Synthesis of methyl 2-amino-3H-1-benzazepine-4-carboxylates and 2-(cyanomethyl)-2,3-dihydro-1H-indole-2-carboxylates from Morita-Baylis-Hillman acetates of 2-(acylamino)benzaldehydes

Article abstract of DOI:10.1055/s-2007-990809

Methyl 2-Amino-3H-1-benzazepine-4-carboxylates or methyl 2-(cyanomethyl)-2,3-dihydro-1H-indole-2-carboxylates were prepared from the reaction of 3-[2-formamido-, 2-acetamido-, or 2-(propanoylamino)phenyl]- substituted methyl 2-(cyanomethyl)propenoates wit

Full text of DOI:10.1055/s-2007-990809

3376
PAPER
Synthesis of Methyl 2-Amino-3H-1-benzazepine-4-carboxylates and
2-(Cyanomethyl)-2,3-dihydro-1H-indole-2-carboxylates from Morita–
Baylis–Hillman Acetates of 2-(Acylamino)benzaldehydes
Synthesis of
Amin
e
o-3
H
-1-ben
e
zazepines
a
nd2,3
N
-Dihydro-1
H
-indo
a
les m Lim, Young Seok Song, 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 19 July 2007; revised 16 August 2007
The Morita–Baylis–Hillman (MBH) reaction2 has attract-
ed the attention of organic chemists in recent years as this
reaction provides synthetically useful multifunctional
molecules that have been successfully employed in the
Abstract: Methyl 2-Amino-3H-1-benzazepine-4-carboxylates or
methyl 2-(cyanomethyl)-2,3-dihydro-1H-indole-2-carboxylates
were prepared from the reaction of 3-[2-formamido-, 2-acetamido-,
or 2-(propanoylamino)phenyl]-substituted methyl 2-(cyanometh-
yl)propenoates with sodium methoxide in methanol, respectively. synthesis of various heterocycles. During continued ef-
forts to develop MBH chemistry,3 we envisioned that we
The latter were readily obtained from the Morita–Baylis–Hillman
reaction of N-protected 2-aminobenzaldehydes with methyl acry-
late followed by acetylation and cyanation.
could synthesize 2-amino-3H-1-benzazepine IV by the
cyanation of the MBH acetate of 2-nitrobenzaldehyde.
Several cyanation reactions of MBH acetates are known
Key words: Morita–Baylis–Hillman, 2-amino-3H-1-benzazepine,
in the literature.3b,4 Unfortunately, the reaction of ethyl 3-
dihydroindole, N-protected 2-aminobenzaldehyde, 3-aryl-2-(cyano-
methyl)propenoate
acetoxy-2-methylene-3-(2-nitrophenyl)propanoate (V) or
ethyl 2-(bromomethyl)-3-(2-nitrophenyl)propenoate (VI)
with potassium cyanide under various conditions yielded
2-Aminobenzazepine derivatives are useful for modulat-
very complex mixtures of products that could not be puri-
ing immune responses in vitro and in vivo. Such com-
fied, thereby indicating the limitation of the method
pounds will find use in a number of clinical applications,
(Scheme 2). So we turned our attention to the cyanation of
such as in methods for abating conditions involving un-
methyl 3-acetoxy-3-[2-(acylamino)phenyl]-2-methylene-
propanoates 3 for the synthesis of methyl 2-amino-3H-1-
benzazepine-4-carboxylates 6. In this reaction, as shown
wanted activity, including inflammatory, autoimmune
disorders, and the treatment of cancer.1 Despite the bio-
logically important aspects of 2-aminobenzazepines IV,
relatively few general synthetic methods have been re-
ported. One of the approaches to this class of heterocycles
involves the Wittig alkenation of 2-nitrobenzaldehyde (I)
with [2-cyano-1-(ethoxycarbonyl)ethylidene]triphenyl-
phosphorane (II) followed by reduction of the nitro group
of 2-(cyanomethyl)-3-(2-nitrophenyl)propenoate III, and
subsequent intramolecular amidine formation as shown in
Scheme 1.1
in Scheme 3, we expected that the amino group, after
cleavage of the amide bond by a suitable base, would at-
tack the cyano group to generate the amidine functional
group.
OAc
O
OEt
OEt
O
NO2
KCN
OEt
V
O
O
NO2 CN
Ph3P
CO2Et
CN
H
III
+
NO2 Br
NO2
VI
I
II
CO2Et
NH2
Scheme 2
CO2Et
Fe, AcOH
Treatment of several N-protected 2-aminobenzaldehydes
1a–i5 with 1.0 equivalents of 1,4-diazabicyclo[2.2.2]oc-
tane in tetrahydrofuran at room temperature produced
MBH adducts, methyl 3-[2-(acylamino)phenyl]-3-hy-
droxy-2-methylenepropanoates 2a–i in 40–84% yields.
The reaction of 2a–i with acetic anhydride in the presence
of a catalytic amount of 4-(dimethylamino)pyridine in
dichloromethane at room temperature gave MBH acetates
3a–i in 60–88% yields. The cyanation reaction of the ace-
tates 3a–i with potassium cyanide in dimethyl sulfoxide–
NO2 CN
III
N
IV
Scheme 1
SYNTHESIS 2007, No. 21, pp 3376–3384
Advanced online publication: 21.09.2007
DOI: 10.1055/s-2007-990809; Art ID: F13507SS
x
x.
x
x
.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Amino-3H-1-benzazepines and 2,3-Dihydro-1H-indoles
3377
H2C CHCO2Me
DABCO, N(CH2CH2OH)3
neat or THF
Ac2O, DMAP
CH2Cl2, r.t.
10 min to 1 h
OH
O
O
X
X
OMe
H
R
0 °C or r.t., 2–72 h
60–88%
40–84%
NH
NH
O
R
O
1
2
OAc
NH
O
O
KCN, DMSO–H2O
r.t., 0.5–1 h
X
X
OMe
OMe
61–81%
NH
CN
O
R
O
R
3
4
O
O
OMe
X
X
X
R = H
OMe
OMe
64–76%
41–65%
NH2 CN
N
NaOMe, MeOH
r.t., 0.5–28 h
NH2
5
6
O
O
R = Me or Et
X
OMe
CN
N
NH
CN
R
O
R
O
7
8
when X = NO2
O2N
O
1, 2, 3, 4
a
b
c
d
e
f
g
h
i
OMe
CN
X
R
H
H
Me
H
Cl
H
H
H
Me Cl
NO2
Me
H
N
H
Me Et
Me
Me
Ph
8f
6
a
8
a
d
b
c
b
c
e
X
X
R
H
Me Cl
H
H
Me Cl
NO2
Me Et
Me Me Me
Scheme 3
water (1:1) at room temperature occurred in an SN2¢ fash- under similar conditions. Apparently under these reaction
ion to give the required key intermediate methyl 3-[2- conditions, base-promoted hydrolysis of the amide bond
(acylamino)phenyl]-2-(cyanomethyl)propenoate
4a–i took place preferentially to give 5, followed by subse-
(61–81%). In all cases, the stereoselectivity was found to quent formation of the amidine functionality between the
be 100% E-selectivity, as determined by 1H NMR analy- amino and cyano groups to produce 6.
sis of alkene and methylene protons by comparison with
Next we examined 3-(2-acetamidophenyl)-2-(cyanometh-
yl)propenoates and 2-(cyanomethyl)-3-[2-(propanoyl-
amino)phenyl]propenoates 4d–i with sodium methoxide
to clarify the generality of this methodology. Interesting-
literature values.3b,6 The N-formylaniline derivatives 2a–
c, 3a–c, and 4a–c showed a mixture of cis- and trans-con-
formers in their 1H and 13C NMR spectra.7
We investigated a model reaction using methyl 2-(cya- ly, the reaction of 4d–h with sodium methoxide in meth-
nomethyl)-3-(2-formamidophenyl)propenoate (4a) with anol under the same conditions proceeded smoothly to
sodium methoxide in methanol. After stirring the mixture produce methyl 2-(cyanomethyl)-2,3-dihydro-1H-indole-
at room temperature for 30 minutes, the desired methyl 2- 2-carboxylates 8a–d in 41–65% yields. In the case of the
amino-3H-1-benzazepine-4-carboxylate (6a) was ob- strongly electron-withdrawing nitro-substituted substrate
tained in 76% yield. Electron-donating methyl-substituted 4h, the deacetylated dihydroindole 8f was produced under
or electron-withdrawing chloro-substituted N-formyl-pro- the reaction conditions, presumably due to the enhance-
tected amino compounds 4b and 4c gave the correspond- ment of the electrophilic carbon center by the significant
ing 2-amino-3H-1-benzazepines 6b (64%) and 6c (72%) resonance stabilization of the nitro group (Table 1). Using
Synthesis 2007, No. 21, 3376–3384 © Thieme Stuttgart · New York

3378
H. N. Lim et al.
PAPER
the benzoyl group for N-protection, 4i was completely Silica gel 60 (70–230 mesh ASTM) used for column chromatogra-
phy was supplied by E. Merck. Analytical TLC was carried out on
consumed, but the reaction gave a complex mixture of
Merck silica gel 60 F254 TLC plates. Melting points were taken us-
products.
ing an Electrothermal melting point apparatus and are uncorrected.
