New synthesis of 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones

Article abstract of DOI:10.1016/j.jfluchem.2004.01.009

N-(1-Ethoxy-2,2,2-trifluoroethyl)anilines 2a-2f, prepared from trifluoroacetaldehyde ethyl hemiacetal and aniline, readily reacted with diethyl malonate in the presence of sodium hydride, giving substituted products 5a-5f in high yields. Compounds 5a-5f s

Full text of DOI:10.1016/j.jfluchem.2004.01.009

Journal of Fluorine Chemistry 125 (2004) 767–773
New synthesis of 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones
Yuefa Gonga, Katsuya Katob,*
aDepartment of Chemistry, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
bNational Institute of Advanced Industrial Science and Technology (AIST), Anagohara, Shimoshidami, Moriya-ku, 2266-98 Nagoya, Japan
Received 8 December 2003; received in revised form 7 January 2004; accepted 9 January 2004
Available online 28 February 2004
Abstract
N-(1-Ethoxy-2,2,2-trifluoroethyl)anilines 2a–2f, prepared from trifluoroacetaldehyde ethyl hemiacetal and aniline, readily reacted with
diethyl malonate in the presence of sodium hydride, giving substituted products 5a–5f in high yields. Compounds 5a–5f subjected to
hydrolysis and decarboxylation under specified conditions yielded the 4,4,4-trifluorobutyric acids 6a–6e or 7. Direct ring-closure of 6a–6e
with polyphosphoric acid gave 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones 9a–9e.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Quinolinone; Trifluoroacetaldehyde; Ring-closure; 3-Anilino-4,4,4-trifluorobutyric acid
1. Introduction
reaction of (1-ethoxy-2,2,2-trifluoroethyl)aniline (2b) with
a-bromocarboxylic ester readily occurred, except with ethyl
2-bromopropionate, the yield of b-trifluoromethyl b-anilino
ester was very low. Both the nucleophilic addition of 1 and
the nucleophilic substitution of 2a with diethyl malonate,
however, proceeded smoothly at room temperature, provid-
ing a high yield of the 2-(1-anilino-2,2,2-trifluoroethyl)ma-
lonic acid diethyl ester (4a) (Eq. (3)). We are concerned,
based on these observations, with establishing a useful
method for synthesizing fluorinated 2,3-dihydroquinolin-4-
one. We describe an approach to obtain 2,3-dihydro-2-tri-
fluoromethylquinolin-4-ones that uses six representative sub-
stituted anilines and trifluoroacetaldehyde ethyl hemiacetal
as the starting materials.
Preparation of fluorinated hetereocyclic compounds has
attracted much attention because selective substitution of
fluorine in bioactive organic compounds has characteristic
effects on their physical, chemical and biological properties
[1]. Of the hetereocyclic compounds, 4-quinolinones and
4-chloroquinolines are very useful intermediates in the
synthesis of the highly active 4-aminoquinoline groups of
antimalarial drugs [2]. Trifluoromethylated quinolines and
2- or 4-quinolinones have been synthesized to clarify the
effects of fluorine substitution [3]. The main synthesis routes
involve the reaction of anilines with ethyl 4,4,4-trifluoroa-
cetoacetate or trifluoromethyl ketones and that of fluorinated
anilines with ketones or ethyl acetoacetate [4]. Preparation
of 2,3-dihydroquinilin-4-one, first done in 1946, through
ring-closure of b-anilinopropionic acid [5] was modified by
Koo [6]. 2,3-Dihydro-4-quinolinone has recently been
shown to be an important intermediate in the preparation
of some nonsteroidal androgen receptor agonists [7], diure-
tic compounds [8], and martinellines with antibacterial
activity [9]. To our knowledge, there has been no report
on the preparation of fluorinated 2,3-dihydroquinolin-4-one,
2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-one.
2. Results and discussion
As reported in the literature [11], imine 1 and N,O-
disubstituted aminal 2a were generated competitively when
equivalent amounts of 4-anisidine and trifluoroacetaldehyde
ethyl hemiacetal (TFAE) were refluxed in toluene in the
presence of a catalytic amount of p-toluenesulfonic acid
(Scheme 1, Eq. (1)). The (1-ethoxy-2,2,2-trifluoroethyl)a-
nilines 2a–2f were, however, readily obtained with dry
ethanol as the solvent (Scheme 1, Eq. (4)). Results are given
in Table 1 (entries 1–6). The reaction of 2a with diethyl
malonate and sodium hydride proceeded smoothly in dry
toluene at room temperature, producing 2-substituted malo-
nic acid diethyl ester 4a in high yield (Scheme 1, Eq. (3),
Previously, we reported a method for preparing b-trifluoro-
methyl b-anilino esters via the Reformastky reaction of
a-trifluoromethyl imine 1 (Scheme 1) [10]. Although the
* Corresponding author. Tel.: þ81-52-736-7275; fax: þ81-52-736-7405.
E-mail address: katsuya-kato@aist.go.jp (K. Kato).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.01.009

768
Y. Gong, K. Kato / Journal of Fluorine Chemistry 125 (2004) 767–773
NHCH(CF3)CH(CH3)CO2H
NHCH(CF3)CH(CH3)CO2Et
1) NaOH (aq)
2) HCl (aq)
(1)
(2)
5 (83 %)
NHCH(CF3)CH(COOEt)2
X
CF3CH(OH)CH2COOH
74 %
h
2
,
x
u
l
f
4
e
r
,
l
C
H
NaOH(aq)-EtOH,
o
.
c
n
reflux 2 h
C
F3C
(1) HCl (aq)
CO2H
NHCH(CF3)CH(COONa)2
(3)
(2) toluene, reflux, 2h
X
+
ArNH2
+
CH3O
HO2CCH2CH(CF3)
NHCH(CF3)CH2COOH
NHCH(CF3)CH2COOH
X
6
7
Scheme 1.
