Suzuki-miyaura cross-coupling reactions of benzyl halides with potassium aryltrifluoroborates

Article abstract of DOI:10.1021/jo061699f

(Chemical Equation Presented) The palladium-catalyzed cross-coupling of potassium aryltrifluoroborates with benzylic halides occurs in good yield with high functional group tolerance. The increased stability of potassium aryltrifluoroborates compared to other boron coupling partners makes this an effective route to functionalized methylene-linked biaryl systems.

Full text of DOI:10.1021/jo061699f

Suzuki-Miyaura Cross-Coupling Reactions of Benzyl Halides with
Potassium Aryltrifluoroborates
Gary A. Molander* and Maxwell D. Elia
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed August 16, 2006
The palladium-catalyzed cross-coupling of potassium aryltrifluoroborates with benzylic halides occurs
in good yield with high functional group tolerance. The increased stability of potassium aryltrifluoroborates
compared to other boron coupling partners makes this an effective route to functionalized methylene-
linked biaryl systems.
Introduction
of methylene-linked biaryl compounds using aryl halide cou-
pling partners requires 2 equiv of B-benzyl-9-BBN.6 Further-
more, the synthetic utility of the coupling of 9-BBN is less than
ideal because of its poor atom economy, low functional group
tolerance, and flammability.
Previous efforts to couple benzyl halides using arylmetallics
to access methylene-linked biaryls engendered significant sto-
ichiometric inefficiencies as well; reported procedures required
either 1.57,8 or 2.09 equiv of boronic acid or 1.5 equiv of an
arylstanane.10
Suzuki-Miyaura cross-coupling has become a powerful
synthetic tool for the synthesis of carbon-carbon bonds,1 and
recent advances have expanded the scope of this coupling to
include alkyl halide cross-coupling.2 High functional group
tolerance, easily separable and nontoxic byproducts, and in-
creasing commercial availability of boron coupling partners have
made the Suzuki-Miyaura coupling both a popular and effective
tool.
Despite recent advances, coupling of traditional benzylic
organoboron compounds has, in general, been difficult.3 Meth-
ods utilizing a Suzuki-Miyaura cross coupling to access
methylene-linked biaryl systems, which are common structural
elements of both biologically active compounds4 and pharma-
ceuticals,5 possess distinct drawbacks. For example, the synthesis
Methylene-linked biaryl systems have also been accessed by
the coupling of both benzyl carbonates11 and benzyl phos-
phates12 with boronic acids; however, coupling of benzylic
electrophiles to heteroaryl boron coupling partners has not been
demonstrated in either method. Furthermore, Cu(I)-catalyzed
cross-coupling reactions between Grignard reagents and benzylic
halides13 and phosphates14 have been reported, but Grignard
reagents make the reaction incompatible with various functional
groups including ketones, aldehydes, and substrates with acidic
protons.
(1) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; VCH: Weinheim, 1998.
(2) Review: Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44,
674.
In addition to their air and moisture stability,15 the greater
nucleophilicity16 of the potassium trifluoroborates over the
corresponding organoboranes and boronic acid derivatives
makes the organotrifluoroborates valuable starting materials for
(3) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol. I, Part III.
(4) (a) McPhail, K. L.; Rivett, D. E. A.; Lack, D. E.; Davies-Coleman,
M. T. Tetrahedron 2000, 56, 9391. (b) Juteau, H.; 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.
(5) (a) Long, Y.-Q.; Jiang, X.-H.; Dayam, R.; Sachez, T.; Shoemaker,
R.; Sei, S.; Neamati, N. J. Med. Chem. 2004, 47, 2561. (b) Forsch, R. A.;
Queener, S. F.; Rosowsky, A. Bioorg. Med. Chem. Lett. 2004, 14, 1811.
(c) Rosowsky, A.; Chen, H.; Fu, H.; Queener, S. F. Bioorg. Med. Chem.
2003, 11, 59. (d) Gangjee, A.; Devraj, R.; Queener, S. F. J. Med. Chem.
1997, 40, 470. (e) Gangjee, A.; Vasudevan, A.; Queener, S. F. J. Med.
Chem. 1997, 40, 3032.
