A convenient synthesis of 3-(1-aminoalkyl)quinolin-2(1H)-one derivatives

Article abstract of DOI:10.1055/s-2005-872086

Treatment of magnesium enolates of 1-methyl-3,4-dihydroquinolin-2(1H)-ones with nitriles, followed by N-acetylation of the resulting vinylogous urea derivatives with acetic anhydride/pyridine and double bond migration with 1,8-diazabicyclo[5.3.0]undec-7-e

Full text of DOI:10.1055/s-2005-872086

PAPER
2673
A Convenient Synthesis of 3-(1-Aminoalkyl)quinolin-2(1H)-one Derivatives
S
ynthesisof 3-(1-A
a
minoalkyl
z
)quinolin-2
u
(1
H
)-ones hiro Kobayashi,* Yuhei Fuchimoto, Kazutaka Hayashi, Masaaki Mano, Miyuki Tanmatsu, Osamu Morikawa,
Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 29 March 2005; revised 12 April 2005
olin-2(1H)-one derivatives 3 in fair to good yields based
Abstract: Treatment of magnesium enolates of 1-methyl-3,4-dihy-
droquinolin-2(1H)-ones with nitriles, followed by N-acetylation of
the resulting vinylogous urea derivatives with acetic anhydride/py-
ridine and double bond migration with 1,8-diazabicyclo[5.3.0]un-
on 1 as summarized in Table 1. Nitriles bearing an a-hy-
drogen, such as 2-methylpropanenitrile and cyclohexane-
carbonitrile, proved to be usable in this sequence to afford
dec-7-ene, affords 3-[1-(acetylamino)alkyl]-1-methylquinolin- the desired products 3c and 3d, respectively, in fair yields
2(1H)-one derivatives in reasonable overall yields.
(entries 3 and 4). Then, in order to investigate the scope of
the sequence, the reactions using propanenitrile and 2,2-
dimethylpropanenitrile were carried out. The reaction of
magnesium enolate of 1a with the former nitrile resulted
in the formation of an intractable mixture of products, in-
cluding a Thorpe condensation product of the nitrile. The
reaction with the latter nitrile proceeded sluggishly, prob-
ably due to its bulkiness, to give only very low yield of the
desired product.
Key words: carbanion, lactams, magnesium, nitriles, quinolines
Substituted quinolin-2(1H)-one derivatives are an impor-
tant class of molecules because of their biological activi-
ties.1 We are interested in developing a simple and general
synthetic method of 3-(1-aminoalkyl)quinolin-2(1H)-one
derivatives, which are also of potential interest from a bi-
ological point of view. While quinolin-2(1H)-one deriva-
tives bearing various kind of substituents have been
prepared, there have been only few reports on the synthe-
sis of quinolin-2(1H)-one derivatives bearing a 1-ami-
noalkyl substituent at the 3-position, though 3-(di-
alkylamino)methyl-4-hydroxyquinolin-2(1H)-ones have
been prepared from 4-hydroxyquinolin-2(1H)-one by the
Mannich method.2 We now report on the preparation of 3-
[1-(acetylamino)alkyl]-1-methylquinolin-2(1H)-one de-
rivatives 4 from readily available starting materials,
1-methyl-3,4-dihydroquinolin-2(1H)-ones 1.
R2
R1
R1
1. MBDA, Et2O, 0 °C
2. R2CN, 0 °C to r.t.
NH2
3. H3O+
O
N
N
O
Me
Me
1a R1 = H
1b R1 = Me
1c R1 = Cl
2
R2
R1
Ac2O, Py
60 °C
NHAc
N
O
R2
Me
3
Transformation of 1 into 4 was conducted as illustrated in
Scheme 1. In previous papers we reported that magne-
sium enolates of carboxylic esters3 or tertiary amides,4
generated by treatment with magnesium bis(diisopropyl-
amide) (MBDA) from diisopropylamine and ethylmagne-
sium bromide, coupled efficiently with a range of nitriles
to afford the corresponding vinylogous urethanes or ureas,
respectively.5 The reaction of magnesium enolates of 1
with nitriles, yielding the corresponding vinylogous urea
derivatives 2, is the key reaction of the present sequence.
