Synthesis of 2(1 H)-quinolinones via Pd-catalyzed oxidative cyclocarbonylation of 2-vinylanilines

Article abstract of DOI:10.1021/ol4006739

Palladium-catalyzed oxidative cyclocarbonylation of N-monosubstituted-2- vinylanilines constitutes a simple, direct, and selective method for the synthesis of 2(1H)-quinolinones. The reaction conditions are attractive in terms of environmental considerations and operational simplicity. 2(1H)-Quinolinones with a variety of functional groups were prepared in up to 97% yield.

Full text of DOI:10.1021/ol4006739

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of 2(1H)‑Quinolinones via
Pd-Catalyzed Oxidative
Cyclocarbonylation of 2‑Vinylanilines
Jamie Ferguson, Fanlong Zeng, Natacha Alwis, and Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry, University of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
howard.alper@uottawa.ca
Received March 12, 2013
ABSTRACT
Palladium-catalyzed oxidative cyclocarbonylation of N-monosubstituted-2-vinylanilines constitutes a simple, direct, and selective method for the
synthesis of 2(1H)-quinolinones. The reaction conditions are attractive in terms of environmental considerations and operational simplicity.
2(1H)-Quinolinones with a variety of functional groups were prepared in up to 97% yield.
Transition metal catalysis has become a powerful tool
for the efficient syntheses of densely functionalized hetero-
cycles from relatively simple starting compounds. Particu-
larly in recent years, methods for catalytic CꢀH bond
activation have emerged, resulting in the syntheses of
numerous heterocycles, while avoiding the harsh reaction
conditions and halogenated starting compounds that are
necessary for many classic metal-catalyzed reactions.1
Along these lines, we recently discovered a new route to
coumarins, via the Pd-catalyzed oxidative cyclocarbonyla-
tion of 2-vinylphenols.2 This was the first report of an
intramolecular oxidative carbonylation, in which a nucleo-
phile such as YH (Y = OR or NRR0) had been coupled
directly with a terminal alkene. Extending this work, we
have investigated the reaction to prepare an analogous
nitrogen-containing heterocycle, i.e., the 2(1H)-quinoli-
none motif, starting from 2-vinylaniline. We were encour-
aged, not only by our work with 2-vinylphenols but also by
the seminal 2004report from Orito’s group, demonstrating
the preparation of benzolactams via Pd-catalyzed direct
aromatic carbonylation of secondary amines.3
2-Quinolinones (as well as their 4-quinolinone isomers)
are a naturally occurring class of compounds, which exhibit
a broad spectrum of pharmacological activity, including
antibiotic,4 anticancer,5 antiviral,6 antihypertensive,6 and
other7 activities. They may also serve as synthetic intermedi-
ates to 2-(pseudo)haloquinolines.8 Understandably, the pre-
paration of these valuable compounds has attracted a great
deal of interest. Classic methods include the base-catalyzed
9a
Friedlander and acid-catalyzed Knorr9b,4a syntheses, while
€
several other9cꢀg nonmetal-catalyzed syntheses have re-
cently been reported. Metal-catalyzed methods10 include
inter-10aꢀf and intramolecular,9g,10gꢀm carbonylative10b,c,f
and noncarbonylative9g,10a,d,e,gꢀm cyclizations, a few of
which have employed CꢀH bond activation.10g,h,m To date,
no reported single method has been demonstrated to prepare
(4) (a) Forbis, R. M.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1973, 95,
5003. (b) Hassanin, H. M.; El-edfawy, S. M. Heterocycles 2012, 85, 2421.
