Improved ester interchange catalysts

Article abstract of DOI:10.1021/ol0067585

(equation presented) Mixed alkoxide/aryloxide clusters are long-lived and milder than previously reported ester interchange catalysts. They completely transform difficult substrates in a single synthetic operation with lower catalyst and reagent ester loadings. In addition to superior activities, these mixed clusters are kinetically less basic toward enolizable esters.

Full text of DOI:10.1021/ol0067585

ORGANIC
LETTERS
2
000
Vol. 2, No. 26
209-4212
Improved Ester Interchange Catalysts
4
Rebecca M. Kissling and Michel R. Gagn e´ *
Department of Chemistry, CB3290 Venable Hall, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
mgagne@unc.edu
Received October 20, 2000
ABSTRACT
Mixed alkoxide/aryloxide clusters are long-lived and milder than previously reported ester interchange catalysts. They completely transform
difficult substrates in a single synthetic operation with lower catalyst and reagent ester loadings. In addition to superior activities, these
mixed clusters are kinetically less basic toward enolizable esters.
In 1997 we reported the high ester interchange activity (up
geometrically facilitated by the cluster framework. Productive
breakdown of the cluster-bound tetrahedral intermediate gives
a product ester and a newly substituted cluster (Scheme 1).4
7
to 10 TO/h) of alkali metal alkoxides in aprotic solvents
1
(
eq 1). Under these conditions alkali metal alkoxide catalysts
Scheme 1
2
exist as tetrameric clusters and react at rates far in excess
of those normally observed in protic solvents (e.g., NaOEt
3
in ethanol).
This mechanism provides a multistep pathway for equilibrat-
ing ester -OR groups. Since interchange rates are rapid and
volatile product esters can be removed, this reaction can be
utilized to synthesize new esters, and in particular the
synthetically useful tert-butyl esters.
Mechanistically, the interchange is thought to proceed by
ester precoordination and intramolecular delivery of alkoxide,
5
(
1) Stanton, M. G.; Gagn e´ , M. R. J. Am. Chem. Soc. 1997, 119, 5075-
5
076.
(
2) (a) Arnett, E. M.; Moe, K. D. J. Am. Chem. Soc. 1991, 113, 7288-
Optimization of this chemistry to the synthesis of tert-
butyl esters from methyl esters resulted in a protocol that
involved multiple additions of 1 mol % of KO Bu and tert-
7
3
293. (b) Jackman, L. M.; Smith, B. D. J. Am. Chem. Soc. 1988, 110, 3829-
835, and references therein. (c) Schmidt, P.; Lochmann, L.; Scneider, B.
J. Mol. Struct. 1971, 9, 403-411. (d) Bauer, W.; Lochmann, L. J. Am.
Chem. Soc. 1992, 114, 7482-7489. (e) Chisholm, M. H.; Drake, S. R.;
Naiini, A. A.; Streib, W. E. Polyhedron 1991, 10, 337-335. (f) Chisholm,
M. H.; Drake, S. R.; Naiini, A. A.; Streib, W. E. Polyhedron 1991, 10,
t
butyl acetate, followed by the evacuative removal of the
8
05-810. (g) Kahn, J. D.; Haag, A.; von Ragu e´ Schleyer, P. J. Phys. Chem.
(4) Stanton, M. G.; Allen, C. B.; Kissling, R. M.; Lincoln, A. L.; Gagn e´ ,
M. R. J. Am. Chem. Soc. 1998, 120, 5981-5989.
(5) For a related transesterification protocol that equilibrates alcohols
and esters using KOMe/18-c-6, see: Rowan, S. J.; Hamilton, D. G.; Brady,
P. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1997, 119, 2578-2579.
1
988, 92, 212-220. (h) Halaska, W.; Lochmann, L.; Lim, D. Collect. Czech.
Chem. Commun. 1968, 33, 3245-3253.
(3) Pregel, M. J.; Dunn, E. J.; Nagelkerke, R.; Thatcher, G. R. J.; Buncel,
E. Chem. Soc. ReV. 1995, 449-455.
1
0.1021/ol0067585 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/02/2000

