A novel synthesis of 2-fluoroalkyl quinolines

Article abstract of DOI:10.1007/s007060050006

2-Fluoroalkyl quinolines are prepared by reacting aniline with α-fluoroalkyl aldehydes or α-fluoroalkyl cyclohexanones in the presence of acetic acid. Under the same reaction condition, 2-aminophenol gives the corresponding 2-fluoroalkyl-8-quinolinols; in some cases, 2-fluoroalkyl benzoxazoles are also formed as minor products.

Full text of DOI:10.1007/s007060050006

Monatshefte fuÈr Chemie 131, 55±63 (2000)
A Novel Synthesis of 2-Fluoroalkyl Quinolines
Ã
Quan-Fu Wang, Yun-Yu Mao, Chao-Yue Qin, Shi-Zheng Zhu ,
and Chang-Ming Hu
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Summary. 2-Fluoroalkyl quinolines are prepared by reacting aniline with ꢀ-¯uoroalkyl aldehydes or
ꢀ-¯uoroalkyl cyclohexanones in the presence of acetic acid. Under the same reaction condition, 2-
aminophenol gives the corresponding 2-¯uoroalkyl-8-quinolinols; in some cases, 2-¯uoroalkyl
benzoxazoles are also formed as minor products.
Keywords. ꢀ-Fluoroalkyl aldehyde; ꢀ-Fluoroalkyl cyclohexanone; Aniline; 2-Fluoroalkyl quino-
line; 2-Fluoroalkyl benzoxazole; Acetic acid.
Eine neue Synthese von 2-Fluoralkylchinolinen
Zusammenfassung. 2-Fluoralkylchinoline werden durch Reaktion von Anilin mit ꢀ-Fluoraldehyden
È
oder ꢀ-Fluorcyclohexanonen in Gegenwart von Essigsaure dargestellt. Unter denselben Reaktions-
È
bedingungen gibt 2-Aminophenol die entsprechenden 2-Fluoralkyl-8-chinolinole; in manchen Fallen
werden 2-Fluoralkylbenzoxazole als Nebenprodukte gebildet.
Introduction
The incorporation of a ¯uorine atom or a ¯uoroalkyl group into quinoline and its
derivatives is of considerable importance due to the biological activities of the
resulting products [1]. Various methods have been reported for the synthesis of
these compounds, such as the electrochemical process of introducing -CF3 into
quinolines [2] and the cyclization of ¯uorine-containing building blocks [3, 4].
Recently, Linderman et al. have reported the synthesis of 2-tri¯uoromethyl
quinoline from the reaction of EtOH=CHCOCF3 with aniline followed by
treatment with PCl3 [5]. During our studies on ꢀ-¯uoroalkyl aldehydes [6] we
have found that these compounds readily react with ethylenediamine to afford 5-
¯uoralkyl-1,4-diazepines [7]. In continuation, of our work on ¯uorinated aldehydes
and ¯uorinated cyclohexanones [8] we recently found that they can be reacted with
aniline and its derivatives to yield 2-¯uoroalkyl substituted quinolines. Here we
wish to report these results.
Ã
Corresponding author

56
Q.-F. Wang et al.
Results and Discussion
ꢀ-Fluoroalkyl aldehydes of the type R1 CF2CH2CHO (1) which can be prepared by
treatment of R1CF2X with EtOCH=CH2 were mixed with two mole equivalents
aniline and re¯uxed in acetic acid for 8 h to afford the 2-¯uoralkyl quinolines 3 in
about 60% yield (Scheme 1).
The ¯uoroalkyl group in 3 is located at position 2 as deduced by comparison of
the 13C NMR chemical shifts with reported values [5]. The in¯uence of the
substituent on the aromatic ring of aniline is evident; 4-methyl-or 4-hydroxyani-
line react smoothly with 1a to from the desired products, whereas 4-nitroaniline or
4-aminobenzoic acid did not. Even under higher reaction temperature and longer
reaction time no reaction occurred. The length of the ¯uoroalkyl chain and the
presence of chlorine or bromine in !-position showed little effect on the reaction,
and all substrates afforded products 3 in nearly equal yield. Acetic acid proved to
be the best solvent. Other solvents such as ethanol, acetonitrile, THF, and 1,4-
dioxane gave complex mixtures.
