Synthesis of diarylmethane derivatives from Stille cross-coupling reactions of benzylic halides

Article abstract of DOI:10.1016/j.tetlet.2007.08.072

A catalyst precursor prepared in situ from palladium acetate and a phosphine ligand was used for the Stille cross-coupling reaction of benzylic bromides and chlorides with aryltributyltin analogues. The reactions were performed at 80 °C using dppf as ligand in the presence of KF, or more conveniently using PPh₃ in the absence of base, furnishing diarylmethane derivatives in high yields (86-99%). Using Pd(OAc)₂/PPh₃ as catalyst precursor competitive Stille and Suzuki cross-coupling reactions with benzyl chloride showed that in the absence of base or in the presence of KF the Stille product is the majority product, and only the Suzuki product was obtained in the presence of KOH as base.

Full text of DOI:10.1016/j.tetlet.2007.08.072

Tetrahedron Letters 48 (2007) 7472–7475
Synthesis of diarylmethane derivatives from Stille
cross-coupling reactions of benzylic halides
Tatiana Z. Nichele and Adriano L. Monteiro*
Laboratory of Molecular Catalysis, Instituto de Quı´mica, UFRGS, Av. Bento Gonc¸alves,
9500 Porto Alegre 91501-970, CP 15003, RS, Brazil
Received 21 May 2007; accepted 20 August 2007
Available online 24 August 2007
Abstract—A catalyst precursor prepared in situ from palladium acetate and a phosphine ligand was used for the Stille cross-cou-
pling reaction of benzylic bromides and chlorides with aryltributyltin analogues. The reactions were performed at 80 °C using dppf
as ligand in the presence of KF, or more conveniently using PPh3 in the absence of base, furnishing diarylmethane derivatives in high
yields (86–99%). Using Pd(OAc)2/PPh3 as catalyst precursor competitive Stille and Suzuki cross-coupling reactions with benzyl chlo-
ride showed that in the absence of base or in the presence of KF the Stille product is the majority product, and only the Suzuki
product was obtained in the presence of KOH as base.
Ó 2007 Elsevier Ltd. All rights reserved.
Transition metal-catalyzed cross-couplings have
emerged as a powerful method for the construction of
carbon–carbon bonds.1 Among transition metals, palla-
dium is the most frequently applied and has found wide-
spread use in organic and polymer synthesis.2
Diarylmethane derivatives, which are important build-
ing blocks in organic synthesis, can be obtained by a
cross-coupling reaction of benzylic halides with an aryl-
metallic coupling partner. However, compared with aryl
halides, benzylic halide couplings have been studied to a
lesser extent, and most of the reactions involve a Pd-cat-
alyzed Suzuki coupling.3–13 Alternatively, Pd-catalyzed
cross-coupling with indium organometallics14 and
Cu(I)-catalyzed cross-coupling reactions between Grig-
nard reagents and benzylic halides15 or phosphates16
have also been reported. Suzuki reactions employing a
benzyl halide have been exploited to produce a macro-
bicycle and antagonists of the human EP3 receptor17
and polybenzyls.18 A Stille coupling between a chiral
stannane and a benzyl bromide was used as the key step
for stereoselective production of a macrolactone.19
Although the toxicity of organotin compounds can pres-
ent problems on an industrial scale, the Stille coupling
reaction presents similar advantages to the Suzuki reac-
tion (accessibility of organostannanes, air and moisture
stability, tolerance toward most functional groups) and
is usually superior for the synthesis of complex mole-
cules, displaying high selectivity and a broad synthetic
scope.2,20 Few Stille couplings of benzyl halides have
been reported,21–26 and despite the very good activity
of some palladium complexes for this reaction the devel-
opment of simple protocols using common palladium
sources is always worthwhile. In this context, we have
successfully demonstrated that
a simple catalyst
precursor prepared in situ from palladium acetate and
triphenylphosphine displays high activity for the Suzuki
cross-coupling reaction of benzylic bromides and
chlorides with arylboronic acids at low catalyst loadings
and under mild conditions.7 In this paper, we wish to
report that a simple system composed of palladium
(Bu)3Sn
X
Pd(OAc)2
+
R1
R1
R2
dppf / KF or
R2
PPh3
Scheme 1.
*
Corresponding author. Tel.: +55 51 33086303; fax: +55 51 33087304; e-mail: almonte@iq.ufrgs.br
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.072

