Synthesis of novel fluorinated 4-aminoquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.09.018

New 4-aminoquinolines having a -CF₂CH-(heteroaryl)-OH moiety are obtained in moderate yields from the electrochemical catalyzed reaction of the corresponding 4-amino-3-chlorodifluoroacetyl-2-methoxyquinoline in the presence of heteroaryl aldehy

Full text of DOI:10.1016/j.tetlet.2005.09.018

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7817–7821
Synthesis of novel fluorinated 4-aminoquinoline derivatives
a,
a
b
*
´
´
Maurice Medebielle, Stephane Hohn, Etsuji Okada,
Hidehiko Myokenb and Dai Shibatab
a
`
`
´
´
´
Universite´ Claude Bernard-Lyon 1, Laboratoire de Synthese, Electrosynthese et Reactivite des Composes Organiques
ˆ
Fluore´s (SERCOF), UMR CNRS 5181, Batiment E. Chevreul, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne Cedex, France
bDepartment of Chemical Science and Engineering, Faculty of Engineering, Kobe University, Rokkodai-cho, Nada-ku,
Kobe 657-8501, Japan
Received 1 July 2005; revised 30 August 2005; accepted 6 September 2005
Available online 21 September 2005
Abstract—New 4-aminoquinolines having a –CF2CH–(heteroaryl)–OH moiety are obtained in moderate yields from the electro-
chemical catalyzed reaction of the corresponding 4-amino-3-chlorodifluoroacetyl-2-methoxyquinoline in the presence of heteroaryl
aldehydes. A one-pot intramolecular zinc mediated aromatic nucleophilic substitution also gave access to novel difluorinated
5-aminodihydropyrano[2,3-b]quinolin-4-ones.
ꢀ 2005 Elsevier Ltd. All rights reserved.
There continues to be an interest in the synthesis of new
gem-difluorinated compounds because of the potential
biological properties of such molecules.1 For example,
electrophilic carbonyl derivatives, such as a,a-difluoro-
ketones, are compounds of great interest because they
have the capability to form stable adducts (such as
hydrates and hemiketals) with nucleophiles;1 it is
believed that this property allows some fluorinated
ketones to mimic the transition states involved in the
hydrolytic action of many enzymes.1 In addition, the
difluoromethylene moiety (CF2) is a key structural unit
in many fluorinated compounds of biological and phar-
maceutical significance. Fluorine substituted aromatics
and heterocycles may find broad applications such as
agrochemicals, anticancer, and antiviral agents.2 Quino-
lines are important heterocyclic systems, constituting the
structure of many naturally occurring products and
having interesting pharmacological properties.3 In par-
ticular quinolylamine derivatives have been used as the
basis in the molecular design for synthetic antimalarial
compounds,4 anti-HIV agents,5 and for the treatment
of AlzheimerÕs disease.6 Recently, we have been inter-
ested in the aromatic nucleophilic substitution reactions
of N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthyl-
amine,7 N,N-dimethyl-2-trifluoroacetyl-4-halo-1-naph-
thyl-amines,8 N,N-dimethyl-5,7-bis(trifluoroacetyl)-8-
quinolylamine,9 with amines, thiols, and alcohols and
we have shown that the corresponding exchanged prod-
ucts could be easily converted to various fluorinated
fused-heterocycles of potential biological importance.
Recently these aromatic nucleophilic substitution reac-
tions were extended to N,N-dimethyl-2-trifluoroacetyl-
1-naphthylamine.10 As part of our ongoing efforts in
search of synthetic approaches for the synthesis of fluo-
rinated compounds with potential biological and syn-
thetic applications,11 we wish to present a method to
prepare, new –CF2CHOH– derivatives that incorporate
a 4-aminoquinoline unit. In addition a one-pot process
for the synthesis of novel difluorinated 5-amino dihy-
dropyrano[2,3-b]quinolin-4-one products is presented
(Scheme 1).
Our major goal was to find the conditions to obtain an
efficient way to prepare new 4-aminoquinoline structures
Keywords: Zinc; Electrochemistry; Fluorine; Reformatsky; 4-Amino-
quinoline; SNAr.