It should be noted that only a trace amount of the corre-
sponding coupling product could be obtained by using
LDA in the reaction of 1a with benzonitrile. The bivalent
magnesium ion is responsible for the success of the
present reaction as described before.3–5 The products 2
were unstable under purification conditions using silica
gel, and the amino group was then acetylated using acetic
anhydride in pyridine at 60 °C without any purification to
give (Z)-3-[1-(acetylamino)alkylidene]-3,4-dihydroquin-
R1
DBU, C6H6
reflux
NHAc
N
O
Me
4
Scheme 1
Table 1 Conversion of 1 into 4, via 2 and 3
Entry
1
R2
3 Yield (%)a 4 Yield (%)a
1
2
3
4
5
6
1a
1a
1a
1a
1b
1c
Ph
3a (84)
3b (69)
3c (60)
3d (60)
3e (78)
3f (79)
4a (88)
4b (84)
4c (78)
4d (80)
4e (83)
4f (82)
2-FC6H4
i-Pr
c-Hex
Ph
Ph
SYNTHESIS 2005, No. 16, pp 2673–2676
Advanced online publication: 20.07.2005
x
x.
x
x
.
2
0
0
5
a Isolated yields.
DOI: 10.1055/s-2005-872086; Art ID: F05805SS
© Georg Thieme Verlag Stuttgart · New York

2674
K. Kobayashi et al.
PAPER
While two stereoisomers were possible in the formation of The melting points were determined on a Laboratory Devices MEL-
TEMP II melting-point apparatus and are uncorrected. The IR spec-
3, in fact only one isomer was isolated in each case. The
stereochemistry of 3 was determined to be Z, because it is
thermodynamically stable. This is ascribed to the hydro-
tra were recorded using KBr disks (unless stated otherwise) on a
Shimadzu FTIR-8300 spectrometer. The 1H NMR spectra were de-
termined using SiMe4 as an internal reference in CDCl3 with a Jeol
gen bonding between the quinolone carbonyl and the NH
ECP500 FT NMR spectrometer operating at 500 MHz. Low-resolu-
proton. The stereochemistry of 3c was unambiguously
confirmed by NOE experiments. Thus, irradiation of the
signal at d = 1.07, assignable to isopropyl methyls, result-
ed in an enhancement (10%) of the signal at d = 3.43, as-
signable to 4-protons.
tion mass spectra were recorded on a Jeol Automass 20 spectrome-
ter (Center for Joint Research and Development, this University).
TLC was carried out on Merck Kieselgel 60 PF254. All of the sol-
vents used were dried over appropriate drying agents and distilled
under argon prior to use. All of the reactions were carried out under
argon.
We conceived that treatment of 3 with 1,8-diazabicy-
clo[5.3.0]undec-7-ene (DBU) would allow them to under- 1-Methyl-3,4-dihydroquinolin-2(1H)-ones 1a–c
These compounds were prepared by N-methylation of the corre-
go double bond migration to give the desired products 4.
Thus, the migration proceeded smoothly by heating 3 in
benzene at reflux temperature in the presence of an
equimolar amount of DBU to give 4 in good yields.
sponding 3,4-dihydroquinolin-2(1H)-ones6 with NaH/MeI in THF
at room temperature.
1a7
Yield: 95%; colorless oil; bp 120 °C (bath temp)/0.15 Torr.
IR (neat): 1673 cm–1.
It is particularly noteworthy that the direct conversion of
the coupling product of 6-chloro-1-methylquinolin-
2(1H)-one (1c) with pyridine-2-carbonitrile into 3-
[(acetylamino)(pyridin-2-yl)methyl]-6-chloro-1-methyl-
quinolin-2(1H)-one (4g) was accomplished under the N-
acetylating conditions described above, without isolating
the corresponding intermediate 3g. It is thought that this
easy formation of 4g is attributable to the feasible depro-
tonation of 4-hydrogen of 3g by pyridine-nitrogen, which
is the initial step of the double bond migration, as shown
in Scheme 2.
The 1H NMRdata for this compound was identical to those reported
previously.8
1b
Yield: 94%; white solid; mp 63–65 °C (hexane–Et2O).
