Efficient synthesis of cyclopentenones from enynyl acetates via tandem Au(I)-catalyzed 3,3-rearrangement and the Nazarov reaction

Article abstract of DOI:10.1021/ja057327q

A highly efficient method for the synthesis of versatile cyclopentenones from readily available enynyl acetates via tandem Au(I)-catalyzed 3,3-rearrangement and the Nazarov reaction is developed. Significant substrate flexibility and excellent control of the double bond position in the cyclopentenone ring render this an attractive method for cyclopentenone synthesis. Copyright

Full text of DOI:10.1021/ja057327q

Published on Web 01/13/2006
Efficient Synthesis of Cyclopentenones from Enynyl Acetates via Tandem
Au(I)-Catalyzed 3,3-Rearrangement and the Nazarov Reaction
Liming Zhang* and Shaozhong Wang
Department of Chemistry/216, UniVersity of NeVada, Reno, 1664 North Virginia Street, Reno, NeVada 89557
Received October 27, 2005; E-mail: lzhang@chem.unr.edu
Au salts have been shown as exceptional catalysts1 to activate
alkynes,2 alkenes,3 and allenes4 toward nucleophilic attacks. A
Scheme 1. Proposed Au(I)-Catalyzed Formation of
2-Cyclopentenones
variety of structural motifs have been efficiently accessed under
exceedingly mild reaction conditions.
Cyclopentenones are key intermediates in organic synthesis.
Among a variety of approaches for their preparation, the Nazarov
reaction5 is arguably one of the most versatile and efficient methods.
However, most synthetically viable applications of the Nazarov
reaction have to include structural elements to control the double
bond position in the enone product.6 Furthermore, the divinyl ketone
starting materials or equivalents are commonly prepared conver-
Table 1. Screen of Reaction Conditions for Cyclopentenone
Formation
gently from substrates containing a double bond or its surrogate,
which limits the substrate scope and hence the utility of this reaction.
Herein, we report a Au(I)-catalyzed highly efficient synthesis
of cyclopentenones from readily available enynyl esters via tandem
3,3-rearrangement and the Nazarov reaction. In this reaction, AuCl-
(PPh3)/AgSbF6 plays dual roles of activating both alkynes and
allenes. Moreover, this reaction allows significant substrate flex-
ibility and has excellent control of the cyclopentenone double bond
position.
Previously, I reported that cationic Au(I) complexes can not only
catalyze 3,3-rearrangement of propargylic esters but also activate
the resulting allenylic esters in situ for subsequent [2 + 2] cycliza-
tion via oxonium intermediate A (Scheme 1).7 We envisage that
when R1 is an alkenyl group, A becomes pentadienylic cation B,
which could undergo the Nazarov reaction and lead to cyclopen-
tenones. Since enynyl alcohols can be prepared in a modular manner
either from aldehyde/enyne or from aldehyde/acetylene/alkenyl
halide, this could constitute either a [1 + 4] or a [1 + 2 + 2]
approach toward versatile 2-cyclopentenone derivatives with high
efficiency and flexibility.
yield (%)a
Time Conv.
(h) (%)
Entry
Catalyst
Conditions
2
3
1
2
3
4
5
6
7
1% AuCl(PPh3)/AgSbF6 dry CH2Cl2, rt
0.5 >99 65b 8c
1% AuCl(PPh3)/AgSbF6 wet CH2Cl2, rt
0.5 >99 <1 92b
5% AuCl3
5% AuCl3
5% PtCl2
dry CH2Cl2, rt
wet CH2Cl2, rt
dry toluene, 80 °C
wet CH2Cl2, rt
dry CH2Cl2, rt
0.5
0.5
4
48 31 <1
96 64
41 32 <1
5
5% AgSbF6
5% TfOH
0.5 <1 <1 <1
0.5
62d <1 <1
a Estimated by 1H NMR using diethyl phthalate as internal standard.
b Isolated yield. c Due to adventitious water. d Decomposed amount.
propargylic position. While the parent vinyl derivative 8 reacted
readily to give 3-pentyl-2-cyclopenten-1-one (9) in good yield (entry
3), various substituents on the C-C double bond were allowed.
For example, treatment of enynyl acetates containing cyclopentene
(entry 4), cyclohexene (entry 5), and cycloheptene (entry 6) moieties
with 1 mol % of AuCl(PPh3)/AgSbF6 led to bicyclic cyclopenten-
ones in fairly good to excellent yields. The relatively low yield of
cis-5,5-fused enone 11 was likely due to ring strain. In addition,
phenyl substitution at the double bond (entry 7) was tolerated,
although a higher catalyst loading (5 mol %) was necessary;
cyclopentenone 17 was isolated in 74% yield. Surprisingly, partial
desilylation occurred during the cyclization of TIPS-protected
acetate 18. As a result, hydroxyl enone 19 was isolated in 81%
yield after treating the resulting reaction mixture with TFA. Less
clean reactions were observed when the hydroxyl group was
protected by either a TBS or a THP group.
Remarkably, treatment of enynyl acetate 20 derived from
benzaldehyde with AuCl(PPh3)/AgSbF6 (5 mol %) resulted in the
formation of cyclopentadienylic acetate 21 in 91% yield even in
wet CH2Cl2 (eq 1). Hydrolysis of 21 in the presence of HNTf2 (1
mol %) gave enone 22 in excellent yield. Similarly, acetate 23 with
a p-CF3-substituted phenyl group underwent smooth cyclization,
and enone 24 was isolated in 96% overall yield after hydrolysis.
We began by treating enynyl acetate 1 with 1 mol % of AuCl-
(PPh3)/AgSbF6 in anhydrous CH2Cl2. 1 was completely consumed
