Synthesis of 2-substituted trifluoromethylquinolines for the evaluation of leishmanicidal activity

Article abstract of DOI:10.1248/cpb.49.480

The synthesis of 2-substituted-trifluoromethylquinolines from aniline, trifluoromethylanilines, 3-aminoquinoline and trifluoromethylquinaldines is reported. In vitro antileishmanial evaluation of 2-alkyl, 2-alkenyl and 2-epoxypropyl-trifluoromethylquinoli

Full text of DOI:10.1248/cpb.49.480

480
Notes
Chem. Pharm. Bull. 49(4) 480—483 (2001)
Vol. 49, No. 4
Synthesis of 2-Substituted Trifluoromethylquinolines for the Evaluation of
Leishmanicidal Activity
a
a
a
b
Joël DADE, Olivier PROVOT, Henri MOSKOWITZ, Joëlle MAYRARGUE, ,a and Eric PRINA
*
Laboratoire de Chimie organique, Faculté de Pharmacie, UPRES-A CNRS 8076, Université de Paris-Sud,a 5 rue J-B
Clément, 92296 Châtenay-Malabry, France and Unité d’Immunophysiologie et Parasitisme Intracellulaire, Institut
Pasteur,b 25 rue du Dr. Roux,75724 Paris cedex 15, France. Received October 19, 2000; accepted December 22, 2000
The synthesis of 2-substituted-trifluoromethylquinolines from aniline, trifluoromethylanilines, 3-amino-
quinoline and trifluoromethylquinaldines is reported. In vitro antileishmanial evaluation of 2-alkyl, 2-alkenyl and
2-epoxypropyl-trifluoromethylquinolines is presented.
Key words leishmaniasis; 2-propyltrifluoromethylquinoline; 2-epoxypropyltrifluoromethylquinoline; 2-(propen-1-yl)-trifluo-
romethylquinoline.
Leishmaniasis are a group of diseases with different clini- cyclization of the trifluoromethylenaminone 4 (Chart 1).
cal manifestations (cutaneous, mucocutaneous and visceral), Condensation of 1-pentynyllithium with 1,1-difluoroethyltri-
which represent a severe public health problem in some trop- fluoroacetate in the presence of BF3–Et2O gave access to 3
ical and subtropical areas. They are often disfiguring and which was transformed into 4 after a Michael reaction with
sometimes fatal protozoan diseases affecting over 12 million aniline. Initial attempts at cyclization of 4 using a variety of
people worldwide and, for which, there is still no effective Lewis acids (AlCl3, BF3–Et2O or TiCl4) failed, resulting in
vaccine.
only the recovery of starting material. The use of trifluo-
Chemotherapy remains the most effective control measure roacetic or sulfuric acid leads to traces of quinoline 1e in a
for leishmaniasis. However, current drugs, like sodium sti- mixture of tarry matters. The yield was finally substantially
bogluconate (Pentostam®) or N-methylglucamine (Glucan- improved in polyphosphoric acid (24 h, reflux, 63%).
time®), are expensive and variable in their efficacy. They also
To prepare the 2-propyl-3-trifluoromethylquinoline 1f, we
require protracted courses of parenteral administration and first synthesized the 2-propyl-3-iodoquinoline 5 by the use of
have toxic side effects,1) which often result in the interruption a large excess of propyllithium on 3-aminoquinoline, fol-
of treatment. Furthermore, the increasing resistance to anti- lowed by diazotisation and subsequent treatment with potas-
monial drugs in many parts of the world clearly indicates the sium iodide. Considerable attention has been devoted to find-
need for a more effective and safer chemotherapeutic ap- ing methods for introducing the trifluoromethyl group onto
proach.
aromatic halide compounds. For example, Kobayashi4) pre-
Based on ethnomedical information obtained from popula- pared a trifluoromethylcopper species by the reaction of CF3I
tions which use traditional remedies, new antileishmanial with activated copper in DMF, Matsui5) has developed a con-
products like quinoline alkaloids have been discovered dur- venient trifluoromethylation of aromatic halides with sodium
ing the last decade.2) Improving efficacy of chemotherapeutic trifluoroacetate, and Fuchikami6) used the (CF3SiMe3/KF/
treatment by introducing structural modifications within CuI) system for trifluoromethylation of halides. Best results
these new drugs constitutes a major goal.
