Synthesis of 2-Quinolinones through Palladium(II) Acetate Catalyzed Cyclization of N -(2-Formylaryl)alkynamides

Article abstract of DOI:10.1055/s-0034-1380751

A Pd(OAc)₂-catalyzed cyclization of N-(2-formylaryl)alkynamides initiated by the oxypalladation of alkynes was developed. The method provides a new approach for the efficient and atom-economical synthesis of 2-quinolinone derivatives.

Full text of DOI:10.1055/s-0034-1380751

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1744–1748
letter
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J. Zhang et al.
Letter
Synlett
Synthesis of 2-Quinolinones through Palladium(II) Acetate Cata-
lyzed Cyclization of N-(2-Formylaryl)alkynamides
Jianbo Zhang
Xiuling Han*
Xiyan Lu*
R3
O
COR3
O
Pd(OAc)2 (5 mol%)
4,4'-(MeO)2bpy (10 mol%)
R2
R1
R1
4 Å MS, AcOH–DCE(1:2), 80 °C
N
R
N
R
O
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
xlhan@mail.sioc.ac.cn
R2
yield up to 92%
16 examples
xylu@mail.sioc.ac.cn
Received: 26.03.2015
Accepted after revision: 20.04.2015
Published online: 01.06.2015
tethered counterparts also gave the same results (Scheme
1, eq. 3). From the results of control experiments, it was
found that the presence of an electron-withdrawing group
attached to the alkyne was the key for this cyclization.5 To
explore the two different paths of alkynyl-tethered alde-
hydes further, herein, we changed the position of the elec-
DOI: 10.1055/s-0034-1380751; Art ID: st-2015-w0217-l
Abstract A
Pd(OAc)2-catalyzed
cyclization
of
N-(2-formyl-
aryl)alkynamides initiated by the oxypalladation of alkynes was devel-
oped. The method provides a new approach for the efficient and atom-
economical synthesis of 2-quinolinone derivatives.
tron-withdrawing
group
by
using
N-(2-formyl-
aryl)alkynamides as substrates.
Key words cascade reaction, cyclization, oxypalladation, palladium,
quinolinones
R
R
Pd(OAc)2/bpy
OH
AcO
(1)
(2)
O
Transition-metal-catalyzed cascade reactions are wide-
ly used in the construction of complex compounds from
simple precursors, and they are regarded as powerful and
useful tools for the synthesis of heterocycles.1 In particular,
the use of carbon–carbon bond-forming reactions catalyzed
by palladium complexes for the synthesis of such com-
pounds has recently gained in importance because of the
possibility of producing highly functionalized heterocyclic
rings with the desired substitution pattern in one-step pro-
cedures under mild reaction conditions.2
Our group has been interested in palladium(II) cata-
lyzed reactions and we have reported a number of exam-
ples.3 In all of these reactions, PdII/PdII catalyzed processes
are utilized without the involvement of PdII/Pd0 or PdII/PdIV
redox systems. In 2002, a first example of Pd(OAc)2-cata-
lyzed intramolecular coupling of alkynyl-tethered alde-
hydes was developed; the reaction was initiated by ace-
toxypalladation of alkynes and quenched by addition to the
carbonyl group (Scheme 1, eq. 1).4 However, an unexpected
cyclization was recently found under similar conditions
when substrates bearing an electron-withdrawing group
(EWG) on the alkyne were used (Scheme 1, eq. 2).5 In this
reaction, the acetic acid added to the carbonyl group first
rather than the triple bond. Furthermore, use of the aryl-
AcOH–1,4-dioxane
80 °C
O
O
OAc
O
CHO
Pd(OAc)2 (5 mol%)
bpy (10 mol%)
AcOH–MeCN (1:4)
80 °C
EWG
EWG
Pd(OAc)2 (5 mol%)
bpy or 4,4'-(MeO)2bpy
(6 mol%)
OAc
O
CHO
R
R
(3)
AcOH–MeCN (1:2)
100 °C
EWG
EWG
Scheme 1 Our previous work
We initiated our study by using N-(2-formylphenyl)but-
2-ynamide (1a) as the substrate. Under similar conditions
to those shown in Scheme 1 (eq. 2), the product 3-acetyl-2-
quinolinone 2a was obtained in 54% yield, and product 2a'
was not found (Scheme 2). From the structure of 2a, it can
be deduced that acetic acid adds to the triple bond of the
substrate 1a first.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1744–1748

