3-Trifloxy-3-trifluoromethylpropeniminium triflate: Reaction with aromatic amines - An efficient synthesis of 2-trifluoromethylquinolines

Article abstract of DOI:10.1002/(SICI)1099-0690(199904)1999:4<937::AID-EJOC937>3.0.CO;2-3

The reaction of iminium triflates 2 and 7 with various aromatic amines were investigated. The 2-R(f)-substituted quinolines 3 and 8 were prepared in excellent yields by the reaction of 2 and 7, respectively, with substituted anilines. The reactions of 2 a

Full text of DOI:10.1002/(SICI)1099-0690(199904)1999:4<937::AID-EJOC937>3.0.CO;2-3

FULL PAPER
3
-Trifloxy-3-trifluoromethylpropeniminium Triflate: Reaction with Aromatic
Amines – An Efficient Synthesis of 2-Trifluoromethylquinolines
[
a]
[a]
[a]
Ivan L. Baraznenok, Valentine G. Nenajdenko,* and Elizabeth S. Balenkova*
Keywords: Iminium salts / Triflic anhydride / Arylamines / 2-Trifluoromethyl quinolines / 3-Trifluoromethyl-
cinnamaldehydes
The reaction of iminium triflates 2 and 7 with various
aromatic amines were investigated. The 2-R -substituted
The reactions of 2 and 7 with diarylamines proceeds,
suprisingly, to afford the corresponding 3-R -substituted
f
f
quinolines 3 and 8 were prepared in excellent yields by the
reaction of 2 and 7, respectively, with substituted anilines.
cinnamaldehydes 4 and 9.
Introduction
Fluorinated compounds have been of great interest to
synthetic and medicinal chemists due to the unique physical
and biological properties imparted by fluorine.[ Among
these compounds, trifluoromethylated quinolines are the
subject of considerable pharmacological attention as potent
antimalarial agents; e.g., mefloquine {[2,8-bis(trifluoro-
methyl)-4-quinolinyl](2-piperidinyl)methanol} has been de-
veloped as an highly effective antimalarial drug.[ The tra-
1]
Scheme 1. Synthesis of iminium triflate 2
2]
ditional methods for the preparation of 2-CF -substituted
It is known[10] that the treatment of trifloxypropenimin-
3
quinolines comprise two possible approaches, namely, fluo-
rination of a suitable functional group [halogen exchange
ium salts with 2 equiv. of a secondary aliphatic amine re-
sults in the replacement of the OTf group by an amino moi-
ety and the formation of vinamidinium salts. We envisioned
the formation of similar compounds from the reaction of 2
with aromatic amines (Scheme 2). Subsequent intermolecu-
lar cyclization could lead to the 2-trifluoromethylquinol-
ines.
[
3]
[4]
of ϪCCl (ϪCBr ) and fluorination of ϪCO H ], and
3
3
2
direct introduction by an Ullmann-type reaction of per-
fluoroalkyl iodides and arylhalides using copper powder.[
5]
In this way 2-R -substituted 4-quinolones have been easily
f
obtained from anilines and R -substituted alkynyl esters or
f
ethyl trifluoroacetoacetate.[ Recently, several authors
have reported the regiospecific synthesis of 4-unsubstituted
-trifluoromethylquinolines by intramolecular acid- (or
6]
[7]
2
POCl -)catalyzed ring closure of 4-anilino-1,1,1-trifluoro-
3
but-3-en-2-ones, which are readily available from the corre-
[
7]
sponding anilines and trifluoroacetylacetylenes
or 4-
Scheme 2. Reaction of trifloxypropeniminium triflate with aro-
alkylamino- or 4-alkoxy-enones.[
these reactions are low.
7,8]
However, the yields in matic amines
Herein we report a simple and general one-pot synthesis
Thus, the successful implementation of Scheme 2 could
of 2-trifluoromethylquinolines from anilines and 4-dimeth- lead to a new and synthetically very useful pathway to this
ylamino-1,1,1-trifluoro-3-buten-2-one (1). The starting type of fluorinated compounds. The reaction was first at-
compound enone 1 can be easily prepared in one pot by tempted using 1,2-dichloroethane as a solvent. However,
trifluoroacetylation of ethyl vinyl ether[ followed by the the desired products were obtained only in the cases of ani-
addition of aqueous dimethylamine (Scheme 1). Treatment lines which have strong electron-donating substituents in m-
of 1 with triflic anhydride caused the formation of 3-tri- position. In the case of unsubstituted aniline, even when the
floxy-3-trifluoromethylpropeniminium triflate (2) which reaction mixture was refluxed for 15 h, the formation of 2-
was found to react with electron-rich aromatic compounds trifluoromethylquinoline was not achieved. It was found
to give 3-trifluoromethylcinnamaldehydes in moderate to that the reaction proceeds successfully when dichloroethane
8]
[
9]
good yields.
was replaced by o-xylene as a solvent (this permits the reac-
tion temperature to be raised from from 83°C to 144°C).
Several anilines were subjected to this new reaction and the
corresponding quinolines 3aϪj were obtained in excellent
yields in the majority of cases (Scheme 3). However, the
[
a]
Department of Chemistry, Moscow State University,
Moscow, 119899, Russia
E-mail: nen@acylium.chem.msu.ru
Eur. J. Org. Chem. 1999, 937Ϫ941

WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0404Ϫ0937 $ 17.50ϩ.50/0
937

I. L. Baraznenok, V. G. Nenajdenko, E. S. Balenkova
FULL PAPER
reaction failed when the o-substituent was a halogen or any electrophilic carbon atom two bulky substituents, CF and
3
electron-withdrawing group.
TfO groups, is much sterically more demanding.
