Metalation/functionalization sequences applied to 2-bromo-3- fluoroquinolines

Article abstract of DOI:10.1016/j.tet.2004.10.053

Mono- and disubstituted 2-bromo-3-fluoroquinolines 3 are readily accessible. They can be converted into the 3-fluoroquinoline-2-carboxylic acids 5 by consecutive halogen/metal permutation and into the 2-bromo-3- fluoroquinoline-4-carboxylic acids 6 by con

Full text of DOI:10.1016/j.tet.2004.10.053

Tetrahedron 61 (2005) 717–725
Metalation/functionalization sequences applied to
2-bromo-3-fluoroquinolines
a
a,b
Levente Ondi, Jean-Noel Volle and Manfred Schlossera,b,
*
¨
a
´ ´
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale, BCh, CH-1015 Lausanne, Switzerland
b
´
´
Faculte des Sciences, Universite, BCh, CH-1015 Lausanne, Switzerland
Received 5 July 2004; revised 13 October 2004; accepted 14 October 2004
Available online 25 November 2004
Abstract—Mono- and disubstituted 2-bromo-3-fluoroquinolines 3 are readily accessible. They can be converted into the 3-fluoroquinoline-
2-carboxylic acids 5 by consecutive halogen/metal permutation and into the 2-bromo-3-fluoroquinoline-4-carboxylic acids 6 by consecutive
deprotonation and carboxylation. The latter compounds can be reduced to afford the 3-fluoroquinoline-4-carboxylic acids 7. The yields are
excellent throughout. Rather than to introduce one functional group alternatively at the 2- or 4-position, one may also attach two different
functional groups sequentially to both sites.
q 2004 Published by Elsevier Ltd.
1. Introduction
Unlike chlorine, bromine atoms can be displaced against
lithium in butyllithium-mediated halogen/metal permu-
tation processes, which can be performed in tetrahydro-
furan, diethyl ether or, often more cleanly, in toluene. The
organometallic intermediates thus generated may be trapped
with any electrophile. Reaction with dry ice afforded the 3-
fluoroquinoline-2-carboxylic acids 5 in an average yield of
75%. To accomplish a site-selective displacement of the
nitrogen-adjacent bromine atom at the 2-position of the
dibromo compound 3e, the interconversion reaction had to
be conducted in toluene at K100 8C as at K75 8C a 9:1
mixture of 2- and 8-lithiated intermediates was produced.
When lithium diisopropylamide was employed as the base
instead, deprotonation occurred at the vacant 4-position and
subsequent carboxylation afforded the 2-bromo-3-fluoro-
quinoline-4-carboxylic acids 6 in 84% average yield.
Pyridine being, particularly at the 4-position, far more
acidic than benzene, the 3,7-difluorinated substrate 3c
underwent deprotonation and subsequent functionalization
selectively in the heterocyclic part. Reductive removal of
the heavy halogen from the acids 6 (by either catalytic
hydrogenation or with tin dichloride4) gave the 3-fluor-
oquinoline-4-carboxylic acids 7, yields averaging 79% this
time. The same compounds 7 are accessible by an
operational inversion of the carboxylation and reduction
steps. Debromination of the 2-bromo-3-fluoroquinolines 3
leads to the 3-fluoroquinolines 4 which, as demonstrated
previously,1 can be deprotonated effectively with lithium
diisopropylamide in the presence of potassium tert-butoxide
(‘Mordini mixture’) in order to be carboxylated sub-
sequently (Scheme 2).
2-Fluoro-3-methoxy-2-propenoic acid, generally employed
as its methyl ester1,2 or acyl chloride,3 is an extremely
versatile building block for the construction of a variety of
heterocyclic compounds.3 The condensation with anilines
provides 2-fluoro-3-methoxy-prop-2-enanilides and, after
acid catalyzed cyclization, 3-fluoroquinolin-2(1H)-ones.
The latter react with phosphoric trichloride (phosphorus
oxychloride) to give 2-chloro-3-fluoro-quinolines which can
be reduced to the 3-fluoroquinolines.1
2. Results
We wish now to report on an extension of these earlier
studies. As key intermediates serve 2-bromo-3-fluoroquino-
lines 3 which were readily obtained by the treatment of 3-
fluoroquinolin-2(1H)-ones 2 with phosphoric tribromide.
The immediate precursors to the fluoroquinolinones 2 were
the open-chain anilides 1 which in turn were made from the
ultimate starting materials, aniline itself and four mono-
substituted and one disubstituted congeners (Scheme 1).
Keywords: Bromine replacement by hydrogen; Carboxylation; Formyl-
ation; 3-Fluoroquinoline-2- and -4-carboxylic acids; Halogen/metal
permutation (‘halogen exchange’) reactions; Hydrogen/metal permutation
(‘metalation’) reactions.
* Corresponding author. Address: Institute of Chemical Sciences and
´ ´
Engineering, Ecole Polytechnique Federale, BCh, CH-1015 Lausanne,
Switzerland. Fax: C41 21 692 39 65; e-mail: manfred.schlosser@epfl.ch
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.10.053

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L. Ondi et al. / Tetrahedron 61 (2005) 717–725
Scheme 1.
Carboxy groups or another functionality may not only be
introduced alternatively into either the 2- or the 4-position
of 2-bromo-3-fluoroquinolines 3 but also sequentially in
both sites. Two series of reactions have been performed to
illustrate this possibility.
bromo-3-fluoroquinoline (3a) and thus the formyl entity was
introduced as the first functional group, the aldehyde 9a
(98%) had to be protected by acetalization with ethylene
glycol, thus producing the 1,3-dioxole 9b (97%). Ensuing
halogen/metal permutation, carboxylation and acetal
hydrolysis gave the formylcarboxylic acid 10b (74%)
(Scheme 4).
2-Bromo-3-fluoro-5,7-dimethylquinoline 3f was converted
into the quinoline-4-carboxylic acid 6f, as described above,
before being subjected to a halogen/metal permutation with
lithium tributylmagnesate5 followed by trapping with
dimethylformamide. The formylacid 8a thus formed was
isolated as the crystalline thiosemicarbazone 8b (78%)
(Scheme 3).
3. Conclusions
The present investigation features methods designed to
install flexibility into the derivatization and, in particular,
functionalization of quinolines. This class of compounds
represents a key segment of heterocyclic chemistry. As
When dimethylformamide was added to the 4-lithiated 2-
Scheme 2.

L. Ondi et al. / Tetrahedron 61 (2005) 717–725
719
Scheme 3.
demonstrated, the elaborated procedures tolerate the presence
of a great variety of substituents located in the benzo ring.
We have previously investigated the functionalization of
4-bromo-2-(trifluoromethyl)quinolines6,7 and 2-bromo-4-
(trifluoromethyl)quinolines.8,9 They differ in two respects
from the present substrates. On one hand they contain a
doubly acidified 3-position and on the other hand, the
trifluoromethyl entity provides relatively little neighbor-
ing group assistance to the deprotonation of ortho
positions but has a long-ranging effect whereas the
fluorine atom is an excellent ortho-metalation-promoting
substituent the activating effect of which, however,
rapidly levels off with distance.10
Notwithstanding such general statements, it deems appro-
priate to examine in detail to what extent this work is novel
and significant. Neither bromofluoroquinolines, readily
accessible on our route, nor organometallic derivatives
thereof have ever been reported. These compounds offer a
manifold of possibilities for further elaboration. Whereas
3-fluoroquinoline itself and its 2-butoxy congener require
mixed-metal reagents to undergo metalation efficaciously,1
lithium diisopropylamide suffices to deprotonate 2-bromo-
3-fluoroquinolines cleanly at the 4-position. The menacing
nucleophilic bromide/amide displacement can be perfectly
controlled and avoided. The lithiated species resulting from
4-deprotonation can be trapped by standard electrophilic
reagents such as carbon dioxide. Alternatively, 2-lithio
species may be generated by permutational halogen/metal
interconversion and subsequently be intercepted again with
dry ice or another electrophile.
