Convenient synthesis of fluorinated quinoline, 1,2-dihydroquinoline, and 1,2,3,4-tetrahydroquinoline derivatives

Article abstract of DOI:10.1016/j.tet.2006.12.086

A convenient synthetic method for 2-polyfluoroalkylated quinoline systems through the efficient generation of perfluoroalkylated imine from o-vinylanilines with perfluorinated hemiacetals or aldehyde hydrates was developed. In most cases, the major produc

Full text of DOI:10.1016/j.tet.2006.12.086

Tetrahedron 63 (2007) 2153–2160
Convenient synthesis of fluorinated quinoline, 1,2-
dihydroquinoline, and 1,2,3,4-tetrahydroquinoline derivatives
a
Hikaru Yanai, Hideyuki Mimura, Kosuke Kawada and Takeo Taguchi
b
b
a,*
a
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b
Research Laboratory, TOSOH F-TECH, Inc., 4988 Kaisei-cho, Shunan, Yamaguchi 746-0006, Japan
Received 7 December 2006; revised 22 December 2006; accepted 25 December 2006
Available online 22 January 2007
Abstract—A convenient synthetic method for 2-polyfluoroalkylated quinoline systems through the efficient generation of perfluoroalkylated
imine from o-vinylanilines with perfluorinated hemiacetals or aldehyde hydrates was developed. In most cases, the major products are 2-poly-
fluoroalkyl-1,2-dihydroquinoline derivatives 3, which can be converted to either quinolines or 1,2,3,4-tetrahydroquinolines.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives using chlorotrimethylsilane (TMSCl) as the
industrially usable dehydrating reagent.
The use of fluorinated heterocyclic compounds as bioactive
or functional molecules has been increasing recently. In
1
a number of fluorinated heterocycles, 2-trifluoromethyl-
quinoline moiety is widely found in development of drugs
such as antimalarials, PDE4 inhibitors, DPP-IVinhibitors,
2. Results and discussion
2
3
4
It has been reported that thermal 6p-cyclization reaction of
o-vinyl anils, which are prepared from o-vinylanilines and
benzaldehyde derivatives, followed by air oxidation gives
5
and other bioactive molecules. Furthermore, 2-trifluoro-
methyl-1,2-dihydroquinoline derivatives have selective
COX-2 inhibitory activity. For the synthesis of 2-trifluoro-
6
16
rise to the corresponding quinoline compounds. This
methylquinoline compounds, the use of fluorinated building
blocks, e.g., trifluoroacetate derivatives, trifluoromethyl-
reaction requires high reaction temperature for the smooth
reaction, although excellent yields are generally observed.
Furthermore, the consecutive imine formation, cyclization,
and oxidation steps can be conducted in one pot. As an ex-
tension of this procedure, we examined the reaction of o-iso-
propenylaniline 1a with TFAE. Thus, as shown in Scheme 1,
the reaction of 1a with TFAE (2.2 equiv) was carried out at
7
8
9
ated 1,3-diketones, trifluoromethylimidoyl chloride, and
trifluoroacetaldehyde, has been reported, but most of these
methods have several problems from a viewpoint of conve-
nience and/or industrial use. Among such fluorinated build-
ing blocks, trifluoroacetaldehyde ethyl hemiacetal (TFAE)
1
0–12
ꢁ
is a cheap and useful trifluoroacetaldehyde equivalent.
100 C for 9 h in toluene to give 2-trifluoromethylquinoline
However, direct use of TFAE for 2-trifluoromethylquinoline
synthesis would not be easy due to the strong ꢀI effects of
trifluoromethyl group, which make the generation of tri-
2a (37% yield) and 2-trifluoromethyl-1,2-dihydroquinoline
3a (6% yield) with the recovery of 1a. Under the similar con-
ditions, addition of pyridine as a base to the reaction mixture
reduced the yield of 2a to a trace amount. Although it was
reported that the reactions of o-vinylanilines with less
1
3
fluoromethylated imines difficult. Indeed, synthesis of
-trifluoromethylquinoline derivativesfromisolatedtrifluoro-
2
1
7
18
methylated anils has been known, but direct synthesis from
trifluoroacetaldehyde hydrate or hemiacetals has not been
reactive ketones are catalyzed by iodine or Lewis acids,
the use of Lewis acids, such as BF $OEt , ZnI , Yb(OTf)
Sc(OTf) , and In(OTf) , did not give any desired products
,
3
3
2
2
1
4,15
reported.
In this paper, we would like to report a conve-
3
3
nient synthesis of 2-polyfluoroalkylated quinolines through
the direct in situ formation of polyfluoroalkylated anils
from fluorinated aldehyde hydrate/hemiacetals and aniline
in this reaction.
Me
Me
Me
1
2
) TFAE, rt, 1 h
) toluene,
N
H
CF3
NH2
1
00 °C, 9 h
N
CF3
Keywords: Fluorinated heterocycles; Quinoline; 1,2-Dihydroquinoline; Tri-
fluoroacetaldehyde ethyl hemiacetal.
1a
2a 37%
3a 6%
*
Corresponding author. Tel./fax: +81 42 676 3257; e-mail: taguchi@ps.
toyaku.ac.jp
Scheme 1.
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.086

2154
H. Yanai et al. / Tetrahedron 63 (2007) 2153–2160
We found that addition of TMSCl as an additive and the use
of pyridine as the solvent remarkably promoted the forma-
tion of the desired products 2a/3a (Table 1). A mixture of
products (entry 3). As shown in Scheme 2, a remarkable dif-
ference in the reactivity between E/Z isomer of a-phenyl-b-
methyl derivative 1e having trisubstituted olefin moiety was
observed. The reaction of an E/Z mixture of 1e (1:1) was
1
for 1 h, was treated with TMSCl (1.5 equiv) at 100 C for
a and TFAE (1.1 equiv), premixed at room temperature
ꢁ
h in toluene to give quinoline 2a (36% yield) and 1,2-dihy-
ꢁ
conducted at 100 C for 10 h to give a mixture of 2e and
9
3e in 57% yield (2e/3e¼1:7.3). Under the same conditions,
pure (E)-1e was converted to a mixture of 2e/3e in 81% yield
(2e/3e¼1:6.9), while (Z)-1e gave a mixture of the cyclized
products in only 7% yield. Thus, (E)-isomer, (E)-1e, is more
reactive than (Z)-isomer. Although a certain limitation
regarding the substituent types would be involved, the pres-
ent reaction provides a convenient preparative method for
3,4-disubstituted 2-trifluoromethylquinoline systems. The
reaction of secondary aniline 1f required longer reaction
time (72 h) than that of primary aniline 1a, obtaining
N-benzyl-1,2-dihydroquinoline 3f in 52% yield (Table 2,
entry 4).
