Heteropoly compound catalyzed synthesis of both z- and e-α,β- unsaturated carbonyl compounds

Article abstract of DOI:10.1002/anie.201106381

An EZ switch: The cationic species of the heteropoly compounds has a critical impact on the Z/E selectivity of the Meyer-Schuster rearrangement of propargyl alcohols (see scheme). The isolation of the thermodynamically unfavorable Z-α,β-unsaturated carbonyl compounds is notable. The high Z selectivities were obtained at a reaction temperature as high as 50°C.

Full text of DOI:10.1002/anie.201106381

DOI: 10.1002/anie.201106381
Synthetic Methods
Heteropoly Compound Catalyzed Synthesis of Both Z- and E-a,b-
Unsaturated Carbonyl Compounds
Masahiro Egi, Megumi Umemura, Takuya Kawai, and Shuji Akai*
a,b-Unsaturated carbonyl compounds have proven to be
versatile components, are present in abundant biologically
active natural products, and widely used as intermediates for
the manufacture of pharmaceuticals, cosmetics, and chem-
icals.[1] While various methods for their synthesis have already
been reported, the development of a more practical method
of preparation having high atom economy is increasingly
desired. In this sense, particularly attractive is the 1,3-
rearrangement of the readily available propargyl alcohols
into a,b-unsaturated carbonyl compounds; the rearrange-
ment is known as the Meyer–Schuster rearrangement.[2]
Starting from the carbonyl compounds and the alkynes, the
two-step reaction sequence shown in Equation (1) is fascinat-
the addenda atom. They possess a strong acidity and redox
properties, both of which can be tuned by simply changing the
cationic moiety and the polyanion chemical composition. In
addition, they are generally recognized as clean and safe
catalysts because of their nontoxicity, high stability, and easy
handling. We sought to take advantage of the modular nature
and steric effect of these catalysts to promote the 1,3-
rearrangement of the propargyl alcohols. We now describe
that the heteropoly compounds afford a new entry to both the
Z- and E-configured a,b-unsaturated carbonyl compounds
from the same propargyl alcohols.[8] The especially highly
selective synthesis of the thermodynamically less stable
Z isomers under heating conditions is worth noting.
The catalytic applicability of the commercially available
H3[PMo12O40]·nH2O to the Meyer–Schuster rearrangement
was initially examined. The reaction of 1a with H3-
[PMo12O40]·nH2O (0.01 equiv) in EtOAc proceeded within
6 hours to afford an 89% yield of the desired enone 2a and
the complete preference for the E isomer was observed
(Table 1, entry 1). More surprisingly, when using a sodium salt
of the same heteropoly acid, (Z)-2a was obtained in better
than a 4:1 ratio with its E isomer (entry 2). This remarkable
ing because it produces a smaller amount of waste materials,
whereas the well-known Wittig and Horner–Wadsworth–
Emmons olefinations are inevitably accompanied by the
discharge of an equimolar amount of phosphorous by-
products.
Table 1: Screening of heteropoly compounds for the Meyer–Schuster
rearrangement of 1a.
The Meyer–Schuster rearrangements have traditionally
required strong acidic media and elevated temperatures, both
of which often result in the formation of a mixture of E and
Z stereoisomers. More recently, the catalysts that include
transition metals, such as Au, Re, and Ru, have been shown to
be useful for the synthesis of the thermodynamically more
stable E isomers.[3,4] We also demonstrated an effective
method using the combination of oxo-Mo and cationic Au
catalysts.[5] In contrast, there have been few effective catalytic
systems for the preparation of the less stable Z isomers.[6]
Entry
Heteropoly
Solvent
t [h]
Yield [%][b]
=
Therefore, the stereocontrol of the C C bond still remains a
compound[a]
(Z)-2a
(E)-2a
3
challenge of the Meyer–Schuster rearrangement.
