Facile and regioselective synthesis of 4-fluoroalkyl-2-quinolinol

Article abstract of DOI:10.1016/S0022-1139(01)00455-9

4-Fluoroalkyl-2-quinolinols were regioselectively synthesized in moderate to high yields by acid-assisted intramolecular ring-closure reaction of the corresponding N-aryl-3-oxa-polyfluoroalkanamides prepared from 2,2-dihydropolyfluoroalkanoic acids in two

Full text of DOI:10.1016/S0022-1139(01)00455-9

Journal of Fluorine Chemistry 111 =2001) 207±212
Facile and regioselective synthesis of 4-¯uoroalkyl-2-quinolinol
Jin-Tao Liu*, He-Jun LuÈ
Laboratory of Organo¯uorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 29 March 2001
Abstract
4-Fluoroalkyl-2-quinolinols were regioselectively synthesized in moderate to high yields by acid-assisted intramolecular ring-closure
reaction of the corresponding N-aryl-3-oxa-poly¯uoroalkanamides prepared from 2,2-dihydropoly¯uoroalkanoic acids in two steps.
# 2001 Elsevier Science B.V. All rights reserved.
Keywords: 4-Fluoroalkyl-2-quinolinol; 2,2-Dihydropoly¯uoroalkanoic acids; Synthesis
1. Introduction
DCC =N,N0-dicyclohexylcarbodiimide), 1 reacted with ani-
lines to give the corresponding amides, which eliminated a
hydro¯uoride with Et3N and NaHCO3 to give N-aryl-3-
¯uoro-3-¯uoroalkyl-2-propen-2-amides =3) in high yields
=Scheme 1).
Because of the unique biological activities imparted by
¯uorine, the development of new methodologies for the
synthesis of ¯uorine-containing heterocyclic compounds
continues to arise considerable interest [1±6]. Quinolines
have been an important class of heterocycles, and some
¯uorine-containing quinolines have been found to possess
special biological properties. For example, me¯oquine, a
tri¯uoromethylated quinoline, has been used as an antima-
larial agent in response to increased resistance to existing
drugs [7]. In the past few decades many approaches to
¯uorine-containing quinolines were reported and most work
involved 2-¯uoroalkyl-substituted quinolines [8±14]. The
synthesis of 4-¯uoroalkyl quinoline and its derivatives
was less studied [15]. In the present paper we wish to
report a facile and regioselective method for the synthesis
of 4-¯uoroalkyl-2-quinolinols and their derivatives from
2,2-dihydropoly¯uoroalkanoic acids.
As shown in Scheme 2, compound 3 could undergo
Michael addition with pyrrolidine. After hydration of the
adduct, N-aryl-3-oxa-poly¯uoroalkanamides =4) were obtai-
ned in high yields. Acid-assisted ring-closure of compound
4 was conducted in the presence of polyphosphoric acid
=PPA) at 165±1708C. The reaction was complete in 5±9 h,
giving the corresponding 4-¯uoroalkyl-2-quinolinols regio-
selectively =5). The results are summarized in Table 1.
Steric effect played an important role in the above reac-
tions. The p- and m-substituted anilines gave satisfactory
results and only one of the two possible products was
isolated with ring-closure taking place at the p-position of
the substituent when a m-substituted aniline was used. In the
case of o-substituted anilines, only trace cyclic products
were obtained. Anilines bearing strong electron-withdraw-
ing groups such as nitro also gave poor results. The length of
¯uoroalkyl groups also affects the yield of the ring-closure
reaction, and better results were obtained with the tri¯uor-
omethyl group.
Similarly, tricyclic compound, 7b was obtained from a-
aminonaphthlene =8) by the following reactions =Scheme 3).
In summary, intramolecular ring-closure reaction of
N-aryl-3-oxa-poly¯uoroalkanamides obtained from 2,2-
dihydropoly¯uoroalkanoic acids was achieved in the pre-
sence of polyphosphoric acid, providing a convenient
method for the synthesis of 4-¯uoroalkyl-2-quinolinols
and their derivatives.
2. Results and discussion
2,2-Dihydropoly¯uoroalkanoic acids =1a±c) were pre-
pared readily through the sodium dithionite-initiated addi-
tion reaction of per=poly)¯uoroalkyl iodides with ethyl vinyl
ether and the following oxidation [16]. In the presence of
* Corresponding author. Fax: ‡86-21-64166128.
E-mail address: jtliu@pub.sioc.ac.cn =J.-T. Liu).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 = 0 1 ) 0 0 4 5 5 - 9

È
J.-T. Liu, H.-J. Lu / Journal of Fluorine Chemistry 111 12001) 207±212
208
Scheme 1.
Scheme 2.
3. Experimental
Table 1
Synthesis of 4-fluoroalkyl-2-quinolinols
Melting points were uncorrected. IRspectra were mea-
Entry Fluorinated
acids
ArNH2
Isolated yield =%)
sured with an IR-440 spectrometer and a Perkin-Elmer 983G
IRspectrophotometer, using liquid ®lms and KBr pellets for
solids. 1H NMRspectra were recorded on a Bruker AM 300
=300 MHz) spectrometer using TMS as internal standard.
19F NMRspectra were recorded on a Varian EM-360L
=56.4 MHz) spectrometer using TFA as external standard.