The preparation and subsequent transformations of 2-
bromo-3-fluoroquinolines 3 deserves attention even if the
outcome might have been anticipated on the basis of
earlier work. The metal was cleanly introduced in the 4-
position when lithium dialkylamide-type bases were
employed. Remarkably, these deprotonations were not
accompanied by any bromine migration.11,12 In compari-
son with chlorine, trifluoromethyl and alkoxy, bromine
disposes of additional reaction modes. It can be easily and
selectively replaced by hydrogen through metal-mediated
reduction or catalytic hydrogenation;12 it can participate
in permutational halogen/metal interconversions to leave
its place to lithium; and it can undergo carbon–carbon
linking Suzuki couplings.13–16
So far without precedent is the combination of both
processes, the metalation followed by functionalization
and the halogen/metal permutation followed by another
functionalization. The feasibility of such a sequence has
been demonstrated in two model cases.
Scheme 4.

720
L. Ondi et al. / Tetrahedron 61 (2005) 717–725
4. Experimental
119.8 (d, JZ8 Hz), 119.3 (dd, JZ18, 4 Hz), 108.0 (s) ppm.
MS: m/z (%)Z242 (32) [MCC1], 241 (100) [MC], 215
(15), 134 (21), 107 (28), 81 (21). Anal. Calcd for
C9H5BrFNO (242.05): C, 44.66; H, 2.08. Found: C, 44.66;
H, 2.03.
4.1. General
Details concerning standard operations and abbreviations
have been given in previous publications from this
laboratory.17,18 1H and (1H-decoupled) 13C NMR spectra
were recorded at 400 and 101 MHz, respectively. If not
specified otherwise the samples were dissolved in deuterio-
chloroform or, if marked by an asterisk, in dimethylsulf-
oxide-d6. Mass spectra were obtained at 70 eV ionization
potential while a source temperature of 200 8C was
maintained. Whenever no molecular peak was observed
under such conditions, chemical ionization (‘c.i.’) in an
ammonia atmosphere at 100 8C source temperature was
applied. To avoid redundancy, in all cases only the [35Cl]
and [79Br] fragments and not the [37Cl] and [81Br]
isotopomers are listed.
4.1.3. 3-Fluoro-5,7-dimethyquinol-2(1H)-one (2f). Pre-
pared analogously from 3,5-dimethylaniline (0.14 L,
0.14 kg, 1.2 mol) using 32% hydrochloric acid at 50 8C
for 5 h; colorless platelets (from N,N-dimethylformamide);
1
mp 278–280 8C (reprod.); yield: 81.8 g (72%). H NMR:
dZ7.70 (d, JZ10.9 Hz, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 2.50
(s, 3H), 2.42 (s, 3H) ppm. 13C NMR*: dZ155.4 (d, JZ
27 Hz), 149.8 (d, JZ249 Hz), 139.0 (s), 136.3 (s), 134.9 (d,
JZ6 Hz), 125.1 (s), 116.5 (d, JZ17 Hz), 114.5 (d, JZ
6 Hz), 113.0 (s), 21.1 (s), 18.3 (s) ppm. MS: m/z (%)Z208
(19%), 192 (24) [MCC1], 191 (100) [MC], 190 (27), 175
(7). Anal. Calcd for C11H10FNO (191.20): C, 69.10; H, 5.27.
Found: C, 68.88; H, 5.10.
The anilides 1a, 1c and 1d have been isolated and
characterized previously.2 In the present work, all anilides
were collected as crude products and cyclized by heating in
70% sulfuric acid without prior purification. The prepar-
ation of the quinolinones 2a,1 2c,2 and 2d2 has already been
reported.
4.1.4. 2-Bromo-3-fluoroquinoline (3a). 3-Fluoroquinol-
2(1H)-one (2a; 33 g, 0.20 mol) and phosphoric tribromide
(0.12 kg, 0.40 mol) were heated together for 30 min to
150 8C before the mixture was poured on crushed ice
(0.50 kg), neutralized with a 5.0 M aqueous solution of
sodium hydroxide (0.30 L) and subjected to a steam
distillation; colorless needles (from hexanes); mp 82–
4.1.1. 6-Chloro-3-fluoroquinol-2(1H)-one (2b). Butyl-
lithium (0.50 mol) in hexanes (0.33 L) and methyl 2-
fluoro-3-methoxyprop-2-enoate1 (Z/Ew1:1; 27 mL, 34 g,
0.25 mol) were added consecutively to 4-chloroaniline
(45 mL, 47 g, 0.50 mol) in tetrahydrofuran (2.7 L) at 0 8C.
After 1 h at 25 8C, the mixture was poured into 2.0 M
hydrochloric acid (0.70 L). The two phases were separated
and the aqueous one extracted with diethyl ether
(3!0.25 L). The combined organic layers were washed
with a saturated aqueous solution (0.25 L) of sodium
hydrogen carbonate, brine (0.25 L) and dried with anhy-
drous sodium sulfate. After evaporation, a brownish-yellow
solid residue was left behind. It was heated in 96% sulfuric
acid (2.0 L) to 50 8C for 5 h. The mixture was poured on
crushed ice. The precipitate was collected by filtration and
washed with water (2!0.10 L); colorless needles (from
aqueous N,N-dimethylformamide); mp 306–308 8C
(reprod.); yield: 89.9 g (88%). 1H NMR: dZ11.29 (s,
broad, 1H), 7.75 (d, JZ2.4 Hz, 1H), 7.71 (d, JZ10.1 Hz,
1H), 7.52 (dd, JZ8.9, 2.4 Hz, 1H), 7.46 (d, JZ8.8 Hz,
1H) ppm. 13C NMR*: dZ155.4 (d, JZ27 Hz), 151.2 (d, JZ
253 Hz), 134.5 (s), 129.2 (s), 126.5 (d, JZ6 Hz), 126.4 (s),
119.4 (d, JZ8 Hz), 118.3 (d, JZ18 Hz), 117.0 (s) ppm.
MS: m/z (%)Z199 (41) [MCC2], 198 (44) [MCC1], 197
(100) [MC], 164 (14), 134 (11), 107 (10). Anal. Calcd for
C9H5ClFNO (197.60): C, 54.71; H, 2.55. Found: C, 54.51;
H, 2.61.
1
83 8C (reprod.); yield: 40.8 g (90%). H NMR: dZ8.07 (d,
JZ8.6 Hz, 1H), 7.80 (d, JZ8.1 Hz, 2H), 7.71 (t, JZ7.5 Hz,
1H), 7.61 (t, JZ7.3 Hz, 1H) ppm. 13C NMR: dZ151.9 (d,
JZ260 Hz), 145.3 (s), 132.1 (d, JZ26 Hz), 129.6 (s), 128.7
(s), 128.1 (s), 127.1 (d, JZ5 Hz), 119.7 (d, JZ18 Hz) ppm.
19F NMR: dZK115.5 (d, JZ8.2 Hz) ppm. MS: m/z (%)Z
242 (30), 226 (62) [MCC1], 225 (100) [MC], 162 (42), 146
(14). Anal. Calcd for C9H5BrFN (226.04): C, 47.82; H, 2.23.
