Synthesis of polysubstituted 4-fluoroquinolinones

Article abstract of DOI:10.1021/ol048257f

(Chemical Equation Presented) A convenient one-pot synthesis of 4-fluoroquinolinones that are active against KDR kinase is described. The mechanism of the reaction is believed to involve the formation of a quinone methide intermediate.

Full text of DOI:10.1021/ol048257f

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4061-4063
Synthesis of Polysubstituted
4-Fluoroquinolinones
Alexander S. Kiselyov,† Evgueni L. Piatnitski,*,‡ and Jacqueline Doody‡
Department of Chemistry, ImClone Systems, 180 Varick Street, 6th Floor,
New York, New York 10014, and Chemical DiVersity, Inc.,
11558 Sorrento Valley Road, Suite 5, San Diego, CA 92121
eVguenip@imclone.com
Received August 31, 2004
ABSTRACT
A convenient one-pot synthesis of 4-fluoroquinolinones that are active against KDR kinase is described. The mechanism of the reaction is
believed to involve the formation of a quinone methide intermediate.
Quinolinones belong to a chemical class that possesses
biological activity depending on the specific substitution
within the molecule.1 The lactam functionality of a quino-
linone moiety may be engaged in hydrogen bond donor-
acceptor interactions similar to ones observed for ATP
molecules as well as for various kinase inhibitors.2 Our goal
was to explore the preparation of 4-fluoro-substituted quino-
linones and, thus, to address the introduction of fluorine into
the critical portion of this molecular motif. The fluorine atom
is often used to block in vivo metabolism at particular
molecular sites. Although the sites of oxidative metabolism
for quinolinone-containing small molecules may vary, the
introduction of a fluorine atom into specific and not easily
accessible positions remains a challenging task for organic
chemists working on medicinal projects.
2-substituted benzothiazoles and benzoxazoles,5 4(5)-dihy-
dro-1H-imidazole,6 triazines,7 and isoxazoles,7 1,3-disubsti-
tuted naphthalenes,8 2,4-di- or 2,3,4-trisubstituted quinolines,9
7-(substituted amino)-5,6-dihydrobenz[c]acridines,10 3-aryl-
4-aminocinnolines,11 and fused fluoronaphthalenes12 and the
recently reported synthesis of polysubstituted naphthalenes.13
It has been suggested that all of the above transformations
proceed via the initial proton abstraction from the anilinic
nitrogen to afford the quinone methide intermediate Q
(Scheme 1). The subsequent reaction of this intermediate
with various nucleophiles leads to the array of products
observed.
(5) Kiselyov, A. S.; Hojjat, M.; Van Aken, K.; Strekowski, L. Hetero-
cycles 1994, 37, 775.
(6) Wydra, R.; Patterson, S. E.; Strekowski, L. J. Heterocycl. Chem. 1990,
27, 803.
(7) Strekowski, L.; Lin, S.-Y.; Nguyen, J.; Redmore, N.; Mason, J. C.;
Kiselyov, A. S. Heterocycl. Commun. 1995, 1, 331.
(8) Strekowski, L.; Wydra, R.; Kiselyov, A. S.; Baird, J. H. Synth.
Commun. 1994, 24, 257.
It has been shown that the anionically activated trifluoro-
methyl group has great utility in the synthesis of various
aromatic, heteroaromatic, and aliphatic compounds.3 These
include syntheses of 2-(substituted 1-alkenyl) anilines,4
(9) (a) Strekowski, L.; Patterson, S. E.; Janda, L.; Wydra, R.; Harden,
D. B.; Lipowska, M.; Cegla, M. J. Org. Chem. 1992, 57, 196. (b)
Strekowski, L.; Wydra, R.; Cegla, M. T.; Czarny, A.; Harden, D. B.;
Patterson, S. E.; Battiste, M. A.; Coxon, J. M. J. Org. Chem. 1990, 55,
4777. (c) Janda, L.; Nguyen, J.; Patterson, S. E.; Strekowski, L. J.
Heterocycl. Chem. 1992, 29, 1753.
(10) Strekowski, L.; Wydra, R.; Harden, D. B.; Honkan, V. A.
Heterocycles 1990, 31, 1565.
(11) Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 1383.
(12) Kiselyov, A. S.; Strekowski, L. Tetrahedron Lett. 1994, 35, 7597.
(13) (a) Kiselyov, A. S. Tetrahedron Lett. 2001, 42, 3053. (b) Kiselyov,
A. S. Tetrahedron 2001, 57, 5321.
† Chemical Diversity, Inc.
‡ ImClone Systems, Inc.
(1) For reviews on kinase-active chemical classes, see: (a) Stover, D.
R.; Lydon, N. B.; Nunes, J. J. Curr. Opin. Drug Discuss. DeV. 1999, 2,
274. (b) Traxler, P. Exp. Opin. Ther. Patents 1998, 8, 1599.
(2) Traxler, P.; Furet, P. Pharmacol. Ther. 1999, 82, 195.
(3) (a) Kiselyov, A. S.; Strekowski, L. Org. Prep. Proc. Int. 1996, 28,
289 and references therein. (b) Strekowski, L.; Kiselyov, A. S. Trends
Heterocycl. Chem. 1993, 73.
(4) Hojjat, M.; Kiselyov, A. S.; Strekowski, L. Synth. Commun. 1994,
24, 267.
10.1021/ol048257f CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/05/2004