droquinoline 3a (17% yield). In toluene, the improvement of
the product yields was not realized by increasing the molar
equivalent of TMSCl (3.0 equiv) or by the use of 2.2 equiv
of TFAE and 3.0 equiv of TMSCl under the similar condi-
tions (entries 2 and 3). On the other hand, using pyridine
as the solvent, the desired quinoline derivatives 2a/3a were
obtained in high yields (2a 9% yield and 3a 89% yield, entry
4
). As shown in entry 5, the reaction rate was also increased
under the concentrated conditions (0.2 M of 1a in pyridine)
without loss of the isolated yields of 2a (8% yield) and 3a
(
87% yield). However, under the concentrated conditions,
the reaction using 1.1 equiv of TFAE and 2.2 equiv of
TMSCl gave poor result (2a 7% yield and 3a 57% yield, en-
try 6). In the absence of TMSCl in pyridine or in the presence
of pyridine hydrochloride, no desired products 2a/3a were
obtained with the recovery of 1a (92%, entry 7). These re-
sults indicate that the concentration of substrate 1a and the
molar ratio of 1a, TFAE, and TMSCl plays an important
role to obtain the products in good yield (see, entry 6). Fur-
thermore, reaction solvents altered the product selectivity.
Thus, while quinoline 2a was favorably formed in toluene,
the reaction in pyridine produced 1,2-dihydroquinoline 3a
as the major product.
Product ratio (2 vs 3) was strongly influenced by the elec-
tronic nature of the substituent(s) on the aryl group. The
reaction of 2-isopropenyl-4,5-dimethoxyaniline 1g, having
electron-donating group proceeded smoothly to give only
quinoline form 2g in 63% yield with small amount of tero-
meric products (entry 5).
In contrast, the reaction of 5-chloro-2-isopropenylaniline 1h
having electron-withdrawing group provided only 1,2-di-
hydroquinoline form 3h in 83% yield without the formation
of the quinoline product (entry 6). The reaction of 3-isopro-
penyl-2-naphthalenamine 1i with TFAE was also examined
to give a complex mixture due to the decomposition of sub-
strate and/or products (entry 7).
Next, the reactions of various o-vinylanilines 1 were exam-
ined under the optimal conditions for 1a. The results are
summarized in Table 2. As shown in entry 1, the reactivity
of non-substituted substrate 1b decreased notably, and the
reaction of 1b using 4.4 equiv of TFAE and 6.0 equiv of
Next, we applied the present TMSCl/pyridine system to the
reaction of 1a with other fluorinated hemiacetals (Table 3).
Treatment of 1a with 2.2 equiv of pentafluoropropanal
hydrate and 4.0 equiv of TMSCl gave a mixture of 2-penta-
fluoroethyl quinoline 2j and dihydroquinoline 3j in 47%
yield (2j/3j¼1:10, entry 1). On using 1.5 equiv of penta-
fluoropropanal hydrate, the yield of 2j/3j was improved to
89% (entry 2). The reaction of 1a and chlorodifluoroacetal-
dehyde ethyl hemiacetal (2.2 equiv) with TMSCl (3.0 equiv)
efficiently proceeded to give a mixture of the products 2k/3k
in 70% yield in a ratio of 1:12.
ꢁ
TMSCl at 120 C for 23 h gave a mixture of 2b/3b in only
3
8% (2b/3b¼1:9.6). As in the case of a-methyl derivative
1
a, a-phenyl derivative 1c was also a good substrate giving
rise to a mixture of 2c and 3c in 87% yield with excellent
selectivity (2c/3c¼1:>20, entry 2). On the other hand, the
reaction of trans-b-phenyl derivative 1d with 4.4 equiv of
TFAE and 6.0 equiv of TMSCl gave imine 4d as a stable
product in 82% yield without the formation of any cyclized
Table 1. Survey of reaction conditions for cyclization of 1a with TFAE
As shown above, since in most cases 1,2-dihydroquinoline
derivatives 3 were obtained as the major products, we exam-
ined the conversion of 3 to quinolines 2 or 1,2,3,4-tetra-
hydroquinolines 5 (Scheme 3). Air oxidation of 3a at room
temperature for 2 days provided quinoline 2a in 98% yield.
Moreover, hydrogenation reaction of 3a catalyzed by palla-
dium on carbon proceeded smoothly to give cis-4-methyl-
Me
Me
Me
TFAE
rt, 1 h
TMSCl
100 °C
1a
1
6
N
H
CF3
NH2
N
CF3
1a
2a
3a
a
Yield (%)
2-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline cis-5a in
quantitative yield with perfect diastereoselectivity.
Entry TFAE
(
TMSCl Solvent
equiv) (equiv) (Concn of 1a, M) (h)
Time
2
a
3a
1
2
3
4
5
6
7
1.1
1.1
2.2
2.2
2.2
1.1
2.2
1.5
3.0
3.0
3.0
3.0
2.2
None
Toluene (0.1)
Toluene (0.1)
Toluene (0.1)
Pyridine (0.1)
Pyridine (0.2)
Pyridine (0.2)
Pyridine (0.2)
9
9
9
9
6
9
9
36
50
36
9
8
7
17
—
18
89
87
57
0
Concerning the reaction mechanism, we assume that TMSCl
promotes the imine formation step through O-silylation re-
action of N,O-hemiacetal intermediate A under basic condi-
tion leading to imine 4 (Scheme 4). The cyclization process
should involve electrocyclic ring-closing of 6p system fol-
lowed by 1,5-H shift to provide 1,2-dihydroquinoline deriv-
b
0
1
6
a
ative 3. It should be noted that TMSCl possibly promotes
not only the imine formation, but also this electrocyclic
Isolated yield.
Compound 1a of 92% was recovered.
b

H. Yanai et al. / Tetrahedron 63 (2007) 2153–2160
Table 2. Reactions of various o-isopropenylanilines 1 with TFAE
2155
R1
R1
R1
N
R2
1) TFAE (2.2 eq)
rt, 1 h
R2
R2
R4
R4
R4
NHR3
2) TMSCl (3.0 eq)
pyridine
N
CF3
CF3
3
R
1
2
3
a
b
Entry
1
Temp
ꢁ
Time
(h)
2–4
Yield
(%)
Ratio
(2/3)
(
C)
c
1
1b
1c
120
100
100
100
23
7
2b
2c
3b
38
87
82
52
1:9.6
N
CF3
CF3
N
H
CF3
CF3
NH2
Ph
Ph
N
Ph
2
3
4
3c
1:>20
—
N
H
NH2
Ph
Ph
1d
5
4d
NH2
Me
N
CF3
Me
1f
72
3f
3f only
N
CF3
NHBn
Me
Bn
Me
MeO
MeO
MeO
d
2
g
5
1g
100
100
100
6
10
12
63
83
2g only
3h only
—
NH2
MeO
N
CF3
Me
Me
6
1h
3h
Cl
N
H
CF3
Cl
NH2
Me
7
1i
—
Complex
NH2
a
Isolated yield.
