Microwave-assisted InCl3-catalyzed Meyer-Schuster rearrangement of propargylic aryl carbinols in aqueous media: a green approach to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2009.06.040

A novel, efficient, simple and environmentally benign protocol for the Meyer-Schuster isomerization of propargylic aryl carbinols into α,β-unsaturated carbonyl compounds has been developed using catalytic amounts of InCl₃, pure water as the solvent, and microwave irradiation as the heating source.

Full text of DOI:10.1016/j.tetlet.2009.06.040

Tetrahedron Letters 50 (2009) 4773–4776
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted InCl3-catalyzed Meyer–Schuster rearrangement
of propargylic aryl carbinols in aqueous media: a green approach
to
a,b-unsaturated carbonyl compounds
*
Victorio Cadierno , Javier Francos, José Gimeno
Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Química Organometálica ‘Enrique Moles’ (Unidad Asociada al C.S.I.C.),
Universidad de Oviedo, 33071, Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, efficient, simple and environmentally benign protocol for the Meyer–Schuster isomerization of
Received 6 May 2009
Revised 3 June 2009
Accepted 8 June 2009
Available online 12 June 2009
propargylic aryl carbinols into a,b-unsaturated carbonyl compounds has been developed using catalytic
amounts of InCl3, pure water as the solvent, and microwave irradiation as the heating source.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
The Meyer–Schuster rearrangement
Propargylic aryl carbinols
a,b-Unsaturated carbonyl compounds
Indium(III) chloride
MW-assisted synthesis
Water as solvent
Isomerization reactions
The use of water as an eco-friendly reaction medium in con-
junction with microwave (MW) irradiation is gaining widespread
acceptance, not only because particular or unexpected reactivities
can be in some cases observed, but also because its significant use-
fulness for Green Chemistry.1 Similarly, the search of organic reac-
tions proceeding with atom-economy (all atoms of reactants end
up in the final products) has also emerged as a major objective
In recent years, it has been described that regioselective Meyer–
Schuster reactions can be efficiently achieved under milder condi-
tions by the aid of transition metals, the reported examples includ-
ing several oxo-complexes10 as well as Ru-,11 Au-12 and Ag-based13
systems. In addition, taking advantage of the affinity shown by
‘soft’ Lewis-acids for
p
-bonds over non-bonded electron pairs,14
Dudley and co-workers have also demonstrated the utility of such
reagents (i.e., InCl3, Sc(OTf)3 and Cu(OTf)2) as catalysts for the
Meyer–Schuster isomerization of ethoxyalkynyl carbinols into
for synthetic chemists.2 In this context, the broad utility of
a,b-
unsaturated carbonyl compounds and the easy preparation of
propargylic alcohols make the isomerization of the latter into the
former a useful transformation.3 To achieve this goal, the well-
known Meyer–Schuster rearrangement represents the simplest
and most widely used approach (Scheme 1).4,5
Successful application of this Brønsted acid-catalyzed isomeri-
zation reaction in the design of novel histamine H3-receptor antag-
onists,6 antifungal mold metabolites7 and aza-analogues of the
biological active Senkyunolide-E,8 as well as in the construction
of the Taxol AB-system,9 has been described confirming its syn-
thetic utility. However, harsh conditions and strong acidic media
are usually required, which often give rise to non-regioselective
transformations due to competitive Rupe-type processes (Scheme
1),5 limiting seriously the applicability of this textbook reaction.
a
,b-unsaturated esters.15
In all the above-mentioned examples the reactions were per-
formed in organic media, the search for alternative catalytic meth-
ods operating in water being highly desirable.16 In this sense, we
report herein an efficient, general and environmentally benign
aqueous protocol for the Meyer–Schuster isomerization of propar-
gylic aryl carbinols into
a,b-unsaturated carbonyl compounds
R2
O
H
O
R1
H+/ Δ
HO
R3
or
R3
R1
R5
R1
R2
R2
R4
Rupe
(only if R3 = CHR4R5)
Meyer-Schuster
* Corresponding author. Tel.: +34 985102985; fax: +34 985103446.
E-mail address: vcm@uniovi.es (V. Cadierno).
