Elemental fluorine Part 15. Selective direct fluorination of quinoline derivatives

Article abstract of DOI:10.1016/j.jfluchem.2003.11.012

Direct fluorination of various quinoline derivatives in acidic reaction media gives fluorinated quinoline products arising from electrophilic substitution processes.

Full text of DOI:10.1016/j.jfluchem.2003.11.012

Journal of Fluorine Chemistry 125 (2004) 661–671
Elemental fluorine
Part 15. Selective direct fluorination of quinoline derivatives$
Richard D. Chambersa,*, Darren Hollinga, Graham Sandforda,1,
Andrei S. Batsanovb, Judith A.K. Howardb
aDepartment of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
bChemical Crystallography Group, Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
Received 24 September 2003; received in revised form 3 November 2003; accepted 4 November 2003
Available online 27 February 2004
Abstract
Direct fluorination of various quinoline derivatives in acidic reaction media gives fluorinated quinoline products arising from electrophilic
substitution processes.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Direct selective fluorination; Elemental fluorine; Fluoroquinoline
1. Introduction
by fluoride ion occurs, is also widely used, but the harsh
reaction conditions sometimes required prevent effective
reaction. For both of these methods, appropriate chloro-
and diazo-heteroaromatic substrates must first be synthe-
sised and this can itself be problematic. An alternative
approach to, for example, fluoroquinoline synthesis,
involves annelation of the fluorinated benzenoid precursors,
e.g. the Skraup synthesis, but, again, preparation of appro-
priate starting materials can be problematic.
Potentially, the most direct and efficient approach to the
synthesis of fluoroheteroaromatic systems is the transforma-
tion of carbon–hydrogen to carbon–fluorine bonds upon
fluorination by an electrophilic fluorinating agent. In this
context, electrophilic reagents such as xenon difluoride [3],
acetyl hypofluorite [4] and N–F reagents have been used to
synthesise a very limited range of, for example, fluoroquino-
line derivatives, with varying degrees of success. All of the
aforementioned electrophilic reagents, however, are pre-
pared from elemental fluorine and it is perhaps surprising
that reports of syntheses of flurooheteroaromatic systems
using fluorine are very few in number. This is despite the fact
that 5-fluorouracil is prepared on a commercial scale using
fluorine, demonstrating the opportunities provided by this
approach. Various fluoro-pyridine [5] and -purine deriva-
tives have been prepared by direct fluorination and, by a
related, though conceptually very different approach, several
2-fluoroquinolines were synthesised by reaction with iodine
monofluoride, prepared in situ from iodine and fluorine [6].
It is now well established that the incorporation of fluorine
atoms into heterocyclic molecules can have a significant
effect upon the chemical and biological properties of these
systems [1]. This has been used to great effect in the
development of various commercially important life-science
products, such as 5-fluorouracil, 5-fluoroprimaquine and
ciprofloxacin (Fig. 1), that owe their useful biological
activity to the presence of a fluorine substituent located
on the heterocyclic ring [1].
However, efficient synthesis of fluorinated heterocyclic
derivatives is not trivial and presents a considerable chal-
lenge. Currently, various routes to fluoroheteroaromatic
systems, involving the selective replacement of a leaving
group by fluorine, are prevalent. The well established Balz–
Schiemann process, involving treatment of a heteroaromatic
diazonium salt with anhydrous hydrogen fluoride, has
allowed the synthesis of, for example, various fluoro-pyr-
idine and -quinoline derivatives [2]. Halogen exchange
processes, in which nucleophilic displacement of chloride
$ For Part 14, see R.D. Chambers, A.M. Kenwright, M. Parsons, G.
Sandford, J.S. Moilliet, J. Chem. Soc., Perkin Trans. 1 (2002) 2190–2197.
* Corresponding author. Tel.: þ44-191-334-2020;
fax: þ44-191-334-4737.
E-mail addresses: r.d.chambers@durham.ac.uk (R.D. Chambers),
graham.sandford@durham.ac.uk (G. Sandford).
1 Tel.: þ44-191-334-2039; fax: þ44-191-384-4737.
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.11.012

662
R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
F
O
O
MeO
F
CO2H
H
O
F
N
N
N
N
N
H
N
N
NH2
H
5-Fluoro-uracil
(anti-cancer)
Ciprofloxacin (Bayer)
(anti-bacterial)
5-Fluoroprimaquine
(anti-malaria)
Fig. 1. Some commercially important fluoro-heterocyclic derivatives.
In this series, we are developing the use of elemental
main monofluorinated products could not be isolated but
were identified by 19F NMR, by comparison with literature
data and authentic samples.
fluorine as a viable reagent for organic synthesis and we
have described effective methodology for the preparation of
various fluoro-aromatic [7,8], dicarbonyl and carbonyl deri-
vatives. In particular, the beneficial role of using acidic media
for direct fluorination processes has been emphasised [7]
allowing effective selective synthesis of, for example, fluoro-
aromatic systems. Here, we report our studies concerning the
direct fluorination of quinoline derivatives with the possibi-
lity in mind of establishing the use of fluorine for the general
synthesis of many fluoro-heteroaromatic systems.
Concentrated sulfuric acid was found to be a muchsuperior
reactionmedium because, essentially, notarwasformedupon
passing fluorine, diluted to a 10% mixture (v/v) in nitrogen,
through a solution of 1 at 0–5 8C. Although conversion of 1
was moderate, even after six equivalents of fluorine had been
passed through the stirred reaction mixture, 2a–c and 2e were
obtained in a total yield of 91% by 19F NMR (Scheme 2). The
reaction mixture was poured into water and neutralised
(sodium bicarbonate) and, although separation of the fluori-
nated products was difficult, difluoro-quinoline 2c was iso-
lated and purified by column chromatography.
2. Results and discussion
Proton/deuterium exchange studies in strong acid media
have established [9] that, generally, the positional order of
reactivity in quinoline towards electrophiles is 8 > 5, 6 > 7 >
3, whereby positions a to the hetero-ring are more readily
attacked than b sites. More specifically, halogenation of
quinoline by chlorine [10], bromine [11,12] and iodine [13]
in sulfuric acid, gave the 5-, 8- and 5,8-halogenated quino-
lines as the major products. As can be seen from Scheme 2,
the positional reactivity towards fluorine is in the order
5 > 8 > 6 in which sites a to the hetero-ring (5 and 8)
are fluorinated almost exclusively. It seems reasonable,
therefore, to conclude that fluorination of quinolines in a
strongly acidic medium follows an electrophilic substitution
process since the orientation of substitution parallels other
halogenations.
2.1. Synthesis
Since use of solvents with high relative permittivity, such
as acetonitrile, formic and sulfuric acids has proved to be
beneficial in direct fluorination reactions with aromatic
substrates [7], we have assessed the effectiveness of these
solvents for the fluorination of quinoline.