Found: C, 47.78; H, 2.26.
4.1.5. 2-Bromo-6-chloro-3-fluoroquinoline (3b). Prepared
analogously from 6-chloro-3-fluoroquinol-2(1H)-one (2b;
59 g, 0.30 mol). The reaction mixture was kept for 30 min at
190 8C; colorless needles (from ethanol); mp 139–141 8C
1
(reprod.); yield: 61.1 g (78%). H NMR: dZ7.97 (d, JZ
9.3 Hz, 1H), 7.76 (d, JZ2.3 Hz, 1H), 7.69 (d, JZ7.5 Hz,
1H), 7.62 (dd, JZ9.3, 2.3 Hz, 1H) ppm. 13C NMR: dZ
153.0 (d, JZ263 Hz), 143.5 (s), 134.2 (s), 132.4 (d, JZ
27 Hz), 130.6 (s), 130.1 (s), 128.8 (d, JZ4 Hz), 125.8 (d,
JZ5 Hz), 118.7 (d, JZ19 Hz) ppm. MS: m/z (%)Z260 (52)
[MCC1], 259 (100) [MC], 196 (11), 181 (5), 144 (9). Anal.
Calcd for C9H5BrClFNO (260.49): C, 41.50; H, 1.55.
Found: C, 41.50; H, 1.51.
4.1.6. 2-Bromo-3,7-difluoroquinoline (3c). Prepared ana-
logously as described for quinoline 3a from the 5:95
mixture of 3,5- and 3,7-difluoroquinol-2(1H)-one (2c; 47 g,
0.26 mol); colorless needles (from hexanes); mp 105–
107 8C (reprod.); yield: 47.6 g (75%). 1H NMR: dZ7.8
(m, 2H), 7.70 (dd, JZ8.5, 2.4 Hz, 1H), 7.42 (dt, JZ8.5,
2.4 Hz, 1H) ppm. 13C NMR: dZ162.4 (d, JZ252 Hz),
151.7 (d, JZ258 Hz), 145.4 (s), 133.3 (dd, JZ26, 7 Hz),
129.0 (dm, JZ164 Hz), 124.6 (s), 119.4 (ddd, JZ165, 20,
5 Hz), 118.4 (ddd, JZ165, 26, 5 Hz), 112.4 (dd, JZ165,
22 Hz) ppm. 19F NMR: dZK116.3 (t, JZ7.6 Hz), K109.5
(quint, JZ7.6 Hz) ppm. MS: m/z (%)Z244 (62) [MCC1],
4.1.2. 8-Bromo-3-fluoroquinol-2(1H)-one (2e). Prepared
analogously from 2-bromoaniline (0.10 kg, 0.60 mol) with
96% aqueous sulfuric acid at 50 8C for 5 h; tiny colorless
needles (from aqueous N,N-dimethylformamide); mp 202–
204 8C (reprod.); yield: 71.4 g (64%). 1H NMR: dZ9.30 (s,
broad, 1H), 7.71 (d, JZ8.0 Hz, 1H), 7.51 (dd, JZ8.0,
1.3 Hz, 1H), 7.46 (d, JZ9.0 Hz, 1H), 7.16 (t, JZ8.0 Hz,
1H) ppm. 13C NMR*: dZ155.7 (d, JZ27 Hz), 150.7 (d, JZ
252 Hz), 133.4 (s), 133.0 (s), 127.7 (d, JZ6 Hz), 123.8 (s),

L. Ondi et al. / Tetrahedron 61 (2005) 717–725
721
243 (100) [MC], 242 (45), 180 (7), 163 (8). Anal. Calcd for
C9H4BrF2N (244.04): C, 44.30; H, 1.65. Found: C, 44.32; H,
1.82.
under an atmosphere of hydrogen (1 atm) at 25 8C. After
2 h, the required amount of hydrogen had been taken up.
Distillation afforded a colorless oil; bp 47–48 8C/
1
1.9 mmHg; mp 4–5 8C (reprod.); yield: 4.34 g (87%). H
NMR: dZ8.82 (d, JZ2.6 Hz, 1H), 8.13 (d, JZ8.3 Hz, 1H),
7.79 (d, JZ8.6 Hz, 1H), 7.76 (dd, JZ9.0, 2.9 Hz, 1H), 7.68
(t, JZ8.0 Hz, 1H), 7.57 (t, JZ8.0 Hz, 1H) ppm. 13C NMR:
dZ156.2 (d, JZ256 Hz), 145.4 (s), 141.5 (d, JZ27 Hz),
129.5 (s), 128.5 (s), 127.6 (s), 127.2 (s), 118.2 (d, JZ
16 Hz) ppm. MS: m/z (%)Z148 (19) [MCC1], 147 (100)
[MC], 120 (9).
4.1.7. 2-Bromo-3-fluoro-7-methoxyquinoline (3d). The
1:4 mixture of 3-fluoro-5- and 3-fluoro-7-methoxyquinol-
2(1H)-one (2d; 28 g, 0.15 mol) was heated together with
phosphoric tribromide (84 g, 0.29 mol) in anhydrous
propionitrile (0.30 L) under reflux for 4 h. After evaporation
of the solvent, the residue was poured on ice (0.30 kg). A
5.0 M aqueous solution (0.20 L) of sodium hydroxide was
added. The precipitate was collected by filtration and
washed with water (4!50 mL). The crude product was
dissolved in ethyl acetate, filtered through a pad of silica gel
and crystallized from a mixture of ethyl acetate and
hexanes; colorless needles; mp 136–138 8C (reprod.);
yield: 24.5 g (62%). 1H NMR: dZ7.73 (d, JZ7.7 Hz,
1H), 7.66 (d, JZ9.1 Hz, 1H), 7.38 (d, JZ2.5 Hz, 1H), 7.25
(dd, JZ9.1, 2.5 Hz, 1H), 3.93 (s, 3H) ppm. 13C NMR: dZ
160.8 (s), 151.4 (d, JZ256 Hz), 146.3 (s), 131.9 (d, JZ
26 Hz), 127.9 (d, JZ4 Hz), 122.9 (d, JZ3 Hz), 121.4 (s),
119.9 (d, JZ19 Hz), 106.9 (s), 55.7 (s) ppm. MS: m/z (%)Z
256 (62) [MCC1], 255 (100) [MC], 254 (48), 211 (6), 175
(7), 132 (6). Anal. Calcd for C10H7BrFNO (256.07): C,
46.90; H, 2.76. Found: C, 46.90; H, 2.71.
4.1.11. 8-Bromo-3-fluoroquinoline (4e). A solution con-
taining 2,8-dibromo-3-fluoroquinoline (3e; 7.6 g, 25 mol)
and butyllithium (25 mmol) in toluene (0.10 L) and hexanes
(20 mL) was kept for 45 min at K100 8C, before being
treated with methanol (10 mL, 8.0 g, 0.25 mol). Afterwards
the solvents were stripped off and the residue was crystal-
lized; colorless needles (aqueous methanol); mp 67–68 8C
1
(reprod.); yield: 5.09 g (90%). H NMR: dZ8.94 (d, JZ
2.9 Hz, 1H), 8.04 (dd, JZ7.4, 1.3 Hz, 1H), 7.81 (dd, JZ8.3,
2.9 Hz, 1H), 7.78 (dd, JZ8.3, 1.3 Hz, 1H), 7.44 (t, JZ
8.0 Hz, 1H) ppm. 13C NMR: dZ156.7 (d, JZ259 Hz),
142.4 (s), 142.1 (s), 132.4 (s), 129.8 (d, JZ5 Hz), 128.2 (s),
127.3 (d, JZ4 Hz), 124.9 (s), 118.9 (d, JZ17 Hz) ppm.
