Synthesis of quinolones by nickel-catalyzed cycloaddition via elimination of nitrile

Article abstract of DOI:10.1021/ol303546p

Substituted quinolones were efficiently synthesized via the nickel-catalyzed cycloaddition of o-cyanophenylbenzamide derivatives with alkynes. The reaction involves elimination of a nitrile group by cleavage of the two independent aryl-cyano and aryl-carbonyl C-C bonds of the amides.

Full text of DOI:10.1021/ol303546p

ORGANIC
LETTERS
2013
Vol. 15, No. 4
856–859
Synthesis of Quinolones by
Nickel-Catalyzed Cycloaddition
via Elimination of Nitrile
Kenichiro Nakai, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto 615-8510, Japan, and JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama,
332-0012, Japan
kurahashi.takuya.2c@kyoto-u.ac.jp; matsubara.seijiro.2e@kyoto-u.ac.jp
Received December 26, 2012
ABSTRACT
Substituted quinolones were efficiently synthesized via the nickel-catalyzed cycloaddition of o-cyanophenylbenzamide derivatives with alkynes.
The reaction involves elimination of a nitrile group by cleavage of the two independent arylÀcyano and arylÀcarbonyl CÀC bonds of the amides.
A number of N-heterocycles containing carbonyl groups
have been recognized as biologically active agents,
quinolones1 and isoquinolones2 being among the most
representative examples of such heterocycles. Because of
their functionality, development of synthetic routes and
methods for the functionalization of these compounds is of
great significance.3 From this perspective, we have devel-
oped cycloaddition reactions of heterocycles with alkynes
to generate such benzopyridones via the elimination of
CO4a (Scheme 1, eq 1) or CO24b (eq 2). We further attempted
to synthesize 2-quinolone from o-cyanophenylbenzamides
and alkynes via the elimination of nitrile, using a nickel
catalyst (eq 3).5
The initial treatment of o-cyanophenylbenzamide deri-
vative 1a and 4-octyne 2a in the presence of a nickel catalyst
(prepared in situ from Ni(cod)2 and P(CH2Ph)3 using
methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide)
(MAD) as a cocatalyst by treatment in toluene at 120 °C for
12 h) generated quinolone 3aa in 36% yield (Table 1, entry 1).
(3) For selected examples of transition-metal-catalyzed syntheses
and functionalizations of 2-quinolone, see: (a) Kadnikov, D. V.; Larock,
R. C. J. Organomet. Chem. 2003, 687, 425. (b) Kadnikov, D. V.; Larock,
R. C. J. Org. Chem. 2004, 69, 6772. (c) Battistuzzi, G.; Bernini, R.;
Cacchi, S.; de Salve, I. Adv. Synth. Catal. 2007, 349, 297. (d) Queiroz, M.
J. R. P.; Abreu, A. S.; Calhelha, R. C.; Carvalho, M. S. D.; Ferreira,
