Regio- and stereoselective dimerization of terminal alkynes to enynes catalyzed by a palladium/imidazolium system

Article abstract of DOI:10.1021/jo010837s

A Palladium/imidazolium chloride system has been used to mediate the dimerization of terminal alkynes to enynes. The combination of 1 mol % Pd(OAc)₂ and 2 mol % IMes·HCl in the presence of Cs₂CO₃ as base shows high activit

Full text of DOI:10.1021/jo010837s

J . Org. Chem. 2002, 67, 591-593
591
Tamao-Corriu coupling reaction,6 various Heck-type
coupling reactions,7 amination of aryl chlorides,8 olefin
metathesis,9 and hydrogenation.10 Most recently, Her-
rmann has reported a palladium complex with mixed
carbene/phosphine ligand showing catalytic activity in
the dimerization of phenylacetylene.11 We wish to now
report a regio- and stereoselective dimerization of ter-
minal alkynes catalyzed by a palladium/imidazolium salt
system.
Regio- a n d Ster eoselective Dim er iza tion of
Ter m in a l Alk yn es to En yn es Ca ta lyzed by a
P a lla d iu m /Im id a zoliu m System
Chuluo Yang and Steven P. Nolan*
Department of Chemistry, University of New Orleans,
New Orleans, Louisiana 70148
snolan@uno.edu
We have established that active Pd-carbene species
can be formed in situ from a palladium precursor with
an imidazolium salt in various C-C coupling reactions
under basic conditions.5b,c,6 In initial experiments, a
catalytic system consisting of 1 mol % Pd(OAc)2 and 2
mol % IMes‚HCl with 2 equiv of Cs2CO3 as base in N,N-
dimethylacetamide (DMAc) at 80 °C was tested for
catalytic activity in the dimerization of 1-heptyne (eq 1).
The reaction reached completion in 2 h. The product
ratio of trans- and cis-1,4-disubstituted enyne (I and II)
and 1,3-disubstituted enyne (III) is 90:3:7, showing high
regio- and stereoselectivity. The stereostructure was
determined by the coupling constant between two vinyl
protons (J ) 16.0 Hz) for trans-enyne compared to cis-
enyne (J ) 11.8 Hz).
Received August 16, 2001
Abstr a ct: A Palladium/imidazolium chloride system has
been used to mediate the dimerization of terminal alkynes
to enynes. The combination of 1 mol % Pd(OAc)2 and 2 mol
% IMes‚HCl in the presence of Cs2CO3 as base shows high
activity and high regio- and steroselectivity for the dimer-
ization of aryl and aliphatic terminal alkynes to enynes.
Transition metal-catalyzed dimerization of terminal
alkynes is an attractive method for the synthesis of
enynes.1 It has found increasing application in the
construction of key structural moieties in natural prod-
ucts and electronic and optical materials.2 Usually, the
dimeric products include 1,3-disubstituted enynes from
the head-to-tail dimerization of alkynes and 1,4-disub-
stituted enynes from the head-to-head dimerization of
alkynes. High regio- and stereoselectivity has been the
continued emphasis in the area of alkyne dimerization.
Recently, some palladium-phosphine systems have dis-
played high activity and selectivity in the conversion of
alkynes into enynes.3
Nucleophilic N-heterocyclic carbenes have attracted
considerable attention as “phosphine mimics”.4 High
catalytic performances have been achieved by using
nucleophilic carbenes in various catalytic reactions such
as the Suzuki-Miyaura coupling reaction,5 the Kumada-
In optimization studies, 1-heptyne was used as the
model substrate. A survey of solvents for this system
showed nearly complete dimerization and similar product
distribution in a variety of solvents. Acetonitrile did not
appear to be a compatible solvent, presumably in view
of its coordinating nature (Table 1). The reaction rates
(1) (a) Straub, T.; Haskel, A.; Eisen, M. S. J . Am. Chem. Soc. 1995,
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Wiley & Sons: Chichester, U.K., 1985; Vol.3.
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9890.
