Synthesis of 2-CF3-tetrahydroquinoline and quinoline derivatives from CF3-N-aryl-aldimine

Full text of DOI:10.1021/jo9918807

J . Org. Chem. 2000, 65, 5009-5013
5009
Syn th esis of 2-CF
a n d Qu in olin e Der iva tives fr om
CF -N-Ar yl-a ld im in e
3
-Tetr a h yd r oqu in olin e
Sch em e 1
3
Beno ˆı t Crousse,* J ean-Pierre B e´ gu e´ , and
Dani e` le Bonnet-Delpon
Biocis UPRES A CNRS 8076, Centre d’Etudes
Pharmaceutiques, Rue J .B. Cl e´ ment,
9
2296 Ch aˆ tenay-Malabry, France
1
. We have already reported that 1 could react as
benoit.crousse@cep.u-psud.fr
Received December 7, 1999
heterodiene of vinyl enol ethers to give tetrahydroquino-
lines in the presence of Lewis acids (Scheme 1). We then
7
extended this reaction to other dienophiles to prepare
3
different patterns of 2-CF -tetrahydroquinolines. We
report here full details of this study and the preparation
In tr od u ction
Various tetrahydroquinoline derivatives bearing simple
or complex substituents are used as pharmaceutical
agents.1 Besides pharmaceutical applications, tetra-
hydroquinoline derivatives are also useful as pesticides,
of new functionalized 2-CF -quinolines.
3
Resu lts a n d Discu ssion
2
Aza-Diels-Alder Reaction with Vin yl En ol Eth er s.
The imine 1 is prepared from trifluoroacetaldehyde and
p-anisidine.8 The aza-Diels-Alder reaction was first
antioxidants, and corrosion inhibitors.
Among different ways for constructing tetrahydro-
quinolines, aza-Diels-Alder reaction between N-arylimines
and dienophiles is an established route to these com-
carried out between 1 and the vinyl ether 2a (Scheme 1,
4
3
Table 1) under conditions of Povarov (10 mol % of BF ‚
pounds. However, this reaction requires a Lewis acid
catalyst such as BF O and lanthanide salts. It is
3
2
Et O). When the reaction was performed in solvents such
3
‚Et
2
as dichloromethane, ether, or THF, the yield of the
cycloadduct was low. However, when toluene was used
as solvent at -78 °C, the tetrahydroquinoline 3a was
obtained in 56% yield with good regio- and stereoselec-
tivities. In the crude product, only traces of the other
stereoisomer could be detected. The cis configuration was
determined by 1H NMR; large coupling constants be-
tween H-4 and H-3ax (10.7 Hz) and H-2 and H-3ax (11.6
Hz) indicate their trans diaxial relationship and hence
usually limited to arylaldimines, and it is much less
4
efficient with alkyl aldimines. In fluorinated series, the
only example of an aza-Diels-Alder reaction reported
concerns a cationic dipolar reaction, where a preformed
5
aryliminium salt is required. Despite this, considering
the extraordinary potential of fluoroalkyl-containing
6
biologically relevant molecules, we have studied the aza-
3
Diels-Alder reaction with the (E)-R-CF -N-aryl-aldimine
3
the cis relationship between OEt and CF (Scheme 2).
(
1) (a) J ohnson, J . V.; Rauckman, S.; Baccanari, P. D., Roth, B. J .
Med. Chem. 1989, 32, 1942-1949. (b) Carling, R. W.; Leeson, P. D.;
Moseley, A. M.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J . A.;
Marshall G. R. J . Med. Chem. 1992, 35, 1942-1953. (c) Leeson, P. D.;
Carling, R. W.; Moore, K. W.; Moseley, A. M.; Smith, J . D.; Stevenson
G.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J . A.;
Marshall G. R.; Hoogsteen, K. J . Med. Chem. 1992, 35, 1954-1968.
The reaction was then extended to other enol ethers
Table 1). Under the same conditions, butyl enol ether
(
2b exhibited a reactivity similar to that of 2a . With cyclic
enol ethers, cycloaddition was efficient; the reaction with
the 2,3-dihydrofuran 2c afforded the tetrahydroquinoline
3c (84%) as a mixture of cis and trans isomers in a ratio
(
d) Carling, R. W.; Leeson, P. D.; Moseley, A. M.; Smith, J . D.; Saywell,
K.; Trickelbank, M. D.; Kemp, J . A.; Marshall, G. R.; Foster, A. C.;
Grimwood, S. Bioorg. Med. Chem. Lett. 1993, 3, 65-70.
2
of 90/10 (cis/trans), which were separated by SiO column
(2) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
chromatography. Similar results were obtained with the
3,4-dihydro-2H-pyran 2d ; however, 1 equiv of catalyst
was required to obtain 86% of the tetrahydroquinoline
4
8, 15031-15070 and references therein.
(3) Weinreb, S. M. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds., Pergamon: Oxford, 1991; Vol. 5, p 401. (b) Boger,
D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic
Synthesis; Academic: San Diego, 1987; Chapters 2 and 9. (c) Nomura,
Y.; Kimura, M.; Takeuchi, Y.; Tomoda, S. Chem. Lett. 1978, 267-270.
3
d in a 64/36 ratio (cis/trans). Configurations were
assigned by comparison of NMR data (coupling constants)
(
d) Boger, D. L. Tetrahedron 1983, 39, 2869-2939. (e) Kametani, T.;
9,10d
with those of nonfluorinated parent compounds.
