Gold(I)-Catalyzed Conia-Ene Reaction of β-Ketoesters with Alkynes

Article abstract of DOI:10.1021/ja049487s

The intramolecular addition of β-ketoesters to unactivated alkynes under neutral conditions and at room temperature is described. The method employs triphenylphosphinegold(I) cation as a catalyst for the formation of exo-methylenecycloalkanes. Both monocyclic and bicyclic cyclopentanes and cyclohexanes can be formed in excellent yields and with good diastereoselectivity. Copyright

Full text of DOI:10.1021/ja049487s

Published on Web 03/16/2004
Gold(I)-Catalyzed Conia-Ene Reaction of â-Ketoesters with Alkynes
Joshua J. Kennedy-Smith, Steven T. Staben, and F. Dean Toste*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California,
Berkeley, California 94720
Received January 28, 2004; E-mail: fdtoste@berkeley.edu
Table 1. Efficiency of Group XI Metal Catalysts in the Conia-Ene
Reaction
Enolate alkylation represents one of the most powerful and
widely employed methods for the formation carbon-carbon bonds.1
The efficiency of this process would be greatly enhanced by the
ability to directly R-functionalize a carbonyl group without requiring
enolate formation. The thermal cyclization of ketones onto alkynes
(Conia-ene reaction) provides access to R-vinylated ketones without
the need for deprotonation; however, the high temperature needed
severely limits its synthetic utility.2 On the other hand, transition
metal-catalyzed3 versions of this reaction generally operate at lower
temperatures. Unfortunately, these catalytic reactions require enolate
generation,4 strong acid5 or photochemical activation.6 A catalytic
version of the Conia-ene reaction that proceeds at ambient tem-
peratures and under neutral conditions7 would dramatically increase
the utility of this reaction. Herein, we report the realization of this
goal by employing phosphinegold(I) complexes as catalysts.
Carbon-carbon bond formation promoted by homogeneous gold
catalysts is extremely rare.8-10 However, recent reports of group
11 metal-catalyzed addition of heteroatom nucleophiles to alkynes,11,12
encouraged us to examined the viability of these complexes as
catalysts for the intramolecular addition of a â-ketoester to an
unactivated alkyne (Table 1). In the event, treatment of ketoester 1
with 10% silver(I) triflate did afford some of the desired cyclo-
pentene (2), but the reaction did not proceed to completion even
after a day at room temperature (entry 1). On the other hand, gold-
(III) chloride rapidly consumed the starting alkyne (2), but produced
only a small amount of the desired adduct (entry 3). While
triphenylphosphinegold(I) chloride was unreactive (entry 4), the
triphenylphosphinegold(I) cation rapidly and cleanly converted 1
into 2 in less than 15 min at room temperature (entry 5). In sharp
contrast to the phosphine inhibition of the silver(I)-catalyzed
reaction (entry 2), a cationic gold(I) complex lacking phosphines
did not catalyze the reaction (entry 6). In accord with the hypothesis
that cationic triphenylphosphinegold(I) is the active catalyst,
generation of this species by protonation12a of [(PPh3Au)3O]BF4
also resulted in a viable catalysts system (entries 7 and 8).
Further optimization revealed that 1 mol % of the gold(I) catalyst,
in dichloromethane13 rapidly converted ketoester 1 into 2 in 94%
yield at room temperature (Table 2, entry 1). Notably, the catalyst
operates under “open-flask” conditions in which no precautions
were taken to exclude air and moisture from the reaction mixture.
Under these conditions a wide range of â-ketoester substrates
participated in the gold(I)-catalyzed cycloisomerization. A longer
reaction time was required with an increase in the steric size of the
ketone substituent (entry 2), while changing the ester group from
methyl to tert-butyl had only a slight impact on the rate of the
reaction (entry 3). Notably, when a propargyl ester was employed,
the reaction was completely chemoselective for formation of the
exo-methylenecyclopentane at the expense of competing lactone
formation (entry 4).
entry
conditions
time
% conv. to 2a
1
2
3
4
5
6
7
8
10 mol % AgOTf, DCE, rt
10 mol % AgOTf, 10 mol% PPh3, DCE, rt
10 mol % AuCl3, DCE, R.T.
10 mol % (PPh3)AuCl, DCE, 60 °C
10 mol % (PPh3)AuOTf, DCE, rt
10 mol % [(CyNC)2Au]PF6, DCE, rt
1 mol % [PPh3Au)3O]BF4, DCE, 60 °C
18 h
18 h
30 min
6 h
<15 min
14 h
50
0
30b
0
>95
0
0
>95
1 h
1 mol % [PPh3Au)3O]BF4, 5% HOTf, DCE, rt <15 min
1
a As judged by H NMR. b No starting material (1) remained.
produced from cyclopentanone 9 as a single diastereomer in