Based on F NMR of a crude mixture.
TFAE (4.4 equiv) and TMSCl (6.0 equiv) were used.
Small amount of teromeric products was obtained.
b
c
d
19
process as a Lewis acid catalyst. By considering this electro-
cyclic cyclization process requiring conformational control
of imine intermediate 4 to be cisoid form, the observed
substituent effect on the reactivity can be explained. For ex-
(Table 2, entry 1 vs entry 2). This would be due to the desta-
bilization of the transoid form 4 by the steric repulsion be-
1
1
tween R (R ¼Me or Ph) and bulky trifluoromethylimine
moiety, whereas such a steric repulsion should be signifi-
cantly diminished in the case of non-substituted substrate
1
ample, as in the cases of 1a and 1c (R ¼Me and Ph), intro-
1
duction of a-substituent facilitated the cyclization reaction
as compared with non-substituted substrate 1b (R ¼H)
1b (R ¼H).
1
Me
Me
air
rt, 2 d
Ph
Ph
Ph
1
) TFAE (2.2 eq)
Me
Me
N
H
CF3
Me
N
CF3
CF3
rt, 1 h
3a
2a 98%
2) TMSCl (3.0 eq)
N
CF3
N
H
CF3
NH2
Me
pyridine, 100 °C, 10 h
H2 (1 atm)
2e
3e
5
% Pd/C (3 mol%)
(
E,Z)-1e (1 : 1)
57% (2e : 3e = 1 : 7.3)
81% (2e : 3e = 1 : 6.9)
MeOH, rt, 3 h
N
H
(
E)-1e
Z)-1e
(
7% (ratio was not determined)
cis-5a quant.
Scheme 2.
Scheme 3.

2156
H. Yanai et al. / Tetrahedron 63 (2007) 2153–2160
Table 3. Reaction of o-isopropenylaniline 1a with aldehyde hydrate or hemiacetal
Me
Me
N
Me
OH
1
) TFAE, rt, 2 h
+
+
R1
R1
OR2
2) TMSCl, pyridine
100 °C
NH2
N
H
R1
1a
2
3
1
R CH(OH)OR
2
a
Yield (%)
b
Ratio (2/3)
Entry
TMSCl (equiv)
Time (h)
Products (2 and 3)
Me
Me
OH
1
2
2.2
1.5
4.0
4.0
16
16
47
89
1:10
1:9.8
C2F5
OH
N
C2F5
N
H
C2F5
2j
3j
Me
Me
OH
OEt
3
2.2
3.0
14
70
1:12
ClF2C
N
CF2Cl
N
H
CF2Cl
2k
3k
a
Isolated yield.
Based on F NMR of a crude mixture.
b
19
R1
R1
OH
R1
R2
R2
F3C OEt
R2
TMSCl, py
py·HCl
TMSCl, py
NH
NH
CF3
NH2
(Me Si) O + py·HCl
3
2
HO
CF3
Me3SiO
1
A
B
R2
R1
R1
N
R1
R2
R2
R2
R1
H
N
CF3
N
CF3
CF3
N
H
CF3
4
cisoid
4 transoid
3
Scheme 4.
3
. Conclusion
recorded on a JASCO FT/IR-620 infrared spectrophoto-
meter. Mass spectra (MS) were obtained on a Micromass
LCT (ESI) or Micromass AutoSpec (EI). Medium pressure
liquid chromatography (MPLC) was performed using
prepacked column (KUSANO prepacked column Si-10,
40ꢂ300 mm i.d., silica gel, 50 mm) with UV detector.
We have developed a convenient preparative method for
-polyfluoroalkyl quinoline systems through an efficient
generation of perfluoroalkylated imine from o-vinylanilines
with perfluorinated hemiacetals or aldehyde hydrates, in
particular TFAE as a stable and cheap fluorinating building
block. Furthermore, in most cases the major product is
2
4.2. Preparation of o-vinylanilines (1)
2
-polyfluoroalkyl-1,2-dihydroquinoline derivative 3, which
can be converted to either quinolines or 1,2,3,4-tetrahydro-
quinolines.
2-Isopropenylaniline 1a is available commercially. 2-Vinyl-
aniline 1b, 2-(1-phenylvinyl)aniline 1c, 2-[(E)-2-phenyl-
1
9
20
2
1
22
ethenyl]aniline 1d, N-benzyl-2-isopropenylaniline 1f,
and 2-isopropenyl-4,5-dimethoxyaniline 1g were prepared
by the reported procedure.
2
3
4. Experimental
4
.1. General
4.2.1. 2-(1-Phenyl-1-propenyl)aniline (1e). To a solution of
2-aminobenzophenone (1.97 g, 10 mmol) in THF (50 mL),
EtMgBr (0.87 M in THF, 35 mL, 31 mmol) was added at
1
All reactions were carried out under Ar atmosphere. H and
C NMR spectra were taken on a Bruker dpx400 spectro-
meter, and chemical shifts were reported in parts per million
1
3
ꢁ
ꢀ78 C. After being stirred at room temperature for
30 min, the reaction mixture was quenched by saturated
aqueous solution of NH Cl and filtered through Celite pad.
1
(
CDCl (77.01 ppm) for C NMR as an internal standard.
