Synthesis of 4-quinolones through nickel-catalyzed intramolecular amination on the β-carbon of o-(N-alkylamino)propiophenones

Article abstract of DOI:10.1055/s-0031-1291146

o-(N-Alkylamino)propiophenones are converted into 4-quinolones in the presence of chlorobenzene, potassium phosphate, morpholine, and nickel(0) catalyst. The reaction proceeds through the nickel-catalyzed formation of β-enaminones from o-(N-alkylamino)propiophenones and morpholine, followed by the intramolecular transamination. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291146

LETTER
▌1639
lSetyternthesis of 4-Quinolones through Nickel-Catalyzed Intramolecular
Amination on the β-Carbon of o-(N-Alkylamino)propiophenones
Synthesis of 4-Quinolones
Satoshi Ueno,* Ryosuke Shimizu, Ryohei Maeda, Ryoichi Kuwano*
Department of Chemistry, Graduate School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Fax +81(92)6422572; E-mail: ueno@chem.kyushu-univ.jp
Received: 09.03.2012; Accepted after revision: 08.04.2012
no)phenyl]prop-2-en-1-one 3 is known to be exchanged
with internal N-arylamino group (Scheme 1).9 Therefore,
we thought that the reaction of 1a with a secondary amine
would afford the 4-quinolone 2a under the same condi-
Abstract: o-(N-Alkylamino)propiophenones are converted into 4-
quinolones in the presence of chlorobenzene, potassium phosphate,
morpholine, and nickel(0) catalyst. The reaction proceeds through
the nickel-catalyzed formation of β-enaminones from o-(N-alkyl-
amino)propiophenones and morpholine, followed by the intramo- tions as shown in Scheme 1. Namely, the present reaction
lecular transamination.
was hypothesized to proceed via dehydrogenative cou-
pling of 1a and a secondary amine followed by the intra-
molecular transamination of β-enaminone 3.
Key words: nickel, cyclization, amination, ketones, oxidation
Table 1 Effect of Amine in the Intramolecular Nickel-Catalyzed
Cyclization of o-(N-methylamino)propiophenone (1a)a
Synthesis of 4-quinolones is an important issue in organic
synthesis because the skeleton is often seen in a variety
of pharmaceutically valuable compounds.1 Conrad–
Limpach reaction2 or Camps cyclization3 has been classi-
cally utilized for the synthesis of the 4-quinolones. Some
researchers are interested in the synthesis of 4-quinolones
from o-haloaryl alkynyl ketones4a or isatoic anhydrides4b
by using transition-metal catalysts. Herein we report a
novel access to 4-quinolones from o-(N-alkylamino)pro-
piophenones, which are easily prepared from N-alkylani-
lines.5,6 The present reaction involves the catalytic
carbon–nitrogen bond formation of ethyl ketones on the β-
carbon.7
O
O
Ni(cod)2 (4.0 mol%)
Me3P (12 mol%)
Me
PhCl, K3PO4, additive
DMF, 100 °C, 48 h
NH
Me
1a
N
Me
2a
Entry
Additive
Yield (%)b
1
2
3
4
5
6
7c
–
0
82
74
<5
36
21
87
morpholine
piperidine
pyrrolidine
dibutylamine
diisopropylamine
morpholine
Recently, we reported that ethyl ketones are converted
into β-enaminones by using a nickel catalyst, chloroben-
zene, and potassium phosphate.7,8 In the reaction, the ethyl
ketone undergoes catalytic dehydrogenation to give α,β-
unsaturated ketone. The generated enone undergoes the
1,4-addition of an amine and subsequent reoxidation of
the resulting β-aminoketone to produce the β-enaminone.
We thought that the reaction of aryl ethyl ketones having
an amino group at the ortho position might afford pharma-
ceutically valuable 4-quinolones through tandem dehy-
a Reactions were conducted on a 0.5 mmol scale in 0.2 mL of DMF.
The ratio of 1a/Ni(cod)2/Me3P/PhCl/K3PO4/additive was
25:1:3:100:100:50.
b The isolated yield of 2a.
c The reaction was conducted by using 10 mol% of morpholine.
drogenation–1,4-addition–reoxidation
sequence.