3,3-Dihalo-4,4,4-tri¯uorobutylaldehyde (CF3CXYCH2CHO, 4), formed by
treatment of the corresponding ¯uoro-halo ethane CF3CXY2 with ethyl vinyl
ether, reacted with aniline in the same way as 1. All educts resulted in product 3a
as shown in Scheme 2.
Scheme 1
Scheme 2

Synthesis of Fluorinated Quinolines
57
Scheme 3
Scheme 4
A possible reaction pathway for the formation of 3 might be formulated as
displayed in Scheme 3. It was found that ꢀ-¯uoroalkyl cyclohexanones undergo a
similar reaction with aniline to afford 2-¯uoroalkyl-3,4-cyclohexa-quinolines
(Scheme 4).
Products 6 are solids and easy to crystallize from C6H6:CHCl3 ˆ 1:1. Their
structures were fully characterized by spectroscopic data, elemental analyses, and
an X-ray diffraction analysis of compound 6a (Fig. 1).
Fig. 1. The structure of compound

58
Table 1. Selected bond lengths (A) and bond angles ( ) of compound 6a
Q.-F. Wang et al.
ꢀ
Ê
Bond lengths
Bond angles
C(2)±N
1.311(3)
1.369(3)
1.510(4)
1.422(3)
1.428(3)
1.517(4)
1.414(3)
1.377(4)
C(2)±N±C(6)
C(4)±C(5)±C(6)
C(2)±C(3)±C(4)
C(4)±C(3)±C(11)
N±C(2)±C(1)
N±C(2)±C(3)
N±C(6)±C(5)
N±C(6)±C(7)
117.2(2)
118.9(2)
117.0(2)
121.6(2)
112.8(2)
126.1(2)
121.8(2)
117.6(2)
C(6)±N
C(1)±C(2)
C(2)±C(3)
C(4)±C(5)
C(3)±C(11)
C(5)±C(6)
C(3)±C(4)
In the case a ¯uoroalkyl ester was used, the corresponding 2-¯uoroalkyl-4-o-
methyl substituted quinoline derivatives could not be obtained.
As discussed above, 4-aminophenol reacted with 1a to afford 2-tri¯uoromethyl-
6-hydroxy-quinolines. 2-Aminophenol behaved similarly when reacted with 1a±c
to yield the corresponding 2-¯uoroalkyl-8-quinolines which are of interest due to
their bioactivity. However, to our knowledge only one patent [9] is concerned with
their synthesis so far. It seems noteworthy that when 2-aminophenol was treated
with aldehydes 1d or 1e, whose ¯uoroalkyl chain is longer, two products were
formed. In addition to the quinolines 7, 2-¯uoroalkyl-benzoxazoles 8 were
obtained as byproducts (Scheme 5). The formation of 8 could be attributed to an
Scheme 5
Scheme 6

Synthesis of Fluorinated Quinolines
59
attack of the -OH group on the ole®nic carbon atom of intermediate A (Scheme 6).
However, no attempts have been undertaken to explain why the reaction of 2-
aminophenol with 1a±c did not give the corresponding benzoxazoles 8 with
R1 ˆ CF2X(X ˆ F, Cl, Br). The reactions of 1 with o-phenylenediamine or 2-
aminothiophenol will be published elsewhere.
Experimental
All melting points uncorrected. IR spectra were measured with a Shimadzu IR-440 spectrometer
(KBr pellets for solids, ®lms for liquids). 1H NMR spectra were recorded at 90 and 300 MHz
13C NMR spectra at 75.6 MHz on JEOL FX-90Q and Bruker AM 300 instruments, respectively using
TMS as internal standard and CDCl3 as solvent unless otherwise noted. 19F NMR spectra were
recorded on a Varian EM-360L spectrometer at 56.4 MHz using TFA as external standard and CDCl3
as solvent unless otherwise noted (positive values for up®eld shifts). MS and HRMS: Finnigan GC-
MS-4021 spectrometer; elemental analyses: Elemental Analysis Group of SIOC. The results (C, H,
N, F) were in good agreement with the calculated values.
