The "off-shore" construction of optionally substituted 4-trifluoromethyl-2-quinolinones

Article abstract of DOI:10.1002/ejoc.200600140

Treatment of ortho-lithiated tert-butyl N-arylcarbamates (i.e., BOC-protected anilines) with N-(trifluoroacetyl)piperidine provides 2-(N-BOC-amino)aryl trifluoromethyl ketones which, upon consecutive reaction with an α-alkoxycarbonyl-substituted phosphoru

Full text of DOI:10.1002/ejoc.200600140

FULL PAPER
DOI: 10.1002/ejoc.200600140
The “Off-Shore” Construction of Optionally Substituted
4-Trifluoromethyl-2-quinolinones
Frédéric Leroux,[a] Olivier Lefebvre,[b] and Manfred Schlosser*[b]
Keywords: Heterocyclic chemistry / ortho-Lithiation of anilines / Trifluoroacetylation / Wittig olefination / Ring closure /
Regiocontrol
Treatment of ortho-lithiated tert-butyl N-arylcarbamates (i.e.,
BOC-protected anilines) with N-(trifluoroacetyl)piperidine
provides 2-(N-BOC-amino)aryl trifluoromethyl ketones
which, upon consecutive reaction with an α-alkoxycarbonyl-
substituted phosphorus ylide and acid (or base) yields 4-tri-
fluoromethyl-2-quinolinones which may bear additional sub-
stituents at any available position. The method is convenient
and expedient.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
The common access to the pharmaceutically attractive 4-
Such uncertainties encouraged us to develop a new
trifluoromethyl-2-quinolinones[1,2] consists of two reaction method that would open a regiochemically unbiased,
steps which have to be controlled carefully (Scheme 1). The though structurally flexible entry to 4-trifluoromethyl-2-
preparation of the prerequisite N-(4,4,4-trifluoroacetoace- quinolinones. We opted for an “off-shore”[6] cyclization ap-
tyl)anilides poses the first problem. In particular anilines proach, that is the construction of the heterocyclic part
carrying electron-withdrawing substituents tend to produce without the active participation of the aromatic ring. In this
concomitantly or exclusively the isomeric “anils”[3] (or β- way, electronegative substituents would not compromise the
anilinocrotonate tautomers thereof), the precursors to 2-tri- electrophilic attachment of a heterofunctional side chain,
fluoromethyl-4-quinolinones.[4] Even if this stumbling block the crucial feature of any “on-shore” process. This design
can be circumvented by applying the “watering protocol”[2] concretized in an ortho-trifluoroacetylation of the aniline
or another suitable regiodiscriminating method,[5] one has starting material bearing an N-tert-butoxycarbonyl
to be aware of another pitfall. The cyclization of the aceto- (“BOC”) protective group at the nitrogen atom, a C2 chain
acetanilide may go astray providing still 2-trifluoromethyl- extension by a suitable condensation reaction and an ulti-
4-quinolinones rather than the targeted 2-quinolinone iso- mate closure of the lactam unit (affording products 1, 2 and
mers if the reaction is not carried out in a most effective 3, respectively) (Scheme 2).
manner using hot concentrated sulfuric acid.[2]
Scheme 2. Projected new reaction sequence leading to 4-trifluoro-
methyl-2-quinolinones: ortho-lithiation, trifluoroacetylation, reac-
tion with an α-(alkoxycarbonyl)-bearing phosphorus ylide and ring
closure.
The ortho-acylation of ortho-lithiated[7–9] BOC-protected
Scheme 1. Known condensation of anilines with ethyl 4,4,4-trifluo-
anilines was accomplished with N-(trifluoroacetyl)piperi-
dine as the reagent. Trifluoroacetic anhydride, previously
successfully employed in the reaction with N,3-dilithiated
N-pivaloyl-3,4-dimethoxyaniline[10] gave only poor results.
The oxacarbamates 1a (71%), 1b (68%), and 1c (51%) thus
obtained were transformed into the cinnamic ester deriva-
tives 2a (79%), 2b (76%), and 2c (74%) by simple Wittig
reaction using 1-methoxy-2-(triphenylphosphonio)ethene
roacetoacetate giving 4-trifluoromethyl-2-quinolinones.
[a] Laboratoire de Stéréochimie (UMR CNRS 7509), Université
Louis Pasteur (ECPM),
25 rue Becquerel, 67087 Strasbourg, France
[b] Institute of Chemical Sciences and Engineering, Ecole Polytech-
nique Fédérale, BCh
1015 Lausanne, Switzerland
Fax: +41-21-6939365
E-mail: manfred.schlosser@epfl.ch
Eur. J. Org. Chem. 2006, 3147–3151
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3147

F. Leroux, O. Lefebvre, M. Schlosser
FULL PAPER
oxide[11] [triphenylphosphonio-α-(methoxycarbonyl)meth- hydrocarbon alkynes so far used by ethoxyacetylene[28]
anide,
(methoxycarbonylmethylene)triphenylphosphor- might open still another entry to 4-trifluoromethyl-2(1H)-
ane,[12] methyl (triphenylphosphoranylidene)acetate]. Treat- quinolinones, although obviously without any reasonable
ment with acid or base afforded eventually the 4-trifluoro- chance to introduce a substituent at the 3-position in this
methyl-2(1H)-quinolinones 3a (73%), 3b (74%), and 3c way.
