Synthesis of 2-substituted-6,7-dimethoxy- and 6,7,8-trimethoxy-3-hydroxyquinolin-4(1H)-ones

Article abstract of DOI:10.1135/cccc19990257

Acetonyl and phenacyl esters of 4,5-dimethoxy- and 3,4,5-trimethoxyanthranilic acids 3 were prepared by reduction of corresponding nitro derivatives 2. Acetonyl 4,5-dimethoxyanthranilate (3a) was prepared by reaction of 4,5-dimethoxyanthranilic acid and c

Full text of DOI:10.1135/cccc19990257

3-Hydroxyquinolin-4(1H)-ones
257
SYNTHESIS OF 2-SUBSTITUTED-6,7-DIMETHOXY- AND
6,7,8-TRIMETHOXY-3-HYDROXYQUINOLIN-4(1H)-ONES
a,
b
c
d
Pavel HRADIL *, Jan VANĚČEK , Jan HLAVÁČ and Juraj ŠEVČÍK
a
Farmak Co., 771 17 Olomouc, Czech Republic; e-mail: research@farmak.cz
Research Institute of Organic Syntheses Ltd., 532 18 Pardubice-Rybitví, Czech Republic;
e-mail: jana.netusilova@vuoas.cz
Department of Organic Chemistry, Palacký University, 771 46 Olomouc, Czech Republic;
e-mail: hlavac@risc.upol.cz
Laboratory of Bioanalytical Research, Palacký University, 771 26 Olomouc, Czech Republic;
e-mail: sevcik@risc.upol.cz
b
c
d
Received March 18,1998
Accepted Septem ber 23, 1998
Dedicated to the memory of Dr Miroslav Protiva.
Aceton yl an d ph en acyl esters of 4,5-dim eth oxy- an d 3,4,5-trim eth oxyan th ran ilic acids 3
were prepared by reduction of correspon din g n itro derivatives 2. Aceton yl 4,5-dim eth oxy-
an th ran ilate (3a ) was prepared by reaction of 4,5-dim eth oxyan th ran ilic acid an d
ch loroaceton e. Cyclization of th ese aceton yl an d ph en acyl esters in polyph osph oric acid
provided th e correspon din g 2-substituted-6,7-dim eth oxy- an d 6,7,8-trim eth oxy-
3-h ydroxyquin olin -4(1H)-on es 4. A n ew m eth od of th e th erm al cyclization is also described.
Th e structure of th e prepared com poun ds was con firm ed by 1H NMR spectroscopy.
Key w ord s: Cyclization ; An th ran ilates; 3-Hydroxyquin olin -4(1H)-on es; Quin olin on es.
2-Aryl-3-h ydroxyquin olin -4(1H)-on es h ave n ot been exten sively studied,
but several m eth ods of th eir preparation h ave been described. Th e oldest
m eth od, leadin g to th e m en tion ed com poun ds in several steps from
2-n itroben zaldeh yde an d ph en acyl brom ide, is based on a m odification of
th e Darzen s reaction 1. Th is m eth od was used for th e preparation of
3,6-dim eth oxy-1-m eth yl-2-ph en ylquin olin -4(1H)-on e, th e plan t alkaloid
japon in e2. Elbs peroxodisulfate oxidation of 2-substituted quin olin -
4(1H)-on es to th e correspon din g 3-h ydroxy derivatives3 an d a rin g expan -
sion of 1-acetyl-2-(aryl-m eth ylen e)in dol-3(2H)-on es4 h ave been described
recen tly. We h ave recen tly described5 a n ew m eth od of preparation of
2-aryl-3-h ydroxyquin olin -4(1H)-on es based on a rearran gem en t observed
durin g cyclization of ph en acyl an th ran ilates. Th e un expected course of th e
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

