A versatile method for the synthesis of fluorine-containing chloroquine analogues starting from 7-chloro-4-(N,N-dimethylamino)quinoline using nucleophilic N-N, N-S, and N-O exchange reactions

Article abstract of DOI:10.3987/COM-13-12849

A new synthetic method was developed to access fluorine-containing chloroquine analogues which have unique potentials contributing to the discovery of novel anti-microorganisms. (7-Chloro-3-trifluoroacetylquinolin-4-yl)amines (7), thiols (8), and ethers (9) were easily synthesized in high yields by the trifluoroacetylation of 7-chloro-4-(N,N-dimethylamino)quinoline (6) with 1-trifluoroacetyl-4-dimethylaminopyridinium trifluoroacetate followed by the nucleophilic N-N, N-S, and N-O exchange reactions.

Full text of DOI:10.3987/COM-13-12849

HETEROCYCLES, Vol. 87, No. 12, 2013, pp. -. © The Japan Institute of Heterocyclic Chemistry
Received, 25th September, 2013, Accepted, 18th October, 2013, Published online, 30
DOI: 10.3987/COM-13-12849
A
VERSATILE
METHOD
FOR
THE
SYNTHESIS
OF
FLUORINE-CONTAINING CHLOROQUINE ANALOGUES STARTING
FROM 7-CHLORO-4-(N,N-DIMETHYLAMINO)QUINOLINE USING
NUCLEOPHILIC N-N, N-S, AND N-O EXCHANGE REACTIONS
Norio Ota, Mizuki Hatakenaka, Takuro Ashida, and Etsuji Okada*
Department of Chemical Science and Engineering, Graduate School of
Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
E-mail: okaetsu@kobe-u.ac.jp
Abstract – A new synthetic method was developed to access fluorine-containing
chloroquine analogues which have unique potentials contributing to the discovery
of novel anti-microorganisms. (7-Chloro-3-trifluoroacetylquinolin-4-yl)amines
(7), thiols (8), and ethers (9) were easily synthesized in high yields by the
trifluoroacetylation of 7-chloro-4-(N,N-dimethylamino)quinoline (6) with
1-trifluoroacetyl-4-dimethylaminopyridinium trifluoroacetate followed by the
nucleophilic N-N, N-S, and N-O exchange reactions.
During recent years, we can recognize that the new spread of malaria is one of the serious issues, and it is
widely known that an improvement of treatment effect is demanded for controlling the infection since
chloroquine which is the classical and standard therapeutic agent has lost effectiveness in a lot of cases
caused by the resistant strain such as Plasmodium falciparum.1 The continual studies on the
modification of 4- and 7-substituents of chloroquine are also addressed to find out new therapeutic agents
intently. In those studies, for instance, it is suggested that the structure for activity against
chloroquine-resistant Plasmodium falciparum demands the chlorine atom at the 7-position which is the
most suitable substituent based on the QSAR analyses.2 This result seems to be well compatible to the
investigation on the activity of chloroquine analogues, which shows that 7-chloro substituent could be
irreplaceable with the other substituent in so far as promising an antimalarial activity.3
Recently, a lot of methodologies have been reported for the syntheses of various kinds of
fluorine-containing heterocycles since these compounds are emphasized on the interest of their versatile

functionalization. Especially, the remarkable biological activities were found quite often in the field of
life science.4-7
In the course of our investigation on the nucleophilic substitutions at aromatic carbon activated by
trifluoroacetyl group, it was found that the N-N, N-S, and N-O exchange occurred by the reactions of
N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine (1) with amines, thiols, and alcohols,
respectively.8 It meant that the dimethylamino group which did not generally show the elimination
reactivity in aromatic systems acted as an excellent leaving group to conduct novel nucleophilic
substitutions enhanced by trifluoroacetyl group through its strong electron-withdrawing effect. We have
continued to explore the similar approaches and also reported with respect to the reaction of
N,N-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine
(2),
N,N-dimethyl-6,8-bis(trifluoroacetyl)-
5-quinolylamine (3), and N,N-dimethyl-3-trifluoroacetyl-4-quinolylamine (4) with various nucleophiles to
afford the corresponding N-N, N-S, and N-O exchanged quinolines.9-11
These situations strongly prompted us to begin a research on the application of these nucleophilic N-N,
N-S, and N-O exchange reactions to the syntheses of new fluorine-containing chloroquine analogues
which might have new characteristic features as a drug.
NMe2
COCF3
NMe2
COCF3
NMe2
COCF3
N
NMe2
COCF3
N
COCF3
COCF3
COCF3
N
1
2
3
4
Here we wish to report the synthesis of a new key intermediate 7-chloro-N,N-dimethyl-3-
trifluoroacetyl-4-quinolylamine (7a) which are keeping the chlorine atom at the 7-position as the essential
moiety to show drug efficacy, and its nucleophilic N-N, N-S, and N-O exchange reactions at 4-position
accessing fluorine-containing chloroquine analogues (7-9).
Firstly, we examined the trifluoroacetylation of 7-chloro-4-dimethylaminoquinoline (6) which was easily
afforded by the reaction of 4,7-dichloroquinoline (5) with dimethylamine (50% aqueous soln.) in
acetonitrile. In the step aimed at selective introduction of trifluoroacetyl group at 3-position, the
acylation using 1-trifluoroacetyl-4-dimethylaminopyridinium trifluoroacetate11,12 in refluxing xylene was
applied to 6 to afford the desired product (7a) in 76% yield (Scheme 1).