(69%) (Scheme 3).
Scheme 3. Condensation of ring-substituted tert-butyl N-[2-(tri-
fluoroacetyl)aryl]carbamates with triphenylphosphonio-α-(meth-
oxycarbonyl)methanide and subsequent cyclization.
Scheme 5. Thermolysis of 2-[(1-trifluoromethyl)vinyl]phenyl isocy-
anate (4) and Lewis acid catalyzed addition of alkynes to 2-ami-
nophenyl trifluoromethyl ketone followed by cyclization of the in-
Air-insensitive resonance-stabilized ester ylides such as
the α-methyl-,[13,14] α-phenyl-,[15] α-cyano-,[16] α-formyl-,[17]
and α-methoxy-substituted[18,19] (methoxycarbonylmethyl-
termediate 5.
ene)triphenylphosphoranes and the α-fluoro-,[20] α-
chloro-,[21] α-bromo-,[22,23] and α-iodo-substituted[24,25]
(ethoxycarbonylmethylene)triphenylphosphoranes can be
Experimental Section
readily prepared and stored. Employed in the reaction se-
quence outlined above, they enable the introduction of a
variety of substituents into the 3-position of the final quin-
olinone. This was exemplified by the conversion of tert-bu-
tyl N-[2-(trifluoroacetyl)phenyl]carbamate (1a) into the in-
termediate esters 2d (78%) and 2e (81%) and thereafter into
the quinolinones 3d (76%) and 3e (83%) (Scheme 4).
General Remarks: Starting materials, if commercial, were pur-
chased from Aldrich-Fluka (9479 Buchs, Switzerland) or Apollo
Scientific (Stockport SK6 2QR, UK) and used as such, provided
that adequate checks (melting ranges, refractive indices, and gas
chromatography) had confirmed the claimed purity. Solutions of
tert-butyllithium in pentanes were supplied by Chemetall (60487
Frankfurt, Germany). When known compounds were prepared ac-
cording to literature procedures, pertinent references are given. Air-
and moisture-sensitive materials were stored in Schlenk tubes or
Schlenk burettes. They were protected by and handled under
99.995% pure nitrogen, using appropriate glassware (Glasgeräte-
bau Pfeifer, 98711 Frauenwald, Germany). Diethyl ether and tetra-
hydrofuran were dried by distillation from sodium wire after the
characteristic blue color of sodium diphenyl ketyl (benzophenone–
sodium “radical anion”) had been found to persist.[29,30] Ethereal
or other organic extracts were dried by washing with brine and
then by storage over sodium sulfate. Prior to distillation, a spatula
tip of hydroquinone or potassium carbonate was added to com-
pounds prone to radical polymerization or sensitive to acids. If no
reduced pressure is specified, boiling ranges (b.p.) refer to ordinary
atmospheric conditions (725 25 Torr). Melting ranges (m.p.) given
were found to be reproducible after resolidification, unless stated
otherwise (“decomp.”), and were corrected using a calibration
curve established with authentic standards. If melting points are
Scheme 4. Condensation of tert-butyl N-[2-(trifluoroacetyl)phenyl]-
carbamate with α-alkyl- or α-hetero-substituted triphenylphos-
phonio-α-(methoxycarbonyl)methanides and subsequent cycli-
zation.
Two methods reported in the literature are reminiscent
of ours to some extent (Scheme 5). Their practical value is
difficult to assess as they were tested so far only on an ana-
lytical scale (Յ 1 mmol). When heated to 150 °C, 2-[(1-tri-
fluoromethyl)vinyl]phenyl isocyanate (4) underwent an in- missing, it means that all attempts to crystallize the liquid at tem-
peratures down to –75 °C failed. The temperature of dry ice/meth-
anol baths is consistently indicated as –75 °C and “room tempera-
ture” (22–26 °C) as 25 °C. Silica gel (Merck Kieselgel 60) of 70–
230 mesh (0.06–0.20 mm) particle size was used for column
chromatography. The solid support was suspended in hexanes and,
when all air bubbles had escaped, was washed into the column.
