Synthesis of Azulenopyridinones through Palladium-Catalyzed Oxidative [4+2] Cyclization Reactions of N-Methoxyazulene-1- and 2-carboxamides with Alkynes

Article abstract of DOI:10.1002/adsc.202000587

Palladium-catalyzed oxidative [4+2] cyclization reactions were developed from the C?H activation reaction of N-methoxyazulene-1- and 2-carboxamides with symmetrical and unsymmetrical alkynes under a molecular oxygen atmosphere, producing azulenopyridinone derivatives with novel azulene skeletons in good to excellent yields with a wide substrate scope and excellent functional group tolerance. (Figure presented.).

Full text of DOI:10.1002/adsc.202000587

Title: Synthesis of Azulenopyridinones through Palladium-Catalyzed
Oxidative [4 + 2] Cyclization Reactions of N-Methoxyazulene-1-
and 2-carboxamides with Alkynes
Authors: Gi Uk Han, Jeong-Yu Son, Dahee Park, Hyeonsik Eom,
Kyungsup Lee, Hee Chan Noh, Kooyeon Lee, and Phil Ho
Lee
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
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using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000587
Link to VoR: https://doi.org/10.1002/adsc.202000587

Advanced Synthesis & Catalysis
10.1002/adsc.202000587
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Synthesis of Azulenopyridinones through Palladium-Catalyzed
Oxidative [4 + 2] Cyclization Reactions of N-Methoxyazulene-1-
and 2-carboxamides with Alkynes
b
b
b
b
b
Gi Uk Han, Jeong-Yu Son, Dahee Park, Hyeonsik Eom, Kyungsup Lee, Hee Chan
b
c
a,b,
Noh, Kooyeon Lee, and Phil Ho Lee *
a
The Korean Academy of Science and Technology, Seongnam 13630, Republic of Korea
Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
b
E-mail: phlee@kangwon.ac.kr
Department of Bio-Health Technology, Kangwon National University, Chuncheon 24341, Republic of Korea
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Palladium-catalyzed oxidative [4 + 2] cyclization without an external oxidant.[7a] Also, Huang and
reactions were developed from the C−H activation reaction coworkers reported the first atom-economical
of N-methoxyazulene-1- and 2-carboxamides with synthesis of isoquinolinones and analogues via
symmetrical and unsymmetrical alkynes under a molecular ligand-free Pd-catalyzed C–H and N–H double
oxygen
atmosphere,
producing
azulenopyridinone activation8e,8f,8g]from
N-methoxybenzamides
and
[
derivatives with novel azulene skeletons in good to
excellent yields with a wide substrate scope and excellent
functional group tolerance.
alkynes.
Keywords: palladium; catalysis; C−H activation; azulene;
azulenopyridinone
Azulenes, which are a class of nonbenzenoid aromatic
hydrocarbons, have received prominent attention due
[1]
to their importance as natural products, bioactive
[
2]
[3]
compounds, and molecular materials. Accordingly,
the establishment of streamlined synthetic approaches
Scheme
1.
Transition-Metal-Catalyzed
Oxidative
for azulene skeletons from easily accessible starting
materials is continuously required.[4] Hafner and
Cyclization Reactions of Substrates Containing an Amide
Directing Group with Alkynes.
coworkers described an efficient method for azulene
[5]
synthesis. However, there is a barrier to the de novo
introduction of useful substituents onto the azulene
ring because of the abnormal reactivity induced by the
polarized π-electron system. For this reason, the
functionalization of azulene through the introduction
of valuable functional groups onto the preformed
azulene ring and its transformation is highly attractive
strategies for the synthesis of azulene derivatives.
After Yu and coworkers reported for the first time
Recently, we developed for the first time Rh- and
Ir-catalyzed oxidative [4 + 2] and [2 + 2 + 2]
cyclization reactions of azulene-1-carboxylic acid and
azulene-2-carboxylic acid, which are nonbenzenoid
aromatic acids, with symmetrical and unsymmetrical
alkynes, leading to the formation of a variety of
azulenolactones and tetra(aryl)benzoazulenes with
[9]
3
novel azulene skeletons (Scheme 2a). Based on
these results, we concluded that C−H activation is a
very useful method for the functionalization of
nonbenzenoid aromatic azulenes. However, no studies
on C−H activation using amide directing groups have
been described for azulene, a nonbenzenoid aromatic
C(sp )−H alkylation and arylation reaction using N-
methoxyamide as a directing group,[6] many oxidative
cyclization reactions of benzenoid aromatic
compounds bearing amide directing groups with
alkyne in the presence of external or internal oxidant
[7,8]
have been reported (Scheme 1).
