Nickel-catalyzed cycloadditions of benzoxazinones with alkynes: Synthesis of quinolines and quinolones

Article abstract of DOI:10.1246/cl.2011.375

A nickel-catalyzed cycloaddition has been developed where readily available benzoxazinones react with alkynes to afford substituted quinolines or quinolones. The specific cycloaddition can be achieved by tuning a substituent on C2 of benzoxazinone in favo

Full text of DOI:10.1246/cl.2011.375

doi:10.1246/cl.2011.375
Published on the web March 5, 2011
375
Nickel-catalyzed Cycloadditions of Benzoxazinones with Alkynes:
Synthesis of Quinolines and Quinolones
Nobuyoshi Maizuru, Tasuku Inami, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510
(Received January 25, 2011; CL-110061; E-mail: tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp,
matsubar@orgrxn.mbox.media.kyoto-u.ac.jp)
A nickel-catalyzed cycloaddition has been developed where
readily available benzoxazinones react with alkynes to afford
substituted quinolines or quinolones. The specific cycloaddition
can be achieved by tuning a substituent on C2 of benzoxazinone in
favor of the formation of quinolines or quinolones selectively.
insertion (Scheme 3). To our delight, we found that 2-ethoxy-
benzoxazinone (1a) reacted with 4-octyne in the presence of
Ni(0)/PMe3 catalyst in refluxing xylene leading to quinoline 3a
in 23% yield (Table 1, Entry 1).10,11 Among phosphine ligands
examined, PCyp3, tricyclopentylphosphine gave the best yield
and the reaction afforded 3a in 90% isolated yield (Entries 2-5).
Trace amounts of 3a were obtained in the cases where N-
heterocyclic carbene ligands, such as IPr: 1,3-bis(2,6-diisopro-
pylphenyl)imidazol-2-ylidene and IMes: 1,3-bis(2,4,6-trimethyl-
phenyl)imidazol-2-ylidene, were used in place of phosphine
ligand. In other reaction solvent, such as toluene and THF, yields
were even lower (Entries 6 and 7).
Under the optimized conditions, the decarboxylative cyclo-
addition of 4-octyne with 2-ethoxybenzoxazinone possessing an
electron-donating or -withdrawing group affords the correspond-
ingly substituted quinolines in moderate to excellent yields
(Table 2). The decarboxylative cycloaddition of 1a with 3-
Transition-metal-catalyzed reactions have emerged as pow-
erful methodologies for the syntheses of structurally diverse
heterocycles.1,2 Recently, we demonstrated nickel-catalyzed
decarbonylative cycloaddition of N-arylphthalimides with al-
kynes via carboamination to give isoquinolones (Scheme 1).3-5
The reaction proceeded via oxidative addition of an amide to
Ni(0), subsequent decarbonylation and alkyne insertion. This
prompted us to investigate such reactions that would allow us to
prepare heterocyclic compound from readily available benzox-
azinone.6,7 Considering the structure of benzoxazinone deriva-
tives 1, two carbonyl moieties (C2 and C4) are potentially
reactive toward nucleophilic attack (Scheme 2). That is, they
possess two different reaction sites toward oxidative addition
that may lead to different types of heterocyclic compound via
cycloaddition with alkynes. Herein we wish to report our success
in controlling the relative reactivity of two carbonyl moieties by
tuning substituent R on the C2-position of benzoxazinone, which
leads to specific cycloaddition of benzoxazinones 1 to alkynes 2
in favor of the formation of quinolines 38 or quinolones 4.9
Our working hypothesis is the following. If oxidative
addition occurs at the C2 carbonyl triggered by the proximate
effect by coordination of the substituent R to Ni(0), we presume
that it would give quinoline 3 via decarboxylation and alkyne
R1
N
O
N
R2
R
O
2
Ni(0)
coordination
Ni(0)Ln
R
3
1
R1
O
R2
Ni
O
Ni
N
N
R
R
ecarboxylation
d
Ni
N
R
R1
R2
CO2
R1
2
O
Ni
R2
Ni(0)/PMe3 cat.
+
N
Ar
R1
R2
Scheme 3. Working hypothesis.
N
Ar
O
O
Table 1. Nickel-catalyzed decarboxylative cycloadditiona
Ni
N
R1
R2
O
Pr
Ni(0)
–CO
Ar
Pr
[Ni(cod)2] (10 mol %)
O
O
+
Pr
Pr
solvent, refluxing, 24 h
N
OEt
N
OEt
2.0 equiv
Scheme 1. Cycloaddition of N-arylphthalimides with alkynes.
1a
2a
3a
Entry
Ligand
Solvent
Yield/%
Decarboxylative Cycloaddition
R1
R = Alkoxy
1
2
3
4
5
6
7
PMe3
PBu3
PPh3
xylene
xylene
xylene
xylene
xylene
toluene
THF
23
34
12
89
90
86
54
R2
Ni(0)/PCyp3
O
N
3
4
Ni
4
– CO2
N
O
R
O
2
R1
R2
+
PCy3
R
2
R1
R2
Ni(0)/PBu3
PCyp3
PCyp3
PCyp3
1
1,3-acyl migration
N
Cycloaddition via Acyl Migration
R = Amino
O
R
aAll reactions were carried out using [Ni(cod)2] (10 mol %),
ligand (40 mol %), 1a (0.5 mmol), and 2a (1.0 mmol) for 24 h.
Scheme 2. Cycloaddition of benzoxazinones with alkynes.
Chem. Lett. 2011, 40, 375-377
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

