Expeditious preparation of 2-substituted quinolines

Article abstract of DOI:10.1016/S0040-4039(01)00604-9

A library of 2-substituted quinolines was synthesized in solution from mixtures of Grignard reagents and a quinolinium salt. Grignard reagents were prepared in one pot, taking advantage of the entrainment method for their preparation from unreactive alkyl halides. Then mixtures of 2-alkylquinolines were readily accessible for biological tests or separated by centrifugal-partition chromatography (CPC) prior to the biological screening.

Full text of DOI:10.1016/S0040-4039(01)00604-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3847–3850
Expeditious preparation of 2-substituted quinolines
Mohamed A. Fakhfakh,a Xavier Franck,a Alain Fournet,a,b Reynald Hocquemillera and
Bruno Figade`rea,*
aLaboratoire de Pharmacognosie, associe´ au CNRS (BIOCIS), Universite´ Paris-Sud, Faculte´ de Pharmacie,
rue Jean-Baptiste Cle´ment, F-92296 Chaˆtenay-Malabry, France
bInstitut de Recherche pour le De´veloppement (IRD), 213 rue La Fayette, F-75480 Paris, France
Received 5 March 2001; accepted 9 April 2001
Abstract—A library of 2-substituted quinolines was synthesized in solution from mixtures of Grignard reagents and a quinolinium
salt. Grignard reagents were prepared in one pot, taking advantage of the entrainment method for their preparation from
unreactive alkyl halides. Then mixtures of 2-alkylquinolines were readily accessible for biological tests or separated by
centrifugal-partition chromatography (CPC) prior to the biological screening. © 2001 Elsevier Science Ltd. All rights reserved.
A fast access to a large number of biologically active
compounds is one of the most challenging targets for
the medicinal chemist today. Combinatorial chemistry
on solid support for the preparation of non-peptidic
libraries has been developed by many groups.1 How-
ever, organic reactions of large scope performed in
solution remain an attractive tool for the preparation of
a large variety of compounds. The ideal process would
be thus to synthesize in solution a large number of
compounds in one pot, then either to perform the
biological tests on the mixture or to separate all sub-
stituents for individual screenings. In this letter, we
wish to report some preliminary results on the one pot
preparation of several 2-alkylquinolines which have
been easily separated by centrifugal-partition chro-
matography (CPC)2 for biological evaluations.
appeared in the literature concerning the synthesis of
2-substituted quinolines.8 Webb reported that phenyl-
magnesium bromide added on N-oxycarbonylisobutyl-
oxyquinolinium chloride at low temperature in good
yield and good regioselectivity, since the desired 2-
phenylquinoline was obtained without any positional
isomers.9 We thus thought that this reaction might be
generalized to the preparation of 2-substituted quinoli-
nes (Fig. 1). First we performed the addition of propyl-
magnesium bromide onto different N-oxycarbonyl-
alkyloxyquinolinium chlorides under various reaction
conditions in order to find the best procedure. TLC and
crude 1H NMR spectra showed complete and clean
formation of the desired product, when the reactions
were run at low temperature.
Several 2-alkyl- and 2-alkenylquinolines, the chima-
nines, have been isolated from Galipea longiflora3 and
have shown very promising activity against several
leishmania strains,4 and in vivo tests have demonstrated
their oral leismanicide property.5 Some activity against
Plasmodium vinckei petteri was also expressed by some
of them.6 Therefore, we were interested in establishing
some structure–activity relationships, based on the
nature of the alkyl chain branched at the 2-position of
quinoline. Several methods were reported for the prepa-
ration of 2-alkylpyridines;7 however, few reports
Keywords: quinolines; Grignard reagents; multi-components reaction.