(5) (a) Claassen, G.; Brin, E.; Crogan-Grundy, C.; Vaillancourt,
M. T.; Zhang, H. Z.; Cai, S. X.; Drewe, J.; Tseng, B.; Kasibhatla, S.
Cancer Lett. 2009, 274, 243. (b) Mabire, D. J.-P.; Guillemont, J. E. G.;
Van Dun, J. A. J.; Somers, M. V. F.; Wouters, W. B. L. WO 2005054210
A1 20050616, 2005. (c) Venet, M. G.; Angibaud, P. R.; Muller, P.; Sanz,
G. C., WO 9721701 A1 19970619, 1997. (d) Ni, Z.-J.; Barsanti, P.;
Brammeier, N.; Diebes, A.; Poon, D. J.; Ng, S.; Pecchi, S.; Pfister, K.;
Renhowe, P. A.; Ramurthy, S.; Wagman, A. S.; Bussiere, D. E.; Le, V.; Zhou,
Y.; Jansen, J. M.; Ma, S.; Gesner, T. G. Bioorg. Med. Chem. Lett. 2006, 16,
3121.
(1) (a) Liu, Q.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2011, 50,
10788. (b) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1.
(2) Ferguson, J.; Zeng, F.; Alper, H. Org. Lett. 2012, 14, 5602.
(3) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126,
14342.
(6) Afonso, A.; Weinstein, J.; Gentles, M. J. (Schering Corp.) WO
9203327, 1992.
r
10.1021/ol4006739
XXXX American Chemical Society

2-quinolinones with both electron-donating and -withdrawing
substituents on the nitrogen.
Scheme 1. Some Possible Products of 2-Vinylanilines11a
As shown in Scheme 1, many products may be derived
from 2-vinylanilines under various conditions. We antici-
pated that the choice of the N-substituent (R1) would
greatly influence the nature of the NH nucleophile and,
thus, the selectivity of this reaction. Our first attempt to
prepare 2(1H)-quinolinone (2, Scheme 1) from 2-vinylaniline
(1, R1 = R2 = R3 = H), using the conditions optimized
with 2-vinylphenols, produced only the urea dimer (7). We
next examined 2-isopropenyl-N-tosylaniline (1e, R1 = Ts,
R2 = Me, R3 = H) as a model substrate. Under higher CO
pressures, we obtained only the saturated lactam 4e (Table 1,
entries 1 and 2). By lowering the CO pressure to e30 psi,
we could avoid the formation of 4e and instead obtain
mixtures of the desired 4-methyl-N-tosyl-2(1H)-quinoli-
none 2e, along with indole 3e. As shown in Table 1, when
starting from this substrate, the selectivity between the
2(1H)-quinolinone and the indole was highly sensitive to
reaction conditions. We probed the utility of different
ligands, co-oxidants, and bases in the system. Eventually,
the simple combination of Pd(OAc)2/Cu(OAc)2 in CH3CN
was found to be highly effective, although it could not
suppress some formation of the indole (Table 1, entry 11).
Hoping we might avoid this side reaction by adjusting
the R1 group, we tested 2-isopropenyl-N-methylaniline
(7) (a) Bonnefous, C.; Payne, J. E.; Roppe, J.; Zhuang, H.; Chen, X. H.;
Symons, K. T.; Nguyen, P. M.; Sablad, M.; Rozenkrants, N.; Zhang, Y.;
Wang, L.; Severance, D.; Walsh, J. P.; Yazdani, N.; Shiau, A. K.; Noble,
S. A.; Rix, P.; Rao, T. S.; Hassig, C. A.; Smith, N. D. J. Med. Chem. 2009,
52, 3047. (b) Kraus, J. M.; Verlinde, C. L. M. J.; Karimi, M.; Lepesheva,
G. I.; Gelb, M. H.; Buckner, F. S. J. Med. Chem. 2009, 52, 1639. (c)
Shiraiwa, M.; Ota, S.; Takefuchi, K.; Uchida, H.; Saegusa, M.; Mitsubori,
T.; Yoshizawa, M. (Teikoku Hormone Mfg. Co., Ltd.) JP 2003146972,
2003 [Chem. Abstr. 2003, 138, 401612]. (d) Carling, R. W.; Leeson, P. D.;
Moore, K. W.; Smith, J. D.; Moyes, C. R.; Mawer, I. M.; Thomas, S.;
Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall,
G. R.; Tricklebank, M. D.; Saywell, K. L. J. Med. Chem. 1993, 36, 3397. (e)
Hewawasam, P.; Fan, W.; Ding, M.; Flint, K.; Cook, D.; Goggins, G. D.;
Myers, R. A.; Gribkoff, V. K.; Boissard, C. G.; Dworetzky, S. I.; Starrett,
J. E.; Lodge, N. J. J. Med. Chem. 2003, 46, 2819. (f) Glasnov, T. N.;
Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70, 3864.
a Y represents any intermolecular coupling partner.
