Expeditious enyne construction from alkynes via oxidative Pd(II)-catalyzed Heck-type coupling

Article abstract of DOI:10.1016/j.tetlet.2009.02.217

The enyne, ubiquitous in natural products, can be a challenge to generate since these moieties require many synthetic transformations to assemble them. We developed a simpler protocol to construct enynes while we found that this oxidative reaction was tolerant in substrate scope. In addition, the utility of this reaction was demonstrated through the attempt in synthesizing antifungal agent Lamisil.

Full text of DOI:10.1016/j.tetlet.2009.02.217

Tetrahedron Letters 50 (2009) 2370–2373
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expeditious enyne construction from alkynes via oxidative Pd(II)-catalyzed
Heck-type coupling
*
Victor Hadi, Kyung Soo Yoo, Min Jeong, Kyung Woon Jung
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The enyne, ubiquitous in natural products, can be a challenge to generate since these moieties require
many synthetic transformations to assemble them. We developed a simpler protocol to construct enynes
while we found that this oxidative reaction was tolerant in substrate scope. In addition, the utility of this
Received 26 January 2009
Revised 26 February 2009
Accepted 27 February 2009
Available online 5 March 2009
TM
reaction was demonstrated through the attempt in synthesizing antifungal agent Lamisil .
Ó 2009 Elsevier Ltd. All rights reserved.
The enyne moiety can be found in many natural products;1
therefore, it is crucial to develop a powerful methodology to
assemble enynes. Also, the enyne is a useful intermediate, because
it can be easily hydroxylated2 or converted to a diene, triene,3 or
furan;4 all of which are commonly present in natural products.
Although there have been numerous known protocols to construct
enynes in the presence of a palladium catalyst,5 these reactions can
be cumbersome since both coupling substrates need to be pre-
pared into reactive alkynes or halide olefins prior to coupling.
as well as high reaction temperatures and longer reaction times.
In order to mitigate these shortcomings, we wish to report a new
synthetic protocol to construct enyne compounds and offer an
TM
example of a synthetic application such as Lamisil :
OH
Pd(OAc)2
O
O
Pyridine
+
+
o
ð3Þ
ð4Þ
R'
R'
R'
R'
MS 3A, toluene
80 oC, O2 (1 atm)
R
R
R
up to 60 %
O
O
Pd(tfa)2
Especially, the reactions of acetylenes with
a,b-unsaturated ke-
H
tones have been barely reported. Recently, Schumacher6a (Eq. 1)
and Boukouvalas6b (Eq. 2) utilized Pd(II)-catalyzed coupling reac-
tion between terminal alkynes and activated olefins to obtain con-
jugated enynes.
K2CO3
DMF, O2, r.t.
R
up to 90 %
While extensively researching for carbon–carbon bond forma-
tion using oxidative palladium(II) catalysis, we found that the cou-
pling of commercially available terminal alkynes and olefins
produced enyne compounds under mild conditions (Eq. 4). Seeking
optimal conditions, we investigated the coupling of 4-ethynyltolu-
ene and tert-butyl acrylate using various bases, palladium cata-
lysts, solvents, and atmospheric conditions as shown in Table 1.
Although a Glasier-type homocoupling compound (3) was formed
as a side product through the condensation of two alkynes, this can
be circumvented by reacting with an excess of olefin to produce
enyne compound (2). Generally, bases are well known to be a piv-
otal component in palladium-catalyzed coupling reactions such as
the Miyaura–Suzuki and Sonogashira reactions. The bases in these
reactions were believed to facilitate transmetallation of the acety-
lene compound via formation of acetylide, resulting in the
enhancement of the coupling reactions. However, homocoupled
compound 3 was concomitantly formed due to the reactive acety-
lide intermediate. The use of organic bases, such as pyridine, tri-
ethyl amine, and diisopropylethyl amine promoted the formation
of homocoupled product 3, which lowers the selectivity 2/3 ratio
(entries 1–3). Due to a possible chelation with the palladium cata-
lyst, the reactions were incomplete when pyridine was used. It was
subsequently determined that inorganic bases led to a better ratio
R
Pd(OAc)2
PPh3
TsO
+
O
O
R
H
ð1Þ
ð2Þ
DMA, DMF, TEA
r.t.
77 ~ 94 %
R
Br
PdCl2(PPh3)2
CuI
iPr2NH
+
R
H
O
O
O
O
THF, r.t.
63 ~ 86 %
Utilization of terminal alkynes has been known for many years
as Glasier and Sonogashira7 coupling, however the sp variant of the
Heck reaction has not been fully investigated yet. In 2003, Uemura,
et al. reported palladium-catalyzed oxidative alkynylation of com-
mercially available olefins using tert-propargylic alcohols as alky-
nylation reagents under an oxygen atmosphere5b (Eq. 3).
However, the reaction required preparation of alkyne substrates,
* Corresponding author. Tel.: +1 213 740 8768; fax: +1 213 821 4096.
E-mail address: kwjung@usc.edu (K.W. Jung).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.217

