The tautomeric persistence of electronically and sterically biased 2-quinolinones

Article abstract of DOI:10.1002/ejoc.200800123

One dozen of tailormade model 3-fluoro-2(1H)-quinolinones were synthesized in order to be investigated by UV-, IR- and NMR spectroscopic techniques. All of these compounds were found to exist predominantly, if not exclusively, in the lactam (carboxamide,

Full text of DOI:10.1002/ejoc.200800123

FULL PAPER
DOI: 10.1002/ejoc.200800123
The Tautomeric Persistence of Electronically and Sterically Biased
2-Quinolinones
Jean-Noël Volle,[a,b] Ursula Mävers,[a] and Manfred Schlosser*[a,c]
Keywords: Acidity constants / Amide–hydroxyimine tautomerism / 3-Fluoro-2(1H)-quinolinones / Keto–enol tautomerism /
Knorr–Effenberger cyclizations
One dozen of tailormade model 3-fluoro-2(1H)-quinolinones
were synthesized in order to be investigated by UV-, IR- and
NMR spectroscopic techniques. All of these compounds were
found to exist predominantly, if not exclusively, in the lactam
(carboxamide, 1,2-dihydro-2-oxoquinoline) form. No tauto-
meric lactim (iminol, azaphenol) structure was detected.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Keto/enol tautomerism remains a classic.[1] It typically
manifests itself in the oxo/hydroxy olefin,[2–5] amide/
hydroxy imine[6–8] and the degenerate carboxy/hydroxy-
carbonyl proton-shift equilibria, but also in phenol/cyclo-
hexadienone,[9–10]
2-pyridinone/2-hydroxypyridine[11–16]
and 2-quinolinone/2-hydroxyquinoline[16–18] equilibria
(Scheme 1).
The position of such equilibria dictates not only the
chemical reactivity of the respective compounds but also
their behavior in living organisms. Molecular recogni-
tion,[19] including the base pairing in desoxyribonucleic
acid, depends widely, though not alone,[20] on hydrogen
bonding. Thus, the detailed knowledge of the tautomeric
preferences and potentialities of all key components is a
prerequisite for the rational design of the biological proper-
ties of an agonist or inhibitor. The structural analysis has
also to take into account the physiological environment in
which the compound is placed. Solvent[21–23] and phase ef-
fects can be critical. For example, an aqueous solution of
2-pyridone contains almost exclusively the amide form (K
= 340,[24] ∆G° = 3.4 kcal/mol), whereas in the gas phase the
2-hydroxypyridine form is slightly favored (K = 2.2[25–26]
∆G° = 0.47 kcal/mol).
Scheme 1. Oxo/hydroxy olefin and carboxamide/hydroxyimine
tautomerism in the aliphatic-acyclic and the aromatic or heterocy-
clic series.
Nitrogen-containing heterocycles play a privileged role in
medicinal chemistry. Therefore, considerable efforts have
been deployed to elucidate their tautomeric profiles.[26–31]
In solution, as opposed to the gas phase, pyridines and
quinolines carrying oxygen at the 2- or 4-position were
found to exist as 2- or 4-pyridinones and 2- or 4-quinol-
inones rather than as 2- or 4-hydroxypyridines and 2- or 4-
hydroxyquinolines. This assignment was based on the com-
parison of their UV[32–37] and IR[38–41] spectra, their dipole
moments[42] and their dissociation constants[24,43] with data
collected from model compounds where the lactam and lac-
tim functions had been made immutable (“frozen”) by N-
and O-methylation, respectively. However, according to all
available evidence, the relative thermodynamic stabilities of
the oxo and hydroxy forms cannot be far apart. We won-
[a] Université, Section de Chimie,
1015 Lausanne, Switzerland
[b] Université, Institut Ch. Gerhardt, UMR5253 CNRS-ENSCM,
34296 Montpellier, France
[c] Ecole Polytechnique Fédérale, ISIC,
1015 Lausanne, Switzerland
Fax: +41-21-6939365
E-mail: manfred.schlosser@epfl.ch
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Tautomerism of 2-Quinolinones
dered whether or not a simple substitution bias would suf- small concentrations, 2H-nonafluorocyclohexanone, 2,2-
fice to alter the tautomeric identity of the parent com- H2-hexafluorocyclopentanone, 2H-heptafluoropentanone
pounds.
and 2H-pentafluorocyclobutanone were enolized to the ex-
We chose to probe, simultaneously or in parallel, three tent of 25, 13, 99 and Ͼ99.5%.[55]
kinds of substitutive perturbations of 2-quinolinone. The
The structures of uracil and of the cancer drug 5-fluoro-
first structural modification was subtle and, at the same uracil have also been extensively investigated. According to
time, quite precise. Although the hypothesis did not remain an early ab initio calculation at the 3-21G level, the tauto-
undisputed,[44] (Z)-2-fluoro-1-ethen-1-ol (i.e., fluoroacetal- meric population of the parent heterocycle and its fluori-
dehyde enol[45,46]) and 2-fluorophenol[47–49] were repeatedly nated congener turned out to be almost identical.[56] The 2-
apostrophed as entities stabilized by intramolecular hydro- hydroxy-4-oxo and the 4-hydroxy-2-oxo species, as the next-
gen bonding. If such an interaction was really operative in best tautomeric entities, proved to be already 17 and
the 3-fluoro-2-quinolinone series it would favor the lactim 20 kcal/mol less stable than the 2,4-dioxo form.[56] A later
at the expense of the lactam form. The latter might be ad- computational study using a more extended basis set main-
ditionally disadvantaged by the close-to-parallel alignment tained the qualitative order of stabilities but placed the 2-
of the C–F and C=O dipoles (Scheme 2). Next, we intro- hydroxy-4-oxo and 4-hydroxy-2-oxo tautomers of uracil
duced into the 8-position heterosubstituents such as a chlo- only 11 and 12 kcal/mol, respectively, and of 5-fluorouracil
rine atom the electron-withdrawing inductive effect of only 7 and 12 kcal/mol, respectively, above the 2,4-dioxo
which should diminish the availability of the nitrogen lone mark.[57] All data so far collected referred exclusively to the
pair and, as a corollary, weaken the amino-carbonyl reso- gas phase. More recently several attempts were made to
nance (Scheme 2). Finally, we placed a tert-butyl group at mimic the aqueous medium by surrounding 5-fluoro-uracil
the 8-position. Owing to its bulkiness it should impede NH with water molecules. Careful assessment of a 5-fluorouracil
solvation and thus discriminate once more against the lac- three water cluster brought the energy of the 2-hydroxy-4-
tam form (Scheme 2).