Table 2, entry 1). The corresponding reactions of 2b–2f
under the same conditions afforded products 4b–4f in high
yields (Table 2, entries 2–6).
by the direct addition of concentrated hydrochloric acid, and
the whole refluxed for 2 h. Product analysis clearly showed
the main products to be 4,4,4-trifluoro-3-hydroxybutyric acid
and 4-anisidine but not the simple decarboxylation product
4,4,4-trifluoro-3-(4-methoxyphenylamino)butyric acid (6a)
(Scheme 2, Eq. (2) and Table 3, entry 1). Decarboxylation
thereforewas investigatedunderalternative conditions(meth-
ods B and C). After the dicarboxylate sodium salt solution had
been neutralized with concentrated hydrochloric acid, the
mixture was extracted with ethyl acetate. The crude dicar-
boxylic acid obtained was refluxed in dry toluene for 2 h
(method B), producing a moderate yield of the target com-
pound 6a (entry 2), as well as certain amounts of 4,4,4-
trifluorobut-2-enoic acid and 4-anisidine (Eq. (3)). The yield
of 6a increased to some extent when hydrolysis and decar-
boxylation were done according to method (C) described in
the experimental section (entry 3). Under those conditions,
compounds 4b–4e were hydrolyzed and decarboxylated,
giving the corresponding butyric acids 6b–6e in 60–66%
yields (entries 4–7). Hydrolysis of 4f gave the corresponding
dicarboxylate sodium salt, but subsequent decarboxyla-
tion afforded complicated products, mainly the unexpected
Hydrolysis of ethyl 3-anilino-4,4,4-trifluoro-2-methylbu-
tyrate [10] went smoothly in aqueous sodium hydroxide
solution, and, after acidification with hydrochloric acid,
butyric acid 5 was obtained in 83% yield (Scheme 2,
Eq. (1)). Similarly, 2-(1-anilino-2,2,2-trifluoroethyl)malonic
acid diethyl ester (4a) was hydrolyzed in a solution of
aqueous sodium hydroxide and ethanol, and then the resulting
dicarboxylate sodium salt solution was acidified to pH 1–2
Table 1
Aniline reactions with TFAEa
Entry
Aniline
Solvent
Product (yield, %)b
1
2
3
4
5
6
4-Anisidine
Aniline
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2a (76)
2b (77)
2c (52)
2d (60)
2e (57)
2f (64)
4-Toludine
4-Bromoaniline
2-Toludine
3-Anisidine
a ArNH2 (10 mmol), TFAE (10 mmol), and TsOH (0.1 g); reflux 3 h.
b Yields isolated.
Table 3
Hydrolysis and decarboxylation of malonates 4a–4f
Table 2
Reaction of 2a–2f with diethyl malonate in toluenea
Entry
Substrate
Method
Product (yield, %)a
Entry
Substrate
Conditions
Product (yield, %)b
1
2
3
4
5
6
7
8
4a
4a
4a
4b
4c
4d
4e
4f
(A)
(B)
(C)
(C)
(C)
(C)
(C)
(C)
6a (none)b
6a (47)
6a (66)
6b (66)
6c (64)
6d (65)
6e (60)
7 (33)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
rt, 36 h
rt, 36 h
rt, 36 h
rt, 36 h
rt, 36 h
rt, 36 h
4a (96)
4b (89)
4c (95)
4d (90)
4e (94)
4f (88)
a Substrate 2 (10.0 mmol), diethyl malonate (10.5 mmol), and NaH
(11.0 mmol).
b Yields isolated.
a Yields isolated.
b 4,4,4-Trifluoro-3-hydroxybutyric acid and 4-anisidine were formed.

Y. Gong, K. Kato / Journal of Fluorine Chemistry 125 (2004) 767–773
769
NH2
N=CHCF3
TsOH
NHCH(OEt)CF3
CF3CH(OH)OEt
+
+
(1)
CH3O
CH3O
CH3O
Toluene, reflux
2a
1
N=CHCF3
NHCH(CF3)CH(R)CO2Et
Toluene, reflux
BrZnCH(R)CO2Et
(2)
(3)
+
CH3O
CH3O
CH3O
1
3
NHCH(OEt)CF3
NHCH(CF3)CH(COOEt)2
NaH/Toluene
rt, 36 h
+
CH2(COOEt)2
CH3O
2a
4a
NHCH(OEt)CF3
NH2
TsOH
X
EtOH, reflux
X
+
CF3CH(OH)OEt
(4)
2
X = a: 4-MeO; b: H; c: 4-Me; d: 4-Br; e: 2-Me; f: 3-MeO
Scheme 2.
product 7 (entry 8). This indicates that a further substitution
reaction readily occurred between the butyric acid 6f and
the 4,4,4-trifluorobut-2-enoic acid generated in situ during
decarboxylation.
a-Alkylation of 9b with bromoacetonitrile in THF pre-
dominantly gave the dialkylated product 10 (Scheme 4,
Eq. (4)).
Based on these findings, we speculated that dicarboxylic
acid decomposition occurs through two pathways via the
six-member transition states outlined in Scheme 3. In acidic
aqueous solution, concerted decarboxylation and dearyla-
mination (path b) is the preferred route, whereas in toluene
simple decarboxylation (path a) is more important.
Cyclization of malonate 4a and butyric acids 5 and 6a–6e
was done by the general method. Treatment of 4a with an
excess of polyphophoric acid at 130 8C for 2 h produced the
dearylamination product, diethyl 2-(2,2,2-trifluoroethylide-
ne)malonate in good yield (Scheme 4, Eq. (1)). In contrast,
treatment of 5 and 6a–6d with an excess of polyphophoric
acid at 130 8C for a short period gave 2-trifluoromethyl-2,3-
dihydroquinolin-4-ones 8 and 9a–9d in fair to good yields
(Scheme 4, Eqs. (2) and (3), and Table 4, entries 1–5). Under
the same conditions, treatment of the 4,4,4-trifluoro-3-o-
tolylaminobutyric acid (6e) gave only a small amount of the
2,3-dihydroquinolin-4-one 9e (entry 6).
