Selective direct fluorination of quinoline derivatives

Article abstract of DOI:10.1016/S0022-1139(02)00156-2

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

Full text of DOI:10.1016/S0022-1139(02)00156-2

Journal of Fluorine Chemistry 117 (2002) 99–101
Selective direct fluorination of quinoline derivatives
Richard D. Chambersa,*, Darren Hollinga, Graham Sandforda,*,
Horst Puschmannb, 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 23 April 2002; received in revised form 23 April 2002; accepted 23 April 2002
Dedicated to Professor Lev M. Yagupolskii on the occasion of his 80th birthday.
Abstract
Direct fluorination of various quinoline derivatives in acidic reaction media gives fluorinated quinoline products arising from selective,
efficient electrophilic substitution processes.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Fluorine; Quinoline; Selective fluorination
1. Introduction
systems at sites adjacent to the heteroatom using fluorine/
iodine mixtures [9] have been established.
Selectively fluorinated quinoline derivatives can have
valuable biological activity and a number of commercially
significant pharmaceuticals [1], such as Ciprofloxacin (anti-
bacterial) and 5-fluoroprimoquine [2] (anti-malarial) make
use of such properties. However, syntheses of quinoline
systems that bear a fluorine substituent on the benzenoid
ring are not trivial and normally involve multi-step
sequences either starting from non-quinolinoid precursors
(Skraup synthesis [2]) or by fluorination of appropriate
chloro-quinolines (Halex reaction [3]) or amino-quinolines
(Balz–Schiemann reaction [4]). The selective replacement
of hydrogen by fluorine offers a more direct strategy for the
synthesis of fluoro-quinolines and a limited number of
electrophilic fluorination processes involving the use of
XeF2, [5] CF3OF [6] and AcOF [7] have been reported in
this context.
Direct selective fluorination of heterocycles by elemental
fluorine has remained undeveloped despite the fact that 5-
fluorouracil, a potent anti-cancer agent, is synthesised on a
commercial scale by direct fluorination methodology [1]
thus indicating the feasibility and opportunities of such an
approach. Also, direct fluorination of various pyridine deri-
vatives [8] and the fluorination of quinoline and quinoxaline
We previously reported that direct selective fluorination
of a range of aromatic systems could be achieved when
acids, such as formic and sulphuric, were used as reaction
media [10] and here, we report that direct fluorination of
quinoline derivatives can also be performed in acidic media,
thus, providing efficient and synthetically viable routes to
these systems.
Fluorination of various quinoline derivatives was
achieved by passing fluorine, diluted by nitrogen (10% v/v),
through a cooled (0–5 8C) mixture consisting of the
quinoline derivative and concentrated sulphuric acid. After
work-up all the fluorinated products shown in the table were
isolated by column chromatography except for compounds 3
and 11. Conversions and yields, estimated by 19F NMR
analysis of the crude product mixture with reference to a
trifluormethyl-benzene standard, of the fluorination reac-
tions are collected in the Table 1.
In all cases, selective fluorination occurred on the benze-
noid ring and we attribute this to deactivation of the hetero-
cyclic ring towards electrophilic attack by the protonation of
the heteroatom in the strongly acidic reaction medium. In
contrast, in neutral medium, such as acetonitrile, the fluor-
ination of quinoline gave many products and a significant
amount of tarry material.
Hydrogen/deuterium exchange studies have established
[11] that the positional order for electrophilic substitution in
quinoline dissolved in strong acid media is 8 > 5,
* Corresponding author. Tel.: þ191-3744639.
E-mail addresses: graham.sandford@durham.ac.uk,
r.d.chambers@durham.ac.uk (R.D. Chambers).
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 5 6 - 2

100
R.D. Chambers et al. / Journal of Fluorine Chemistry 117 (2002) 99–101
Table 1
2 in N2ðv=vÞ
Quinoline derivative10% F
!
fluoro À quinoline products
conc:H2SO4; 5 ꢀ
C
Substrate
Conversion
Product yield (%)
67
54
59
13
51
56
6 > 7 > 3, i.e. sites adjacent to the pyridyl ring (5 and 8) are
the most reactive. Therefore, the results of direct fluorination
reactions of quinoline derivatives give products that are
consistent with an electrophilic aromatic substitution pro-
cess. For example, fluorination of quinoline 1 yields pro-
ducts 2–5 resulting largely from substitution at the 5 and 8
positions and fluorination of 6-methylquinoline 6 gives 5
rather than 7-fluoro-substitution.
Scheme 1.

