Synthesis of (Z)-2-(2H-isoquinolin-1-ylidene)acetamides by iodine-mediated cyclization of (Z)-3-amino-3-(2-vinylphenyl)propenamides

Article abstract of DOI:10.1055/s-2007-965934

(Z)-2-(2-Acetyl-2H-isoquinolin-1-ylidene)acetamides have been synthesized from 2-vinylbenzonitrile derivatives in three steps. The key step involves the iodine-mediated 6-endo cyclization of (Z)-3-acetylamino-3-(2-vinylphenyl) propenamides, which are prep

Full text of DOI:10.1055/s-2007-965934

824
PAPER
Synthesis of (Z)-2-(2H-Isoquinolin-1-ylidene)acetamides by Iodine-Mediated
Cyclization of (Z)-3-Amino-3-(2-vinylphenyl)propenamides
Synthesis of
(
Z
)
-2-
a
(2
H
-Isoqui
z
nolin-1-ylid
u
ene)acetami
hdes iro Kobayashi,* Kenichi Hashimoto, Taiyo Shiokawa, Osamu Morikawa, Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 27 October 2006; revised 11 December 2006
ones, on treatment with iodine.3 In this paper we wish to
Abstract: (Z)-2-(2-Acetyl-2H-isoquinolin-1-ylidene)acetamides
report a synthesis of (Z)-2-(2-acetyl-2H-isoquinolin-1-
ylidene)acetamides 4. We have found that a 6-endo cy-
clization takes places by treating (Z)-3-acetylamino-3-(2-
have been synthesized from 2-vinylbenzonitrile derivatives in three
steps. The key step involves the iodine-mediated 6-endo cyclization
of (Z)-3-acetylamino-3-(2-vinylphenyl)propenamides, which are
prepared by the coupling of 2-vinylbenzonitriles with magnesium vinylphenyl)propenamides 3 with iodine to give 4. Al-
enolates of tertiary amides followed by N-acetylation.
though a number of methods for the preparation of iso-
quinoline derivatives have been reported4 because of their
Key words: 6-endo cyclization, iodine, isoquinoline, magnesium
biological importance,5 there have been few reports on the
amide, magnesium enolate
general synthesis of 2-(2H-isoquinolin-1-ylidene)acetic
acid derivatives.6
In our previous paper,7a we reported on the formation of
vinylogous urea derivatives by the magnesium bis(diiso-
propylamide) (MBDA)-mediated coupling reaction be-
tween tertiary amides and nitriles. As shown in Scheme 1,
the first step of our sequence was this coupling reaction
with 2-vinylbenzonitrile derivatives 1, which could be
easily prepared by conventional synthetic methods (see
experimental section). The coupling products (Z)-3-ami-
no-3-(2-vinylphenyl)propenamides 2 were obtained in
good yields. Subsequent N-acetylation of these enamino
amides 2 with acetic anhydride in pyridine afforded good
yields of (Z)-3-acetylamino-3-(2-vinylphenyl)propen-
amide derivatives 3, which cyclized on treatment with
three molar amounts each of iodine and sodium hydrogen-
carbonate for one hour to give the corresponding (Z)-2-(2-
acetyl-2H-isoquinolin-1-ylidene)acetamides 4 in 50–59%
yields, via 6-endo iodoamination intermediates 6; 5-exo
cyclization products 7, which have more strained struc-
tures, were not detected (Scheme 2). The results obtained
Recently, we have reported a few syntheses of nitrogen
heterocycles utilizing iodoamination of styrene deriva-
tives carrying a substituent including a NH moiety. Thus,
2-(arylamino)styrenes were allowed to react with iodine
in the presence of sodium hydrogencarbonate to give the
5-endo cyclization products, 1-aryl-1H-indoles,1 whereas
a similar treatment of 2-(acylamino)styrenes gave the 4-
exo cyclization products, 2-iodomethylbenzazetines.2 We
also found that secondary 2-vinylbenzamides gave the 5-
exo cyclization products, 3-(iodomethyl)isoindolin-1-
R1
R1
R2
R2
CH3CON(R3)2, MBDA
NH2
Et2O, 0 °C to r.t.
CN
CON(R3)2
1
2
R1
R2
R1
Ac2O, Py
I+
R2
NHAc
60 °C
I2
3
NHAc
CON(R3)2
3
CON(R3)2
5
R1
R2
R1
I
I2, NaHCO3
R1
I
R2
R2
NAc
MeCN, 0 °C
NAc
not
NAc
CON(R3)2
CON(R3)2
4
CON(R3)2
7
6
Scheme 1
– HI
SYNTHESIS 2007, No. 6, pp 0824–0828
Advanced online publication: 13.02.2007
x
x
.