Scheme 1. The Meyer–Schuster and Rupe rearrangements.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.040

4774
V. Cadierno et al. / Tetrahedron Letters 50 (2009) 4773–4776
Table 1
MW-assisted InCl3-catalyzed Meyer–Schuster rearrangement of terminal propargylic aryl carbinolsa
Entry
1
Propargylic alcohol
% InCl3 (mol %)
Time (min)
Product
GC yield (%)
>99
Isolated yield (%)
91
H
O
H
HO
1
5
O
H
HO
H
2
3
4
1
1
1
5
5
>99
>99
>99
87
93
89
H
O
H
HO
MeO
MeO
OMe
OMe
H
O
HO
Me
H
15
Me
Me
Me
H
O
H
HO
F
5
1
30
>99
90
F
F
F
H
O
HO
Cl
H
6
7
1
1
150
>99
>99
93
Cl
Cl
Cl
HO
H
O
H
5
90b
H
O
HO
8
9
5
1
300
10
H
96
85
92
OH
H
O
H
>99
MeO
MeO
H
MeO
MeO
HO
H
O
10
2
180
97
86
H
H
H
O
H
OH
11
12
1
1
10
10
98
97
88
91
H
OMe
OMe
OH
H
O
H
MeS
H
MeS
OH
H
O
H
13
1
120
97
84
H

V. Cadierno et al. / Tetrahedron Letters 50 (2009) 4773–4776
4775
Table 1 (continued)
Entry
Propargylic alcohol
% InCl3 (mol %)
Time (min)
120
Product
GC yield (%)
99
Isolated yield (%)
90
H
O
H
OH
14
2
H
OH
H
O
H
15
2
1
360
10
94
81
95
Cl
H
Cl
H
O
H
OH
S
16
S
>99
H
a
Reactions were performed under air atmosphere in a CEM DiscoverÒ S-Class microwave synthesizer at 160 °C through moderation of the initial microwave power
(300 W); 1 mmol of the corresponding propargylic aryl carbinol (1 M in water) was used.
b
Isolated as a mixture of stereoisomers (E/Z ratio = 61:39).
using catalytic amounts of the water-compatible and inexpensive
Lewis-acid InCl3. Microwave irradiation is used as the heating
source resulting in short reaction times, almost quantitative yields
and complete E-stereoselectivity. Results obtained in the isomeri-
zation of a variety of terminal propargylic aryl carbinols are sum-
marized in Table 1.
thermodynamically more stable E isomer, regardless of the elec-
tronic properties of the aromatic or heteroaromatic substituent
present in the molecule. Such a remarkable stereoselectivity has
been rarely observed.10b,12d,19
Finally, it is also worth to note that the scope of this aqueous
isomerization process is not restricted to propargylic aryl carbinols
bearing a terminal C„C bond, the internal ones being also effi-
ciently transformed into the corresponding enones. Moreover, as
exemplified in Scheme 2, complete E-stereoselectivity was once
again reached starting from secondary alcohols.
At the beginning, the isomerization of commercially available
1,1-diphenyl-2-propyn-1-ol into 3,3-diphenylpropenal was used
as a model reaction. Thus, we found that, under optimized condi-
tions (1 mol % InCl3; 1 M solution of the substrate in water,
160 °C), complete and selective conversion of the alkynol into the
enal takes place after only 5 min of MW-irradiation (entry 1), the
use of lower temperatures and/or catalyst loadings slowing down
the reaction considerably.17 Remarkably, neither an inert atmo-
sphere nor an organic co-solvent was required. Under these opti-
mal reaction conditions,18 other tertiary propargylic aryl
carbinols were efficiently transformed into the corresponding en-
als (P87% isolated yields; quantitative yields were in all cases ob-
served by GC) within 5–150 min (entries 1–7). Influence of the
electronic properties of the aryl rings on the reaction rates was ob-
served. Thus, alkynols with electron-withdrawing groups showed
less reactivity (entries 5–6) as compared to the substrates with
electron-donating functionalities (entries 3–4). Interestingly, no
competitive Rupe-type rearrangement of 2-phenyl-3-butyn-2-ol
was observed under these conditions, a mixture of the E and Z ster-
eoisomers of 3-phenyl-2-butenal being exclusively formed (entry
7).19 As shown in entry 8, InCl3 is also able to catalyze the isomer-
ization of the dialkyl-substituted alkynol 2-ethynyl-adamantan-2-
ol in water. However, a higher catalyst loading (5 mol %) and a
longer reaction time (5 h) were in this case required.