NMe2
N
CF3CO2 (3eq)
Cl
N
NMe2
N
NMe2
N
aq. Me2NH (5 eq)
COCF3
COCF3
50 oC, 48 h in MeCN
reflux, 18 h in Xylene
Cl
Cl
Cl
7a 76%
6
90%
5
Scheme 1
Secondly, we tried the aromatic nucleophilic N-N exchange reaction of 7a with amines to access novel
7-chloro-3-trifluoroacetylquinolin-4-amines (7b-i, Scheme 2, Table 1). Reaction of 7a with aq.
o
ammonia at 50 C for 18 h was performed to give the Me2N-NH2 exchanged product (7b) in 85% yield
(Entry 1). The N-N exchange reactions with simple aliphatic primary amines such as n-butyl-,
isopropyl-, and tert-butylamines were conducted to afford the corresponding N-N exchanged products
cleanly even though the reaction completion in the preparation of 7h demanded more severe conditions
NMe2
Nu
COCF3
COCF3
NuH (a eq)
Cl
N
Cl
N
7a
,
, ,
,
7b-i 8a b 9a b
Scheme 2
Table 1. Synthesis of N-N, N-S, and N-O exchanged quinolines (7b-i, 8a,b, 9a,b).
Entry
NuH
a (eq) Solvent
Temp (oC) Time (h) Product Yield (%)a
1
2
3
4
5
6
7
8
9
NH3
n-BuNH2
Me2N(CH2)3NH2
i-PrNH2
3b
1
1
3
1
1
3
3
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
xylene
xylene
50
rt
18
8
8
8
8
7b
7c
7d
7e
7f
7g
7h
7i
8a
8b
9a
9b
85
100
99
100
100
95
84
92
47
63
reflux
rt
reflux
reflux
100c
reflux
reflux
reflux
reflux
reflux
Me(CH2)4CH(Me)NH2
Et2N(CH2)3CH(Me)NH2
t-BuNH2
8
72
48
24
48
72
96
p-MeOC6H4NH2
PhCH2SH
p-O2NC6H4SH
n-BuOH
10
11
12
3
10
5
96
68
p-MeOC6H4OH
a Isolated yields.
b 28% aq. ammonia was used as a nucleophilic agent.
c The reaction was carried out in a sealed-tube.

