Enhanced selectivities for the hydroxyl-directed methanolysis of esters using the 2-acyl-4-aminopyridine class of acyl transfer catalysts: Ketones as binding sites

Article abstract of DOI:10.1021/jo991202k

In this paper we describe the preparation of a series of 2-acyl-4- aminopyridines, and their use as catalysts for the hydroxyl-directed methanolysis of α-hydroxy esters in preference to α-methoxy esters. Hydroxyl-direction with these catalysts, which contain ketones at the 2- position of the pyridine, is achieved by reversible addition of the alcohol of the hydroxy ester to the ketone to provide the corresponding hemiketal. Their activity is compared to that of the previously described catalyst 2- formyl-4-pyrrolidinopyridine (FPP), which contains an aldehyde at the 2- position of the pyridine. The catalysts which contain ketones at the 2- position range in reactivity from 10 times slower to slightly faster than FPP, and certain of these are much more selective for the methanolysis of hydroxy esters than FPP. This increase in selectivity is ascribed to a decrease in the rate of the nondirected methanolysis reaction with the ketone-derived catalysts. The evidence suggests that the nondirected reaction does not proceed by an intermolecular general base mechanism, but rather via a nucleophilic catalysis mechanism in which the hydroxyl group of the hemiacetal formed upon addition of methanol to the aldehyde of FPP acts as the nucleophile. Since the hydroxyl group derived from a hemiketal is more hindered and less nucleophilic than that derived from a hemiacetal, the nondirected reaction is much slower for the catalysts containing ketones as binding sites.

Full text of DOI:10.1021/jo991202k

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74
J . Org. Chem. 2000, 65, 974-978
En h a n ced Selectivities for th e Hyd r oxyl-Dir ected Meth a n olysis of
Ester s Usin g th e 2-Acyl-4-a m in op yr id in e Cla ss of Acyl Tr a n sfer
Ca ta lysts: Keton es a s Bin d in g Sites
Tarek Sammakia* and T. Brian Hurley
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received J uly 27, 1999
In this paper we describe the preparation of a series of 2-acyl-4-aminopyridines, and their use as
catalysts for the hydroxyl-directed methanolysis of R-hydroxy esters in preference to R-methoxy
esters. Hydroxyl-direction with these catalysts, which contain ketones at the 2-position of the
pyridine, is achieved by reversible addition of the alcohol of the hydroxy ester to the ketone to
provide the corresponding hemiketal. Their activity is compared to that of the previously described
catalyst 2-formyl-4-pyrrolidinopyridine (FPP), which contains an aldehyde at the 2-position of the
pyridine. The catalysts which contain ketones at the 2-position range in reactivity from 10 times
slower to slightly faster than FPP, and certain of these are much more selective for the methanolysis
of hydroxy esters than FPP. This increase in selectivity is ascribed to a decrease in the rate of the
nondirected methanolysis reaction with the ketone-derived catalysts. The evidence suggests that
the nondirected reaction does not proceed by an intermolecular general base mechanism, but rather
via a nucleophilic catalysis mechanism in which the hydroxyl group of the hemiacetal formed upon
addition of methanol to the aldehyde of FPP acts as the nucleophile. Since the hydroxyl group
derived from a hemiketal is more hindered and less nucleophilic than that derived from a hemiacetal,
the nondirected reaction is much slower for the catalysts containing ketones as binding sites.
We recently described a new strategy for the design of
Sch em e 1
1
catalysts for hydroxyl-directed reactions in which the
catalysts contain spatially separate binding and catalytic
2
sites (Scheme 1). This strategy offers numerous advan-
tages for selective catalysis, including the ability to
convert catalysts which are not hydroxyl-directed into
ones which are by the incorporation of a binding site. We
have demonstrated the feasibility of this strategy by
rendering the 4-aminopyridine class of acyl transfer
catalysts hydroxyl-directed by incorporating a binding
site at the 2-position of the pyridine. The binding site
for our initial studies was an aldehyde, and the parent
compound 2-formyl-4-pyrrolidinopyridine (FPP, 1; Scheme
1
) was found to display about 100:1 selectivity for the
methanolysis of R-hydroxy esters over R-methoxy esters.
In this paper we describe our work on the use of ketones
as binding sites for this class of catalysts, report that
certain ketone derivatives can provide greater than
Sch em e 2
1
700:1 selectivities for the same process, and offer a
mechanistic explanation for the origin of these enhanced
selectivities.