(1a) with Pd(OAc)2/Cu(OAc)2 in CH3CN and were
pleased to obtain 1,4-dimethylquinolin-2(1H)-one (2a) in
58% yield, with no indole formation (Table 1, entry 12).
However, we did isolate 2-isopropenyl-N-acetyl-N-methyl-
aniline (type 6, Scheme 1) as a byproduct, under these
and other conditions starting from 1a, usually in about
10ꢀ20% yield. Even when copper(II) pivalate12 was used
with Pd(OAc)2 instead of copper(II) acetate, the bypro-
duct was 2-isopropenyl-N-acetyl-N-methylaniline, rather
than 2-isopropenyl-N-pivalyl-N-methylaniline. It was also
notedthattheproductmixturesfromPd(OAc)2/Cu(OAc)2
in CH3CN contained acetic acid, observable in some
product NMR spectra.
By adding a small amount of air to the system, the
amount of Cu(OAc)2 required could be reduced to 0.5 equiv
(Table 1, entry 15). All other changes in our reaction
parameters;the Pd precursor and loading [10% Pd(OAc)2],
solvent (CH3CN), time (∼20 h), temperature (110 °C), and
pressures of CO (30 psi) or air (10 psi);either decreased or
did not improve the yield of 2a. Completely ineffective for
obtaining 2a from 1a (ceteris paribus) were the following
oxidants and/or additives: air/dppb (20 psi/10%), air/BQ
(8) (a) Anzini, M.; Cappelli, A.; Vomero, S. J. Heterocycl. Chem.
1991, 28, 1809. (b) Godard, A.; Fourquez, J. M.; Tamion, R.; Marsais,
ꢀ
F.; Queguine, G. Synlett 1994, 235.
ꢀ ꢀ ꢀ
(9) (a) Domı
´
nguez-Fernandez, F.; Lopez-Sanz, J.; Perez-Mayoral,
´
ꢁ
ꢀ
n-Aranda, R. M.; Lopez-Peinado, A. J.; Cejka, J.
E.; Bek, D.; Martı
Chem. Cat. Chem. 2009, 1, 241 and references cited therein. (b) Marull,
M.; Lefebvre, O.; Schlosser, M. Eur. J. Org. Chem. 2004, 54 and
references cited therein. (c) Reddy, M. S.; Thirupathi, N.; Babu, M. H.
Eur. J. Org. Chem. 2012, 5803. (d) Gao, W.-T.; Hou, W.-D.; Zheng,
M.-R.; Tang, L.-J. Synth. Commun. 2010, 40, 732. (e) Yasui, Y.;
Kakinokihara, I.; Takeda, H.; Takemoto, Y. Synthesis 2009, 23, 3989.
(f) Huang, C.-C.; Chang, N.-C. Org. Lett. 2008, 10, 673. (g) Angibaud,
P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y. A.; Muller, P.;
Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004, 479.
(10) (a) Iwai,T.;Fujihara,T.;Terao,J.;Tsuji,Y.J. Am. Chem. Soc. 2010,
132, 9602. (b) Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004, 69, 6772.
(c) Kadnikov, D. V.; Larock, R. C. J. Organomet. Chem. 2003, 687, 425. (d)
Cortese, N. A.; Ziegler, C. B., Jr.; Hrnjez, B. J.; Heck, R. F. J. Org. Chem.
1978, 43, 2952. (e) Harishkumar, H. N.; Hulikal, V. K.; Mahadevan, K. M.
Synth. Commun. 2010, 40, 3281. (f) Tadd, A. C.; Matsuno, A.; Fielding, M.;
Willis, M. C. Org. Lett. 2009, 11, 583. (g) Wasa, M.; Yu, J.-Q. J. Am. Chem.
