DOI: 10.1002/cctc.201402849

Highlights

Towards the Ideal Synthesis of Homoallylic Ketones
Sofía Ferrer,[a] Michael E. Muratore,[a] and Antonio M. Echavarren*[a, b]

Homoallylic ketones combine arguably two of the most synthetically useful functional groups in organic chemistry and
are, therefore, very valuable synthetic intermediates. General
methods for the synthesis of these intermediates include the
allylation of carbonyl compounds via p-allyl palladium(II) complexes,[1] the 1,4-addition of vinylmetal nucleophiles onto a,bunsaturated compounds,[2] and the Claisen rearrangement of
allyl vinyl ethers (Scheme 1).[3] The control of the regioselectivity in the latter procedure can be achieved by a domino process consisting of a copper-catalyzed CÀO bond coupling of alkenyl iodides with allylic alcohols, followed by sigmatropic
rearrangement.[4]
The synthetic equivalence of acetylenes with carbonyl compounds was first recognized in this context by the group of
Trost who found that homoallylic ketones could be obtained
by the RuII-catalyzed addition of allyl alcohols to terminal alkynes, in a process that probably took place by means of the
cycloaddition of both unsaturated substrates to form a ruthenacyclopentene intermediate.[5]

In the last decade, cationic gold(I) complexes have emerged
as the most reactive catalysts for the activation of alkynes towards the nucleophilic addition of a wide range of hetero- and
carbonucleophiles.[6] Although the first synthetically useful applications of homogeneous gold catalysis in organic synthesis
involved the attack of alcohols onto alkynes,[7] it was not until
2013 that a method for the preparation of allyl vinyl ethers
based on this process was developed. This process was achieved by the group of Aponick, who developed a tandem intermolecular
hydroalkoxylation/Claisen
rearrangement
(Scheme 2).[8] This new cascade reaction led to the direct formation of g,d-unsaturated ketones from simple starting materials in a single step and with excellent stereoselectivity in most
cases. This transformation was performed by using 5 mol % of
both neutral gold(I) complex [Au(Cl)(IPr)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) and AgBF4, which was required to generate the gold(I) cationic species in situ.
In a step towards the development of a highly efficient synthesis of homoallylic ketones, the group of Nolan has pushed
this method towards its limits by reducing the amount of
gold(I) catalyst by an order of magnitude and by conducting
the reaction in the absence of solvent, using a 1:3 alkyne to
allyl alcohol ratio.[9] Importantly, by using [Au(NTf2)(IPrCl)] (Tf =
triflate;
IPrCl = 4,5-dichloro-1,3-bis(2,6-diisopropylphenyl)-1Himidazol-2-ylidene) as the catalyst, which proved to be robust

Scheme 1. General methods for the synthesis of homoallylic ketones.
NPhth = Phthalimide.
[a] S. Ferrer, Dr. M. E. Muratore, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
[b] Prof. A. M. Echavarren
Departament de Química Analítica i Química Orgànica
Universitat Rovira i Virgili
C/Marcel·li Domingo s/n, 43007 Tarragona (Spain)
 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and
is not used for commercial purposes.

ChemCatChem 2015, 7, 228 – 229

Scheme 2. Gold(I)-catalyzed synthesis of homoallylic ketones by hydroalkoxylation/Claisen rearrangement.

228

 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Highlights
enough to withstand the relatively harsh reaction conditions,
the addition of a hygroscopic and light-sensitive silver salt was
no longer necessary. By reducing the catalyst loading to 0.2–
0.5 mol %, the new process took place with turnover numbers
(TON) from 96 to 465 and turnover frequencies (TOF) from 6 to
1396 hÀ1.
The regioselectivity of this process was largely controlled by
the electronic nature of the alkyne substituents (Scheme 2).[8]
Thus, the most electron-rich alkyne substituent (Scheme 2,
blue) ended up at the ketone terminus, whereas the least electron-rich group (Scheme 2, green) became the a-substituent of
the final ketone product. This result can be explained by the
initial attack of the alcohol onto the alkyne gold(I) complex in
a Markovnikov manner, hence by attack at the carbon bearing
the most electron-rich group.
The overall mechanistic scenario is reasonably well-understood and follows well-known principles in homogeneous
gold(I) catalysis (Scheme 3).[8, 10] However, even with the assis-

absence of solvent and with lower catalyst loadings than those
usually employed in most gold(I)-catalyzed transformations.
However, there are still some challenges to be met. Firstly,
although in a number of examples the diastereoselectivity was
good, lower diastereoselectivities were achieved with lower
catalyst loadings. In addition, terminal alkynes were relatively
poor substrates in this reaction, requiring 0.5 mol % catalyst
and furnishing lower yields (48–77 %, five examples) even
under optimized conditions.[9] Moreover, and assuming gold(I)
catalyzes the final sigmatropic rearrangement, the development of an enantioselective synthesis of homoallylic ketones
employing this method would present a formidable challenge.
In this scenario, the gold(I) catalyst should act as a chiral Lewis
acid in the enantio-discriminating Claisen rearrangement, and
this would require overcoming the intrinsic limitation posed
by the linear dicoordination of gold(I) complexes, which tends
to place the chiral ligand far away from the reactive center.

Acknowledgements
We thank MINECO (Severo Ochoa Excellence Accreditation 20142018 (SEV-2013-0319) and project CTQ2013-42106-P), the European Research Council (Advanced Grant No. 321066), the AGAUR
(2014 SGR 818), and the ICIQ Foundation. M. E. M. acknowledges
the receipt of a COFUND (Marie Curie program) postdoctoral
fellowship.
Keywords: alkynes · Claisen rearrangement · gold · green
chemistry · homoallylic ketones
Scheme 3. Catalytic cycle for the gold(I)-catalyzed synthesis of homoallylic
ketones by hydroalkoxylation/Claisen rearrangement.

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tance of high-level computations, no unambiguous conclusion
could be drawn on whether the final step proceeded by
simple thermal [3,3]-sigmatropic rearrangement, or if it was
promoted by gold(I) through lowering of the activation energy
by coordination to the enol ether oxygen. A direct [3,3]-sigmatropic rearrangement could also take place from the allyloxy vinylgold(I) intermediate to form a CÀgold(I) ketone enolate,
which would undergo protonolysis to give the final compounds. Regarding the observed diastereoselectivity, the major
products resulted from a Claisen rearrangement proceeding
through chair transition states.[8]
One may legitimately wonder whether this process constitutes a significant improvement and if it is the most efficient
synthesis of homoallylic ketones. From the point of view of
catalytic efficiency and simplicity, the reaction discovered by
Aponick is the best method for the synthesis of a wide variety
of homoallylic ketones from inexpensive and commercially
available materials. The further refinement by the group of
Nolan is also an excellent example of green chemistry in chemical synthesis.[10] In particular, the demonstration that this process can be carried out efficiently under solvent-free conditions
should encourage other groups to develop even more challenging processes, including cascade transformations, in the
ChemCatChem 2015, 7, 228 – 229

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Received: October 22, 2014
Published online on December 4, 2014

229

 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim