DOI: 10.1002/chem.200902982
Fluorous 4-N,N-Dimethylaminopyridine (DMAP) Salts as Simple Recyclable
Acylation Catalysts
Daniela Vuluga, Julien Legros,* Benoit Crousse, and Daniꢀle Bonnet-Delpon[a]
Dedicated to Dr. Jean-Pierre Bꢀguꢀ on the occasion of his 70th birthday
The recyclability of organic- and metal-based catalysts is
of prime interest for the development of sustainable synthe-
sis processes.[1,2] Since the pioneering work of the groups of
Litvinenko and Steglich, who independently reported orga-
nocatalyzed acylation reactions with 4-N,N-dimethylamino-
pyridine (DMAP),[3] dialkylaminopyridines still remain in
the limelight. Thus, remarkable developments are regularly
reported, as exemplified by the emergence of more potent
analogues, even chiral,[4,5] as catalysts for a diverse range of
reactions.[6] Unfortunately, these powerful organocatalysts
exhibit acute dermal toxicity,[7] whereas the corresponding
salts only produce local irritation by skin contact.[8] To avoid
dissemination of these harmful chemicals in the environ-
ment, recyclable 4-aminopyridines have been prepared
through immobilization on organic or inorganic sup-
ports.[9–11] Although some remarkable systems emerged,
those exhibiting significant activity coupled with complete
recyclability are scarce. In 2007, Gunꢀko, Connon, and co-
workers reported a very elegant magnetic-nanoparticle-sup-
ported DMAP that can be used several times without loss in
activity and that is simply recovered by using an external
magnet.[11a,12] However, a limit in the molecular weight of
the support is highly desirable to avoid the use of a quantity
of immobilized catalyst larger than that of the substrate.
Alternatively, fluorous techniques also offer a very attrac-
tive way to selectively recover a compound tagged with per-
fluorinated chains from a complex reaction mixture.[13] Al-
though this strategy originally involved fluorous solvents[14]
or silica,[15] the current trend tends toward simple solubility
modulation of fluorous catalysts in conventional media, for
recovery through precipitation.[16,17] In the field of catalysis,
the fluorous approach has been widely applied to metal cat-
alysts by means of fluorinated ligands.[13,14] In contrast, re-
ports on fluorous organocatalysis are still scarce,[18,19] and
the field is only at an early stage of development. In this
context, we recently reported the preparation of an efficient
fluorous aminopyridine for esterification of hindered alco-
hols, which suffered from poor recyclability.[18d] We now
report the use of an easily accessible fluorous salt of DMAP,
1-Rf, as an active and recyclable acylation catalyst, under
simple conditions.
Usually, the DMAP-catalyzed esterification reaction of an
alcohol is performed in nonpolar solvents with an anhydride
as the acyl donor, in the presence of a base in stoichiometric
amounts (triethylamine or Hꢁnigꢀs base). According to the
pathway depicted in Scheme 1 with acetic anhydride,
DMAP is protonated by the acetic acid released at the end
of the cycle, and the assistance of the auxiliary base is essen-
tial for regenerating the catalyst in neutral form.[6a,20]
Nevertheless, in a recent study, Ishihara and co-workers
reported that this catalytic acylation reaction could occur
without any external base, if the reaction was performed in
a concentrated medium (neat), or in a highly apolar solvent,
such as heptane.[21] Under these conditions, the regeneration
of DMAP occurs in situ, allowing continuation of the cata-
lytic cycle and affords ester products in excellent yields. At
the end of the reaction, the catalyst is in the acetate salt
form (AcOH·DMAP), which is soluble in organic media
and, therefore, often difficult to separate from the product.
[a] D. Vuluga, Dr. J. Legros, Dr. B. Crousse, Dr. D. Bonnet-Delpon
BioCIS-CNRS, Facultꢂ de Pharmacie-Paris Sud
5 rue Jean-Baptiste Clꢂment
F-92296 Chꢃtenay-Malabry (France)
Fax : (+33)146-83-57-40
Supporting information for this article is available on the WWW
1776
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1776 – 1779