Soc. 2008, 130, 14058. (h) Inamoto, K.; Kawasaki, J.; Hiroya, K.; Kondo,
Y.; Doi, T. Chem. Commun. 2012, 48, 4332. (i) Shibuya, T.; Shibata, Y.;
Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed. 2012, 50, 3963. (j) Minville,
J.; Poulin, J.; Dufresne, C.; Sturino, C. F. Tetrahedron Lett. 2008, 49, 3677.
(k) Liu, Z.; Shi, C.; Chen, Y. Synlett 2008, 1734. (l) Battistuzzi, G.; Bernini,
R.; Cacchi, S.; De Salve, I.; Fabrizi, G. Adv. Synth. Catal. 2007, 349, 297. (m)
Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. J. Org. Chem. 2010, 75, 3900.
(11) (a) Okuma, K.; Yasuda, T.; Takeshita, I.; Shioji, K.; Yokomori,
Y. Tetrahedron 2007, 63, 8250. (b) Kobayashi, K.; Miyamoto, K.;
Yamase, T.; Nakamura, D.; Morikawa, O.; Konishi, H. Bull. Chem.
Soc. Jpn. 2006, 79, 1580. (c) El Ali, B.; Okuro, K.; Vasapollo, G.; Alper,
H. J. Am. Chem. Soc. 1996, 118, 4264. (d) Larock, R. C.; Hightower,
T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584.
B
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Table 1. Selected Optimization Experiments to Form
2(1H)-Quinolones (2), Starting with 1 (R2 = Me, R3 = H)
Table 2. Optimized Oxidative Cyclocarbonylation of
2-Vinylanilines to 2(1H)-Quinolinonesa
Reaction conditions: 0.75 mmol of 1, 10% Pd(OAc)2, 110 °C, 20 h.
a BQ = 1,4-benzoquinone. b Obtained 39% of 4e. c Obtained 25% of 4e.
d Product was detected by TLC, but yield was not determined. e T = 75 °C.
(10 psi/1%), air/BQ/dppb (10 psi/1%/10%), PhI(OAc)2
(1.5 equiv), AgOAc (2 equiv), CuCl2 (2 equiv), Cu(CF3SO3)2
(2 equiv), and Cu(OAc)2 alone [without Pd(OAc)2]. Also
ineffective were the following solvents: THF, toluene, diox-
ane, and DMSO. With the optimized conditions in hand,
we explored the generality of this reaction toward other
N-monosubstituted-2-vinylanilines (Table 2).
It was necessary for the aniline to be a secondary amine,
and the yields were clearly higher with electron-donating
R1 groups than with electron-withdrawing groups. The
most favorable R1 group tested was isopropyl (Table 2, 2c,
2h-2j). It is likely that the steric demand, very near to the
nitrogen, deterred the side reaction that produced 2-iso-
propenyl-N-acetyl-N-methylaniline from 1a. The analogous
type 6 byproduct was not observed with substrate 1f or 1g.
a Isolated yields using the following experimental conditions: 1
(0.75 mmol), Pd(OAc)2 (0.075 mmol), Cu(OAc)2 (0.375 mmol), CH3CN
(5 mL), CO (30 psi), air (10 psi), 110 °C, 20 h.