When the level of the liquid was still 3–5 cm above the support
layer, the dry powder, obtained by adsorption of the crude mixture
to some 25 mL of silica and subsequent evaporation of the solvent,
was poured on top of the column. Whenever possible and appropri-
tramolecular C–H bond addition to an activated (ketene-
like) double bond, thus giving 4-trifluoromethyl-2-quinoli-
none (1a).[26] A new route to 2-alkyl- or 2-aryl-4-trifluoro-
methylquinolines started from 2-aminophenyl trifluoro-
methyl ketone and a few congeners thereof. After treatment
with cyclopropylacetylene or phenylacetylene in the pres-
ence of zinc(II) chloride or trifluoromethanesulfonate
(“triflate”) and triethylamine, the adduct 5 or the quinoline
6 were isolated depending on whether the reaction was exe-
cuted at +25 °C or +50 °C, respectively.[27] Replacing the ate, yields of products were determined, prior to isolation, by gas
3148 Eur. J. Org. Chem. 2006, 3147–3151
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Optionally Substituted 4-Trifluoromethyl-2-quinolinones
FULL PAPER
chromatographic comparison of their peak areas with those of
known amounts of reference substances (“internal standards”), the
ratios thus obtained being corrected by means of separately estab-
lished calibration factors. The purity of distilled compounds was
checked on at least two columns loaded with stationary phases of
contrasting polarity. Chromosorb G-AW of 80–100 and 60–
80 mesh particle size was used as the support for packed columns
on the analytical and preparative scales (2 or 3 m long, 2 mm inner
diameter and 3 or 6 m long, 1 cm inner diameter, respectively).
Packed columns were made of glass, while quartz was the material
selected for capillary columns (Ͼ10 m long). For programmed tem-
perature increase, a constant rate of 10 °C/min was applied. The
stationary phases employed are encoded as DB-23 (of the silicon
type) and DB-WAX (belonging to the polyethylene glycol family).
1H and (1H-decoupled) 13C nuclear magnetic resonance (NMR)
spectra were recorded at 400 and 101 MHz, respectively. The sam-
ples were dissolved in deuteriochloroform or, if marked by an aster-
isk (*), in [2H6]dimethyl sulfoxide. Chemical shifts δ refer to the
signal of tetramethylsilane (δ = 0.00 ppm) and coupling constants
J are given in Hz. Coupling patterns are abbreviated as, for exam-
ple, s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet),
sext (sextet), sept (septet), oct (octet), non (nonet), td (triplet of
doublets), and m (multiplet). The carbamate NH signals were fre-
quently too broad to be unambiguously identified. Mass spectra
were taken by electron impact fragmentation at 70 eV ionization
potential and 200 °C source temperature. Whenever no molecular
peak was observed under such standard conditions, chemical ion-
ization (“c.i.”) in an ammonia atmosphere was applied. Elementary
analyses were performed by the laboratories of I. Beetz (96301
Kronach, Germany) or Solvias (4002 Basle, Switzerland). The ex-
pected percentages were calculated using the atomic weight num-
bers listed in the 1999 IUPAC recommendations.
[M+], 319 (27), 257 (100), 214 (38). C14H13F6NO3 (357.25): calcd.
C 47.07, H 3.67; found C 47.35, H 3.44.
tert-Butyl N-[3-Methoxy-2-(trifluoroacetyl)phenyl]carbamate (1c):
Analogously as described for the preparation and isolation of
ketone 1a but starting from tert-butyl N-(2-methoxyphenyl)carba-
mate[34–36] (34 g, 0.15 mol); yellowish needles; m.p. 84–85 °C; yield
1
24.4 g (51%). H NMR: δ = 8.50 (br. s, 1 H), 7.83 (d, J = 8.5 Hz,
1 H), 7.49 (t, J = 8.6 Hz, 1 H), 6.64 (d, J = 8.2 Hz, 1 H), 3.89 (s,
3 H), 1.51 (s, 9 H) ppm. 13C NMR: δ = 186.1 (q, J = 37 Hz), 160.5,
152.4, 141.0, 135.9, 129.6, 116.4 (q, J = 290 Hz), 112.8, 105.2, 81.4,
56.0, 28.2 (3 C) ppm. MS (c.i.): m/z (%) = 319 (20) [M+], 318 (70),
317 (58), 286 (100). C14H16F3NO4 (319.28): calcd. C 52.67, H 5.05;
found C 53.02, H 4.86.
Phenylbutenoates (2)
Ethyl 3-{2-[(tert-Butoxycarbonyl)amino]phenyl}-4,4,4-trifluorobut-2-
enoate (2a): A solution containing the carbamate 1a (8.7 g,
30 mmol) and ethyl (triphenylphosphoranylidene)acetate (10.5 g,
30 mmol) in toluene (60 mL) was heated at 100 °C for 2 h. After
evaporation of the solvent, the residue was dissolved in hexanes.
The insoluble triphenylphosphane oxide was removed by filtration.
