Palladium-catalyzed cycloisomerisation reaction of 1,6-enyne acetic esters to form five-membered nitrogenated heterocyclic conjugated trienes

Article abstract of DOI:10.1016/j.tetlet.2017.11.018

A palladium-catalyzed cycloisomerisation reaction of 1,6-enyne acetic esters have been developed. This cyclization reaction shows excellent regioselectivity and good functional group tolerance to obtain five-membered nitrogenated heterocyclic conjugated t

Full text of DOI:10.1016/j.tetlet.2017.11.018

Accepted Manuscript
Palladium-catalyzed cycloisomerisation reaction of 1, 6-enyne acetic esters to
form five-membered nitrogenated heterocyclic conjugated trienes
Ting He, Pin Gao, Shan Fang, Yaling Chi, Yuantao Chen
PII:
S0040-4039(17)31421-1
https://doi.org/10.1016/j.tetlet.2017.11.018
TETL 49461
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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16 October 2017
7 November 2017
10 November 2017
Please cite this article as: He, T., Gao, P., Fang, S., Chi, Y., Chen, Y., Palladium-catalyzed cycloisomerisation
reaction of 1, 6-enyne acetic esters to form five-membered nitrogenated heterocyclic conjugated trienes, Tetrahedron
Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.018
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Graphical Abstract
Palladium-Catalyzed Cycloisomerisation
Reaction of 1, 6-Enyne Acetic Esters to Form
Five-membered Nitrogenated Heterocyclic
Conjugated Trienes
Ting He, Pin Gao, Shan Fang, Yaling Chi and Yuantao Chen

1
Tetrahedron Letters
journal homepage: www.els evier.com
Palladium-catalyzed cycloisomerisation reaction of 1, 6-enyne acetic esters to form
five-membered nitrogenated heterocyclic conjugated trienes
Ting He a, ∗, Pin Gao b, c, Shan Fang a, Yaling Chi a and Yuantao Chen a, *
a School of Chemistry and Chemical Engineering, Qinghai Normal University, Xining 810008, China
b Department of Chemistry, School of Science, Xi’an Jiaotong University, Xi’an 710049, China
c MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong University, Xi’an 710049, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A palladium-catalyzed cycloisomerisation reaction of 1,6-enyne acetic esters have been
developed. This cyclization reaction shows excellent regioselectivity and good functional group
tolerance to obtain five-membered nitrogenated heterocyclic conjugated trienes in moderate to
excellent yields. The resulting conjugated trienes could be facilely converted to highly
substituted benzenes through Diels-Alder reactions.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Cycloisomerisation
1, 6-enynes
Palladium-catalyzed
Nitrogenated heterocyclic
Conjugated trienes
1. Introduction
1, 6-enynes, which are well known for their transition metal-
catalyzed cycloisomerisation reactions, are a specific class of
6
Five-membered nitrogenated heterocycles play an important
role in organic chemistry, not only as key motifs in many
biologically active natural products and pharmaceuticals such as
domoic acid, 1 kainic acid 2 and conessine 3 (Figure 1), but also as
building blocks to construct cyclic and polycyclic structures.
The propargylic structures of 1, 6-enynes could be easily
activated by transition-metal and subsequent react with olefin to
form carbon-carbon bond. For example, Liang’ group has
developed a palladium-catalyzed divergent cyclization reactions
4
useful building blocks in synthetic chemistry. During the past
several decades, a plenty of methods based on simple acyclic
building blocks to synthesize five-membered nitrogenated
heterocycles have been developed. Within this synthetic toolbox,
transition metal-catalyzed cyclization of enynes represent
extremely attractive processes due to their atom-economy, high
efficiency and environmental sustainability. 5
of 1, 6-enyne carbonates to construct five- or six-membered
7
heterocyclic allenes.
Tenaglia and co-works have reported
ruthenium-catalyzed 1, 6-enynes cyclization in the presence of
terminal alkyne to achieve highly substituted five-membered
8
cyclics with a 1, 5-enyne motif. Tong and co-works have
synthesized a series of five- or six-membered heterocyclic
compounds bearing sulfonyl group through the cycloaddition
reactions of 1, 6-enynes and sulfonyl chlorides by rhodium
9
catalysts. Although many efforts of cycloisomerisation of 1, 6-
enynes have been made to synthesize novel cyclic compounds, 10
five-membered nitrogenated heterocycles with a high degree of
structural complexity, such as conjugated trienes (useful
synthetic building block), have been rarely reported. 11
Herein, we report a novel and efficient palladium-catalyzed
cycloisomerisation of 1, 6-enyne acetic esters to construct five-
membered nitrogenated heterocyclic conjugated trienes. To our
delight, the resulting conjugated trienes could be converted to
highly substituted benzenes by a Diels-Alder process.
Figure 1. Natural products with five-membered nitrogenated
heterocycles motifs.
———
∗ Corresponding author.
E-mail: ht15@tju.edu.cn (T. He); ytchen@lzu.edu.cn (Y. Chen).

2
Tetrahedron Letters
2. Results and Discussion
Table 1. Optimization of the palladium-catalyzed cyclization of 1, 6-enyne acetic esters 1a a
Entry
1
Catalyst(mol %)
Pd(PPh3)4 (10)
Base
Ligand (mol %)
Solvent
DMF
T(°C)
85
Yield(%)d
16
KOAc
(p-CF3)3P b (10)
2
3
Pd2(dba)3 (5)
PdI2 (5)
KOAc
KOAc
KOAc
NaOAc
Na2CO3
KOH
(p-CF3)3P (10)
(p-CF3)3P (10)
(p-CF3)3P (10)
(p-CF3)3P (10)
(p-CF3)3P (10)
(p-CF3)3P (10)
(3.5-CF3)3 P c (10)
(p-CF3)3 P(10)
(p-CF3)3 P(10)
(p-CF3)3 P(10)
(p-CF3)3 P(20)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
85
85
85
85
85
85
85
85
75
95
85
57
61
70
55
48
4
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd (dba)2(20)
5
6
e
7
—
8
KOAc
KOAc
KOAc
KOAc
KOAc
39
60
57
65
90
9
10
11
12
a The reaction was carried out with 1a (0.2 mmol), Pd catalysts, phosphine ligand and 2 equiv of base in solvent (2 mL) at 85°C for 4 h under argon.
b tris(4-(trifluoromethyl)phenyl)phosphine. c tris(3,5-bis(trifluoromethyl)phenyl)phosphine.
d Isolated yields. e Decomposed.
We first investigated the cyclization of methyl 5-(4-methyl-N-
(3-methylbut-2-en-1-yl)phenylsulfonamido)-2-phenylpent-3-
ynoate 1a in the presence of 10 mol % Pd(PPh3)4, 10 mol % (p-
CF3)3P [tris(4-(trifluoromethyl)phenyl)phosphine] and 2 equiv of
KOAc in DMF at 85°C under an argon atmosphere. (E)-3-(prop-
1-en-2-yl)-4-styryl-1-tosyl-2, 5-dihydro-1H-pyrrole 2a was
isolated in 16 % yield (Table 1, entry 1). Next, the catalytic
activity of palladium catalyst was tested (entries 2-4), Pd(dba)2
was the most effective catalyst of for this reaction and the yield
of 2a increased to 70 %. Other base such as NaOAc and Na2CO3
were less efficient and using KOH as the base led to a
decomposed (entries 5-7). When (3, 5-CF3)3P was used as
phosphine ligand, no improvement was found (entry 8).
Changing the solvent from DMF to DMSO also did not enhance
the yield of 2a (entry 9). During a survey of the temperature of
the reaction, it was determined that 85°C gave the best yield
(entries 10, 11). To our delight, significant improvement was
achieved by increasing the amount of catalyst to 20 mol %, a
good yield of 90 % of 2a was obtained after 4 h. The optimum
reaction conditions for 2a thus for developed employ 20 mol %
Pd(dba)2, 20 mol % (p-CF3)3P and 2 equiv of KOAc in DMF at
85°C under argon.
Table 2. Palladium-catalyzed cyclization of 1, 6-enyne acetic esters 1a a
Entry
1
1
R1
H
R2
2
Yield (%)b
90
1a
Ph-
2a
2
3
4
1b
1c
1d
H
H
H
p-MeC6H4-
m-MeC6H4-
o-MeC6H4-
2b
2c
2d
72
80
96
5
6
1e
1f
H
H
H
H
H
H
H
H
H
H
H
p-ClC6H4-
m-ClC6H4-
2e
2f
65
69
78
83
99
82
91
50
58
76
42
7
1g
1h
1i
o-ClC6H4-
2g
2h
2i
8
p-MeOC6H4-
o-MeOC6H4-
3,4-dimethylphenyl-
2,6-dimethoxyphenyl-
Furyl-
9
10
11
12
13
14
15
1j
2j
1k
1l
2k
2l
1m
1n
1o
Thienyl-
2m
2n
2o
Naphthyl-
Styryl-
a The reaction was carried out with 1a (0.2 mmol), 20 mol % Pd(dba)2, 20 mol % (p-CF3)3P and 2 equiv of KOAc in DMF (2 mL) at 85°C for 4 h under argon.
b Isolated yields.