Yields of 2(1H)-quinolinones were reduced substantially
when R1 = acetyl or tosyl. Interestingly, the acetylated
substrate 1d produced the deprotected 2(1H)-quinolinone
2d*, albeit in low yield. We also noted, with the benzylated
substrate 1b, that no competing reaction took place between
the nitrogen and its benzyl substituent, as might be expected,
based on Orito et al.’s preparation of benzolactams via
(12) Fomina, I. G.; Dobrokhotova, Zh. V.; Kiskin, M. A.; Aleksandrov,
G. G.Proshenkina, O. Yu.; Emelina, A. L.; Ikorskii, V. N.; Novotortsev,
V. M.; Eremenko, I. L. Russ. Chem. Bull., Int. Ed 2007, 56, 1712.
Org. Lett., Vol. XX, No. XX, XXXX
C

intramolecular aromatic carbonylation under nearly iden-
tical conditions.3
Scheme 2. Possible Mechanism of Oxidative
Cyclocarbonylation
Regarding R2 substitution, both methyl and phenyl
groups worked well. 4-Phenyl-2(1H)-quinolinones could
be obtained in as few as two steps, since the substrates were
prepared simply by heating the appropriate aniline and
phenylacetylene at 140 °C with montmorillonite KSF
(acidic) resin.13 Some compounds belonging to this class
of 2-quinolones have already shown promise in clinical
trials.7a,e,f,14
Finally, substitutions on the aniline aromatic ring met
with mixed results. Chloro (1h) and methyl (1i) substituents
para to the nitrogen did not strongly affect the reaction
outcome, whereas substrate 1g, with p-methoxy substitu-
tion, completely decomposed or polymerized under the
reaction conditions into an unknown, highly polar product.
Based on there being no need for additional P or N
ligands, and the performance of copper(II) salts in the
order of Cu(OAc)2 > [Cu2(pivalate)4]n . CuCl2, we
reasoned that the active catalytic species in this reaction
is a multinuclear cluster of type CumPdn(OAc)2(nþm), with
acetate bridges between Cu and Pd.15 That is, Cu(OAc)2
acts as both an oxidant and a ligand, similar to its role in
the Pd-catalyzed direct aromatic carbonylation with sec-
ondary amines.3 The mechanism we propose, with 1a as
the model substrate (Scheme 2), is based on these con-
siderations and on our proposed mechanism for coumarin
synthesis. To begin the cycle, the aniline nitrogen adds to
the active PdII species to form a PdꢀN bond, with elimina-
tion of acetic acid. Coordination and insertion of CO leads
to a Pdꢀcarbamoyl species. Alkene insertion of the vinyl
group into the PdꢀCO bond then could generate an
alkylpalladium intermediate. The 2(1H)-quinolinone pro-
duct is finally released by β-hydride elimination, and the
resulting palladium(II) hydride, LPdIIHOAc, may be re-
duced to a Pd0 species through the loss ofacetic acid. PdII is
regenerated by CuII or O2 to complete the catalytic cycle.
An alternative pathway may involve attack by the electron-
rich alkene to palladium(II) to form a pallacycle intermediate,
which could then undergo reductive elimination to give the
product. Carbon monoxide insertion could take place before,
or after, palladacycle formation.
In conclusion, we have developed an efficient Pd-cata-
lyzed oxidative cyclocarbonylation of 2-vinylanilines to
prepare (1H)-quinolinones in high yields, using simple and
mild conditions. This reaction constitutes a new route to a
highly important class of natural compounds. It is also, to
our knowledge, the first oxidative carbonylation in which
an aniline has been coupled directly with a terminal alkene.
These results add value to the scope of Pd-catalyzed
oxidative carbonylation reactions.
Acknowledgment. We are grateful to CYTEC and to
the Natural Sciences and Engineering Research Council
of Canada for support of this research.
(13) Arienti, A.; Bigi, F.; Maggi, R.; Marzi, E.; Moggi, P.; Rastelli,
M.; Sartori, G.; Tarantola, F. Tetrahedron 1997, 53, 3795.
(14) Garrido-Laguna, I.; Janku, F.; Falchook, G. S.; Fu, S.; Hong,
D. S.; Naing, A.; Aaron, J.; Wang, X.; Kies, M.; Kurzrock, R. Clin.
Cancer Res. 2010, 16, 4031.
(15) (a) Sloan, O. D.; Thornton, P. Inorg. Chim. Acta 1986, 120, 173.
(b) Brandon, R. W.; Claridge, D. V. J. Chem. Soc., Chem. Commun.
1968, 677. (c) Kozitsyna, N. Y.; Nefedov, S. E.; Dolgushin, F. M.;
Cherkashina, N. V.; Vargaftik, M. N.; Moiseev, I. I. Inorg. Chim. Acta
2006, 359, 2072.
Supporting Information Available. Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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