T. Z. Nichele, A. L. Monteiro / Tetrahedron Letters 48 (2007) 7472–7475
7473
acetate and triphenylphosphine or dppf is able to effect
the Stille cross-coupling reaction of benzylic bromides
and chlorides under mild conditions.
base, and dioxane as solvent (Scheme 1). Initially, the
reaction was carried out in the absence of base giving
low yield (17%: 2 mol % Pd, Pd/PPh3 = 2, 80 °C, 3 h).
Both CsF and KF improve the yield (38% yield for
CsF and 40% yield for KF) and since KF is a cheaper
source of fluoride ions we decided to follow the optimi-
zation using KF. No reaction was observed without the
In our initial study, we investigated the coupling of ben-
zyl chloride with phenyltributyltin using Pd(OAc)2 as
catalyst precursor in the presence of phosphine ligand,
Table 1. Pd-Catalyzed Stille cross-coupling reaction of benzyl bromide and chloride with aryltributyltinsa
Entry
ArX
ArSnBu3
Ligand
Base
Diarylmethane
Yieldb (%)
94
Bu3Sn
Cl
1
dppf
KF
Bu3Sn
Bu3Sn
Bu3Sn
Bu3Sn
Bu3Sn
Bu3Sn
Bu3Sn
Cl
Cl
2
3
4
5
6
7
8
9
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
KF
KF
KF
KF
KF
KF
KF
KF
90
99
98
93
89
74
96
92
Br
NC
NC
Cl
O2N
O2N
Cl
Cl
Cl
Cl
Br
NC
O2N
NC
O2N
Bu3Sn
Bu3Sn
Cl
Cl
10c
PPh3
—
99
F
F
Bu3Sn
Bu3Sn
Bu3Sn
Cl
Br
11c
12c
13c
PPh3
PPh3
PPh3
—
—
—
98
98
94
Cl
Cl
Cl
Cl
CN
CN
Cl
O2N
O2N
OCH3
OCH3
a Reaction conditions: benzylic halide (1 mmol), aryltributyltin (1.5 mmol), KF (4 mmol), Pd(OAc)2 (0.04 mmol), dppf (0.08 mmol), 1,4-dioxane
(6 mL), 80 °C, 3 h.
b Isolated yields.
c Reaction conditions: benzylic halide (1 mmol), aryltributyltin (1.5 mmol), Pd(OAc)2 (0.04 mmol), PPh3 (0.08 mmol), 1,4-dioxane (6 mL), 80 °C,
20 h.