Because the introduction of fluorine into molecules modi-
fies the physiological activity of the resulting compounds, the
development of fluorinated analogues has received increas-
ing attention in recent years. We wish to present the method-
ology we used in the preparation of 2-propyltrifluoromethyl-
quinolines 1 and the chemical transformations of trifluo-
romethylquinaldines 2 into 2-alkenyl and 2-epoxypropyltri-
fluoromethylquinolines via the corresponding aldehydes.
Preliminary in vitro evaluation of these synthetic compounds
will be presented.
Chemistry In a previous paper,3) Song has described the
synthesis of 6- and 7-fluorinated quinaldines by the Skraup
reaction from the corresponding fluorinated anilines. We
have revisited this reaction with poorly nucleophilic tri-
fluoroanilines which were converted into 2-propyltrifluo-
romethylquinolines 1a—d. The best yields were obtained by
changing p-chloranil with air flow as the oxidant in refluxing
butanol. The use of m-trifluoromethylaniline gave access to
1b and 1d in a 10/1 ratio (Chart 1).
In order to introduce a trifluoromethyl group on the pyri-
dine ring of the quinoline skeleton, we have first studied the
Chart 1
To whom correspondence should be addressed. e-mail: Joelle.Mayrargue@chimorg.u-psud.fr
© 2001 Pharmaceutical Society of Japan

April 2001
481
ucts showed consistent and reproductible leishmanicidal ac-
tivity proving the validity of our assays.
Unfortunately, the various molecular changes made on nat-
ural products did not further improve their activity. On the
contrary, for all the compounds we have tested, i.e., 2-alkyl,
2-alkenyl and 2-epoxypropyl-trifluoromethylquinolines, we
have noted a decrease of antileishmanial activity compared to
control drugs and natural products. For example, from a con-
centration of 1.5 mg/ml, the natural 2-prop-1-enylquinoline
showed a leishmanicidal activity against Leishmania amazo-
nensis; in contrast, trifluoromethylated analogues were only
efficient at a concentration of 50 mg/ml. The 2-propylquino-
line was active at 12.5 mg/ml, whereas 1f (the most efficient
compound 1) was only active at 25 mg/ml. The 2-epoxypropyl-
trifluoromethylquinolines were poorly active around 100
mg/ml.
Chart 2
Preliminary works point out that natural quinolines, such
as 2-propylquinoline, are transformed in liver cells into oxi-
dized metabolits.10) Moreover, these metabolits should be the
active drugs because the natural 2-propylquinoline is more
Chart 3
were obtained in the preparation of 1f by using difluorocar- efficient by oral administration than by parenteral route.11)
benes generated from methylchlorodifluoroacetate in the The introduction of a trifluoromethyl substituent must pre-
presence of KF and CuI in DMF7) (Chart 1).
vent or slow down this oxidizing mechanism which could ex-
To prepare 2-propenyltrifluoromethylquinolines 7 and 2- plain the above antileishmanial results. Introduction of elec-
epoxypropyl-trifluoromethylquinolines 8, we first synthesised tro-donnor groups on 2-substituted-quinolines should give
the quinaldines 2 as described for 1. The transformation of highly promising results.
quinaldines into 2-quinolinecarboxaldehydes 6 with SeO2 in
dioxane was not affected by the electron-withdrawing effect Experimental
19F-NMR chemical shifts are reported in ppm, negative upfield relative to
of the trifluoromethyl group.
Wittig olefination with ethyltriphenylphosphonium iodide
afforded 2-propenyltrifluoromethylquinolines 7 as single E
internal CFCl3, 1H- and 13C-NMR chemical shifts are reported in ppm, posi-
tive downfield relative to internal TMS. Spectra were recorded on Bruker
1
AC 200P spectrometer (188, 200 and 50 MHz for 19F, H and 13C, respec-
isomers in good yields. To prepare 2-epoxypropylpropyle-
neoxyde-trifluoromethylquinolines 8 as fluorinated analogues
of the natural product isolated by Fournet,2) we used the reac-
tion of the sulfur ylide generated from ethyldiphenylsulfoni-
umtetrafluoroborate on 2-trifluoromethylquinolinecarbox-
aldehydes 6 as previously described by Brochet8) and us.9)
Epoxides were then obtained in good yields as a separable
mixture of Z and E isomers (1/1). The stereochemistry of
tively). Analytical thin-layer chromatography was performed on Merck silica
gel 60F254 glass precoated plates. All liquid chromatography separations
were performed using Merck silica gel 60 (230—400 mesh ASTM). Ele-
mental analyses12) were performed by the Service de microanalyses, Centre
d’Etudes Pharmaceutiques, Châtenay-Malabry, France, with a Perkin Elmer
2400 analyzer.
