The reaction of 2-fluoroalkyl-1-iodoethylenes with arylamines: A facile method for the synthesis of fluoroalkylated quinolines and enaminoketones

Article abstract of DOI:10.1016/j.tet.2004.08.041

The reaction of 2-fluoroalkyl-1-iodoethylenes with arylamines (1) and the subsequent acid promoted transformation of the products were described. In the presence of ZnCl₂ and triethylamine, 1 reacted readily with various p-substituted anilines in HMPA under a vacuum of 60-70 mmHg to give the corresponding enaminoaldehydes (2) as a mixture of E- and Z-isomers. Cyclization of 2, without further purification in refluxing toluene, catalyzed by strong acids such as p-toluene sulfonic acid and trifluoromethanesulfonic acid gave 2-fluoroalkylquinolines (3) in good yields, while fluoroalkylated enaminoketones (4) were obtained predominantly when 2 was treated with acids in aqueous THF solution. A possible mechanism was proposed for the formation of 3 and 4. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.08.041

Tetrahedron 60 (2004) 9945–9951
The reaction of 2-fluoroalkyl-1-iodoethylenes with arylamines:
a facile method for the synthesis of fluoroalkylated quinolines
and enaminoketones
*
Fulu Zhao, Xianjin Yang and Jintao Liu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, People’s Republic of China
Received 17 May 2004; revised 11 August 2004; accepted 12 August 2004
Available online 15 September 2004
Abstract—The reaction of 2-fluoroalkyl-1-iodoethylenes with arylamines (1) and the subsequent acid promoted transformation of the
products were described. In the presence of ZnCl2 and triethylamine, 1 reacted readily with various p-substituted anilines in HMPA under a
vacuum of 60–70 mmHg to give the corresponding enaminoaldehydes (2) as a mixture of E- and Z-isomers. Cyclization of 2, without further
purification in refluxing toluene, catalyzed by strong acids such as p-toluene sulfonic acid and trifluoromethanesulfonic acid gave
2-fluoroalkylquinolines (3) in good yields, while fluoroalkylated enaminoketones (4) were obtained predominantly when 2 was treated with
acids in aqueous THF solution. A possible mechanism was proposed for the formation of 3 and 4.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
fluorinated precursors are not easily available and the yields
of some reactions are low. Herein we report a facile
synthesis of 2-fluoroalkylquinolines and fluorinated
enaminoketones from 2-fluoroalkyl-1-iodoethylenes.
Recently fluorinated compounds have been of great interest
to both synthetic and medicinal chemists due to their unique
physical and biological properties imparted by fluorine.1
Among these compounds, fluorinated quinolines are the
focus of considerable research and some of them have found
applications in medicinal and pharmaceutical fields. For
example, mefloquine ((2,8-bis(trifluoromethyl)-4-quino-
linyl)(2-piperidinyl) methanol) has been used as highly
effective antimalarial drug.2 Therefore many methods have
been developed for the preparation of fluoroalkylated
quinolines. The traditional methods comprise two main
approaches, namely, fluorination of suitable functional
groups, such as –CX3 (XZCl, Br)3 and –CO2H,4 and direct
introduction of fluoroalkyl group by the reaction of
fluoroalkyl iodides and haloquinolines in the presence of
copper powder.5 Recently much attention was paid to the
synthesis of these fluorinated compounds by means of
fluorine-containing building blocks. Many fluorinated pre-
cursors such as fluorine-containing enaminoketones,6
N-arylimines,7 propynoic acid esters,8 a-fluoroalkyl alde-
hydes9 and a-fluoroalkyl esters10 have been used to
synthesize 2-fluoroalkylquinolines. However, these
2-Fluoroalkyl-1-iodoethylene (1), easily prepared from the
reaction of fluoroalkyl iodides and acetylene,11 are versatile
fluorine-containing precursors. They have been reported to
react with various nucleophilic reagents, and many
fluoroalkylated heterocyclic compounds such as pyra-
zoles,12 isoxazoles,13 pyrimidines,14 indolizines15 and
1,4-diazepines16 were prepared from these reactions. In
the continuation of our study on their applications in the
synthesis of fluorine-containing compounds, it was found
that 2-fluoroalkylquinolines or fluoroalkylated enamino-
ketones could be conveniently synthesized in good yields
from the reaction of 1 and substituted anilines under
different conditions.
2. Results and discussion
In the presence of excess Et3N, the reaction of 1-iodo-
3,3,4,4,5,5,6,6,6-nonafluorohexene (1a) and p-methoxy
aniline occurred at 80 8C in DMF (monitored by TLC or
19F NMR). After workup a new compound was obtained.