7474
T. Z. Nichele, A. L. Monteiro / Tetrahedron Letters 48 (2007) 7472–7475
PPh3 ligand and the increment of the ratio of PPh3/Pd
over 2 equiv had a negative effect on the yield (only
12% with 8 equiv). The effects of different phosphines
were also investigated and among the phosphines evalu-
ated (PCy3, PoTol3, dppe, dppp, dppb, xantphos, binap,
dppf) dppf gave the best results. The coupling of benzyl
halides with aryltributyltin was evaluated using 4 mol %
of Pd(OAc)2, dppf as ligand and KF as base under opti-
mized reaction conditions (Table 1, entries 1–9).27
Therefore benzyl chlorides and bromides were coupled
under mild conditions furnishing the diarylmethanes in
high yields (74–99%). No significant effect was observed
by changing the position of a methyl group in the ring or
the substituent group on the aromatic ring of benzyl
chloride and arylboronic acid. After having established
a successful protocol for the coupling of benzyl halides
we decided to investigate the alternative of a free-base
protocol. Although long reaction times were necessary
(20 h instead of 3 h), we have found that PPh3 was the
best ligand under free-base conditions that gave the cou-
pling products in high yields (94–99%; Table 1, entries
10–13).
enhancement for the Stille coupling of aryl halides in
aqueous solution.34,35 However, determination of initial
rates for the Stille reaction showed that in dioxane med-
ia, KOH gave a detrimental effect and the reaction was
two times slower compared with those carried out in the
absence of base (Table 3). On the other hand, the Suzuki
reaction between benzyl chloride and phenylboronic
acid was 92 times faster in the presence of KOH (Table
3). We have recently described the synthesis of tri- and
tetrasubstituted olefins via a Suzuki coupling where
the base of choice was KOH (MeOH/THF as solvent,
room temperature and low loading of Pd).36 No reaction
was observed in the absence of base and electrospray
ionization mass spectrometry analysis indicated that
the base initially reacts with the arylboronic acid to form
trihydroxyarylborate anions,37 which was the species
involved in the transmetallation process with the palla-
dium catalyst.38 In the presence of KF both coupling
products are formed with a slight selectivity for the Stille
product since the reactional conditions were optimized
for this coupling (Table 2, entries 3 and 6). Despite some
examples of free-base Suzuki reactions,37,39–47 in
general, the Suzuki protocol needs a stoichiometric or
excess amount of base for efficient conversion. There-
fore, we were expecting to obtain only the Stille product
in the absence of base. The Stille product was the major
product although we also observed some Suzuki product
(Table 2, entries 1 and 4). We reinvestigated the cou-
pling of benzyl chloride with phenylboronic acid and
using the palladium loading as we have described for
the Suzuki reaction (0.002–1 mmol %) and no reaction
was observed in the absence of base. We have only
observed coupling product in the absence of base using
a higher loading of palladium (10–20% conversion with
4 mol % of Pd after 24 h). The observation of intramo-
lecular transmetallation from boron to rhodium without
the participation of added activators was recently
described and this process should be considered as a
possible pathway also for palladium.48
The accepted catalytic cycle for cross-coupling reac-
tions, which employs Pd(0) as the catalyst, centers
around a standard oxidative addition/transmetallation/
reductive elimination sequence. In both Stille28 and
Suzuki29,30 coupling reactions, bases are used to increase
the reactivity of organometallic species, via hypercoordi-
nate intermediates, which enhances the polarization of
the organic ligand, and facilitates transmetallation
step.31–33 We have found protocols for Stille and Suzu-
ki7 couplings of benzyl chlorides having in common
the use of Pd(OAc)2/PPh3 as catalyst precursor. There-
fore, we decided to run competitive Stille and Suzuki
cross-coupling reactions with benzyl chloride in the
absence of base and the presence of base (Table 2). Only
the Suzuki product was obtained when the reaction was
carried out in the presence of KOH (Table 2, entries 3
and 6). Hydroxide ions gave rise to an important rate
In summary, we have found that a simple catalyst pre-
cursor prepared in situ from palladium acetate and a
phosphine ligand can be used for the Suzuki cross-cou-
pling reaction of benzylic bromides and chlorides with
aryltributyltins. The reactions were performed at 80 °C
using dppf as ligand in the presence of KF or more con-
veniently using PPh3 in the absence of base furnishing
diarylmethane derivatives in high yields (74–99%). From
a synthetic point of view this protocol is a cheap and
easy alternative for the synthesis of diarylmethanes from
benzylic halides.
Table 2. Competitive Pd-catalyzed Stille and Suzuki cross-coupling
reactions with benzyl chloridea
Sn(Bu)3
B(OH)2
Pd(OAc)2
PPh3
R1
Cl
Stille coupling product
base
dioxane, 80oC
R1
1.5 equiv
R2
R2
Suzuki coupling product
1.0 equiv
1.5 equiv
Entry R1
R2
Base Stille product Suzuki product
Table 3. Relative reactivity for the Pd-catalyzed Stille and Suzuki
cross-coupling reactions with benzyl chloridea
1
2
3
4
5
6
CH3
CH3
CH3
CH3O CH3
CH3O CH3
CH3O CH3
CH3O
CH3O KF
CH3O KOH
—
79
60
0
68
52
0
21
40
100
32
Ph-M
Without base
KF
KOH
—
PhSnBu3
PhB(OH)2
1
1
2
5
0.5
92
KF
KOH
49
100
a Reactions conditions: benzyl chloride (0.25 mmol), phenylboronic
acid or phenyltributyltin (0.375 mmol), base (1 mmol), Pd(OAc)2
(0.01 mmol), PPh3 (0.02 mmol), 1,4-dioxane (6 mL), 10–50 min
(conversion < 10%).
a Reactions conditions: benzyl chloride (0.25 mmol), arylboronic acid
(0.375 mmol), aryltributyltin (0.375 mmol), base (1 mmol), Pd(OAc)2
(0.01 mmol), PPh3 (0.02 mmol), 1,4-dioxane (6 mL), overnight.