2-Propyltrifluoromethylquinolines 1a—d
A mixture of trifluoro-
methylaniline (30 mmol), butanol (40 ml), HCl 12 N (10 ml) was heated
under reflux and then trans-hexenal (150 mmol) was slowly added. The re-
sulting solution was heated under reflux and under draught for 8 h. The
cooled reaction mixture was made alkaline with KOH and extracted with
CH2Cl2. After drying, and the removal of the solvent, chromatographic pu-
rification on silica gel afforded the desired quinolines.
1
these epoxides was determinated by studying their H-NMR
spectra : measure of J
(4.5 and 2 Hz for Z and E isomers
H2Ј–H3Ј
respectively), NOE experiments and comparison with the 1H-
NMR spectra of the E antileishmanial natural epoxide.9)
We have also synthesized the 2-(3,3,3-trifluoropropyl)
quinoline 9 by the use of a Grignard reagent on N-quinoli-
neoxide, but a more efficient way consisted in the preparation
1
2-Propyl-8-trifluoromethylquinoline 1a: 52%. H-NMR (CDCl3) d: 1.00
(3H, t, Jϭ7.9 Hz), 1.90 (2H, m), 3.00 (2H, t, Jϭ7.9 Hz), 7.35 (1H, d, Jϭ8.4
Hz), 7.50 (1H, t, Jϭ7.9 Hz), 7.85 (1H, d, Jϭ7.9 Hz), 8.10 (1H, d, Jϭ7.9 Hz),
8.35 (1H, d, Jϭ8.4 Hz). 19F-NMR (CDCl3) d: Ϫ60.31 (CF3, s). 13C-NMR
(CDCl3) d: 13.8, 22.1, 41.1, 122.3, 124.1, 127.0, 127.2 (q, Jϭ29 Hz), 127.5
of the lithium salt of 3-bromo-1,1,1-trifluoromethylpropane (q, Jϭ5.4 Hz), 129.7 (q, Jϭ268 Hz), 131.9, 135.8, 144.6, 163.7.
1
2-Propyl-7-trifluoromethylquinoline 1b: 56%. H-NMR (CDCl3) d: 1.00
(3H, t, Jϭ7.3 Hz), 1.90 (m, 2H), 3.00 (2H, t, Jϭ7.3 Hz), 7.40 (1H, d, Jϭ8.5
Hz), 7.65 (1H, dd, Jϭ8.5 Hz, Jϭ1.4 Hz), 7.85 (1H, d, Jϭ8.5 Hz), 8.10 (1H,
d, Jϭ8.5 Hz), 8.35 (1H, d, Jϭ1.4 Hz). 19F-NMR (CDCl3) d: Ϫ62.81 (CF3,
s). 13C-NMR (CDCl3) d: 13.9, 22.9, 41.2, 121.3, 123.3, 124.8 (q, Jϭ242
Hz), 126.8, 128.2, 128.6, 131.0, 135.8, 146.9, 164.5.
that reacts with quinoline to give 9 in a 60 % yield (Chart 3).
Antileishmanial Activity Various in vitro tests were
used to assess the antileishmanial activity of 2-substituted tri-
fluoromethylquinolines. These tests have been done at both
the Pasteur Institute (Paris, France) and at the Swiss Tropical
Institute (Basel, Switzerland). They were based upon the use
of axenic amastigotes and peritoneal or bone marrow-derived
mouse macrophages infected with amastigotes from different
Leishmania species, including L. donovani (MHOM/ET/
1967/L82), L. infantum (IPZ 229/1/89) and L. amazonensis
(MPRO/BR/1972/M1841).