A
mixture of o-(N-methylamino)propiophenone (1a), chlo-
robenzene, and potassium phosphate in DMF was heated
at 100 °C for 48 hours in the presence of a catalytic
amount of Ni(cod)2 and trimethylphosphine (Table 1, en-
try 1). Although 1a completely disappeared, no 4-quino-
lone 2a was detected by 1H NMR analysis. In the reaction,
the oligomerization of α,β-unsaturated ketone intermedi-
ate was observed. The nucleophilicity of the internal N-ar-
ylamino group might not be enough for the intramolecular
1,4-addition leading to the formation of the desired 4-qui-
nolone. The amino group of 3-amino-1-[o-(N-methylami-
Hence, the cyclization of 1a was conducted in the pres-
ence of a secondary amine (Table 1, entries 2–6). Mor-
pholine was the most effective for the production of 2a,
which was obtained in 82% yield (Table 1, entry 2).10 Use
of piperidine in place of morpholine decreased the yield of
2a (Table 1, entry 3). In contrast to six-membered ring
amines, pyrrolidine failed to produce 2a (Table 1, entry
4). Acyclic amines were not suitable for the present reac-
tion (Table 1, entries 5 and 6). The reaction proceeded ef-
ficiently even when the amount of morpholine was
decreased from 200 mol% to 10 mol% (Table 1, entry 7).
SYNLETT 2012, 23, 1639–1642
Advanced online publication: 13.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291146; Art ID: ST-2012-U0217-L
© Georg Thieme Verlag Stuttgart · New York

1640
S. Ueno et al.
LETTER
Table 2 Effect of the Substituent on a Nitrogen Atom of 1a
O
O
O
R2
R2
R2
Ni(cod)2 (4.0 mol%)
Me3P (12 mol%)
Me
+
PhCl, K3PO4, morpholine
DMF, 100 °C
NH
R1
3
N
NH
R1
1
N
R1
O
2
Entry o-(N-Alkylamino)propiophenone 1 Time
4-Quinolone 2
Yield of 2
β-Enaminone 3
Yield of 3
(h)
(%)b
(%)c
O
O
Me
Me
Me
1
2
48
48
93
81
–
–
–
N
NH
Me
Me
1b
2b
O
N
O
Me
–
NH
1c
2c
2d
2e
O
O
O
Me
Me
Me
Me
3
48
48
not detected
73
trace
9
4d
NH
Et
N
NH
Et
N
O
O
O
O
Et
1d
3d
3e
3f
O
O
O
5d
48
48
71
70
9
NH
Bu
N
N
N
NH
Bu
N
Bu
1e
1f
O
O
O
6d
trace
NH
Bn
NH
Bn
N
Bn
2f
O
O
O
7d
120
48
10
72
75
trace
NH
8d,e
N
NH
i-Pr
i-Pr
i-Pr
1g
2g
3g
a Reactions were conducted on a 0.5 mmol scale in 0.2 mL of DMF. The ratio of 1 (0.5 mmol)/Ni(cod)2/Me3P /PhCl /K3PO4/morpholine was
100:4:12:400:400:10 unless otherwise noted.
b The isolated yield of 4-quinolone 2.
c The isolated yield of β-enaminone 3.
d The reaction was conducted by using 2 equiv of morpholine.
e To the crude reaction mixture was added EtOH (1.0 mL) and a drop of AcOH, and then the resulting solution was refluxed for 4 d.
Synlett 2012, 23, 1639–1642
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 4-Quinolones
1641
O
O
Supporting Information for this article is available online at
cat. Ni(cod)2–Me3P
HNR1R2
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Me
PhCl, K3PO4
NH
N
References
Me
Me
(1) For some selected reports, see: (a) Frutos, R. P.; Haddad, N.;
Houpis, I. N.; Johnson, M.; Smith-Keenan, L. L.; Fuchs, V.;
Yee, N. K.; Farina, V.; Faucher, A.-M.; Brochu, C.; Hache,
B.; Duceppe, J.-S.; Beaulieu, P. Synthesis 2006, 2563.
(b) 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.