Resu lts
Syn th esis of th e Keton e Ca ta lysts. Amide 3 was
found to be a versatile, readily accessible intermediate
for the synthesis of the catalysts described in this study.
The synthesis of 3 (Scheme 2) begins with the conversion
of picolinic acid to 4-chloropicolinyl chloride according to
3
the procedure of Sundberg, followed by condensation of
the crude acid chloride with pyrrolidine to provide the
4
-chloro amide 2. Nucleophilic aromatic substitution of
(
1) For a review of substrate-directable reactions, see: Hoveyda, A.
H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
2) (a) Sammakia, T.; Hurley, T. B. J . Am. Chem. Soc. 1996, 118,
967. (b) Sammakia, T.; Hurley, T. B. J . Org. Chem. 1999, 64, 4652.
3) Sundberg, R. J .; Songchun, J . Org. Prep. Proced. Int. 1997, 29,
17.
the 4-chloro substituent of 2 in refluxing pyrrolidine then
provides 3. Both amide formation and nucleophilic aro-
matic substitution can be performed in one pot as a single
step; however, we find that purification of 2 prior to
(
8
1
(
1
0.1021/jo991202k CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/26/2000

Selectivities for Methanolysis of Esters
J . Org. Chem., Vol. 65, No. 4, 2000 975
Sch em e 3
Discu ssion
The hydroxyl-direction in these reactions requires the
formation of a hemiacetal or hemiketal between the
hydroxyl group of the substrate and the carbonyl of the
catalyst.2b Since ketones are less prone to hemiketal
8
formation than aldehydes are to hemiacetal formation,
we reasoned that they may make less effective binding
sites, and expected the ketone-containing catalysts to be
slower and less selective. The remarkably high selectivity
observed with the ketone-containing catalysts requires
a reappraisal of our rationale for the origin of the
selectivity observed with this class of catalysts. We have
extensively studied the mechanism of the hydroxyl-
directed reaction with FPP and conclude that it proceeds
substitution provides 3 in higher yield and purity. The
synthesis of the ketone catalysts 6-10 consists of the
addition of an alkyl- or aryllithium reagent to amide 3
in tetrahydrofuran at -78 °C.4
The trifluoromethyl ketone 5 was synthesized in a
three-step procedure also starting from 3 (Scheme 3).
DIBAL reduction of the amide to the aldehyde 1 (FPP)5
was followed by addition of a trifluoromethyl group
according to the procedure of Prakash and Olah6 to
provide the corresponding trifluoromethyl alcohol 4.
2b
by the path shown in Scheme 4. In this mechanism,
the hydroxyl group of the R-hydroxy ester adds to the
aldehyde of FPP to provide hemiacetal 13. The nitrogen
of the pyridine then acts as a general base, deprotonating
the hydroxyl group of the hemiacetal while the oxygen
acts as a nucleophile, attacking the bound ester to provide
dioxolanone 14. Methanolysis of the dioxolanone then
occurs with general-base assistance from the pyridine,
and is the turnover-limiting step of the catalytic cycle.
The resting state of the catalyst is, therefore, dioxolanone
7
Swern oxidation of this species provided the partially
hydrated trifluoromethyl ketone, which was dehydrated
by azeotropic removal of water with benzene to provide
5
.
Ester Meth a n olysis. We have studied the hydroxyl-
directed methanolysis of esters using the ketone deriva-
tives shown in Table 1, and compared these results with
the same reaction using FPP (1). Using the p-nitrophenyl
1
4, and we have observed this species by NMR in
9
reactions in progress. Because the rate of the hydroxyl-
directed reaction is comparable with the ketone and
aldehyde catalysts, the increase in selectivity observed
with the ketone catalysts must be due to a decrease in
the rate of the nondirected reaction. We had assumed
that this reaction proceeds via a simple intermolecular
general-base catalysis pathway catalyzed by FPP, the
corresponding methanol hemiacetal of FPP, or dioxol-
anone 14. However, if this were the case, then the ketone-
containing catalysts should provide rates of nondirected
methanolysis similar to that of FPP. The difference in
behavior of the ketone and aldehyde catalysts prompted
us to consider an alternative mechanism for the nondi-
rected reaction.
