A simple and versatile re-catalyzed meyer-schuster rearrangement of propargylic alcohols to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1002/chem.200802622

The development of a general catalytic procedure for the rapid and efficient 1,3-rearrangement of free secondary and tertiary propargylic alcohols to the corresponding α,β-unsaturated carbonyl compounds using available [ReOCl₃(OPPh₃)-(SMe₂)] complex, was reported. The reaction was carried out under neutral environmental conditions with no racemization of potentially enolizable stereocenters with virtually complete E stereoselectivity. The reaction under dimethoxyethane, proceeded at the lower rate than in THF, but with reduced by-products and the yield obtained were highly significant. The reaction was reported to increase constantly at the expense of the (Z)-isomer 2b, where the double bong isomerization was attributed to a catalytic effect of the rhenium complex. The resulted new version of Meyer-Schuster rearrangement will find enormous application in organic synthesis to develop one-pot multistep reaction sequences.

Full text of DOI:10.1002/chem.200802622

DOI: 10.1002/chem.200802622
A Simple and Versatile Re-Catalyzed Meyer–Schuster Rearrangement of
Propargylic Alcohols to a,b-Unsaturated Carbonyl Compounds
Massimo Stefanoni, Marco Luparia, Alessio Porta, Giuseppe Zanoni, and
Giovanni Vidari*[a]
a,b-Unsaturated carbonyl groups are found in a large
number of biologically active natural products and their im-
portance in organic synthesis as substrates for countless
transformations can be hardly underestimated.[1] Their tradi-
tional preparations through well-known protocols, such as
aldol-like condensations, Wittig and Horner–Wadsworth–
Emmons olefinations,[2] usually require basic conditions,
which might be incompatible with the presence of different
functional groups and/or preservation of the original stereo-
chemistry. Moreover, these procedures are often multistep
sequences and exhibit low atom economy.[2] By contrast, the
Meyer–Schuster (M.S.) rearrangement of propargylic alco-
hols to a,b-unsaturated carbonyl compounds (Scheme 1),[3]
intrinsically complies with the principles of atom economy.[4]
Moreover, considering the easy access to starting propargyl-
ic alcohols,[5] this methodology is synthetically very attrac-
tive. However, the M.S. rearrangement has seldom been
used in total synthesis so far due to different drawbacks in-
herent in present methodologies.
are based on catalytic organometallic species. Thus, gold(I)[6]
or mercury(II)[7] species catalyze the ready rearrangement
of esters of propargylic alcohols to allenic esters and ulti-
mately to the corresponding a,b-unsatured carbonyl com-
pounds; however, the atom and step economy of the overall
transformations are obviously only moderate. Alternatively,
Ru complexes promote the direct M.S. rearrangement of
propargylic alcohols;[8] however, this reaction is limited to
the conversion of terminal alkynes to the corresponding
enals. On the contrary, a,b-enones have been prepared by
[9]
means of silver(I)/CO2 or gold(I)-/silver(I)[10]-catalyzed iso-
merization of propargylic alcohols, albeit with general mod-
erate stereoselectivity. AuIII also catalyzes the rearrange-
ment, but often in low yields and in competition with nucleo-
philic substitution of the propargylic alcohol.[11]
Finally, different oxo complexes of transition metals [va-
nadium(V),[12]
molybdenum(VI),[13]
titanium(IV)/cop-
per(I),[14] rhenium(VII)[15] promote the M.S. rearrangement
AHCTUNGTERNNUNG
in a catalytic fashion. These reactions are envisioned to pro-
ceed via a [3,3]-sigmatropic rearrangement of an initially
formed metal–alkoxide, followed by protonation of the iso-
merized species to afford the desired product
(Scheme 2).[12,13] Although the last procedures require tem-
peratures ꢀ1008C and/or acidic conditions, often resulting
in moderate yields and low stereoselectivity,[16] we were at-
tracted by the high air and moisture tolerance of high oxida-
tion-state metal–oxo complexes which, in addition, might be
recovered at the end of the reaction and reused.
Recently, during their studies on rhenium(V)-catalyzed
nucleophilic substitution reactions of propargylic alcohols,
Toste et al. occasionally detected the formation of the M.S.
products as the result of an undesired side-reaction.[17d] This
observation was, however, not followed by other attempts to
optimize and generalize the formation of a,b-unsaturated
carbonyl compounds. Since rhenium(V) is endowed with a
rich coordination chemistry,[17] and catalyst recovery has
been observed in some cases,[17c] we envisaged the possibility
to develop an efficient M.S. rearrangement based on a rhe-
nium(V)–oxo complex, by finely tuning the steric and elec-
Scheme 1. Meyer–Schuster rearrangement of propargylic alcohols.