oxo and 4-hydroxy-2-oxo relative to the 2,4-dioxo species
down to 5 and 10 kcal/mol, respectively.[58] Thus, all evi-
dence points at an effective stabilization of the 4-hydroxy-
2-oxo relative to the 2,4-dioxo form by the 5-fluorine sub-
stituent. In combination with the other factors considered
above this may suffice to close the gap between the two
competing tautomeric species further and eventually give
the preference to the lactime (hydroxyimine).
Synthesis of the Model Compounds
3-Fluoro-2(1H)-quinolinones can be readily made by a
Knorr–Effenberger-type reaction[59–60] employing an ani-
line and a 2-fluoro-3-methoxyacrylic acid derivative which
are first condensed to give a (Z/E) isomeric carboxamide
intermediate to be subsequently cyclized under acidic con-
ditions (Scheme 3).[61–63] This method was used to produce
a series of 8-substituted 3-fluoro-2(1H)-quinolinones 1a–1h
in yields ranging from 51 to 88%.
Scheme 2. Three structural modifications potentially causing the 2-
quinolinone form to shift to its 2-hydroxyquinoline tautomer.
Despite numerous in-depth investigations into fluorine
effects on keto/enol and related tautomeric equilibria, the
subject has remained a controversial issue. According to
Bumgardner et al., a fluorine atom at the 2-position of a
cyclic 1,3-dicarbonyl compound does not noticeably alter
the preference for the enol form whereas it reverses the
equilibrium position and makes the keto form predominant
upon fluorination of acyclic substrates.[50] This rule is at
variance with earlier[51] but in agreement with later[52] find-
ings. For example, the enol content of 3-fluoroacetonylace-
tone approximates 20%[52] in contrast to the 80% deter-
mined for the halogen-free analog.[53] Ethyl 2-fluoroace-
toacetate and ethyl 2-fluorobenzoylacetate are enolized to
the extent of 4% and Ͻ 3%, respectively,[52] less than half
as much as the corresponding parent compounds.[53–54]
Spectacular substituent effects on the oxo/enol equilibria of
polyfluoroketones were reported by Lemal et al.[55] Whereas
the enol forms of both cyclopentanone and 3H-hep-
Scheme 3. 8-Substituted 3-fluoro-2(1H)-quinolinones by acid-cata-
tafluoro-2-butanone were present only in undetectably lyzed cyclization of N-(2-fluoro-3-methoxy-2-propenoyl)anilines.
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For the sake of completeness, also the three other
tert-butyl-substituted quinolinones 2–4 were prepared
(Scheme 4). Whereas 4-tert-butylaniline afforded the 6-iso-
mer 2 without any problem, the same sequence applied to
the 3-tert-butylaniline produced an inseparable mixture of
the 5- and 7-isomers 3 and 4.
Scheme 6. Di-tert-butyl-3-fluoro-2(1H)-quinolinones 5–7 by con-
densation of 3,5-, 3,6- and 2,4-di-tert-butylaniline with methyl 2-
fluoro-3-methoxy-2-propenoate and subsequent acid-catalyzed cy-
clization.
To prepare further model compounds for spectroscopic
studies, the parent quinolinone 1a and the 8-fluoro and 8-
tert-butyl-substituted congeners 1b and 1h were consecu-
tively treated with potassium hydride in dimethylformamide
and dimethyl sulfate (Scheme 7). The first two compounds
gave predominantly the N-methylated quinolinones 9a
(62%) and 9b (77%) along with some of the O-methylated
quinolines 8a (8%) and 8b (15%). The pairs of regioisomers
were readily separated by column chromatography. In con-
trast, the 8-tert-butyl analog 1h afforded exclusively the 2-
methoxyquinoline 8h (90%). Obviously, steric congestion
prevented the access of the reagent to the nitrogen atom.
Scheme 4. Acid-catalyzed cyclization of N-(2-fluoro-3-methoxy-2-
propenoyl)anilines affording 5-, 6- and 7-tert-butyl-3-fluoro-2(1H)-
quinolinones.
Isomer 3 (82%) was isolated along with some 8-tert-bu-
tyl-2(1H)-quinolinone (1h; 11%) after treatment of 5,8-di-
tert-butyl-3-fluoro-2(1H)-quinolinone (6) with sulfuric acid
(98%) (Scheme 5).
A similar selective monodealkyl-
ation[64–66] applied to 5,7-di-tert-butyl-2(1H)-quinolinone
(5) gave isomer 4 (14%).
