A novel short-step synthesis of functionalized 4-hydroxy-2-quinolones using a 1-hydroxybenzotriazole methodology

Article abstract of DOI:10.1246/bcsj.77.1505

A novel method for the synthesis of 3-substituted 4-hydroxy-1-methyl- and 1-phenyl-2-quinolones is presented. The compounds are produced in a one-step reaction in very good yields (51-76%). The major advantage of the methodology is the short time for the

Full text of DOI:10.1246/bcsj.77.1505

Ó 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 1505–1508 (2004) 1505
A Novel Short-Step Synthesis of Functionalized 4-Hydroxy-2-quinolones
Using a 1-Hydroxybenzotriazole Methodology
Lamprini Zikou, Giorgos Athanasellis, Anastasia Detsi, Alexandros Zografos,
ꢀ
Christos Mitsos, and Olga Igglessi-Markopoulou
Laboratory of Organic Chemistry, School of Chemical Engineering, National Technical University of Athens,
Zografou Campus, Athens 157 73, Greece
Received January 20, 2004; E-mail: ojmark@orfeas.chemeng.ntua.gr
A novel method for the synthesis of 3-substituted 4-hydroxy-1-methyl- and 1-phenyl-2-quinolones is presented. The
compounds are produced in a one-step reaction in very good yields (51–76%). The major advantage of the methodology is
the short time for the synthesis in contrast to previous methodologies requiring several steps and harsh conditions for the
synthesis of quinolone derivatives.
4-Hydroxy-2-quinolones (Fig. 1) constitute an important
class of heterocyclic compounds with widespread biological
action. This class of compounds is comprised of many alkaloids
isolated from a variety of plants such as Haplophyllum tubercu-
latum,1 Galipea Officinalis,2 and Glycosmis citrifolia.3 These
alkaloids have shown remarkable biological and pharmacolog-
ical properties, such as antimicrobial, anticoccidial, and antitu-
mor activities.4–8 Particularly, compounds bearing a methyl
group attached to N-1 have shown anti-inflammatory and an-
tithyroid activity.9,10 Recently, a series of quinoline-3-carbo-
thioamides have shown antinephritic and immunomodulating
activity,11 whereas a novel 1-methylquinolone derivative, de-
signed as an antioxidant to scavenge reactive oxygen species,
may be of therapeutic use for bronchial asthma.12 Antagonistic
activity against the glycine site of the N-methyl-D-aspartate
(NMDA) subtype of excitatory amino acid receptor has also
been reported for 4-hydroxy-2-quinolones.13,14 Finally, 1-meth-
ylquinoline derivatives have been used for treatment of mam-
mals suffering from autoimmune and pathological inflamma-
tion15 diseases and a prostaglandin E mediated condition.16
Many research groups have been involved in the synthesis of
functionalized quinolines. The most common route to these
compounds is the use of anthranilic acid and active methylene
compounds as acylating agents.17,18 Coppola’s group has pub-
lished some very good results on this subject using isatoic an-
hydrides as starting materials.19,20 Our research group has also
been involved in the synthesis of 3-substituted quinoline-2,4-
(1H,3H)-dione21 and quinoline alkaloid analogues.22 We have
recently presented a very flexible one-step method for the syn-
thesis of tetramic acids,23 tetronic acids,24 and functionalized
butenoates.25 We attempted to apply this methodology to the
synthesis of ‘‘quinolones’’ by using as starting materials N-
methyl- or N-phenylanthranilic acid activated with 1-hydroxy-
benzotriazole for elaboration of different types of quinolinone
skeletons. In this paper, we report the ‘‘one-pot’’ synthesis of
3-substituted 4-hydroxy-1-methyl- and 1-phenyl-2-quinolones
starting from the activated 1-hydroxybenzotriazole ester of
the appropriate N-substituted anthranilic acid and a suitable
active methylene compound as building blocks. This approach
allows for a wide variation of the substitution pattern of the
‘‘quinolone’’ ring at the 1 and 3 position (Scheme 1).
