Synthetic protocols mutually applicable to 4-oxoquinolines and 4-oxo-1,8-naphthyridines: Synthesis of 1-aryl-2-substituted and 1-aryl-3-fluoro-4-oxoquinolines and 4-oxo-1,8-naphthyridines

Article abstract of DOI:10.1055/s-0031-1290079

We have achieved the synthesis of 1-aryl-2-substituted 4-oxoquinoline and 4-oxo-1,8-naphthyridine derivatives, which cannot be synthesized by known methods, via two useful synthons, 2-formyl-4-oxoquinoline and 2-methylsulfonyl-4-oxo-1,8-naphthyridine. We

Full text of DOI:10.1055/s-0031-1290079

448
LETTER
Synthetic Protocols Mutually Applicable to 4-Oxoquinolines and 4-Oxo-1,8-
naphthyridines: Synthesis of 1-Aryl-2-substituted and 1-Aryl-3-fluoro-4-oxo-
quinolines and 4-Oxo-1,8-naphthyridines
S
ynthetic Protocol
e
s
of 4-Quin
n
olones and 1
-
, 8-Napht
i
hyrido
c
nes hiro Awasaguchi,* Hiromi Hayashi, Hyouei Kawai, Hiroko Tominaga, Yuichiro Sato, Kazuya Hayashi,
Yozo Todo
Discovery Research Department, Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama 930-8508, Japan
Fax +81(76)4318208; E-mail: kenichiro_awasaguchi@toyama-chemical.co.jp
Received 5 October 2011
and co-workers have reported a synthesis of 1,2-disubsti-
Abstract: We have achieved the synthesis of 1-aryl-2-substituted
tuted 4-oxoquinolines via copper-catalyzed heterocy-
4-oxoquinoline and 4-oxo-1,8-naphthyridine derivatives, which
clization of 1-(2-bromophenyl)- or 1-(2-chlorophenyl)-2-
cannot be synthesized by known methods, via two useful synthons,
en-3-amin-1-ones.10 Zhao and Xu have also reported a
2-formyl-4-oxoquinoline and 2-methylsulfonyl-4-oxo-1,8-naph-
thyridine. We also succeeded in the synthesis of 1-aryl-3-fluoro-4- palladium-catalyzed tandem amination reaction for the
synthesis of 1,2-disubstituted 4-oxoquinolines.11 Al-
oxoquinoline by fluorocyclization of N-arylenaminone with Select-
fluor® and potassium carbonate in DMF in a one-pot procedure. To
though these methods are effective, the reactions cannot
the best of our knowledge, this is the first synthesis of 3-fluoro-4-
be applied to a synthesis of 1-aryl-2-carboxyl-, amino-,
oxoquinoline derivatives. We confirmed that these protocols were
mutually applicable to the synthesis of 4-oxoquinoline and 4-oxo-
hydroxyl-, hydroxymethyl-, aminomethyl-, cyano-, azi-
do-, or methoxy-4-oxoquinoline and 4-oxo-1,8-naphthy-
ridine derivatives. Here we report a synthesis of 1-aryl-2-
substituted 4-oxoquinoline and 4-oxo-1,8-naphthyridine
derivatives via two synthetically useful intermediates, 1-
aryl-2-formyl-4-oxoquinoline 3, which is produced by ox-
idizing 1-aryl-2-methyl-4-oxoquinoline 2 with selenium
dioxide, and 1-aryl-2-methylsulfonyl-4-oxo-1,8-naphthy-
ridine 10b. We also report a synthesis of a novel 1-aryl-3-
fluoro-4-oxoquinoline 15 via a fluorocyclization reaction.
1,8-naphthyridine derivatives.