Scheme 3. Regioselective synthesis of 2-trifluoromehylquinolines
When the aniline carries only one substituent in m-posi-
tion, the formation of 5- and 7-isomers can take place. The
reaction of 2 with m-substituted anilines revealed the excep-
tionally strong preference for the 7-isomer; only in the case
of m-toluidine was a mixture of regioisomers 3i and 3j (1:8)
isolated (Scheme 4). The other 3-substituted anilines gave
only the 7-isomers 3bϪd in good to excellent yields. These
results are in agreement with the known empirical rule[
that strong ϩM substituents tend to discriminate against
3
Scheme 5. Stereoselective synthesis of 3-CF -cinnamaldehydes
7c,11]
In all the cases investigated the formation of unsaturated
an attack of the electrophile in the o-position, and to favor aldehydes proceeds in a highly stereoselective manner to
attack at the p-position.
yield predominantly E isomers; only the carbazole deriva-
tive 4e was found to contain a significant amount (nearly
1
9
% from H NMR) of (Z)-aldehyde. A similar stereochem-
[9][13]
istry was observed earlier
for the reaction of 3-trifloxy-
propeniminium triflates with electron-rich aromatic and
hetaromatic compounds; E isomers of unsaturated alde-
1
hydes show in their H-NMR spectra signals of an aldehyde
proton at δ ϭ 9.3Ϫ9.6, whereas the corresponding proton
Scheme 4. Reaction of 2 with m-toluidine
signal of a Z isomers appear at lower field (δ ϭ
9]
9
.95Ϫ10.31).[
In view of the simplicity of the experimental procedure
compared with other existing methods the use of the imin- product proved to be the 4-trifluoromethylquinolinium salt
When 2-naphthylphenylamine was treated with 2, the sole
ium triflate 2 is an excellent preparative method for the syn- 5 (Scheme 6) resulting from the initial attack at the 1-posi-
thesis of 2-CF -substituted quinolines. Anilines have been tion of the naphthalene ring followed by cyclization at the
3
converted to 2-CF -substituted quinolines in a one-pot re- nitrogen atom.
3
action and in excellent yields. Furthermore, target quino-
lines were obtained with 95% purity after aqueous workup,
without the need for recrystallization or chromatographic
purification.
We have also tested several secondary and tertiary aro-
matic amines in the reaction with 2. Dimethylaniline re-
acted smoothly to afford the corresponding cinnamal-
Scheme 6. Reaction of 2 with 2-naphthylphenylamine
dehyde 4a in an almost quantitative yield (Scheme 5). It is
In addition, we have found that the reaction may be ex-
surprising that very similar results were obtained from the tended to the preparation of other 2-R -containing quino-
f
reaction of 2 with a variety of diarylamines: in each case lines and 3-R -substituted cinnamaldehydes. For example 1-
f
only C-acylation occurred giving the cinnamaldehydes (dimethylamino)-4,4,5,5,5-pentafluoro-1-penten-3-one (6)
bϪe as the sole products. It is known[ that even the was prepared from ethyl vinyl ether and pentafluoropropi-
12]
4
weak N-nucleophile carbazole is formylated by the classic onic anhydride in the same manner as 1. Complex 7 (from
Vilsmeier reagent (DMFA/POCl complex) at the nitrogen 6 and Tf O) was found to react with aromatic amines under
3
2
atom. Probably steric factors are critical in the apparent conditions similar to those by which CF analogs were pre-
3
difference in behavior between 2 and the Vilsmeier reagent pared to afford the C F -substituted quinolines 8 and cin-
2
5
in a reaction with diarylamines. Obviously, 2, bearing at the namaldehyde 9, albeit in slightly lower yield (Scheme 7). It
938
Eur. J. Org. Chem. 1999, 937Ϫ941

Efficient Synthesis of 2-Trifluoromethylquinolines
FULL PAPER
would appear that the approach described is also applicable (E)-1-(Dimethylamino)-4,4,5,5,5-pentafluoro-1-penten-3-one
This was prepared using the above procedure from ethyl vinyl ether
9.0 g, 0.125 mol), pentafluoropropionic anhydride (43 g, 0.15 mol)
and aqueous Me NH (34 mL of a 30% solution, 0.22 mol), recrys-
tallized from hexane. Yield 20.6 g (76%), colorless crystals, m.p.
(6):
for the synthesis of quinolines with any R substituent in
f
(
2
-position.
2
1
4
9Ϫ50°C. Ϫ H NMR (CDCl
H, CH ), 5.35 (d, J ϭ 12.2 Hz, 1 H, 2-H), 7.89 (d, J ϭ 12.2 Hz, 1
H, 1-H). Ϫ C NMR (CDCl
ϭ 36.8 Hz, 264.3 Hz, CF ), 118.43 (qt, J
CF ), 156.56, 178.13 (t, J ϭ 22.2 Hz, CϭO). Ϫ C
217.1): calcd. C 38.72, H 3.71; found C 38.82, H 3.82.
3 3
): δ ϭ 2.97 (s, 3 H, CH ), 3.23 (s, 3
3
1
3
3
): δ ϭ 37.47, 45.50, 88.37, 108.32 (tq,
ϭ 35.7 Hz, 286.7 Hz,
NO
J
F
2
F
3
F
7 8 5
H F
(
Preparation of 2-Trifluoromethylquinolines from Anilines Containing
Strong Electron-Donating Substituents. ؊ General Procedure I (GP
I): A solution of 0.5 g (2.93 mmol) of 1 in anhydrous C
mL) was cooled to 0°C. Over a period of 10 min, 0.83 g (2.93
mmol) of triflic anhydride in C Cl (10 mL) was added dropwise.
The corresponding aniline (5.86 mmol) in C Cl (10 mL) was
then added. The reaction mixture was refluxed for 1Ϫ6 h and then
poured into aqueous Na CO . The organic layer was separated,
washed with 1  HCl (10 mL) and dried with MgSO . The organic
2 4 2
H Cl (10
2
H
4
2
2
H
4
2
2
3
4
solvents were removed in vacuo. The residue was purified by col-
umn chromatography [silica gel, hexane/diethyl ether (10:1)] to af-
ford pure quinolines.
