Gold-catalyzed efficient formation of α,β-unsaturated ketones from propargylic acetates

Article abstract of DOI:10.1002/adsc.200600579

An efficient gold-catalyzed method for the preparation of α,β-unsaturated ketones from propargylic acetates has been developed. Under mild reaction conditions, β-monosubstituted enones were formed mostly with excellent E-selectivity. β,β-Disubstituted enones can be prepared from propargylic acetates derived from ketones. The high efficiency and mild nature of this reaction render it a viable alternative for the synthesis of α,β-unsaturated ketones.

Full text of DOI:10.1002/adsc.200600579

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DOI: 10.1002/adsc.200600579
Gold-Catalyzed Efficient Formation of a,b-Unsaturated Ketones
from Propargylic Acetates
Meng Yu,a Guotao Li,a Shaozhong Wang,a and Liming Zhanga,*
a
Department of Chemistry/MS216, University of Nevada, 1664 North Virginia Street, Reno, Nevada 89557, USA
Fax : (+1)-775-784-6804; e-mail: lzhang@chem.unr.edu
Received: November 8, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient gold-catalyzed method for
the preparation of a,b-unsaturated ketones from
propargylic acetates has been developed. Under
mild reaction conditions, b-monosubstituted enones
were formed mostly with excellent E-selectivity.
b,b-Disubstituted enones can be prepared from
propargylic acetates derived from ketones. The high
efficiency and mild nature of this reaction render it
a viable alternative for the synthesis of a,b-unsatu-
rated ketones.
acetates. Notably, besides the ready access to sub-
strates[9] and high efficiency of this reaction, excellent
E-selectivities were observed in most cases of b-mon-
osubstituted enones.
We have previously shown that propargylic esters
derived from aldehydes can be converted into a range
of synthetically important products, including alkenyl
enol esters/carbonates,[8a] a-ylidene-b-diketones,[8b] cy-
clopentenones[8c] and highly functionalized 2,3-indo-
line-fused cyclobutanes[8d] in the presence of gold cat-
alysts. All these transformations can be rationalized
by invoking a common, reactive, Au-containing alke-
Keywords: catalysis; gold; hydrolysis; ketones;
propargylic acetates; rearrangement
nylacyloxocarbenium intermediate (i.e.,
A
in
Scheme 1), formed via tandem Au-catalyzed 3,3-rear-
a,b-Unsaturated ketones are essential functional
groups in organic synthesis. Among various general
methods for their preparation, isomerizations of read-
ily accessible propargylic alcohols, i.e., the Meyer–
Schuster rearrangement[1] and the Rupe rearrange-
ment,[2] have, however, rather limited usage largely
due to narrow substrate scopes and harsh reaction
conditions.[3]
Recent discoveries of the exceptional ability of Au
catalysts to activate carbon-carbon triple bonds[4]
have created new opportunities for developing much
milder reactions for the formation of a,b-unsaturated
ketones/esters from propargylic precursors.[5] For ex-
ample, Utimoto[6] reported an efficient transformation
of methyl propargyl ethers into a,b-unsaturated ke-
tones using NaAuCl4·2H2O in refluxing MeOH. Re-
Scheme 1. Design of the Au-catalyzed formation of a,b-un-
saturated ketones from propargylic esters.
cently, Dudley[7] developed an AuCl3-catalyzed rangement of propargylic esters and activation of the
Meyer–Schuster rearrangement of terminally ethoxy- in situ generated carboxyallenes. Following this line of
substituted proparyl alcohol, leading to an efficient reasoning, propargylic esters could be converted into
formation of a,b-unsaturated ethyl esters.
a,b-unsaturated ketones via hydrolysis/protodeutera-
In our continuing effort in developing new synthet- tion of intermediate A, as shown in Scheme 1. While
ic methods via Au catalysis,[8] we discovered and conceptually straightforward, this reaction would be
herein report an efficient, Au
A
synthesis of a,b-unsaturated ketones from propargylic ketones, as elimination to form enynes can be delete-
Adv. Synth. Catal. 2007, 349, 871 – 875
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871