Key words: antiviral agents, heterocycles, HIV, 4-oxoquinoline,
4-oxo-1,8-naphthyridine, fluorocyclization
4-Oxoquinoline-3-carboxylic acid and 4-oxo-1,8-naph-
thyridine-3-carboxylic acid derivatives possess antimi-
crobial activities that reflect their ability to inhibit
bacterial DNA-gyrase.1 Furthermore, their decarboxylic
acid compounds such as 4-oxoquinoline and 4-oxo-1,8-
naphthyridine derivatives are abundant in many biologi-
Our strategy of synthesizing 1-aryl-2-substituted 4-oxo-
quinolines is shown in Scheme 1. We envisioned that 1-
aryl-2-formyl-4-oxoquinoline 3, which is useful for trans-
formations into other substituents, would be prepared by
oxidizing a methyl group of 1-aryl-2-methyl-4-oxoquino-
line 2. Quinolone 2 would readily be synthesized from 4-
bromo-2-fluoroacetophenone (1).
2
cally active compounds that contain anticancer or anti-
viral agents.3 Recently, we have also found that 4-
oxoquinoline and 4-oxo-1,8-naphthyridine derivatives
possessed strong anti-HIV activity (Figure 1).4
Owing to their interesting pharmacological activities,
many synthetic methods for 4-oxoquinoline and 4-oxo-
1,8-naphthyridine derivatives have been documented.1,5
Among these methods, a classical and commonly used ap-
proach is the condensation of an aniline with Meldrum’s
acid and trimethylorthoformate to afford the correspond-
ing enamine, followed by cyclization under harsh reaction
conditions.6 Alternatively, Camps-type cyclization has
been widely used because of its mild reaction conditions.7
To date, many other synthetic methods for 4-oxoquinoline
and 4-oxo-1,8-naphthyridine derivatives have been devel-
oped. Despite this variety, little is known about the syn-
thesis of 1-aryl-2-substituted 4-oxoquinoline and 4-oxo-
1,8-naphthyridine derivatives.8 Several efforts have been
made to introduce a polyfluoroalkyl group (e.g., a trifluo-
romethyl, difluoromethyl, or pentafluoroethyl group) on
the C-2 position of 4-oxoquinolines.9 Recently, Bernini
O
CO2H
X
N
H
4-oxoquinoline-3-carboxylic acid (X = CH)
4-oxo-1,8-naphthyridine-3-carboxylic acid (X = N)
O
O
N
O
N
F
R
N
NH2
R
R
N
F
F
F
OH
F
F
F
R = 3,5-dimethylisoxazol-4-yl
these 4-oxoquinoline and 4-oxo-1,8-naphthryidine derivatives
show strong anti-HIV activity
SYNLETT 2012, 23, 448–452
Advanced online publication: 03.01.2012
x
x.
x
x.
2
0
1
2
DOI: 10.1055/s-0031-1290079; Art ID: U51611ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 4-Oxoquinoline and 1,8-naphthyridin-4-one derivatives

LETTER
Synthetic Protocols of 4-Quinolones and 1,8-Naphthyridones
449
reduction of the resulting azide group with Ph3P in tet-
rahydrofuran (THF) and water at room temperature af-
forded 2-aminomethyl-4-oxoquinoline 6b in 30% yield
via two steps (entry 2). Reductive amination of the alde-
hyde 3 and dimethylamine with sodium triacetoxyborohy-
dride in dichloromethane at room temperature gave 2-
dimethylaminomethyl-4-oxoquinoline 6c in 51% yield
(entry 3). Horner–Wadsworth–Emmons reaction of 3 in
the presence of ethyl diethylphosphonoacetate and sodi-
um hydride in THF at 5 °C to room temperature provided
the a,b-unsaturated ester 6d in 58% yield (entry 4). Pin-
nick oxidation of 3 in the presence of sodium chlorite, so-
dium phosphate, and 2-methyl-2-butene in tert-butanol,
THF and water afforded carboxylic acid 6e in 87% yield
(entry 5). Curtius rearrangement of the resulting 6e with
DPPA and triethylamine in tert-butanol at 85 °C provided
carbamate, which was treated with trifluoroacetic acid
(TFA) and ethanol at room temperature to afford 2-amino-
4-oxoquinoline 6f in 38% yield via two steps (entry 6).
Although not explicitly shown in the scheme, a series of
1-aryl-2-substituted 4-oxo-1,8-naphthyridine derivatives
could be prepared from 3-acetyl-2,6-dichloropyridine via
the same synthetic protocol.