In 19F NMRspectra, chemical shifts =ppm) are regarded as
positive for up®eld shifts and the values are reported as
dCFCl ꢀdCFCl ˆ dTFA ‡ 76:8†. Mass spectra were taken on a
R0
R00
3
5
1
2
1a
1b
1c
1a
1b
1c
1a
1b
1c
1b
1a
1b
1c
1a
1b
1c
1b
1b
2d
2d
2d
2e
2e
2e
2f
2f
2f
2g
2h
2h
2h
2i
H
H
3ad, 99.0
3bd, 99.0
3cd, 98.0
3ae, 99.0
3be, 98.5
3ce, 97.0
3af, 99.5
3bf, 99.5
3cf, 99.0
3bg, 99.0
3ah, 99.5
3bh, 99.5
3ch, 99.0
3ai, 99.0
3bi, 98.5
3ci, 98.5
3bj, 97.0
6b, 95.0
5ad, 84.0
5bd, 70.5
5cd, 68.5
5ae, 80.0
5be, 59.5
5ce, 62.0
5af, 82.5
5bf, 58.0
5cf, 56.5
5bg, 58.5
5ah, 80.5
5bh, 61.0
5ch, 65.4
5ai, 85.0
5bi, 62.5
5ci, 66.0
5bj, 33.5a
7b, 56.3
H
H
3
H
H
4
Br
Br
Br
H
H
5
H
6
H
7
CH3
CH3
CH3
Cl
H
3
3
8
H
GC±MS 4021 spectrometer. Column chromatography was
performed using silica gel H, particle size 10±40 mm.
9
H
10
11
12
13
14
15
16
17
18
H
Cl
Cl
Cl
CH3
CH3
CH3
I
H
3.1. Preparation of compound 3
H
H
Typical procedure: a mixture of 2,2-dihydropoly¯uor-
oalkanoic acid =1, 5 mmol), anilne =2, 5 mmol), DCC
=5 mmol) and CH2Cl2 =25 ml) was stirred at room tempera-
ture for 5±8 h. Then Et3N =10 mmol) and NaHCO3
=10 mmol) was added and the resulting mixture was stirred
2i
H
2i
H
2j
8
H
a 30.0% of 5bd was isolated in addition to 33.5% of 5bj.

È
J.-T. Liu, H.-J. Lu / Journal of Fluorine Chemistry 111 12001) 207±212
209
Scheme 3.
under re¯ux for 5 h. After reaction, the reaction mixture was
®ltered by suction. Solvent was removed from the ®ltrate by
evaporation and the crude product was puri®ed by ¯ash
chromatography using petroleum ether and ethyl acetate
3291 =N±H), 1652 =C=O), 1200 =C±F); MS m/z: 313, 311
‡
‡
=M ), 171 =M À CF3CF=CHCO ‡ 1). Anal.: found: C,
38.74; H, 2.16; N, 4.39. C10H6BrF4NO requires: C,
38.49; H, 1.94; N, 4.49%.
1
=5:1) as eluent to give compound 3 as white solids.
1
Compound 3be: mp 138±1408C. H NMR=CDCl ) d:
3
Compound 3ad: mp 110±111.58C. H NMR=CDCl ) d:
7.86 =1H, s, NH), 7.37±7.51 =4H, m, ArH), 6.12 =1H, d,
J ˆ 32:3 Hz, =CH) ppm; 19F NMR=CDCl ) d: 67.1 =2F, s,
3
7.95 =1H, s, NH), 7.52 =2H, d, J ˆ 7:6 Hz, ArH-2,6), 7.34
=2H, t, J ˆ 7:6 Hz, ArH-3,5), 7.18 =1H, t, J ˆ 7:6 Hz, ArH-
4), 6.09 =1H, d, J ˆ 32:8 Hz, =CH) ppm; 19F NMR=CDCl 3)
d: 72.2 =3F, s, CF3), 119.1 =1F, m, =CF) ppm; IR nmax
=cmÀ1): 3308 =N±H), 1660 =C=O), 1200 =C±F); MS m/z: 233
3
ClCF2), 113.8 =1F, m, CF), 117.1 =2F, m, CF2), 120.6 =2F, m,
CF2) ppm; IR nmax =cmÀ1): 3286 =N±H), 1709 =C=O), 1131±
1259 =C±F); MS m/z: 431, 429, 427 =M ), 171
‡
‡
[M À Cl=CF2)3CF=CHCO ‡ 1]. Anal.: found: C, 33.78;
‡
‡
‡
=M ), 214 =M À F), 93 [M À Cl=CF2)3CF=CHCO ‡ 1].
H, 1.63; N, 3.35. C12H6BrClF7NO requires: C, 33.63; H,
1.41; N, 3.27%.
Anal.: found: C, 51.59; H, 3.08; N, 5.84. C10H7F4NO
requires: C, 51.51; H, 3.03; N, 6.01%.
Compound 3bd: mp 112±1148C. H NMR=CDCl ) d:
Compound 3ce: mp 123±1248C. 1H NMR=CDCl 3) d: 7.75
=1H, s, NH), 7.39±7.48 =4H, m, ArH), 6.12 =1H, d, J ˆ 31:4
Hz, =CH) ppm; 19F NMR=CDCl 3) d: 79.9 =3F, s, CF3), 113.0
=1F, m, =CF), 117.8±125.5 =8F, m, 4CF2) ppm; IR nmax
=cmÀ1): 3321 =N±H), 1701 =C=O), 1141±1201 =C±F); MS
1
3
7.71 =1H, s, NH), 7.54 =2H, d, J ˆ 7:8 Hz, ArH-2,6), 7.36
=2H, t, J ˆ 7:8 Hz, ArH-3,5), 7.18 =1H, t, J ˆ 7:8 Hz, ArH-
4), 6.15 =1H, d, J ˆ 31:3 Hz, =CH) ppm; 19F NMR=CDCl 3)
d: 68.8 =2F, s, ClCF2), 116.0 =1F, m, =CF), 118.3 =2F, m,
CF2), 122.1 =2F, m, CF2) ppm; IR nmax =cmÀ1): 3282 =N±H),
‡
‡
m/z: 513, 511 =M ), 171 [M À CF3=CF2)4CF=CHCO ‡ 1].