3
-(Trifluoromethyl)benzo[f]quinoline (3a): According to GP I, yield
1
0
.69 g (95%), colorless crystals, m.p. 113Ϫ114°C. Ϫ H NMR
(
CDCl
3
): δ ϭ 7.65Ϫ7.71 (m, 2 H, 8-H, 9-H), 7.81 (d, J ϭ 8.7 Hz,
Scheme 7. Synthesis of C
dehydes
2 5
F -subtituted quinolines and cinnamal-
1 H, 2-H), 7.85Ϫ7.89 (m, 1 H, 7-H), 7.97 (s, 2 H, 5-H, 6-H),
1
3
8
.50Ϫ8.54 (m, 1 H, 10-H), 8.96 (d, J ϭ 8.7 Hz, 1 H, 1-H). Ϫ
NMR (CDCl ): δ ϭ 117.05, 121.82 (q, J ϭ 273.6 Hz, CF
Thus, the reaction of arylamines with iminium triflates 122.91, 126.72, 127.56, 127.70, 128.31, 128.72, 128.79, 132.12,
and 7 provide a useful method for the preparation of 132.22, 132.28, 147.18 (q, J ϭ 34.7 Hz, 3-C), 147.48. Ϫ C14
-R -substituted quinolines. The reaction of iminium tri- (247.2): calcd. C 68.02, H 3.26; found C 68.13, H 3.34.
C
3
F
3
),
2
F
8 3
H F N
2
f
flates 2 and 7 with diarylamines gives rise to 3-R -substi-
f
7
-(Methylsulfanyl)-2-(trifluoromethyl)quinoline (3b): According to
tuted cinnamaldehydes in excellent yields. Taken in con-
1
GP I, yield 0.63 g (89%), pale pink crystals, m.p. 90Ϫ91°C. Ϫ H
junction with our previous paper,[ this new pathway NMR (CDCl ): δ ϭ 2.58 (s, 3 H, CH ), 7.32 (dd, J ϭ 8.7 Hz, 1.8
9]
3
3
represent a mild and effective route to some types of Hz, 1 H, 6-H), 7.59 (d, J ϭ 8.4 Hz, 1 H, 3-H), 7.66 (d, J ϭ 8.7
fluorinated compounds.
Hz, 1 H, 5-H), 7.79 (d, J ϭ 1.8 Hz, 1 H, 8-H), 8.18 (d, J ϭ 8.4 Hz,
1
3
1
J
1
H, 4-H). Ϫ C NMR (CDCl
ϭ 275.3 Hz, CF ), 122.53, 126.22, 127.15, 127.74, 137.60,
43.64, 147.64, 147.98 (q, J ϭ 34.4 Hz, 2-C). Ϫ C11 NS
3
): δ ϭ 14.70, 115.59, 121.15 (q,
F
3
F
8 3
H F
Experimental Section
General: M.p.: Uncorrected values. Ϫ NMR: Varian VXR-400,
(
243.2): calcd. C 54.31, H 3.31; found C 54.49, H 3.30.
1
13
7-Methoxy-2-(trifluoromethyl)quinoline (3c): According to GP I,
Bruker AM 400C (400 MHz and 100 MHz, for H and C, respec-
tively), with TMS as an internal standard. Ϫ IR: UR-20, films. Ϫ
Column chromatography: Silica gel 60 (63Ϫ200 mesh, Merck). Ϫ
All solvents used were dried and distilled according to the standard
procedure. Triflic anhydride was prepared according to a literature
[
7c]
yield 0.62 g (93%), colorless crystals, m.p. 67Ϫ68°C. (ref.
m.p.
), 7.27 (dd,
J ϭ 9.2 Hz, 2.4 Hz, 1 H, 6-H), 7.46 (d, J ϭ 2.4 Hz, 1 H, 8-H),
.56 (d, J ϭ 8.4 Hz, 1 H, 3-H), 7.71 (d, J ϭ 9.2 Hz, 1 H, 5-H),
1
6
3 3
5Ϫ66°C). Ϫ H NMR (CDCl ): δ ϭ 3.93 (s, 3 H, CH
7
1
3
[
14]
8.19 (d, J ϭ 8.4 Hz, 1 H, 4-H). Ϫ C NMR (CDCl
): δ ϭ 55.54,
), 122.13, 124.17,
ϭ 33.7 Hz, 2-C), 148.99, 161.58. These
procedure
E)-4-(Dimethylamino)-1,1,1-trifluoro-3-buten-2-one (1): A solution
of (E)-4-ethoxy-1,1,1-trifluoro-3-buten-2-one in CH Cl was pre-
from trifluoromethanesulfonic acid (Merck).
3
1
F 3
07.31, 114.44, 121.45 (q, J ϭ 274.2 Hz, CF
(
1
28.46, 137.41, 147.87 (q, J
F
2
2
[
7c]
spectral data are in good accord with those reported in ref.
pared from ethyl vinyl ether (18.0 g, 0.25 mol) and trifluoroacetic
anhydride (63.0 g, 0.30 mol) according to the Hojo protocol[ and
8a]
2-(Trifluoromethyl)-7-quinolinol (3d): Crude product, obtained ac-
cooled to Ϫ20°C. Then aqueous Me
tion, 0.45 mol) was added dropwise over 10 min with vigorous stir-
ring. The resulting mixture was allowed to warm to room temp., 250Ϫ255°C (dec.). Ϫ IR (nujol): ν˜ ϭ 3100 cm (OH). Ϫ H NMR
the aqueous layer extracted with CH Cl (2 ϫ 50 mL), combined (CDCl ): δ ϭ 7.38 (dd, J ϭ 9.2 Hz, 2.4 Hz, 1 H, 6-H), 7.45 (d, J ϭ
organic layers washed with brine, dried with MgSO and then con- 2.4 Hz, 1 H, 8-H,), 7.65 (d, J ϭ 8.4 Hz, 1 H, 3-H), 7.96 (d, J ϭ
2
NH (70 mL of a 30% solu-
cording to GP I (without chromatographic purification), was crys-
2 4 2
tallized from C H Cl , yield 0.41 g (65%), pale-gray crystals, m.p.