*
Corresponding author. Tel.: +33 (4) 7243 19 89; fax: +33 (4) 7243
13 23; e-mail: medebiel@univ-lyon1.fr
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.018

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M. Me´debielle et al. / Tetrahedron Letters 46 (2005) 7817–7821
for biological evaluation; these new difluoromethylene
heterocycles were designed as part of a project devoted
to the synthesis and biological evaluation of fluorinated
analogs of reported potential antiviral agents, and
memory enhancing agents (for potential application for
the treatment of Alzheimer disease; Fig. 1). For example,
some 2,3-dihydropyrano[2,3-b]pyridine structures have
been evaluated as new acetylcholinesterase inhibitor
analogs of TACRINE (THA),12 or have demonstrated
some in vitro antiviral activity.13
was then cyclized in refluxing CF3SO3H for 5 min to
give the corresponding 3 in a modest 34% isolated
yield.14 Other acids were tested such as CF3CO2H,
CH3CO2H, C2H5CO2H, HCl, H2SO4, but they either
afforded no desired target or gave very complex mix-
tures. Careful examination, by cyclic voltammetry, of
the reduction potential of starting material 3 (Epc1
=
À1.27 V vs SCE, first peak potential measured in
DMF/0.1 M NBu4PF6), indicated that this substrate
might be a good electron-acceptor, and this therefore
prompted us to use electron-transfer activation for the
in situ generation and trapping of the corresponding
a,a-difluoroacetyl anion with a series of aromatic and
heterocyclic aldehydes. Since we have already developed
some useful carbon–carbon bond forming reactions be-
tween aromatic and heterocyclic chlorodifluoromethyl-
ated ketones and unsaturated compounds, by utilizing
tetrakis(dimethylamino)ethylene (TDAE)15 as a syn-
thetic electron-transfer reagent or electrochemical reduc-
tion, we first intended to apply these electron-transfer
induced approaches to the coupling reaction of 3 and
benzaldehyde.
Our starting material, 4-amino-3-chlorodifluoroacetyl-
2-methoxyquinoline 3 was synthesized in three steps
(Scheme 2). Chlorodifluoroacetylation of methyl ortho-
acetate [chlorodifluoroacetic anhydride (CDFAA)/
pyridine in anhydrous CH2Cl2] followed by O–N
exchange reaction of the resulting 1-chloro-1,1-difluoro-
4,4-dimethoxybut-3-en-2-one 1 with 2-aminobenzonitrile
in refluxing MeCN afforded 1-chloro-1,1-difluoro-4-
methoxy-4-(2-cyanophenyl)aminobut-3-en-2-one 2. The
much deshielded peak of the amino proton at dH =
12.03–12.60 ppm due to hydrogen bonding between
NH and C@O indicated E configuration. Compound 2
Using our usual conditions, 1.2equiv of TDAE was
added dropwise to 1 equiv of ketone 3 and 2equiv of
PhCHO in anhydrous DMF at À20 ꢁC, warming to
room temperature reaction and then stirring at room
temperature for 18 h, led to rather disappointing results,
with reduction product 4 being the major component
(54% 19F NMR yield, with PhOCF3 as internal stan-
dard); alcohol 5 was also formed along with another
gem-difluorinated product in a 5/1 ratio as minor com-
ponents. Other fluorinated impurities were also ob-
served in the crude reaction mixture. Isolation and
characterization of the third compound, demonstrated
that it was the cyclized structure 6 (12% isolated yield),16
resulting from an intramolecular displacement of the
OMe group (Scheme 3).
When the reaction was conducted in PhCHO as solvent
and electrophile, it was cleaner but yields of 5 and 6 were
not improved. Indium has been found to be a suitable
reagent for the coupling reactions of b-aminovinyl chlo-
rodifluoromethylated ketones with a series of hetero-
aldehydes.17 However using our described conditions
[In 1.2equiv, PhCHO 1.2equiv, THF/H 2O (1/4, v/v)
at room temperature for 18 h], starting material 3 was
Figure 1. 2,3-Dihydropyrano[2,3-b]pyridine structures of biological
importance.
