Palladium(II)-Catalyzed Three-Component Coupling Reaction Initiated by Acetoxypalladation of Alkynes: An Efficient Route to γ,δ-Unsaturated Carbonyls

Article abstract of DOI:10.1021/ol026741h

(Matrix Presented) A divalent palladium-catalyzed coupling reaction of electron-deficient alkynes and acrolein or MVK (methyl vinyl ketone) was developed. The reaction provides an efficient method to synthesize γ,δ-unsaturated carbonyls. A mechanism involving acetoxypalladation of alkyne, followed by insertion of alkene and protonolysis of the C-Pd bond, is proposed. The protonolysis of the carbon-palladium bond with the assistance of bidentate nitrogen containing ligands is the key step in this tandem reaction.

Full text of DOI:10.1021/ol026741h

ORGANIC
LETTERS
2
002
Vol. 4, No. 22
903-3906
Palladium(II)-Catalyzed
3
Three-Component Coupling Reaction
Initiated by Acetoxypalladation of
Alkynes: An Efficient Route to
γ,δ-Unsaturated Carbonyls
Ligang Zhao and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
xylu@pub.sioc.ac.cn
Received August 15, 2002
ABSTRACT
A divalent palladium-catalyzed coupling reaction of electron-deficient alkynes and acrolein or MVK (methyl vinyl ketone) was developed. The
reaction provides an efficient method to synthesize γ,δ-unsaturated carbonyls. A mechanism involving acetoxypalladation of alkyne, followed
by insertion of alkene and protonolysis of the C−Pd bond, is proposed. The protonolysis of the carbon−palladium bond with the assistance
of bidentate nitrogen containing ligands is the key step in this tandem reaction.
Constructing polyfunctionalized molecules by linking several
the reactions of vinylpalladium species which can also easily
be obtained from nucleopalladation of alkynes under Pd(II)
catalysis have received only limited attention. The main
organic moieties through carbon-carbon coupling in one step
1
3b,4
is a very attractive strategy for synthetic chemists. During
recent years, transition metal-catalyzed processes toward this
end have grown at an exponential rate, in particular to the
construction of polyfunctionalized molecules. A tremendous
reason is that methods of quenching the carbon-palladium
bond to regenerate the divalent palladium species are rarely
reported, thus an excess amount of oxidants is often required
to regenerate the Pd(II) species from Pd(0) species.5
During our ongoing study on the Pd(II)-catalyzed reac-
tions, we studied the different kinds of nucleopalladation
2
amount of attention has been paid to various types of Pd(0)-
catalyzed reactions starting from vinylic halides (or triflates)
3
with vinylpalladium species as the intermediate. However,
(
1) (a) Ho, T.-L. Tandem Organic Reactions; Wiley-Interscience: New
(4) (a) Maitlis, P. M. The Organic Chemistry of Palladium; Academic
Press: New York, 1971; Vol. 1, p 79. (b) Maitlis, P. M. Acc. Chem. Res.
1976, 9, 93-99. (c) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.;
Teranishi, S. J. Org. Chem. 1979, 44, 55. (d) Lambert, C.; Utimoto K.;
Nozaki, H. Tetrahedron Lett. 1984, 25, 5323. (e) Yanagihara, N.; Lambert,
C.; Iritani, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 2753.
(f) B a¨ ckvall, J.-E.; Nilsson, Y. I. M.; Andersson, P. G.; Gatti, R. G. P.;
Wu, J. Tetrahedron Lett. 1994, 35, 5713. (g) B a¨ ckvall, J.-E.; Nilsson, Y. I.
M.; Gatti, R. G. P. Organometallics 1995, 14, 4242. (h) Lu, X.; Ma, S.
New Age of Divalent Palladium Catalysis. In Transition Metal Catalyzed
Reaction; Murahashi, S.-I., Davies, S. G., Eds.; Blackwell Science: Oxford,
UK, 1999; Chapter 6, p 133. (i) Lu, X.; Zhu, G.; Wang, Z. Synlett 1998,
115.
York, 1992. (b) Bunce, R. A. Tetrahedron 1995, 51, 13103.
(
2) (a) Trost, B. M.; Fleming, I. ComprehensiVe Organic Synthesis:
SelectiVity, Strategy and Efficiency in Modern Organic Chemistry;
Pergamon: Oxford, UK, 1991; Vol. 3, p 413. (b) Trost B. M.; Pinkerton,
A. B. J. Am. Chem. Soc. 2000, 122, 8081 and references therein.
(
3) (a) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G.
Principles and Applications of Organotransition Metal Chemistry; Univer-
sity Science Books: Mill Valley, CA, 1987. (b) Tsuji, J. Palladium Reagents
and Catalysts, InnoVations in Organic Synthesis; John Wiley: Chichester,
UK, 1995. (c) Negishi, E.-I.; Cop e´ ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem.
ReV. 1996, 96, 365. (d) de Meijere, A.; Meyer, F. E. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2379.
1
0.1021/ol026741h CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/26/2002

