Olefination of ketones using a gold(III)-catalyzed Meyer-Schuster rearrangement

Article abstract of DOI:10.1021/ol0616743

An atom-economical and efficient olefination strategy for ketones is described. Ethoxyacetylide addition followed by a gold-catalyzed Meyer-Schuster rearrangement affords α,β-unsaturated esters, generally in excellent overall yield from the starting ketones. The alkynophilicity of Au³⁺ promotes an interaction with the electron-rich acetylenes that catalyzes the Meyer-Schuster rearrangement selectively over other conceivable pathways.

Full text of DOI:10.1021/ol0616743

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4027-4029
Olefination of Ketones Using a
Gold(III)-Catalyzed Meyer−Schuster
Rearrangement
Douglas A. Engel and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State UniVersity,
Tallahassee, Florida 32306-4390
gdudley@chem.fsu.edu
Received July 7, 2006
ABSTRACT
An atom-economical and efficient olefination strategy for ketones is described. Ethoxyacetylide addition followed by a gold-catalyzed Meyer
−
Schuster rearrangement affords
r,â-unsaturated esters, generally in excellent overall yield from the starting ketones. The alkynophilicity of
+
Au3 promotes an interaction with the electron-rich acetylenes that catalyzes the Meyer
−Schuster rearrangement selectively over other conceivable
pathways.
The Meyer-Schuster reaction is a little-known but poten-
tially powerful rearrangement that converts propargyl alco-
hols into R,â-unsaturated carbonyl compounds.1 The process
formally involves a 1,3-shift of the hydroxyl moiety (Scheme
1), followed by tautomerization of the presumed allenol
the acetylenic alcohol, but limited scope, harsh conditions,
and a prevalence of side reactions have detracted from the
utility of the Meyer-Schuster rearrangement.
Closely related to the Meyer-Schuster is the Rupe
rearrangement of propargyl alcohols,1 which yields an
isomeric R,â-unsaturated carbonyl compound via an inter-
mediate enyne.6 For the Meyer-Schuster reaction to succeed,
the initial dehydration leading to the Rupe rearrangement
must be blocked7 or otherwise suppressed.
Scheme 1. Meyer and Schuster’s Rearrangement
(4) (a) Erman, M. B.; Aul’chenko, I. S.; Kheifits, L. A.; Dulova, V. G.;
Novikov, J. N.; Vol’pin, M. E. Tetrahedron Lett. 1976, 2981. (b) Chabardes,
P. Tetrahedron Lett. 1988, 29, 6253. (c) Choudary, B. M.; Durga Prasad,
A.; Valli, V. L. K. Tetrahedron Lett. 1990, 31, 7521. (d) Narasaka, K.;
Kusama, H.; Hayashi, Y. Chem. Lett. 1991, 1413. (e) Lorber, C. Y.; Osborn,
J. A. Tetrahedron Lett. 1996, 37, 853. (f) Picquet, M.; Ferna´ndez, A.;
Bruneau, C.; Dixneuf, P. H. Eur. J. Org. Chem. 2000, 2361. (g) Suzuki,
T.; Tokunaga, M.; Wakatsuki, Y. Tetrahedron Lett. 2002, 43, 7531.
(5) Chabardes, P.; Kuntz, E.; Varagnat, J. Tetrahedron 1977, 33, 1775.
(6) The Rupe rearrangement (Rupe, H.; Kambli, E. HelV. Chim. Acta
1926, 9, 672):
intermediate, I.2 The reactions first reported by Meyer and
Schuster3 were conducted in acidic media at elevated
temperatures. Transition metals4 and metal oxide5 catalysts
promote the rearrangement via more targeted activation of
(1) Swaminathan, S.; Narayanan, K. V. Chem. ReV. 1971, 71, 429.
(2) (a) Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Sciavelli, M. D.
J. Org. Chem. 1977, 42, 3403. (b) Andres, J.; Cardenas, R.; Silla, E.; Tapia,
O. J. Am. Chem. Soc. 1988, 110, 666.
(7) For example, per-phenyl propargyl alcohol 2a cannot undergo the
Rupe rearrangement without breaking aromaticity. Most early examples of
the Meyer-Schuster reaction were on substrates with aryl or tert-butyl
substituents. See ref 1.
(3) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819.
10.1021/ol0616743 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/02/2006