o
(100 C, 72 h) than the cases of 7c and 7e, which was assumed to be caused by the bulkiness of a
nucleophile (Entries 2, 4, and 7). In the cases of 3-(N,N-dimethylamino)propylamine and more bulky
heptan-2-amine, the both reactions proceeded easily in refluxing acetonitrile to yield the N-N exchanged
products (7d and 7f) quantitatively (Entries 3 and 5). For the purpose of the introduction of the same
substituent as chloroquine at 4-position of quinoline ring, 5-(N,N-diethylamino)pentan-2-amine
underwent the exchange reaction under the similar conditions as 7d and 7f to yield the target compound
(7g) in 95% as we expected (Entry 6). This type of N-N exchange reaction was applicable for the
reaction with p-substituted aniline such as p-anisidine, which gave N-(p-methoxyphenyl)-4-quinolylamine
derivative (7i) in 92% yield in acetonitrile under reflux conditions with prolonged reaction time (48 h),
too (Entry 8).
Next, we attempted the nucleophilic N-S exchange reactions of 7a with thiols, which tended to take place
less easily than the reactions with amines. The reaction of 7a with phenylmethanethiol proceeded in
refluxing acetonitrile within 24 h to yield the desired 4-(benzylthio)quinoline derivative (8a) in 47% yield
(Entry 9). p-Nitrobenzenethiol, highly electron-deficient aromatic thiol, was also used as the
S-nucleophile, and the dimethylamino-arylthio exchange consequently took place in refluxing toluene for
48 h to give 8b in 63% yield (Entry 10).
This exchange reaction was further investigated to be expanded to the O-nucleophiles which relatively
have less reactivity compared with the corresponding amines and thiols. Contrary to our expectations,
the reaction of 7a with n-butanol occurred very cleanly, even though it took 72 h for the reaction
completion in refluxing xylene, to give N-O exchanged product (9a) in excellent yield (Entry 11).
p-Methoxyphenol was also adaptable to the dimethylamino-aryloxy exchange reaction giving aryl
4-quinolyl ether derivative (9b) in 68% yield under similar conditions as 9a (Entry 12).
As presented above, our attempts resulted in success to develop the versatile and simple method for the
preparation of various (7-chloro-3-trifluoroacetylquinolin-4-yl)amines, thiols, and ethers which cannot be
easily accessed by other synthetic methods.
On the other programs for seeking the potential as the anti-microorganism agent in these compounds, it
was verified that the typical chloroquine analogue 7g having the 5-diethylaminopentan-2-ylamino
substituent at the 4-position exhibited good activity to combat the Plasmodium berghel of mouse malarial
model. In that evaluation of drug efficacy, it was found that the extension of median survival period for
malarial infected mouse was performed well with the administration of 7g giving more than 11.6 days
compared with the non-administration group which resulted in 7 days.13
As the similar research in the antimalarial field, we have also achieved discovery of lead compounds like
7g and 9b having preferable activities as the novel fungicide for the plant protection. The evaluation of
these compounds has been tried in comparison with a known fungicide as a control in respect to the

efficacy for plant protection. In the application to Pseudoperonospora cubensis (downy mildew of
cucumber), we have reached the aim for the creation of new lead compounds by finding 7g and 9b which
showed almost the same or obviously lower concentration as the value of the half maximal effective
concentration of control (7g: less than 7.8 ppm, 9b and oxadixyl: 7.8 ppm).13 Such character is counted
on as for the contribution to the development of new anti-oomycetes since the acquisition of
drug-resistance against available phenylamide fungicides (e.g. metalaxyl, oxadixyl, benalaxyl, and so on)
has become a serious problem currently.14
In summary, we have gotten successful in the development of a versatile and simple method for the
synthesis of novel (7-chloro-3-trifluoroacetylquinolin-4-yl)amines (7), thiols (8), and ethers (9). This
method could allow us to prepare chloroquine analogues having trifluoroacetyl group with ease. In
general, the drug-resistant infection has become an important study subject in the process of seeking new
drug against harmful microorganisms, and many challenges are attempted to find out new chemical
skeletons having a potential to get over such problem currently.15,16 Therefore, our methodology would
be regarded as a potential tool to provide one of solutions which may enable a creation of new active
ingredients performing unique activities against harmful microorganisms.
EXPERIMENTAL
Mps were determined on an electrothermal digital melting point apparatus and are uncorrected. 1H
13
NMR spectra were obtained on a Bruker AVANCE500 spectrometer (1H at 500 MHz, C at 126 MHz)
and a JEOL PMX 60SI spectrometer (1H at 60 MHz) using TMS as an internal standard. IR spectra
were taken with PerkinElmer Spectrum ONE spectrophotometer. Microanalyses were taken with a
YANACO CHN-Coder MT-5 analyzer.
Synthesis of 7-Chloro-N,N-dimethylquinolin-4-amine (6).
To a solution of 4,7-dichloroquinoline (1.98 g, 10.0 mmol) in MeCN (40 mL) was added 50% aq.
dimethylamine (4.51 g, 50.0 mmol) and the mixture was stirred at 50 °C for 48 h. The reaction mixture
was washed with 10% aq. Na2CO3 (50 mL) and H2O (50 mL), extracted with CH2Cl2 (50 mL) and dried
1
(Na2SO4). The solvent was removed under reduced pressure to give 6 (1.85 g, 90%). 6: H NMR
(CDCl3):  8.51 (1H, d, J = 5.0 Hz, 2-H), 7.98 (1H, d, J = 2.0 Hz, 8-H), 7.86 (1H, d, J = 9.0 Hz, 5-H),
7.18 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 6.52 (1H, d, J = 5.0 Hz, 3-H), 2.84 (6H, s, N(CH3)2).
Synthesis of 1-(7-chloro-4-dimethylaminoquinolin-3-yl)-2,2,2-trifluoroethanone (7a).
To a solution of DMAP (3.30 g, 27.0 mmol) in xylene (18 mL) was added dropwise trifluoroacetic
anhydride (5.68 g, 27.0 mmol) to generate 1-trifluoroacetyl-4-dimethylaminopyridinium trifluoroacetate
in situ. After vigorously stirring for 1 h, 6 (1.86 g, 9.0 mmol) was added and subsequently refluxed for
18 h. The evaporated residual reaction mixture was washed with 10% aq. Na2CO3 (50 mL) and H2O (50