Strong protic or Lewis acids were mostly used as promot-
ers in the earliest versions of the M.S. reaction,[3] which gen-
erally afforded products in poor yields, due to unselective
rearrangements and side reactions. More recent procedures
[a] M. Stefanoni, Dr. M. Luparia, Dr. A. Porta, Dr. G. Zanoni,
Prof. G. Vidari
Dipartimento di Chimica Organica, Universitꢀ di Pavia
Via Taramelli 10, Pavia (Italy)
Fax : (+39)0382-987322
E-mail: vidari@unipv.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802622.
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Chem. Eur. J. 2009, 15, 3940 – 3944

COMMUNICATION
ing (E)-a-ionone 2a and (Z)-a-ionone 2b in an encouraging
69% combined yield. Addition of H2O to THF severely in-
hibited the isomerization, possibly because it competed with
alcohol 1 in coordinating the rhenium(V) complex, thus re-
ducing the concentration of the active catalytic species. Fur-
ther studies were, therefore, performed in dry solvents and
in the presence of the catalyst previously dried under
vacuum. In dimethoxyethane the reaction proceeded at
lower rate than in THF, but afforded less by-products and
the yields were significantly higher. By contrast, mostly un-
reacted starting material 1 was recovered when the reaction
was performed in 1,4-dioxane. In conclusion, dry dimethoxy-
ethane was selected as the solvent of choice for further reac-
tion optimization. Next, either the catalyst loading or the
temperature of the reaction was changed (Table 1).
Scheme 2. Mechanism envisioned for the Meyer–Schuster rearrangement
catalyzed by oxo-metal complexes.
Table 1. Optimization of catalyst loading and reaction temperature in
the formation of 2a.[a]
tronic properties of ligands. In this paper, we describe our
efforts in this field, culminating in a new simple protocol of
the M.S. rearrangement.
Entry
Catalyst[c]
T [8C]
2a[d]
2b[d]
Unreacted 1[d]
3[d]
We selected the easily accessible propargylic alcohol 1[18]
as the ideal substrate for studying the rearrangement to
enones 2a–b under highly-demanding steric and electronic
conditions. In fact, the OH group resided in a highly crowd-
ed environment and simple dehydration could afford a stabi-
lized conjugated dienyne 3.
1
2
3
4
10
10
20
5
60
80
60
80
41
68
26
75
24
17
24
20
29
0
27
0
5
15
23
5
[a] Reactions were carried out on a 0.5 mmol scale in a screw plastic cap
vial in 1 mL of solvent and heated with an external oil bath set at the in-
dicated temperature. [b] Alkyne 1 was a 6:1 mixture of racemic diaste-
reomeric carbinols. [c] Catalyst loading in mol%. [d] Percentage of each
compound in the reaction mixture was estimated by GC-MS analysis.
At first, we chose the easily obtainable complex [ReOCl3-
ACHTUNGTRENNUNG(OPPh3)ACHTUNGTRENNUNG
(SMe2)] as a viable catalyst,[17b,19] focusing our atten-
tion on finding the best reaction solvent (Scheme 3).
Increasing the catalyst loading from 10 to 20 mol% result-
ed in larger amounts of the dehydration product 3 and in
only a slightly higher conversion of substrate 1 (Table 1,
compare entries 1 and 3). On the other hand, with 10 mol%
catalyst, an increase of the temperature from 60 to 808C,
significantly enhanced both the conversion of 1 and the
yield of ionones 2, although the amount of compound 3 in-
creased as well (Table 1, compare entries 1 and 2). Eventual-
ly, 5 mol% catalyst and a temperature of 808C were found
to be the optimal conditions, under which model substrate 1
was completely converted in 24 h to 95% 2, while com-
pound 3 accounted for only 5% (Table 1, entry 4).[20]
We noticed that with the progress of the reaction the
amount of (E)-2a constantly increased at the expense of the
(Z)-isomer 2b. Such double-bond isomerization was attrib-
uted to a catalytic effect of the rhenium complex. In fact, in
a separate experiment, pure (Z)-2b was completely convert-
Scheme 3. Model reaction for the optimization of solvents in Re-cata-
lyzed Meyer–Schuster rearrangement.