x
x
.2
0
0
7
4
DOI: 10.1055/s-2007-965934; Art ID: F17906SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

PAPER
Synthesis of (Z)-2-(2H-Isoquinolin-1-ylidene)acetamides
825
Table 1 Preparation of 2-(2H-Isoquinolin-1-ylidene)acetamides 4 from 2-Vinylbenzonitriles 1
Entry
1
N(R3)2 in amide
NMe2
2 (Yield, %)a
2a (91)
2b (87)
2c (83)
3 (Yield, %)a
3a (73)
3b (73)
3c (70)
4 (Yield, %)a
1
2
3
4
5
6
7
1a (R1 = Ph, R2 = H)
1a
4a (51)
4b (59)
4c (56)
4d (55)
4e (50)
4f (58)
4g (53)
NEt2
1a
morpholin-4-yl
NMe2
1b (R1 = 4-ClC6H4, R2 = H)
1c (R1 = Me, R2 = H)
1d (R1 = Et, R2 = H)
1e (R1 = Ph, R2 = OMe)
2d (87)
2e (85)
3d (78)
3e (75)
NMe2
NMe2
2f (90)
3f (60)
NMe2
2g (80)
3g (77)
a Isolated yields.
erating at 125 MHz in CDCl3. Low-resolution mass spectra (EI)
were recorded on a Jeol Automass 20 spectrometer (Center for Joint
Research and Development, this University). TLC analyses were
carried out on Merck Kieselgel 60 PF254. Column chromatography
was performed using Merck Kieselgel 60 (0.063–0.200 mm). All
solvents were dried over appropriate drying agents and distilled un-
der argon prior to use.
2-(1-Phenylvinyl)benzonitrile (1a),8 2-[1-(4-chlorophenyl)vi-
nyl]benzonitrile (1b), and 4-methoxy-2-(1-phenylvinyl)benzoni-
trile (1e) were prepared by the procedure reported previously by us.9
2-Acetylbenzonitrile10 and 1-(2-bromophenyl)propan-1-one11 were
prepared according to appropriate literature procedures. All other
chemicals used in this study were commercially available.
from this sequence are summarized in Table 1. The use of
less than three molar amounts each of iodine and sodium
hydrogencarbonate did not give satisfactory results. For
example, the reaction of 3a with two molar amounts each
of iodine and sodium hydrogencarbonate for a prolonged
time (5 h) gave only 29% yield of the desired product 4a,
and a considerable amount (40%) of the starting material
was recovered. The reaction of 3a with iodine using potas-
sium tert-butoxide as base in toluene gave a rather com-
plex mixture of products, from which only 28% yield of
the desired product 4a was obtained. It should be noted
that all attempts for direct conversion of 2 into the corre-
sponding (isoquinolinylidene)acetamide derivatives were
unsuccessful and resulted in the formation of intractable
mixtures of products.
2-(1-Methylvinyl)benzonitrile (1c)12
This compound was prepared by treating 2-acetylbenzonitrile10
with methylenetriphenylphosphorane under the conditions reported
by us for the preparation of 1a;9 yield: 64%; colorless liquid;
Rf = 0.41 (CH2Cl2–hexane, 1:2).
The stereochemistry of 2 and 3 were assigned to be Z in
analogy with earlier results7 on the basis of their spectral
(IR and 1H NMR) data (see experimental section). The Z
preference is ascribed to intramolecular hydrogen bond-
ing between the N-hydrogen and amide carbonyl. Unam-
biguous determination of the stereochemistry of 4 was
carried out by NOE experiments. Thus, irradiation of the
signal at d = 5.33 assignable to the vinyl proton a to car-
boxamide of compound 4e resulted in an enhancement
(13%) of the signal at d = 7.23 assignable to the proton at
the 8-position of the isoquinoline ring.
IR (neat): 2224, 1638 cm–1.
The 1H NMR data for this compound were identical to those report-
ed previously.12
2-Propanoylbenzonitrile
A mixture of 1-(2-bromophenyl)propan-1-one11 (2.3 g, 11 mmol) in
DMF (30 mL) containing CuCN (1.1 g, 13 mmol) was heated at re-
flux temperature for 30 min. Toluene and H2O (50 mL each) were
added to the cooled mixture and the precipitate was filtered through
a Celite pad. The layers were separated and the organic layer was
washed with H2O (3 × 10 mL) and then brine (10 mL). After drying
(Na2SO4), the solvent was evaporated. The residue was purified by
column chromatography on silica gel (1:2 hexane–Et2O) to give the
title compound; yield: 0.88 g (52%); white solid; mp 45–48 °C
(hexane–Et2O).
In conclusion, (Z)-2-(2H-isoquinolin-1-ylidene)acet-
amide derivatives have been synthesized in three steps
from 2-vinylbenzonitrile derivatives. Although total
yields of the products were moderate, the present se-
quence may find some value in organic synthesis, because
the reactions are simple to conduct and the starting mate-
rials are readily available.
IR (KBr): 2222, 1695 cm–1.
