Fluorous 4-N,N-dimethylaminopyridine (DMAP) salts as simple recyclable acylation catalysts

Article abstract of DOI:10.1002/chem.200902982

The use of an easily accessible fluorous salt of DMAP, 1-R, as an active and recyclable acylation catalyst, under simple conditions has been reported. The recyclability of organic- and metal-based catalysts is of prime interest for the development of sustainable synthesis processes. The alcohol and the anhydride were mixed in a 10 mL round-bottomed flask and 1-R was added. 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. The simplicity of the process (readily accessible catalyst, easy to handle and to recover) makes it an attractive alternative for cleaner and safer acylation reactions, which could be used with asymmetric dialkylaminopyridines, or in other transformations, such as the Baylis Hillman reaction.

Full text of DOI:10.1002/chem.200902982

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
E-mail: julien.legros@u-psud.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902982.
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Chem. Eur. J. 2010, 16, 1776 – 1779

COMMUNICATION
Scheme 1. DMAP-catalyzed esterification with acetic anhydride.
In relation to these observations, we reasoned that a com-
pound RfCO2H·DMAP (1, Rf =perfluoroalkyl) could pro-
vide the following advantages as a catalyst: 1) according to
the particular solubility of perfluorinated molecules, com-
pound 1 could be solubilized in an appropriate reaction
medium to deliver active DMAP, and then promote acyla-
tion; 2) in spite of the release of acetic acid during the
esterification step, the stronger acidity of RfCO2H (pKa-
Figure 1. Influence of various catalysts (0.2 mmol) on the acetylation of
1-phenylethanol (2 mmol) with Ac2O (2.2 mmol) under solvent- and
base-free conditions at 258C (monitoring by 1H NMR spectroscopy): 1-
~
&
^
*
Rf15 ( ), 1-Rf23
( ), Rf15CO2H alone ( ), without catalyst ( ).
conversion after 8 h. To prove that the promotion of the re-
action was not the result of acid catalysis, 1-phenylethanol
and acetic anhydride were treated with C7F15CO2H
(Rf15CO2H, 10 mol%): it appeared that Rf15CO2H catalyzed
the reaction, but had only a low activity (42% for Rf15CO2H
versus 92% for 1-Rf15 after 8 h).[24] From these results, it can
be assumed that the overall kinetics of the catalytic esterifi-
cation largely depend on the equilibrium between 1-Rf15 and
free DMAP, the latter being the active catalytic species.[25]
These experiments thus validate our model for 1-Rf-type
catalysts as esterification promoters and the recyclability of
the best catalyst 1-Rf15 was tested for the same reaction
(Table 1). The reaction was conducted overnight for com-
plete conversion to take place. Then the acetic acid was
evaporated and catalyst 1-Rf15 partially precipitated in the
medium; complete precipitation occurred by adding a small
amount of pentane or toluene. After filtration, the catalyst
was separated from the ester product (95% yield), and re-
covered quantitatively (>99%; Table 1, entry 1). Catalyst 1-
A
the regeneration of 1 after completion of the reaction, al-
lowing its recovery with an appropriate work up; 3) since
there is no modification of the backbone of DMAP, the re-
activity of 1 should only depend on the presence of proton-
free DMAP (even in tiny amounts) in the medium; 4) cata-
lyst 1 can be readily prepared in a single step and since ami-
nopyridinium salts are innocuous, the handling of 1 would
be safe.[8]
Thus,
two
fluorous
aminopyridinium
salts
C7F15CO2H·DMAP 1-Rf15 and C11F23CO2H·DMAP 1-Rf23
were prepared by simply mixing the amine with the acid
(>98% yield each after crystallization). To assess the
1
second point of our strategy (see above), H NMR spectros-
copy experiments with DMAP, AcOH, C7F15CO2H, and
related pyridinium salts were performed: they confirmed
that the competition between AcOH·DMAP and
C7F15CO2H·DMAP was in favor of the latter.[23] Subsequent-
ly, to assess the ability of 1-Rf to release free DMAP in a re-
action medium for catalysis purposes, the acetylation of 1-
phenylethanol with acetic anhydride (1.1 equiv) was per-
formed in the presence of 1-Rf15 or 1-Rf23 as the catalyst
(10 mol%) under the conditions reported by Ishihara and
co-workers (base- and solvent-free at room temperature).
The results are presented in Figure 1.
In the absence of catalyst, no reaction took place and the
alcohol remained unchanged, even after 8 h. Delightfully,
with fluorous salts 1-Rf15 and 1-Rf23 the reaction occurred to
afford the corresponding ester. It emerged that 1-Rf15 exhib-
