The first palladium-catalyzed 1,4-addition of terminal alkenes to acrylate esters

Article abstract of DOI:10.1039/c3cc41742e

A novel and efficient procedure for the synthesis of δ,γ- alkenyl esters with complete E-stereochemistry by the 1,4-addition of alkenes to acrylate esters in the presence of a catalytic amount of palladium chloride has been developed. This method provides

Full text of DOI:10.1039/c3cc41742e

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The first palladium-catalyzed 1,4-addition of terminal
alkenes to acrylate esters†
Cite this: Chem. Commun., 2013,
49, 5295
Pei Liu, Heng-shan Wang, Ying-ming Pan,* Wei-long Dai, Hong Liang and
Zhen-Feng Chen*
Received 7th March 2013,
Accepted 17th April 2013
DOI: 10.1039/c3cc41742e
www.rsc.org/chemcomm
A novel and efficient procedure for the synthesis of d,c-alkenyl using indium(III) chloride (InCl3) as a catalyst.8 As a result of the
esters with complete E-stereochemistry by the 1,4-addition of development of the transition-metal-catalyzed addition of alkynyl
alkenes to acrylate esters in the presence of a catalytic amount of derivatives,9 herein, we wish to report a highly efficient reaction for
palladium chloride has been developed. This method provides a the synthesis of d,g-alkenyl esters with complete E-stereochemistry
rapid and efficient access to substituted d,c-alkenyl esters.
from alkenes and acrylate esters using PdCl2 as the catalyst. To our
delight, preliminary experiments, in which those substrates were
The 1,4-addition of carbanions to a,b-unsaturated carbonyl compounds subjected to the standard conditions used for the palladium chloride
is one of the most attractive methods for constructing a new carbon– catalyzed 1,4-addition reaction, revealed that the target products
carbon bond in organic synthesis.1 Among them, a direct and reliable were obtained in good yields.
approach to a wide variety of g,d-alkynyl ketones and g,d-alkynyl esters is
To identify the suitable conditions for the 1,4-addition reaction,
the 1,4-addition of terminal alkynes to unsaturated carbonyl com- a variety of catalysts and solvents were screened using styrene 1a
pounds catalyzed by transition metals.2 In contrast, related transition with ethyl acrylate 2a as a model system (Table 1).10 Initially, the
metal-catalyzed 1,4-addition of alkenes to unsaturated carbonyl com- reaction of 1a and 2a gave 3aa in 79% yield in the presence of
pounds is relatively rare because C(sp2)–H bonds of simple alkenes are 6 mol% PdCl2 in chlorobenzene at 110 1C for 72 h (Table 1, entry 1).
less reactive toward transition metals than alkynes.
In 1989, an efficient reaction between 4-(phenylsulfonyl)butanoic Table 1 Optimization of reaction conditionsa
acid and benzaldehyde to generate (E)-methyl 5-phenylpent-4-enoate in
the presence of n-BuLi was reported by Thompson and Frick.3 More-
over, Chatterjee et al. have reported the synthesis of (E)-methyl
cinnamate along with ethylene release directly from methyl acrylate
Entry
Catalyst
Solvent
Yieldb (%)
and styrene catalyzed by a ruthenium complex.4 Several years later,
ruthenium-catalyzed synthesis of enamides from acrylate esters5 and
nickel-catalyzed synthesis of d,g-alkenyl esters from alkyl zinc halides6
were developed. Recently, an efficient 1,4-addition of simple alkenes to
enones in the presence of Ni(cod)2 and PCy3, which led to the synthesis
of d,g-alkenyl ketones, has been reported.7 The regiochemistry of
the carbon–carbon bond at the b-position could be controlled by
the formation of an Z3-oxaallylnickel species. However, to date,
direct 1,4-addition of alkenes to alkene esters, which have low
reactivity, remains an elusive goal.
1
2
3
4
5
6
7
8
PdCl2
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DMF
PhCH3
DMSO
CH3COOH
CH3NO3
THF
79
50
80
55
0
0
0
0
0
0
0
PdCl2(3 mol%)
PdCl2(10 mol%)
Pd(OAc)2
Pd(OH)2
Pd(PPh3)4
Pd(acac)2
PdO
Pd2(dba)3
In(OTf)3
FeCl3
RhCl3
AuBr3
PdCl2
PdCl2
9
10
11
12
13
14
15
16
17
18
19
20
0
0
More recently, we reported a convenient one-pot process for the
synthesis of d,g-alkynyl esters from alkynylsilanes and acrylate esters
15
20
48
40
45
46
55
PdCl2
PdCl2
PdCl2
PdCl2
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal
Resources (Ministry of Education of China), School of Chemistry & Chemical
Engineering of Guangxi Normal University, Guilin 541004, People’s Republic of
China. E-mail: panym2004@yahoo.com.cn, chenzfubc@yahoo.com;
Fax: +86-773-5803930; Tel: +86-773-5846279
PdCl2
DCE
a
Reaction conditions: styrene 1a (0.5 mmol), ethyl acrylate 2a
(0.75 mmol), catalyst (6 mol% to 1a), solvent (2.0 mL), 110 1C, sealed
† Electronic supplementary information (ESI) available: Experimental section
and NMR data of the prepared compounds. See DOI: 10.1039/c3cc41742e
b
tube 72 h. Isolated yield of the pure product based on 1a.