IR (KBr): 1664 cm–1.
1H NMR: d = 2.31 (3 H, s), 2.63 (2 H, t, J = 6.8 Hz), 2.86 (2 H,
J = 6.8 Hz), 3.34 (3 H, s), 6.87 (1 H, d, J = 8.2 Hz), 6.98 (1 H, br s),
7.05 (1 H, dd, J = 8.2, 1.4 Hz).
Anal. Calcd for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C,
75.32; H, 7.50; N, 8.00.
N
1c
1. MBDA
H
2. H3O+
Yield: 96%; white solid; mp 77–78 °C (hexane–Et2O–CH2Cl2).
IR (KBr): 1670 cm–1.
1c +
Cl
NHAc
3. Ac2O, Py, 60 °C
CN
N
1H NMR: d = 2.65 (2 H, J = 6.9 Hz), 2.89 (2 H, t, J = 6.9 Hz), 3.34
(3 H, s), 6.89 (1 H, d, J = 8.2 Hz), 7.15 (1 H, d, J = 2.7 Hz), 7.22 (1
H, dd, J = 8.2, 2.7 Hz).
N
O
Me
3g
Anal. Calcd for C10H10ClNO: C, 61.39; H, 5.15; N, 7.16. Found: C,
61.24; H, 5.20; N, 7.05.
N
All other chemicals used in this study were commercially available.
Cl
NHAc
(Z)-3-(1-Acetylaminoalkylidine)-3,4-dihydroquinolin-2(1H)-
one Derivatives 3; (Z)-3-(1-Acetylamino-1-phenylmethylene)-1-
methyl-3,4-dihydroquinolin-2(1H)-one (3a); Typical Procedure
To a turbid solution of MBDA (1.0 mmol), which was prepared by
treatment of i-Pr2NH (0.20 g, 2.0 mmol) with EtMgBr (2.0 mmol,
3.0 M in Et2O) in Et2O (5 mL) at reflux temperature for 1 h, was
added a solution of 1a (0.15 g, 0.96 mmol) in Et2O (5 mL) with stir-
ring at 0 °C. After 5 min, PhCN (98 mg, 0.98 mmol) was added and
the mixture was stirred for 40 min at r.t. Sat. aq NH4Cl (10 mL) was
added to quench the reaction and the layers were separated. The
aqueous layer was extracted with Et2O (2 × 5 mL) and the combined
organic layers were washed with brine. After drying and evapora-
tion of the solvent the residue was dissolved in a mixture of pyridine
and Ac2O (1 mL, 1:1). The mixture was heated at 60 °C for 10 h,
after which excess pyridine and Ac2O were removed under reduced
pressure. The residue was separated by preparative TLC on SiO2
(hexane–THF, 3:1) to give 3a (0.26 g, 84%); white solid; mp 162–
164 °C (hexane–THF) (Table 1).
N
O
Me
4g
65% from 1c
Scheme 2
We attempted the direct conversion of 2a–2f into 4a–4f
using acetic anhydride and DBU at 80 °C. The results,
however, were not so good; rather complicated mixtures
of products were obtained and only 30–35% yields of the
desired products were isolated.
In summary, we have developed an efficient synthetic
route to 3-(1-aminoalkyl)quinolin-2(1H)-one derivatives.
The present method may find some value in organic syn-
thesis because of simple manipulations as well as the
ready availability of the starting materials.
IR (KBr): 3343, 1709, 1632 cm–1.
Synthesis 2005, No. 16, 2673–2676 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-(1-Aminoalkyl)quinolin-2(1H)-ones
MS: m/z (%) = 340 (2.4, [M+]), 297 (100).
2675
1H NMR: d = 2.05 (3 H, s), 3.39 (3 H, s), 3.43 (2 H, s), 6.95–7.45 (9
H, m), 11.63 (1 H, s).
MS: m/z (%) = 306 (6.4, [M+]), 263 (100).
Anal. Calcd for C19H17ClN2O2: C, 66.96; H, 5.03; N, 8.22. Found:
C, 66.98; H, 4.99; N, 8.25.
Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C,
74.28; H, 6.00; N, 9.05.
