Facile and selective copper-palladium catalyzed addition of terminal alkynes to activated alkynes in water

Article abstract of DOI:10.1016/j.tetlet.2004.02.038

The combination of palladium and copper catalyzes the addition of terminal alkynes to electron-deficient alkynes selectively and effectively in water without the competition of terminal alkynes' homo-coupling.

Full text of DOI:10.1016/j.tetlet.2004.02.038

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2771–2774
Facile and selective copper–palladium catalyzed addition of
terminal alkynes to activated alkynes in water
Liang Chena and Chao-Jun Lia,b,
*
aDepartment of Chemistry, Tulane University, New Orleans, LA 70118, USA
bDepartment of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, Canada H3A 2K6
Received 17 December 2003; revised 8 February2004; accepted 9 February2004
Abstract—The combination of palladium and copper catalyzes the addition of terminal alkynes to electron-deficient alkynes
selectivelyand effectivelyin water without the competition of terminal alkynes Õ homo-coupling.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Addition reaction is an atom economical wayto con-
struct more complex structures from simpler units.1
Recently, increased interest has been shown on the
addition reaction of terminal alkynes. Most of these
studies are related to the terminal alkynesÕ addition to
compounds that involve sp2 carbon, such as a,b-unsat-
urated carbonyl compound,2 aldehydes,3 imines,4 nit-
rones.5 On the other hand, onlya veryfew examples on
the selective addition of terminal alkynes to internal
alkynes involving sp carbon have been reported,6 pos-
siblydue to the facile competition of the homo-coupling
or dimerization of the terminal alkynes.7 Trost et al.
discovered that a catalytic amount of Pd(OAc)2 and
triphenylphosphine in dichloroethane resulted in high
yield of homo-coupling of terminal alkynes.8 For cross-
coupling of terminal alkynes to activated alkyne, a
palladium catalyst involving an electron rich ligand
tris(2,6-dimethoxyphenyl)phosphine (TDMPP) and an
inert atmosphere are essential.8 Since the conjugated
enynes are found to be important building blocks and
essential units in a varietyof biologicallyactive com-
pounds,9 herein we wish to report a facile and simple
method to generate conjugated enynes by using a com-
bination of Cu/Pd together with common ligand, PPh3,
in water and under an air atmosphere (Scheme 1).10 It is
noteworthy that this simple catalytic system was able to
catalyze only the cross-addition of terminal alkyne to
5 mol% CuBr/
R'
EWG
2.5 mol% PdCl2(PPh3)2
+
R'
EWG
R
water/60oC or r.t.
R
Scheme 1.
electron-deficient internal alkynes but not the homo-
coupling or dimerization of the terminal alkyne.
As the salts of group 11 element are highlyeffective in
forming acetylide from terminal acetylene,11 we planed
Table 1. Catalysts optimization for the addition of phenylacetylene to
4-phenyl-3-butyn-2-one in water
EntryCatsatly
Time (h),
temperature: rt
Yield (%)
1
CuCN/PdCl2(PPh3)2
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
15
21
<10a
2
CuCl/PdCl2(PPh3)2
CuSO4/PdCl2(PPh3)2
CuBr/PdCl2(PPh3)2
CuI/PdCl2(PPh3)2
AuBr3/PdCl2(PPh3)2
AuCl/PdCl2(PPh3)2
AgBr/PdCl2(PPh3)2
AgNO3/PdCl2(PPh3)2
AgCl/PdCl2(PPh3)2
CuBr
3
4
63
5
48
6
NDb
<10a
<10a
NDb
<10a
NDb
<10a
46
7
8
9
10
11
12
13
14
15
PdCl2(PPh3)2
Pd(OAc)2/PPh3/CuBr
Pd(OAc)2/TDMPP/CuBr
Pd(OAc)2/TDMPP
<10a
Keywords: Palladium–copper catalysis; Water; Alkyne–alkyne
coupling; Enyne.
31
a Determined by 1H NMR.
b Not detected.
* Corresponding author. Tel.: +1-504-398-8457; fax: +1-504-398-3797;
e-mail addresses: cjli@tulane.edu; cj.li@mcgill.ca
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.038