1
2-Propyl-6-trifluoromethylquinoline 1c: 51%. H-NMR (CDCl3) d: 0.95
(3H, t, Jϭ7.3 Hz), 1.65 (2H, m), 2.45 (2H, t, Jϭ7.3 Hz), 7.30 (1H, d, Jϭ8.4
Hz), 7.75 (1H, d, Jϭ8.9 Hz), 8.00 (3H, m). 19F-NMR (CDCl3) d: Ϫ62.42
(CF3, s). 13C-NMR (CDCl3) d: 13.8, 22.9, 41.2, 122.5, 124.1 (q, Jϭ270.4
Hz), 124.8, 125.3, 125.5, 127.5 , 130.0, 136.6, 148.8, 165.3.
2-Propyl-5-trifluoromethylquinoline 1d: 6%. 1H-NMR (CDCl3) d: 1.00
(3H, t, Jϭ7.5 Hz), 1.85 (2H, m), 3.00 (2H, t, Jϭ7.9 Hz), 7.40 (1H, d, Jϭ8.8
Hz), 7.70 (1H, t, Jϭ7.9 Hz), 7.85 (1H, d, Jϭ7.9 Hz), 8.20 (1H, d, Jϭ8.8 Hz),
8.40 (1H, d, Jϭ7.9 Hz). 19F-NMR (CDCl3) d: Ϫ59.44 (CF3, s). 13C-NMR
(CDCl3) d: 13.8, 22.9, 41.0, 122.6, 124.1, 124.3 (q, Jϭ274 Hz), 126.1 (q,
Jϭ32 Hz), 127.0, 127.5 132.4, 133.7, 148.1, 163.7.
The reference drugs used were sodium stibogluconate, am-
photericin B, allopurinol or allopurinol riboside and leucine-
methyl ester (L. amazonensis). For all the tests, these prod-

482
Vol. 49, No. 4
2-Methyl-trifluoromethylquinolines 2a,b These compounds were pre- was concentrated and the residue was purified on silica gel to give 6.
pared as described above by changing trans-butenal to trans-hexenal.
8-Trifluoromethyl-2-quinolinecarboxaldehyde 6a: 81%. 1H-NMR (CDCl3) d:
1
2-Methyl-8-trifluoromethylquinoline 2a: 51%. H-NMR (CDCl3) d: 2.85 7.75 (1H, m), 8.10 (3H, m), 8.40 (1H, d), 10.20 (1H, s). 19F-NMR (CDCl3)
(3H, s), 7.35 (1H, d, Jϭ9 Hz), 7.50 (1H, t, Jϭ8.0 Hz), 7.95 (1H, d, Jϭ9 Hz), d: Ϫ60.28 (CF3, s).
8.05 2H, m). 19F-NMR (CDCl3) d: Ϫ60.22 (CF3, s). 13C-NMR (CDCl3) d:
25.8, 122.7, 124.1, 124.3 (q, Jϭ274 Hz), 126.5 (q, Jϭ29 Hz), 126.8, 127.5
(q, Jϭ5.3 Hz), 132.0, 135.9, 144.5, 160.2.
6-Trifluoromethyl-2-quinolinecarboxaldehyde 6b: 75%. 1H-NMR (CDCl3)
d: 8.00 (1H, d, Jϭ8.6 Hz), 8.10 (1H, d, Jϭ8.6 Hz), 8.25 (1H, s), 8.40 (2H, t,
Jϭ8.6 Hz), 10.20 (1H, s). 19F-NMR (CDCl3) d: Ϫ62.93 (CF3, s).