Ϫ1
1
2
2
3
4
1
3
centrated under reduced pressure. The orange crystalline residue
was purified by passing it through a short (7 cm) silica-gel column
9.2 Hz, 1 H, 5-H,), 8.48 (d, J ϭ 8.4 Hz, 1 H, 4-H). Ϫ C NMR
(CDCl ): δ ϭ 111.14, 114.65, 122.44, 122.85 (q, J ϭ 272.8 Hz,
CF ), 124.65, 130.38, 139.02, 148.32 (q, J ϭ 33.7 Hz, 2-C), 149.94,
3
F
(
CHCl
Yield 31.0 g (74%) of colorless solid, m.p. 57Ϫ58°C (ref.
8°C).
3
) followed by recrystallization from hexane/benzene (5:1).
3
F
[8d]
m.p.
160.63. Ϫ C10
H
7
F
3
N (213.2): calcd. C 56.35, H 2.84; found C
5
56.11, H 2.93.
Eur. J. Org. Chem. 1999, 937Ϫ941
939

I. L. Baraznenok, V. G. Nenajdenko, E. S. Balenkova
FULL PAPER
7
-Methoxy-2-(1,1,2,2,2-pentafluoroethyl)quinoline (8a): Obtained (CDCl
according to GP I from 6 (0.64 g, 2.93 mmol), Tf O (0.83 g, 2.93 8.38 (d, 1 H). Remaining signals covered by those of the major
mmol) and m-anisidine (0.72 g, 5.86 mmol). Yield 0.54 g (67%), isomer. Ϫ C NMR (CDCl
3 3
) of 3i δ ϭ 2.62 (s, 3 H, CH ), 7.65 (d, 1 H), 8.00 (d, 1 H),
2
1
3
3
) of 3j: δ ϭ 21.70, 121.60, 121.60 (q,
F 3
J ϭ 273.3 Hz, CF ), 126.82, 127.14, 128.75, 130.76, 137.53,
1
white crystals, m.p. 57Ϫ59°C. Ϫ H NMR (CDCl
H, CH ), 7.29 (dd, J ϭ 9.0 Hz, 2.5 Hz, 1 H, 6-H), 7.50 (d, J ϭ 2.5 141.27, 147.27, 147.64 (q, J
Hz, 1 H, 8-H), 7.58 (d, J ϭ 8.4 Hz, 1 H, 3-H), 7.73 (d, J ϭ 9.0 of 3i: δ ϭ 18.37, 116.13, 128.11, 130.38, 134.40. Remaining signals
Hz, 1 H, 5-H), 8.20 (d, J ϭ 8.4 Hz, 1 H, 4-H). Ϫ 13C NMR
coincide with those of the major isomer or are not detected. The
CDCl ): δ ϭ 55.63, 107.50, 112.24 (tq, J ϭ 36.9 Hz, 253.7 Hz,
CF ), 115.72, 119.46 (qt, J ϭ 37.2 Hz, 284.1 Hz, CF ), 122.36,
24.11, 128.53, 137.24, 148.33 (t, J ϭ 25.2 Hz, 2-C), 149.23,
N (277.2): calcd. C 52.00, H 2.91; found C
3
): δ ϭ 3.94 (s, 3
1
3
3
F 3
34.6 Hz, 2-C). Ϫ C NMR (CDCl )
[
7c]
(
3
F
spectral data for 3j are in good accord with those reported in ref.
-(1,1,2,2,2-Pentafluoroethyl)quinoline (8b): Obtained according to
GP II from 6 (0.64 g, 2.93 mmol), Tf O (0.83 g, 2.93 mmol) and
aniline (0.55 g, 5.86 mmol). Yield 0.53 g (73%), pale yellow oil,
2
F
3
2
1
1
5
F
2
9 5
61.63. Ϫ C12H F
1.73, H 2.77.
16
1
n
D
ϭ 1.4955. Ϫ H NMR (CDCl
8.4 Hz, 1 H, 6-H or 7-H), 7.64 (d, J ϭ 8.3 Hz, 1 H, 3-H), 7.70 (dd,
Strong Electron-Donating Substituents. ؊ General Procedure II (GP J ϭ 8.5 Hz, 7.5 Hz, 1 H, 6-H or 7-H), 7.77 (d, J ϭ 8.4 Hz, 1 H,
II): The reaction mixture was prepared according to GP I from 1
5-H), 8.14 (d, J ϭ 8.5 Hz, 1 H, 8-H), 8.22 (d, J ϭ 8.3 Hz, 1 H, 4-
0.5 g, 2.93 mmol), Tf O (0.83 g, 2.93 mmol) and the corresponding
aniline (5.86 mmol). Then, C Cl was evaporated, anhydrous o-
xylene (15 mL) added and the reaction mixture was refluxed for
3
): δ ϭ 7.55 (dd, J ϭ 7.5 Hz,
Preparation of 2-Trifluoromethylquinolines from Anilines without
1
3
(
2
H). Ϫ C NMR (CDCl
CF ), 117.70, 118.95 (qt, J
128.26, 128.61, 130.14, 130.65, 137.75, 147.28, 147.42 (t, J
Hz, 2-C). Ϫ C11 N (247.2): calcd. C 53.45, H 2.45; found C
3.10, H 2.49.