O
N
O
F
transformations
Me
Br
R
2-substituted
4-oxoquinolines
F
Br
1
2: R = Me
3: R = CHO
oxidation
F
a key intermediate
Scheme 1 Synthetic strategy of 1-aryl-2-substituted 4-oxoquino-
lines via 1-aryl-2-formyl-4-oxoquinoline
The synthesis of the key intermediate 3 is shown in
Scheme 2. Our synthetic procedure commenced with
treatment of acetophenone 1 with N,N-dimethylacetamide
dimethylacetal (DMADA) under reflux to afford the N,N-
dimethylenaminone 4 in 52% yield.12 The enaminone 4
underwent substitution with 2,4-difluoroaniline in acetic
acid at 50 °C to give N-arylenaminone 5 in 92% yield. Al-
1
though the H NMR spectrum of 5 in CDCl3 indicated a
single isomer, the geometry of the trisubstituted olefin
could not be determined.13 Cyclization of the N-arylen-
aminone 5 in the presence of potassium carbonate in di-
methylsulfoxide (DMSO) at 90 °C afforded 1-aryl-2-
methyl-4-oxoquinoline 2 in 98% yield. We examined the
oxidation of a C-2 methyl group of 2 with a variety of ox-
idizing agents. We found that oxidation of the C-2 methyl
group of 2 with selenium dioxide in 1,4-dioxane under re-
flux gave the best result of obtaining 1-aryl-2-formyl-4-
oxoquinoline 3 in 60% yield.
Table 1 Transformation of 2-Formyl-4-oxoquinoline 3
O
O
conditions
Br
N
R
Br
N
CHO
F
F
O
O
R
6
3
F
F
i
iii
Me
Me
Entry
Conditionsa R
Product
6a
Yield (%)
Br
F
Br
F
1
i
CH2OH
CH2NH2
90
30
51c
58
87
38
1
4: R = NMe2
5: R = NHAr
ii
2b
3
ii
6b
iii
iv
v
CH2NMe2
CH=CHCO2Et
CO2H
6c
O
N
O
4
6d
iv
Br
Me
Br
N
CHO
5
6e
F
F
6b
vi
NH2
6f
a Reagents and conditions: (i) 3, NaBH(OAc)3, CH2Cl2, r.t., 4 h; (ii)
6a, DPPA, DBU, 1,4-dioxane, r.t., 6 h, then Ph3P, THF–H2O, r.t., 60.5
h; (iii) 3, NHMe2·HCl, Et3N, NaBH(OAc)3, CH2Cl2, r.t., 3 h; (iv) 3,
(EtO)2P(O)CH2CO2Et, NaH, THF, 5 °C to r.t., 2 h; (v) 3, NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH, THF, H2O, r.t., 3 h; (vi) 6e,
DPPA, Et3N, t-BuOH, 85 °C, 5 h, then TFA, EtOH, r.t., 17.5 h.
b In entries 2 and 6, the product 6a and 6e were used as starting mate-
rials, respectively.
F
F
2
3
Scheme 2 Reagents and conditions: (i) DMADA, reflux, 8 h, 52%;
(ii) 2,4-difluoroaniline, AcOH, 50 °C, 3 h, 92%; (iii) K2CO3, DMSO,
90 °C, 1 h, 98%; (iv) SeO2, 1,4-dioxane, reflux, 4 h, 60%.
c Compound 6a was obtained as a by-product in 35% yield.
With the requisite aldehyde 3 in hand, we then focused on
further transformation of 3 into other functional groups
(Table 1). Reduction of the aldehyde group in 3 with so-
dium triacetoxyborohydride in dichloromethane at room
temperature afforded methylol 6a in 90% yield (entry 1).
Azidation of 6a in the presence of diphenylphosphoryl
azide (DPPA) and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) in 1,4-dioxane at room temperature, followed by
As shown in Table 1, however, this synthetic method
could not be applied to 1-aryl-4-oxoquinoline and 4-oxo-
1,8-naphthyridine derivatives with a hydroxy, alkoxy,
cyano, azido or alkyl group at the C-2 position. Therefore,
we proposed an alternative synthetic route to these 2-sub-
© Thieme Stuttgart · New York
Synlett 2012, 23, 448–452

450
K.-i. Awasaguchi et al.