2772
L. Chen, C.-J. Li / Tetrahedron Letters 45 (2004) 2771–2774
Table 2. Addition of terminal alkynes to acceptor alkynes using CuBr/PdCl2(PPh3)2 co-catalyst in water and in toluenea;b
Entry
Terminal alkyne
Activated alkyne
Conditions
Product
Yield (%)
Ph
1
2
3
48 h/rt/water
48 h/rt/toluene
24 h/60 ꢁC/toluene
63
<10c
65
COCH3
Ph
Ph
COCH3
Ph
Ph
Ph
4
5
42 h/rt/water
24 h/60 ꢁC/toluene
75
55
Ph
Ph
CO2CH3
CO2CH3
CO2CH3
Ph
Ph
6
7
24 h/60 ꢁC/water
24 h/60 ꢁC/toluene
62
––
CO2CH3
Ph
Ph
CO2CH3
8
24 h/60 ꢁC
30 h/60 ꢁC
30 h/60 ꢁC
56
86
88
Ph
Ph
CO2CH3
CO2CH3
CO2CH3
COCH3
9
CO2CH3
10
Ph
CO2CH3
Ph
CO2CH3
11
12
28 h/60 ꢁC
38 h/60 ꢁC
74
78
Cl
Cl
Cl
Cl
CO2CH3
CO2CH3
CH3
CO2
13
14
25 h/60 ꢁC
40 h/60 ꢁC
48
54
CO2CH3
CO2CH3
CO2CH3
Me3Si
Me3Si
a The reaction was conducted using 2 mmol of terminal alkyne, 1 mmol internal alkynes, 5 mol % CuBr, and 2.5 mol % PdCl2(PPh3)2 in water or
toluene at room temperature or 60 ꢁC.
b Absolute configuration of the products was established bycorrelation with known compounds.
c Determined byNMR.
to use copper, silver, and gold salts to generate acetylide
species and palladium to catalyze the addition. This
would allow us to avoid using drastic catalysts that both
activate the C–H bond and catalyze the addition reac-
tion, which could also lead to the competing dimeriza-
tion and homo-coupling.
entry4). When CuBr alone was used as the catalyst, no
desired product was detected (Table 1, entry11),
whereas with PdCl2(PPh3)2 alone, onlya small amount
of the product (Table 1, entry12) was observed. The
reason for the lack of catalytic activity with either one
alone is possiblythat PdCl (PPh3)2 is not as effective as
2
Cu(I) to form acetylide species or to activate the C–H
bond of terminal alkynes; on the other hand, the Cu(I)
is not as good as Pd(II) to catalyze the addition reac-
tion.12 Finally, we tested the phenylacetylenesÕ homo-
coupling reaction using catalyst CuBr/PdCl2(PPh3)2, no
noticeable reaction was observed. Without the co-cata-
lyst, ligand TDMPP appeared more effective than PPh3
(Table 1, entries 12 and 15). With the co-catalyst, the
Pd(II)/TMDPP/CuBr system generated more unde-
sired by-product (Table 1, entry 14). Reaction of
Toward such a goal, a mixture of phenylacetylene
(R ¼ Ph)
and
4-phenyl-3-butyn-2-one
(R0 ¼ Ph,
R00 ¼ COCH3) was treated with Cu/Pd, Ag/Pd, and Au/
Pd catalytic system in water at room temperature. As
shown in Table 1, Cu/Pd (Table 1, entries 1–5) system
provides better results than both Au/Pd (Table 1, entries
6 and 7), and Ag/Pd (Table 1, entries 8–10) systems.
Among the Cu/Pd catalysts being tested, the CuBr/
PdCl2(PPh3)2 achieved the best yield of 63% (Table 1,