1H NMR (500 MHz): d = 1.27 (t, J = 7.3 Hz, 3 H), 3.06 (q, J = 7.3
Hz, 2 H), 7.64 (ddd, J = 7.8, 7.3, 1.4 Hz, 1 H), 7.70 (ddd, J = 7.8,
7.3, 1.4 Hz, 1 H), 7.82 (dd, J = 7.8, 1.4 Hz, 1 H), 7.93 (dd, J = 7.8,
1.4 Hz, 1 H).
The melting points were determined on a Laboratory Devices Mel-
Temp II melting-point apparatus and are uncorrected. The IR spec-
tra were recorded on a Shimadzu FTIR-8300 spectrometer. The 1H
NMR spectra were determined using SiMe4 as an internal reference
in CDCl3 with a Jeol ECP500 FT NMR spectrometer operating at
500 MHz, a Jeol LA400 FT NMR spectrometer operating at 400
MHz, or a Jeol JNM-GX270 FT NMR spectrometer operating at
270 MHz. The 13C NMR spectrum was determined using SiMe4 as
an internal reference with a Jeol ECP500 FT NMR spectrometer op-
Anal. Calcd for C10H9NO: C, 75.45; H, 5.70; N, 8.80. Found: C,
75.41; H, 5.80; N, 9.00.
2-(1-Ethylvinyl)benzonitrile (1d)
This compound was prepared by treating 2-propanoylbenzonitrile
with methylenetriphenylphosphorane under the conditions reported
by us for the preparation of 1a;9 yield: 59%; colorless liquid; Rf =
0.33 (CH2Cl2–hexane, 1:2).
Synthesis 2007, No. 6, 824–828 © Thieme Stuttgart · New York

826
K. Kobayashi et al.
PAPER
IR (neat): 2224, 1636 cm–1.
(Z)-3-Amino-N,N-dimethyl-3-[2-(1-methylvinyl)phenyl]prop-
enamide (2e)
Pale-yellow solid; mp 79–82 °C (hexane–Et2O).
IR (KBr): 3381, 3275, 1614 cm–1.
1H NMR (500 MHz): d = 2.07 (dd, J = 1.4, 0.9 Hz, 3 H), 2.99 (s, 6
H), 4.94 (s, 1 H), 5.06 (quint, 0.9 Hz, 1 H), 5.12–5.14 (m, 1 H), 6.0–
7.0 (br, 2 H), 7.25 (dd, J = 7.3, 1.4 Hz, 1 H), 7.29 (ddd, J = 7.8, 7.3,
1.4 Hz, 1 H), 7.33 (td, J = 7.3, 1.4 Hz, 1 H), 7.39 (dd, J = 7.8, 1.4
Hz, 1 H).
1H NMR (270 MHz): d = 1.08 (t, J = 7.3 Hz, 3 H), 2.51 (qd, J = 7.3,
0.9 Hz, 2 H), 5.19 (d, J = 0.9 Hz, 1 H), 5.36 (q, J = 0.9 Hz, 1 H),
7.33 (d, J = 7.3 Hz, 1 H), 7.35 (td, J = 7.3, 0.9 Hz, 1 H), 7.54 (ddd,
J = 7.8, 7.3, 1.4 Hz, 1 H), 7.66 (dd, J = 7.8, 0.9 Hz, 1 H).
Anal. Calcd for C11H11N: C, 84.04; H, 7.05; N, 8.91. Found: C,
83.64; H, 7.14; N, 9.13.
3-Amino-3-(2-vinylphenyl)propenamides 2; (Z)-3-Amino-N,N-
dimethyl-3-[2-(1-phenylvinyl)phenyl]propenamide (2a); Typi-
cal Procedure
Anal. Calcd for C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C,
73.64; H, 8.03; N, 12.15.
To a stirred turbid solution of MBDA at 0 °C, generated by treating
diisopropylamine (1.8 g, 18 mmol) with EtMgBr (18 mmol, 3 M so-
lution in Et2O) in Et2O (15 mL) at reflux temperature for 1 h, were
added N,N-dimethylacetamide (0.76 g, 8.8 mmol) and 1a (0.45 g,
2.2 mmol) successively. After stirring for 10 min at the same tem-
perature, aq NH4Cl (20 mL) was added and the mixture was extract-
ed with Et2O (3 × 20 mL). The combined extracts were washed with
brine (20 mL), dried (Na2SO4), and evaporated. The residue was pu-
rified by column chromatography on silica gel to give 2a; yield:
0.46 g (91%); yellow oil; Rf = 0.31 (EtOAc–hexane, 1:3).
(Z)-3-Amino-3-[2-(1-ethylvinyl)phenyl]-N,N-dimethylpropen-
amide (2f)
White solid; mp 75–77 °C (hexane–Et2O).
IR (KBr): 3381, 3275, 1614 cm–1.