ppm) using CHCl (7.26 ppm) in CDCl for H NMR and
3
3
4
1
3
After the filtrate was extracted with EtOAc (50 mLꢂ3),
3
1
9
F NMR spectra were taken on a Bruker dpx400 spectro-
the organic layer was washed with brine, dried over an-
hydrous MgSO , and evaporated. The residue was purified
meter or a Varian Mercury 300 spectrometer, and chemical
shifts were reported in parts per million using benzotri-
fluoride (0 ppm) as a standard. Infrared (IR) spectra were
4
with silica gel column chromatography (hexane/EtOAc¼
10:1) to give 1-(2-aminophenyl)-1-phenyl-1-propanol

H. Yanai et al. / Tetrahedron 63 (2007) 2153–2160
2157
ꢁ
(
2.01 g, 8.8 mmol, 88% yield) as yellow crystals. Mp
4.5 mmol) for 30 min at 160 C and the subsequent purifica-
tion by silica gel column chromatography (hexane/EtOAc¼
40:1) gave 5-chloro-2-isopropenylaniline 1i (177 mg,
1.05 mmol, 70% yield) as a colorless oil. IR (neat, n
ꢁ
454, 1161, 748. H NMR (400 MHz, CDCl , d ppm):
ꢀ1
1
1
0
2
6
(
7
(
02 C. IR (neat, n cm ): 3388, 2970, 2935, 1614, 1493,
1
3
.81 (3H, t, J¼7.3 Hz), 2.06 (1H, dq, J¼13.7, 7.3 Hz),
ꢀ1
.20 (1H, dq, J¼13.7, 7.3 Hz), 3.66 (3H, br, NH +OH),
cm ): 3475, 3384, 3080, 2970, 1612, 1491, 1417, 1110,
899. H NMR (400 MHz, CDCl , d ppm): 2.05 (3H, s),
2
1
.49 (1H, br d, J¼7.9 Hz), 6.77 (1H, t, J¼7.5 Hz), 7.02
3
1H, t, J¼7.5 Hz), 7.09–7.16 (1H, m), 7.17–7.24 (2H, m),
3.95 (2H, br, NH), 5.06 (1H, s), 5.31 (1H, s), 6.69 (1H, s),
6.71 (1H, d, J¼7.9 Hz), 6.95 (1H, d, J¼7.9 Hz). C NMR
1
3
13
.27 (2H, d, J¼7.8 Hz), 7.33 (1H, d, J¼7.8 Hz). C NMR
100.6 MHz, CDCl , d ppm): 7.9, 34.8, 78.4, 118.6, 118.7,
3
(100.6 MHz, CDCl , d ppm): 23.7, 115.0, 115.8, 118.0,
3
1
25.8, 126.6, 126.6, 127.9, 128.3, 131.7, 144.5, 145.8.
127.5, 129.2, 133.1, 142.4, 144.0. EIMS (m/z): 168
[M+H] . Anal. Calcd for C H ClN: C, 64.48; H, 6.01; N,
8.36. Found: C, 64.68; H, 6.16; N, 7.96.
+
+
+
ESI-MS (m/z): 228 [M+H] , 210 [(MꢀOH)+H] . HRMS
9
10
+
Calcd for C H NO [M+H] : 228.1388. Found: 228.1371.
1
5 18
The above carbinol (1.93 g, 8.5 mmol) was treated with solid
ꢁ
NH Cl (1.36 g, 25.5 mmol) for 20 min at 180 C. The
4
4.2.3. 3-Isopropenyl-2-naphthalenamine (1j). After a
mixture of 2-(3-amino-2-naphthyl)-2-propanol (300 mg,
2
5
reaction mixture was cooled to ambient temperature and
purified with silica gel column chromatography (hexane/
EtOAc¼40:1) to give the E/Z mixture of 2-(1-phenyl-1-pro-
penyl)aniline (1.30 g, 6.2 mmol, 73% yield, E/Z¼1:1). The
E/Z mixture was separated by MPLC (hexane/EtOAc¼20:1)
to give (Z)-1e (593 mg, 2.83 mmol) as the less polar isomer
and (E)-1e (599 mg, 2.86 mmol) as the more polar isomer.
The stereochemistry of 1e was confirmed by X-ray crystallo-
1.49 mmol) and NH Cl (250 mg, 4.5 mmol) was stirred for
4
ꢁ
1.5 h at 160 C, purification of the resulting mixture by silica
gel column chromatography (hexane/EtOAc¼20:1) gave
3-isopropenyl-2-naphthalenamine 1j (193.2 mg, 1.05 mmol,
67% yield). Yellow crystals. Mp 37.0 C. IR (KBr, n
ꢁ
cm ): 3467, 3377, 3053, 2968, 1633, 1504, 1215, 893,
ꢀ1
1
864. H NMR (400 MHz, CDCl , d ppm): 2.09 (3H, s),
3
2
4
graphic analysis of (E)-1e. Isomer (Z)-1e: colorless oil. IR
neat, n cm ): 3467, 3377, 3018, 2848, 1612, 1493, 1452,
3.95 (2H, br, NH), 5.06 (1H, br s), 5.29 (1H, br s), 7.10–
7.18 (1H, m), 7.23–7.29 (1H, m), 7.44 (1H, s), 7.49 (1H,
ꢀ
1
(
1
1
13
298, 845. H NMR (400 MHz, CDCl , d ppm): 1.74 (3H,
3
d, J¼8.2 Hz), 7.58 (1H, d, J¼8.2 Hz).
C NMR
(100.6 MHz, CDCl , d ppm): 24.1, 108.9, 116.0, 122.5,
d, J¼6.9 Hz), 3.88 (2H, br, NH), 6.41 (1H, q, J¼6.9 Hz),
3
6
7
1
1
.80–6.90 (2H, m), 7.04 (1H, dd, J¼7.5, 1.5 Hz), 7.17–
125.3, 126.0, 127.1, 127.5, 127.8, 132.5, 134.0, 141.5,
143.4. ESI-MS (m/z): 184 [M+H] . HRMS Calcd for
1
3
+
.38 (6H, m). C NMR (100.6 MHz, CDCl , d ppm):
3
+
5.5, 115.8, 118.8, 125.4, 126.0, 126.2, 127.0, 128.3,
28.4, 130.9, 138.7, 140.8. ESI-MS (m/z): 210 [M+H] .
C H N [M+H] : 184.1126. Found: 184.1140.
13 14
+
+
HRMS Calcd for C H N [M+H] : 210.1283. Found:
1
4.3. Typical procedure for cyclization reaction of
o-vinylanilines with TFAE: 4-methyl-2-(trifluoro-
methyl)quinoline (2a) and 4-methyl-2-(trifluoro-
methyl)-1,2-dihydroquinoline (3a)
5 16
ꢁ
IR (KBr, n cm ): 3465, 2796, 1614, 1493, 1450, 1298,
2
10.1286. Isomer (E)-1e: colorless crystals. Mp 67.8 C.
ꢀ
1
1
8
50. H NMR (400 MHz, CDCl , d ppm): 2.00 (3H, br d,
3
J¼7.1 Hz), 3.60 (2H, s, NH), 6.04 (1H, q, J¼7.1 Hz), 6.69
(
1H, d, J¼7.7 Hz), 6.80–6.89 (1H, m), 7.12–7.21 (2H, m),
Under Ar atmosphere, a mixture of 2-isopropenylaniline
(66.7 mg, 0.50 mmol) and TFAE (128 mL, 1.09 mmol) was
stirred for 1 h at room temperature. To the reaction mixture,
chlorotrimethylsilane (190 mL, 1.5 mmol) and dehydrated
pyridine (2.5 mL) were added at room temperature. After
1
3
7
.30–7.48 (5H, m).
C NMR (100.6 MHz, CDCl ,
3
d ppm): 15.5, 115.8, 118.3, 127.1, 128.3, 128.4, 129.3,
30.2, 131.0, 139.5, 140.1, 144.0. ESI-MS (m/z): 210
1
+
+
[M+H] . HRMS Calcd for C H N [M+H] : 210.1283.