Reaction of quinoline 1 and fluorine in acetonitrile led to a
crude mixture that contained many fluorinated products and
considerable amounts of intractable tar, from which no
useful product could be obtained. Similarly, using formic
acid as solvent gave a complex mixture containing many
fluorinated products and significant amounts of tar but, in this
case, four major products 2a–d could be identified by 19F
NMR. (Scheme 1). 5-Fluoro-2a, 8-fluoro-2b, 5,8-difluoro-
quinoline-2c and the addition product 2d were present in the
crude reaction mixture in the ratio of 3.8:2.7:1:3.2 but in
overall low yield. Column chromatography gave only an
enriched sample of 2d but the coupling patterns observed in
The neutralisation of large quantities of sulfuric acid in
the work-up stage by sodium bicarbonate is a limiting factor
so we carried out the fluorination reaction in a medium
consisting of sulfuric acid and a perfluorocarbon fluid
(FlutecTM PP11, 20% v/v) as an inert heat transfer and
bulking agent. The product profile of the reaction was
1
both H and 19F NMR confirmed the structure. The three
F
F
F
H
F
10% F2 in N2
+
+
+
H
HCOOH, 0 - 5oC
N
N
N
N
N
F
F
1
2c
2a
2b
2d
2a : 2b : 2c : 2d, 3.8 : 2.7 : 1 : 3.2
Low unquantified yield
Scheme 1.

R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
663
F
F
F
10% F2 in N2
+
+
+
medium 0 - 5oC
N
N
N
N
N
F
F
2a
1
2e
2b
2c
Yield (%)
F2
medium
c. H2SO4
c. H2SO4
conversion (%)
2a
44
27
48
2e
11
8
2b
2c
13
32
8
6 equiv.
12 equiv.
7 equiv.
42
67
23
14
27
c. H2SO4/PP11 22
11
F
PP 11 =
F
F
Scheme 2.
unaffected by the presence of the large volume of perfluor-
ocarbon fluid and the work-up could be achieved more
conveniently due to the lower quantity of acid present.
As a result of these studies, we adopted, as a medium of
choice, either sulfuric acid or sulfuric acid/perfluorocarbon
fluid for subsequent direct fluorination reactions of the
following quinoline derivatives.
process, and all products could be isolated (Scheme 4). The
regioselectivity of these reactions is also consistent with an
electrophilic substitution process.
Unusually, 8-methylquinoline 8 gave a mixture contain-
ing both the 5-fluoroquinoline 12a and a fluoro-ketone
system 12b while excess fluorine (12 equiv.) leads to an
increase in the yield of 12b. A mechanism for the formation
of 12b, requiring two equivalents of fluorine and nucleo-
philic attack by water in the reaction work-up to complete
the transformation is given in Scheme 5.
Fluorination of 6-methoxyquinoline 13 gave either the
5-fluoroderivative 14a or an a,a-difluoro-ketone 14b in 74
and 26% yield, respectively (Scheme 6), upon reaction with
three equivalents of fluorine in a very efficient, clean process
and both products could be isolated by column chromato-
graphy. The yield of 14b was increased simply by passing of
a large excess of fluorine through the reaction mixture, and a
mechanism for the formation of 14b is outlined in Scheme 6.
Similarly, the aldehyde 15 gave the corresponding difluor-
oketone 16b (ꢀ10 g scale) as a single, crude product, that
was essentially pure, after reaction with excess fluorine
(Scheme 7). The nitro-methoxy quinoline 17, however, gave
only the mono-fluorinated product 18 reflecting the deacti-
vating influence of the nitro group on the second fluorine
addition step (Scheme 7).
Having established that controlled, direct fluorination of 1
was possible using sulfuric acid, we then assessed the affect
of substituents located on either the carbocyclic or hetero-
cyclic ring of various quinoline substrates on the process.
Fluorination of 2-chloro-3 and 4-methyl-quinoline 4 in sul-
furic acid and oleum/PP11 media, respectively, gave a mix-
ture of four fluoroquinoline derivatives, 5a–d and 6a–d,
respectively (Scheme 3). For both reactions, products were
identified by 19F NMR and GC/MS but, unfortunately, no
individual fluorinated products 5a–d or 6a–d could be iso-
lated pure from the crude mixtures. The presence of sub-
stituents on the heterocyclic ring of quinoline does not,
therefore, appear to effect the regioselectivity of the fluorina-
tion reaction because a similar product profile is observed in
fluorination of 3, 4 and 1 itself (compare Schemes 2 and 3).
Fluorination of quinolines bearing electron withdrawing
and/or electron releasing groups on the carbocyclic ring
were next studied to determine the effect of ring substituents
upon the fluorination process. Fluorination of various
methyl-quinoline derivatives 7–9 were observed to be rea-
sonably selective, although difluorination is a competing
Quinoline derivatives with electron withdrawing substi-
tuents located on the carbocyclic ring were also fluorinated
efficiently to give the products indicated in Scheme 8.
F
Y
Y
Y
Y
N
F
Y
F
X
10% F2 inN2
medium 0 - 5oC
N
N
X
N
X
X
N
X
F
F
3, 4
5a,6a
5b,6b
5c,6c
5d,6d
F2
medium
conversion (%)
Yield (%)
12 equiv.
3, X = Cl, Y = H
4, X = H, Y = CH
33 equiv.
oleum/PP11
c. H2SO4
68
26
5a, 25
6a, 48
5b,11
6b, 14
5c, 16
6c, 23
5d, 21
6d, 6
Scheme 3.

664
R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
F
F
CH3
CH3
CH3
10% F2 in N2
+
c. H2SO4, 0 - 5oC
N
N
N
54% conv.
F
10a, 75%
10b, 5%
7
O
F
10% F2 in N2
+
c. H2SO4, 0 - 5oC
N
CH3
N
N
F
CH3
CH3
8
12a
12b
F2 (3 equiv.)
F2 (12 equiv.)
6% conv.
7% conv.
68%
2%
16%
58%
F
F
10% F2 in N2
c. H2SO4, 0 - 5oC
H3C
N
CH3
C
H3
N
C
H3
H3C
N
H3C
F
9
11a
11b
F2 (2.5 equiv.)
40% conv.
62% conv.
82%
28%
12%
23%
F2 (10 equiv.)
Scheme 4.
The direct fluorination reactions described above give rise
OH2
to products that are all consistent with an electrophilic
substitution process. Electron releasing groups (CH3,
OCH3) gave products derived from substitution at positions
ortho and para to the substituent, in which a positions are
favoured over b sites if two sites are available. (e.g. 15 gives
16 rather than substitution at the 6-position). Fluorination of
quinolines bearing electron withdrawing groups (NO2) gave
fluorination at sites meta to the substituent, as would be
predicted for electrophilic substitution. These reactions
further demonstrate that fluorine is a viable controllable
reagent.
F
F
F2
F2
H
- HF
N
N
N
F
F
CH3
CH3
CH3
O
8
F
OH
- HF
N
N
2.2. X-ray crystallography
F
H
C
F
CH3
3
12b
The structures of several of the fluorinated products
described above were confirmed by X-ray crystallography.
Molecular structures are shown in Fig. 2 and the following
Scheme 5.
F
F
F
O
CH3O
CH3O
10% F2 in N2
+
c. H2SO4, 0 - 5oC
N
N
N
14b, 26%
13
14a, 74%
71% conv.
F
F
F
F
F
CH3O
CH3O
CH3O
O
- CH3F
F2
F2
F
- HF
N
N
N
N
Scheme 6.

R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
665
O
F
O
O
F
F
CH3O
CH3O
O
H
H
H
10% F2 in N2
c. H2SO4, 0 - 5oC
N
Cl
N
Cl
N
Cl
15
16a
16b
F
2 (6 equiv.)
66% conv.
100% conv.
73%
-
27%
89%
F2 (15 equiv.)