Anal.: found: C, 33.15; H, 1.40; N, 3.03. C14H6BrF12NO
requires: C, 32.84; H, 1.18; N, 2.74%.
‡
1702 =C=O), 1126±1189 =C±F); MS m/z: 351, 349 =M ),
‡
93 [M À Cl=CF2)3CF=CHCO ‡ 1]. Anal.: found: C, 41.80;
Compound 3af: mp 124±1258C. 1H NMR=CDCl 3) d: 8.34
=1H, s, NH), 7.36 =1H, s, ArH-2), 7.30 =1H, d, J ˆ 7:2 Hz,
ArH-6), 7.21 =1H, t, J ˆ 7:2 Hz, ArH-5), 6.98 =1H, d,
J ˆ 7:2 Hz, ArH-4), 6.09 =1H, d, J ˆ 32:7 Hz, =CH),
H, 1.90; N, 4.00. C12H7ClF7NO requires: C, 41.20; H, 2.00;
N, 4.01%.
1
Compound 3cd: mp 108±1098C. H NMR=CDCl ) d:
3
7.91 =1H, s, NH), 7.51 =2H, d, J ˆ 7:6 Hz, ArH-2,6), 7.33
=2H, t, J ˆ 7:6 Hz, ArH-3,5), 7.16 =1H, t, J ˆ 7:6 Hz, ArH-
4), 6.18 =1H, d, J ˆ 30:5 Hz, =CH) ppm; 19F NMR=CDCl 3)
d: 79.8 =3F, s, CF3), 113.4 =1F, m, =CF), 117.4±123.3 =8F, m,
4CF2) ppm; IR nmax =cmÀ1): 3342 =N±H), 1702 =C=O),
2.32 =3H, s, CH3) ppm; 19F NMR=CDCl ) d: 71.9 =3F, s,
3
CF3), 119.2 =1F, m, =CF) ppm; IR nmax =cmÀ1): 3158 =N±H),
1618 =C=O), 1201 =C±F); MS m/z: 247 =M ); 107
‡
‡
=M À CF3CF=CHCO ‡ 1). Anal.: found: C, 53.44; H,
3.74; N, 5.61. C11H9F4NO requires: C, 53.45; H, 3.67; N,
5.67%.
‡
‡
1143±1201 =C±F); MS m/z: 433 =M ), 93 [M À CF3=CF2)4-
CHCO ‡ 1]. Anal.: found: C, 39.04; H, 1.69; N, 3.36.
1
Compound 3bf: mp 88±898C. H NMR=CDCl ) d: 8.20
3
C14H7F12NO requires: C, 38.82; H, 1.63; N, 3.23%.
1
=1H, s, NH), 7.35 =1H, s, ArH-2), 7.31 =1H, d, J ˆ 7:6 Hz,
ArH-6), 7.19 =1H, t, J ˆ 7:6 Hz, ArH-5), 6.97 =1H, d,
J ˆ7:6 Hz, ArH-4), 6.17 =1H, d, J ˆ 30:6 Hz, =CH), 2.35
=3H, s, CH3) ppm; 19F NMR=CDCl 3) d: 66.9 =2F, s, ClCF2),
113.8 =1F, m, =CF), 116.8 =2F, m, CF2), 120.3 =2F, m, CF2)
Compound 3ae: mp 118±1198C. H NMR=CDCl ) d:
3
7.76 =1H, s, NH), 7.46 =4H, m, ArH), 6.10 =1H, d,
J ˆ 33:1 Hz, =CH) ppm; 19F NMR=CDCl 3) d: 72.0
=3F, s, CF3), 118.7 =1F, m, =CF) ppm; IR nmax =cmÀ1):

È
J.-T. Liu, H.-J. Lu / Journal of Fluorine Chemistry 111 12001) 207±212
210
ppm; IR nmax =cmÀ1): 3295 =N±H), 1702 =C=O), 1127±1180
=M À CF3CF=CHCO ‡ 1). Anal.: found: C, 53.52; H,
3.68; N, 5.69. C11H9F4NO requires: C, 53.45; H, 3.67;
N, 5.67%.
‡
‡
‡
=C±F); MS m/z: 365, 363 =M ), 107 [M À Cl=CF2)3-
CHCO ‡ 1]. Anal.: found: C, 43.09; H, 2.44; N, 3.97.
C13H9ClF7NO requires: C, 42.94; H, 2.49; N, 3.85%.