Takeda, H.; Suzuki, Y.; Honda, T. Heterocycles 1984, 22, 275-276. (e)
Kametani, T.; Takeda, H.; Suzuki, Y.; Kasai, H.; Honda, T. Heterocycles
1
986, 24, 3385-3395. (f) Koichi, N.; Takanori, S. Heterocycles 1993,
5, 1039-1053. (g) Borrione, E.; Lucchini, V.; Prato, M.; Scorrano, G.;
(7) Crousse, B.; B e´ gu e´ , J . P.; Bonnet-Delpon, D. Tetrahedron Lett.
1998, 39, 5765-5768.
3
Stivanello, M. J . Heterocycl. Chem. 1988, 25, 1831-1833. (h) Borrione,
E.; Prato, M.; Scorrano, G.; Stivanello, M.; Lucchini, V.; Valle, G. J .
Chem. Soc., Perkin Trans. 1 1989, 2245-2250. (i) J oh, T.; Hagihara,
N. Tetrahedron Lett. 1967, 42, 4199-4200.
(8) (a) Guanti, G.; Banfi, L.; Narisano, E.; Scolastico, C.; Bosone, E.
Synthesis, 1985, 609-611. (b) The E configuration of 1 was determined
by hetero-NOE experiments.
(9) (a) Kametani, T.; Furuyama, F.; Fukuoka, Y.; Takeda, H.;
Suzuki, Y.; Honda, T. J . Heterocycl. Chem. 1986, 23, 185-187. (b)
Kametani, T.; Takeda, H.; Suzuki, Y.; Honda, T. Synth. Comm. 1985,
15, 499-505. (c) Elslager, E. F.; Worth, D. F. J . Heterocycl. Chem. 1969,
697-698. (d) Worth, D. F.; Perricone, S. C.; Elslager, E. F. J . Heterocycl.
Chem. 1970, 1353-1356. (e) Gilchrist, T. L.; Stannard, A. M. Tetra-
hedron Lett. 1988, 29, 3585-3586.
(10) (a) Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara,
Y. Synthesis 1995, 801-804. (b) Kobayashi, S.; Ishitani, H.; Nagayama,
S. Chem. Lett. 1995, 423-424. (c) Kobayashi, S.; Ishitani, H.; Na-
gayama, S. Synthesis 1995, 1195-1202. (d) Ma, Y.; Qian C.; Xie, M.;
Sun, J . J . Org. Chem. 1999, 64, 6462-6467.
(
4) Povarov, L. S. Russ. Chem. Rev., Engl. Transl. 1967, 36, 656-
6
75.
(
(
5) Fuchigami, T.; Ichikawa, S. J . Org. Chem. 1994, 59, 607-615.
6) Organofluorine Compounds in Medicinal Chemistry and Bio-
chemical Applications; Filler, R., Kobayashi, Y., Yagupolski, L., Eds.;
Elsevier: Amsterdam, 1993. (b) Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J . R., Welch, J . T., Eds.; American
Chemical Society: Washington, DC, 1996; p 228. (c) Edwards, P. N.
Use of Fluorine in Chemotherapy. In Organofluorine Chemistry:
Principles and commercial Applications; Banks, R. E., Tatlow, J . C.,
Eds.; Plenum Press: New York, 1994; pp 501-541.
1
0.1021/jo9918807 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/08/2000

5
010 J . Org. Chem., Vol. 65, No. 16, 2000
Notes
Ta ble 1. Syn th eses of Tetr a h yd r oqu in olin e Der iva tives
10 m ol % BF 3‚Et2O)
Ta ble 2. Syn th eses of Tetr a h yd r oqu in olin e Der iva tives
(5 m ol % Yb(OTf)3)
(
entry
2
t
3
cis/trans
yield (%)a
1
2
3
4
2a
2b
2c
2d
15 min
40 min
30 min
6 h
3a
3b
3c
3d
>98/2
>98/2
70/30
70/30
56
67
74
87
a
Isolated yield.
Lewis acid. This suggests that with the imine 1 a
concerted mechanism rather than a two-step electrophilic
process is favored. This could also explain the high
stereoselectivity of the reaction; stabilizing secondary
orbital interactions between the alkoxy group and the
heterodiene in the six-membered ring transition state
favor an endo approach of enol ethers as usually observed
in Diels-Alder reaction.13 This high stereoselectivity is
not observed with nonfluorinated aldimines, when a two-
step process is generally postulated.1
0c,14
In the peculiar
case of cyclic enol ethers, steric hindrance due to meth-
ylene groups could oppose these stabilizing orbital inter-
actions. Despite this activating effect of the CF group,
3
the presence of Lewis acid is required for the success of
the reaction. We observed that without Lewis acid, no
reaction occurred even under heating.
Rea ction w ith Oth er Dien op h iles. We then ex-
plored this reaction with terminal vinylsulfide and with
other unsaturated compounds that are expected to be less
reactive in this reaction: enamide, vinylcarbamate, and
styrene (Table 3).
a
Isolated yield. b 1 equiv of Lewis Acid was required.
Reactions were performed under the same conditions
Sch em e 2
as for enol ethers under BF
3
2
‚Et O catalysis. The vinyl
sulfide 2e was a good heterodienophile in this [4 + 2]
cycloaddition reaction, which led to the tetrahydroquino-
line 3e in 86% yield. With the enamide 2f and the vinyl-
carbamate 2g,15 which are less electron-rich, reaction
required a higher temperature (-20 °C) and tetra-
hydroquinolines 3f and 3g were also obtained in good
yields, 70% and 82%, respectively. Even styrene smoothly
reacted with imine 1 to afford the corresponding tetrahy-
droquinoline 3h in high yield. In all cases, only one regio-
and stereoisomer was obtained. The cis configuration
between substituents was determined by measurement
of H-H coupling constants in NMR spectra. These
results seem to confirm a concerted process previously
postulated.
