Efficient preparation of 4-hydroxyquinolin-2(1 H)-one derivatives with silver-catalyzed carbon dioxide incorporation and intramolecular rearrangement

Article abstract of DOI:10.1021/ol401571r

Although 4-hydroxyquinolin-2(1H)-one derivatives have attracted much attention due to their biological benefits, conventional reactions under harsh heat conditions must be employed to provide these key compounds. In the presence of a catalytic amount of s

Full text of DOI:10.1021/ol401571r

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3710–3713
Efficient Preparation of
4‑Hydroxyquinolin-2(1H)‑one Derivatives
with Silver-Catalyzed Carbon Dioxide
Incorporation and Intramolecular
Rearrangement
Tomonobu Ishida, Satoshi Kikuchi, and Tohru Yamada*
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama,
223-8522, Japan
yamada@chem.keio.ac.jp
Received June 4, 2013
ABSTRACT
Although 4-hydroxyquinolin-2(1H)-one derivatives have attracted much attention due to their biological benefits, conventional reactions under harsh
heat conditions must be employed to provide these key compounds. In the presence of a catalytic amount of silver salt, various o-alkynylanilines
were treated with carbon dioxide and a base under mild reaction conditions to afford the corresponding 4-hydroxyquinolin-2(1H)-one derivatives in
high yield.
Interest in 4-hydroxyquinolin-2(1H)-one derivatives
has been growing due to their potential biological benefits.
Studies on their medicinal properties have been promising,
for example, in treatment of central nervous system dis-
orders,1 sex hormone-related conditions,2 and suppression
of allergy-associated inflammations,3 and some of their
derivatives have been reported as HIV-1 inhibitors.4 Their
preparations have been based on conventional heterocyclic
chemistry including nucleophilic additionꢀelimination
reactions under harsh heat conditions, such as the reaction
of 4-halocarbostyril with potassium hydroxide,5 or an
aniline derivative and a carbonyl compound with high
leaving-group ability.6
The rearrangement reaction is one of the most effective
strategies for the preparation of heterocycles in industrial
and academic laboratories. Various complex natural pro-
ducts and pharmaceutical agents have been synthesized by
drastic transformation of the molecular framework induced
by a rearrangement reaction.7 Among these rearrangement
(1) (a) McQuaid, L. A.; Smith, E. C. R.; Lodge, D.; Pralong, E.;
Wikel, J. H.; Calligaro, D. O.; O’Malley, P. J. J. Med. Chem. 1992, 35,
3423–3425. (b) Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone,
D.; Stevenson, G. I.; Carling, R. W.; Baker, R.; Marshall, G. R.; Kemp,
J. A.; Foster, A. C.; Grimwood, S.; Hargreaves, R.; Hurley, C.; Saywell,
K. L.; Tricklebank, M. D.; Leeson, P. D. J. Med. Chem. 1997, 40, 4053–
4068.
(2) (a) DeVita, R. J.; Hollings, D. D.; Goulet, M. T.; Wyvratt, M. J.;
Fisher, M. H.; Lo, J.-L.; Yang, Y.-T.; Cheng, K.; Smith, R. G. Bioorg.
Med. Chem. Lett. 1999, 9, 2615–2620. (b) DeVita, R. J.; Goulet, M. T.;
Wyvratt, M. J.; Fisher, M. H.; Lo, J.-L.; Yang, Y.-T.; Cheng, K.; Smith,
R. G. Bioorg. Med. Chem. Lett. 1999, 9, 2621–2624.
(3) Sherlock, M. H.; Kaminski, J. J.; Tom, W. C.; Lee, J. F.; Wong,
S.-C.; Kreutner, W.; Bryant, R. W.; McPhail, A. T. J. Med. Chem. 1988,
31, 2108–2121.
(4) McCormick, J. L.; McKee, T. C.; Cardellina, J. H., II; Boyd,
M. R. J. Nat. Prod. 1996, 59, 469–471.
(5) Okamoto, T.; Kimura, E.; Iwasaki, S.; Yamamoto, K. Chem.
Pharm. Bull. 1969, 17, 2083–2087.
(6) (a) Zeigler, E.; Wolf, R.; Kappe, J. Monatsh. Chem. 1965, 96, 418–
422. (b) Yamaguchi, S.; Yoshimoto, Y.; Murai, R.; Masuda, F.;
Yamada, M.; Kawase, Y. J. Heterocycl. Chem. 1984, 21, 737–739.
(c) Mitsos, C. A.; Zografos, A. L.; Igglessi-Markopoulou, O. J. Org.
Chem. 2003, 68, 4567–4569. (d) Leeson, P. D.; Baker, R.; Carling, R. W.;
Kulagowski, J. J.; Mawer, I. M.; Ridgill, M. P.; Rowley, M.; Smith,
J. D.; Stansfield, I.; Stevenson, G. I.; Foster, A. C.; Kemp, J. A. Bioorg.
Med. Chem. Lett. 1993, 3, 299–304. (e) Jung, J.-C.; Jung, Y.-J; Park, O.-
S. Synth. Commun. 2001, 31, 1195–1200. (f) Dittmer, D. C.; Li, Q.;
Avilov, D. V. J. Org. Chem. 2005, 70, 4682–4686. (g) Arya, K.; Agarwal,
M. Bioorg. Med. Chem. Lett. 2007, 17, 86–93. (h) Zhang, S.-L.; Huang,
Z.-S.; Li, Y.-M.; Chan, A. S. C.; Gu, L.-Q. Tetrahedron 2008, 64, 4403–
4407. (i) Im, I.; Lee, E. S.; Choi, S. J.; Lee, J.-Y.; Kim, Y.-C. Bioorg. Med.
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r
10.1021/ol401571r
Published on Web 07/02/2013
2013 American Chemical Society