Scheme 2.
Scheme 3.

M. Me´debielle et al. / Tetrahedron Letters 46 (2005) 7817–7821
7819
recovered with no fluorinated products being formed.
Strong binding of nitrogen atoms at the indium center
may be an explanation for this disappointing result.
Electrochemical activation of substrate 3 in the presence
of 2equiv of PhCHO, using an undivided cell (carbon
felt cathode/magnesium anode, at room temperature)
at controlled potential electrolysis corresponding to
the first peak potential measured by cyclic voltammetry,
afforded cleanly the reduction product 4 and alcohol
adduct 5 in a 1/2ratio with a consumption of electricity
close to 1.6 F/mol. None of the cyclized product 6 was
observed. Product 5 was isolated after silica gel chroma-
tography in 49% isolated yield as a viscous yellowish oil.
The electrolysis reaction was also extended with other
aldehydes to yield the corresponding alcohol adducts
in moderate yields (Scheme 4).18
yield. With 3,4-dimethoxybenzaldehyde, reaction was
slower (24 h) with a 22% isolated yield of 12. An
increased amount of activated zinc (4 equiv) resulted in
shorter reaction time but the final product unfortu-
nately had decomposed into unidentified fluorinated
compounds.
In conclusion we have demonstrated that the method
used to activate the C–Cl bond of a suitable 4-amino-
3-chlorodifluoroacetyl-2-methoxyquinoline, can lead to
different types of fluorinated 4-aminoquinoline derived
products.
Under electrochemical activation, gem-difluorinated
alcohol adducts can be obtained in reasonable yields,
whereas a Reformatsky type reaction gave directly
gem-difluorinated 5-aminodihydropyrano[2,3-b]quino-
lin-4-one cyclized products in modest yields. The yields
of the products 5–12 need to be improved, but using
the present methodology has been adequate for prepara-
tion of these novel molecules in sufficient quantity for
biological screening. We are currently trying to optimize
the yields of the dihydropyrano[2,3-b]quinolines as well
as to extend these reactions with other electrophiles and
new chlorodifluoromethylated heterocyclic substrates.
The products described in this letter are currently being
screened as potential acetylcholinesterase inhibitors and
antivirals.
The Reformatsky reaction of halogenodifluoromethyl
ketones with carbonyl compounds mediated by zinc1,19
is one of the well-known synthetic methodologies to
obtain the corresponding carbon–carbon coupling
products. Using 2.2 equiv of acid washed, activated zinc,
and 2equiv of PhCHO in anhydrous DMF at 110 ꢁC
(oil bath temperature) for 16 h, starting material 3 was
totally consumed and gave the cyclized compound 6 as
major product (42% isolated yield) along with reduction
product 4 (Scheme 5).20 19F NMR monitoring clearly
indicated that 5 was an intermediate and that it was
subsequently transformed into 6. This approach was
then applied to other aldehydes. When using
p-CF3C6H4CHO, cyclized product 10 was obtained in
19% isolated yield because of partial decomposition
during silica gel chromatography (19F NMR yield using
PhOCF3 as internal standard was close to 38%). In addi-
tion pinacol coupling product was observed by 19F
NMR (dF = À62.1 ppm). With p-FC6H4CHO, some
pinacol was also formed but in lesser amount, and
cyclized product 11 could be obtained in 40% isolated
Acknowledgments
M.M. would like to thank the CNRS for support of this
research, the Direction des Relations Internationales
(DRI) of the CNRS for travel funds and JSPS for a
research fellowship.
References and notes
´
´
1. (a) Begue, J. P.; Bonnet-Delpon, D. Tetrahedron 1991, 47,
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Swartling, D. J. Fluorine Substituted Analogues of
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Liebman, J. F., Greenberg, A., Dolbier, W. R., Jr., Eds.;
VCH: New York, 1988; p 259.
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Scheme 4.