* Corresponding author. Fax: (33)
bruno.figadere@cep.u-psud.fr
1 46 83 53 99; e-mail:
Figure 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00604-9

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M. A. Fakhfakh et al. / Tetrahedron Letters 42 (2001) 3847–3850
Finally 2-propylquinoline was best obtained when
isobutyl chloroformate was added at room temperature
to quinoline N-oxide, followed by addition at −78°C of
1.2 equiv. of a 1 M solution of propylmagnesium
bromide and, after 2.5 h of stirring, the reaction was
quenched at −78°C with NaHCO3. After usual workup
and purification by flash chromatography through
evaporation of the solvents under a slight vacuum (>30
mm Hg), the desired 2-propylquinoline was obtained in
67% yield (Table 1, entry 1). We then prepared sepa-
rately several 2-substituted quinolines under the same
reaction conditions as described above, in typical chem-
ical yields ranging from 32 to 82% (Table 1). It is worth
noting that primary alkyl Grignard reagents gave good
yields (entries 1, 4 and 7), whereas secondary Grignard
reagent such as i-PrMgBr gave lower yields (Table 1,
entry 6). Alkenyl or alkynylmagnesium halides gave the
desired products with good to excellent yields (Table 1:
entries 2, 3, 5 and 8).
mide or butyl bromide with tridecanyl bromide or
hexadecyl bromide, respectively, allowed us to prepare
in THF the desired alkylmagnesium bromides in good
yields, and therefore molar solution of several Grignard
reagents. We thus prepared two different mixtures of
Grignard reagents: mixture A containing n-propyl-,
n-pentyl-, n-heptyl-, n-nonyl-, n-undecanyl and n-tride-
canylmagnesium bromides and mixture B containing
n-ethyl-, n-butyl-, n-hexyl-, n-octyl-, n-decyl-, n-dode-
cyl-, n-tetradecyl-, and n-hexadecylmagnesium bro-
mides. GC analyses of hydrolyzed aliquots from these
mixtures led us to conclude that all organometallic
reagents were formed in similar yields (around 80% for
mixtures A and B), and usual Grignard titrations11
showed molarities ranging from 0.8 to 1 M, depending
on the experiment. Then we separately added these two
mixtures of Grignard reagents to a cooled solution
(−78°C) containing N-oxycarbonylisobutyloxyquinolin-
ium chloride, and followed the procedure described
above. After work-up, the crude mixtures were first
analyzed by GC, showing that the expected alkylquino-
lines were present equally in the mixtures. TLC of the
crude mixtures showed in both cases broad spots,
hardly separable by flash chromatography. Preparative
HPLC analyses of these mixtures would have required
large quantities of solvents, as well as the desired
columns and equipment. Therefore we turned our
attention to the separation by CPC (solvent12: heptane/
CH3CN/MeOH), which combined an inexpensive pro-
cedure (few solvent without expensive columns13) and a
very efficient separation process.2 Thus, all expected
2-alkylquinolines were obtained as pure materials in
yields ranging from 30 to 50% (Fig. 2). Purities were
checked by GC and showed to be greater to 96%.
Lower yields of 2-alkylquinolines so prepared, com-
pared to those obtained in the single reaction experi-
ments, may be rationalized by involving two factors.
The first one is due to the split of the mobile phase
where 10% was flushed through the evaporating light-
scattering detector14, used as an universal detector, thus
10% of the mixture was consumed. Finally discrepan-
cies in the observed yields is explained by the volatility
of the smaller molecules compared to those of larger
Then, we decided to prepare several 2-alkylquinolines,
possessing very long aliphatic chains, in one pot by first
preparing mixtures with odd number aliphatic chain
and even number aliphatic chain Grignard reagents,
mixtures A and B, respectively. Indeed, it is known that
entrainment methods for the preparation of reluctant
alkyl halides involve the use of active alkyl halides (e.g.
ethyl bromide) in conjunction with unreactive halide to
initiate the reaction by activation of the metal surface.10
Indeed, in our case, the presence of either propyl bro-
Table 1.