(7) (a) Yang, C.; Lee, H. M.; Nolan, S. P. Org. Lett. 2001, 3, 1511-
1514. (b) Yang, C.; Nolan, S. P. Synlett. 2001, 1539-1542. (c) McGuin-
ness, D. S.; Cavell, K. J . Organometallics 1999, 18, 1596-1605. (d)
Herrmann, W. A.; Fischer, J .; Elison, M.; Ko¨cher, C.; Artus, G. R. J .
Chem. Eur. J . 1996, 2, 772-780. (e) Herrmann, W. A.; Elison, M.;
Fischer, J .; Ko¨cher, C.; Artus, G. R. J . Angew. Chem., Int. Ed. Engl.
1995, 34, 2371-2373.
(3) (a) Lu¨cking, U.; Pfaltz, A. Synlett. 2000, 1261-1264. (b) Trost,
B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ru¨ther, G. J . Am. Chem.
Soc. 1997, 119, 698-708 and references therein. (c) Trost, B. M.; Chan,
C.; Ru¨ther, G. J . Am. Chem. Soc. 1987, 109, 3486-3487.
(4) (a) Bourissou, D.; Guerret, O.; Gabba¨ı, F. P.; Bertrand, G. Chem.
Rev. 2000, 100, 39-91 and references therein. (b) Chatterjee, A. K.;
Grubbs, R. H. Org. Lett. 2000, 2, 1751-1753. (c) J afarpour, L.; Schanz,
H. J .; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 5416-
5419. (d) Dullius, J . E. L.; Suarez, P. A. Z.; Einloft, S.; de Souza, R. F.;
Dupont, J .; Fischer, J .; De Cian, A. Organometallics 1998, 17, 815-
819. (e) Aduengo, A. J ., III; Krafczyk, R. Chem. Z. 1998, 32, 6-14. (f)
Herrmann, W. A.; Ko¨cher, C. Angew. Chem., Int. Ed. Engl. 1997, 36,
2162-2187. (g) Regitz, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 725-
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10.1021/jo010837s CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/28/2001

592 J . Org. Chem., Vol. 67, No. 2, 2002
Notes
Ta ble 1. Effect of th e Solven t on P d (OAc)2/
Ta ble 3. Dim er iza tion of 1-Hep tyn e Usin g P d (OAc)2 w ith
Differ en t Im id a zoliu m Ch lor id esa
IMes‚HCl-Ca ta lyzed Dim er iza tion of 1-Hep tyn ea
entry
L.HCl
none
product ratiob I:II:III
yield (%)c
entry
solvent
product ratiob I:II:III
yield (%)c
1
2
3
4
5
6
7
8
39:15:46
40:0:60
47:6:47
90:3:7
88:1:11
47:3:50
92:1:7
27d
34
34
97
76
45
88
14
1
2
3
4
5
THF
87:2:11
90:2:8
91:0:9
90:3:7
90:3:7
95
95
45
94
97
ICy (1)
dioxane
CH3CN
DMF
ITol (2)
IMes (3)
IPr (4)
IAd (5)
SIMes (6)
SIPr (7)
DMAc
a
Reaction conditions: 1.0 mmol of 1-heptyne, 2 mL of solvent.
Determined by GC. c GC yields based on 1-heptyne (an average
b
54:10:36
of two runs).
a
Reaction conditions: 1.0 mmol of 1-heptyne, 2 mL of DMAc.
Determined by GC. c GC yields based on 1-heptyne (an average
of two runs). Reaction time 6 h.
b
Ta ble 2. Effect of th e Ba se on P d (OAc)2/
IMes‚HCl-Ca ta lyzed Dim er iza tion of 1-Hep tyn ea
d
Ta ble 4. Dim er iza tion of Ter m in a l Alk yn es to En yn es
entry
base
product ratiob I:II:III
yield (%)c
Ca ta lyzed by th e P d (OAc)2/IMes‚HCl/Cs2CO3 System a
1
2
3
4
5
6
none
20:8:72
17d
0
0
31
92
97
NaOMe
KOtBu
NaOAc
K2CO3
Cs2CO3
11:2:87
11:1:89
90:3:7
a
Reaction conditions: 1.0 mmol of 1-heptyne, 2 mL of DMAc.