F
CH3O
CH3O
10% F2 in N2
c. H2SO4, PP11, 0 - 5oC
59% conv.
N
N
NO2
NO2
17
18, 99%
Scheme 7.
points are of note. In 12b, the heterocycle is planar, while the
carbocycle shows a small boat-like distortion, C(5), C(8) and
O tilting out of the C(6), C(7), C(9), C(10) plane to the side
while the methoxy group lies in the latter plane. In the
structure of pure 18, the methoxy group also adopts an in-
plane conformation, but differing from that in 17 by 1808
rotation, while the inclination of the nitro group is reduced to
53.88.
Crystallisation of 22a produced a solid solution of 22b in
22a in a ca. 1:5 ratio. As in the case of 17/18, the position 5 at
the quinoline nucleus is shared by the F(5) substituent of 22b
(the occupancy of which was refined to 16.7 (8)%) and H(5)
of 22a, while the positions of all other atoms are the same for
22a and 22b. Molecules, related by the b translation, form
˚
of the methyl group, by 0.05, 0.08 and 0.13 A, respectively.
In 16a, the formyl and methoxy groups are rotated out of the
quinoline plane by 12.2 and 3.58, respectively. In 16b, the
fused-ring system is planar, except the difluorinated atom
˚
C(5) which is tilted out of the plane by 0.07 A; the formyl
group lies in the same plane. The crystal of 17 was obtained
as a solid solution of 18 (ca. 2.5%) in 17, as indicated by the
small but significant peak of electron density near H(5),
which was interpreted and successfully refined as F(5) of 18
(all other atoms of either component share the same posi-
tions in the crystal lattice). The nitro-group is almost per-
pendicular to the quinoline plane (dihedral angle 88.48),
˚
continuous stacks with the interplanar separations of 3.38 A.
Each chlorine atom participates in two intra-stack contacts
˚
of 3.77 A with its translational equivalents, and in one inter-
˚
stack contact Clð4Þ Á Á Á Clð7Þ of 3.57 A between stacks,
F
F
Cl
Cl
Cl
10% F2 in N2
c. H2SO4, 0 - 5oC
N
N
N
59% conv.
F
19
20a, 79%
Cl
20b, 5%
F
Cl
Cl
10% F2 in N2
medium, 0 - 5oC
Cl
N
Cl
N
Cl
N
F
F
21
2 (6 equiv.) oleum/PP11
F2 (6 equiv.) c. H2SO4
22b
22a
F
62% conv.
19% conv.
46%
76%
11%
4%
NO2
NO2
10% F2 in N2
medium, 0 - 5oC
N
N
F
23
F2 (18 equiv.) c.H2SO4
2 (15 equiv.) oleum/PP11
24
41% conv.
61% conv.
74%
59%
F
Scheme 8.

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R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
Fig. 2. X-ray molecular structures, showing displacement ellipsoids at 50% probability level. Atoms, belonging to impurities, are shown in dashed lines.
related via a c translation. These contacts, although exceed-
˚
ing the doubled van der Waals radius of Cl (1.76 A), [14]
3. Experimental
indicate the usual tendency of chlorine atoms to ‘‘stick
together’’ in a condensed phase [14,15]. These stacks form
a layer, parallel to the (1 0 0) plane. All molecules within a
layer are parallel to each other, but inclined by 538 to those
of the adjacent layers (related via the n glide plane).
The asymmetric unit in the crystal of 24 comprises two
molecules, both of which show traces of fluorine substitution
in positions 3 and 5. The occupancies of 6% for F(3), F(5),
F(13) and F(15) gave the best agreement with the data and
the crystal can be described as a solid solution in 24 of 6%
of 3,5,8-trifluoro-6-nitroquinoline, a minor by-product of the
synthesis which was not isolated. In both independent mole-
cules, the dihedral angles between the nitro group and the
quinoline system are small, 3.2(1) and 4.1(1).
3.1. General
All starting materials were obtained commercially
(Sigma-Aldrich) and all solvents were dried using literature
procedures. NMR spectra were recorded in deuteriochloro-
form, unless otherwise stated, on a Varian VXR 400S NMR
spectrometer with tetramethylsilane and trichlorofluoro-
methane as internal standards. Spectral assignments were
1
1
made with the aid of data collected by HÀ H COSY and
13
1HÀ C HETCOR experiments and coupling constants are
given in Hz. Mass spectra were recorded on either a VG
7070E spectrometer or a Fissons VG Trio 1000 spectrometer
coupled with a Hewlett-Packard 5890 series II gas chroma-
tograph. Accurate mass measurements were performed by

R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
667
the EPSRC National Mass Spectrometry service, Swansea,
UK. Elemental analyses were obtained on either a Perkin-
Elmer 240 or a Carlo Erba Elemental Analyser. Melting
points were recorded at atmospheric pressure and are uncor-
rected. Column chromatography was carried out on silica gel
(Merck No. 1-09385, 230–400 mesh) and TLC analysis was
performed on silica gel TLC plates using dichloromethane
as eluant.
difluoroquinoline 2c and 5,6-difluoro-5,6-dihydroquinoline
2dintheratioof3.8:2.7:1:3.2.Conversionandyieldscouldnot
be determined accurately due to the tar present in the crude
product. Columnchromatographyoversilicagel usingdiethyl
ether as eluant gave only an enriched sample of 5,6-difluoro-
1
3
5,6-dihydroquinoline 2d; dH 5.28 (1H, ddt, JHF 49.2, JFF
17.2, 3JHF 4.4, H-6), 5.58 (1H, ddd, 1JHF 48.8, 3JFF 21.6, 3JHF
4.0, H-5), 6.39 (1H, m, H-7), 6.86(1H, dd, 3JHH 10.0, 4JHF 2.8,
H-8), 7.23 (1H, dd, 3JHH 7.6, 3JHH 4.8, H-3), 7.78 (1H, d, 3JHH
7.6, H-4), 8.56 (1H, d, 3JHH 4.8, H-2); dF –201.1 (1F, dm, 2JHF
49.6, F-6), À201.7 (1F, dd, 2JHF 48.1 3JFF 11.7, F-5); dC 84.5
3.2. Reactions with elemental fluorine
1
2
1
2
3.2.1. General procedure
(dd, JCF 180.5, JCF 17.8, C-6), 87.7 (dd, JCF 185.9, JCF
18.2, C-5), 115.2 (d, 2JCF 20.5, C-4a), 122.9 (s, C-3), 127.2
(dd, 2JCF 18.2, 3JCF 6.1, C-7), 129.9 (d, 3JCF 7.9, C-8a), 133.3
(dd, 3JCF 9.2, 4JCF 1.6, C-8), 134.4 (d, 3JCF 6.1, C-4), 150.2
(d, 5JCF 2.2, C-2).
Elemental fluorine, as a 10% (v/v) mixture with nitrogen,
was passed at a rate of ca. 50 ml minÀ1 through a stirred,
cooled (0 8C) mixture which consisted of the substrate and
the reaction medium. After addition of the fluorine, the
reaction mixture was poured into water (1500 ml), neutra-
lised (NaHCO3) and extracted with dichloromethane
(3 Â 100 ml). The combined, dried (MgSO4), organic
extracts were evaporated to give a crude product. The
composition of a weighed crude reaction mixture was deter-
mined by GC/MS analysis and the conversion of starting
material was calculated from calibrated GC peak intensities.