Entry
R (of RMgBr)
Yield (%)
1
2
3
4
5
6
7
8
n-Pr
Vinyl
Me3SiCꢀC
But-3-en-1-yl
Prop-1-en-1-yl
i-Pr
67
82
53
73
68
32
79
63
n-Decyl
Methyl-2-prop-1-en-1-yl
Mixture A or B
THF, -78°C
n
, Cl-
N
O
N
R
+
Oi-Bu
CPC
O
6 pure and separated compounds
or 8 pure and separated compounds
THF
n (RBr) + Mg
n (RMgBr)
20 °C
Yield : 30-50 %
C9H19, C11H23, C13H27
C3H7, C5H11, C7H15
Mixture A, R =
Mixture B, R =
,
C2H5, C4H9, C6H13, C8H17
,
C10H21, C12H25, C14H29, C16H33
Figure 2.

M. A. Fakhfakh et al. / Tetrahedron Letters 42 (2001) 3847–3850
3849
ClCO2i-Bu, then
R
R
BrMg
+
N
N
THF, -78°C
-
O
R= C-8OH
R= C-6Me
: 23 %
: 30 %
Figure 3.
molecules (as already observed for the separate prepa-
rations of 2-propylquinoline and 2-decylquinoline, see
Table 1).
2. Foucault, A. P. CPC in Chromatography Sciences Series;
Marcel Dekker: New York, 1995; Vol. 68.
3. Fournet, A.; Hocquemiller, R.; Roblot, F.; Cave´, A.;
Richomme, P.; Bruneton, J. J. Nat. Prod. 1993, 56,
1547–1553.
4. Fournet, A.; Barrios, A. A.; Munoz, V.; Hocquemiller,
R.; Cave´, A.; Bruneton, J. Antimicrob. Agents Chemother.
1993, 37, 859–863.
It is worth noting that crude mixtures could then be
tested, as well as the separated quinolines so obtained,
in several biological screenings (results not shown15).
In order to increase the structural diversity, we are now
investigating both introduction of functions on the
Grignard reagent and on the quinoline nucleus. For
instance, 2-propenyl-8-hydroxyquinoline and 2-pro-
penyl-6-methylquinoline have been prepared, albeit in
moderate 23 and 30% yields, respectively, by applying
the reaction conditions described above (Fig. 3). Opti-
mization and generalization of this procedure is now
under study.
5. Fournet, A.; Ferreira, M. E.; Rojas de Arias, A.; Torres
de Ortiz, S.; Fuentes, S.; Nakayama, H.; Schinini, A.
Antimicrob. Agents Chemother. 1996, 40, 2447–2451.
6. Gantier, J. C.; Fournet, A.; Munos, M. H.; Hoc-
quemiller, R. Planta Med. 1996, 62, 285–286.
7. (a) Ochiai, E. Aromatic Amine Oxides; Elsevier: Amster-
dam, 1976; p. 269; (b) Fife, W. K. J. Org. Chem. 1983,
48, 1375–1377; (c) Eisner, U.; Kuthan, J. Chem. Rev.
1972, 72, 1–42; (d) von Doering, W. E.; Pasternack, V. Z.
J. Am. Chem. Soc. 1950, 72, 143–147; (e) Benkeser, R. A.;
Holtar, D. S. J. Am. Chem. Soc. 1951, 73, 5861–5863; (f)
Giam, C. S.; Knaus, E. E.; Pasutto, F. M. J. Org. Chem.
1974, 39, 3565–3568; (g) Frankel, G.; Cooper, J. W.;
Fink, C. M. Angew. Chem., Int. Ed. Engl. 1970, 9,
523–524; (h) Lyle, R. E.; Marshall, J. L.; Comins, D. L.
Tetrahedron Lett. 1977, 1005–1018.
In conclusion, this study shows for the first time that
long aliphatic chain Grignard reagents can be prepared
in a very efficient manner as mixtures of alkylmagnes-
ium bromides (GC analyses as well as titration’s
showed no detectable cross-coupling reactions between
Grignard reagents). These mixtures are synthetically
useful reagents and can react, for instance, with N-oxy-
carbonylisobutyloxyquinolinium chloride at low tem-
perature to afford the desired 2-alkylquinolines in good
yields.16 CPC allowed us to obtain the pure isolated
compounds which were then submitted to different
biological tests. The use of mixtures of several function-
alized quinolines as starting material, in conjunction
with mixtures of Grignard reagents would improve the
structural diversity of the desired 2-alkylquinolines, and
this is now under way in our laboratory. Indeed, the
CPC technique, combined with multi-Grignard compo-
nent reactions (MGCR), seems a very attractive tool
for a quick access to structurally related compounds of
biological interests.