1H NMR (500 MHz): d = 0.98 (t, J = 7.3 Hz, 3 H), 2.38 (q, J = 7.3
Hz, 2 H), 2.99 (s, 6 H), 4.93 (s, 1 H), 5.06 (d, J = 0.9 Hz, 1 H), 5.13
(d, J = 0.9 Hz, 1 H), 6.0–7.0 (br, 2 H), 7.21 (dd, J = 7.3, 1.8 Hz, 1
H), 7.29 (td, J = 7.3, 1.4 Hz, 1 H), 7.33 (td, J = 7.3, 1.8 Hz, 1 H),
7.39 (dd, J = 7.3, 1.4 Hz, 1 H).
IR (neat): 3383, 3275, 1614 cm–1.
1H NMR (500 MHz): d = 2.82 (br s, 6 H), 4.69 (s, 1 H), 5.30 (d,
J = 1.4 Hz, 1 H), 5.69 (d, J = 1.4 Hz, 1 H), 6.0–7.0 (br, 2 H), 7.20–
7.26 (m, 5 H), 7.31 (dd, J = 7.3, 1.8 Hz, 1 H), 7.35–7.42 (m, 2 H),
7.44 (dd, J = 7.3, 1.8 Hz, 1 H).
Anal. Calcd for C15H20N2O: C, 73.74; H, 8.25; N, 11.47. Found: C,
73.70; H, 8.35; N, 11.35.
(Z)-3-Amino-3-[4-methoxy-2-(1-phenylvinyl)phenyl]-N,N-di-
methylpropenamide (2g)
Yellow viscous oil; Rf = 0.19 (EtOAc–hexane, 1:3).
IR (neat): 3385, 3277, 1614 cm–1.
Anal. Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C,
77.96; H, 6.91; N, 9.27.
1H NMR (400 MHz): d = 2.81 (br s, 6 H), 3.83 (s, 3 H), 4.68 (s, 1
H), 5.30 (s, 1 H), 5.69 (s, 1 H), 6.0–7.0 (br, 2 H), 6.84 (d, J = 2.6 Hz,
1 H), 6.90 (dd, J = 8.4, 2.6 Hz, 1 H), 7.21–7.26 (m, 5 H), 7.38 (d,
J = 8.4 Hz, 1 H).
(Z)-3-Amino-N,N-diethyl-3-[2-(1-phenylvinyl)phenyl]propen-
amide (2b)
Pale-yellow solid; mp 100–101 °C (hexane–Et2O).
IR (KBr): 3381, 3273, 1616 cm–1.
1H NMR (500 MHz): d = 1.04 (br s, 6 H), 3.08 (br s, 2 H), 3.31 (br
s, 2 H), 4.65 (s, 1 H), 5.30 (d, J = 0.9 Hz, 1 H), 5.69 (d, J = 0.9 Hz,
1 H), 6.0–7.0 (br, 2 H), 7.20–7.26 (m, 5 H), 7.32 (dd, J = 7.3, 2.3
Hz, 1 H), 7.35–7.42 (m, 2 H), 7.45 (dd, J = 7.3, 1.8 Hz, 1 H).
Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C,
74.18; H, 6.89; N, 8.47.
3-Acetylamino-3-(vinylphenyl)propenamides 3; (Z)-3-Acetyl-
amino-N,N-dimethyl-3-[2-(1-phenylvinyl)phenyl]propenamide
(3a); Typical Procedure
A mixture of 2a (0.41 g, 1.8 mmol), pyridine (1 mL), and Ac2O (1
mL) was heated at 60 °C for 4 h. After removal of excess pyridine
and Ac2O under reduced pressure, the residue was purified by pre-
parative TLC on silica gel to give 3a; yield: 0.44 g (73%); yellow
viscous oil; Rf = 0.48 (EtOAc–hexane, 1:1).
Anal. Calcd for C21H24N2O: C, 78.71; H, 7.55; N, 8.74. Found: C,
78.57; H, 7.73; N, 8.58.
(Z)-Amino-1-(morpholin-4-yl)-3-[2-(1-phenylvinyl)phenyl]pro-
penone (2c)
White solid; mp 150–153 °C (hexane–Et2O).
IR (KBr): 3402, 3292, 1614 cm–1.
1H NMR (500 MHz): d = 3.1–3.5 (br, 4 H), 3.56 (br s, 4 H), 4.61 (s,
1 H), 5.28 (d, J = 0.9 Hz, 1 H), 5.71 (d, J = 0.9 Hz, 1 H), 6.0–7.0 (br,
2 H), 7.22–7.27 (m, 5 H), 7.34 (dd, J = 7.3, 1.4 Hz, 1 H), 7.36–7.45
(m, 3 H).
IR (neat): 3408, 1711, 1622 cm–1.
1H NMR (500 MHz): d = 1.95 (s, 3 H), 2.74 (s, 3 H), 2.90 (s, 3 H),
5.05 (s, 1 H), 5.28 (d, J = 1.4 Hz, 1 H), 5.66 (d, J = 1.4 Hz, 1 H),
7.19–7.30 (m, 7 H), 7.32–7.39 (m, 2 H), 11.71 (br s, 1 H).