Lanthanide triflates have been used to activate im-
ines10 and promote Diels-Alder reactions. We explored
3
the reaction under 5 mol % of Yb(OTf) in acetonitrile at
room temperature. The results were roughly similar to
those obtained with BF ‚Et O (Table 2). Tetrahydro-
3
When Yb(OTf) was used as catalyst, the reaction was
3
2
quinolines 3a ,b were isolated in good yield and with a
good diastereoselectivity (cis configuration). Lack of
stereoselectivity was observed with 2c and 2d ; tetrahy-
droquinolines 3c,d were obtained as a 70/30 mixture of
cis and trans isomers.
successful with 2e and led selectively to the tetrahydro-
quinoline 3e in 84% yield (cis/trans: >98/2). However,
with less electron-rich 2f, 2g, and 2h , no reaction was
observed. Starting material was recovered.
3
Reaction with Dien es. CF -N-tosyl-imines are known
to react as dienophiles with dienes.16 We have thus
investigated the reactivity of the imine 1 toward dienes.
At first, the reaction was performed between imine 1
If we compare these results to those described with
4
nonfluorinated alkyl aldimines, it seems that the CF
3
group favors this aza-Diels-Alder cycloaddition reac-
tion.11 This could be explained by its electron-withdraw-
and cyclopentadiene under BF
sis (Scheme 3).
3
2 3
‚Et O or Yb(OTf) cataly-
ing character, which lowers the LUMO level of the
molecule.1
1,12
3
However, concomitantly the CF group also
significantly reduces the basicity of carbonyl and imine
groups and hence the strength of complexation with a
(13) Fukui, K., Acc. Chem. Res 1971, 4, 57.
14) (a) Lucchini, V.; Prato, M.; Scorrano, G.; Tecilla, P. J . Org.
Chem. 1988, 53, 2251-2258. (b) Lucchini, V.; Prato, M.; Scorrano, G.;
Stivanello, M.; Valle, G. J . Chem. Soc., Perkin Trans. 2 1992, 259-
266. (c) Cheng, Y.-S.; Ho, E.; Mariano, P. S.; Ammon, H. L. J . Org.
Chem. 1985, 50, 5678-5686.
(15) Wieber, G. M.; Hegedus, L. S.; Åkermark, B.; Michalson, E. T.
J . Org. Chem. 1989, 54, 4649-4653.
(16) Krow, G. R.; Pyun, C.; Rodebaugh, R.; Marakowski, J . Tetra-
hedron 1974, 30, 2977.
(
(
11) Bonnet-Delpon, D.; B e´ gu e´ , J . P.; Lequeux, T.; Our e´ vitch, M.,
Tetrahedron 1996, 52, 59-70.
12) (a) Linderman, R. J .; J amois, E. A. J . Fluorine Chem. 1991,
(
5
3, 79-91. (b) Mikami, K.; Yajima, T.; Terada, M.; Uchimaru, T.
Tetrahedron Lett. 1993, 34, 7591-7594. (c) Drumond, D. F.; McMahon,
T. B. J . Phys. Chem. 1981, 85, 3746-3748.

Notes
J . Org. Chem., Vol. 65, No. 16, 2000 5011
Ta ble 3. Syn th eses of Tetr a h yd r oqu in olin e Der iva tives
Sch em e 4
(
10 m ol % BF 3‚Et2O)
Sch em e 5
Sch em e 6
a
Isolated yield. b -78 to -20 °C.
Sch em e 3
gioisomer (Scheme 4). This type of cycloaddition with
Danishefsky’s diene had already been reported in cyclo-
addition reaction with the CF H parent of the imine 1.
2
1
8
P r ep a r a tion of Qu in olin es. Because of their poten-
tial biological activity, considerable interest has been
1
9
directed toward the synthesis of fluorinated quinolines,
e.g., mefloquine has been developed as a highly effective
antimalarial drug.20 We thus studied the conversion of
tetrahydroquinolines, stemming from vinyl ethers, into
1
0a
quinolines. Under acidic conditions (2 N HCl in MeCN),
a and 3b provided the quinoline 7 in 56% and 76%,
3
respectively (Scheme 5).
With the tetrahydroquinolines 3c and 3d , quinolines
(51%) and 9 (70%), with a functionalized substituent
in C-3, could be obtained (Scheme 6).
3
In conclusion, we have reported a route to new CF -
The use of BF
the tetrahydroquinoline 5 in a trace amount, and no other
cycloadduct was obtained. In the presence of Yb(OTf) (5
mol %), compound 5 (cis configuration) could be isolated
at room temperature in a 56% yield. In this reaction, the
imine 1 acted as an azadiene and reacted with one of the
double bonds of cyclopentadiene. The striking efficiency
3
‚Et
2
O (1 equiv or 10 mol %) afforded
8
3
substituted tetrahydroquinolines and quinolines. We
have shown that the imine 1 exhibits a high reactivity
in aza-Diels-Alder reactions catalyzed by Lewis acids
(
BF
3
2 3
‚Et O, Yb(OTf) ). With substituted olefins, 1 acts as
of Yb(OTf)
3
compared to that of BF
3
2
‚Et O has not been
heterodiene involving the unsaturation of the aryl group.