Although the isolation of the isomerized intermediate 7
was unsuccessful under the reaction conditions, an in-
tramolecular Michael reaction of the anion of amide
would attack the b-position of an a,b-unsaturated nitrile
by the 5-exo-trigonal mode8 to produce the dihydroin-
doles 8.
Microanalyses were obtained using Thermo Electron Corporation
Flash EA 1112 element analyzer. MS (EI) and HRMS were ob-
tained using a Jeol SX 102 mass spectrometer. IR spectra were re-
1
corded on a Nicolet Magna 550 FTIR spectrophotometer. The H
and 13C NMR spectra were measured on a Gemini 300 spectrometer
using CDCl3 with TMS as internal standard.
The known N-protected 2-aminobenzaldehydes 1a–i5 and 2-[(4-
methoxyphenylsulfonyl)amino]benzaldehyde (9)17 were prepared
according to literature procedures. Petroleum ether (PE) used refers
to the fraction with bp 30–60 °C.
Table 1 2-Amino-1-benzazepines 6 and Dihydroindoles 8
Entry
Substrate
Time (h)
Product
6a
Yield (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
1
1
76
64
72
65
41
46
62
56
Methyl 3-(2-Formamidophenyl)-3-hydroxy-2-methylene-
propanoate (2a); Typical Procedure
6b
A mixture of 2-formamidobenzaldehyde (1a, 1.49 g, 10 mmol), me-
thyl acrylate (2.70 mL, 30 mmol), DABCO (1.12 g, 10 mmol), and
triethanolamine (1.06 mL, 8 mmol) was stirred at 0 °C for 2 h. The
mixture was diluted with H2O (20 mL) and extracted with EtOAc (3
× 40 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo. The resulting mixture was chromatographed
(silica gel, hexane–EtOAc, 3:1) to produce 2a (1.11 g, 47%) as a
white solid that was recrystallized (Et2O–PE); ratio cis/trans ca.
60:40;7 mp 83–84 °C.
0.5
12
24
28
4
6c
8a
8b
8c
4g
4h
8d
IR (KBr): 3355, 3294, 1700, 1655, 1599, 1441 cm–1.
2
8f
1H NMR (CDCl3): d = 3.68 (d, J = 4.0 Hz, 0.4 H, OH), 3.77 (s, 1.2
H, OCH3), 3.79 (s, 1.8 H, OCH3), 3.87 (d, J = 3.4 Hz, 0.6 H, OH),
5.70 (s, 1 H, CH), 5.76 (s, 0.6 H, CH), 5.83 (s, 0.4 H, CH), 6.37 (s,
0.6 H, CH), 6.38 (s, 0.4 H, CH), 7.11–7.35 (m, 3.4 H, arom), 8.04–
8.06 (m, 0.6 H, arom), 8.37 (s, 0.6 H, CH), 8.51 (d, J = 11.6 Hz, 0.4
H, CH), 8.87 (d, J = 11.6 Hz, 0.4 H, NH), 9.00 (br s, 0.6 H, NH).
13C NMR (CDCl3): d = 52.2, 70.3, 70.9, 120.6, 123.8, 125.2, 125.6,
126.3, 126.7, 128.2, 128.9, 129.1, 130.5, 131.7, 135.0, 135.5, 139.9,
140.3, 159.6, 162.7, 166.8, 167.3.
Dihydroindoles (indolines) are incorporated in many bio-
logically active compounds and natural products such as
(+)-CC-1065,9 vindoline,10 and vincristine.11 Classical ap-
proaches to such dihydroindoles, which typically involve
reduction of the corresponding indole, have been exten-
sively documented.12 In addition, several procedures me-
diated by free radical,13 anionic,14 transition-metal
species,15 and samarium (II) iodide16 have been reported.
Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C,
61.12; H, 5.43; N, 5.81.
To further probe the effect of the N-protection group, we
Methyl 3-(2-Formamido-5-methylphenyl)-3-hydroxy-2-methyl-
enepropanoate (2b)
allowed
known
2-[(4-methoxyphenylsulfonyl)ami-
no]benzaldehyde (9)17 to react with methyl acrylate in the
presence of 1,4-diazabicyclo[2.2.2]octane in tetrahydro-
furan. The product was cis and trans (2:8) mixture of
1,2,3,4-tetrahydroquinoline 10 by tandem Michael–aldol
reaction pathways, originally reported by Hamada et al.
(Scheme 4).18
Following the typical procedure for 2a, a mixture of 2-formamido-
5-methylbenzaldehyde (1b, 1.63 g, 10 mmol), methyl acrylate (2.70
mL, 30 mmol), DABCO (1.12 g, 10 mmol), and triethanolamine
(1.06 mL, 8 mmol) in THF (5 mL) was stirred at 0 °C for 8 h. Work-
up gave 2b (1.00 g, 40%) as a colorless oil; ratio cis/trans ca.
60:40.7
IR (CH2Cl2): 3334, 1723, 1677, 1514, 1439, 1294 cm–1.
In summary, a new method for the synthesis of 2-amino-
3H-1-benzazepines and dihydroindoles from Morita– 1H NMR (CDCl3): d = 2.30 (s, 1.8 H, CH3), 2.32 (s, 1.2 H, CH3),
3.74 (br s, 1 H, OH), 3.76 (s, 1.2 H, OCH3), 3.78 (s, 1.8 H, OCH3),
Baylis–Hillman adducts of N-protected 2-aminobenzal-
5.66 (s, 0.6 H, CH), 5.68 (s, 0.4 H, CH), 5.80 (s, 0.6 H, CH), 5.85
dehydes has been developed through the acetylation and
(s, 0.4 H, CH), 6.36 (s, 0.6 H, CH), 6.38 (s, 0.4 H, CH), 7.00–7.13
cyanation, as well as base-assisted cyclization.
(m, 2.6 H, arom), 7.85–7.88 (m, 0.4 H, arom), 8.35 (d, J = 1.5 Hz,
0.6 H, CH), 8.45 (d, J = 11.6 Hz, 0.4 H, CH), 8.71 (br d, J = 11.6
Hz, 0.4 H, NH), 8.83 (br s, 0.6 H, NH).
H2C CHCO2Me
DABCO, N(CH2CH2OH)3
THF, r.t., 30 h
O
OH
O
13C NMR (CDCl3): d = 20.8, 20.9, 52.3, 52.4, 70.2, 71.0, 121.1,
124.0, 126.3, 126.8, 128.6, 129.3, 129.5, 129.8, 130.4, 131.6, 132.4,
132.8, 135.0, 135.6, 139.9, 140.4, 159.5, 162.7, 166.9, 167.4.
H
OMe
73%
NHMbs
N
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.56; H, 5.98; N, 5.45.
Mbs
9
10
Mbs = 4-MeOC6H4SO2
Scheme 4
Synthesis 2007, No. 21, 3376–3384 © Thieme Stuttgart · New York

PAPER
Synthesis of Amino-3H-1-benzazepines and 2,3-Dihydro-1H-indoles
3379
Methyl 3-(5-Chloro-2-formamidophenyl)-3-hydroxy-2-methyl-
enepropanoate (2c)
IR (CH2Cl2): 3339, 1722, 1667, 1597, 1519, 1439 cm–1.