LETTER
stituted compounds. Rudorf and co-workers have reported
the synthesis of 1-phenyl-2-methylthio-4-oxoquinoline
via ketene-S,N-acetal derived from phenylisothiocyanate
and o-chloroacetophenone.14 Although 1-aryl-2-meth-
ylthio-4-oxoquinoline derivatives could be synthesized by
this method in moderate yield,15 this method could be in-
applicable to a synthesis of 1-aryl-2-methylthio-4-oxo-
1,8-naphthyridine derivatives. We then attempted to im-
prove their reaction conditions for a synthesis of 4-oxo-
1,8-naphthyridine derivatives by changing the solvent,
base, and reaction temperature. When 3-acetyl-2,6- Entry
dichloropyridine (7) was used as the starting material, the
enolate formation was conducted with lithium diisopropy-
lamide (LDA) as a base in THF at –40 °C. The enolate was
reacted with a corresponding phenyl isothiocyanate at the
same temperature and then the reaction was quenched
with iodomethane at 5 °C to give ketene-S,N-acetal 8 in
35% yield. Cyclization of 8 with potassium phosphate in
DMSO at 100 °C afforded 2-methylthio-4-oxo-1,8-naph-
thyridine 9 in 94% yield. Suzuki–Miyaura cross-coupling
Table 2 Transformation of 2-Methylsulfonyl Compound 10b
O
O
N
Me
Me
conditions
SO2Me
N
F
N
N
F
R
N
O
N
O
Me
Me
10b
F
11
F
Conditionsa
R
Product
11a
Yield (%)
1
i
OMe
N3
98
87
90
96
64
2
3
4
5
ii
iii
iv
v
11b
CN
OH
Et
11c
11d
11e
a Reagents and conditions: (i) NaOMe, MeOH, r.t., 15 min; (ii) NaN3,
reaction of 9 and 3,5-dimethylisoxazole-4-boronic acid in DMSO, THF, r.t., 4 h; (iii) KCN, DMSO, THF, r.t., 4 h; (iv) NaOH,
H2O, 1,4-dioxane, 50 °C, 30 min; (v) EtMgBr, THF, -60 °C to r.t., 2 h.
the presence of palladium diacetate, 2-dicyclohexylphos-
phino-2¢,6¢-dimethoxybiphenyl (S-Phos)16 and triethy-
Additionally, we also have developed an efficient synthet-
ic method for the preparation of novel 1-aryl-3-fluoro-4-
oxoquinolines by fluorocyclization (Scheme 4). Treat-
ment of b-keto ester 12 with hydrochloric acid in 1,4-di-
oxane under reflux, followed by reaction with N,N-
dimethylformamide dimethylacetal (DMFDA) under re-
flux afforded N,N-dimethylenaminone 13 in 68% yield in
two steps. Amine exchange reaction of the enaminone 13
with a corresponding aniline in acetic acid at 50 °C gave
N-arylenaminone 14 in 92% yield, followed by fluorocy-
clization, a reaction in which both fluorination and cy-
clization occur in a one-pot procedure, of the resulting N-
arylenaminone 14. Fluorination of 14 in the presence of
Selectfluor®17 in N,N-dimethylformamide (DMF) at room
temperature, followed by cyclization with potassium car-
bonate at 80 °C afforded 1-aryl-3-fluoro-4-oxoquinoline
15 in 38% yield in two steps.
lamine in 1,4-dioxane under reflux provided 10a in 95%
yield. The methylthio group in 10a was readily oxidized
to a methylsulfonyl group with m-chloroperbenzoic acid
(MCPBA) in dichloromethane at room temperature in
59% yield (Scheme 3).
F
F
O
i
ii
O
HN
Me
SMe
Cl
N
Cl
Cl
N
Cl
7
8
O
N
O
N
Me
iii
Cl
N
F
SMe
N
F
R
N
O
O
O
O
Me
i
ii
OEt
NMe2
Br
F
Br
F
F
F
9
10a: R = SMe
10b: R = SO2Me
12
13
iv
O
Scheme 3 Reagents and conditions: (i) LDA, THF, –40 °C, 30 min,
then 2,4-difluorophenyl isothiocyanate, –40 °C to r.t., 1.5 h and MeI,
5 °C to r.t., 20 min, 35%; (ii) K3PO4, DMSO, 100 °C, 30 min, 94%;
(iii) 3,5-dimethylisoxazole-4-boronic acid, Et3N, S-Phos, Pd(OAc)2,
1,4-dioxane, reflux, 5 h, 95%; (iv) MCPBA, CH2Cl2, r.t., 21 h, 59%.
