Lewis acid-catalyzed Meyer-Schuster reactions: methodology for the olefination of aldehydes and ketones

Article abstract of DOI:10.1016/j.tet.2008.02.030

In principle, the most efficient and atom-economical means of converting an aldehyde or ketone into the homologated α,β-unsaturated ester is through addition/rearrangement sequences involving acetylenic π-bonds (Scheme 1). Implementation of such a strategy for the synthesis of α,β-unsaturated esters is presented: addition of ethoxyacetylene followed by scandium(III) triflate-catalyzed Meyer-Schuster rearrangement reaction. Stereoselectivities range from good to excellent in the formation of disubstituted α,β-unsaturated esters from aldehydes (Table 3). The two-stage olefination of even the most hindered ketones proceeds with near perfect efficiency (Table 4).

Full text of DOI:10.1016/j.tet.2008.02.030

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6988e6996
www.elsevier.com/locate/tet
Lewis acid-catalyzed MeyereSchuster reactions: methodology
for the olefination of aldehydes and ketones
*
Douglas A. Engel, Susana S. Lopez, Gregory B. Dudley
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, United States
Received 15 January 2008; received in revised form 7 February 2008; accepted 8 February 2008
Available online 14 February 2008
Abstract
In principle, the most efficient and atom-economical means of converting an aldehyde or ketone into the homologated a,b-unsaturated ester is
through addition/rearrangement sequences involving acetylenic p-bonds (Scheme 1). Implementation of such a strategy for the synthesis of
a,b-unsaturated esters is presented: addition of ethoxyacetylene followed by scandium(III) triflate-catalyzed MeyereSchuster rearrangement
reaction. Stereoselectivities range from good to excellent in the formation of disubstituted a,b-unsaturated esters from aldehydes (Table 3).
The two-stage olefination of even the most hindered ketones proceeds with near perfect efficiency (Table 4).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: MeyereSchuster; Scandium(III) triflate; Ethoxyacetylene; Aldehyde; Ketone; Olefination
1. Introduction
of this strategy depends on the nature of the alkyne. Highly
electron-rich alkynes (i.e., ynolates,4 ynamines,5 or ynamides,6
Scheme 1a) react with carbonyl compounds via an annulation
(formal [2þ2] cycloaddition) process to produce an intermedi-
ate oxetene, which can undergo electrocyclic ring opening to
produce the homologated enoate/amide. Notably, Shindo
recently extended the use of ynolates to the homologation
(olefination) of esters (Y¼OLi, R1¼OR).7
The homologation of aldehydes and ketones to a,b-unsatu-
rated esters, an indispensable tool for generating carbonecar-
bon bonds, is typically achieved using aldol condensation,1
Wittig, HornereWadswortheEmmons (HWE), or other olefi-
nation method.2 Of these, the aldol condensation is most
attractive from an atom economy3 standpoint in that water is
the only by-product, but Wittig or HWE reaction using stoi-
chiometric phosphines, phosphine oxides, or phosphonates
often provides higher yields of a,b-unsaturated ester products.
Furthermore, these reactions produce phosphorus by-products
that can interfere with the isolation of the desired products.
Whether using designer olefination reagents or a traditional
aldol condensation protocol, these homologation reactions
are sensitive to steric congestion around the carbonyl, such
that olefination of hindered ketones can be problematic.
In principle, an efficient and atom-economical means of
converting an aldehyde or ketone into the homologated
a,b-unsaturated ester is through addition/rearrangement se-
quences involving acetylenic p-bonds (Scheme 1). Realization
O
R2
4
electrocyclic
[2 + 2]
Y
O
O
ring-opening
annulation
R2
Y
R1
R3
Y
R1 R2
R3
(a) stepwise annulation / electrocyclic ring-opening
R1
R3
O
R2
acetylide
addition
Meyer–Schuster
rearrangement
R2
O
R3
R1
R1
R3
H
R1 R2
R3
(b) nucleophilic 1,2-addition / rearrangement
Scheme 1. Atom-economical carbonyl olefination strategies.
HO
2
H
3
1
Terminal alkynes offer an alternative addition/rearrange-
ment pathway for the homologation of aldehydes and ketones
that can be executed in the two-stage process outlined in
Scheme 1b: (1) alkyne addition to the carbonyl and (2)
* Corresponding author. Tel.: þ1 850 644 2333.
E-mail address: gdudley@chem.fsu.edu (G.B. Dudley).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.030

D.A. Engel et al. / Tetrahedron 64 (2008) 6988e6996
6989
R2
intermediate tertiary ethoxyalkynyl carbinols occurred within
minutes of adding the catalyst. The MeyereSchuster reactions
were conducted open to the air without external heating or
cooling. Yields for both the acetylide addition and the formal
rearrangement18 were essentially quantitative in the majority
of cases, but stereocontrol of the olefin geometry was non-
existent. The second drawback of the reported conditions is
the requirement for 5 mol % of the (expensive) gold catalyst.
At 5 mol % catalyst loading, the reactions were complete
within minutes, but at 1 mol %, the reaction failed to reach
full conversion even after prolonged reaction times.15
-bonded electrons
of alkyne:
soft Lewis base
non-bonded electrons
on oxygen:
hard Lewis base
R1
R3
OH
Figure 1. Lewis basic sites on a propargyl alcohol.
MeyereSchuster rearrangement.8 The strength of this latter
approach stems from the use of acetylide nucleophiles to gen-
erate the initial carbonecarbon bond; acetylide nucleophiles
are suitable for addition to even the most hindered of carbonyl
systems. Therefore, step (1) of the two-step process is quite
general. The MeyereSchuster rearrangement, on the other
hand, has received little attention9 over the years due to the
limited scope, harsh conditions, and the competing Rupe rear-
rangement pathway.10
Efficient methods for promoting MeyereSchuster rearrange-
ments thereby enable progress in the olefination of aldehydes
and ketones, including hindered ketones that may not be suit-
able substrates for any of the other olefination strategies listed
above. The recent emergence of ‘soft’ Lewis acids11e13doften
late transition metal salts with an affinity for p-bonds over non-
bonded electron pairsdbrings attention to alternative Lewis
basic sites (Fig. 1) and suggests the possibility of exploiting
a previously unexplored mechanism for promoting the Meyere
Schuster rearrangement: activation of the propargylic alcohol
via the alkyne p-bond rather than the hydroxyl group.14
5 mol % AuCl•AgSbF6
10 equiv EtOH
OH
O
R
THF–CH2Cl2 (1:1)
rt, 30–60 min
R
OEt
OEt
2d
2e
R= n-C7H15 (3d): 91% yield, 63:37 E/Z ratio
R = n-C7H15 (3d): 90%, 86:14 (1.0 CSA added)
R = t-butyl (3e): 91%, 97:3
Scheme 2. Gold-catalyzed MeyereSchuster reactions of secondary ethoxy-
alkynyl carbinols 2.
