Convenient synthetic routes to 5-substituted 3-(4-methoxyphenyl)-4(1H)-quinolones

Article abstract of DOI:10.1055/s-2003-40845

5-Substituted 3-(4-methoxyphenyl)-4(1H)-quinolones 5-18 have been synthesised in good yields from the corresponding 3-(4-methoxyphenyl)-5-trifluoromethanesulfonate-4(1H)-quinolones 4 via palladium-mediated cross-coupling reactions or aromatic nucleophilic

Full text of DOI:10.1055/s-2003-40845

1542
LETTER
Convenient Synthetic Routes to 5-Substituted 3-(4-Methoxyphenyl)-4(1H)-
quinolones
S
ynthetic Routes
e
to 5-Substi
n
tuted 3-(4-M
o
ethoxypheny
î
l)-4(1
Ht
)-quinolonesJoseph,*a,b Aurélie Béhard,b Brigitte Lesur,c Gérald Guillaumetb
a
Laboratoire de Chimie Organique 1, UMR-CNRS 5622, Université Claude Bernard - Lyon 1, CPE - Bâtiment 308, 43 Boulevard
du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72431214; E-mail: benoit.joseph@univ-lyon1.fr
b
c
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Université d’Orléans, B.P. 6759, 45067 Orléans Cedex 2, France
Cephalon France, Centre de Recherche et de Développement, 19 Avenue du Professeur Cadiot, 94701 Maisons-Alfort Cedex, France
Received 26 May 2003
Stille3 or Suzuki reactions.4 Because of the intense interest
in nitrogen-based biologically active heterocycles, we
have also investigated the introduction of a primary or
secondary amine at the same position via an aromatic nu-
cleophilic substitution reaction.5 These two synthetic
pathways required the preparation of 3-(4-methoxyphe-
nyl)-5-trifluoromethanesulfonate-4(1H)-quinolones 4. To
our knowledge, very little attention has been devoted to
the study of the displacement of triflate group of 4-quino-
lones.6
Abstract: 5-Substituted 3-(4-methoxyphenyl)-4(1H)-quinolones
5–18 have been synthesised in good yields from the corresponding
3-(4-methoxyphenyl)-5-trifluoromethanesulfonate-4(1H)-quinolo-
nes 4 via palladium-mediated cross-coupling reactions or aromatic
nucleophilic substitution (SNAr) reactions.
Key words: quinolones, Stille reaction, Suzuki reaction, nucleo-
philic aromatic substitutions, aminations.
3-Aryl-5-hydroxy-7-methoxy-4(1H)-quinolones, close
analogues of the natural product genistein,1 have received
attention because several of them were reported to possess
potent EGFR tyrosine kinase inhibition activity.2 The
preparation of new compounds of this series requires the
development of new synthetic strategies. For our part, we
became interested in the C-C bond formation at the 5-po-
sition of the 4-quinolone moiety using well documented
palladium-mediated cross-coupling reactions such as
Herein we report two convenient methods for the synthe-
sis of 5-substituted 3-(4-methoxyphenyl)-4(1H)-quinolo-
nes from 4. Triflates 4 were prepared in three steps from
easily available starting materials 1a7a,b and 1b7b
(Scheme 1).
The 5-methoxy group was, first, selectively cleaved with
HBr 48% in DMF to give the corresponding quinolones 2
Scheme 1
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1542,1544,ftx,en;G11803ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthetic Routes to 5-Substituted 3-(4-Methoxyphenyl)-4(1H)-quinolones