ited a significantly better activity than 1-Rf23: 92 versus 58%
Table 1. Assessment of 1-Rf15 as a recyclable catalyst in the acetylation
of 1-phenylethanol under solvent- and base-free conditions[a]
Run
Recovery of
Yield of
Run
Recovery of
Yield of
1-Rf15 [%]
ester [%]
1-Rf15 [%]
ester [%]
1
2
3
4
5
>99
>99
>99
>99
98
95
96
95
97
94
6
7
8
>99
98
>99
>99
99
95
96
94
97
96
9
10[b]
[a] Reaction conditions: 1-phenylethanol (2 mmol), Ac2O (2.2 mmol) and
1-Rf15 (0.2 mmol; 107 mg), neat, 258C, 17 h. [b] 103 mg of 1-Rf15 recov-
ered after the 10th run.
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J. Legros et al.
Rf15 was then engaged in further runs. Remarkably, the cata-
lyst was able to undergo 10 iterative runs without any loss in
activity and with excellent recovery (Table 1, entries 2–10).
The scope of this acylation reaction with 1-Rf15 was then
extended to several secondary and tertiary alcohols, with
acetic and isobutyric anhydrides (Table 2). Benzylic alcohols
a 10 g scale. After 17 h, the acetic acid was distilled, the cat-
alyst was precipitated and fully recovered, and the ester was
obtained in 98% yield.
In summary, we prepared a simple fluorous salt of DMAP
as an effective and recyclable organocatalyst for esterifica-
tion reactions, under solvent- and base-free conditions. The
simplicity of the process (readily accessible catalyst, easy to
handle and to recover) makes it an attractive alternative for
cleaner and safer acylation reactions, which could be used
with asymmetric dialkylaminopyridines, or in other transfor-
mations, such as the Baylis–Hillman reaction. Moreover,
these results constitute an interesting approach for fluorous
labeling with noncovalent bonds.
Table 2. 1-Rf15-catalyzed esterification of alcohols with anhydrides under
solvent- and base-free conditions[a]
Entry
Product
R
T
[8C]
t
Yield
[%]
[h]
1
2
Me
iPr
25
25
17
17
97
89
3
4
Me
iPr
25
25
17
17
93
97
Experimental Section
5
6
Me
iPr
25
25
17
17
98
91
The alcohol (2 mmol) and the anhydride (2.2 mmol) were mixed in a
10 mL round-bottomed flask and 1-Rf15 (0.2 mmol) was added. The flask
was then capped and the reaction mixture was stirred at room tempera-
ture (except for 1-methylcyclopentanol: 608C). After 17 h (8 h for cyclo-
hexanol), the acid effluent was evaporated in vacuo. The residue was
then allowed to cool to room temperature and the catalyst was precipitat-
ed by adding pentane or toluene (2 mL). After filtration, catalyst 1-Rf15
was recovered and evaporation of the solvent from the filtrate afforded
the pure ester product.
7
8
Me
iPr
25
25
8
8
85
92
9
Me
iPr
Me
iPr
60
60
25
25
24
24
17
17
70
68
90
93
10
11
12
13
14
Me
iPr
25
25
17
17
98
93
15
16
Me
iPr
25
25
17
17
92
95
Acknowledgements
The European Union within the EST network BIOMEDCHEM (MEST-
CT-2005-020580) is gratefully acknowledged for the Ph.D. grant of D.V.
and for financial support. The Region Ile-de-France is also thanked for
support.
[a] Reaction conditions: alcohol (2 mmol), anhydride (2.2 mmol), and 1-
Rf15 (0.2 mmol), neat, 258C.
(1-phenylethanol, 1-indanol) underwent facile esterification
with both anhydrides within 17 h. After removal of the acid
released and precipitation of the catalyst, the corresponding
products were afforded with excellent purity and in excel-
lent yields (89–97%; Table 2, entries 1–4). Aliphatic alco-
hols, dodecanol and cyclohexanol, also behaved very well
and full conversions were obtained within 17 and 8 h, re-
spectively, (85–98% yield; Table 2, entries 5–8). Even the
tertiary alcohol 1-methylcyclopentanol was a suitable part-
ner in this reaction, but reacted more sluggishly: warming
the reaction mixture to 608C for 24 h was required to obtain
a good conversion (68–70% yield; Table 2, entries 9 and
10). As substrates, aromatic alcohols 4-methylphenol and 4-
nitrophenol also yielded the corresponding esters (>90%
yield; Table 2, entries 11–14). Our last concern dealt with
the possible negative impact of the strong acid C7F15CO2H
on the stability of the reaction products. It is worth noting
that starting from (À)-menthol as the substrate, the products
were afforded in high yields, with acetic and isobutyric anhy-
drides, without any trace of epimerization products (Table 2,
entries 15 and 16).
Keywords: esterification
organocatalysis · sustainable chemistry
· fluorine · green chemistry ·
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Fluorous 4-N,N-Dimethylaminopyridine Salts
COMMUNICATION
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Received: October 28, 2009
Published online: January 8, 2010
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