MS: m/z (%)Z226 (22) [MCC1], 225 (49) [MC], 146
(100), 126 (35), 119 (30), 100 (20). Anal. Calcd for
C9H5BrFN (226.05): C, 47.82; H, 2.23. Found: C, 47.54; H,
2.07.
4.1.8. 2,8-Dibromo-3-fluoroquinoline (3e). Prepared ana-
logously as described for quinoline 3a from 8-bromo-3-
fluoroquinol-2(1H)-one (2e; 58 g, 0.24 mol); colorless
needles (from ethanol); mp 129–131 8C (reprod.); yield:
1
56.5 g (77%). H NMR: dZ7.99 (d, JZ7.5 Hz, 1H), 7.77
4.1.12. 3-Fluoroquinoline-2-carboxylic acid (5a). A
solution containing 2-bromo-3-fluoroquinoline (3a; 10 g,
45 mol) and butyllithium (45 mmol) in diethyl ether (0.20 L)
and hexanes (20 mL) was kept for 45 min at K75 8C before
being poured onto an excess of freshly crushed dry ice. After
addition of water (0.10 L), the reaction mixture was
extracted with diethyl ether (3!45 mL) and the aqueous
layer was acidified with 2.0 M aqueous solution of
hydrochloric acid (10 mL) to pH 1. The precipitate was
collected by filtration and washed with water (2!10 mL);
colorless needles (from aqueous N,N-dimethylformamide);
(d, JZ7.5 Hz, 1H), 7.74 (d, JZ8.4 Hz, 1H), 7.43 (t, JZ
7.5 Hz, 1H) ppm. 13C NMR: dZ153.0 (d, JZ263 Hz),
142.4 (s), 133 (m), 129.2 (d, JZ4 Hz), 128.5 (s), 126.9 (d,
JZ5 Hz), 123.6 (s), 119.9 (d, JZ19 Hz) ppm. MS: m/z
(%)Z304 (56) [MCC1], 303 (100) [MC], 224 (42), 145
(76), 118 (16). Anal. Calcd for C9H4Br2FN (304.94): C,
35.45; H, 1.32. Found: C, 35.64; H, 1.17.
4.1.9. 2-Bromo-3-fluoro-5,7-dimethylquinoline (3f). 3-
Fluoro-5,7-dimethylquinol-2(1H)-one (2f; 4.8 g, 25 mmol)
and phosphoric tribromide (14 g, 50 mmol) were heated in
anhydrous propionitrile (50 mL) under reflux for 2 h. After
evaporation of the volatiles, the residue was poured on ice
(50 g). A 2.0 M aqueous solution (84 mL) of sodium
hydroxide was added. The precipitate was collected by
filtration, and washed with water (4!10 mL). The crude
product was dissolved in ethyl acetate, filtered through a pad
of silica gel and recrystallized from ethanol; colorless
1
mp 129–130 8C (decomp.); yield: 6.19 g (72%). H NMR:
dZ8.17 (d, JZ8.6 Hz, 1H), 8.06 (d, JZ10.2 Hz, 1H), 7.91
(d, JZ8.3 Hz, 1H), 7.83 (td, JZ7.8, 1.4 Hz, 1H), 7.75 (t,
JZ7.5 Hz, 1H) ppm. 13C NMR: dZ161.0 (s), 155.9 (d, JZ
271 Hz), 143.0 (s), 136.0 (d, JZ11 Hz), 131.9 (d, JZ6 Hz),
130.5 (m), 129.6 (s), 127.4 (d, JZ4 Hz), 123.4 (d, JZ
18 Hz) ppm. MS: m/z (%)Z208 (31), 193 (10) [MCC2],
192 (45) [MCC1], 191 (100) [MC], 147 (78). Anal. Calcd
for C10H6FNO2 (191.16): C, 62.83; H, 3.16. Found: C,
63.18; H, 3.29.
1
needles; mp 126–128 8C (reprod.); yield: 5.21 g (82%). H
NMR: dZ7.86 (d, JZ8.3 Hz, 1H), 7.68 (s, 1H), 7.27 (s,
1H), 2.60 (s, 3H), 2.50 (s, 3H) ppm. 13C NMR: dZ151.7 (d,
JZ258 Hz), 145.8 (s), 139.6 (s), 133.7 (d, JZ5 Hz), 131.0
(d, JZ26 Hz), 130.7 (s), 125.7 (s), 125.5 (s), 116.5 (d, JZ
19 Hz), 21.7 (s), 18.6 (s) ppm. MS: m/z (%)Z254 (93)
[MCC1], 253 (100) [MC], 252 (18), 240 (22), 238 (27).
Anal. Calcd for C11H9BrFN (254.10): C, 51.99; H, 3.57.
Found: C, 52.16; H, 3.59.
4.1.13. 6-Chloro-3-fluoroquinoline-2-carboxylic acid
(5b). Prepared analogously from 2-bromo-6-chloro-3-
fluoroquinoline (3b; 6.5 g, 25 mmol) but, to improve the
yield, using toluene (0.11 L) rather than diethyl ether as the
solvent; colorless needles (from acetone) mp 147–149 8C
1
(decomp.); yield: 4.60 g (82%). H NMR: dZ8.11 (d, JZ
9.1 Hz, 1H), 7.97 (d, JZ10.2 Hz, 1H), 7.90 (d, JZ2.3 Hz,
1H), 7.75 (dd, JZ9.1, 2.3 Hz, 1H) ppm. 13C NMR
(D3CCOCD3): dZ163.4 (d, JZ6 Hz), 156.4 (d, JZ
267 Hz), 143.0 (s), 140.9 (d, JZ14 Hz), 135.8 (s), 132.3
(s), 132.1 (d, JZ6 Hz), 131.4 (s), 126.9 (d, JZ4 Hz), 121.8
4.1.10. 3-Fluoroquinoline1 (4a). Palladium (10% on
charcoal, 0.20 g) was added to a solution of 2-bromo-3-
fluoroquinoline (3a; 7.9 g, 35 mmol) and triethylamine
(9.8 mL, 7.1 g, 70 mmol) in methanol (60 mL), stirred

722
L. Ondi et al. / Tetrahedron 61 (2005) 717–725
(d, JZ19 Hz) ppm. MS: m/z (%)Z226 (24) [MCC1], 225
(7) [MC], 208 (24), 181 (100), 146 (21). Anal. Calcd for
C10H5ClFNO2 (225.60): C, 53.24; H, 2.32. Found: C, 53.13;
H, 1.91.
4.1.18. 2-Bromo-3-fluoroquinoline-4-carboxylic acid
(6a). Diisopropylamine (7.0 mL, 5.1 g, 50 mmol) and 2-
bromo-3-fluoroquinoline (3a; 11 g, 50 mmol) were added
consecutively to a solution of butyllithium (50 mmol) in
hexanes (30 mL) and tetrahydrofuran (0.21 L) cooled in a
methanol/dry ice bath. After 2 h at K75 8C, the mixture was
poured onto an excess of freshly crushed solid carbon
dioxide. The solvents were removed under reduced
pressure. The residue was taken up in water (0.15 L) and
washed with diethyl ether (3!25 mL). The aqueous layer
was acidified with 2.0 M hydrochloric acid (25 mL) to pH 1.