Secondary ethoxyalkynyl carbinols could be converted into
the corresponding ethyl trans-a,b-unsaturated esters with
moderate to good stereocontrol using a mixed catalyst system
of gold(I) chloride and silver(I) hexafluoroantimonate
19
(Scheme 2); inclusion of camphorsulfonic acid as a
co-catalyst resulted in better selectivity for the trans isomer.
1.1. Gold-catalyzed MeyereSchuster reaction
of ethoxyalkynyl carbinols
1.2. Recent advances in the MeyereSchuster reaction
In 2006, we reported gold-catalyzed MeyereSchuster reac-
tions of tertiary ethoxyalkynyl carbinols for the synthesis of
a,b-unsaturated ethyl esters (Eqs. 1e3).15,16 In conjunction
with ethoxyacetylide addition to ketones, this work provided
the blueprint for general implementation of the two-stage ole-
fination strategy outlined above (1/3, R3¼OEt, Scheme 1b)
for the synthesis of a,b-unsaturated esters.
The last few years have seen a surge of interest in the
MeyereSchuster reaction.20 Whereas our Laboratory has
focused on electronically activated propargyl alcohols for the
synthesis of a,b-unsaturated esters,15,19 Zhang and co-workers
reported a method for obtaining a,b-unsaturated ketones
through independent activation of both of the aforementioned
Lewis basic sites of electronically neutral propargyl alcohols
(Eq. 4).20d They and others20f have shown that pre-activation
of the hydroxyl group as an acetate ester followed by
a gold-catalyzed hydrolysis process21 of the propargyl acetate
delivers MeyereSchuster products.22,23 The Yamada Lab used
high-pressure carbon dioxide, base, and a silver catalyst to
merge this multi-step process into a single operation (Eq. 5).20i
A major advantage of using the acetylide addition/Meyere
Schuster reaction strategy for the olefination of aldehydes and
O
CO2Et
1. BuLi, H– –OEt, THF
ð1Þ
ð2Þ
2. AuCl3 (5 mol%)
EtOH (5 equiv), CH2Cl2
99% overall
1a
3a
CO2Et
O
99%, ca. 4:3 ratio of
olefin isomers
1b
3b
OAc (from OH)
O
2 mol% Au(PPh3)NTf2
ð4Þ
2-butanone, 16 h, 97%
Et
Et
O
ð3Þ
CO2Et
1c
3c
96%, ca. 2:1 ratio of
olefin isomers
OH
1.0 MPa CO2
10 mol% AgOMs
O
The combination of the electron-rich ethoxyacetylenic p-
system and soft gold(III) chloride catalyst17 provided excellent
reactivity in the MeyereSchuster reaction: consumption of the
ð5Þ
1.0 equiv i-Pr2NEt
formamide, 48 h, 90%
Ph
Ph

6990
D.A. Engel et al. / Tetrahedron 64 (2008) 6988e6996
ketones (see Scheme 1b, above) is the efficiency of the initial
carbonecarbon bond-forming reaction: alkyne addition. How-
ever, the second stage of this strategydthe MeyereSchuster
reactiondis generally limiting. Therefore, advances in the
MeyereSchuster reaction translate directly into advances in
olefination methods.
however, such as when specific p-Lewis acidity is desired,
this versatility becomes unnecessary and can even be confound-
ing with respect to understanding the reaction mechanism and
predicting new reactivity. Furthermore, the high cost of precious
metals places a premium on maximizing the number and fre-
quency of catalyst turnovers.
In summary, the emergence of late transition metal ‘soft’
Lewis acids has contributed to a renewed interest in the
MeyereSchuster reaction. Several tactics have been employed
to broaden the scope of this reaction and minimize competing
pathways like the Rupe rearrangement, and they all feature the
use of late transition metal (gold, silver, and/or mercury) salts.
This paper describes recent advances in our methodology for
the olefination of aldehydes and ketones using the Meyere
Schuster reaction of ethoxyacetylenes. Data and observations
reported herein include (1) alternative catalysts that are more
economical and widely available than gold or silver salts, (2)
lower catalyst loadings than our previously reported methods
using gold and silver salts, (3) excellent stereoselectivity in
the formation of the E-alkene isomer for most disubstituted
alkenes, and (4) new mechanistic data suggesting that the higher
stereoselectivity associated with the new catalysts may stem
from a subtle alteration of the reaction mechanism.
2.1. Alternative catalysts for the MeyereSchuster reaction
Under the hypothesis that late transition metal-catalysis of
the MeyereSchuster reaction of ethoxyalkynyl carbinols is
strictly derived from Lewis acid/base interactions, we became
interested in identifying similar (or better) catalytic activity in
other Lewis acids. Table 1 provides a summary of our catalyst
screenings, which focused primarily (though not exclusively)
on soft transition metal salts.16
In an open reaction vessel, ethoxyacetylene 2d was dissolved
in methylene chloride and treated with reagent-grade ethanol
(ca. 5e10 equiv) and 1 mol % of various Lewis acid catalysts
(and one protic acid, camphorsulfonic acid, entry1) at room tem-
perature. Reactions were allowed to continue for up to 24 h or
untilTLCanalysisindicated that no2dremained. Theloneprotic
acid (CSA) is listed first; the rest of the table is arranged by the
typical cost of the catalysts (per mole), from lowest to highest.
Fromthis general catalyst screening emerged three top choices:
copper(II) triflate, indium(III) chloride, and scandium(III) triflate.
Of these, indium(III) chloride is the least reactive; the copper and
scandium catalysts are comparable in reactivity. All three are
air-stable powders and are convenient to handle and use.
2. Results and discussion
The use of cationic gold and other precious metal catalysts
offers manyadvantages in synthesis.24 One of thegeneraladvan-
tages of palladium, platinum, gold, and other precious metal cat-
alysts is their ability to engage in redox chemistry through easy
interconversion between oxidation states. In some cases,
Further information on these Lewis acid-catalyzed Meyere
Schuster reactions was gleaned by observing the effect of
additives on the reaction rate (qualitatively) and stereoselectiv-
ity (quantitatively). Table 2 recounts the outcome of a small
Table 1
Screening of alternative catalysts
Table 2
Effect of additives
OH
1 mol% catalyst
CO2Et
C5H11
C5H11
CH2Cl2/EtOH
1 mol% catalyst
<additive>
OH
OEt
2d
3d
CO2Et
C5H11
C5H11
CH2Cl2/EtOH
E/Z Ratioa
OEt
Entry
Catalyst
Time (h)
Conversion
2d
3d
1
CSA
NiCl2$xH2O
CuI
24
24
24
24
24
24
24
24
24
24
1.5
24
0.3
24
1.2
24
24
0
d
d
Entry
Catalyst
Additive
Amount
Time (h)
E/Z Ratioa
2
0
3
0
d
1
2
3
4
5
InCl3
InCl3
InCl3
InCl3
InCl3
None
CSA
d
24
6
84:16
67:33
75:25
91:9
4
Cu(OAc)2
CeCl3$7H2O
HfCl4
Trace
0
n.d.
