A simple and highly efficient synthesis of N-phenyl-2-polyfluoroalkyl-4-quinolones from 2-anilinoacetophenone and RFCO2Et

Article abstract of DOI:10.1016/j.jfluchem.2004.04.010

The condensation of 2-anilinoacetophenone with R_FCO₂Et (R_F = CF₂H, CF₃, C₂F₅) in the presence of LiH in THF affords the corresponding N -phenyl-2-polyfluoroalkyl-4-quinolones in

Full text of DOI:10.1016/j.jfluchem.2004.04.010

Journal of Fluorine Chemistry 125 (2004) 1393–1395
A simple and highly efficient synthesis of
N-phenyl-2-polyfluoroalkyl-4-quinolones from
2-anilinoacetophenone and RFCO2Et
Boris I. Usachev, Vyacheslav Ya. Sosnovskikh*
Department of Chemistry, Ural State University, Lenina 51, Ekaterinburg 620083, Russia
Received 18 February 2004; received in revised form 26 April 2004; accepted 28 April 2004
Available online 2 July 2004
Abstract
The condensation of 2-anilinoacetophenone with RFCO2Et (RF ¼ CF2H, CF3, C2F5) in the presence of LiH in THF affords the
corresponding N-phenyl-2-polyfluoroalkyl-4-quinolones in excellent yields.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Condensation; 2-Anilinoacetophenone; Polyfluorocarboxylic esters; N-phenyl-2-polyfluoroalkyl-4-quinolones
1. Introduction
nication [8] of the reaction of N-arylated trifluoroacetimi-
doyl chlorides with 2-chloroacetophenones followed by the
cyclization of the intermediate aminoenones to give 1-aryl-
2-trifluoromethyl-4-(1H)-quinolones. We have found that
the condensation of 2-anilinoacetophenone with RFCO2Et
on boiling in THF for 1 h in the presence of LiH using a 1:1.2
molar ratio of ketone to ester affords previously unknown N-
phenyl-2-RF-4-quinolones 1a–c in 90–93% yields. It should
be noted that 2-aminoacetophenone gives N-unsubstituted 2-
RF-4-quinolones in only 12–19% yields under the same
reaction conditions [10]. 2-Anilinoacetophenone, employed
for the present study, was prepared from N-phenyl anthra-
nilic acid and MeLi in THF and Et2O at room temperature
for 4 h in 81% yield. Note that 1-(2-anilinophenyl)pentan-1-
one, derived from N-phenyl anthranilic acid, and BuLi, was
not reactive enough in this reaction; only a complex mixture
of unidentified products was isolated in this case. The
procedure we have developed for the synthesis of quinolones
1 is outlined in Scheme 1.
The growing importance of the fluoroquinolone antibio-
tics has led to increased interest in the synthesis of 2-
polyfluoroalkyl-4-quinolones [1–10]. It is known that 2-
(trifluoroacetylamino)acetophenones undergo cyclization
in the presence of alkylating agents and KOH to form N-
alkyl-2-trifluoromethyl-4-quinolones [9]. We have recently
reported that the condensation of 2-aminoacetophenone with
polyfluorocarboxylic esters can be used for the synthesis of
N-unsubstituted 2-polyfluoroalkyl-4-quinolones and N-
methyl-2-trifluoromethyl-4-quinolone [10]. As an extension
of this work, we now report a highly efficient synthesis of N-
phenyl-2-polyfluoroalkyl-4-quinolones from 2-anilinoace-
tophenone and RFCO2Et.
2. Results and discussion
The characteristic feature of the 1H NMR spectra of
quinolones 1a–c is the unusually upfield signal from the
H(8) aromatic proton (d 6.62–6.72). Such a strong shielding
of the H(8) atom, which is manifested at d 7.61 in N-methyl-
2-trifluoromethyl-4-quinolone [10], might be due to the
conformation where the phenyl ring is twisted out of the
quinolone molecular plane and has a shielding effect on the
H(8) and, in part, the H(7) atoms because of the ring current
effect. The 1H NMR signal for the H(5) proton was shifted
downfield to d 8.43–8.45 due to the deshielding effect of the
The procedure of Combs et al. [9] (trifluoroacetylami-
noacetophenones, RHal, KOH) is an effective method for the
preparation of N-alkylated 2-trifluoromethyl-4-quinolones.
However, this transformation requires a good alkylating
agent and cannot be used for the synthesis of N-arylated
2-RF-4-quinolones. Very recently there has been a commu-
* Corresponding author. Tel.: þ7 343 261 6824; fax: þ7 343 261 5978.
E-mail address: vyacheslav.sosnovskikh@usu.ru (V.Ya. Sosnovskikh).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.04.010