Both CH2Cl2 and CHCl3 proved to be unsatisfactory,
whereas a serious lack of reactivity was noticed in apolar
solvents such as hexane. Surprisingly, no reaction was also
observed in acetone, while starting material 1 readily de-
composed in MeCN or DMSO, without formation of the de-
sired product 2. We reasoned that these highly coordinating
polar solvents might sequester ReV species while favoring
ꢁ
unproductive pathways via cleavage of the propargylic C
ed into (E)-2a upon exposure to 5 mol% [ReOCl
ACHTUNGTRENNUNG
3ACHTUNGTRENUNG(OPPh3)-
OH bond. Consequently, we turned our attention to ethers,
which are less coordinating solvents but polar enough to sta-
bilize partially charged species presumably developing
during the M.S. rearrangement (see below). Indeed, in THF
starting material 1 was almost completely consumed, afford-
in the absence of the catalyst, no isomerization occurred
and (Z)-2b was recovered unchanged.
In a subsequent pivotal experiment, (S)-2a was produced
in 91% isolated yield and 95% ee (chiral GC) upon expo-
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3941

G. Vidari et al.
sure of enantioenriched (6S)-1 (95% ee, 6:1 mixture of dia-
stereomeric carbinols)[18] to 5 mol% catalyst in dimethoxy-
ethane at 808C for 36 h (Scheme 4).
This synthesis, further representing the most straightfor-
ward enantioselective approach to the important perfume
ingredient (S)-a-ionone 2a[21,22] nicely proved the configura-
tion integrity of stereocenters under our conditions for the
M.S. rearrangement. Notably, in previous studies of this re-
action, this important issue, namely, the stereochemical sta-
bility of potentially enolizable stereocenters has never been
examined in detail.
Scheme 4. Enantioselective synthesis of (S)-a-ionone (2a).
Subsequently, we turned our attention to the M.S. rear-
rangement of different secondary and tertiary propargylic
alcohols to demonstrate the vast
applicability of our protocol.
Table 2. Re-catalyzed Meyer–Schuster rearrangement of propargylic alcohols.[a]
Both alkyl and aryl substituted
alkynols were well tolerated af-
fording the corresponding a,b-
unsaturated
carbonyl
com-
pounds in high isolated yields
(Table 2). Also terminal alkynes
led to the corresponding enals
in high yield (Table 2, entries 9,
10). Notably, an ester group at-
tached to the alkyne moiety was
not of impediment to the reac-
tion (Table 2, entry 7), and even
in the presence of a carboxylic
acid group the product was
formed in acceptable yield
(Table 2, entry 8).
The possibility to recycle the
catalyst gives this procedure an
additional attractiveness. As an
example, in the rearrangement
of 4b (Table 2, entry 2), the rhe-
nium catalyst was recovered by
filtration at the end of the reac-
tion and reused two additional
consecutive times, with the
same catalytic efficiency.
Although still preliminary, ad-
ditional experiments shed some
light on the reaction mecha-
nism. In particular, M.S. rear-
rangement of O-deuterated al-
cohol 6 afforded [2D]-labelled
enone 7 (Scheme 5).[23] On the
other hand, treatment of 4b
with stoichiometric amounts of
18O=Re enriched complex[24] led
to significant 18O incorporation
Entry
1
Substrate
Product
t [h]
Yield [%]
90
24
2
24
96
3
4
5
24
24
7
98
94
90
6
7
8
0.5
1.5
3
60
98
60
9
20
20
94
96
10
into
rearranged
enone
8
(Scheme 5).[23]
[a] A solution of propargylic alcohol 4 (0.5 mmol) in dimethoxyethane (1 mL), placed in a screw plastic cap
vial, was heated with an external oil bath at the indicated temperature; yields refer to isolated product (aver-
age of two runs). [b] TLC analysis indicated complete disappearance of minor Z isomer. [c] The reaction was
interrupted before complete disappearance (TLC) of starting alkynol. [d] Products of decomposition were
Both results were consistent
with the catalytic cycle general-
ly accepted for oxo–metal cata- formed on prolonged reaction times. [e] 5h was characterized as ester 5g. [f] E/Z 12.5:1.