d
n.d.
n.d.
d
1 mol %
1 mol %
1.0 equiv
1.0 equiv
5
DTBMP
AcOH
MgO
24
24
24
6
Trace
Trace
0
7
ZrCl4
78:22
b
8
Cu(C5H4F3O2)2
Hg(CF3CO2)2
NaReO4
6
7
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
None
CSA
d
1.5
1.5
24
89:11
86:14
76:24
89:11
76:24
9
Trace
0
n.d.
d
1 mol %
1 mol %
1.0 equiv
1.0 equiv
10
11
12
13
14
15
16
17
a
8
DTBMP
AcOH
MgO
Cu(OTf)2
InCl3
Ag(OTf)2
Pd(OAc)2
Sc(OTf)3
PtCl4
100%
100%
100%
<100%c
100%
Trace
<100%c
89:11
84:16
43:57
63:37
90:10
n.d.
>20:1
9
10
<1
24b
11
12
13
14
15
a
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
None
CSA
d
1.2
<1
4
90:10
92:8
91:9
92:8
n.d.
1 mol %
1 mol %
1.0 equiv
1.0 equiv
DTBMP
AcOH
MgO
AuCl3
<1
24c
As observed by 1H NMR.
b
Copper(II) trifluoroacetylacetonate.
Ethoxyacetylene 2d could be detected by TLC analysis but not by 1H
NMR after workup.
As observed by 1H NMR.
Conversion (60%).
Conversion (30%).
c
b
c

D.A. Engel et al. / Tetrahedron 64 (2008) 6988e6996
6991
grid of reactions in which the three top Lewis acid catalyst
choices were each coupled with two acidic and two basic
additives: 1 mol % CSA, 1.0 equiv acetic acid (AcOH),
1 mol % 2,6-di-tert-butyl-4-methylpyridine (DTBMP), and
1.0 equiv magnesium oxide (MgO).
Studying the effect of additives aids in the identification of
optimal conditions, and it provides insight into the reaction
mechanism. Lewis and protic acids catalyze the Meyere
Schuster reaction, so one would expect acidic additives to
accelerate the reaction and basic additives to quench or retard
the reaction. This hypothesis is supported by the data pre-
sented in Table 2. However, the fact that basic additives retard
but do not quench the reaction suggests that protic acid,
though helpful, is not required for catalytic activity. Therefore,
one can choose between a short reaction time (e.g., entries 9 or
14) and reaction conditions that are presumably free of protic
acid (e.g., entry 5).
similar results, with scandium(III) triflate consistently (albeit
perhaps insignificantly) out-performing copper(II) triflate.
From an industrial perspective, the scarcity of scandium salts
is off-set by the fact that scandium(III) triflate is water-soluble,
recoverable after aqueous workup, and reusable without
noticeable loss of activity.25
Entries 1e4 in Table 3 document the comparison between
including ethanol as an additive (5 equiv, as in our earlier stud-
ies)15,19 and employing ethanol as a co-solvent, which pro-
vided superior results under the current conditions (entries 3
and 4). Aliphatic substituents on the propargyl alcohols were
universally tolerated, whether the substituent was linear (2d),
branched (2f), or even quaternary (2e). Some erosion of ste-
reoselectivity was observed in the benzylic case (2g/3g,
entries 11 and 12). Entries 7e10 reveal that stereoselectivity
was better for disubstituted alkenes than trisubstituted alkenes.
OH
All of these experiments were conducted on an exploratory
scale to gauge reactivity and selectivity. Because the scandiu-
m(III) and copper(II) catalysts in the absence of additives were
significantly more reactive and slightly more selective than
indium(III) chloride, the triflate salts were employed through-
out the next stage of the methodology (Table 3).
CO2Et
OEt
3f, 75% yield
2f
1 mol% Sc(OTf)3, 1 h
ð6Þ
rt, CH2Cl2/EtOH (4:1)
O
O
H
N
H
N
Boc
OMe
Boc
OMe
OTBS
R = H: 4
R = TBS: 5
5, 99%
recovery
OR
2.2. Two-stage olefination of aldehydes and ketones
The experiment outlined in Eq. 6 provides insight into the
compatibility of the MeyereSchuster reaction conditions with
common functionality. N-Boc-serine methyl ester (4) was
converted into tert-butyldimethylsilyl (TBS) ether 5, which
was then included in the reaction mixture during the conver-
sion of 2f to 3f (75% yield; cf. Table 3, entry 6). Recovery
of 5 from this control experiment in 99% yield indicates that
the present MeyereSchuster reaction conditions will prove
to be compatible with typical alkyl esters, amine carbamates,
and silyl ethers.
When performed immediately following addition of ethoxy-
acetylene to a carbonyl compound, the MeyereSchuster
reactions described above complete a two-stage olefination of
aldehydes and ketones. Illustrative examples are presented in
this section.
Scandium(III) and copper(II)-catalyzed MeyereSchuster
reactions of secondary and tertiary propargyl alcohols are
shown in Table 3 (2/3). In all cases, both catalysts provided
Table 3
Scope and stereoselectivity
OH
R2
R1
R2
O
1 mol% catalyst
EtO–C≡C–H
n-BuLi, THF
CO2Et
R1 R2
R1
CH2Cl2/EtOH (4:1)
OEt
1
2
3
Entry
1
2 (Yield %)a
Catalyst
R1
R2
H
3
Yield (%)
E/Z Ratioa
1b
2b
3
Cu(OTf)2
Sc(OTf)3
Cu(OTf)2
Sc(OTf)3
53
63
64
70
91:9
(E only)
97:3
CO2Et
Octanal (1d)
2d (>99)
n-Heptyl
3d
C5H11
4
(E only)
CO2Et
5
6
Cu(OTf)2
Sc(OTf)3
71
75
(E only)
(E only)
Cyclohexane-carboxaldehyde (1f)
Pivaldehyde (1e)
2f (76)
2e (97)
2b (83)
Cyclohexyl
tert-Butyl
tert-Butyl
H
3f
CO2Et
7
8
Cu(OTf)2
Sc(OTf)3
94
97
(E only)
(E only)
H
3e
3b
9
10
Cu(OTf)2
Sc(OTf)3
86
89
57:43
58:42
CO2Et
CO2Et
Pinacolone (1b)
Me
11
12
Cu(OTf)2
Sc(OTf)3
90
93
76:24
77:23
Benzaldehyde (1g)
2g (92)
Phenyl
H
3g
a
As observed by 1H NMR.