<1[c]
67
89[c]
16
no reaction
0
0
Interestingly, heteropoly acids and their salts have
attracted much attention in the fields of chemistry, biology,
and materials science.[7] One of the most common heteropoly
acids is the Keggin-type compounds with the general formula
Hn[XM12O40] in which X is the central heteroatom and M is
1
2
3
4
5
6
7
8
9
H3[PMo12O40]
Na3[PMo12O40]
Na4[SiMo12O40]
Na3[PW12O40]
K3[PMo12O40]
Cs3[PMo12O40]
Ag3[PMo12O40]
Ag3[PMo12O40]
Ag3[PMo12O40]
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
acetone
acetone[d]
6
5
5
5
5
5
3
1.5
1
0
54
12
66
79
88[c]
0
14
1
18
17
8[c]
70
18
17
0
0
0
[*] Dr. M. Egi, M. Umemura, T. Kawai, Prof. Dr. S. Akai
School of Pharmaceutical Sciences, University of Shizuoka
52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526 (Japan)
E-mail: akai@u-shizuoka-ken.ac.jp
[a] Using the hydrate of the heteropoly compound. [b] Yield determined
by NMR spectroscopy using 1,4-dimethoxybenzene as the internal
standard. [c] Yield of isolated product. [d] Conducted at a concentration
of 0.05m.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106381.
Angew. Chem. Int. Ed. 2011, 50, 12197 –12200
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12197

Communications
change in the stereochemistry stimulated us to study the Z-
selective synthesis of the unsaturated carbonyl compounds.
Catalyst screening led to the finding that [PMo12O40]3À was
superior to [SiMo12O40]4À and [PW12O40]3À as an anionic
moiety to produce a better yield of (Z)-2a (entries 2–4). In
contrast, the Na3[PW12O40]·nH2O-catalyzed reaction did not
afford 2a, but instead the dimeric ether 3 (entry 4). Among
the various cations, a silver salt exhibited higher reactivity and
Z selectivity (entries 2, and 5–7). The reaction of 1a with
Ag3[PMo12O40]·nH2O in EtOAc gave (Z)-2a in 66% yield
(NMR spectroscopy); furthermore, the use of the same silver
salt in acetone dramatically improved both the yield and the
stereoselectivity (entries 7–9).[9]
Figure 1. Reaction profile as a function of time for the rearrangement
Under the optimal reaction conditions, we subsequently
examined the reactions of a series of secondary propargyl
alcohols 1b–g (Table 2). Using 0.01 equivalents of
Ag3[PMo12O40]·nH2O in acetone (method A), (Z)-2b–g
were selectively prepared in all cases. The tendency of the
transformation into Z isomers was found to depend on the
electronic nature of the aryl substituent at the propargyl
position (Table 2, entries 1 and 3 and Table 1, entry 8).
Especially, the reaction of 1b, having an electron-donating
group, smoothly proceeded at room temperature within
1 hour to give (Z)-2b in 90% yield (Table 2, entry 1).
Particularly noteworthy is the high Z selectivity and chemical
yield obtained with 1e, having a sterically demanding tert-
butyl group, even though it took longer to complete the
reaction. In contrast, the use of H3[PMo12O40]·nH2O in
EtOAc (method B) for the same substrates 1b–d allowed
the exclusive formation of (E)-2b–d (entries 2, 4, and 6).
On the basis of several experiments mentioned below, the
unprecedented Z selectivity can be accounted for by the
characteristic bulkiness and acidity of the heteropoly com-
pounds. First, monitoring the reaction of 1a with
Ag3[PMo12O40]·nH2O by 1H NMR spectroscopy revealed
that (Z)-2a formed about ten times more quickly than (E)-
2a (Figure 1). Although a large amount of the dimer 3 was
~
&
*
of 1a using Ag3[PMo12O40]·nH2O. : 1a, ꢀ: (E)-2a, : (Z)-2a, : 3.
generated at the beginning of the reaction, 3 was found to
react with Ag3[PMo12O40]·nH2O under the same conditions to
preferentially afford (Z)-2a [(Z)-2a/(E)-2a ꢀ 10:1].[10] We
also observed a similar selective formation of (Z)-2a with
Na3[PMo12O40]·nH2O as the catalyst. It is worth noting that
even H3[PMo12O40]·nH2O preferentially generated (Z)-2a at
an early stage of the reaction.[11] Therefore, it is clear that
regardless of the kind of counter cation, the heteropoly
compound catalyzed rearrangement initially gives (Z)-2.