3
Scheme 1. Cyclization of 1p to form five-membered allene 2p. 7
Scheme 2. Cyclization of 1a and intramolecular Diels-Alder reaction.
With the optimized conditions in hand, various 1, 6-enyne
acetic esters 1 were surveyed to clarify the scope of this reaction,
as shown in Table 2. A tandem carbon-carbon bond formation of
1, 6-enyne acetic esters 1a-1o proceeded smoothly to provide
corresponding E-five-membered nitrogenated heterocyclic
conjugated trienes 2a-2o in moderate to excellent yields. The
reaction worked well with a variety of functional groups such as
methyl-, chloro-, methoxyl- at the ortho-, meta-, and para-
positions of the phenyl moiety in substituted R2 group (2b-2i),
whereas ortho-positions give a better yields (2d vs 2b, 2c; 2g vs
2e, 2f; 2i vs 2h). Electron-donating aromatic groups showed
better results than those with an electron-withdrawing group in
this reaction (2d, 2i vs 2h). The structure of 2f was confirmed by
Scheme 3. Deuterium-labeling experiments.
Based on the above observations, a plausible mechanism is
proposed in Scheme 4. It might be rationalized in terms of the
following steps: (a) transformation of 1, 6-enyne acetic ester 1 by
Pd(0)-catalyzed generates allenylpalladium intermediate A; (b)
olefin as a nucleophile attacks the intermediate A to form a five-
membered palladium complex B; (c) reductive elimination of B
gives a five-membered allene compound C and regenerates the
Pd(0) catalyst; (d) isomerization of the compound C to form the
desired product 2.
12
X-ray crystal structure analysis (Figure 2). The substrate scope
can also be extended to naphthyl- and styryl-enyne acetic esters
(2n, 2o). To our delight, substrate with heteroaromatic R2 groups
can also afford the desired products 2l and 2m in 50 % and 58 %
yields, respectively. However, the substrate with aliphatic R1 and
R2 groups cannot afford the desired product, a five-membered
allene was obtained in 52 % yield, which had been reported (2p,
Scheme 1). 7 When propyl group is used at R2 positon (R1=H), no
product is achieved. It seems that aromatic substituent groups are
indispensable for the synthesis of conjugated triene products.
TsN
isomerization
.
R1
R2
TsN
O
C
O
R2
Pd(0)
R1
1
TsN
2
R1 R2
Base
TsN
OAc
Pd
TsN
R2
R1
(
)
Ⅱ
.
(
)
Pd
Ⅱ
AcO
.
R1
A
R2
B
Scheme 4. Plausible mechanism.
Figure 1. X-Ray Structure of 2f.
3. Conclusions
To our surprise, when the substrate 1a was reacted in the
presence of 20 mol % Pd(dba)2, 20 mol % (p-CF3)3P and 2 equiv
of KOAc in DMSO (2 mL) at 85°C for 4h under argon, then 2
equiv of CuO was added to the solution and the reaction
continued for another 2h at 150°C under oxygen, 4-methyl-6-
phenyl-2-tosylisoindoline 3a was obtained in 53% yield (Scheme
2), this result is beneficial to further researches of five-membered
nitrogenated heterocyclic conjugated trienes. To further acquire
the information with respect to the mechanism, we conducted
some deuterium-labeling studies. As shown in Scheme 3, 1q was
reacted under identical conditions with 1a to afford desired
deuterium-substituted products 2q and 3q. These data suggested
that the hydrogen in α position of products were obtained from
the carbon-carbon double bond of 1p through a proton migration.
In summary, we have developed
intramolecular cyclization reaction of 1, 6-enyne acetic esters to
afford straightforward approach to (E)-five-membered
heterocyclic conjugated trienes. Deuterium-labeling experiments
show that intramolecular proton migration is occurred to
construct conjugated triene structures. The resulting conjugated
trienes could be oxidated to polysubstituted benzene in one-pot.
a
Pd-catalyzed
a
Acknowledgments
The authors gratefully acknowledge the National Natural
Science Foundation of China (NSFC21667024, 21602168),
Natural Science Foundation of Qinghai Province (2016-2J-912)
and Qinghai Normal University (15RZ12) for financial support.

4
Tetrahedron
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Ali, S.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2012, 77, 2763-
2772.
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5
1. Importance of five-membered nitrogenated
heterocyclics as pharmaceutical and bioactive
agents.
2. A one-pot to construct five-membered
nitrogenated heterocyclics bearing conjugated
trienes motif.
3. The reactions show excellent regioselectivity,
good functional group tolerance and high
yields.
4. The resulting conjugated trienes could be
facilely converted to highly substituted
benzenes through Diels-Alder reactions.