(c) Nakamura, S.; Kozuka, M.; Bastow, K. F.; Tokuda, H.;
Nishino, H.; Suzuki, M.; Tatsuzaki, J.; Morris Natschke, S.
L.; Kuo, S.-C.; Lee, K.-H. Bioorg. Med. Chem. 2005, 13,
4396. (d) Hadjeri, M.; Peiller, E.-L.; Beney, C.; Deka, N.;
Lawson, M. A.; Dumontet, C.; Boumendjel, A. N. J. Med.
Chem. 2004, 47, 4964. (e) Koyama, J.; Toyokuni, I.;
Tagahara, K. Chem. Pharm. Bull. 1999, 47, 1038.
(2) For recent developments of Conrad–Limpach reaction, see:
(a) Zewge, D.; Chen, C.-Y.; Deer, C.; Dormer, P. G.;
Hughes, D. L. J. Org. Chem. 2007, 72, 4276. (b) Son, J. K.;
Kim, S. I.; Jahng, Y. Heterocycles 2001, 55, 1981.
(c) Giardina, G. A. M.; Sarau, H. M.; Farina, C.; Medhurst,
A. D.; Grugni, M.; Rveglia, L. F.; Schmidt, D. B.; Rigolio,
R.; Luttmann, M.; Vecchietti, V.; Hay, D. W. P. J. Med.
Chem. 1997, 40, 1794. (d) Ogata, Y.; Kawasaki, A.;
Tsujimura, K. Tetrahedron 1971, 27, 2765.
(3) For recent developments of Camps-type cyclization, see:
(a) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani, M.;
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. (c) Ding, D.; Li, X.; Wang, X.; Du,
Y.; Shen, J. Tetrahedron Lett. 2006, 47, 6997.
(4) For recent reports of 4-quinolone syntheses by using
transition-metal catalyst, see: (a) Zhao, T.; Xu, B. Org. Lett.
2010, 12, 212. (b) Yoshino, Y.; Kurahashi, T.; Matsubara, S.
J. Am. Chem. Soc. 2009, 131, 7494.
(5) See details in Supporting Information. For references of
Sugasawa reaction, see: (a) Atechian, S.; Nock, N.;
Norcross, R. D.; Ratni, H.; Thomas, A. W.; Verron, J.;
Masciadri, R. Tetrahedron 2007, 63, 2811. (b) Prasad, K.;
Lee, G. T.; Chaudhary, A.; Girgis, M. J.; Streemke, J. W.;
Repic, O. Org. Process Res. Dev. 2003, 7, 723. (c) Houpis,
I. N.; Molina, A.; Douglas, A. W.; Xavier, L.; Lynch, J.;
Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1994, 35,
6811. (d) Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura,
K. J. Am. Chem. Soc. 1978, 100, 4842.
(6) For a report on the formation of N-containing six-membered
rings via direct C(sp3)–H functionalization by nickel
catalysis, see: Nakao, Y.; Morita, H.; Idei, H.; Hiyama, T.
J. Am. Chem. Soc. 2011, 133, 3264.
(7) Ueno, S.; Shimizu, R.; Kuwano, R. Angew. Chem. Int. Ed.
2009, 48, 4543.
1a
2a
O
ref. 7
NR1R2
– HNR1R2
NH
Me
3
Scheme 1 A new synthetic route from 1a to 4-quinolone 2a via the
formation of β-enaminone 3
The reaction conditions were applied to the cyclization of
various o-(N-alkylamino)propiophenones (Table 2). The
reaction of 1b with 10 mol% of morpholine proceeded to
give 4-quinolone 2b in high yield (Table 2, entry 1). Tet-
rahydroquinoline 1c was smoothly cyclized to give tricy-
clic 4-quinolone 2c in 81% yield (entry 2). However, the
reaction of o-(N-ethylamino)propiophenone (1d) failed to
afford 2d (Table 2, entry 3), but 2d was successfully
formed by using two equivalents of morpholine (Table 2,
entry 4). In the reaction, β-enaminone 3d, which is consid-
ered as an intermediate for the formation of 2d, was re-
covered in 9% yield. The method using two equivalents of
morpholine was applicable to the reaction of N-butylated
substrate 1e (Table 2, entry 5). The N-benzyl-protected 4-
quinolone 2f was obtained in 70% yield (Table 2, entry 6).