3
): δ ϭ 111.35 (tq, J
F
ϭ 37.6 Hz, 255.1 Hz,
), 127.57,
ϭ 25.2
2
H
4
2
2
F
ϭ 37.5 Hz, 286.9 Hz, CF
3
F
5
Ϫ15 h. The products were isolated according to GP I.
6 5
H F
5
2
(
-(Trifluoromethyl)quinoline (3e): According to GP II, yield 0.50 g
m.p.
7.0Ϫ57.5°C). Ϫ H NMR (CDCl ): δ ϭ 7.65 (dd, J ϭ 7.4 Hz, 8.4
3
83%), colorless crystals, m.p. 57Ϫ58°C. (ref.[
7c]
Preparation of 3-Trifluoromethylcinnamaldehydes. ؊ General Pro-
cedure III (GP III): The reaction mixture was prepared according
1
5
to GP I from 1 (0.5 g, 2.93 mmol), Tf
the corresponding arylamine (5.86 mmol). After stirring at
0Ϫ40°C for 2Ϫ4 h, the mixture was poured into aqueous Na CO
and the resulting mixture was stirred for 3Ϫ5 h. The organic layer
was separated, the aqueous layer was extracted with Et O (2 ϫ 20
mL). The combined organic layers were dried with MgSO and
2
O (0.83 g, 2.93 mmol) and
Hz, 1 H, 6-H or 7-H), 7.71 (d, J ϭ 8.4 Hz, 1 H, 3-H), 7.81 (dd,
J ϭ 8.5 Hz, 7.4 Hz, 1 H, 6-H or 7-H), 7.89 (d, J ϭ 8.4 Hz, 1 H,
2
2
3
5-H), 8.21 (d, J ϭ 8.5 Hz, 1 H, 8-H), 8.32 (d, J ϭ 8.4 Hz, 1 H, 4-
13
H). Ϫ C NMR (CDCl
CF ), 127.36, 128.36, 128.61, 129.84, 130.57, 137.87, 146.94, 147.75
q, J ϭ 34.3 Hz, 2-H). These spectral data are in good accord
with those reported in ref.
3 F
): δ ϭ 116.51, 121.58 (q, J ϭ 274.5 Hz,
2
3
(
F
4
[
7c]
concentrated in vacuo. The residue was chromatographed on silica
gel [benzene, hexane/diethyl ether (4:1)].
8
-Methyl-2-(trifluoromethyl)quinoline (3f): According to GP II,
1
6
[7c]
20
(E)-3-[4-(Dimethylamino)phenyl]-4,4,4-trifluoro-2-butenal (4a): Ob-
yield 0.55 g (90%), colorless oil, n
1
J ϭ 8.6 Hz, 7.0 Hz, 1 H, 6-H), 7.62 (d, J ϭ 7.0 Hz, 1 H, 7-H),
D
ϭ 1.5248 (ref.
n
D
ϭ
1
tained according to GP III, yield 0.68 g (96%), yellow-orange vis-
.5236). Ϫ H NMR (CDCl
3
): δ ϭ 2.86 (s, 3 H, CH
3
), 7.53 (dd,
Ϫ1
1
cous oil. Ϫ IR (Nujol): ν˜ ϭ 1660 cm (CϭH), 1590 (CϭC). Ϫ H
NMR (CDCl ): δ ϭ 2.96 (s, 6 H, 2 CH ), 6.47 (d, J ϭ 7.4 Hz, 1
H, 2-H), 6.64 (d, J ϭ 8.8 Hz, 2 H, 3Ј-H, 5Ј-H), 7.19 (d, J ϭ 8.8
3
3
7
8
1
1
.68 (d, J ϭ 8.6 Hz, 1 H, 5-H), 7.71 (d, J ϭ 8.4 Hz, 1 H, 3-H),
.23 (d, J ϭ 8.4 Hz, 1 H, 4-H). Ϫ 1 C NMR (CDCl
16.27, 121.75 (q, J ϭ 275.0 Hz, CF ), 125.41, 128.22, 128.75,
30.57, 137.93, 138.27, 146.17, 146.54 (q, J ϭ 34.1 Hz, 2-C). These
3
3
): δ ϭ 17.51,
1
3
Hz, 2 H, 2Ј-H, 6Ј-H), 9.54 (d, J ϭ 7.4 Hz, 1 H, CHO). Ϫ
NMR (CDCl ): δ ϭ 40.04 (2 C), 111.50 (2 C), 123.30 (q, J
276.1 Hz, CF ), 125.69, 128.30 (q, J ϭ 4.9 Hz, 2-C), 131.68 (2 C),
48.15 (q, J ϭ 30.4 Hz, 3-C), 151.77, 192.55 (CϭO). Ϫ
N (243.2): calcd. C 59.26, H 4.97; found C 58.89, H 4.90.
C
F
3
3
F
ϭ
F
[
7c]
3
F
spectral data are in good accord with those reported in ref.
-(Trifluoromethoxy)-2-(trifluoromethyl)quinoline (3g): According
to GP II, yield 0.59 g (72%), pale yellow crystals, m.p. 52Ϫ53°C.
1
F
6
12 13 3
C H F
1
(E)-3-(4-Anilinophenyl)-4,4,4-trifluoro-2-butenal (4b): Obtained ac-
3
Ϫ H NMR (CDCl ): δ ϭ 7.65 (dd, J ϭ 9.2 Hz, 2.1 Hz, 1 H, 7-
H), 7.71 (d, J ϭ 2.1 Hz, 1 H, 5-H), 7.78 (d, J ϭ 8.7 Hz, 1 H, 3-
cording to GP III, yield 0.80 g (94%), yellow-orange crystals, m.p.
