Copper/silver-cocatalyzed conia-ene reactions of 2-alkynic 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/jo802133w

(Chemical Equation Presented) A copper/silver-catalyzed Conia-ene reaction has been developed for selectively constructing five-membered and six-membered rings. In the presence of (CuOTf)₂?C₆H₆ and AgBF₄, a vari

Full text of DOI:10.1021/jo802133w

SCHEME 1. Copper/Silver-Cocatalyzed Conia-Ene
Reaction of Linear ꢀ-Alkynic ꢀ-Ketoesters
Copper/Silver-Cocatalyzed Conia-Ene Reactions
of 2-Alkynic 1,3-Dicarbonyl Compounds
Chen-Liang Deng,† Tao Zou,‡ Zhi-Qiang Wang,†
Ren-Jie Song,† and Jin-Heng Li*,†,‡
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), Hunan Normal
UniVersity, Changsha 410081, China, and College of
Chemistry and Materials Science, Wenzhou UniVersity,
Wenzhou 325035, China
cyclization2 and transition-metal-catalyzed cyclization.3-7 How-
ever, the former suffers from the requirement of high temper-
atures, which significantly limits its application in organic
synthesis. The latter transformation could be conducted smoothly
at lower temperature, but additives, such as strong base,3 strong
acid,4 and photochemical activation (often UV irradiation), are
often needed.5 Balme and co-workers, for instance, have
reported the CuI-catalyzed Conia-ene reactions of R-alkynic
ꢀ-ketoesters under mild conditions in the presence of a strong
base, t-BuOK.3 As a result, much recent attention has been
attracted on the development of mild and neutral conditions for
the Conia-ene reaction.6-8 These efficiently catalytic systems
include Au/Ag,6 Ni(acac)2/Yb(OTf)3,7 and In(NTf2)3.8 Recently,
we also developed a mild and effective protocol for the
Conia-ene reactions of linear ꢀ-alkynic ꢀ-ketoesters using
(CuOTf)2 ·C6H6 and Ag(I) (AgSbF6or AgOAc) catalytic system
(Scheme 1).9 In the presence of (CuOTf)2 ·C6H6 and Ag(I)
(AgSbF6or AgOAc), a variety of linear ꢀ-alkynic ꢀ-ketoesters
underwent the Conia-ene intramolecular reaction smoothly to
selectively afforded the corresponding exo- or endo-products
in moderate to good yields. Encouraged by the results, we
decided to apply the Cu/Ag catalytic system in the cyclization
of R-alkynic ꢀ-ketoesters. To our delight, the Cu/Ag catalytic
system also displayed high efficiency for a wide range of
2-alkynic 1,3-dicabonyl compounds including R-alkynic ꢀ-ke-
toesters, R-alkynic ꢀ-diketo, 2-phenylacetylhept-6-ynenitrile, and
diethyl 2-(pent-4-ynyl)malonate. Herein, we wish to report a
general and selective protocol for the synthesis of exo- and endo-
products by copper/silver-cocatalyzed Conia-ene reactions of
2-alkynic 1,3-dicabonyl compounds (Scheme 2).
jhli@hunnu.edu.cn
ReceiVed September 24, 2008
A copper/silver-catalyzed Conia-ene reaction has been
developed for selectively constructing five-membered and
six-membered rings. In the presence of (CuOTf)2 · C6H6 and
AgBF4, a variety of 2-alkynic 1,3-dicarbonyl compounds
underwent the Conia-ene intramolecular reaction smoothly
in moderate to good yields. It is noteworthy that both
2-phenylacetylhept-6-ynenitrile and diethyl 2-(pent-4-ynyl)-
malonate are also suitable substrates under the standard
conditions, and the selectivity toward endo- or exo-products
depends on the substitutents at the terminal of alkynes.
Methyl 2-acetylhept-6-ynoate (1a) was chosen as a model to
screen the optimal reaction conditions, and the results are
summarized in Table 1. Without Ag salts, treatment of substrate
1a with (CuOTf)2 ·C6H6 afforded only moderate yield of the
The intramolecular ene reaction of unsaturated ketones and
aldehydes (the Conia-ene reaction) has emerged as a powerful
method for carbon-carbon bond formation.1-7 The reaction
generally proceeds via two common transformations, thermal
(4) Hg: (a) Boaventura, M. A.; Drouin, J.; Conia, J. M. Synthesis 1983, 801.
(b) Boaventura, M.-A.; Drouin, J Synth. Commun. 1987, 17, 975. Co: (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. Au: (g) Corkey, B. K.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168.
† Hunan Normal University.
‡ Wenzhou University.
(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: Le Conia, J. M.; 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.
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1992, 48, 3891. (e) Monteiro, N.; Gore, J.; Balme, G. Tetrahedron 1992, 48,
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(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.
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2004, 126, 4526. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew.
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412 J. Org. Chem. 2009, 74, 412–414
10.1021/jo802133w CCC: $40.75 2009 American Chemical Society
Published on Web 11/18/2008