Anal. Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C,
75.37; H, 6.65; N, 7.99.
Anal. Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C,
75.38; H, 6.80; N, 8.21.
(Z)-3-Acetylamino-N,N-diethyl-3-[2-(1-phenylvinyl)phe-
nyl]propenamide (3b)
Brownish-yellow viscous oil; Rf = 0.39 (EtOAc–hexane, 1:2).
IR (neat): 3402, 1711, 1622 cm–1.
1H NMR (500 MHz): d = 0.94 (t, J = 7.3 Hz, 3 H), 1.09 (t, J = 7.3
Hz, 3 H), 1.96 (s, 3 H), 3.03 (q, J = 7.3 Hz, 2 H), 3.31 (q, J = 7.3 Hz,
2 H), 4.98 (s, 1 H), 5.29 (d, J = 1.4 Hz, 1 H), 5.66 (d, J = 1.4 Hz, 1
H), 7.19–7.30 (m, 7 H), 7.32–7.39 (m, 2 H), 11.83 (br s, 1 H).
(Z)-3-Amino-3-{2-[1-(4-chlorophenyl)vinyl]phenyl}-N,N-di-
methylpropenamide (2d)
Yellow viscous oil; Rf = 0.42 (EtOAc–hexane, 1:1).
IR (neat): 3383, 3275, 1614 cm–1.
1H NMR (500 MHz): d = 2.84 (br s, 6 H), 4.63 (s, 1 H), 5.32 (d,
J = 0.9 Hz, 1 H), 5.65 (s, 1 H), 6.0–7.0 (br, 2 H), 7.16 (d, J = 8.7 Hz,
2 H), 7.20 (d, J = 8.7 Hz, 2 H), 7.31 (dd, J = 8.7, 1.8 Hz, 1 H), 7.36–
7.44 (m, 3 H).
Anal. Calcd for C23H26N2O2: C, 76.21; H, 7.23; N, 7.73. Found: C,
76.18; H, 7.40; N, 7.74.
Anal. Calcd for C19H19ClN2O: C, 69.83; H, 5.86; N, 8.57. Found: C,
69.63; H, 5.92; N, 8.43.
Synthesis 2007, No. 6, 824–828 © Thieme Stuttgart · New York

PAPER
Synthesis of (Z)-2-(2H-Isoquinolin-1-ylidene)acetamides
827
(Z)-N-{3-(Morpholin-4-yl)-3-oxo-1-[2-(1-phenylvinyl)phe-
nyl]propenyl}acetamide (3c)
Yellow viscous oil; Rf = 0.23 (EtOAc–hexane, 1:1).
IR (neat): 3402, 1713, 1622 cm–1.
1H NMR (500 MHz): d = 1.97 (s, 3 H), 3.07 (br s, 2 H), 3.45–3.62
(m, 6 H), 4.96 (s, 1 H), 5.28 (d, J = 1.4 Hz, 1 H), 5.70 (d, J = 1.4 Hz,
1 H), 7.21–7.42 (m, 9 H), 11.54 (br s, 1 H).
mL). The combined extracts were washed with sat. aq NaHCO3 (20
mL) and then brine (10 mL), and dried (K2CO3). Evaporation of the
solvent gave a residue, which was purified by preparative TLC on
silica gel to afford 4a; yield: 0.13 g (51%); pale-yellow solid; mp
167–168 °C (hexane–CH2Cl2).
IR (KBr): 1664 cm–1.
1H NMR (500 MHz): d = 2.26 (s, 3 H), 2.28 (s, 3 H), 2.62 (s, 3 H),
5.45 (s, 1 H), 6.36 (s, 1 H), 7.23 (td, J = 7.3, 1.4 Hz, 1 H), 7.31 (td,
J = 7.3, 1.4 Hz, 1 H), 7.33 (d, J = 7.3 Hz, 1 H), 7.40–7.49 (m, 4 H),
7.59 (dd, J = 8.2, 1.4 Hz, 2 H).
Anal. Calcd for C23H24N2O3: C, 73.38; H, 6.43; N, 7.44. Found: C,
73.27; H, 6.71; N, 7.39.
(Z)-3-Acetylamino-3-{2-[1-(4-chlorophenyl)vinyl]phenyl}-N,N-
dimethylpropenamide (3d)
Yellow oil; Rf = 0.22 (EtOAc–pentane, 1:2).
IR (KBr): 3404, 1709, 1622 cm–1.
MS: m/z (%) = 332 (7.3, [M+]), 272 (18), 231 (87), 189 (100).
Anal. Calcd for C21H20N2O2: C, 75.88; H, 6.06; N, 8.43. Found: C,
76.00; H, 6.12; N, 8.32.