The amount of fluorinated product in the crude product was
determined by adding a known amount of trifluoromethyl-
benzene to a weighed amount of the crude product mixture.
Comparison of the relative intensities of the appropriate
19F NMR resonances gave the yield of fluorinated derivative,
based upon the conversion obtained above. Analytical sam-
ples of fluorinated products were obtained by either pre-
parative scale GC or column chromatography. Yields of
fluorinated products are quoted as yields based on the con-
version of starting material.
For reactions involving the use of perfluorocarbon fluids
(e.g. PP11) as reaction media, the following work-up pro-
cedure was used. The reaction was poured onto ice-water
(400 ml) and the PP11 separated as a lower layer. The PP11
layer was further washed with water (50 ml), dried (MgSO4)
and re-used without further purification. The aqueous
phase was neutralised with sodium hydrogencarbonate
and extracted with dichloromethane. The combined extracts
were dried over magnesium sulfate and solvent was removed
by rotary evaporation to leave crude reaction product.
3.2.2.3. Sulfuric acid. 1 (4.0 g, 30 mmol), sulfuric acid
(150 ml) and fluorine (360 mmol, 12 equiv.) gave a dark
yellow oil (4.97 g, conv. 67%) that consisted of 5-fluoro-
quinoline 2a (27%), 6-fluoroquinoline 2e (8%), 8-fluoro-
quinoline 2b (14%) and 5,8-difluoroquinoline 2c (32%).
Purification by column chromatography on silica gel using
diethyl ether as elutant gave analytical samples of 5-
fluoroquinoline 2a as a yellow oil [2]; dH 7.03 (1 H, m, H-
6), 7.25 (1H, dd, 3JHH 8.5,3JHH 4.0, H-3), 7.46 (1 H, td, 3JHH
8.0, 4JHF 6.0, H-7), 7.77 (1 H, d, 3JHH 8.5, H-8), 8.23 (1 H, dm,
3JHH 8.5, H-4), 8.77 (1 H, dd, 3JHH 4.5, 4JHH 1.5, H-2); dF –
123.3(dd, 3JHF 9.4,4JHF 5.6, F-5);dC 109.8(d,2JCF 18.9,C-6),
118.8 (d, 2JCF 16.5, C-4a), 120.9 (d, 4JCF 6.9, C-3), 125.0 (s,
C-8), 128.7 (d, 3JCF 8.9, C-7), 129.0 (d, 3JCF 4.5, C-4), 148.6
(d, 4JCF 3.0, C-8a), 150.9 (s, C-2), 157.5 (d, 1JCF 255.0, C-5);
m/z(EIþ)147(Mþ,100%);(Found:Mþ 147.048546.C9H6FN
requires Mþ 147.048427); and, 8-fluoroquinoline 2b as a
yellow oil [2]; dH 7.33–7.21 (3 H, m, H-3,5,7), 7.43 (1 H, dm,
3JHH 8.0, H-6), 8.00 (1 H, dm, 3JHH 8.5, H-4), 8.81 (1 H, dm,
3JHH 4.0, H-2); dF À126.2 (dd, 3JHF 10.3, 4JHF 4.7, F-8); dC
113.1 (d, 2JCF 18.5, C-7), 121.7 (d, 3JCF 7.6, C-6), 123.1 (d,
4JCF 4.5, C-5), 126.0(m, C-3), 129.4(d, 3JCF 2.5, C-4a), 135.6
(s, C-4), 138.0 (d, 2JCF 12.0, C-8a), 150.1 (s, C-2), 157.6 (d,
1JCF 257.0, C-8); m/z (EIþ) 147 (Mþ, 100%); (Found: Mþ
147.048437. C9H6FN requires Mþ 147.048427); and, 5,8-
difluoroquinoline 2c as a white solid [16]; mp 59–61 8C
3
3
(hexane); dH 7.16 (1 H, td, JHF 8.5, JHH 4.0, H-6), 7.35
3
3
3
3.2.2. Fluorination of quinoline 1: solvent survey
(1 H, td, JHF 9.5, JHH 4.5, H-7), 7.55 (1 H, dd, JHH 8.5,
3JHH4.0, H-3), 8.43 (1 H, dm, 3JHH 8.5, H-4), 9.02 (1 H, dd,
3JHH 4.0, 4JHH 1.0, H-2); dF À127.4 (1 F, ddd, 5JFF 21.6, 3JHF
9.4, 4JHF 5.2, F-5), À130.2 (1 F, ddd, 5JFF 22.1, 3JHF 9.9, 4JHF
3.3, F-8); dC 109.5 (dd, 2JCF 22.0, 3JCF 7.7, C-6), 112.6 (dd,
2JCF 21.6, 3JCF 9.1, C-7), 120.0 (dd, 2JCF 18.3, 3JCF 2.7, C-
4a), 122.1 (d, 4JCF 2.1, C-3), 129.5 (dd, 2JCF 3.7, 4JCF 2.4, C-
4), 138.3 (m, C-8a), 151.3 (d, 4JCF 1.6, C-2), 153.5 (dd, 1JCF
250.1, 4JCF 3.8, C-5), 154.3 (dd, 1JCF 251.2, 4JCF 3.8, C-8);
m/z (EIþ) 165 (Mþ, 100%); (Found: Mþ, 165.038984.
C9H5F2N requires M, 165.039006). 6-Fluoroquinoline 2e
was not isolated but could be identified [2] in the 19F NMR
3.2.2.1. Acetonitrile. Quinoline 1 (2.0 g, 15 mmol) and
fluorine (47 mmol, 3 equiv.) in acetonitrile (50 ml) gave a
dark oil (13.0 g) and significant tar. Analysis of this crude
product by 19FF NMR showed a complex mixture of products
that could not be identified and were not investigated further.
3.2.2.2. Formic acid. 1 (6.0 g, 45 mmol), formic acid
(150 ml) and fluorine (90 mmol, 2 equiv.) gave a dark
brown tar. 19F NMR analysis showed the presence of four
products; 5-fluoroquinoline 2a, 8-fluoroquinoline 2b, 5,8-

668
R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
spectrum of the crude reaction mixture; dF –114.3 (d, 3JHF
4.7, F-6).
H-7), 7.48 (1 H, dd, 3JHH 8.4, 3JHH 4.4, H-3), 8.35 (1 H, dm,
3JHH 7.2, H-4), 8.93 (1 H, dm, 3JHH 4.4, H-2); dF –131.6 (1 F,
dd, 5JFF 21.8, 4JHF 10.2, F-8), À132.3 (1 F, dm, 5JFF 21.8, F-
5); dC 14.4 (d, 3JCF 3.4, 4JCF 0.8, Me), 115.6 (dd, 2JCF 20.8,
3JCF 5.6, C-4a), 119.7 (dd, 2JCF 18.2, 3JCF 5.0, C-7), 119.8
(d, 2JCF 18.3, C-6), 122.0 (d, 4JCF 2.3, C-3), 128.9 (dd, 3JCF
3.2.2.4. Sulfuric acid/perfluorocaron fluid FlutecTM PP 11.
1 (4.0 g, 30 mmol), sulfuric acid (20 ml), FlutecTM
PP11(80 ml) and fluorine (220 mmol, 7 equiv.) gave a
dark yellow oil (8.26 g, conv. 22%) that consisted of
5-fluoroquinoline 2a (48%), 6-fluoroquinoline 2e (11%),
8-fluoroquinoline 2b (27%) and 5,8-difluoroquinoline 2c
(8%); spectral data as above.