P. M. T.; Fabrizi, G. Tetrahedron 2008, 64, 5139. (e) Tadd, A. C.;
Matsuno, A.; Fielding, M. R.; Willis, M. C. Org. Lett. 2009, 11, 583. (f)
Tang, D.-J.; Tang, B.-X.; Li, J.-H. J. Org. Chem. 2009, 74, 6749. (g)
Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. J. Org. Chem. 2010, 75, 3900.
(h) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2010,
132, 9602. (i) Fu, L.; Huang, X.; Wang, D.; Zhao, P.; Ding, K. Synthesis
2011, 1547. (j) Kato, H.; Ishigame, T.; Oshima, N.; Hoshiya, N.;
Shimawaki, K.; Arisawa, M.; Shuto, S. Adv. Synth. Catal. 2011, 353,
2676. (k) Tang, B.-X.; Song, R.-J.; Wu, C.-Y.; Wang, Z.-Q.; Liu, Y.;
Huang, X.-C.; Xiea, Y.-X.; Li, J.-H. Chem. Sci. 2011, 2, 2131. (l)
Borhade, S. R.; Waghmode, S. B. Can. J. Chem. 2011, 89, 1355.
(4) (a) Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2008, 130, 6058. (b) Yoshino, Y.; Kurahashi, T.; Matsubara, S. J. Am.
Chem. Soc. 2009, 131, 7494.
(1) For selected examples, see: (a) Hamann, L. G.; Higuchi, R. I.; Zhi,
L.; Edwards, J. P.; Wang, X.-N.; Marschke, K. B.; Kong, J. W.; Farmer,
L. J.; Jones, T. K. J. Med. Chem. 1998, 41, 623. (b) Naito, Y.;
Yoshikawa, T.; Tanigawa, T.; Sakurai, K.; Yamasaki, K.; Uchida,
M.; Kondo, M. Free Radical Biol. Med. 1995, 18, 117. (c) Joseph, B.;
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Darro, F.; Behard, A.; Lesur, B.; Collignon, F.; Decaestecker, C.;
Frydman, A.; Guillaumet, G.; Kiss, R. J. Med. Chem. 2002, 45, 2543.
(d) 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.
(2) For selected examples, see: (a) Krane, B. D.; Shamma, M. J. Nat.
Prod. 1982, 45, 377. (b) Calogero, A. E.; Kamilaris, T. C.; Bernardini, R.;
Johnson, E. O.; Chrousos, G. P.; Gold, P. W. J. Pharmacol. Exp. Ther.
1990, 253, 729. (c) Ikeura, Y.; Tanaka, T.; Kiyota, Y.; Morimoto, S.;
Ogino, M.; Ishimaru, T.; Kamo, I.; Doi, T.; Natsugari, H. Chem. Pharm.
Bull. 1997, 45, 1642. (d) Miura, T.; Yamauchi, M.; Murakami, M. Org.
Lett. 2008, 10, 3085. (e) Maezaki, H.; Banno, Y.; Miyamoto, Y.;
Moritou, Y.; Asakawa, T.; Kataoka, O.; Takeuchi, K.; Suzuki, N.;
Ikedo, K.; Kosaka, T.; Sasaki, M.; Tsubotani, S.; Tani, A.; Funami, M.;
Yamamoto, Y.; Tawada, M.; Aertgeerts, K.; Yano, J.; Oi, S. Bioorg.
Med. Chem. 2011, 19, 4482. (f) Du, J.; Xi, L.; Lei, B.; Liu, H.; Yao, X.
Chem. Biol. Drug Des. 2011, 77, 248.
(5) We recently reported a new method for generating coumarins from
o-arylcarboxybenzonitriles and alkynes via elimination of nitrile in the
presence of a nickel catalyst; see: Nakai, K.; Kurahashi, T.; Matsubara, S.
J. Am. Chem. Soc. 2011, 133, 11066.
r
10.1021/ol303546p
Published on Web 01/25/2013
2013 American Chemical Society