(H3PO4)n
130 oC, 2 h
4a
5
CF3CH=C(COOEt)2
64 %
(1)
(2)
O
(H3PO4)n
CH3
120 C, 30 min
N
H
CF3
8
O
(H3PO4)n
(3)
X
6
120 oC, 30 min
N
H
CF3
9
O
O
CH2CN
NaH, BrCH2CN
Toluene, rt
CH2CN
CF3
(4)
N
H
CF3
N
H
10 (37 %)
9b
Scheme 4.
HO
O
H
O
CF3
Table 4
Formation of 2,3-dihydro-4-quinolinones 8 and 9a–9ea
CO2H
CF3
NHAr
Entry
Substrate
Conditions
Product (yield, %)b
CO2H
CO2H
NHAr
O
CF3
1
2
3
4
5
6
5
120 8C, 30 min
120 8C, 30 min
120 8C, 30 min
120 8C, 30 min
120 8C, 30 min
120 8C, 30 min
8 (71)
6a
6b
6c
6d
6e
9a (56)
9b (62)
9c (48)
9d (73)
9e (8)
CO2H
CF3
NHAr
CO2H
CF3
Ar
O
+
NH
O
H
ArNH2
a Substrate (2.0 mmol) and poly-H3PO4 (5.0 g).
b Yields isolated.
Scheme 3.

770
Y. Gong, K. Kato / Journal of Fluorine Chemistry 125 (2004) 767–773
In summary, ring-closure of 3-anilino-4,4,4-trifluorobu-
(76), 200 (100), 182 (71), 155 (52), 121 (67), 93 (55), 76
(68). HRMS. Calcd: 296.9976. Found: 296.9975.
tyric acids in the presence of polyphosphric acid was an
efficient route in preparing 2-trifluoromethyl-2,3-dihydro-
1H-quinolin-4-ones.
3.1.3. (1-Ethoxy-2,2,2-trifluoroethyl)-o-tolylamine (2e)
1
A colorless oil. H NMR (CDCl3) d 7.15 (2H, m), 6.80
(2H, m), 5.07 (1H, dq, J ¼ 10:1 and 4.7 Hz), 4.09 (1H, d,
J ¼ 10:1 Hz), 3.77 (1H, q, J ¼ 7:0 Hz), 3.74 (1H, q,
J ¼ 7:0 Hz), 2.21 (3H, s), 1.21 (3H, t, J ¼ 7:0 Hz). 19F
NMR (CDCl3) d 81.50 (3F, d, J ¼ 4:7 Hz). MS m/z (%)
233 (Mþ, 14), 187 (37), 164 (4), 136 (13), 118 (65), 107
(100), 91 (78). HRMS. Calcd: 233.1027. Found: 233.1027.
3. Experimental
All the starting materials were obtained commercially
˚
and used without purification. Toluene was dried over 4 A
molecular sieves. H NMR spectra, with tetramethylsilane
1
(TMS) as the internal standard, were recorded at 90 MHz
with a Hitachi R-90H FT spectrometer and at 299.95 MHz
with a Varian INOVA-300 FT spectrometer. 19F NMR
spectra were recorded at 84.7 and 282.22 MHz, respectively,
by the same spectrometers with hexafluorobenzene as the
internal standard. Mass spectra (70 eV) were measured
with a Shimadzu QP-5000 spectrometer, high-resolution
mass spectra with a JEOL JMS-SX102A MS spectrometer.
Melting points, measured in glass capillary tubes on a
heating block, were uncorrected.
3.1.4. (1-Ethoxy-2,2,2-trifluoroethyl)-
(3-methoxyphenyl)amine (2f)
A colorless oil. 1H NMR (CDCl3) d 7.13 (1H, t,
J ¼ 8:2 Hz), 6.42 (1H, d, J ¼ 8:2 Hz), 6.34 (1H, d,
J ¼ 8:2 Hz), 6.31 (1H, s), 5.04 (1H, dq, J ¼ 10:1 and
4.8 Hz), 4.21 (1H, d, J ¼ 10:1 Hz), 3.77 (3H, s), 3.69
(1H, q, J ¼ 7:0 Hz), 3.66 (1H, q, J ¼ 7:0 Hz), 1.21 (3H,
t, J ¼ 7:0 Hz). 19F NMR (CDCl3) d 81.53 (3F, d,
J ¼ 4:8 Hz). MS m/z (%) 249 (Mþ, 18), 204 (31), 203
(26), 180 (11), 152 (27), 134 (51), 123 (100), 92 (35), 77
(52). HRMS. Calcd: 249.0977. Found: 249.0977.
3.1. Typical procedure for the preparation of
(1-ethoxy-2,2,2-trifluoroethyl)amines 2a–2f
3.2. Typical procedure for the preparation of
2-[2,2,2-trifluoro-(1-phenylamino)ethyl] malonic
acid diethyl esters 4a–4f
A solution of 1.23 g (0.010 mol) of 4-anisidine, 1.44 g
(0.010 mol) of trifluoroacetaldehyde ethyl hemiacetal, and
0.10 g of 4-toluenesulfonic acid in ethanol (15 ml) was heated
for 3 h at 90 8C under continuous stirring. After the solution
cooled, the solvent was removed under reduced pressure. The
residue was purified on a silica gel column with hexane:ethyl
acetate (8:1, v/v) as the elution agent, giving a colorless oil in
76% yield (1.89 g). For 2a spectral data see [10].
The same procedure was used for the corresponding
reactions of the other substituted anilines, the product 2b
from aniline was obtained in 77% yield (1.69 g) as colorless
oil. For its spectral data see [10].