Scheme 5. Acid-catalyzed monodealkylation of di-tert-butyl-substi-
tuted quinolinones 5 and 6 producing 5-, 7- and 8-tert-butyl-3-
fluoro-2(1H)-quinolinones 1h, 3 and 4.
Scheme 7. Methylation of quinolinones 1a, 1b and 1h giving rise to
O-methylquinolinones 8a, 8b and 8h and N-methylquinolinones 9a
and 9b.
The 5,7-, 5,8- and 6,8-di-tert-butylquinolinones 5 (51%),
6 (82%) and 7 (71%) were obtained in the usual way from
the corresponding aniline and methyl 2-fluoro-3-methoxy-
The missing N-methyl derivative of the quinolinone 9h
acrylate (Scheme 6). The N-acryloanilides were again cy- had to be accessed in a different way. To this end, 2-tert-
clized without prior isolation. butylaniline was N-methylated and deprotonated with po-
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Tautomerism of 2-Quinolinones
tassium hydride before being condensed with 2-fluoro-3- pKa value by 1.0, the second one at the 8-position by even
methoxyacryloyl chloride. Subsequent acid-mediated cycli- 1.5 units. The second substituent is syn-oriented with re-
zation of the aniline-derived amide afforded the N-methyl- spect to the nitrogen and hence closer than the anti-oriented
quinolinone 9h in 37% over-all yield (Scheme 8).
first one although both are equidistant in terms of the
number of interposed bonds. Alkyl substituents at the 8-
position either diminish the acidity slightly (ethyl and iso-
propyl) or do not affect it at all (methyl and tert-butyl). At
first sight, the charge-stabilizing inductive electron-donat-
ing effect is largely offset by the steric hindrance to NH
solvation which disfavors the acid form. However, the same
dissociation constant as the one recorded for 8-tert-butyl-3-
fluoro-2(1H)-quinolinone was also found for the 6-tert-bu-
tyl isomer. The N-acryloylaniline precursors such as com-
pound 10 proved to be considerably less acidic than the
corresponding 2H-quinolinones. This was to be expected as
the ring-open counterparts offer a less extensive area for
charge delocalization and, in addition, the coplanarity of
all resonance-active centers is not secured in such floppy
structures.
Scheme 8. Conversion of 2-tert-butyl-N-methylaniline into 8-tert-
butyl-3-fluoro-1-methyl-2(1H)-quinolinone (9h).
Dissociation Constants
Attempts have previously been undertaken to deduce lac-
tam/lactime equilibrium constants from a pKa-comparison
of 2-, 3- and 4-hydroxypyridines and -quinolines,[24,43] al-
though the validity of such an approach remains question-
able. The acidity data reported below (see Table 1), were
only collected to probe substituent effects. The introduction
of the first fluorine atom at the 3-position diminished the
Table 2. Comparison on the 13C and 19F chemical shifts of model
quinolinones 1 with those of their O- and N-methylated derivatives
8 and 9, respectively.
Table 1. Dissociation constants pKa of 2(1H)-quinolinone, 3-
fluoro-2(1H)-quinolinone (1a), 8-substituted congeners thereof (1b,
1e, 1f, 1g, and 1h) and 2-tert-butyl-N-(2-fluoro-3-methoxyacryloyl)-
aniline (10).
[a] Coinciding with a literature value.[24] [b] The same number was
found for 6-tert-butyl- and 5,8-di-tert-butyl-3-fluoro-2(1H)-quin-
olinone. [c] (E)-Isomer. [d] Not acidic enough to be assessed under
the standard conditions applied.
[a] Chemical shifts (in ppm relative to tetramethylsilane) of the oxy-
gen-bearing carbon nuclei at the 2-position and, in parentheses,
vicinal C(2)–F coupling constants (in Hz). [b] Chemical shift (rela-
tive to Cl3CF) of the fluorine nucleus at the 3-position.
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Nuclear Magnetic Resonance Spectra
The 13C signal of the C-2 nucleus reveals whether the
latter is connected to a singly or doubly bonded oxy-
gen.[67–70] In the same manner, the resonance frequency of
the fluorine atom at the 3-position can tell whether the
halogen is neighbored by a carbonyl or hydroxyl group.[71]
When comparing the 13C and 19F NMR spectra of the three
model quinolinones 1a, 1b and 1h with those of their O-
and N-methylated derivatives (8 and 9, respectively), the an-
ticipated chemical shift differences were observed indeed
(Table 2).
There was little difference (Յ 2 ppm) between the 13C fre-
quencies of quinolinones 1 and the corresponding N-methyl
derivatives 9 whereas the 2-methoxyquinolines 8 resonated
at a 5 (Ϯ2) ppm higher field. The 19F chemical shifts of the
quinolinones 1 and their N-methyl congeners 9 were also
quite similar (∆δ = 0.7–3.1 ppm), whereas those of the 2-
methoxyquinolines 8 appeared again at a distinctly higher
field (∆δ = 6.6–8.2 ppm). Most characteristic are the C(2)–
F coupling constants. They fall for both quinolinones 1 and
N-methylquinolinones 9 in the same narrow range of 26.4–
27.8 Hz whereas they shrink to 13.2–14.4 Hz in the case of
the O-methyl derivatives (see Table 2). Evidently com-
pounds 1 exist predominantly or exclusively in the lactam
form. The presence of minute proportions of the lactim (2-
hydroxyquinoline) tautomers competing with the predomi-
nant lactam forms in a dynamic equilibrium can neverthe-
less not be ruled out.
Figure 2. UV-absorption spectra of the 8-fluoro-substituted 2-
quinolinone 1b, 2-methoxyquinoline 8b and N-methyl-2-quino-
linone 9b (2ϫ10–4  concentrations in ethanol).