1H NMR (CDCl3): d = 2.11 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 3.75
(s, 3 H, OCH3), 3.97 (br s, 1 H, OH), 5.63 (s, 1 H, CH), 5.94 (s, 1 H,
CH), 6.36 (s, 1 H, CH), 7.02–7.11 (m, 2 H, arom), 7.65–7.68 (m, 1
H, arom), 8.70 (br s, 1 H, NH).
13C NMR (CDCl3): d = 20.9, 24.2, 52.2, 70.1, 124.3, 126.2, 128.3,
129.3, 131.7, 133.2, 134.8, 140.3, 167.3, 169.1.
Following the typical procedure for 2a, a mixture of 5-chloro-2-
formamidobenzaldehyde (1c, 1.84 g, 10 mmol), methyl acrylate
(2.70 mL, 30 mmol), DABCO (1.12 g, 10 mmol), and triethanol-
amine (1.06 mL, 8 mmol) in THF (15 mL) was stirred at 0 °C for 30
h. Workup gave 2c (1.29 g, 48%) as a white solid that was recrys-
tallized (Et2O); ratio cis/trans ca. 70:30;7 mp 112–113 °C.
IR (KBr): 3436, 3337, 1686, 1659, 1504, 1443 cm–1.
Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.69; H, 6.40; N, 5.09.
1H NMR (CDCl3): d = 3.76 (s, 0.9 H, OCH3), 3.79 (s, 2.1 H, OCH3),
4.09 (br s, 1 H, OH), 5.64 (s, 1 H, CH), 5.89 (s, 0.7 H, CH), 5.97 (s,
0.3 H, CH), 6.40 (s, 0.7 H, CH), 6.42 (s, 0.3 H, CH), 7.07–7.29 (m,
2.3 H, arom), 7.93–7.96 (m, 0.7 H, arom), 8.35 (d, J = 1.8 Hz, 0.7
H, CH), 8.39 (d, J = 11.6 Hz, 0.3 H, CH), 8.82 (d, J = 11.6 Hz, 0.3
H, NH), 9.00 (s, 0.7 H, NH).
13C NMR (CDCl3): d = 52.3, 52.4, 69.3, 70.2, 122.2, 125.2, 126.7,
127.2, 128.1, 128.8, 128.9, 129.1, 130.4, 131.3, 132.6, 133.4, 133.8,
133.9, 139.3, 139.9, 159.5, 162.5, 166.7, 167.2.
Methyl 3-(2-Acetamido-5-chlorophenyl)-3-hydroxy-2-methyl-
enepropanoate (2g)
Following the typical procedure for 2a, a mixture of 2-acetamido-5-
chlorobenzaldehyde (1g, 1.98 g, 10 mmol), methyl acrylate (2.70
mL, 30 mmol), DABCO (1.12 g, 10 mmol), and triethanolamine
(1.06 mL, 8 mmol) in THF (15 mL) was stirred at r.t. for 72 h.
Workup gave 2g (2.38 g, 84%) as a white solid that was recrystal-
lized (Et2O–PE); mp 102–103 °C.
Anal. Calcd for C12H12ClNO4: C, 53.44; H, 4.49; N, 5.19. Found: C,
53.38; H, 4.28; N, 5.03.
IR (KBr): 3333, 1720, 1671, 1585, 1514, 1439 cm–1.
1H NMR (CDCl3): d = 2.11 (s, 3 H, CH3), 3.77 (s, 3 H, OCH3), 4.10
(br s, 1 H, OH), 6.62 (s, 1 H, CH), 5.99 (s, 1 H, CH), 6.40 (s, 1 H,
CH), 7.21–7.26 (m, 2 H, arom), 7.78–7.81 (m, 1 H, arom), 8.89 (s,
1 H, NH).
13C NMR (CDCl3): d = 24.3, 52.4, 69.5, 125.4, 126.7, 127.8, 128.6,
130.1, 133.5, 134.3, 139.8, 167.2, 169.1.
Methyl 3-(2-Acetamidophenyl)-3-hydroxy-2-methylene-
propanoate (2d)
Following the typical procedure for 2a, a mixture of 2-acetamido-
benzaldehyde (1d, 1.63 g, 10 mmol), methyl acrylate (2.70 mL, 30
mmol), DABCO (1.12 g, 10 mmol), and triethanolamine (1.06 mL,
8 mmol) was stirred at r.t. for 12 h. Workup gave 2d (1.62 g, 65%)
as a white solid, that was recrystallized (Et2O–PE); mp 84–86 °C.
Anal. Calcd for C13H14ClNO4: C, 55.04; H, 4.97; N, 4.94. Found: C,
55.24; H, 4.91; N, 4.69.
IR (KBr): 3349, 1697, 1671, 1629, 1590, 1530, 1444 cm–1.
Methyl 3-(2-Acetamido-5-nitrophenyl)-3-hydroxy-2-methyl-
enepropanoate (2h)
1H NMR (CDCl3): d = 2.14 (s, 3 H, CH3), 3.77 (s, 3 H, OCH3), 3.86
(d, J = 3.4 Hz, 1 H, OH), 5.68 (s, 1 H, CH), 5.87 (s, 1 H, CH), 6.37
(s, 1 H, CH), 7.09–7.33 (m, 3 H, arom), 7.89–7.91 (m, 1 H, arom),
8.86 (s, 1 H, NH).
13C NMR (CDCl3): d = 24.2, 52.2, 70.6, 123.9, 124.9, 126.3, 128.0,
128.7, 131.1, 136.0, 140.2, 167.3, 169.0.
Following the typical procedure for 2a, a mixture of 2-acetamido-5-
nitrobenzaldehyde (1h, 2.08 g, 10 mmol), methyl acrylate (2.70 mL,
30 mmol), DABCO (1.12 g, 10 mmol), and triethanolamine (1.06
mL, 8 mmol) in THF (20 mL) was stirred at r.t. for 10 h. Workup
gave 2h (1.94 g, 66%) as a white solid that recrystallized (Et2O–
PE); mp 139–141 °C.
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.50; H, 5.87; N, 5.44.
IR (KBr): 3431, 3361, 1704, 1632, 1588, 1504, 1339, 1275 cm–1.
1H NMR (CDCl3): d = 2.18 (s, 3 H, CH3), 3.82 (s, 3 H, OCH3), 4.11
(br s, 1 H, OH), 5.75 (s, 1 H, CH), 5.91 (s, 1 H, CH), 6.46 (s, 1 H,
CH), 8.10–8.34 (m, 3 H, arom), 9.46 (br s, 1 H, NH).
13C NMR (CDCl3): d = 24.8, 52.6, 70.8, 122.7, 123.9, 124.3, 127.7,
130.2, 139.0, 142.4, 143.4, 167.2, 169.0.
Methyl 3-Hydroxy-2-methylene-3-[2-(propanoylamino)phe-
nyl]propanoate (2e)
Following the typical procedure for 2a, a mixture of 2-(propanoy-
lamino)benzaldehyde (1e, 1.77 g, 10 mmol), methyl acrylate (2.70
mL, 30 mmol), DABCO (1.12 g, 10 mmol), and triethanolamine
(1.06 mL, 8 mmol) was stirred at r.t. for 16 h. Workup gave 2e (1.47
g, 56%) as a white solid that was recrystallized (Et2O–PE); mp 116–
118 °C.
Anal. Calcd for C13H14N2O6: C, 53.06; H, 4.80; N, 9.52. Found: C,
52.94; H, 4.55; N, 9.34.
IR (KBr): 3363, 3268, 1699, 1659, 1626, 1588, 1520 cm–1.
Methyl 3-(2-Benzamidophenyl)-3-hydroxy-2-methylene-
propanoate (2i)
Following the typical procedure for 2a, a mixture of 2-benzamido-
benzaldehyde (1i, 2.25 g, 10 mmol), methyl acrylate (2.70 mL, 30
mmol), DABCO (1.12 g, 10 mmol), and triethanolamine (1.06 mL,
8 mmol) was stirred at r.t. for 28 h. Workup gave 2i (1.80 g, 58%)
as a white solid that was recrystallized (Et2O–PE); mp 119–121 °C.