The spectral data showed that it was a mixture of E- and
Z-isomer of 3-heptafluoropropyl-3-enaminoaldehyde (2aa).
Treatment of 2aa with polyphosphoric acid (PPA) at 170 8C
Keywords: 2-Fluoroalkyl-1-iodoethylene; Aniline; Fluoroalkylated quino-
line; Fluoroalkylated enaminoketone; Acid.
* Corresponding author. Tel.: C86-21-64163300; fax: C86-21-64166128;
e-mail: jtliu@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.041

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F. Zhao et al. / Tetrahedron 60 (2004) 9945–9951
Scheme 1.
gave the corresponding cyclization product, 2-heptafluoro-
propyl-6-methoxyquinoline (3aa) (Scheme 1). The structure
of 3aa was characterized by its spectral data and further
confirmed by the X-ray crystallography of its analogue,
2-(1,1,2,2,3,3-hexafluoro-3-chloropropyl)-6-methylquino-
line (3bb) (Fig. 1).
obtained: 4bb was formed as the major product. As shown
in Table 1, solvent had distinct effect on the reaction and the
best result was obtained in THF, as 4bb being formed in
almost quantitative yield when THF was used as the solvent
(entry 4). The same result was obtained with TsOH or
CF3SO3H when the reaction was carried out in aqueous
THF solution (entries 8 and 9), confirming that water was
essential for the formation of compound 4.
A possible mechanism for the formation of 3 and 4 was
proposed as shown in Scheme 2. Nucleophilic addition of
the amino group in anilines to 1 followed by the elimination
of a HI gave intermediate A, which eliminated a HF in the
presence of base to afford intermediate B. Nucleophilic
substitution of B by another aniline resulted in the formation
of intermediate C. Hydrolysis of C gave the corresponding
aldehyde 2, which underwent cyclization promoted by
strong acids to give 3.17 While intermediate D was formed
from 2 in the presence of acid and water, an aniline was
released at the same time. Similar transformation has been
reported in the literature.18 Subsequent reaction of D with
aniline gave compound 4. As a proof, intermediate C (ArZ
4-MeOC6H4, RfZC3F7) was isolated from the reaction
mixture and characterized by its spectral data.
Figure 1. X-ray crystallographic structure of 3bb.
Obviously, an acid promoted cyclization reaction was
involved in the second step. In order to simplify the reaction
and improve the yields of 3, other acids such as p-toluene
sulfonic acid, trifluoromethanesulfonic acid and concen-
trated hydrochloric acid were tested. It was found that the
cyclization reaction of 2bb took place readily in toluene at
120 8C in the presence of catalytic amount of TsOH or
CF3SO3H (about 10 mol% based on 1) to give compound
3bb in nearly quantitative yields. However, a by-product,
fluoroalkylated enaminoketone (4bb), was obtained in
addition to the expected product 3bb when concentrated
hydrochloride acid was used in the reaction. It was
hypothesized that the formation of 4bb was attributed to
the water in concentrated hydrochloric acid. Thus, 5%
hydrochloric acid was tested and the expected results were
From the above results, it is very convenient to make
fluoroalkylated quinolines and enaminoketones selectively
from 1 by the two-step reaction using different conditions,
but yields of the first step were unsatisfactory. Therefore,
the conditions of the first step were optimized using the
reaction of p-methoxyaniline with 1a as a model reaction. It
was found that in the presence of equal mole of ZnCl2 and
excess Et3N, the reaction proceeded smoothly in HMPA
under a vacuum of 60–70 mmHg to give 2aa in high yield.
Without purification, 2aa was treated with TsOH directly in
Table 1. The acid promoted reaction of 2bb
Entry
Acid
Solvent
Temperature (8C)
Time (h)
3bb (%)a
4bb (%)a
1
2
3
4
5
6
7
8
PPA
TsOH
—
170
120
120
70
60
70
3
3
4
1
6
1
2
2
O98
O99
85
—
—
33
—
—
—
—
15
O99
Trace
67
O99
O99
Toluene
Toluene
THF
CH2Cl2
EtOH (95%)
THF/H2O
THF/H2O
HCl(conc)
5% HCl
5% HCl
5% HCl
TsOH
70
70
CF3SO3H
a
Determined by 19F NMR.

F. Zhao et al. / Tetrahedron 60 (2004) 9945–9951
9947
Scheme 2.
Table 2. The reaction of 1a with p-methoxyaniline under different conditions
Entry
Conditiona
Temperature (8C)b
Time (h)b
Yield (%)c
1
2
3
4
A
A
A
B
80
110
80
24
24
48
24
58
61
61
92
110
a
Condition A: Et3N/DMF, 6; condition B: Et3N/ZnCl2/HMPA, 60–70 mmHg, 6.