L. Chen, C.-J. Li / Tetrahedron Letters 45 (2004) 2771–2774
2773
electron-deficient terminal alkyne, such as ethyl propi-
olate, with an internal alkyne methyl 2-butynoate was
also examined but it did not generate the desired prod-
uct under the same reactions conditions.
2.5 mol %) in 1 mL water was stirred at room tempera-
ture or 60 ꢁC. After the starting material was consumed
as monitored byTLC, the reaction mixture was
extracted with ethyl ether (3 · 10 mL). The combined
organic phase was dried byanhydrous sodium sulfate
and concentrated in vacuo. The residue was purified by
column chromatography(hexane–ethly acetate ¼ 10:1)
to give the pure product.
Subsequently, the terminal alkynes were extended from
aromatic alkynes (Table 2, entries 1–7) to conjugated
alkynes (Table 2, entries 8 and 9), aliphatic alkynes
(Table 2, entries 11–13) and triethylsilylacetylene (Table
2, entry14) and the activated alkynes were extended
from ketone (Table 2, entries 1–3 and 8) to ester (Table
2, entries 4–7 and 9–14), from aromatic substituted
alkynes (Table 2, entries 1–5, 8, 9 and 11) to aliphatic
substituted alkynes (Table 2, entries 6, 7, 10 and 12–14).
As shown in Table 2, the yields are from good to
excellent. Toluene was also examined as solvent, how-
ever, it resulted in much lower reactivityin the reactions
(Table 2, entries 1–7), possiblybecause water lowers the
energyof the transition state. A tentative mechanism is
proposed, which involves the activation of C–H bond by
Cu(I) to form the copper acetylide; transmetalation
between the copper intermediate with palladium gener-
ates palladium acetylide, which undergoes addition to
activated alkynes (Scheme 2).
Acknowledgements
We are grateful to NSF and NSF-EPA Joint Program
for a Sustainable Environment for partial support of our
research.
References and notes
1. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259;
Trost, B. M. Science 1991, 254, 1471.
2. Knopfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003,
125, 6054–6055.
3. Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002,
4, 2605–2606; Sasaki, H.; Boyall, D.; Carreira, E. M. Helv.
Chim. Acta 2001, 84, 964–971; Anand, N. K.; Carreira, E.
M. J. Am. Chem. Soc. 2001, 123, 9687–9688; Frantz, D.
E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806–1807.
4. Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
10778–10779; Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003,
125, 9584–9585; Li, C.-J.; Wei, C. Chem. Commun. 2002,
268–269; Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124,
5638–5639; Zhang, J.; Wei, C.; Li, C.-J. Tetrahedron Lett.
2002, 43, 5731–5733; Wei, C. M.; Li, Z. G.; Li, C. J. Org.
Lett. 2003, 5, 4473–4475; Fischer, C.; Carreira, E. M. Org.
Lett. 2001, 3, 4319–4321.
5. Patel, S. K.; Py, S.; Pandya, S. U.; Chavant, P. Y.; Vallee,
Y. Tetrahedron: Asymmetry 2003, 14, 525–528; Fassler,
R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew.
Chem., Int. Ed. 2002, 41, 3054–3056; Frantz, D. E.;
Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121,
11245–11246.
In conclusion, we have described a facile method for the
synthesis of conjugated enynes from terminal alkynes
and electron-deficient alkynes. The noteworthy feature
of the reaction process includes: (1) the catalyst system is
effective enough to catalyze the desired reaction but does
not catalyze the undesired competition reaction; (2) the
catalysts are common, inexpensive, and commercially
available; (3) the reactions run well in water and
importantly, it is actually better than toluene solvent in
the reaction process; (4) the reaction procedure is easyto
execute. The scope, mechanism, and synthetic applica-
tion of this reaction in water are under investigation.
A general experimental procedure. A mixture of terminal
alkyne (1 mmol), acceptor alkyne (0.5 mmol), CuBr
(4.5 mg, 5 mol %), and Pd(II)Cl2(PPh3)2 (9.3 mg,
6. Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.;
Ruhter, G. J. Am. Chem. Soc. 1997, 119, 698–708; Trost,
B. M.; Harms, A. E. Tetrahedron Lett. 1996, 37, 3971–
3974; Trost, B. M.; Chan, C.; Ruhter, G. J. Am. Chem.
Soc. 1987, 109, 3486–3487; Trost, B. M.; Li, C. J. Synthesis
1994, 1267.
R'
EWG
R'
EWG
L
Pd
R
X
Pd
L
R
X
-L
L
7. Melis, K.; Opstal, T.; Verpoort, F. Eur. J. Org. Chem. 2002,
3779–3784; Melis, K.; Vos, D. D.; Jacobs, P.; Verpoort, F.
J. Organomet. Chem. 2002, 659, 159–164; Dash, A. K.;
Eisen, M. S. Org. Lett. 2000, 2, 737–740; Trost, B. M.;
Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G. J. Am.
Chem. Soc. 1997, 119, 698–708; Evans, W. J.; Keyer, R. A.;
R
CuX
+L
R
Cu
HX
€
Ziller, J. W. Organometallics 1993, 12, 2618; Schafer, M.;
R'
EWG
Mahr, N.; Wolf, J.; Werner, H. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1315; Horton, A. D. J. Chem. Soc., Chem.
Commun. 1992, 185; Wakatsuki, Y.; Yamazaki, H.;
Kumegawa, N.; Satoh, T.; Satoh, J. Y. J. Am. Chem.
Soc. 1991, 113, 9604; Bianchini, C.; Peruzzini, M.; Zano-
bini, F.; Frediani, P.; Albinati, A. J. Am. Chem. Soc. 1991,
113, 5453; Heeres, H. J.; Teuben, J. H. Organometallics
1991, 10, 1980; Ohshita, J.; Furumori, K.; Matsuguchi, A.;
Ishikawa, M. J. Org. Chem. 1990, 55, 3277; Thompson, M.
E.; Baxter, S. M.; Bulls, A. R.; Burger, B. J.; Nolan, M. C.;
L
Pd
L
L
X
X
Pd
L
X
R'
EWG
R
R
Scheme 2. Tentative mechanism for the addition reaction.