1H NMR (CDCl3): d = 1.22 (t, J = 7.6 Hz, 3 H, CH3), 2.38 (q,
J = 7.6 Hz, 2 H, CH2), 3.77 (s, 3 H, CH3), 3.87 (s, 1 H, OH), 5.67 (s,
1 H, CH), 5.82 (s, 1 H, CH), 6.36 (s, 1 H, CH), 7.08–7.34 (m, 3 H,
arom), 7.94–7.96 (m, 1 H, arom), 8.87 (s, 1 H, NH).
13C NMR (CDCl3): d = 9.7, 30.7, 52.2, 70.9, 123.8, 124.7, 126.4,
128.1, 128.7, 130.7, 136.2, 140.0, 167.3, 172.7.
IR (KBr): 3475, 3310, 1704, 1658, 1600, 1520 cm–1.
Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.77; H, 6.48; N, 5.20.
1H NMR (CDCl3): d = 3.77 (s, 3 H, OCH3), 4.05 (s, 1 H, OH), 5.75
(s, 1 H, CH), 5.80 (s, 1 H, CH), 6.32 (s, 1 H, CH), 7.09–7.56 (m, 6
H, arom), 7.92–8.18 (m, 3 H, arom), 9.88 (s, 1 H, NH).
13C NMR (CDCl3): d = 52.3, 71.8, 123.7, 124.7, 126.9, 127.2,
128.2, 128.7, 129.0, 130.2, 131.7, 134.6, 136.8, 139.8, 165.5, 167.5.
Methyl 3-(2-Acetamido-5-methylphenyl)-3-hydroxy-2-methyl-
enepropanoate (2f)
Following the typical procedure for 2a, a mixture of 2-acetamido-5-
methylbenzaldehyde (1f, 1.77 g, 10 mmol), methyl acrylate (2.70
mL, 30 mmol), DABCO (1.12 g, 10 mmol), and triethanolamine
(1.06 mL, 8 mmol) in THF (5 mL) was stirred at r.t. for 24 h. Work-
up gave 2f (1.79 g, 68%) as a colorless oil.
Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.54; H, 5.55; N, 4.34.
Synthesis 2007, No. 21, 3376–3384 © Thieme Stuttgart · New York

3380
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PAPER
Methyl 3-(2-Acetamidophenyl)-3-acetoxy-2-methylene-
Methyl 3-Acetoxy-3-[2-(acylamino)phenyl]-2-methylene-
propanoates 3a–i; General Procedure
propanoate (3d)
A mixture of 2 (5 mmol), Ac2O (0.71 mL, 7.5 mmol), and DMAP
(0.12 g, 1.0 mmol) in CH2Cl2 (15 mL) was stirred at r.t. for 10–60
min. After solvent evaporation, the mixture was neutralized with
sat. aq NaHCO3. The resulting mixture was extracted with CH2Cl2
(2 × 30 mL) and the organic layers were dried (MgSO4) and concen-
trated in vacuo. The resulting crude oil was chromatographed (silica
gel, hexane–EtOAc, 2:1) to produce 3.
Reaction time: 1 h; colorless oil: yield: 88%.
IR (CH2Cl2): 3342, 1743, 1692, 1590, 1525, 1453 cm–1.
1H NMR (CDCl3): d = 2.12 (s, 3 H, CH3), 2.26 (s, 3 H, CH3), 3.69
(s, 3 H, OCH3), 6.10 (s, 1 H, CH), 6.43 (s, 1 H, CH), 6.74 (s, 1 H,
CH), 7.12–7.17 (m, 1 H, arom), 7.30–7.35 (m, 2 H, arom), 7.76–
7.80 (m, 1 H, arom), 8.79 (br s, 1 H, NH).
13C NMR (CDCl3): d = 21.0, 24.3, 52.4, 68.1, 125.0, 125.2, 125.3,
127.7, 129.2, 135.5, 138.9, 166.0, 168.8, 170.2.
Methyl 3-Acetoxy-3-(2-formamidophenyl)-2-methylene-
propanoate (3a)
Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C,
61.90; H, 5.84; N, 4.72.
Reaction time: 10 min; white solid after recrystallization (Et2O):
yield: 60%; ratio cis/trans ca. 60:40;7 mp 75–76 °C.
IR (KBr): 3341, 1750, 1716, 1662, 1589, 1537, 1445 cm–1.
Methyl 3-Acetoxy-2-methylene-3-[2-(propanoylamino)phe-
nyl]propanoate (3e)
Reaction time: 1 h; colorless oil; yield: 84%.
IR (CH2Cl2): 3348, 1729, 1696, 1590, 1518, 1452 cm–1.
1H NMR (CDCl3): d = 1.32 (t, J = 7.6 Hz, 3 H, CH3), 2.11 (s, 3 H,
CH3), 2.51 (q, J = 7.6 Hz, 2 H, CH2), 3.68 (s, 3 H, OCH3), 6.10 (s,
1 H, CH), 6.43 (s, 1 H, CH), 6.74 (s, 1 H, CH), 7.11–7.35 (m, 3 H,
arom), 7.79–7.81 (m, 1 H, arom), 8.78 (br s, 1 H, NH).
13C NMR (CDCl3): d = 9.8, 21.0, 30.6, 52.3, 68.1, 125.0, 125.1,
125.2, 127.8, 129.1, 129.2, 135.5, 138.8, 165.9, 170.1, 172.5.
1H NMR (CDCl3): d = 2.10 (s, 1.2 H, CH3), 2.12 (s, 1.8 H, CH3),
3.68 (s, 3 H, OCH3), 6.11 (s, 0.6 H, CH), 6.14 (s, 0.4 H, CH), 6.44
(s, 1 H, CH), 6.66 (s, 0.4 H, CH), 6.73 (s, 0.6 H, CH), 7.15–7.36 (m,
3.4 H, arom), 7.83–7.86 (m, 0.6 H, arom), 8.49 (d, J = 11.6 Hz, 0.4
H, CH), 8.52 (d, J = 1.5 Hz, 0.6 H, CH), 8.66 (d, J = 11.6 Hz, 0.4 H,
NH), 8.76 (br s, 0.6 H, NH).
13C NMR (CDCl3): d = 20.8, 20.9, 52.2, 52.3, 68.1, 68.6, 123.0,
125.1, 125.8, 126.5, 128.0, 128.5, 129.2, 129.6, 130.9, 134.2, 135.2,
138.3, 138.6, 159.6, 163.0, 165.4, 165.8, 169.5, 170.0.
Anal. Calcd for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C,
60.45; H, 5.31; N, 4.97.
Anal. Calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C,
62.76; H, 6.11; N, 4.43.
Methyl 3-Acetoxy-3-(2-formamido-5-methylphenyl)-2-methyl-
enepropanoate (3b)
Methyl 3-(2-Acetamido-5-methylphenyl)-3-acetoxy-2-methyl-
enepropanoate (3f)
Reaction time: 1 h; colorless oil; yield: 83%.
IR (CH2Cl2): 3349, 1728, 1693, 1594, 1518, 1439 cm–1.
1H NMR (CDCl3): d = 2.12 (s, 3 H, CH3), 2.24 (s, 3 H, CH3), 2.29
(s, 3 H, CH3), 3.68 (s, 3 H, OCH3), 6.10 (s, 1 H, CH), 6.43 (s, 1 H,
CH), 6.71 (s, 1 H, CH), 7.09–7.15 (m, 2 H, arom), 7.60–7.63 (m, 1
H, arom), 8.65 (br s, 1 H, NH).
13C NMR (CDCl3): d = 20.9, 21.0, 24.2, 52.3, 68.2, 124.9, 125.4,
128.0, 129.2, 130.0, 132.9, 135.1, 138.8, 165.9, 168.8, 170.1.
Reaction time: 1 h; colorless oil: yield: 79%; ratio cis/trans ca.
60:40.7
IR (CH2Cl2): 3347, 1730, 1692, 1514, 1439, 1371 cm–1.