mL), extracted with CH2Cl2 (50 mL) and dried (Na2SO4). The solvent was removed under reduced
pressure and the crude product was chromatographed on silica gel column using n-hexane/EtOAc (4/1) as
eluent to give 1-(7-chloro-4-dimethylaminoquinolin-3-yl)-2,2,2-trifluoroethanone (7a) (2.08 g, 76%).
7a: mp 107-108 °C (n-hexane/EtOAc); 1H NMR (CDCl3): 8.98 (1H, q, J = 2.0 Hz, 2-H), 8.15 (1H, d, J
= 9.0 Hz, 5-H), 8.06 (1H, d, J = 2.0 Hz, 8-H), 7.45 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 3.15 (6H, s, N(CH3)2);
IR (KBr): 1698, 1167, 1137 cm-1. Anal. Calcd for C13H10ClF3N2O: C, 51.59; H, 3.33; N, 9.26. Found:
C, 51.46; H, 3.49; N, 9.27.
General procedure for the N-N exchange reactions of 7a with amines.
To a solution of 7a (154 mg, 0.5 mmol) in MeCN (4 mL) was added amines (0.5 mmol for 7c, d, f, and g;
1.5 mmol for 7b, e, h, and i) and the mixture was stirred under respective conditions (see Table 1). The
sole case applying sealed tube reaction was for the synthesis of 7h. The solvent was removed under
reduced pressure and the crude mixture was chromatographed on silica gel column using n-hexane/EtOAc
(3/1) as eluent to give N-N exchanged products, 7b-i.
1-(4-Amino-7-chloroquinolin-3-yl)-2,2,2-trifluoroethanone (7b): mp 225-226 °C (n-hexane/EtOAc);
1H NMR (CDCl3):  9.02-6.88 (2H, br, NH2), 8.88 (1H, q, J = 2.0 Hz, 2-H), 8.09 (1H, d, J = 9.0 Hz, 5-H),
7.87 (1H, d, J = 2.0 Hz, 8-H), 7.50 (1H, dd, J = 2.0, 9.0 Hz, 6-H); IR(KBr): 3331, 1641, 1175, 1132 cm-1.
Anal. Calcd for C11H6ClF3N2O: C, 48.11; H, 2.20; N, 10.20. Found: C, 48.13; H, 2.50; N, 9.88.
1-(4-Butylamino-7-chloroquinolin-3-yl)-2,2,2-trifluoroethanone (7c): mp 98-99 °C (n-hexane/EtOAc);
1H NMR (CDCl3):  10.85-10.37(1H, br, NH), 8.77 (1H, q, J = 2.0 Hz, 2-H), 8.12 (1H, d, J = 9.0 Hz,
5-H), 7.78 (1H, d, J = 2.0 Hz, 8-H), 7.25 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 4.00 - 3.70 (2H, m, NCH2),
2.11-0.71 (7H, m, CH2CH2CH3); IR (KBr): 3258, 1633, 1168, 1146 cm-1. Anal. Calcd for
C15H14ClF3N2O: C, 54.47; H, 4.27; N, 8.47. Found: C, 54.42; H, 4.23; N, 8.55.
1-[7-Chloro-4-(3-dimethylaminopropylamino)quinolin-3-yl]-2,2,2-trifluoroethanone
(7d):
mp
1
89-90 °C (n-hexane/EtOAc); H NMR (CDCl3): 10.70-10.53 (1H, br, NH), 8.81 (1H, q, J = 2.0 Hz,
2-H), 8.13 (1H, d, J = 9.0 Hz, 5-H), 7.80 (1H, d, J = 2.0 Hz, 8-H), 7.27 (1H, dd, J = 2.0, 9.0 Hz, 6-H),
4.01-3.71 (2H, m, NCH2), 2.30 (6H, s, N(CH3)2), 2.63-1.70 (4H, m, (CH2)2N); IR (KBr): 3269, 1646,
1174, 1130 cm-1. Anal. Calcd for C16H17ClF3N3O: C, 53.41; H, 4.76; N, 11.68. Found: C, 53.22; H,
4.67; N, 11.60.
1-(7-Chloro-4-isopropylaminoquinolin-3-yl)-2,2,2-trifluoroethanone
(7e):
mp
119-120
°C
(n-hexane/EtOAc); 1H NMR (CDCl3): 10.96-10.49 (1H, br, NH), 8.86 (1H, br s, 2-H), 8.06 (1H, d, J =
9.0 Hz, 5-H), 7.83 (1H, d, J = 2.0 Hz, 8-H), 7.28 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 4.80-4.20 (1H, m, CH),
1.49 (6H, d, J = 6.0 Hz, CH3); IR (KBr): 3359, 1647, 1172, 1140 cm-1. Anal. Calcd for C14H12ClF3N2O:
C, 53.09; H, 3.82; N, 8.85. Found: C, 52.91; H, 4.05; N, 8.80.