1
2-Methyl-6-trifluoromethylquinoline 2b: 55%. H-NMR (CDCl3) d: 2.77
(E)-2-(Propen-1-yl)-trifluoromethylquinolines 7 To a 0 °C cooled so-
(3H, s), 7.36 (1H, d, Jϭ8.8 Hz), 7.80 (1H, dd, Jϭ8.8 Hz, Jϭ2.3 Hz), 8.10 lution of ethyltriphenylphosphonium iodide (5.8 g, 13.86 mmol) in THF (20
(3H, m). 19F-NMR (CDCl3) d: Ϫ62.42 (CF3, s). 13C-NMR (CDCl3) d: 25.5,
123.2, 125.0, 125.1 (q, Jϭ278 Hz), 125.3, 125.5 (q, Jϭ5.1 Hz), 128.1 (q, tion was stirred at 0 °C for 10 min then quinolinecarboxaldehydes 6 (1.5 g,
ml) was added PhLi (1.8 M in cyclohexan/ether, 7.7 ml). The red ylide solu-
Jϭ29 Hz), 129.8, 136.7, 148.9, 161.5
6.6 mmol) in THF (10 ml) were slowly added via syringe. The resulting mix-
1,1,1-Trifluoromethylhept-3-yn-2-one 3 Butyllithium (1.6 M in hexane,
ture was allowed to warm to 20 °C and stirred further for 24 h. The solution
46 ml, 74 mmol) was added to pent-1-yne (4.59 g, 67 mmol) in THF (120 ml) was poured into water, extracted with dichloromethane and dried. After
at Ϫ78 °C and this mixture was stirred at this temperature for 30 min. 2,2-di- evaporation of the solvent, the residue was purified by column chromatogra-
fluoroethyl trifluoroacetate (13.35 g, 75 mmol) in THF (100 ml) was added phy.
followed immediately by boron trifluoride-diethyl ether complex (11.3 g, 80
(E)-2-(Propen-1-yl)-8-trifluoromethylquinoline 7a: 53%. 1H-NMR (CDCl3)
mmol). The mixture was stirred at Ϫ78 °C for 90 min. Saturated aqueous d: 1.90 (3H, dd, Jϭ6.7 Hz, Jϭ1.6 Hz), 6.60 (1H, qd, Jϭ1.6 Hz, Jϭ13.2 Hz),
ammonium chloride (40 ml) was added and the solution was allowed to 6.90 (1H, qd, Jϭ6.7 Hz, Jϭ13.2 Hz), 7.30 (2H, m), 7.75 (1H, d, Jϭ8.2 Hz),
warm to ambient temperature. The THF was evaporated and the residue, 7.90 (2H, m). 19F-NMR (CDCl3) d: Ϫ60.91 (CF3, s). 13C-NMR (CDCl3) d:
taken up in dichloromethane, was washed with water and twice with brine 18.5, 119.9, 124.1, 124.3 (q, Jϭ273.9 Hz), 127.0, 127.3 (q, Jϭ29 Hz), 127.8
and dried. The residue was then purified by silica gel column chromatogra- (q, Jϭ5.3 Hz), 131.8, 131.9, 134.1, 136.1, 144.6, 156.7.
phy to give 3 (9.1 g , 85%).
(E)-2-(propen-1-yl)-6-trifluoromethylquinoline 7b: 67%. 1H-NMR (CDCl3)
1H-NMR (CDCl3) d: 1.00 (3H, t, Jϭ7.3 Hz), 1.65 (2H, m), 2.45 (2H, t, d: 1.90 (3H, dd, Jϭ6.5 Hz, 1.3 Hz), 6.60 (1H, qd, Jϭ1.3 Hz, Jϭ15.6 Hz),
Jϭ7.3 Hz). 19F-NMR (CDCl3) d: Ϫ78.51 (CF3, s).
6.80 (1H, qd, Jϭ6.5 Hz, Jϭ15.6 Hz), 7.40 (1H, d, Jϭ8.7 Hz), 7.70 (1H, dd,
1,1,1-Trifluoromethyl-4-phenylaminohept-3-en-2-one 4 Aniline (5.3 Jϭ2.1 Hz, Jϭ8.7 Hz), 8.00 (3H, m). 19F-NMR (CDCl3) d: Ϫ62.30 (CF3, s).
g, 56.9 mmol) and 3 (9.34 g, 57 mmol) were stirred in methanol (50 ml) for 13C-NMR (CDCl3) d: 18.6, 121.4, 124.0 (q, Jϭ273 Hz), 125.2 (q, Jϭ5.6
24 h at ambient temperature. After evaporation of the solvent, the residue Hz), 125.4 (q, Jϭ5.0 Hz), 126.9 (q, Jϭ29 Hz), 127.9, 130.2, 131.9, 134.4,
was purified by silica gel column chromatography to give 4 (11.23 g, 77%).