Meng Yu et al.
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Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
Solvent
Time
Conversion [%][b]
Yield [%][b]
1
2
3
4
5
10 mol% AuCl3
wet CH2Cl2
wet CH2Cl2
2 h
2 h
>99
25
90
55
55
95
90
95[e]
95
55
95
10 mol% (Ph3P)AuCl/AgSbF6
2 mol% (Ph3P)AuCl/AgSbF6
2 mol% (Ph3P)AuCl/AgSbF6
2 mol% (Ph3P)AuCl/AgSbF6
>99
[c]
wet CH2Cl2
16h
16h
16h
16h
16 h
16 h
16h
16h
60
62
2-butanone[d]
acetone[d]
[c]
>99
>99
>99
62 mol% Au
7
8
9
A
wet CH2Cl2
U
2-butanone[d]
2-butanone/H2O (160/1)
acetone[d]
2 mol% Au
2 mol% Au
U
>99
[c]
60
[f]
10
2 mol% LAuNTf2
2-butanone[d]
>99
[a]
[b]
The concentration of 1 is 0.05M.
Conversion refers to consumption of propargylic acetate. Yield estimated by H NMR using 1,2,3,4-tetramethylbenzene
1
as internal standard.
Catalyst decomposed.
Regular acetone or 2-butanone was used.
[c]
[d]
[e]
80% isolated yield in small scales due to the volatility of 2. In a large scale with 0.5M of 1 (2-butanone/H2O=80 :1), the
reaction finished in 4 h, and 2 was isolated in 90% yield.
L=2-(dicyclohexylphosphino)biphenyl.
[f]
rious and the formation of A could be hindered by 2-butanone was probed, and a mixture of dried 2-bu-
adverse steric interactions. tanone and H2O (160/1) again led to high yield of 2
We began with oct-3-yn-2-yl acetate (1), readily (entry 8). More elaborate phosphine ligands, such as
available from 1-hexyne and acetaldehyde. A range of 2-(dicyclohexylphosphino)biphenyl, also worked well
reaction conditions were tested and some of the re- for this reaction (entry 10). We decided to choose the
sults are listed in Table 1. While AuCl3 indeed led to reaction conditions in entry 7 to further study this re-
the desired enone 2 albeit in low yield (entry 1), action.
(Ph3P)AuCl/AgSbF6 catalyzed the formation of 2 effi-
The scope of this chemistry with propargylic ace-
ciently (entry 2), indicating cationic Au(I) complexes tates derived from aldehydes is shown in Table 2. Var-
to be the preferred catalysts. Noteworthy is the high ious substituents at the propargylic position of acetate
E-selectivity of this reaction, and Z-2 was not ob- 3 were allowed, including aryl groups (entries 1, 5, 6
served. In an attempt to lower catalyst loading, we and 7) and sterically demanding groups (entries 3 and
screened different solvents. With
(Ph3P)AuCl/AgSbF6, the reaction was incomplete date a range of substituents such as phenyl (entries 1
even after 16h due to catalyst decomposition in and 2) and cyclohexyl (entry 5) groups. Good to ex-
2
mol% of 4). Likewise, the alkyne terminus of 3 can accommo-
either wet CH2Cl2 or regular 2-butanone. Interesting- cellent yields of the desired b-monosubstituted enone
ly, acetone proved to be a suitable solvent, and enone 4 were obtained. Moreover, excellent E-selectivity
2 was formed in excellent yield (entry 5). Although a was observed in all the studied cases except in entry 5
combination of (Ph3P)AuCl/AgSbF6 and acetone (E/Z=8/1). Not surprisingly, acetate 3 with a terminal
seemed ideal, [Au
(PPh3)]+[SbF6]À was prone to de- alkyne (R1 =Ph and R2 =H) did not yield enone 4,
A
composition and had to be prepared in situ; more- and the major product was 1-acetoxy-1-phenylpropan-
over, we were concerned that the high reactivity of 2-one, formed via Au-catalyzed Markovnikov hydra-
this catalyst could result in significant elimination in tion of the carbon-carbon triple bond in 54% yield.[11]
the cases of propargylic acetates dervied from ketones
(vida infra). Consequently, we chose as catalyst Au- derived from ketones proved to be challenging as
(PPh3)NTf2,[10] which is isolable and less reactive. As elimination to form enynes and other side reactions
Expansion of this chemistry to include substrates
ACHTREUNG
shown in entries 6–9, this compound did catalyze the became significant. After much effort in optimizing
formation of 2, and regular 2-butanone turned out to the reaction conditions, we found that 5 mol % of
be the best solvent (entry 7). The amount of H2O in Au(PPh3)NTf2 (prepared as a 0.05M solution in ace-
A
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Formation of a,b-Unsaturated Ketones from Propargylic Acetates
Table 2. Preparation of b-monosubstituted E-a,b-unsaturated ketones.
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Entry
1
Propargylic acetate 3
Time [h]
16
Enone 4
Yield [%][a]
3a
3b
4a
4b
82
78
2
3
24
16
3c
4c
92
90
4
5
6
3d
16
16
12
12
4d
3e
3f
3g
4e
4f
4g
88[b]
88
7
90
[a]
Isolated yield.
An E/Z (8/1) mixture was formed and isolated.
[b]
tone) in acetonitrile/H2O (80/1) gave rather clean re- alkyl groups including the sterically demanding cyclo-
actions. The use of acetonitrile presumably attenuated hexyl (entry 6), but only 22% of the enone product
the reactivity of Au
(PPh3)NTf2 through solvent coor- was isolated when R3 =Ph and R1, R2 =cyclohexyl,
G
dination as the conditions in Table 2 (2-butanone as and the enal was not formed when R3 =H and R1,
solvent) always led to competitive elimination. Inter- R2 =cyclohexyl. Attempts to expand this reaction to
estingly, Au(PPh3)NTf2 generated as a solution in ace- include substrates derived from hindered ketones
G
tonitrile instead of acetone led to much slower reac- were not successful. For example, in the case of 1-ada-
tions under otherwise identical conditions. Table 3 mantyl methyl ketone, the enone formation was very
shows the scope of this reaction using the optimized sluggish, while elimination to form enyne became the
conditions. Hence, not only was the propargylic ace- predominant process when 2-butanone was used as
tate 5a derived from acetone an excellent substrate solvent.
(entry 1), but also 5b with more steric hinderance at
the propargylic position reacted well under the condi-
In summary, we have developed an efficient Au-
(PPh3)NTf2-catalyzed reaction for the formation of
ACHTREUNG
tions (entry 2). Compound 5 derived from cyclic ke- a,b-unsaturated ketones. Under mild reaction condi-
tones such as cyclopentanone (entry 5), cyclohexa- tions, not only propargylic acetates derived from alde-
none (entry 3), and cycloheptanone (entry 4) under- hydes but also those from ketones can be converted
went similar efficient reactions, leading to the corre- into a,b-unsaturated ketones in good to excellent
sponding enones in good to excellent yields. Interest- yields. Moreover, excellent E-selectivity was observed
ingly, R3 of compound
substantially. Hence, the reaction was efficient with
5 affects the reaction in most cases of b-monosubstituted enones.
Adv. Synth. Catal. 2007, 349, 871 – 875
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873