Elution from silica gel using a 1:4 (v/v) mixture of ethyl acetate/
hexanes afforded the (Z) and (E) isomers in a ratio of 5:95; yield
8.5 g (79%). MS (c.i.): m/z (%) = 360 (14) [M+ +1], 359 (3) [M+],
304 (100), 260 (47), 259 (31), 214 (79). C17H20F3NO4 (359.34):
calcd. C 56.82, H 5.61; found C 56.79, H 5.46. (E) isomer: 1H
NMR: δ = 7.90 (d, J = 9.0 Hz, 1 H), 7.41 (ddd, J = 8.4, 5.6, 3.4 Hz,
1 H), 7.11 (t, J = 1.0 Hz, 1 H), 7.10 (s, 1 H), 6.80 (q, J = 1.3 Hz,
1 H), 6.29 (s, 1 H), 4.04 (qq, J = 7.0, 5.5 Hz, 2 H), 1.50 (s, 9 H),
1.03 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR: δ = 163.6, 152.8, 138.9
(q, J = 32 Hz), 136.3, 130.0, 128.9, 127.7, 127.6 (q, J = 5 Hz), 123.4,
122.3 (q, J = 276 Hz), 114.6, 80.6, 61.5, 28.3 (3 C), 13.6 ppm.
Ethyl 3-{2-[(tert-Butoxycarbonyl)amino]-5-(trifluoromethyl)phenyl}-
4,4,4-trifluorobut-2-enoate (2b): Analogously as described for the
preparation and isolation of butenoate 2a but starting from carba-
mate 1b (11 g, 30 mmol); (Z)/(E) = 13:87; yield 9.7 g (76%). MS:
m/z (%) = 427 (4) [M+], 371 (6), 327 (12), 282 (69), 254 (18), 57
(100). C18H19F6NO4 (427.34): calcd. C 50.59, H 4.48; found C
50.84, H 4.43. (Z) isomer: 1H NMR: δ = 8.24 (d, J = 8.7 Hz, 1 H),
7.87 (d, J = 8.9 Hz, 1 H), 7.48 (s, 1 H), 7.14 (s, 1 H), 6.40 (s, 1 H),
4.37 (q, J = 7.3 Hz, 2 H), 1.55 (s, 9 H), 1.39 (t, J = 7.1 Hz, 3 H)
tert-Butyl N-[2-(Trifluoroacetyl)phenyl]carbamates (1)
tert-Butyl N-[2-(Trifluoroacetyl)phenyl]carbamate (1a): At –30 °C,
tert-butyllithium (0.33 mol) in pentanes (0.22 L) was added drop-
wise in the course of 45 min to a solution of tert-butyl N-phenylcar-
bamate[7,8] (29 g, 0.15 mol) in dry diethyl ether (0.45 L). After 4 h
at –10 °C, the mixture was treated at +25 °C with 1-(trifluoroace-
tyl)piperidine[31,32] (29 mL, 36 g, 0.20 mol) in diethyl ether (50 mL).
The mixture was washed with brine (0.15 L) and the solvents were
evaporated. The residue was extracted with pentanes (3×0.10 L)
and the combined organic layers were filtered through a pad of
silica (50 mL). Upon concentration of the solution and cooling,
yellowish needles were obtained; m.p. 60–61 °C; yield 30.8 g (71%).
1H NMR: δ = 10.45 (s, 1 H), 8.59 (dd, J = 8.8, 1.2 Hz, 1 H), 7.92
(dt, J = 8.2, 2.0 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.09 (t, J =
7.2 Hz, 1 H), 1.54 (s, 9 H) ppm. 13C NMR: δ = 181.9 (q, J =
32 Hz), 152.4, 144.5, 137.3, 131.6 (q, J = 4 Hz), 121.1, 119.6, 116.5
(q, J = 292 Hz), 114.6, 81.4, 28.2 (3 C) ppm. MS (c.i.): m/z (%) =
289 (3) [M+], 233 (20), 216 (5), 189 (10), 146 (32). C13H14F3NO3
(289.25): calcd. C 53.98, H 4.88; found C 54.11, H 4.71.
1
ppm. (E) isomer: H NMR: δ = 8.19 (d, J = 8.9 Hz, 1 H), 7.68 (d,
J = 8.7 Hz, 1 H), 7.37 (s, 1 H), 6.89 (s, 1 H), 6.44 (s, 1 H), 4.08
(qq, J = 7.1, 5.4 Hz, 2 H), 1.52 (s, 9 H), 1.06 (t, J = 7.1 Hz, 3 H)
ppm. 13C NMR: δ = 163.1, 152.3, 139.9, 137.4 (q, J = 32 Hz), 129.6
(q, J = 6 Hz), 127.3 (q, J = 4 Hz), 127.0, 126.3 (q, J = 4 Hz), 120.9,
120.1, 117.9, 115.3, 81.7, 61.8, 28.2 (3 C), 13.6 ppm.