(
(
PNP) esters of glycolic acid (11) and methoxyacetic acid
12), we measured the rates of methanolysis of these
substrates using 5 mol % catalyst in CDCl
0 equiv of methanol-d (Table 1). We find that the
ketones are competent catalysts for the methanolysis of
3
containing
1
4
1
6
1, though the methyl and phenyl ketones (compounds
and 7) are 10 and 5 times slower than FPP, respec-
tively. Catalysts 8-10 contain an additional basic site
and are comparable in reactivity to FPP, with catalysts
9
and 10 being slightly faster. Catalyst 5, which contains
a trifluoromethyl ketone, is also more active than FPP,
presumably because the electron-withdrawing trifluo-
romethyl group renders the dioxolanone intermediate
Our study of the mechanism of the non-hydroxyl-
directed reaction began with the observation that in
competition experiments between 11 and 12 using 6-
(
which is the resting state of the catalyst under the
2
b
reaction conditions) more susceptible to methanolysis.
Interestingly, the selectivity for methanolysis of PNP
glycolate over PNP methoxyacetate was significantly
greater with catalysts 5-8 than with FPP. As previously
mentioned, FPP catalyzes the methanolysis of 11 about
10
methyl-FPP and 6-triethylsilyl-FPP (15), there is a
delay prior to the onset of the nondirected reaction. This
is illustrated in Scheme 5 in which the 6-triethylsilyl
11
derivative of FPP is used as a catalyst. Interestingly,
1
00 times faster than 12. However, with catalysts 6-8,
the delay roughly corresponds to the length of time that
the hydroxyl-directed reaction (i.e., the methanolysis of
we saw no evidence of methanolysis of 12 even after 5
days, while with catalyst 5, only 5% methanolysis of 12
was observed after 6 days. With catalyst 5, 4.2 min is
required for 5% conversion of 11 to the corresponding
methyl ester, indicating that the selectivity for hydroxyl-
directed methanolysis is 1700:1. This selectivity repre-
sents an approximate lower limit for catalysts 6-8 since
we saw no evidence of methanolysis of 12 after 5 days.
Catalysts 9 and 10 display selectivities comparable to
that of the parent FPP.
1
1) is occurring. Since the resting state of the catalyst
(8) For reviews on the hydration of aldehydes and ketones see: (a)
Bell, R. P. In Advances in Physical Organic Chemistry; Gold, V., Ed.;
Academic: New York, 1966; Vol. 4, pp 1-29. (b) Ogata, Y.; Kawasaki,
A. In The Chemistry of the Carbonyl Group; Patai, S., Ed.; Inter-
science: London, 1970; Vol. 2, pp 1-61. For a recent study, see: (c)
Wiberg, K. B.; Morgan, K. M.; Malltz, H. J . Am. Chem. Soc. 1994, 116,
11067. For a study of the hydration of pyridine carboxaldehydes, see:
Pocker, Y.; Meany, J . E.; Nist, B. J . J . Phys. Chem. 1967, 71, 4509.
Gianni, P.; Matteoli, E. Gazz. Chim. Ital. 1975, 105, 125.
(
9) See the Supporting Information in ref 2a for the characterization
(
4) For compounds 8-10, inverse addition of the amide to the
of compound 14.
organolithium was required to obtain high yields. Though an excess
of the organilithium reagent was used in most cases, double addition
to form the tertiary alcohol was not observed.
(10) The synthesis of 6-methyl-FPP has been previously reported.
See ref 2b. 6-Triethylsilyl-FPP was synthesized from 2,6-diiodo-4-
(pyrrolidin-1-yl)pyridine in two steps by sequential metal halogen
exchange reactions trapping with chlorotriethylsilane and then DMF.
(11) The 6-triethylsilyl-FPP catalyst (15) was chosen to illustrate
this point because it is the least selective of the FPP derivatives we
have prepared, displaying the largest rate of the nondirected reaction.
Due to the high rate of this reaction, a delay in the methanolysis of 12
would be most evident with this catalyst.
(
5) Reduction of amide 3 provides a simpler and higher yielding
alternative to the previously reported route to FPP.
6) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J . Am. Chem.
Soc. 1989, 111, 393.
7) Mancuso, A. J .; Huang, S.; Swern, D. J . Org. Chem. 1978, 43,
480.