Ultraviolet Absorption Spectra
The UV spectra of the quinolinones 1 were once again
compared with those of the O- and N-methyl-substituted
congeners 8 and 9. The 2-methoxyquinolines 8 exhibit a
UV profile that unmistakably features a triplet of maxima
in the range of 300–320 nm followed by an abrupt drop to
zero (Figures 1, 2, and 3). In contrast, the UV curves of the
quinolinones 1 and their N-methyl derivatives level off only
Figure 3. UV-absorption spectra of the 8-tert-butyl-substituted 2-
quinolinone 1h, 2-methoxyquinoline 8h and N-methyl-2-quino-
linone 9h (2ϫ10–4  concentrations in ethanol).
at or beyond 350 nm. The spectra of the 8-unsubstituted or
8-fluorinated compound pairs 1a/9a and 1b/9b are virtually
identical (Figures 1 and 2). In contrast, N-methylation of
the 8-tert-butyl-substituted quinolinone 1h, affording deriv-
ative 9h, brings about a red shift of the long-wave absorp-
tion band (Figure 3). This spectral change has to be attrib-
uted to a structural distortion caused by the severe steric
repulsion between the tert-butyl and N-methyl groups.
Infrared Absorption Spectroscopy
In principle, infrared (IR) spectra should offer the most
unambiguous tool to differentiate between lactam and lac-
tim tautomers. The stretching frequencies of phenolic hy-
droxy groups typically can be found in the range of 3600–
3590 cm–1 and those of secondary amides or vinylogous an-
alogs thereof in the range of 3450–3390 cm–1.[38,40,72] How-
Figure 1. UV-absorption spectra of 3-fluoroquinolinone 1a, 3-
fluoro-2-methoxyquinoline (8a) and 3-fluoro-1-methyl-2-quino-
linone (9a) (2ϫ10–4  concentrations in ethanol).
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Tautomerism of 2-Quinolinones
ever, the majority of our compounds were found to exist as
Viewed against this background there was little reason to
hydrogen-bonded dimers as revealed by a broad and struc- expect the yet unknown 3-fluoro-2(1H)-pyridinone or re-
tured band in the region between 3200 and 2400 cm–1 (Fig- gioisomers thereof (e.g., the 6-fluoro analog[75]) not to favor
ure 4). In contrast, 8-tert-butyl-3-fluoro-2(1H)-quinolinone the lactam form. As the driving force for switching into the
(Figure 5) and other quinolinones carrying a bulky substit- aromatic hydroxyimine structures is in the quinoline series
uent at the 8-position, are monomeric and hence give rise even smaller than in the pyridine series,[17,76–78] we did not
to slim NH frequencies in the range of 3430 to 3350 cm–1 really believe 3-fluoro-2(1H)-quinolinones, assisted or not
typical for an ordinary secondary carboxamide.
by a bulky 8-substituent, to populate the lactim tautomer to
a significant extent. This sceptical expectation having been
confirmed by the present investigation, we are happy to fol-
low Katritzky’s advice to “call a spade a spade”[79] and to
call a 3-fluoro-substituted 2(1H)-quinolinone also in the fu-
ture a quinolinone.
Experimental Section
General: Working practices and abbreviations have been specified
in previous articles from this laboratory.[80–83] Elementary analyses
were performed by the laboratories of I. Beetz (96301 Kronach,
Germany) or Solvias (4002 Basel, Switzerland). The expected per-
centages were calculated using the atomic weight numbers listed in
the 1999 IUPAC recommendations.
Figure 4. Infrared spectrum of solid 3,8-difluoro-2(1H)-quin-
olinone, a dimer.
1H, 13C and 19F NMR spectra were recorded at 400, 101 and
376 MHz, respectively, relative to the internal standards (δ =
0.00 ppm) tetramethylsilane and trichlorofluoromethane. The sam-
ples were dissolved in CDCl3 or, if marked by an asterisk, in [D6]-
DMSO. UV spectra were recorded using a Varian Carry 50 spectro-
photometer. A Perkin–Elmer 1420 was used to register the infrared
spectra of 3-fluoro-2(1H)-quinolinone powders incorporated in po-
tassium bromide pellets.
The pKa values of 2(1H)-quinolinone, of the 3-fluoro-2(1H)-quino-
linones 1a–1h and the 1h-precursor 10 have been determined by
potentiometric titration[84] using a GlpKa instrument.[85] The 0.5–
5.0 m aqueous solutions of the samples contained also a 0.10 
concentration of potassium nitrate as an ionic strength adjuster.
The solutions were acidified to pH 1.8 by adding 0.5  hydrochloric
acid before being titrated with 0.5  aqueous potassium hydroxide
at 22 °C to pH 12.2. Typically, more than 25 readings were col-
lected for each run. Furthermore, spectrophotometrically moni-
tored titrations[86] were performed using a D-PAS module[85] in
conjunction with the GlpKa instrument providing a series of pH-
variable spectra in the pH range from 12 to 2. The pKa values were
calculated by means of the target factor analysis method[87] using
the absorption data of 15–20 wavelength channels.
Figure 5. Infrared spectrum of solid 8-tert-butyl-3-fluoro-2(1H)-
quinolinone, a monomer.