Ethyl
3-{2-[(tert-Butoxycarbonyl)amino]-6-methoxyphenyl}-4,4,4-
trifluorobut-2-enoate (2c): Analogously as described for the prepa-
ration and isolation of butenoate 2a but starting from carbamate
1c (9.6 g, 30 mmol); (Z)/(E) = 23:77; yield 8.6 g (74%). MS: m/z
(%) = 389 (16) [M+], 289 (30), 244 (44), 216 (100). C18H22F3NO5
(389.37): calcd. C 55.53, H 5.70; found C 55.32, H 5.49. (Z) isomer:
1H NMR: δ = 7.60 (d, J = 8.3 Hz, 1 H), 7.17 (t, J = 8.6 Hz, 1 H),
6.84 (s, 1 H), 6.58 (dd, J = 8.0, 2.2 Hz, 1 H), 6.24 (s, 1 H), 4.32 (q,
J = 7.4 Hz, 2 H), 3.80 (s, 3 H), 1.52 (s, 9 H), 1.36 (t, J = 7.4 Hz, 3
H) ppm. 13C NMR: δ = 160.0, 157.1, 152.3, 139.4, 136.7 (q, J =
tert-Butyl
N-[2-(Trifluoroacetyl)-4-(trifluoromethyl)phenyl]carba-
mate (1b): Analogously as described for the preparation and isola-
tion of ketone 1a but starting from tert-butyl N-[4-(trifluorometh-
yl)phenyl]carbamate[33] (13 g, 50 mmol) and replacing diethyl ether
by tetrahydrofuran (0.15 L) as the solvent; colorless needles; m.p.
95–96 °C; yield 12.1 g (68%). 1H NMR: δ = 10.45 (br. s, 1 H), 8.78 32 Hz), 131.5 (q, J = 3 Hz), 130.4, 129.6, 112.7 (q, J = 275 Hz),
1
(d, J = 9.2 Hz, 1 H), 8.16 (s, 1 H), 7.86 (dd, J = 9.1, 2.0 Hz, 1 H),
1.55 (s, 9 H) ppm. 13C NMR: δ = 182.1 (q, J = 35 Hz), 152.0,
147.3, 133.6 (q, J = 3 Hz), 128.8 (q, J = 4 Hz), 123.5 (q, J = 35 Hz),
123.2 (q, J = 272 Hz), 120.0, 114.9 (q, J = 292 Hz), 118.9, 82.4,
28.2 (3 C) ppm. MS (c.i.): m/z (%) = 358 (11) [M+ +1], 357 (9)
105.8, 103.9, 80.9, 61.7, 55.2, 28.2 (3 C), 13.8 ppm. (E) isomer: H
NMR: δ = 7.53 (d, J = 8.3 Hz, 1 H), 7.34 (t, J = 8.3 Hz, 1 H), 6.81
(s, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 6.22 (s, 1 H), 4.05 (qq, J = 10.9,
7.0, 2 H), 3.77 (s, 3 H), 1.48 (s, 9 H), 1.04 (t, J = 7.4 Hz, 3 H) ppm.
13C NMR: δ = 163.5, 157.1, 152.7, 137.1, 136.7 (q, J = 32 Hz),
Eur. J. Org. Chem. 2006, 3147–3151
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3149

F. Leroux, O. Lefebvre, M. Schlosser
FULL PAPER
130.5, 129.5, 128.8 (q, J = 5 Hz), 122.2 (q, J = 275 Hz), 108.6,
105.9, 80.6, 61.2, 55.9, 28.2 (3 C), 13.6 ppm.
32 Hz), 128.9 (q, J = 3 Hz), 124.8 (q, J = 6 Hz), 123.4 (q, J =
276 Hz), 122.8 (q, J = 275 Hz), 122.6, 121.9, 118.6, 113.5 ppm. MS
(c.i.): m/z (%) = 299 (14) [M+ +NH4], 282 (100) [M+ +1], 281 (33),
253 (7). C11H5F6NO (281.16): calcd. C 46.99, H 1.79; found C
47.21, H 1.88.
Ethyl 3-{2-[(tert-Butoxycarbonyl)amino]phenyl}-2-methyl-4,4,4-tri-
fluorobut-2-enoate (2d): Analogously as described for the prepara-
tion and isolation of butenoate 2a but using ethyl methyl(tri-
phenylphosphoranylidene)acetate as the reagent[13,14] (11 g,
30 mmol); (Z)/(E) ratio 33:67; yield 8.8 g (78%). MS (c.i.): m/z (%)
= 374 (1) [M+], 318 (6), 200 (100). C18H22F3NO4 (373.37): calcd.