376
Table 2. Decarboxylative cycloaddition of benzoxazinones 1 with
alkynes 2a,b
Table 3. Nickel-catalyzed cycloaddition via acyl migrationa
O
O
Pr
R1
[Ni(cod)2] (10 mol %)
O
O
Ni
[Ni(cod)2] (10 mol %)
PCyp3 (40 mol %)
+
Pr
Pr
R2
solvent, 24 h
O
2
N
Pr
N
NR'2
R3
R1
2.0 equiv
R2
R3
+
1.2 equiv
2a
xylene, reflux, 24 h
N
OEt
N
OEt
O
NR'2
1
4
1
2
3
Entry
NR¤2
Ligand
Yield/%
Pr
N
Pr
Pr
Pr
1
2
3
4
5
6
7
8
NMe2
pyrrolidinyl
piperidino
morpholino
morpholino
morpholino
morpholino
morpholino
PBu3
PBu3
PBu3
PBu3
PMe3
PPh3
PCy3
PCyp3
82
93
96
90
62
<1
<1
<1
Pr
F
Pr
OEt
OEt
N
OEt
N
F
3a 90% yield
3b 82% yield
3c 51% yield
Pr
Pr
Pr
Pr
OEt
Me
Pr
MeO
Pr
N
N
OEt
N
OEt
MeO
3d 79% yield
3e 79% yield
3f 82% yield
iPr
aAll reactions were carried out using [Ni(cod)2] (10 mol %),
ligand (40 mol %), 1 (0.5 mmol), and 2a (1.0 mmol) in xylene
(80 °C) for 24 h.
Pr
Bu
MeO
MeO
Pr
Et
Me
N
OEt
N
OEt
N
OEt
3g 87% yield
3h 74% yield (1/1)c
3i 65% yieldd
Table 4. Cycloaddition of benzoxazinones 1 with alkynes 2 via
acyl migrationa,b
aAll reactions were carried out using [Ni(cod)2] (10 mol %),
PCyp3 (20 mol %), 1 (0.5 mmol), and 2 (1.0 mmol) in 2 mL of
refluxing xylene for 24 h. Isolated yields. Ratio of regioisom-
O
O
Ni
[Ni(cod)2] (10 mol %)
PBu3 (40 mol %)
4
R1
R2
b
c
O
R3
R1
1.2 equiv
R2
R3
+
d
xylene, 80 °C, 24 h
ers. Only a single regioisomer was formed.
N
N
N
1
N = morpholino
2
4
O
N
Ni
O
N
O
N
O
O
O
[Ni(cod)2] (10 mol %)
PCyp3 (40 mol %)
4
Pr
Pr
Pr
Pr
Pr
Pr
O
+
+
Pr
2.0 equiv
Pr
Pr
4′
3′
xylene, reflux, 24 h
48% yield
O
N
Pr
F3C
N
Pr
N
MeO
O
O
O
N
O
N
O
N
4a 90% yield
4b 99% yield
4c 99% yieldc
O
O
O
O
N
Pr
N
Ni
[Ni(cod)2] (10 mol %)
PCyp3 (40 mol %)
tBu
Me
SiMe3
Me
SiMe3
Ph
Pr
O
O
Pr
2.0 equiv
2
N
N
N
xylene, reflux, 24 h
88% yield
O
O
N
O
N
O
N
4d 99% yieldd
4e 99% yieldd
4f 96% yieldd
O
O
O
Scheme 4. Effects of substituent.
SiMe3
Me
Ph
Ph
Ph
N
N
N
octyne gave the quinoline 3h consisting of regioisomers in 1/1
ratio, whereas reaction with 4-methyl-2-pentyne gave the
quinoline 3i with high selectivity.
O
N
O
N
O
N
4g 99% yieldd
4h 87% yieldd
4i 92% yielde
aAll reactions were carried out using [Ni(cod)2] (10 mol %), PBu3
(40 mol %), 1 (0.5 mmol), and 2 (0.6 mmol) in 2 mL of xylene
(80 °C) for 24 h. bIsolated yields. c120 °C. dOnly a single
regioisomer was formed. e3 equivalents of alkyne was employed.
During the course of our study, we found that the reaction of
2-isopropoxybenzoxazinone with an alkyne gave a quinolone 4¤
exclusively in 48% yield instead of a quinoline 3, while the
reaction of 2-methoxybenzoxazinone with an alkyne furnished
quinoline 3¤ (Scheme 4). Taking these results into account, we
suspected that, with bulky heteroatom substituent on C2-position
of benzoxazinone, we could control the oxidative addition to
Ni(0) in favor of the formation of quinolones 4. After thorough
screening, it was found that an amino group is the most effective
for that purpose (Table 3). The cycloaddition of 2-dimethyl-
aminobenzoxazinone and 4-octyne with Ni(0) (10 mol %) and
PBu3 (40 mol %) in xylene (80 °C) led to quinolone 4 in 82%
yield (Entry 1). Among dialkyl amines examined, morpholino
afforded the highest yield of product 4 (90% yield, Entry 4). The
reaction of 2-morpholinobenzoxazinone with 4-octyne (2a) did
not gave any cycloadduct 4 in the case of using ligands, such as
PPh3, PCy3, PCyp3, instead of PBu3 (Entries 6-8).
ring-substituents tolerated the reaction conditions well enough
to furnish the corresponding quinolones 4b and 4c in excellent
yields. Bulky tert-butyl- or trimethylsilyl-substituted alkynes
reacted with 1 to provide adducts with complete regiocontrol in
excellent yields. Monoaryl-substituted alkyne also reacted with
1 to give 4h in 87% yield. The reaction is also compatible with
diphenylacetylene and afforded 4i in 92% yield.
A plausible reaction pathway to account for the formation
of quinolones 4 based on the observed results is outlined in
Scheme 5. The catalytic cycle of the present reaction may
consist of the oxidative addition of an ester CO-O bond on the
C4 carbonyl to a Ni(0) complex.12 Subsequent acyl migration
prior to decarbonylation and coordination of alkyne 2 take place.
The alkyne would then insert into the C-Ni bond to give 7-
With the optimized conditions in hand, we next investigated
the scope of this reaction (Table 4). Methoxy or trifluoromethyl
Chem. Lett. 2011, 40, 375-377
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