(Z)-2-(2-Acetyl-4-phenyl-2H-isoquinolin-1-ylidene)-N,N-di-
ethylacetamide (4b)
Pale-yellow solid; mp 157–158 °C (hexane–CH2Cl2).
IR (KBr): 1661 cm–1.
1H NMR (500 MHz): d = 1.95 (s, 3 H), 2.82 (s, 3 H), 2.93 (s, 3 H),
5.02 (s, 1 H), 5.30 (d, J = 0.9 Hz, 1 H), 5.62 (d, J = 0.9 Hz, 1 H),
7.20 (br s, 4 H), 7.27 (dd, J = 8.7, 2.3 Hz, 1 H), 7.33–7.40 (m, 3 H,),
11.75 (br s, 1 H).
Anal. Calcd for C21H21ClN2O2: C, 68.38; H, 5.74; N, 7.59. Found:
C, 68.29; H, 5.77; N, 7.41.
1H NMR (500 MHz): d = 0.73 (t, J = 7.3 Hz, 3 H), 0.84 (t, J = 7.3
Hz, 3 H), 2.28 (s, 3 H), 2.41 (dq, J = 15.3, 7.3 Hz, 1 H), 2.83–2.91
(m, 2 H), 3.37 (dq, J = 15.3, 7.3 Hz, 1 H), 5.37 (s, 1 H), 6.35 (s, 1
H), 7.20 (td, J = 7.3, 1.4 Hz, 1 H), 7.28 (ddd, J = 7.8, 7.3, 1.4 Hz, 1
H), 7.38–7.50 (m, 5 H), 7.59 (dd, J = 8.2, 1.4 Hz, 2 H).
(Z)-3-Acetylamino-N,N-dimethyl-3-[2-(1-methylvinyl)phe-
nyl]propenamide (3e)
Pale-yellow viscous oil; Rf = 0.36 (EtOAc–hexane, 1:1).
IR (neat): 3402, 1713, 1622 cm–1.
1H NMR (500 MHz): d = 2.02 (s, 3 H), 2.07 (s, 3 H), 3.02 (s, 3 H),
3.03 (s, 3 H), 4.99 (d, J = 0.9 Hz, 1 H), 5.09 (d, J = 0.9 Hz, 1 H),
5.33 (s, 1 H), 7.21–7.32 (m, 4 H), 11.92 (br s, 1 H).
MS: m/z (%) = 360 (6.2, [M+]), 300 (11), 231 (100).
Anal. Calcd for C23H24N2O2: C, 76.64; H, 6.71; N, 7.77. Found: C,
76.31; H, 6.81; N, 7.39.
(Z)-2-(2-Acetyl-4-phenyl-2H-isoquinolin-1-ylidene)-1-(mor-
pholin-4-yl)ethanone (4c)
Pale-yellow solid; mp 204–205 °C (hexane–CH2Cl2).
IR (KBr): 1670, 1655 cm–1.
1H NMR (500 MHz): d = 2.28 (s, 3 H), 2.29–2.32 (m, 1 H), 2.61–
2.65 (m, 1 H), 2.91–2.94 (m, 1 H), 2.99–3.09 (m, 2 H), 3.30–3.33
(m, 1 H), 3.51–3.54 (m, 1 H), 3.67–3.70 (m, 1 H), 5.37 (s, 1 H), 6.33
(s, 1 H), 7.27 (t, J = 7.3 Hz, 1 H), 7.33–7.40 (m, 2 H), 7.41–7.49 (m,
4 H), 7.57 (d, J = 8.2 Hz, 2 H).
13C NMR: d = 14.27, 41.71, 44.70, 65.49, 66.22, 78.71, 83.49,
121.28, 125.50, 127.02, 127.50, 128.78, 128.88, 128.99, 134.03,
135.12, 142.28, 144.86, 146.29, 165.56, 168.56.
Anal. Calcd for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C,
70.52; H, 7.40; N, 10.28.
(Z)-3-Acetylamino-3-[2-(1-ethylvinyl)phenyl]-N,N-dimethyl-
propenamide (3f)
Colorless viscous oil; Rf = 0.39 (EtOAc–hexane, 1:1).
IR (neat): 3402, 1713, 1622 cm–1.
1H NMR (500 MHz): d = 1.00 (t, J = 7.3 Hz, 3 H), 2.06 (s, 3 H),
2.33 (q, J = 7.3 Hz, 2 H), 3.02 (s, 3 H), 3.03 (s, 3 H), 4.99 (s, 1 H),
5.08 (q, J = 1.4 Hz, 1 H), 5.34 (s, 1 H), 7.18 (dd, J = 7.3, 1.4 Hz, 1
H), 7.23 (dd, J = 7.3, 1.4 Hz, 1 H), 7.25 (td, J = 7.3, 1.4 Hz, 1 H),
7.30 (td, J = 7.3, 1.4 Hz, 1 H), 11.87 (br s, 1 H).
MS: m/z (%) = 374 (6.4, [M+]), 314 (15), 231 (83), 189 (100).
