LETTER
Regioselective Hiyama Cross-Coupling
83
philic position.2,15 While it is unlikely that the oxidative
addition is rate-determining for the Hiyama cross-cou-
pling reaction, the preference for substitution to occur at
the most electrophilic position may still be attributed to
this process as long as there are no other factors slowing
down the subsequent steps that take place at this position.
(2) For reviews, see: (a) Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. (b) Fairlamb, I. J. S. Chem.
Soc. Rev. 2007, 36, 1036.
(3) Bach, T.; Bartels, M. Synthesis 2003, 925.
(4) (a) Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama,
T. Tetrahedron Lett. 1994, 35, 6507. (b) Matsuhashi, H.;
Asai, S.; Hirabayashi, K.; Hatanaka, Y.; Mori, A.; Hiyama,
T. Bull. Chem. Soc. Jpn. 1997, 70, 437.
(5) For reviews, see: (a) Hiyama, T. in Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998, 421–453. (b) Denmark, S. E.;
Sweis, R. F. in Metal-Catalyzed Cross-Coupling Reactions,
2nd ed., Vol. 1; de Meijere, A.; Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004, 163–216.
Despite successful reactions with most substrates, a few
heterocycles reacted either sluggishly or with insufficient
regioselectivity. In particular, thiophenes (2,3-dibromo-
and 2,4-dibromothiophene) were not suitable as sub-
strates; in these cases, either no products were obtained or
significant amounts of hydrodebrominated material
resulted, even under optimized conditions. The reactions
of 2,4-dibromopyridine suffered from low regio-
selectivity16,17 due to the similar reactivity at the two elec-
trophilic positions.
(6) (a) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew. Chem.
Int. Ed. 2007, 46, 3556. (b) Dai, X.; Strotman, N. A.; Fu,
G. C. J. Am. Chem. Soc. 2008, 130, 3302.
(7) (a) Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121,
5821. (b) Denmark, S. E.; Wu, Z. Org. Lett. 1999, 1, 1495.
(c) Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002,
50, 1531. (d) Denmark, S. E.; Ober, M. H. Adv. Synth. Catal.
2004, 346, 1703. (e) Denmark, S. E.; Regens, C. S. Acc.
Chem. Res. 2008, 41, 1486. (f) Denmark, S. E.; Werner,
N. S. J. Am. Chem. Soc. 2008, 130, 16382. (g) Denmark,
S. E.; Smith, R. C.; Chang, W.-T. T.; Muhui, J. M. J. Am.
Chem. Soc. 2009, 131, 3104.
In a preliminary series of experiments we tested whether
other primary silanes could also be employed as nucleo-
philes in the regioselective Hiyama cross-coupling reac-
tion (Scheme 2). Benzyltrifluorosilane,18 (2-phenylethyl)-
trifluorosilane,9,18a and methyl 3-(trifluorosilyl)propano-
ate,4b,18a all reacted smoothly to yield the expected 2-sub-
stituted products 4b–d.
(8) Bury, P.; Hareau, G.; Kocieński, P.; Dhanak, D. Tetrahedron
1994, 50, 8793.
(9) Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1990, 31, 2719.
(10) Activating reagents were screened in the reaction of
substrate 3 with n-octyltrifluorosilane in THF at 100 °C,
employing Pd2dba3/P(2-furyl)3 as the catalyst. Almost no
conversion was achieved with the given activating reagents,
while anhydrous CsF delivered a significant conversion after
18 h (26% 4a, 34% 5).
F3Si
R
, CsF
Br
Br
[Pd2dba3, P(2-furyl)3]
(PhH), Δ
R
Br
MeOOC
MeOOC
O
O
b R = Ph
48%
51%
74%
3
c
d
4
R = Bn
R = CH2CO2Me
(11) (a) Bach, T.; Krüger, L. Tetrahedron Lett. 1998, 39, 1729.
(b) Bach, T.; Krüger, L. Synlett 1998, 1185. (c) Bach, T.;
Krüger, L. Eur. J. Org. Chem. 1999, 2045.
(12) Other ligands that have been tested include tri-tert-butyl-
phosphonium tetrafluoroborate (PtBu3·HBF4), tricyclo-
hexylphosphane (PCy3), 1,2-bis(diphenylphosphino)ethane
(dppe), 1,2-bis(di-2-furylphosphino)ethane (dfpe), and 1,4-
bis(diphenylphosphino)butane (dppb).
(13) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113,
9585. (b) Amatore, C.; Jutand, A.; Meyer, G.; Atmani, H.;
Khalil, F.; Chahdi, F. O. Organometallics 1998, 17, 2958.
(c) For a review, see: Andersen, N. G.; Keay, B. A. Chem.
Rev. 2001, 101, 997.
(14) Typical procedure: A flame-dried Schlenk tube was charged
with Pd2dba3 (9.2 mg, 0.01 mmol), P(2-furyl)3 (18.6 mg,
0.08 mmol) and benzene (2 mL) under an atmosphere of
argon. The solution was stirred at r.t. for 15 min then n-
octyltrifluorosilane (74 mL, 0.40 mmol) and CsF (122 mg,
0.80 mmol, which was stored and weighed in a glove box)
were added, followed by dibromofuran 3 (56.8 mg, 0.20
mmol). The tube was closed with a Teflon screw plug,
situated behind an explosion shield (CAUTION!), heated to
80 °C and stirred for 15 h. The reaction mixture was cooled
to room temperature and diluted with EtOAc (5 mL) and
H2O (5 mL). After separation of the layers, the aqueous
phase was extracted with EtOAc (3 × 5 mL) and the
combined organic layers were dried over Na2SO4 and
concentrated in vacuo. Purification of the crude product by
flash column chromatography (silica gel; pentane–Et2O,
99:1) yielded compound 4a (45.6 mg, 0.14 mmol, 72%) as a
colorless liquid. 1H NMR (500 MHz, CDCl3): d = 0.88 (t,
3J = 7.0 Hz, 3 H), 1.20–1.36 (m, 10 H), 1.68 (quint,
Scheme 2 Reaction of methyl 2,3-dibromo-5-furancarboxylate (3)
with various silanes in a regioselective Hiyama cross-coupling reac-
tion to products 4b–d
In summary, conditions of the Hiyama cross-coupling
reaction were successfully varied to achieve moderate to
high yields in regioselective reactions of various dihalo-
substituted heterocycles. The method opens a new route to
multiply substituted heterocycles and allows researchers
to take advantage of the known benefits of using Hiyama
cross-coupling reactions (easily accessible starting mate-
rials, high stability to air and heat, low cost, and low tox-
icity).
Acknowledgment
The authors thank WACKER Chemie AG for financial support.
References and Notes
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell: Oxford, 2000. (b) Gilchrist, T. L. Heterocyclic
Chemistry, 3rd ed.; Longman: Harlow, 1997. (c) Eicher, T.;
Hauptmann, S. The Chemistry of Heterocycles, 2nd ed.;
Wiley-VCH: Weinheim, 2003. (d) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Pergamon Press:
Oxford, 2000.
Synlett 2010, No. 1, 81–84 © Thieme Stuttgart · New York