TABLE 2. Copper/silver-cocatalyzed Conia-Ene reactions of
r-alkynic ꢀ-ketoesters (1)a
SCHEME 2
TABLE 1. Screening Optimal Conditionsa
entry
cocatalyst
time (h)
yield (%)
1
2
3
4
5
6
7
8b
24
24
22
22
23
25
46
24
62
50
40
55
100
71
AgOAc
AgSbF6
Ag2O
AgBF4
In(OTf)3
AuCl
50
75
AgBF4
a Reaction conditions: 1a (0.2 mmol), (CuOTf)2 ·C6H6 (10 mol %),
cocatalyst (10 mol %), CH2ClCH2Cl (DCE; 5 mL) at 100 °C under
argon atmosphere. b Without (CuOTf)2 ·C6H6.
corresponding exo-product 2a after 23 h (entry 1). In our
previous paper, Ag(I) salts could improve the reaction.9 Thus,
a series of Ag(I) salts were then examined (entries 2-5).
Surprisingly, the results indicated that both AgSbF6 and AgOAc,
the reported efficient cocatalysts, disfavored the reaction (entries
2 and 3). Identical results were observed in the presence of Ag2O
(entry 4). To our delight, AgBF4 displayed highly active to
improve the (CuOTf)2 ·C6H6-catalyzed reaction providing quan-
titative yield (entry 5). The other reported effective catalysts
including In(OTf)3 and AuCl were also tested, and both are less
effective than AgBF4 (entries 6 and 7). We found that 73% yield
was still achieved from the reaction of substrate 1a using AgBF4
catalyst alone (entry 8). Note that no decarbonylated products
are observed in the present reaction.9
With the standard conditions in hand, we decided to explore
scope of the Cu/Ag-catalyzed Conia-ene reaction. As demon-
strated in Table 2, a number of R-alkynic ꢀ-ketoesters 1b-g
were first examined in the presence of (CuOTf)2 ·C6H6 and
AgBF4 (entries 1-6). The results showed that both ester groups
and ꢀ-substitutents affected the reaction to some extent. Benzyl
ester 1d was a suitable substrate providing high yields under
the standard conditions (entry 3), but both ethyl ester 1b and
isopropyl ester 1c were less active than methyl ester 1a (entries
1 and 2). Ethyl ester 1b, for instance, was treated with
(CuOTf)2 ·C6H6 and AgBF4 to afford the corresponding target
exo-product 2b in 67% yield (entry 1). While ꢀ-phenyl
ꢀ-ketoester 1f gave the desired product in 86% yield (entry 5),
only 40% yield was isolated from R-alkynic ꢀ-ketoester 1g
bearing an i-propyl group at the ꢀ-position (entry 6). Interest-
ingly, ꢀ-ethyl ꢀ-ketoester 1e could undergo the cyclization
efficiently to give the corresponding cyclopentene product 2e
in 95% yield (entry 4). Next, substrate 1h, a R-alkynic ꢀ-diketo,
was investigated under the standard conditions (entry 7). It was
encouraging to find that substrate 1h underwent the Conia-ene
reaction with (CuOTf)2 ·C6H6 and AgBF4 smoothly in good yield
(entry 7). Gratifyingly, cyclization of 2-phenylacetylhept-6-
ynenitrile (1i) could also be conducted successfully to afford
a Reaction conditions: 1 (0.2 mmol), (CuOTf)2•C6H6 (10 mol %),
AgBF4 (10 mol %), CH2ClCH2Cl (5 mL) at 100 °C under argon
atmosphere. All substrates were consumed completely determined by
GC-MS analysis and TLC. b CuOTf)2•C6H6 (20 mol %) and AgBF4 (20
mol %).
J. Org. Chem. Vol. 74, No. 1, 2009 413