Ϫ1
5
7Ϫ58°C. Ϫ IR (Nujol): ν˜ ϭ 3330 cm (NϪH), 1670 (CϭH),
H), 8.25 (d, J ϭ 9.2 Hz, 1 H, 8-H), 8.34 (d, J ϭ 8.7 Hz, 1 H, 4-
1
H). Ϫ 1 C NMR (CDCl
3
1600 (CϭC). Ϫ H NMR (CDCl
dq, 1 H, J ϭ 7.4 Hz, J ϭ 1.1 Hz, H-2), 7.02Ϫ7.07 (m, 3 H),
.17Ϫ7.21 (m, 2 H), 7.26 (d, J ϭ 8.3 Hz, 2 H), 7.30 (dd, J ϭ 7.9
Hz, 7.4 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 9.62 (d, J ϭ 7.4 Hz, 1 H, CHO).
3
): δ ϭ 6.25 (br. s, 1 H, NH), 6.53
3
): δ ϭ 116.84, 117.47, 120.87 (q, J
H), 121.95 (q, J ϭ 273.0 Hz, CF C), 124.56, 128.82,
32.24, 137.70, 144.99, 148.05 (q, J ϭ 34.1 Hz, 2-C), 148.17. Ϫ
N (281.2): calcd. C 46.99, H 1.79; found C 46.58, H 1.97.
F
ϭ
(
F
2
1
56.9 Hz, CF
3
F
3
7
F
11 6 6
C H F
1
3
Ϫ
3
C NMR (CDCl ): δ ϭ 115.24 (2 C), 119.40, 119.98 (2 C),
5,7-Dichloro-2-(trifluoromethyl)quinoline (3h): Obtained according
122.82, 123.05 (q, JF ϭ 275.6 Hz, CF ), 129.18 (q, JF ϭ 4.9 Hz, 2-
3
to GP II, yield 0.73 g (94%), pale yellow crystals, m.p. 86Ϫ87°C.
C), 129.38 (2 C), 131.49 (2 C), 140.85, 146.35, 147.78 (q, J ϭ 30.9
F
1
Ϫ H NMR (CDCl
J ϭ 8.8 Hz, 1 H, 3-H), 8.09 (d, J ϭ 2.0 Hz, 1 H, 8-H), 8.66 (d,
J ϭ 8.8 Hz, 1 H, 4-H). Ϫ 13C NMR (CDCl
): δ ϭ 117.62, 121.05
q, J ϭ 274.0 Hz, CF ), 125.41, 128.15, 129.19, 132.21, 135.15,
36.17, 147.60, 149.62 (q, J ϭ 34.8 Hz, 2-C). Ϫ C10 Cl
266.0): calcd. C 45.15, H 1.52; found C 44.79. H 1.65.
3
): δ ϭ 7.67 (d, J ϭ 2.0 Hz, 1 H, 6-H), 7.79 (d, Hz, 3-C), 192.18 (CϭO). Ϫ C H F N (291.3): calcd. C 65.98, H
16 13 3
4.15; found C 65.88, H 4.13.
E)-3-(4-Anilino-1-naphthyl)-4,4,4-trifluoro-2-butenal (4c): Obtained
according to GP III, yield 0.95 g (95%), bright yellow crystals, m.p.
3
(
(
F
3
1
F
H
4
2 3
F N
Ϫ1
1
05Ϫ107°C. Ϫ IR (Nujol): ν˜ ϭ 3350 cm (NϪH), 1680 (CϭH),
(
1
1
600 (CϭC). Ϫ H NMR (CDCl ): δ ϭ 6.25 (br. s, 1 H, NH), 6.83
3
5
-Methyl-2-(trifluoromethyl)quinoline (3i) and 7-Methyl-2-(trifluor-
F
(dq, J ϭ 7.3 Hz, J 1.2 Hz, 1 H, 2-H), 7.04 (t, J ϭ 7.8 Hz, 1 H,
1
omethyl)quinoline (3j). ؊ Mixture 1:8 ( H NMR): Obtained accord- 4ЈЈ-H), 7.15 (d, J ϭ 8.4 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 7.35Ϫ7.30 (m, 3
ing to GP II, yield 0.56 g (91%), colorless crystals. Ϫ 1H NMR
H), 7.58Ϫ7.48 (m, 3 H), 7.74 (d, J ϭ 7.9 Hz, 1 H, 2Ј-H), 8.07 (m,
CDCl ) of 3j: δ ϭ 2.51 (s, 3 H, CH ), 7.40 (d, J ϭ 8.6 Hz, 1 H, 1 H, 8Ј-H), 9.31 (d, J ϭ 7.7 Hz, 1 H, CHO). Ϫ C NMR (CDCl
-H), 7.57 (d, J ϭ 8.6 Hz, 1 H, 5-H), 7.68 (d, J ϭ 8.4 Hz, 1 H, 3- δ ϭ 110.49, 119.14, 119.82 (2 C), 120.64, 121.46, 122.42, 122.49 (q,
1
3
(
6
3
3
3
):
1
H), 7.91 (s, 1 H, 8-H), 8.17 (d, J ϭ 8.4 Hz, 1 H, 4-H). Ϫ H NMR
J
F
ϭ 274.7 Hz, CF
3
), 125.47, 125.74, 126.08, 127.69, 128.90, 129.50
940
Eur. J. Org. Chem. 1999, 937Ϫ941

Efficient Synthesis of 2-Trifluoromethylquinolines
FULL PAPER
(
(
2 C), 132.91 (q, J
F
ϭ 4.5 Hz, 2-C), 133.46, 141.17, 142.36, 147.17
N (341.3): calcd.
extracted with CH
were dried with MgSO
tion from 1,2-dichloroethane gave 1.08 g (78%) of 5 as yellow pow-
2
Cl
2
(2 ϫ 40 mL). The combined organic layers
4
and concentrated in vacuo. Recrystalliza-
q, J ϭ 32.1 Hz, 3-C), 192.01 (CϭO). Ϫ C20
F
H
15
F
3
C 70.38, H 4.13; found C 69.97, H 4.08.