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B.I. Usachev, V.Ya. Sosnovskikh / Journal of Fluorine Chemistry 125 (2004) 1393–1395
O
O
the residual oil was distilled to give the fraction with bp 178–
186 8C (10 Torr). The crude product was treated with 10 ml
of 80% ethanol and the crystalline material was isolated by
filtration, washed with aqueous ethanol, and dried to give the
title compound as a yellow crystals. Yield 4.24 g (81%), mp
63–64 8C ([16] mp 64 8C). IR: n 3210 (NH), 1645 (C¼O),
OH
Me
MeLi
NHPh
NHPh
LiH R CO Et
F
2
1585, 1570 (Ar) cmꢀ1 1H NMR (400 MHz, CDCl3): d
.
O
2.65 (s, 3H, Me), 6.73 (ddd, 1H, Ar, Jo ¼ 8.1, 6.8, Jm
¼
RF = CF2H (a),
RF = CF3 (b),
RF = C2F5 (c)
1.3), 7.11 (tt, 1H, Ph, Jo ¼ 7.3, Jm ¼ 1.2), 7.23–7.38 (m, 6H,
Ar, Ph), 7.82 (dd, 1H, Ar, Jo ¼ 8.1, Jm ¼ 1.5), 10.54 (s, 1H,
NH).
N
RF
Ph
1a-c
4.2. 1-(2-Anilinophenyl)pentan-1-one
Scheme 1.
The title compound was obtained analogously from N-
phenyl anthranilic acid and BuLi. Yield 67%, bp 211–
20
carbonyl group in the peri-position as indicated in the case of
chromones [11], thiochromones [12] and quinolones
[10,13]. The IR spectra of quinolones 1a–c showed absorp-
tion bands in the range normally associated with the C¼O
stretch of the 4-oxo group at 1625–1630 cmꢀ1 (vinylogous
amide) [13–15].
213 8C (10 Torr), nD 1.6180. IR: n 3250, 3050 (NH),
1640 (C¼O), 1590, 1575 (Ar) cmꢀ1. H NMR (400 MHz,
1
CDCl3): d 0.97 (t, 3H, Me, J ¼ 7.3), 1.43 (sext, 2H, CH2, J ¼
7.4), 1.73 (quint, 2H, CH2, J ¼ 7.5), 3.00 (t, 2H, CH2, J ¼
7.5), 6.73 (ddd, 1H, Ar, Jo ¼ 8.1, 5.9, Jm¼2.4), 7.09 (tt, 1H,
Ph, Jo ¼ 7.3, Jm ¼ 1.2), 7.23–7.37 (m, 6H, Ar, Ph), 7.84–
7.86 (m, 1H, Ar), 10.60 (s, 1H, NH).
3. Conclusion
4.3. Typical procedure for preparation of 1-phenyl-2-
polyfluoroalkyl-4-quinolones 1a–c
The reaction of 2-anilinoacetophenone with fluorinated
esters provides a simple and efficient process from readily
available starting materials to N-phenyl-2-polyfluoroalkyl-
4-quinolones, which may be considered as new RF-contain-
ing substrates for the synthesis of a wide variety of
heterocyclic compounds with potential biological activity.
A mixture of 2-anilinoacetophenone (1.05 g, 5.0 mmol),
RFCO2Et (6.0 mmol), and finely dispersed LiH (0.14 g,
17.5 mmol) in anhydrous THF (5 ml) was refluxed with
stirring for 1 h and concentrated to dryness on a water bath
under reduced pressure. The residue was treated with AcOH
(3 ml) and then 50 ml of H2O was added. The precipitate
that formed was filtered off, washed with water, and dried.