Determined by GC. c GC yields based on 1-heptyne (an average
of two runs). Reaction time 6 h.
b
d
Sch em e 1. Str u ctu r es of Im id a zoliu m Sa lts
also proved to be significantly influenced by the identity
of the base used in the reaction (Table 2). High activity
and regio- and stereoselectivity could be achieved with
Cs2CO3 as the base. In this case, trans-1,4-disubstituted
enyne was the predominant product. Surprisingly, em-
ploying K2CO3 as base resulted in a high yield and
dramatically influenced the product distribution with 1,3-
disubstituted enyne being the dominant product. Strong
bases such as NaOMe and KOtBu did not show any
activity in this system.
In an effort to select the most effective imidazolium
salts, a series of 1,3-disubstituted imidazolium chlorides
(Scheme 1) with different electronic and steric properties
were used in the model reaction (Table 3). Use of IMes
(3), SIMes (6), and IPr (4) led to highly efficient, regio-
and stereoselective dimerization with trans-1,4-disubsti-
tuted enyne as the major product. Other imidazolium
salts showed lower reactivity and regioselectivity.
a
Reaction conditions: 1.0 mmol of alkyne, 2 mL of DMAc.
Determined by GC. c GC yields based on alkyne are an average
of two runs (numbers in parentheses are isolated yields). 0.5 mol
% Pd(OAc)2, 1 mol % IMes‚HCl. e Reaction time 0.5 h. f 1 mol %
Pd(dba)2 as Pd source.
b
d
Under optimized conditions (1 mol % Pd(OAc)2, 2 mol
% IMes‚HCl, 2 equiv of Cs2CO3, DMAc, 80 °C), excellent
yields of regio- and stereocontrolled dimeric products
could be obtained from a wide array of terminal alkynes
in a short time (Table 4). For aryl terminal alkynes,
complete conversion to 1,4-disubstituted enynes could be
achieved in 0.5 h (entries 1, 2). For aliphatic terminal
alkynes, reactions reached near completion in 2 h with
the 1,4-disubstituted enynes being the predominant
product (entries 3-6, 8-10). The length of the aliphatic
chain did not affect the reactivity and selectivity. Steri-
cally demanding substrates favored the formation of 1,4-
disubstituted products via head-to-head dimerization
(entries 1, 2, 5, 8). The dimerization in a head-to-head
mode is reasonable in view of steric requirements associ-
(11) Herrmann, W. A.; Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.;
Grosche, M.; Reisinger, C.-P.; Weskamp, T. J . Organomet. Chem. 2001,
617-618, 616-628.

Notes
J . Org. Chem., Vol. 67, No. 2, 2002 593
Ta ble 5. Dim er iza tion of Ter m in a l Alk yn es to En yn es
observation that we are presently exploring. Using Cs2-
CO3 as base, trans-1,4-disubstituted enynes, from the
head-to-head dimerization, are the predominant prod-
ucts. Replacement of Cs2CO3 with K2CO3 results in a
significant increase of 1,3-disubstituted enynes from the
head-to-tail dimerization. For less hindered alkynes, the
1,3-disubstituted enynes become the dominant product.
In both cases (Cs2CO3 or K2CO3 as base), sterically
demanding substrates prefer to form 1,4-disubstituted
products. The catalytic system also shows excellent
stereoselectivity with trans-enynes being the almost
exclusive product over cis-enynes. The Pd complexes
usually dimerize terminal alkynes to branched enynes,3
while, in this work, the Pd/imidazolium system provide
linear enynes as predominant products. Elaboration of
this methodology and investigation of other catalytic
applications using nucleophilic carbenes, as ligands, are
ongoing.