General procedure for the preparation of 2-¯uoroalkyl-substituted quinolines
Compound 1a (10 mmol) and aniline (20 mmol) were dissolved in 40 cm3 acetic acid. After re¯uxing
at 120ꢀC for 8 h the mixture was cooled, poured into 50 cm3 ice water, and extracted with diethyl
ether (3Â40 cm3). The organic extracts were combined, washed with aq. NaHCO3 and brine, and
dried over Na2SO4. The solvent was removed by distillation and the crude product was further
puri®ed by ¯ash chromatography using petroleum ether (b.p.: 60±90ꢀC) and ethyl acetate as eluents
(10:1 by volume).
General procedure for the preparation of 2-¯uoroalkyl-benzoxazoles
and 2-¯uoroalkyl-8-hydroxyquinolines
A mixture of 2.8 g 1d (10 mmol), 2.2 g o-hydroxylaniline (20 mmol), and 20 cm3 acetic acid was
re¯uxed for 6 h. The reaction mixture was poured into a 150 ml beaker containing 50 cm3 ice water
and extracted with ether (3Â30 cm3). The organic layer was washed with NaHCO3 solution and dried
over Na2SO4. The solvent was removed by distillation, and the crude product was further puri®ed by
¯ash chromatography using petroleum ether (b.p.: 60±90ꢀC) and ethyl acetate as eluents (10:1 by
volume) to give 7d (1.5 g) and 8d (0.4 g).
2-Tri¯uoromethyl-quinoline (3a; C10H6F3N)
Yield: 60%; m.p.: 55±56ꢀC; 1H NMR (CD3COCD3, ꢁ, 300 MHz): 8.34 (d, J ˆ 8.5 Hz, 1H), 8.23 (d,
J ˆ 8.5 Hz, 1H), 7.90 (d, J ˆ 8.3 Hz, 1H), 7.82 (t, J ˆ 8.0 Hz, 1H), 7.74 (d, J ˆ 8.5 Hz, 1H), 7.67 (t,
2
J ˆ 8.0 Hz, 1H) ppm; 13C NMR (CD3COCD3, ꢁ, 75 MHz): 147.58, (q, JCF ˆ 0.4 Hz), 147.25,
1
138.16, 130.87, 130.18, 128.93, 128.65, 127.73, 121.65 (q, JCF ˆ 3.7 Hz), 116.82 ppm; 19F NMR
(CD3COCD3, ꢁ, 54.6 MHz): 10.0 (s, CF3) ppm; IR ꢂ ˆ 3060, 1620, 1599, 1573, 1566, 1510,
‡
1479, 1434, 1379, 1344, 1299, 1251, 1216, 1175, 1120, 1087 cm 1; MS: m/z (%) ˆ 197 (M , 100),
‡
‡
178 (M -F, 9.56), 128 (M -CF3, 49); HRMS: calc. for C10H6F3N: 197.0453, found: 197.0458.
2-Tri¯uoromethyl-6-hydroxylquinoline (3b; C10H6F3NO)
Yield: 75%; m.p.: 47±49ꢀC; 1H NMR (CD3COCD3, ꢁ, 300 MHz): 8.39 (d, J ˆ 8.7 Hz, 1H), 8.06 (d,
J ˆ 9.2 Hz, 1H), 7.77 (d, J ˆ 8.6 Hz, 1H), 7.56 (dd, J1 ˆ 9.2 Hz, J2 ˆ 2.7 Hz, 1H), 7.25 (d, J ˆ 2.7 Hz,

60
Q.-F. Wang et al.