initiated tandem reactions4h,i and developed methods of
quenching the carbon-palladium bond to regenerate Pd(II)
species.4 In the previous report, we developed a Pd(II)-
catalyzed tandem addition of lithium halides to alkynes and
ligands can play the similar important role as halide ions in
inhibiting â-H elimination and regenerating Pd(II) species
i,7
10
via â-heteroatom elimination. These results prompted us
to explore the possibility of a Pd(II)-catalyzed tandem
reaction via acetoxypalladation of alkynes and regeneration
of Pd(II) species via protonolysis of the C-Pd bond in the
presence of nitrogen-containing ligands. Herein, we report
the preliminary results of this novel Pd(II)-catalyzed tandem
addition reaction of alkynes to acrolein or MVK by applying
this supposition.
We first investigated the reaction of methyl 2-butynoate
2
1a with acrolein in the presence of Pd(OAc) and bpy in
HOAc (Scheme 2). The reaction was complete within 4 h at
6a
R,â-unsaturated carbonyl compounds. The halide ions act
not only as a nucleophile but also as a ligand that plays the
key role in inhibiting the usual â-hydride elimination making
7
the catalytic cycle proceed smoothly, thus the halide ion is
necessary in the halopalladation initiated reaction as a ligand.
To extend this tandem process to other nucleophiles and
develop the asymmetric version of this reaction, a suitable
nucleophile and ligand must be found in place of the halide
ion. Hydroacetoxylation of alkynoates was developed in early
work where acetate ion attacked the triple bond under
palladium catalyst via trans-acetoxypalladation followed by
8
protonolysis, implying that acetate might be a good nucleo-
Scheme 2
phile to replace the halide ion. If we can trap the vinyl-
palladium species generated from acetoxypalladation with
an olefin, the pure geometrical isomer of an enol ester
derivative, which is the important precursor in stereoselective
9
synthesis, will be synthesized. However, much effort failed
when we used acetate as the nucleophile and halide ion as
the ligand in the coupling reaction of alkynoates with alkenes.
The reaction gave only halopalladation products because the
rate of halopalladation is much faster than that of acetoxy-
palladation (Scheme 1), indicating that the acetoxypalladation
8
1
0 °C and gave the expected coupling products 4a (yield:
7%) and 5a (yield: 23%), as well as the protonolysis
product 3a (yield: 18%) (entry 1, Table 1).
Scheme 1
Table 1. The Solvent Effect on the Distribution of Products of
the Tandem Reactionsa
entry
solventb
yield (%)c
t (h)
3a (%)
4a :5a
1
2
3
4
5
6
7
HOAc
40
d
4
12
5
18
-
trace
trace
trace
-
43:57
HOAc:DMF
HOAc:PhH
HOAc:DCE
HOAc:acetone
HOAc:THF
HOAc:MeCN
38
66
30
17
72
94:6
5
72:28
87:13
97:3
initiated coupling reaction can occur only in the absence of
halide ions. However, when the acetoxypalladation initiated
reaction was carried out in the absence of halide ions, it gave
no coupling products but the black precipitates of palladium.
Recently, we found that some bidendate nitrogen-containing
24
24
12
-
97:3
a
Reaction conditions: Pd(OAc)2 (0.05 mol), bpy (0.06 mol), 1a (1
mmol), 2a (10 mmol), solvent (4 mL), at 80 °C. The ratio of 4a and 5a
1
b
was determined by H NMR (300 MHz). The volume ratio of mixed
(
5) (a) Jonasson, C.; Howath, A.; B a¨ ckvall, J.-E. J. Am. Chem. Soc. 2000,
solvent is 1:3. c Isolated total yield of 4a and 5a. d A black precipitate
1
22, 9600. (b) B a¨ ckvall, J.-E.; Jonasson, C. Tetrahedron Lett. 1997, 38,
appeared within several minutes.
2
91. (c) Kimura, M.; Saeki, N.; Uchida, S.; Harayama, H.; Tanaka, S.;
Fugami, K.; Tamaru, Y. Tetrahedron Lett. 1993, 34, 7611. (d) Walkup, R.
D.; Mosher, M. D. Tetrahedron 1993, 49, 9285. (e) Gallagher, T.; Davies,
I. W.; Jones, S. W.; Lathbury, D.; Mahon, M. F.; Molloy, K. C.; Shaw, R.
W.; Vernon, P. J. Chem. Soc., Perkin. Trans. 1 1992, 433. (f) Andersson,
P. G.; B a¨ ckvall, J.-E. J. Am. Chem. Soc. 1992, 114, 8696. (g) Walkup, R.
D.; Park, G. Tetrahedron Lett. 1987, 28, 1023. (h) Hegedus, L. S.; Kambe,
N.; Ishii, Y.; Mori, A. J. Org. Chem. 1985, 50, 2240. (i) Alper, H.; Hartstock,
F. W.; Despeyroux, B. J. Chem. Soc., Chem. Commun. 1984, 905.
The formation of compound 4a (codimerization product)
and 5a (cotrimerization product) was rationalized by the
mechanism shown in Scheme 3. Vinylpalladium intermediate
I was first formed by trans-acetoxypalladation of 1a in
(
6) (a) Wang, Z.; Lu, X. J. Chem. Soc., Chem. Commun. 1996, 535. (b)
Wang, Z.; Lu, X. J. Org. Chem. 1996, 61, 2254. (c) Wang, Z.; Lu, X.; Lei,
A.; Zhang, Z. J. Org. Chem. 1998, 63, 3806. (d) Xie, X.; Lu, X. Synlett
(8) (a) Lu, X.; Zhu, G.; Ma, S. Tetrahedron Lett. 1992, 33, 7205. (b)
Wakabayashi, T.; Ishii, Y.; Murata, T.; Mizobe, Y.; Hidai, M. Tetrahedron
Lett. 1995, 36, 5585.
(9) (a) House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin:
London, UK, 1972; p 313. (b) Nogradi, M. In StereoselectiVe Synthesis;
Verlag Chemie: Weinheim, Germany, 1987; p 193. (c) Evans, D. A. In
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, FL,
1984; Vol. 3, p 119.
2
000, 707. (e) Lei. A.; Lu, X. Org. Lett. 2000, 2, 2699. (f) Liu. G.; Lu, X.
Org. Lett. 2001, 3, 3879. (g) Lei, A.; Liu, G.; Lu, X. J. Org. Chem. 2002,
7, 974.
7) In the Pd(II)-catalyzed coupling reactions, the halide ion can block
6
(
the â-H elimination of a carbon-palladium bond, giving preferentially the
protonolysis or â-heteroatom elimination product, see: (a) Wang, Z.; Zhang,
Z.; Lu, X. Organometallics 2000, 19, 775. (b) Zhang, Z.; Lu, X.; Xu, Z.;
Zhang, Q.; Han, X. Organometallics 2001, 20, 3724.
(10) (a) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604. (b) Zhang,
Q.; Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676.
3904
Org. Lett., Vol. 4, No. 22, 2002

