Replacing dichloroethane as a solvent for rhodium-catalysed intermolecular alkyne hydroacylation reactions: The utility of propylene carbonate

Article abstract of DOI:10.1039/c1gc15293a

Propylene carbonate is an excellent solvent for rhodium-catalysed intermolecular alkyne hydroacylation reactions, allowing a variety of β-S-aldehydes and alkynes to be combined in high yields, to deliver enone products. The effective use of propylene carb

Full text of DOI:10.1039/c1gc15293a

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COMMUNICATION
Replacing dichloroethane as a solvent for rhodium-catalysed intermolecular
alkyne hydroacylation reactions: the utility of propylene carbonate†
Philip Lenden,a Paul M. Ylioja,a Carlos Gonza´lez-Rodr´ıguez,a David A. Entwistleb and Michael C. Willis*a
Received 17th March 2011, Accepted 17th May 2011
DOI: 10.1039/c1gc15293a
Propylene carbonate is an excellent solvent for rhodium-
catalysed intermolecular alkyne hydroacylation reactions,
allowing a variety of b-S-aldehydes and alkynes to be
combined in high yields, to deliver enone products. The
effective use of propylene carbonate removes the need to
employ dichloroethane as solvent.
functional groups, including free hydroxyl groups, halogens, and
silyl ethers.
Currently, the preferred solvents for this process are acetone
and 1,2-dichloroethane (DCE); however, neither are without
their drawbacks. The limitation conferred by acetone is its low
boiling point of 56 ◦C (760 mmHg), which can increase reaction
times or reduce yields in the case of more challenging reaction
systems. DCE, while higher boiling, has significant toxicity
issues and – like other halogenated solvents – is undesirable for
use on scale due to the environmental hazards associated with
its use and disposal. Propylene carbonate, on the other hand,
is gaining prominence as a useful solvent in organic synthesis
due to its many desirable properties. Organic carbonates are
used in a variety of industrial applications, such as degreasing,
paint stripping, and as electrolytes in lithium ion batteries.5
Propylene carbonate itself is a polar aprotic solvent which is
non-toxic (to the extent that it has been used as a carrier
solvent in cosmetics and topically applied medicines6), non-
corrosive and biodegradable.7 In addition to excellent solvency
of metal ions8 and organic compounds, its physical properties
are also desirable: it has low viscosity, low vapour pressure
and is miscible with water. A recent paper in this journal by
Jessop9 urged scientists to assess the green-ness of solvents for a
given application based on “the environmental effects of solvents,
including their synthesis, use and disposal”. Propylene carbonate
can be synthesised in an atom-efficient manner from propylene
oxide and carbon dioxide,10–12 resulting in a short “synthesis
tree” with none of the downsides which would prevent it from
being considered as a green solvent. More importantly, the use
of propylene carbonate as a direct replacement solvent for DCE
avoids the production of any chlorinated waste. These factors
show propylene carbonate as being clearlyadvantageous toDCE
in a like-for-like comparison.13
Introduction
The transition-metal catalysed intermolecular hydroacylation
of alkenes and alkynes is a highly atom-efficient transformation
which allows the construction of synthetically useful ketones via
the addition of an acyl group and a hydrogen atom across an
unsaturated C–C bond.1 Intermolecular hydroacylation has yet
to be extended to a general process due to the propensity of
the acyl-metal intermediate to undergo decarbonylation as an
unproductive side reaction. Our group has previously disclosed
a chelation-controlled intermolecular hydroacylation process,
which utilises a thioether (or dithiane) chelate2 in the aldehyde
component to stabilise the key acyl-rhodium intermediate and
thus suppress decarbonylation3,4 (Scheme 1). The resulting
methodology permits the atom efficient synthesis of a range of
1,4-dicarbonyl compounds (with alkene substrates) and enones
(with alkyne substrates), and is tolerant of a wide variety of
Scheme 1 b-S-Chelating aldehydes in rhodium-catalysed intermolecu-
lar alkene and alkyne hydroacylation reactions.
Despite the existing commercial uses, propylene carbonate has
not seen extensive use as a solvent for transition metal catalysis.
Several examples of its use are known: Bo¨rner and coworkers
have published a number of accounts of the use of propylene
carbonate as a solvent for catalytic asymmetric hydrogenations
with rhodium and iridium catalysts;8,14 Behr and coworkers have
described examples of catalysis with propylene carbonate as
a solvent,15–19 including platinum-catalysed hydrosilylation and
rhodium-catalysed hydroformylation reactions; and Reetz and
coworkers described its use in stabilising palladium clusters and
aDepartment of Chemistry, University of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford, UK, OX1 3TA.
E-mail: michael.willis@chem.ox.ac.uk; Fax: +44 1865 285002; Tel: +44
1865 285126
bResearch API, Pfizer Global Research and Development, Sandwich,
Kent, UK, CT13 9NJ
† Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for all new compounds. See DOI:
10.1039/c1gc15293a
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their use in catalysing Heck reactions.20 A review on the use