Second, in these reactions, it was speculated that the
allenolates are initially generated by the 1,3-shift of the
hydroxy group of 1, similar to the conventional Meyer–
Schuster rearrangements.[2,4a,b] The stereochemistry of the
protonation of the allenolates directly reflects the Z/E-
selectivity of the products 2. Zimmerman and Pushechnikov
reported on the protonation of the allenolate 5, which is
generated from 4 and Bu4NF, with varous proton sources and
found that the bulkiness of the acid had little effect on the
stereoselectivity (Scheme 1).[12] In contrast, we found that a
similar reaction using Ag3[PMo12O40]·nH2O
achieved a high Z selectivity to give a 8.2:1 mixture of (Z)-
and (E)-2 f. A similar reaction in acetone at 508C,
using the conditions of method A, produced (Z)-2 f
Table 2: Heteropoly compound catalyzed rearrangement of 1b–g into (Z)- and (E)-
2b–g.
with even higher selectivity (Z/E = 11.6:1). These
results indicate that there is a potential influence of
heteropoly compounds as a sterically demanding
proton source. It is noteworthy that in spite of
reacting at 508C, our developed reaction afforded
the products with high Z selectivities.
Finally, we disclose that the H3[PMo12O40]·nH2O-
catalyzed formation of (E)-2 arose from the isomer-
ization of the primary product (Z)-2. Actually, a
catalytic amount of H3[PMo12O40]·nH2O promoted
the double bond isomerization of (Z)-2a into (E)-2a
in EtOAc (Table 3, entry 1), whereas similar treat-
ment of (Z)-2a with Ag3[PMo12O40]·nH2O in ace-
tone (entry 3) or without any heteropoly acid in
EtOAc retained its stereochemistry (entry 2).
Entry
Substrate
R
Method[a] t [h]
Yield [%][b]
Ar
Z
E
1[c]
2[c]
3
4
5
6
7
8
9
1b 4-MeC6H4 n-C6H13
1b 4-MeC6H4 n-C6H13
1c 4-ClC6H4 n-C6H13
1c 4-ClC6H4 n-C6H13
A
B
A
B
A
B
A
A
A
1
72
2b 90
2b
8
85
11
86
9
1
3.5 2c 69
2c
1.5 2d 74
6
1
1d Ph
1d Ph
1e Ph
1 f Ph
1g Ph
Me
Me
tBu
Ph
5
24
5
2d
1
80
2e 79 (Z/E=93:7)[d]
2 f 83 (Z/E=80:20)[d]
1-cyclohexenyl
0.33 2g 57 (Z/E=93:7)[d]
In conclusion, we have demonstrated the stereo-
selective preparation of both the Z- and E-a,b-
unsaturated ketones by simply changing the cationic
moiety of the heteropoly compounds. The use of
Ag3[PMo12O40]·nH2O preferentially produced the
[a] Method A: Ag3[PMo12O40]·nH2O (0.01 equiv), 0.05m in acetone, 508C; method
B: H3[PMo12O40]·nH2O (0.01 equiv), 0.3m in EtOAc, 508C. [b] Yield of isolated
product. [c] Conducted at room temperature. [d] The products were obtained as an
inseparable mixture of Z and E isomers.
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Angew. Chem. Int. Ed. 2011, 50, 12197 –12200

Rearrangement of propargyl alcohols 1 into a,b-unsaturated
ketones 2:
Z isomer: Ag3[PMo12O40]·nH2O (5.4 mg, 0.0025 mmol) was
added to a solution of the propargyl alcohols 1 (0.25 mmol) in
acetone (5.0 mL, 0.05m). The reaction mixture was stirred at 508C or
room temperature until complete consumption of both 1 and the
dimer 3, and then quenched with saturated aqueous NaHCO3. The
organic materials were extracted with EtOAc, and the combined
organic extracts were washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was purified by column chroma-
tography (silica gel, usually hexanes/EtOAc = 30:1) to give (Z)-2 and
(E)-2, unless otherwise noted.