The precipitate formed was collected and washed with water
(2!20 mL); colorless needles (from acetone); mp 196–
197 8C (decomp.); yield: 12.7 g (94%). 1H NMR*: dZ8.13
(d, JZ7.6 Hz, 1H), 8.08 (dd, JZ8.2, 1.2 Hz, 1H), 7.92 (td,
JZ7.6, 1.2 Hz, 1H), 7.85 (td, JZ7.6, 1.2 Hz, 1H) ppm. 13C
NMR*: dZ164.3 (s), 148.6 (d, JZ261 Hz), 145.6 (d, JZ
2 Hz), 132.5 (d, JZ27 Hz), 131.5 (s), 130.3 (s), 129.5 (s),
126.6 (d, JZ16 Hz), 126.1 (d, JZ5 Hz), 124.8 (s) ppm. 19F
NMR*: dZK114.3 (s) ppm. MS: m/z (%)Z270 [MCC1]
(100), 269 (56) [MC], 252 (2), 207 (4). Anal. Calcd for
C10H5BrFNO2 (270.06): C, 44.48; H, 1.87. Found: C, 44.40;
H, 1.91.
4.1.14. 3,7-Difluoroquinoline-2-carboxylic acid (5c).
Analogously as described in the preceding paragraph from
2-bromo-3,7-difluoroquinoline (3c; 4.9 g, 20 mmol); color-
less needles (from aqueous N,N-dimethylformamide); mp
1
136–137 8C (decomp.); yield: 2.80 g (67%). H NMR: dZ
8.09 (d, JZ9.9 Hz, 1H), 7.93 (dd, JZ9.1, 5.6 Hz, 1H), 7.81
(dd, JZ9.1, 2.7 Hz, 1H), 7.56 (tm, JZ8.6 Hz, 1H) ppm. 13C
NMR*: dZ164.8 (d, JZ5 Hz), 162.8 (dm, JZ247 Hz),
154.1 (d, JZ259 Hz), 144.9 (s), 143.0 (dd, JZ17, 4 Hz),
130.8 (dm, JZ166 Hz), 127.3 (d, JZ7 Hz), 122.4 (ddd, JZ
169, 19, 5 Hz), 120.4 (dd, JZ166, 26 Hz), 113.4 (dd, JZ
167, 20 Hz) ppm. MS: m/z %Z210 (22) [MCC1], 209 (20)
[MC], 192 (14), 165 (100). Anal. Calcd for C10H5F2NO2
(209.15): C, 57.43; H, 2.41. Found: C, 57.38; H, 2.68.
4.1.15. 3-Fluoro-7-methoxyquinoline-2-carboxylic acid
(5d). Prepared analogously as described for acid 5a, from 2-
bromo-3-fluoro-7-methoxyquinoline (3d; 6.40 g, 25 mmol);
pale yellow prisms (from aqueous N,N-dimethylforma-
4.1.19. 2-Bromo-6-chloro-3-fluoroquinoline-4-carboxylic
acid (6b). Prepared analogously from 2-bromo-6-chloro-3-
fluoroquinoline (3b; 6.5 g, 25 mmol); colorless needles
(from aqueous N,N-dimethylformamide); mp 207–209 8C
(decomp.); yield: 6.62 g (87%). 1H NMR*: dZ8.1 (m, 2H),
7.89 (dd, JZ9.1, 2.2 Hz, 1H) ppm. 13C NMR*: dZ162.9
(s), 148.9 (d, JZ264 Hz), 143.0 (d, JZ3 Hz), 134.0 (s),
132.4 (d, JZ27 Hz), 130.8 (s), 130.5 (s), 124.9 (s), 124.2 (d,
JZ16 Hz), 123.9 (s) ppm. MS: m/z (%)Z304 (47) [MCC
1], 303 (100) [MC], 259 (6), 224 (15), 179 (16). Anal. Calcd
for C10H4BrClFNO2 (304.50): C, 39.44; H, 1.32. Found: C,
39.55; H, 1.16.
1
mide); mp 135–136 8C (decomp.); yield: 4.52 g (82%). H
NMR: dZ7.98 (d, JZ10.2 Hz, 1H), 7.77 (d, JZ9.0 Hz,
1H), 7.4 (m, 2H), 3.99 (s, 3H) ppm. 13C NMR: dZ161.7 (s),
161.4 (d, JZ6 Hz), 155.3 (d, JZ267 Hz), 144.9 (s), 135.5
(d, JZ10 Hz), 128.1 (d, JZ3 Hz), 127.3 (d, JZ5 Hz), 124.7
(s), 123.6 (d, JZ18 Hz), 106.7 (s), 56 (m) ppm. MS: m/z
(%)Z223 (5) [MCC2], 222 (31) [MCC1], 221 (45) [MC],
204 (25), 177 (100). Anal. Calcd for C11H8FNO3 (221.19):
C, 59.73; H, 3.65. Found: C, 59.66; H, 3.72.
4.1.16. 8-Bromo-3-fluoroquinoline-2-carboxylic acid
(5e). Prepared from 2,8-dibromo-3-fluoroquinoline (3e;
7.6 g, 25 mmol) in the same way as described for acid 5b
but starting the reaction at K100 8C; colorless tiny prisms
(from diethyl ether); mp 137–138 8C (decomp.); yield:
4.1.20. 2-Bromo-3,7-difluoroquinoline-4-carboxylic acid
(6c). Prepared analogously from 2-bromo-3,7-difluoro-
quinoline (3c; 6.1 g, 25 mmol); colorless needles (from
methanol); mp 200–202 8C (decomp.); yield: 4.90 g (68%).
1H NMR (D3CCOCD3): dZ8.27 (dd, JZ9.5, 6.5 Hz, 1H),
7.79 (dd, JZ9.5, 2.4 Hz, 1H), 7.70 (tdd, JZ9.3, 2.4, 1.0 Hz,
1H) ppm. 13C NMR*: dZ163.6 (s), 162.9 (dm, JZ244 Hz),
148.2 (d, JZ259 Hz), 146.0 (symm. m), 133.7 (d, JZ
27 Hz), 128.5 (dm, JZ166 Hz), 126.3 (dd, JZ16, 3 Hz),
121.8 (symm. m), 120.2 (ddd, JZ167, 25, 4 Hz), 113.3 (dd,
JZ168, 22 Hz) ppm. 19F NMR: dZK115.0 (d, JZ7.6 Hz),
K109.0 (quint, JZ7.6 Hz) ppm. MS: m/z (%)Z288 (55)
[MCC1], 287 (100) [MC], 243 (4), 208 (16), 163 (18).
Anal. Calcd for C10H4BrF2NO2 (288.05): C, 41.70; H, 1.40.
Found: C, 41.75; H, 1.42.
1
4.57 g (79%). H NMR: dZ8.15 (d, JZ7.5 Hz, 1H), 8.12
(d, JZ9.8 Hz, 1H), 7.89 (dd, JZ8.3, 1.1 Hz, 1H), 7.60 (t,
JZ7.9 Hz, 1H) ppm. 13C NMR (D3CCOCD3): dZ163.3
(d, JZ6 Hz), 156.3 (d, JZ267 Hz), 141.5 (s), 141.3 (d, JZ
15 Hz), 134.4 (s), 132.7 (d, JZ6 Hz), 131.0 (s), 128.5 (d,
JZ4 Hz), 125.3 (s), 123.3 (d, JZ18 Hz) ppm. MS: m/z
(%)Z270 (48) [MCC1], 269 (100) [MC], 251 (20), 225
(40), 191 (8). Anal. Calcd for C10H5BrFNO2 (270.05): C,
44.48; H, 1.87. Found: C, 44.41; H, 2.11.