F
F
F
iii
O
HN
Br
N
F
Treatment of methylsulfonyl compound 10b with various
nucleophiles afforded 1-aryl-2-substituted 4-oxo-1,8-
naphthyridine derivatives 11a–e in moderate to high
yields (Table 2).
Br
F
F
14
15
Scheme 4 Reagents and conditions: (i) HCl, 1,4-dioxane, reflux,
3.5 h, then DMFDA, reflux, 2.5 h, 68%; (ii) 2,4-difluoroaniline,
AcOH, 50 °C, 2 h, 92%; (iii) Selectfluor®, DMF, r.t., 1.5 h, then
K2CO3, 80 °C, 30 min, 38%.
Synlett 2012, 23, 448–452
© Thieme Stuttgart · New York

LETTER
Synthetic Protocols of 4-Quinolones and 1,8-Naphthyridones
451
(8) (a) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani, M.;
In summary, we have developed new synthetic methods
for the preparation of 1-aryl-2-substituted 4-oxoquinoline
and 4-oxo-1,8-naphthyridine derivatives via two key in-
termediates, 1-aryl-2-formyl-4-oxoquinoline prepared by
oxidation of the C-2 methyl group in 1-aryl-2-methyl-4-
oxoquinoline with selenium dioxide and 1-aryl-2-methyl-
sulfonyl-4-oxo-1,8-naphthyridine prepared by improving
Rudorf’s method.18,19 These intermediates were useful
synthons for the modification at the C-2 functional group
of 4-oxoquinolines and 4-oxo-1,8-naphthyridines. We
transformed these useful synthons (3 and 10b) into other
1-aryl-2-substituted 4-oxoquinoline and 4-oxo-1,8-naph-
thyridine derivatives. We have also developed a method
of synthesizing novel 1-aryl-3-fluoro-4-oxoquinoline de-
rivatives by fluorocyclization of N-arylenaminone 14
with Selectfluor® and potassium carbonate in DMF in a
one-pot procedure.20 These synthetic methods could be
applied to both 4-oxoquinoline and 4-oxo-1,8-naphthyri-
dine derivatives.
Larsen, R. D.; Faul, M. M. Org. Lett. 2008, 10, 2609.
(b) Jones, C. P.; Anderson, K. W.; Buchwald, S. L. J. Org.
Chem. 2007, 72, 7968.
(9) (a) Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.;
Röschenthaler, G.-V. J. Fluorine Chem. 2005, 126, 779.
(b) Usachev, B. I.; Sosnovskikh, V. Y. J. Fluorine Chem.
2004, 125, 1393. (c) López, S. E.; Rebollo, O.; Salazar, J.;
Charris, J. E.; Yánez, C. J. Fluorine Chem. 2003, 120, 71.
(d) Kim, D. H. J. Heterocycl. Chem. 1981, 18, 1393.
(e) Friary, R. J.; Seidl, V.; Schwerdt, J. H.; Cohen, M. P.;
Hou, D.; Nafissi, M. Tetrahedron 1993, 49, 7169.
(10) Bernini, R.; Cacchi, S.; Fabrizi, G.; Sferrazza, A. Synthesis
2009, 1209.
(11) Zhao, T.; Xu, B. Org. Lett. 2010, 12, 212.
(12) Radl, S.; Obadalova, I. Collect. Czech. Chem. Commun.
2004, 69, 822.