4
2
3
4.6, JCF 2.7, C-4), 136.9 (dd, JCF 13.7, JCF 3.0, C-8a),
4
1
4
150.3 (d, JCF 1.6, C-2), 150.7 (dd, JCF 246.2, JHF 3.1,
C-5), 153.6 (dd, JCF 250.7, JCF 3.þ0, C-8); m/z (EIþ) 179
(Mþ, 100%), 178 (91); (Found: M 179.0549. C10H7F2N
requires Mþ 179.0547).
1
4
3.2.3. Fluorination of 2-chloroquinoline 3
2-Chloroquinoline 3 (2.5 g, 15 mmol), oleum (10 ml),
PP11 (90 ml) and fluorine (180 mmol, 12 equiv.) qave a
yellow oil (3.4 g, conv. 68%) that contained 2-chloro-5-
3.2.6. Fluorination of 8-methylquinoline 8
8-Methylquinoline 8 (2.86 g, 20 mmol), sulfuric acid
(150 ml) and fluorine (65 mmol, 3.25 equiv.) gave an
orange oil (3.98 g, conv. 26%) which contained 5-fluoro-
8-methylquinoline 12a (68%) and 8-fluoro-8-methyl-8-
hydroquinoline-5-one 12b (16%). Purification by column
chromatography on silica gel using diethyl ether: hexane
(4:1) as elutant, gave 5-fluoro-8-methylquinoline 12a as a
colourless oil; dH 2.74 (3 H, s, Me), 7.08 (1 H, dd, 3JHH 8.0,
3JHF 9.6, H-6), 7.43 (2 H, m, H-3,7), 8.38 (1 H, dd, 4JHF 8.4,
3JHH 1.6, H-4), 8.96 (1 H, dd, 4JHH 4.4, 3JHH 2.0, H-2); dF –
3
fluoroquinoline [17] 5a (25%); dF –122.4 (dd, JHF
10.2, JHF 6.4, F-5); 2-chloro-6-fluoroquinoline 5b (11%);
4
dF –113.2 (m, F-6); 2-chloro-8-fluoroquinoline 5c (16%); dF
–125.5 (dd, JHF 9.0, JHF 4.5, F-8); and, 2-chloro-5,8-
3
4
5
difluoroquinoline 5d (21%); dF –126.5 (1 F, ddd, JFF
3
4
5
21.1, JHF 8.3 JHF 4.5, F-5), –129.6 (1 F, ddd, JFF 22.0
3JHF 9.2 4JHF 2.8, F-8); which could not be separated from
the reaction mixture.
2
126.9 (m, F-5); dC 17.6 (s, Me), 109.4 (d, JCF 18.6, C-6),
3.2.4. Fluorination of 4-methylquinoline 4
118.9 (d, 2JCF 16.3, C-4a), 120.7 (d, 4JCF 3.0, C-4), 128.4 (d,
3
3
4-Methylquinoline 4 (1.70 g, 12 mmol), sulfuric acid
(150 ml) and fluorine (39 mmol, 3.25 equiv.) gave a dark
oil (2.18 g, conv. 26%) which contained 5-fluoro-4-methyl-
quinoline [18] 6a (48%); dF –112.1 (m, F-5); 6-fluoro-4-
methylquinoline [19] 6b (14%); dF –113.7 (m, F-6); 8-
3JCF 8.4, C-7), 129.3 (d, JCF 5.0, C-4), 132.7 (d, JCF 4.5,
4
C-8a), 147.3 (d, JCF 2.7, C-8), 149.9 (s, C-2), 156.2 (d,
1JCF 250.7, C-5); m/z (EIþ) 161 (Mþ, 100%), 160 (77);
found: [M þ H]þ 162.0719. C10H9FN requires [M þ H]þ
162.0719; and, 8-fluoro-8-methyl-8-hydroquinolin-5-one
12b as a white solid; mp 68–70 8C; (Found: C, 67.5; H,
4.5; N, 8.0. C10H8FNO requires C, 67.8; H, 4.5; N, 7.9%); dH
1.90 (3 H, d, 3JHF 21.2, Me), 6.44 (1 H, dd, 3JHH 10.4, 4JHF
1.2, H-6), 7.16 (1 H, dd, 3JHH 10.4, 3JHF 7.2, H-7), 7.49 (1 H,
ddd, 3JHH 8.0, 3JHH 4.8, 6JHF 0.8, H-3), 8.36 (1 H, ddd, 3JHH
7.6, 4JHH 1.6, 5JHF 0.8, H-4), 8.89 (1 H, dd, 3JHH 4.8, 4JHH
2.0, H-2); dF À144.4 (qd, 3JHF 20.3, 3JHF 5.6, F-8); dC 26.3
(d, 2JCF 28.8, Me), 87.4 (d, 1JCF 169.9, C-8), 124.4 (d, 5JCF
1.9, C-3), 125.2 (d, 3JCF 2.7, C-4a), 128.1 (d, 3JCF 7.6, C-6),
134.6 (s, C-4), 147.4 (d, 2JCF 22.0, C-7), 153.5 (d, 4JCF 1.6,
C-2), 158.6 (d, 2JCF 16.3, C-8a), 183.9 (d, 4JCF 3.4, C-5); m/z
(EIþ) 177 (Mþ, 30%), 159 (100), 158 (78).
3
fluoro-4-methylquinoline 6c (23%); dF –125.7 (dd, JHF
10.0, JHF 5.5, F-8); and, 5,8-difluoro-4-methylquinoline
4
5
6d (6%); dF –116.2 (1 F, m, F-5), –129.0 (1 F, ddd, JFF
22.0, 3JHF 9.2, 4JHF 3.8, F-8) which could not be separated
from the reaction mixture.
3.2.5. Fluorination of 6-methylquinoline 7
6-Methylquinoline 7 (2.86 g, 20 mmol), sulfuric acid
(150 ml) and fluorine (65 mmol, 3.25 equiv.) gave an orange
oil (3.55 g, conv. 54%) that contained 5-fluoro-6-methyqui-
noline 10a (75%) and 5,8-difluoro-6-methylquinoline 10b
(5%). Purification by column chromatography on silica gel
using diethyl ether: hexane (4:1) as elutant, gave 5-fluoro-6-
methylquinoline 10a as a pale yellow oil; dH 2.37 (3 H, m,
8 (2.02 g, 14 mmol) and fluorine (170 mmol, 12 equiv.)
gave an orange oil (4.76 g, conv. 47%) which contained 12a
(12%) and 12b (58%) by 19F NMR analysis.