The proposed strategy consists of a C-acylation reaction be-
tween an active methylene compound 3a–3d and the 1-hydroxy-
benzotriazole ester of the N-substituted anthranilic acid 1a–b.
The requisite 1-hydroxybenzotriazole ester of the N-alkylan-
thranilic acid was synthesized by condensation of equimolar
amounts of 1a or 1b with 1-hydroxybenzotriazole aꢁnd dicyclo-
hexylcarbodiimide (DCC) in anhydrous THF at 0 C. After a
reaction time of 24 h, the reaction mixture was filtered and
the filtrate containing the non-isolated active ester was used
as the acylating agent in the next step. In a typical C-acylation
reaction the active methylene compound 3a–3d (1 molar
amount) was treated with sodium hydride (2 molar amounts)
in anhydrous THF at r.t. and then the active ester solution
was added. After stirring for 2.5 h, the solvent was removed un-
der reduced pressure, the residue was diluted with water, wash-
ed with diethyl ether and the aqueous layer was acidified with
10% HCl to give the 3-substituted 4-hydroxy-1-methyl- and 1-
phenyl-2-quinolones 4–8 or the C-acylation compounds 9 and
10. Cyclization of the C-acylation compounds 9 and 10 to the
corresponding 3-cyano-4-hydroxy-1-phenyl-2-quinolone 11
was accomplished by treatment with a methanolic 10% HCl
solution at r.t. for 48 h.
OH
O
Y
Y
Remarkably, the type of product obtained from the C-acyla-
tion–cyclization reaction depends on the N-substituent of an-
thranilic acid and the active methylene compound used. Thus,
utilization of dimethyl and diethyl malonate resulted in the for-
mation of the 3-substituted 4-hydroxy-1-methyl- and 1-phenyl-
N
O
N
O
Fig. 1. 3-Substituted 4-hydroxy-2-quinolones.
Published on the web August 6, 2004; DOI 10.1246/bcsj.77.1505

1506 Bull. Chem. Soc. Jpn., 77, No. 8 (2004)
A Novel Synthesis of 4-Hydroxy-2-quinolones
COOH
N
N
Y
H2C
+
+
N
NHR
COOR'
3a R' = Me Y = COOMe
OH
2
3b
3c
3d
Et
COOEt
CN
1a R = Me
Me
Et
1b
Ph
CN
NaH, DCC, THF anhyd.
OH
4
OH
5
8
OH
6
4a
Y
CN
8
1
5
4
6
7
5
7
10% HCl
MeOH, rt, 48 h
3
4a
8a
Y
6
7
N 2
R
3
2
COOR'
NH
Ph
4
2
3
O
8a
O
N
8
Ph
4 R = Me Y = COOMe
5
6
7
8
Ph
Me
Ph
Me
COOMe
COOEt
COOEt
CN
9 R' = Me
10 = Et
11 Y = CN
Scheme 1. Synthesis of 3-substituted 4-hydroxy-1-methyl- and 1-phenyl-2-quinolones.
2-quinolones 4–7, as was expected. However, with cyanoace-
tates 3c and 3d, an alternative route involves formation of the
C-acylation functionalized ‘‘intermediates’’ (9 and 10) or 3-cy-
ano-4-hydroxy-1-methyl-2-quinolone (8) depending on the
substituent of the nitrogen of the anthranilic acid. The closing
of the heterocyclic ring of the ꢀ-3-(2-anilinophenyl)-2-cyano-
3-hydroxypropenoates 9 and 10 is achieved by treatment with
HCl (10%) in methanol to the desired 3-cyano-4-hydroxy-1-
phenyl-2-quinolone.
vantage is that there is no need for isolating the intermediate ac-
tive ester. This fact reduces the reaction time, in contrast to pre-
viously described methodologies, and is beneficial for the over-
all yield of the reaction. Additionally, the methodology is sim-
ple, inexpensive and easily scaled up.