R.D. Chambers et al. / Journal of Fluorine Chemistry 117 (2002) 99–101
101
Acknowledgements
We thank EPSRC (Studentship to DH) and the Royal
Society (University Research Fellowship to GS).
References
[1] R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organofluorine
Chemistry, Principles and Commercial Applications, Plenum Press,
New York, 1994.
[2] P.M. O’Neill, R.C. Storr, B.K. Park, Tetrahedron 54 (1998) 4615.
[3] J. Hamer, W.J. Link, A. Jurjevich, T.L. Vigo, Recl. Trav. Chim. Pays-
Bas 81 (1962) 1058.
Fig. 1.
[4] A. Roe, G.F. Hawkins, J. Am. Chem. Soc. 71 (1949) 1785.
[5] S.P. Anand, R. Filler, J. Fluorine Chem. 7 (1976) 179.
[6] H. Gershon, M.W. McNeil, R. Parmegiani, P.K. Godfrey, J. Med.
Chem. 15 (1972) 987.
However, fluorination of 6-methoxyquinoline 14 gave a
mixture of two products which could be identified as the
mono- and difluorinated compounds 15 and 16.1 The yield of
16, which was identified by X-ray crystallography (Fig. 1)
could be increased by simply passing an excess of fluorine
through the reaction mixture and a proposed mechanism for
its formation is given in Scheme 1.
Direct selective fluorination of quinoline derivatives,
therefore, provides effective methodology for the synthesis
of fluorinated heterocyclic analogues and the application of
this new methodology to the synthesis of related fluoro-
heteroaromatic derivatives is in progress.
[7] S. Rozen, O. Lerman, Y. Tor, D. Hebel, J. Org. Chem. 49 (1984) 806.
[8] M.V.D. Puy, Tetrahedron Lett. 28 (1987) 255.
[9] R.D. Chambers, M. Parsons, G. Sandford, C.J. Skinner, M.J.
Atherton, J.S. Moilliet, J. Chem. Soc. Perkin Trans 1 (1999)
803.
[10] R.D. Chambers, J. Hutchinson, M.E. Sparrowhawk, G. Sandford, J.S.
Moilliet, J. Thomson, J. Fluorine Chem. 102 (2000) 169.
[11] A.R. Katritzky, R. Taylor, Adv. Heterocycl. Chem. 47 (1990) 1.
1 5,5-Difluoro-5-hydroquinolin-6-one: yellow solid; m.p. 105–107 8C;
(found: C, 59.7; H, 2.8; N, 7.8. C9H5FNO requires C, 59.7; H, 2. 8; N,
7.7%); dH: 8.75 (1H, dq, 3JHH 4.8 4JHH 1.2, H-2), 8.10 (1H, dm, 4JHF 8.1,
H-4), 7.64 (1H, d, 3JHH 10.4, H-8), 7.44 (1H, dd, 3JHH 7.6, 4JHH 9.2, H-3),
3
4
2
6.46 (1H, dt, JHH 10.4 JHF 4.0, H-7); dF –102.4 (s); dC 186.2 (t, JCF
24.2, C-6), 152.8 (t, 5JCF 1.9, C-2), 149.3 (t, 3JCF 6.1, C-8a), 146.9 (s, C-8),
134.7 (t, JCF 2.7, C-4), 129.7 (t, 2JCF 24.3, C-4a), 126.8 (t, 3JCF 2.7, C-7),
124.4 (s, C-3), 104.9 (t, JCF 245.0, C-5); m/z (EIþ) 181 (Mþ, 100%),
3
1
153 (82); X-ray crystallography (selected data). Temp. 100(2) K, l ¼
˚
˚
˚
0:71073 A, orthorhombic, Pnma, a ¼ 12:2462ð9Þ A, b ¼ 6:6912ð5Þ A,
3
ꢀ
ꢀ
ꢀ
˚
˚
c ¼ 9:1757ð7Þ A, a ¼ 90 , b ¼ 90 , g ¼ 90 , V ¼ 751:87ð10Þ A , density
ðcalc:Þ ¼ 1:600 g/cm-3, RðintÞ ¼ 0:0527, crystal size ¼ 0:4 mm ꢁ 0:4 mmꢁ
0:4 mm.