(
(
2

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76 J . Org. Chem., Vol. 65, No. 4, 2000
Sammakia and Hurley
Ta ble 1. Selectivities a n d Rela tive Ra tes for th e Meth a n olysis of p-Nitr op h en yl Ester s of Glycolic Acid a n d
Meth oxya cetic Acid
a
% methanolysis of 12 was observed after 6 days. b No detectable methanolysis of 12 after 5 days.
5
Sch em e 4
Sch em e 5
during the methanolysis of 11 is the dioxolanone, this
suggests that this species is not an effective catalyst for
the nondirected reaction.
To test this hypothesis, we prepared the dioxolane
acetal of FPP (17) as a model for dioxolanone 14, and
examined its ability to catalyze the methanolysis of 12
under our reaction conditions. We were unable to prepare
1
7 by standard acid-catalyzed acetal formation from FPP.
However, when FPP was subjected to bromoethanol in
DMF or neat, dioxolane hydrobromide 16 was isolated
in 49% yield after purification (Scheme 6). The formation
of 16 presumably occurs via a mechanism similar to that
proposed for the formation of dioxolanone 14. This
reaction provides further evidence for the nucleophilicity
of the FPP hemiacetal hydroxyl group and the general-
base assistance by the pyridyl nitrogen for the formation
of the dioxolanone intermediate.12 Surprisingly, we were
unable to convert 16 to 17 without extensive hydrolysis
and ultimately prepared 17 from 2-formyl-4-chloropyri-
(12) No reaction is observed between benzaldehyde and bromo-
ethanol.

Selectivities for Methanolysis of Esters
J . Org. Chem., Vol. 65, No. 4, 2000 977
Sch em e 6
Sch em e 9
Sch em e 7
Sch em e 8
general-base assistance from the pyridyl nitrogen. The
product of this step is ester 19, and this compound can
then undergo methanolysis with general-base assistance
from the pyridyl nitrogen to provide the methyl ester and
regenerate hemiacetal 18.16 Ketones are incapable of
functioning by this mechanism for two reasons. First, the
hemiketal formed upon addition of methanol to a ketone
(
20) is more hindered and less nucleophilic than the
dine by the method of Agrawal (Scheme 7).13 In the event,
the use of 17 as a catalyst for the methanolysis of 12
under our standard reaction conditions results in very
slow methanolysis of the ester with a half-life of 9 days
hemiacetal produced from the aldehyde-containing cata-
lysts. Second, ketones are less prone to form hemiketals
than aldehydes are to form hemiacetals. Thus, there is
17
a lower concentration of the hemiketal which is less
reactive, leading to a decrease in the nondirected rate of
reaction. Consistent with this mechanism is the fact that
when the FPP-catalyzed methanolysis of 11 versus 12 is
4
(Scheme 8).
If the nondirected reaction were operating by a general-
base mechanism, there would be no obvious reason
dioxolanone 14 or dioxolane 17 should not be effective
catalysts for the methanolysis of 12. The lack of reactivity
of these species suggests that the nondirected reaction
is operating by a mechanism other than intermolecular
general-base catalysis, and offers an explanation for the
enhanced selectivity observed with catalysts 5-8. We
suggest that the nondirected reaction is catalyzed by the
hemiacetal formed upon addition of methanol to the
aldehyde of FPP (18; Scheme 9). In fact, examination of
run in methanol-d as the solvent, the selectivity for the
methanolysis of 11 decreases from 96:1 (in CDCl ) to 4:1.
This is due to an increase in the concentration of the
methanol hemiacetal of FPP and a corresponding in-
crease in the rate of the nondirected reaction which is
catalyzed by this species.
3
The mechanism for the nondirected reaction is similar
to that first proposed by Werber and Shalitin for the
reaction of tertiary â-amino alcohols with active esters
1
the resting state of catalyst 15 by H NMR during the
18
in buffered aqueous solution. In this system the tertiary
methanolysis of 12 shows the catalyst exists as either
the methanol hemiacetal or the acylated hemiacetal 19.14
The hemiacetal hydroxyl group is more acidic than those
of ordinary alcohols15 and can attack active esters with
amino group acts as an intramolecular general base to
assist attack by the hydroxyl oxygen. When the ester
contains an activated acyl moiety (such as that present
(
a
15) Carbonyl hydrates are about 4 pK units more acidic than the
(
13) Agrawal, K. C.; Booth, B. A.; DeNuzzo, S. M.; Sartorelli, A. C.