V. Hadi et al. / Tetrahedron Letters 50 (2009) 2370–2373
2371
Table 1
Table 2, tert-butyl and ethyl acrylates were converted efficiently
to enyne compounds 2 and 4 in 50% and 41% yields, respectively
(entries 1 and 2). However, the reaction with methyl and ethyl vi-
nyl ketone afforded enyne compounds 5 and 6 in poor yields (en-
tries 3 and 4). In addition to these substrates, acrylamide, acrylic
acid, styrene, or acrylonitrile as the coupling partner could not give
the desired coupled products.
Evaluation of various reaction conditionsa
O
O
OtBu
Pd
2
OtBu
+
O2, base, r.t.
sovent, 4 h
2
1
3
Entry
Catalyst
Base
Solvent
Conv.b (%)
Selectivityb (2/3)
To further investigate the scope and limitation of this method-
ology, we carried out the cross-coupling of various aryl- and alkyl-
acetylenes with tert-butyl acrylate as summarized in Table 3. The
coupling reaction involving a straight chain alkyne, a hindered al-
kyne, and a cyclic alkyne proceeded to afford the corresponding
cross-coupling compounds 7, 8, and 9 in 72, 71, and 43% yields,
respectively (entries 1–3). In addition, the reactions of tert-butyl
acrylate with an aryl bearing an electron-donating group (methoxy
and dimethylamino) afforded compounds 10 and 11 in good yields
(entries 4–5). On the contrary, although the cross-coupling still oc-
curs when employing an aryl bearing an electron-deficient group
such as p-trifluoro methyl and p-nitrophenylacetylene, the yields
are low at 39% and 33% yields, respectively (entries 9 and 10).
We believe that the acidity of the terminal acetylenic proton plays
a role in the product composition. The compounds bearing less
acidic protons give better selectivity than more acidic substrates.
This can be explained by the fact that the increased acidity of cer-
tain substrates allows them to quickly react to form reactive palla-
dium-alkynyl intermediates, which then undergo a homo-coupling
process more easily. However, the less acidic substrates are not as
reactive, thus the formation of the palladium-alkynyl complexes is
much slower, and the complexes react more selectively with ole-
fins to generate the desired cross-coupling products. Overall, the
kinetic of the palladium intermediate governs the yields of the
enyne products.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17c
18d
19e
20f
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2dba3
PdCl2(PPh3)2
Pd(PPh3)2
None
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pyridine
TEA
DIPEA
Na2CO3
K2CO3
None
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DMA
DMSO
MeCN
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
37
100
100
100
100
12
0/100
32/68
34/66
55/45
57/43
23/77
—
50/50
0/100
26/74
31/69
22/78
25/75
—
0
100
100
88
66
100
100
0
0
100
62
51
39
100
—
67/33
47/53
50/50
53/47
70/30
a
All reactions were carried out with
1 (0.31 mmol) and tert-butyl acrylate
(1.24 mmol) in the presence of 2 mol % of Pd and base (0.62 mmol).
b
Calculated by GC analysis.
Under air condition.
Under N2 condition.
Under Ar condition.
c
d
e
f
10 equiv of tert-butyl acylate under O2 condition.
We believe that this reaction may be the first example of
coupling a terminal acetylene with an olefin, where a Heck type
mechanism may be involved. Based on a mechanism proposed
by Cheng, Martensson, and our previous research results,8 we
postulated that this coupling reaction undergoes process similar
to the sp2 counterparts (Scheme 2). The reaction can be initiated
by the formation of an alkynyl palladium complex II via base-as-
sisted deprotonation. The second incorporation of an alkenyl
group can be carried out by migratory insertion, which would
be followed by b-hydride elimination to produce cross-coupling
product IV and Pd(0) species. Molecular oxygen would then oxi-
of cross-coupling product 2 and homocoupled product 3 than or-
ganic bases (entries 4 and 5). Among the bases evaluated, K2CO3
was the best in the coupling reaction.
In addition, we demonstrated the coupling reactions in various
solvent systems. There was no observable cross-coupling reaction
when toluene was used (entry 7). In the cases of THF and acetoni-
trile, the reactions were incomplete; on the other hand, 4-ethynyl-
toluene was consumed in polar solvents such as DMF, DMA, and
DMSO. However, only in the DMF and DMA solvent systems was
the desired enyne product 2 obtained in modest yields.
a
peroxopalladium complex VI,9
On the basis of these results, we screened other reaction vari-
ants, such as atmosphere, sources of palladium, loading of catalyst,
and concentration to determine optimal conditions. Varying the
palladium source showed that palladium trifluoroacetate has bet-
ter selectivity to generate the cross-coupled product 2 (entry 16).
However, in the presence of Pd2dba3 and PdCl2(PPh3)2, coupling
reactions were converted mostly to homocoupled compound 3
(entries 12 and 13). We found that the reaction did not proceed
at all in the presence of Pd(PPh3)4 (entry 14). Under an air, nitro-
gen, or argon atmosphere, the conversion was not complete and
selectivity was lower (entries 17–19). Many efforts to minimize
the formation of the homocoupled product from the reaction of
acetylide were investigated, such as slow addition of acetylene
via a syringe pump and using large excess of olefins (>10 equiv);
however, none of these methods helped suppress formation of
the Glasier-type side product, which results in decreasing the over-
all yield of the cross-coupling product. Overall, although the homo-
coupling reaction of acetylide cannot be avoided under various
reaction conditions due to its high reactivity, we found that the
oxidative palladium-catalyzed coupling reactions between acey-
lide and olefin afforded (E)-selective enyne product in our protocol.
With optimized conditions in hand, we carried out the coupling
reaction with various olefins and 4-ethynyltoluene. As shown in
dize the resulting Pd(0) to
which can react with another alkyne compound to regenerate al-
kyne–Pd–L complex II. This reactive intermediate would react
with either the olefin or the alkyne. However, the stronger affin-
ity of alkynes is responsible for the formation of the homocou-
pled side product.
Table 2
The effect of various olefin with 4-ethynyltoluenea
O
Olefin (8 eq.)
R
Pd(TFA)2
O2, K2CO3, r.t.
DMF, 4 h
Entry
Olefin
Product (yield)b
1
2
3
4
R:OtBu
OEt
Me
2 (50%)
4 (41%)
5 (45%)
6 (25%)
O
R
Et
a
All reactions were carried out with 4-ethynyltoluene (0.31 mmol), olefin
(3.1 mmol), Pd(TFA)2 (2 mol %), and K2CO3 (0.62 mmol) in DMF (1.5 mL).
b
Isolated yields.