(13) Analytical and Spectral Data of N-Arylenaminone 5:
pink solid; mp 112–113 °C. 1H NMR (400 MHz, CDCl3):
d = 7.75 (dd, J = 8.3, 8.0 Hz, 1 H), 7.36 (dd, J = 8.3, 1.7 Hz,
1 H), 7.29 (dd, J = 10.4, 1.7 Hz, 1 H), 7.22 (ddd, J = 8.8, 8.5,
5.8 Hz, 1 H), 6.88–6.98 (m, 2 H), 5.89 (d, J = 2.2 Hz, 1 H),
2.02 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 184.6 (d,
J = 4.1 Hz), 163.8, 161.1 (dd, J = 249.6, 10.8 Hz), 160.1 (d,
J = 256.2 Hz), 157.0 (dd, J = 250.4, 12.4 Hz), 131.7 (d, J =
3.3 Hz), 128.5 (d, J = 9.1 Hz), 127.7 (d, J = 3.3 Hz), 127.2
(d, J = 13.2 Hz), 125.1 (d, J = 9.9 Hz), 122.6 (dd, J = 13.2,
4.1 Hz), 119.8 (d, J = 27.2 Hz), 111.6 (dd, J = 22.3, 4.1 Hz),
104.9 (dd, J = 26.0, 24.4 Hz), 98.6 (d, J = 10.7 Hz), 19.8 (d,
J = 2.5 Hz). IR (neat): 1590, 1568, 1541, 1433, 1395, 1318,
1304, 1283, 1094, 882, 857, 778 cm–1. HRMS (DART):
m/z [M + H]+ calcd for C16H12BrF3NO: 370.00544; found:
370.00546.
References and Notes
(1) For reviews, see: (a) Mitscher, L. A. Chem. Rev. 2005, 105,
559. (b) Andriole, V. T. The Quinolones, 3rd ed.; Academic
Press: San Diego, 2000.
(2) (a) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Nakanishi,
Y.; Nampoothiri, P.; Hamel, E.; Brossi, A.; Lee, K.-H.
Bioorg. Med. Chem. Lett. 2003, 13, 2891. (b) Tsuzuki, Y.;
Tomita, K.; Shibamori, K.; Sato, Y.; Kashimoto, S.; Chiba,
K. J. Med. Chem. 2004, 47, 2097.
(14) Rudorf, W.-D.; Schierhorn, A.; Augustin, M. Tetrahedron
1979, 35, 551.
(3) (a) Lucero, B. d’A.; Gomes, C. R. B. V.; de Souza, T. M. L.;
Ferreira, V. F. Bioorg. Med. Chem. Lett. 2006, 16, 1010.
(b) Moyer, M. P.; Weber, F. H.; Gross, J. L. J. Med. Chem.
1992, 35, 4595. (c) Santo, R. D.; Costi, R.; Roux, A.; Artico,
M.; Lavecchia, A.; Marinelli, L.; Novellino, E.; Palmisano,
L.; Andreotti, M.; Amici, R.; Galluzzo, C. M.; Nencioni, L.;
Palamara, A. T.; Pommier, Y.; Marchand, C. J. Med. Chem.
2006, 49, 1939. (d) Sato, M.; Motomura, T.; Aramaki, H.;
Matsuda, T.; Yamashita, M.; Ito, Y.; Kawakami, H.;
Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Ikeda, S.;
Kodama, E.; Matsuoka, M.; Shinkai, H. J. Med. Chem. 2006,
49, 1506. (e) Massari, S.; Daelemans, D.; Barreca, M. L.;
Knezevich, A.; Sabatini, S.; Cecchetti, V.; Marcello, A.;
Pannecouque, C.; Tabarrini, O. J. Med. Chem. 2010, 53, 641.
(4) (a) These three compounds having a substituent on the C-2
or C-3 position in Figure 1 exhibited potent anti-HIV
activity in the nanomolar range (IC50 = 0.23–9.2 nM).
(b) An anti-HIV activity was evaluated using MaRBLE cells
obtained by transfection of HPB-Ma derived from human T-
lymphocytes with a luciferase gene and a CCR5 gene etc. of
which expressions were regulated by HIV-1 LTR. (c) For
more details, see: Oonishi, Y.; Awasaguchi, K.; Nomura, N.;
Todo, K.; Kawai, H.; Wakatsuki, T. Int. Patent Appl.,
WO2011090095, 2011. (d) Chiba-Mizutani, T.; Miura, H.;
Matsuda, M.; Matsuda, Z.; Yokomaku, Y.; Miyauchi, K.;
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Microbiol. 2007, 45, 447.