1H) ppm; 19F NMR (CD3COCD3, ꢁ, 54.6 MHz): 9.0 (s, CF3) ppm; IR: ꢂ ˆ 3107, 1622, 1527, 1481,
‡
1436, 1398, 1352, 1328, 1304, 1231, 1184, 1154, 1127, 1095 cm 1; MS: m/z (%) ˆ 213 (M , 100),
‡
194 (M -F, 9.07).
2-Tri¯uoromethyl-6-methylquinoline (3c; C11H8F3N)
1
Yield: 62%; oil; H NMR (CDCl3, ꢁ, 300 MHz): 8.22 (d, J ˆ 8.5 Hz, 1H), 8.10 (d, J ˆ 9.2 Hz, 1H),
7.67 (d, J ˆ 8.5 Hz, 1H), 7.63 (m, 2H) ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 9.7 (s, CF3) ppm; IR:
‡
ꢂ ˆ 1504, 1348, 1339, 1307, 1195, 1132, 1117, 1087, cm 1; MS: m/z (%) ˆ 211 (M , 100), 191
‡
‡
(M -1-F, 9.07), 142 (M -CF3, 24.46).
2-Chlorodi¯uoromethyl-quinoline (3d; C10H6F2NCl)
Yield: 62%; m.p.: 27±29ꢀC; 1H NMR (CDCl3, ꢁ, 300 MHz): 8.33 (d, J ˆ 8.5 Hz, 1H), 8.22 (d,
J ˆ 8.5 Hz, 1H), 7.89 (d, J ˆ 8.3 Hz, 1H), 7.81 (t, J ˆ 8.0 Hz, 1H), 7.73 (d, J ˆ 8.5 Hz, 1H), 7.66 (t,
J ˆ 8.0 Hz, 1H) ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 23.5 (s, CF2Cl) ppm; IR: ꢂ ˆ 3064, 1948,
1836, 1637, 1619, 1596, 1568, 1506, 1496, 1431, 1378, 1348, 1309, 1290, 1273, 1245, 1207, 1125,
‡
‡
‡
1070, 1017 cm 1; MS: m/z (%) ˆ 213 (M , 50.98), 178 (M -Cl, 100), 128 (M -CF2Cl, 48.09);
HRMS: calc. for 35ClC10H6F2N: 213.0157, found: 213.0157.
2-Bromodi¯uoromethyl-quinoline (3e; C10H6F2NBr)
Yield: 58%; m.p.: 30±32ꢀC; 1H NMR (CDCl3, ꢁ, 300 MHz): 8.33 (d, J ˆ 8.5 Hz, 1H), 8.22 (d,
J ˆ 8.5 Hz, 1H), 7.90 (d, J ˆ 8.3 Hz, 1H), 7.81 (t, J ˆ 8.0 Hz, 1H), 7.73 (d, J ˆ 8.5 Hz, 1H), 7.66 (t,
J ˆ 8.0 Hz, 1H) ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 27.5 (s, CF2Br) ppm; IR: ꢂ ˆ 1618, 1595,
1504, 1467, 1430, 1376, 1346, 1309, 1291, 1268, 1247, 1214, 1148, 1127, 1081, 1017 cm 1; MS: m/
‡
‡
z(%) ˆ 259 (5.13), 257 (5.33), 178 (M -Br, 100), 128 (M -CF2Br, 34.59); HRMS: calc. for
79BrC10H6F2N: 256.9652, found: 256.9654.