1. 3-Fluoro-2(1H)-quinolinones
Discussion and Conclusion
The preparation of 3-fluoro-2(1H)-quinolinone[61] (1a), 3,8-di-
fluoro-2(1H)-quinolinone[62] (1b) and 3-fluoro-8-methyl-2(1H)-
quinolinone[62] (1e) has already been reported. The other com-
pounds were made accordingly.[61–63]
On the basis of pKa, UV, IR and NMR evidence, the
structure of 2,3,5,6-tetrafluoro-4-hydroxypyridine rather
than that of 2,3,5,6-tetrafluoro-4-(1H)-pyridinone was as-
signed to the product formed by the reaction of penta-
fluoropyridine with sodium hydroxide.[73] Whereas 2(1H)-
and 4(1H)-pyridinone and even 3,5-dichloro-4(1H)-pyrid-
inone[74] exist mainly, if not exclusively, in the lactam form,
6-chloro-2(1H)- and 2-chloro-4(1H)-pyridinone contain ap-
preciable proportions of the hydroxy tautomer if dissolved
in moderately polar media (ethanol as opposed to water).[74]
The hydroxy forms of 2,6-dichloro- and 2,3,5,6-tetrachloro-
4-(1H)-pyridinone and 3,4,5,6-tetrachloro-2(1H)-pyrid-
inone prevail whatever the solvent.[74]
General Procedure:[61–63] Butyllithium (40 mmol) in hexanes
(25 mL) and methyl 2-fluoro-3-methoxy-2-propenoate[61] (2.7 g,
20 mmol) were consecutively added to a solution of the aniline
(40 mmol) in tetrahydrofuran (50 mL), kept in an ice bath. After
2 h at 25 °C, the mixture was poured into 2.0  hydrochloric acid
(0.10 L). The organic layer was decanted and the aqueous one ex-
tracted with diethyl ether (3ϫ0.10 L). The combined organic
phases were washed with brine (2ϫ25 mL) and the solvents evapo-
rated. The residue was dissolved in 70% (approx. 12 ) aqueous
sulfuric acid (50 mL). After 5 h at 60 °C, the mixture was poured
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J.-N. Volle, U. Mävers, M. Schlosser
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into ice/water (0.5 L) and the precipitate collected by filtration. The
raw material was adsorbed on silica gel (15 mL) and eluted with a
3:7 (v/v) mixture of ethyl acetate and hexanes from a column filled
with more silica gel (0.15 L).
9 H) ppm. 19F NMR: δ = –132.8 (d, J = 10.0 Hz) ppm. C13H14FNO
(219.26): calcd. C 71.21, H 6.44; found C 70.88, H 6.72.
5,7-Di-tert-butyl-3-fluoro-2(1H)-quinolinone (5): From 3,5-di-tert-
butylaniline[88] (8.2 g, 40 mmol); colorless needles; m.p. 232–
233 °C; yield 2.8 g (51%). 1H NMR: δ = 8.18 (d, J = 13.0 Hz, 1
H), 7.36 (s, 1 H), 7.31 (d, J = 1.5 Hz), 1.54 (s, 9 H), 1.38 (s, 9 H)
ppm. 19F NMR: δ = –133.5 (d, J = 13.0 Hz) ppm. C17H22FNO
(275.36): calcd. C 74.15, H 8.05; found C 74.14, H 7.91.
3-Fluoro-2(1H)-quinolinone (1a):[61] 19F NMR: δ = –132.0 (d, J =
9.7 Hz) ppm. 13C NMR: δ = 158.0 (d, J = 26.4 Hz, 1 C), 150.8 (d,
J = 253 Hz, 1 C), 135.2 (s, 1 C), 129.8 (s, 1 C), 127.4 (d, J = 6.0 Hz,
1 C), 123.6 (s, 1 C), 120.3 (d, J = 16.4 Hz, 1 C), 118.8 (d, J =
7.9 Hz, 1 C), 116.2 (s, 1 C) ppm.
5,8-Di-tert-butyl-3-fluoro-2(1H)-quinolinone (6): From 2,5-di-tert-
butylaniline (8.2 g, 40 mmol); colorless needles; m.p. 198–199 °C;
3,8-Difluoro-2(1H)-quinolinone (1b):[62] 19F NMR: δ = –128.6 (dd,
J = 9.2, 2.3 Hz), –134.3 (m) ppm. 13C NMR: δ = 155.9 (d, J =
27.8 Hz, 1 C), 151.8 (d, J = 257 Hz, 1 C), 149.2 (d, J = 246 Hz, 1
C), 147.9 (s, 1 C), 124.1 (d, J = 13.2 Hz, 1 C), 123.3 (d, J = 6.6 Hz,
1 C), 123.0 (dd, J = 5.9, 3.7 Hz, 1 C), 120.4 (dd, J = 6.6, 2.9 Hz, 1
C), 119.3 (dd, J = 16.8, 2.9 Hz, 1 C), 114.7 (dd, J = 16.8, 2.9 Hz,
1 C) ppm.
1
yield 4.5 g (82%). H NMR: δ = 9.25 (s, broadened, 1 H), 8.23 (d,
J = 13.4 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz,
1 H), 1.55 (s, 9 H), 1.53 (s, 9 H) ppm. 19F NMR: δ = –132.7 (dd,
J = 13.2, 5.9 Hz) ppm. C17H22FNO (275.36): calcd. C 74.15, H
8.05; found C 74.13, H 8.02.
6,8-Di-tert-butyl-3-fluoro-2(1H)-quinolinone (7): From 2,4-di-tert-
butylaniline[88–89] (8.2 g, 40 mmol); colorless needles; m.p. 134–
8-Chloro-3-fluoro-2(1H)-quinolinone (1c): From 2-chloroaniline
(4.2 mL, 5.1 g, 40 mmol); colorless needles (from ethanol); m.p.