Anal. Calcd for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C,
71.28; H, 7.78; N, 9.53.
Anal. Calcd for C23H22N2O3: C, 73.78; H, 5.92; N, 7.48. Found: C,
73.86; H, 5.75; N, 7.18.
(Z)-3-Acetylamino-3-[4-methoxy-2-(1-phenylvinyl)phenyl]-
N,N-dimethylpropenamide (3g)
(Z)-2-[2-Acetyl-4-(4-chlorophenyl)-2H-isoquinolin-1-ylidene]-
N,N-dimethylacetamide (4d)
Pale-yellow solid; mp 179–181 °C (hexane–CH2Cl2).
IR (KBr): 1658 cm–1.
1H NMR (500 MHz): d = 2.24 (s, 3 H), 2.27 (s, 3 H), 2.62 (s, 3 H),
5.44 (s, 1 H), 6.36 (s, 1 H), 7.24 (td, J = 7.3, 0.9 Hz, 1 H), 7.32 (td,
J = 7.3, 0.9 Hz, 1 H), 7.33 (d, J = 7.3 Hz, 1 H), 7.38 (d, J = 7.3 Hz,
1 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.52 (d, J = 8.7 Hz, 2 H).
Yellow viscous oil; Rf = 0.26 (EtOAc–hexane, 3:2).
IR (neat): 3410, 1709, 1622 cm–1.
1H NMR (400 MHz): d = 1.94 (s, 3 H), 2.74 (s, 3 H), 2.89 (s, 3 H),
3.82 (s, 3 H), 5.04 (s, 1 H), 5.29 (d, J = 1.0 Hz, 1 H), 5.66 (d, J = 1.0
Hz, 1 H), 6.82 (d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 8.2, 2.4 Hz, 1 H),
7.19–7.30 (m, 6 H), 11.65 (br s, 1 H).
Anal. Calcd for C22H24N2O3: C, 72.50; H, 6.64; N, 7.69. Found: C,
72.29; H, 6.68; N, 7.77.
MS: m/z (%) = 366 (2.9, [M+]), 306 (11), 265 (46), 189 (100).
Anal. Calcd for C21H19ClN2O2: C, 68.76; H, 5.22; N, 7.64. Found:
C, 68.89; H, 5.37; N, 7.51.
2-(2H-Isoquinolin-1-ylidene)acetamides 4; (Z)-2-(2-Acetyl-4-
phenyl-2H-isoquinolin-1-ylidene)-N,N-dimethylacetamide(4a);
Typical Procedure
To a stirred solution of 3a (0.25 g, 0.74 mmol) in MeCN (5 mL)
containing NaHCO3 (0.19 g, 2.2 mmol) at 0 °C, was added I2 (0.56
g, 2.2 mmol) in portions and the mixture was stirred for 1 h at the
same temperature. Aq 10% Na2S2O3 was added until the color of I2
had disappeared, and the mixture was extracted with Et2O (3 × 15
(Z)-2-(2-Acetyl-4-methyl-2H-isoquinolin-1-ylidene)-N,N-di-
methylacetamide (4e)
Pale-yellow solid; mp 123–127 °C (hexane–CH2Cl2).
IR (KBr): 1653 cm–1.
Synthesis 2007, No. 6, 824–828 © Thieme Stuttgart · New York

828
K. Kobayashi et al.
PAPER
1H NMR (500 MHz): d = 2.13 (d, J = 1.4 Hz, 3 H), 2.15 (s, 3 H),
2.23 (s, 3 H), 2.60 (s, 3 H), 5.33 (s, 1 H), 6.01 (q, 1.4 Hz, 1 H), 7.17
(td, J = 7.3, 0.9 Hz, 1 H), 7.19 (d, J = 7.3 Hz, 1 H), 7.23 (d, J = 7.3
Hz, 1 H), 7.30 (td, J = 7.3, 1.4 Hz, 1 H).
(4) For recent reports, see: (a) Konno, T.; Chae, J.; Miyabe, T.;
Ishihara, T. J. Org. Chem. 2005, 70, 10172. (b) Ichikawa,
J.; Sakoda, K.; Moriyama, H.; Wada, Y. Synthesis 2006,
1590. (c) Alonso, R.; Campos, P. J.; García, B.; Rodoríguez,
M. A. Org. Lett. 2006, 8, 3521. For earlier reports, see
pertinent references cited in these papers and ref. 9
(5) For recent reports on the biological activity of isoquinoline
derivatives: (a) Barber, C. G.; Dickinson, R. P.; Fish, P. V.
Bioorg. Med. Chem. Lett. 2005, 14, 3227. (b) Jiang, J.;
Thomas, C. J.; Neumann, S.; Lu, X.; Rice, C. K.;
Gershengorn, M. C. Bioorg. Med. Chem. Lett. 2005, 15,
733. (c) Cui, W.; Iwasa, K.; Tokuda, H.; Kashihara, A.;
Mitani, Y.; Hasegawa, T.; Nishiyama, Y.; Moriyasu, M.;
Nishino, H.; Hanaoka, M.; Mukai, C.; Takeda, K.