15 16
Found: 210.1288.
ꢁ
being stirred for 6 h at 100 C, the reaction mixture was
quenched by H O (4 mL), and extracted with Et O
2
2
4.2.2. 5-Chloro-2-isopropenylaniline (1i). To a solution of
methyl 2-amino-4-chlorobenzoate (0.81 g, 4.36 mmol) in
(3 mLꢂ3). The organic layer was dried over anhydrous
2
2
MgSO , concentrated under reduced pressure, and purified
4
Et O (20 mL), MeMgBr (0.96 M in THF, 21 mL, 20 mmol)
2
was added at ꢀ78 C. After being stirred for 24 h at room
by silica gel column chromatography (hexane/EtOAc¼50:1
to 10:1) to give a mixture of 4-methyl-2-(trifluoromethyl)-
quinoline 2a and 4-methyl-2-(trifluoromethyl)-1,2-dihydro-
quinoline 3a. Further purification by MPLC (hexane/
EtOAc¼20:1) gave 3a (retention time¼24.4 min, 91.9 mg,
0.43 mmol, 87% yield) and 2a (retention time¼26.4 min,
8.6 mg, 0.05 mmol, 8% yield). 4-Methyl-2-(trifluoro-
ꢁ
temperature, the reaction mixture was quenched by saturated
aqueous solution of NH Cl, and filtered through Celite pad.
4
After the filtrate was extracted with EtOAc (30 mLꢂ3), the
organic layer was washed with brine, dried over anhydrous
MgSO , and evaporated. The residue was purified with silica
4
ꢁ
gel column chromatography (hexane/EtOAc¼10:1) to give
methyl)quinoline 2a: colorless crystals. Mp 55.2 C. IR
(KBr, n cm ): 3067, 2954, 1714, 1597, 1151. H NMR
ꢀ1
1
2
6
2
-(2-amino-4-chlorophenyl)-2-propanol (553 mg, 2.98 mmol,
8% yield) as brown oil. IR (neat, n cm ): 3365, 2976,
931, 1612, 1493, 1417, 1142, 1109, 908. H NMR
ꢀ1
(400 MHz, CDCl , d ppm): 2.78 (3H, s), 7.56 (1H, s),
3
1
7.67–7.70 (1H, m), 7.79–7.83 (1H, m), 8.04 (1H, d,
J¼8.3 Hz), 8.21 (1H, d, J¼8.5 Hz). C NMR (100.6 MHz,
1
3
(
400 MHz, CDCl , d ppm): 1.59 (6H, s), 4.01 (3H, br,
3
NH +OH), 6.55 (1H, d, J¼2.1 Hz), 6.61 (1H, dd, J¼8.3,
CDCl , d ppm): 19.4, 117.8, 122.1 (q, J¼275.3 Hz), 124.2,
2
3
1
3
2.1 Hz), 6.97 (1H, d, J¼8.3 Hz). C NMR (100.6 MHz,
CDCl , d ppm): 29.1, 73.7, 116.6, 117.2, 126.8, 129.0,
133.3, 146.8. ESI-MS (m/z): 186 [M+H] . HRMS Calcd
for C H ClNO [M+H] : 186.0663. Found: 186.0686. In
128.7, 129.2, 130.8, 131.1, 147.3, 147.4, 148.0 (q,
J¼34.5 Hz). F NMR (376 MHz, CDCl , d ppm): ꢀ4.9
1
9
3
3
+
+
(3F, s). ESI-MS (m/z): 212 [M+H] . HRMS Calcd for
C H F N: 212.0687. Found: 212.0696 [M+H] . 4-Methyl-
+
+
9
13
11 9 3
a similar manner for the preparation of 1e, reaction of the
above carbinol (278 mg, 1.5 mmol) with NH Cl (262 mg,
2-(trifluoromethyl)-1,2-dihydroquinoline 3a: colorless oil.
IR (neat, n cm ): 3410, 3059, 2923, 1607, 1256, 1121,
ꢀ
1
4

2158
H. Yanai et al. / Tetrahedron 63 (2007) 2153–2160
1
7
(
6
(
50. H NMR (400 MHz, CDCl , d ppm): 2.08 (3H, s), 4.15
3
118.9 (q, J¼271.6 Hz), 123.7, 126.1, 126.8, 127.9, 128.4,
1H, br s, NH), 4.64–4.73 (1H, m), 5.41 (1H, br d, J¼3.8 Hz),
128.6, 128.7, 131.0, 132.2, 137.3, 145.4, 147.2 (q,
J¼38.6 Hz). F NMR (376 MHz, CDCl , d ppm): ꢀ8.21
1
9
.50 (1H, br d, J¼8.0 Hz), 6.68–6.74 (1H, m), 7.01–7.08
3
1
3
+
1H, m), 7.12 (1H, br d, J¼7.7 Hz). C NMR (100.6 MHz,
(3F, d, J¼3.5 Hz). ESI-MS (m/z): 276 [M+H] , 196
+
+
CDCl , d ppm): 18.8, 54.7 (q, J¼31.0 Hz), 110.9, 112.7,
[MꢀC HF +3H] . HRMS Calcd for C H F N [M+H] :
3
2
3
16 13 3
1
1
18.3, 120.0, 124.2, 124.2 (q, J¼285.0 Hz), 129.4, 135.8,
276.1000. Found: 276.0992.
1
9
41.7. F NMR (376 MHz, CDCl , d ppm): ꢀ13.0 (3F, d,
3
+
J¼7.2 Hz). ESI-MS (m/z): 214 [M+H] . HRMS Calcd for
4.3.4. 3-Methyl-4-phenyl-2-(trifluoromethyl)quinoline
(2e) and 3-methyl-4-phenyl-2-(trifluoromethyl)-1,2-di-
hydroquinoline (3e). 3-Methyl-4-phenyl-2-(trifluoromethyl)-
+
C H F N [M+H] : 214.0844. Found: 214.0847.
11 11 3
ꢁ
4.3.1. 2-(Trifluoromethyl)quinoline (2b) and 2-(trifluoro-
methyl)-1,2-dihydroquinoline (3b). Compounds 2b/3b
were obtained as an inseparable mixture (a ratio was
quinoline 2e: colorless crystals. Mp 93.7 C. IR (KBr, n
cm ): 3028, 2935, 1572, 1489, 1373, 1178, 1125, 1039,
ꢀ
1
1
766, 704. H NMR (400 MHz, CDCl , d ppm): 2.35 (3H, q,
3
1
:9.6). The structure of 2b was confirmed by comparison
of spectrum data from a commercially available sample.
-(Trifluoromethyl)-1,2-dihydroquinoline 3b: colorless oil.
