Copper/silver-cocatalyzed conia-ene reaction of linear β-alkynic β-ketoesters

Article abstract of DOI:10.1021/ol7023289

A novel and general copper/silver catalytic system has been developed for the Conia-ene intramolecular reaction of linear β-alkynic β-ketoesters. In the presence of (CuOTf)₂·C ₆H₆ and AgSbF₆ (or AgOAc), a variety of the linear β-alkynic β-ketoesters selectively underwent the Conia-ene intramolecular reaction in moderate to good yields.

Full text of DOI:10.1021/ol7023289

ORGANIC
LETTERS
2007
Vol. 9, No. 24
5111-5114
Copper/Silver-Cocatalyzed Conia-Ene
Reaction of Linear -Alkynic
-Ketoesters
â
â
Chen-Liang Deng, Ren-Jie Song, Sheng-Mei Guo, Zhi-Qiang Wang, and
Jin-Heng Li*
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research
(Ministry of Education), Hunan Normal UniVersity, Changsha 410081, China
jhli@hunnu.edu.cn
Received September 25, 2007
ABSTRACT
A novel and general copper/silver catalytic system has been developed for the Conia-ene intramolecular reaction of linear
â-alkynic â-ketoesters.
In the presence of (CuOTf)2 C6H6 and AgSbF6 (or AgOAc), a variety of the linear -alkynic -ketoesters selectively underwent the Conia-ene
‚
â
â
intramolecular reaction in moderate to good yields.
The intramolecular ene reaction of unsaturated ketones and
aldehydes, namely, the Conia-ene reaction, is an important
method for the formation of carbon-carbon bonds.1-7 There
are two common transformations, one involving thermal
cyclization2 and the other transition-metal-catalyzed cycliza-
tion (eq 1).3-7 However, the application of the former in
organic synthesis is limited because of the requirement of
high temperature. Although the latter transformation could
be conducted smoothly at lower temperature, additives such
as strong base,3 strong acid,4 and photochemical activation
(often UV irradiation) are often needed.5 Balme and co-
(1) Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, pp 1-63.
(2) For a review, see: Conia, J. M.; Le Perchec, P. Synthesis 1975, 1.
(3) Pd: (a) Fournet, G.; Balme, G.; Van, Hemelryck, B.; Gore, J.
Tetrahedron Lett. 1990, 31, 5147. (b) Fournet, G.; Balme, G.; Gore, J.
Tetrahedron 1991, 47, 6293. (c) Bouyssi, D.; Balme, G.; Gore, J.
Tetrahedron Lett. 1991, 32, 6541. (d) Balme, G.; Bouyssi, D.; Faure, R.;
Gore, J.; Van Hemelryck, B. Tetrahedron 1992, 48, 3891. (e) Monteiro,
N.; Gore, J.; Balme, G. Tetrahedron 1992, 48, 10103. Mo: (f) McDonald,
F. E.; Olson, T. C. Tetrahedron Lett. 1997, 38, 7691. Cu: (g) Bouyssi, D.;
Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40, 1297. (h) Perez-
Hernandez, N.; Febles, M.; Perez, C.; Perez, R.; Rodriguez, M. L.; Foces-
Foces, C.; Martin, J. D. J. Org. Chem. 2006, 71, 1139. Ti: (i) Kitagawa,
O.; Suzuki, T.; Inoue, T.; Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998,
63, 9470.
(4) (a) Boaventura, M. A.; Drouin, J.; Conia, J. M. Synthesis 1983, 801.
(b) Boaventura, M. A.; Drouin, J. Synth. Commun. 1987, 17, 975. (c)
Cruciani, P.; Aubert, C.; Malacria, M. Tetrahedron Lett. 1994, 35, 6677.
(d) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org. Chem.
1996, 61, 2699. (e) Renaud, J.-L.; Petit, M.; Aubert, C.; Malacria, M. Synlett
1997, 931. (f) Renaud, J.-L.; Aubert, C.; Malacria, M. Tetrahedron 1999,
55, 5113. (g) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
17168.
(5) (a) Stammler, R.; Malacria, M. Synlett 1994, 92. (b) Cruciani, P.;
Stammler, R.; Aubert, C.; Malacria, M. J. Org. Chem. 1996, 61, 2699. (c)
Renaud, J.-L.; Aubert, C.; Malacria, M. Tetrahedron 1999, 55, 5113.
(6) Au: (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am.
Chem. Soc. 2004, 126, 4526. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste,
F. D. Angew. Chem., Int. Ed. 2004, 43, 5350. (c) Mezailles, N.; Ricard, L.;
Gagosz, F. Org. Lett. 2005, 7, 4133. (d) Atsuko, O.; Hideto, I.; Masaya, S.
J. Am. Chem. Soc. 2006, 128, 16486. (e) Pan, J.-H.; Yang, M.; Gao, Q.;
Zhu, N.-Y.; Yang, D. Synthesis 2007, 2539. Ni: (f) Gao, Q.; Zheng, B.-F.;
Li, J.-H.; Yang, D. Org. Lett. 2005, 7, 2185.
(7) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 13002. (b) Nakamura, M.; Endo, K.; Nakamura, E. Org. Lett. 2005,
7, 3279. (c) Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett. 2005, 7, 4823.
(d) Nishimura, Y.; Ameniya, R.; Yamaguchi, M. Tetrahedron Lett. 2006,
47, 1839. (e) Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J.
Am. Chem. Soc. 2007, 129, 5264.
10.1021/ol7023289 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/01/2007