1745
J. Zhang et al.
Letter
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AcO
O
O
O
O
Pd(OAc)2 (5 mol%)
bpy (6 mol%)
AcOH–DCE (1:2)
80 °C
HN
N
H
N
H
O
O
1a
2a (54%)
2a' (not found)
Scheme 2 Preliminary results of the reaction of 1a with acetic acid under the catalysis of Pd(OAc)2
The functionalized 2-quinolinone core is found widely
in various alkaloids and other natural products,6 and the
ring system has attracted great interest because of its di-
verse biological7 and medicinal activities.8 Although many
routes are available to achieve the synthesis of 2-quinoli-
nones,9 only a few involve transition-metal-catalyzed cy-
clizations.10 This inspired us to study our new reaction in
detail to provide an efficient alternative method for the
synthesis of these compounds.
A selection of palladium catalysts was screened to test
the reaction conditions. Pd(OAc)2/bpy gave the product 2a
in 54% yield (Table 1, entry 1). The reaction was totally sup-
pressed by using PdCl2 or Pd(MeCN)2Cl2 as the catalyst (Ta-
ble 1, entries 2 and 3). Pd(TFA)2 gave a comparable yield of
2a to that with Pd(OAc)2 (Table 1, entry 4). Under the catal-
ysis of Pd(OAc)2 or Pd(TFA)2, byproduct 3a, which came
from the N-transacylation of amide 1a with acetic acid,11
was also formed (Table 1, entries 1 and 4).
ther screening revealed that an AcOH-to-DCE ratio of 1:2
was optimal for the reaction (Table 2, entries 5–9). Reduc-
ing the temperature did not improve the yield of cyclization
(Table 2, entries 10–12).
Table 2 Optimization of the Reaction Conditionsa with Respect to Dif-
ferent Solvents
Pd(OAc)2
(5 mol%)
bpy
O
O
O
CHO
(6 mol%)
+
solvent
80 °C
NHAc
N
H
O
N
H
1a
2a
3a
Entry
Solvent
AcOH
Time (h)
Yield (%)b
2a
3a
1
2
18
12
24
12
12
16
16
9
29
30
24
trace
19
3
AcOH–1,4-dioxane (1:4)
AcOH–MeCN (1:4)
AcOH–toluene (1:4)
AcOH–DCE (1:4)
AcOH–DCE (1:1)
AcOH–DCE (1:2)
AcOH–DCE (1:6)
AcOH–DCE (1:8)
AcOH–DCE (1:2)
AcOH–DCE (1:2)
AcOH–DCE (1:2)
26
42
44
44
49
54
33
49
44
54
N.R.
Table 1 Optimization of the Reaction Conditions with Palladium Cata-
3
lystsa
4
catalyst
(5 mol%)
bpy
5
O
O
O
CHO
6
13
25
12
6
(6 mol%)
7
+
AcOH–DCE
(1:2)
80 °C
N
H
O
NHAc
N
8
H
1a
2a
3a
9
20
18
96
144
10c
11d
12e
13
19
Entry
Catalyst
Time (h)
Yield (%)b
2a
3a
1
2
3
4
Pd(OAc)2
PdCl2
16
24
24
10
54
25
a Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (5 mol%), bpy (6 mol%), sol-
vent (1 mL), 80 °C.
b Isolated yield.
c At 60 °C.
N.R.
N.R.
49
Pd(MeCN)2Cl2
Pd(TFA)2
d At 40 °C.
31
e At r.t.
a Reaction conditions: 1a (0.1 mmol), catalyst (5 mol%), bpy (6 mol%),
AcOH–DCE (1:2, 1 mL), 80 °C.
b Isolated yield.
The influence of ligand on the reaction was investigated.
Bipyridines bearing a range of substituents and phenanth-
roline were examined, and the results revealed that only
4,4′-(MeO)2bpy was as effective as bpy. In consideration of
the reduced amount of byproduct, 4,4′-(MeO)2bpy was cho-
sen as the ligand for further screening of conditions (Table
3, entries 1–7). To our delight, the yield could be improved
greatly by increasing the amount of 4,4′-(MeO)2bpy to 10
Pd(OAc)2 was then used as the catalyst to screen sol-
vents. When acetic acid was used as the only solvent, a low
yield (29%) of 2a was obtained (Table 2, entry 1). Upon the
inclusion of other solvents, most systems gave moderate
yields except for that with dioxane, which resulted in lower
yield. The AcOH–DCE system gave the best yield, and fur-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1744–1748