similar to the mechanism proposed by Toste.6 The intramo-
lecular attack of the M-enolate on the M-complex alkyne is
subsequently taken place to form intermediates B or intermedi-
ates C. Intermediates B undergoes the protonation/isomerization
sequence to give the corresponding exo-products 2, and
intermediates C undergoes the overprotonation/isomerization to
give the corresponding endo-products. The present results
showed obviously that the selectivity toward endo- or exo-
products depended on the substitutes at the terminal of alkynes.
Based on the previous and present results,1-7 we deduced that
the endo-products were obtained exclusively from R-arylacety-
lenic ꢀ-ketoesters due to the properties, such as steric hindrance,
of the aryl group at the terminal of alkynes. The source of
hydrogen in the overhydrogenation process may be from H2O.
Further study of the true mechanism for the selectivity is in
progress.
TABLE 3. Copper/Silver-Cocatalyzed Conia-Ene Reactions of
r-(Substituted alkynic) ꢀ-Ketoesters (1)a
entry
R
yield (%)
1
2
3
C6H5 (1m)
4-MeOC6H4 (1n)
Me (1o)
35 (2m)
30 (2n)
messy
a Reaction conditions: 1 (0.2 mmol), (CuOTf)2 ·C6H6 (10 mol %),
AgBF4 (10 mol %), CH2ClCH2Cl (5 mL) at 100 °C under argon
atmosphere. All substrates were consumed completely determined by
GC-MS analysis and TLC. The byproduct are complex including some
decarbonylation and/or hydrolysis products.
In summary, we have developed a copper/silver-cocatalyzed
Conia-ene intramolecular reaction of 2-alkynic 1,3-dicarbonyl
compounds protocol for selectively synthesizing exo- and endo-
products. We found that the reaction could be conducted by
either (CuOTf)2 ·C6H6 or AgBF4, but the best results were
observed using the Cu/Ag cocatalysts. In the presence of
(CuOTf)2 ·C6H6 and AgBF4, a variety of 2-alkynic 1,3-dicar-
bonyl compounds, including R-alkynic ꢀ-ketoesters, R-alkynic
ꢀ-diketo, 2-phenylacetylhept-6-ynenitrile, and diethyl 2-(pent-
4-ynyl)malonate, selectively underwent the Conia-ene intramo-
lecular reaction in moderate to good yields. It is worth noting
that both acetylhept-6-ynenitrile and 2-(pent-4-ynyl)malonate
are suitable substrates under the standard conditions, and the
selectivity toward endo- or exo-products depends on the
substitutents at the terminal of alkynes.
SCHEME 3. A Working Mechanism
the target product 2i in 30% yield under the standard conditions
and 55% yield at 20 mol % loadings of both (CuOTf)2 ·C6H6
and AgBF4 (entries 8 and 9). However, cyclization of 2-(pent-
4-ynyl)malononitrile (1j) was unsucessful (entry 10). It is
noteworthy that diethyl 2-(pent-4-ynyl)malonate (1k) is a
suitable substrate for the reaction, which represents the first
example of the cyclization of diester (entries 11 and 12). In the
presence of 20 mol % of (CuOTf)2 · C6H6 and 20 mol % of
AgBF4, the desired product 2k was isolated in 50% yield after
46 h from the cyclization of diester 1k (entry 12). Interesting,
2-(pent-4-ynyl)cyclopentane-1,3-dione (1l) could also underwent
the cyclization smoothly to affored a spiro[4,4]cyclic prdouct
2l in moderate yield under the same conditions (entry 13).
Surprisingly, copper/silver-cocatalyzed Conia-ene reactions
of R-arylalkynic ꢀ-ketoesters gave overhydrogenated endo-
products under the standard conditions, and the results are
summarized in Table 3. In the presence of (CuOTf)2 ·C6H6 and
AgBF4, both R-phenylalkynic ꢀ-ketoester 1m and R-(4-meth-
oxyphenyl)alkynic ꢀ-ketoester 1n could undergo the Conia-ene
reaction to afford the corresponding over- hydrogenated endo-
products in 35% and 30% yields, respectively (entries 1 and
2). However, aliphatic alkyne 1o, a substrate bearing a methyl
group at the terminal alkyne, gave messy results under the
standard conditions.
To elucidate the above results, a working mechanism as
outlined in Scheme 3 was proposed on the basis of the
previously reported mechanism.1-8 Generally, two mechanisms
are proposed for the Conia-ene reaction of R-alkynic ꢀ-ke-
toesters: (1) nucleophilic attack on a M-alkyne complex by
the enol form of the ketoester and (2) a M-enolate formation
by directly complex with the ꢀ-ketoester, followed by a cis-
carbonmetalation of the alkyne.6 The present results suggested
that intermediate A may be generated by the complex of one
metal with alkyne and another metal with ꢀ-ketoester, which is
Experimental Section
Typical Experimental Procedure for the Conia-Ene
Reaction. A mixture of 2-alkynic 1,3-dicarbonyl compound 1 (0.2
mmol), (CuOTf)2 ·C6H6 (10 mol %), and AgBF4 (10 mol %) in
CH2ClCH2Cl (5 mL) was stirred at 100 °C under argon atmosphere
until complete consumption of starting material as monitored by
TLC and GC-MS analysis. Then the mixture was filtered by a
crude column, washed with diethyl ether, and evaporated under
vacuum. The residue was purified by flash column chromatography
to afford the pure product (hexane/ethyl acetate).
Ethyl 1-acetyl-2-methylcyclopent-2-enecarboxylate (2b): col-
orless oil; 1H NMR (500 MHz, CDCl3) δ 5.70 (t, J ) 2.5 Hz, 1H),
4.25-4.21 (m, 2H), 2.65-2.60 (m, 1H), 2.41-2.30 (m, 2H),
2.24-2.22 (m, 1H), 2.22 (s, 3H), 1.83 (s, 3H), 1.29 (t, J ) 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 204.9, 171.7, 137.5, 132.0,
70.4, 61.2, 32.8, 30.3, 26.7, 14.8, 14.1; IR (KBr, cm-1) 1726, 1669;
LRMS (EI, 70 eV) m/z 196 (M+, 10), 123 (-CO2Et, 100); HRMS
(EI) for C11H16O3 (M+) calcd 196.1099, found 196.1097.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20572020), New Century Excellent
Talents in University (No. NCET-06-0711), and Specialized
Research Fund for the Doctoral Program of Higher Education
(No. 20060542007) for financial support.
Supporting Information Available: General experimental
procedures, characterization data for compounds 2 and 3, and
copies of spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO802133W
414 J. Org. Chem. Vol. 74, No. 1, 2009