Recrystallization from toluene–CCl4 mixture yielded color-
less crystals.
4. Experimental
1H and 19F NMR spectra were recorded on a Bruker DRX-
400 spectrometer (1H at 400.1 MHz and 19F at 376.5 MHz)
in CDCl3 with TMS and HFB as internal standards, respec-
4.4. 2-(Difluoromethyl)-1-phenylquinolin-4(1H)-one (1a)
Yield 93%, mp 210–212 8C (toluene:CCl4, 1:1). IR: n
1
tively. The digital resolution in the H NMR spectra was
0.12–0.14 Hz per point. The IR spectra were measured on an
IKS-29 instrument as suspensions in Nujol. Melting points
are uncorrected. All solvents used were dried and distilled
per standard procedures.
1630 (C¼O), 1605, 1590 (C¼C, Ar) cmꢀ1
.
1H NMR
2
(400 MHz, CDCl3): d 6.17 (t, 1H, CF2H, JH;F ¼ 53:4),
6.72 (d, 1H, H-8, Jo ¼ 8.7), 6.76 (s, 1H, H-3), 7.37–7.41
(m, 3H, H-6, Ph), 7.49 (ddd, 1H, H-7, Jo ¼ 8.7, 7.0, Jm
¼
1.7), 7.64–7.68 (m, 3H, Ph), 8.45 (dd, 1H, H-5, Jo ¼ 8.0, Jm
¼ 1.7). 19F NMR (376 MHz, CDCl3, HFB): d 44.61 (d,
CF2H, 2JF;H ¼ 53:4). Anal. Calculated for C16H11F2NO: C,
70.8; H, 4.1; N, 5.2. Found: C, 70.6; H, 4.2; N, 5.1.
4.1. 2-Anilinoacetophenone
A mixture of N-phenyl anthranilic acid (5.3 g, 0.025 mol)
and finely dispersed LiH (0.30 g, 0.038 mol) in anhydrous
THF (20 ml) was refluxed for 0.5 h. Then the mixture was
cooled to ꢁ20 8C and 100 ml of 1 M (0.10 mol) methyl-
lithium in Et2O was added under a nitrogen atmosphere. The
mixture was allowed to stand at ꢁ20 8C for 4 h. It was then
poured into water (100 ml), the aqueous layer was saturated
with ammonium chloride, and the organic phase was sepa-
rated. After removal of the solvent under reduced pressure,
4.5. 1-Phenyl-2-(trifluoromethyl)quinolin-4(1H)-one (1b)
Yield 90%, mp 227–228 8C (toluene:CCl4, 1:1). IR: n
1630 (C¼O), 1610, 1590 (C¼C, Ar) cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d 6.67 (d, 1H, H-8, Jo ¼ 8.7), 6.87
(s, 1H, H-3), 7.36–7.39 (m, 2H, Ph), 7.40 (ddd, 1H, H-6, Jo ¼
8.0, 7.0, Jm ¼ 1.0), 7.50 (ddd, 1H, H-7, Jo ¼ 8.7, 7.0, Jm ¼

B.I. Usachev, V.Ya. Sosnovskikh / Journal of Fluorine Chemistry 125 (2004) 1393–1395
1395
1.7), 7.58–7.64 (m, 3H, Ph), 8.43 (dd, 1H, H-5, Jo ¼ 8.0,
References
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Acknowledgements
This work was financially supported by the Russian
Foundation for Basic Research (grant 02-03-32706) and
by the US Civilian Research and Development Foundation
and Russian Federation Ministry of Education (grants EK-
005-X1 and Y1-005-04).
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