c
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a
Table 2 Synthesis of d,g-alkenyl esters 3 catalyzed by PdCl2
When the amount of PdCl2 was decreased to 3 mol%, the yield of
product 3aa decreased to 50% (Table 1, entry 2). However, no
improvement in the yield of 3aa could be obtained when the
amount of PdCl2 was increased to 10 mol% (Table 1, entry 3). A
moderate yield was obtained when Pd(OAc)2 was used (Table 1,
entry 4). In addition, in the presence of other palladium catalysts
such as Pd(OH)2, Pd(PPh3)4, Pd(acac)2, PdO, or Pd2(dba)3, most
of the starting material 1a was recovered (Table 1, entries 5–9).
Furthermore, with the other metal catalysts such as In(OTf)3,
FeCl3, RhCl3, or AuBr3, the product 3aa was also not obtained at
all (Table 1, entries 10–13). Further optimization suggested that
solvents had a strong effect on this process. The reactions were
obviously restrained when they were performed in DMF and
toluene (Table 1, entries 14 and 15). Moreover, in other solvents,
such as DMSO, CH3COOH, CH3NO3, THF and DCE, the yields of
3aa decreased to 40–55% (Table 1, entries 16–20). When organic
and inorganic bases were used, such as K2CO3, Cs2CO3, Et3N,
CH3COONa, DABCO or DMAP, the reaction failed to afford the
desired products. Subsequently, various ligands were tested for
this reaction using PdCl2 as the catalyst. No desired product was
observed when PPh3 or 1,10-phen was used as the ligand. Hence,
it was concluded that the best conditions involved 6 mol% PdCl2
in chlorobenzene at 110 1C for 72 h.
With the optimized reaction conditions established, the
scope of the 1,4-addition reaction with respect to various
alkenes and acrylate esters was investigated. Typical results
are shown in Table 2. Varied acrylate esters were suitable
reaction partners for styrene 1a to form the d,g-alkenyl esters
with complete E-stereochemistry. Promoted by PdCl2, almost
all the acrylate esters are effective under the standard condi-
tions. Methyl acrylate 2b, n-butyl acrylate 2c, isobutyl acrylate
2d, and t-butyl acrylate 2e gave the corresponding d,g-alkenyl
esters 3ab–3ae in 73–85% yields with complete E-selectivity
(Table 2, entries 2–5). However, the methyl methacrylate 2f did
not form the desired d,g-alkenyl ester 3af with 1a, presumably
due to the steric effect of acrylate ester 2f (Table 2, entry 6). The
terminal aryl alkenes 1b and 1c possessing an electron-donating
group at the aryl ring (R = 2-MeC6H4, 4-MeC6H4) reacted without
a hitch and afforded the desired products 3bd and 3ca in 81% and
85% yields, respectively (Table 2, entries 7 and 8). Substrates 1d
and 1e possessing an electron-withdrawing group (R = 4-BrC6H4,
4-FC6H4) at the benzene ring also reacted smoothly and gave the
desired d,g-alkenyl esters 3da and 3ed in 74% and 68% yields with
complete E-selectivity, respectively (Table 2, entries 9 and 10).
Obviously, electron-rich terminal alkenes provided the desired
products in higher yields than electron-poor terminal alkenes.