3-(1-Acetylaminoalkyl)quinolin-2(1H)-one Derivatives 4; 3-(1-
Acetylamino-1-phenylmethyl)-1-methylquinolin-2(1H)-one
(4a); Typical Procedure
A solution of 3a (0.15 g, 0.49 mmol) in benzene (5 mL) containing
DBU (76 mg, 0.49 mmol) was refluxed for 1 h. After cooling to r.t.,
the mixture was diluted with CHCl3 (25 mL), washed with 1% HCl,
and dried (Na2SO4). Evaporation of the solvent gave a residual sol-
id, which was recrystallized from hexane–CH2Cl2 to give pure 4a
(0.13 g, 88%); white solid; mp 190–192 °C.
(Z)-3-[1-Acetylamino-1-(2-fluorophenyl)methylene]-1-methyl-
3,4-dihydroquinolin-2(1H)-one (3b)
Yield: 69%; white solid; mp 143–145 °C (hexane–CH2Cl2).
IR (KBr): 3256, 1709, 1641 cm–1.
1H NMR: d = 2.07 (3 H, s), 3.34 (1 H, d, J = 16.5 Hz), 3.37 (1 H, d,
J = 16.5 Hz), 3.44 (3 H, s), 6.97–7.00 (3 H, m), 7.14 (1 H, t, J = 8.7
Hz), 7.19–7.25 (3 H, m), 7.38–7.43 (1 H, m), 11.83 (1 H, br s).
IR (KBr): 3311, 1653 cm–1.
MS: m/z (%) = 324 (2.7, [M+]), 281 (100).
1H NMR: d = 2.12 (3 H, s), 3.70 (3 H, s), 6.30 (1 H, d, J = 8.8 Hz),
7.15 (1 H, t, J = 7.3 Hz), 7.28–7.31 (4 H, m), 7.37 (2 H, dd, J = 7.3,
2.3 Hz), 7.59 (1 H, ddd, J = 8.2, 7.3, 1.4 Hz), 7.63 (1 H, dd, J = 7.8,
1.4 Hz), 7.78 (1 H, br d, J = 8.8 Hz), 7.87 (1 H, s).
Anal. Calcd for C19H17FN2O2: C, 70.36; H, 5.28; N, 8.64. Found; C,
70.14; H, 5.29; N, 8.64.
MS: m/z (%) = 306 (7.6, [M+]), 263 (100).
(Z)-3-(1-Acetylamino-2-methylpropylidene)-1-methyl-3,4-dihy-
droquinolin-2(1H)-one (3c)
Yield: 60%; white solid; mp 196–198 °C (hexane–CH2Cl2).
IR (KBr): 3321, 1697, 1651 cm–1.
Anal. Calcd for C19H18N2O2: C, 74.49, H, 5.92; N, 9.14. Found: C,
74.47; H, 6.23; N, 8.85.
1H NMR: d = 1.07 (6 H, d, J = 6.9 Hz), 2.21 (3 H, s), 3.41 (3 H, s),
3.43 (2 H, s), 3.76 (1 H, septet, J = 6.9 Hz), 6.53 (1 H, br s), 6.96 (1
H, d, J = 7.8 Hz), 6.98 (1 H, t, J = 7.8 Hz), 7.10 (1 H, d, 7.8 Hz),
7.23 (1 H, t, J = 7.8 Hz).
3-[1-Acetylamino-1-(2-fluorophenyl)methyl]-1-methylquino-
lin-2(1H)-one (4b)
Yield: 84%; pale-yellow solid; mp 215–218 °C (hexane–CH2Cl2).
IR (KBr): 3306, 1651 cm–1.
1H NMR: d = 2.09 (3 H, s), 3.69 (3 H, s), 6.54 (1 H, d, J = 9.2 Hz),
6.96 (1 H, ddd, J = 8.7, 7.8, 1.4 Hz), 7.13 (1 H, td, J = 7.3, 1.4 Hz),
7.18–7.23 (1 H, m), 7.28 (1 H, td, J = 7.8, 1.0 Hz), 7.34 (1 H, d,
J = 8.2 Hz), 7.57 (1 H, td, J = 8.7, 1.4 Hz), 7.63–7.67 (2 H, m), 7.92
(1 H, br d, J = 9.2 Hz), 7.95 (1 H, d, J = 2.3 Hz).