1543
in 80–89% yield.8 As reported in the literature, the proton benzylamine.12 The latter were heated in a sealed tube in
of hydroxy in 5-position was observed in NMR around 1,4-dioxane at 100 °C for 6 h to afford N-benzyl deriva-
14–15 ppm as sharp singlet (internal hydrogen bond).2,7 tive 9.13 Optimal reaction yield (83%) was obtained
Selective N-methylation of 2 with iodomethane (1 equiv) with 5 equivalents of benzylamine. As expected when
in basic medium afforded 3 in good yield. Finally, triflates the methoxy group was found at the para position (com-
49 were obtained by treatment of 3 with trifluoromethane- pound 4b), displacement of the triflate group, under the
sulfonic anhydride (3 equiv) in the presence of pyridine in same conditions, failed. Following these results, the meth-
CH2Cl2. The triflates 4 were purified by column chroma- odology was applied to 4a with several primary or sec-
tography.
ondary amines such as 4-methoxybenzylamine, N,N-
diethylamine, pyrrolidine, piperidine, morpholine, N-me-
thylpiperazine, N-allylamine, N,N-dimethylaminoethyl-
amine. Thus, the desired N-substituted derivatives 9–1714
were obtained in good yields (Table 2).
The palladium-mediated cross-coupling reaction for the
conversion of 4 to 5-vinyl derivative 5 was carried out
under Stille protocol.3 The reaction between 4, vinyltri-
butyltin (1.5 equiv), lithium chloride (2.8 equiv) and
freshly prepared tetrakis(triphenylphosphine)palladium
(6% mol) as catalyst in DMF at 90 °C for 1.5 h afforded 5
in 67–85% yield (optimised conditions). In the same
way, compound 6 was obtained by reaction of 4a with 2-
thienyltributyltin (Scheme 2).
5-Phenyl derivatives 7 were synthesised through a modi-
fied Suzuki methodology10 using 4, phenylboronic acid
(1.5 equiv), tetrakis(triphenylphosphine)palladium (6%
mol) and NaHCO3 as base in 1,4-dioxane/ethanol at reflux
for 3 h (Scheme 2).11 According to the same protocol, 5-
(2-furanyl) derivative 8 was also prepared from 4a. Yields
of compounds 5–8 are reported in Table 1.
Scheme 3
Table 2 Synthesis of N-Substituted Derivatives 9–17
Compd
-NR1R2
Yield (%)
83
9
10
11
86
50
12
13
97
75
Scheme 2
Table 1 Synthesis of C-Substituted Derivatives 5–8
Compound
X
Y
H
R
Yield (%)
14
15
93
90
5a
5b
6
OCH3
H
CH2=CH-
CH2=CH-
67
85
64
OCH3
H
OCH3
16
17
90
90
7a
7b
8
OCH3
H
H
OCH3
H
71
60
75
Finally, the cleavage of the nitrogen-protecting groups
was investigated to obtain the 5-amino derivative 18. In
our hands, the catalytic debenzylation [Pd/C or
Pd(OH)2]15 of 9 or deallylation16 of 16 failed. Treatment
of N-4-methoxybenzyl derivative 10 with DDQ17 in
CH2Cl2/H2O afforded 1818 in low yield (34%). Finally,
compound 10 in the presence of TFA at 60 °C for 1 h led
to 18 with an improved yield (69%) (Scheme 4).19
OCH3
Then, we studied the amination reaction of 4 with various
amines in relation to a medicinal project (Scheme 3). The
first attempts were carried out with reactive triflate 4a and
Synlett 2003, No. 10, 1542–1544 © Thieme Stuttgart · New York