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1989, 870; (b) Hojo, M.; Masuda, R.; Okada, E. Tetra-
hedron Lett. 1987, 28, 6199.
Scheme 5.

7820
M. Me´debielle et al. / Tetrahedron Letters 46 (2005) 7817–7821
´
8. Okada, E.; Tsukushi, N.; Otsuki, Y.; Nishiyama, S.;
15. (a) Medebielle, M.; Kato, K.; Dolbier, W. R., Jr.
´
Fukuda, T. Synlett 1999, 126.
Tetrahedron Lett. 2003, 44, 7871; (b) Medebielle, M.;
9. (a) Okada, E.; Tsukushi, N.; Shimomura, N. Synthesis
2000, 237; (b) Okada, E.; Tsukushi, N. Synlett 1999, 210.
Kato, K.; Dolbier, W. R., Jr. Synlett 2002, 1541; (c)
´
Medebielle, M.; Keirouz, R.; Okada, E.; Ashida, T.
´
10. Okada, E.; Otsuki, Y.; Shinohara, M.; Medebielle, M.;
Synlett 2001, 821; (d) Billard, T.; Langlois, B. R.;
´
Shimizu, Y.; Takeuchi, H. Tetrahedron Lett. 2003, 44, 741.
Medebielle, M. Tetrahedron Lett. 2001, 42, 3463.
´
11. (a) Fujii, S.; Kato, K.; Medebielle, M. Tetrahedron 2000,
16. A typical procedure for the reaction between 3, TDAE
and benzaldehyde is as follows: Into a two-necked flask
equipped with a silica gel drying tube and a nitrogen inlet
were added, under nitrogen at À20 ꢁC, a 5 ml anhydrous
DMF solution of 3 (0.436 g, 1.52mmol) and benzaldehyde
(0.32g, 3.04 mmol; 0.15 ml). The solution was stirred and
maintained at this temperature for 30 min and then was
56, 2655; (b) Burkholder, C.; Dolbier, W. R., Jr.;
Medebielle, M. J. Fluorine Chem. 2000, 102, 369; (c)
´
Okada, E.; Tsukushi, N.; Shimomura, N. Synthesis 2000,
1822; (d) Okada, E.; Sakaemura, T.; Shimomura, N.
Chem. Lett. 2000, 50; (e) Okada, E.; Tsukushi, N.
Synthesis 2000, 499; (f) Okada, E.; Tsukushi, N. Hetero-
cycles 2000, 53, 127; (g) Burkholder, C.; Dolbier, W. R.,
added dropwise (via
a syringe) the TDAE (0.30 g,
´
Jr.; Medebielle, M.; Ndedi, A. Tetrahedron Lett. 1998, 39,
1.52mmol, 0.15 ml). A red color immediately developed
with the formation of a white fine precipitate. The solution
was vigorously stirred at À20 ꢁC for 1 h and then warmed
up to room temperature for 18 h. After this time fluorine
NMR showed that the ketone 3 was totally consumed.
The orange-red turbid solution was filtered (to remove the
octamethyloxamidinium dichloride) and hydrolyzed with
30 ml of H2O. The aqueous solution was extracted with
CHCl3 (3 · 30 ml), the combined organic solutions washed
with brine (3 · 30 ml), H2O (3 · 30 ml), and dried over
Na2SO4. Evaporation of the solvent left an orange viscous
liquid as crude product. Purification by silica gel chroma-
tography (EtOAc/Petroleum ether, 90/10 as eluent) gave
first 4, with 5 and 6 as the most polar compounds. 1-(4-
Amino-2-methoxyquinolin-3-yl)-2,2-difluoro-3-hydroxy-3-
´
8853; (h) Burkholder, C.; Dolbier, W. R., Jr.; Medebielle,
M. J. Org. Chem. 1998, 63, 5385.
12. (a) Martin-Santamaria, S.; Munoz-Muriedas, J.; Luque,
˜
J.; Gago, F. J. Med. Chem. 2004, 47, 4471; (b) Desai, M.