MS: m/z (%) = 272 (1.1, [M+]), 229 (100).
Anal. Calcd for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found; C,
70.48; H, 7.40; N, 10.25.
(Z)-3-(1-Acetylamino-1-cyclohexylmethylene)-1-methyl-3,4-di-
hydroquinolin-2(1H)-one (3d)
Yield: 60%; white solid; mp 183–185 °C (hexane–CH2Cl2).
IR (KBr): 3242, 1688, 1643 cm–1.
MS: m/z (%) = 324 (17, [M+]), 281 (100).
Anal. Calcd for C19H17FN2O2: C, 70.36; H, 5.28; N, 8.64. Found; C,
70.19; H, 5.67; N, 8.68.
1H NMR: d = 1.12–1.19 (2 H, m), 1.36–1.42 (2 H, m), 1.69–1.81 (6
H, m), 2.20 (3 H, s), 3.41–3.47 (6 H, m including 2 s at 3.41, 3.42),
6.55 (1 H, br s), 6.96 (1 H, d, J = 7.8 Hz), 6.98 (1 H, t, J = 7.8 Hz),
7.09 (1 H, d, J = 7.8 Hz), 7.23 (1 H, t, J = 7.8 Hz).
3-(1-Acetylamino-2-methylpropyl)-1-methylquinolin-2(1H)-
one (4c)
Purified by preparative TLC on SiO2 (EtOAc); yield: 78%; white
solid; mp 128–129 °C (hexane–CH2Cl2).
MS: m/z (%) = 312 (6.2, [M+]), 269 (100).
IR (KBr): 3312, 1645 cm–1.
Anal. Calcd for C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found; C,
73.12; H, 8.01; N, 8.64.
1H NMR: d = 0.79 (3 H, d, J = 6.4 Hz), 1.04 (3 H, d, J = 6.9 Hz),
1.99 (3 H, s), 2.29–2.38 (1 H, s), 3.74 (3 H, s), 4.60 (1 H, t, J = 10.1
Hz), 7.26 (1 H, t, J = 7.3 Hz), 7.37 (1 H, d, J = 8.7 Hz), 7.55–7.59
(3 H, m), 7.63 (1 H, s).
(Z)-3-(1-Acetylamino-1-phenylmethylene)-1,5-dimethyl-3,4-di-
hydroquinolin-2(1H)-one (3e)
Yield: 78%; white solid; mp 144–146 °C (hexane).
IR (KBr): 3240, 1703, 1635, 1614 cm–1.
1H NMR: d = 2.04 (3 H, s), 2.28 (3 H, s), 3.35 (2 H, s), 3.41 (3 H,
s), 6.80 (1 H, br s), 6.87 (1 H, d, J = 8.2 Hz), 7.04 (1 H, br d, J = 8.2
Hz), 7.24–7.26 (2 H, m), 7.39–7.45 (3 H, m), 11.67 (1 H, br s).
MS: m/z (%) = 272 (0.16, [M+]), 229 (43), 187 (100).
Anal. Calcd for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found; C,
70.38; H, 7.43; N, 10.27.
3-(1-Acetylamino-1-cyclohexylmethyl)-1-methylquinolin-
2(1H)-one (4d)
Yield: 80%; white solid; mp 210–212 °C (hexane–CH2Cl2).
MS: m/z (%) = 320 (20, [M+]), 277 (100).
Anal. Calcd for C20H20N2O2: C, 74.81; H, 6.26; N, 8.70. Found: C,
74.98; H, 6.29; N, 8.74.
IR (KBr): 3314, 1647 cm–1.
1H NMR: d = 0.84–0.94 (1 H, m), 0.99–1.08 (1 H, m), 1.11–1.27 (2
H, m), 1.36–1.41 (1 H, m), 1.59–1.65 (4 H, m), 1.74–1.80 (1 H, m),
1.94–2.03 (4 H, m including s at 1.98), 3.74 (3 H, s), 4.67 (1 H, t,
J = 10.1 Hz), 7.24–7.28 (2 H, m), 7.37 (1 H, d, J = 8.7 Hz), 7.54–
7.58 (2 H, m), 7.60 (1 H, s).