EtOH (5.0 equiv) in CH2Cl2.
b

6992
D.A. Engel et al. / Tetrahedron 64 (2008) 6988e6996
5 mol% [Au+]
Given the dearth of methods suitable for the homologation
OH
of hindered ketones into a,b-unsaturated esters,26 the two-
stage acetylide addition/MeyereSchuster strategy as applied
to hindered ketones is particularly valuable. We earlier inves-
tigated the utility of gold(III) chloride (5 mol %) as a catalyst
for such processes.15 Table 4 illustrates that only 1 mol % of
the less-expensive scandium(III) triflate provides similarly
outstanding results: near-quantitative overall yield for the ole-
fination of menthone (entry 1, 1h/3h, 98%),26 verbenone
(entry 2, 1c/3c, 97%), benzophenone (entry 3, 1i/3i,
99%), and adamantanone (entry 4, 1a/3a, 96%). Verbenone
gave rise to 3c as a 58:42 mixture of olefin isomers, whereas
the isomeric mixture of esters 3h could not be reliably esti-
5.0 equiv EtOH
CO2Et
R
R
THF–CH2Cl2 (1:1)
OEt
2
3
EtOH
–H2O
H3O+
–EtOH
R
OH
R
O
OH
+H2O
R
•
OEt
OEt
OEt
OEt
OEt
6
7
8
(not observed)
5 mol% AuSbF6
5 equiv n-PrOH
n
CO2 Pr
CO2Et
1
mated by H NMR.
+
2e
THF–CH2Cl2 (1:1)
3e
3e'
ca. 1:1
transesterification:
5 mol% AuSbF , 5 equiv n-PrOH
6
THF–CH Cl (1:1)
2.3. Mechanistic studies
(does not occur)
2
2
Earlier experiments in our Lab using gold and silver salts to
catalyze the MeyereSchuster reaction of ethoxyalkynyl carbi-
nols support a mechanism in which the alcoholic additive
included in the reaction mixture (i.e., ethanol) becomes incor-
porated into 50% of the product via an intermediate 1,1-dieth-
oxy-allene (7, Scheme 3).19 This gold-catalyzed reaction
pathway is distinct from that of analogous reactions catalyzed
by protic or hard Lewis acids,16 which are known16b,c to pro-
duce b-hydroxy ester by-products (i.e., 6) from initial hydra-
tion of the alkyne. b-Hydroxy esters (6) have not been
observed in any of the MeyereSchuster reactions catalyzed
by soft Lewis acids in our study.
Scheme 3. Hypothesis and data on the mechanism of gold-catalyzed Meyere
Schuster reactions.19
mixture comprised ethyl and propyl esters in a roughly 1:1
ratio (2e/3eþ3e0, Scheme 3).
1 mol% Sc(OTf)3
n
CO2 Pr
CO2Et
3e
5 equiv n-PrOH
+
2e
ð7Þ
ð8Þ
CH2Cl2
3e'
25 : 75 ratio!
n
CO2 Pr
1 mol% Sc(OTf)3
CO2Et
5 equiv n-PrOH
Perhaps the most compelling observation relevant to the
mechanistic hypothesis laid out in Scheme 3 is that when
n-propanol was used in place of ethanol, the resulting product
3e
3e'
(not observed)
CH2Cl2
When this experiment was repeated on 2e using scand-
ium(III) triflate as the catalyst (Eq. 7), the ratio of ethyl to pro-
Table 4
Two-stage olefination of ketones
1
pyl esters (3e:3e0) was 25:75 (as estimated by H NMR). In
R2
O
1. EtO–C≡C–Li
2. Meyer–Schuster
other words, there was only about 25% retention of the ethyl
ester in the product mixture. According to the mechanism out-
lined in Scheme 3, however, the ethoxy group should be at
least 50% retained, even at high levels of n-propanol. Transes-
terification does not occur under the reaction conditions (Eq.
8), so we conclude that the scandium(III) triflate-catalyzed re-
actions proceed by a slightly different mechanism than those
catalyzed of cationic gold salts. One such potential mechanism
is outlined in Scheme 4.
CO2Et
R1
R2
R1
Entry
1
1
3
Yield (%)
98
Menthone (1h)
Verbenone (1c)
3h
3c
CO2Et
2
97
OH
CO2Et
1 mol% ScOTf3
CO2Et
R
R
CH2Cl2/EtOH
OEt
2
3
EtOH
–H2O
–EtOH
OH
3
4
Benzophenone (1i)
Adamantanone (1a)
3i
99
96
CO2Et
CO2Et
OEt
OEt
OEt
R
•
H2O
–EtOH
OEt
OEt
EtOH
OEt
OEt
R
R
7
9
8
3a
Scheme 4. Revised mechanistic hypothesis for scandium-catalyzed Meyere
Schuster reactions.

D.A. Engel et al. / Tetrahedron 64 (2008) 6988e6996
6993
Table 5
Incorporation of the external alcohol additive into the product ester
Many different Lewis and protic acids catalyze Meyere
Schuster reactions of ethoxyacetylenes; Lewis acids that
demonstrate an affinity for p-bonds were most effective in
our methodology. After a detailed screening of many catalysts,
we recommend scandium(III) triflate for the excellent reactiv-
ity and optimal stereoselectivity that it provides in the Meyere
Schuster reactions, even at low catalyst loading. This method
is likely to find widespread application in organic synthesis,
particularly for its unique ability to complete the olefination
of hindered ketones in excellent yield.
OH
1 mol% Sc(OTf)3
<n-propanol>
CO2R
R = Et: 3e
CH2Cl2
OEt
n
R = Pr: 3e'
2e
a
Entry
PrOH (equiv)
2e:PrOH
3e:3e0
1
2
3
4
5
6
a
1
2
50:50
33:67
25:75
17:83
9:91
55:45
42:58
38:62
25:75
22:78
16:84
3
5
10
100
1:99
4. Experimental section
As observed by 1H NMR.
4.1. General information
Based on the consistent lack of b-hydroxy ester by-prod-
ucts (i.e., 6), the scandium(III) triflate-catalyzed Meyere
Schuster reactions of secondary alcohols 227 likely also
proceed via intermediate 1,1-diethoxy-allene 7 (Scheme 4).
Addition of a second equivalent of ethanol to allene 7 would
give rise to ortho-ester 9, which can then hydrolyze via 8 to
reach the a,b-unsaturated ester (3). ortho-Ester intermediate
9 thus easily accounts for up to 67% incorporation of the alco-
hol additive, but we observed 75% (nearly statistical) incorpo-
ration of n-propanol in the experiment recounted in Eq. 7. This
high level of incorporation can be explained by dynamic alco-
hol exchange reactions of ortho-ester 9.