A solution of 1.76 g (0.011 mol) of diethyl malonate in
toluene (10 ml) was dropped at 0–5 8C for 30 min into a dis-
persion of 0.44 g (60% in oil, 0.011 mol) of sodium hydride
in dry toluene (25 ml), after which 2.49 g (0.010 mol) of
(1-ethoxy-2,2,2-trifluoroethyl)-(4-methoxyphenyl)amine 2a
was added, and the mixture stirred vigorously at room tem-
perature for 36 h. After the reaction was complete, 20 ml of
distilled water was added, and the mixture neutralized with
dilute hydrochloric acid. The organiclayer was separated, and
the aqueous layer extracted twice with ethyl acetate. The
organic layers were combined and dried over magnesium
sulfate, evaporation yielding an oily residue. This residue was
purified by silica gel column chromatography with hexa-
ne:ethyl acetate as the elution agent (6:1, v/v), giving
3.45 g (96%) of the malonate 4a, as a colorless oil.
3.1.1. (1-Ethoxy-2,2,2-trifluoroethyl)-p-tolylamine (2c)
A colorless oil. 1H NMR (CDCl3) d 7.03 (2H, d,
J ¼ 8:4 Hz), 6.65 (2H, d, J ¼ 8:4 Hz), 5.00 (1H, dq,
J ¼ 10:1 and 4.8 Hz), 4.07 (1H, d, J ¼ 10:1 Hz), 3.69
(1H, q, J ¼ 7:0 Hz), 3.66 (1H, q, J ¼ 7:0 Hz), 2.25 (3H,
s), 1.18 (3H, t, J ¼ 7:0 Hz). 19F NMR (CDCl3) d 81.56 (3F,
d, J ¼ 4:8 Hz). MS m/z (%) 233 (Mþ, 4), 187 (39), 164 (4),
136 (6), 118 (60), 107 (78), 91 (100). HRMS. Calcd:
233.1027. Found: 233.1027.
The same procedure was used for the corresponding
reactions of the other N,O-disubstituted hemiaminals 2b–2f.
3.2.1. 2-(2,2,2-Trifluoro-1-p-tolylaminoethyl)malonic
acid diethyl ester (4c)
3.1.2. (4-Bromophenyl)-(1-ethoxy-2,2,2-
Colorless plates, mp 57.5–59 8C. 1H NMR (CDCl3) d 7.00
(2H, d, J ¼ 8:1 Hz), 6.64 (2H, d, J ¼ 8:1 Hz), 4.82(1H, br, s),
4.68 (1H, m), 4.22 (2H, q, J ¼ 7:0 Hz), 4.12 (2H, q, J ¼
7:0 Hz), 3.82 (1H, d, J ¼ 3:7 Hz), 2.23 (3H, s), 1.27 (3H, t,
J ¼ 7:0 Hz), 1.14 (3H, t, J ¼ 7:0 Hz). 19F NMR (CDCl3) d
87.74(3F, d, J ¼ 6:8 Hz). MSm/z (%) 347(Mþ, 20), 278(19),
188 (100), 167 (22), 160 (58), 118 (91), 107 (57), 106 (64), 91
(98), 77 (66). HRMS. Calcd: 347.1344. Found: 347.1343.
trifluoroethyl)amine (2d)
A colorless oil. 1H NMR (CDCl3) d 7.32 (2H, d,
J ¼ 8:8 Hz), 6.64 (2H, d, J ¼ 8:8 Hz), 4.98 (1H, dq,
J ¼ 10:0 and 4.7 Hz), 4.21 (1H, d, J ¼ 10:0 Hz), 3.70
(1H, q, J ¼ 7:0 Hz), 3.67 (1H, q, J ¼ 7:0 Hz), 1.20 (3H,
t, J ¼ 7:0 Hz). 19F NMR (CDCl3) d 81.65 (3F, d,
J ¼ 4:7 Hz). MS m/z (%) 297 (Mþ, 43), 252 (57), 228

Y. Gong, K. Kato / Journal of Fluorine Chemistry 125 (2004) 767–773
771
3.2.2. 2-[1-(4-Bromophenylamino)-2,2,2-
3.4. Preparation of 4,4,4-trifluoro-3-(phenylamino)butyric
acids 6a–6e
trifluoroethyl]malonic acid diethyl ester (4d)
A colorless oil. 1H NMR (CDCl3) d 7.28 (2H, d,
J ¼ 8:7 Hz), 6.61 (2H, d, J ¼ 8:7 Hz), 5.17 (1H, d,
J ¼ 10:1 Hz), 4.68 (1H, m), 4.68 (1H, m), 4.26 (2H,
q, J ¼ 7:0 Hz), 4.14 (2H, q, J ¼ 7:0 Hz), 3.84 (1H, d,
J ¼ 4:0 Hz), 1.28 (3H, t, J ¼ 7:0 Hz), 1.15 (3H, t,
J ¼ 6:8 Hz). MS m/z (%) 411 (Mþ, 25), 342 (17), 252
(72), 224 (53), 195 (55), 182 (75), 171 (70), 167 (84),
145 (49), 123 (80), 115 (90), 91 (100). HRMS. Calcd:
411.0293. Found: 411.0291.
Method (A): a mixture of 4a (1.82 g, 5.0 mmol), 2N
aqueous solution of sodium hydroxide (15 ml), and ethanol
(10 ml) was refluxed for 2 h. When cool, the mixture was
acidified to pH 1 with concentrated hydrochloric acid, then
refluxed for 2 h. The work-up was done as usual, and the
products obtained were 3-hydroxy-4,4,4-trifluorobutyric
acid and 4-anisidine rather than the target compound 6a.
Method (B): the procedure for the saponification of 4a
was used. When cool, the mixture was neutralized to pH 3–4,
then extracted with ethyl acetate. The organic layer was
dried over sodium sulfate, evaporated under reduced pres-
sure, and the residue mixed with dry toluene (15 ml). That
mixture was refluxed for 1 h under continuous stirring, and
the solvent removed under reduced pressure. The residue,
separated by column chromatography (hexane:ethyl acetate,
4:1), gave 0.62 g (47%) of 6a, as colorless needles.