4
4
Me), 7.33 (1 H, m, H-3), 7.45 (1 H, td, JHH 8.0, JHF 3.2,
H-7), 7.77 (1 H, dd, 3JHH 8.8, 5JHF 2.0, H-8), 8.27 (1 H, dd,
3JHH 8.4, 4JHH 2.0, H-4), 8.83 (1 H, br. m, H-2), dF –128.2 (d,
4JHF 8.6, F-5); dC 14.0 (d, 3JCF 3.5, Me), 118.6 (d, 2JCF 16.7,
3.2.7. Fluorination of 2,7-dimethylquinoline 9
2,7-Dimethylquinoline 9 (1.5 g, 10 mmol), sulfuric acid
(150 ml) and fluorine (50 mmol, 5 equiv.) gave a yellow
solid (1.5 g, conv. 51%) which contained 8-fluoro-2,7-
dimethylquinoline 11a (61%) and 5,8-difluoro-2,7-dim-
ethylquinoline 11b (15%). Purification by column chroma-
tography on silica gel using diethyl ether/hexane (4:1) as
elutant, gave 8-fluoro-2,7-dimethylquinoline 11a as a white
solid; mp 90–92 8C; dH 2.38 (3 H, d, 4JHF, 2.5, 7-Me), 2.68
(3 H, s, 2-Me), 7.20–7.14 (2 H, m, H-3,6), 7.34 (1 H, d, 3JHH
2
4
C-6), 119.4 (d, JCF 14.8, C-4a), 120.8 (d, JCF 3.0, C-3),
124.3 (d, JCF 4.2, C-8), 128.5 (d, JCF 5.4, C-4), 131.9 (d,
4
3
3JCF 6.1, C-7), 147.2 (d, JCF 2.7, C-8a), 149.9 (s, C-2),
4
156.6 (d, JCF 250.4, C-5); m/z (EIþ) 161 (Mþ, 92%), 160
1
(100), 133 (63); found: [M þ H]þ 162.0719. C10H9FN
requires [M þ H]þ 162.0719; and, 5,8-difluoro-6-methyl-
quinoline 10b as a pale yellow solid; mp 81À82 8C; dH 2.43
4
3
4
(3 H, d, JHF 2.4, Me), 7.22 (1 H, dd, JHF 10.8, JHF 6.4,

R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
669
4.0, H-5), 7.89 (1 H, dd, 3JHH 8.5, 4JHH 1.5, H-4); dF –131.8
(s, F-8); dC 14.6 (d, 3JCF 4.3, 7-Me), 25.5 (s, 2-Me), 122.0 (s,
C-3), 122.1 (d, JCF 5.3, C-5), 123.3 (d, JCF 15.8, C-7),
equiv) gave a yellow solid (1.6 g, conv. 66%) which con-
tained 2-chloro-5-fluoro-6-methoxyquinoline-3-carbalde-
hyde 16a (73%) and 2-chloro-5,5-difluoro-6-oxo-5-
hydroquinoline-3-carbaldehyde 16b (27%). Purification by
column chromatography on silica gel using hexane: diethyl
ether (7:3) then dichloromethane as elutant, gave 2-chloro-
5-fluoro-6-methoxyquinoline-3-carbaldehyde 16a as a yel-
low solid; mp 146–1478C; (Found: C, 54.87; H, 2.91; N,
5.80. C11H7ClFNO2 requires C, 55.14; H, 2.94; N, 5.85%);
dH 4.06 (3 H, s, OMe), 7.66 (1 H, t, 3JHH ¼ 4JHF 9.0, H-7),
7.83 (1 H, d, 3JHH 9.9, H-8), 8.91 (1 H, s, H-4), 10.52 (1 H, s,
4
2
126.2 (d, 3JCF 2.4, C-4a), 128.4 (d, 3JCF 4.8, C-6), 135.6 (d,
2
1
4JCF 3.4, C-4), 137.9 (d, JCF 11.9, C-8a), 155.1 (d, JCF
251.0, C-8), 159.2 (d, JCF 6.0, C-2); m/z (EIþ) 175 (Mþ,
4
100%), 174 (79); Mþ, 175.079991. C11H10FN requires M,
175.079728; (Found: C, 74.91; H, 5.59; N, 7.87. C11H10FN
requires C, 75.41; H, 5.75; N, 7.99%); and, 5,8-difluoro-2,7-
dimethylquinoline 11b as a white solid; dH 2.46 (3 H, d, 4JHF
2.4, 7-Me), 2.78 (3 H, s, 2-Me), 6.95 (1 H, dd, 3JHF 10.0, 4JHF
5.2, H-6), 7.31 (1 H, d, 3JHH 8.8, H-3), 8.21 (1 H, d, 3JHH 8.8,
H-4); dF À129.2 (1 F, dd, 5JFF 21.8, 3JHF 9.4, F-5), À135.9 (1
4
4
CHO); dF À141.8 (d, JHF 8.6, F-5); dC 57.5 (d, JCF 1.0,
OMe), 118.3 (d, 2JCF 13.7, C-4a), 122.7 (d, 3JCF 2.8, C-7),
124.6 (d, 4JCF 4.5, C-8), 126.4 (d, 3JCF 2.3, C-8a), 133.2 (d,
4JCF 4.5, C-4), 143.6 (s, C-2), 144.4 (d, 2JCF 8.7, C-6), 146.7
5
3
F, d, JFF 21.1, F-8); dC 14.9 (d, JCF 3.1, 7-Me), 25.6 (s,
2-Me), 111.5 (dd, 2JCF 21.4, 3JCF 4.6, C-6), 116.3 (dd, 2JCF
3
4
1
18.6, JCF 2.3, C-4a), 122.1 (d, JCF 2.2, C-3), 123.1 (dd,
(d, JCF 257.3, C-5), 148.5 (s, CHO), 188.6 þ(m, C-3); m/z
2JCF 18.0, JCF 8.4, C-7), 129.3 (t, JCF ¼ 4JCF 2.7, C-4),
(EIþ) 241 (Mþ [37Cl], 75%), 240 (66), 239 (M [35Cl], 100),
241 (75), 238 (74), 224 (78), 196 (82), 175 (86), 168 (70),
132 (86); and, 2-chloro-5,5-difluoro-6-oxo-5-hydroquino-
line-3-carbaldehyde 16b as a yellow solid; mp 122–
123 8C; (Found: C, 49.13; H, 1.59; N, 5.71. C10H4ClF2NO
requires C, 49.31; H, 1.66; N, 15.60%); dH 6.64 (1 H, dt,
3JHH 10.0, 4JHF 2.5, H-7), 7.64 (1 H, d, 3JHH 10.5, H-8), 8.58
(1 H, s, H-4), 10.45 (1 H, s, CHO); dF –102.4 (2 F, s, F-5); dC
104.1 (t, 1JCF 248.1, C-5), 128.5 (s, C-2), 129.1 (t, 2JCF 25.1,
C-4a), 130.0 (t, 3JCF 2.8, C-7), 136.7 (t, 3JCF 2.3, C-4), 143.9
(s, C-8), 153.3 (t, 3JCF 5.9, C-8a), 156.1þ(s, CHO), þ184.9 (t,
2JCF 24.3, C-6), 187.2 (m, C-3); m/z (EI ) 245 (M [37Cl],
74%), 243 (Mþ [35Cl], 100), 217 (60), 216 (67), 215 (80),
214 (97), 186 (86), 179 (51), 152 (68), 151 (88), 125 (65),
100 (52), 99 (67), 75 (81).
3
3
137.9 (dd, 2JCF 13.7, 3JCF 3.8, C-8a), 151.4 (dd, 1JCF 246.3,
4JCF 3.8, C-5), 152.8 (dd, JCF 249.0, 4JCF 3.8, C-8), 160.4
1
(s, C-2); m/z (EIþ) 193 (Mþ, 100%); Mþ, 193.070315.
C11H9F2N requires M, 193.070306.