of arylacetic acids. The desired product 3 was easily
separated by column chromatography. The reaction results
for selected examples are listed in Table 1.
Scheme 1. Transformations of Quinone Methide Intermediate
Table 1. Selected Examples for the Preparation of
4-Fluoroquinolinone Derivatives
In this paper we report a facile synthesis of 4-fluorinated
quinolinones via the condensation of (2-trifluoromethyl)
aniline with esters of arylacetic acids under basic conditions
(Scheme 2). To optimize the yield of 3 and to turn this
Scheme 2
methodology into a successful synthetic tool we studied the
effects of several factors on the outcome of this reaction,
including (i) reaction temperature, (ii) the ratio of substrate
1 to base, (iii) reaction time, (iv) solvent, and (v) nature of
base. Temperature was found to have a profound effect on
the reaction course. For example, treatment of 1 with 1 equiv
of 2 (generated from the corresponding ester of arylacetic
acid and LDA) in THF at -78 °C for 24 h followed by the
aqueous quench of the reaction mixture with water yielded
only starting material 1. Similar treatment of 1 at -30 °C
(MeCN/ethylene glycol/dry ice mixture) for 8 h allowed the
isolation of 3 in 22% yield along with starting material 1
(69%).
a Yields refer to isolated analytically pure compounds.
The reported observations can be rationalized by the
mechanism presented below (Scheme 3).
Scheme 3. Suggested Mechanism for 4-Fluoroquinolinone
Formation
Notably, further increase in the reaction temperature to 0
°C and room-temperature did not affect the yield of 3. The
optimal empirically found ratio of 1 to base was 1:6; lower
ratios resulted in lower yields of 3, whereas higher ratios
(6-12) did not significantly affect the reaction outcome. THF
as well as dimethoxyethane (DME) were efficacious solvents
for the reaction (31-66% yields of 3); the reactions
conducted in diethyl ether afforded only 12-20% yield of
3. Several amide bases, including LDA, LiTMP (2,2,6,6-
tetramethylpiperidide), and LiHMDS (1,1,1,3,3,3-hexameth-
yldisilazide) furnished essentially similar yields of 3. The
nature of the cation did not affect the outcome of this
reaction. The reaction times of 4-5 h were essential to ensure
the complete conversion of 1 to 3 at ambient temperature.12
Various amounts of 4 (11-52%) were detected in the
reaction mixture; the highest yields of 4 were observed when
the reactions were conducted with anions derived from esters
The initial step involves reversible deprotonation of 1 to
form the corresponding anion, which is stable at temperatures
below -30 °C. At higher temperatures, it undergoes slow
elimination of HF to form the quinone methyde intermediate
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Org. Lett., Vol. 6, No. 22, 2004

Q. This active species reacts with 2 to afford condensation
product 3 after a series of addition/elimination steps.
Alternatively, anilide-anion reacts with the excess of 2′ to
afford 4. Formation of a similar quinone methyde intermedi-
ate was suggested in several relevant transformations of (2-
trifluoromethyl)aniline.3
quinolinone class representatives exhibited activity against
KDR tyrosine kinase.
Acknowledgment. We thank Daniel Milligan for in vitro
assay activity data.
In summary, we have described a protocol for a rapid
assembly of 4-fluoroquinolinones from 2-(trifluoromethyl)-
aniline and arylacetic acids. The proposed reaction mecha-
nism for this process involves the formation of the quinone
methide as an intermediate. Detailed mechanistic studies of
this reaction are in progress in our lab. The selected
Supporting Information Available: General experimen-
tal procedure and structural characterization for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL048257F
Org. Lett., Vol. 6, No. 22, 2004
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