Table 1. Scope of the Cycloadditiona
Scheme 1. Synthetic Approaches toward All of the Structural
Isomers of Benzopyridones
In order to promote oxidative addition of the ArÀCN
bond, a more electron-rich nickel(0) catalyst prepared
from Ni(cod)2/PMe3/MAD was used, which increased
the reaction efficiency. Eventually, it was found that the
use of Ni(cod)2 (5 mol %), PMe3 (20 mol %), and MAD
(10 mol %) generated 3aa in 80% yield (entry 2). PCy3,
PPh3, IPr, and other ligands were less reactive in this case.
The cycloaddition reactions of several amides and 2a were
carried out under the optimized conditions. Amides sub-
stituted with electron-donating or -deficient aryl groups
on the nitrogen atom gave the corresponding quinolones
3ba, 3ca, and 3da in good-to-excellent yields (entries 3À5).
A substrate possessing a benzyl group (1e) also gave the
corresponding product 3ea in high yield (entry 6).
To extend the applicability of this protocol, various
alkynes were evaluated (Table 2). It was found that
2-octyne and 1-methoxy-3-heptyne were also well suited
for this reaction (entries 1, 2). 4-Methyl-2-pentyne gave
the corresponding adduct 3bd in low yield under the same
conditions mentioned above (entry 3). However, a slight
modification of the conditions (using PMe2Ph instead of
PMe3 and twice the amount of MAD) increased the yield
to 96% (entry 4). Bulkier alkynes (2e, 2f) also reacted with
substrate 1b to afford the relevant cycloadducts in high
yields, although a slightly larger quantity of the Lewis acid
(20À30 mol %) was required (entries 5, 6). The molecular
structures of the major cycloadducts 3bd and 3be were
determined via X-ray crystal structure analysis (see
Supporting Information). Under the conditions listed in
entry 4, diphenylacetylene 2g afforded the corresponding
product in 86% yield (entry 7). The monoaryl-substituted
internalalkyne2halsoreacted with1btoafford1bh in99%
yield (entry 8). Enyne 2i and diyne 2j participated in the
reaction with 1b to afford the desired products, 3bi and 3bj,
in respective yields of 99% and 59% without any evidence
of oligomerization of the alkynes (entries 9, 10). Almost
all of these examinations were performed without high
regioselectivity, except in the case of alkynes possessing the
a Reactions were carried out using Ni(cod)2 (5 mol %), PMe3
(20 mol %), MAD (10 mol %), 1 (0.5 mmol), and 2a (1.5 mmol) in
3 mL of toluene at 120 °C for 12 h in a sealed tube. b Isolated yields
are given. c Using Ni(cod)2 (5 mol %), P(CH2Ph)3 (10 mol %), MAD
(10 mol %); see ref 5.
trimethylsilyl group, which may be attributed to the electro-
nic nature of the silyl group. Terminal alkynes such as
1-octyne or phenylacetylene failed to participate in the
reaction, because of the rapid oligomerization of the alkynes.
The proposed mechanism for this reaction, shown in
Scheme 2, involves the initial oxidative addition of sub-
strate 1 to nickel(0) to form complex A.6À8 Subsequent
ipso-electrophilic attack of the leaving aryl group affords
the seven-membered intermediate B.9 Ensuing elimination
(6) For studies on an oxidative addition of CÀCN bond to nickel(0),
see: (a) Atesin, T. A.; Li, T.; Lachaize, S.; Garcıa, J. J.; Jones, W. D.
Organometallics 2008, 27, 3811. (b) Brunkan, N. M.; Brestensky, D. M.;
Jones, W. D. J. Am. Chem. Soc. 2004, 126, 3627. (c) Garcıa, J. J.;
ꢀ
Arevalo, A.; Brunkan, N. M.; Jones, W. D. Organometallics 2004, 23,
3997. (d) Garcıa, J. J.; Brunkan, N. M.; Jones, W. D. J. Am. Chem. Soc.
2002, 124, 9547. (e) Favero, G.; Morvillo, A.; Turco, A. J. Organomet.
Chem. 1983, 241, 251. (f) Abla, M.; Yamamoto, T. J. Organomet. Chem.
1997, 532, 267. (g) Parshall, G. W. J. Am. Chem. Soc. 1974, 96, 2360.
(h) Morvillo, A.; Turco, A. J. Organomet. Chem. 1981, 208, 103.
(7) For examples of nickel-catalyzed CÀCN bond activation in
coupling reactions with organometallic reagents, see: (a) Miller, J. A.;
Dankwardt, J. W. Tetrahedron Lett. 2003, 44, 1907. (b) Miller, J. A.
Tetrahedron Lett. 2001, 42, 6991. (c) Sun, M.; Zhang, H.-Y.; Han, Q.;
Yang, K.; Yang, S.-D. Chem.;Eur. J. 2011, 17, 9566. (d) Liu, N.; Wang,
Z.-X. Adv. Synth. Catal. 2012, 354, 1641. (e) Yu, D.-G.; Yu, M.; Guan,
B.-T.; Li, B.-J.; Zheng, Y.; Wu, Z.-H.; Shi, Z.-J. Org. Lett. 2009, 11,
3374.
(8) For examples of nickel-catalyzed CÀCN bond activation in
insertion reactions with carbonÀcarbon unsaturated compounds, see:
(a) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126, 13904.
(b) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem. Soc. 2007,
129, 2428. (c) Nakao, Y.; Yukawa, T.; Hirata, Y.; Oda, S.; Satoh, J.;
Hiyama, T. J. Am. Chem. Soc. 2006, 128, 7116. (d) Hirata, Y.; Yukawa,
T.; Kashihara, N.; Nakao, Y.; Hiyama, T. J. Am. Chem. Soc. 2009, 131,
10964.
(9) A reaction via the same type of ipso-electrophilic attack has
already been known as the Hayashi rearrangement; see: (a) Hayashi,
M. J. Chem. Soc. 1927, 2516. (b) Sandin, R. B.; Melby, R.; Crawford, R.;
McGreer, D. J. Am. Chem. Soc. 1956, 78, 3817.
Org. Lett., Vol. 15, No. 4, 2013
857