For example,
[
4e,10]
compound.
Stimulated by the seminal results of
Guimond and coworkers have developed a new
synthetic method to oxidative [4 + 2] cyclization
reaction from benzhydroxamic acids and alkynes
[
8e,8f,8g]
[9]
Huang and coworkers
envisioned that the development of C−H activation
and our results, we
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000587
using azulene-bearing amide directing groups would atmosphere, the desired product (3a) and
be a significant milestone for the expansion of the
C−H activation field. Although C−H activation has
been applied to azulene for its functionalization, these
are exclusively done at the 1,3-position, making use
of their natural reactivity.[ As far as we know, there
has been no attempt to make use of directed C−H
activation to overcome the natural reactivity, so as to
enable functionalization of azulene at other positions.
demethoxylated
azulene-1-carboxamide
were
produced in 35 and 28% yields, respectively,
indicating that the methoxy group does not act as an
internal oxidant but that an external oxidant is
required for this reaction to proceed (entry 13).
This is consistent with the optimum reaction
4e]
[7b,8e]
conditions under a molecular oxygen atmosphere. N-
Herein, we have developed Pd-catalyzed oxidative [4 Ethoxy and N-benzyloxyazulene-1-carboxamides
+
2] cyclization reactions of N-methoxyazulene-1- yielded inferior results (entries 14 and 15). The best
and 2-carboxamides bearing nonbenzenoid aromatic result of the cyclization reaction was obtained from
azulene rings with symmetrical and unsymmetrical
alkynes, leading to the formation of a number of
the reaction of 1a (0.15 mmol, 1.0 equiv) with 2a (1.2
equiv) in the presence of Pd(OAc) (4.0 mol %) and
2
azulenopyridinones
bearing
novel
azulene
KI (1.0 equiv) in DMF at 120 °C for 4 h under a
molecular oxygen atmosphere, providing 3a in
quantitative yield (entry 8). To demonstrate the
applicability of the present method to larger-scale
processes, 3.0 mmol of N-methoxyazulene-1-
carboxamide (1a) (0.18 g) was treated with
diphenylacetylene (2a) (1.2 equiv) under the optimal
reaction conditions, providing the corresponding
compound 3a (0.18 g, 84%). The structure of 3a was
frameworks (Scheme 2b).
Table 1. Reaction Optimization.[a]
Scheme
2.
Transition-Metal-Catalyzed
Oxidative
T
°C]
yield
[%]
Cyclization Reactions of Azulenes Containing a Directing entry additive solvent
Group with Alkynes.
t [h]
[
b]
[
1
2
3
4
5
6
7
8
9
KI
KI
KI
KI
KI
KI
KI
KI
-
KCl
LiI
LiCl
KI
KI
KI
DCE
EtOH
toluene
TFE
80
80
80
80
80
60
100
120
120
120
120
120
120
120
120
24
24
24
24
24
24
12
4
24
12
4
12
12
4
5
6
0
0
First, we investigated the reaction of N-
methoxyazulene-1-carboxamide (1a) with
diphenylacetylene (2a) in the presence of Pd(OAc)
as a catalyst and potassium iodide (KI) as an additive
under a molecular oxygen atmosphere (Table 1). A
variety of solvents, including dichloroethane (DCE),
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
99
39
99
99 (84)
13
64
86
16
35 (28)
30
2
[c]
[e]
EtOH, toluene, trifluoroethanol (TFE), and N,N- 10
dimethylformamide (DMF), were screened (entries 1- 11
5
), and DMF was the solvent of choice. Although the 12
[
[
[
d]
f]
1
1
1
3
4
5
desired azulenopyridinone (3a) was obtained in
quantitative yield, the reaction time of 24 h was too
long. When the reaction temperature was increased to
g]
4
27
[
a]
Reaction conditions: 1a (0.15 mmol, 1.0 equiv) reacted
with 2a (1.2 equiv) in the presence of catalyst (4.0
mol %) and additive (1.0 equiv) in solvent (0.1 M) in a
test tube under a molecular oxygen atmosphere.
NMR yields using dibromomethane as an internal
standard.
Reaction scale is 3.0 mmol. Isolated yield.
Air atmosphere.
Numbers in parentheses are NMR yields of azulene-1-
carboxamide.