4.1.17. 3-Fluoro-5,7-dimethylquinoline-2-carboxylic
acid (5f). Prepared analogously from 2-bromo-5,7-
dimethyl-3-fluoroquinoline (3f; 6.4 g, 25 mmol) as described
for acid 5b; colorless needles (from aqueous methanol); mp
4.1.21. 2-Bromo-3-fluoro-7-methoxyquinoline-4-carboxylic
acid (6d). Prepared analogously from 2-bromo-3-fluoro-7-
methoxyquinoline (3d; 6.4 g, 25 mmol); colorless needles
(from aqueous N,N-dimethylformamide); mp 210–212 8C
(decomp.); yield: 6.23 g (83%). 1H NMR*: dZ7.94 (d, JZ
9.3 Hz, 1H), 7.50 (d, JZ2.5 Hz, 1H), 7.46 (dd, JZ9.3,
2.5 Hz, 1H), 3.93 (s, 3H) ppm. 13C NMR*: dZ163.5 (s),
160.6 (s), 146.5 (d, JZ258 Hz), 146.4 (s), 131.2 (d, JZ
27 Hz), 126.0 (d, JZ4 Hz), 125.8 (d, JZ16 Hz), 121.9 (s),
118.5 (s), 107.2 (s), 55.8 (t, JZ27 Hz) ppm. MS: m/z (%)Z
1
125–126 8C (decomp.); yield: 3.67 g (67%). H NMR: dZ
8.11 (d, JZ11.2 Hz, 1H), 7.78 (s, 1H), 7.40 (s, 1H), 2.67 (s,
3H), 2.56 (s, 3H) ppm. 13C NMR (D3CCOCD3): dZ163.3
(d, JZ6 Hz), 155.6 (d, JZ265 Hz), 145.0 (s), 140.6 (s),
138.6 (d, JZ14 Hz), 135.1 (d, JZ5 Hz), 132.9 (s), 129.1 (d,
JZ5 Hz), 127.1 (s), 119.7 (d, JZ18 Hz) ppm. MS: m/z
(%)Z219 (10) [MC], 218 (100), 175 (80), 160 (70). Anal.
Calcd for C12H10FNO2 (219.21): C, 65.75; H, 4.60. Found:
C, 65.46; H, 4.33.

L. Ondi et al. / Tetrahedron 61 (2005) 717–725
723
300 (100) [MCC1], 299 (36) [MC], 256 (4), 222 (16).
Anal. Calcd for C11H7BrFNO3 (300.08): C, 44.03; H, 2.35.
Found: C, 44.26; H, 2.38.
[MC], 190 (3), 208 (11), 181 (5). Anal. Calcd for C10H5-
ClFNO2 (225.60): C, 53.24; H, 2.23. Found: C, 53.18; H, 1.96.
4.1.26. 3,7-Difluoroquinoline-4-carboxylic acid (7c). Pre-
pared as described above for the acid 7a, from 2-bromo-3,7-
difluoroquinoline-4-carboxylic acid (6c; 7.2 g, 25 mmol);
colorless tiny needles (from aqueous N,N-dimethylforma-
4.1.22. 2,8-Dibromo-3-fluoroquinoline-4-carboxylic acid
(6e). Prepared analogously from 2,8-dibromo-3-fluoro-
quinoline (3e; 24 g, 79 mmol); colorless needles (from
acetonitrile); mp 175–176 8C (decomp.); yield: 25.4 g
1
mide); mp 250–251 8C (decomp.); yield: 4.90 g (70%). H
1
(92%). H NMR*: dZ8.26 (d, JZ7.6 Hz, 1H), 8.05 (d,
NMR (D3CCOCD3): dZ9.13 (s, 1H), 8.17 (dd, JZ9.6,
5.6 Hz, 1H), 7.93 (dd, JZ9.6, 2.8 Hz, 1H), 7.73 (td, JZ8.6,
2.8 Hz, 1H) ppm. 13C NMR*: dZ163.8 (s), 161.6 (d, JZ
245 Hz), 151.3 (d, JZ258 Hz), 146 (symm. m), 143.1 (dd,
JZ186, 28 Hz), 127.5 (dm, JZ166 Hz), 123.7 (d, JZ
14 Hz), 121.0 (s), 119.4 (dd, JZ25, 4 Hz), 113.4 (dd, JZ26,
4 Hz) ppm. MS: m/z (%)Z210 (29) [MCC1], 209 (100)
[MC], 208 (17), 192 (14), 15 (8). Anal. Calcd for
C10H5F2NO2 (209.15): C, 57.43; H, 2.41. Found: C,
57.15; H, 2.44.
JZ7.9 Hz, 1H), 7.70 (t, JZ7.9 Hz, 1H) ppm. 13C NMR*:
dZ163.0 (s), 148.5 (d, JZ263 Hz), 141.4 (s), 134.0 (s),
132.8 (d, JZ27 Hz), 129.0 (s), 126.1 (d, JZ17 Hz), 125.4
(s), 125.2 (d, JZ4 Hz), 123.0 (s) ppm. MS: m/z (%)Z348
(75) [MCC1], 347 (100) [MC], 346 (8), 268 (12), 145 (15).
Anal. Calcd for C10H4Br2FNO2 (348.95): C, 34.42; H, 1.16.
Found: C, 34.59; H, 1.27.
4.1.23. 2-Bromo-3-fluoro-5,7-dimethylquinoline-4-
carboxylic acid (6f). Prepared analogously from 2-bromo-
3-fluoro-5,7-dimethylquinoline (13; 43 g, 0.17 mol);
colorless needles (from aqueous acetone); mp 192–194 8C
4.1.27. 3-Fluoro-7-methoxyquinoline-4-carboxylic acid
(7d). Prepared analogously from 2-bromo-3-fluoro-7-meth-
oxyquinoline-4-carboxylic acid (6d; 7.5 g, 25 mmol);
golden yellow platelets (from N,N-dimethylformamide);
mp 267–270 8C (decomp.); yield: 3.81 g (69%). 1H NMR*:
dZ9.00 (s, 1H), 7.99 (d, JZ8.9 Hz, 1H), 7.52 (d, JZ
2.5 Hz, 1H), 7.44 (dd, JZ8.9, 2.5 Hz, 1H), 3.95 (s,
3H) ppm. 13C NMR*: dZ164.5 (s), 159.8 (s), 150.7 (d,
JZ256 Hz), 146.7 (s), 141.7 (d, JZ27 Hz), 125.9 (s), 123.8
(d, JZ14 Hz), 121.6 (s), 118.6 (s), 107.9 (s), 56 (m) ppm.
MS: m/z (%)Z223 (5) [MCC2], 222 (37) [MCC1],
221 (100) [MC], 191 (4), 178 (11). Anal. Calcd for
C11H8FNO3 (221.18): C, 59.73; H, 3.65. Found: C, 59.92;
H, 3.60.
1
(decomp.); yield: 41.6 g (82%). H NMR (D3CCOCD3):
dZ7.70 (s, 1H), 7.43 (s, 1H), 2.70 (s, 3H), 2.50 (s, 3H) ppm.
13C NMR*: dZ165.7 (s), 148.5 (s), 146.0 (s), 140.1 (s),
133.6 (d, JZ5 Hz), 133.2 (s), 129.9 (d, JZ26 Hz), 126.8 (d,
JZ19 Hz), 126.2 (s), 20.8 (s), 19.5 (s) ppm. MS: m/z (%)Z
298 (100) [MCC1], 297 (36) [MC], 281 (10), 254 (18), 253
(17), 172 (26). Anal. Calcd for C12H9BrFNO2 (298.11): C,
48.35; H, 3.04. Found: C, 48.76; H, 3.10.