Ca ta lyzed by th e P d (OAc)2/IMes‚HCl/K2CO3 System a
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All terminal alkynes (Aldrich),
Pd(dba)2 (Strem), Pd(OAc)2 (Strem), and N,N-dimethylacetamide
(Aldrich, anhydrous) were used as received. Flash chromatog-
raphy was performed on silica gel 60 (230-400 mesh) (Natland
International Corp.). Imidazolium salts L‚HCl (L ) ICy (1), ITol
(2), IMes (3), IPr (4), IAd (5), SIMes (6), and SIPr (7)) were
synthesized according to the literature procedure.12,13 1H NMR
spectra were recorded using a Varian 400 MHz spectrometer.
GC analyses were performed on an Agilent 6890 GC spectrom-
eter with an FID detector and an HP-5 column. GC-MS analyses
were performed on a MicroMass AutoSpec instrument.
a
Reaction conditions: 1.0 mmol of alkyne, 2 mL of DMAc.
Determined by GC. c GC yields based on alkyne (an average of
two runs). Reaction time 1 h.
b
d
ated with congested terminal alkynes. It is noteworthy
that the catalytic system shows excellent stereoselectivity
with the trans-enynes being the dominant product over
cis-enynes (only 1-6%). Substitution of Pd(OAc)2 with
Pd(dba)2 led to a significant decrease in reactivity but
still high regio- and stereoselectivity (entry 7).
To investigate the scope of the opposite regio-selectivity
when using K2CO3 as base, we tested the generality of
this observation on a series of terminal alkynes (Table
5). In these experiments, good to excellent yields were
obtained. For less hindered substrates, the 1,3-disubsti-
tuted enynes via a head-to-tail dimerization are the
prevailing products (entries 3, 4, 6, 7, 8). For more
congested substrates, the 1,4-disubstituted enynes formed
by a head-to-head dimerization are the major products
(entries 1, 2). The highly hindered substrate tert-butyl-
acetylene suffered from low reactivity and low regio-
selectivity (entry 5). However the ratio of 1,3-disubsti-
tuted enynes obviously increased compared to the case
when Cs2CO3 was used as base.
Most recently, Trost has reported a palladium-cata-
lyzed highly regio- and stereoselective cross-dimerization
of terminal alkynes and internal alkynes.3b,c We also
attempted to apply the optimized protocol effective to self-
dimerization to cross-dimerization. Preliminary results
showed that the self-dimerization products were still
major products.
In summary, a Pd/imidazolium salt system has been
successfully applied to the dimerization of terminal
alkynes. Pd(OAc)2/IMes‚HCl has been shown to be a
highly efficient and regio- and stereoselective catalytic
system in the dimerization of a variety of aryl and
aliphatic terminal alkynes. The role of the base in
controlling product distribution represents an interesting
Ca ta lytic Dim er iza tion Rea ction s. In a typical catalytic
run, a scintillation vial equipped with a cap and a septum was
charged with Pd(OAc)2 (0.01 mmol), IMes·HCl (0.02 mmol), Cs2-
CO3 (2.0 mmol), and 2.0 mL of N,N-dimethylacetamide in a
glovebox. The mixture was stirred for 10 min. Then 1.0 mmol of
alkynes was added to the vial. The reaction mixture was allowed
to stir in an oil bath at 80 °C. The product yields were monitored
and determined by GC analyses. The product distribution was
determined by GC and confirmed by 1H NMR. The workup
procedure was as follows: 30 mL of water was added to the
reaction mixture, followed by extraction with diethyl ether. The
combined organic layer was dried over MgSO4 and filtered, and
ether was evaporated to give a crude product. The pure product
was obtained by flash chromatography (eluent: hexane). The
1
product identity was confirmed by GC-MS and H NMR as well
as by comparison with literature data.
Ack n ow led gm en t. The National Science Founda-
tion, the Louisiana Board of Regents, and the Petroleum
Research Fund, administered by the American Chemi-
cal Society, are gratefully acknowledged for support of
this research.
Su p p or tin g In for m a tion Ava ila ble: Text providing ex-
perimental procedures, details of reaction conditions, and 1H
NMR spectroscopic data for the dimerization products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O010837S
(12) Arduengo, A. J ., III. U.S. Patent 5 077 414, 1991.
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