Tetrahydroquinolines are obtained in good yields with
electron-rich and electron-poor olefins. Unlike what was
elucidated. Examples of an aza-Diels-Alder reaction in
which cyclopentadiene acts as dienophile have been
reported with InCl .
3
1
7
Conversely, when the imine 1 was treated with 1-meth-
oxy-3-(trimethylsiloxy)buta-1,3-diene (Danishefsky’s di-
(
18) Kitazume, T.; Murata, K.; Okabe, A.; Takahashi, Y.; Yamazaki,
T. Tetrahedron: Asymmetry 1994, 5, 1029-1040.
19) (a) Dey, A. S.; J ouilli e´ , M. M. J . Heterocycl. Chem. 1965, 2, 113.
(
(
(
ene) in the presence of 1 equiv of BF
Yb(OTf) , it reacted as a dienophile and afforded smoothly
the corresponding tetrahydropyridine 6 as the sole re-
3
‚Et
2
O or 5 mol % of
b) Linderman, R. J .; Kirollos, K. S. Tetrahedron Lett. 1990, 31, 2689.
c) Froissard, J .; Greiner, R.; Pastor, R.; Cambon, A. J . Fluorine Chem.
1981, 17, 249. (d) Keller, H.; Schlosser, M. Tetrahedron 1996, 52, 4637-
644. (e) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Eur.
3
4
J . Org. Chem. 1999, 937-941.
(20) Ohnmatch, C. J .; Patel, A. R.; Lutz, R. E. J . Med. Chem. 1971,
14, 926-928.
(
17) (a) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1997, 38, 5025-
5
026. (b) Babu, G.; Perumal, P. T. Tetrahedron 1998, 54, 1627-1638.

5
012 J . Org. Chem., Vol. 65, No. 16, 2000
Notes
observed in nonfluorinated series, the reaction is highly
stereoselective, strongly suggesting a concerted process.
With dienes, 1 reacts either as heterodiene or as dieno-
8.0, 5.0 Hz, 1H); 2.7 (dq, H-3a J ) 8.3, 6.6 Hz, 1H); 3.56 (qd,
H-4, J ) 7.0, 6.6 Hz, 1H); 3.75 (s, OCH , 3H); 3.85 (td, H-2, J )
3
8
1
1
1
.0, 7.2 Hz, 1H); 3.93 (td, H-2, J ) 8.5, 5.0 Hz, 1H); 3.95 (s, NH,
H); 4.77 (d, H-9b, J ) 6.5 Hz, 1H); 6.58 (d, H-6, J ) 9.0 Hz,
H); 6.74 (dd, H-7, J ) 9.0, 3.0 Hz, 1H); 6.9 (d, H-9, J ) 2.9 Hz,
3
phile depending on the structure of the diene. CF -
substituted tetrahydroquinolines could be converted in
acidic medium into corresponding quinolines. These
compounds are under biological assays for potential
antiparasitic activity.
13
2
H). C NMR: δ 29.2, 35.9, 54.8 (q, J C-F ) 28 Hz), 55.7, 65.6,
1
73.9, 113.5, 116.4, 115.8, 121.0, 125.5 (q, J
C-F
) 278 Hz), 135.0,
153.0. 19F NMR: δ -75.9 (d, J ) 7.0 Hz). Anal. Calcd for
NF : C, 57.09; H, 5.16; N, 5.12. Found: C, 56.97; H,
.24; N, 5.04.
-Meth oxy-5-tr iflu or om eth yl-3,4,4a ,5,6,10b-h exa h yd r o-
C
5
13
H
14
O
2
3
9
Exp er im en ta l Section
2H-p yr a n o[3,2-c]qu in olin e (3d ). cis-3d . Mp: 164 °C (petro-
1
leum ether/ether: 30%); white solid. H NMR: δ 1.52-1.85 (m,
Structures of compounds were determinated by COSY, hmqc,
and hmbc experiments and by NOE measurements. Elemental
analyses were performed by the Service de Microanalyses of the
Centre d′Etudes Pharmaceutiques, Ch aˆ tenay-Malabry. All reac-
tions were performed in an oven-dried apparatus under an inert
atmosphere of argon.
H-3, H-4, 4H); 2.46 (m, H-4a, 1H); 3.44 (td, H-2ax, J ) 12.0, 2.2
Hz, 1H); 3.62 (ddt, H-2eq, J ) 11.5, 4.4, 1.6 Hz, 1H), 3.74 (s,
NH, 1H); 3.76 (s, OCH , 3H); 3.87 (qd, H-5, J ) 7.4, 2.3 Hz, 1H);
3
5
6
1
6
.09 (d, H-10b, J ) 5.5 Hz, 1H); 6.6 (d, H-7, J ) 8.7 Hz, 1H);
.73 (dd, H-8, J ) 8.7, 2.8 Hz, 1H); 6.98 (d, H-10, J ) 2.9 Hz,
13
2
H). C NMR: δ 18.6, 24.7, 32.0, 55.7, 57.1 (q, J C-F ) 29.6 Hz),
Typ ica l P r oced u r e for t h e Syn t h esis of Su b st it u t ed
0.6, 71.1, 111.6, 115.3, 116.8, 121.6, 125.3 (q, 1J C-F ) 280.4
Tetr a h yd r oqu in olin es. With BF
mg, 1.5 mmol) in dry toluene (5 mL) was added, at -78 °C, BF
Et O (0.02 mL, 0.15 mmol). After the mixture stirred for 10 min,
a (166 mg, 2.26 mmol) in dry toluene (1 mL) was added. The
reaction mixture was stirred for 20 min, then saturated aqueous
NaHCO (10 mL) was added, and the product was extracted with
3
‚Et
2
O. To a solution of 1 (306
19
Hz), 136.6, 153.8. F NMR: δ -74.1 (d, J ) 7.5 Hz). Anal. Calcd
for C14
3
‚
16 2 3
H O NF : C, 58.52; H, 5.62; N, 4.88. Found: C, 58.66;
2
H, 5.80; N, 4.79.
2
tr a n s-3d . Mp: 106 °C (petroleum ether/ether, 30%); white
1
solid. H NMR: δ 1.6-1.9 (m, H-3, H-4, 4H); 2.28 (m, H-4a, 1H);
3
3
.75 (s × 2, OCH
3
and NH, 4H); 3.80 (m, H-2, 2H); 3.90 (qd,
ether (3 × 10 mL). After the usual workup, chromatography on
H-5, J ) 6.8, 6.6 Hz, 1H); 4.6 (br, H-10b, 1H); 6.56 (d, H-7, J )
8
silica gel (petroleum ether/ethyl acetate, 20%) afforded 232 mg
.6 Hz, 1H); 6.74 (dd, H-8, J ) 8.6, 2.9 Hz, 1H); 6.85 (d, H-10, J
(56%) of 3a .
13
2
)
2.9 Hz, 1H). C NMR: δ 23.3, 24.6, 31.8, 54.4 (q, J C-F ) 29.4
1
With Yb(OTf)
3
. To a solution of Yb(OTf)
3
(31 mg, 0.05 mmol)
Hz), 55.8, 65.4, 72.0, 110.3, 113.3, 115.8, 120.4, 125.0 (q, J C-F
in MeCN (1 mL) was added imine 1 (203 mg, 1.0 mmol) and 2a
0.108 mg, 1.5 mmol) in MeCN (1.5 mL) at room temperature.
The reaction mixture was stirred for 15 min, then a saturated
aqueous NaHCO solution (10 mL) was added, and the product
19
)
280.2 Hz), 135.9, 152.9. F NMR: δ -75.6 (d, J ) 6.8 Hz).
Anal. Calcd for C14 NF C, 58.52; H, 5.62; N, 4.88.
Found: C, 58.52; H, 5.73; N, 4.80.
-Met h oxy-4-t h iop h en yl-2-t r iflu or om et h yl-1,2,3,4-t et -
r a h yd r oqu in olin e (3e). Mp: 112 °C (petroleum ether/ether,
(
H
16
O
2
3
:
3
6
was extracted with ether (10 mL × 3). After usual workup,
chromatography on silica gel afforded 154 mg (56%) of 3a .
1
3
1
3
5
8
2
1
1
0%); yellow solid. H NMR: δ 2.15 (td, H-3, J ) 12.9, 11.5 Hz,
H); 2.46 (ddd, H-3, J ) 13.0, 5.7, 3.0 Hz, 1H); 3.75 (s, OCH
4
-E t h oxy-6-m et h oxy-2-t r iflu or om et h yl-1,2,3,4-t et r a h y-
3
,
d r oqu in olin e (3a ). Mp: 99 °C (petroleum ether); white solid.
H); 3.80 (s, NH, 1H); 3.82 (m, H-2, 1H); 4.46 (dd, H-4, J ) 11.5,
.7 Hz, 1H); 6.57 (d, H-8, J ) 8.7 Hz, 1H); 6.71 (dd, H-7, J )
.7, 2.3 Hz, 1H); 7.25-7.33 (m, H-5 and Ph, 4H); 7.44 (m, Ph,
1
H NMR: δ 1.31 (t, CH , J ) 7.0 Hz, 3H); 1.97 (ddd, H-3ax, J )
3
1
1
3
3
1
)
2.1, 11.6, 10.7 Hz, 1H); 2.48 (ddd, H-3eq, J ) 12.2, 5.5, 2.2 Hz,
H); 3.60 (qd, 1H, OCH
2
CH
3
, J ) 9.0, 7.0 Hz); 3.70 (s, NH, 1H);
CH , J ) 9.0, 7.0 Hz, 1H);
13
2
H). C NMR: δ 30.2, 44.1, 54.1 (q, J C-F ) 30.2 Hz), 55.8, 113.7,
.76 (s, OCH
3
, 3H); 3.77 (qd, OCH
2
3
1
15.3, 116.9, 122.2, 127.7, 129.2, 130.8 (q, J C-F ) 300 Hz), 132.5,
.91 (dqd, H-2, J ) 11.6, 6.9, 3.2 Hz, 1H); 4.66 (dd, H-4, J )
19
36.5, 153.2, 175.8. F NMR: δ -79.1 (d, J ) 6.4 Hz). Anal.
16ONSF : C, 60.16; H, 4.76; N, 4.13. Found: C,
0.14; H, 4.86; N, 4.05.