1H NMR (CDCl3): d = 2.10 (s, 1.2 H, CH3), 2.12 (s, 1.8 H, CH3),
2.30 (s, 1.8 H, CH3), 2.32 (s, 1.2 H, CH3), 3.67 (s, 3 H, OCH3), 6.10
(s, 0.6 H, CH), 6.12 (s, 0.4 H, CH), 6.44 (s, 1 H, CH), 6.62 (s, 0.4
H, CH), 6.69 (s, 0.6 H, CH), 7.03–7.22 (m, 2.6 H, arom), 7.66–7.69
(m, 0.4 H, arom), 8.42 (d, J = 11.6 Hz, 0.4 H, CH), 8.49 (d, J = 1.5
Hz, 0.6 H, CH), 8.52 (br d, J = 11.6 Hz, 0.4 H, NH), 8.62 (br s, 0.6
H, NH).
13C NMR (CDCl3): d = 20.9, 21.0, 52.2, 52.3, 68.2, 68.7, 123.4,
125.0, 125.2, 128.3, 129.0, 129.2, 130.0, 130.3, 130.9, 131.6, 132.6,
135.6, 136.5, 138.4, 138.6, 159.6, 163.2, 165.4, 165.8, 169.5, 170.1.
Anal. Calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C,
62.81; H, 6.08; N, 4.53.
Methyl 3-(2-Acetamido-5-chlorophenyl)-3-acetoxy-2-methyl-
enepropanoate (3g)
Reaction time: 1 h; colorless oil; yield: 87%.
IR (CH2Cl2): 3347, 1729, 1697, 1510, 1439, 1371 cm–1.
Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C,
61.78; H, 5.79; N, 4.69.
Methyl 3-Acetoxy-3-(5-chloro-2-formamidophenyl)-2-methyl-
enepropanoate (3c)
1H NMR (CDCl3): d = 2.14 (s, 3 H, CH3), 2.26 (s, 3 H, CH3), 3.71
(s, 3 H, OCH3), 6.14 (s, 1 H, CH), 6.46 (s, 1 H, CH), 6.67 (s, 1 H,
CH), 7.27–7.30 (m, 2 H, arom), 7.74–7.77 (m, 1 H, arom), 8.81 (br
s, 1 H, NH).
13C NMR (CDCl3): d = 20.9, 24.2, 52.5, 67.4, 125.6, 126.6, 127.5,
129.3, 130.5, 131.1, 134.0, 138.4, 165.9, 168.9, 170.0.
Reaction time: 1 h; colorless oil: yield: 87%; ratio cis/trans ca.
60:40.7
IR (CH2Cl2): 3341, 1731, 1697, 1586, 1504, 1440 cm–1.
1H NMR (CDCl3): d = 2.12 (s, 1.2 H, CH3), 2.14 (s, 1.8 H, CH3),
3.71 (s, 3 H, OCH3), 6.16 (s, 0.6 H, CH), 6.20 (s, 0.4 H, CH), 6.48
(s, 1 H, CH), 6.57 (s, 0.4 H, CH), 6.66 (s, 0.6 H, CH), 7.07–7.32 (m,
2.4 H, arom), 7.79–7.82 (m, 0.6 H, arom), 8.45 (d, J = 11.4 Hz, 0.4
H, CH), 8.51 (d, J = 1.5 Hz, 0.6 H, CH), 8.65 (d, J = 11.4 Hz, 0.4 H,
NH), 8.79 (br s, 0.6 H, NH).
13C NMR (CDCl3): d = 20.8, 20.9, 52.4, 52.5, 67.4, 67.9, 124.6,
125.5, 125.6, 126.5, 127.8, 128.4, 129.3, 129.7, 131.0, 131.2, 132.1,
132.7, 133.2, 133.9, 137.8, 138.1, 159.5, 162.8, 165.3, 165.8, 169.4,
169.9.
Anal. Calcd for C15H16ClNO5: C, 55.31; H, 4.95; N, 4.30. Found: C,
55.22; H, 4.78; N, 4.11.
Methyl 3-(2-Acetamido-5-nitrophenyl)-3-acetoxy-2-methyl-
enepropanoate (3h)
Reaction time: 1 h; colorless oil; yield: 86%.
IR (CH2Cl2): 3348, 1731, 1712, 1589, 1509, 1342 cm–1.
1H NMR (CDCl3): d = 2.17 (s, 3 H, CH3), 2.32 (s, 3 H, CH3), 3.75
(s, 3 H, OCH3), 6.27 (s, 1 H, CH), 6.54 (s, 1 H, CH), 6.72 (s, 1 H,
CH), 8.15–8.26 (m, 3 H, arom), 9.30 (br s, 1 H, NH).
Anal. Calcd for C14H14ClNO5: C, 53.94; H, 4.53; N, 4.49. Found: C,
53.88; H, 4.35; N, 4.40.
Synthesis 2007, No. 21, 3376–3384 © Thieme Stuttgart · New York

PAPER
Synthesis of Amino-3H-1-benzazepines and 2,3-Dihydro-1H-indoles
3381
13C NMR (CDCl3): d = 20.9, 24.6, 52.7, 66.9, 123.4, 123.9, 124.5,
126.7, 129.3, 138.0, 141.4, 143.9, 166.2, 169.0, 170.0.
Methyl (E)-3-(5-Chloro-2-formamidophenyl)-2-(cyanometh-
yl)propenoate (4c)
Reaction time: 0.5 h; white solid after crystallization (Et2O); yield:
Anal. Calcd for C15H16N2O7: C, 53.57; H, 4.80; N, 8.33. Found: C,
53.50; H, 4.66; N, 8.13.
62%; ratio cis/trans ca. 80:20;7 mp 138–139 °C.
IR (KBr): 3333, 2261, 1698, 1678, 1566, 1486 cm–1.
Methyl 3-Acetoxy-3-(2-benzamidophenyl)-2-methylene-
propanoate (3i)
Reaction time: 1 h; white solid after recrystallization (Et2O–PE);
yield: 82%; mp 109–110 °C.
IR (KBr): 3361, 1741, 1668, 1637, 1596, 1521, 1452 cm–1.
1H NMR (CDCl3): d = 2.12 (s, 3 H, CH3), 3.64 (s, 3 H, OCH3), 6.12
(s, 1 H, CH), 6.43 (s, 1 H, CH), 6.80 (s, 1 H, CH), 7.16–7.57 (m, 6
H, arom), 7.88–7.91 (m, 1 H, arom), 8.07–8.10 (m, 2 H, arom), 9.60
(br s, 1 H, NH).
13C NMR (CDCl3): d = 20.9, 52.3, 68.6, 124.7, 125.5, 125.8, 127.4,
128.1, 128.7, 129.3, 129.8, 131.7, 134.7, 135.8, 138.8, 165.6, 165.7,
170.3.
1H NMR (acetone-d6): d = 3.54 (s, 1.6 H, CH2), 3.61 (s, 0.4 H, CH2),
3.87 (s, 3 H, OCH3), 7.35–7.54 (m, 2.2 H, arom), 7.86 (s, 1 H, CH),
8.02 (s, 0.2 H, CH), 8.15–8.19 (m, 0.8 H, arom), 8.38 (s, 0.8 H, CH),
8.54 (br s, 0.2 H, NH), 9.10 (br s, 0.8 H, NH).
13C NMR (acetone-d6): d = 17.3, 19.3, 50.8, 53.0, 117.7, 124.2,
124.9, 125.0, 127.6, 127.9, 128.3, 129.1, 129.5, 129.9, 130.5, 131.2,
135.5, 139.2, 160.3, 160.4, 163.4, 166.1.
Anal. Calcd for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05. Found:
C, 55.93; H, 3.85; N, 9.86.
Methyl (E)-3-(2-Acetamidophenyl)-2-(cyanomethyl)propeno-
ate (4d)
Reaction time: 12 h; white solid after recrystallization (Et2O–PE);
yield: 77%; mp 94–96 °C.
IR (KBr): 3258, 2241, 1701, 1669, 1578, 1531 cm–1.
Anal. Calcd for C20H19NO5: C, 67.98; H, 5.42; N, 3.96. Found: C,
67.78; H, 5.33; N, 3.77.
