A simple synthetic method for 3-trifluoroacetylated 4-aminoquinolines from 4-dimethylaminoquinoline by novel trifluoroacetylation and N-N exchange reactions

Article abstract of DOI:10.1246/cl.2000.50

Acylation of 4-dimethylaminoquinoline with 1-trifluoroacetyl-4-dimethylaminopyidinium trifluoroacetate proceeded cleanly to give 3-trifluoroacetyl-4-dimethylaminoquinoline, which underwent nucleophilic aromatic substitutions with various amines to afford

Full text of DOI:10.1246/cl.2000.50

50
Chemistry Letters 2000
A Simple Synthetic Method for 3-Trifluoroacetylated 4-Aminoquinolines
from 4-Dimethylaminoquinoline by Novel Trifluoroacetylation and N-N Exchange Reactions
Etsuji Okada,* Takushi Sakaemura, and Naofumi Shimomura
Department of Chemical Science and Engineering, Faculty of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501
(Received September 30, 1999; CL-990841)
Acylation of 4-dimethylaminoquinoline with 1-trifluo-
roacetyl-4-dimethylaminopyridinium trifluoroacetate proceed-
ed cleanly to give 3-trifluoroacetyl-4-dimethylaminoquinoline,
which underwent nucleophilic aromatic substitutions with vari-
ous amines to afford the corresponding N-N exchanged 3-tri-
fluoroacetyl-4-aminoquinolines in excellent yields.
Firstly, synthesis of 3-trifluroacetylated 4-dimethylamino-
quinoline 4 was attempted. Trifluoroacetylation of 4-dimethyl-
aminoquinoline with general electrophilic trifluoroacetylating
reagent, trifluoroacetic anhydride, resulted in almost no reac-
tions. Fortunately, as depicted in Scheme 1, the desired acyla-
tion with a novel agent, 1-trifluoroacetyl-4-dimethylaminopyri-
dinium trifluoroacetate 3,9 which was generated in situ, was
successfully performed to give 3-trifluoroacetyl-4-dimethyl-
aminoquinoline 410 in 87% yield with the formation of 3-tri-
fluoroacetyl-4-dimethylaminopyridine 511 as a by-product.
The yield was nearly optimized under the indicated conditions.
For example, the reaction was run for 12 h in refluxing toluene
to afford only 21% yield of 4.
Malaria remains one of the most important widespread dis-
eases in the world.1 4-Aminoquinolines have been greatly used
as the basis in the molecular design for synthetic antimalarial
compounds.2 The most important 4-aminoquinoline antimalar-
ials, chloroquine, has remained as a major chemotherapeutic
agent for over 40 years. However, it has lost much of its value
by emergence of chloroquine-resistant Plasmodium falciparum.
Therefore, there is the necessity for the urgent development of
alternative antimalarial drugs.3 Moreover, in recent years, con-
siderable attention has been paid to the development of new
methodologies for the syntheses of many kinds of fluorine-con-
taining heterocycles, since these compounds are now widely
recognized as important organic materials showing interesting
biological activities for their potential use in medicinal and
agricultural scientific fields.4 Previously, we have found that
in 1-aminonaphthalenes 1 and 8-aminoquinolines 2 activated
by trifluoroacetyl group, the dimethylamino group, which is
not generally lost in aromatic systems, actually behaves as an
excellent leaving group and undergoes the novel aromatic
nucleophilic substitutions with various nucleophiles including
amines.5 This situation prompted strongly us to investigate the
design of various novel 4-aminoquinoline derivatives 4 and 6 -
16, substituted with a trifluoroacetyl group at the 3-position.