J¼1.7 Hz), 7.22–7.28 (2H, m), 7.40 (1H, d, J¼8.5 Hz),
7.46–7.60 (4H, m), 7.69–7.76 (1H, m), 8.22 (1H, d,
J¼8.5 Hz). C NMR (100.6 MHz, CDCl , d ppm): 15.5,
1
3
2
3
ꢀ
1
IR (neat, n cm ): 3689, 3051, 2927, 1649, 1606, 1491,
1255, 1167, 1132, 1120, 840, 748. H NMR (400 MHz,
CDCl , d ppm): 4.14 (1H, br s), 4.73–4.81 (1H, m), 5.48
122.3 (q, J¼276.5 Hz), 125.9, 126.1, 128.3, 128.4, 128.6,
1
128.8, 129.1, 129.4, 130.0, 136.4, 144.7, 146.6 (q,
J¼32.2 Hz), 150.1. F NMR (282 MHz, CDCl , d ppm):
1
9
3
3
(
1H, dd, J¼9.9, 4.6 Hz), 6.48 (1H, d, J¼7.9 Hz), 6.62 (1H,
ꢀ2.5 (3F, s). ESI-MS (m/z): 288. HRMS Calcd for
+
J¼9.9 Hz), 6.66 (1H, t, J¼7.4 Hz), 6.92 (1H, br d,
C H F N [M+H] : 288.1000. Found: 288.1012. 3-Methyl-
1
7 13 3
1
3
J¼7.4 Hz), 7.03 (1H, t, J¼7.9 Hz). C NMR (100.6 MHz,
4-phenyl-2-(trifluoromethyl)-1,2-dihydroquinoline 3e: color-
less oil. IR (neat, n cm ): 3406, 3055, 3026, 2914, 2856,
ꢀ
1
CDCl , d ppm): 54.8 (q, J¼31.2 Hz), 112.6, 113.6, 118.5,
3
1
9
1
1
24.0 (q, J¼284.8 Hz), 129.7, 130.5, 141.5. F NMR
1604, 1489, 1251, 1161, 1124. H NMR (400 MHz, CDCl ,
3
(
MS (m/z): 200 [M+H] . HRMS Calcd for C H F N:
282 MHz, CDCl , d ppm): ꢀ18.1 (3F, d, J¼7.9 Hz). ESI-
d ppm): 1.77 (3H, s), 4.43 (1H, q, J¼7.4 Hz), 6.51 (1H, dd,
J¼7.8, 1.4 Hz), 6.57 (1H, br d, J¼7.5 Hz), 6.61 (1H, d,
J¼7.8 Hz), 7.01 (1H, td, J¼7.5, 1.4 Hz), 7.06–7.14 (1H, m),
3
+
1
0 9 3
+
2
00.0687. Found: 200.0676 [M+H] .
1
3
7.22–7.14 (1H, m), 7.33–7.50 (3H, m).
C NMR
4
4
4
.3.2. 4-Phenyl-2-(trifluoromethyl)quinoline (2c) and
-phenyl-2-(trifluoromethyl)-1,2-dihydroquinoline (3c).
-Phenyl-2-(trifluoromethyl)quinoline 2c: colorless crystals.
(100.6 MHz, CDCl , d ppm): 19.8, 58.5 (q, J¼29.3 Hz),
3
112.5, 118.5, 119.4, 122.4, 125.2 (q, J¼290.2 Hz), 126.6,
19
127.3, 128.3, 128.4, 128.5, 129.1, 130.2, 137.8, 137.9,
ꢁ
ꢀ1
Mp 59.8 C. IR (KBr, n cm ): 3062, 2777, 1589, 1468,
140.6. F NMR (376 MHz, CDCl , d ppm): ꢀ14.5 (3F, d,
3
1
1383, 1263, 1187, 1136, 1093, 887. H NMR (400 MHz,
CDCl , d ppm): 7.50–7.59 (6H, m), 7.59–7.67 (1H, m),
J¼7.4 Hz). ESI-MS (m/z): 290. HRMS Calcd for
+
C H F N [M+H] : 290.1157. Found: 290.1162.
17 15 3
3
7
.69 (1H, s), 8.00 (1H, d, J¼8.4 Hz), 8.31 (1H, d,
3
1
3
J¼8.4 Hz). C NMR (100.6 MHz, CDCl , d ppm): 117.4,
4.3.5. 1-Benzyl-4-methyl-3-phenyl-2-(trifluoromethyl)-
1,2-dihydroquinoline (3f). Colorless crystals. Mp 82.1 C.
ꢁ
IR (KBr, n cm ): 3021, 2921, 1658, 1602, 1495, 1157,
1
1
1
22.1 (q, J¼275.5 Hz), 126.3, 127.8, 129.0, 129.2, 129.4,
ꢀ1
29.9, 130.9, 131.0, 137.6, 148.0 (q, J¼34.4 Hz), 148.2,
1
9
1
51.3. F NMR (376 MHz, CDCl , d ppm): ꢀ4.7 (3F, s).
1124, 858. H NMR (400 MHz, CDCl , d ppm): 2.12 (3H,
3
3
+
ESI-MS (m/z): 274 [M+H] . HRMS Calcd for C H F N
1
[M+H] : 274.0844. Found: 274.0839. Anal. Calcd for
C H F N: C, 70.33; H, 3.69; N, 5.13. Found: C, 70.26;
s), 4.32–4.42 (1H, m), 4.44 (1H, d, J¼15.8 Hz), 4.86 (1H,
d, J¼15.8 Hz), 5.47 (1H, d, J¼6.0 Hz), 6.65 (1H, d,
J¼8.2 Hz), 6.72 (1H, t, J¼8.2 Hz), 7.04–7.10 (1H, m),
6 11 3
+
1
6 10 3
1
3
H, 3.96; N, 4.89. 4-Phenyl-2-(trifluoromethyl)-1,2-dihydro-
quinoline 3c: colorless oil. IR (neat, n cm ): 3410, 3057,
7.16–7.32 (6H, m).
C NMR (100.6 MHz, CDCl ,
3
ꢀ1
d ppm): 19.0, 54.5, 58.7 (q, J¼29.6 Hz), 112.0, 112.7,
1
3
(
028, 1604, 1487, 1313, 1257, 1165, 1122, 864. H NMR
400 MHz, CDCl , d ppm): 4.27 (1H, br s, NH), 4.83 (1H,
117.8, 123.0, 124.3, 125.4 (q, J¼291.0 Hz), 127.3, 127.4,
1
9
128.7, 129.2, 136.1, 137.0, 143.0. F NMR (376 MHz,
CDCl , d ppm): ꢀ14.0 (d, J¼6.9 Hz). ESI-MS (m/z): 304
3
qd, J¼7.0, 4.9 Hz), 5.54 (1H, d, J¼4.9 Hz), 6.59 (1H, d,
3
+
+
J¼7.9 Hz), 6.62–6.68 (1H, m), 6.91 (1H, br d, J¼7.7 Hz),
[M+H] . HRMS Calcd for C H F N [M+H] : 304.1313.