Methyl 3-[2-(Acylamino)phenyl]-2-(cyanomethyl)propenoates
4a–i; General Procedure
1H NMR (CDCl3): d = 2.20 (s, 3 H, CH3), 3.39 (s, 2 H, CH2), 3.92
(s, 3 H, OCH3), 7.10 (br s, 1 H, NH), 7.25–7.30 (m, 2 H, arom),
7.41–7.46 (m, 1 H, arom), 7.85–7.89 (m, 2 H, arom, CH).
13C NMR (CDCl3): d = 17.0, 24.2, 53.0, 116.6, 125.3, 126.1, 127.8,
128.1, 130.3, 130.7, 134.0, 139.1, 165.1, 168.7.
A mixture of MBH acetates 3 (2 mmol) and KCN (0.20 g, 3 mmol)
in DMSO–H2O (1:1, 10 mL) was stirred at r.t. for 0.5–1 h. The mix-
ture was diluted with H2O (10 mL) and extracted with Et2O (3 × 20
mL). The combined organic layers were dried (MgSO4) and con-
centrated in vacuo. The resulting mixture was chromatographed
(silica gel, hexane–EtOAc, 2:1) to produce 4.
Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C,
65.03; H, 5.38; N, 10.74.
Methyl (E)-2-(Cyanomethyl)-3-(2-formamidophenyl)propeno-
ate (4a)
Methyl (E)-2-(Cyanomethyl)-3-[2-(propanoylamino)phe-
nyl)propenoate (4e)
Reaction time: 24 h; white solid after recrystallization (Et2O–PE);
yield: 80%; mp 82–84 °C.
IR (KBr): 3270, 2249, 1707, 1659, 1578, 1533 cm–1.
Reaction time: 1 h; white solid after recrystallization (CH2Cl2–PE);
yield: 64%; ratio cis/trans ca. 50:50;7 mp 106–108 °C.
IR (KBr): 3261, 2251, 1705, 1671, 1578, 1537, 1453 cm–1.
1H NMR (CDCl3): d = 3.41 (s, 1 H, CH2), 3.46 (s, 1 H, CH2), 3.92
(s, 3 H, OCH3), 7.27–7.54 (m, 3.5 H, arom), 7.92 (s, 1 H, CH), 7.99
(br s, 0.5 H, NH), 8.03–8.05 (m, 0.5 H, arom), 8.17 (br d, J = 11.0
Hz, 0.5 Hz, NH), 8.41 (d, J = 1.2 Hz, 0.5 H, CH), 8.55 (d, J = 11.0
Hz, 0.5 H, CH).
13C NMR (CDCl3): d = 17.1, 52.9, 115.6, 116.8, 116.9, 121.0,
123.6, 125.4, 125.6, 125.8, 126.1, 126.3, 128.7, 129.7, 130.6, 131.1,
134.5, 135.2, 139.2, 140.0, 159.3, 162.8, 165.3, 165, 5.
1H NMR (CDCl3): d = 1.24 (t, J = 7.3 Hz, 3 H, CH3), 2.42 (q,
J = 7.3 Hz, 2 H, CH2), 3.39 (s, 2 H, CH2), 3.91 (s, 3 H, OCH3), 7.04
(br s, 1 H, NH), 7.25–7.27 (m, 2 H, arom), 7.40–7.46 (m, 1 H,
arom), 7.89 (m, 2 H, arom, CH).
13C NMR (CDCl3): d = 9.6, 17.0, 30.3, 52.8, 117.1, 124.1, 124.7,
125.5, 126.5, 128.6, 130.5, 135.6, 140.5, 165.5, 172.4.
Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C,
66.10; H, 5.83; N, 10.17.
Anal. Calcd for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C,
63.81; H, 4.77; N, 11.40.
Methyl (E)-3-(2-Acetamido-5-methylphenyl)-2-(cyanometh-
yl)propenoate (4f)
Reaction time: 28 h; white solid after recrystallization (Et2O–PE);
yield: 81%; mp 119–120 °C.
Methyl (E)-2-(Cyanomethyl)-3-(2-formamido-5-methylphe-
nyl)propenoate (4b)
Reaction time 1 h; white solid after recrystallization (CH2Cl2–PE);
IR (KBr): 3253, 2249, 1703, 1665, 1630, 1530 cm–1.
yield: 68%; ratio cis/trans ca. 50:50;7 mp 140–141 °C.
1H NMR (CDCl3): d = 2.17 (s, 3 H, CH3), 2.36 (s, 3 H, CH3), 3.38
(s, 2 H, CH2), 3.90 (s, 3 H, OCH3), 7.04 (br s, 1 H, NH), 7.17–7.23
(m, 2 H, arom), 7.63–7.65 (m, 1 H, arom), 7.85 (s, 1 H, CH).
13C NMR (CDCl3): d = 17.1, 20.9, 24.1, 52.8, 117.2, 124.5, 124.6,
127.1, 128.9, 131.1, 132.8, 135.7, 140.9, 165.6, 168.8.
IR (KBr): 3458, 2251, 1709, 1688, 1515, 1434 cm–1.
1H NMR (CDCl3): d = 2.37 (s, 1.5 H, CH3), 2.40 (s, 1.5 H, CH3),
3.39 (s, 1 H, CH2), 3.45 (s, 1 H, CH2), 3.90 (s, 3 H, OCH3), 7.06–
7.32 (m, 2.5 H, arom), 7.83–7.86 (m, 0.5 H, arom), 7.88 (s, 1 H,
CH), 7.94 (br s, 0.5 H, NH), 8.01 (br d, J = 11.0 Hz, 0.5 H, NH),
8.37 (s, 0.5 H, CH), 8.47 (d, J = 11.0 Hz, 0.5 H, CH).
13C NMR (CDCl3): d = 17.1, 20.8, 20.9, 52.8, 116.8, 117.0, 121.5,
123.9, 125.2, 126.0, 126.3, 128.9, 129.0, 129.9, 131.2, 131.7, 131.8,
132.6, 135.9, 136.4, 139.5, 140.4, 159.3, 163.0, 165.4, 165.5.
Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C,
66.04; H, 5.77; N, 10.04.
Methyl (E)-3-(2-Acetamido-5-chlorophenyl)-2-(cyanometh-
yl)propenoate (4g)
Reaction time: 4 h; white solid after recrystallization (Et2O–PE);
Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C,
64.97; H, 5.34; N, 10.79.
yield: 75%; mp 122–123 °C.
IR (KBr): 3347, 2254, 1716, 1672, 1518, 1293 cm–1.
Synthesis 2007, No. 21, 3376–3384 © Thieme Stuttgart · New York

3382
H. N. Lim et al.
PAPER
IR (KBr): 3460, 3425, 1695, 1668, 1626, 1589, 1436 cm–1.
1H NMR (CDCl3): d = 2.35 (s, 3 H, CH3), 2.93 (s, 2 H, CH2), 3.84
(s, 3 H, OCH3), 5.40 (br s, 2 H, NH2), 7.10–7.18 (m, 3 H, arom),
7.76 (s, 1 H, CH).
13C NMR (CDCl3): d = 20.6, 31.0, 52.2, 122.7, 126.7, 126.8, 130.9,
131.0, 131.3, 138.9, 145.9, 154.0, 166.3.
MS (EI): m/z (%) = 230 (100) [M+], 216 (19), 198 (52), 170 (53),
1H NMR (CDCl3): d = 2.19 (s, 3 H, CH3), 3.37 (s, 2 H, CH2), 3.92
(s, 3 H, OCH3), 7.18–7.20 (m, 2 H, NH, arom), 7.36–7.40 (m, 1 H,
arom), 7.79 (s, 1 H, CH), 7.84–7.87 (m, 1 H, arom).
13C NMR (CDCl3): d = 17.0, 24.2, 53.0, 116.6, 125.3, 126.1, 127.8,
128.1, 130.3, 130.8, 134.0, 139.1, 165.1, 168.7.
Anal. Calcd for C14H13ClN2O3: C, 57.44; H, 4.48; N, 9.57. Found:
C, 57.54; H, 4.43; N, 9.51.
143 (25), 115 (21).
HRMS (EI): m/z [M]+ calcd for C13H14N2O2: 230.1055; found:
230.1069.
Methyl (E)-3-(2-Acetamido-5-nitrophenyl)-2-(cyanometh-
yl)propenoate (4h)
Reaction time: 2 h; white solid after recrystallization (Et2O–PE);
yield: 67%; mp 45–47 °C.