excellent yield (entry 5). When the ester was located in the ring,
such as lactone 13, longer reaction times were required but the
yield remained excellent (entry 7). The Au-catalyzed reaction was
also employed in the synthesis of cis-6,5-bicylic ring systems by
annulating a six-membered ring onto a cyclopentanone (entry 6)
or a five-membered ring onto a cyclohexanone (entry 8); the former
requiring an increase in catalyst loading to 5 mol % in order to
proceed to completion in 18h. Similarly, 5 mol % triphenylphos-
phinegold(I)-catalyst was needed for the diastereoselective construc-
tion of cis-7,5-bicyclic ketone 20 (entry 10). Notably, the gold-
catalyzed reaction was also employed in the construction of a ketone
(18) containing Vicinal-quaternary carbons (entry 9). Additionally,
bicyclo-[3.2.1]-octanone 22 was prepared, in excellent yield, by
the Au-catalyzed cycloisomerization of â-ketoester 21 (entry 11).
Having established that the Au-catalyzed reaction shows excellent
levels of diastereoselectivity in the creation of bicyclic systems,
we examined the diastereoselectivity of the cyclopentane formation.
Compared to other catalyst systems,6 significantly better 1,2-
diastereoselectivity was observed when 2-ethyl- (23) and 2-phenyl-
(24) substituted â-ketoesters were subjected to the Au-catalyzed
Conia reaction (entries 12 and 13). Additonally, exo-methlyenecy-
clopentanes 28 and 30 were prepared with good control of 1,3-
diastereoselectivity starting from 3- or 4-substituted ketoesters
(entries 14 and 15).
We envisioned two possible mechanisms for the Au-catalyzed
addition of â-ketoesters to alkynes (eq 1). Mechanism A involves
nucleophilic attack on a Au(I)-alkyne complex by the enol form of
The gold(I)-catalyzed reaction also allows for the synthesis of
bicyclic ring systems. Cis-fused 5,5-bicyclic ketone 10 was
9
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J. AM. CHEM. SOC. 2004, 126, 4526-4527
10.1021/ja049487s CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Gold(I)-Catalyzed Conia-Ene Reactiona
result underscore the potential of Au(I) as a homogeneous catalyst
for the formation of carbon-carbon bonds.9 Studies extending the
range of Au(I)-catalyzed C-C bond forming reactions are currently
underway in our laboratories.
Acknowledgment. We gratefully acknowledge Merck Research
Laboratories, Amgen Inc. and Eli Lilly & Co. for financial support.
J.J.K.S. thanks Eli Lilly & Co. for a graduate fellowship. The Center
for New Directions in Organic Synthesis is supported by Bristol-
Myers Squibb as a Sponsoring Member and Novartis Pharma as a
Supporting Member.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org
References
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(15) In accord with this hypothesis diester 37 and ketoamide 38 (enol form
destabilized by 1,3-allylic strain) fail to participate in the reaction.
a Reaction Conditions: 1 mol % (PPh3)AuCl, 1 mol % AgOTf, 0.4 M
(ketoester) in dichloromethane, rt. b 5 mol % (PPh3)AuCl and 5 mol %
AgOTf.
the ketoester, affording vinyl-Au intermediate 31 that is protonated
to form the product. An alternative mechanism (B) proceeds by
formation of a Au-enolate, by direct auration14 of the â-ketoester,
followed by a cis-carboauration12a of the alkyne to produce vinyl-
Au intermediate 32.
To probe these mechanistic hypotheses, selectively deutrated
â-ketoesters 33 and 34 were prepared. The Au-catalyzed Conia-
ene reaction of deutroacetylene 33 furnished cyclopentane 35
selectively deuterated (90%) syn to the ketoester (eq 2). On the
other hand, 34 afforded adduct 36 in which the exo-methylene was
selectively (48%) deuterated anti to the ketoester. These deuterium-
labeling experiments support a mechanism involving enol15 addition
to a Au-alkyne complex (mechanism A).16
In conclusion, we have developed a Au(I)-catalyzed Conia-ene
reaction that proceeds under neutral conditions at room temperature.
In most cases, the reaction requires low catalyst loadings, short
reaction times and proceeds under “open-flask” conditions. The high
diastereoselectivities and mildness of these reaction conditions
should make this reaction a valuable tool for synthesis of quaternary
carbon centers17 and exo-methylenecycloalkanes. Additionally, these
(16) This mechanism also provides an explanation for the poor reactivity (<10%
conversion) of non-terminal alkynes, since severe 1,3-allylic strain
develops in the transition state (A) for cyclization.
(17) For a review see: Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105.
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