A series of experiments were conducted in which the incor-
poration of the alcohol additive (propanol) was tracked with
respect to the amount of alcohol added (Table 5).28 In each
case, the ratio of propyl and ethyl esters (3e:3e0) was less
than but close to statistical incorporation of propanol. These
data are consistent with a hemi-labile intermediate (e.g., 9)
that can undergo partial equilibration before giving way irre-
versibly to the observed a,b-unsaturated ester (3).
1H NMR and 13C NMR spectra were recorded on 300 MHz
spectrometer using CDCl3 as the deuterated solvent. The
chemical shifts (d) are reported in parts per million (ppm)
1
relative to the residual CHCl3 peak (7.26 ppm for H NMR,
77.0 ppm for 13C NMR). The coupling constants (J) were
reported in hertz (Hz). IR spectra were recorded on an FTIR
spectrometer on NaCl discs. Mass spectra were recorded using
chemical ionization (CI) or electron ionization (EI) technique.
Yields refer to isolated material judged to be ꢀ95% pure by
1H NMR spectroscopy following silica gel chromatography.
All chemicals were used as received unless otherwise stated.
Tetrahydrofuran (THF) and methylene chloride (CH2Cl2)
were purified by passing through a column of activated
alumina. The n-BuLi solutions were titrated with menthol
dissolved in tetrahydrofuran using 1,10-phenanthroline
as the indicator. The purifications were performed by flash
chromatography using silica gel F-254 (230e499 mesh
particle size).
An attractive feature of this mechanistic hypothesis is that it
can account for the high stereoselectivity observed for the
E-olefin isomer in the scandium(III) triflate-catalyzed
MeyereSchuster reactions of secondary alcohols.27 Direct
hydrolysis of allene 7 would most likely occur under kinetic
control, whereas vinyl ortho-ester 9 provides the opportunity
for thermodynamic establishment of olefin geometry using
the exaggerated steric profile of ortho-ester 9.
4.2. General procedure for the preparation of ethoxyalkynyl
carbinols (1/2)
To a THF solution (7 mL) of ethyl ethynyl ether (0.7 g, ca.
40% by weight in hexanes, ca. 9 mmol) was added n-BuLi
(1.5 mL, 3.4 mmol, 2.3 M) dropwise over 5 min at ꢁ78 ꢂC
under argon atmosphere. The solution was allowed to warm
to 0 ꢂC over 1 h and held at 0 ꢂC for an additional 30 min.
The solution was then recooled to ꢁ78 ꢂC and pinacolone
(1b, 0.30 mL, 2.4 mmol) was added in one portion. The solu-
tion was allowed to warm to room temperature over 1 h and
held at room temperature for an additional 3 h. Saturated aque-
ous NH4Cl solution was added to quench the reaction, and the
mixture was extracted with ethyl acetate. The organic layer
was washed sequentially with water, saturated aqueous sodium
bicarbonate, and brine. The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified using silica gel column chromatogra-
phy (gradient elution with 20:1 to 7:1 hexanes/ethyl acetate) to
give 1-ethoxy-3-methyl-3-tert-butyl-1-propyn-3-ol (2b) in
83% yield (0.34 g).
3. Conclusion
We have outlined and discussed a strategy for the olefina-
tion of aldehydes and ketones using the MeyereSchuster reac-
tion of ethoxyalkynyl carbinols. The method would appear to
be limited only by the ability to access the requisite propargyl
alcohols via ethoxyacetylide addition to carbonyls, and such
reactions are known to be quite general. Stereoselectivities
in the two-stage olefination of aldehydes range from good to
excellent, whereas a,b-unsaturated esters derived from ke-
tones are obtained with little to no stereocontrol. Nonetheless,
it is for the olefination of ketones, especially hindered ketones,
that this method is expected to be most useful.

6994
D.A. Engel et al. / Tetrahedron 64 (2008) 6988e6996
4.2.1. 1-Ethoxy-3-methyl-3-tert-butyl-1-propyn-3-ol (2b)
1H NMR (300 MHz, CDCl3) d 1.03 (s, 9H), 1.37 (t, J¼7.1 Hz,
3H), 1.41 (s, 3H), 1.71 (s, 1H), 4.08 (q, J¼7.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 14.3, 25.2, 25.6, 38.4, 41.9, 73.9, 74.2, 92.8;
IR (neat) 3479, 2971, 2873, 2261, 1481, 1392, 1369, 1219, 1094,
1007, 908, 878 cmꢁ1; HRMS (CI) calcd for C10H19O2
([MþH]þ) 171.1385. Found 171.1390.
4.3.1. (E/Z)-3,4,4-Trimethyl-1-pent-2-enoic acid ethyl ester
(3b)
The title compound was prepared in a similar manner as
described above (89% yield, E/Z ratio, 58:42); 1H NMR
(300 MHz, CDCl3, E isomer) d 1.10 (s, 9H), 1.28 (t,
J¼7.1 Hz, 3H), 2.16 (br d, J¼1.1 Hz, 3H), 4.14 (q,
1
J¼7.1 Hz, 2H), 5.74 (q, J¼1.1 Hz, 1H); H NMR (300 MHz,
CDCl3, Z isomer) d 1.20 (s, 9H), 1.28 (t, J¼7.1 Hz, 3H),
1.84 (br d, J¼1.3 Hz, 3H), 4.14 (q, J¼7.1 Hz, 2H), 5.63 (q,
J¼1.3 Hz, 1H); 13C NMR (75 MHz, CDCl3, E/Z mixture)
d 14.1, 14.3, 15.1, 23.9, 28.5, 29.0, 36.4, 37.9, 59.4, 60.0,
112.9, 116.6, 158.5, 167.2, 167.5, 167.9; IR (neat, E/Z mix-
ture) 2970, 2873, 1719, 1634, 1466, 1372, 1262, 1182, 1123,
1054, 868 cmꢁ1; HRMS (EI) calcd for C10H18O2 (Mþ)
170.1307. Found 170.1306.
4.2.2. 1-Ethoxy-dec-1-yn-3-ol (2d)
The title compound was prepared in a similar manner as
1
described above (>99% yield); H NMR (300 MHz, CDCl3)
d 0.86e0.90 (m, 3H), 1.21e1.46 (m, 10H), 1.37 (t,
J¼7.1 Hz, 3H), 1.56e1.70 (m, 3H), 4.09 (q, J¼7.1 Hz, 2H),
4.39 (q, J¼6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.0,
14.2, 22.6, 25.3, 29.2, 29.2, 31.7, 38.7, 39.7, 62.4, 74.4,
93.6; IR (neat) 3381, 2927, 2263, 1722, 1467 cmꢁ1; HRMS
(CI) calcd for C12H22O2 (MþHþ) 199.1698. Found 199.1692.