377
Ni
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O
N
O
N
R1
R2
4
O
R'
2
N
Ni(0)Ln
4
1
R'
O
NR'2
O
R1
O
R2
Ni
3
4
Ni
O
N
N
O
NR'2
NR'2
O
acyl migration
Ni
N
R1
R2
5
NR'2
2
O
Scheme 5. Plausible reaction mechanism.
Pr
Ni
O
[Ni(cod)2] (10 mol %)
PBu3 (40 mol %)
Pr
tBu
5a 45% yield
4
N
O
6
7
+
Pr
Pr
xylene, reflux, 24 h
2a
2.0 equiv
N
tBu
O
1c
Pr
Pr
Ni
2a
O
Ni
– CO
decarbonylation
N
tBu
N
insertion
&
migration
O
tBu
Scheme 6. Cycloaddition via decarbonylation and acyl migration.
8
9
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to give 4,13 and regenerates the starting Ni(0) complex.
It should be noted that the reaction of 2-tert-butylbenzox-
azinone (1c) reacted with 4-octyne (2a) in the presence of Ni/
PBu3 catalyst to give indole 5a in 45% yield as a sole product
via decarbonylation and acyl migration (Scheme 6). Thus,
all the results described above may suggest the effects of
substituents on the C2-position of benzoxazinone as follows; (1)
sterically hindered substituents led to the oxidative addition of
less sterically hindered C4 carbonyl to Ni(0), and (2) dialkyl
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decarbonylation.
In conclusion, we developed a nickel-catalyzed cycloaddi-
tion of benzoxazinones and alkynes. It was demonstrated that
specific cycloaddition can be achieved by tuning substituents in
favor of the formation of quinolines or quinolones. Further
efforts to expand the scope of the chemistry and studies of the
detailed mechanism are currently underway in our laboratories.14
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C4 carbonyl carbon was 159.50 ppm. Therefore, oxidative addition may
occur at the more electrophilic carbonyl C2 to provide quinolines.
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This work was supported by Grants-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan. T.K. also acknowledges Asahi Glass Foundation, and
Kansai Research Foundation.
References and Notes
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14 Supporting Information is available electronically on the CSJ-Journal Web
site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2011, 40, 375-377
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/