Moreover, the 1-hydroxybenzotriazole is a powerful acylat-
ing agent, bearing no other active sites on its molecule. We
could therefore apply stronger bases (e.g., LDA) without the
fear of side reactions and by-products.
We can therefore assume that the inductive effect of the
group attached to the nitrogen atom plays the most important
role on the derivative produced when cyanoacetates are used
as the active methylene compounds. When the group is a meth-
yl, characterized by a þI inductive effect, the heterocyclic ring-
closure takes place spontaneously under the reaction condi-
tions, and the intermediate C-acylation compound is not isolat-
ed. On the other hand, when a phenyl group, characterized by a
ꢂI inductive effect, is attached to N-1, the C-acylation com-
pound is isolated, and the cyclization reaction is effected when
this derivative is stirred in a mild acidic solution (10% hydro-
chloric acid in methanol).
In conclusion, the synthesis of a series of 3-substituted 4-hy-
droxy-2-quinolones has been achieved through a one-step
methodology, utilizing 1-hydroxybenzotriazole esters of N-
methyl- and N-phenylanthranilic acid as acylating agents of ap-
propriate active methylene compounds. The reaction gives high
yields and has a short reaction time in contrast to previous
methodologies. Work currently in progress includes application
of the proposed methodology to the preparation of other quino-
lone derivatives bearing different functional groups at position
3 and the aromatic nucleus. Also, the application of this meth-
odology in the synthesis of natural products containing the
quinolone nucleus is in our near future plans.
The results from the 1H and 13C NMR chemical shifts, com-
pared with previous spectral data,21b,26 indicated the enolic
form as predominant for the 4-hydroxy-2-quinolinones (4–8,
11) and the C-acylation product 10. However, the 1H NMR
spectrum of methyl 3-(2-anilinophenyl)-2-cyano-3-hydroxy-
propenoate (9) exhibited two tautomers, the enolic and the keto
form (see Experimental). The assignments of the 13C NMR
spectra were based on HECTOR experiments, effected by our
laboratory for ‘‘quinolone’’ analogues in the past.21b,22,27,28
An important feature of the proposed methodology has been
the use of 1-hydroxybenzotriazole ester as a useful precursor
for the synthesis of compounds with interesting biological
properties. The activation of N-alkylanthranilic acid as its hy-
droxybenzotriazole ester, without any protection on the amine
group, is an attractive alternative to other activated anthranilic
acid species, permitting mild reaction conditions. Another ad-
Experimental
Melting points were determined on a Galenkamp MFB-595
melting point apparatus and are uncorrected. IR spectra were re-
corded on a Nicolet Magna IR 560. NMR spectra were recorded
on a Varian Gemini 2000, 300 MHz spectrometer. Chemical shifts
are quoted in ppm (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad). J values are given in Hz. Elemental
analyses were recorded on a Euro EA3000 Series Euro Vector
CHNS Elemental Analyser.
General Procedure for the Synthesis of 3-Substituted 4-
Hydroxy-2-quinolones. To a solution of anthranilic acid (1)
(10 mmol) and 1-hydroxybenzotriazole (2) (10 mmol) in anhy-
drous tetrahydrofuran (40 mL) was added dropwise a solution of
dicyclohexylcarbodiimide (DCC) (10 mmol) in anhydrous tetrahy-
ꢁ
drofuran (5–10 mL) at 0 C over the course of 1 h. The resulting