reactions, isocyanates have been employed as effective inter-
mediates because of their high reactivity,8 e.g., in Schmidt
rearrangement,9 Hofmann rearrangement,10 Curtius
rearrangement,11 Lossen rearrangement,12 and Buchererꢀ
Bergs reaction.13
sole product. Single-crystal X-ray diffraction analysis
revealed the structure of this product (Figure 1).15
A
few quinoline syntheses from o-alkynylaniline deriva-
tives have been reported, for example, using Masamuneꢀ
Bergman type cyclization of enyne-isocyanates synthesized
from o-alkynylanilines,16 carbocyclization of N-(o-alkynyl)-
malonamides with base17a or an electrochemical method,17b
and Michael Addition of NH group of carbamate to con-
jugated enones from alkyne-carbonyl metathesis of o-alky-
nylanilines and aldehydes.18 These reactions are considered
to be conceptually different from the present reaction with
carbon dioxide incorporation and rearrangement. Herein,
we would like to report an efficient preparation of 4-hydro-
xyquinolin-2(1H)-one derivatives from o-alkynylanilines and
carbon dioxide.
We recently reported the silver-catalyzed preparation
of benzoxazin-2-one derivatives from o-alkynylaniline de-
rivatives and carbon dioxide.14 It was considered that the
amino group and carbon dioxide would form the corre-
sponding carbamate followed by 6-exo-dig cyclization on
the alkyne activated by a silver catalyst. Upon optimiza-
tion, it was found that DBU was the most effective base for
the reaction of secondary o-alkynylanilines to afford the
corresponding benzoxazin-2-one derivatives in high yield
(eq 1). However, for primary o-alkynylanilines, DABCO
was the most suitable base (eq 2). When DBU was
employed for the reaction of primary o-alkynylanilines,
the corresponding products were not obtained at all (eq 3);
nevertheless, the starting material was completely con-
sumed. After carefully investigating the reaction mixture,
4-hydroxyquinolin-2-one was surprisingly generated asthe
Figure 1. Single-crystalX-raydiffractionanalysisfor2a0. Thermal
ellipsoids are shown at the 50% probability level. The single
crystal was obtained after methylation of 2a with trimethyl-
silyldiazomethane.
(7) (a) Aucejo, A.; Burguet, M. C.; Corma, A.; Fornes, V. Appl.
Catal. 1986, 22, 187–200. (b) Curtin, T.; McMonagle, J. B.; Hodnett,
B. K. Appl. Catal., A 1992, 93, 75–89. (c) Kob, N.; Drago, R. S. Catal.
Lett. 1997, 49, 229–234. (d) Holton, R. A.; Somoza, C.; Kim, H.-B.;
Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.;
Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.;
Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116,
1597–1598. (e) Shimizu, Y.; Shi, S.-L.; Usuda, H.; Kanai, M.; Shibasaki,
M. Angew. Chem., Int. Ed. 2010, 49, 1103–1106.
(8) Delebecq, E.; Pascault, J.-P.; Boutevin, B.; Ganachaud, F. Chem.
Rev. 2013, 113, 80–118.
(9) (a) Schmidt, K. F. Z. Angew. Chem. 1923, 36, 511. (b) Schultz,
A. G.; Wang, A.; Alva, C.; Sebastian, A.; Glick, S. D.; Deecher, D. C.;
Bidlack, J. M. J. Med. Chem. 1996, 39, 1956–1966.
(10) Hofmann, A. W. Ber. Dtsch. Chem. Ges. 1881, 14, 2725–2736. (b)
Evans, D. A.; Scheidt, K. A.; Downey, C. W. Org. Lett. 2001, 3, 3009–3012.
(11) (a) Buchner, E.; Curtius, T. Chem. Ber. 1885, 18, 2371–2377. (b)
Carda, M.; Gonzalez, F.; Sanchez, R.; Marco, J. A. Tetrahedron:
Asymmetry 2002, 13, 1005–1010.
(12) (a) Lossen, W. Liebigs Ann. Chem. 1869, 150, 313–325.
(b) Ohmoto, K.; Yamamoto, T.; Horiuchi, T.; Kojima, T.; Hachiya,
K.; Hashimoto, S.; Kawamura, M.; Nakai, H.; Toda, M. Synlett 2001,
299–301.
(13) (a) Bucherer, H. T.; Fischbeck, H. T. J. Prakt. Chem. 1934, 140,
69. (b) Sarges, R.; Goldstein, S. W.; Welch, W. M.; Swindell, A. C.;
Siegel, W. S.; Beyer, T. A. J. Med. Chem. 1990, 33, 1859–1865.
(14) Ishida, T.; Kikuchi, S.; Tsubo, T.; Yamada, T. Org. Lett. 2013,
15, 848–851.
(15) Crystallographic data reported in this paper have been deposited
with Cambridge Crystallographic Data Centre as supplementary pub-
lication no. CCDC-904718. Copies of the data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge,
CB2 1EZ, U.K.; Fax þ44 1223 336033; or deposit@ccdc.cam.ac.uk).
Scheme 1 shows the hypothetical reaction mechanism
to explain these observations. First, the corresponding
benzoxazin-2-one would form from the o-alkynylaniline
and carbon dioxide catalyzed by the silver catalyst. In
the second step, the benzoxazine would immediately be
deprotonated with DBU base to generate the isocyanate
and the enolate from CꢀO bond cleavage of the carbamate
functionality. The enolate would then attack the carbon
atom of the isocyanate to afford the 1,3-diketone inter-
mediate, which would producethe corresponding 4-hydro-
xyquinolin-2(1H)-one after enolization. Thus, in this pro-
posed mechanism, a new CꢀC bond is formed with carbon
dioxide. It is expected that the corresponding quinoline
derivative should contain carbon dioxide.
On the basis of our previous report, if a benzoxazin-2-
one is formed as an intermediate, a silver-catalyzed process
shouldberequired. Variousmetal salts expectedtoactivate
(16) Li, H.; Yang, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem.
2004, 69, 4500–4508.
(17) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P.
Synlett 1998, 446–448. (b) Arcadi, A.; Inesi, A.; Marinelli, F.; Rossi, L.;
Verdecchia, M. Eur. J. Org. Chem. 2007, 2430–2437.
(18) Saito, A.; Kasai, J.; Odaira, Y.; Fukaya, H.; Hanzawa, Y. J. Org.
Chem. 2009, 74, 5644–5647.
Org. Lett., Vol. 15, No. 14, 2013
3711