Compound 3cf: mp 101±1028C. 1H NMR=CDCl 3) d: 7.93
=1H, s, NH), 7.36 =1H, s, ArH-2), 7.31 =1H, d, J ˆ 7:8 Hz,
ArH-6), 7.21 =1H, t, J ˆ 7:8 Hz, ArH-5), 6.98 =1H, d,
J ˆ 7:8 Hz, ArH-4), 6.18 =1H, d, J ˆ 31:3 Hz, =CH),
Compound 3bi: mp 115±1178C. 1H NMR=CDCl 3) d: 8.27
=1H, s, NH), 7.37 =2H, d, J ˆ 8:3 Hz, ArH-2,6), 7.10 =2H, d,
J ˆ 8:3 Hz, ArH-3,5), 6.14 =1H, d, J ˆ 32:3 Hz, =CH), 2.37
=3H, s, CH3) ppm; 19F NMR=CDCl 3) d: 67.2 =2F, s, ClCF2),
113.0 =1F, m, =CF), 116.5 =2F, m, CF2), 120.4 =2F, m, CF2)
ppm; IR nmax =cmÀ1): 3287 =N±H), 1703 =C=O), 1129±1191
2.36 =3H, s, CH3) ppm; 19F NMR=CDCl ) d: 79.8 =3F, s,
3
‡
‡
CF3), 113.3 =1F, m, CF), 117.6±123.1 =8F, m, 4CF2) ppm; IR
nmax =cmÀ1): 3295 =N±H), 1701 =C=O), 1141±1199 =C±F);
=C±F); MS m/z: 365, 363 =M ), 107 [M À Cl=CF2)3-
CHCO ‡ 1]. Anal.: found: C, 43.03; H, 2.49; N, 3.97.
C13H9ClF7NO requires: C, 42.94; H, 2.49; N, 3.85%.
Compound 3ci: mp 105±1068C. 1H NMR=CDCl 3) d: 7.98
=1H, s, NH), 7.40 =2H, d, J ˆ 8:2 Hz, ArH-2,6), 7.12 =2H, d,
J ˆ 8:2 Hz, ArH-3,5), 6.15 =1H, d, J ˆ 32:9 Hz, =CH), 2.32
‡
‡
MS m/z: 447 =M ), 107 [M À CF3=CF2)4CF=CHCO ‡ 1].
Anal.: found: C, 40.75; H, 2.27; N, 3.42. C15H9F12NO
requires: C, 40.29; H, 2.03; N, 3.13%.
Compound 3bg: mp 102±1048C. H NMR=CDCl ) d:
1
3
7.89 =1H, s, NH), 7.65 =1H, s, ArH-2), 7.37 =1H, d, J ˆ 8:0
Hz, ArH-6), 7.26 =1H, t, J ˆ 8:0 Hz, ArH-5), 7.14 =1H, d,
J ˆ 8:0 Hz, ArH-4), 6.17 =1H, d, J ˆ 32:3 Hz, =CH) ppm;
19F NMR=CDCl 3) d: 66.8 =2F, s, ClCF2), 112.9 =1F, m, =CF),
117.0 =2F, m, CF2), 120.4 =2F, m, CF2) ppm; IR nmax =cmÀ1):
3297 =N±H), 1705 =C=O), 1123±1181 =C±F); MS m/z: 387,
=3H, s, CH3) ppm. 19F NMR=CDCl ) d: 80.0 =3F, s, CF3),
3
117.5 =1F, m, =CF), 122.0±125.7 =8F, m, 4CF2) ppm; IR nmax
=cmÀ1): 3337 =N±H), 1702 =C=O), 1143±1200 =C±F); MS
‡
‡
m/z: 447 =M ), 107 [M À CF3=CF2)4CF=CHCO ‡ 1].
Anal.: found: C, 40.60; H, 2.39; N, 3.48. C15H9F12NO
requires: C, 40.29; H, 2.03; N, 3.13%.
‡
‡
385, 383 =M ), 127 [M À Cl=CF2)3CF=CHCO ‡ 1]. Anal.:
Compound 3bj: mp 152±1538C. 1H NMR=CDCl 3) d: 7.82
=1H, s, NH), 7.65 =2H, d, J ˆ 8:3 Hz, ArH-2,6), 7.31 =2H, d,
J ˆ 8:3 Hz, ArH-3,5), 6.10 =1H, d, J ˆ 33:1 Hz, =CH) ppm;
found: C, 37.83; H, 1.77; N, 3.79. C12H6Cl2F7NO requires: C,
37.53; H, 1.57; N, 3.65%.
Compound 3ah: mp 120±1228C. H NMR=CDCl ) d:
1
19F NMR=CDCl ) d: 68.3 =2F, s, ClCF2), 114.8 =1F, m,
3
3
7.75 =1H, s, NH), 7.46 =4H, m, ArH), 6.10 =1H, d,
J ˆ 33:1 Hz, =CH) ppm; 19F NMR=CDCl ) d: 72.9 =3F,
=CF), 118.0 =2F, m, CF2), 121.8 =2F, m, CF2) ppm; IR nmax
=cmÀ1): 3313 =N±H), 1697 =C=O), 1124±1177 =C±F); MS
3
‡
s, CF3), 118.6 =1F, m, =CF) ppm; IR nmax =cmÀ1): 3264 =N±
H), 1653 =C=O), 1193 =C±F); MS m/z: 269, 267 =M ), 248
m/z: 477, 475 =M ), 219 [M À Cl=CF2)3CF=CHCO ‡ 1].
Anal.: found: C, 30.22; H, 1.47; N, 3.13. C12H6ClF7INO
requires: C, 30.28; H, 1.27; N, 2.95%.
‡
‡
‡
‡
=M À F), 127 =M À CF3CF=CHCO ‡ 1). Anal.: found:
C, 44.92; H, 2.33; N, 5.19. C10H6ClF4NO requires: C, 44.88;
H, 2.26; N, 5.23%.