1H-NMR (CDCl3) d: 0.80 (3H, t, Jϭ7.3 Hz), 1.20 (1H, bs), 1.50 (2H, m),
2.25 (2H, t, Jϭ7.3 Hz), 5.50 (1H, s), 7.00—7.40 (5H, m). 19F-NMR (CDCl3)
d: Ϫ62.65 (CF3, s).
136.7, 149.1, 158.4.
2-Epoxypropyltrifluoromethylquinolines
8 Ethyldiphenylsulfonium
tetrafluoroborate13) (673 mg, 2.23 mmol) in CH3CN (10 ml), KOH (125 mg,
2.20 mmol) and water (31 mg, 1.74 mmol) were stirred for 20 min at ambient
temperature. Quinolinecarboxaldehyde 6 (400 mg, 1.86 mmol) in CH3CN
2-Propyl-4-trifluoromethylquinoline 1e 4 (2 g, 7.8 mmol) and polyphos-
phoric acid (10 ml) were stirred under reflux for 24 h. The cooled reac- (10 ml) was then added to the resulting solution and stirred for 20 h at room
tion mixture was basified with KOH (1 N, 40 ml) and extracted with temperature. The reaction was quenched by the addition of water (50 ml),
dichloromethane. After drying, and the removal of the solvent, chromato- and after phase separation, the aqueous layer was extracted several times
graphic purification on silica gel afforded 1e (1.17 g, 63%). with dichloromethane. After evaporation of the solvent, the residue was pu-
1H-NMR (CDCl3) d: 1.00 (3H, t, Jϭ7.3 Hz), 1.85 (2H, m), 2.95 (2H, t, rified by column chromatography to give 8.
Jϭ7.3 Hz), 7.50 (2H, m), 7.70 (1H, m), 8.10 (2H, m). 19F-NMR (CDCl3) d:
Ϫ61.81 (CF3, s). 13C-NMR (CDCl3) d: 13.7, 22.8, 41.1, 118.2, 121.3, 123.6
(q, Jϭ273 Hz), 123.7, 127.2, 129.8 (2), 134.2 (q, Jϭ30.5 Hz), 148.7, 162.2.
3-Iodo-2-propylquinoline 5 tert-Butyllithium (1.5 M in pentane, 35.5
cis-2-(2-Methyloxirane)-8-trifluoromethylquinoline 8a: 40%. 1H-NMR
(CDCl3) d: 1.50 (3H, d, Jϭ5.2 Hz), 3.20 (1H, qd, Jϭ2.1 Hz, Jϭ5.2 Hz), 3.90
(1H, d, Jϭ2.1 Hz), 7.25 (1H, d, Jϭ8.7 Hz), 7.50 (1H, t, Jϭ8.0 Hz), 7.90 (1H,
d, Jϭ8.0 Hz), 7.95 (1H, d, Jϭ8.0 Hz), 8.10 (1H, d, Jϭ8.7 Hz). 19F-NMR
ml) was slowly added at Ϫ78 °C to a stirred solution of iodopropane (5.1 g, (CDCl3) d: Ϫ60.30 (CF3, s). 13C-NMR (CDCl3) d: 17.8, 58.4, 60.4, 117.5,
30 mmol) in ether. The mixture was stirred 30 min at this temperature and al- 122.0 (q, Jϭ29 Hz), 124.1 (q, Jϭ275.5 Hz), 125.0, 128.0 (q, Jϭ5.9 Hz),
lowed to warm to 0 °C for 1 h. The solution was then cooled at Ϫ78 °C and 132.1 (2), 136.9, 147.1, 159.1.
