Communications
DOI: 10.1002/anie.200703103
Asymmetric Catalysis
Practical Implications of Boron-to-Zinc Transmetalation for the
Catalytic Asymmetric Arylation of Aldehydes**
Ciril Jimeno, Sonia Sayalero, Torstein Fjermestad, Gisela Colet, Feliu Maseras,* and
Miquel A. Pericàs*
Enantiopure diaryl methanols are valuable compounds in the
pharmaceutical field as active ingredients or as synthetic
intermediates,[1] and the catalytic asymmetric arylation of
aldehydes is now the method of choice for their preparation.[2]
This straightforward process was initially hampered by
complications arising from the undesired, fast, noncatalytic
addition of diphenylzinc to aldehydes. However, the intro-
duction of the highly selective arylating reagent Ph2Zn/Et2Zn
by Bolm and co-workers,[3] and the subsequent proposal that
PhZnEt is formed in a transmetalation reaction and is the real
arylating agent,[4] boosted the practical application of the
arylation of aldehydes.
While the enantioselectivity control of this process has
been solved by varying the ligands,[3,4] substantial effort has
been devoted in recent times to improving its economy by
replacing the expensive reagent Ph2Zn by more convenient
aryl sources. A variety of aryl boron species have been used
for this purpose,[5–7] as well as several other reagents.[8,9] In
fact, a catalytic enantioselective aldehyde arylation involving
a triaryl boroxine[10] as the ultimate source of the aryl group
has recently found an industrial application.[11]
contributing to the development of truly practical approaches
to the catalytic enantioselective arylation of aldehydes.
The theoretical study was performed with a slightly
simplified system consisting of dimethyl(phenyl)boroxine
and ethylmethylzinc. A thorough exploration of the possibil-
ity of a direct metathesis, in analogy with the Et2Zn/Ph2Zn
exchange,[4] did not lead to the location of any transition state
connecting reagents and products. Similarly, the participation
of an external nucleophile leading to the formation of borates,
from which phenyl groups could be more easily transferred,
was also investigated. This route also turned out to be a dead
end because no low-energy pathway compatible with a
catalytic process (with respect to the external nucleophile)
could be located.[13] Finally, a stepwise mechanism involving
sequential zinc-to-boron and boron-to-zinc transmetalations
(Scheme 1) proved to be a viable alternative, as indicated by
the potential-energy profile calculated at the density func-
tional theory level [B3LYP/6-31G(d)] for this reaction
(Figure 1).
In spite of this practical importance, nothing is known
about the mechanism of the boron-to-zinc transmetalation.
Given the key role played by this fundamental process in the
enantioselective arylation of aldehydes, and our current
interest in transmetalation mechanisms,[12] we decided to
undertake a theoretical and experimental study of the
mechanism of this transmetalation with the ultimate goal of
[*]Dr. C. Jimeno, Dr. S. Sayalero, T. Fjermestad, Dr. G. Colet,
Prof. Dr. F. Maseras, Prof. Dr. M. A. Pericàs
Intitute of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans, 16, 43007 Tarragona (Spain)
Fax: (+34)977-920-222
Scheme 1. Mechanisms considered for boron-to-zinc transmetalation.
The computed profile connecting the initial (ADD1) and
final (ADD2) adducts is smooth, with the highest barrier
(TS1) being only 16.2 kcalmolÀ1. Our calculations predict the
existence of an intermediate (INT) with a four-coordinate
boron center and the zinc atom bound to oxygen. Intermedi-
ates with four-coordinate boron have been reported in
calculations on the Suzuki–Miyaura reaction.[12] This inter-
mediate is unlikely to be isolable because of the low barrier
(9.4 kcalmolÀ1) that separates it from the transmetalation
product. The whole process is predicted to be easily rever-
sible, with the equilibrium being shifted towards ethylphe-
nylzinc. Overall, the key feature associated with this predicted
pathway is the fact that the transmetalation process consists of
two easy steps involving migration of a carbon chain from an
anionic center to an adjacent site with Lewis acid character-
istics.[14]
E-mail: mapericas@iciq.es
Prof. Dr. F. Maseras
Departament de Química
Edifici Cn, Universitat Autònoma de Barcelona
08193 Bellaterra (Spain)
Prof. Dr. M. A. Pericàs
Departament de Química Orgànica
Universitat de Barcelona, 08080 Barcelona (Spain)
[**]We thank the MEC (grant no.: CTQ2005-02193/BQU), DURSI (grant
no.: 2005SGR225), the Consolider Ingenio 2010 (grant no.:
CSD2006-0003), and the ICIQ Foundation for financial support. T.F.
thanks the MEC for a predoctoral fellowship.
Supporting information for this article (cartesian coordinates of
computed structures) is available on the WWW under http://
1098
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 1098 –1101