E)-3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-2-yl)-4,4,4-trifluoro-
-butenal (4d): Obtained according to GP III, yield 0.83 g (89%),
yellow-green crystals, m.p. 133Ϫ135°C (dec). Ϫ IR (Nujol): ν˜ ϭ
1
der, m.p. 229Ϫ231°C. Ϫ H NMR {CD
δ ϭ 7.64 (d, J ϭ 9.5 Hz, 1 H, 6-H,), 7.85Ϫ7.79 (m, 5 H), 7.96Ϫ8.00
m, 2 H), 8.24Ϫ8.27 (m, 1 H), 8.52 (d, J ϭ 9.5 Hz, 1 H, 5-H),
3 6
OD/[D ]acetone (1:1)}:
(
2
(
1
3
Ϫ1
(NϪH), 1670 (CϭH), 1610 (CϭC). Ϫ 1H NMR
), 6.37 (br. s, 1 H, NH), 6.55 (d,
8.82Ϫ8.86 (m, 2 H), 9.65 (d, J ϭ 6.4 Hz, 1 H, 3-H). Ϫ C NMR
CD OD/[D ]acetone (1:1)}: δ ϭ 118.27, 121.63 (q, J ϭ 319.1 Hz,
CF S), 122.97 (q, J ϭ 7.2 Hz), 123.93 (q, J ϭ 274.6 Hz, CF C),
27.02, 127.47 (2 C), 129.25 (q, J ϭ 33.2 Hz, 1-C), 129.53 (q, J
.2 Hz), 130.74, 131.00, 131.63 (2 C), 132.21, 133.04, 133.85,
NS (473.4): calcd. C
3
350 cm
CDCl ): δ ϭ 3.00 (s, 4 H, 2 CH
J ϭ 7.3 Hz, 1 H, 2-H), 6.76 (d, J ϭ 8.2 Hz, 1 H, 4Ј-H or 6Ј-H),
.79 (d, J ϭ 8.0 Hz, 1 H, 4Ј-H or 6Ј-H), 6.85 (dd, J ϭ 7.6 Hz, 7.2
Hz, 1 H, 8Ј-H), 7.14Ϫ7.04 (m, 4 H), 9.64 (d, J ϭ 7.3 Hz, 1 H,
{
3
6
F
(
3
2
3
F
F
3
1
7
F
F
ϭ
6
CHO). Ϫ 1 C NMR (CDCl
1
1
J
3
140.61, 141.98, 145.12, 148.19. Ϫ C21
3.28, H 2.77; found C 53.00, H 2.44.
16 6
H F
3
): δ ϭ 34.59, 35.25, 117.95, 118.41,
ϭ 274.8 Hz, CF ), 127.02, 127.71,
28.84, 129.29, 129.38, 130.52, 133.06, 141.17, 144.73, 147.76 (q,
ϭ 30.9 Hz, 3-C), 192.31 (CϭO). Ϫ C18 N (317.3): calcd.
5
18.92, 120.64, 123.06 (q, J
F
3
F
15 3
H F
C 68.13, H 4.45; found C 68.20, H 4.51.
Acknowledgments
3
-(9H-Carbazol-3-yl)-4,4,4-trifluoro-2-butenal (4e): According to
1
The research described in this publication was partially sup-
ported by the Russian Fundamental Investigation Foundation
(Grant 97-03-33006a). We also thank the International Soros Sci-
ence Education Program and the Moscow Government (Grant a97-
GP III, yield 0.66 g (78%), E/Z ϭ 10:1 ( H NMR), pale yellow
powder, m.p. 94Ϫ96°C. Ϫ IR (Nujol): ν˜ ϭ 3400 cm (NϪH),
1
Ϫ1
1
695 (CϭH), 1610 (CϭC). Ϫ H NMR (CDCl
3
) of E-4e: δ ϭ 6.70
(d, J ϭ 7.4 Hz, 1 H, 2-H), 7.26 (dd, J ϭ 7.7 Hz, 7.0 Hz, 1 H, 6Ј-
2
3) for the financial support.
H), 7.49Ϫ7.35 (m, 4 H), 8.03 (d, J ϭ 8.2 Hz, 1 H, 2Ј-H), 8.07 (s, 1
H, 4Ј-H), 8.34 (br. s, 1 H, NH), 9.60 (d, J ϭ 7.4 Hz, 1 H, CHO).
1
[1] [1a]
Ϫ H NMR (CDCl
3
) of Z-4e: δ ϭ 6.49 (d, J ϭ 7.8 Hz, 1 H, 2-H),
M. Hudlicky, Chemistry of Organic Fluorine Compounds,
[1b]
Ellis Horwood Ltd., Chichester, 1992. Ϫ
I. Ojima, J. R.
8
.28 (br. s, 1 H, NH), 10.26 (d, J ϭ 7.8 Hz, 1 H, CHO), remaining
13
McCarthy, J. T. Welch, Biomedical Frontiers of Fluorine Chemis-
try, ACS Symposium Series, no. 639, Washington, 1996.
C. J. Ohnmatch, A. R. Patel, R. E. Lutz, J. Med. Chem. 1971,
14, 926Ϫ928.
signals covered by those of the major isomer. Ϫ C NMR (CDCl
for E-4e: δ ϭ 110.86, 110.98, 119.61, 120.31, 120.56, 122.56, 122.62,
3
)
[2]
1
J
1
1
22.98 (q, J
F
ϭ 275.5 Hz, CF
3
), 123.43, 126.92, 127.36, 130.09 (q,
ϭ 31.3 Hz, 3-C),
) for Z-4e: δ ϭ 125.52, 126.78,
28.31, 131.85, 190.05 (CϭH). Remaining signals coincide with
[
[
3]
4]
J. B. Dickey, J. G. McNally (Eastman Kodak Co), US 2432393,
1947; Chem. Abstr. 1948, 2441Ϫ2444.