protonolysis of the vinylpalladium bond. When HOAc (entry
) or HOAc/1,2-dichloroethane (entry 4) was used, the
1
Scheme 3
reaction gave moderate total yield but with poor chemo-
selectivity. However, the reaction gave low yield but high
chemoselectivity on using HOAc/benzene (entry 3) or HOAc/
THF (entry 6) as solvent. The best result was acquired when
HOAc and MeCN were used as mixed solvent.
The scope and generality of the present reaction was
studied as shown in Table 2. Most of the electron-deficient
alkynes gave good yields of the 1:1 codimerization product
with acrolein or methylvinyl ketone (entries 1-10). However,
in the present catalytic system, the terminal propiolate cannot
afford the tandem coupling product (entry 11), which might
be attributed to the possible formation of alkynylpalladium
11
species. In addition, when the above reaction was performed
in the absence of Pd(OAc) or bpy, no coupling products
HOAc, followed by acrolein insertion (path A) or subsequent
alkyne and acrolein insertion (path B). The competing alkyne
insertion may be ascribed to the higher reactivity of alkynes
2
were obtained at all. The regiochemistry was controlled by
the electron-withdrawing properties of the substituents on
6a
than olefins. Both reaction paths involved the protonolysis
of the carbon-palladium bond to regenerate the catalytic
Pd(II) species, giving 4a and 5a, respectively. It is note-
worthy that bidentate nitrogen-containing ligands are im-
portant in stabilizing vinylpalladium intermediates and as-
4c
the triple bond, The stereochemistry of the double bond in
1
10
4
was assigned as the Z-configuration based on H NMR
and that of 4a was confirmed by NOESY spectra, which
indicated the trans-acetoxypalladation involved in this reac-
tion. The stereochemistry of acetoxypalladation seems dif-
ferent from that of chloropalladation reported by B a¨ ckvall,
where the alkynes undergo both cis and trans chloropalla-
1
0
sisting the protonolysis of the carbon-palladium bond.
Further experiments confirmed the solvent effect played
a significant role in the distribution of products (Table 1).
In most cases, mixed solvents can inhibit the formation of
product 3a, implying that low solvent acidity can inhibit the
4g
dation according to the concentration of halide ion.
To probe the role of nitrogen-containing ligands, we
investigated a catalytic process incorporating Pd(II)-mediated
3
b
transmetalation. The reaction of phenylmercuric acetate
with acrolein or MVK in the presence of 5 mol % of
Table 2. Reactions of 1 with R,â-Unsaturated Carbonyls
2
Pd(OAc) in HOAc was conducted by different loading of
Catalyzed by Pd(II) Speciesa
bpy as shown in Table 3. With an increase in the amount of
bpy, the total yield increased obviously and the protonolysis
product 7 was dominant as compared to the â-H elimination
product 6. Employment of phenanthroline as the ligand gave
a similar result to that of bpy. The results strongly supported
the fact that these nitrogen-containing ligands play a crucial
Table 3. Pd(II)-Catalyzed Reactions of Phenylmercuric Acetate
with Acrolein or MVKa
entry
1
R1
R2
R3 t (h)
yield, % (4:5)b
1
2
3
4
5
6
7
8
9
1a Me
1b Me
1c Ph
1d n-Pr
1e Me
OMe
OBn
OMe
OMe
n-Pr
Ph
H
H
H
H
H
H
H
H
H
12
24
30
26
12
24
24
27
48
7
72 (4a :5a > 97:3)
78 (4b:5b > 97:3)
91 (4c:5c ) 81:19)
76 (4d :5d ) 93:7)
78 (4e:5e ) 88:12)
c
1f
Me
70 (4f:5f ) 94:6)
t
1g Me
O Bu
OMe
58 (4g:5g > 97:3)
78 (4h :5h ) 94:6)
60 (4i:5i ) 92:8)
1h
n-C7H15
entry
R
bpy (mol %)
t (°C)
yield (%)b
6:7c
1i
MeOCH2 OMe
d
1
1
0
1
1a Me
OMe Me
OMe
63 (only 4k )
1
2
3
4
5
6
H
H
H
Me
Me
Me
0
10
25
0
10
25
70
70
70
50
50
50
6
48
78
7
47
47
86:14
15:85
<3:97
>97:3
27:73
15:85
1j
H
H
24
e
a
Reaction conditions: A mixture of 1 (1 mmol), Pd(OAc)2 (0.05 mmol),
bpy (0.06 mmol), and unsaturated carbonyl compound (10 mmol) in a mixed
solution of HOAc (1 mL) and MeCN (3 mL) at 80 °C. The ratio of product
and 5 was determined by H NMR, and new compounds were
characterized by H NMR, IR, MS, and HRMS. Substrate 1f was recovered
in 28%. Another product: 1-acetoxylacetone (97 mg) was also obtained.
The reaction system turned to black after half an hour, and no obvious
product can be found.
b
1
4
1
c
d
a
Reaction conditions: PhHgOAc (1 mmol), acrolein or MVK (5 mmol),
and Pd(OAc)2 (0.05 mol). 1 Isolated total yield of 6 and 7. c The ratio of 6
and 7 was determined by H NMR spectra.
e
b
Org. Lett., Vol. 4, No. 22, 2002
3905