workers, for example, have reported that the Conia-ene
reactions of R-alkynic â-ketoesters could be conducted
smoothly in moderate to excellent yields using CuI as the
catalyst. However, a strong base, tert-BuOK, was necessary
to improve the reaction. Consequently, much recent attention
has focused on the development of mild and neutral
conditions for the Conia-ene reaction.6 Toste, for instance,
reported a mild and efficient (PPh3)AuCl/AgOTf-catalyzed
Conia-ene intramolecular reaction of R-alkynic â-ketoesters
in good yields.6a Recently, Yang also developed a mild and
effective protocol for the Conia-ene reactions of R-alkynic
â-ketoesters using the Ni(acac)2/Yb(OTf)3 catalytic system.6d
Unfortunately, almost all of these catalytic protocols are
focused on the reactions of R-alkynic â-ketoesters, and a
linear â-alkynic â-ketoester was only employed as substrate
in the [Au(N(SO2CF3)2(triethynyphosphine)]-catalyzed Co-
nia-ene reaction to afford an exo-product in quantitative
yield.6c Thus, the development of an inexpensive and general
catalytic system for the Conia-ene reactions of the linear
â-alkynic â-ketoesters under neutral conditions is still
interesting (eq 2). Herein, we wish to report a Cu(I)/Ag
catalytic system for the Conia-ene reactions of the linear
â-alkynic â-ketoesters in moderate to good yields.3g,h
Table 1. Screening Conditions for the Conia-Ene Reactiona
isolated
yield (%)
entry
[Cu]
[Ag]
2a
3a
1
2b
3
4
5
6
7
8
9
CuI
CuI
CuI
(CuOTf)2‚C6H6
-
(CuOTf)2‚C6H6
(CuOTf)2‚C6H6
(CuOTf)2‚C6H6
(CuOTf)2‚C6H6
(CuOTf)2‚C6H6
(CuOTf)2‚C6H6
-
-
AgOTf
-
AgOAc
AgOAc
AgBF4
AgOTf
AgSbF6
AgSbF6
AgSbF6
trace
trace
<5
8
24
67
62
trace
61
56
trace
trace
trace
trace
trace
trace
trace
26
31
0
57
10c
11d
trace
a Reaction conditions: 1a (0.2 mmol), [Cu] (10 mol %) and [Ag] (10
mol %) at 95 °C in CH2ClCH2Cl (DCE; 5 mL) under argon atmosphere
for 23 h. b tert-BuOK (15 mol %) in THF (5 mL) at 30 °C for 4 h then
95 °C for 24 h. c At 50 °C for 46 h. d At 155 °C for 46 h.
a 31% yield of 3a (entry 9). Although in the presence of
(CuOTf)2‚C6H6 and AgSbF6 the product 2a could be obtained
alone at 50 °C, the yield was reduced to some extent even
with prolonging the time (entry 10). Finally, attempts to
enhance the yield of the decarboxylated product 3a by
increasing the temperature were successful, and the product
3a was obtained exclusively in a 57% yield at 155 °C (entry
11).9
With the standard reaction conditions in hand, a variety
of linear â-arylacetylenic â-ketoesters were surveyed to
investigate scope (Table 2). The results demonstrated that
only endo-products were observed, but the yield and
selectivity were affected by the structures of â-ketoesters.
Substrates 1b-d bearing electron-rich or electron-neutral aryl
groups at the terminal of alkyne, for instance, were treated
with (CuOTf)2‚C6H6 and AgSbF6 smoothly to afford the
corresponding endo-products in good total yields (entries
1-4). However, substrate 1e having an electron-deficient
group at the terminal of alkyne gave a low yield together
with another byproduct (entry 5).10 Subsequently, the groups
of ester were tested under the standard conditions, and
methyl, ethyl, or isopropyl was tolerated well (entry 9 in
Table 1 and entries 6 and 8 in Table 2). Isopropyl ester (1g),
for instance, was treated with (CuOTf)2‚C6H6 and AgSbF6
smoothly at 95 °C in a 69% total yield. Interestingly, the
reactions of the hindered 4-substituted 3-ketoesters 1h and
As listed in Table 1, methyl 7-(4-methoxyphenyl)-3-
oxohept-6-ynoate (1a), a linear â-alkynic â-ketoester, was
chosen as a model substrate to screen the optimal reaction
conditions.8 No reaction was observed using CuI, CuI/tert-
BuOK (Balme’s conditions3g), or CuI/AgOTf catalytic system
(entries 1-3). To our delight, an endo-product 2a was
isolated in a 8% yield using (CuOTf)2‚C6H6 as the catalyst
(entry 4). Interestingly, AgOAc also provided the target
product 2a in a 24% yield (entry 5). These prompted us to
examine the Cu/Ag cocatalysts’ effect on the reaction. In
the presence of (CuOTf)2‚C6H6, a number of silver salts,
including AgOTf, AgOAc, AgSbF6, AgBF4, AgNO3, Ag2O,
and Ag2CO3, were first tested. The results indicated that
AgOAc, AgSbF6, or AgBF4 gave the better results.6 A 67%
yield of 2a was achieved from the reaction of substrate 1a
catalyzed by (CuOTf)2‚C6H6 combined with AgOAc (entry
6). Identical results were also obtained using (CuOTf)2‚C6H6/
AgBF4 cocatalysts (entry 7). Surprisingly, the Conia-ene
cyclization/decarboxylation sequence occurred in the reaction
substrate 1a with (CuOTf)2‚C6H6 and AgOTf to afford a
decarboxylated endo-product 3a alone in a 26% yield (entry
8).9 Interestingly, AgSbF6 combined with (CuOTf)2‚C6H6
provided a 92% total yield involving a 61% yield of 2a and
(9) The decarboxylated products are readily observed in the presence of
transition-metal catalyst under higher reaction temperature conditions; see:
(a) Yamamoto, A. AdV. Organomet. Chem. 1992, 34, 111. (b) Lin, Y.-S.;
Yamamoto, A. In ActiVation of UnreactiVe Bonds and Organic Synthesis;
Murai, S., Ed.; Springer: Berlin, Germany, 1999; pp 161-192.
(10) See eq S1 in Supporting Information.
(8) For detailed experimental data, see Table S1 in Supporting Informa-
tion.
5112
Org. Lett., Vol. 9, No. 24, 2007