Conditions for the first step.
Isolated yields based on 1a.
b
c
toluene and 3aa was obtained in 92% overall yield. Some of
the results are summarized in Table 2.
with various substituted anilines was studied and the results
were listed in Table 3. As shown in the table, the length of
fluoroalkyl chains had little influence on the reaction, but
the reaction results were obviously affected by the
Using the optimized reaction conditions, the reaction of 1
Table 3. Synthesis of 2-fluoroalkylquinolines from 1
Entry
1
R
Rf
3
Yield (%)a
1
2
3
4
5
6
7
8
9
10
1a
1a
1b
1c
1d
1a
1a
1a
1b
1a
MeO
Me
Me
Me
Me
H
Cl
Br
Br
NO2
C3F7
C3F7
C3F6Cl
CF2Cl
C5F11
C3F7
C3F7
C3F7
C3F6Cl
C3F7
3aa
3ab
3bb
3cb
3db
3ac
3ad
3ae
3be
3afb
92
87
83
85
75
79
75
71
75
31
a
Isolated yields based on 1.
Obtained directly from the first step without further treatment with acid.
b

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F. Zhao et al. / Tetrahedron 60 (2004) 9945–9951
Table 4. Synthesis of fluoroalkylated enaminoketones from 1
Entry
1
R
Rf
4
Yields (%)a
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1b
1b
1a
1c
1b
1b
MeO
Me
Me
Me
Me
MeO
H
H
H
Cl
C3F7
C3F7
4aab
4ab
4bb
4cb
4db
4bab
4bc
4ac
4cc
68
74
73
64
73
68
75
74
71
68
68
C3F6Cl
CF2Cl
C5F11
C3F6Cl
C3F6Cl
C3F7
CF2Cl
C3F6Cl
C3F6Cl
9
10
11
4bd
4be
Br
a
Isolated yields based on 1.
Hydrolysis was performed at 50 8C for 1 h.
b
substituent in anilines and better results were obtained with
electron-donating substituents such as methoxy and methyl.
In the case of p-nitroaniline, the reaction was kind of slow,
and the yield of 3af was very low due to its weak
nucleophilicity caused by strong electron-withdrawing
nitro group (entry 10).
Perkin–Elmer jeol 983 spectrophotometer. 1H NMR spectra
were measured on a Bruker AM300 (300 MHz) spectro-
meter using TMS as internal standard. 19F NMR spectra
were taken on a Bruker AM300 (282 MHz) spectrometer.
Chemical shifts were reported using CFCl3 as external
standard [d(CFCl3)Z0], upfield shift being designated as
negative. Mass spectra were obtained on a Hewlett-Packard
HP-5989A spectrometer. Column chromatography was
performed using silica H, particle size 10–40 m.
Similarly, reaction of 1 with various anilines in HMPA in
the presence of Et3N and ZnCl2 at 70–80 8C under a vacuum
of 60–70 mmHg followed by the treatment of the product
with 5% hydrochloric acid at 50–70 8C gave compound 4 in
good overall yields. The results were summarized in Table
4. In the case of p-methoxyaniline, acidic hydrolysis was
performed at 50 8C because cyclization products were
formed at higher temperature. The reaction of 1a with
p-nitroaniline gave only cyclization product 3af, and the
corresponding fluoroalkylated enaminoaldehyde 2af was
not obtained. All fluoroalkylated enaminoketones obtained
were in Z-configuration as indicated by the coupling
constants (JZ7.3–7.8 Hz) of the two olefinic protons in
their 1H NMR spectra. This is probably due to the formation
of an intramolecular hydrogen bond between N–H and
carbonyl oxygen. Similar result was reported in the
literature.19
3.2. General procedure for the preparation of
intermediate 2
A mixture of 1 (1 mmol), arylamine (3 mmol), Et3N
(5 mmol) and anhydrous ZnCl2 (1 mmol) were stirred in
HMPA (10 mL) at 70–80 8C under a vacuum of 60–
70 mmHg. After 24–48 h, the mixture was cooled to room
temperature, diluted with 1% HCl (15 mL) and then
extracted with ether (3!20 mL). The organic layer was
combined, washed with saturated NaCl solution and dried
over sodium sulfate. After the solvent was removed by
rotary evaporation, the residue was chromatographed on
silica gel eluting with petroleum–ethyl ether to give 2.