192–194 °C; yield 2.3 g (58%). 1H NMR: δ = 9.37 (s, broadened, 1
H), 7.56 (d, J = 7.8 Hz, 1 H), 7.48 (d, J = 9.4 Hz, 2 H), 7.22 (t, J
= 7.8 Hz, 1 H) ppm. 19F NMR: δ = –129.4 (d, J = 9.5 Hz) ppm.
C9H5ClFNO (197.60): calcd. C 54.71, H 2.55; found C 54.68, H
2.63.
1
135 °C; yield 3.9 g (71%). H NMR: δ = 9.13 (s, broad, 1 H), 7.57
(d, J = 1.9 Hz, 1 H), 7.48 (d, J = 10.2 Hz, 1 H), 7.37 (d, J = 2.1 Hz),
1.55 (s, 9 H), 1.36 (9 H) ppm. 19F NMR: δ = –133.5 (dd, J = 10.0,
5.5 Hz) ppm. C17H22FNO (275.36): calcd. C 74.15, H 8.05; found
C 74.12, H 8.04.
5-tert-Butyl-3-fluoro-2(1H)-quinolinone (3): Concentrated (98%)
sulfuric acid (10 mL) was added to 5,8-di-tert-butyl-3-fluoro-
2(1H)-quinolinone (6; 5.6 g, 20 mmol) in heptanes (0.20 L). After
having been heated for 24 h under reflux, the mixture was poured
on ice. The organic layer was decanted and the aqueous one was
extracted with ethyl acetate (3ϫ0.10 L). The combined organic
phases were dried and the solvents evaporated. The residue was
absorbed on silica gel (25 mL) and eluted with a 3:7 (v/v) mixture
of ethyl acetate and hexanes from a column filled with more silica
gel (0.25 L). The by-product 8-tert-butyl-3-fluoro-2(1H)-quinoli-
none (1h, see above; yield 0.50 g, 11%) had a considerably shorter
retention time than the main component, isomer 3; colorless need-
les; m.p. 219–221 °C; yield 3.6 g (82%). 1H NMR: δ = 8 26 (d, J =
13.2 Hz, 1 H), 7.46 (dd, J = 8.4, 1.0 Hz, 1 H), 7.43 (t, J = 7.9 Hz,
1 H), 7.31 (dd, J = 7.7, 1.0 Hz, 1 H), 1.54 (s, 9 H) ppm. 19F NMR:
δ = –132.1 (d, J = 13.0 Hz) ppm. C13H14FNO (219.26): calcd. C
71.21, H 6.44; found C 71.33, H 6.70.
8-Bromo-3-fluoro-2(1H)-quinolinone (1d): From 2-bromoaniline
(6.9 g, 40 mmol); colorless stars; m.p. 201–202 °C (from ethanol);
yield 2.9 g (59%). 1H NMR: δ = 9.35 (s, broadened, 1 H), 7.71 (dd,
J = 7.8, 1.1 Hz, 1 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.46 (d, J = 9.5 Hz,
1 H), 7.15 (t, J = 7.8 Hz, 1 H) ppm. 19F NMR: δ = –129.5 (d, J =
9.5 Hz) ppm. C9H5BrFNO (242.05): calcd. C 44.66, H 2.08; found
C 45.19, H 2.37.
8-Ethyl-3-fluoro-2(1H)-quinolinone (1f): From 2-ethylaniline
(5.0 mL, 4.9 g, 40 mmol); colorless needles; m.p. 149–151 °C; yield
1
2.8 g (73%). H NMR: δ = 10.05 (s, broadened, 1 H), 7.49 (d, J =
10.0 Hz, 1 H), 7.49 (d, J = 9.8 Hz, 1 H), 7.40 (d, J = 7.7 Hz, 1 H),
7.36 (d, J = 7.9 Hz, 1 H), 7.20 (t, J = 7.7 Hz, 1 H), 2.90 (q, J =
7.5 Hz, 2 H), 1.35 (t, J = 7.5 Hz, 3 H) ppm. 19F NMR: δ = –132.9
(dd, J = 10.0, 4.5 Hz) ppm. C11H10FNO (191.20): calcd. C 69.10,
H 5.27; found C 69.23, H 5.29.
3-Fluoro-8-isopropyl-2(1H)-quinolinone (1g): From 2-isopropylani-
line (5.6 mL, 5.4 g, 40 mmol); colorless needles; m.p. 156–158 °C;
yield 2.9 g (71%). H NMR: δ = 9.89 (s, broadened, 1 H), 7.49 (d,
J = 9.9 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1
H), 7.26 (t, J = 7.8 Hz, 1 H), 3.33 (sept, J = 6.8 Hz, 1 H), 1.36 (d,
J = 6.8 Hz, 6 H) ppm. 19F NMR: δ = –133.1 (dd, J = 10.0, 5.0 Hz)
ppm. C12H12FNO (205.23): calcd. C 70.23, H 5.89; found C 70.16,
H 5.75.
7-tert-Butyl-3-fluoro-2(1H)-quinolinone (4): 5,7-Di-tert-butyl-3-
fluoro-2(1H)-quinolinone (5; 2.2 g, 8.0 mmol) were stirred in con-
centrated (98%) sulfuric acid (40 mL) for 5 h at 60 °C. When the
mixture was worked up as described in the preceding paragraph,
most of the starting material (1.7 g, 77%) was recovered and a
small amount of compound 4 was obtained; colorless needles; m.p.