C.; Thadeio, P. F.; Lipinski, C. A.; Liston, D. R.; Spencer,
R. W.; Williams, I. H. Bioorg. Med. Chem. Lett. 1991, 1,
411.
13. Bargar, T. M.; Dulworth, J. K.; Kenny, M. T.; Massad,
R.; Daniel, J. K.; Wilson, T.; Sargent, R. N. J. Med.
Chem. 1986, 29, 1590.
14. 1-Chloro-1,1-difluoro-4,4-dimethoxybut-3-en-2-one (1). To
a
stirred solution of methyl orthoacetate (12.02 g,
10.0 mmol) and pyridine (1.62ml, 20.0 mmol) in CH 2Cl2
(20 ml) was added dropwise chlorodifluoroacetic anhy-
dride (3.48 ml, 20.0 mmol) and the mixture was stirred at
room temperature for 18 h. CH2Cl2 (20 ml) was added to
the reaction mixture and then it was washed with aqueous
10% Na2CO3 (50 ml) and with H2O (2 · 50 ml) and the
organic layer was separated and dried (Na2SO4). The
solvent was removed in vacuo to give practically pure
product 1 (1.99 g, 99%). Mp 48–49 ꢁC (hexane/EtOAc).
1H NMR (CDCl3): dH 5.10 (s, 1H, CH), 4.07 (s, 3H, CH3),
4.03 (s, 3H, CH3). 19F NMR (CDCl3/CFCl3): dF À67.5
(2F, s). IR (KBr) mC@O = 1680 cmÀ1. Anal. Calcd for
C6H7ClF2O3: C, 35.93; H, 3.52. Found: C, 35.73; H, 3.61.
(E)-1-Chloro-1,1-difluoro-4-methoxy-4-(2-cyano-phenyl)-
aminobut-3-en-2-one (2). To a solution of 1 (1.00 g,
5.0 mmol) in MeCN (10 ml) was added 2-aminobenzonit-
rile (0.6 g, 5.05 mmol) and the mixture was stirred under
reflux for 18 h. The solvent was removed in vacuo and the
crude mixture was recrystallized from hexane/EtOAc to
afford 2 (1.15 g, 80%). Mp 143–144 ꢁC (hexane/EtOAc);
1H NMR (CDCl3): dH 12.60–12.03 (br, 1H, NH), 8.03–
7.23 (m, 4H, C6H4), 5.53 (s, 1H, CH), 4.08 (s, 3H, CH3).
19F NMR (CDCl3/CFCl3): dF À64.7 (2F, s). IR (KBr)
1
phenyl-propan-1-one (5). Yellowish viscous oil. H NMR
(CDCl3): dH 4.07 (3H, s, OMe), 5.55 (1H, dd, J = 18.1,
6.40 Hz, –CHOH), 7.02(2H, br s, NH 2), 7.29–7.71 (9H,
m). 19F NMR (CDCl3/CFCl3): dF À108.5 (1F, dd,
J = 266.2, 6.90 Hz), À119.7 (1F, dd, J = 266.2, 18.3 Hz).
HRMS: Calcd for C19H16F2N2O3 358.1129, Found
358.1135. 5-Amino-3,3-difluoro-2-phenyl-2,3-dihydropyr-
ano[2,3-b]quinolin-4-one (6). Yellow solid. Mp 161–
164 ꢁC (decomp). 1H NMR (CDCl3): dH 5.87 (1H, d,
J = 20.8 Hz), 6.99–8.12 (11H, m). 19F NMR (CDCl3/
CFCl3): dF À121.6 (1F, dd, J = 283.3, 21.8 Hz), À125.3
(1F, d, J = 283.3). 13C NMR (DMSO-d6) dC 80.1, 117.3,
1
125.2, 128.6 (t, JC–F = 279.1 Hz), 129.1, 129.4, 129.6 (t,
2JC–F = 10.7 Hz), 130.2, 130.5, 131.9, 132.5, 133.0, 134.9,
2
145.1, 148.9, 159.5, 161.7, 181.7 (C@O, JC–F = 33.4 Hz).
HRMS: calcd for C18H12F2N2O2 326.0867, Found
326.0923.