5-Methoxy-4-(trifluoromethyl)quinolin-2(1H)-one (3c): Prepared
and isolated analogously but starting from the but-2-enoate 2c
(3.9 g, 10 mmol); colorless needles (from ethanol); m.p. 280–
1
1
283 °C; yield 1.68 g (69%). H NMR*: δ = 7.6 (m, 1 H), 7.1 (m, 1
C 57.90, H 5.94; found C 57.86, H 5.86. (Z) isomer: H NMR: δ
H), 7.0 (m, 2 H); 3.92 (s, 3 H) ppm. 13C NMR*: δ = 160.7, 156.4,
142.4, 136.5 (q, J = 32 Hz), 133.4, 123.5 (q, J = 274 Hz), 123.2 (q,
J = 8 Hz), 109.8, 105.9, 105.4, 56.9 ppm. MS (c.i.): m/z (%) = 243
(100) [M+], 200 (27), 172 (16). C11H8F3NO2 (243.18): calcd. C
54.33, H 3.32; found C 54.23, H 5.18.
= 8.03 (d, J = 8.1 Hz, 1 H), 7.40 (t, J = 8.5 Hz, 1 H), 7.11 (t, J =
7.9 Hz, 1 H), 7.03 (d, J = 4.5 Hz, 1 H), 4.37 (qq, J = 7.02, 5.2 Hz,
2 H), 1.78 (q, J = 1.8 Hz, 3 H), 1.59 (s, 9 H), 1.38 (t, J = 8.0 Hz,
3 H) ppm. 13C NMR: δ = 168.3, 152.9, 140.9 (q, J = 4 Hz), 136.7,
130.2, 130.0, 129.6 (q, J = 32 Hz), 129.0, 123.6, 122.4 (q, J =
275 Hz), 121.5, 80.9, 62.1, 28.3 (3 C), 18.3, 13.9 ppm. (E) isomer:
1H NMR: δ = 7.85 (d, J = 8.0 Hz, 1 H), 7.34 (td, J = 8.1, 4.9 Hz,
1 H), 7.15 (t, J = 7.2 Hz, 1 H), 7.03 (d, J = 4.5 Hz, 1 H), 3.89 (qq,
J = 7.8, 6.2 Hz, 2 H), 2.30 (q, J = 2.5 Hz, 3 H), 1.52 (s, 9 H), 0.84
(t, J = 7.3 Hz, 3 H) ppm. 13C NMR: δ = 168.0, 153.0, 142.4 (q, J
= 3 Hz), 137.0, 130.1, 129.9, 129.5 (q, J = 32 Hz), 129.0, 123.1 (q,
J = 276 Hz), 123.4, 121.2, 80.7, 61.5, 28.3 (3 C), 16.5 (q, J = 2 Hz),
13.4 ppm.
3-Methyl-4-(trifluoromethyl)quinolin-2(1H)-ones (3d): Analogously
as described for the preparation and isolation of quinolinone 3a
but starting from but-2-enoate 2b (3.7 g, 10 mmol); colorless need-
les (from ethanol); m.p. 237–239 °C; yield 1.73 g (76%). 1H NMR*:
δ = 7.71 (d, J = 7.1 Hz, 1 H), 7.53 (t, J = 6.8 Hz, 1 H), 7.38 (d, J
= 8.0 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 1 H), 2.32 (s, 3 H) ppm. 13C
NMR*: δ = 161.6, 138.3, 133.3, 132.2 (q, J = 29 Hz), 131.0, 129.1,
129.0 (q, J = 4 Hz), 123.4 (q, J = 279 Hz), 119.1, 116.8, 13.8 ppm.
MS (c.i.): m/z (%) = 228 (22) [M+ +1], 227 (100) [M+], 198 (44),
130 (30). C11H8F3NO (227.19): calcd. C 58.16, H 3.55; found C
58.19, H 3.33.