100 °C and 120 °C, the reaction time was
dramatically decreased (entries 7 and 8). These results
indicated that the efficiency of the present method is
largely dependent on the reaction temperature. In
addition, control reactions without KI were
ineffective, suggesting that KI is essential for Pd-
catalyzed oxidative [4 + 2] cyclization (entry 9).
Accordingly, various additives performing a hard/soft
ligand exchange process were investigated (entry 10-
[b]
[
[
[
c]
d]
e]
[
[
f]
N-Ethoxy azulene was used.
12). The anion of the additive has a greater effect on
g]
N-Benzyloxy azulene was used.
the reaction, and KI is the most effective additive in
the reaction. When 1a reacted with 2a under an air
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000587
confirmed by X-ray crystallography and the redox providing
the
corresponding
3,4-
potential of 3a was obtained from electrochemical di(heteroaryl)azulenopyridinones (3k and 3l) in 61
analysis
results
using
cyclic
voltammetry and 68% yields, respectively. Unsymmetrical
disubstituted alkynes could be used to demonstrate
measurements (see the Supporting Information).
After these encouraging results were obtained, the the unique reactivity and effectiveness of the present
scope and limitations of the alkynes (2) in the reaction reaction. When unsymmetrical diarylacetylenes with
with N-methoxyazulene-1-carboxamide (1a) were 4-methyl and 4-methoxy groups were used, the
examined (Table 2). The reaction efficiency was not desired products (3m) were obtained in 55% (1:1.3)
influenced by the electronic properties of the alkynes. yield. 1-Phenyl-1-propyne was converted to desired
C−H activation followed by cyclization also displays product 3n (72%, 3.8:1), indicating that
a wide functional group tolerance with respect to the azulenopyridinone with a phenyl group proximal to
alkyne substituent. Substrate 1a was smoothly nitrogen was the major product due to the extended
cyclized with a variety of symmetrical electron-rich conjugation effect and the steric effect of the alkynes.
diarylacetylenes
diarylazulenopyridinones 3b-3e in good to excellent provide 3o (72%, 4.6:1).
yields. Moreover, symmetrical electron-deficient Next, the scope of N-methoxyazulene-1-
diarylacetylenes with fluoro, chloro, and carboxamides 1 and alkynes 2 was examined (Table
2
to
afford
3,4- In addition, ethyl but-2-ynoate reacted with 1a to
trifluoromethyl groups were reactive, and the 3). A substrate with a phenyl group attached to the 7-
corresponding 3,4-diarylazulenopyridinones 3f-3h membered ring reacted with diphenylacetylene and
were obtained in good yields ranging from 82 to 99%. di(3-chlorophenyl)acetylene,
providing
3,4-
To our delight, the present oxidative cyclization diarylazulenopyridinones (3p and 3q) in 95 and 80%
proceeded despite the presence of labile formyl and yields, respectively. Azulene-1-carboxamides with a
acetyl groups on the phenyl ring, affording desired methyl group on the 5-membered ring worked equally
compounds 3i and 3j in good yield. Symmetrical well with a variety of alkynes, leading to the
di(heteroaryl)acetylenes with pyridine and thiophene formation of 3,4-diarylazulenopyridinones 3r-3t in
moieties are also applicable to the present method,
moderate to good yields ranging from 52 to 90%.
Electron-deficient azulene-1-carboxamide with a
chloro group on the 5-membered ring underwent
efficient C−H activation followed by cyclization with
diphenylacetylene, affording the desired 3,4-
diphenylazulenopyridinone 3u in quantitative yield.
Table 2. Substrate Scope of Alkynes.[a]
Table 3. Substrate Scope of Azulenes and Alkynes.[a]
[
[
a]
b]
Reaction conditions: 1 (0.2 mmol, 1.0 equiv) reacted
with 2 (1.2 equiv) in the presence of Pd(OAc) (4.0
mol %) and KI (1.0 equiv) in DMF (0.1 M) in a test tube
under a molecular oxygen atmosphere.
2
8
h.
Stimulated by these results, N-methoxyazulene-2-
[
a]
carboxamide (4a) was investigated (Table 4).
Substrate (4a) reacted with diphenylacetylene in the
Reaction conditions: 1a (0.2 mmol, 1.0 equiv) reacted
with 2 (1.2 equiv) in the presence of Pd(OAc) (4.0
mol %) and KI (1.0 equiv) in DMF (0.1 M) in a test tube
under a molecular oxygen atmosphere.
2
presence of Pd(OAc) (4.0 mol %) and KI (1.0 equiv)
2
o
in DMF at 60 C for 4 h, providing azulenopyridinone
5a in quantitative yield. When substrate (4a) reacted
with di(4-methoxyphenyl)acetylene and di(3-
[
[
b]
c]
2
(2.0 equiv) was used.