3.2.8. Fluorination of 6-methoxyquinoline 13
6-Methoxyquinoline 13 (2.50 g, 16 mmol), sulfuric acid
(150 ml) and fluorine (52 mmol, 3.25 equiv.) gave an orange
oil (3.43 g, conv. 71%) that contained 5-fluoro-6-methox-
yquinoline 14a (74%) and 5,5-difluoro-5-hydroquinoline-6-
one 14b (26%). Purification by column chromatography on
silica gel using diethyl ether as elutant, gave 5-fluoro-6-
methoxyquinoline 14a (1.1 g) as a white solid; mp 44–
46 8C; (Found: C, 67.76; H, 4.56; N, 8.03. C10H8FNO
requires C, 67.79; H, 4.55; N, 7.91%); dH 7.36 (1 H, dd,
3JHH 8.4, 5JHF 4.0, H-8), 7.48 (1 H, t, 3JHH ¼ 4JHF 9.2, H-7),
7.85 (1 H, dm, 3JHH 9.2, H-3), 8.31 (1 H, dm, 3JHF 8.4, H-4),
8.78 (1 H, dd, 4JHH 4.0, 3JHH 1.6, H-2); dF –147.5 (s, F-5); dC
15 (10.4 g, 47 mmol), sulphuric acid (150 ml) and fluor-
ine (707 mmol, 15 equiv.) gave a yellow solid (10.23 g,
100% conv.), which consisted of 16b (10.23 g, 89%) as the
sole product and no further purification was necessary;
spectral and physical data as above.
3
57.4 (d, 4JCF 1.1, MeO), 118.5 (d, JCF 2.7, C-7), 119.6 (d,
2JCF 13.7, C-4a), 121.2 (d, 3JCF 3.1, C-3), 125.4 (d, 4JCF 4.5,
4
2
C-8), 128.0 (d, JCF 5.3, C-4), 143.1 (d, JCF 14.4, C-6),
143.2 (d, 3JCF 7.2, C-8a), 145.1 (d, 1JCF 250.0, C-5), 149.0
(s, C-2); m/z (EIþ) 177 (Mþ, 100%), 134 (76); and, 5,5-
difluoro-5-hydroquinolin-6-one 14b (0.44 g) as a yellow
solid; mp 105–107 8C; (Found: C, 59.68; H, 2.77; N,
7.82. C9H5FNO requires C, 59.68; H, 2.78; N, 7.73%);
dH 6.46 (1 H, dt, JHH 10.4, JHF 4.0, H-7), 7.44 (1 H,
dd, 3JHH 7.6, 4JHH 9.2, H-3), 7.64 (1 H, d, 3JHH 10.4, H-8),
8.10 (1 H, dm, 4JHF 8.1, H-4), 8.75 (1H, dq, 3JHH 4.8, 4JHH
1.2, H-2); dF –102.4 (2 F, s, F-5); dC 104.9 (t, 1JCF 245.0, C-
5), 124.4 (s, C-3), 126.8 (t, 3JCF 2.7, C-7), 129.7 (t, 2JCF 24.3,
C-4a), 134.7 (t, 3JCF 2.7, C-4), 146.9 (s, C-8), 149.3 (t, 3JCF
6.1, C-8a), 152.8 (t, 5JCF 1.9, C-2), 186.2 (t, 2JCF 24.2, C-6);
m/z (EIþ) 181 (Mþ, 100%), 153 (82).
3.2.10. Fluorination of 6-methoxy-8-nitroquinoline 17
6-Methoxy-8-nitroquinoline 17 (0.5 g, 2.5 mmol), sulfu-
ric acid (15 ml), PP11 (85 ml) and fluorine (36 mmol,
14 equiv.) gave a yellow/orange solid (0.45 g, conv. 59%)
which contained 5-fluoro-6-methoxy-8-nitroquinoline 18 as
the only product. Purification by column chromatography on
silica gel using diethyl ether: hexane (9:1) as elutant, gave 5-
fluoro-6-methoxy-8-nitroquinoline 18 (0.28 g) as a yellow
solid; mp 154–155 8C; (Found: C, 53.8; H, 3.0; N, 12.4.
C10H7FNO3 requires C, 54.1; H, 3.2; N, 12.6%); dH 4.01 (3
H, d, 5JHF 0.8, OMe), 7.57 (1 H, dd, 3JHH 8.8, 3JHH 4.4, H-3),
8.01 (1 H, d, 4JHF 8.0, H-7), 8.44 (1 H, d, 3JHH 8.4, 4JHH 1.6,
3
4
3
4
H-4), 9.01 (1 H, dd, JHH 4.4, JHH 1.6, H-2); dF –136.5
4
3
(d, JHF 7.9, F-5); dC 57.8 (s, OMe), 114.4 (d, JCF 3.6,
2
4
C-7), 119.9 (d, JCF 14.2, C-4a), 122.8 (d, JCF 3.6, C-3),
3
3
3.2.9. Fluorination of 2-chloro-6-methoxyquinoline-3-
carbaldehyde 15
2-Chloro-6-methoxyquinoline-3-carbaldehyde 15 (1.5 g,
8 mmol), sulfuric acid (150 ml) and fluorine (48 mmol, 6
128.4 (d, JCF 5.1, C-4), 134.8 (d, JCF 2.8, C-8a), 142.1
2
1
(d, JCF 10.6, C-6), 143.6 (s, C-8), 147.2 (d, JCF 259.7,
C-5), 151.4 (s, C-2); m/z (EIþ) 222 (Mþ, 100%), 192 (84),
133 (52).

670
R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
3.2.11. Fluorination of 6-chloroquinoline 19
(67); Mþ{35;35Cl}, 232.961345. C9H335Cl2F2N requires
M, 232.961061. Purification using column chromatography
on silica gel using diethyl ether: hexane (2:1) as elutant,
gave 4,7-dichloro-8-fluoroquinoline 22a as a white solid;
dH 7.54 (1 H, d, 3JHH 4.4, H-3), 7.58 (1 H, dd, 3JHH 9.2, 4JHF
6-Chloroquinoline 19 (2.35 g, 14 mmol), sulfuric acid
(150 ml) and fluorine (168 mmol, 12 equiv.) gave a dark
brown oil (3.29 g, conv. 59%) which contained 6-chloro-5-
fluoroquinoline 20a (79%) and 6-chloro-5,8-difluoroquino-
line 20b (5%); dF –128.3 (1 F, dd, 5JFF 19.9, 3JHF 9.6, F-8), –
3
5
6.4, H-6), 7.92 (1 H, dd, JHH 9.2, JHF 2.0, H-5), 8.82
(1 H, d, 3JHH 4.0, H-2); dF À124.5 (s, F-8); dC 114.0 (d, 2JCF
5
4
129.1 (1 F, dd, JFF 19.9, JHF 3.8, F-5). Purification by
column chromatography using silica gel and diethyl ether as
elutant, gave 6-chloro-5-fluoroquinoline 20a as a white
3
2
27.3, C-8a), 119.9 (d, JCF 6.0, C-6), 121.3 (d, JCF 16.3,
C-7), 123.1 (s, C-3), 128.7 (s, C-5), 139.7 (d, JCF 11.4,
3
3
3
4
solid; dH 7.48 (1 H, dd, JHH 8.5, JHF, 4.5, H-3), 7.65
(1 H, dd, 3JHH 9.0, 4JHF 8.0, H-7), 7.86 (1 H, dm, 3JHH 9.0,
H-8), 8.39 (1 H, dm, 3JHH 8.5, H-4), 8.94 (1 H, dd, 3JHH 4.0,
C-4a), 142.7 (d, JCF 3.8, C-4), 150.8 (s, C-2), 153.6
(d, JCF 257.5, C-8); m/z (EIþ) 217 (Mþ
{
35;37Cl}, 75%),
1
21þ5 (Mþ
{
35;35Cl}, 100%), 180 (91), 145 (69); (Found:
4JHH 1.5, H-2); dF –124.2 (s, F-5); dC 116.5 (d, JCF 16.5,
M {35;35Cl}, 214.971234. C9H435Cl2FN requires M,
214.970483).