2-(1,1,2,2,3,3-Hexa¯uoro-3-chloropropyl)-quinoline (3f; C12H6F6NCl)
Yield: 64%; m.p.: 38±39ꢀC; 1H NMR (CDCl3, ꢁ, 300 MHz): 8.33 (d, J ˆ 8.5 Hz, 1H), 8.25 (d,
J ˆ 8.5 Hz, 1H), 7.90 (d, J ˆ 8.3 Hz, 1H), 7.82 (t, J ˆ 8.0 Hz, 1H), 7.73 (d, J ˆ 8.5 Hz, 1H), 7.69 (t,
J ˆ 8.0 Hz, 1H) ppm; 19F NMR (CDCl3, 54.6 MHz): 10.7 (s, CF2Cl), 35.3 (m, CF2), 42.6 (m,
CF2) ppm; IR: ꢂ ˆ 3060, 1622, 1597, 1573, 1508, 1475, 1432, 1378, 1318, 1301, 1254, 1191, 1134,
‡
‡
‡
1118, 1010 cm 1; MS: m/z (%) ˆ 313 (M , 13.34), 278 (M -Cl, 6.83), 178 (M -C2F4Cl, 100), 128
(M -C3F6Cl, 53.46); HRMS: calc. for 35ClC12H6F6N: 313.0093, found: 313.0092.
‡
2-Per¯uoroheptyl-quinoline (3g; C14H6F11N)
Yield: 65%; m.p.: 43±44ꢀC; 1H NMR (CDCl3, ꢁ, 300 MHz): 8.35 (d, J ˆ 8.5 Hz, 1H), 8.26 (d,
J ˆ 8.5 Hz, 1H), 7.91 (d, J ˆ 8.3 Hz, 1H), 7.83 (t, J ˆ 8.0 Hz, 1H), 7.74 (d, J ˆ 8.5 Hz, 1H), 7.68 (t,
J ˆ 8.0 Hz, 1H) ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 3.5 (s, 3F), 36.2 (m, 2F), 44.7 (m, 4F), 49.0
(m, 2F) ppm; IR: ꢂ ˆ 3057, 3028, 1599, 1573, 1509, 1472, 1434, 1363, 1317, 1296, 1242, 1205,
‡
‡
‡
1189, 1162, 1138, 1109, 1091 cm 1; MS: m/z (%) ˆ 397 (M , 33.77), 378 (M -F, 6.83), 178 (M -
‡
C4F9, 100), 128 (M -C5F11, 35.54).
7,8,9,10-Tetrahydro-6-tri¯uoromethylphenanthridine (6a; C14H12F3N)
1
Yield: 66%; m.p.: 116±117ꢀC; H NMR (CDCl3, ꢁ, 300 MHz): 8.13 (d, J ˆ 8.5 Hz, 1H), 7.94 (d,
J ˆ 8.5 Hz, 1H), 7.70 (t, J ˆ 7.5 Hz, 1H), 7. (t, J ˆ 7.5 Hz, 1H), 3.17 (t, J ˆ 6.0 Hz, 2H), 3.03 (t,

Synthesis of Fluorinated Quinolines
61
2
J ˆ 6.0 Hz, 2H), 1.92 (m, 4H) ppm; 13C NMR (CDCl3, ꢁ, 75 MHz): 146.31 (q, JCF ˆ 0.4 Hz),
1
144.71, 144.09, 130.67, 129.14, 128.38, 127.45, 122.56, 122.36 (q, JCF ˆ 3.7 Hz), 25.95, 24.96,
22.01, 21.75 ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 12.0 (s, CF3) ppm; IR: ꢂ ˆ 2952, 2877, 1571,
1
1501, 1462, 1434, 1369, 1360, 1341, 1325, 1289, 1252, 1192, 1174, 1157, 1126, 1096, 1078 cm
‡
;
‡
‡
MS: m/z (%) ˆ 251 (M , 100), 232 (M -F, 5.30), 182 (M -CF3, 14.05); X-ray data: triclinic,
ꢀ
Ê
a ˆ 8.261(2), b ˆ 10.358(2), c ˆ 7.452(3) A, ꢀ ˆ 98.02(2), ꢃ ˆ 114.83(2), ꢄ ˆ 84.42(2) ,
3
Ê 3
V ˆ 572.5(3) A , Dc ˆ 1.46 g/cm ; crystal dimensions: 0.20Â0.20Â0.40 mm. Data were measured
at 293 K on a Rigaku AFC7R diffractomer with graphite monochromated MoKꢀ radiation and a
12 kW rotating anode generator.