(6) Flaherty, A.; Trunkfield, A.; Barton, W. Org. Lett. 2005, 7, 4975.
(7) Chahen, L.; Doucet, H.; Santelli, M. Synlett 2003, 11, 1668.
(8) Chodhury, S.; Georghiou, P. Tetrahedron Lett. 1999, 40, 7599.
(9) Nobre, S. M.; Monteiro, A. L. Tetrahedron Lett. 2004, 45, 8225.
(10) Asselt, R.; Elsevier, C. Tetrahedron 1994, 50, 323.
(11) Kuwano, R.; Yokogi, M. Org. Lett. 2005, 7, 945.
(12) McLaughlin, M. Org. Lett. 2005, 7, 4875.
10.1021/jo061699f CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/03/2006
9198
J. Org. Chem. 2006, 71, 9198-9202

Suzuki-Miyaura Cross-Coupling Reactions of Benzyl Halides
TABLE 1. Screening Pd Catalyst Systemsa
entry
Pd source (mol %)
ligand (mol %)
solvent
conversionb,c (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (1.5)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(dppf)‚CH2Cl2 (9)
Pd(dppf)‚CH2Cl2 (3)
Pd(dppf)‚CH2Cl2 (2.5)
Pd(dppf)‚CH2Cl2 (1.5)
PPh3 (10)
PPh3 (5)
PPh3 (3)
S Phos (4)
X Phos (4)
Ru Phos (4)
none
none
none
none
toluene/H2O
toluene/H2O
toluene/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
70 (20, 3)
92 (6, 2)
73 (3, 11)
60 (0, 0)
70 (10, 10)
50 (8, 12)
90 (6, 1)
98 (3, 1)
98 (0, 2)
73 (0, 5)
10
a Reaction conditions: 0.5 mmol of 1, 0.505 mmol of 2, and 1.5 mmol of base (K3PO4 for entries 1-3; Cs2CO3 for entries 4-7) in 5 mL of solvent.
Solvent ratios are solvent/H2O (10:1). dppf ) 1,1′- bis(diphenylphosphino)ferrocene. S Phos ) [2-(dicyclohexylphosphino) dimethoxybiphenyl]. X Phos )
2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl. Ru Phos ) 2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl. b Reactions were monitored
by gas chromatography after 24 h. c The ratio of homocoupled products is given: (biphenyl, bibenzyl).
TABLE 2. Solvent Optimizationa
palladium-catalyzed cross coupling with sp3-hybridized benzylic
electrophiles. Furthermore, the use of potassium aryltrifluo-
roborates expands the range of tolerated functionalized coupling
partners while increasing atom economy.
Potassium aryltrifluoroborates for this procedure can be easily
synthesized by various methods. However, aryltrifluoroborates
are most commonly accessed by the addition of a Grignard
reagent to trimethylborate17 followed by the addition of aqueous
of KHF2.18 Addition of inexpensive, aqueous KHF2 to either
an aryl boronic acid or aryl boronate ester will also afford the
potassium organotrifluoroborate directly.
entry
solvent (10:1)
T (°C)
assay yieldb (%)
1
2
3
4
5
6
7
toluene/H2O
DMF/H2O
dioxane/H2O
CPME/H2O
THF/H2O
95
95
95
95
77
53
rt
88
0
93
97
74
0
MTBE/H2O
acetone/H2O
30
Results and Discussion
a Reaction conditions: 0.5 mmol of benzyl bromide, 0.505 mmol of
potassium phenyltrifluoroborate, and 1.5 mmol of Cs2CO3 with 2 mol %
of PdCl2(dppf)‚CH2Cl2. All reaction concentrations were 0.1 M. b GC yields
based on n-dodecane as an internal standard.
Initial efforts focused on optimizing conditions under which
benzyl bromide 1 couples to potassium phenyltrifluoroborate 2
(Table 1).
The screening indicated that there are numerous systems
through which the desired cross-coupling could occur, but
PdCl2(dppf)‚CH2Cl2 with Cs2CO3 afforded the optimum GC
conversion to diphenylmethane 3 while requiring the lowest
catalyst loading. With catalyst loading above the optimum, the
starting material was consumed, but the percentage of homo-
coupled product was found to rise quickly.
Optimization revealed the requirement for 3 equiv of base.