3.2.1. Data for compound 2aa. Yellow solid. Mp 108–
110 8C. IR (KBr): 3231, 3120, 3036, 2903, 2841, 1623,
1587, 1519, 1412, 1350, 1289, 1220, 1181, 1146, 1079, 959,
In conclusion, the reaction of 2-fluoroalkyl-1-iodoethylenes
with various anilines and the subsequent acid promoted
transformation of products are achieved under mild
conditions, providing a convenient method for the prepa-
ration of 2-fluoroalkylquinolines and fluoroalkylated (Z-)
enaminoketones. Compared to the reported procedures, this
method has the advantage of easily available starting
material, mild reaction conditions and good selectivity.
1
830, 730 cmK1. H NMR (CDCl3): d 10.92 (br, 1H, NH),
9.69 (d, 1H, JZ8.4 Hz), 9.39 (d, 1H, JZ2.7 Hz), 7.13–7.08
(m, 4H), 6.95–6.85 (m, 4H), 6.22 (br, 1H, NH), 5.62 (d,
1H, JZ8.4 Hz), 5.56 (d, 1H, JZ2.7 Hz), 3.82 (s, 6H). 19F
NMR (CDCl3): d K80.28 (3F), K80.54 (3F), K110.71
(2F), K111.64 (2F), K125.19 (2F), K126.72 (2F). EIMS
m/z (%): 345 (MC, 57.08), 176 (MCKC3F7, 100.00).
EI-HRMS: calcd for C13H10F7NO2 [MC] 345.0600, found
345.0612.
3. Experimental
3.1. General
3.2.2. Data for intermediate C. IR (film): 3208, 3095,
3003, 2960, 2839, 1641, 1596, 1575, 1516, 1467, 1443,
Melting points were uncorrected. IR spectra were taken on a
1296, 1243, 1181, 1151, 1037, 824 cmK1 1H NMR
.

F. Zhao et al. / Tetrahedron 60 (2004) 9945–9951
9949
(acetone-d6): d 8.71 (br, 1H), 7.58 (br, d, JZ13.5 Hz, 1H),
7.02–6.76 (m, 8H), 5.55 (d, JZ13.5 Hz, 1H), 3.83
(s, 3H), 3.76 (s, 3H). 19F NMR (acetone-d6): d K80.54
(3F), K111.59 (2F), K125.78 (2F). EIMS m/z (%): 451
(MCC1, 52.01), 450 (MC, 59.99), 328 (MCKNHC6H4-
OMe, 3.19), 281 (MCKC3F7, 100.00). EI-HRMS: calcd
for C20H17F7N2O2 [MC] 450.1170, found: 450.1158.
3.3.5. 6-Methyl-2-undecafluoropentylquinoline (3db).
Mp 64–66 8C. IR (KBr): 3064, 2978, 2918, 1599, 1502,
1
1364, 1243, 1205, 1137, 727, 663, 630 cmK1. H NMR
(CDCl3): d 8.26 (d, 1H, JZ9.0 Hz), 8.15 (d, 1H, JZ9.0 Hz),
7.71–7.66 (m, 3H), 2.60 (s, 3H). 19F NMR (CDCl3): d
K81.20 (3F), K113.82 (2F), K122.11 (2F), K122.62 (2F),
K126.51 (2F). EIMS m/z (%): 411 (MC, 46.68), 392
(MCKF, 10.69), 192 (MCKC4F9, 100.00). EI-HRMS:
calcd for C15H8F11N [MC] 411.0481, found 411.0495.
3.3. General procedure for the preparation of
2-fluoroalkylquinolines (3)
3.3.6. 2-Heptafluoropropylquinoline (3ac).21 Light yellow
oil. IR (film): 3070, 1622, 1598, 1508, 1352, 1230, 1183,
1118, 1056, 911, 820, 757, 741 cmK1. 1H NMR (CDCl3): d
8.38 (d, 1H, JZ8.7 Hz), 8.27 (d, 1H, JZ8.7 Hz), 7.94–7.67
(m, 4H). 19F NMR (CDCl3): d K80.40 (3F), K114.81 (2F),
K126.42 (2F).
A mixture of 1 (1 mmol), arylamine (3 mmol), Et3N
(5 mmol) and anhydrous ZnCl2 (1 mmol) were stirred in
HMPA (10 mL) at 110 8C under a vacuum of 60–70 mmHg.
After 24 h, the mixture was cooled to room temperature,
diluted with 1% HCl (15 mL) and then extracted with ether
(3!20 mL). The organic layer was combined, washed with
saturated NaCl solution and dried over sodium sulfate. After
the solvent was removed by rotary evaporation, the residue
was dissolved in toluene (5 mL), and TsOH (0.1 mmol) was
added. The mixture was stirred under reflux for 3–4 h
(monitored by TLC). After the reaction was complete,
the solvent was removed under vacuum, the residue was
chromatographed on silica gel eluting with petroleum–ethyl
ether to give 3 as a solid.