7,8,9,10-Tetrahydro-6-chlorodi¯uoromethylphenanthridine (6b; C14H12ClF2N)
1
Yield: 68%; m.p.: 102±104ꢀC; H NMR (CDCl3, ꢁ, 300 MHz): 8.15 (d, J ˆ 8.5 Hz, 1H), 7.97 (d,
J ˆ 8.5 Hz, 1H), 7.71 (t, J ˆ 7.5 Hz, 1H), 7.62 (t, J ˆ 7.5 Hz, 1H), 3.21 (t, J ˆ 6.0 Hz, 2H), 3.13 (t,
J ˆ 6.0 Hz, 2H), 1.95 (m, 4H) ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 25.0 (s, CF2Cl) ppm; IR:
ꢂ ˆ 2954, 2870, 1579, 1568, 1499, 1459, 1431, 1380, 1367, 1346, 1335, 1317, 1284, 1245, 1188,
‡
‡
1149, 1133, 1094, 1085, 1078, 1029 cm 1; MS: m/z (%) ˆ 267 (M , 82.47), 232 (M -Cl, 100).
7,8,9,10-Tetrahydro-6-(1,1,2,2,3,3-hexa¯uoro-3-chloropropyl)-phenanthridine (6c; C16H12F6NCl)
Yield: 68%; m.p.: 50±52ꢀC; 1H NMR (CDCl3, ꢁ, 300 MHz): 8.14 (d, J ˆ 8.5 Hz, 1H), 7.97 (d,
J ˆ 8.5 Hz, 1H), 7.70 (t, J ˆ 7.5 Hz, 1H), 7.62 (t, J ˆ 8.0 Hz, 1H), 3.21 (t, J ˆ 6.0 Hz, 2H), 3.06 (t,
J ˆ 6.0 Hz, 2H), 1.89 (m, 4H) ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 11.5 (s, CF2Cl), 28.3 (m,
CF2), 40.5 (m, CF2) ppm; IR: ꢂ ˆ 2950, 2926, 2864, 1828, 1616, 1574, 1498, 1459, 1450, 1437,
1425, 1413, 1366, 1343, 1318, 1290, 1241, 1191, 1181, 1159, 1143, 1126, 1114, 1084, 1038,
‡
‡
‡
‡
1013 cm 1; MS: m/z (%) ˆ 367 (M , 100), 339 (M -C2H4, 41.07), 332(M -Cl, 23.19), 232 (M -
C2F4Cl, 95.88); HRMS: calc. for 35ClC16H12F6N: 367.0563, found: 367.0565.
7,8,9,10-Tetrahydro-6-per¯uoropentyl-phenanthridine (6d; C16H12F6NCl)
Yield: 64%; m.p.: 36±37ꢀC; 1H NMR (CDCl3, ꢁ, 300 MHz): 8.12 (d, J ˆ 8.5 Hz, 1H), 7.98 (d,
J ˆ 8.5 Hz, 1H), 7.71 (t, J ˆ 7.5 Hz, 1H), 7.63 (t, J ˆ 7.5 Hz, 1H), 3.22 (t, J ˆ 6.0 Hz, 2H), 3.08 (t,
J ˆ 6.0 Hz, 2H), 1.93 (m, 4H) ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 3.2 (s, 3F), 28.9 (m, 2F), 41.8
(m, 2F), 43.0 (m, 2F), 48.7 (m, 2F) ppm; IR: ꢂ ˆ 2957, 2878, 1575, 1503, 1464, 1440, 1352, 1322,
‡
1297, 1286, 1236, 1202, 1161, 1149, 1133, 1087, 1077, 1066, 1016 cm 1; MS: m/z (%) ˆ 451 (M ,
‡
‡
‡
100), 432 (M -F, 21.34), 423 (M -C2H4, 25.53), 232 (M -C4F9, 86.93); HRMS: calc. for
C18H12F11N: 451.0795, found: 451.0764.