Methyl 3-{2-[(tert-Butoxycarbonyl)amino]phenyl}-2-methoxy-4,4,4-
trifluorobut-2-enoate (2e): Analogously as described for the prepa-
ration and isolation of butenoate 2a but using methyl methoxy(tri-
phenylphosphoranylidene)acetate as the reagent (11 g, 30 mmol);
(Z)/(E) = 72:28; yield 9.1 g (81%). MS: m/z (%) = 375 (2) [M+],
243 (100), 211 (85). C17H20F3NO5 (375.34): calcd. C 54.40, H 5.37;
found C 54.82, H 5.53. (Z) isomer: 1H NMR: δ = 7.98 (d, J =
8.4 Hz, 1 H), 7.37 (td, J = 7.0, 1.7 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1
H), 7.08 (td, J = 7.6, 1.2 Hz, 1 H), 3.97 (s, 3 H), 3.62 (s, 3 H), 1.63
(s, 9 H) ppm. 13C NMR: δ = 163.5, 152.7, 137.1, 136.7 (q, J =
32 Hz), 130.5, 129.5, 128.8 (q, J = 4 Hz), 122.2 (q, J = 275 Hz),
3-Methoxy-4-(trifluoromethyl)quinolin-2(1H)-ones (3e): A solution
of but-2-enoate 2e (3.7 g, 10 mmol) in 5.0  ethanolic hydrogen
chloride (20 mL) was heated under reflux for 4 h. After evaporation
of the volatiles, the residue was crystallized from acetone; colorless
1
needles; m.p. 153–154 °C; yield 2.02 g (83%). H NMR*: δ = 7.84
(d, J = 8.3 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.50 (t, J = 8.3 Hz,
1 H), 7.31 (ddd, J = 8.0, 7.0, 1.2 Hz, 1 H), 4.08 (s, 3 H) ppm. 13C
NMR*: δ = 171.5, 158.0, 150.0, 136.2, 129.6, 125.0, 124.1 (q, J =
277 Hz), 123.3, 123.0 (q, J = 29 Hz), 116.2, 60.6 ppm. MS (c.i.):
m/z (%) = 244 (18) [M+ +1], 243 (100) [M+], 215 (11). C11H8F3NO2
(243.18): calcd. C 54.33, H 3.32; found C 53.96, H 3.17.found C
53.96, H 3.17.
1
114.1, 108.6, 80.6, 61.2, 55.9, 28.2 (3 C), 13.6 ppm. (E) isomer: H
NMR: δ = 7.89 (d, J = 8.4 Hz, 1 H), 7.35 (td, J = 9.0, 2.0 Hz, 1
H), 7.09 (dd, J = 7.6, 1.7 Hz, 1 H), 7.02 (td, J = 7.5, 1.3 Hz, 1 H),
3.83 (s, 3 H), 3.49 (s, 3 H), 1.63 (s, 9 H) ppm. 13C NMR: δ = 163.0,
152.6, 137.9, 136.7 (q, J = 32 Hz), 130.1, 129.2, 128.8 (q, J = 4 Hz),
120.0 (q, J = 273 Hz), 111.6, 111.0, 80.8, 63.0, 55.1, 29.6 (3 C),
13.6 ppm.
Acknowledgments
4-(Trifluoromethyl)quinolin-2(1H)-ones (3)
This work was financially supported by the Schweizerische Nation-
alfonds zur Förderung der wissenschaftlichen Forschung (grant 20-
63Ј584-00), Bern, and the Bundesamt für Berufsbildung und Tech-
nologie (KTI-Projekt 5474.1 KTS), Bern.
4-(Trifluoromethyl)quinolin-2(1H)-one (3a): But-2-enoate 2a (3.6 g,
10 mmol) was heated under reflux in 5.0  hydrochloric acid
(50 mL) for 4 h. After cooling, the precipitate was collected by fil-
tration, dried, washed with chloroform and crystallized from etha-
nol; colorless needles; m.p. 246–247 °C; yield 1.55 g (73%). 1H
NMR*: δ = 7.71 (d, J = 8.4 Hz, 1 H), 7.65 (td, J = 7.6, 1.0 Hz, 1
H), 7.43 (d, J = 8.5 Hz, 1 H), 7.32 (td, J = 7.7, 1.0 Hz, 1 H), 6.98
(s, 1 H) ppm. 13C NMR*: δ = 160.0, 139.8, 136.6 (q, J = 31 Hz),
131.7, 124.3, 122.8, 122.6 (q, J = 277 Hz), 122.0 (q, J = 5 Hz),
116.5, 113.1 ppm. MS (c.i.): m/z (%) = 231 (27) [M+ +NH4], 214
(100) [M+ +1], 213 (34) [M+], 185 (8), 166 (2). C10H6F3NO
(213.16): calcd. C 56.35, H 2.84; found C 56.19, H 3.00. The same
compound was obtained in 92% yield by starting from the but-2-
enoate 2a (1.8 g, 5.0 mmol) in ethanol (10 mL) with sodium ethan-
olate (0.34 g, 5.0 mmol) under reflux for 4 h.
[1] O. Lefebvre, M. Marull, M. Schlosser, Eur. J. Org. Chem. 2003,
2115–2121.
[2] M. Marull, O. Lefebvre, M. Schlosser, Eur. J. Org. Chem. 2004,
54–63.
[3] M. Schlosser, M. Marull, unpublished results, 2004.
[4] M. Marull, M. Schlosser, Eur. J. Org. Chem. 2003, 1576–1588.
[5] D. O. Berbasov, V. A. Soloshonok, Synthesis 2003, 2005–2010.
[6] M. Schlosser, Mod. Synth. Methods 1992, 6, 227–271, spec.
252.
[7] J. M. Muchowski, M. C. Venuti, J. Org. Chem. 1980, 45, 4798–
4801.
[8] P. Stanetty, H. Koller, M. Mihovilovic, J. Org. Chem. 1992, 57,
6833–6837.