258
Hradil, Vaněček, Hlaváč, Ševčík:
reaction was con firm ed by 1H NMR an d 13C NMR studies, an d for several
kn own com poun ds also by com parin g th eir m eltin g poin ts with th e pub-
lish ed values.
2-Arylquin olin -4(1H)-on es are isosteric with flavon es, n aturally occurrin g
com poun ds with a wide spectrum of biological activities. Th e flavon e m oi-
ety is often substituted by h ydroxy an d/or m eth oxy groups at various posi-
tion s, especially at position 3 an d in th e ben zen e part of th e m olecule.
Som e of th ese com poun ds are sim ple, for exam ple 3,7-dih ydroxy-2-ph en yl-
ben zopyran -4(1H)-on e isolated from Platymiscium praecox6 or 3,7-dih ydroxy-
8-m eth oxy-2-ph en ylben zopyran -4(1H)-on e (zuccagin e) isolated from
Zuccagnia punctata7. Oth ers are polysubstituted, for exam ple 3,5-dih ydroxy-
6,7,8-trim eth oxy-2-ph en ylben zopyran -4(1H)-on e isolated from Achyrocline
bogotensis or Achillea nobilis8. Th e best kn own com poun d of th is class is
3,5,7-trih ydroxy-2-(3,4-dih ydroxyph en yl)ben zopyran -4(1H)-on e (quercetin )
with effects on th e cardiovascular system , circulation , as well as an tican cer,
an algesic, an d an ti-free radical activities9. 3-Hydroxy-6,7,8-trim eth oxy-
2-(4-m eth oxyph en yl)ben zopyran -4(1H)-on e, isolated from Citrus aurantium,
sh ows im m un osuppressan t activity10
.
Th e above-m en tion ed activities of 3-h ydroxyflavon es in spired us to prove
th e applicability of our m eth od of syn th esis of 2-aryl-3-h ydroxyquin olin -
4(1H)-on es to th e preparation of th ese com poun ds bearin g substituen ts typ-
ical of flavon es. In our previous paper5, we h ave sh own th at th e reaction is
com patible with a wide ran ge of substituen ts on th e 2-ph en yl group. In or-
der to sh ow applicability of our m eth od to th e preparation of poly-
m eth oxyquin olin e flavon e isosteres, th e presen t paper describes th e
syn th esis of 2-substituted-3-h ydroxyquin olin -4(1H)-on es with two or th ree
m eth oxy groups in th e quin olin e part of th e m olecule. Cyclization of sim i-
lar aceton yl esters un der th e described con dition s as well as th erm al
cyclization of th ese com poun ds are also studied.
Startin g 4,5-dim eth oxy- (1a) an d 3,4,5-trim eth oxy-2-n itroben zoic (1b)
acids were prepared by described m eth ods11,12. Th ese acid treated with
ch loroaceton e an d ph en acyl brom ide provided th eir respective aceton yl
an d ph en acyl esters 2. Sim ple reduction of th ese in term ediates th en yielded
correspon din g am in o derivatives 3 (Sch em e 1). However, som e un ex-
plain ed differen ces were observed in th e reduction . Th ough com poun d 2b
was reduced un der con dition s previously used for reduction of ph en acyl es-
ters of un substituted 2-n itroben zoic acid13, th is m eth od did n ot work for
oth er derivatives. A very sim ilar com poun d 2d did n ot react with iron un -
der th e described con dition s, zin c dust an d acetic acid m ust be used in th is
case. Aceton yl esters were m ore sen sitive to h ydrolysis th an ph en acyl esters
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

3-Hydroxyquinolin-4(1H)-ones
259
an d startin g acids were form ed in th e m ixture durin g wash in g an d th ere-
fore on ly lim ited wash in g an d rapid work up is essen tial. Aceton yl deriva-
tive 2c was reduced in th e sam e way as 2d . However, we failed to prepare
3a usin g th is way an d th erefore we started from 4,5-dim eth oxyan th ran ilic
acid an d th e sam e procedure described for un substituted an th ran ilic acid
was used5. Th e h igh er stability of com poun d 2c in com parison with 2a
could be caused by a steric effect of th e 3-m eth oxy group. Th e lower reac-
tivity of 2d com pared with 2b could h ave th e sam e reason .
O
MeO
MeO
COOH
2
2
R
MeO
MeO
R COCH X
2
O
Et N
3
X = Cl, Br
O
NO
2
NO
2
1
R
1
2
R
1
1a, R = H
1
1b, R = OMe
for 2b-2c
O
O
O
2
R
MeO
MeO
MeO
MeO
OH
O
2
NH
2
R
N
1
1
3
R
R
H
4
MeCOCH Cl
2
NaHCO /DMF
3
1
2
R
R
2-4
MeO
MeO
COOH
H
H
Me
Ph
Me
Ph
a
b
c
d
MeO
MeO
NH
2
SCHEME 1
Cyclization of th ese substituted ph en acyl an th ran ilates occurred in
polyph osph oric acid, except with com poun d 3a. In th is case, com poun d 4a
was presen t in th e reaction m ixture (TLC) but we failed to isolate it an d
th erefore an altern ative procedure was applied. Th erm al cyclization of 3 in
N-m eth ylpyrrolidon e yielded th e required product. 3,4,5-Trim eth oxy-
an th ran ilates could also be successfully cyclized by th is m eth od but a lon -
ger reaction tim e was n ecessary, probably for steric reason s. Gen erally, th e
th erm al cyclization m eth od is sim ple an d affords very pure products.
Sin ce n atural flavon es often possess h ydroxy groups, we tried to prepare
h ydroxy substituted quin olon es by dem eth ylation of th e correspon din g
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