J . Med. Chem. 1976, 19, 1209.
14) We cannot readily distinguish between these species because
corresponding alcohol. See ref 8a, pp 12-16. For data on the acidity
of pyridine carboxaldehyde hydrates, see: Owen, T. C. J . Heterocycl.
Chem. 1990, 27, 987.
(
the chemical shifts vary as the reaction progresses and p-nitrophenol
(16) Menger has described the use of aldehyde hydrates as catalysts
for the hydrolysis of active esters. See: Menger, F. M.; Ladika, M. J .
Am. Chem. Soc. 1987, 109, 3145. The use of the corresponding ketones
results in a less active catalyst, consistent with our findings. See:
Menger, F. M.; Persichetti, R. A. J . Org. Chem. 1987, 52, 3451.
(17) For example, under our reaction conditions the 6-triethylsilyl
is liberated. The data are most consistent with the resting state being
1
the methanol hemiacetal 18. Examination of the H NMR spectrum
of the competition reaction described in Scheme 5 at 100% conversion
of 11 and 40% conversion of 12 revealed resonances for the catalyst at
δ ) 5.61 (s, 1H), 6.45 (d, J ) 2.5 Hz, 1H), and 6.61 (d, J ) 2.5 Hz, 1H).
1
The remaining resonances are obscured by the reactants. The H NMR
catalyst 15 exists as a 1:3 mixture of hemiacetal to aldehyde whereas
1
spectrum of catalyst 15 (0.005 M) in CD
M) in chloroform reveals resonances for the methanol hemiacetal at δ
5.51 (s, 1H), 6.45 (br, 1H), and 6.55 (br, 1H). The ratio of the
3
OD (1.0 M) and PNPOH (0.1
catalysts 6-8 exist exclusively as the ketones as determined by
H
NMR. The exception to this is the trifluoromethyl ketone 5, which is
found to exist as a 10:1 ratio of hemiketal/hydrate (due to adventitious
moisture), with none of the free ketone being observed. In this case,
the selectivity is due to the steric hindrance and resulting lack of
nucleophilicity of the hemiketal adduct.
)
methanol hemiacetal to the aldehyde under these conditions is 2.7:1
in favor of the hemiacetal. If 19 were the resting state, we would expect
to observe the acetal methine proton further downfield at about δ )
6
.0.
(18) Werber, M. M.; Shalitin, Y. Bioorg. Chem. 1973, 2, 202.

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78 J . Org. Chem., Vol. 65, No. 4, 2000
Sammakia and Hurley
in a methoxyacetate ester), a subsequent deacylation step
is also observed, which is believed to occur by intramo-
lecular general-acid catalysis by the protonated amine.
The overall reaction then consists of the hydrolysis of
active esters using an amino alcohol to facilitate the
reaction via an acylation-deacylation mechanism. Sub-
sequently, there have been extensive investigations of the
as a nucleophile. Further experiments to exploit this
finding are in progress.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (Grant GM48498), Novartis Pharma-
ceuticals Corp., and Pfizer for financial support of this
research. T.S. is a recipient of an American Cancer
Society J unior Faculty Research Award and is an Alfred
P. Sloan Research Fellow. T.B.H. is a recipient of an
American Chemical Society Division of Organic Chem-
istry Fellowship sponsored by Eli Lilly and Co.
1
9
use of amino alcohols as models for protease enzymes.
In our system, it is interesting to note that both the
directed and nondirected reactions proceed by mecha-
nisms in which the hydroxyl group of a hemiacetal acts
Su p p or tin g In for m a tion Ava ila ble: Preparation and
spectral characterization of compounds 2, 3, 5-10, and 15-
(
19) (a) Hine, J .; Khan, N. M. J . Am. Chem. Soc. 1977, 99, 3847. (b)
Khan, N. M. J . Chem. Res. (S) 1986, 290. (c) Khan, N. M. J . Org. Chem.
985, 50, 4851. (d) Brown, R. S. J . Am. Chem. Soc. 1989, 111, 1445.
e) Khan, N. M. Indian J . Chem. 1992, 31B, 427. (f) De Clercq, P. J .;
Madder, A.; Declercq, J .-P. J . Org. Chem. 1998, 63, 2548.
1
17, and H spectra for compounds 9, 15, and 16. This material
1
(
is available free of charge via the Internet at http://pubs.acs.org.
J O991202K