1746
J. Zhang et al.
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mol% (76% yield; Table 3, entry 8). Finally, molecular sieves
were added and a further improved yield was obtained
(82%; Table 3, entry 10). Without either the catalyst or li-
gand, no reaction occurred. The optimized reaction condi-
tions were thus established to be: Pd(OAc)2 (5 mol%), 4,4′-
(MeO)2bpy (10 mol%), MS (20% w/w), AcOH–DCE (1:2) (0.1
M), at 80 °C under N2.
Table 4 The Scope of the Reactiona
Pd(OAc)2
R3
O
COR3
O
4,4'-(MeO)2bpy
MS
R2
R1
R1
AcOH–DCE
(1:2)
80 °C
N
R
N
R
O
R2
2
1
Table 3 Optimization of the Reaction Conditions with Respect to the
Entry
R
R1
R2
R3
Yield (%)b
Liganda
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Bn
H
Me
Ph
H (1a)
H (1b)
H (1c)
H (1d)
H (1e)
H (1f)
H (1g)
H (1h)
H (1i)
82 (2a)
62 (2b)
52 (2c)
N.R.
Pd(OAc)2
(5 mol%)
ligand
H
H
H
O
O
O
CHO
3
n-Bu
t-Bu
Me
Me
Me
Me
Me
(6 mol%)
4
+
AcOH–DCE
(1:2)
80 °C
NHAc
N
H
2a
N
H
1a
O
5
4-Cl
5-I
74 (2e)
92 (2f)
92 (2g)
54 (2h)
85 (2i)
80 (2j)
79 (2k)
69 (2l)
80 (2m)
42 (2n)
51 (2o)
85 (2p)
88 (2q)
3a
6
7
5-Br
5-Cl
4-F
Entry
Ligand
Yield (%)b
8
2a
3a
9
1
2
bpy
54
54
43
49
33
22
38
76
49
82
25
10
11
12
13
14
15
16
17
5-Me
5-Ph
5-OMe
4-CF3
H
Me
Me
Me
Me
Me
Me
Me
Me
H (1j)
4,4′-(MeO)2bpy
4,4′-(NO2)2bpy
4,4′-(MeO2C)2bpy
o-phenanthroline
4,4′-(t-Bu)2bpy
5,5′-(Me)2bpy
4,4′-(MeO)2bpy
4,4′-(MeO)2bpy
4,4′-(MeO)2bpy
19
H (1k)
H (1l)
3
24
4
25
H (1m)
Me (1n)
Ph (1o)
H (1p)
H (1q)
5
6
6
trace
trace
12
H
7
H
8c
9d
10c,e
H
31
a Reaction conditions: 1 (0.2 mmol, 1.0 equiv), Pd(OAc)2 (5 mol%), 4,4′-
(MeO)2bpy (10 mol%), MS (20% w/w), AcOH–DCE (1:2, 2 mL), 80 °C under
N2 until complete consumption of the substrate as monitored by TLC.
b Isolated yield.
15
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv), catalyst (5 mol%), ligand (6
mol%), AcOH–DCE (1:2) (1 mL), 80 °C under N2 overnight.
b Isolated yield.
c Ligand: 10 mol%.
A possible mechanism, similar to that described in our
previous work (Scheme 1, eq. 1), is proposed for this reac-
tion and is shown in Scheme 3. First, oxypalladation of the
alkyne forms intermediate A. The carbon–palladium bond
in species A then adds to the intramolecular carbonyl group
to form B. Protonolysis of B gives intermediate C and regen-
erates the catalyst. Finally, attack on protonated alcohol D
by water gives rise to product 2a with the loss of a molecule
of acetic acid.13 From the catalytic cycle, it is clear that this
new reaction proceeds with complete atom economy, with
acetic acid just serving as an initiator and cosolvent that is
regenerated in the final step. In this cyclization, although
alkynes containing electron-withdrawing groups are used,
product 2a′ (formed through a path similar to those shown
in Scheme 1, eq. 2 or 3) was not found. The reason may be
due to the difficulty of forming the eight-membered benzo-
fused lactam (2a′). Thus, besides the electronic properties
of the alkyne, other factors can also influence the paths of
the reactions of alkynyl-tethered aldehydes with acetic acid
under the catalysis of Pd(II).
d Catalyst: 2.5 mol%, ligand: 5 mol%.
e MS molecular sieves (4 Å, 20% w/w) were added.
With the optimized reaction conditions in hand, a num-
ber of N-(2-formylaryl)alkynamides 2 were successfully
employed in this 2-quinolinone synthesis.12 Phenyl or butyl
substituted alkynes gave the corresponding products in
moderate yields, whereas a tert-butyl group blocked the cy-
clization (Table 4, entries 2–4). Variation of the electronic
properties and the positions of the substituents on the ben-
zene ring were then examined. Except for chlorine, the re-
action tolerated halogen atoms well (Table 4, entries 5–9).
Electron-donating and electron-withdrawing groups had
little influence on the reaction (Table 4, entries 10–13). Ke-
tones 1n and 1o also proceeded well, albeit in diminished
yields (Table 4, entries 14 and 15). When the hydrogen
atom on the nitrogen was changed to a methyl or benzyl
group, the corresponding products were obtained in good
yields (Table 4, entries 16 and 17).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1744–1748