1
3-aminoquinoline (1.44 g, 10 mmol) in ether (10 ml) was slowly added. After
trans-2-(2-Methyloxirane)-8-trifluoromethylquinoline 8a: 40%. H-NMR
stirring 24 h at ambient temperature, the solution was quenched by the addi- (CDCl3) d: 1.10 (3H, d, Jϭ5.6 Hz), 3.40 (1H, m), 4.25 (1H, d, Jϭ4.5 Hz),
tion of saturated aqueous NH4Cl. After extraction (CHCl3), the solution was 7.40 (2H, m), 7.90 (1H, d, Jϭ8.3 Hz), 7.95 (1H, d, Jϭ7.6 Hz), 8.10 (1H, d,
dried and concentrated. The crude product was subjected to chromatography Jϭ8.3 Hz). 19F-NMR (CDCl3) d: Ϫ60.27 (CF3, s). 13C-NMR (CDCl3) d:
to give 3-amino-2-propylquinoline (1.16 g, 60%). This latest compound 12.8, 55.5, 58.7, 119.9, 124.1 (q, Jϭ 273 Hz), 124.9, 127.2 (q, Jϭ29 Hz),
(1.12 g) was dissolved in acetic acid (18 ml) at 0 °C and sodium nitrite (1.48
g, 21.5 mmol) in H2O (10 ml) then potassium iodide (3.57 g, 21.5 mmol) in
127.8, 128.1 (q, Jϭ5.5 Hz), 132.1, 136.0, 144.2, 157.7.
cis-2-(2-Methyloxirane)-6-trifluoromethylquinoline 8b: 38%. 1H-NMR
H2O (15 ml) were added to the mixture. After 2 h, the solution was treated (CDCl3) d: 1.55 (3H, d, Jϭ5.0 Hz), 3.25 (1H, qd, Jϭ2.0 Hz, Jϭ5.0 Hz), 4.00
with NaOH (1 N, 30 ml) and extracted with dichloromethane, then dried. (1H, d, Jϭ2.0 Hz), 7.40 (1H, d, Jϭ8.8 Hz), 7.80 (1H, dd, Jϭ2.1 Hz, Jϭ8.8
After evaporation, the residue was purified by silica gel column chromatog- Hz), 8.20 (3H, m). 19F-NMR (CDCl3) d: Ϫ62.50 (CF3, s). 13C-NMR
raphy to give 5 (1.02 g, 57%). (CDCl3) d: 17.8, 58.4, 60.1, 117.9, 124.0 (q, Jϭ277 Hz), 125.5,126.7, 128.3
1H-NMR (CDCl3) d: 1.00 (3H, t, Jϭ7.4 Hz), 1.75 (2H, m), 3.00 (2H, t, (q, Jϭ29 Hz), 130.1, 137.7, 148.5, 160.5.
Jϭ7.4 Hz), 7.35 (1H, m), 7.55 (2H, m), 7.90 (1H, d, Jϭ8.4 Hz), 8.45 (1H, s). trans-2-(2-Methyloxirane)-6-trifluoromethylquinoline 8b: 40%. H-NMR
1
13C-NMR (CDCl3) d: 14.1, 22.4, 43.6, 93.4, 126.2, 126.4, 128.2, 128.8, (CDCl3) d: 1.10 (3H, d, Jϭ5.3 Hz), 3.40 (1H, qd, Jϭ4.4 Hz, Jϭ5.3 Hz),
129.8, 146.2, 147.0, 162.0.
2-Propyl-3-trifluoromethylquinoline 1f Under argon, 0.80 g (2.69
mmol) of 5, 1.27 g (8.08 mmol) of methyl 2-chloro-2,2-difluoroacetate, 0.84 (CDCl3) d: 12.8, 55.3, 58.3, 120.3, 124.0 (q, Jϭ272 Hz), 125.5 (2), 126.4,
g (4.40 mmol) of CuI and 0.255 g (4.39 mmol) of KF were stirred in DMF at 128.3 (q, Jϭ28.5 Hz), 130.1, 136.8, 148.5, 159.1.
4.25 (1H, d, Jϭ4.4 Hz), 7.40 (1H, d, Jϭ8.5 Hz), 7.80 (1H, dd, Jϭ8.7 Hz,
Jϭ2.0 Hz), 8.10 (3H, m). 19F-NMR (CDCl3) d: Ϫ62.62 (CF3, s). 13C-NMR
120 °C for 8 h. The resulting solution was poured into water, extracted with
2-3,3,3-(Trifluoropropyl)-quinoline 9 tert-Butyllithium (1.5 M in pen-
dichloromethane and dried. After evaporation, the residue was purified by tane, 7.5 ml) was slowly added at Ϫ78 °C to a stirred solution of 3-bromo-
silica gel column chromatography to give 1f (0.37 g, 57%).