Method (C): a mixture of 4a (1.82 g, 0.005 mol) and a
solution of 2.0 g (0.050 mol) of sodium hydroxide in 4 ml of
distilled water and 20 ml of ethanol was stirred at room
temperature for 24 h. The solvent was removed carefully
under reduced pressure, leaving a white solid which was
transferred to a Bucher funnel and washed twice with ether.
The residue was dissolved in 10 ml of distilled water,
neutralized to pH 4 with a 6N aqueous solution of hydro-
chloric acid, then extracted with ethyl acetate. Subsequent
procedures were the same as in method (B). Finally, 0.87 g
(66%) of 6a was collected.
J ¼ 7:0 Hz). 19F NMR (CDCl3)
d 87.74 (3F, d,
3.2.3. 2-(2,2,2-Trifluoro-1-o-tolylaminoethyl)malonic
acid diethyl ester (4e)
1
A colorless oil. H NMR (CDCl3) d 7.10 (2H, m), 6.74
(2H, m), 5.22 (1H, d, J ¼ 9:9 Hz), 4.80 (1H, m), 4.27 (2H, q,
J ¼ 7:2 Hz), 4.08 (2H, q, J ¼ 7:2 Hz), 3.88 (1H, d,
J ¼ 3:7 Hz), 2.19 (3H, s), 1.29 (3H, t, J ¼ 7:2 Hz), 1.08
(3H, t, J ¼ 7:2 Hz). 19F NMR (CDCl3) d 87.65 (3F, d,
J ¼ 6:9 Hz). MS m/z (%) 347 (Mþ, 17), 278 (23), 195
(15), 188 (73), 167 (39), 160 (49), 148 (13), 130 (23),
118 (92), 107 (83), 106 (100), 91 (96), 77 (71). HRMS.
Calcd: 347.1344. Found: 347.1344.
3.2.4. 2-[2,2,2-Trifluoro-1-(3-methoxyphenylaminoethyl)]
malonic acid diethyl ester (4f)
A colorless oil. 1H NMR (CDCl3) d 7.08 (1H, t,
J ¼ 8:2 Hz), 6.33 (2H, d, J ¼ 8:2 Hz), 6.29 (1H, s), 5.08
(1H, d, J ¼ 10:3 Hz), 4.76 (1H, m), 4.25 (2H, q,
J ¼ 7:2 Hz), 4.13 (2H, q, J ¼ 7:2 Hz), 3.84 (1H, d,
J ¼ 4:4 Hz), 3.76 (3H, s), 1.27 (3H, t, J ¼ 7:2 Hz), 1.14
(3H, t, J ¼ 7:2 Hz). 19F NMR (CDCl3) d 87.77 (3F, d,
J ¼ 6:7 Hz). MS m/z (%) 363 (Mþ, 23), 294 (23), 244
(13), 204 (100), 195 (15), 176 (55), 167 (25), 134 (70),
123 (68), 107 (49), 95 (40), 77 (76). HRMS. Calcd:
363.1294. Found: 363.1291.
3.4.1. 4,4,4-Trifluoro-3-(4-methoxyphenylamino)butyric
acid (6a)
Colorless needles, mp 81–84 8C. 1H NMR (CDCl3) d 6.72
(4H, s), 4.82 (2H, br, s), 4.40 (1H, m), 3.74 (3H, s), 2.78 (1H,
d, J ¼ 5:3 Hz), 2.68 (1H, d, J ¼ 8:8 Hz). 19F NMR (CDCl3)
d 85.90 (3F, d, J ¼ 7:0 Hz). MS m/z (%) 263 (Mþ, 40), 219
(14), 204 (16), 194 (20), 148 (19), 123 (62), 108 (100).
HRMS. Calcd: 263.0769. Found: 263.0769.
3.3. Preparation of 4,4,4-trifluoro-2-methyl-3-
phenylaminobutyric acid (5)
3.4.2. 4,4,4-Trifluoro-3-phenylaminobutyric acid (6b)
Colorless needles, mp 90–91 8C. 1H NMR (CDCl3) d 7.26
(2H, m), 6.74 83H, m), 4.42 (1H, m), 4.02 (2H, br, s), 2.77
(1H, d, J ¼ 4:8 Hz), 2.67 (1H, d, J ¼ 8:8 Hz). 19F NMR
(CDCl3) d 85.81 (3F, d, J ¼ 6:6 Hz). MS m/z (%) 233
(Mþ, 74), 174 (11), 164 (41), 104 (35), 93 (100). HRMS.
Calcd: 233.0664. Found: 233.0664.
A mixture of 2.75 g (0.010 mol) of ethyl 4,4,4-trifluoro-2-
methyl-3-phenylamino-butyrate, 2N aqueous solution of
sodium hydroxide (15 ml) and 95% of ethanol (10 ml)
was heated at 90 8C for 2 h under continuous stirring. When
cool, the mixture was neutralized with concentrated hydro-
chloric acid, and extracted with ethyl acetate. The organic
layer was dried over sodium sulfate, and evaporated under
reduced pressure. The residue was purified on a silica gel
column (hexane:ethyl acetate, 4:1), giving 2.05 g (83%) of
product 5, as a yellowish oil. 1H NMR (CDCl3) d 7.26 (2H,
m), 6.78 (3H, m), 4.91 (2H, br, s), 4.59 (1H, dq, J ¼ 7:0 and
5.8 Hz), 3.00 (1H, dq, J ¼ 7:0 and 5.3 Hz), 1.33 (3H, d,
J ¼ 7:0 Hz). 19F NMR (CDCl3) d 88.65 (3F, d, J ¼ 7:0 Hz).
MS m/z (%) 247 (Mþ, 52), 178 (32), 174 (100), 132 (41), 104
(64), 93 (30). HRMS. Calcd: 247.0820. Found: 247.0820.