1
1
199–201 °C; yield 0.24 g (14%). H NMR: δ = 7.50 (d, J = 9.6 Hz,
1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.40 (s, broad, 1 H), 7.34 (ddd, J
= 8.2, 1.8, 0.6 Hz, 1 H), 1.38 (s, 9 H) ppm. 19F NMR: δ = –133.3
(d, J = 10.0 Hz) ppm. C13H14FNO (219.26): calcd. C 71.21, H 6.44;
found C 71.16, H 6.68.
8-tert-Butyl-3-fluoro-2(1H)-quinolinone (1h): From 2-tert-butylani-
line (6.2 mL, 6.0 g, 40 mmol); colorless platelets; m.p. 136–138 °C;
1
yield 2.9 g (66%). H NMR: δ = 9.17 (s, broadened, 1 H), 7.52 (d,
J ≈ 8 Hz, 1 H), 7.49 (d, J = 10.1 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1
H), 7.21 (t, J = 7.7 Hz, 1 H), 1.54 (s, 9 H) ppm. 19F NMR: δ =
–132.9 (dd, J = 10.0, 5.5 Hz) ppm. 13C NMR: δ = 155.6 (d, J =
27.8 Hz, 1 C), 150.0 (d, J = 253 Hz, 1 C), 134.3 (d, J = 1.5 Hz, 1
C), 133.2 (d, J = 1.5 Hz, 1 C), 127.3 (d, J = 2.2 Hz, 1 C), 126.7 (d,
J = 5.9 Hz, 1 C), 123.1 (s, 1 C), 120.9 (d, J = 16.1 Hz, 1 C), 119.7
(d, J = 6.6 Hz, 1 C), 34.1 (s, 1 C), 30.4 (s, 3 C) ppm. C13H14FNO
(219.26): calcd. C 71.21, H 6.44; found C 71.09, H 6.66.
2. O-Methyl and N-Methyl 3-fluoro-2(1H)-quinolinones
3-Fluoro-2-methoxyquinoline (8a) and 3-Fluoro-1-methyl-2(1H)-quin-
olinone (9a): Under vigorous stirring, potassium hydride (0.80 g,
20 mmol) and, 30 min later, dimethyl sulfate (1.9 mL, 2.5 g,
20 mmol) were added to 3-fluoro-2(1H)-quinolinone (1a) in di-
methylformamide (40 mL). After having been left for 1 h at 25 °C,
the mixture was evaporated to dryness and the residue absorbed
on silica gel (25 mL). Products 8a and 9a were successively eluted
from a column filled with more silica gel (0.25 L) using a 1:9 (v/v)
mixture of ethyl acetate and hexanes. Quinoline 8a: Colorless
6-tert-Butyl-3-fluoro-2(1H)-quinolinone (2): From 4-tert-butylani-
line (6.3 mL, 6.0 g, 40 mmol); colorless needles; m.p. 216–218 °C;
yield 2.4 g (55%). 1H NMR: δ = 7.6 (m, 2 H), 7.5 (m, 2 H), 1.37 (s,
1
prisms; m.p. 47–48 °C; yield 0.29 g (8%). H NMR: δ = 7.85 (d, J
2436
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2430–2438

Tautomerism of 2-Quinolinones
= 8.3 Hz, l H), 7.67 (d, J = 8.1 Hz, 1 H), 7.64 (d, J = 10.3 Hz, 1
H), 7.59 (t, J = 7.5 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 1 H), 4.16 (s, 3
8.3 Hz, 1 H), 7.28 (t, J = 8.3 Hz, 1 H), 7.17 (t, J = 7.7 Hz, 1 H),
6.95 (d, J = 7.7 Hz, 1 H), 6.88 (d, J = 17.9 Hz, 1 H), 3.75 (s, 3 H),
H) ppm. 19F NMR: δ = –138.6 (d, J = 10.4 Hz). 13C NMR: δ = 3.20 (s, 3 H), 1.38 (s, 9 H) ppm. 19F NMR: δ = –147.3 (d, J =
153.1 (d, J = 13.8 Hz, 1 C), 147.7 (d, J = 263 Hz, 1 C), 142.7 (s, 1 17.9 Hz) ppm. C15H20FNO2 (265.33): calcd. C 67.90, H 7.60; found
C), 128.5 (s, 1 C), 127.0 (s, 1 C), 126.9 (d, J = 4.8 Hz, 1 C), 125.4 C 67.64, H 7.86]. The viscous liquid (6.6 g, 25 mmol) was heated
(d, J = 3.5 Hz, 1 C), 124.9 (s, 1 C), 119.3 (d, J = 14.8 Hz, 1 C),
53.9 (s, 1 C) ppm. C10H8FNO (177.18): calcd. C 67.79, H 4.55;
found C 67.85, H 4.66. Quinolinone 9a: Colorless needles; m.p. 111–
with 70% (approx. 12 ) aqueous sulfuric acid (50 mL) for 5 h to
60 °C. The mixture was poured into ice/water, neutralized with so-
lid sodium hydrogen carbonate and extracted with ethyl acetate
112 °C; yield 2.2 g (62%). 1H NMR: δ = 7.58 (ddd, J ≈ 8.5, 1.6, (3ϫ0.25 L). The combined organic layers were dried and the sol-
0.6 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.42 (d, J = 9.1 Hz, 1 H), vents evaporated. The residue was purified by chromatography on
7.39 (d, J = 8.3 Hz, 1 H), 7.29 (t, J = 7.7 Hz, 1 H), 3.79 (s, 3 H)
silica gel (0.25 L) using a 1:9 (v/v) mixture of ethyl acetate and
hexanes as the eluent; colorless needles; m.p. 126–127 °C (after sub-
ppm. 19F NMR: δ = –128.9 (d, J = 9.0 Hz) ppm. 13C NMR: δ =
156.4 (d, J = 26.4 Hz, 1 C), 150.6 (d, J = 252 Hz, 1 C), 137.0 (s, 1 limation); yield 2.6 g (37%; 45% with respect to the amide interme-
C), 129.7 (d, J = 2.9 Hz, 1 C), 128.4 (d, J = 5.9 Hz, 1 C), 123.1 (s,
1 C), 118.8 (d, J = 8.1 Hz, 1 C), 118.0 (d, J = 16.8 Hz, 1 C), 114.3
(d, J = 1.5 Hz, 1 C), 29.9 (s, 1 C) ppm. C10H8FNO (177.18): calcd.