Table 2. Cycloaddition with Various Alkynesa
Scheme 2. Proposed Reaction Mechanism
electron-deficient group. The substrate possessing an elec-
tron-rich aryl group (1f) gave quinolone 3ba in 82% yield
(Table 3, entry 1), whereas the substrates having relatively
electron-deficient aryl groups (1b, 1g) afforded 3ba in
lower yields (entries 2, 3). Furthermore, substrates with
alkyl groups (1h) remained intact under the present nickel-
catalyzed reaction conditions.
Table 3. Effect of the Leaving Groupa
entry
R
yield (%)b
1
2
3
4
p-MeOC6H4 (1f)
Ph (1b)
82
80
39
<1
p-CF3C6H4 (1g)
Me (1h)
a Reactions were carried out using Ni(cod)2 (5 mol %), PMe3
(20 mol %), MAD (10 mol %), 1 (0.5 mmol), and 2a (1.5 mmol) in
3 mL of toluene at 120 °C for 12 h in a sealed tube. b Isolated yields.
a Reactions were carried out using Ni(cod)2 (5 mol %), PMe3
(20 mol %), MAD (10 mol %), 1b (0.5 mmol), and 2 (1.5 mmol) in
3 mL of toluene at 120 °C for 12 h in a sealed tube. b Isolated yields
are given. c Using PMe2Ph instead of PMe3, MAD 20 mol %. d Using
PMe2Ph instead of PMe3, MAD 30 mol %. e Ratio of regioisomers.
In conclusion, we have illustrated the efficacy of a new
nickel-catalyzed reaction based on carbonÀcarbon bond
cleavage of amides for the synthesis of quinolones. This
technique should prove useful for the synthesis of a variety
ofcomplicated quinolones from simple substrates. Current
efforts are directed toward further clarifying the reaction
mechanism and discovering new catalytic processes trig-
gered by carbonÀcarbon bond activation.
of the nitrile and coordination of alkyne 2 give the five-
membered nickelacycle C. Finally, the seven-membered
nickelacycle D is generated after alkyne insertion, and
reductive elimination gives quinolone 3 with regeneration
of the nickel(0) catalyst. The regioselectivity of the reaction
can be rationalized in terms of the direction of alkyne
insertion, in which the repulsive steric interaction is mini-
mal between the bulkier RL group and the ligand (a
phosphine or an eliminated nitrile) on the nickel atom, to
give the nickel(II) intermediate C.
Acknowledgment. This work was supported by JST,
ACT-C, and Grants-in-Aid from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan.
T.K. also acknowledges the Asahi Glass Foundation,
The formation of B is consistent with the electron-
rich aryl being a stronger leaving group than the
858
Org. Lett., Vol. 15, No. 4, 2013

Tokuyama Science Foundation, and Kurata Memorial
Hitachi Science and Technology Foundation.
new compounds (PDF) and X-ray data (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available. Experimental pro-
cedures including spectroscopic and analytical data of
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
859