Meng Yu et al.
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Table 3. Preparation of b,b-disubstituted a,b-unsaturated ketones.
Entry
1
Propargylic acetate 5
Time [h]
16
Enone 6
Yield [%][a]
98
5a
5b
5c
6a
6b
6c
2
3
24
16
88[b]
97
4
5
5d
5e
16
16
6d
6e
83
82
6
5f
20
6f
93
[a]
Isolated yield.
E/Z=4/1.
[b]
(hexanes/ethyl acetate=20/1) to yield the desired b,b-disub-
stituted ketones.
Experimental Section
General Procedure for the Preparation of b-
Monosubstituted a,b-Unsaturated Ketones
Acknowledgements
To a solution of propargylic acetate derived from an alde-
hyde (0.2 mmol) in regular 2-butanone (4 mL) was added
This work is supported by the University of Nevada, Reno
and ACS PRF (#43905-G1).
Au(PPh3)NTf2 (2.7 mg, 0.004 mmol) at room temperature.
A
The reaction mixture was stirred for the indicated time
before being quenched with NEt3. The reaction mixture was
concentrated, and the resulting residue was purified through
silica gel flash column chromatography (hexanes/ethyl ace-
tate=20/1) to yield the desired a,b-unsaturated ketones 4.
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Disubstituted a,b-Unsaturated Ketones 6
To a solution of propargylic acetate 5 derived from a ketone
(0.2 mmol) in anhydrous acetonitrile (4 mL) cooled in ice-
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was purified through silica gel flash column chromatography
874
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Formation of a,b-Unsaturated Ketones from Propargylic Acetates
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Adv. Synth. Catal. 2007, 349, 871 – 875
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
875