[9] M. Schlosser, in: Organometallics in Synthesis: A Manual (Ed.:
M. Schlosser), Wiley, Chichester, 2002, pp. 1–352, spec. 225
(Table 121).
[10] R. A. Conley, D. L. Barton, S. M. Stefanick, M. M. Lam, G. C.
Lindabery, C. F. Kasulanis, S. Cesco-Cancian, S. Currey, A. C.
Fabian, S. D. Levine, J. Heterocycl. Chem. 1995, 32, 761–770.
4,6-Bis(trifluoromethyl)quinolin-2(1H)-one (3b): Analogously as de-
scribed for the preparation and the isolation of quinolinone 3a but
starting from the but-2-enoate 2b (4.3 g, 10 mmol); colorless need-
les (from ethanol); m.p. 219–221 °C; yield 2.08 g (74%). 1H NMR*:
δ = 7.94 (d, J = 8.7 Hz, 1 H), 7.78 (s, 1 H), 7.56 (d, J = 9.0 Hz, 1
H), 7.09 (s, 1 H) ppm. 13C NMR*: δ = 161.1, 143.1, 136.8 (q, J =
3150
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3147–3151

Optionally Substituted 4-Trifluoromethyl-2-quinolinones
FULL PAPER
[11]
[12]
[25] X. Zhang, F.-L. Qing, Y. Peng, J. Fluorine Chem. 2001, 108,
79–82.
[26] L. Luo, M. D. Bartberger, W. R. Dolbier, J. Am. Chem. Soc.
1997, 119, 12366–12367.
[27] B. Jiang, Y.-G. Si, J. Org. Chem. 2002, 67, 9449–9451.
[28] J. F. Arens, D. A. van Dorp, Recl. Trav. Chim. Pays-Bas. 1948,
67, 973–979.
[29] K. Ziegler, F. Crössmann, H. Kleinert, O. Schäfer, Justus Lie-
bigs Ann. Chem. 1929, 473, 1–35, spec. 20.
[30] H. Metzger, E. Müller, in: Houben-Weyl: Methoden der or-
ganischen Chemie (Ed.: E. Müller), Thieme, Stuttgart, 1959,
vol. 1/2, pp. 337–338.
C. Rüchardt, P. Panse, S. Eichler, Chem. Ber. 1967, 100, 1144–
1164.
M. Schlosser, T. Jenny, B. Schaub, Heteroatom Chem. 1990, 1,
151–156.
H. J. Bestmann, H. Schulz, Chem. Ber. 1962, 95, 2921–2927.
T. M. Werkhoven, R. van Nispen, J. Lugtenburg, Eur. J. Org.
Chem. 1999, 2909–2914.
H. J. Bestmann, H. Schulz, Justus Liebigs Ann. Chem. 1964,
674, 11–17.
[13]
[14]
[15]
[16]
[17]
L. Horner, H. Oediger, Chem. Ber. 1958, 91, 437–442.
G. Märkl, Tetrahedron Lett. 1962, 3, 1027–1030.
[18] P. Seneci, I. Leger, M. Souchet, G. Nadler, Tetrahedron 1997,
[31] W. F. Cockburn, R. A. B. Bannard, Can. J. Chem. 1957, 35,
53, 17097–17114.
1285–1292.
[19] S. Gagliardi, G. Nadler, E. Consolandi, C. Parini, M. Morvan,
M.-N. Legave, P. Belfiore, A. Zocchetti, G. D. Clarke, I. James,
P. Nambi, M. Gowen, C. Farina, J. Med. Chem. 1998, 41,
1568–1573.
[32] M. Nassal, Liebigs Ann. Chem. 1983, 1510–1523.
[33] S. Takagishi, G. Katsoulos, M. Schlosser, Synlett 1992, 360–
362.
[34] R. Taylor, M. P. Thorpe, J. Chem. Soc., Perkin Trans. 2 1976,
[20] A. Thenappan, D. J. Burton, J. Org. Chem. 1990, 55, 2311–
799–802.
2317.
[35] S. J. Gould, R. L. Eisenberg, J. Org. Chem. 1991, 56, 6666–
6671.
[36] Y. Kondo, S. Kojima, T. Sakamoto, J. Org. Chem. 1997, 62,
[21] R. M. Moriarty, I. Prakash, O. Prakash, W. A. Freeman, J.
Am. Chem. Soc. 1984, 106, 6082–6084.
[22] A. J. Speziale, K. W. Ratts, J. Org. Chem. 1963, 28, 465–469.
[23] G. Märkl, Chem. Ber. 1961, 94, 2996–3004.
[24] J. Chenault, J.-F. E. Dupin, Synthesis 1987, 498–499.
6507–6511.
Received: February 17, 2006
Published Online: May 9, 2006
Eur. J. Org. Chem. 2006, 3147–3151
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3151