Also, a-methylstyrene 1f reacted smoothly with methyl acrylate 2b
and isobutyl acrylate 2d affording 3fb and 3fd in good yields
(Table 2, entries 11 and 12). In addition, the reaction of 4-chloro-a-
methylstyrene 1g under the same conditions resulted in the
formation of 3gd in a good yield (Table 2, entry 13). These results
indicated that the steric effect of alkenes has no influence on this
process. However, the reaction of 1-hexene 1h and ethyl acrylate
Acrylate
ester
Yieldb
(%)
Entry Alkene
Product
1a: R1 = Ph;
2a: R3 = Et;
1
79
R2 = H
R4 = H
1a: R1 = Ph;
2b: R3 = Me;
2
3
4
5
78
73
85
75
R2 = H
R4 = H
1a: R1 = Ph;
2c: R3 = n-Bu;
R2 = H
R4 = H
1a: R1 = Ph;
2d: R3 = i-Bu;
R2 = H
R4 = H
1a: R1 = Ph;
2e: R3 = t-Bu;
R2 = H
R4 = H
1a: R1 = Ph;
2f: R3 = Me;
6
7
0
R2 = H
R4 = Me
1b: R1
=
2d: R3 = i-Bu;
2-Me-C6H4;
81
R4 = H
R2 = H
1c: R1
=
2a: R3 = Et;
8
4-Me-C6H4;
85
74
68
R4 = H
R2 = H
1d: R1
=
2a: R3 = Et;
9
4-Br-C6H4;
R4 = H
R2 = H
1e: R1
=
2d: R3 = i-Bu;
10
4-F-C6H4;
R4 = H
R2 = H
1f: R1 = Ph;
2b: R3 = Me;
11
12
13
78
77
R2 = Me
R4 = H
1f: R1 = Ph;
2d: R3 = i-Bu;
R2 = Me
R4 = H
1g: R1
=
2d: R3 = i-Bu;
4-Cl-C6H4;
72
0
R4 = H
R2 = Me
1h: R1 = C4H9; 2a: R3 = Et;
14
R2 = H
R4 = H
a
Reaction conditions: alkenes
1 (0.5 mmol), acrylate esters 2
(0.75 mmol), PdCl2 (6 mol% to 1), PhCl (2.0 mL), 110 1C, sealed tube
b
72 h. Isolated yield of the pure product based on 1.
2a failed to afford the desired products and led to the recovery of The camphene derivatives have good antiviral effects, particu-
starting materials (Table 2, entry 14).
larly noticeable is the activity of the camphene derivatives
To our delight, camphene 1i reacted smoothly with methyl acrylate against influenza A virus.11 Herein, we have provided a rapid
2b giving the corresponding product 3ib in 65% yield (Scheme 1). method for the synthesis of the camphene derivative.
c
5296 Chem. Commun., 2013, 49, 5295--5297
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were formed in good yields. The reaction showed very good
selectivity, and (E)-alkenyl esters were found as the sole products in
all cases. Further investigation, including the scope, mechanism
and synthetic application of this reaction, is in progress in our
laboratory.
We thank the project 973 (2011CB512005), Ministry of Educa-
tion of China (IRT1225), the National Natural Science Foundation
of China (41206077 and 81260472), Guangxi Natural Science
Foundation of China (2012GXNSFAA053027, 2011GXNSFD018010
and 2010GXNSFF013001), and Bagui Scholar Program of Guangxi
for financial support.
Scheme 1 Synthesis of d,g-alkenyl ester 3ib from camphene 1i and ethyl
acrylate 2b.
Scheme 2 Deuterium labeling experiment.
Notes and references
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A deuterium labeling experiment gave us some information
about the reaction pathway. Thus, treatment of styrene-d 1a–d with
ethyl acrylate 2a in PhCl at 110 1C for 72 h gave the d,g-alkenyl
esters 3aa–d in 77% yield with complete E-stereochemistry, where
78% of deuterium was incorporated (Scheme 2).
˜
´
˜
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On the basis of the above results, a tentative mechanism for the
palladium catalyzed 1,4-addition of terminal alkenes to conjugated
acrylate esters is illustrated in Scheme 3. The Z2-coordination
of the double bond to the palladium center followed by
direct deprotonation of the coordinated terminal alkene to
the palladium catalyst generated the alkenyl palladium inter-
mediate. Then, Z2-coordination of the CQC double bond to the
palladium center followed by carbopalladation and substitution
of Pd with hydrogen produced the d,g-alkenyl ester products with
concomitant regeneration of the Pd catalyst.
´
˜
´
6 V. B. Phapale, M. Guisan-Ceinos, E. Bunuel and D. J. Cardenas,
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´
˜
10 We tried to synthesize d,g-alkenyl esters from alkenes and acrylate
esters using the previously reported reaction conditions (e.g. ref. 3–7).
However, the reaction failed to afford the desired products.
In conclusion, we have developed a general and efficient
method which is catalyzed by the commercially available palladium
catalyst for the synthesis of d,g-alkenyl esters from alkenes and
acrylate esters in a one-pot manner. Various d,g-alkenyl esters
´
´
´
11 A. Garcıa Martınez, E. Teso Vilar, A. Garcıa Fraile, S. de la Moya
´
´
Cerero, M. E. Rodrıguez Herrero, P. Martınez Ruiz, L. R. Subramanian
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´
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5295--5297 5297