3.4.3. 4,4,4-Trifluoro-3-p-tolylaminobutyric acid (6c)
Colorless needles, mp 83–84 8C. 1H NMR (acetone-d6) d
6.92 (2H, d, J ¼ 8:2 Hz), 6.71 (2H, d, J ¼ 8:2 Hz), 5.15
(1H, br, s), 4.58 (1H, m), 2.83 (1H, d, J ¼ 4:6 Hz), 2.73 (1H,
d, J ¼ 8:6 Hz), 2.18 (3H, s). 19F NMR (acetone-d6) d 88.21
(3F, d, J ¼ 6:7 Hz). MS m/z (%) 247 (Mþ, 19), 188 (13), 178
(32), 132 (22), 118 (100), 91 (55), 77 (36). HRMS. Calcd:
247.0820. Found: 247.0819.

772
Y. Gong, K. Kato / Journal of Fluorine Chemistry 125 (2004) 767–773
3.4.4. 3-(4-Bromophenylamino)-4,4,4-trifluorobutyric
acid (6d)
and 7.4 Hz), 6.80 (1H, dd, J ¼ 7:7 and 7.4 Hz), 6.72 (1H, d,
J ¼ 8:1 Hz), 4.75 (1H, br, s), 3.78 (1H, m), 2.89 (1H, m),
1.40 (3H, d, J ¼ 7:3 Hz). 19F NMR (CDCl3) d 86.28 (3F, d,
J ¼ 7:0 Hz). MS m/z (%) 229 (Mþ, 58), 160 (100), 132 (30),
119 (25), 92 (30). Anal. Calcd for C11H10F3NO: C, 57.64; H,
4.40; N, 6.11. Found: C, 57.58; H, 4.39; N, 6.02.
Colorless needles, mp 146–147 8C. 1H NMR (acetone-d6)
d 7.28 (2H, d, J ¼ 8:5 Hz), 6.80 (2H, d, J ¼ 8:5 Hz), 5.59
(1H, d, J ¼ 9:0 Hz), 4.63 (1H, m), 2.84 (1H, d, J ¼ 2:6 Hz),
2.76 (1H, d, J ¼ 9:4 Hz), 2.18 (3H, s). 19F NMR (acetone-
d6) d 88.12 (3F, d, J ¼ 6:6 Hz). MS m/z (%) 311 (Mþ, 28),
252 (21), 242 (41), 224 (13), 182 (100), 155 (34), 145 (14),
117 (69), 91 (66). HRMS. Calcd: 310.9769. Found:
310.9767.
3.5.2. 2-Trifluoromethyl-6-methoxy-2,3-dihydro-1H-
quinolin-4-one (9a)
Yellowish plates, mp 149–151 8C. IR (KBr) nmax (cmꢀ1):
3310, 1655, 1630, 1589, 1497, 1425, 1389, 1280, 1177,
1
3.4.5. 4,4,4-Trifluoro-3-o-tolylaminobutyric acid (6e)
1
1123, 1036, 922, 862, 829, 702, 687. H NMR (CDCl3) d
A colorless oil. H NMR (CDCl3) d 7.12 (2H, m), 6.74
7.30 (1H, d, J ¼ 2:9 Hz), 7.04 (1H, dd, J ¼ 8:8 and 2.9 Hz),
6.70 (1H, d, J ¼ 8:8 Hz), 4.37 (1H, br, s), 4.09 (1H, m), 3.78
(3H, s), 2.89 (2H, d, J ¼ 8:1 Hz). 19F NMR (CDCl3) d 84.46
(3F, d, J ¼ 6:8 Hz). MS m/z (%) 245 (Mþ, 75), 176 (100),
160 (21), 133 (28), 123 (64), 108 (39), 69 (63). Anal. Calcd
for C11H10F3NO2: C, 53.88; H, 4.11; N, 5.71. Found: C,
53.83; H, 4.10; N, 5.68.
(2H, m), 5.60 (2H, br, s), 4.54 (1H, m), 2.84 (1H, d,
J ¼ 5:3 Hz), 2.76 (1H, d, J ¼ 8:1 Hz), 2.16 (3H, s). 19F
NMR (CDCl3) d 85.69 (3F, d, J ¼ 6:6 Hz). MS m/z (%)
247 (Mþ, 18), 188 (13), 178 (32), 132 (22), 118 (100), 106
(15), 91 (60), 77 (28). HRMS. Calcd: 247.0820. Found:
247.0819.
3.4.6. 3-[4-(1-Carboxymethyl-2,2,2-trifluoroethylamino)-
2-methoxyphenyl]-4,4,4-trifluoro-butyric acid (7)
Colorless needles, mp 169–172 8C. 1H NMR (acetone-d6)
d 7.12 (1H, d, J ¼ 9:0 Hz), 6.51 (1H, s), 6.45 (1H, d,
J ¼ 9:0 Hz), 5.56 (1H, d, J ¼ 9:5 Hz), 4.05–4.80 (2H,
m), 3.81 (3H, s), 2.91 (1H, d, J ¼ 7:4 Hz), 2.87 (1H, d,
J ¼ 8:8 Hz), 2.84 (1H, d, J ¼ 4:8 Hz), 2.76 (1H, d,
J ¼ 9:2 Hz). 19F NMR (acetone-d6) d 93.51 (3F, d,
J ¼ 9:8 Hz), 88.21 (3F, d, J ¼ 6:5 Hz). MS m/z (%) 403
(Mþ, 66), 344 (100), 334 (40), 298 (11), 292 (17), 284 (31),
274 (28), 204 (17). HRMS. Calcd: 403.0854. Found:
403.0854.