(Z)-3-(1-Acetylamino-1-phenylmethylene)-6-chloro-1-methyl-
3,4-dihydroquinolin-2(1H)-one (3f)
Yield: 79%; pale-yellow solid; mp 161–162 °C (hexane–CH2Cl2).
IR (KBr): 3200, 1703, 1637, 1622 cm–1.
1H NMR: d = 2.05 (3 H, s), 3.36 (2 H, s), 3.41 (3 H, s), 6.89 (1 H, d,
8.7 Hz), 6.97 (1 H, d, 2.3 Hz), 7.20–7.25 (3 H, m), 7.39–7.45 (3 H,
m), 11.62 (1 H, br s).
MS: m/z (%) = 312 (0.31, [M+]), 229 (54), 187 (100).
Anal. Calcd for C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C,
72.84; H, 7.84; N, 8.73.
Synthesis 2005, No. 16, 2673–2676 © Thieme Stuttgart · New York

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K. Kobayashi et al.
PAPER
Rohrer, S. P.; Schaeffer, J. M.; Rohdes, L.; Drisko, J. E.;
3-(1-Acetylamino-1-phenylmethyl)-1,6-dimethylquinolin-
2(1H)-one (4e)
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Yield: 83%; white solid; mp 156–158 °C (hexane–CH2Cl2).
IR (KBr): 3304, 1651 cm–1.
1H NMR: d = 2.09 (3 H, s), 2.44 (3 H, s), 3.68 (3 H, s), 6.27 (1 H, d,
J = 9.2 Hz), 7.21 (1 H, t, J = 7.3 Hz), 7.25–7.30 (3 H, m), 7.35–7.42
(4 H, m), 7.80 (1 H, s), 7.84 (1 H, br d, J = 9.2 Hz).
MS: m/z (%) = 277 (56, [(M – Ac)+]), 248 (100).
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C,
74.88; H, 6.48; N, 8.84.
3-(1-Acetylamino-1-phenylmethyl)-6-chloro-1-methylquinolin-
2(1H)-one (4f)
Yield: 82%; pale-yellow solid; mp 226–227 °C (hexane–CH2Cl2).
IR (KBr): 3296, 1653, 1628 cm–1.
1H NMR: d = 2.09 (3 H, s), 3.67 (3 H, s), 6.28 (1 H, d, J = 9.2 Hz),
7.21–7.32 (4 H, m), 7.35 (2 H, d, J = 7.8 Hz), 7.52 (1 H, dd, J = 8.7,
2.3 Hz), 7.60 (1 H, d, J = 2.3 Hz), 7.64 (1 H, br d, J = 9.2 Hz), 7.77
(1 H, s).
MS: m/z (%) = 340 (2.5, [M+]), 297 (100).
Anal. Calcd for C19H17ClN2O2: C, 66.96; H, 5.03; N, 8.22. Found:
C, 67.00; H, 5.05; N, 8.13.
(2) See, e.g.: (a) Asherson, J. L.; Young, D. W. J. Chem. Soc.,
Chem. Commun. 1977, 916. (b) Jha, I. S.; Kanth, A. K.;
Singh, L. Orient. J. Chem. 1998, 14, 489; Chem. Abstr.
1999, 130, 281972h.
(3) (a) Hiyama, T.; Kobayashi, K. Tetrahedron Lett. 1982, 23,
1597. (b) Kobayashi, K.; Suginome, H. Bull. Chem. Soc.
Jpn. 1986, 59, 2635. (c) Hiyama, T.; Kobayashi, K.;
Nishide, K. Bull. Chem. Soc. Jpn. 1987, 60, 2127.