1-[7-Chloro-4-(heptan-2-ylamino)quinolin-3-yl]-2,2,2-trifluoroethanone (7f): bp 180 °C/3 mmHg
1
(oven temperature); H NMR (CDCl3): 10.63 (1H, d, J = 8.0 Hz, NH), 8.88 (1H, q, J = 2.0 Hz, 2-H),
8.10 (1H, d, J = 9.0 Hz, 5-H), 7.88 (1H, d, J = 2.0 Hz, 8-H), 7.33 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 4.67-4.03
(1H, m, NCH), 2.03-0.80 (14H, m); IR (neat): 3269, 1647, 1173, 1144 cm-1. Anal. Calcd for
C18H20ClF3N2O: C, 57.99; H, 5.41; N, 7.51. Found: C, 58.01; H, 5.22; N, 7.60.
1-[7-Chloro-4-(5-diethylaminopentan-2-ylamino)quinolin-3-yl]-2,2,2-trifluoroethanone (7g): bp
1
175 °C / 3 mmHg (oven temperature); H NMR (CDCl3):  10.90-10.47 (1H, br, NH), 8.90 (1H, q, J =
2.0 Hz, 2-H), 8.13 (1H, d, J = 9.0 Hz, 5-H), 7.92 (1H, d, J = 2.0 Hz, 8-H), 7.37 (1H, dd, J = 2.0, 9.0 Hz,
6-H), 4.77-4.16 (1H, m, NCH), 2.67-2.30 (6H, m, (CH3CH2)2NCH2), 1.73-1.45 (7H, m, (CH3)C(CH2)2),
0.97 (6H, t, J = 7.0 Hz, (CH3CH2)2N): IR (neat): 3286, 1646, 1173, 1143 cm-1. Anal. Calcd for
C20H25ClF3N3O: C, 57.76; H, 6.06; N, 10.10. Found: C, 58.05; H, 5.90; N, 9.97.
1-(4-tert-butylamino-7-chloroquinolin-3-yl)-2,2,2-trifluoroethanone (7h): mp 142-143 °C (n-hexane/
1
EtOAc); H NMR (CDCl3): 10.47-10.17 (1H, br, NH), 8.85 (1H, q, J = 2.0 Hz, 2-H), 8.13 (1H, d, J =
9.0 Hz, 5-H), 7.87 (1H, d, J = 2.0 Hz, 8-H), 7.33 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 1.55 (9H, s, (CH3)3); IR
(KBr): 3305, 1656, 1168, 1138 cm-1. Anal. Calcd for C15H14ClF3N2O: C, 54.47; H, 4.27; N, 8.47.
Found: C, 54.43; H, 4.25; N, 8.52.
1-[7-Chloro-4-(p-methoxyphenyl)aminoquinolin-3-yl]-2,2,2-trifluoroethanone (7i): mp 135-136 °C
1
(n-hexane/EtOAc); H NMR (CDCl3): 11.90-11.63 (1H, br, NH), 9.03 (1H, q, J = 2.0 Hz, 2-H), 7.87
(1H, d, J = 2.0 Hz, 8-H), 7.47 (1H, d, J = 9.0 Hz, 5-H), 7.25-6.82 (5H, m, 6-H / C6H4), 3.85 (3H, s,
CH3O); IR (KBr): 3202, 1648, 1174, 1130 cm-1. Anal. Calcd for C18H12ClF3N2O2: C, 56.78; H, 3.18; N,
7.36. Found: C, 56.62; H, 3.45; N, 7.25.
A typical procedure for the N-S exchange reactions of 8a with thiols.
To a solution of 7a (121 mg, 0.4 mmol) in MeCN (3 mL) was added benzyl mercaptan (50 mg, 0.4 mmol)
and the mixture was refluxed for 24 h. The solvent was removed under reduced pressure and the crude
mixture was chromatographed on silica gel column using n-hexane/EtOAc (39/1) as eluent to give N-S
exchanged products (8a, 72mg, 47%).
The similar procedure gave 8b by the reaction of 8a with 3 molar equivalents of p-nitrothiophenol in
toluene under reflux condition for 48 h.
1-(4-Benzylthio-7-chloroquinolin-3-yl)-2,2,2-trifluoroethanone (8a): mp 102-103 °C (n-hexane/
1
EtOAc); H NMR (CDCl3): 8.93 (1H, s, 2-H), 8.43 (1H, d, J = 9.0 Hz, 5-H), 8.17 (1H, d, J = 2.0 Hz,
8-H), 7.58 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 7.35-6.90 (5H, m, C6H5), 4.07 (2H, s, SCH2); IR (KBr): 1737,
1215, 1150 cm-1. Anal. Calcd for C18H11ClF3NOS: C, 56.62; H, 2.90; N, 3.67. Found: C, 57.02; H,
3.18; N, 3.56.