4.1.24. 3-Fluoroquinoline-4-carboxylic acid.1 (7a) Palla-
dium (10% on charcoal, 0.13 g) was added to a solution of
2-bromo-3-fluoroquinoline-4-carboxylic acid (6a; 6.8 g,
25 mmol) and triethylamine (7.0 mL, 5.1 g, 50 mmol) in
methanol (50 mL), which was stirred under an atmosphere
of hydrogen (1 atm) at 25 8C. After 4 h, the required amount
of hydrogen had been taken up. The reaction mixture was
filtered and concentrated. Upon acidification with a 1.0 M
aqueous solution of hydrochloric acid (30 mL) to pH 1, a
precipitate settled out which was collected by filtration;
colorless needles (from acetone); mp 242–243 8C
(decomp.); yield: 4.06 g (85%). 1H NMR*: dZ9.07 (d,
JZ1.0 Hz, 1H), 8.14 (dd, JZ8.2, 1.0 Hz, 1H), 8.06 (dd, JZ
8.2, 1.0 Hz, 1H), 7.84 (td), JZ7.0, 1.0 Hz, 1H), 7.78 (t, JZ
7.0 Hz) ppm. 13C NMR*: dZ164.3 (s), 151.6 (d, JZ259 Hz),
144.9 (s), 141.9 (d, JZ28 Hz), 129.5 (s), 129.2 (s), 128.9 (s),
124.9 (d, JZ5 Hz), 123.9 (s), 123.7 (d, JZ13 Hz) ppm. MS:
m/z (%)Z192 (32) [MCC1], 191 (100) [MC], 174 (16), 173
(9), 147 (4), 135 (11).
4.1.28. 8-Bromo-3-fluoro-4-quinolinecarboxylic acid
(7e). Prepared as described above for the acid 7b 2,8-
dibromo-3-fluoroquinoline-4-carboxylic acid (6e; 10 g,
30 mmol) was treated with tin(II) chloride (5.7 g,
30 mmol) to afford colorless tiny needles (from aqueous
N,N-dimethylformamide); mp 224–225 8C (decomp.);
1
yield: 6.89 g (85%). H NMR*: dZ9.19 (s, 1H), 8.23 (d,
JZ7.3 Hz, 1H), 8.07 (d, JZ8.6 Hz, 1H), 7.67 (t, JZ8.0 Hz,
1H) ppm. 13C NMR*: dZ164.0 (s), 152.2 (d, JZ262 Hz),
142.9 (d, JZ28 Hz), 141.5 (s), 133.0 (s), 129.5 (s), 125.6 (d,
JZ3 Hz), 125.2 (s), 124.7 (s), 124.5 (d, JZ14 Hz) ppm.
MS: m/z (%)Z270 (56) [MCC1], 269 (100) [MC], 251 (6),
225 (26), 190 (8), 146 (24). Anal. Calcd for C10H5BrFNO2
(270.06): C, 44.48; H, 1.87. Found: C, 44.66; H, 1.82.
4.1.25. 6-Chloro-3-fluoroquinoline-4-carboxylic acid
(7b). 2-Bromo-6-chloro-3-fluoroquinoline-4-carboxylic acid
(6b;7.6 g, 25 mmol)andtin(II)chloride(4.8 g, 25 mmol)were
added to a 5.0 M solution (0.10 mL) of hydrogen chloride in
anhydrous ethanol and heated under reflux for 4 h. After
evaporation of the solvent, the residue was treated with water
(50 mL). The precipitate was collected and washed with water
(2!20 mL); colorless needles (from acetone); mp 251–254 8C
(decomp.);yield:4.85 g(86%).1HNMR*:dZ9.11(s, 1H), 8.2
(m, 2H), 7.85 (dd, JZ11.5, 2.3 Hz, 1H) ppm. 13C NMR*: dZ
163.8(s), 152.6 (d, JZ263 Hz), 143.4(s), 142.7(d, JZ27 Hz),
133.7 (s), 131.6 (s), 129.7 (s), 125.0 (s), 123.7 (s), 122.3 (d, JZ
13 Hz) ppm. MS: m/z (%)Z226 (100) [MCC1], 225 (72)
4.1.29. 3-Fluoro-5,7-dimethylquinoline-4-carboxylic
acid (7f). Prepared as described for the acid 7a from 2-
bromo-3-fluoro-5,7-dimethylquinoline-4-carboxylic acid
(6f; 7.5 g, 25 mmol); colorless prisms (from ethanol); mp
196–197 8C (decomp.); yield: 4.38 g (80%). 1H NMR
(D3CCOCD3): dZ8.99 (s, 1H), 7.78 (s, 1H), 7.42 (s, 1H),
2.65 (s, 3H), 2.48 (s, 3H) ppm. 13C NMR*: dZ167.0 (s),
151.6 (d, JZ253 Hz), 146.2 (s), 140.4 (d, JZ27 Hz), 133.4
(d, JZ5 Hz), 132.8 (s), 127.3 (s), 125.1 (d, JZ17 Hz),
120.6 (s), 20.8 (s), 19.7 (s) ppm. MS: m/z (%)Z221 (9)
[MCC2], 220 (57) [MCC1], 219 (100) [MC], 201 (33),
175 (35), 172 (56). Anal. Calcd for C12H9BrFNO2 (219.21):
C, 65.75; H, 4.60. Found: C, 65.64; H, 4.51.

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L. Ondi et al. / Tetrahedron 61 (2005) 717–725
4.1.30. 3-Fluoro-5,7-dimethyl-2-[(thiocarbamoyl)hydra-
zonomethyl]quinoline-4-carboxylic acid (8b). Butylmag-
nesium chloride (25 mmol) in tetrahydrofuran (12 mL) and
2-bromo-3-fluoro-5,7-dimethylquinoline-4-carboxylic acid
(6f, 7.5 g, 25 mmol) were added consecutively to a solution
of butyllithium (50 mmol) in hexanes (35 mL) and tetra-
hydrofuran (80 mL) kept in an ice bath. After 2 h at 0 8C, the
mixture was treated with N,N-dimethylformamide (2.1 mL,
2.0 g, 25 mmol). At 25 8C, it was poured into a 2.0 M
aqueous solution of citric acid (50 mL) and extracted with
ethyl acetate (3!25 mL). The combined organic layers
were washed with brine (2!25 mL). The bright yellow
powder obtained after the evaporation of the volatiles
was dissolved in 70% aqueous ethanol (50 mL). Thiosemi-
carbazide (2.3 g, 25 mmol) was added and the mixture was
heated under reflux for 1 h. The golden yellow tiny needles
were collected by filtration and washed with 70% aqueous
ethanol (2!10 mL); 195–196 8C (decomp.); 6.24 g (78%).
1H NMR*: dZ11.93 (s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 7.77
(s, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 2.64 (s, 3H), 2.48 (s,
3H) ppm. 13C NMR*: dZ178.7 (s), 166.6 (s), 150.0 (d, JZ
263 Hz), 145.5 (s, broad), 142.0 (d, JZ12 Hz), 139.2 (s),
138.6 (s, broad), 133.3 (s, broad), 133.1 (d, JZ5 Hz), 126.9
(s), 126.5 (s), 120.6 (s), 20.8 (s), 19.4 (s) ppm. MS: m/z
(%)Z276 (31), 221 (96), 189 (100), 172 (61), 146 (30).