highyield (entries 15ꢀ17). These results would suggest that
a silver salt effectively activates the CꢀC triple bond to
generate a benzoxazin-2-one from the o-alkynylaniline and
carbon dioxide in the earlier stage of the reaction.
Scheme 1. Hypothetical Reaction Mechanism
Isotopic labeling experiments with C18O2 were con-
ducted to reveal whether the quinoline contained carbon
dioxide (Scheme 2). As a result, the 18O-labeled quinoline
(MW 242) was detected by mass spectral analysis, and
the nonlabeled quinoline (MW 238) was not detected at all,
which strongly suggested that the quinoline was derived
from the o-alkynylaniline and carbon dioxide. In addition,
in situ IR measurement of the reaction of the benzoxazin-2-
one and DBU was carried out. After DBU was added to the
THF solution of the benzoxazine, absorption at 2150 cmꢀ1
assigned as isocyanate group was observed.19 This result
would also support the proposed reaction mechanism.
Table 1. Examination of Metal SaltsandConditionOptimization
Scheme 2. Isotopic Labeling Experiments with C18O2
entry
metal salt
none
solvent
X/MPa
yielda (%)
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
tolune
EtOH
DCE
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.1
0.1
0.1
0.1
0.1
0
0
2
CuI
3
RhCl3 3H2O
0
3
4
PdCl2
0
5
PtCl2
0
6
AuCl
0
7
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgBF4
AgOC(O)CF3
AgOAc
94
82
9
8
9
10
11
12
13b
14
15
16
17
3
THF
70
93
93
97
91
95
92
MeCN
MeCN
DMSO
DMSO
DMSO
DMSO
Under the optimized reaction conditions, various o-alky-
nylaniline derivatives were applied to the CꢀC bond-form-
ing carbon dioxide incorporation reaction (Table 2).
In the presence of 10 mol % of AgNO3 and 1.0 equiv of
DBU under atmospheric pressure of carbon dioxide in
DMSO, aniline derivative 1a was transformed into 4-hydro-
xyquinoilne-2-one derivative 2a in excellent yield (entry 1).
Anilines with substituents (R1) at the para-position rela-
tive to the amino group were next subjected to the reaction.
When o-alkynylaniline 1b substituted with an electron-
donating group on the phenyl group was employed, the cor-
responding product 2b was obtained in high yield (entry 2).
The 4-hydroxyquinoline derivatives with electron-with-
drawing groups at the 6-position, 2c, 2d, and 2e, derived
from 1c, 1d, and 1e, respectively, were also generated
in high to excellent yields (entries 3ꢀ5). The meta- and
ortho-substituted substrates 1f and 1g were converted
into the corresponding products 2f and 2g in high yields
a Isolated yield. b The reaction was carried out for 48 h.
the CꢀC triple bond were examined (Table 1). In the
absence of any metal salts, the corresponding hydroxy-
quinoline was not obtained (entry 1). Although copper(I),
rhodium(III), palladium(II), platinum(II), and gold(I)
salts were expected to activate the CꢀC triple bond, the
corresponding products were not afforded at all (entries
2ꢀ6). Silver(I) nitrate effectively promoted the reaction in
DMSO orMeCN(entries7and 12). Thehydroxyquinoline
was generated in good yield in toluene or THF; however,
the reaction proceeded inadequately in EtOH or DCE
(entries 8ꢀ11). Under atmospheric pressure of carbon
dioxide, the product was afforded in MeCN or DMSO;
however, a longer reaction time was required in MeCN
compared to DMSO (entries 13 and 14). It was found that
other silver salts also promoted the reaction to produce the
corresponding 4-hydroxyquinolin-2(1H)-one derivative in
(19) The details about the experiment were described in the Support-
ing Information.
3712
Org. Lett., Vol. 15, No. 14, 2013