2774
L. Chen, C.-J. Li / Tetrahedron Letters 45 (2004) 2771–2774
Santarsiero, B. D.; Schaefer, W. P.; Bercaw, J. E. J. Am.
2003, 5, 3057–3060; Kamijo, S.; Jin, T.; Huo, Z.;
Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786–7787;
Chowdhury, C.; Kundu, N. G. Tetrahedron 1999, 55,
7011–7016; Kuro, K.; Furuune, M.; Enna, M.; Miura, M.;
Nomura, M. J. Org. Chem. 1993, 58, 4716–4721; Castro,
C. E.; Havlin, R.; Honwad, V. K.; Malte, A. M.; Moje, S.
W. J. Am. Chem. Soc. 1969, 91, 6464–6470; (Ag) Tao,
Y.-T.; Pandian, K. Polym. Prepr. 1999, 40, 500; Lewandos,
G. S.; Maki, J. W.; Ginnebaugh, J. P. Organometallics
1982, 1, 1700–1705; Ginnebaugh, J. P.; Maki, J. W.;
Lewandos, G. S. J. Organomet. Chem. 1980, 190, 403–416;
Agawa, T.; Miller, S. I. J. Am. Chem. Soc. 1961, 83, 449–
453; Davis, R. B.; Scheiber, D. H. J. Am. Chem. Soc. 1956,
78, 1675–1678; (Au) Wei, C.; Li, C.-J. J. Am. Chem. Soc.
2003, 125, 9584–9585.
Chem. Soc. 1987, 109, 203; Akita, M.; Yasuda, H.;
Nakamura, A. Bull. Chem. Soc. Jpn. 1984, 57, 480;
Hagihara, N.; Tamura, M.; Yamazaki, H.; Fujiwara, M.
Bull. Chem. Soc. Jpn. 1961, 34, 892; Singer, H.; Wilkinson,
G. J. Chem. Soc. A 1968, 849; Colthup, E. C.; Meriwether,
L. S. J. Org. Chem. 1962, 27, 3930; Meriwether, L. S.;
Colthup, E. C.; Kennerly, G. W.; Reusch, R. N. J. Org.
Chem. 1961, 26, 5155; Nieuwland, J. A.; Calcott, W. S.;
Downing, F. B.; Carter, A. S. J. Am. Chem. Soc. 1931, 53,
4197; Strauss, F. Annalen 1905, 342, 201.
8. Trost, B. M.; Chan, C.; Ruhter, G. J. Am. Chem. Soc.
1987, 109, 3486–3487.
9. Nicolaou, K. C.; Dai, W. M.; Tsay, S. C.; Estevez, V. A.;
Wrasidlo, W. Science 1992, 256, 1172; Trost, B. M.
Science 1991, 254, 1471.
10. For the example of terminal alkynesÕ addition reaction in
water, see: Li, C.-J.; Wei, C. Chem. Commun. 2002, 268–
269; Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584–
9585; Knopfel, T. F.; Carreira, E. M. J. Am. Chem. Soc.
2003, 125, 6054–6055; Wei, C.; Li, C.-J. J. Am. Chem. Soc.
2002, 124, 5638–5639; Boyall, D.; Frantz, D. E.; Carreira,
E. M. Org. Lett. 2002, 4, 2605–2606.
12. Trost, B. M.; Toste, F. D.; Greenman, K. J. Am. Chem.
Soc. 2003, 125, 4518–4526; Nishimura, T.; Araki, H.;
Maeda, Y.; Uemura, S. Org. Lett. 2003, 5, 2997–2999;
Damle, S. V.; Seomoon, D.; Lee, P. H. J. Org. Chem.
2003, 68, 7085–7087; Trost, B. M.; Frontier, A. J. J. Am.
Chem. Soc. 2000, 122, 11727–11728; Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698–1712; Trost, B. M.; Sorum,
M. T.; Chan, C.; Harms, A. E.; Ruhter, G. J. Am. Chem.
Soc. 1997, 119, 698–708; Qing, F.-L.; Zhang, Y. Tetrahe-
dron Lett. 1997, 38, 6729–6732.
11. (Cu) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
10778–10779; Ahmed, M. S. M.; Mori, A. Org. Lett.