F
4.8 Hz, 2-C), 139.88, 140.47, 149.01 (q, J
F
92.67 (CϭO). Ϫ 1 C NMR (CDCl
3
3
M. S. Raasch, J. Org. Chem. 1962, 27, 1406Ϫ1409.
Y. Kobayashi, I. Kumadaki, Tetrahedron Lett. 1969,
4095Ϫ4097.
[5]
11 3
those of the major isomer or are not detected. Ϫ C16H F N
[
[
6] [6a]
G. S. Bajwa, M. M. Jouille, J. Heterocycl. Chem. 1972, 9,
(
289.3): calcd C 66.44, H 3.48; found C 66.23, H 3.49.
E)-3-(4-Anilinophenyl)-4,4,5,5,5-pentafluoro-2-pentenal (9): Ob-
O (0.83
[
6b]
1
403Ϫ1405. Ϫ
J. Froissard, J. Grenier, R. Pastor, A. Cam-
(
bon, J. Fluorine Chem. 1981, 17, 249Ϫ263.
7] [7a]
tained according to GP III from 6 (0.64 g, 2.93 mmol), Tf
2
R. J. Linderman, K. S. Kirollos, Tetrahedron Lett. 1990, 31,
[7b]
2
689Ϫ2692. Ϫ
I. I. Gerus, L. V. Kropachev, M. G. Gorbu-
g, 2.93 mmol) and diphenylamine (1.00 g, 5.86 mmol). Yield 0.85
nova, A. Ya. Ilchenko, V. P. Kukhar, Ukr. Khim. Zh. (Russ. Ed.)
g (85%), yellow-green crystals, m.p. 112°C. Ϫ IR (Nujol): ν˜ ϭ 3380
[7c]
1
993, 59, 408Ϫ411; Chem. Abstr. 1994, 120, 8458x. Ϫ
H.
[7d]
cm (NϪH), 1685 (CϭH), 1600 (CϭC). Ϫ 1H NMR (CDCl
Ϫ1
3
):
Keller, M. Schlosser, Tetrahedron 1996, 52, 4637Ϫ4644. Ϫ
δ ϭ 5.20 (br. s, 1 H, NH), 6.58 (d, 1 H, J ϭ 7.3 Hz, H-2), 7.03Ϫ7.06
m, 3 H), 7.30 (dd, J ϭ 8.5 Hz, 1.1 Hz, 2 H), 7.26 (d, J ϭ 8.6 Hz,
M. Schlosser, H. Keller, Shin-ichi Sumida, J. Yang, Tetrahedron
Lett. 1997, 38, 8523Ϫ8526.
8] [8a]
(
[
M. Hojo, R. Masuda, Y. Kokuryo, H. Shioda, S. Matsuo,
2
7
3
2
H), 7.30 (dd, J ϭ 8.5 Hz, 8.4 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 9.57 (d, J ϭ
.3 Hz, 1 H, CHO). Ϫ 13C NMR (CDCl
): δ ϭ 112.55 (tq, J
6.7 Hz, 256.4 Hz, CF ), 115.24 (2 C), 118.76 (qt, J ϭ 37.7 Hz,
85.6 Hz, CF ), 119.72, 120.1 (2 C), 122.98, 129.48 (2 C), 131.85
ϭ 22.0 Hz, 3-C), 191.85
N (341.3): calcd. C 59.83, H 3.54; found C
[8b]
Chem. Lett. 1976, 499Ϫ502. Ϫ
Takata, J. Org. Chem. 1995, 60, 3523Ϫ3528. Ϫ
A. P. Martins, G. Clar, S. Krimmer, P. Fischer, Synthesis 1991,
T. Moriguchi, T. Endo, T.
[8c]
3
F
ϭ
A. Colla, M.
2
F
[
8d]
4
83Ϫ486. Ϫ
S. I. Vdovenko, I. I. Gerus, M. G. Gorbunova,
3
J. Chem. Soc., Perkin Trans. 2 1993, 559Ϫ562.
I. L. Baraznenok, V. G. Nenajdenko, E. S. Balenkova, Tetra-
hedron 1998, 54, 119Ϫ128.
(2 C), 132.80, 140.86, 146.16, 147.62 (t, J
CϭO). Ϫ C17
F
[9]
(
13 5
H F
[10]
5
9.56, H 3.55.
B. Singer, G. Maas, Chem. Ber. 1987, 1683Ϫ1690.
M. P. Palmer, J. Chem. Soc. 1962, 3645Ϫ3652.
N. P. Buu-Hoi, N. Noan, J. Am. Chem. Soc. 1951, 73, 96Ϫ100.
G. Maas, R. Rahm, M. Schletz, E.-U. Würthwein, J. Org.
Chem. 1994, 59, 6862Ϫ6864.
[11]
4
-Phenyl-1-(trifluoromethyl)-4-benzo[f]quinolinium Trifluorometh-
[12]
[13]
anesulfonate (5): A suspension of 2 was prepared according to GP
I from 1 (0.5 g, 2.93 mmol) and Tf O (0.83 g, 2.93 mmol), then N-
phenyl-2-naphthylamine (1.28 g, 5.86 mmol) was added and the
reaction mixture was stirred at 40Ϫ60°C for 2 h. After quenching
with water, the organic layer was separated, the aqueous layer was
2
[14]
P. J. Stang, M. Hanack, L. R. Subramanian, Synthesis 1982,
2
, 85Ϫ126.
Received November 2, 1998
[O98486]
Eur. J. Org. Chem. 1999, 937Ϫ941
941