C 67.79, H 4.55; found C 67.85, H 4.63.
diate). 1H NMR: δ = 7.67 (dm, J = 7.5 Hz, 1 H), 7.3 (m, 2 H),
7.19 (t, J = 7.5 Hz, 1 H), 3.72 (s, 3 H), 1.50 (s, 9 H) ppm. 19F
NMR: δ = –132.2 (d, J = 8.8 Hz) ppm. 13C NMR: δ = 159.6 (d, J
= 26.4 Hz, 1 C), 149.7 (d, J = 255 Hz, 1 C), 139.8 (s, 1 C), 139.2
(s, 1 C), 131.5 (d, J = 2.9 Hz, 1 C), 125.8 (d, J = 5.9 Hz, 1 C),
123.1 (s, 1 C), 121.9 (d, J = 5.9 Hz, 1 C), 118.9 (d, J = 16.8 Hz, 1
C), 43.8 (d, J = 1.5 Hz, 1 C), 36.9 (s, 1 C), 32.6 (s, 3 C) ppm.
C14H16FNO (233.28): calcd. C 72.08, H 6.91; found C 72.20, H
6.91.
3,8-Difluoro-2-methoxyquinoline (8b) and 3,8-Difluoro-l-methyl-
2(1H)-quinolinone (9b): An analogous reaction with 3,8-difluoro-
2(1H)-quinolinone (1b; 4.0 g, 20 mmol) also afforded a mixture of
regioisomers which were separated again by chromatography. Quin-
oline 8b: Colorless prisms; m.p. 89–91 °C; yield 0.60 g (15%). 1H
NMR: δ = 7.67 (dd, J = 10.3, 1.7 Hz, 1 H), 7.47 (dd, J ≈ 8.5,
2.0 Hz, 1 H), 7.3 (m, 2 H), 4.21 (s, 3 H) ppm. 19F NMR: –126.5
(m), –136.8 (dd, J = 10.3, 3.4 Hz). 13C NMR: δ = 156.8 (d, J =
255 Hz, 1 C), 153.3 (d, J = 14.4 Hz, 1 C), 147.7 (d, J = 264 Hz, 1
C), 132.4 (dd, J = 11.9, 3.1 Hz, 1 C), 127.4 (dd, J = 4.1, 2.2 Hz, 1
C), 124.9 (d, J = 8.2 Hz, 1 C), 122.4 (t, J = 4.7 Hz, 1 C), 119.2 (dd,
J = 15.1, 2.5 Hz, 1 C), 113.3 (dd, J = 19.5, 2.5 Hz, 1 C), 54.2 (s, 1
C) ppm. C10H7F2NO (195.17): calcd. C 61.54, H 3.61; found C
61.76, H 4.05. Quinolinone 9b: Colorless needles; m.p. 144–145 °C;
Acknowledgments
This work was supported by the Schweizerische Nationalfonds zur
Förderung der wissenschaftlichen Forschung, Bern (grants 20-
49Ј307-96, 20-55Ј303-98 and 20-100Ј336-00). The authors are
obliged to Mr. Björn Wagner, Dr. Manfred Kansy and Prof. Klaus
Müller, all from Hoffmann-La Roche (Basel, Switzerland) for the
reported pKa measurements.
1
yield 3.0 g (77%). H NMR: δ = 7.38 (dd, J = 8.7, 1.2 Hz, 1 H),
7.15–7.35 (m, 3 H), 3.84 (d, J = 8.4 Hz, 3 H) ppm. 19F NMR: δ =
–121.6 (m), –127.0 (dd, J = 8.6, 2.4 Hz) ppm. 13C NMR: δ = 156.6
(d, J = 26.4 Hz, 1 C), 150.7 (d, J = 254 Hz, 1 C), 150.1 (d, J =
247 Hz, 1 C), 126.1 (d, J = 7.5 Hz, 1 C), 124.3 (dd, J = 6.3, 3.8 Hz,
1 C), 123.4 (d, J = 8.8 Hz, 1 C), 121.3 (dd, J = 7.5, 3.1 Hz, 1 C),
117.7 (dd, J = 17.6, 3.1 Hz, 1 C), 117.0 (dd, J = 23.9, 3.1 Hz, 1 C),
33.6 (dd, J = 15.7, 1.3 Hz, 1 C) ppm. C10H7F2NO (195.17): calcd.
C 61.54, H 3.61; found C 61.73, H 3.92.
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145.9 (s, 1 C), 141.1 (d, J = 3.7 Hz, 1 C), 126.9 (d, J = 2.9 Hz, 1
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8-tert-Butyl-3-fluoro-1-methyl-2(1H)-quinolinone (9h): At 0 °C, po-
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3-methoxyacryloyl chloride[63] (4.1 g, 30 mmol) was added to a vig-
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Eur. J. Org. Chem. 2008, 2430–2438
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2437

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