1544
B. Joseph et al.
LETTER
(10) Carrera, G. M.; Sheppard, G. S. Synlett 1994, 93.
(11) Typical procedure: To a solution of 4a (100 mg, 0.22 mmol)
in anhyd 1,4-dioxane (10 mL) was added freshly prepared
tetrakis(triphenylphosphine)palladium (17 mg, 0.014
mmol). The solution was stirred at r.t. for 30 min.
Phenylboronic acid (42 mg, 0.34 mmol) diluted in absolute
EtOH (2 mL) was then added, followed immediately by sat
aq NaHCO3 (3 mL). The heterogeneous solution was stirred
at reflux for 3 h. After cooling, palladium catalyst was
removed by filtration. Brine solution was then added, the
two layers were separated and the aqueous phase was
extracted with EtOAc (3 × 5 mL). The combined organic
extracts were dried over MgSO4 and evaporated. The crude
residue was purified by flash chromatography on silica gel
(CH2Cl2/EtOAc, 9:1) to afford 60 mg (71%) of 7a.
(12) Typical procedure: A mixture of triflate 4a (200 mg, 0.45
mmol) and benzylamine (0.24 mL, 2.20 mmol) in 1,4-
dioxane (2 mL) was heated at 100 °C for 6 h. After cooling,
the solvent was evaporated. The crude residue was purified
by flash chromatography on silica gel (petroleum ether/
EtOAc/NH4OH 4:6:0.1) to afford 150 mg (83%) of 9.
(13) Physical data of 9: mp 176–177 °C (EtOAc); IR (KBr):
3174, 1632, 1607, 1570, 1557, 1508, 1471 cm–1; 1H NMR
(250 MHz, CDCl3): d 3.62 (s, 3 H, NCH3), 3.77 (s, 3 H,
OCH3), 3.82 (s, 3 H, OCH3), 4.44 (d, 2 H, J = 5.6 Hz, CH2),
5.85 (s, 1 H, Ar-H), 5.87 (s, 1 H, Ar-H), 6.94 (d, 2 H, J = 8.8
Hz, Ar-H), 7.22–7.33 (m, 3 H, Ar-H), 7.38–7.41 (m, 3 H,
=CH + Ar-H), 7.48 (d, 2 H, J = 8.8 Hz, Ar-H), 11.02 (broad
t, 1 H, J = 5.6 Hz, NH); 13C NMR (62.90 MHz, CDCl3): d
41.6, 47.3, 55.2, 55.5, 85.2, 89.7, 108.1, 113.8 (2), 122.0,
127.1, 127.4 (2), 128.1, 128.7 (2), 130.2 (2), 138.8, 140.5,
144.4, 153.8, 158.8, 163.6, 178.9; MS (IS): m/z 401 (MH+);
Anal. Calcd for C25H24N2O3: C, 74.98; H, 6.04; N, 6.99.
Found: C, 75.25; H, 5.89; N, 7.13.
Scheme 4
In summary, we have developed efficient routes to 5-sub-
stituted 3-(4-methoxyphenyl)-4(1H)-quinolones 5–17
from the corresponding triflates 4 via either palladium-ca-
talysed reactions or SNAr reactions.
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1628, 1593, 1513 cm–1; 1H NMR (250 MHz, CDCl3): d 3.76
(s, 3 H, NCH3), 3.81 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3),
6.71 (s, 1 H, Ar-H), 6.74 (s, 1 H, Ar-H), 6.89 (d, 2 H, J = 8.5
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=CH); 13C NMR (62.90 MHz, DMSO-d6): d 41.2, 55.1, 56.4,
99.5, 106.7, 113.2, 113.4 (2), 121.1, 127.2, 129.8 (2), 143.0,
143.1, 149.0, 158.3, 160.9, 172.9; MS (IS): m/z 444 (MH+).
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1630, 1610, 1592, 1560, 1515 cm–1; 1H NMR (250 MHz,
CDCl3): d 3.78 (s, 3 H, NCH3), 3.93 (s, 3 H, OCH3), 4.05 (s,
3 H, OCH3), 6.85 (d, 2 H, J = 8.8 Hz, Ar-H), 6.98 (d, 1 H,
J = 8.8 Hz, Ar-H), 7.03 (d, 1 H, J = 8.8 Hz, Ar-H), 7.46 (s, 1
H, =CH), 7.53 (d, 2 H, J = 8.8 Hz, Ar-H); 13C NMR (62.90
MHz, DMSO-d6): d 46.3, 54.4, 55.6, 110.8, 112.8 (2), 116.1,
121.1, 122.4, 125.9, 128.9 (2), 132.7, 141.2, 143.6, 149.2,
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(18) Physical data of 18: mp 161–162 °C (EtOAc/petroleum
ether); IR (KBr): 3446, 3381, 1635, 1610, 1569, 1511 cm–1;
1H NMR (250 MHz, CDCl3): d 3.62 (s, 3 H, NCH3), 3.82 (s,
3 H, OCH3), 3.84 (s, 3 H, OCH3), 5.92 (d, 1 H, J = 2.2 Hz
Ar-H), 5.98 (d, 1 H, J = 2.2 Hz, Ar-H), 6.94 (d, 2 H, J = 8.8
Hz, Ar-H), 7.11 (broad s, 2 H, NH2), 7.40 (s, 1 H, =CH), 7.49
(d, 2 H, J = 8.8 Hz, Ar-H); 13C NMR (62.90 MHz, CDCl3):
d 41.5, 55.3, 55.5, 87.1, 93.8, 108.4, 113.8 (2), 121.8, 128.1,
130.2 (2), 140.9, 144.2, 153.7, 158.8, 163.2, 179.1; MS (IS):
m/z 311 (MH+); Anal. Calcd for C18H18N2O3: C, 69.66; H,
5.85; N, 9.03. Found: C, 70.01; H, 5.69; N, 8.92.
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Synlett 2003, No. 10, 1542–1544 © Thieme Stuttgart · New York