4.3.2. (E)-Dec-2-enoic acid ethyl ester (3d)
The title compound was prepared as described above (70%
1
yield); H NMR (300 MHz, CDCl3) d 0.86e0.90 (m, 3H),
4.2.3. 1-Ethoxy-4,4-dimethyl-pent-1-yn-3-ol (2e)
The title compound was prepared in a similar manner as
1
described above (97% yield); H NMR (300 MHz, CDCl3)
d 0.97 (s, 9H), 1.38 (t, J¼7.1 Hz, 3H), 4.03 (d, J¼6.0 Hz,
1H), 4.10 (q, J¼7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 14.2, 25.2, 35.8, 38.0, 71.0, 74.3, 94.0; IR (neat) 3431,
2956, 2714, 2264, 1629 cmꢁ1; HRMS (EI) calcd for
C9H16O2 (Mþ) 156.1150. Found 156.1103.
1.26e1.31 (m, 8H), 1.28 (t, J¼7.1 Hz, 3H), 1.42e1.47 (m,
2H), 2.19 (ddd, J¼14.6, 7.1, 1.2 Hz, 2H), 4.18 (q, J¼7.1 Hz,
2H), 5.80 (br d, J¼15.6 Hz, 1H), 6.96 (dt, J¼15.6, 7.0 Hz, 1H).29
4.3.3. (E)-4,4-Dimethyl-pent-2-enoic acid ethyl ester (3e)
The title compound was prepared in a similar manner as
1
described above (97% yield); H NMR (300 MHz, CDCl3)
d 1.08 (s, 9H), 1.29 (t, J¼7.1 Hz, 3H), 4.19 (q, J¼7.1 Hz,
4.2.4. 1-Cyclohexyl-3-ethoxy-prop-2-yn-1-ol (2f)
The title compound was prepared in a similar manner as
2H), 5.73 (d, J¼15.9 Hz, 1H), 6.97 (d, J¼15.9 Hz, 1H).30
1
described above (76% yield); H NMR (300 MHz, CDCl3)
4.3.4. (E)-3-Cyclohexyl-acrylic acid ethyl ester (3f)
The title compound was prepared in a similar manner as
1
described above (75% yield); H NMR (300 MHz, CDCl3)
d 1.12e1.31 (m, 5H), 1.29 (t, J¼7.1 Hz, 3H), 1.64e1.77 (m,
5H), 2.04e2.17 (m, 1H), 4.18 (q, J¼7.1 Hz, 2H), 5.75 (dd,
J¼15.8, 1.4 Hz, 1H), 6.91 (dd, J¼15.8, 6.7 Hz).29
d 0.83e1.3 (m, 6H), 1.38 (t, J¼7.1 Hz, 3H), 1.57e1.84 (m,
6H), 4.10 (q, J¼7.1 Hz, 2H), 4.18 (t, J¼5.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 14.3, 25.9, 25.9, 26.4, 28.1, 28.6,
38.3, 44.6, 67.0, 74.5, 94.3; IR (neat) 3411, 2980, 2460,
1719, 1450 cmꢁ1; HRMS (CI) calcd for C11H18O2 (MþHþ)
183.1385. Found 183.1390.
4.3.5. (E/Z)-3-Phenyl-2-propenoic acid ethyl ester (3g)
4.2.5. 3-Ethoxy-1-phenyl-prop-2-yn-1-ol (2g)
The title compound was prepared in a similar manner as
The title compound was prepared in a similar manner as
described above (93% yield, E/Z ratio, 77:23); 1H NMR
(300 MHz, CDCl3, E isomer) d 1.34 (t, J¼7.1 Hz, 3H), 4.27
(q, J¼7.1 Hz, 2H), 6.44 (d, J¼16.0 Hz, 1H), 7.37e7.40 (m,
3H), 7.51e7.54 (m, 2H), 7.69 (d, J¼16.0 Hz, 1H);30 1H
NMR (300 MHz, CDCl3, Z isomer) d 1.24 (t, J¼7.1 Hz,
3H), 4.17 (q, J¼7.1 Hz, 2H), 5.95 (d, J¼12.6 Hz, 1H), 6.95
(d, J¼12.6 Hz, 1H), 7.33e7.38 (m, 3H), 7.56e7.59 (m, 2H).31
1
described above (92% yield); H NMR (300 MHz, CDCl3)
d 1.39 (t, J¼7.1 Hz, 3H), 2.02 (d, J¼6.0 Hz, 1H), 4.15 (q,
J¼7.1 Hz, 2H), 5.51 (d, J¼6.0 Hz, 1H), 7.31e7.40 (m, 3H),
7.52e7.56 (m, 2H); 13C NMR (75 MHz, CDCl3) d 14.4,
38.8, 64.6, 74.8, 95.4, 126.5, 128.0, 128.5, 129.2; IR (neat)
3401, 2981, 2226, 1718, 1450 cmꢁ1; HRMS (EI) calcd for
C11H12O2 (Mþ) 176.0834. Found 176.0837.
4.4. General two-step procedure for the preparation
4.3. General procedure for the preparation
of a,b-unsaturated esters (1/3)
of a,b-unsaturated esters (2/3)
To a THF solution (2.6 mL) of ethyl ethynyl ether (0.13 g,
ca. 40% by weight in hexanes, ca. 2 mmol) was added n-BuLi
(0.40 mL, 0.75 mmol, 2.0 M) dropwise over 5 min at ꢁ78 ꢂC
under argon atmosphere. The solution was allowed to warm to
0 ꢂC over 1 h and held at 0 ꢂC for an additional 30 min. The
solution was then recooled to ꢁ78 ꢂC and 2-adamantanone
(1a, 75 mg, 0.50 mmol) was added in one portion. The solu-
tion was allowed to warm to room temperature over 1 h and
To a 4:1 v/v CH2Cl2/ethanol solution (10 mL) of 1-ethoxy-
dec-1-yn-3-ol (2d, 0.10 g, 0.51 mmol) in an open flask was
added Sc(OTf)3 (2.5 mg, 0.005 mmol). Progress of the reaction
was monitored by TLC analysis. After 1 h, the reaction mixture
was concentrated under reduced pressure and purified using
silica gel column chromatography (hexanes/ethyl acetate,
50:1) to give ethyl (E)-dec-2-enoate (3d) in 70% yield (70 mg).

D.A. Engel et al. / Tetrahedron 64 (2008) 6988e6996
6995
held at room temperature for an additional 3 h. Saturated aque-
Acknowledgements
ous NH4Cl solution was added to quench the reaction and the
mixture was extracted with ethyl acetate. The organic layer
was washed sequentially with water, saturated aqueous sodium
bicarbonate, and brine. The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure.
