ligands, were not as good for this specific transformation);
a THF/H2O solvent mixture and Cs2CO3 (3 equiv) base were
preferred. Kuwano and Yokogi reported that benzylic
acetates can be used in Suzuki-Miyaura cross-couplings
using a catalyst system composed of DPEphos-[Pd(η3-
C3H5)Cl]2.11 Given the considerable interest in diarylmethanes
in medicinal chemistry12 and in view of the efficiency of
the PdII complex PdBr(N-Succ)(PPh3)2 (1) (Sigma-Aldrich;
Cat. No. 643742) in Stille cross-couplings of allylic and
benzylic halides with organostannanes, we envisaged that
efficient Suzuki-Miyaura cross-couplings of benzylic sub-
strates13 could be achieved using this simple Pd source.14
PPh3 is a strong enough activating ligand for benzylic
substrates. The imidate anion15 is also likely to play an
important role in the global catalyst efficacy. Our findings
using precatalyst 116 in Suzuki-Miyaura cross-couplings of
benzylic halides with organoboronic acids are thus reported
herein. Other tricky cross-couplings are presented, in addition
to a valuable recycling protocol.
Scheme 1. Cross-Coupling of Benzyl Halides and Arylboronic
Acids (Isolated Yields Given)c
The initial benchmark was the reaction of substituted
benzylic halides with an equivalent amount of substituted
arylboronic acids using 1 mol % of 1, in a mixture of 2 M
Na2CO3 and THF (1:2, v/v) at 60 °C (Scheme 1). Under
these simple conditions, a library of cross-coupled products
could be formed efficiently. For example, benzyl bromide
effectively reacted with phenylboronic acid to give diphe-
nylmethane 2 in 88% yield after 2 h. The catalyst loading
may be lowered to 0.01 mol %, which after 20 h gave an
81% yield (turnover number of 8100). The incorporation of
substituents onto the aryl group of the boronic acid (Z )
4-OMe, 4-F, and 3,5-F) was also possible, giving high yields
of the corresponding cross-coupled products (3-5, respec-
tively). Where the yield dropped slightly for 3, it could be
improved by heating to 80 °C. Benzyl chlorides can also be
a
b
Using 0.01 mol % of 1, 81% (20 h). Using 0.01 mol % of
c
1, >99% (20 h). All BnCl couplings were run at 80 °C.
used (at 80 °C). 3-Nitrobenzyl bromide reacts with various
organoboronic acids to give cross-coupled products in very
good yields (Z ) H, 4-F, and 4-OMe, 6-8). In a reaction
with PhB(OH)2, the catalyst loading was once again lowered
to 0.01 mol % (>99% conversion in 20 h; TON ) ∼10 000),
exemplifying the stability and longevity of the catalyst
system.17
Heteroarylboronic acids are also coupled effectively with
benzylic halides (Scheme 2). For example, thiophene-2-
boronic acid couples with BnBr to give 9 in 91% yield. Other
thiopheneboronic acids (Z ) 5-Cl, 5-acetyl) participate well
in these reactions affording 10 and 11 in ∼80% yields for
both BnBr and BnCl. For 5-formylthiophene-2-boronic acid,
a small amount of protodeborylation was observed (∼10%).
Thiophene-3-boronic acid reacts equally well with BnBr and
BnCl to give 13 in 93% and 91% yields, respectively.
Coupling of furan-2-boronic acid18 with BnBr and 3-meth-
oxybenzyl bromide was possible, giving the coupled products
14 and 15 in excellent yields (94% and >99%, respectively).
Organotrifluoroborates19 can be used as replacements for the
organoboronic acid coupling components. However, under
our reaction conditions, there is no real advantage over
related organoboronic acids in terms of yields and reaction
times.
(11) Kuwano, R.; Yokogi, M. Chem. Commun. 2005, 5899.
(12) (a) McPhail, K. L.; Rivett, D. E. A.; Lack, D. E.; Davies-Coleman,
M. T. Tetrahedron 2000, 56, 9391. (b) Long, Y.-Q.; Jiang, X.-H.; Dayam,
R.; Sachez, T.; Shoemaker, R.; Sei, S.; Neamati, N. J. Med. Chem. 2004,
47, 2561.
(13) Benzylic carbonates have been employed in Suzuki-Miyaura cross-
couplings. See: Kuwano, R.; Yokogi, M. Org. Lett. 2005, 7, 945.
(14) (a) Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Taylor, R. J.
K.; Whitwood, A. C. Chem. Commun. 2003, 2194. (b) Crawforth, C. M.;
Fairlamb, I. J. S.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 461. (c)
Burling, S.; Crawforth, C. M.; Fairlamb, I. J. S.; Kapdi, A. R.; Taylor, R.
J. K.; Whitwood, A. C. Tetrahedron 2005, 61, 9736. Note that cis-1 was
used in these studies. The commerical source of PdBr(N-Succ)(PPh3)2 has
a trans-geometry. This material was used in all of the examples presented
in this paper.
(15) (a) Fairlamb, I. J. S.; Kapdi, A. R.; Lynam, J. M.; Taylor, R. J. K.;
Whitwood, A. C. Tetrahedron 2004, 60, 5711. (b) Chaignon, N. M.;
Fairlamb, I. J. S.; Kapdi, A. R.; Taylor, R. J. K.; Whitwood, A. C. J. Mol.
Catal. A: Chem. 2004, 219, 191. (c) Serrano, J. L.; Fairlamb, I. J. S.;
Sa´nchez, G.; Garc´ıa, L.; Pe´rez, J.; Vives, J.; Lo´pez, G.; Crawforth, C. M.;
Taylor, R. J. K. Eur. J. Inorg. Chem. 2004, 2706. (d) Crawforth, C. M.;
Fairlamb, I. J. S.; Kapdi, A. R.; Serrano, J. L.; Taylor, R. J. K.; Sanchez,
G. AdV. Synth. Catal. 2006, 348, 405. (e) Young, G. L.; Smith, S. A.; Taylor,
R. J. K. Tetrahedron Lett. 2004, 45, 3797. (f) Fairlamb, I. J. S.; Taylor, R.
J. K.; Serrano, J. L.; Sanchez, G. New J. Chem. 2006, 30, 1685.
(16) In ref 15a, we reported that Pd(N-Succ)2(PPh3)2 is an effective
precatalyst for Suzuki-Miyaura cross-couplings of aryl halides with
arylboronic acids. The coupling of 4-nitrobromobenzene with phenylboronic
acid was tested with cis-1 as the precatalyst in this paper. For this specific
example, cis-1 was less effective than Pd(N-Succ)2(PPh3)2. Since this report,
it has emerged that couplings of this aryl halide, and related compounds,
can be complicated by electron-transfer processes, making it a poor
benchmark substrate for screening catalysts/precatalysts.
(17) For selected examples given in Schemes 1 and 2, Pd(N-Succ)2(PPh3)2
has been tested (see Supporting Information). Precatalyst 1 compares well
with Pd(N-Succ)2(PPh3)2; it is clear that both are useful precatalysts for
coupling benzylic halide components in this reaction.
(18) Commercial sources of furan-2-boronic acid and thiophene-2-boronic
acid were found to degrade at 25 °C in the presence of moisture.
(19) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49.
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Org. Lett., Vol. 9, No. 26, 2007