T. Z. Nichele, A. L. Monteiro / Tetrahedron Letters 48 (2007) 7472–7475
7475
25. 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.
26. Appukkuttan, P.; Husain, M.; Gupta, R. K.; Parmar, V.
S.; Van der Eycken, E. Synlett 2006, 1491.
Acknowledgments
We thank FAPERGS, PRONEX, and CNPq for partial
financial support. We also thank CAPES (T.Z.N.) for
scholarship.
27. In a typical experiment an oven-dried resealable Schlenk
flask was evacuated and back-filled with argon and
charged with Pd(OAc)2 (0.04 mmol), dppf (0.08 mmol),
and KF (4 mmol). The flask was evacuated and back-filled
with argon and then the benzyl halide (1 mmol), aryltri-
butyltin (1.5 mmol), and 1,4-dioxane (6 mL) were added.
The reaction mixture was stirred at the desired temper-
ature until complete conversion as judged by GC (3–20 h).
After purification by flash-chromatography the diaryl-
References and notes
1. Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-coupling
Reactions; VCH: Weinheim, 1998.
2. Corbet, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
3. Miyaura, N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980,
21, 2865.
1
methane product was characterized by H and 13C NMR
and GC-MS.
4. Chowdhury, S.; Georghiou, P. E. Tetrahedron Lett. 1999,
40, 7599.
5. Chahen, L.; Doucet, H.; Santelli, M. Synlett 2003, 1668.
6. Langle, S.; Abarbri, M.; Duchene, A. Tetrahedron Lett.
2003, 44, 9255.
28. Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed.
2004, 43, 4704.
29. Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004,
2419.
30. Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
31. Smith, P. J. Chemistry of Tin; Blackie: New York, 1998.
32. Miyaura, N. J. Organomet. Chem. 2002, 653, 54.
33. Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38,
49.
7. Nobre, S. M.; Monteiro, A. L. Tetrahedron Lett. 2004, 45,
8225.
8. Kuwano, R.; Yokogi, M. Chem. Commun. 2005, 5899.
9. Kuwano, R.; Yokogi, M. Org. Lett. 2005, 7, 945.
10. McLaughlin, M. Org. Lett. 2005, 7, 4875.
11. Molander, G. A.; Elia, M. D. J. Org. Chem. 2006, 71,
9198.
34. Roshchin, A. I.; Bumagin, N. A.; Beletskaya, I. P.
Tetrahedron Lett. 1995, 36, 125.
35. Rai, R.; Aubrecht, K. B.; Collum, D. B. Tetrahedron Lett.
1995, 36, 3111.
12. Bandgar, B. P.; Bettigeri, S. V.; Phopase, J. Tetrahedron
Lett. 2004, 45, 6959.
36. Nunes, C. M.; Steffens, D.; Monteiro, A. L. Synlett 2007,
103.
13. Singh, R.; Viciu, M. S.; Kramareva, N.; Navarro, O.;
Nolan, S. P. Org. Lett. 2005, 7, 1829.
37. Cammidge, A. N.; Goddard, V. H. M.; Gopee, H.;
Harrison, N. L.; Hughes, D. L.; Schubert, C. J.; Sutton, B.
M.; Watts, G. L.; Whitehead, A. J. Org. Lett. 2006, 8,
4071.
14. Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem.
Soc. 2001, 123, 4155.
15. Dohle, W.; Lindsay, D. M.; Knochel, P. Org. Lett. 2001,
3, 2871.
38. Nunes, C. M.; Monteiro, A. L. J. Braz. Chem. Soc. 2007,
18, in press.
39. Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149.
40. Yasuike, S.; Qin, W. W.; Sugawara, Y.; Kurita, J.
Tetrahedron Lett. 2007, 48, 721.
16. Kofink, C. C.; Knochel, P. Org. Lett. 2006, 8, 4121.
17. Juteau, H. N.; Gareau, Y.; Labelle, M.; Sturino, C. F.;
Sawyer, N.; Tremblay, N.; Lamontagne, S.; Carriere, M.
C.; Denis, D.; Metters, K. M. Bioorg. Med. Chem. 2001, 9,
1977.
41. Yan, J.; Zhu, M.; Zhou, Z. Eur. J. Org. Chem. 2006,
2060.
18. Klarner, C.; Greiner, A. Macromol. Rapid Commun. 1998,
19, 605.
42. Darses, S.; Jeffery, T.; Genet, J. P.; Brayer, J. L.; Demoute,
J. P. Tetrahedron Lett. 1996, 37, 3857.
43. Andrus, M. B.; Song, C. Org. Lett. 2001, 3, 3761.
44. Sengupta, S.; Bhattacharyya, S. J. Org. Chem. 1997, 62,
3405.
45. Yan, J.; Zhou, Z. S.; Zhu, M. Tetrahedron Lett. 2005, 46,
8173.
46. Tsukamoto, H.; Sato, M.; Kondo, Y. Chem. Commun.
2004, 1200.
47. Dai, M. J.; Liang, B.; Wang, C. H.; Chen, J. H.; Yang, Z.
Org. Lett. 2004, 6, 221.
48. Zhao, P. J.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem.
Soc. 2007, 129, 1876.
19. Holloway, G. A.; Hugel, H. M.; Rizzacasa, M. A. J. Org.
Chem. 2003, 68, 2200.
20. Derdau, V.; Oekonomopulos, R.; Schubert, G. J. Org.
Chem. 2003, 68, 5168.
21. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101,
4992.
22. Kamlage, S.; Sefkow, M.; Peter, M. G. J. Org. Chem.
1999, 64, 2938.
23. Crawforth, C. M.; Fairlamb, I. J. S.; Taylor, R. J. K.
Tetrahedron Lett. 2004, 45, 461.
24. Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Kapdi,
A. R.; Taylor, R. J. K.; Whitwood, A. C. Tetrahedron
2005, 61, 9736.