To the concentrated mixture in an open flask were added
CH2Cl2 (8 mL), absolute ethanol (2 mL), and Sc(OTf)3
(2.5 mg, 0.005 mmol). After 6 h, the reaction mixture was
concentrated under reduced pressure and purified using silica
gel column chromatography (hexanes/ethyl acetate, 50:1) to
give adamantan-2-ylidene-acetic acid ethyl ester (3a) in 96%
yield over two steps (106 mg).
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 by the FSU Department of Chemistry
and Biochemistry. D.A.E. is the recipient of graduate fellow-
ships from FSU and the MDS Research Foundation. We are
profoundly grateful to all of these agencies for their support.
We thank Dr. Umesh Goli (FSU) for providing the mass spec-
trometry data and the Krafft Lab for the use of their FT-IR
instrument.
References and notes
4.4.1. Adamantan-2-ylidene-acetic acid ethyl ester (3a)
1H NMR (300 MHz, CDCl3) d 1.27 (t, J¼7.1 Hz, 3H), 1.86
(br s, 6H), 1.93e1.96 (m, 6H), 2.43 (br s, 1H), 4.07 (br s, 1H),
4.13 (q, J¼7.1 Hz, 2H), 5.58 (s, 1H).32
´
1. Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic
¨
Synthesis; Elsevier: New York, NY, 2003; pp 8e9 and references cited.
2. (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863e927; (b)
Kelly, S. E. Alkene Synthesis; Trost, B. M., Fleming, I., Eds.; Comprehen-
sive Organic Synthesis; Pergamon: Oxford, 1991; Vol. 1, pp 729e817.
3. Trost, B. M. Science 1991, 254, 1471e1477.
4.4.2. (4,6,6-Trimethyl-bicyclo[3.1.1]hept-3-en-(2E/Z)-
ylidene)-acetic acid ester (3c)
4. Shindo, M. Synthesis 2003, 2275e2288.
5. (a) Fuks, R.; Viehe, H. G. Chem. Ber. 1970, 103, 564e572; (b) Hsung,
R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas, C. J.; Xiong, H.; Mulder,
J. A. Org. Lett. 1999, 1, 1237e1240.
Title compound was prepared in a similar manner as
described above (97% yield); 1H NMR (300 MHz, CDCl3,
minor isomer) d 0.86 (s, 3H), 1.28 (t, J¼7.1 Hz, 3H), 1.40
(s, 3H), 1.68 (d, J¼7.9 Hz, 1H), 1.90 (d, J¼1.5 Hz, 3H),
2.20e2.45 (m, 1H), 2.53e2.63 (m, 2H), 4.08e4.20 (m, 2H),
6. (a) You, L.; Al-Rashid, Z. F.; Figueroa, R.; Ghosh, S. K.; Li, G.; Lu, T.;
Hsung, R. P. Synlett 2007, 1656e1662; (b) Hsung, R. P., Ed. Chemistry
of electron-deficient ynamines and ynamides (Tetrahedron Symposium-
in-Print Number 118). Tetrahedron 2006, 62, 3771e3938.
1
7. Shindo, M.; Kita, T.; Kumagai, T.; Matsumoto, K.; Shishido, K. J. Am.
Chem. Soc. 2006, 128, 1062e1063.
5.32 (s, 1H), 7.13 (s, 1H); H NMR (300 MHz, CDCl3, major
isomer) d 0.84 (s, 3H), 1.26 (t, J¼7.1 Hz, 3H), 1.44 (s, 3H),
1.58 (d, J¼8.8 Hz, 1H), 1.86 (d, J¼1.4 Hz, 3H), 2.20e2.45
(m, 1H), 2.53e2.63 (m, 2H), 4.08e4.20 (m, 2H), 5.46 (s,
1H), 5.77 (s, 1H); 13C NMR (75 MHz, CDCl3, E/Z mixture)
d 14.3, 14.4, 21.7, 21.8, 23.2, 23.6, 26.4, 26.5, 37.5, 38.1,
45.3, 47.8, 48.2, 49.0, 49.1, 53.1, 59.2, 59.3, 107.6, 110.0,
117.6, 121.6, 156.9, 158.0, 159.6, 161.2, 166.8, 167.4; IR
(neat) 2979, 2930, 2870, 1708, 1622, 1466, 1443, 1380,
1370, 1226, 1164, 1040, 874, 705 cmꢁ1; HRMS (EI) calcd
for C14H20O2 (Mþ) 220.1463. Found 220.1462.
8. (a) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819e822; (b)
Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429e438.
9. Examples: (a) Erman, M. B.; Aul’chenko, I. S.; Kheifits, L. A.; Dulova,
V. G.; Novikov, J. N.; Vol’pin, M. E. Tetrahedron Lett. 1976,
2981e2984; (b) Chabardes, P. Tetrahedron Lett. 1988, 29, 6253e
6256; (c) Choudary, B. M.; Durga Prasad, A.; Valli, V. L. K. Tetrahe-
dron Lett. 1990, 31, 7521e7522; (d) Narasaka, K.; Kusama, H.; Haya-
shi, Y. Chem. Lett. 1991, 1413e1416; (e) Yoshimatsu, M.; Naito, M.;
Kawahigashi, M.; Shimizu, H.; Kataoka, T. J. Org. Chem. 1995, 60,
4798e4802; (f) Lorber, C. Y.; Osborn, J. A. Tetrahedron Lett. 1996,
37, 853e856; (g) Suzuki, T.; Tokunaga, M.; Wakatsuki, Y. Tetrahedron
Lett. 2002, 43, 7531e7533.
10. The Rupe rearrangement (Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9,
672).
4.4.3. (2-Isopropyl-5-methyl-cyclohexylidiene)-acetic acid
ethyl ester (3h)
The title compound was prepared in a similar manner as
R2
H
R2
R2
H+
+H2O
H+
–H2O
R1
R3
1
R1
R3
R3
described above (98% yield); H NMR (300 MHz, CDCl3,
R1
OH
O
E/Z mixture, diagnostic peaks) d 2.55 (ddd, J¼12.9, 5.5,
1.5 Hz), 3.14 (dd, J¼12.9, 4.3 Hz), 3.48e3.52 (m), 4.13 (q,
J¼7.1 Hz), 4.14 (q, J¼7.1 Hz), 5.63 (br s); 13C NMR
(75 MHz, CDCl3, E/Z mixture) d 14.3, 18.1, 19.5, 20.5,
20.8, 21.8, 23.4, 26.1, 26.8, 27.0, 27.6, 30.4, 31.6, 33.6,
33.9, 35.4, 36.1, 40.0, 43.5, 50.8, 52.6, 55.9, 59.3, 59.4,
113.3, 116.3, 164.8, 167.1.
11. Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: New
York, NY, 2000.