260
Hradil, Vaněček, Hlaváč, Ševčík:
m eth oxy com poun ds. We failed to dem eth ylate com poun ds 4b an d 4d un -
der various con dition s kn own to be used in th e literature for dem eth ylation
of sim ilar com poun ds. Th e used agen ts in cluded pyridin ium h ydroch lo-
ride14, alum in ium trich loride15, as well as h ydrobrom ic acid16. No reaction
was observed un der m ild con dition s an d wh en h igh er tem perature was ap-
plied, com plex m ixtures were obtain ed. Sim ilar results were obtain ed with
boron tribrom ide17. If th e reaction was perform ed at room tem perature an d
th e excess of boron tribrom ide was lower th an 3 equivaletn s, th e startin g
com poun d was isolated after th e workup with sodium h ydroxide. Wh en ei-
th er h igh er excess of th e agen t was used or th e reaction was perform ed in
boilin g ch loroform solution s, n on separable com plex m ixtures were ob-
tain ed from wh ich n o com poun d was successfully isolated an d iden tified.
EXPERIMENTAL
Th e m eltin g poin ts were m easured on a Koffler block an d are un corrected. Th e 1H NMR
spectra were m easured in h exadeuteriodim eth yl sulfoxide solution s on an AMX-360 Bruker
spectrom eter (360 MHz) with tetram eth ylsilan e as an in tern al stan dard. Ch em ical sh ifts are
given in ppm (δ-scale), couplin g con stan ts (J) in Hz. Elem en tal an alyses were perform ed us-
in g an EA 1108 Elem en tal An alyser (Fison In strum en t). TLC was perform ed on a Polygram
Sil G/UV254 with UV detection . Ch aracteristic data of th e prepared com poun ds are presen ted
in Table I, th eir 1H NMR spectra in Table II.
Aceton yl an d Ph en acyl 4,5-Dim eth oxy- an d 3,4,5-Trim eth oxy-2-n itroben zoates 2.
Gen eral Procedure
Ch loroaceton e or 2-brom acetoph en on e (44 m m ol) was added to a solution of correspon din g
acid 1a or 1b (44 m m ol) an d trieth ylam in e (6.2 m l, 44 m m ol) in aceton e (200 m l) an d th e
reaction m ixture was refluxed un til n o startin g m aterial was detected by TLC (toluen e–eth yl
acetate 1 : 1). Th en th e reaction m ixture was cooled to 5 °C, th e precipitated trieth yl-
am m on ium salt was filtered off an d th e filtrate was evaporated. Th e residual dark oil was
dissolved in eth yl acetate (200 m l) an d quickly wash ed with water. Aceton yl esters were
wash ed on ly on ce because of th eir rapid h ydrolysis. Th e organ ic layer was dried with so-
dium sulfate an d th e residual oil after evaporation was crystallized from eth an ol. Th e yields
an d ch aracteristic data are presen ted in Table I.
Aceton yl 2-Am in o-3,4-dim eth oxyben zoate (3a)
Sodium h ydrogen carbon ate (1.3 g, 15.5 m m ol) was added to a solution of 4,5-dim eth oxy-
2-am in oben zoic acid (2.4 g, 12.2 m m ol) in N,N-dim eth ylform am ide (13 m l) an d th e reaction
m ixture was stirred at 95–100 °C for 2 h . Ch loroaceton e (0.9 m l, 12.2 m m ol) was added to
th e suspen sion at 20 °C. Th e tem perature in creased spon tan eously to 25 °C an d th e m ixture
was stirred for 1 h at am bien t tem perature. Th en th e reaction m ixture was h eated at 60 °C
for 2 m in , poured in to water (200 m l), th e precipitated solid was cooled to 0–5 °C, filtered
off, an d wash ed successively with 1% solution of NaHCO3 (100 m l) an d water (50 m l). Crys-
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

