Novel and convenient synthesis of polyfunctionalized quinolines, quinolones and their annulation reactions

Article abstract of DOI:10.1016/S0040-4039(01)00231-3

The reaction of α-aroylketene dithioacetals with esters of o-aminobenzoic acid under different conditions afforded preferentially 2-methylthio-3-aroylquinolones and 2-anilino-3-aroylquinolines through, respectively, α-aroylketene N,S-acetal and α-aroylket

Full text of DOI:10.1016/S0040-4039(01)00231-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2553–2555
Novel and convenient synthesis of polyfunctionalized quinolines,
quinolones and their annulation reactions
Mei-Xiang Wang,* Yong Liu and Zhi-Tang Huang
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China
Received 11 December 2000; revised 26 January 2001; accepted 7 February 2001
Abstract—The reaction of a-aroylketene dithioacetals with esters of o-aminobenzoic acid under different conditions afforded
preferentially 2-methylthio-3-aroylquinolones and 2-anilino-3-aroylquinolines through, respectively, a-aroylketene N,S-acetal and
a-aroylketene aminal intermediates. The annulation reaction of 2-methylthio-3-aroylquinolones with hydrazine gave both
pyrazolo[3,4-b]quinolone and pyrazolo[4,3-c]quinoline, the selectivity being determined by the reaction conditions employed.
Intramolecular cyclocondensation of 2-anilino-3-aroylquinolines produced quino[2,1-b]quinazolines in high yield. © 2001 Elsevier
Science Ltd. All rights reserved.
Quinoline and quinolone derivatives are very important
organic compounds because they occur widely in nature
and possess interesting biological and pharmacological
activities.1 Synthetic fluoroquinolones such as norflox-
acin and ciprofloxacin, for example, have been used
clinically as orally active antibiotics. Currently, there is
a renaissance of interest in searching for novel and
potent antibacterial agents due to a dramatic and
alarming increase in the incidence of bacterial infections
resistant to most common antibiotics including
fluoroquinolones.2 Although many preparative methods
are available in the literature,1 it is still challenging to
explore new and simple synthetic methods for quinoli-
nes and quinolones, particularly for the highly func-
tionalized ones.3
a-Oxoketene dithioacetals are versatile intermediates in
organic synthesis.4 They have been extensively used as
an electrophilic three-carbon segment in the construc-
tion of various five- and six-membered heterocycles.4
The reaction of a-oxoketene dithioacetals with amines
or diamines, however, yielded a-oxoketene N,S-acetals
or (heterocyclic) ketene aminals.5 Previous studies have
shown that ketene aminals5 and ketene N,S-acetals6 are
excellent carbon nucleophiles able to react with a wide
variety of electrophiles. We therefore envisaged that a
tandem reaction comprising the formation of ketene
aminals between a-aroylketene dithioacetals7 and o-
aminobenzoic acid esters followed by an intramolecular
enaminic cyclization would furnish quinolines or
quinolones. The resulting multi-functionalized com-
O
OH
N
Ar
O
O
NH2
Ar
SMe
Ar
O
MeS
+
+
CO2R
N
H
3
N
SMe
H
CO2R
2a R = Me
2b R = Et
1
4
1, 3, 4
a
b
c
Ar
C6H5
4-ClC6H4 4-MeOC6H4
Scheme 1.
* Corresponding author. Fax: +86-10-62569564; e-mail: mxwang@infoc3.icas.ac.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00231-3