3.3.7. 2-Heptafluoropropyl-6-chloro-quinoline (3ad). Mp
112–115 8C. IR (KBr): 3045, 3071, 1597, 1498, 1466, 1355,
1286, 1230, 1116, 865, 831, 747 cmK1. 1H NMR (acetone-
d6): d 8.57 (d, 1H, JZ9.0 Hz), 8.09 (d, 2H, JZ9.0 Hz),
7.88–7.78 (m, 2H). 19F NMR (acetone-d6): d K81.01 (3F),
K114.53 (2F), K126.82 (2F). EIMS m/z (%): 333 (MCC2,
15.66), 331 (MC, 47.38), 312 (MCKF, 7.42), 212
(MCKC2F5, 100.00). EI-HRMS: calcd for C12H5ClF6N
[(MKF)C] 312.0015, found 312.0015.
3.3.1. 2-Heptafluoropropyl-6-methoxyquinoline (3aa).
Mp 70–72 8C. IR (KBr): 3018, 2965, 2938, 1627, 1593,
3.3.8. 2-Heptafluoropropyl-6-bromoquinoline (3ae). Mp
126–128 8C. IR (KBr): 3042, 1595, 1496, 1465, 1355, 1286,
1230, 1116, 857, 829, 746 cmK1. 1H NMR (CDCl3): d 8.27
(d, 1H, JZ8.7 Hz), 8.14–8.09 (m, 2H), 7.92–7.88 (m, 1H),
7.76 (d, 1H, JZ8.7 Hz). 19F NMR (CDCl3): d K80.39 (3F),
K114.83 (2F), K126.36 (2F). EIMS m/z (%): 377 (MCC2,
46.18), 375 (MC, 47.31), 356 (MCKF, 5.89), 258 (97.11),
256 (MCKC2F5, 100.00). EI-HRMS: calcd for
C12H5BrF7N [MC] 374.9494, found 374.9523.
1506, 1485, 1386, 1230, 1109, 1032, 885, 854, 748 cmK1
.
1H NMR (acetone-d6): d 8.42 (d, 1H, JZ9.0 Hz), 7.95 (d,
1H, JZ9.0 Hz), 7.72 (d, 1H, JZ9.0 Hz), 7.44–7.36 (m, 2H),
3.87 (s, 3H). 19F NMR (acetone-d6): d K81.37 (3F), K
114.42 (2F), K127.18 (2F). EIMS m/z (%): 327 (MC,
76.59), 308 (MCKF, 10.92), 208 (MCKC2F5, 100.00).
EI-HRMS: calcd for C13H8F7NO [MC] 327.0494, found
327.0479.
3.3.2. 6-Methyl-2-heptafluoropropylquinoline (3ab).20
Mp 75–77 8C. IR (KBr): 3077, 2928, 1594, 1574, 1503,
1357, 1225, 1111, 931, 879, 836 cmK1. 1H NMR (acetone-
d6): d 8.72 (d, 1H, JZ8.7 Hz), 8.23 (d, 1H, JZ8.7 Hz), 8.03
(d, 2H, JZ9.0 Hz), 7.94 (d, 1H, JZ8.7 Hz), 2.74 (s, 3H).
19F NMR (acetone-d6): d K81.02 (3F), K114.33 (2F),
K126.80 (2F).
3.3.9. 2-(1,1,2,2,3,3-Hexafluoro-3-chloropropyl)-6-bro-
moquinoline (3be). Mp 118–120 8C. IR (KBr): 3042,
1595, 1492, 1464, 1315, 1296, 1187, 1113, 797, 757 cmK1
.
1H NMR (CDCl3): d 8.24 (d, 1H, JZ9.0 Hz), 8.11–8.06 (m,
2H), 7.89–7.85 (m, 1H), 7.73 (d, 1H, JZ9.0 Hz). 19F NMR
(CDCl3): d K67.20 (2F), K113.20 (2F), K120.43 (2F).
EIMS m/z (%): 393 (MCC2, 46.15), 391 (MC, 35.71), 372
(MCKF, 2.18), 356 (MCKCl, 9.55), 258 (96.56), 256
(MCKC2F4Cl, 100.00). EI-HRMS: calcd for C12H5BrClF6-
N [MC] 390.9198, found 390.9174.
