8240
J . Org. Chem. 1997, 62, 8240-8242
volatile, resulting in an optimized protocol which requires
several charges of this reagent (see Experimental Sec-
tion).
A Mild P r otocol for th e Con ver sion of
Sim p le Ester s to ter t-Bu tyl Ester s
This reaction has many attractive features including
short reaction times, ambient temperature conditions,
toleration of high substrate concentrations, and relatively
low catalyst loadings,6 the latter feature being especially
significant in maintaining mild reaction conditions. The
ability to push the reaction to high conversion (>98%)
also simplifies workup to removing the catalyst by
filtering through silica gel and concentrating in vacuo.7
Alternatively, a standard aqueous workup (or pH 7
buffer) can be utilized which obviates the need for silica
gel in the workup.
Optimization of reaction conditions led to the reported
stepwise addition of 1 mol % KOtBu (as a 1 M solution
in THF) and 1 equiv of tert-butyl acetate under dynamic
vacuum to remove the volatile methyl acetate.8,9 Catalyst
deactivation was observed to occur under low catalyst
loadings and under single-addition conditions (addition
of 8 mol % KOtBu and 8 equiv of tert-butyl acetate to
ethyl hydrocinnamate under dynamic vacuum leads to
24% conversion, cf. entry 1). Due to the difficulties we
often encountered in separating products from starting
esters, we recommend the stepwise approach which
routinely gives >98% conversion and high isolated yields,
except as noted below.
The entries in Table 1 highlight the fact that both
aromatic and aliphatic esters are good substrates for the
interchange reaction. One of the criteria for this reaction
protocol is that the starting ester be nonvolatile. Quali-
tatively, methyl benzoates containing electron-withdraw-
ing groups (entries 2-5) are more reactive than those
with electron-donating groups (entries 6-8), though the
latter can easily be driven to high conversions. The
exception to this observation is the p-nitro-substituted
substrate which proceeded sluggishly and formed several
unidentified byproducts. The noninnocence of this func-
tionality presumably disrupts the structure of the active
alkoxide cluster.3 Also problematic were substrates
containing acidic hetero functionalities such as methyl
p-amino- and p-hydroxybenzoate which failed to give tert-
butyl ester products (not shown), presumably due to
competing deprotonation processes.
Matthew G. Stanton and Michel R. Gagne´*
Department of Chemistry, The University of North Carolina
at Chapel Hill, Chapel Hill, North Carolina 27599
Received J une 23, 1997
In tr od u ction
The ester functional group is ubiquitous throughout
the natural and synthetic world of organic chemistry and
has resulted in decades of effort being devoted to its
synthesis and manipulation. In addition to being valu-
able synthetic targets themselves, esters also serve the
role of protective groups for other functionalities. Simple
esters, however, are problematic in that harsh reaction
conditions are normally required for net hydrolysis. To
circumvent such undesirable reaction conditions, a num-
ber of alternative ester types have been presented which
may be deprotected under mild, and oftentimes, orthogo-
nal reaction conditions (e.g., acid, H2-Pd/C, F-).1,2 The
tert-butyl ester has found a unique and desirable role in
this scheme in that it can be converted to the carboxylic
acid under mild acid conditions.
Recently, we reported on the ability of certain alkali-
metal alkoxides to catalyze the ester-interchange reaction
(eq 1).3 The extremely rapid rates of reaction effected
by such catalysts (>106 times more active than previously
reported catalysts)4 allow one to process tert-butyl esters
at reasonable rates. The enhanced reactivity coupled
with the low cost and commercial availability of catalyst
solutions makes the ester-interchange reaction a viable
alternative to transesterification-type processes.5 We
report herein the synthesis of a number of tert-butyl
esters from their corresponding methyl or ethyl esters
as a demonstration of the synthetic utility and viability
of the catalyzed ester-interchange reaction.
Resu lts a n d Discu ssion
We ascribe the reduced and lack of reactivity of the
substrates in entries 10 and 11, respectively, to the
enhanced acidities of these esters. Since the -OPh ester
is expected to be ∼1.8 pKa units more acidic than the
-OMe ester, these substrates apparently represent a
As a demonstration of the synthetic utility of the alkali-
metal alkoxide cluster-catalyzed ester-interchange reac-
tion, a number of simple esters were refunctionalized to
the more useful tert-butyl ester using a commercial
source of potassium tert-butoxide in THF as the catalyst
(eq 1, Table 1). As shown in eq 1, the employed catalyst
only equilibrates the esters, and so reaction conditions
were developed wherein one product ester is volatile
(methyl acetate) and is removed in vacuo to drive the
reaction forward. Unfortunately tert-butyl acetate is also
(6) Since this reaction is entropically controlled (i.e., ∆Hrxn ∼ 0), no
exotherms accompany large-scale reactions.
(7) It is imperative that all of the catalyst be completely inactivated
on silica gel before washing with ethyl acetate as any remaining active
catalyst will convert the product tert-butyl esters into ethyl esters.
(8) Aspirator vacuum often works well for reactive substrates but
requires the use of an intermediate drying tube. More convenient, and
utilized in the above experimental, was the use of a standard vacuum
pump.
(9) Attempts to recycle the tert-butyl acetate using traps or condens-
ers failed to improve the optimized conditions at the reported scales.
Large-scale reactions may benefit from such an experimental setup.
(10) These estimates are based on the known pKa’s of methoxy-
acetophenone (22.9) and phenoxyacetophenone (21.1) in DMSO; see:
Bordwell, S. G.; Van Der Puy, M.; Vanier, N. R. J . Org. Chem. 1976,
41, 1885-1886.
(11) We estimate, on the basis of a pKa value of 30.3 for tert-butyl
acetate (DMSO), that the pKa of the esters in entries 10 and 11 are
28.8 and 27.0, respectively.
(1) Protective Groups In Organic Synthesis, 2nd ed.; Greene, T. W.,
Wuts, P. G. M., Eds.; J ohn Wiley & Sons, Inc.: New York, 1991; pp
227-269.
(2) For an alternative alkali-metal-catalyzed approach to the equili-
bration of esters and alcohols, see: (a) Rowan, S. J .; Hamilton, D. G.;
Brady, P. A.; Sanders, J . K. M. J . Am. Chem. Soc. 1997, 119, 2578-
2579. (b) Brady, P. A.; Bonar-Law, R. P.; Rowan, S. J .; Suckling, C. J .;
Sanders, J . K. M. Chem. Commun. 1996, 319-320.
(3) Stanton, M. G.; Gagne´, M. R. J . Am. Chem. Soc. 1997, 119, 5075-
5076.
(4) Okanu, T.; Hayashizaki, Y.; Kiji, J . Bull. Chem. Soc. J pn. 1993,
66, 1863-1865.
(5) For a recent review on the transesterification reaction, see:
Otera, J . Chem. Rev. 1993, 93, 1449-1470.
(12) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463 and
references therein.
S0022-3263(97)01138-9 CCC: $14.00 © 1997 American Chemical Society