1,1,1-trifluoropropane (1 g, 5.65 mmol) in ether (5 ml). The solution was
1H-NMR (CDCl3) d: 0.95 (3H, t, Jϭ7.5 Hz), 1.80 (2H, m), 2.95 (2H, t, then stirred 30 min at Ϫ78 °C and allowed to warm to 0 °C for 1 h. The solu-
Jϭ7.5 Hz), 7.40 (1H, t, Jϭ7.8 Hz), 7.70 (2H, m), 8.00 (1H, d, Jϭ7.8 Hz), tion was cooled at Ϫ78 °C and quinoline (0.4 g, 3.1 mmol) in ether (5 ml)
8.30 (1H, s). 13C-NMR (CDCl3) d: 14.1, 22.9, 37.9, 122.7 (q, Jϭ28 Hz), was slowly added to the mixture. After stirring at ambient temperature for
124.1 (q, Jϭ273 Hz), 124.8, 126.9, 128.2, 128.8, 131.5, 134.9 (q, Jϭ6 Hz), 24 h, the solution was quenched (NH4Cl), extracted (CHCl3) and dried, then
148.7, 159.2. 19F-NMR (CDCl3) d: Ϫ60.79 (CF3, s).
Trifluoromethyl-2-quinolinecarboxaldehydes 6 500 mg (2.3 mmol) of
purified by silica gel column chromatography to give 9 (0.42 g, 60%).
1H-NMR (CDCl3) d: 2.75 (2H, m), 3.25 (2H, m), 7.30 (1H, d, Jϭ8.5 Hz),
trifluoromethylquinaldine 2 and SeO2 (0.38 g, 3.45 mmol) were stirred in 7.50 (1H, t, Jϭ8.5 Hz), 7.75 (2H, m), 8.05 (1H, d, Jϭ8.5 Hz), 8.10 (1H, d,
dioxane (10 ml) under reflux for 4 h. After cooling and filtration, the solution Jϭ8.5 Hz). 19F-NMR (CDCl3) d: Ϫ66.64 (CF3, t). 13C-NMR (CDCl3) d:

April 2001
483
5) Matsui K., Tobita E., Ando M., Kondo K., Chem. Lett., 1981, 1719.
25.5 (q, Jϭ3 Hz), 31.4 (q, Jϭ29.6 Hz), 119.4, 122.5, 125.6, 126.8 (q, Jϭ275
6) Urata H., Fuchikami T., Tetrahedron Lett., 32, 91 (1991).
7) Su D. B., Duan J. X., Chen Q. Y., Tetrahedron Lett., 32, 7689 (1991).
8) Brochet C., Syssa J. L., Mouloungui Z., Delmas M., Gaset A., Syn-
thetic Commun., 21, 1735 (1991).
9) Munos M. H., Mayrargue J., Fournet A., Gantier J. C., Hocquemiller
R., Moskowitz H., Chem. Pharm. Bull., 42, 1914 (1994).
10) Iglarz M., Baune B., Gantier J. C., Hocquemiller R., Farinotti R., J.
Chromatogr. B, 714, 335, 1998.
Hz), 128.3 (2), 129.5, 130.7, 141.6, 145.5.
References and Notes
1) Croft S. L., Trends Pharmacol. Sci., 9, 376 (1988).
2) Fournet A., Barrios A., Munoz V., Hoquemiller R., Robelot F., Brune-
ton J., International Patent PCT/FR92/00903; Fournet A., Hoc-
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Prod., 56, 1547 (1993).
11) Munos M. H., Thèse de l’Université de Paris-Sud, N° 497, 1997.
12) Satisfactory microanalyses obtained : CϮ0.35, HϮ0.11
13) Mischitz M., Mirtl C., Saf R., Faber K., Tetrahedron: Asymmetry, 7,
2041 (1996).
3) Song Z., Mertzman M., Hughes D. L., J. Heterocyclic Chem., 30, 17
(1993).
4) Kobayashi Y., Kumadaki I., Tetrahedron Lett., 47, 4095 (1969);
Kobayashi Y., Kumadaki I., Sato S., Hara N., Chikami E., Chem.
Pharm. Bull., 18, 2334 (1970).