Compound 6b: mp 133±1358C. 1H NMR=CDCl 3) d: 8.50
=1H, s, NH), 7.24±8.00 =7H, m, ArH), 6.31 =1H, d,
Compound 3bh: mp 130±1328C. 1H NMR=CDCl 3) d: 7.89
=1H, s, NH), 7.48 =2H, d, J ˆ 8:8 Hz, ArH-2,6), 7.30 =2H, d,
J ˆ 8:8 Hz, ArH-3,5), 6.15 =1H, d, J ˆ 29:8 Hz, =CH) ppm;
19F NMR=CDCl 3) d: 68.8 =2F, s, ClCF2), 117.4 =1F, m, CF),
118.2 =2F, m, CF2), 122.0 =2F, m, CF2) ppm; IR nmax =cmÀ1):
3282 =N±H), 1702 =C=O), 1125±1189 =C±F); MS m/z: 387,
J ˆ 33:1 Hz, =CH) ppm; 19F NMR=CDCl ) d: 66.8 =2F,
3
s, ClCF2), 113.8 =1F, m, CF), 116.6 =2F, m, CF2), 120.2 =2F,
m, CF2) ppm; IR nmax =cmÀ1): 3272 =N±H), 1701 =C=O),
1547±1648 =ArH, C±H), 1129±1184 =C±F); MS m/z: 401,
‡
‡
399 =M ), 143 [M À Cl=CF2)3CF=CHCO ‡ 1]. Anal.:
found: C, 48.17; H, 2.38; N, 3.52. C16H9ClF7NO requires:
C, 48.08; H, 2.27; N, 3.50%.
‡
‡
385, 383 =M ), 127 [M À Cl=CF2)3CF=CHCO ‡ 1]. Anal.:
found: C, 37.50; H, 1.67; N, 3.47. C12H6Cl2F7NO requires:
C, 37.53; H, 1.57; N, 3.65%.
Compound 3ch: mp 111±1128C. H NMR=CDCl ) d:
3.2. Preparation of 4-fluoroalkyl-2-quinolinols 15)
1
3
7.96 =1H, s, NH), 7.50 =2H, d, J ˆ 8:6 Hz, ArH-2,6), 7.30
A typical procedure was as follows: a mixture of 3
=5 mmol), pyrrolidine =10 mmol) and CH2Cl2 =25 ml) was
stirred under re¯ux for 1±2 h. Then the mixture was cooled
to room temperature and 10 ml of 2N hydrochloride acid
was added. The resulting mixture was stirred for 1 h at room
temperature and separated. The organic layer was washed
with water and saturated NaCl solution and dried over
anhydrous sodium sulfate. Removal of CH2Cl2 gave the
crude product of compound 4, which was used directly in the
next step without further puri®cation.
The above crude product of 4 #1.0 g) and 20 g of PPAwas
heated with stirring at 165±1708C for 6±8 h. The mixture
was cooled to room temperature, diluted with water, and
neutralized to pH ˆ 7. The resulting mixture was extracted
=2H, d, J ˆ 8:6 Hz, ArH-3,5), 6.15 =1H, d, J ˆ 8:6 Hz,
=CH) ppm; 19F NMR=CDCl ) d: 79.7 =3F, s, CF3), 113.0
3
=1F, m, =CF), 117.5±125.2 =8F, m, 4CF2) ppm; IR nmax
=cmÀ1): 3301 =N±H), 1701 =C=O), 1142±1203 =C±F); MS m/
‡
‡
z: 469, 467 =M ), 127 [M À CF3=CF2)4CF=CHCO ‡ 1].
Anal.: found: C, 36.11; H, 1.49; N, 3.00. C14H6ClF12NO
requires: C, 35.96; H, 1.29; N, 3.00%.
Compound 3ai: mp 121±1238C. 1H NMR=CDCl ) d:
3
7.93 =1H, s, NH), 7.39 =2H, d, J ˆ 8:4 Hz, ArH-2,6), 7.12
=2H, d, J ˆ 8:4 Hz, ArH-3,5), 6.08 =1H, d, J ˆ 32:7 Hz,
=CH), 2.32 =3H, s, CH3) ppm; 19F NMR=CDCl ) d: 72.2
3
=3F, s, CF3), 119.3 =1F, m, =CF) ppm; IR nmax =cmÀ1): 3321
=N±H), 1648 =C=O), 1208 =C±F); MS m/z: 247 =M ); 107
‡

È
J.-T. Liu, H.-J. Lu / Journal of Fluorine Chemistry 111 12001) 207±212
211
with ether for three times. The combined etheral solution
was washed with water and saturated NaCl solution, and
dried over anhydrous sodium sulfate. Removal of the sol-
vent followed by column chromatography using petroleum
ether and ethyl acetate =5:1) as eluent gave compounds 5
as white solids.
d: 61.7 =3F, s, CF3) ppm; IR nmax =cmÀ1): 3425 =O±H), 1421±
1677 =ArH, C±H), 1188 =C±F); MS m/z: 227 =M ). Anal.:
‡
found: C, 58.33; H, 3.58; N, 5.99. C11H8F3NO requires: C,
58.16; H, 3.55; N, 6.17%.