6
9
volatile methyl acetate byproduct. This procedure gave high
should form mixed clusters wherein the alkoxide participates
conversion to tert-butyl ester products, typically using 5-10
mol % of catalyst and 5-8 equiv of reagent ester and was
also applicable to the synthesis of phosphonates.
in alkyl ester interchange, while the aryloxides, being
insulated from interchange, are able to provide long-term
solubility and cluster integrity. This strategy additionally
provides a handle for systematically varying the steric and
electronic properties of the cluster substituents.
7
Although reaction rates are high, catalyst precipitation
limited the number of achievable turnovers, a problem that
was partially overcome by the multiple addition protocol.
The efficacy of new catalyst mixtures was gauged by
monitoring the approach to equilibrium of the transformation
t
Isolation of a precipitate with a 3:1 NaOMe:NaO Bu stoi-
t
chiometry pointed to the replacement of solubilizing cluster
in eq 2 using 1 mol % of NaO Bu and varying amounts of
tert-butyl groups as the cause of catalyst loss (Scheme 2),
8
as NaOMe and KOMe are insoluble sheetlike materials.
Scheme 2
an aryloxide additive. Establishing global equilibrium in this
reaction is challenging, as DIMP formation is slow, although
equilibrium between DMMP and IMMP is established
7
,10
quickly.
Catalyst performance, as judged by the final [DIMP],
t
11
6 4
improved as the ratio of NaOC H -4- Bu to tert-butoxide
increased from 0 to 1 to 2, and peaked at 3, 4, and 5. Under
conditions where equilibrium was not achieved, increasing
the ratio from 3 to 4 to 5 did not change the product ratios.
Varying the para substituent of the aryloxide additive
revealed a nonlinear Hammett-type relationship with the
Since extending the lifetime of these catalysts required a
strategy that prevented the formation of insoluble poly-
methoxide (or similar) clusters or arrays, we chose to
incorporate several nonreacting but solubilizing components
into the cluster. The first substituents investigated were
aryloxides (A, X ) Ar), since the steric and electronic
4
-tert-butyl- and 4-chloro-derived catalysts being superior
t
(
4-CF
also superior to potassium salts.
A combination of 1 mol % of NaO Bu and 3 mol % of
3
, 4-H ≈ 4-OMe < 4- Bu e 4-Cl). Sodium salts were
t
t
6 4
NaOC H -4- Bu establishes equilibrium in 20 min (eq 2)
while 5 mol % of NaO Bu could not. The coordination
chemistry of Na-alkoxides and aryloxides suggests that the
t
1
2
active catalyst is the mixed cluster 1.
properties of this group can be readily modified. We reasoned
that because aryloxides are better leaving groups, they would
stay in the cluster since breakdown of any putative tetrahedral
intermediate would always redeposit -OAr into the cube
(Scheme 3). This notion is consistent with the observation
The optimum catalyst mixture for phosphonates proved
to also be an excellent catalyst for carbonyl ester interchange
and provided a mild straightforward methodology for ester
synthesis.
Scheme 3
(9) For relevant examples of characterized mixed alkali metal alkoxide,
aryloxide, or acetylide clusters, see: (a) Jackman, L. M.; Rakiewicz, E. F.
J. Am. Chem. Soc. 1991, 113, 1202-1210. (b) Jackman, L. M.; Rakiewicz,
E. F.; Benesi, A. J. J. Am. Chem. Soc. 1991, 113, 4101-4109. (c) Thompson,
A.; Corley, E. G.; Huntington, M.; Grabowski, E. J. J.; Remenar, J. F.;
Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028-2038.
i
that alkyl and aryl esters do not undergo productive
interchange. Thus, mixtures of alkoxide and aryloxide salts
(10) Equilibrium values for eq 2: using 2 equiv of PrOAc dimethyl
4
methylphosphonate (DMMP) 11%, isopropyl methyl methylphosphonate
(
IMMP) 51%; diisopropyl methylphosphonate (DIMP) 38%.
11) Control experiments showed that NaOAr is not a competent catalyst.
(12) NMR experiments indicate that at this ratio some 2:2 and 0:4 also
(
(6) Stanton, M. G.; Gagn e´ , M. R. J. Org. Chem. 1997, 62, 8240-8242.
(7) Kissling, R. M.; Gagn e´ , M. R. J. Org. Chem. 1999, 64, 1585-1590.
(8) Weiss, E. Z. Anorg. Allg. Chem. 1964, 332, 197-203.
exist in solution, the former of which undoubtedly contributes to catalysis
as well.
4210
Org. Lett., Vol. 2, No. 26, 2000