8 17 3
1
1
3
7
.04–7.12 (1H, m), 7.34–7.48 (5H, m).
C NMR
Found: 304.1306.
(
1
1
100.6 MHz, CDCl , d ppm): 54.7 (q, J¼31.1 Hz), 112.6,
3
13.1, 118.4, 119.6, 124.3 (q, J¼285.2 Hz), 126.7, 127.9,
4.3.6. 6,7-Dimethoxy-4-methyl-2-(trifluoromethyl)quino-
ꢁ
1
9
ꢀ1
28.3, 128.8, 129.7, 138.5, 142.1, 142.5.
F NMR
line (2g). Colorless crystals. Mp 99.0 C. IR (KBr, n cm ):
2968, 1622, 1496, 1248, 1122, 919. H NMR (400 MHz,
1
(
MS (m/z): 276 [M+H] . HRMS Calcd for C H F N
376 MHz, CDCl , d ppm): ꢀ17.5 (3F, d, J¼7.0 Hz). ESI-
3
+
CDCl , d ppm): 2.69 (3H, s), 4.02 (3H, s), 4.04 (3H, s), 7.13
3
1
6
13
3
+
13
[
M+H] : 276.1000. Found: 276.0990.
(1H, s), 7.43 (1H, s), 7.94 (1H, s). C NMR (100.6 MHz,
CDCl , d ppm): 19.4, 56.1, 56.3, 101.1, 108.8, 116.0, 121.9
3
4.3.3. 2-[(E)-2-Phenylethenyl]-N-(2,2,2-trifluoroethyl-
idene)aniline (4d). Colorless crystals. Mp 27.0 C. IR (KBr,
(q, J¼274.8 Hz), 124.6, 144.2, 144.3, 145.4 (q, J¼34.0 Hz),
ꢁ
n cm ): 2742, 2360, 1643, 1357, 1284, 1165, 964. H
19
151.1, 153.1. F NMR (376 MHz, CDCl , d ppm): ꢀ4.5
3
ꢀ
1
1
+
(3F, s). ESI-MS (m/z): 272 [M+H] . HRMS Calcd for
C H F NO [M+H] : 272.0898. Found: 272.0877.
+
NMR (400 MHz, CDCl , d ppm): 6.98 (1H, dd, J¼7.9,
3
13 13
3
2
1
7
.0 Hz), 7.12 (1H, d, J¼16.4 Hz), 7.27–7.41 (4H, m),
.46–7.57 (3H, m), 7.76 (1H, br d, J¼7.7 Hz), 7.81 (1H, q,
4.3.7. 7-Chloro-4-methyl-2-(trifluoromethyl)-1,2-di-
hydroquinoline (3h). Colorless oil. IR (neat, n cm ): 3419,
1
3
ꢀ1
J¼3.5 Hz). C NMR (100.6 MHz, CDCl , d ppm): 117.8,
3

H. Yanai et al. / Tetrahedron 63 (2007) 2153–2160
2159
1
3
(
059, 2979, 2924, 1602, 1257, 1126, 810. H NMR
400 MHz, CDCl , d ppm): 2.06 (3H, s), 4.21 (1H, br s,
4.3.10. Air oxidation reaction of 1,2-dihydroquinoline
(3a). After the treatment of 4-methyl-2-(trifluoromethyl)-
1,2-dihydroquinoline 3a (8.6 mg, 0.04 mmol) with air at
room temperature for 2 days, the resulting mixture was puri-
fied by MPLC (hexane/EtOAc¼20:1) to give 4-methyl-2-
(trifluoromethyl)quinoline 2a (26.4 min, 8.3 mg, 0.04 mmol,
98% yield).
3
NH), 4.62–4.70 (1H, m), 5.39 (1H, br d, J¼4.4 Hz), 6.50
(
1H, d, J¼2.0 Hz), 6.66 (1H, dd, J¼8.2, 2.0 Hz), 7.01 (1H,
1
3
d, J¼8.2 Hz). C NMR (100.6 MHz, CDCl , d ppm): 19.1,
3
5
(
(
4.9 (q, J¼31.2 Hz), 111.4, 112.9, 118.7, 119.0, 124.4
19
q, J¼289.3 Hz), 125.8, 135.2, 135.6, 143.1. F NMR
376 MHz, CDCl , d ppm): ꢀ13.0 (3F, d, J¼7.2 Hz). ESI-
3
+
MS (m/z): 246 [M+H] . HRMS Calcd for C H ClF N
1
1
18
3
4
(
.3.11. Hydrogenation reaction of 1,2-dihydroquinoline:
2R*,4R*)-4-methyl-2-(trifluoromethyl)-1,2,3,4-tetra-
hydroquinoline (5a). To a suspension of 5% Pd/C containing
50% w/w H O (42 mg, 0.01 mmol, 3 mol %) in MeOH
+
[M+H] : 246.0297. Found: 246.0285.
4
.3.8. 4-Methyl-2-(1,1,2,2,2-pentafluoroethyl)quinoline
2j) and 4-methyl-2-(1,1,2,2,2-pentafluoroethyl)-1,2-di-
2
(
hydroquinoline (3j). 4-Methyl-2-(1,1,2,2,2-pentafluoro-
(1.0 mL), a solution of 4-methyl-2-(trifluoromethyl)-1,2-di-
hydroquinoline 3a (71.7 mg, 0.34 mmol) in MeOH (1.0 mL)
was added. After being stirred at room temperature for 3 h
ꢁ
n cm ): 2960, 2920, 1593, 1383, 1330, 1198, 1144, 1109,
ethyl)quinoline 2j: colorless crystals. Mp 73.1 C. IR (KBr,
ꢀ1
under H atmosphere (1 atm), the reaction mixture was fil-
2
1
tered through Celite pad. The filtrate was concentrated under
reduced pressure, and purified by column chromatography on
silica gel (hexane/EtOAc¼50:1) to give (2R*,4R*)-4-methyl-
1028, 766. H NMR (400 MHz, CDCl , d ppm): 2.80 (3H,
3
s), 7.58 (1H, s), 7.67–7.71 (1H, m), 7.79–7.83 (1H, m),
1
3
8
NMR (100.6 MHz, CDCl , d ppm): 19.1, 118.4, 123.8,
.07 (1H, br td, J¼8.3 Hz), 8.23 (1H, d, J¼8.5 Hz).
C
2-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline 5a (73.1 mg,
3
1
9
1
28.4, 128.7, 130.3, 130.9, 146.7, 147.1.
