The first palladium-catalyzed 1,4-addition of terminal alkynes to conjugated enones

Article abstract of DOI:10.1039/b407936a

The first palladium-catalyzed 1,4-addition of terminal alkynes to conjugated enones has been developed in water and in acetone, producing the corresponding γ,δ-alkynyl ketones in high yields.

Full text of DOI:10.1039/b407936a

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The first palladium-catalyzed 1,4-addition of terminal alkynes to
conjugated enones
Liang Chena and Chao-Jun Li*a,b
a Department of Chemistry, Tulane University, New Orleans, Louisiana, 70118, USA
b Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec, H3A 2K6,
Canada. E-mail: cj.li@mcgill.ca; Fax: 11 514 3983797; Tel: 11 514 3988457
Received (in Corvallis, OR) 25th May 2004, Accepted 30th July 2004
First published as an Advance Article on the web 8th September 2004
The first palladium-catalyzed 1,4-addition of terminal alkynes
presence of a base, especially in the case of the base NEt3 (Table 1,
entries 11 and 12) possibly because of a competing coordination
between NEt3 and the phosphine ligand. The Pd(OAc)2/base
system without a phosphine ligand also was tested, and little
product was observed. As a further effort to determine the
responsible catalyst, reactions were performed with either PMe3
alone or Pd(OAc)2 alone. Whereas Pd(OAc)2 alone as the catalyst
was only slightly effective, PMe3 did not show any catalytic activity
(although phosphines have been shown to catalyze conjugate
additions with alcohols, amines, and activated methylene as
nucleophiles).15 The reason for lacking of catalytic activity for
alkynes with PMe3 is possibly due to the relatively weak
nucleophilicity of terminal alkynes. Since PMe3 is easily oxidized
to trimethylphosphine oxide, we also tested the Pd(OAc)2/
trimethylphosphine oxide as a catalyst. Almost no catalytic activity
was observed (Table 1, entry 13) and trimethylphosphine oxide
alone did not show any catalytic activity. Finally, when the ratio of
PMe3/Pd(OAc)2 was increased to 4:1, the desired product was
obtained in 91% yield (Table 1, entry 17). The yield enhancement
with increasing the amount of trimethylphosphine possibly because
either the extra phosphine activated the vinyl ketone16 or
trimethylphosphine was lost partially due to oxidation. However
too much phosphine may occupy all the coordination sites on
palladium and decreases the catalytic activity17 (Table 1, entry 18).
Subsequently, a broad range of substrates were examined with
this new palladium-catalyzed reaction in water and in acetone
(Table 2). It was shown that alkynes bearing silyl, alkenyl,
aromatic, aliphatic or halide all reacted smoothly with vinyl
ketone to afford good yields of the desired 1,4-addition products.
to conjugated enones has been developed in water and in
acetone, producing the corresponding c,d-alkynyl ketones in
high yields.
Within the past few decades, the development of palladium-
catalyzed C–C bond formation reactions has dramatically
advanced the ‘‘state-of-the-art’’ of organic synthesis.1 The well
known palladium catalyzed C–C bond formation reactions include
the Heck reaction,2 the Stille reaction,3 the Suzuki reaction,4 the
Trost–Tsuji reaction,5 the Sonogashira-coupling,6 to name a few.
On the other hand, an addition reaction is an atom-economical
way to construct more complex molecules from simpler units.7
Recently, increased interest has been shown in the addition of
terminal alkynes to those compounds that involve sp2 carbon, such
as CLO bonds8 or CLN bonds.9 However, only a few examples of
addition of terminal alkynes to CLC bonds have been reported.10
Furthermore, although palladium is one of the most used metals
from the periodic table in catalysis, palladium-catalyzed conjugated
addition of alkynes to enones has not been reported to the best of
our knowledge.11 We hypothesized that the failure could be
attributed to (1) either the facile homo- or heterodimerization of
terminal alkynes (a well-known, synthetically useful process)12 to
form by-products or (2) a lower reactivity of the alkynyl palladium
intermediate towards enones. Conceivably, such obstacles can be
overcome by tuning the electronic properties of the ligands to
coordinate with palladium. As part of a continued interest in
developing organic synthesis in water,13 herein we wish to report a
simple and highly efficient Pd-catalyzed addition of a terminal
alkyne to a CLC double bond such as a conjugated enone, either in
water or in acetone in air (Scheme 1).
Table 1 Addition of phenylacetylene to ethylvinylketone catalyzed by
various palladium catalysts in watera
In order to increase the reactivity of the alkynyl–palladium bond,
we plan to examine palladium catalysts with electron-rich ligands.14
The initial investigation started with the reaction of phenylacetylene