role in inhibiting the â-H elimination of alkylpalladium(II)
species and assisting the protonolysis of the carbon-
palladium bond, making the catalytic cycles possible.
The products obtained by palladium(II)-induced three-
component coupling can be used in further synthetic
transformation. Vinyl acetates not only are important precur-
sors in the synthesis of functionalized molecules but also
developed with high atom economy. The present catalytic
system provides not only an efficient route to γ,δ-unsaturated
carbonyl compounds but also a method of quenching the
carbon-palladium bond via protonolysis with assistance
from nitrogen-containing ligands. Further application of the
present catalytic system is underway.
1
2
can be conveniently converted into the 1,5-diketones.
Acknowledgment. We thank the Major State Basic
Research Program (Grant G20000077502-A). We also thank
the National Natural Sciences Foundation of China and
Chinese of Sciences for financial support.
In summary, a Pd(II)-catalyzed three-component tandem
coupling reaction of acetate ion, alkyne, and R,â-unsaturated
carbonyls initiated by acetoxypalladation of alkynes was
(
11) (a) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; R u¨ hter, G.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds 4a-k and NOESY
spectra of 4a. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Am. Chem. Soc. 1997, 119, 698. (b) Melikyan, G. G.; Nicholas, K. M.
In Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH:
New York, 1995; p 79.
(
12) (a) Mahrwald, R.; Schick, H. Angew. Chem., Int. Ed. Engl. 1991,
0, 593. (b) Ono, M.; Itoh, I. Tetrahedron Lett. 1989, 30, 207. (c) Yakemoto,
T.; Nishikimi, Y.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1992, 33,
527.
3
3
OL026741H
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