3-Hydroxyquinolin-4(1H)-ones
261
tallization from eth an ol yielded 3a (2 g, 65%), m .p. 129–132 °C. For C12H15NO5 (253.3) cal-
culated: 56.91% C, 5.97% H, 5.53% N; foun d: 57.02% C, 6.07% H, 5.40% N.
Ph en acyl 2-Am in o-4,5-dim eth oxyben zoate (3b)
Iron dust (1.0 g, 18.4 m m ol) was added to a solution of 2b (1 g, 2.9 m m ol ) in a m ixture of
aceton e (5 m l), water (1 m l), an d acetic acid (0.12 m l, 2.1 m m ol) an d th e m ixture was
stirred un der reflux for 2 h . Th en th e reaction was diluted with aceton e (15 m l) an d sodium
h ydrogen carbon ate (0.32 g, 3.8 m m ol) was added. Th e m ixture was refluxed with ch arcoal
TABLE I
Yields an d ch aracteristic data for com poun ds 2 an d 4
Calculated/Foun d
Com -
poun d
Reaction
tim e, m in
M.p., °C
Yield, %
Form ula
M.w.
% C
% H
% N
2a
2b
2c
2d
4a
4b
4c
4d
120
90
114–115
52
C12H13NO7
283.2
50.89
50.95
4.63
5.10
4.95
4.74
144–147
86
C17H15NO7
345.3
59.13
59.02
4.38
4.63
4.06
3.97
240
40
58–59
58
C13H15NO8
313.3
49.84
49.58
4.83
4.99
4.47
4.01
92
85
C18H17NO8
375.3
57.60
57.62
4.57
4.58
3.73
3.45
10a
60a
15a
180a
315–321
0/69b
C12H13NO4
235.2
61.27
61.58
5.57
5.43
6.95
6.21
332–335
87/70b
C17H15NO4
297.3
68.68
68.19
5.09
5.01
4.71
4.63
243–245
48/22b,c
C13H15NO5
265.3
59.08
59.48
5.70
5.96
5.28
5.23
240–242
89/53b
C18H17NO5
327.3
66.05
65.89
5.23
5.33
4.28
4.09
a
b
c
Procedure B; procedure A/procedure B; based on 2c.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

262
Hradil, Vaněček, Hlaváč, Ševčík:
for 30 m in , th e h ot solution was filtered an d th e filtrate was evaporated to dryn ess. Crystal-
lization from a m ixture eth an ol–aceton e (2 : 1) afforded 3b (0.72 g, 79%), m .p. 142–143 °C.
For C17H17NO5 (315.3) calculated: 64.75% C, 5.43% H, 4.44% N; foun d: 64.58% C, 5.92% H,
4.49% N.
TABLE II
1H NMR data (δ, ppm ; J, Hz) for com poun ds 2, 3 an d 4
Com -
poun d
CH3
CH2
C6H5
CH3O
Oth ers
2a
2b
2.21 s (3 H) 5.05 s (2 H)
–
3.96 s (3 H)
3.97 s (3 H)
7.37 s (1 H)
7.70 s (1 H)
–
5.81 s (2 H) 7.63 t; 8 (2 H)
7.64 t; 8 (1 H)
3.98 s (3 H)
4.00 s (3 H)
7.42 s (1 H)
7.72 s (1 H)
8.07 d; 8 (2 H)
2c
2d
2.15 s (3 H) 5.03 s (2 H)
–
3.96 s (3 H)
4.00 s (3 H)
4.02 s (3 H)
7.39 s (1 H)
7.49 s (1 H)
–
5.82 s (2 H) 7.63 t; 8 (2 H)
7.77 t; 8 (1 H)
3.96 s (3 H)
4.00 s (3 H)
4.02 s (3 H)
8.05 d; 8 (2 H)
3a
3b
2.14 s (3 H) 4.89 s (2 H)
–
3.66 s (3 H)
3.76 s (3 H)
6.39 s (1 H)
7.19 s (1 H)
–
–
5.67 s (2 H) 7.60 t; 8 (2 H)
7.75 t; 8 (1 H)
3.72 s (3 H)
3.82 s (3 H)
6.45 s (1 H)
7.29 s (1 H)
8.05 d; 8 (2 H)
3d
5.72 s (2 H) 7.63 t; 8 (2 H)
7.76 t; 8 (1 H)
3.78 s (3 H)
3.79 s (3 H)
3.91 s (3 H)
7.22 s (1 H)
8.06 d; 8 (2 H)
4a
4b
2.33 s (3 H)
–
–
–
–
3.83 s (3 H)
3.85 s (3 H)
6.90 s (1 H)
7.39 s (1 H)
7.55 t; 7.5 (1 H)
7.60 t; 7.5 (2 H)
7.86 t; 7.5 (2 H)
3.90 s (3 H)
3.91 s (3 H)
7.23 s (1 H)
7.48 s (1 H)
4c
4d
2.41 s (3 H)
–
–
–
–
3.88 s (6 H)
3.95 s (3 H)
7.28 s (1 H)
7.37 s (1 H)
7.53–7.59 m ; (3 H) 3.93 s (3 H)
7.76 d; 7 (2 H)
3.95 s (3 H)
3.99 s (3 H)
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