(RLPh) and ethyl vinyl ketone (R’LEt) in the presence of 5 mol% of
Pd(OAc)2 and 10 mol% of the common ligand PPh3 in water at
60 uC for 40 h. As expected, the reaction yielded only a tiny amount
of the desired product (Table 1, entry 1). Then we tested a more
electron-rich ligand, tris(4-methoxyphenyl)phosphine, and the yield
increased significantly to 27% (Table 1, entry 2). Encouraged by
this result, we tested other electron-rich ligands. PMe3, both an
electron-rich and a smaller size ligand, was the most effective for the
coupling, providing a 77% yield of the desired product (Table 1,
entry 5). Other palladium salts were also tested; the results showed
that the counter ion of the palladium salt also had an effect on the
reaction. With an electron-deficient trifluoroacetate as the counter
ion, the reaction was less effective (Table 1, entry 8). To examine
whether the phosphine ligand served as a base or a real ligand, we
also tested the catalyst system in the presence of inorganic base and
organic base. The Pd(OAc)2/PMe3 yielded less product in the
L/C Yield
ratio (%)
Entry Catalyst
1
Pd(OAc)2/PPh3
2
2
2
v10b
2
3
4
5
Pd(OAc)2/tris(4-methoxyphenyl)phosphine
Pd(OAc)2/tris(2,6-dimethoxyphenyl)phosphine
Pd(OAc)2/tris(2,4,6-trimethoxyphenyl)phosphine
Pd(OAc)2/PMe3
27
31
2
17
2
—
2
2
—
2
2
2
2
—
0
77
6
7
PdCl2(PPh3)2
PdCl2(PPh3)2/PMe3
v10b
v10b
v10b
N.Dc
32
8
9
Pd(O2CCF3)2/PMe3
Pd(0) (PPh3)4
Pd(0) (PPh3)4/PMe3
Pd(OAc)2/PMe3/Et3N(1 eq)
Pd(OAc)2/PMe3/NaOAc(1 eq)
Pd(OAc)2/trimethylphosphine oxide
PMe3
Pd(OAc)2
Pd(OAc)2/Et3N(1 eq)
Pd(OAc)2/PMe3
Pd(OAc)2/PMe3
10
11
12
13
14
15
16
17
18
v10b
43
v10b
N.Dc
15
0
4
v10b
91
6
86
a All reactions were carried out by using 1 mmol of an alkyne,
2 mmol of a vinyl ketone, 5 mol% of palladium catalyst and the
given amount of ligand in water at 60 uC for 40 h. b Measured by
1H NMR. c Not detected by 1H NMR.
Scheme 1
2 3 6 2
C h e m . C o m m u n . , 2 0 0 4 , 2 3 6 2 – 2 3 6 4
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 Addition of terminal alkyne to vinyl ketone catalyzed by
Pd(OAc)2/PMe3 in water and in acetonea
Terminal
EntryVinylketone alkyne
Product
isolated
Yield
(%)
Conditions
1
2
40 h/acetone
40 h/water
85
91
3
43 h/water
74
4
5
43 h/acetone
43 h/water
61
70
Scheme 2 Tentative mechanism for the palladium-catalyzed 1,4-addition of
terminal alkynes to conjugated enones.
6
7
42 h/acetone
42 h/water
70
67
solvent, the deuterated product was obtained in 52% yield with
more than 95% d-incorporation. No deuterium incorporation was
observed at any position when 7-phenyl-6-heptyn-3-one, a c,d-
ynone product, was reacted with D2O in D2O solvent.18
8
44 h/water
65
A tentative mechanism for the palladium-catalyzed 1,4-addition
of terminal alkynes to conjugated enones is illustrated in Scheme 2.
The g2-coordination of the triple bond to the palladium center
followed by direct deprotonation of the coordinated terminal
alkyne to palladium catalyst19 generated the alkynyl-palladium
intermediate. Then, g2-coordination of CLC double bond to the
palladium center followed by the carbopalladation,20 and a
substitution of Pd with hydrogen (either from the solvent or
terminal alkyne) to produce the c,d-ynone product with con-
comitant regeneration of the Pd catalyst (Scheme 2).
9
10
44 h/acetone
44 h/water
63
72
11b
12b
44 h/acetone
44 h/water
57
62
In conclusion, the first palladium-catalyzed 1,4-addition of
terminal alkynes to the CLC double bond of conjugated enones
was developed in water and in acetone, under an air atmosphere.
The corresponding c,d-alkynyl ketones were obtained in high
yields. The process is simple and can generate a wide range of
alkynyl ketones. The scope, mechanism, and synthetic application
of these novel catalytic properties of palladium are under
investigation.
13
14
42 h/acetone
42 h/water
51
56
15
45 h/water
58
We are grateful to NSF (No. 0207363) and NSF-EPA joint
program for a sustainable environment for support of our research.
16
17
43 h/acetone
43 h/water
49
52
Notes and references
18
45 h/water
53
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19
20
39 h/acetone
39 h/water
66
61
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alkyne, 2 mmol of a vinylketone, 5 mol% of Pd(OAc)2 and 20 mol%
of PMe3 at 60 uC in water or acetone. The product structures were
determined by comparison with known compounds in the literature
(see supplementary materials). b 1.0 mmol of terminal alkyne reacted
with 4 mmol of vinylketone.
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C h e m . C o m m u n . , 2 0 0 4 , 2 3 6 2 – 2 3 6 4
2 3 6 3

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deuterated product was determined by H NMR.
1
19 For previous examples involving direct deprotonation of terminal
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2 3 6 4
C h e m . C o m m u n . , 2 0 0 4 , 2 3 6 2 – 2 3 6 4