Molecular oxygen bubbling.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000587
o
chlorophenyl)acetylene in DMF at 100 C for 2 h, the C(3)-position of azulene is more reactive than the C(2)
desired products 5b and 5c were produced in 78 and one, the deuterium exchange reaction occurred partly
7
1% yields, respectively. Azulene-2-carboxamides at the C(3)-position. Next, we performed kinetic
with a methyl group on the 5-membered ring and a isotope effect (KIE) studies to gain insight into the
phenyl group on the 7-membered ring reacted with reaction mechanism. The KIE was obtained (K
H
/K =
D
diphenylacetylene, leading to the formation of 5d and 1.9) via parallel reactions and
5e in quantitatively yields. These results indicate that
N-methoxyazulene-2-carboxamide is more reactive
than N-methoxyazulene-1-carboxamide due to two
reactive sites (1,3-positions) as well as the highly
reactive 1,3-positions[ caused by the polarized π-
electron system of azulenes, making use of their
natural reactivity.
11]
Table 4. Substrate Scope of N-Methoxyazulene-2-
[
a]
Carboxamides.
[
[
a]
b]
Reaction conditions: 1e (0.2 mmol, 1.0 equiv) reacted
with 2 (1.2 equiv) in the presence of Pd(OAc) (4.0
2
Scheme 3. Synthetic Application of Azulenopyridinones.
mol %) and KI (1.0 equiv) in DMF (0.1 M) in a test tube
under a molecular oxygen atmosphere.
o
The reaction was performed at 100 C for 2 h.
The synthetic applications of azulenopyridinone
(
3a) were explored. As shown in Scheme 3,
demethoxylation was performed with NaH in DMF,
providing the desired N−H azulenopyridinone 6 in
9
1% yield (a).[
8e,12]
Additionally, 3a reacted with
DMSO in the presence of trifluoroacetic anhydride
followed by diethyl amine to give methylsulfenylated
[13]
azulenopyridinone (7) in 86% yield (b). Formylated
4
5
azulenopyridinone (8) was generated from 3a and
(c).[ To our delight, 3a was converted to the
14]
40
y = 0.64x + 1.10
y = 0.36x + 0.51
POCl
3
3
3
5
0
corresponding haloazulenopyridinones (9a and 9b)
[
15]
with excellent yields using NBS and NIS (d).
25
20
15
Suzuki-Miyaura coupling of 9a with phenyl boronic
3a (%)
[
16]
3a-[D2] (%)
acid provided 10 in quantitative yield (e).
1
0
5
0
Additionally, iodoazulenopyridinone (9b) was
transformed to desired compound 11 in 70% yield by
the Sonogashira reaction (f).[17]
0
20
40
60
80
Time (min)
Catalytic C−H activation in DMF:D O (5:1) was
2
conducted under the optimal reaction conditions, and
mechanistic studies with isotopically labeled substrate
Scheme 4. Experiments with Isotopically Labeled
Compounds.
1
a revealed that the C(2)−H bond metalation was
irreversible (Scheme 4a). Because the electron-rich
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000587
purified by column chromatography on silica gel to afford
was measured (K
H
/K
D
= 1.5) from the intermolecular
] (Scheme
b). Additionally, the KIE was observed (K /K
.78) by independent reactions using 1a or 1a-[D
product 3.
competition reaction using 1a and 1a-[D
2
4
1
H
D
=
CCDC-1894161
contains
the
supplementary
2
] as
crystallographic data for this paper (3a). These data can be
the substrate under standard conditions (Scheme 4c). obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
These results suggested that the cleavage of the C−H
bond at the 2-position of N-methoxyazulene-1-
carboxamide is not involved in the rate-determining
step.
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
A proposed mechanism for C−H activation
followed by cyclization of N-methoxyazulene-1- This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korean government (MSIP)
carboxamide (1) with alkynes 2 is described in
Scheme 5. Coordination of the amide to Pd(OAc)
(2011-0018355).
2
yields five-membered palladacycle A, and alkyne
insertion followed by reductive elimination delivers
azulenopyridinones 3. Finally, the oxidation of Pd(0)
by molecular oxygen regenerates the catalytically
active Pd(II) species. Potassium iodide seems to be an
effective additive, possibly due to the soft ligand
exchange processes.[
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5
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Advanced Synthesis & Catalysis
10.1002/adsc.202000587
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