L. Zikou et al.
Bull. Chem. Soc. Jpn., 77, No. 8 (2004) 1507
ꢁ
suspension was kept overnight at 3–5 C. The precipitated solid
(DCU) was filtered off and the filtrate was added to a solution of
the anion of the appropriate active methylene compound [generat-
ed from sodium hydride (20 mmol) and 3a–3d (10 mmol) in anhy-
drous tetrahydrofuran (60 mL)]. The resulted mixture was stirred at
r.t. for 2.5 h and then concentrated in vacuo. The obtained gummy
solid was dissolved with water and washed with diethyl ether. The
aqueous extract was acidified with 10% hydrochloric acid in an ice
water bath. The precipitated white solid (1-hydroxybenzotriazole)
was filtered off, washed with dichloromethane and the combined
aqueous and organic filtrate was extracted with DCM (3 ꢃ 15
mL). The combined organic extracts were dried with Na2SO4, fil-
tered and concentrated in vacuo to afford either the 3-substituted 4-
hydroxy-1-methyl- and 1-phenyl-2-quinolones 4–8 as white solids
or the C-acylation compounds 9 and 10 as oily products. The solid
products were collected by filtration, washed with light petroleum
and dried in vacuo. The C-acylation compounds 9 and 10 (5 mmol)
were dissolved in 10 mL methanol and treated with 10 mL 10% hy-
drochloric acid. The resulting mixture was stirred at r.t. for 48 h to
afford the 3-cyano-2-quinolone (11) as solid product which was
collected by filtration, washed with diethyl ether, and dried in
vacuo.
98.1 (C-3), 114.7 (C-4a), 116.0 (C-8), 122.2 (C-6), 125.4 (C-5),
128.9/129.3/130.2/137.6 (aromatic carbons), 134.0 (C-7), 142.4
(C-8a), 159.9 (C-2), 172.7 (C-4), 172.9 (COOCH2CH3).
3-Cyano-4-hydroxy-1-methyl-2-quinolone (8): 1.2 g, 60%
ꢁ
ꢁ
yield; mp 300–301 C (lit.19 290–293 C); IR (KBr) 2227 (CN),
1
1620 (CO), 1590 (C=C) cmꢂ1; H NMR (DMSO-d6) ꢁ 3.55 (3H,
s, N-CH3), 7.32 (1H, pt, H-6), 7.54 (1H, d, J ¼ 8:7, H-8), 7.76
(1H, pt, J ¼ 7:5, H-7), 8.10 (1H, d, J ¼ 7:8, H-5); 13C NMR
(DMSO-d6) ꢁ 29.2 (N-CH3), 86.2 (C-3), 115.0 (C-4a), 115.4 (C-
8), 115.5 (CN), 122.3 (C-6), 124.7 (C-5), 134.3 (C-7), 140.7 (C-
8a), 160.5 (C-2), 168.6 (C-4).
Methyl 3-(2-Anilinophenyl)-2-cyano-3-hydroxypropenoate
(9): 2.0 g, 75% yield; mp 80–82 ꢁC (precipitated as yellow solid
after several extractions of the oily product with pentene); 1H NMR
(CDCl3) ꢁ 3.95 (3H, s, COOCH3), 5.30 (0.3H, s, methine proton
keto), 6.90–7.38 (9H, m, aromatic protons and NH), 7.69 (1H,
dd, J ¼ 7:6=1:5, H-5), 14.57 (0.7H, s, OH); 13C NMR (CDCl3) ꢁ
53.4 (COOCH3), 81.2 (CCN), 113.9 (CN), 115.4/117.3/119.6/
123.0/129.5/130.9/131.8/132.9/133.9/134.3/141.2/143.9 (aro-
matic carbons), 171.9 (COOCH3), 184.5 (C=CCN). Anal. Found:
C, 69.12; H, 4.56; N, 9.50%. Calcd for C17H14N2O3: C, 69.38; H,
4.79; N, 9.52%.