2
2
4
C-4a), 119.4 (d, JCF 15.5, C-6), 121.7 (d, JCF 7.9,
C-3), 126.1 (d, JCF 4.5, C-8), 128.8 (d, JCF 4.0, C-4),
4
4
3
3
130.3 (d, JCF 2.9, C-7), 147.2 (d, JCF 2.4, C-8a), 151.2
3.2.13. Fluorination of 6-nitroquinoline 23
(d, JCF 4.5, C-2), 152.9 (d, JCF 257.5, C-5), m/z (EIþ)
183 (Mþ{37Cl}, 53%), 181 (Mþ{35Cl}, 100%), 180 (66);
(Found: Mþ,183.006533. C9H5 37ClFN requires Mþþ,
183.006505; Mþ, 181.009566. C9H5 35ClFN requires M ,
181.009540).
6-Nitroquinoline 23 (2.8 g, 16 mmol), oleum (10 ml),
PP11 (90 ml) and fluorine (240 mmol, 15 equiv.) at15 8C,
gave a yellow solid (3.4 g, conv. 61%) which contained
8-fluoro-6-nitroquinoline 24 (59%). Purification by column
chromatography on silica gel using dichloromethane:
methanol (19:1) as elutant, gave 8-fluoro-6-nitroquinoline
5
1
3
3
3.2.12. Fluorination of 4,7-dichloroquinoline 21
24 as a yellow solid; dH 7.67 (1 H, dd, JHH 8.5, JHH 4.5,
H-3), 8.17 (1 H, dd, 3JHF 10.0, 4JHH 2.5, H-7), 8.41 (1 H, dm,
3JHH 8.5, H-4), 8.62 (1 H, t, 4JHH ¼ 5JHF 2.0, H-5), 9.13 (1
H, dd, 3JHH 4.0, 4JHH 1.5, H-2); dF –119.5 (d, 3JHF 9.9, F-8);
dC 108.0 (d, 2JCF 24.8, C-7), 120.0 (d, 4JCF 4.9, C-5), 123.9
(s, C-3), 128.2 (d, 3JCF 3.0, C-4a), 137.7 (d, 4JCF 3.1, C-4),
140.8 (d, 2JCF 12.2, C-8a), 145.0 (d, 3JCF 8.7, C-6), 153.8 (d,
4,7-Dichloroquinoline 21 (2.4 g, 15 mmol), oleum
(15 ml), PP11 (85 ml) and fluorine (180 mmol, 12 equiv.)
gave an orange solid (3.3 g, conv. 62%) which contained 4,7-
dichloro-8-fluoroquinoline 22a (46%) and 4,7-dichloro-5,8-
difluoroquinoline 22b (11%); dF À114.8 (1 F, dd, 5JFF 20.3,
3JHF 11.7, F-5), 127.7 (1 F, d, JFF 20.3, F-8); m/z (EIþ)
5
235 (Mþ
{
35;37Cl}, 54%), 233 (Mþ
{
35;35Cl}, 100%), 198
4JCF 1.5, C-2), 158.0 (d, JCF 260.7, C-8); m/z (EIþ) 192
1
Table 1
Crystal data
Compound
12b
16a
16b
17
18
22a
24
C9H4Cl2FNb
216.03
120
C9H5FN2O2
192.15
a
c
Formula
Formula weight
T (K)
C
10H8FNO
C11H7ClFNO2
239.63
120
C10H4ClF2NO2 C10H8N2O3
243.59
120
C10H7FN2O3
222.18
120
177.17
110
204.18
120
120
Crystal system
Space group
Orthorhombic
Pbca (# 61)
11.426(1)
6.726(1)
21.586(2)
90
Monoclinic
P21/c (# 14)
3.8149(4)
20.897(2)
12.275(1)
90
Monoclinic
P21/c (# 14)
8.876(2)
6.093(2)
17.224(4)
90
Monoclinic
Monoclinic
P21/c (# 14)
7.401(1)
16.214(6)
7.992(1)
90
Orthorhombic
Pna21 (# 33)
23.335(4)
3.772(1)
9.601(2)
90
Triclinic
¯
P1 (No. 2)
P21/c (# 14)
6.714(2)
16.015(3)
8.624(2)
90
˚
a (A)
8.790(3)
9.748(3)
10.395(3)
86.21(1)
65.30(1)
77.07(1)
788.3(4)
4
˚
b (A)
˚
c (A)
a (8)
b (8)
g (8)
V (A )
Z
90
91.12(1)
90
91.56(1)
90
96.27(1)
90
108.19(2)
90
90
90
90
3
˚
1658.9(3)
8
978.38(16)
4
931.2(4)
4
921.7(4)
4
911.1(4)
4
845.1(3)
4
Reflections collected
Reflections unique
Rint
18687
2219
13816
9784
11035
2447
11044
9321
9714
2797
2473
2430
2231
4146
0.038
1776
0.048
1998
0.020
2286
0.033
2217
0.030
2133
0.067
1873
0.028
3355
Reflections with I > 2s(I)
R [I > 2s(I)]
0.042
0.038
0.029
0.041
0.033
0.047
0.049
wR(F2), all reflections
0.125
0.105
0.081
0.122
0.102
0.100
0.141
a Contains 2.5% of 18; mean fw ¼ 204:63.
b Contains 16.7(8)% of C9H3Cl2F2N (22b), mean fw ¼ 219:00.
c Contains ca. 6% of C9H3F3N2O2, mean fw ¼ 194:40.

R.D. Chambers et al. / Journal of Fluorine Chemistry 125 (2004) 661–671
671
(Mþ, 100%), 146 (62), 134 (54), 126 (60); (Found: Mþ
192.0336. C9H5FNO2 requires Mþ 192.0335).
References
[1] R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organofluorine
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3.3. X-ray crystallography
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circle diffractometer with a 1K CCD area detector (6K CCD
ꢀ
˚
for 16a), using Mo Ka radiation (l ¼ 0:71073 A). The
crystals were cooled with a Cryostream open-flow N2 cryo-
stat (Oxford Cryosystems). Full sphere of reciprocal space to
2y ꢁ 588 was covered by five sets of 0.38 o scans, each set
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7291.
Acknowledgements
[20] G.M. Sheldrick, SADABS: program for scaling and correction of
area detector data. University of Gottingen, Gottingen, 1998.
[21] SHELXTL ver. 5.10. Bruker AXS, Madison, Wisconsin, 1997.
We thank EPSRC for funding a Quota studentship (to
D.H.) and a Senior Research Fellowship (to J.A.K.H.).