Propargyl alcohols 2 are commonly prepared by addition
of acetylide nucleophiles to carbonyl compounds. Compared
to many carbanion nucleophiles, acetylides are less basic and
less sensitive to steric congestion around the electrophilic
carbonyl partner. The idealized sequence of (1) addition of
a terminal acetylene and (2) Meyer-Schuster rearrangement
results in olefination of the carbonyl with complete atom
economy (Scheme 2).8 This two-step strategy would be
Table 1. Initial Screening of Substratesa
entry
R1
R2 R3
2
time
3
yield (%)c
1
2
3
4
5
6
7
8b
Ph
Et
Ph
Ph
Ph Ph 2a o/nd
Et Ph 2b o/nd
H
Ph OEt 2d <5 min 3d
OEt 2e <5 min 3e
OEt 2f <5 min 3f
Me OEt 2g <5 min 3g
Me OEt 2g 1 h
3a
3b
3c
86
<20e
32
>95
82
>95
86
<15f
Ph 2c o/nd
Scheme 2. Atom-Economical HWE-Type Olefination Strategy
4-t-Bu-cyclohexyl
adamantyl
t-Bu
t-Bu
3g
a Typical procedure: Gold(III) chloride (0.1 mmol) added to a solution
of propargyl alcohol 2 (0.5 mmol), EtOH (2.5 mmol), and CH2Cl2 (8 mL)
at room temperature. See Supporting Information for details. b TsOH‚H2O
(0.1 mmol) was employed in lieu of AuCl3 in entry 8. c Isolated yield of
pure product, unless otherwise indicated. d Overnight (12-16 h). e The major
product of this reaction was the enyne derived from dehydration of 2b (57%
yield). f The isolated mixture consisted of three major componentss2g, 3g,
and an unknown byproduct in a ca. 70:15:15 mole ratiosalong with minor
decomposition products.
particularly valuable for the Horner-Wadsworth-Emmons
(HWE)-type olefination9 of hindered ketones. It was this
potential utility that stimulated our interest in developing a
mild and generally efficient protocol for conducting the
Meyer-Schuster reaction.
Gold(III) chloride (AuCl3) emerged as the preferred choice
from our initial screening of various catalysts and condi-
tions.10 The high affinity of late transition-metal Lewis acids,
particularly gold-based catalysts, for acetylenic π-bonds
enables many important processes to be achieved under mild
conditions.11 This mode of activation has become increas-
ingly important in recent years.12 In contrast, Brønsted, main-
group, and early transition-metal Lewis acids bind prefer-
entially to harder Lewis basic sites.13 Thus, AuCl3 likely
promotes the Meyer-Schuster rearrangement through a
fundamentally different type of catalyst-substrate interaction
than known metal oxide or protic acid catalysts. The
alkynophilicity of gold catalysts should be advantageous in
improving the selectivity for the Meyer-Schuster reaction
in preference to the Rupe or dehydration processes.
Table 1 shows gold catalysis of the Meyer-Schuster
rearrangement,14 with the “original” substrate (2a) listed in
entry 1. The relatively high catalyst loading (20 mol %)
provided complete and efficient conversion in a reasonable
time frame (12-16 h), affording 3a in 86% yield. However,
the experiments illustrated in entries 215 and 316 serve as a
reminder of the limited scope of the Meyer-Schuster
process.
The use of oxygen-activated alkynes expands the scope
to a much wider range of substitution patterns (entries 4-7).
The ethoxyacetylene substrates were easily prepared using
ethyl ethynyl ether,17 and the gold-catalyzed Meyer-Schuster
rearrangements were complete within minutes. The resulting
R,â-unsaturated ethyl esters (3, R3 ) OEt) are versatile
synthetic intermediates.18 Entries 7 and 8 illustrate the
difference between gold(III) chloride and a catalyst (TsOH)
that is less alkynophilic. The acid-catalyzed reaction (entry
8) was sluggish and less selective for the desired Meyer-
Schuster product (3g).19
(8) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259.
Table 2 recounts efforts to determine the minimum catalyst
loading needed to effect the Meyer-Schuster rearrangement
of ethoxyacetylene 2f: full conversion was achieved at 5
mol % (entries 1-5).20 These conditions were appropriate
(9) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(10) Metal oxides, protic acids of varying strengths, and silica gel were
explored. These oxophilic reagents did not provide good prospects for
expanding the scope of the Meyer-Schuster rearrangement.
(11) Recent reviews with leading references: (a) Dyker, G. Angew.
Chem., Int. Ed. 2000, 39, 4237. (b) Hashmi, A. S. K. Gold Bull. 2003, 36,
3. (c) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200.
(12) Selected examples of gold(III) catalysis of organic reactions: (a)
Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729. (b) Fukuda, Y.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 2013. (c) Asao, N.; Takahashi,
K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,
12650. (d) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
11164. (e) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962.
(f) Antoniotti, S.; Genin, E.; Michelet, V.; Geneˆt, J.-P. J. Am. Chem. Soc.
2005, 127, 9976. (g) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am.
Chem. Soc. 2005, 127, 14180 (including two examples of Meyer-Schuster
products). (h) Kusama, H.; Miyashita, Y.; Takaya, J.; Iwasawa, N. Org.
Lett. 2006, 8, 289. Examples and leading references on gold(I) catalysis:
(i) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2005, 127, 18002. (j) Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour,
C.; Geneˆt, J.-P.; Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112.
(13) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-
VCH: New York, 2000.
(14) Small amounts of an alcoholic cosolvent (e.g., 5.0 equiv of ethanol)
increased the efficiency of the reaction.
(15) Entry 2 highlights the competition between simple dehydrations
leading to an undesired enyne in 57% yieldsand the formal 1,3-hydroxy
shift en route to 3b.
(16) Mixtures of alkene stereoisomers were obtained in entries 3, 7, and
8. No effort was made to optimize selectivity; the E:Z ratios were nearly
1:1 in some cases (e.g., entry 7). Given the general thermodynamic
preference for E-isomers, these data suggest the possibility of a kinetic
preference for the Z-isomers, which will be investigated further.
(17) A commercial 40% solution in hexane was used as received.
(18) Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139.
(19) Aqueous acidic conditions were also tested for 2e f 3e (cf. Table
1, entry 5): reactions in THF-H2O (1:1) promoted by either AcOH or
HCl were incomplete after 1 h. Such acidic conditions are also more likely
to promote undesired side reactions.
4028
Org. Lett., Vol. 8, No. 18, 2006

