of benzyl tosylate with a 0.7 M solution of triethylamine in
acetonitrile resulted in quantitative loss of starting material
after 15 min at room temperature. Heating p-toluene-
sulfonate-functionalized Argogel-MBOH resin in aceto-
nitrile in the presence of 10 equiv of triethylamine (0.195
M) at 60 °C for 18 h did show loss of some sulfonic acid,
giving the product sulfonic acid in a slightly reduced yield
(83%, vs 95% for the non-base-treated resin) following
hydrolysis. Curiously, increasing the heating time to 36 h
did not further reduce the yield, suggesting that at least a
portion of the sulfonates are particularly well protected from
nucleophilic displacement.
initial test case, we examined the ability of resin-bound
sulfonate 5 to participate in Suzuki coupling reactions.19 As
shown in Table 3, yields for the two-step coupling and
Table 3. Suzuki Coupling Reactions of Supported Sulfonate 5
Va´gner and co-workers have shown that at most 15% of
sites functionalized with a polypeptide are accessible to
enzyme-mediated hydrolysis;18 this is consistent with reports
by others that in reactions employing a solid-supported
catalyst reaction rates are dependent on the size of the
substrate. However, what are we to make of this reaction,
in which partial protection is observed even in the presence
of a small, readily diffusible nucleophile? Gel-phase NMR
(Varian Nanoprobe) of a sample of the p-toluenesulfonate
resin following 18 h of reflux with 10 equiv of triethylamine
in acetonitrile indicated the presence of two separate sets of
signals corresponding to the sulfonate. Furthermore, we can
also observe triethylammonium resonances, even after ex-
tensive washing of the resin. This suggests that a portion
(roughly 20%) of the sulfonate may be retained on the resin
via an ionic bond (i.e., 4), resulting from nucleophilic
displacement of the sulfonate by triethylamine and its
subsequent recapture by the triethylammonium salt, rather
than via a covalent bond. The observation that only a portion
of the sulfonate is displaced in this manner may be due to
differences in surface vs bead interior microenvironmental
effects.2 Alternatively, the more kinetically accessible surface
positions of the bead may undergo displacement first,
creating a “charge coat” to the bead which prevents further
reaction.
cleavage procedure are modest; however, these should be
regarded as unoptimized procedures.20
In summary, differences in the physical environment of a
solid-supported compound vis a vis its solvated counterpart
can provide significant differences in reactivity; these in turn
may be useful in the context of synthetic chemistry. We have
observed a significant “resin protection” effect on the
nucleophilic displacement of benzyl tosylates. Further ex-
periments examining the structural and mechanistic causes
of this observation, as well as synthetic studies on resin-
supported sulfonates, are in progress.
Acknowledgment. The authors thank Drs. Frederick
Sauter and Steve Godleski for helpful discussions during the
course of this work. The authors also thank Dr. William
Lenhart for his help with nanoprobe NMR experiments. This
research was supported by a generous grant from the Eastman
Kodak Corporation.
OL991163Z
(19) Representative Experimental Procedure: To the 4-iodobenzene-
sulfonate bound to Argogel-MBOH resin (100 mg, 0. 037 mmol) taken in
a biospin chromatography column (BIO-RAD) in 20% DMF/CH2Cl2 were
added Pd2dba3 (2.2 mg, 0.0024 mmol, 0.06 equiv) and K2CO3 (13.8 mg,
0.1 mmol, 2.4 equiv), and the solution was shaken for 15 min. Then
p-tolylboric acid (7.3 mg, 0.054 mmol, 1.34 equiv) was added, and the
solution was further shaken for 18 h. The reaction mixture was then
transferred to a round-bottom flask and further heated to reflux temperature
for 2 h. Then the resin was tranferred back to the biospin column and washed
sequentially with CH2Cl2, CH3CN, H2O, CH3OH, and CH2Cl2. Cleavage
of the product from resin was achieved by treatment with 20% TFA/CH2Cl2
for 1 h. The solvent was collected, and the resin washed with CH3OH. The
combined organic elutions were evaporated to give essentially pure
4-methylbiphenylsulfonic acid (5.1 mg, 55%).
(20) All products gave satisfactory NMR and mass spectral data and are
identical to published data, where available. Biphenyl-4-sulfonic acid and
4′-methylbiphenyl-4-sulfonic acid have been prepared previously: Korte-
kaas, T. A.; Cerfontain, H. J. Chem. Soc., Perkin Trans. 2 1977, 1560-
1562. Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112,
4324-4330.
Of course, this “protection” scheme is only useful in the
context of synthetic chemistry to the extent that it allows
additional synthetic transformations to be carried out. As an
(16) All sulfonic acids were analyzed by HPLC, NMR, and MS and
exhibit spectroscopic and chromatographic data identical to authentic
samples.
(17) (a) Yoh, S.-D.; Cheong, D. Y. J. Phys. Org. Chem. 1996, 9, 701-
705. (b) Yamataka, H.; Ando, T. Tetrahedron Lett. 1982, 23, 4805-4808.
(c) Ando, T.; Tanabe, H.; Yamataka, H. J. Am. Chem. Soc. 1984, 106,
2084-2088.
(18) Va´gner, J.; Barany, G.; Lam, K. S.; Krchna´k, V.; Sepetov, N. F.;
Ostrem, J. A.; Strop, P.; Lebl, M. Proc. Natl. Acad. Sci. U.S.A. 1996, 93,
8194-8199.
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