3.3.3. 6-Methyl-2-(1,1,2,2,3,3-hexafluoro-3-chloropro-
pyl)quinoline (3bb). Mp 50–52 8C. IR (KBr): 3030, 2971,
1
1595, 1499, 1320, 1193, 1112, 823, 760 cmK1. H NMR
(CDCl3): d 8.25 (d, 1H, JZ9.0 Hz), 8.15 (d, 1H, JZ9.0 Hz),
7.71–7.65 (m, 3H), 2.60 (s, 3H). 19F NMR (CDCl3): d
K66.80 (2F), K112.81 (2F), K120.22 (2F). EIMS m/z (%):
329 (MCC2, 9.73), 327 (MC, 28.85), 292 (MCKCl,
10.35), 192 (MCKC2F4Cl, 100.00). EI-HRMS: calcd for
C13H8ClF6N [MC] 327.0250, found 327.0228.
3.3.10. 2-Heptafluoropropyl-6-nitroquinoline (3af). Mp
140–143 8C. IR (KBr): 3099, 1628, 1608, 1549, 1502, 1355,
1284, 1230, 1117, 937, 817, 749 cmK1. 1H NMR (acetone-
d6): d 9.19 (d, 1H, JZ2.4 Hz), 9.10 (d, 1H, JZ9.0 Hz), 8.68
(dd, 1H, JZ9.0, 2.4 Hz), 8.45 (d, 1H, JZ9.0 Hz), 8.18
(d, 1H, JZ9.0 Hz). 19F NMR (acetone-d6): d K81.30 (3F),
K115.22 (2F), K127.01 (2F). EIMS m/z (%): 342 (MC,
98.70), 296 (MCKNO2, 40.17), 223 (MCKC2F5, 100.00),
177 (MCKC2F5-NO2, 48.78). EI-HRMS: calcd for
C12H5F7N2O2 [MC] 342.0239, found 342.0207.
3.3.4. 6-Methyl-2-chlorodifluoromethylquinoline (3cb).
Mp 68–70 8C. IR (KBr): 3053, 2959, 1594, 1501, 1314,
1294, 1145, 1127, 1081, 965, 937, 833, 775, 734 cmK1. 1H
NMR (CDCl3): d 8.26 (d, 1H, JZ9.0 Hz), 8.13 (d, 1H, JZ
9.0 Hz), 7.74–7.66 (m, 3H), 2.60 (s, 3H). 19F NMR
(CDCl3): d K55.12 (s). EIMS m/z (%): 229 (MCC2,
9.43), 227 (MC, 28.38), 192 (MCKCl, 100.00). EI-HRMS:
calcd for C11H8ClF2N [MC] 227.0313, found 227.0295.
3.4. General procedure for the preparation of
fluoroalkylated enaminoketones (4)
A mixture of 1 (1 mmol), arylamine (3 mmol), Et3N

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F. Zhao et al. / Tetrahedron 60 (2004) 9945–9951
(5 mmol) and anhydrous ZnCl2 (1 mmol) were stirred in
HMPA (10 mL) at 80 8C under a vacuum of 60–70 mmHg.
After 48 h, the mixture was cooled to room temperature,
diluted with 1%HCl (15 mL) and then extracted with ether
(3!20 mL). The organic layer was combined, washed with
water and saturated NaCl solution and dried over sodium
sulfate. After the solvent was removed by rotary evapo-
ration, the residue was dissolved in THF (5 mL) and 5%
HCl (1 mL) was added. The mixture was stirred at 50–70 8C
for 0.5–2 h (monitored by 19F NMR). After the reaction was
complete, the mixture was cooled to room temperature,
diluted with water (10 mL) and then extracted with ether
(3!20 mL). The organic layer was combined, washed with
water and saturated NaCl solution, and dried over sodium
sulfate. After the solvent was removed, the residue was
chromatographed on silica gel eluting with petroleum–ethyl
ether to give 4 as a light yellow solid.
(dd, 1H, JZ13.2, 7.5 Hz), 7.21 (d, 2H, JZ8.4 Hz), 7.04 (d,
2H, JZ8.4 Hz), 5.64 (d, 1H, JZ7.5 Hz), 2.36 (s, 3H). 19F
NMR (CDCl3): d K65.20 (s).
3.4.6. cis-4,4,5,5,6,6,7,7,8,8,8-Undecafluoro-1-(tolyl-
amino)oct-1-en-3-one (4db). Mp 94–95 8C. IR (KBr):
1647, 1598, 1563, 1496, 1310, 1197, 1143, 811, 778,
1
746 cmK1. H NMR (CDCl3): d 11.98 (br, 1H, NH), 7.65
(dd, 1H, JZ13.2, 7.5 Hz), 7.21 (d, 2H, JZ8.4 Hz), 7.05 (d,
2H, JZ8.4 Hz), 5.70 (d, 1H, JZ7.5 Hz), 2.36 (s, 3H). 19F
NMR (CDCl3): d K81.01 (3F), K120.52 (2F), K122.84 (4
F), K126.50 (2F). EIMS m/z (%): 429 (MC, 38.30), 410
(MCKF, 3.47), 160 (MCKC5F11, 100.00). Anal. calcd for
C15H10F11NO: C, 41.97; H, 2.35; N, 3.26. Found C, 42.30;
H, 2.60; N, 3.24.