1
Compound 5bf: mp 195±1968C. H NMR=CD COCD3)
3
d: 7.75 =1H, d, J ˆ 8:5 Hz, ArH-5), 7.32 =1H, s, ArH-8),
7.18 =1H, d, J ˆ 8:5 Hz, ArH-6), 6.86 =1H, s, ArH-3), 2.93
=1H, s, OH), 2.46 =3H, s, CH3) ppm; 19F NMR=CD 3COCD3)
d: 86.1 =2F, s, ClCF2), 107.8 =2F, s, ArCF2), 119.5 =2F, s,
CF2) ppm; IR nmax =cmÀ1): 3350 =O±H), 1620±1685 =ArH,
Compound 5ad: mp 215±2168C. 1H NMR=CD 3COCD3)
d: 7.35±7.82 =4H, m, ArH), 6.98 =1H, s, ArH-3), 3.34 =1H, s,
OH) ppm; 19F NMR=CD 3COCD3) d: 63.3 =3F, s, CF3) ppm;
IR nmax =cmÀ1): 3431 =O±H), 1411±1671 =ArH, C±H), 1262
‡
‡
=C±F), 1127 =C±O); MS m/z: 213 =M ). Anal.: found: C,
56.12; H, 2.88; N, 6.46. C10H6F3NO requires: C, 56.35; H,
2.84; N, 6.57%.
C±H), 1100±1210 =C±F); MS m/z: 345, 343 =M ). Anal.:
found: C, 45.58; H, 2.50; N, 4.32. C13H8ClF6NO requires: C,
45.44; H, 2.35; N, 4.08%.
Compound 5cf: mp 190±1918C. H NMR=CD COCD3)
Compound 5bd: mp 180±1818C. 1H NMR=CD 3COCD3)
d: 7.50±8.42 =4H, m, ArH), 6.86 =1H, s, ArH), 2.65 =1H, s,
1
3
d: 8.24 =1H, d, J ˆ 8:8 Hz, ArH-5), 7.92 =1H, s, ArH-8),
7.56 =1H, d, J ˆ 8:8 Hz, ArH-6), 7.25 =1H, s, ArH-3), 2.95
=1H, s, OH), 2.55 =3H, s, CH3) ppm; 19F NMR=CD 3COCD3)
d: 81.5 =3F, s, CF3), 108.9 =2F, s, ArCF2), 117.4±120.8 =6F,
m, 3CF2) ppm; IR nmax =cmÀ1): 3400 =O±H), 1525±1630
OH) ppm. 19F NMR=CD COCD3) d: 67.8 =2F, s, ClCF2),
3
113.5 =2F, s, ArCF2), 121.1 =2F, s, CF2) ppm; IR nmax
=cmÀ1): 3360 =O±H), 1470±1640 =ArH, C±H), 1120±1200
‡
‡
=C±F); MS m/z: 331, 329 =M ), 294 =M À Cl), 194. Anal.:
found: C, 43.91; H, 2.02; N, 4.29. C12H6ClF6NO requires: C,
43.73; H, 1.83; N, 4.25%.
‡
=ArH, C±H), 1125±1230 =C±F); MS m/z: 427 =M ), 408
‡
=M À F). Anal.: found: C, 42.83; H, 2.24; N, 3.30.
Compound 5cd: mp 201±2028C. 1H NMR=CD 3COCD3)
d: 7.66±8.42 =4H, m, ArH), 7.10 =1H, s, ArH-3), 3.07 =1H, s,
C15H8F11NO requires: C, 42.67; H, 1.89; N, 3.28%.
Compound 5bg: mp 250±2528C. 1H NMR=CD 3COCD3)
d: 8.32 =1H, d, J ˆ 8:0 Hz, ArH-5), 8.08 =1H, s, ArH-8),
7.74 =1H, d, J ˆ 8:0 Hz, ArH-6), 7.36 =1H, s, ArH-3), 3.15
OH) ppm; 19F NMR=CD COCD3) d: 81.8 =3F, s, CF3),
114.0 =2F, s, ArCF2), 122.6±126.9 =6F, m, 3CF2) ppm; IR
3
nmax =cmÀ1): 3400 =O±H), 1439±1630 =ArH, C±H), 1185±
=1H, s, OH) ppm; 19F NMR=CD COCD3) d: 66.7 =2F, s,
3
‡
‡
1230 =C±F); MS m/z: 413 =M ), 394 =M À F), 194. Anal.:
found: C, 40.74; H, 1.66; N, 3.18. C15H6F12NO requires: C,
40.29; H, 2.03; N, 3.13%.
ClCF2), 113.0 =2F, s, ArCF2), 120.9 =2F, s, CF2) ppm; IR
nmax =cmÀ1): 3350 =O±H), 1450±1635 =ArH, C±H), 1110±
1185 =C±F); MS m/z: 367, 365, 363 =M ). Anal.: found: C,
‡
Compound 5ae: mp 201±2038C. 1H NMR=CD 3COCD3)
d: 7.96±8.42 =3H, m, ArH), 7.17 =1H, s, ArH-3), 3.56 =1H, s,
OH) ppm; 19F NMR=CD 3COCD3) d: 62.3 =3F, s, CF3) ppm;
IR nmax =cmÀ1): 3435 =O±H), 1467±1611 =ArH, C±H), 1196
=C±F), 1150 =C±O); MS m/z: 293, 291 =M ). Anal.: found:
C, 41.50; H, 2.02; N, 4.61. C10H5BrF3NO requires: C, 41.12;
39.07; H, 1.90; N, 3.38. C12H5Cl2F6NO requires: C, 39.39;
H, 1.88; N, 3.35%.
Compound 5ah: mp 189±1908C. 1H NMR=CD 3COCD3)
d: 7.35±7.64 =3H, m, ArH), 7.05 =1H, s, ArH-3), 3.14 =1H, s,
OH) ppm; 19F NMR=CD 3COCD3) d: 63.9 =3F, s, CF3) ppm;
IR nmax =cmÀ1): 3441 =O±H), 1432±1614 =ArH, C±H), 1176
‡
‡
H, 1.72; N, 4.80%.