-Meth oxy-4-pyr r olidin -(2′-on e)-2-tr iflu or om eth yl-1,2,3,4-
tetr a h yd r oqu in olin e (3f). Mp: 178 °C (petroleum ether/AcOEt,
0.7, 5.5 Hz, 1H); 6.55 (d, H-8, J ) 8.8 Hz, 1H); 6.70 (dd, H-7, J
Calcd for C17
6
H
3
1
3
8.8, 2.2 Hz, 1H); 6.96 (d, H-5, J ) 2.9 Hz, 1H). C NMR: δ
2
1
1
5.5, 27.3, 53.2 (q, J C-F ) 30 Hz), 55.7, 64.0, 72.3, 111.8, 115.0,
6
1
1
9
16.3, 124.3, 125.5 (q, J C-F ) 278 Hz), 135.8, 153.3. F NMR:
NF : C, 56.72;
H, 5.85; N, 5.08. Found: C, 56.58; H, 6.01; N, 4.95.
-Bu t yl-6-m et h oxy- 2-t r iflu or om et h yl-1,2,3,4-t et r a h y-
d r oqu in olin e (3b). Mp: 85 °C (petroleum ether); white solid.
δ -78.4 (d, J ) 6.9 Hz). Anal. Calcd for C13
H
16
O
2
3
1
2
0%); white solid. H NMR: δ 1.94-2.26 (m, H-3 and CH
2 2
CH -
CO, 4H); 2.50 (m, CH CO, 2H); 3.22 (m, CH N, 2H); 3.71 (s,
2
2
4
OCH , 3H); 3.82 (s, NH, 1H); 3.98 (m, H-2, 1H); 5.60 (dd, H-4, J
3
) 11.6, 6.0 Hz, 1H); 6.42 (d, H-5, J ) 2.5 Hz, 1H); 6.61 (d, H-8,
1
13
H NMR: δ 0.96 (t, CH
CH , 4H); 1.95 (dt, H-3ax, J ) 12.0, 10.7 Hz, 1H); 2.49 (ddd,
H-3eq, J ) 12.2, 5.4, 3.2 Hz, 1H); 3.54 (dt, OCH , J ) 9.0, 6.6
3
, J ) 7.3 Hz, 3H); 1.47-1.66 (m, CH
2
CH
2
-
J ) 8.7 Hz, 1H); 6.71 (dd, H-7, J ) 8.9, 2.7 Hz, 1H). C NMR:
2
3
δ 18.1, 25.0, 31.1, 42.1, 46.7, 53.6 (q,
J
C-F
) 30.6 Hz), 55.6,
1
2
111.6, 114.5, 117.1, 120.3, 125.0 (q, J C-F ) 279.3 Hz), 137.1,
Hz, 1H); 3.70 (s, NH, 1H); 3.72 (dt, OCH2, J ) 9.0, 6.6 Hz, 1H);
3
4
Hz, 1H); 6.69 (dd, H-7, J ) 8.6, 2.9 Hz, 1H); 6.96 (d, H-5, J )
2
153.3, 175.8. 19F NMR: δ -78.7 (d, J ) 5.7 Hz). Anal. Calcd for
.75 (s, OCH
3
, 3H); 3.91 (dqd, H-2, J ) 11.7, 6.5, 3.2 Hz, 1H);
C15H17O N F : C, 57.32; H, 5.45; N, 8.91. Found: C, 57.10; H,
2
2
3
.64 (dd, H-4, J ) 11.6, 6.6, 3.2 Hz, 1H); 6.55 (d, H-8, J ) 8.6
5.31; N, 8.70.
6-Met h oxy-4-ca r b a m ic Acid Ben zyl E st er -2-t r iflu or o-
m eth yl-1,2,3,4-tetr a h yd r oqu in olin e (3g). Mp: 148 °C (petro-
1
3
2
.9 Hz, 1H). C NMR: δ 13.9, 19.5, 27.2, 32.2, 53.3 (q, J C-F
)
3
0.2 Hz), 55.7, 68.5, 72.5, 111.7, 114.9, 116.3, 124.4, 125.5 (q,
leum ether/AcOEt, 20%); white solid. H NMR: δ 1.87 (dt, H-3ax,
1
1
19
J
C-F ) 278 Hz), 135.8, 153.2. F NMR: δ -78.4 (d, J ) 6.5
NF : C, 59.25; H, 6.64; N, 4.61.
Found: C, 59.25; H, 6.82; N, 4.50.
-Met h oxy-4-t r iflu or om et h yl-2,3,3a ,4,5,9b -h exa h yd r o-
J ) 12.6, 11.0 Hz, 1H); 2.52 (ddd, H-3eq, J ) 12.7, 5.6, 3.2 Hz,
Hz). Anal. Calcd for C15
H
20
O
2
3
1H); 3.76 (s, NH, 1H); 3.7 (s, OCH , 3H); 3.95 (dqd, H-2, J )
3
13.2, 6.5, 3.2 Hz, 1H); 4.97 (d, NH, J ) 9.3 Hz, 1H); 5.07 (dt,
8
H-4, J ) 10.3, 5.6 Hz, 1H); 5.18 (s, OCH Ph, 2H); 6.56 (d, H-8,
2
fu r o[3,2-c]qu in olin e (3c). cis-3c. Mp: 154 °C (petroleum ether);
J ) 8.7 Hz, 1H); 6.70 (dd, H-7, J ) 8.6, 3.0 Hz, 1H); 6.75 (d,
1
13
white solid. H NMR: δ 1.99 (m, H-3, 1H); 2.22 (m, H-3, 1H);
H-5, J ) 3.2 Hz, 1H); 7.38 (m, Ph, 5H). C NMR: δ 29.0, 46.7,
2
2
.84 (m, H-3a, 1H); 3.67 (s, NH, 1H); 3.75 (s, OCH
3
, 3H); 3.81
53.1 (q, J
) 30.6 Hz), 55.7, 67.0, 111.7, 115.1, 116.6, 123.7,
) 280 Hz), 128.1, 128.2, 128.5, 136.1, 136.2, 153.2,
C-F
1
(
td, H-2, J ) 9.0, 4.0 Hz, 1H); 3.87 (td, H-2, J ) 8.0, 7.4 Hz,
125.1 (q, J
C-F
156.2. 19F NMR: δ -78.2 (d, J ) 6.6 Hz). Anal. Calcd for
1
7
9
3
1
H); 4.01 (qdd, H-4, J ) 7.0, 2.4, 1.5 Hz, 1H); 5.2 (d, H-9b, J )
.5 Hz, 1H); 6.58 (d, H-6, J ) 9.0 Hz, 1H); 6.72 (dd, H-7, J )
C19H19O N F : C, 59.97; H, 5.04; N, 7.37. Found: C, 59.97; H,
3
2
3
1
3
.0, 2.9 Hz, 1H); 6.89 (d, H-9, J ) 3.0 Hz, 1H). C NMR: δ 24.1,
5.07; N, 7.32.
