We could find no examples of Schrock carbenes (nucleo-
philic metal alkylidenes6) bearing organoboronates or orga-
notin moieties. Chromium-containing 1,1-bimetallics bearing
such groups were known and had been used to alkylidenate
aldehydes,7 but they do not react with carboxylic acid
derivatives. Trimethylsilyl groups are tolerated in the titanium
alkylidenes8 and 1,1-bimetallics9 that alkylidenate esters.10
However, unlike (alken-1-yl)trimethylsilanes, aryltrimeth-
ylsilanes are not substrates for palladium-catalyzed cross-
couplings.11
Scheme 2. Synthesis of Simple Boronate Substrate
We decided that organoboronate functionality would be
the most useful for introducing diversity. Although Suzuki
cross-couplings12 of resin-bound halides or triflates are some
of the most common reactions in combinatorial library
synthesis,13 polymer-bound boronates have rarely been
employed. This is surprising as there are many more
commercially available aryl halides than arylboronates. The
few reported examples involve using resin-bound boronates
in polymer functionalization,14 in standard solid-phase syn-
thesis,5,15 in soluble polymer-supported convergent synthe-
sis,16 and as linkers that are cleaved during cross-coupling
reactions.17
scale, began from 4-bromobenzaldehyde 8. Aldehyde 8 was
protected as tetramethyldioxolane 9. Lithium-bromine ex-
change, reaction with triisopropylborate, and transesterifi-
cation of the resulting arylboronate gave acetal 10.18 Reaction
with propanedithiol then gave the desired thioacetal 7. It is
important to match the acetal and boronate ester, as partial
transesterification of the pinacolatoboronate occurred in this
step when a 1,3-dioxane protecting group was used. Acetal
protection was necessary as neither lithiation-boronation nor
Grignard formation-boronation were successful using the
1,3-dithiane formed from aldehyde 8.
Thioacetal 7 reacted with 4 equiv of Cp2Ti[P(OEt)3]2 to
give a titanium reagent, presumably titanium benzylidene
12, that converted Merrifield resin-bound ester 11a contained
in an IRORI macrokan into enol ether 13. Treatment with
mild acid then gave boronate 14 cleanly and in high yield
(based on resin loading of commercial Merrifield resin)
following solvent removal. We then investigated Suzuki
cross-couplings on solid support in DMF. A range of bases
(K3PO4, K2CO3, Tl2CO3, CsF, Ag2CO3 and Cs2CO3) and
water-DMF mixtures (including anhydrous DMF) were
tested. Under the optimum conditions (1 equiv of water with
cesium carbonate as nucleophilic base), both electron-rich
p-iodotoluene and electron-poor p-nitrophenyl iodide coupled
smoothly, and ketones 15 and 16 were isolated in high yield
and purity following cleavage from resin and solvent removal
(with no further purification required; see Supporting Infor-
mation for 1H NMR spectra). We had previously shown that
benzylic thioacetals with an ortho trimethylsiloxy group can
be used to make benzofurans,2 so we embarked on a synthesis
of benzylic thioacetal 22 (Scheme 4). Methoxymethyl
protection of bromosalicylaldehyde 17 gave aryl bromide 18,
which underwent cross-coupling with bis(pinacolato)dibo-
ron19 19 to give boronate 20. The mild conditions reported
Initially, we wished to determine whether a titanium
alkylidene bearing an arylboronate group could be generated
from a thioacetal and used to alkylidenate esters. Therefore,
we prepared thioacetal 7 in high yield from commercially
available boronic acid 6 (Scheme 2). A cheaper route, which
involved no chromatography and was amenable to multigram
(6) Review: Do¨rwald, F. Z. Metal Carbenes in Organic Synthesis; Wiley-
VCH: Weinheim, 1999.
(7) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake, T.;
Utimoto, K. Synlett 1995, 963-964. (b) Hodgson, D. M.; Boulton, L. T.;
Maw, G. N. Tetrahedron Lett. 1994, 35, 2231-2234. (c) Hodgson, D. M.
Tetrahedron Lett. 1992, 33, 5603-5604.
(8) Be´gue´, J.-P.; Rock, M. H. J. Organomet. Chem. 1995, 489, C7-C8.
(b) Petasis, N. A.; Bzowej, E. I. J. Org. Chem. 1992, 57, 1327-1330.
(9) Takai, K.; Tezuka, M.; Kataoka, Y.; Utimoto, K. Synlett 1989, 27-
28.
(10) For a review of titanium reagents that alkylidenate esters, see:
Hartley, R. C.; McKiernan, G. J. J. Chem. Soc., Perkin Trans. 1 2002,
2763-2793.
(11) Review: Hiyama, T.; Shirakawa, E. In Organopalladium Chemistry
for Organic Synthesis, Negishi, E., Ed.; Wiley: New York, 2002; Vol. 2,
Chapter III.2.4, pp 285-301.
(12) Reviews: (a) Suzuki, A. Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998;
Chapter 2. (b) Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley: New York, 2002; Vol. 2, Chapter III.
(13) For annual reviews of combinatorial library synthesis, see: (a) Dolle,
R. E. J. Comb. Chem. 2002, 4, 369-418. (b) Dolle, R. E. J. Comb. Chem.
2001, 3, 477-517.
(14) Kell, R. J.; Hodge, P.; Nisar, M.; Williams, R. T. J. Chem. Soc.,
Perkin Trans. 1 2001, 3403-3408. (b) Vanier, C.; Wagner, A.; Mioskowski,
C. Tetrahedron Lett. 1999, 40, 4335-4338. (c) Wulff, G.; Schmidt, H.;
Witt, H.; Zentel, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 188-191.
(15) Kang, S.-K.; Yoon, S.-K.; Lim, K.-H.; Son, H.-J.; Baik, T.-G. Synth.
Commun. 1998, 28, 3645-3655. (b) Piettre, S. R.; Baltzer, S. Tetrahedron
Lett. 1997, 38, 1197-1200 (c) Tempest, P. A.; Armstrong, R. W. J. Am.
Chem. Soc. 1997, 119, 7607-7608. (d) Brown, S. D., Armstrong, R. W. J.
Am. Chem. Soc. 1996, 118, 6331-6332. (e) Guiles, J. W.; Johnson, S. G.;
Murray, W. V. J. Org. Chem. 1996, 61, 5169-5171.
(16) Ahn, J.-M.; Wentworth, P., Jr.; Janda, K. D. Chem. Commun. 2003,
480-481.
(17) Hebel, R.; Haag, R. J. Org. Chem. 2002, 67, 9452-9455. (b) Gravel,
M.; Thompson, K. A.; Zak, M.; Be´rube´, C.; Hall, D. G. J. Org. Chem.
2002, 67, 3-15. (c) Pourbaix, C.; Carreaux, F., Carboni, B. Org. Lett. 2001,
3, 803-805. (d) Gravel, M.; Be´rube´, C. D.; Hall, D. G. J. Comb. Chem.
2000, 2, 228-231. (e) Li, W.; Burgess, K. Tetrahedron Lett. 1999, 40,
6527-6530.
(18) For a similar procedure, see: Bouillon, A.; Lancelot, J.-C.; Collot,
V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58, 4369-4373.
(19) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510.
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