8. Mani, N. S.; Chen, P.; Jones, T. K. J. Org. Chem. 1999,
64, 6911–6914 and references cited therein.
9. Webb, T. R. Tetrahedron Lett. 1985, 26, 3191–3194.
10. Rieke, R. D.; Sell, M. S. In Handbook of Grignard
Reagents; Silverman, G. S.; Rakita, P. E., Eds.; Marcel
Dekker: New York, 1996; pp. 58–59.
11. Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967,
9, 165–168.
12. Stationary phase: saturated heptane with CH3CN (200
mL); mobile phase: heptane/CH3CN/CH3OH (22/16/62
v/v); rotation: 1000 rpm; detector ELSD (2.1 bar at
30°C); injector: 4 g in 15 mL; MP total: 990 mL.
13. Viron, C.; Pennanec, R.; Andre´, P.; Lafosse, M. J. Liq.
Chrom. Rel. Technol. 2000, 23, 1681–1688.
14. Dreux, M.; Lafosse, M.; Morin-Allory, L. LC–GC Int.
1996, 9, 148–153.
Acknowledgements
15. Results of the structure–activity relationships in this
series will be shortly reported elsewhere.
16. Spectroscopic data (1H and 13C NMR in CDCl3 at 200
and 50 MHz, respectively, CI-MS (NH+4), IR) are in
accord with the proposed structures. Some representative
We thank J. C. Jullian for NMR experiments, and Dr.
P. Duret for the CPC experiments.
1
data are given: 1-(2-quinolyl)propane: H NMR (l ppm):
1.03 (t, J=7.3 Hz, 3H), 1.86 (sext., J=7.6 Hz, 2H), 2.96
(t, J=7.8 Hz, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.48 (dd,
J=7.5, 7.3 Hz, 1H), 7.68 (dd, J=7.4, 7.3 Hz, 1H), 7.78
(d, J=8.0 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 8.08 (d,
J=8.2 Hz, 1H); 13C NMR (l ppm): 13.57, 22.77, 40.79,
120.90, 125.15, 126.30, 127.02, 128.42, 128.80, 135.61,
147.51, 162.30; CI-MS (m/z) 172 (MH+, 100), 143 (12);
References
1. (a) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem.
Rev. 1997, 97, 449–472; (b) Hermkens, P. H. H.; Otten-
heijm, H. C. J.; Rees, D. C. Tetrahedron 1997, 53,
5643–5678.

3850
M. A. Fakhfakh et al. / Tetrahedron Letters 42 (2001) 3847–3850
1-(2-quinolyl)ethylene: 1H NMR (l ppm): 5.66 (d, J=10.9
1H), 8.06 (d, J=8.1 Hz, 1H); 13C NMR (l ppm): 18.60,
118.70, 125.80, 127.40, 129.10, 129.50, 129.46, 130.40,
132.30, 132.70, 148.00, 156.40; ESI-MS (m/z) 170 (MH+);
Hz, 1H), 6.26 (d, J=17.7 Hz, 1H), 7.04 (dd, J=17.7, 10.9
Hz, 1H), 7.49 (dd, J=7.2, 6.9 Hz, 1H), 7.60 (d, J=8.7
Hz, 1H), 7.69 (ddd, J=7.0, 8.3, 0.6 Hz, 1H), 7.77 (d,
J=7.9 Hz, 1H), 8.06 (d, J=9.9 Hz, 1H), 8.08 (d, J=8.8
Hz, 1H); 13C NMR (l ppm): 118.26, 119.68, 126.17,
126.90, 127.34, 129.22, 129.46, 136.17, 137.87, 147.93,
155.96; CI MS (m/z) 156 (MH+, 100); 2-(2-