in 0.5 h, and gratifyingly, the desired cyclopentenone 3 was formed
in 8% yield along with unhydrolyzed cyclopentadienylic acetate
28 (65% yield; Table 1, entry 1). When wet CH2Cl2 was used as
9
reaction solvent, the yield of 3 was increased dramatically to 92%,
while a small amount of 2 was observed by 1H NMR during most
of the reaction period (Table 1, entry 2). No double bond isomer
of 3 was observed. It is noteworthy that C-3 of cyclopentenone 3
was derived from the carbonyl group of hexanal, and the other
ring carbons were from the enyne moiety of 2-methylbut-1-en-3-
yne. The effectiveness of AuCl(PPh3)/AgSbF6 was evident, as other
catalysts were either less efficient (e.g., AuCl3 and PtCl2; Table 1,
entries 3-5) or incompetent (e.g., AgSbF6 and TfOH; Table 1,
entries 6 and 7).
With these results in hand, we set out to examine the scope of
this reaction. As shown in Table 2, enynyl acetates derived from
R-branched aldehydes (i.e., compounds 4 and 6) underwent smooth
reaction, and the corresponding cyclopentenones were isolated in
excellent yields (entries 1 and 2), indicating steric tolerance at the
9
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J. AM. CHEM. SOC. 2006, 128, 1442-1443
10.1021/ja057327q CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. AuCl(PPh3)/AgSbF6-Catalyzed Formation of
mation of H in both pathways. It is striking that cations D, E, and
G do not undergo hydrolysis to any significant extent, presumably
due to rapid ensuing transformations. When R in H is an alkyl
group, hydrolysis of the enol acetate moiety occurs, and cyclopen-
Cyclopentenonesa
tenone J is formed as final product. The catalyst for hydrolysis of
-
H is proposed to be H3O+SbF6-, instead of [Au(PPh3)]+SbF6
,
based on the following observations: (1) AuCl(PPh3)/AgSbF6 (up
to 5 mol %) hydrolyzed 2 in wet CD2Cl2 very slowly; (2) AuCl-
(PPh3)/AgSbF6 (1 mol %) hydrolyzed 2 quickly (in less than 30
min) when 2 was mixed with 1 equiv of enynyl acetate 1; (3) when
a mixture of 1 and 2 was treated with the Au(I) catalyst, the
consumption of 1 could be stopped halfway by the addition of
BnSMe,11 while 2 was continuously hydrolyzed; (4) HOAc did not
efficiently promote the hydrolysis; however, 2 was completely
converted into enone 3 in 10 min with 1 mol % of HNTf2.
-
Presumably a small amount of H3O+SbF6 was generated during
-
the reaction of [Au(PPh3)]+SbF6 with 1. In the cases of aryl
-
compounds 20 and 23, either H3O+SbF6 was not generated or it
was consumed via the formation of a stable benzylic-type cation.
In conclusion, we have developed a highly efficient method for
the synthesis of versatile cyclopentenones from enynyl acetates via
tandem Au(I)-catalyzed 3,3-rearrangement and the Nazarov reaction.
Significant substrate flexibility and excellent control of the double
bond position in the cyclopentenone ring render this an attractive
method for cyclopentenone synthesis.
Acknowledgment. This research was supported by the Uni-
versity of Nevada, Reno. We thank one of the reviewers for insight-
ful suggestions and Professors Masato Koreeda and Thomas W.
Bell for helpful discussions.
Supporting Information Available: Experimental procedures,
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Substrate concentrations are 0.05 M. b Isolated yields. c Containing
about 6% of the trans-5,7-fused enone and 6% of an isomer with the C-C
double bond at ring juncture. d See text.
Scheme 2. Proposed Mechanism for the Formation of
Cyclopentenones
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The mechanism of this remarkable reaction is hypothesized in
Scheme 2. Pentadienylic cation D is generated via cationic Au(I)-
catalyzed tandem 3,3-rearrangement of enynyl acetate C and activa-
tion of the in situ generated allenylic acetate. Subsequent electro-
cyclic ring closure of D forms Au-containing cyclopentenylic cation
E, which should be in resonance with Au carbenoid species F.
While cyclopentadienylic acetate H can be formed from E/F via
either regioselective 1,2-hydride shift followed by the collapse of
cation G or E1-type elimination assisted by H2O and protonation
of alkenylgold intermediate I, interestingly, both pathways seem
operative as partial deuterium incorporation at the cyclopentenone
2 position of 3 was observed when CH2Cl2 saturated with D2O
was used.10 Remarkably, Au(I) seems to assist highly selective for-
(7) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804-16805.
(8) Compound 2 was not very stable on silica gel column. However, quick
flash column allowed its isolation and characterization.
(9) Generated by shaking distilled CH2Cl2 with deionized water in a separatory
funnel.
(10) This experiment was suggested by one reviewer. The incorporation of
deuterium was estimated to be 24% by 1H NMR and 2H NMR.
(11) BnSMe was used to poison the cationic Au(I) catalyst, while it is not
basic enough to neutralize the acid generated during the reaction.
JA057327Q
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