2554
M.-X. Wang et al. / Tetrahedron Letters 42 (2001) 2553–2555
pounds would serve as useful intermediates for further
chemical manipulations. Herein, we wish to report a
novel and very convenient synthesis of highly function-
alized quinoline and quinolone derivatives, and also to
demonstrate their potential in the preparation of quino-
line- and quinolone-fused heterocycles.
isolated predominantly in moderate yield (Table 1). It
should be noted that no reaction took place under the
identical conditions between 3 and methyl o-aminoben-
zoate 2a, suggesting that ketene N,S-acetal intermediate
A and ketene aminal intermediate B are responsible,
respectively, for the formation of 3 and 4 (Scheme 2).
No reaction was observed when a-benzoylketene
dithioacetal 1a was refluxed with methyl o-aminoben-
zoate 2a in toluene or in DMF. The addition of a
strong base such as NaH did not help the reaction
either. Only when the reaction was performed in reflux-
ing acetic acid did the reaction proceed smoothly to
give a mixture of methylthio-substituted quinolone 3a
and anilino-substituted 4-hydroxyquinoline 4a (Scheme
1). When 2.5 equivalents of 2 were used, the reaction
gave 4 as the major product. Selective formation of 4
was also effected in some cases when a neat reaction
between 1 and 2 was heated at an elevated temperature.
Interestingly, when a mixture of equal equivalents of 1
and 2 was refluxed in propionic acid, compound 3 was
Quinolones 3 are highly functionalized compounds and
they are useful intermediates in synthesis. Assembling
methylthio, secondary amino and aroyl groups into a
molecule, 3-aroyl-2-methylthio-4-quinolone 3 can be
viewed as a pseudo-a-oxoketene N,S-acetal. Both the
substituents 2-methylthio and 3-aroyl substituents
could be reactive towards nucleophiles and therefore 3
could serve as a new electrophilic three-carbon unit. It
was envisaged that fused five- and six-membered hete-
rocycles would result from treatment of 3 with appro-
priate bis-nucleophiles. Reaction between
3
and
hydrazine, for instance, afforded hydrazone 5 in almost
quantitative yield. Interestingly, however, a mixture of
compounds 68 and 7 was obtained by further heating of
Table 1. Reaction of a-aroylketene dithioacetals 1 with o-aminobenzoic acid esters 2
Entry
1
2
1:2
Reaction conditions
3 (%a)
4 (%a)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1c
1b
1c
1a
1b
1c
2a
2b
2b
2b
2b
2b
2b
2a
2a
2a
1:2
CH3CO2H, reflux 12 h
CH3CO2H, reflux 20 h
CH3CO2H, reflux 20 h
CH3CO2H, reflux 24 h
CH3CO2H, reflux 24 h
Neat, Ar, 180°C, 20 h
Neat, Ar, 180°C, 20 h
C2H5CO2H, reflux 5 days
C2H5CO2H, reflux 5 days
C2H5CO2H, reflux 5 days
31
17
6
12
7
6
5
46
28
32
34
23
42
54
74
59
80
2
1:1.5
1:2.5
1:2.5
1:2.5
1:2.4
1:2.4
1:1.1
1:1.1
1:1.1
Trace
Trace
10
a Isolated yield.
OR
O
O
route A
Ar
SMe
3
- MeSH
- ROH
- ROH
N
H
A
1
+
2
O
ORO
route B
Ar
4
N
N
- 2MeSH
H
H
CO2R
B
Scheme 2.
H
Ar
O
NNH2
O
N
N
NH2NH2
Ar
N
3
Ar
+
N
N
H
N
H
SMe
H
N
SMe
5
6
7
Scheme 3.

M.-X. Wang et al. / Tetrahedron Letters 42 (2001) 2553–2555
Table 2. Selective annulation reaction of hydrazone 5
2555
and 2-anilino-3-aroyl quinolines through, respectively,
a-aroylketene N,S-acetal and a-aroylketene aminal
intermediates. Annulation reaction of 2-methylthio-3-
aroylquinolones with hydrazine gave both pyrazolo-
[3,4-b]quinolone and pyrazolo[4,3-c]quinoline, the
selectivity being determined by the reaction conditions
employed. Intramolecular cyclocondensation of 2-ani-
lino-3-aroylquinolines produced quino[2,1-b]quinazo-
lines in high yield.
Entry
5
Reaction conditions
6 (%)b 7 (%)b
1
2
3
4
5
6
5a Pyridine, Ar, reflux 60 h
5b Pyridine, Ar, reflux 60 h
5c Pyridine, Ar, reflux 60 h
5a Resin,a EtOH, reflux 18 h
5b Resin,a EtOH, reflux 24 h
5b Resin,a CH3CN/DMF, reflux
32 h
70
69
76
28
18
17
5
4
9
52
54
56
7
8
5c Resin,a EtOH, reflux 32 h
5c Resin,a CH3CN/DMF, reflux
32 h
18
24
42
52
Acknowledgements
a Ion exchange resin Amberlyst-732.
b Isolated yield.
We thank the National Natural Science Foundation of
China and the Chinese Academy of Sciences for finan-
cial support.
O
N
Ar
H
N
O
NaOH/C2H5OH, reflux 3h
4
References
89 - 99%
O
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8
Scheme 4.
5 (Scheme 3). Apparently, they were formed from
cyclocondensation reactions of the hydrazone with
either 2-methylthiol or with quinolone carbonyl groups.
Selective synthesis of linear fused heterocycles 6, or
angular fused heterocycles 7, was readily effected by
carrying out the reaction in refluxing pyridine or in the
presence the of the ion exchange resin, Amberlyst-732,
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Attempts to prepare quino[2,1-b]quinazoline 8 through
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various reaction conditions. Only when heated in
ethanolic NaOH solution did cyclization of 4 proceed
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In summary, we have provided novel and simple meth-
ods for the preparation of functionalized quinolone and
quinoline compounds, and demonstrated their useful-
ness in the synthesis of fused heterocycles. The reaction
of a-aroylketene dithioacetals with esters of o-
aminobenzoic acid under different conditions can
afford preferentially 2-methylthio-3-aroylquinolones
6. (a) Huang, Z.-T.; Shi, X. Synthesis 1990, 162; (b) Huang,
Z.-T.; Shi, X. Chem. Ber. 1990, 123, 541.
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