3.4.7. cis-6-Chloro-4,4,5,5,6,6-hexafluoro-1-(phenyl-
amino)hex-1-en-3-one (4bc). Mp 73–75 8C. IR (KBr):
3076, 1647, 1610, 1581, 1486, 1290, 1194, 1113, 754,
3.4.1. cis-4,4,5,5,6,6,6-Heptafluoro-1-(4-methoxyphenyl-
amino)hex-1-en-3-one (4aa). Mp 58–60 8C. IR (KBr):
3015, 2966, 1643, 1598, 1565, 1494, 1301, 1243, 1212,
1
710 cmK1. H NMR (CDCl3): d 11.94 (br, 1H, NH), 7.68
(dd, 1H, JZ13.2, 7.5 Hz), 7.44–7.39 (m, 2H), 7.25–7.14 (m,
3H), 5.73 (d, 1H, JZ7.5 Hz). 19F NMR (CDCl3): d K67.63
(2F), K119.94 (2F), K121.21 (2F). EIMS m/z (%): 333
(MCC2, 9.44), 331 (MC, 27.77), 146 (MCKC3F6Cl,
100.00). MALDI-HRMS: calcd for C12H9ClF6NO [(MC
H)C] 332.0271, found 332.0282.
1
1120, 889, 835, 780, 752, 715 cmK1. H NMR (CDCl3):
d 12.05 (br, 1H, NH), 7.58 (dd, 1H, JZ13.2, 7.5 Hz), 7.10
(d, 2H, JZ9.0 Hz), 6.93 (d, 2H, JZ9.0 Hz), 5.68 (d, 1H,
JZ7.5 Hz), 3.83 (s, 3H). 19F NMR (CDCl3): d K80.84 (3F),
K121.43 (2F), K127.21 (2F). EIMS m/z (%): 345 (MC,
46.42), 326 (MCKF, 2.36), 176 (MCKC3F7, 100.00).
EI-HRMS: calcd for C13H10F7NO2 [MC] 345.0600, found
345.0579.
3.4.8. cis-4,4,5,5,6,6,6-Heptafluoro-1-(phenylamino)hex-
1-en-3-one (4ac).10 Mp 48–50 8C. IR (KBr): 3120, 3050,
1648, 1605, 1581, 1489, 1459, 1309, 1216, 1122, 888, 777,
1
3.4.2. cis-6-Chloro-4,4,5,5,6,6-hexafluoro-1-(4-methoxy-
phenylamino)hex-1-en-3-one (4ba).19 Mp 70–72 8C. IR
(KBr): 2966, 2843, 1645, 1598, 1565, 1493, 1289, 1182,
1122, 1035, 836, 770, 705 cmK1. 1H NMR (CDCl3): d 12.03
(br, 1H, NH), 7.57 (dd, 1H, JZ13.2, 7.2 Hz), 7.10
(d, 2H, JZ9.0 Hz), 6.93 (d, 2H, JZ9.0 Hz), 5.68 (d, 1H,
JZ7.2 Hz), 3.83 (s, 3H). 19F NMR (CDCl3): d K67.62 (2F),
K119.84 (2F), K121.20 (2F).
753, 720 cmK1. H NMR (CDCl3): d 11.96 (br, 1H, NH),
7.68 (dd, 1H, JZ13.2, 7.5 Hz), 7.44–7.38 (m, 2H), 7.27–
7.15 (m, 3H), 5.73 (d, 1H, JZ7.5 Hz). 19F NMR (CDCl3): d
K80.82 (3F), K121.54 (2F), K127.21 (2F).
3.4.9. cis-1-Chloro-1,1-difluoro-4-(phenylamino)but-3-
en-2-one (4cc). Mp 88–90 8C. IR (KBr): 3249, 1675,
1604, 1565, 1483, 1370, 1303, 1209, 1139, 1071, 954,
1
754 cmK1. H NMR (CDCl3): d 11.73 (br, 1H, NH), 7.69
3.4.3. cis-4,4,5,5,6,6,6-Heptafluoro-1-(tolylamino)hex-1-
en-3-one (4ab).20 Mp 63–64 8C. IR (KBr): 1644, 1598,
(dd, 1H, JZ13.2, 7.5 Hz), 7.43–7.37 (m, 2H), 7.23–7.12 (m,
3H), 5.67 (d, 1H, JZ7.5 Hz). 19F NMR (CDCl3): d K65.30
(s). EIMS m/z (%): 233 (MCC2, 6.40), 231 (MC, 19.53),
146 (MCKCF2Cl, 100.00). Anal. calcd for C10H8ClF2NO:
C, 51.85; H, 3.48; N, 6.05. Found C, 52.06; H, 3.77; N, 5.89.