into quinoline derivative 2i containing the trisubstituted
olefin in 75% yield (entry 9). An alkyl group on alkyne 1j
was subjected to the conditions to afford the correspond-
ing 3-alkyl-4-hydroxyquinoline 2j in 69% yield (entry 10).
Substrates with a 2-pyridyl group 1k and a 1-naphthyl
group 1l successfully afforded the corresponding products
2k and 2l, respectively, in excellent yields (entries 11 and 12).
The product having an enone structure 2m derived from the
corresponding ynone-substituted aniline 1m was formed in
satisfactory yield.
Table 2. CO2 Incorporation with CꢀC Bond Formation
through Intramolecular Rearrangement with Various
o-Alkynylaniline Derivatives
Substituent R3 effects were examined on the phenyl ring
attached to the alkyne terminus. An electron-donating
group at the para-position 1n afforded the corresponding
product 2n quantitatively. Substrates with electron-with-
drawing groups, e.g., nitro 1o or trifluoromethyl 1p, were
subjected to the reaction conditions to produce the quino-
line derivatives 2o and 2p, respectively.
In conclusion, we developed a conceptually new syn-
thetic method of 4-hydroxyquinolin-2-one derivatives,
which have been reported as biologically active com-
pounds for treatment of several diseases, from o-alkyny-
lanilines, DBU, silver catalyst, and atmospheric pressure
of carbon dioxide under mild reaction conditions. The key
step in the reaction mechanism is proposed as the generation
of the isocyanate and the enolate through CꢀO bond
cleavage and new CꢀC bond formation induced by depro-
tonation of the amide after formation of the benzoxazin-2-
one. The obtained quinoline derivatives were composed of
the starting o-alkynylaniline and carbon dioxide as revealed
by isotopic labeling experiments. Various substrates could
be subjected to the optimized reaction conditions and
smoothly transformed into the corresponding quinoline
derivatives in high yields. Further applications are currently
being investigated in our laboratory.
a Isolated yield.
Note Added after ASAP Publication. Scheme 2 contained
an error in the version published ASAP on July 2, 2013;
the correct version reposted on July 9, 2013.
despite the steric hindrance of the substituents (entries 6ꢀ7).
The highly conjugated aniline derivative 1h was also an
excellent substrate for this reaction, and the corresponding
three-ring fused compound 2h was produced quantitatively
(entry 8).
Substituents R2 on the alkynyl terminal were examined
next. The substrate with terminal alkyne 1i was transformed
Supporting Information Available. Experimental proce-
dure and analytical data for new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 14, 2013
3713