Experiments attempting to reduce the amount of base prevented
reactions from reaching completion. Additionally, there seems
to be a requirement for Cs2CO3. Reactions using 3 equiv of
K2CO3 resulted in 3% each of the biphenyl and bibenzyl
homocoupled product; however, when 1 equiv of Cs2CO3 was
combined with 2 equiv of K2CO3, the reaction yielded full
conversion to the desired product. Additionally, the reaction
reached completion in comparable time with only 1% biphenyl
homocoupled product when only 2 equiv of Cs2CO3 was used.
The use of KHCO3 and K3PO4 resulted in lower assay yields,
and reactions using these bases were not pursued.
Solvent optimization revealed that ethereal solvents tended
to offer the highest isolated yields with minimal homocoupling
(Table 2). Additionally, the rate of reaction was clearly
accelerated by the use of solvents when heated at or above 90
°C. Reactions in cyclopentyl methyl ether (CPME) were the
fastest and occurred with the least homocoupled product as
determined by gas chromatography. Even under optimized
conditions, homocoupling of both coupling partners was seen
in all reactions, each representing no more than 1.5% of the
product mixture. This homocoupling was observed to occur
progressively throughout the reaction.
(13) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (b)
Novak, J.; Salemink, C. A. Synthesis 1983, 597. (c) Onuma, K.; Hashimoto,
H. Bull. Chem. Soc. Jpn. 1972, 45, 2582. (d) Normant, J. F.; Villieras, J.;
Scott, F. Tetrahedron Lett. 1977, 18, 3263. (e) Friedman, L.; Shani, A. J.
Am. Chem. Soc. 1974, 96, 7101. (f) Fouquet, G.; Schlosser, M. Angew.
Chem., Int. Ed. Engl. 1974, 13, 82. (g) Derguini-Boumechal, F.; Lin-
strumelle, G. Tetrahedron Lett. 1976, 17, 3225. (h) Leder, J.; Fujioka, H.;
Kishi, Y. Tetrahedron Lett. 1983, 24, 1463. (i) Yanagisawa, A.; Nomura,
N.; Yamamoto, H. Synlett 1993, 689. (j) Dohle, W.; Lindsay, D. M.;
Knochel, P. Org. Lett. 2001, 3, 2871.
(14) Kofink, C. C.; Knochel, P. Org. Lett. 2006, 8, 4121.
(15) For reviews of organotrifluoroborate salts, see: (a) Molander, G.
A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49. (b) Darses, S.; Geneˆt, J.-P.
Eur. J. Org. Chem. 2003, 4313.
(16) (a) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A. J. Synthesis
2000, 990. (b) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999,
1, 1683. (c) Batey, R. A.; Thadani, A. N.; Smil, D. V. Tetrahedron Lett.
1999, 40, 4289. (d) Batey, R. A.; MacKay, D. B.; Santhakumar, V. J. Am.
Chem. Soc. 1999, 121, 5075.
(17) Matteson, D. S. Tetrahedron 1989, 45, 1859.
(18) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020. (b) Vedejs, E.; Fields, S. C.; Hayashi,
R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem. Soc.
1999, 121, 2460.
Several general reactivity trends were observed (Table 3).
Benzyl chloride is a viable partner when coupled to activated,
electron-rich potassium aryltrifluoroborates (entry 3); however,
J. Org. Chem, Vol. 71, No. 24, 2006 9199

Molander and Elia
TABLE 3. Coupling of Potassium Aryltrifluoroborates with
Benzyl Bromidea
TABLE 4. Coupling of Functionalized Potassium Trifluoroborates
with Benzyl Bromidea
a Reaction conditions: 0.25 mmol of benzyl bromide, 0.25 mmol of
aryltrifluoroborate, and 0.75 mmol of Cs2CO3 with 2 mol % of
PdCl2(dppf)‚CH2Cl2. All reaction concentrations were 0.1 M. b Condition
A: THF/H2O (10:1) at 77 °C. Condition B: CPME/H2O (10:1) at 90 °C.
c The yield refers to isolated material. d Reaction scale was 0.35 mmol with
the same ratio of all other reagents. e Reaction scale was 0.055 mmol with
the same ratio of all other reagents.
than THF typically results in an increase in reaction rate while
achieving approximately the same yield, this higher boiling
solvent was required for the cross-coupling of compound 9 to
occur. When THF was used to couple compound 9, the reaction
resulted in full conversion to the homocoupled bibenzyl product
and decomposition of the aryltrifluoroborate starting material.