2372
V. Hadi et al. / Tetrahedron Letters 50 (2009) 2370–2373
Table 3
O
The effect of various alkynes with tert-butyl acrylatea
R
R'
Alkyne
Pd(TFA)2
O
IV
L
Pd
O
O
Ot Bu
O2, K2CO3, r.t.
DMF, 4 h
Ot Bu
R
R'
L
Pd
V
H
R
III
R'
Entry
1
Alkyne
Productb (yield)
O
LH
7 (72%)
8 (71%)
PdL2
R
Pd L
R
H
Pd(0)
O2
II
I
B:
B-LH
H2O+1/2O2
2
3
LH
Pd OOH
9 (43%)
O
R
Pd
VII
O
VI
4
5
10 (92%)
R
H
(Me)2N
Scheme 2. Plausible mechanism pathway.
11 (67%)
2 (50%)
obtained from tert-butylacetylene (17) and acrolein by an oxida-
tive Pd(II)-catalyzed coupling reaction. The reductive amination
of enyne compound 18 with 1-naphthylmethylamine afforded
allylic amine compound 19. Finally, methylation of the secondary
amine will produce the target antifungal drug.
O
6
Therefore, we have demonstrated a simple protocol to synthesize
an enyne from commercially available substrates utilizing an oxida-
tive palladium Heck coupling reaction under simple and mild condi-
tions. The substrate limitation was explored; and it was determined
that there are no limitations for the alkynyl coupling partner; how-
7
12 (48%)
13 (45%)
14 (39%)
15 (33%)
16 (37%)
8
TM
ever, limitations are found for the olefin. Lamisil was also synthe-
sized to show the utility of this oxidative Heck reaction.
F
Typical procedure for the coupling reaction: To a pre-weighed
oven-dried vial equipped with magnetic stir bar were placed anhy-
drous K2CO3 (0.62 mmol) and DMF (1.5 mL). Then, alkyne
(0.31 mmol) and olefin (3.1 mmol) were added simultaneously,
followed by Pd(TFA)2 (2 mol %). Immediately, the vial was capped
with a balloon filled with oxygen. Within 1 min, immediate color
change of the reaction mixture was observed. After 4 h, the mix-
ture was quenched with addition of water (3 mL) and extracted
with hexanes (3 ꢀ 5 mL). The organic layer was dried over anhy-
drous MgSO4, and the solvent was evaporated to afford a crude
mixture, which was purified by silica gel chromatography (2% ethyl
acetate in hexanes) to afford the cross-coupled products.
9
F3C
O2N
10
11
a
All reactions were carried out with alkyne (0.31 mmol), tert-butyl acrylate
(2.5 mmol), Pd(TFA)2 (2 mol %), and K2CO3 (0.62 mmol) in DMF (1.5 mL).
b
Isolated yields.
Acknowledgments
O
We acknowledge generous financial supports from the National
Institute of General Medical Sciences of the National Institutes of
Health (RO1 GM 71495) as well as Loker Hydrocarbon Research
Institute. We also thanked T.J. Williams for allowing to use GC/
MS instrument.
O
H
H2N
NaBH4
MeOH
41% for two stpes
H
Pd(OAc)2
K2CO3
DMF, O 2
65%
18
17
References and notes
CH3I
N
N
H
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LamisilTM
TM
Scheme 1. Synthesis of Lamisil .
Finally, we applied this methodology to the synthesis of Terbi-
TM
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V. Hadi et al. / Tetrahedron Letters 50 (2009) 2370–2373
2373
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