This substituent might regulate important biological functions
and might increase the biological activity of this type of hetero-
cyclic compound, being similar to a phosphine oxide group in
behavior.6
Secondly, we examined the aromatic nucleophilic N-N
exchange reaction of 4 with various amines to prepare a variety
of 3-trifluoroacetylated 4-aminoquinolines and the results are
shown in Scheme 1 and summarized in Table 1.12 Reaction of
4 with ammonia occurred readily at 50 °C for 18 h to give the
Me2N-NH2 exchanged product 6 in 81% yield (Entry 1). The
N-N exchange reactions of aliphatic primary amines such as
methyl-, ethyl-, benzyl -, and isopropylamines took place more
easily even at room temperature within 8 h to afford the desired
4-aminoquinoline derivatives 7 - 10 in over 93% yields
(Entries 2-5). Bulky tert-butylamine also reacted cleanly to
provide 11 by merely elevating reaction temperature (100 °C)
and elongating reaction time (72 h) (Entry 6). More function-
alized 4-allylaminoquinolines 12 was easily synthesized in
93% yield from 4 and allylamine (Entry 7). In propargylamine,
the reaction was performed in refluxing acetonitrile to obtain
exclusively the desired product 13 (Entry 8). While secondary
amines showed lower reactivity than primary ones in the pres-
ent system, pyrrolidine revealed considerable enhanced reactiv-
ity to afford 14 in 91% yield (Entry 9). Aromatic amines such
as p-substituted anilines, for example, p-anisidine underwent
cleanly the desired dimethylamino − p-methoxyphenylamino
exchange under not much forced conditions to give the corre-
The present synthetic route is very simple and consists of
only two steps, novel trifluoroacetylation of 4-dimethylamino-
quinoline and subsequent aromatic nucleophilic N-N exchange
reaction. Many heterocycles such as furans, pyrans, thio-
phenes, pyrroles, and indoles, except for quinolines and
pyridines, can be acylated in good yields.7 Electrophilic substi-
tution of quinolines takes place preferentially in the carbocyclic
rings because the reactivity of pyridine is much less than that
of benzene due to the electron deficiency of the former.8
Trifluoroacetylation in the pyridine ring of quinolines has not
been reported in the past.
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
51
Interscience, New York (1992), Chap. 11 , p. 540; J. F.
Begue and D. Bonnet-Delpon, Tetrahedron, 47, 3207
(1991).
T. L. Gilchrist, in "Heterocyclic Chemistry," Pitman,
London (1985), Chap. 8, p.276; D. L. Comins and S.
O'Connor, Adv. Heterocycl. Chem., 44, 199 (1988).
G. Simchen and A. Schmidt, Synthesis, 1996, 1093.
sponding 4-(p-anisidino)quinoline derivative 15 in almost
quantitative yield (Entry 10). This reaction can also be appli-
cable to amino acids. For instance, reaction of 4 with ethyl
glycinate hydrochloride in the presence of sodium acetate pro-
ceeded very readily at room temperature to provide ethyl N-[3-
trifluoroacetyl-4-quinolyl]glycinate 16 in 92% yield (Entry 11).
It seems noteworthy that this type of N-N exchange reaction
did not occur under considerably forced conditions in 3-trifluo-
roacetyl-4-dimethylaminopyridine 5.13
Thus, we have developed a simple and efficient access to
3-trifluoroacetyl-4-aminoquinolines 4 and 6 - 16, which are not
easily accessible by other methods, in two steps, the novel tri-
fluoroacetylation and N-N exchange reactions, starting from 4-
dimethylaminoquinoline. Further works on the synthetic appli-
cation of 4 to the fluorine-containing heterocycles having a
quinoline skeleton such as diazepinoquinolines and pyrazolo-
quinolines are currently continued in our laboratory and the
results will be published elsewhere in our forthcoming papers.
8
9
10 Procedure for the synthesis of 4: To a solution of 4-
dimethylaminopyridine (1833 mg, 15 mmol) in xylene (30
mL) was added trifluoroacetic anhydride (3150 mg, 15
mmol) and the solution was stirred at room temperature for
0.5 h to generate 1-trifluoroacetyl-4-dimethylaminopyridini-
um trifluoroacetate 3.9 To the stirred suspension was added
the solution of 4-dimethylaminoquinoline (862 mg, 5 mmol)
in xylene (10 mL) and the mixture was refluxed for 18 h.
After removal of the solvent under reduced pressure, CH2Cl2
(100 mL) was added to the residue. The solution was
washed with 20% aq Na2CO3 (50 mL), dried (Na2SO4) and
evaporated to give the crude mixture, which was purified by
chromatography on silica gel using n-hexane/EtOAc (3:1)
and EtOAc to afford 4 (1167 mg, 87%) and 511 (841 mg),
References and Notes
1
respectively. 4: mp 98-99 °C (n-hexane/EtOAc); H-NMR
1
L. H. Miller, M. F. Good, and G. Milon, Science, 264, 1878
(1994).