Compound 5be: mp 210±2128C. H NMR=CD SOCD3)
=C±F), 1140 =C±O); MS m/z: 249, 247 =M ). Anal.: found:
C, 48.44; H, 2.16; N, 5.49. C10H5ClF3NO requires: C, 48.51;
H, 2.04; N, 5.66%.
1
3
d: 7.86±8.31 =3H, m, ArH), 7.00 =1H, s, ArH-3), 2.95 =1H, s,
OH) ppm; 19F NMR=CD SOCD3) d: 67.8 =2F, s, ClCF2),
Compound 5bh: mp 238±2408C. 1H NMR=CD 3COCD3)
d: 8.26 =1H, s, ArH-5), 8.05 =1H, d, J ˆ 9:0 Hz, ArH-8),
7.85 =1H, d, J ˆ 9:0 Hz, ArH-7), 7.24 =1H, s, ArH-3), 3.46
3
113.7 =2F, s, ArCF2), 121.3 =2F, s, CF2) ppm. IR nmax
=cmÀ1): 3350 =O±H), 1455±1620 =ArH, C±H), 1100±1160
‡
=C±F); MS m/z: 412, 410, 408 =M ). Anal.: found: C, 35.33;
H, 1.34; N, 3.43. C12H5BrClF6NO requires: C, 35.28; H,
=1H, s, OH) ppm; 19F NMR=CD COCD3) d: 67.2 =2F, s,
3
ClCF2), 112.9 =2F, s, ArCF2), 120.4 =2F, s, CF2) ppm; IR
1.23; N, 3.43%.
Compound 5ce: mp 215±2178C. H NMR=CD COCD3)
nmax =cmÀ1): 3400 =O±H), 1460±1635 =ArH, C±H), 1110±
1195 =C±F); MS m/z: 367, 365, 363 =M ). Anal.: found: C,
39.61; H, 1.51; N, 3.80. C12H5Cl2F6NO requires: C, 39.59;
‡
1
3
d: 7.99±8.46 =3H, m, ArH), 7.36 =1H, s, ArH-3), 2.93 =1H, s,
OH) ppm; 19F NMR=CD COCD3) d: 81.7 =3F, s, CF3),
114.1 =2F, s, ArCF2), 122.8 =4F, m, 2CF2), 127.1 =2F, m,
H, 1.38; N, 3.85%.
3
Compound 5ch: mp 250±2528C. 1H NMR=CD 3COCD3)
d: 8.27 =1H, s, ArH-5), 8.08 =1H, d, J ˆ 8:9 Hz, ArH-8),
7.88 =1H, d, J ˆ 8:9 Hz, ArH-7), 7.33 =1H, s, ArH-3), 3.10
CF2) ppm; IR nmax =cmÀ1): 3300 =O±H), 1460±1620 =ArH,
C±H), 1130±1220 =C±F); MS m/z: 493, 491 =M ). Anal.:
‡
found: C, 36.14; H, 1.79; N, 2.83. C14H5BrF11NO requires:
C, 36.17; H, 1.62; N, 2.85%.
=1H, s, OH) ppm; 19F NMR=CD COCD3) d: 81.3 =3F, s,
3
CF3), 113.8 =2F, s, ArCF2), 122.3±127.0 =6F, m, 3CF2) ppm;
IR nmax =cmÀ1): 3350 =O±H), 1490±1600 =ArH, C±H),
1110±1180 =C±F); MS m/z: 449, 447 =M ). Anal.: found:
1
Compound 5af: mp 193±1948C. H NMR=CD SOCD3)
3
‡
d: 7.60 =1H, d, J ˆ 8:2 Hz, ArH-5), 7.23 =1H, s, ArH-8),
7.14 =1H, d, J ˆ 8:2 Hz, ArH-6), 6.90 =1H, s, ArH-3), 3.41
=1H, s, OH), 2.42 =3H, s, CH3) ppm; 19F NMR=CD 3SOCD3)
C, 38.44; H, 1.48; N, 3.10. C14H5ClF11NO requires: C,
38.56; H, 1.13; N, 3.13%.

È
J.-T. Liu, H.-J. Lu / Journal of Fluorine Chemistry 111 12001) 207±212
212
Compound 5ai: mp 205±206.58C. 1H NMR=CD 3SOCD3)
112.4 =2F, s, ArCF2), 120.6 =2F, s, CF2) ppm; IR nmax
d: 7.32±7.47 =3H, m, ArH), 6.93 =1H, s, ArH-3), 3.34 =1H, s,
OH), 2.36 =3H, s, CH3) ppm; 19F NMR=CD 3SOCD3) d: 61.7
=3F, s, CF3) ppm; IR nmax =cmÀ1): 3439 =O±H), 1435±1677
=cmÀ1): 3400 =O±H), 1520±1620 =ArH, C±H), 1115±1170
‡
‡
=C±F); MS m/z: 381, 379 =M ), 360 =M À F). Anal.: found:
C, 50.94; H, 2.33; N, 3.73. C16H8ClF6NO requires: C, 50.61;
H, 2.12; N, 3.69%.
‡
=ArH, C±H), 1267 =C±F), 1126 =C±O); MS m/z: 227 =M ).
Anal.: found: C, 58.36; H, 3.54; N, 5.89. C11H8F3NO
requires: C, 58.16; H, 3.55; N, 6.17%.