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J. Zhang et al.
Letter
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O
H+
+ AcOH
N
H
O
PdII
oxypalladation
O
1a
OAc
O
N
H
A
Pd(II)
insertion
protonolysis
OH
OPdII
OAc
OAc
H+
N
H
O
N
H
O
C
B
H+
+
+
OH2
O
AcOH
OH2
O
O
O
H2O
O
O
H2O
N
H
O
N
H
O
N
H
D
2a
Scheme 3 Possible mechanism for the formation of 2-quinolinones
In conclusion, we have accomplished a Pd(OAc)2-cata-
lyzed cyclization of alkynamide substituted aromatic alde-
hydes or ketones initiated by the oxypalladation of alkynes,
which provides a new approach for the synthesis of 2-quin-
olinone derivatives in an efficient and atom economical
way. Further studies on the factors that influence the path-
way followed by the reactions of alkynyl-tethered alde-
hydes with acetic acid or other nucleophiles are in progress
in our laboratory.
References and Notes
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Acknowledgment
We thank the National Basic Research Program of China
(2011CB808706), the National Natural Science Foundation of China
(21232006, 21272249), and the Chinese Academy of Sciences for fi-
nancial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380751.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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Chem 2013, 8, 652. (f) Chaturvedula, P. V.; Mercer, S. E.; Pin, S.
S.; Thalody, G.; Xu, C.; Conway, C. M.; Keavy, D.; Signor, L.;
3-Acetylquinolin-2(1H)-one (2a)
Yield: 31 mg (82%); white solid; 1H NMR (400 MHz, DMSO-d6):
δ = 12.09 (s, 1 H), 8.43 (s, 1 H), 7.85 (dd, J = 1.0, 7.8 Hz, 1 H),
7.62–7.58 (m, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.23–7.19 (m, 1 H),
2.61 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ = 197.8, 160.9,
143.5, 140.9, 133.3, 130.6, 129.8, 122.8, 118.5, 115.4, 31.1.
(13) Menashe, N.; Shvo, Y. J. Org. Chem. 1993, 58, 7434.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1744–1748