3-Hydroxyquinolin-4(1H)-ones
263
Aceton yl 2-Am in o-3,4,5-trim eth oxyben zoate (3c)
Zin c dust (2 g, 30.6 m m ol) an d acetic acid (20 m l, 0.35 m ol) was added to a solution of 2c
(5 g, 16 m m ol) in eth yl acetate (130 m l) an d th e reaction m ixture was stirred un der reflux
an d th e reaction was ch ecked by TLC (toluen e–eth yl acetate 20 : 1). After 1 h , an addition al
am oun t of zin c dust (0.5 g, 7.6 m m ol) an d acetic acid (1 m l, 17.5 m m ol) were added an d
th e reaction con tin ued for an oth er 1 h . Th en th e reaction m ixture was cooled, th e
precipitate zin c acetate was collected by filtration , th e filtrate was diluted with eth yl ace-
tate (150 m l) an d wash ed successively with water (50 m l) an d 5% solution of sodium
h ydrogen carbon ate to pH 7. Th e organ ic layer was dried with sodium sulfate, filtered with
ch arcoal (0.5 g) an d evaporated to dryn ess. Com poun d 3c was obtain ed as a yellowish oil
an d th e crude product was used for th e n ext step with out furth er purification .
Ph en acyl 2-Am in o-3,4,5-trim eth oxyben zoate (3d )
Th is com poun d was prepared from 2d in th e sam e way as described for th e preparation of
3c (reaction tim e 4 h ). Th e crude product after evaporation of th e solven t was crystallized
from a m in im um am oun t of eth an ol to provide 3d (68%), m .p. 144–146 °C. For C18H19NO6
(345.4) calculated: 62.60% C, 5.55% H, 4.06% N; foun d: 62.35% C, 6.04% H, 3.98% N.
2-Substituted-3-h ydroxy-6,7-dim eth oxy- an d 6,7,8-Trim eth oxyquin olin -4(1H)-on es 4.
Gen eral Procedures
A) An an th ran ilate 3 (1 m m ol) was added to polyph osph oric acid (5 g) at 100 °C an d th e
reaction m ixture was stirred at th is tem perature for 1 h . Reaction was con tin ued un til n o
startin g m aterial was detected by TLC (toluen e–eth yl acetate 1 : 1, eth yl acetate–aceton e 4 : 1
or toluen e–eth yl acetate 4 : 1). Th en th e reaction m ixture was diluted with cold water (80 m l),
th e m ixture was cooled to room tem perature an d n eutralized to pH 7 with a 10% solution
of sodium h ydroxide. Th e precipitated crystallin e m aterial was filtered off, wash ed with wa-
ter (20 m l), dried at 60 °C an d crystallized from N,N-dim eth ylform am ide. Th e yields an d
ch aracteristic data are given in Table I.
B) A solution of an an th ran ilate 3 (2.5 m m ol) in N-m eth ylpyrrolidon e (1.5 m l) was
refluxed un til n o startin g m aterial was detected by TLC (see Table II). Th e reaction m ixture
was cooled to 60 °C, eth yl acetate (20 m l) was added, th e suspen sion was stirred at 0–5 °C
for 30 m in an d th en left to stan d overn igh t in a refrigerator. Th e precipitated product was
collected by filtration , successively wash ed with water (30 m l) an d cold eth an ol (10 m l), an d
dried at 100 °C. Th e yields an d ch aracteristic data are presen ted in Table I.
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