Methyl 2-Amino-7-chloro-3H-1-benzazepine-4-carboxylate
(6c)
IR (KBr): 3341, 2253, 1714, 1581, 1537, 1508, 1342 cm–1.
1H NMR (CDCl3): d = 2.27 (s, 3 H, CH3), 3.41 (s, 2 H, CH2), 3.95
(s, 3 H, OCH3), 7.48 (s, 1 H, NH), 7.84 (s, 1 H, CH), 8.05 (d, J = 2.1
Hz, 1 H, CH), 8.28 (dd, J = 9.2, 2.1 Hz, 1 H, arom), 8.46 (d, J = 9.2
Hz, 1 H, arom).
13C NMR (CDCl3): d = 17.0, 24.8, 53.3, 116.1, 122.2, 124.0, 124.4,
125.7, 128.1, 137.6, 141.3, 143.4, 164.7, 168.9.
A mixture of 4c (139 mg, 0.5 mmol) and NaOMe (40 mg, 0.75
mmol) in MeOH (2 mL) was stirred at r.t. for 0.5 h. After the solvent
was evaporated, the mixture was crystallized and washed with cold
MeOH. The precipitate was then collected by filtration and dried in
vacuo to produce 6c (90 mg, 72%) as a pale yellow solid; mp 256–
257 °C (dec.).
IR (KBr): 3458, 1693, 1666, 1630, 1584, 1467, 1434 cm–1.
Anal. Calcd for C14H13N3O5: C, 55.45; H, 4.32; N, 13.86. Found: C,
55.21; H, 4.16; N, 13.69.
1H NMR (DMSO-d6): d = 2.87 (s, 2 H, CH2), 3.78 (s, 3 H, OCH3),
6.98 (br s, 2 H, NH2), 7.03 (d, J = 8.9 Hz, 1 H, arom), 7.28 (dd,
J = 8.9, 2.4 Hz, 1 H, arom), 7.51 (d, J = 2.4 Hz, 1 H, arom), 7.72 (s,
1 H, CH).
Methyl (E)-3-(2-Benzamidophenyl)-2-(cyanomethyl)propeno-
ate (4i)
Reaction time: 0.5 h; white solid after recrystallization (Et2O–PE);
yield: 61%; mp 107–109 °C.
IR (KBr): 3307, 2247, 1721, 1705, 1651, 1524 cm–1.
1H NMR (CDCl3): d = 3.43 (s, 2 H, CH2), 3.87 (s, 3 H, OCH3),
7.31–7.60 (m, 6 H, arom), 7.73 (br s, 1 H, NH), 7.83–7.93 (m, 3 H,
arom), 7.95 (s, 1 H, CH).
13C NMR (CDCl3): d = 17.0, 52.8, 117.0, 124.5, 125.3, 126.0,
127.2, 127.3, 128.7, 128.9, 130.6, 132.2, 134.1, 135.7, 140.3, 165.5,
165.9.
13C NMR (DMSO-d6): d = 30.7, 52.2, 123.5, 123.8, 127.5, 128.7,
129.0, 130.4, 137.1, 148.4, 154.6, 165.2.
MS (EI): m/z (%) = 252 (55), 250 (100) [M+], 237 (3), 235 (10), 210
(5), 208 (13), 192 (33), 190 (75), 155 (30), 128 (17).
HRMS (EI): m/z [M]+ calcd for C12H11ClN2O2: 250.0509; found:
250.0499.
Methyl 1-Acetyl-2-(cyanomethyl)-2,3-dihydro-1H-indole-2-
carboxylate (8a); Typical Procedure
A mixture of 4d (258 mg, 1 mmol) and NaOMe (81 mg, 1.5 mmol)
in MeOH (3 mL) was stirred at r.t. for 12 h. After solvent evapora-
tion, H2O (5 mL) was added to the mixture and then the mixture was
extracted with Et2O (3 × 15 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The resulting crude mix-
ture was chromatographed (silica gel, hexane–EtOAc, 2:1) to pro-
duce 8a (168 mg, 65%) as a white solid that was recrystallized
(Et2O–PE); mp 145–147 °C.
Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C,
71.04; H, 5.15; N, 8.86.
Methyl 2-Amino-3H-1-benzazepine-4-carboxylate (6a)
A mixture of 4a (122 mg, 0.5 mmol) and NaOMe (40 mg, 0.75
mmol) in MeOH (2 mL) was stirred at r.t. for 1 h. After solvent
evaporation, H2O (5 mL) was added to the mixture. The resulting
precipitate was collected by filtration and washed with cold H2O to
produce 6a (82 mg, 76%) as a white solid, which was recrystallized
(MeOH–hexane); mp 173–175 °C.
IR (KBr): 2256, 1738, 1647, 1596, 1488, 1377 cm–1.
1H NMR (CDCl3): d = 2.50 (s, 3 H, CH3), 3.26 (d, J = 16.8 Hz, 1 H,
CH), 3.34 (d, J = 17.1 Hz, 1 H, CH), 3.43 (d, J = 16.8 Hz, 1 H, CH),
3.55 (d, J = 17.1 Hz, 1 H, CH), 3.77 (s, 3 H, OCH3), 7.08–7.31 (m,
4 H, arom).
13C NMR (CDCl3): d = 24.7, 25.1, 38.8, 53.1, 67.9, 113.7, 116.3,
124.3, 125.7, 128.4, 128.5, 140.6, 168.9, 170.8.
IR (KBr): 3467, 1701, 1667, 1623, 1584, 1438, 1273 cm–1.
1H NMR (CDCl3): d = 2.94 (s, 2 H, CH2), 3.86 (s, 3 H, OCH3), 5.40
(br s, 2 H, NH2), 7.04–7.09 (m, 1 H, arom), 7.20–7.23 (m, 1 H,
arom), 7.33–7.39 (m, 2 H, arom), 7.81 (s, 1 H, CH).
13C NMR (CDCl3): d = 31.1, 52.3, 121.5, 123.0, 126.9, 129.6,
131.4, 131.5, 138.8, 148.4, 154.1, 166.2.
MS (EI): m/z (%) = 258 (6) [M+], 216 (42), 176 (45), 157 (100), 144
(15), 130 (44), 117 (44).
HRMS (EI): m/z [M]+ calcd for C14H14N2O3: 258.1004; found:
MS (EI): m/z (%) = 216 (100) [M+], 184 (56), 156 (72), 129 (43),
115 (24).
258.1010.
HRMS (EI): m/z [M]+ calcd for C12H12N2O2: 216.0899; found:
216.0880.
Methyl 2-(Cyanomethyl)-1-propanoyl-2,3-dihydro-1H-indole-
2-carboxylate (8b)
Following the typical procedure for 8a, a mixture of 4e (272 mg, 1
mmol) and NaOMe (81 mg, 1.5 mmol) in MeOH (3 mL) was stirred
at r.t. for 24 h. Workup gave 8b (112 mg, 41%) as a white solid that
was recrystallized (Et2O–hexane); mp 134–136 °C.
Methyl 2-Amino-7-methyl-3H-1-benzazepine-4-carboxylate
(6b)
A mixture of 4b (129 mg, 0.5 mmol) and NaOMe (40 mg, 0.75
mmol) in MeOH (2 mL) was stirred at r.t. for 1 h. After solvent
evaporation, H2O (5 mL) was added to the mixture. The resulting
precipitate was collected by filtration and washed with cold H2O to
produce 6b (74 mg, 64%) as a yellow solid that was recrystallized
(MeOH–hexane); mp 170–171 °C
IR (KBr): 2253, 1741, 1642, 1595, 1487, 1387 cm–1.
Synthesis 2007, No. 21, 3376–3384 © Thieme Stuttgart · New York

PAPER
Synthesis of Amino-3H-1-benzazepines and 2,3-Dihydro-1H-indoles
3383
1H NMR (CDCl3): d = 1.25 (t, J = 7.3 Hz, 3 H, CH3), 2.76 (q,
J = 7.3 Hz, 2 H, CH2), 3.26 (d, J = 17.1 Hz, 1 H, CH), 3.34 (d,
J = 16.8 Hz, 1 H, CH), 3.44 (d, J = 17.1 Hz, 1 H, CH), 3.54 (d,
J = 16.8 Hz, 1 H, CH), 3.77 (s, 3 H, OCH3), 7.07–7.20 (m, 1 H,
arom), 7.23–7.30 (m, 3 H, arom).
