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Cite this: DOI: 10.1039/c1gc15293a

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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 Gonzalez-Rodrguez,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 toemploy dichloroethane as solvent.

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 CC 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.

aDepartment of Chemistry, University of Oxford, Chemistry ResearchLaboratory, Mansfield Road, Oxford, UK, OX1 3TA.E-mail: michael.willis@chem.ox.ac.uk; Fax: +44 1865 285002; Tel: +441865 285126bResearch API, Pfizer Global Research and Development, Sandwich,Kent, UK, CT13 9NJ

Electronic supplementary information (ESI) available: Experimentaldetails and spectroscopic data for all new compounds. See DOI:10.1039/c1gc15293a

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 lowboiling 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,1012 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 factorsshowpropylenecarbonate as beingclearly advantageousto DCE

in a like-for-like comparison.13

Despite the existing commercial uses, propylene carbonatehas

not seen extensive use as a solvent for transition metal catalysis.

Several examples of its use are known: Borner 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,1519 including platinum-catalysed hydrosilylation and

rhodium-catalysed hydroformylation reactions; and Reetz and

coworkers described its use in stabilising palladium clusters and

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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 ofS-

chelatingaldehydeswith a variety of alkynes. Thisreactionrepre-

sents a synthetically useful and operationally simple protocolforintermolecular hydroacylation as a method for the construction

of enones.

Results and discussion

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-

scribedusing eitherDCE or acetone as thereaction solvent.For

comparrison, a representative transformation performed in both

acetone and DCE, is shown in Scheme 2.

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

Table 1 Propylene carbonate as solvent in intermolecular rhodium-catalysed alkyne hydroacylation reactionsa

Entry Aldehyde Alkyne (R2) ProductYield(%)b

1 Ph 90

2 1a Bu 91c

3 1a Hex 91

Table 1 (Contd.)

Entry Aldehyde Alkyne (R2) ProductYield(%)b

4 1a C2H4Ph 83

5 Ph 86

6 1b Hex 95

7 1b C2H4Ph 87

8 1b cyclopropyl 90

9 Ph 84

10 1c Hex 86

11 1c C3H6Cl 74

12 1c C2H4Ph 94

13d Ph 73

14d 1d Bu 73

15d 1d Hex 83

16d 1d C2H4Ph 75

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 performedusing 1 mol.% catalyst delivered a 91% yield. d Alkyne (2.25 mmol) andDPEphos 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 14). 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 productwas still obtained in 91% yield. Entries 58 document the

successful use of a more hindered alkyl aldehyde (1b) with

four representative alkynes (entries 69). The aromatic aldehyde,

2-(methylthio)benzaldehyde (1c), was also employed without

issue (entries 1013). 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 thedesired hydroacylation products to be synthesisedin good yields.

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

We thank the EPSRC, Pfizer, Xunta de Galicia PGIDIT-

INCITE and FSE (Angeles Alvarino contract and Estadas

grants: 2008/178, 2009/188 and 2010/163 to CGR) for funding,

and Mr Angus Logan for technical assistance.

Representative experimental procedure: exemplified by the preparationof (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 for1 h. The reaction mixture was loaded directly onto silica and eluted with30% Et2O/petrol to furnish the pure product as a yellow oil (139 mg,90%).

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