Heterocycles examined participated effectively in the reac-
tions (Table 4, entries 1, 2, and 5). The cross-coupling of
potassium aryltrifluoroborates 13 and 14, synthesized via Wittig
reactions on the trifluoroborato benzaldehydes,20 highlights one
advantage of aryltrifluoroborate coupling partners over boronic
acids. No Wittig reactions on boronic acid aldehydes have been
reported because of the incompatibility of the acidic protons of
the boronic acids with the ylide,20 and there have been few
reports of Wittig reactions on aromatic boronate esters, which
suffer from poor atom economy.21 Functionalized potassium
aryltrifluoroborates, however, are readily synthesized using
Wittig chemistry. Additionally, potassium organo[1,2,3]triazol-
1-yltrifluoroborates22 are easily accessed via a one-pot synthesis
using haloalkyl starting materials, and the coupling of one of
these reagents, 15, occurs in high yield.
a Reaction conditions: 0.5 mmol of benzyl bromide, 0.505 mmol of aryl
trifluoroborate,and1.5mmolofCs2CO3 with2mol%ofPdCl2(dppf)‚CH2Cl2.
All reaction concentrations were 0.1 M. b Condition A: THF/H2O (10:1)
at 77 °C. Condition B: CPME/H2O (10:1) at 90 °C. c The yield refers to
isolated material. d Benzyl chloride was used.
attempts to react benzyl chloride with electron poor potassium
aryltrifluoroborates resulted in low yields of the coupled
products. Although no detailed mechanistic studies have been
performed, we speculate that the electron rich organotrifluo-
roborates facilitate the transmetalation step of the process.
Because of the more favorable oxidative addition, benzyl
bromides are coupled with better yields and higher functional
group tolerance than the benzyl chlorides, although other factors
could certainly play a role as well.
Because the SPhos ligand19 is known to increase the rate of
some cross-coupling reactions yielding diarylmethanes,12 cata-
lytic amounts of Pd(OAc)2 and SPhos were used in an attempt
to increase the yield of reactions using benzyl chloride.
Unfortunately, the Pd(OAc)2/SPhos system led to decomposition
of the chloride starting material with only moderate conversion
to the desired product 3 when using potassium phenyltrifluo-
roborate as a coupling partner.
Steric hindrance from aryltrifluoroborate 6 has no significant
effect on the coupling. Furthermore, the coupling of benzyl
bromide to potassium aryltrifluoroborates is tolerant of a broad
range of functionality. Nitro groups seem to be the exception,
as coupling of the nitro-substituted trifluoroborate results in low
yields (entry 10). Interestingly, although the use of CPME rather
Several functionalized benzyl bromides were examined as
substrates for the reaction (Table 5). The pattern of reactivity
(19) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(20) Molander, G. A.; Figueroa, R. J. Org. Chem. 2006, 71, 6135.
(21) Wittig: (a) Lautens, M.; Mancuso, J. J. Org. Chem. 2004, 69, 3478.
(b) Lautens, M.; Marquardt, T. J. Org. Chem. 2004, 69, 4607. Wittig-
Horner under Masamune conditions: (c) Kobayashi, Y.; Tokoro, Y.;
Watatani, K. Tetrahedron Lett. 1998, 39, 7537. (d) Kobayashi, Y.; Tokoro,
Y.; Watatani, K. Eur. J. Org. Chem. 2000, 3825.
9200 J. Org. Chem., Vol. 71, No. 24, 2006

Suzuki-Miyaura Cross-Coupling Reactions of Benzyl Halides
TABLE 5. Coupling of Potassium Aryltrifluoroborates with
Functionalized Benzyl Halidesa
TABLE 6. Coupling of Benzyl Carbonates with Potassium
4-Methoxyphenyl Trifluoroboratea
a Reaction conditions: 0.5 mmol of benzyl bromide, 0.505 mmol of aryl
trifluoroborate,and1.5mmolofCs2CO3 with2mol%ofPdCl2(dppf)‚CH2Cl2.