13C NMR (CDCl3): d = 8.6, 24.7, 30.2, 38.7, 53.1, 67.9, 114.0,
116.4, 124.1, 125.7, 128.3, 128.4, 140.4, 170.9, 172.7.
13C NMR (acetone-d6): d = 28.3, 39.5, 54.0, 69.2, 108.1, 117.6,
121.8, 127.1, 127.9, 140.9, 157.0, 173.1.
MS (EI): m/z (%) = 261 (24) [M+], 221 (20), 202 (100), 156 (94),
146 (22), 116 (23).
HRMS (EI): m/z [M]+ calcd for C12H11N3O4: 261.0750; found:
261.0735.
MS (EI): m/z (%) = 272 (5) [M+], 216 (46), 176 (50), 157 (100), 144
(11), 130 (29), 117 (24).
Methyl 4-Hydroxy-1-[(4-methoxyphenyl)sulfonyl]-1,2,3,4-
tetrahydroquinoline-3-carboxylate (10)
A mixture of 2-[(4-methoxyphenylsulfonyl)amino]benzaldehyde
(9, 1.46 g, 5 mmol), methyl acrylate (1.25 mL, 15 mmol), DABCO
(0.56 g, 5 mmol), and triethanolamine (0.53 mL, 4 mmol) in THF
(10 mL) was stirred at r.t. for 30 h. The mixture was diluted with
H2O (10 mL) and extracted with EtOAc (3 × 30 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo. The
resulting mixture was chromatographed (silica gel, hexane–EtOAc,
3:1) to produce 10 (1.38 g, 73%) as a colorless oil; ratio cis/trans ca.
20:80.
HRMS (EI): m/z [M]+ calcd for C15H16N2O3: 272.1161; found:
272.1177.
Methyl 1-Acetyl-2-(cyanomethyl)-5-methyl-2,3-dihydro-1H-
indole-2-carboxylate (8c)
Following the typical procedure for 8a, a mixture of 4f (272 mg, 1
mmol) and NaOMe (81 mg, 1.5 mmol) in MeOH (3 mL) was stirred
at r.t. for 28 h. Workup gave 8c (125 mg, 46%) as a white solid that
was recrystallized (Et2O–hexane); mp 124–125 °C.
IR (CH2Cl2): 3500, 1733, 1595, 1496, 1349, 1262 cm–1.
IR (KBr): 2254, 1731, 1637, 1595, 1493, 1387 cm–1.
1H NMR (CDCl3): d (trans form) = 2.52 (ddd, J = 10.8, 9.3, 4.6 Hz,
1 H, CH), 2.75 (d, J = 4.9 Hz, 1 H, OH), 3.67 (dd, J = 14.0, 10.8 Hz,
1 H, CH), 3.76 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 4.39 (dd,
J = 14.0, 4.6 Hz, 1 H, CH), 4.71 (dd, J = 9.3, 4.9 Hz, 1 H, CH),
6.86–7.81 (m, 8 H, arom).
13C NMR (CDCl3): d (trans form) = 43.6, 45.8, 52.5, 55.6, 67.4,
114.4, 123.8, 125.5, 127.3, 128.4, 129.2, 129.3, 130.4, 130.6, 163.3,
172.2.
MS (EI): m/z (%) = 377 (100) [M+], 328 (24), 206 (74), 188 (52),
171 (57), 144 (87), 130 (64).
HRMS (EI): m/z [M]+ calcd for C18H19NO6S: 377.0933; found:
1H NMR (CDCl3): d = 2.33 (s, 3 H, CH3), 2.48 (s, 3 H, CH3), 3.25
(d, J = 16.8 Hz, 1 H, CH), 3.30 (d, J = 17.1 Hz, 1 H, CH), 3.43 (d,
J = 17.1 Hz, 1 H, CH), 3.51 (d, J = 16.8 Hz, 1 H, CH), 3.76 (s, 3 H,
OCH3), 7.07 (m, 3 H, arom).
13C NMR (CDCl3): d = 20.7, 24.6, 25.0, 38.6, 53.1, 67.8, 113.4,
116.4, 126.4, 128.4, 128.8, 134.1, 138.3, 168.7, 170.8.
MS (EI): m/z (%) = 272 (52) [M+], 230 (98), 190 (98), 171 (100),
158 (54), 144 (74), 131 (98), 103 (30).
HRMS (EI): m/z [M]+ calcd for C15H16N2O3: 272.1161; found:
272.1160.
377.0918.
Methyl 1-Acetyl-5-chloro-2-(cyanomethyl)-2,3-dihydro-1H-
indole-2-carboxylate (8d)
Following the typical procedure for 8a, a mixture of 4g (292 mg, 1
mmol) and NaOMe (81 mg, 1.5 mmol) in MeOH (3 mL) was stirred
at r.t. for 4 h. Workup gave 8d (181 mg, 62%) as a white solid that
was recrystallized (Et2O–hexane); mp 126–127 °C.
Acknowledgment
This work was supported, in part, by grant from University IT
Research Center Project, Korea.
IR (KBr): 2249, 1747, 1660, 1481, 1376, 1318 cm–1.
1H NMR (CDCl3): d = 2.48 (s, 3 H, CH3), 3.23 (d, J = 17.1 Hz, 1 H,
CH), 3.32 (d, J = 17.3 Hz, 1 H, CH), 3.48 (d, J = 17.1 Hz, 1 H, CH),
3.52 (d, J = 17.3 Hz, 1 H, CH), 3.77 (s, 3 H, OCH3), 7.10–7.23 (m,
3 H, arom).
13C NMR (CDCl3): d = 24.7, 25.1, 38.4, 53.3, 68.1, 114.4, 116.1,
125.9, 128.4, 129.5, 130.3, 139.4, 168.7, 170.4.
References and Notes
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J. EP 825,186, 1998; Chem. Abstr. 1998, 128, 192567.
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(2) 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.
MS (EI): m/z (%) = 294 (2), 292 (7) [M+], 252 (17), 250 (53), 210
(49), 193 (31), 191 (100), 166 (10), 164 (28), 151 (34).
Tetrahedron 1996, 52, 8001. (c) Ciganek, E. Org. React.
1997, 51, 201. (d) Langer, P. Angew. Chem. Int. Ed. 2000,
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HRMS (EI): m/z [M]+ calcd for C14H13ClN2O3: 292.0615; found:
292.0617.
Methyl 2-(Cyanomethyl)-5-nitro-2,3-dihydro-1H-indole-2-car-
boxylate (8f)
Following the typical procedure for 8a, a mixture of 4h (303 mg, 1
mmol) and NaOMe (81 mg, 1.5 mmol) in MeOH (3 mL) was stirred
at r.t. for 2 h. Workup gave 8f (146 mg, 56%) as a yellow solid that
was crystallized (Et2O–hexane); mp 159–160 °C.
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IR (KBr): 3422, 2251, 1750, 1616, 1597, 1428, 1493, 1316, 1281
cm–1.
1H NMR (acetone-d6): d = 3.23 (d, J = 0.5 Hz, 2 H, CH2), 3.39 (d,
J = 17.4 Hz, 1 H, CH), 3.71 (d, J = 17.4 Hz, 1 H, CH), 3.78 (s, 3 H,
OCH3), 6.75 (d, J = 8.9 Hz, 1 H, arom), 7.11 (br s, 1 H, NH), 7.97–
8.04 (m, 2 H, arom).
Synthesis 2007, No. 21, 3376–3384 © Thieme Stuttgart · New York

3384
H. N. Lim et al.
PAPER
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coupling constants C3–H and C4–H (Jcis = 3.4 Hz/Jtrans = 9.3
Hz) according to: Makino, K.; Hara, O.; Takiguchi, Y.;
Katano, T.; Asakawa, Y.; Hatano, K.; Hamada, Y.
Tetrahedron Lett. 2003, 44, 8925.
Synthesis 2007, No. 21, 3376–3384 © Thieme Stuttgart · New York