56-7.62 (m, 2 H), 7.96
(s, 1 H); 13C nmr (deuteriochloroform): ꢀ 19.5, 116.0, 116.7,
118.4, 118.7, 124.9, 128.0, 132.3, 140.6, 153.4, 160.1. Anal.
Calcd. for C11H7NO2: C, 71.35; H, 3.81; N, 7.56. Found: C,
71.12; H, 3.75; N, 7.33.
Acknowledgement. This study was supported by a grant of
University IT Research Center Project, Republic of Korea
REFERENCES AND NOTES
[18] Chen, Han.; Fan, Y.-H.; Natarajan, A.; Guo, Y.; Iyasere, J.;
Harbinski, F.; Luus, L.; Christ, W.; Aktas, H.; Halperin, J. A. Bioorg.
Med. Chem. Lett. 2004, 14, 5401.
*
Author to whom correspondence should be addressed.
[19] Drewes, S. E.; Njamela, O. L.; Emslie, N. D.; Ramesar, N.;
Field, J. S. Synth. Commun. 1993, 23, 2807.
[20] Kaye, P. T.; Musa, M. A. Synth. Commun. 2003, 33, 1755.
[21] Colson, P.-j.; Awasthi, A. K.; Nagarajan, S. R. WO
9,944,985, 1999; Chem. Abstr. 1999, 131, 185252.
[1a] For reviews of the Baylis-Hillman reaction, see: 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.; Santyanarayana, T. Chem. Rev.