3-[1-Acetylamino-1-(pyridin-2-yl)methyl]-6-chloro-1-methyl-
quinolin-2(1H)-one (4g)
6-Chloro-1-methyl-3,4-dihydroquinolin-2(1H)-one (1c; 0.19 g,
0.96 mmol) was allowed to react with pyridine-2-carbonitrile (0.10
g, 0.98 mmol) and worked up in a manner similar to that described
for the reaction of 1-methyl-3,4-dihydroquinolin-2(1H)-one (1a)
with benzonitrile. The crude mixture was treated with Ac2O–pyri-
dine at 60 °C as described for the preparation of 3a. Purification of
the reaction mixture by preparative TLC on SiO2 (hexane–THF,
2:3) gave directly 4g; pale-yellow solid; yield: 0.21 g (65%); mp
202–205 °C (hexane–CH2Cl2).
(d) Kobayashi, K.; Kanno, Y.; Seko, S.; Suginome, H. J.
Chem. Soc., Chem. Commun. 1992, 780.
(4) Kobayashi, K.; Kitamura, T.; Nakahashi, R.; Shimizu, A.;
Morikawa, O.; Konishi, H. Heterocycles 2000, 53, 1021.
(5) For other recent reports from our laboratory on the
heterocycle synthesis utilizing magnesium enolates, see:
(a) Kobayashi, K.; Takabatake, H.; Kitamura, T.; Morikawa,
O.; Konishi, H. Bull. Chem. Soc. Jpn. 1997, 70, 1697.
(b) Kobayashi, K.; Nakahashi, R.; Shimizu, A.; Kitamura,
T.; Morikawa, O.; Konishi, H. J. Chem. Soc., Perkin Trans.
1 1999, 1747. (c) Kobayashi, K.; Matoba, T.; Irisawa, S.;
Takanohashi, A.; Tanmatsu, M.; Morikawa, O.; Konishi, H.
Bull. Chem. Soc. Jpn. 2000, 73, 2805. (d) Kobayashi, K.;
Nakashima, T.; Mano, M.; Morikawa, O.; Konishi, H. Chem.
Lett. 2001, 602. (e) Kobayashi, K.; Nakahashi, R.; Mano,
M.; Morikawa, O.; Konishi, H. Bull. Chem. Soc. Jpn. 2003,
76, 1257. (f) Kobayashi, K.; Honma, K.; Kondo, S.;
Morikawa, O.; Konishi, H. Heterocycles 2005, 65, 619; and
references cited therein.
IR (KBr): 3352, 1643, 1622 cm–1.
1H NMR: d = 2.13 (3 H, s), 3.65 (3 H, s), 6.36 (1 H, d, J = 7.8 Hz),
7.16 (1 H, ddd, J = 7.3, 4.1, 0.9 Hz), 7.25 (1 H, d, J = 8.7 Hz), 7.48
(1 H, dd, J = 8.7, 2.3 Hz), 7.58–7.61 (2 H, m), 7.65 (1 H, td, J = 7.8,
1.8 Hz), 7.70 (1 H, br d, J = 7.8 Hz), 7.82 (1 H, s), 8.49 (1 H, d,
J = 4.1 Hz).
MS: m/z (%) = 341 (12, [M+]), 298 (100).
Anal. Calcd for C18H16ClN3O2: C, 63.25; H, 4.72; N, 12.29. Found:
C, 62.96; H, 4.70; N, 12.18.
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research (C) 15550092 from Japan Society for the Promotion of
Science.
(6) 2,3-Dihydroquinolin-2(1H)-one was commercially
available and the others were prepared by the procedure
reported in the following paper: Guaruna, A.; Machetti, F.;
Occhiato, E. G.; Scarpi, D. J. Med. Chem. 2000, 43, 3718.
(7) Morfat, A.; Carta, M. Synthesis 1987, 515.
References
(1) (a) DeVita, R. J.; Walsh, T. F.; Young, J. R.; Jiang, J.;
Ujjainwalla, F.; Toupence, R. B.; Parikh, M.; Huang, S. X.;
Fair, J. A.; Goulet, M. T.; Wyvratt, M. J.; Lo, J.-L.; Ren, N.;
Yudkovitz, J. B.; Yang, Y. T.; Cheng, K.; Cui, J.; Mount, G.;
(8) Venkov, A. P.; Statkova-Abeghe, S. M. Tetrahedron 1996,
52, 1451.
Synthesis 2005, No. 16, 2673–2676 © Thieme Stuttgart · New York