(15) (a) In a synthesis of 4-oxoquinoline derivatives, enolate
formation of 2,4-dichloroacetophenone was conducted with
t-BuOK as a base in THF at r.t. to give a good result of
obtaining ketene-S,N-acetal. (b) When 4-bromo-2-fluoro-
acetophenone (1) was used as a starting material, 2-anilino-
7-bromo-1-thiochromone was produced via the same
synthetic protocol.
(16) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(17) For a review of recent highlights, see: Singh, R. P.; Shreeve,
J. M. Acc. Chem. Res. 2004, 37, 31.
(18) General Procedure for the Synthesis of Aldehyde 3: To a
solution of 1-aryl-2-methyl-4-oxoquinoline 2 (1.58 g, 4.51
mmol) in 1,4-dioxane (18 mL) was added selenium dioxide
(0.53 g, 4.51 mmol) at r.t. The mixture was heated under
reflux for 4 h. The solvent was concentrated in vacuo, then
the residue was diluted with EtOAc and the suspension was
filtered. The filtrate was washed with sodium thiosulfate
solution and brine, dried over MgSO4, filtered and concen-
trated in vacuo. The residue was subjected to silica gel
column chromatography (hexane–EtOAc, 2:1 → 1:1,
gradient) to afford aldehyde 3 (0.99 g, 60% yield) as a pale
yellow solid. Analytical and Spectral Data of Aldehyde 3:
pale yellow solid; mp 195–196 °C. 1H NMR (400 MHz,
DMSO-d6): d = 9.64 (s, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 7.75
(ddd, J = 8.9, 8.9, 6.0 Hz, 1 H), 7.68 (dd, J = 8.5, 1.7 Hz, 1
H), 7.64–7.72 (m, 1 H), 7.36–7.42 (m, 1 H), 7.01 (br s, 1 H),
6.97 (s, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 188.4,
177.3, 163.0 (dd, J = 250.0, 12.0 Hz), 158.3 (dd, J = 250.9,
13.6 Hz), 143.9, 142.7, 132.2 (d, J = 10.7 Hz), 128.2, 127.9,
127.8, 125.2, 121.1 (dd, J = 13.2, 4.1 Hz), 119.4, 118.5,
113.3 (dd, J = 22.3, 3.3 Hz), 105.7 (dd, J = 26.9, 23.6 Hz).
(5) For a recent review, see: Kouznetsov, V. V.; Mendez,
L. Y. V.; Gomez, M. M. Curr. Org. Chem. 2005, 9, 141.
(6) (a) Werner, W. Tetrahedron 1969, 25, 255. (b) Chen, B.;
Huang, X.; Wang, J. Synthesis 1987, 482. (c) Madrid, P. B.;
Sherrill, J.; Liou, A. P.; Weisman, J. L.; DeRisi, J. L.; Guy,
R. K. Bioorg. Med. Chem. Lett. 2005, 15, 1015.
(7) Camps, R. Chem. Ber. 1899, 32, 3228.
© Thieme Stuttgart · New York
Synlett 2012, 23, 448–452

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K.-i. Awasaguchi et al.
LETTER
IR (neat): 1702, 1631, 1595, 1512, 1448, 1271, 1149, 1008,
972, 947, 856, 830 cm–1. HRMS (DART): m/z [M + H]+
calcd for C16H9BrF2NO2: 363.97847; found: 363.97898.
IR (neat): 1575, 1512, 1468, 1411, 1260, 1143, 1045, 966,
846, 730 cm–1. HRMS (DART): m/z [M + H]+ calcd for
C15H11Cl2F2N2OS: 374.99372; found: 374.99405.