E isomer: H3[PMo12O40]·nH2O (4.6 mg, 0.0025 mmol) was added
to a solution of the propargyl alcohols 1 (0.25 mmol) in EtOAc
(0.80 mL, 0.3m). The reaction mixture was stirred at 508C until
complete consumption of (Z)-2, and then quenched with saturated
aqueous NaHCO3. The organic materials were extracted with EtOAc,
and the combined organic extracts were washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by column
chromatography (silica gel, usually hexanes/EtOAc = 30:1) to give
(E)-2.
Scheme 1. Effect of Ag3[PMo12O40]·nH2O on protonation of allenolate
5.
Table 3: Influence of heteropoly compounds on isomerization of (Z)-2a
to (E)-2a.
Received: September 8, 2011
Published online: October 25, 2011
Keywords: heteropoly compounds · olefination · alcohols ·
.
rearrangements · synthetic methods
Entry
Heteropoly Compound
Solvent
Yield [%][a]
Z
E
1
H3[PMo12O40]·nH2O
None
Ag3[PMo12O40]·nH2O
EtOAc
EtOAc
acetone
4
80
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[a] Yield determined by NMR spectroscopy using 1,4-dimethoxybenzene
as the internal standard. [b] Conducted for 1.5 h.
thermodynamically unfavorable Z isomers, whose practical
synthesis has been limited.[13] To the best of our knowledge
this is the first successful transformation of propargyl alcohols
into the Z-a,b-unsaturated ketones through the Meyer–
Schuster rearrangement. It was suggested that the heteropoly
compounds could serve not only as an acidic catalyst, but also
as a bulky proton source. Because of the facile access to the
propargyl alcohols through the additions of alkynes to
carbonyl compounds, the two-step process is highly atom
economical and produces a reduced amount of waste
materials. Additional investigation of the detailed effects of
the heteropoly compounds on the reaction and a practical
extension of this method is now in progress.
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[6] Shiꢀs group developed the triazole/gold that converted the
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Experimental Section
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Procedure for the preparation of Ag3[PMo12O40]·nH2O: Ag3-
[PMo12O40]·nH2O was prepared by a minor modification of Haas-
nootꢀs method.[14] To a stirring solution of H3[PMo12O40]·nH2O
(1.00 g, 0.55 mmol) in water (1.0 mL) was dropwise added a solution
of AgNO3 (279 mg, 1.64 mmol) in water (1.0 mL). A yellow precip-
itate was immediately formed, and separated by centrifugation and
washed with acetone. After drying in vacuo at room temperature
overnight, Ag3[PMo12O40]·nH2O (539 mg, 46%) was obtained. The
main element contents were analyzed by ICP-AES. Found: Ag 13.9
wt%; P 1.37 wt%; Mo 50.0 wt%. The atom ratio of Ag:P:Mo is equal
to 3:1:12.
Angew. Chem. Int. Ed. 2011, 50, 12197 –12200
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Communications
[9] For more information, see the Supporting Information.
[10] The reaction of the dimer 3 with Ag3[PMo12O40]·nH2O pro-
ceeded within 2 h to give (Z)-2a (82%) and (E)-2a (8%).
[11] For the detailed time-course of the rearrangement of 1a using
either H3[PMo12O40]·nH2O or Na3[PMo12O40]·nH2O. See the
Supporting Information.
[12] H. E. Zimmerman, A. Pushechnikov, Eur. J. Org. Chem. 2006,
3491 – 3497.
[13] a) W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405 –
4408; b) K. Ando, Tetrahedron Lett. 1995, 36, 4105 – 4108.
[14] A. F. Stassen, E. M. Ferrero, C. Gimꢃnez-Saiz, E. Coronado,
J. G. Haasnoot, J. Reedijk, Monatsh. Chem. 2003, 134, 255 – 264.
12200 www.angewandte.org
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Angew. Chem. Int. Ed. 2011, 50, 12197 –12200