In contrast, the reaction of 1g, possessing the bulkier iso-
propyl group on the nitrogen atom, gave undesirable β-en-
aminone 3g as the major product (Table 2, entry 7). The
compound 3g scarcely underwent transamination even
when the reaction was conducted for 120 hours. The cor-
responding 4-quinolone 2g was obtained from 3g by treat-
ment of the crude mixture with acetic acid (Table 2, entry
8).9 No cyclization of o-(N-methylamino)butyrophenone
occurred because 1,4-addition of morpholine was hin-
dered by the steric repulsion of the methyl group on the β-
carbon of the generated internal α,β-unsaturated ketones.
In conclusion, we successfully developed the nickel-cata-
lyzed intramolecular amination of o-(N-alkylamino)pro-
piophenones on the β-carbon. The reaction offers a new
synthetic route to pharmaceutically valuable 4-quino-
lones. The cyclization occurred through tandem catalytic
formation of β-enaminone from o-(N-alkylamino)propio-
phenone and an external secondary amine–intramolecular
transamination sequence.
(8) Recently, Pihko et al. reported that the carbon–carbon bond
formation at the -position of saturated carbonyl compounds
was achieved through a tandem palladium-catalyzed
dehydrogenation–1,4-addition sequence, see: Leskinen, M.
V.; Yip, K.-T.; Valkonen, A.; Pihko, P. M.
Acknowledgment
This work was supported by Grant-in-Aid for Scientific Research
on Innovative Areas ‘Molecular Activation Directed toward
Straightforward Synthesis’, the Global COE program ‘Science for
Future Molecular Systems’, and Young Scientists (B), from the Mi-
nistry of Education, Culture, Sports, Science and Technology, Ja-
pan. We acknowledge Prof. Tsutomu Katsuki for GCMS analyses.
J. Am. Chem. Soc. 2012, 134, 5750.
(9) The similar intramolecular transamination of β-enaminones
was known to occur by treatment with the Brønsted acid. For
the reference, see: Friary, R. J.; Seidl, V.; Schwerdt, J. H.;
Cohen, M. P.; Hou, D.; Nafissi, M. Tetrahedron 1993, 49,
7169.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1639–1642

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S. Ueno et al.
LETTER
was filtered through a Celite pad to remove the insoluble
(10) Typical Procedure for the Transformation of 1a into 2a
In a nitrogen-filled drybox, a 4 mL screw-capped vial was
charged with Ni(cod)2 (5.6 mg, 0.020 mmol), K3PO4 (424.5
mg, 2.0 mmol), and DMF (0.2 mL). After a magnetic stir
bar was added, the vial was fitted with a septum cap and
removed from the drybox. A solution of trimethylphosphine
in THF (60 μL, 1 M solution, 0.060 mmol), chlorobenzene
(0.20 mL, ρ = 1.106 g/mL, 1.97 mmol), o-(N-methylamino)-
propiophenone (1a, 81.3 mg, 0.50 mmol), and morpholine
(4.5 μL, ρ = 0.996, 0.05 mmol) were added. The resulting
mixture was heated at 100 °C for 48 h. The reaction mixture
inorganic salt. The filtrate was concentrated and purified by
silica gel column chromatography (EtOAc–MeOH = 5:1) to
give 4-quinolone 2a (69.1 mg, 87%) as a pale yellow solid.
1H NMR (400 MHz, CDCl3, TMS): δ = 3.81 (s, 3 H), 6.28
(d, J = 7.7 Hz, 1 H), 7.37–7.48 (m, 2 H), 7.51 (d, J = 7.7 Hz,
1 H), 7.69 (ddd, J = 8.7, 7.1, 1.6 Hz, 1 H), 8.48 (dd, J = 8.2,
1.6 Hz, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 40.6,
109.9, 115.3, 123.7, 126.7, 126.9, 132.1, 140.5, 143.7,
178.2.
Synlett 2012, 23, 1639–1642
© Georg Thieme Verlag Stuttgart · New York

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