1-[7-Chloro-4-(p-nitrophenylthio)quinolin-3-yl]-2,2,2-trifluoroethanone (8b): bp 200 °C/3 mmHg
1
(oven temperature); H NMR (CDCl3): 9.16 (1H, s, 2-H), 8.43-7.17 (7H, m, 5-H/6-H/8-H/C6H4); IR
(neat): 1737, 1211, 1155 cm-1. Anal. Calcd for C17H8ClF3N2O3S: C, 49.47; H, 1.95; N, 6.79. Found: C,
49.46; H, 1.94; N, 6.71.
A typical procedure for the N-O exchange reactions of 7a with alcohols.
To a solution of 7a (121 mg, 0.4 mmol) in xylene (3 mL) was added n-butanol (296 mg, 4.0 mmol) and
the mixture was refluxed for 72 h. A removal of the solvent under reduced pressure gave precipitation
of N-O exchanged product which was isolated by filtration (9a, 127 mg, 96%).
The similar procedure gave 9b by the reaction of 7a with 5 molar equivalents of p-methoxyphenol for 96
h.
1-(4-n-Butoxy-7-chloroquinolin-3-yl)-2,2,2-trifluoroethanone (9a): mp 89-90 °C (n-hexane/EtOAc);
1H NMR (CDCl3): 9.08 (1H, q, J = 2.0 Hz, 2-H), 8.25 (1H, d, J = 9.0 Hz, 5-H), 8.13 (1H, d, J = 2.0 Hz,
8-H), 7.58 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 4.17 (2H, t, J = 6.0 Hz, CH2O), 2.04-0.83 (7H, m, (CH2)2CH3);
IR (KBr): 1610, 1182, 1130 cm-1. Anal. Calcd for C15H13ClF3NO2: C, 54.31; H, 3.95; N, 4.22. Found:
C, 54.71; H, 3.97; N, 4.30.
1-[7-Chloro-4-(p-methoxy)phenoxyquinolin-3-yl]-2,2,2-trifluoroethanone (9b): bp 150 °C/3 mmHg
(oven temperature); 1H NMR (CDCl3): 9.13 (1H, s, 2-H), 8.18 (1H, d, J = 2.0 Hz, 8-H), 8.06 (1H, d, J =
9.0 Hz, 5-H), 7.50 (1H, dd, J = 2.0, 9.0 Hz, 6-H), 6.83 (4H, s, C6H4), 3.77 (3H, s, CH3O); IR (neat): 1679,
1188, 1150 cm-1. Anal. Calcd for C18H11ClF3NO3: C, 56.63; H, 2.90; N, 3.67. Found: C, 56.61; H,
3.21; N, 3.71.
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