(CDCl3) δ 8.97 (q, 1H, JHF=2 Hz, H-2), 8.33-8.00 (m, 2H,
H-5, -8), 7.90-7.38 (m, 2H, H-6, -7), 3.17 (s, 6H CH3); IR
(KBr) νC=O = 1690 cm-1; Anal Caled for C13H11F3N2O: C,
58.21; H, 4.13; N, 10.44%. Found: C, 58.27; H, 4.31; N,
10.20%.
2
D. J. Krogstad, I. Y. Gluzman, D. E. Kyle, A. M. J. Oduola,
S. K. Martin, W. K. Milhous, and P. H. Schlesinger, Science,
238, 1283 (1987); D. De, J. T. Mague, L. D. Byers, and D. J.
Krogstad, Tetrahedron Lett., 36, 205 (1995).
11 It is now in progress in our laboratbry to study the mecha-
nism for the formation of 5 under the present reaction condi-
3
For recent examples: P. M. O’Neill, P. G. Bray, S. R.
Hawley, S. A. Ward, and B. K. Park, Pharmacol. Ther. , 77,
29 (1998); D. De, F. M. Krogstad, L. D. Byers, and D. J.
Krogstad, J. Med. Chem., 41, 4918 (1998); T. O. Nguyen, J.
D. Capra, and R. D. Sontheimer, Lupus, 7, 148 (1998); D.
De, L. D. Byers, and D. J. Krogstad, J. Heterocycl. Chem.,
34, 315 (1997).
1
tions. 5: bp 70 °C/4 mmHg (oven temp); H-NMR (CDCl3)
δ 8.78 (q, 1H, JHF=2 Hz, H-2), 8.31 (d, 1H, J=6.2 Hz, H-6),
6.79 (d, 1H, J=6.2 Hz, H-5), 2.97 (s, 6H, CH3); IR (film)
ν
C=O=1682 cm-1; Anal Calcd for C9H9F3N2O: C, 49.55; H,
4.16; N, 12.84%. Found: C, 49.64; H, 4.13; N, 12.78%.
12 Typical procedure for the N-N exchange reaction of 4 with
amines: To a solution of 4 (268 mg, 1 mmol) in MeCN (7
mL) was added benzylamine (107 mg, 1 mmol) and the mix-
ture was stirred at room temperature for 3 h. Evaporation of
the solvent gave 9 (310 mg, 94%); mp 148-149 °C (n-hexa-
ne/EtOAc); 1H-NMR (CDCl3) δ 11.10-10.57 (br, 1H, NH),
8.93 (br s, IH, H-2), 8.33-7.13 (m, 9H, H-5, -6, -7, -8, C6H5),
5.10 (d, 2H, J=5.6 Hz, CH2); IR (KBr) νNH=3250-2245,
4
5
R. Filler and S. M. Naqvi, in "Biomedicinal Aspects of
Fluorine Chemistry," ed by R. Filler and Y. Kobayashi,
Kodansha & Elsevier Biomedical, Tokyo (1982), Chap. 1,
p.1; J. T. Welch, Tetrahedron, 43, 3123 (1987).
M. Hojo, R. Masuda, and E. Okada, Tetrahedron Lett., 28,
6199 (1987); M. Hojo, R. Masuda, E. Okada, and H. Miya,
Synthesis, 1989, 870; E. Okada, N. Tsukushi, Y. Otsuki, S.
Nishiyama, and T. Fukuda, Synlett, 1999, 126; E. Okada and
N. Tsukushi, Synlett, 1999, 210.
ν
C=O=1645 cm-1; Anal Calcd for C18H13F3N2O: C, 65.45; H,
3.97; N, 8.48%. Found: C, 65.37; H, 4.19; N, 8.33%.
13 For example, the reaction of 5 with benzylamine (3 eq) in
refluxing valeronitrile for 48 h did not take place and almost
all of substrate 5 was recovered.
6
7
F. Palacios, D. Aparicio, and J. Garcia, Tetrahedron, 54,
1647 (1998).
J. March, in "Advanced Organic Chemistry," 4th ed, Wiley-