F NMR
0.34 mmol, 100% yield) as a single product. Colorless crys-
tals. Mp 42.3 C. IR (KBr, n cm ): 3396, 3058, 2964,
ꢁ
973, 1610, 1489, 1279, 1140. H NMR (400 MHz, CDCl ,
ꢀ1
(376 MHz, CDCl , d ppm): ꢀ54.1 (2F, s), ꢀ20.0 (3F, s).
ESI-MS (m/z): 262 [M+H] . HRMS Calcd for C H F N
3
1
+
2
3
1
2 9 5
+
d ppm): 1.43 (3H, d, J¼6.8 Hz), 1.75 (1H, q, J¼12.1 Hz),
2.22 (1H, dt, J¼12.1, 4.3 Hz), 2.97–3.04 (1H, m), 3.93–
3.99 (1H, m), 4.02 (1H, br s, NH), 6.61 (1H, d, J¼7.9 Hz),
[
(
M+H] : 262.0655. Found: 262.0655. 4-Methyl-2-
1,1,2,2,2-pentafluoroethyl)-1,2-dihydroquinoline 3j: color-
less oil. IR (neat, n cm ): 3419, 3060, 2979, 2925, 1657,
1608, 1491, 1315, 1205, 1119, 1032, 1007, 833, 748. H
NMR (400 MHz, CDCl , d ppm): 2.08 (br s, 3H), 4.76–
ꢀ1
1
6
.79–6.84 (1H, m), 7.05–7.10 (1H, m), 7.19 (1H, d,
1
3
J¼7.5 Hz). C NMR (100.6 MHz, CDCl
, d ppm): 19.5,
3
3
4
.84 (1H, m), 5.39 (1H, d, J¼4.9 Hz), 6.50 (1H, d,
29.2, 30.5, 53.9 (q, J¼30.2 Hz), 115.0, 118.9, 125.5 (q,
1
9
J¼279.6 Hz), 126.1, 126.3, 127.2, 129.6, 142.2. F NMR
(376 MHz, CDCl
, d ppm): ꢀ4.27 (3F, d, J¼6.4 Hz). ESI-
MS (m/z): 216 [M+H] . HRMS Calcd for C11
J¼7.9 Hz), 6.68–6.73 (1H, m), 7.02–7.07 (1H, m), 7.10
1
3
(
1
1
1H, d, J¼7.6 Hz). C NMR (100.6 MHz, CDCl , d ppm):
3
3
+
8.9, 53.8 (t, J¼23.7 Hz), 110.4, 112.7, 118.4, 120.2,
H F N
13 3
+
1
9
[M+H] : 216.1000. Found: 216.0979.
24.2, 129.4, 136.1, 141.8. F NMR (376 MHz, CDCl ,
3
d ppm): ꢀ65.0 (1F, dd, J¼270, 13.0 Hz), ꢀ63.0 (1F, dd,
J¼270, 10.5 Hz), ꢀ18.1 (3F, s). ESI-MS (m/z): 264
References and notes
+
+
[
Found: 264.0799.
M+H] . HRMS Calcd for C H F N [M+H] : 264.0812.
12 11 5
1
. (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum:
New York, NY, 1994; (b) Hiyama, T. Organofluorine Com-
pounds: Chemistry and Applications; Springer: Berlin, 2000;
(c) Uneyama, K. Organofluorine Chemistry; Blackwell:
Oxford, 2006.
2. (a) Lutz, R. E.; Ohnmacht, C. J.; Patel, A. R. J. Med.
Chem. 1971, 14, 926–928; (b) Grellepois, F.; Grellier, P.;
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3. (a) Dyke, H. J.; Montana, J. G. WO 2000026208, 2000; (b)
Kuang, R.; Blythin, D.; Shih, N.-Y.; Shue, H.-J.; Chen, X.;
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Wong, S.-C.; Xiao, L. WO 2005116009, 2005.
4. Sakashita, H.; Yoshida, T.; Kitajima, H.; Takeuchi, M.; Tanaka,
Y.; Yoshimura, T.; Akahoshi, F.; Hayashi, Y. WO 2003024942,
2003.
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2001058900, 2001; (b) Kym, P. R.; Hartandi, K.; Gao, J.;
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4.3.9. 2-[Chloro(difluoro)methyl]-4-methylquinoline (2k)
and 2-[chloro(difluoro)methyl]-4-methyl-1,2-dihydro-
quinoline (3k). 2-[Chloro(difluoro)methyl]-4-methylquino-
line 2k: colorless crystals. Mp 52.5 C. IR (KBr, n cm ):
ꢁ
924, 1637, 1593, 1219, 1134, 1092, 957, 874, 764. H
ꢀ1
1
2
NMR (400 MHz, CDCl , d ppm): 2.80 (3H, s), 7.58 (1H,
3
s), 7.68 (1H, br t, J¼8.5 Hz), 7.81 (1H, dd, J¼8.5, 8.2 Hz),
1
3
8
NMR (100.6 MHz, CDCl , d ppm): 19.1, 116.7, 124.7 (t,
.05 (1H, br td, J¼8.2 Hz), 8.221 (1H, d, J¼8.5 Hz).
C
3
1
9
J¼308.1 Hz), 128.2, 128.6, 130.4, 130.7, 146.7, 147.1.
F
NMR (376 MHz, CDCl , d ppm): ꢀ7.51 (2F, s). ESI-MS
3
+
(
[
m/z): 228 [M+H] . HRMS Calcd for C H ClF N
9
1
1
2
+
M+H] : 228.0392. Found: 228.0376. 2-[Chloro(difluoro)-
methyl]-4-methyl-1,2-dihydroquinoline 3k: due to the rapid
decomposition, analyses by IR and mass spectroscopies
1
have not been carried out. Colorless oil. H NMR
(
400 MHz, CDCl , d ppm): 2.10 (3H, s), 4.70–4.76 (1H,
3
m), 5.48 (1H, d, J¼4.6 Hz), 6.52 (1H, d, J¼7.9 Hz), 6.70–
6
.73 (1H, m), 7.05–7.09 (1H, m), 7.13 (1H, d, J¼7.7 Hz).
1
3
C NMR (100.6 MHz, CDCl , d ppm): 18.9, 60.0 (t,
3
J¼26.5 Hz), 111.9, 112.6, 118.2, 120.0, 124.2, 126.6,
1
9
1
29.4, 136.0, 141.6. F NMR (376 MHz, CDCl , d ppm):
3
ꢀ
11.7 (1F, dd, J¼160, 9.1 Hz), ꢀ11.2 (1F, dd, J¼160,
7
.6 Hz).

2160
H. Yanai et al. / Tetrahedron 63 (2007) 2153–2160
7
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1
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1
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