of organic carbonates as solvents and in catalysis has recently
been published,21 and contains further examples of catalysis
which use propylene carbonate as a solvent. Herein we describe
the use of propylene carbonate as a solvent for the chelation-
assisted rhodium-catalysed intermolecular hydroacylation of S-
chelatingaldehydes with avarietyof alkynes. This reaction repre-
sents a synthetically useful and operationally simple protocol for
intermolecular hydroacylation as a method for the construction
of enones.
Table 1 (Contd.)
Yield
(%)b
Entry Aldehyde
Alkyne (R2) Product
–C2H4Ph
4
1a
83
Results and discussion
5
Ph
86
The viability of using propylene carbonate as a solvent for our
intermolecular hydroacylation methodology was investigated by
carrying out reactions between representative aldehydes and
alkynes selected from classes which had previously been de-
scribed using either DCE or acetone as the reaction solvent.‡ For
comparrison, a representative transformation performed in both
acetone and DCE, is shown in Scheme 2.
6
7
1b
1b
Hex
95
87
–C2H4Ph
8
9
1b
cyclopropyl
Ph
90
84
10
11
12
13d
1c
1c
1c
Hex
86
74
94
73
Scheme 2 Representative alkyne hydroacylation reactions performed
in acetone and DCE.
It was found that these reactions could be carried out in
propylene carbonate with a catalyst system comprising commer-
cially available rhodium complex [Rh(nbd)2]BF4 in combination
with dppe as the ligand. The catalysts did not require pre-
activation by hydrogenation. Table 1 summarises the results,
which are grouped by aldehyde class: b-methylthiopropanal
–C3H6Cl
–C2H4Ph
Ph
Table 1 Propylene carbonate as solvent in intermolecular rhodium-
catalysed alkyne hydroacylation reactionsa
14d
15d
16d
1d
1d
1d
Bu
73
83
75
Yield
Entry Aldehyde
1
Alkyne (R2)
Ph
Product
(%)b
Hex
90
–C2H4Ph
2
3
1a
1a
Bu
91c
91
Hex
a Aldehyde (1.5 mmol), alkyne (1.65 mmol), catalyst (5 mol.%), propy-
lene carbonate, 70 ◦C, 1 h. b Isolated yields. c A reaction performed
using 1 mol.% catalyst delivered a 91% yield. d Alkyne (2.25 mmol) and
DPEphos ligand employed, 16 h.
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(1a) is the simplest aldehyde that fulfils the requirement of
a chelating b-S-substituent, and this was combined with four
alkynes, in all cases delivering the expected hydroacylation
adducts in excellent yields (entries 1–4). Although the reactions
were routinely performed using a 5 mol.% catalyst loading
it was also possible to reduce this loading and retain good
activity. For example, performing the reaction shown in entry
2, but employing a 1 mol.% catalyst loading, the enone product
was still obtained in 91% yield. Entries 5–8 document the
successful use of a more hindered alkyl aldehyde (1b) with
four representative alkynes (entries 6–9). The aromatic aldehyde,
2-(methylthio)benzaldehyde (1c), was also employed without
issue (entries 10–13). The final group of reactions all employ
b-dithiane-aldehyde 1d. This sterically demanding aldehyde
proved to be a more challenging substrate for the catalyst
system described in this paper, and several modifications were
required to drive these reactions to completion: a larger excess
of alkyne (1.5 equivalents, compared to 1.1 equivalents in the
previously described examples), a prolonged reaction time, and
changing the ligand from dppe to the “second generation”
DPEphos catalyst system.2d These modifications enabled the
desired hydroacylation products to be synthesised in good yields.
R. L. Woodward and G. S. Currie, Org. Lett., 2005, 7, 2249–2251;
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3 For alternative chelation-controlled intermolecular hydroacylation
reactions, see: (a) C.-H. Jun, H. Lee, J.-B. Hong and B.-I. Kwon,
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1144–1145; (c) T. Tanaka, M. Tanaka and H. Suemune, Tetrahedron
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Hagiwara and M. Hirano, Org. Lett., 2007, 9, 1215–1218; (e) R. T.
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Conclusion
In conclusion, we have demonstrated that propylene carbonate
is a viable solvent for our previously described intermolecular
hydroacylation methodology. The reactions described employ
commercially available pre-catalysts and ligands, require no
activation of the pre-catalyst by hydrogenation and use a solvent
which is environmentally benign, non-flammable, non-toxic, and
more attractive for use on scale than the previously used 1,2-
dichloroethane.
Acknowledgements
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‡ Representative experimental procedure: exemplified by the preparation
of (E)-5-(methylthio)-1-phenylpent-1-en-3-one. [Rh(nbd)2]BF4 (14 mg,
0.0375 mmol) and dppe (15 mg, 0.0375 mmol) were dissolved in propy-
lene carbonate (2.5 mL) and stirred at room temperature for 10 min. 3-
(methylthio)propionaldehyde (75 mL, 0.75 mmol) then phenylacetylene
(90 mL, 0.83 mmol) were added and the reaction heated at 70 ◦C for
1 h. The reaction mixture was loaded directly onto silica and eluted with
30% Et2O/petrol to furnish the pure product as a yellow oil (139 mg,
90%).
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1982 | Green Chem., 2011, 13, 1980–1982
This journal is
The Royal Society of Chemistry 2011
©