1565, 1496, 1305, 1233, 1212, 1120, 888, 815, 752 cmK1
.
1H NMR (CDCl3): d 11.96 (br, 1H, NH), 7.63 (dd, 1H, JZ
13.2, 7.5 Hz), 7.19 (d, 2H, JZ8.4 Hz), 7.04 (d, 2H, JZ
8.4 Hz), 5.69 (d, 1H, JZ7.5 Hz), 2.35 (s, 3H). 19F NMR
(CDCl3): d K81.02 (3F), K121.63 (2F), K127.41 (2F).
3.4.10. cis-6-Chloro-4,4,5,5,6,6-hexafluoro-1-(4-chloro-
phenylamino)hex-1-en-3-one (4bd). Mp 62–64 8C. IR
(KBr): 1639, 1593, 1558, 1488, 1306, 1287, 1177, 829,
3.4.4. cis-6-Chloro-4,4,5,5,6,6-hexafluoro-1-(tolylamino)-
hex-1-en-3-one (4bb). Mp 77–79 8C. IR (KBr): 2926, 1641,
1600, 1561, 1496, 1365, 1313, 1286, 1197, 1175, 1123, 812,
1
771 cmK1. H NMR (CDCl3): d 11.90 (br, 1H, NH), 7.60
(dd, 1H, JZ13.2, 7.5 Hz), 7.39 (d, 2H, JZ9.0 Hz), 7.10 (d,
2H, JZ9.0 Hz), 5.75 (d, 1H, JZ7.5 Hz). 19F NMR
(CDCl3): d K67.44 (2F), K119.72 (2F), K120.92 (2F).
EIMS m/z (%): 367 (MCC2, 29.25), 365 (MC, 45.10), 180
(MCKC3F6Cl, 100.00). EI-HRMS: calcd for C12H7Cl2F6-
NO [MC] 364.9809, found 364.9797.
1
706 cmK1. H NMR (CDCl3): d 11.98 (br, 1H, NH), 7.64
(dd, 1H, JZ13.2, 7.2 Hz), 7.21 (d, 2H, JZ8.4 Hz), 7.05 (d,
2H, JZ8.4 Hz), 5.69 (d, 1H, JZ7.2 Hz), 2.36 (s, 3H). 19F
NMR (CDCl3): d K67.67 (2F), K119.93 (2F), K121.26
(2F). EIMS m/z (%): 347 (MCC2, 13.92), 345 (MC, 42.31),
310 (MCKCl, 7.27), 160 (MCKC3F6Cl, 100.00).
EI-HRMS: calcd for C13H10ClF6NO [MC] 345.0355,
found 345.0357.
3.4.11. cis-6-Chloro-4,4,5,5,6,6-hexafluoro-1-(4-bromo-
phenylamino)hex-1-en-3-one (4be). Mp 80–82 8C. IR
(KBr): 1639, 1593, 1558, 1585, 1305, 1286, 1178, 827,
1
3.4.5. cis-1-Chloro-1,1-difluoro-4-(tolylamino)but-3-en-
2-one (4cb).22 Mp 72–74 8C. IR (KBr): 2805, 1641, 1602,
1568, 1494, 1310, 1211, 1157, 1141, 1074, 945, 900, 757,
771 cmK1. H NMR (CDCl3): d 11.86 (br, 1H, NH), 7.61
(dd, 1H, JZ13.2, 7.8 Hz), 7.52 (d, 2H, JZ9.0 Hz), 7.03 (d,
2H, JZ9.0 Hz), 5.75 (d, 1H, JZ7.8 Hz). 19F NMR (CDCl3)
d K67.73 (2F), K120.02 (2F), K121.23 (2F). EIMS m/z
1
713 cmK1. H NMR (CDCl3): d 11.76 (br, 1H, NH), 7.65

F. Zhao et al. / Tetrahedron 60 (2004) 9945–9951
9951
(%): 411 (MCC2, 57.78), 409 (MC, 44.42), 224 (MCK
C3F6Cl, 86.08), 145 (MCKC3F6Cl–Br, 100.00). EI-HRMS:
calcd for C12H7BrClF6NO [MC] 408.9304, found 408.9330.
Lett. 2001, 3, 1108–1112. (c) Yu, H. B.; Huang, W. Y.
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Monatsh. Chem. 2000, 13, 55–64.
Acknowledgements
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We thank the National Natural Science Foundation for
financial support (No. 20172065).
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