Compound Spectroscopic and Analytical Data. Methyl 4-
Hydroxy-1-methyl-2(1H)-oxoquinoline-3-carboxꢁylate (4): 1.5
g, 64% yield; mp 163–164 ꢁC; (lit.29 166–167 C); IR (KBr)
Ethyl
3-(2-Anilinophenyl)-2-cyano-3-hydroxypropenoate
(10): 2.1 g, 76% yield (oily product); 1H NMR (CDCl3) ꢁ 1.40 (3H,
t, J ¼ 7:2, COOCH2CH3), 4.40 (2H, q, J ¼ 7:2, COOCH2CH3),
6.92–7.38 (9H, m, aromatic protons and NH), 7.68 (1H, dd,
J ¼ 8:0=1:4, H-5); 13C NMR (CDCl3) ꢁ 14.4 (COOCH2CH3), 63.3
(COOCH2CH3), 81.1 (CCN), 115.7 (CN), 117.6/119.8/120.7/
122.5/123.1/129.4/129.7/131.1/132.0/134.0/141.7/144.0 (aro-
matic carbons), 171.7(COOCH2CH3), 184.8 (C=CN).
1
1652 (CO ester), 1624 (CO amide), 1561 (C=C) cmꢂ1; H NMR
(CDCl3) ꢁ 3.65 (3H, s, N-CH3), 4.03 (3H, s, COOCH3), 7.24–
7.33 (2H, m, H-6/H-8), 7.69 (1H, pt, H-7), 8.18 (1H, dd,
J ¼ 8:0=1:4, H-5), 14.07 (1H, br s, OH); 13C NMR (CDCl3) ꢁ
29.1 (N-CH3), 52.9 (COOCH3), 97.8 (C-3), 114.2 (C-4a), 114.9
(C-8), 122.1 (C-6), 125.8 (C-5), 134.6 (C-7), 141.4 (C-8a), 159.8
(C-2), 171.8 (C-4), 173.2 (COOCH3).
Methyl 4-Hydroxy-2(1H)-oxo-1-phenylquinoline-3-carbox-
ylate (5): 2.1 g, 55% yield; mp 172–173 ꢁC; IR (KBr) 1678
(CO ester), 1619 (CO amide), 1558 (C=C) cmꢂ1 1H NMR
;
(CDCl3) ꢁ 3.99 (3H, s, COOCH3), 6.61 (1H, d, J ¼ 8:4, H-8),
7.20–7.60 (7H, m, aromatic protons), 8.20 (1H, dd, J ¼ 8:2=1:5,
H-5), 14.27 (1H, s, OH); 13C NMR (CDCl3) ꢁ 52.8 (COOCH3),
97.9 (C-3), 114.6 (C-4a), 116.0 (C-8), 122.2 (C-6), 125.4 (C-5),
128.8/129.2/130.1/137.5 (aromatic carbons), 134.1 (C-7), 142.3
(C-8a), 159.9 (C-2), 172.6 (C-4), 173.2 (COOCH3). Anal. Found:
C, 69.02; H, 4.29; N, 4.69%. Calcd for C17H13NO4: C, 69.15; H,
4.44; N, 4.74%.
3-Cyano-4-hydroxy-1-phenyl-2-quiꢁnolone (11): 0.6 g, 51%
yield, mp 290–291 C; (lit.30 298–300 C); IR (KBr) 2232 (CN),
ꢁ
1618 (CO), 1566 (C=C) cmꢂ1; H NMR (DMSO-d6) ꢁ 6.51 (1H,
1
d, J ¼ 8:7, H-8), 7.25–7.64 (7H, m, aromatic protons), 8.12 (1H,
d, J ¼ 7:8, H-5); 13C NMR (DMSO-d6) ꢁ 86.1 (C-3), 113.9 (C-
4a), 115.7 (CN), 116.0 (C-8), 122.3 (C-6), 124.7 (C-5), 129.0/
129.5/130.2/137.3 (aromatic carbons), 133.8 (C-7), 141.7 (C-
8a), 160.7 (C-2), 169.8 (C-4).
We thank Ms. V. Skouridou (National Technical University
of Athens, Biotechnology Laboratory) for recording the IR
spectra.
Ethyl 4-Hydroxy-1-methyl-2(1H)-oxoquinoline-3-carbox-
ylate (6): 1.5 g, 61% yield; mp 101–102 ꢁC (lit.19,20 100–102
ꢁC); IR (KBr) 1657 (CO ester), 1628 (CO amide), 1562 (C=C)
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