2-Tri¯uoromethyl-8-hydroxy-quinoline (7a; C10H6F3NO)
1
Yield: 60%; m.p.: 40±42ꢀC; H NMR (CDCl3, ꢁ, 300 MHz): 8.29 (d, J ˆ 8.6 Hz, 1H), 7.71, (d,
J ˆ 8.6 Hz, 1H), 7.56 (t, J ˆ 8.0 Hz, 1H), 7.34 (d, J ˆ 8.2 Hz, 1H), 7.25 (d, J ˆ 7.6 Hz, 1H) ppm; 13
C
NMR (CDCl3, ꢁ, 75 MHz): 145.76 (q, 2JCF ˆ 0.4 Hz), 145.52, 138.24, 137.21, 130.14, 129.30, 121.53
1
(q, JCF ˆ 3.7 Hz), 117.91, 117.49, 111.61 ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 10.0 (s,
CF3) ppm; IR: ꢂ ˆ 3230, 2966, 1629, 1556, 1469, 1450, 1262, 1096, 1027 cm 1; MS: m/z ˆ 213
‡
‡
‡
(M , 73.57), 194 (M -F, 11.08), 165 (M ‡1-CF3, 100); HRMS: calc. for C10H6F3NO: 213.0404,
found: 213.0386.
2-Chlorodi¯uoromethyl-8-hydroxy-quinoline (7b; C10H6F2NOCl)
1
Yield: 62%; m.p.: 46±48ꢀC; H NMR (CD3COCD3, ꢁ, 300 MHz): 8.61 (d, J ˆ 8.7 Hz, 1H), 7.89
(d, J ˆ 8.7 Hz, 1H), 7.63 (t, J ˆ 8.0 Hz, 1H), 7.54 (d, J ˆ 8.1 Hz, 1H), 7.26 (d, J ˆ 7.4 Hz, 1H), 3.48

62
Q.-F. Wang et al.
(s, -OH) ppm; 19F NMR (CD3COCD3, ꢁ, 54.6 MHz): 22.0 (s, CF2Cl) ppm; IR: ꢂ ˆ 3230, 1629,
‡
‡
1556, 1469, 1450, 1321, 1289, 1262, 1135, 1096, 1029 cm 1; MS: m/z ˆ 229 (M , 100), 194 (M -Cl,
87.09), 144 (M -CF2Cl, 14.26); HRMS: calc. for 35ClC10H6F2NO: 229.0106, found: 229.0133.
‡
2-Bromodi¯uoromethyl-8-hydroxy-quinoline (7c; C10H6F2NOBr)
Yield: 58%; m.p.: 41±42ꢀC; 1H NMR (CDCl3, ꢁ, 300 MHz): 8.32 (d, J ˆ 8.6 Hz, 1H), 7.95 (s, -OH),
7.74 (d, J ˆ 8.6 Hz, 1H), 7.59 (t, J ˆ 8.0 Hz, 1H), 7.41 (d, J ˆ 8.1 Hz, 1H), 7.27 (d, J ˆ 7.4 Hz,
1H) ppm; 19F NMR (CDCl3, ꢁ, 54.6 MHz): 27.3 (s, CF2Br) ppm; IR: ꢂ ˆ 3427, 1578, 1510, 1475,
1405, 1365, 1335, 1298, 1261, 1246, 1214, 1134, 1083, 1042 cm 1; MS: m/z ˆ 275 (29.58), 273
(28.59), 194 (M -Br, 100), 144 (M -CF2Br, 18.08); HRMS. calc. for 79BrC10H6F2NO: 272.9600,
81BrC10H6F2NO: 274.9580, found: 274.9625, 274.9563.