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a,b-Unsaturated Carbonyl Compounds
COMMUNICATION
to stabilize a dipolar intermediate (enolate, allyl cation), al-
lowing Z!E enone isomerization (Scheme 7).
Scheme 5. Formation of [D]- and 18O-labelled enones.
Scheme 7. Mechanism envisioned for the catalyzed isomerisation of (E)/
(Z)-unsaturated carbonyl compounds.
lyzed M.S. rearrangements (Scheme 2);[12,13] however, no
free acid could be detected in the reaction mixture,[25] con-
trarily to what was expected to arise from the chlorine–
alkoxy ligand exchange in the first step of the cycle
(Scheme 2). On the basis of these evidences, we propose a
slightly different mechanism for the M.S. rearrangement cat-
In summary, using the readily available [ReOCl
3ACHTUNGTRENUNG(OPPh3)-
AHCTUNGTRENNUNG
catalytic procedure for the rapid and efficient 1,3-rearrange-
ment of free secondary and tertiary propargylic alcohols to
the corresponding a,b-unsaturated carbonyl compounds.
with virtually complete E stereoselectivity. The reaction pro-
ceeds under neutral conditions and no racemization of po-
tentially enolizable stereocenters was observed. Given its
simplicity and reliability, we anticipate that this new version
of the Meyer–Schuster rearrangement will find ample appli-
cation in organic synthesis. Our efforts are now aimed at de-
veloping the use of this protocol in one-pot multistep reac-
tion sequences.
alyzed by [ReOCl3ACHTUNGTRENNUNG(OPPh3)HCATUNGTERN(NUGN SMe2)] (Scheme 6). In the first
step, the propargylic -OH group adds across the Re=O bond
of the catalyst, forming a monoalkoxy complex with the al-
cohol.[17b] Likely, this complexation strongly polarizes the
ꢁ
C ORe bond, facilitating its cleavage. The partial positive
charge developing on the propargylic carbon then boosts a
concerted six-electron bond migration,[26] which ultimately
results in regeneration of the oxo–rhenium catalyst along
with concurrent delivery of the OH group, initially bound to
Re, to the adjacent terminus of the incipient allene moiety.
The allenol thus formed eventually rearranges to an a,b-un-
saturated carbonyl product via a ready prototropic shift
(Scheme 6).
Experimental Section
Typical
reaction
procedure:
[ReOCl
(OPPh3)
N
(18 mg,
0.026 mmol), propargylic alcohol
1
(100 mg, 0.52 mmol), dimethoxy-
ethane (1.05 mL) were placed in a screw cap vial and heated under stir-
ring in an oil bath at 808C. After 36 h, the undissolved catalyst was fil-
tered off and the solvent was evaporated under vacuum. Column chro-
matography of the residue on silica gel afforded, by elution with hexane/
Et2O 98:2, chromatographically pure (E)-a,b-enone 2a (91 mg, 91%),
identical with a commercial authentic sample.
Acknowledgements
Financial support from the Italian MIUR (Funds PRIN 2007) is acknowl-
edged. We thank Prof. Mariella Mella for expert NMR spectra determi-
nation.
Scheme 6. Mechanism envisioned for the Meyer–Schuster rearrangement
catalyzed by the [ReOCl3ACHTUNRGTENNUG(OPPh3)ACHUTGNTREN(NUGN SMe2)] complex.
Keywords: carbonyl
compounds
·
Meyer–Schuster
rearrangement ·
isomerization
rhenium
·
propargylic alcohols
·
Formation of a mixture of (E)- and (Z)-olefins at the
early stages of the reaction appears to be due to a kinetical-
ly controlled tautomerization of the intermediate allenol de-
rivative (Scheme 6). By contrast, without excluding other
mechanistic hypotheses, stereoconvergence of a,b-unsaturat-
ed carbonyl compounds to the thermodynamically more
stable E isomer on prolonged heating, could be explained
by complexation of the carbonyl oxygen to the rhenium
complex.[17a] This Lewis acid-like catalysis might be expected
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presence of 1 equiv [ReOCl3ACTHNUTRGENN(UG OPPh3)ACHTUNGTREN(NUNG SMe2)], pH of the mixture re-
mained constantly neutral; moreover, deliberately added excess
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decomposed in the presence of traces of HCl in dimethoxyethane at
808C.
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Received: December 12, 2008
Published online: March 12, 2009
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Chem. Eur. J. 2009, 15, 3940 – 3944