3.5.3. 2-Trifluoromethyl-2,3-dihydro-1H-quinolin-4-one
(9b)
Colorless plates, mp 146–148 8C. IR (KBr) nmax (cmꢀ1):
3308, 1663, 1616, 1281, 1250, 1161, 1136, 918, 764, 689. 1H
NMR (CDCl3) d 7.83 (1H, d, J ¼ 7:9 Hz), 7.38 (1H, dd,
J ¼ 8:3 and 7.7 Hz), 6.82 (1H, dd, J ¼ 7:9 and 7.7 Hz), 6.75
(1H, d, J ¼ 8:3 Hz), 4.62 (1H, br, s), 4.15 (1H, m, J ¼ 7:0
and 6.6 Hz), 2.92 (2H, d, J ¼ 7:0 Hz). 19F NMR (CDCl3) d
84.43 (3F, d, J ¼ 6:6 Hz). MS m/z (%) 215 (Mþ, 42), 146
(100), 118 (7), 92 (11). Anal. Calcd for C10H8F3NO: C,
55.82; H, 3.75; N, 6.51. Found: C, 55.79; H, 3.75; N, 6.46.
3.5.4. 2-Trifluoromethyl-6-methyl-2,3-dihydro-1H-
quinolin-4-one (9c)
3.5. Preparation of 2-trifluoromethyl-2,3-dihydro-1H-
quinolin-4-ones 8, 9a–9e
Yellowish plates, mp 171–172 8C. IR (KBr) nmax (cmꢀ1):
3308, 1663, 1626, 1516, 1456, 1283, 1177, 1124, 922, 827,
706, 689. 1H NMR (CDCl3) d 7.64 (1H, d, J ¼ 1:1 Hz), 7.21
(1H, dd, J ¼ 8:1 and 1.1 Hz), 6.66 (1H, d, J ¼ 8:1 Hz), 4.43
(1H, br, s), 4.13 (1H, m, J ¼ 6:8 Hz), 2.89 (2H, d,
J ¼ 6:8 Hz), 2.26 (3H, s). 19F NMR (CDCl3) d 84.34 (3F,
d, J ¼ 6:8 Hz). MS m/z (%) 229 (Mþ, 37), 202 (10), 160
(100), 141 (11), 132 (6), 130 (10), 104 (11), 91 (12), 77 (25),
69 (21). Anal. Calcd for C11H10F3NO: C, 57.64; H, 4.40; N,
6.11. Found: C, 57.58; H, 4.38; N, 6.05.
A mixture of 0.50 g (0.002 mol) of acid 5 and 5.0 g of
polyphosphoric acid was heated in an oil bath with hand
stirring until the temperature reached 120 8C, after which it
was kept between 120 and 130 8C for 30 min. After being
cooled to 80 8C, the cherry-red mixture was poured
with stirring into 20 ml of ice-water, then extracted three
times with ethyl acetate. The organic layer was dried over
magnesium sulfate and evaporated under reduced pressure.
The residue was purified on a silica gel column, and
0.33 g (71%) of product 8 eluted with hexane:ethyl acetate
(4:1, v/v).
3.5.5. 6-Bromo-2-trifluoromethyl-2,3-dihydro-1H-
quinolin-4-one (9d)
Procedures for the cyclization of butyric acids 6a–6e were
used.
Yellowish plates, mp 164–165 8C. IR (KBr) nmax (cmꢀ1):
3337, 1655, 1620, 1558, 1508, 1339, 1271, 1188, 1126, 824.
1H NMR (CDCl3) d 7.93 (1H, d, J ¼ 1:5 Hz), 7.46 (1H, dd,
J ¼ 8:5 and 1.5 Hz), 6.66 (1H, d, J ¼ 8:5 Hz), 4.61 (1H, br,
s), 4.15 (1H, m), 2.89 (2H, d, J ¼ 6:7 Hz). 19F NMR
(CDCl3) d 84.46 (3F, d, J ¼ 6:6 Hz). MS m/z (%) 293
(Mþ, 46), 276 (28), 224 (100), 201 (22), 145 (59), 117
(72), 90 (53), 75 (55). Anal. Calcd for C10H7BrF3NO: C,
40.84; H, 2.40; N, 4.76. Found: C, 40.76; H, 2.41; N, 4.58.
3.5.1. 2-Trifluoromethyl-3-methyl-2,3-dihydro-1H-
quinolin-4-one (8)
Colorless plates, mp 83–85 8C. IR (KBr) nmax (cmꢀ1):
3310, 1666, 1612, 1587, 1526, 1485, 1443, 1377, 1340,
1263, 1234, 1209, 1126, 1041, 970, 860, 754, 689. 1H NMR
(CDCl3) d 7.82 (1H, d, J ¼ 7:7 Hz), 7.36 (1H, dd, J ¼ 8:1

Y. Gong, K. Kato / Journal of Fluorine Chemistry 125 (2004) 767–773
773
(c) W.T. Ashton, S.M. Hutchins, W.J. Greenlee, G.A. Doss, R.S.L.
Chang, J. Med. Chem. 36 (1993) 3595–3605;
(d) H. Li, I. Delucca, S. Drummond, G.A. Boswell, Heterocycle 43
(1996) 937–940;
3.5.6. 2-Trifluoromethyl-8-methyl-2,3-dihydro-1H-
quinolin-4-one (9e)
Yellowish plates, mp 104–106 8C. IR (KBr) nmax (cmꢀ1):
3383, 1668, 1605, 1508, 1456, 1338, 1273, 1242, 1171,
(e) Y. Hayakawa, H. Kimoto, L.A. Cohen, K.L. Kirk, J. Org. Chem.
63 (1998) 9448–9454;
1
1122, 1103, 968, 945, 794, 772, 741. H NMR (CDCl3) d
(f) M. Antolini, A. Bozzoli, C. Ghiron, G. Kennedy, Bioorg. Med.