(19) General Procedure for the Synthesis of Ketene-S,N-
acetal 8: To a solution of 3-acetyl-2,6-dichloropyridine (7)
in THF (26 mL) was added lithium diisopropylamide (2.0 M,
3.0 mL, 6.05 mmol) dropwise at –40 °C under nitrogen
atmosphere. After stirring at –40 °C for 30 min, to the
mixture was added a solution of 2,6-difluorophenyl
(20) General Procedure for the Synthesis of 1-Aryl-3-fluoro-
4-oxoquinoline 15: To a solution of N-arylenaminone 14
(100 mg, 0.28 mmol) in DMF (2.8 mL) was added
Selectfluor® (149 mg, 0.42 mmol) at r.t. The mixture was
stirred for 30 min at the same temperature. To the mixture
was added K2CO3 (116 mg, 0.84 mmol) and the mixture was
heated to 80 °C. After stirring for 30 min at 80 °C, the
mixture was cooled and diluted with EtOAc and H2O. The
organic layer was washed with brine, dried over MgSO4,
filtered and concentrated in vacuo. The residue was
isothiocyanate (2.08 g, 12.1 mmol) in THF (11 mL). The
mixture was gradually warmed up to r.t. while stirring for 1.5
h. After stirring, the mixture was cooled in an ice bath. To
the mixture was added iodomethane (0.75 mL, 12.1 mmol)
at 5 °C and the mixture was warmed up to r.t. while stirring
for 20 min. The reaction was quenched with sat. NH4Cl
solution at 5 °C and the mixture was extracted with EtOAc.
The organic layer was washed with brine, dried over MgSO4,
filtered and concentrated in vacuo. The residue was
subjected to silica gel column chromatography (hexane–
EtOAc, 20:1 → 10:1, gradient) to afford ketene-S,N-acetal 8
(0.66 g, 35% yield) as a pale yellow solid. Analytical and
Spectral Data of Ketene-S,N-acetal 8: pale yellow solid;
mp 164–165 °C. 1H NMR (400 MHz, CDCl3): d = 12.78 (br
s, 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 7.41 (ddd, J = 8.7, 8.7, 5.9
Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 6.90–7.00 (m, 2 H), 5.70
(s, 1 H), 2.41 (s, 3 H). 13C NMR (100 MHz, CDCl3): d =
183.6, 170.5, 161.7 (dd, J = 250.4, 10.8 Hz), 157.3 (dd, J =
252.5, 12.8 Hz), 150.5, 146.7, 141.0, 135.6, 129.4 (d, J =
10.7 Hz), 123.1, 121.8 (dd, J = 12.4, 4.1 Hz), 111.5 (dd, J =
22.3, 4.1 Hz), 105.0 (dd, J = 26.5, 24.0 Hz), 92.9, 14.7.
subjected to silica gel column chromatography (hexane–
EtOAc, 3:1) to afford 1-aryl-3-fluoro-4-oxoquinoline 15 (38
mg, 38% yield) as a pale yellow solid. Analytical and
Spectral Data of 1-Aryl-3-fluoro-4-oxoquinoline 15: pale
yellow solid; mp 197–198 °C. 1H NMR (400 MHz, DMSO-
d6): d = 8.66 (d, J = 8.3 Hz, 1 H), 8.24 (d, J = 8.6 Hz, 1 H),
7.89 (ddd, J = 8.8, 8.8, 5.9 Hz, 1 H), 7.69–7.76 (m, 1 H), 7.64
(dd, J = 8.6, 1.6 Hz, 1 H), 7.40–7.46 (m, 1 H), 7.17 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 167.8 (d, J = 14.9 Hz),
162.9 (dd, J = 249.6, 11.6 Hz), 157.7 (dd, J = 252.5, 13.6
Hz), 146.6 (d, J = 238.0 Hz), 140.6, 132.0 (d, J = 28.9 Hz),
131.7 (d, J = 3.3 Hz), 127.8 (d, J = 4.1 Hz), 127.2, 126.6,
125.4 (d, J = 9.9 Hz), 123.5 (dd, J = 12.8, 3.7 Hz), 119.1,
113.4 (dd, J = 22.7, 3.7 Hz), 106.0 (dd, J = 27.3, 23.1 Hz).
IR (neat): 1624, 1587, 1509, 1328, 1217, 1193, 1143, 1101,
968, 926, 853, 834, 772 cm–1. HRMS (DART): m/z [M + H]+
calcd for C15H8BrF3NO: 353.97414; found: 353.97405.
Synlett 2012, 23, 448–452
© Thieme Stuttgart · New York

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