1
Compound 5bi: mp 205±2068C. H NMR=CD COCD3)
Acknowledgements
3
d: 8.10 =1H, s, ArH), 7.95 =1H, d, J ˆ 8:6 Hz, ArH), 7.75
=1H, d, J ˆ 8:6 Hz, ArH), 7.27 =1H, s, ArH), 3.62 =1H, s,
OH), 2.60 =3H, s, CH3) ppm; 19F NMR=CD 3COCD3) d: 67.8
=2F, s, CF2Cl), 113.1 =2F, s, ArCF2), 120.9 =2F, s, CF2) ppm;
IR nmax =cmÀ1): 3400 =O±H), 1595±1680 =ArH, C±H),
We thank the National Natural Science Foundation
of China =nos. 29772041 and 29902008) and Shanghai
Municipal Scienti®c Committee =no. 00QA14030) for
®nancial support.
‡
1100±1180 =C±F); MS m/z: 345, 343 =M ). Anal.: found:
C, 45.78; H, 2.37; N, 4.18. C13H8ClF6NO requires: C, 45.44;
References
H, 2.35; N, 4.08%.
Compound 5ci: mp 210±2128C. H NMR=CD COCD3)
1
3
[1] M.J. Silvester, Aldrichim. Acta 24 =1991) 31.
[2] R.D. Chambers, C.R. Sargent, Adv. Heterocycl. Chem. 28 =1981) 1.
[3] R. Filler, Y. Kobayashi =Eds.), Biomedicinal Aspects of Fluorine
Chemistry, Kodansha, Tokyo, 1982.
d: 8.07 =1H, s, ArH-5), 7.92 =1H, d, J ˆ 8:4 Hz, ArH-8),
7.72 =1H, d, J ˆ 8:4 Hz, ArH-7), 7.25 =1H, s, ArH-3), 2.65
=1H, s, OH), 2.56 =3H, s, CH3) ppm; 19F NMR=CD 3COCD3)
d: 81.3 =3F, s, CF3), 113.5 =2F, s, ArCF ), 122.4 =4F, m,
2
[4] R.E. Banks =Ed.), Preparation, Properties and Industrial Application
of Organofluorine Compounds, Ellis Horwood, Chichester, 1982.
[5] J.T. Welch, Tetrahedron 43 =1987) 3123.
2CF2), 126.6 =2F, m, CF2) ppm; IR nmax =cmÀ1): 3350 =O±
H), 1500±1600 =ArH, C±H), 1130±1225 =C±F); MS m/z: 427
‡
[6] X.-C. Zhang, W.-Y. Huang, J. Fluorine Chem. 92 =1998) 13, and
references cited therein.
‡
=M ), 408 =M À F). Anal.: found: C, 42.23; H, 2.11; N,
3.25. C15H8F11NO requires: C, 42.17; H, 1.89; N, 3.28%.
1
[7] C.J. Ohnmacht, A.R. Patel, R.E. Lutz, J. Med. Chem. 14 =1971) 926.
[8] R.E. Banks, R.N. Haszeldine, J.M. Robinson, J. Chem. Soc., Perkin
Trans. 1 =1976) 1226.
Compound 5bj: mp 216±2188C. H NMR=CD COCD3)
3
d: 8.68 =1H, s, ArH-5), 8.14 =1H, d, J ˆ 7:0 Hz, ArH-8),
[9] H. Uno, S. Okada, Y. Shiraishi, K. Shimokawa, H. Suzuki, Chem.
Lett. =1988) 1165.
7.85 =1H, d, J ˆ 7:0 Hz, ArH-7), 7.15 =1H, s, ArH-3), 3.57
=1H, s, OH) ppm. 19F NMR=CD COCD3) d: 67.5 =2F, s,
ClCF2), 113.4 =2F, s, ArCF2), 120.8 =2F, s, CF2) ppm; IR
3
[10] G.M. Brooke, I.M. Egglesion, F.A. Hale, J. Fluorine Chem. 38 =1988)
421.
nmax =cmÀ1): 3350 =O±H), 1460±1625 =ArH, C±H), 1110±
[11] J. Froissard, J. Greiner, R. Pastor, J. Fluorine Chem. 17 =1981)
249.
‡
‡
1180 =C±F); MS m/z: 457, 455 =M ), 420 =M À Cl), 320
‡
[12] F. Clemence, O. Martret, F. Delevallee, J. Benzoni, S. Jouquey, M.
Mouren, R. Deraedt, J. Med. Chem. 31 =1988) 1453.
[13] W.-Y. Huang, Y.-S. Liu, L. Lu, J. Fluorine Chem. 66 =1994) 209.
[14] H.-B. Yu, Q.-S. Zhang, W.-Y. Huang, Chin. J. Chem. 15 =1997) 278.
[15] R.J. Linderman, K.S. Kirollos, Tetrahedron Lett. 31 =1990) 2689.
[16] W.-Y. Huang, L. Lu, Y.-F. Zhang, Chin. J. Chem. 8 =1990) 281.
=M À ClCF2CF2). Anal.: found: C, 31.60; H, 1.33; N, 3.12.
C12H5ClF6INO requires: C, 31.64; H, 1.11; N, 3.07%.
Compound 7b: mp 240±2428C. 1H NMR=CD 3COCD3) d:
9.25 =1H, m, ArH), 7.42±8.26 =6H, m, ArH), 3.00 =1H, s,
OH) ppm; 19F NMR=CD COCD3) d: 67.5 =2F, s, ClCF2),
3