Chem. Lett. 9 (1999) 1023–1028;
7.75 (1H, d, J ¼ 8:1 Hz), 7.28 (1H, d, J ¼ 7:5 Hz), 6.77
(1H, dd, J ¼ 8:1 and 7.5 Hz), 4.36 (1H, br, s), 4.19 (1H, m),
2.92 (2H, d, J ¼ 7:7 Hz), 2.21 (3H, s). 19F NMR (CDCl3) d
84.28 (3F, d, J ¼ 6:6 Hz). MS m/z (%) 229 (Mþ, 42), 160
(100), 130 (8), 117 (7), 104 (9), 91 (8), 69 (20). Anal. Calcd
for C11H10F3NO: C, 57.64; H, 4.40; N, 6.11. Found: C,
57.42; H, 4.36; N, 5.87.
(g) M. Medebielle, M.A. Oturan, J. Pinson, J. Saveant, J. Org. Chem.
61 (1996) 1331–1340;
(h) G.L. Grunewald, T.M. Caldwell, Q. Li, K.R. Criscione, J. Med.
Chem. 42 (1999) 3315–3323;
(i) G.L. Grunewald, T.M. Caldwell, Q. Li, M. Slavica, K.R.
Criscione, R.T. Borchart, W. Wang, J. Med. Chem. 42 (1999)
3588–3601.
[2] M.P. LaMontagne, P. Blumbergs, D.C. Smith, J. Med. Chem. 32
(1989) 1728–1732.
3.6. Synthesis of 3,3-dicyanomethyl-2-trifluoromethyl-2-
hydro-1H-quinolin-4-one (10)
[3] (a) E.R. Bissell, A.R. Mitchell, R.E. Smith, J. Org. Chem. 45 (1980)
2283–2287;
(b) J.G. Reid, J.M.R. Runge, Tetrahedron Lett. 31 (1990) 1093–
1096;
A solution of 1.08 g (0.005 mol) of 2-trifluoromethyl-2,3-
dihydro-1H-quinlin-one 9b in toluene (10 ml) was dropped
at 0–5 8C for 15 min into a dispersion of 0.20 g (60% in oil,
0.005 mol) of sodium hydride in dry THF (10 ml), after
which 0.76 g (0.006 mol) of bromoacetonitrile was added,
and the whole stirred at room temperature for 12 h. The
reaction was quenched by the addition of 15 ml of distilled
water. The mixture, worked-up as usual, gave 0.54 g (37%)
of product 10. Colorless needles, mp 170–171 8C. IR (KBr)
nmax (cmꢀ1): 3389, 2251, 1663, 1616, 1583, 1518, 1483,
1443, 1421, 1344, 1317, 1271, 1230, 1173, 1161, 1136,
1049, 941, 775, 746, 681. 1H NMR (acetone-d6) d 7.75 (1H,
d, J ¼ 7:9 Hz), 7.49 (1H, t, J ¼ 7:5 Hz), 7.02 (1H, d,
J ¼ 8:6 Hz), 6.86 (1H, t, J ¼ 7:5 Hz), 4.51 (1H, m), 3.35
(4H, s), 2.79 (1H, d, J ¼ 5:3 Hz). 19F NMR (acetone-d6) d
96.12 (3F, d, J ¼ 7:9 Hz). MS m/z (%) 293 (Mþ, 51), 224
(77), 214 (19), 197 (16), 184 (59), 119 (100), 92 (50). Anal.
Calcd for C14H10F3N3O: C, 57.34; H, 3.44; N, 14.33. Found:
C, 57.28; H, 3.41; N, 14.21.
(c) K.V. Komarov, N.D. Chkanikov, S.V. Sereda, M.Y. Antipin, Y.T.
Struchkov, Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.) 37
(1988) 1717–1719.
[4] (a) L. Strekowski, S.E. Patterson, L. Janda, R.L. Wydra, D.B.
Harden, J. Org. Chem. 57 (1992) 196–201;
(b) M. Schlosser, H. Keller, S. Sumida, J. Yang, Tetrahedron Lett. 38
(1997) 8523–8526;
(c) J. Chen, P.R. Selvin, J. Photochem. Photobiol. A: Chem. 135
(2000) 27–32.
[5] R.C. Elderfield, W.J. Gensler, T.H. Bembry, C.B. Kremer, F.
Brody, H.A. Hageman, J.D. Head, J. Am. Chem. Soc. 68 (1946)
1259–1262.
[6] (a) J. Koo, J. Org. Chem. 26 (1961) 2440–2442;
(b) J. Koo, J. Org. Chem. 28 (1963) 1134–1135.
[7] (a) R.I. Higuchi, J.P. Edwards, T.R. Caferro, J.D. Ringgenberg,
J.W. Kong, L.G. Hamann, L. Arienti, K.B. Marschke, R.L. Davis,
L.J. Farmer, T.K. Jones, Bioorg. Med. Chem. Lett. 9 (1999) 1335–
1340;
(b) Z. Lin, C.M. Tegley, K.B. Marschke, T.K. Jones, Bioorg. Med.
Chem. Lett. 9 (1999) 1009–1012.
[8] K. Nishijima, T. Shinkawa, Y. Yamashita, N. Sato, H. Nishida, K.
Kato, Y. Onuki, M. Mizota, K. Ohtomo, S. Miyano, Eur. J. Med.
Chem. 33 (1998) 267–277.
[9] (a) J.A. Nieman, M.D. Ennis, Org. Lett. 2 (2000) 1395–1397;
(b) J.A. Nieman, M.D. Ennis, J. Org. Chem. 66 (2001) 2175–
2177.
References
[10] Y. Gong, K. Kato, J. Fluorine Chem. 111 (2001) 77–80.
´ ´
[11] A. Abouabdellah, J.P. Begue, D. Bonnet-Delpon, T.T.T. Nga, J. Org.
[1] (a) B.E. Smart, J. Fluorine Chem. 109 (2001) 3–11;
(b) J.P. Edwards, S.J. West, C.L.F. Pooley, K.B. Marschke, L.J.
Farmer, T.K. Jones, Bioorg. Med. Chem. Lett. 8 (1998) 745–750;
Chem. 62 (1997) 8826–8833.