‡
‡
2-(1,1,2,2,3,3-Hexa¯uoro-3-chloro-propyl)-8-hydroxy-quinoline (7d; C12H6F6NOCl)
1
Yield: 46%; oil; H NMR (CD3COCD3, ꢁ, 300 MHz): 8.60 (d, J ˆ 8.6 Hz, 1H), 7.86 (d, J ˆ 8.6 Hz,
1H), 7.60 (t, J ˆ 8.0 Hz, 1H), 7.53 (m, 1H), 7.29 (m, 1H), 3.42 (s, -OH), 19F NMR (CD3COCD3, ꢁ,
300 MHz): 10.0 (s, CF2Cl), 36.3 (m, CF2), 43.7 (m, CF2) ppm; IR: ꢂ ˆ 3453, 3059, 2931, 1633,
‡
‡
1579, 1476, 1367, 1309, 1246, 1184, 1129, 1100 cm 1; MS: m/z ˆ 329 (M , 87.19), 294 (M -Cl,
17.26), 194 (M -C2F4Cl, 100), 144 (M -C3F6Cl, 16.98); HRMS; calc. for 35ClC12H6F6NO:
‡
‡
329.0043, found: 329.0028.
2-Per¯uoropentyl-8-hydroxy-quinoline (7e; C14H6F11NO)
Yield: 48%; m.p.: 53±54ꢀC; 1H NMR (CDCl3, ꢁ, 300 MHz): 8.37 (d, J ˆ 8.6 Hz, 1H), 7.77 (d,
J ˆ 8.6 Hz, 1H), 7.62 (t, J ˆ 8.0 Hz, 1H), 7.59 (m, 1H), 7.29 (m, 1H) ppm; 19F NMR (CDCl3, ꢁ,
54.6 MHz): 3.3 (s, 3F), 35.5 (m, 2F), 44.7 (m, 4F), 48.7 (m, 2F) ppm; IR: ꢂ ˆ 3439, 1636, 1581,
‡
1508, 1473, 1363, 1331, 1305, 1238, 1195, 1164, 1143, 1116, 1088 cm 1; MS: m/z ˆ 413 (M ,
‡
‡
‡
87.05), 394 (M -Cl, 12.25), 194 (M -C4F9, 100), 144 (M -C5F11, 18.79); HRMS: calc. for
C14H6F11NO: 413.0278, found: 413.0281.
2-(1,1,2,2,3,3-Hexa¯uoro-3-chloro-propyl)-benzoxazole (8d; C10H4F6NOCl)
Yield: 14%; oil; 1H NMR (CDCl3, ꢁ, 300 MHz): 7.91 (m, 1H), 7.68 (m, 1H), 7.57 (m, 2H) ppm; 19
F
NMR (CDCl3, ꢁ, 54.6 MHz): 9.0 (s, CF2Cl), 36.0 (m, CF2), 44.5 (m, CF2) ppm; IR: ꢂ ˆ 1616,
‡
1573, 1480, 1359, 1312, 1239, 1193, 1135, 1113, 1101, 1013 cm 1; Ms: m/z ˆ 303 (M , 37.66), 268
(M -Cl, 13.45), 168 (M -C2F4Cl, 100); HRMS: calc. for 35ClC10H4F6NO: 302.9886, found:
‡
‡
302.9892.
2-(Per¯uoropentyl)-benzoxazole (8e; C12H4F11NO)
Yield: 16%; oil; 1H NMR (CDCl3, ꢁ, 300 MHz): 7.92 (m, 1H), 7.69 (m, 1H), 7.58 (m, 2H) ppm; 19
F
NMR (CDCl3, ꢁ, 54.6 MHz): 3.3 (s, 3F), 35.5 (m, 2F), 44.7 (m, 4F), 48.7 (m, 2F) ppm; IR: ꢂ ˆ 1616,
1573, 1481, 1452, 1363, 1311, 1240, 1207, 1144, 1129, 1109, 1097, 1072, 1049, 1004 cm 1; MS: m/
‡
‡
‡
z ˆ 387 (M , 52.37), 368 (M -F, 14.49), 168 (M -C4F9, 100); HRMS: calc. for C12H4F11NO:
387.0116, found: 387.0111.
Acknowledgements
We thank the National Natural Science Foundation of China for ®nancial support (No. 29872051).

Synthesis of Fluorinated Quinolines
63
References
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Received June 25, 1999. Accepted (revised) July 19, 1999