In summary, a simple, general,20 selective and efficient protocol
for the the Meyer–Schuster isomerization of propargylic aryl carbi-
nols into a,b-unsaturated carbonyl compounds, very valuable raw
materials in organic synthesis, has been developed using inexpen-
sive InCl3.21 Moreover, the process is truly sustainable since, in
addition to its atom-economy, it proceeds in a pure aqueous med-
ium, employs MW-irradiation as the heating source, and the cata-
lyst can be recycled.22 Further investigations into the application of
this methodology to more challenging substrates, as well as in the
development of sequential C–C coupling processes,23 are now in
progress in our laboratories.
Acknowledgments
Financial support by the Ministerio de Ciencia e Innovación
(MICINN) of Spain (Projects CTQ2006-08485/BQU and Consolider
Ingenio 2010 (CSD2007-00006)) and the Gobierno del Principado
de Asturias (FICYT Project IB08-036) is gratefully acknowledged.
J.F. also thanks MICINN and the European Social Fund for the award
of a PhD grant.
Probably, the most significant results of this study were ob-
tained in the isomerization of secondary terminal alkynols (entries
9–16), since the resulting enals were generated in all cases as the
References and notes
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37, 1546–1557; (c) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629–
639; (d) Polshettiwar, V.; Nadagouda, M. N.; Varma, R. S. Aust. J. Chem. 2009, 62,
16–26.
2. (a) Trost, B. M. Science 1991, 254, 1471–1477; (b) Trost, B. M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 259–281; (c) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705;
(d) Trost, B. M.; Fredericksen, M. U.; Rudd, M. T. Angew. Chem., Int. Ed. 2005, 44,
6630–6666.
3. Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008, 130, 11970–11978, and
references therein.
4. Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819–823.
5. For a review, see: Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429–
438.
H
Me
O
HO
R
InCl3 (1 mol%)
Me
R
MW / H2O / 160 ºC / 10 min
H
H
R = Ph (89%), 4-C6H4OMe (91%), 4-C6H4SMe (88%)
Ph
HO
Ph
InCl3 (1 mol%)
Ph
Ph
O
MW / H2O / 160 ºC / 20 min
Ph
Ph
6. Stark, H.; Sadek, B.; Krause, M.; Hüls, A.; Ligneau, X.; Ganellin, C. R.; Arrang, J.-
M.; Schwartz, J.-C.; Schunack, W. J. Med. Chem. 2000, 43, 3987–3994.
7. Welch, S. C.; Hagan, C. P.; White, D. H.; Fleming, W. P.; Trotter, J. W. J. Am. Chem.
Soc. 1977, 99, 549–556.
(87%)
Scheme 2. Meyer–Schuster isomerization of internal alkynols.

4776
V. Cadierno et al. / Tetrahedron Letters 50 (2009) 4773–4776
8. Eddine, A. C.; Daïch, A.; Jilale, A.; Decroix, B. Heterocycles 1999, 51, 2907–2915.
9. Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139–7158.
10. For recent examples, see: (a) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org.
Lett. 2008, 10, 1867–1870; (b) Stefanoni, M.; Luparia, M.; Porta, A.; Zanoni, G.;
Vidari, G. Chem. Eur. J. 2009, 15, 3940–3944, and references cited therein.
11. Cadierno, V.; Crochet, P.; Gimeno, J. Synlett 2008, 1105–1124, and references
cited therein.
