ORGANIC
LETTERS
2
002
Vol. 4, No. 26
717-4718
Practical Synthesis of Aryl Triflates
under Aqueous Conditions
4
Doug E. Frantz,* Damian G. Weaver, James P. Carey, Michael H. Kress, and
Ulf H. Dolling
Department of Process Research, Merck Research Laboratories, Merck & Co.,
466 DeVon Park DriVe, Wayne, PennsylVania 19087
Received October 23, 2002 (Revised Manuscript Received November 19, 2002)
ABSTRACT
A practical and efficient synthesis of aryl triflates under biphasic basic aqueous conditions is described. The current methodology provides
entry into these valuable substrates that omits the use of amine bases and allows facile isolation by simple solvent evaporation after phase
separation. Good yields can also be obtained without the use of organic solvent.
7
Aryl triflates are extensively used as synthetic precursors in
a vast array of coupling reactions. Conventional preparation
catalyzed cyanation of the crude triflate. We were surprised
by the large catalyst loading (3-5 mol % Pd) necessary to
achieve complete conversion. Upon closer inspection of the
1
of these substrates involves the treatment of the correspond-
ing phenol with triflic anhydride in the presence of an amine
1
19
crude aryl triflate by H and F NMR, it was evident that it
was contaminated with 1-3% of triethylammonium triflate.
We suspected this ammonium salt might be interfering with
the catalytic process.
2
base such as pyridine or triethylamine. More convenient
3
protocols have utilized imidazole triflate, N-phenyltriflim-
4
5
ide, N-(2-pyridyl)triflimide, and recently, polymer-sup-
6
ported N-phenyltriflimide. The drawbacks to these special-
ized reagents are that a prior step is needed for their
formation (most derived from triflic anhydride itself) and
the relative reactivities of these triflating reagents are often
low in comparison to the anhydride.
As part of our ongoing research efforts we recently needed
a practical synthesis of ester nitrile 3 that was amenable to
large scale. We envisioned arriving at 3 via Pd-catalyzed
cyanation of the corresponding aryl triflate 2 (Scheme 1).
Our initial efforts toward 3 were via the traditional amine
2
base synthesis of aryl triflate 2 followed by direct Pd-
(
1) For reviews, see: (a) Ritter, K. Synthesis 1993, 735-762. (b) Stang,
P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85-126. (c) Stang,
P. J. Acc. Chem. Res. 1978, 11, 107-114.
(
2) Stille, J. K.; Echavarren, A. M. J. Am. Chem. Soc. 1987, 109, 5478-
5
486.
Given these results, we hypothesized that formation of
the triflate under Schotten-Baumann conditions might prove
to be advantageous, eliminating ammonium triflate salts
(
3) Effenberger, F.; Mack, K. E. Tetrahedron Lett. 1970, 11, 3947-
3
948.
(
4) (a) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14,
4
9
1
607-4610. (b) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24,
79-982. (c) Bengtson, A.; Hallberg, A.; Larhed, M. Org. Lett. 2002, 4,
231-1233.
(7) For related procedures involving the Pd-catalyzed cyanation of aryl
triflates, see: Drechsler, U.; Hanack, M. Synlett 1998, 1207. Anderson, B.
A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.; Wepsiec, J. P. J.
Org. Chem. 1998, 63, 8224-8228.
(
5) Comins, D. L.; Dehgani, A. Tetrahedron Lett. 1992, 33, 6299-6302.
(6) Wentworth, A. D.; Wentworth, P., Jr.; Mansoor, U. F.; Janda, K. D.
Org. Lett. 2000, 2, 477-480.
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0.1021/ol027154z CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/04/2002