2
7.2, 54.7 (q,
J
C-F ) 29.4 Hz), 55.6, 66.8, 75.3, 113.1, 116.1,
6-Met h oxy-4-p h en yl-2-t r iflu or om et h yl-1,2,3,4-t et r a h y-
d r oqu in olin e (3h ). Mp: 160 °C (petroleum ether); white solid.
1
19
16.7, 123.1, 125.3 (q, J C-F ) 278.2 Hz), 135.8, 153.9. F NMR:
1
δ -76.1 (d, J ) 7.0 Hz). Anal. Calcd for C13
H, 5.16; N, 5.12. Found: C, 56.89; H, 5.28; N, 4.98.
tr a n s-3c. Mp: 98 °C (petroleum ether); white solid. H NMR:
δ 2.12 (dq, H-3, J ) 13.0, 7.0 Hz, 1H); 2.27 (dtd, H-3, J ) 13.0,
H
14
O
2
NF
3
: C, 57.09;
H NMR: δ 2.16 (td, H-3ax, J ) 12.7, 12.0 Hz, 1H); 2.38 (ddd,
H-3eq, J ) 12.7, 5.3, 3.1 Hz, 1H); 3.57 (s, OCH , 3H); 3.9 (s,
NH, 1H), 4.02 (m, H-2, 1H); 4.13 (dd, H-4, J ) 12.6, 5.1 Hz, 1H);
6.18 (m, H-8, 1H); 6.63 (m, H-5, H-7, 2H); 7.18-7.4 (m, Ph, 5H).
3
1

Notes
J . Org. Chem., Vol. 65, No. 16, 2000 5013
The organic layer was dried over MgSO and concentrated in
1
3
2
C NMR: δ 31.4, 43.0, 54.4 (q, J C-F ) 30 Hz), 55.6, 113.5, 115.0,
4
1
1
1
C
16.2, 125.3 (q, J C-F ) 278 Hz), 126.3, 127.1, 128.7, 128.8, 136.6,
43.7, 152.9. F NMR: δ -78.7 (d, J ) 6.7 Hz). Anal. Calcd for
: C, 66.43; H, 5.26; N, 4.56. Found: C, 66.44; H,
.37; N, 4.50.
-Met h oxy-4-t r iflu or om et h yl-3a ,4,5,9b -t et r a h yd r o-3H -
vacuo. The residue was chromatographed on silica gel (petroleum
ether/AcOEt, 40%) to give analytically pure quinoline derivatives
7-9.
1
9
17
H
16ONF
3
5
6-Meth oxy-2-tr iflu or om eth yl-qu in olin e (7). Mp: 59 °C
(petroleum ether) (lit.1 54.5-57 °C), colorless solid. H NMR:
9d
1
8
cyclop en ta [c]qu in olin e (5). Mp: 123 °C (petroleum ether/
ether, 30%); brown solid. H NMR: δ 2.33 (ddd, H-3, J ) 16.5,
3
δ 3.95 (s, 3H, OCH ); 7.11 (d, H-5, J ) 2.7 Hz, 1H); 7.45 (dd,
1
H-7, J ) 9.3, 2.7 Hz, 1H); 7.68 (d, H-8, J ) 8.6 Hz, 1H); 8.1 (d,
13
9
.0, 2.8, 1H); 2.72 (dd, H-3, J ) 16.5, 8.7 Hz, 1H); 3.00 (qd, H-3a,
H-4, J ) 9.3 Hz, 1H); 8.21 (d, H-3, J ) 8.6 Hz, 1H). C NMR: δ
1
J ) 9.0, 2.9 Hz, 1H); 3.59 (s, NH, 1H); 3.74 (s, OCH
3
, 3H); 3.93
55.6, 104.7, 117.1, 121.8 (q, J C-F ) 280 Hz), 124.0, 130.3, 131.5,
(qd, H-4, J ) 7.5, 3.0 Hz, 1H); 4.01 (d, H-9b, J ) 9.0 Hz, 1H);
136.4, 143.3, 145.1, 159.3. 19F NMR: -67.4 (s). Anal. Calcd for
5
2
3
.76 (dtd, H-2, J ) 5.8, 2.9, 1.3 Hz, 1H); 5.88 (ddt, H-1, J ) 5.9,
C
11
H
8
ONF
3
: C, 58.10; H, 3.52; N, 6.16. Found: C, 57.98; H, 3.53;
1
3
.9, 1.3 Hz, 1H); 6.60 (m, H-6, H-7, H-9, 3H). C NMR: δ 31.2,
N, 6.09.