12. See, for example: (a) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027–4029;
(b) Lopez, S. S.; Engel, D. A.; Dudley, G. B. Synlett 2007, 949–953; (c) Lee, S. I.;
Baek, J. Y.; Sim, S. H.; Chung, Y. K. Synthesis 2007, 2107–2114; (d) Ramón, R. S.;
Marion, N.; Nolan, S. P. Tetrahedron 2009, 65, 1767–1773.
microwave synthesizer and power was held at 300 W until the desired
temperature was reached (160 °C). Microwave power was automatically
regulated for the remainder of the experiment to maintain the temperature
(monitored by a built-in infrared sensor). The internal pressure during the
reaction ranged between 10 and 90 psi. After completion of the reaction (see
Table 1 and Scheme 2), the vial was cooled and the organic product was
extracted with diethyl ether (15 mL). After drying with MgSO4, the solvent was
evaporated under vacuum, and the crude residue was purified by flash
chromatography over silica gel using EtOAc/hexane (1:10) as a eluent. The
identity of the resulting carbonyl compounds was assessed by comparison of
their 1H and 13C{1H} NMR spectroscopic data with those reported in the
literature and by their fragmentation in GC/MS.
13. See, for example: (a) Shigemasa, Y.; Oikawa, H.; Ohrai, S.-I.; Sashiwa, H.;
Saimoto, H. Bull. Chem. Soc. Jpn. 1992, 65, 2594–2598; (b) Sugawara, Y.;
Yamada, W.; Yoshida, S.; Ikeno, T.; Yamada, T. J. Am. Chem. Soc. 2007, 129,
12902–12903.
19. See, for example: Cadierno, V.; García-Garrido, S. E.; Gimeno, J. Adv. Synth.
Catal. 2006, 348, 101–110.
20. The only limitation of this method concers the use of primary propargylic
alcohols. Thus, while the internal alkynols RC„CCH2(OH) (R = Ph, n-Bu)
remained unreacted after 3 h of MW-heating in the presence of InCl3
(1 mol %), propargylic alcohol itself led to a polymeric material formation.
21. One referee suggested a hypothetical reaction sequence involving an initial
anti-Markovnikov C„C hydration to form a b-hydroxy aldehyde, followed by
thermal elimination of water under MW-irradiation. Such a possibility has
been discarded since no aldehyde intermediates were detected by monitoring
the course of the reactions by GC/MS. A classical Meyer–Schuster reaction
pathway involving indium-hydroxo derivatives is therefore proposed.
22. After a simple extraction of the final product with diethyl ether, the aqueous
phase containing the catalyst can be re-used in at least two consecutive runs
with only a slight decrease in the activity. For example, using the isomerization
of 1,1-diphenyl-2-propyn-1-ol into 3,3-diphenylpropenal as model reaction,
>99% GC conversion was achieved in the third cycle after 20 min of MW-
heating (to be compared with entry 1 in the table).
14. See, for example: (a) Santelli, M.; Pons, J.-M. In Lewis Acids and Selectivity in
Organic Synthesis; CRC Press: Boca Raton, 1995; (b) Lewis Acids in Organic
Synthesis; Yamamoto, H., Ed.; Wiley-Interscience: New York, 2000.
15. Engel, D. A.; Lopez, S. S.; Dudley, G. B. Tetrahedron 2008, 64, 6988–6996.
16. Uncatalyzed Meyer–Schuster rearrangement of 2-phenyl-3-butyn-2-ol into (E/
Z)-3-phenyl-2-butenal (34% yield after 1 h) under high-temperature neutral
aqueous conditions (200 °C) has been described: An, J.; Bagnell, L.; Cablewski,
T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997, 62, 2505–2511.
17. (a) As an example, using 1 mol % of InCl3 at 100 °C, complete conversion of 1,1-
diphenyl-2-propyn-1-ol into 3,3-diphenylpropenal was only achieved after
24 h of MW-irradiation. (b) It must also be noted that conventional instead of
MW-heating was found to be much less effective (34% yield after 24 h at 100 °C
using 1 mol % of InCl3). (c) As expected, no isomerization of 1,1-diphenyl-2-
propyn-1-ol takes place in the absence of InCl3 (160 °C under MW-irradiation).
18. Typical experimental procedure:
A pressure-resistant septum-sealed glass
microwave reactor vial was charged with the corresponding propargylic aryl
carbinol (1 mmol), InCl3 (1–5 mol %), a magnetic stirring bar and water (1 mL).
The vial was then placed inside the cavity of
23. Cadierno, V.; Díez, J.; García-Garrido, S. E.; Gimeno, J.; Nebra, N. Adv. Synth.
Catal. 2006, 348, 2125–2132.
a
CEM DiscoverÒ S-Class