Anal. Calcd for C14H13FN4O2S (320.34): C, 52.49; H, 4.09.
Found: C, 52.75; H, 4.17.
8.6 Hz, 1H), 7.70 (t, JZ8.3 Hz, 1H), 7.61 (t, JZ8.3 Hz,
1H), 6.49 (s), 4.4 (symm. m, 2H), 4.2 (symm. m, 2H) ppm.
13C NMR: dZ150.7 (d, JZ264 Hz), 145.5 (d, JZ3 Hz),
132.2 (d, JZ28 Hz), 129.3 (s), 128.0 (s), 126 (m), 124.8 (d,
JZ5 Hz), 98.1 (d, JZ4 Hz), 665.7 (s) ppm. MS: m/z (%)Z
298 (98) [MCC1], 297 (22) [MC], 254 (5), 218 (9), 145
(25). Anal. Calcd for C12H9BrFNO2 (298.11): C, 48.35; H,
3.04. Found: C, 48.40; H, 2.80.
4.1.33.
4-(1,3-Dioxolan-2-yl)-3-fluoroquinoline-2-
carboxylic acid (10a). A solution containing 2-bromo-4-
(1,3-dioxolan-2-yl)-3-fluoroquinoline (9b; 10 g, 35 mmol)
and butyllithium (35 mmol) in tetrahydrofuran (50 mL),
diethyl ether (0.10 L) and hexanes (25 mL) was stored 6 h at
K100 8C before being poured onto an excess of freshly
crushed dry ice. After addition of water (0.15 L) the reaction
mixture was washed with diethyl ether (3!35 mL). When
the aqueous layer was acidified to pH 1, the product
precipitated. It was collected and washed with water (2!
20 mL); colorless prisms (from acetone); mp 117–118 8C
1
(decomp.); yield: 8.66 g (94%). H NMR (D3CCOCD3):
dZ8.49 (d, JZ8.6 Hz, 1H), 8.17 (d, JZ8.6 Hz, 1H), 7.85
(dd, JZ8.3, 7.0 Hz, 1H), 7.76 (dd, JZ8.0, 6.7 Hz, 1H),
6.56 (s, 1H), 4.4 (m, 2H), 4.2 (m, 2H) ppm. 13C NMR*: dZ
164.4 (d, JZ5 Hz), 152.2 (d, JZ267 Hz), 143.9 (d, JZ
3 Hz), 141.9 (d, JZ19 Hz), 130.1 (s broad), 129.6 (s),
129.3 (s), 126.4 (d, JZ6 Hz), 125.0 (d, JZ5 Hz), 96.9 (d,
JZ7 Hz), 65.4 (s) ppm. MS: m/z (%)Z263 (2) [MC], 219
(46), 200 (8), 147 (64), 73 (100). Anal. Calcd for
C13H10FNO4 (263.22): C, 59.32; H, 3.83. Found: C,
59.05; H, 3.70.
4.1.31. 2-Bromo-3-fluoroquinoline-4-carbaldehyde (9a).
Diisopropylamine (10 mL, 7.1 g, 70 mmol) and 2-bromo-3-
fluoroquinoline (3a; 16 g, 70 mmol) were added consecu-
tively to a solution of butyllithium (70 mmol) in hexanes
(45 mL) and tetrahydrofuran (0.30 L) cooled in a dry ice/
methanol bath at -75 8C. After 2 h the mixture was treated
with N,N-dimethylformamide (5.9 mL, 5.6 g, 70 mmol).
Again 2 h later, it was poured into a 2.0 M aqueous solution
of citric acid (0.15 L) and extracted with diethyl ether (3!
70 mL). The combined organic layers were washed with
brine (0.10 L) and evaporated; pale yellow needles (from
4.1.34. 3-Fluoro-4-formylquinoline-2-carboxylic acid
(10b). 4-(1,3-Dioxolan-2-yl)-3-fluoro-quinoline-2-carboxylic
acid (10a; 6.6 g, 25 mmol) in tetrahydrofuran (60 mL) and
2.0 M hydrobromic acid (0.19 L) was stored 24 h at 25 8C
before being extracted with diethyl ether (3!25 mL). The
combined organic layers were washed with brine (2!
25 mL) and dried with anhydrous sodium sulfate. After
evaporation of the volatiles a light yellow solid was left
behind, which crystallized from aqueous acetone and was
isolated as colorless tiny needles; mp 114–115 8C
(decomp.); 8.65 g (79%). 1H NMR*: dZ10.75 (s, 1H),
8.90 (symm. m, 1H), 8.2 (symm. m, 1H), 7.9 (symm. m,
2H) ppm. 13C NMR*: dZ189.4 (symm. m), 163.8 (d, JZ
4 Hz), 156.1 (d JZ277 Hz), 143.8 (d JZ3 Hz), 142.2 (d,
JZ18 Hz), 131.6 (s)129.9 (s), 124.6 (s), 124.4 (d, JZ4 Hz),
122.7 (d, JZ4 Hz) ppm. MS: m/z (%)Z219 (4) [MC], 218
(10), 200 (8), 175 (94), 147 (100), 127 (20), 120 (20). Anal.
Calcd for C11H6FNO3 (219.17): C, 60.28; H, 2.76. Found:
C, 60.22; H, 2.75.
1
heptanes); mp 76–78 8C (reprod.); yield: 17.4 g (98%). H
NMR: dZ10.81 (s, 1H), 9.0 (m, 1H), 8.1 (m, 1H), 7.77
(symm. m, 2H) ppm. 13C NMR: dZ188.7 (symm. m), 155.5
(d, JZ274 Hz), 145.8 (d, JZ3 Hz), 132.5 (d, JZ27 Hz),
130.7 (s), 130.1 (s), 129.1 (s), 125.2 (d, JZ6 Hz), 123.3 (s),
122.0 (d, JZ4 Hz) ppm. MS: m/z (%)Z254 (23) [MCC1],
253 (55) [MC], 225 (24), 146 (100), 126 (40). Anal. Calcd
for C10H5BrFNO (254.06): C, 47.28; H, 1.98. Found: C,
47.50; H, 1.90.
4.1.32. 2-Bromo-4-(1,3-dioxolan-2-yl)-3-fluoroquinoline
(9b). At 0 8C, the boron trifluoride diethyl ether complex
(25 mL, 28 g, 80 mmol) was added to a solution of 2-
bromo-3-fluoro-quinoline-4-carbaldehyde (9a; 10 g,
40 mmol) and ethylene glycol (3.4 mL, 3.7 g, 60 mmol) in
anhydrous dichloromethane (0.44 L). After 24 h at 25 8C,
the mixture was poured into a 1.0 M aqueous solution of
sodium hydrogen carbonate (0.30 L). The aqueous layer
was extracted with dichloromethane (3!40 mL). The
combined organic layers were washed with water (2!
40 mL) and dried. Evaporation of the solvent afforded the
product as colorless needles (from a mixture of hexanes and
diethyl ether); mp 121–123 8C (reprod.); yield: 11.5 g
Acknowledgements
This work was financially supported by the Schweizerische
¨
Nationalfonds zur Forderung der wissenschaftlichen For-
schung, Bern (grant 20-55’303-98), the Bundesamt fu¨r
Bildung und Wissenschaft, Bern (grant 97.0083 linked to
the TMR project FMRXCT-970129), and F. Hoffmann-La
Roche, Basel.
1
(97%). H NMR: dZ8.25 (d, JZ8.6 Hz, 1H), 8.06 (d, JZ

L. Ondi et al. / Tetrahedron 61 (2005) 717–725
725
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