2
8.0, 46.2, 55.6, 55.8 (q, J C-F ) 29 Hz), 112.8, 113.8, 117.5, 125.7
3-(2′-Hyd r oxy)eth yl-2-tr iflu or om eth yl-6-m eth oxy-qu in o-
1
19
1
(q, J C-F ) 279.5 Hz), 126.4, 131.0, 132.7, 136.3, 153.7. F NMR:
lin e (8). Mp: 103 °C (petroleum ether/ether, 30%). H NMR: δ
δ -74.6 (d, J ) 7.5 Hz). Anal. Calcd for C14
H, 5.24; N, 5.20. Found: C, 62.46; H, 5.37; N, 5.08.
-Tr iflu or om eth yl-1-p-m eth oxyp h en yl-2,3-d ih yd r o-1H-
p yr id in -4-on e (6). To a solution of imine 1 (203 mg, 1.0 mmol)
and BF ‚Et O (1.0 mmol, 0.12 mL) in THF (8 mL) was added at
78 °C 2-[(trimethylsilyl)oxy]-1,3-butadiene (258 mg, 1.5 mmol).
H
14ONF
3
: C, 62.44;
3
1.80 (s, OH, 1H); 3.18 (t, H-2, J ) 6.4 Hz, 2H); 3.93 (s, OCH ,
3H); 3.97 (t, H-1, J ) 6.4 Hz, 2H); 7.04 (d, H-5, J ) 2.7 Hz, 1H);
7.38 (dd, H-7, J ) 9.2, 2.7 Hz, 1H); 8.03 (d, H-8, J ) 9.2 Hz,
2
1
3
1H); 8.10 (s, H-4, 1H). C NMR: δ 34.4, 55.6, 62.4, 104.1, 122.3
1
3
2
(q, J C-F ) 274 Hz), 123.4, 129.3, 130.2, 131.1, 138.2, 141.2, 143.6
2
19
-
(q, J C-F ) 31.7 Hz), 159.5. F NMR: δ -63.6 (s). Anal. Calcd
After 7 h of stirring, the reaction mixture was quenched with
for C13
12 2 3
H O NF : C, 57.56; H, 4.46; N, 5.16. Found: C, 57.67;
water (15 mL) and extracted with ether (3 × 10 mL). The
H, 4.40; N, 5.07.
extracts were dried over anhydrous MgSO
4
and concentrated.
3-(3′-Hyd r oxy)p r op yl-2-tr iflu or om eth yl-6-m eth oxy-qu i-
n olin e (9). Brown oil. 1H NMR: δ 1.96 (m, H-2, 2H); 2.30 (s,
OH, 1H); 3.01 (t, H-3, J ) 7.5 Hz, 2H); 3.76 (t, H-1, J ) 6.4 Hz,
1
Flash chromatography gave 6 (176 mg, 65%) as a brown oil. H
NMR: δ 2.77 (d, H-3, J ) 17.4 Hz, 1H); 3.14 (dd, H-3, J ) 17.4,
7
1
.5 Hz, 1H); 3.82 (s, OCH
H); 5.22 (d, H-5, J ) 8.1 Hz, 1H); 6.92 (m, Ph, 2H); 7.14 (m,
3
, 3H); 4.48 (quint, H-2, J ) 7.5 Hz,
3
2H); 3.91 (s, OCH , 3H); 7.01 (d, H-5, J ) 2.7 Hz, 1H); 7.35 (dd,
H-7, J ) 9.3, 2.7 Hz, 1H); 8.00 (s, H-4, 1H); 8.02 (d, H-8, J ) 9.3
1
3
1
3
1
Ph, 2H); 7.26 (d, H-6, J ) 8.1 Hz, 1H). C: δ 34.4, 55.4, 59.8 (q,
Hz, 1H). C NMR: δ 27.5, 33.8, 55.6, 61.9, 104.0, 122.4 (q, J C-F
) 273.5 Hz), 123.2, 130.5, 131.1, 132.6, 137.1, 141.1, 143.6 (q,
2
1
J
C-F ) 29.2 Hz), 101.4, 114.9, 123.5, 125.9 (q,
J
C-F ) 286.4
Hz), 138.1, 149.8, 157.8, 188.2. F NMR: δ -72.7 (d, J ) 7.5
Hz). Anal. Calcd for C13 NF : C, 57.56; H, 4.46; N, 5.16.
Found: C, 57.62; H, 4.60; N, 5.21.
1
9
2
19
J
C-F ) 33.1 Hz), 159.4. F NMR: δ -63.8 (s). Anal. Calcd for
NF : C, 58.94; H, 4.94; N, 4.91. Found: C, 59.20; H,
5.06; N, 5.12.
H
12
O
2
3
C
14
H
14
O
2
3
Gen er a l P r oced u r e for t h e Syn t h esis of Su b st it u t ed
Qu in olin es. Tetrahydroquinoline (0.9 mmol) (3a -d ) was added
to a solution of 2 N HCl (2 mL) in acetonitrile, and the mixture
was stirred at room temperature or at reflux. The reaction was
followed by GC and TLC. The mixture was quenched with a
Ack n ow led gm en t. We thank the “Fondation pour
la Recherche M e´ dicale” for financial support and Dr.
Maruta (Central Glass) for starting material.
saturated solution of Na
2
CO
3
and washed with water and brine.
J O9918807