Phytochemistry 2006, 67, 70. (d) Markmee, S.; Ruchirawat,
S.; Prachyawarakorn, W.; Ingkaninan, K.; Khorana, N.
Bioorg. Med. Chem. Lett. 2006, 16, 2170. (e) Zhu, G.-D.;
Gong, J.; Claiborne, A.; Woods, K. W.; Gandhi, V. B.;
Thomas, S.; Luo, Y.; Liu, X.; Shi, Y.; Guan, R.; Magnone,
S. R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.; Shoemaker,
A.; Oleksijew, A.; Stoll, V. S.; De Jong, R.; Olterdorf, T.; Li,
Q.; Rosenberg, S. H.; Girranda, V. L. Bioorg. Med. Chem.
Lett. 2006, 16, 3150.
(6) A synthesis of (2H-isoquinolin-1-ylidene)acetates by
reactions of 2-alkyl-1-methylthioisoquinolinium salts with
active methylene compounds has been reported: (a) Fujita,
R.; Watanabe, N.; Tomisawa, H. Chem. Pharm. Bull. 2001,
50, 225. (b) Fujita, R.; Watanabe, N.; Tomisawa, H.
Heterocycles 2001, 55, 435. For other reports on the
synthesis of related compounds, see: (c) Stanovnik, B.;
Drofenik, I.; Tisler, M.; Durst, T. Heterocycles 1987, 26,
1805. (d) Finke, J. A.; Huisgen, R.; Temme, R. Helv. Chim.
Acta 2000, 83, 2363.
MS: m/z (%) = 270 (3.0, [M+]), 198 (7.9), 183 (14), 169 (100).
Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C,
70.96; H, 6.82; N, 10.34.
(Z)-2-(2-Acetyl-4-ethyl-2H-isoquinolin-1-ylidene)-N,N-dimeth-
ylacetamide (4f)
Pale-yellow solid; mp 102–103 °C (hexane–Et2O–CHCl3).
IR (KBr): 1663 cm–1.
1H NMR (500 MHz): d = 1.27 (t, J = 7.3 Hz, 3 H), 2.15 (s, 3 H),
2.24 (s, 3 H), 2.49–2.56 (m, 2 H), 2.60 (s, 3 H), 5.34 (s, 1 H), 6.01
(t, J = 1.4 Hz, 1 H), 7.16 (td, J = 7.3, 0.9 Hz, 1 H), 7.21 (d, 7.3 Hz,
1 H), 7.23 (d, J = 7.3 Hz, 1 H), 7.28 (td, J = 7.3, 0.9 Hz, 1 H).
MS: m/z (%) = 284 (2.9, [M+]), 212 (9.0), 183 (100).
Anal. Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85. Found: C,
71.73; H, 7.20; N, 9.73.
(Z)-2-(2-Acetyl-6-methoxy-4-phenyl-2H-isoquinolin-1-ylidene)-
N,N-dimethylacetamide (4g)
Pale-yellow solid; mp 176–178 °C (hexane–CH2Cl2).
IR (KBr): 1668 cm–1.
1H NMR (500 MHz): d = 2.26 (s, 3 H), 2.30 (s, 3 H), 2.66 (s, 3 H),
3.80 (s, 3 H), 5.42 (s, 1 H), 6.37 (s, 1 H), 6.74 (dd, J = 8.2, 2.3 Hz,
1 H), 6.97 (d, J = 2.3 Hz, 1 H), 7.23 (d, J = 8.2 Hz, 1 H), 7.40–7.49
(m, 3 H), 7.57 (dd, J = 8.2, 1.4 Hz, 2 H).
MS: m/z (%) = 362 (10, [M+]), 317 (19), 290 (42), 261 (100).
Anal. Calcd for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73. Found: C,
72.90; H, 6.10; N, 7.53.
(7) (a) Kobayashi, K.; Kitamura, T.; Nakahashi, R.; Shimizu,
A.; Morikawa, O.; Konishi, H. Heterocycles 2000, 53, 1021.
(b) Hiyama, T.; Kobayashi, K.; Nishide, K. Bull. Chem. Soc.
Jpn. 1987, 60, 2127.
(8) Dordor, I. M.; Mellor, J. M. J. Chem. Soc., Perkin Trans. 1
1984, 1253.
(9) Kobayashi, K.; Shiokawa, T.; Omote, H.; Hashimoto, K.;
Morikawa, O.; Konishi, H. Bull. Chem. Soc. Jpn. 2006, 79,
1126.
Acknowledgment
We thank Mrs. Miyuki Tanmatsu of this Department for determi-
ning mass spectra and performing combustion analyses.
References
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Synthesis 2007, No. 6, 824–828 © Thieme Stuttgart · New York