Beilstein Journal of Organic Chemistry 2009, 5, No. 56.
with the aryl group bearing electron-withdrawing substituents, under batch conditions with the same arylating agents [30], or
can be prepared easily by phenylation of the corresponding even with the heterogeneous catalyst 2 used under batch condi-
aldehyde. On the other hand, if a diarylcarbinol has to be tions with PhZnEt generated from diethylzinc and the very
prepared where one of the aryl groups bears electron donating expensive diphenylzinc [22], the addition products could be
substituents, the phenylation of the electron rich benzaldehyde easily crystallized in order to improve their enantiomeric
is not efficient, so that the use of an electron rich boroxin in purities. For instance, phenyl(4-tolyl)methanol could be
combination with benzaldehyde is preferred (Scheme 5).
obtained in pure form, in 76% yield and 93% ee after a single
crystallization and 4-chlorophenyl(phenyl)methanol in
We have summarized in Table 3 the results of the continuous 67% yield and 86% ee after the same process.
flow arylation of a family of aldehydes. This study was done
under the set of experimental conditions previously optimized Conclusion
for the phenylation of p-tolualdehyde (see Table 2, above), and In summary, the first single-pass, continuous flow enantiose-
the results given in the table refer to instant conversion and lective arylation of aldehydes has been developed. In this
enantioselectivity after given reaction times.
manner, enantioenriched diarylmethanols can be prepared in
large scale through a simple and efficient process. The system
In all the studied cases tested, except in the phenylation of has been optimized for the use of arylboroxins as an atom
α-methylcinnamaldehyde (entry 5), the reaction could be run for economical, cheap and readily available source of aryl groups.
some hours without significant decrease in the conversion of the The simple procedures required for the purification and enan-
starting aldehydes, thus allowing the preparation of enantioen- tioenrichment of the resulting carbinols converts this flow
riched carbinol products in multigram scale. Most attention was process into a convenient alternative for the multigram produc-
devoted to the use of PhZnEt (from triphenylboroxin and tion of these compounds.
diethylzinc) in combination with different aromatic aldehydes
(
entries 1–4). Among these cases, the best results were obtained The observed decrease in the enantioselectivity induced by the
with p-tolualdehyde (entry 1). With o-fluorobenzaldehyde catalyst in comparison to its homogeneous analogue 1, suggests
entry 2), p-chlorobenzaldehyde (entry 3) and 2-naphthalde- some participation of triethylboroxin in a competing, non-enan-
(
hyde (entry 4) conversions were excellent over the whole flow tioselective catalytic event. In fact, boroxins present adjacent
experiments (3 or 4 h), although enantioselectivities were atoms with complementary Lewis base (O) and Lewis acid (B)
slightly lower [30]. When an α,β-unsaturated aldehyde, such as character that could coordinate the reactant molecules (alde-
α-methylcinnamaldehyde was used (entry 5), a fast reaction hyde and arylethylzinc) in an arrangement suitable for reaction.
took initially place, although conversion was observed to slowly In this sense, it is noteworthy that when control experiments
decrease after 2 h. Finally, (4-MeOC6H4)ZnEt [from tri(p-meth- were done by using resin 2 under batch conditions with the
oxyphenyl)boroxin and diethylzinc] could also be used in the Ph2Zn/Et2Zn combination of reagents for the generation of
continuous flow process with excellent conversion and PhZnEt, the observed enantioselectivities were comparable to
moderate enantioselectivity (entry 6).
those recorded with the homogeneous catalyst 1. Thus, further
improvement of the present continuous flow system could
It is interesting to note that, although enantioselectivities were possibly be achieved with the use of alternative sources of the
not as high as those obtained with the homogeneous catalyst 1 arylating species [33-35].
Scheme 5: Continuous flow enantioselective preparation of diarylmethanols.
Page 5 of 8
(page number not for citation purposes)