Table 2. Cu/Ag-Cocatalyzed Conia-Ene Reactiona
Scheme 1. The Conia-Ene Cyclizations of Substrates 1m-r
hydration followed by Knovenagel condensation process.11
To verify it, substrate 1c was first hydrated to give methyl
Scheme 2. Some Controlled Reactions
a Reaction conditions: 1 (0.2 mmol), (CuOTf)2‚C6H6 (10 mol %),
AgSbF6 (10 mol %), at 95 °C in DCE (5 mL) under argon atmosphere.
b Isolated yield. c At 155 °C. d See eq S1 in Supporting Information. A
byproduct 5e was isolated in 30% yield. e AgOAc (10 mol %) instead of
AgSbF6.
1i selectively afforded the desired products 2h and 2i
exclusively in moderate yields (entries 10-12). We were
happy to find that 3-arylacetylenic 1,3-diketos 1j-l were also
suitable substrates under the standard conditions (entries 13-
15). Note that the decarboxylated products 3 can still be
obtained alone in moderate yields at 155 °C (entries 3, 7,
and 9). Unfortunately, no target product was observed from
the reaction of methyl 7-(4-methoxyphenyl)-2-methyl-3-
oxohept-6-ynoate, a substrate bearing a methyl group at the
R-position.
The reactions of terminal alkynes 1m-q or a middle
alkylalkyne 1r were conducted under the standard conditions,
and the results are summarized in Scheme 1. In the presence
of (CuOTf)2‚C6H6 and silver salt (AgSbF6 or AgOAc), a
number of terminal alkynes 1m-q underwent the Conia-
ene cyclizations successfully to selectively generate the
corresponding exo-products 4m-q alone in 33-53% yields.
Interestingly, alkyne 1r, a substrate bearing a methyl group
at the terminal of alkyne, gave a mixture of the endo-product
4q and exo-product 4r in 22 and 21% yields, respectively.
To elucidate the mechanism of the present protocol, some
controlled reactions were conducted as shown in Scheme 2.
1-Phenylpropyne (6) was hydrated readily by (CuOTf)2‚C6H6
and AgSbF6 to afford propiophenone (7) in a 50% yield,
which was determined by GC-MS analysis. The results
implied that the present protocol may proceed via the alkyne
3,7-dioxo-7-p-tolylheptanoate (8) in the presence of PdCl2-
(MeCN)2.12 Subsequently, the compound 8 was treated with
(CuOTf)2‚C6H6 and AgSbF6 at 95 °C for 24 h; however, no
target products 2c and 3c were observed by GC-MS
analysis. On the other hand, a hydrated decarboxylated
product 5e, not the decarboxylated cyclization products 3e,
was isolated from the reaction of alkyne 1e (entry 5 in Table
2). All the results demonstrated that there was competition
between the Conia-ene cyclization reaction and the hydration
reaction.
Thus, another working mechanism as outlined in Scheme
3 was proposed on the basis of the previously reported
mechanism.1-7 During the Conia-ene reaction of R-alkynic
â-ketoesters, two mechanisms were proposed: (1) nucleo-
philic attack on a M-alkyne complex by the enol form of
the ketoester, and (2) a M-enolate formation by directly
complexing it with the â-ketoester, followed by a cis-
carbonmetalation of the alkyne.6 The present results sug-
gested that intermediate A may be generated by the complex
of one metal with alkyne and another metal with â-ketoester,
(11) (a) Chang, H.-K.; Datta, S.; Das, A.; Odedra, A.; Liu, R.-S. Angew.
Chem., Int. Ed. 2007, 46, 4744. (b) Chang, H.-K.; Liao, Y.-C.; Liu, R.-S.
J. Org. Chem. 2007, 72, 8139.
(12) Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 3127.
Org. Lett., Vol. 9, No. 24, 2007
5113

â-alkynic â-ketoesters. In the presence of (CuOTf)2‚C6H6
and AgSbF6 (or AgOAc), a variety of the linear â-alkynic
â-ketoesters selectively underwent the Conia-ene intramo-
lecular reaction in moderate to good yields. Work to probe
the detailed mechanism and apply the reaction in organic
synthesis is currently underway.
Scheme 3. A Working Mechanism
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (No. 20572020), New Century
Excellent Talents in University (No. NCET-06-0711), Spe-
cialized Research Fund for the Doctoral Program of Higher
Education (No. 20060542007), Fok Ying Tung Education
Foundation (No. 101012), and the Key Project of Chinese
Ministry of Education (No. 206102) for financial support.
We also thank Professor Dan Yang (The University of Hong
Kong) for helpful discussions.
which is similar to the mechanism proposed by Toste.6 The
intramolecular attack of the M-enolate on the M-alkyne
complex then occurred to form intermediates B and C,
followed by a protonation/isomerization sequence to give the
corresponding endo- or exo-products. The present results
showed that the selectivity toward endo- or exo-products
depended on the substitutes at the terminal of alkynes. On
the basis of the previous and present results,1-7 we deduced
that the endo-products were obtained exclusively from
γ-arylacetylenic â-ketoesters due to the properties, such as
steric hindrance, of the aryl group at the terminal alkyne.
In summary, we have developed a novel copper/silver-
cocatalyzed Conia-ene intramolecular reaction of the linear
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products 2-5; typical
procedure for the copper/silver-cocatalyzed Conia-ene in-
tramolecular reaction of the linear γ-alkynic â-ketoesters.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL7023289
5114
Org. Lett., Vol. 9, No. 24, 2007