´
17. Medebielle, M.; Onomura, O.; Keirouz, R.; Okada, E.;
Yano, H.; Terauchi, T. Synthesis 2002, 2601.
18. A typical procedure for the electrochemical coupling of 3
and benzaldehyde is as follows: The reaction was con-
ducted in an undivided cylindrical Pyrex cell, fitted with a
carbon felt cathode (S = 15 cm2) and a magnesium rod as
m
NH = 3463, mCN = 2226, mC@O = 1639 cmÀ1. Anal. Calcd
for C12H9ClF2N2O2: C, 50.28; H, 3.16; N, 9.77. Found: C,
50.41; H, 3.02; N, 9.78. 4-Amino-3-chlorodifluoroacetyl-2-
methoxyquinoline (3). Trifluoromethanesulfonic acid
(3.2ml, 36 mmol) was added to compound 2 (450 mg,
1.57 mmol) and the reaction mixture was refluxed with
stirring for 5 min. Saturated aqueous solution of Na2CO3
(50 ml) was added to the reaction mixture, then aqueous
mixture was extracted with EtOAc (50 ml), and the
organic layer was separated and dried (Na2SO4). The
solvent was evaporated in vacuo and the crude mixture
was purified by silica gel chromatography using hexane/
EtOAc (10/1) as eluent to give 3 (151 mg, 34%). Mp 136–
anode under nitrogen. Starting material
3 (0.436 g,
1.52mmol) was added to a solution of anhydrous DMF
(40 ml) containing NBu4Br (0.38 g, 1.18 mmol) and benz-
aldeyhde (0.32g, 3.04 mmol; 0.15 ml). The electrolysis
was performed under a constant current (I = 0.035 A) till
1.6–2F/mol of electricity had passed. The solution was
hydrolyzed with saturated aqueous NaCl (60 ml) and the
organic portion was extracted with ethyl acetate
(3 · 60 ml). The combined organic layers were washed
with saturated aqueous NaCl (3 · 60 ml), water
(3 · 60 ml), and dried over Na2SO4. Filtration and evapo-
ration of the solvent under reduced pressure left a residue,
which was purified by silica gel chromatography using
petroleum ether/EtOAc (90/10) as eluent to give com-
pounds 5–9.
1
137 ꢁC (hexane/EtOAc). H NMR (CDCl3): dH 8.30–7.26
(m, 6H, H-5, H-6, H-7, H-8, NH2), 4.17 (s, 3H, CH3). 19
F
NMR (CDCl3/CFCl3): dF À61.5 (2F, s). IR (KBr)
m
NH = 3461, 3338, mC@O = 1603 cmÀ1. Anal. Calcd for
C12H9ClF2N2O2: C, 50.28; H, 3.16; N, 9.77. Found: C,
50.47; H, 3.32; N, 9.42.
19. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60,
9325.

M. Me´debielle et al. / Tetrahedron Letters 46 (2005) 7817–7821
7821
20. A typical procedure for the reaction of 3, benzaldehyde and
zinc is as follows: Into a two-necked flask equipped with a
reflux condenser and a nitrogen inlet were added, under
nitrogen, a 10 ml anhydrous DMF solution of 3 (0.436 g,
1.52mmol) and benzaldehyde (0.32g, 3.04 mmol; 0.15 ml).
The solution was stirred at room temperature until complete
dissolution and then was added activated zinc at once
(0.198 g, 3.04 mmol). The yellowish solution was then
heated at 110 ꢁC (oil bath temperature) for 16–24 h until
all starting ketone 3 was consumed (19F NMR monitoring).
The dark-brown mixture was cooled down to room
temperature, filtrated, and DMF was evaporated to dry-
ness. The crude product was diluted with EtOAc and the
organic solution was washed with a saturated aqueous
NH4Cl solution (3 · 30 ml), and dried over Na2SO4. Evapo-
ration of the solvent left a viscous oil as crude product.
Purification by silica gel chromatography using petroleum
ether/EtOAc (90/10) as eluent gave the products 6–12.