12. (a) Ho, T.-L. Hard and Soft Acids and Bases Principle in Organic
Chemistry; Academic: New York, NY, 1977; (b) Chattaraj, P. K.; Lee,
H.; Parr, R. G. J. Am. Chem. Soc. 1991, 113, 1855e1856.
13. Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410e3449.
¨
14. For seminal examples illustrating this concept, see: Georgy, M.; Boucard,
V.; Campagne, J.-M. J. Am. Chem. Soc. 2005, 127, 14180e14181.
15. Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027e4029.
16. Examples of MeyereSchuster reactions of ethoxyalkynyl carbinols using
hard Lewis or protic acids: (a) Duraisamy, M.; Walborsky, H. M. J. Am.
Chem. Soc. 1983, 105, 3252e3264; (b) Welch, S. C.; Hagan, C. P.; White,
D. H.; Fleming, W. P.; Trotter, J. W. J. Am. Chem. Soc. 1977, 99,
549e556; (c) Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997,
53, 7139e7158.
4.4.4. Ethyl 3,3-diphenylpropenoate (3i)
The title compound was prepared in a similar manner as
1
described above (99% yield); H NMR (300 MHz, CDCl3)
d 1.11 (t, J¼7.1 Hz, 3H), 4.05 (q, J¼7.1 Hz, 2H), 6.37 (s,
1H), 7.20e7.23 (m, 2H), 7.30e7.39 (m, 8H).33

6996
D.A. Engel et al. / Tetrahedron 64 (2008) 6988e6996
17. The combination of an electron-rich p-system and soft Lewis acid
catalyst has also been used in cycloisomerization reactions: Sun, J.;
Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2006, 128,
9705e9710.
23. Recent review on gold-catalyzed reactions of propargyl esters: Correa, A.;
Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo, L.
Angew. Chem., Int. Ed. 2008, 47, 718e721.
24. Forrecentreviews,seeRefs. 13and23and:(a)Gorin,D. J.;Toste, F. D. Nature
2007, 446, 395e403;(b)Hashmi,A. S.K. Chem. Rev.2007, 107, 3180e3211;
18. Because the 1,3-hydroxy shift is not concerted and there is ample oppor-
tunity for the hydroxy to exchange with water in the reaction medium, the
MeyereSchuster reaction is not a true rearrangement. For mechanistic
investigations of the MeyereSchuster reaction, see: (a) Edens, M.;
Boerner, D.; Chase, C. R.; Nass, D.; Sciavelli, M. D. J. Org. Chem.
1977, 42, 3403e3408; (b) Andres, J.; Cardenas, R.; Silla, E.; Tapia, O.
J. Am. Chem. Soc. 1988, 110, 666e674; (c) Yamabe, S.; Tsuchida;
Yamazaki, S. J. Chem. Theory Comput. 2006, 2, 1379e1387.
´
~
(c) Jimenez-Nunez, E.; Eschavarren, A. M. Chem. Commun. 2007, 333e346;
(d) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200e203.
25. Kobayashi, S. Sc(III) Lewis Acids; Yamamoto, H., Ed.; Lewis Acids in
Organic Synthesis; Wiley-VCH: New York, NY, 2000; Vol. 2, Chapter
19, pp 883e910.
26. For example, it was our inability to achieve HornereWadsworthe
Emmons olefination reactions on either menthone (cf. 1h/3h) or
menthone derivatives that initially prompted our interest in MeyereSchus-
ter reaction methodology. For more information on the steric congestion
of menthone derivatives, see: Dudley, G. B.; Engel, D. A.; Ghiviriga, I.;
Lam, H.; Poon, K. W. C.; Singletary, J. A. Org. Lett. 2007, 9, 2839e2842.
27. The MeyereSchuster reactions of tertiary alcohols 2 may take a different
course. Further investigations are planned and will be communicated in
due course.
19. Lopez, S. S.; Engel, D. A.; Dudley, G. B. Synlett 2007, 949e953.
20. Recent examples: Refs. 15 and 19, and (a) Imagawa, I.; Asai, Y.; Takano,
H.; Hamagaki, H.; Nishizawa, M. Org. Lett. 2006, 8, 447e450; (b)
´
´
Cadierno, V.; Dıez, J.; Garcıa-Garrido, S. E.; Gimeno, J.; Nebra, N.
Adv. Synth. Catal. 2006, 348, 2125e2132; (c) Sun, C.; Lin, X.; Weinreb,
S. M. J. Org. Chem. 2006, 71, 3159e3166; (d) Yu, M.; Li, G.; Wang, S.;
Zhang, L. Adv. Synth. Catal. 2007, 349, 871e875; (e) Bustelo, E.;
Dixneuf, P. H. Adv. Synth. Catal. 2007, 349, 933e942; (f) Marion, N.;
28. Reactions conducted with less than a full equivalent of propanol were
slow and inefficient, and are omitted from Table 5.
´
Carlqvist, P.; Gealageas, R.; de Fremont, P.; Maseras, F.; Nolan, S. P.
´
29. For full characterization, see: Concellon, J. M.; Concellon, C.; Mejica, C.
´
´
Chem.dEur. J. 2007, 13, 6437e6451; (g) Lee, S. I.; Baek, J. Y.; Sim,
S. H.; Chung, Y. K. Synthesis 2007, 2107e2114; (h) Sandelier, M. J.;
DeShong, P. Org. Lett. 2007, 9, 3209e3212; (i) Sugawara, Y.; Yamada,
W.; Yoshida, S.; Ikeno, T.; Yamada, T. J. Am. Chem. Soc. 2007, 129,
12902e12903.
J. Org. Chem. 2005, 70, 6111e6113.
30. For full characterization, see: Zeitler, K. Org. Lett. 2006, 8, 637e640.
31. For full characterization, see: Imashiro, R.; Seki, M. J. Org. Chem. 2004,
69, 4216e4226.
21. The question as to what reaction pathway(s) leading from the propargyl
acetate to the a,b-unsaturated ketone is catalyzed by cationic gold salts
remains open. For further discussion, see Ref. 20f.
32. For full characterization, see: Griaud, L.; Huber, V.; Jenny, T. Tetrahedron
1998, 54, 11899e11906.
33. For full characterization, see: (a) Le Tadic-Biadatti, M.-H.; Callier-
Dublanchet, A.-C.; Horner, J. H.; Quiclet-Sire, B.; Zard, S. Z.;
Newcomb, M. J. Org. Chem. 1997, 62, 559e563; (b) Rathke, M. W.;
Bouhlel, E. Synth. Commun. 1990, 20, 869e875.
22. Related reactions of propargyl acetates: (a) Yu, M.; Zhang, G.; Zhang, L.
Org. Lett. 2007, 9, 2147e2150; (b) Barluenga, J.; Riesgo, L.; Vincente,
R.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2007, 129, 7772e7773.