Table 2. Catalyst Loading and Optimizationa
Table 3. Olefination of Hindered Ketonesa
entry
R1
R2
2
AuCl3
3
conversion (%)
1
2
3
4
5
6
7
8
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
Ph
2f 20 mol % 3f
2f 10 mol % 3f
>95
>95
>95
ca. 50b
<5b
>95
>95
>95
2f 5 mol %
2f 1 mol %
3f
3f
2f 0.1 mol % 3f
Ph
Me
2d 5 mol %
2g 5 mol %
n-Bu 2h 5 mol %
3d
3g
3h
t-Bu
n-Bu
a Typical procedure: Gold(III) chloride added to a solution of propargyl
alcohol 2 (1 equiv), EtOH (5 equiv), and CH2Cl2 in an open flask at room
temperature. See Supporting Information for details. b After 24 h.
for aliphatic, aromatic, hindered, and unhindered substrates
(entries 6-8). In conjunction with addition of ethoxyacety-
lene to ketones (1 f 2, R3 ) OEt), the Meyer-Schuster
rearrangement (2 f 3) completes, in principle, an efficient
HWE-type olefination strategy.
a See Supporting Information for details. b Ca. 4:3 ratio of olefin isomers.
c Ca. 2:1 ratio of olefin isomers. d 10 mol % of AuCl3 employed. Value in
parentheses is the calculated yield based on recovered ketone 1.
Diverse ketone substrates were subjected to the two-stage
olefination process without purification of the intermediate
propargyl alcohols (Table 3). Benzophenone (1d), adaman-
tanone (1f), and pinacolone (1g) gave rise to alkenes 3d, 3f,
and 3g in good to excellent yields (entries 1-3). Dienonate
3i was obtained from verbenone (1i) in nearly quantitative
yield (entry 4). The efficiency of the acetylide addition
dropped for camphor (1j) and 3,3,5,5-tetramethylcyclohex-
anone (1k), although alkenoates 3j and 3k were isolated in
reasonable overall yields (entries 5 and 6).
In summary, an atom-economical olefination strategy is
realized. The ketones evaluated herein comprise aromatic,
aliphatic, and vinyl ketones; cyclic and acyclic ketones; and
primary, secondary, tertiary, and methyl ketones. The power-
ful catalyst-substrate interaction between Au3+ and electron-
rich acetylenes is selective for the Meyer-Schuster rear-
rangement over other conceivable pathways. Current and
future work includes efforts to control the stereoselectivity
of the Meyer-Schuster reaction with respect to E- and
Z-isomers and to apply this olefination strategy to solve
problems in chemical synthesis.
Acknowledgment. This research was supported by the
James and Ester King Biomedical Research Program, Florida
Department of Health, the Donors of the American Chemical
Society Petroleum Research Fund, and the FSU Department
of Chemistry and Biochemistry. D.A.E. is the recipient of
graduate fellowships from FSU and the MDS Research
Foundation. We are profoundly grateful to all of these
agencies for their support. We thank Dr. Joseph Vaughn
(FSU) for assistance with the NMR facilities, Dr. Umesh
Goli (FSU) for providing the mass spectrometry data, and
the Krafft Lab for the use of their FT-IR instrument.
Supporting Information Available: Experimental pro-
cedures, characterization data for all new compounds, and
1
copies of H NMR spectra. This material is available free
(20) On the basis of qualitative (TLC) monitoring of the experiments
using a lower catalyst loading (entries 4 and 5), the reactions appeared to
proceed rapidly and then stall at a certain point. Efforts to increase the
turnover number will be addressed in future work.
of charge via the Internet at http://pubs.acs.org.
OL0616743
Org. Lett., Vol. 8, No. 18, 2006
4029