quinolyl)trimethylsilylethyne: 1H NMR (l ppm): 0.30 (s,
9H), 7.52 (m, 2H), 7.69 (dd, J=7.5, 7.5 Hz, 1H), 7.75 (d,
J=8.4 Hz, 1H) 8.08 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.3
Hz, 1H); 13C NMR (l ppm): −0.35, 95.50, 104.19, 124.24,
126.99, 127.30, 127.40, 129.26, 129.84, 135.90, 143.09,
147.94; CI-MS (m/z) 225 (M+, 100); 4-(2-quinolyl)butene:
1H NMR (l ppm): 2.48 (dt, J=7.6, 7.0 Hz, 2H), 2.99 (t,
J=7.4 Hz, 2H), 4.96 (m, 1H), 5.82 (dddd, J=16.8, 10.2,
6.6, 6.6 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H), 7.38 (dd,
J=7.4, 7.4 Hz, 1H), 7.59 (dd, J=7.2, 7.1 Hz, 1H), 7.67
(d, J=8.0 Hz, 1H), 7.96 (d, J=8.4 Hz, 2H); 13C NMR (l
ppm): 33.67, 38.45, 115.12, 121.20, 125.83, 126.82, 127.00,
129.50, 130.10, 136.14, 137.70, 147.76, 161.87; EI-MS (70
eV, m/z) 183 (M+, 71), 182 (100), 168 (53), 167 (32), 156
1
2-(2-quinolyl)propane: H NMR (l ppm): 1.40 (d, J=6.7
Hz, 6H), 3.30 (hept, J=6.8 Hz, 1H), 7.35 (d, J=8.6 Hz,
1H), 7.48 (dd, J=7.9, 7.2 Hz, 1H), 7.68 (ddd, J=6.9, 6.8,
1.5 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.9 Hz,
1H), 8.09 (d, J=8.6 Hz, 1H); 13C NMR (l ppm): 22.24,
36.94, 118.96, 125.30, 126.67, 127.11, 128.79, 129.01,
136.01, 147.53, 167.24; ESI-MS (m/z) 172 (MH+, 100);
1-(2-quinolyl)decane: 1H NMR (l ppm): 0.87 (t, J=6.6
Hz, 3H), 1.20–1.48 (m, 14H), 1.81 (quint., J=7.5 Hz,
2H), 2.96 (t, J=7.9 Hz, 2H), 7.29 (d, J=8.6 Hz, 1H),
7.47 (dd, J=7.9, 7.2 Hz, 1H), 7.67 (ddd, J=8.4, 7.1, 1.2
Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.3 Hz,
2H); 13C NMR (l ppm): 14.04, 22.62, 26.84, 29.26, 29.51,
30.02, 31.84, 39.34, 121.26, 125.50, 127.37, 127.13, 128.78,
129.18, 136.03, 147.83, 163.01; CI-MS (m/z) 270 (MH+,
100); 1-(2-quinolyl)-2-methylpropene: 1H NMR (l ppm):
2.01 (s, 3H), 2.17 (s, 3H), 6.52 (s, 1H), 7.32 (d, J=8.4 Hz,
1H), 7.47 (dd, J=7.3, 7.2 Hz, 1H), 7.67 (ddd, J=7.1, 6.9,
1.2 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.04 (d, J=8.4 Hz,
1H), 8.06 (d, J=8.4 Hz, 1H); 13C NMR (l ppm): 19.78,
27.26, 122.17, 125.22, 125.50, 126.03, 127.14, 128.94,
129.06, 135.40, 142.20, 147.80, 157.51; ESI-MS (m/z) 184
(MH+, 100).
1
(23), 149 (20), 143 (18); E-(2-quinolyl)propene: H NMR
(l ppm): 2.01 (d, J=5.6 Hz, 3H), 6.73 (d, J=16.0 Hz,
1H), 6.86 (dq, J=16.0, 5.6 Hz, 1H), 7.47 (dd, J=7.6, 7.5
Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.68 (ddd, J=8.5, 7.1,
1.2 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 8.02 (d, J=8.1 Hz,
.