J. Am. Chem. Soc. 1996, 118, 8967-8968
2-Formyl-4-pyrrolidinopyridine (FPP): A New
8967
Catalyst for the Hydroxyl-Directed Methanolysis of
Esters
Tarek Sammakia* and T. Brian Hurley
Department of Chemistry and Biochemistry
UniVersity of Colorado
Boulder, Colorado 80309-0215
ReceiVed April 25, 1996
Catalysts for the acylation of alcohols with active esters are
well known and widely used.1 Species such as 4-pyrrolidi-
nopyridine (PPY) or 4-(dimethylamino)pyridine (DMAP)2 can
display remarkable enhancements in the rate of acylation of a
variety of alcohols under mild conditions. However, catalysts
that are capable of the selective hydrolysis of one ester in the
presence of another are less common.3,4 We describe in this
communication a derivative of PPY, 2-formyl-4-pyrrolidinopyr-
idine (FPP, 1), which is a selective catalyst for the hydroxyl-
directed5 methanolysis of hydroxy esters and which operates
by a novel mechanism.
FPP is unique in that it contains a basic component (a
4-aminopyridine) in conjugation with a deactivating electrophilic
component (an aldehyde, eq 1). The 4-aminopyridine nucleus
Figure 1. Graph of selective hydrolysis using 5% FPP.
reversibly bind to the alcohol of a hydroxy ester with concomi-
tant formation of a hemiacetal (eq 1). This binding serves two
important functions; it brings the ester in close proximity to
the pyridine nitrogen (induced approximation),6 and it activates
the catalyst once the alcohol is bound by converting the electron-
withdrawing aldehyde to a hemiacetal which is not as electron-
withdrawing.7 This activation of the pyridine upon binding is
crucial for selectivity because it ensures that substrates that do
not bear a hydroxyl group will encounter a less active catalyst,
thereby slowing the rate of non-hydroxyl-directed background
hydrolysis.8
We first compared the reactivity of FPP with DMAP in the
acylation of menthol using acetic anhydride and 2% catalyst in
the absence of triethylamine. Under these conditions, the
DMAP-catalyzed reaction is about 300 times faster than the
FPP-catalyzed reaction.9 In fact, we observed no increase in
the rate of acylation using FPP as compared to a control
containing no catalyst. The reactivity of these two catalysts
was then compared in the methanolysis of the p-nitrophenyl
(PNP) ester of glycolic acid in CDCl3 (10 equiv of methanol, 5
mol % catalyst, 0.1 M substrate at 20 °C). With this substrate,
which is an R-hydroxy ester, DMAP and FPP displayed very
similar reactivities (krel(DMAP/FPP) ) 690/511 ) 1.35, Figure
1).10,11 To further probe the selectivity of FPP, we compared
the rate of methanolysis of the PNP esters of propionic acid,
methoxyacetic acid, and glycolic acid with DMAP and with
FPP (5 mol %) in CDCl3 containing 10 equiv of methanol
(Figure 1). As expected due to electronic and hydrogen-bonding
(1)
is known to be a very active system for acyl transfer catalysis.2
Our interest in the preparation of a selective catalyst led us to
consider attenuating the activity of this species toward ordinary
active esters while maintaining its activity toward hydroxy
esters. Attenuation can be accomplished by substituting the
pyridine with an electron-withdrawing group, thereby diminish-
ing the basicity and nucleophilicity of the pyridine nitrogen.
We chose to use an aldehyde for this purpose because of its
electron-withdrawing character and because of its ability to
(1) For a review on methods of synthesis of esters, see: (a) Mulzer, J.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, Chapter 2.2. For recent examples of
nucleophilic catalysts, see: (b) Vedejs, E.; Diver, S. T. J. Am. Chem. Soc.
1993, 115, 3358. (c) Vedejs, E.; Bennett, N. S.; Conn, L. M.; Diver, S. T.;
Gingras, M.; Lin, S.; Oliver, P. A.; Peterson, M. J. Org. Chem. 1993, 58,
7286. (d) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61,
430. (e) Menger, F. M.; Whitesell, L. G. J. Am. Chem. Soc. 1985, 107,
707.
(2) (a) Steglich, W.; Hofle, G. Angew. Chem., Int. Ed. Engl. 1969, 8,
981. Reviews: (b) Cherkasova, E. M.; Bogatkov, S. V.; Golovina, Z. P.
Russ. Chem. ReV. 1977, 46, 246;. (c) Hofle, G.; Steglich, V.; Vorbruggen,
H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569. (d) Scriven, E. F. V. Chem.
Soc. ReV. 1983, 12, 129.
(3) Enzymes are sensitive to the structure of an ester and will hydrolyze
similar esters with exquisite selectivity. They are not, however, as general
in their scope as man-made catalysts. For reviews on the use of acyl transfer
enzymes in organic synthesis, see: Wong, C.-H.; Whitesides, G. M. Enzymes
in Synthetic Organic Chemistry; Pergamon: Oxford, 1994; Chapter 2. Sih,
C. J. Top. Stereochem. 1989, 19, 63. Chen, C.-S.; Sih, C. J. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 695. Klibanov, A. M. Acc. Chem. Res. 1990, 23,
114. Haraldsson, G. G. The Application of Lipases in Organic Synthesis.
In The Chemistry of the Functional Groups, Suppl. B, The Chemistry of
Acid DeriVatiVes; Patai, S., Ed.; John Wiley and Sons: Chichester, 1992;
Vol. 2.
(6) For a discussion, see: Jencks, W. P. Catalysis in Chemistry and
Enzymology; Dover: New York, 1986: pp 31-40.
(7) This is a variation of Sharpless’s concept of ligand-accelerated
catalysis with the exception that the ligand is the substrate for the reaction.
For a review in this area, see: Berrisford, D. J.; Bolm, C.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1059.
(8) This catalyst is used in the presence of methanol, and while it is true
that the addition of methanol to the aldehyde of the catalyst produces a
hemiacetal, this species is sterically deactivated.
(9) In the presence of triethylamine, the DMAP-catalyzed reaction is
too fast to conveniently monitor by GC. We note that the acetic acid that
is produced as a byproduct is known to inhibit the activity of DMAP if no
other base is present. This value therefore represents a lower limit on the
relative rates of the DMAP- versus the FPP-catalyzed reaction.
(10) All relative rates reported were determined under identical conditions
and are normalized to the slowest reaction.
(4) Evans has applied Weinreb’s transamination method (Basha, A.;
Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 18, 4171. Levin, J. I.;
Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989) to his acyl
oxazolidinone reagents and found that a â-hydroxyl or an R-heteroatom is
required in order to avoid attack at the oxazolidinone carbonyl. See: Evans,
D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799.
(11) The rates of methanolysis of the PNP ester of glycolic acid using
DMAP and PPY are comparable.
(5) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
S0002-7863(96)01362-5 CCC: $12.00 © 1996 American Chemical Society