generally lead to quantitative conversions to desired product
in less than 1 h with as little as 0.5 mol % of 1 and 1.2
equiv of reagent ester. Bulky reagent esters such as tert-
butyl acetate interchange more slowly and require higher
catalyst loadings and more equivalents of reagent ester to
achieve high (>98%) conversion. Compared to our first
Table 1. Conversion of Methyl to Benzyl Esters with Benzyl
Acetate and 1
6
generation catalyst, this methodology provides high product
yields with lower catalyst loadings and operationally requires
only a single catalyst addition. Moreover, several substrates
were found to react more smoothly using 1 as catalyst. For
example, acidic substrates such as those in entries 5 and 6
and the nitro-substituted substrate of Tables 1 and 2 are now
satisfactorily converted to the desired product. In the case
of the bulky adamantyl esters in entries 8, benzyl ester
formation proceeded smoothly but formation of the tert-butyl
ester did not, effectively establishing an upper limit on the
steric encumbrance tolerated by the catalyst. The reaction is
also scalable as methyl benzoate was readily converted to
benzyl (>99%) and tert-butyl (96%) benzoate on a 100 mmol
scale.
2
Typically the esters were distilled from CaH or sublimed
and stirred together neat in a Schlenk flask under inert an
atmosphere. A 0.5 M THF solution of 1, prepared by mixing
t
freshly sublimed NaO Bu and NaOAr in the proper ratio,
was added to the stirring esters and the flask opened to
vacuum (0.15 mmHg, 25 °C). Reactions with high boiling
esters were left open to the vacuum and were typically
complete in 10 min-2 h. Reactions with a volatile reactant
were treated with catalyst as above and the methyl acetate
distilled into a cooled receptor under static pressure (40-55
mmHg). These conditions typically required 2-6 h for
complete conversion (>98%) to product.
Tables 1 and 2 illustrate the effectiveness of catalyst 1
under optimized conditions. Sterically undemanding reagent
esters such as benzyl acetate interchange quickly and
The successful utility of 1 at lower catalyst loadings
Table 2. Conversion of Methyl to tert-butyl Esters with
tert-Butyl Acetate and 1
prompted a reexamination of R-amino acid methyl esters
t
6
4
which were racemized by [KO Bu] catalysts. The integrity
of the R-chiral center was most conveniently monitored by
using an enantiopure reagent ester and determining the ratio
Figure 1. % conversion and % de versus time for eq 3 as catalyzed
t
by 2 mol % of 1 (dash) and 5 mol % of NaO Bu (solid).
Org. Lett., Vol. 2, No. 26, 2000
4211

of diastereomers in the product esters by gas chromatography
In summary, we have developed a new family of ester
interchange catalysts that are milder and more robust than
the simple alkali metal alkoxide catalysts previously reported.
Application of these catalysts to ester interchange allows the
one-step synthesis of protected esters from simple methyl
or ethyl esters.
t
4
(eq 3). Unlike [KO Bu] catalysis, the R-stereocenter was
Acknowledgment. We thank the United States Army
Research Office (DAAG55-95-1-0257), 3M, DuPont, Union
Carbide, and the UNC University Research Council for
funding of this research. M.R.G. is a Camille Dreyfus
Teacher Scholar (2000).
appreciably more stable to racemization using 1. Figure 1
shows the conversion to product superimposed on the
diastereomeric excess (% de) for 2 mol % of 1 (dash) and 5
mol % of NaO Bu (solid). Inspection of the curves indicates
that catalyst 1 provides superior conversion versus racem-
ization rates, even at reduced loadings. Future experiments
will optimize this interchange vs racemization activity by
further variations in the aryloxide additive.
t
13
Supporting Information Available: Experimental pro-
cedures for all syntheses, characterization of new compounds,
1
13
and H and C NMR for all synthesized compounds in
Tables 1 and 2. This material is available free of charge via
the Internet at http://pubs.acs.org.
t
(
13) Under identical conditions, 5 mol % of KO Bu gave a rate of
conversion similar to 2 mol % of 1; however, the % de drops to 15% and
% after 1 and 5 min, respectively. Thus 1 is not only less basic but more
active than [KO Bu]4.
5
t
OL0067585
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Org. Lett., Vol. 2, No. 26, 2000