All reaction concentrations were 0.1 M. b Condition A: THF/H2O (10:1)
at 77 °C. Condition B: CPME/H2O (10:1) at 90 °C. c The yield refers to
isolated material.
a Reaction conditions: 0.25 mmol of benzyl carbonate, 0.25 mmol of
aryltrifluoroborate, and 0.75 mmol of Cs2CO3 with 2 mol % of
PdCl2(dppf)‚CH2Cl2. All reaction concentrations were 0.1 M. b The yield
refers to isolated material.
is consistent throughout the study as electron rich nucleophiles
and electron poor electrophiles generally offer the best yields.
Moreover, electron-poor aryltrifluoroborates are more prone to
homocoupling than are electron rich trifluoroborates, probably
due to the slower rate of the desired coupling, which is similarly
observed with boronic acid coupling partners.23
desired cross-coupling reaction, and styrene was isolated as the
major byproduct (eq 2).
Previous work11 synthesizing diarylmethanes via a Suzuki-
Miyaura cross-coupling of benzyl carbonates did not demon-
strate examples of heteroaryl substrates as either coupling
partner. Our attempts to use benzylic carbonate electrophiles
(Table 6) showed limited success with potassium aryl trifluo-
roborates, and additionally the method did not tolerate the
heteroaromatics tested. Carbonate starting material as well as
protodeboronated product were isolated from these failed
reactions.
While reactions were optimized with 2 mol % catalyst for
0.5 mmol reactions, catalyst loading can be successfully
decreased on a 1 g reaction scale without significantly affecting
the yield or reaction times (eq 1).
Consequently, bromodiphenylmethane was selected as a
model substrate to determine whether secondary benzylic
coupling could transpire in the absence of a mechanistic pathway
for â-elimination (eq 3). The yield for the secondary benzylic
bromide cross-coupling was approximately 30%; however, the
homocoupled product of bromodiphenylmethane and the desired
coupling product could not be separated by either column
chromatography or by recrystallization.
Early studies13 demonstrated the inability to couple secondary
benzylic halides to aryl boronic acids. Unfortunately, we also
noted that in the presence of a Pd(II) species, â-hydride
elimination of 1-bromoethylbenzene proceeded faster than the
In conclusion, the palladium-catalyzed cross-coupling of
benzyl halides with potassium aryltrifluoroborates occurs in high
(22) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2767.
(23) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087. .
J. Org. Chem, Vol. 71, No. 24, 2006 9201

Molander and Elia
1H NMR (360 MHz, CDCl3) δ 4.14 (s, 2H), 7.24-7.30 (m, 6H),
7.43 (t, J ) 7.5 Hz, 4H); 13C {1H} NMR (90 MHz, CDCl3) δ 42.2,
126.3, 128.7, 129.2, 141.3.
yield with good functional group tolerance. With low catalyst
loading and broad reaction scope, this procedure is an effective
method to access both highly functionalized natural products
and pharmaceuticals with diarylmethane substructures.
Acknowledgment. We acknowledge Frontier Scientific for
the donation of boronic acids used to make many of the
aryltrifluoroborates, Zeon for the donation of CPME, Professor
Stephen L. Buchwald (MIT) for a donation of phosphine ligands,
and Johnson Matthey for the donation of catalysts. We also
thank the NIH (GM35249), Amgen, Merck Research Labora-
tories, and the Vagelos Program in the Molecular Life Sciences
for financial support.
Experimental Section
General Procedure for the Suzuki-Miyaura Cross-Coupling
Reactions. Preparation of Diphenylmethane. A solution of
potassium phenyltrifluoroborate (98.4 mg, 0.5 mmol), Cs2CO3 (489
mg, 1.5 mmol), PdCl2(dppf)·CH2Cl2 (8 mg, 0.01 mmol), and benzyl
bromide (90 mg, 0.5 mmol) in THF/H2O (10:1) (5 mL) was heated
under a N2 atmosphere in a sealed tube. The reaction mixture was
stirred at 77 °C for 23 h and then cooled to rt and diluted with
water (2 mL) followed by extraction with CH2Cl2 (10 mL × 3).
The solvent was removed in vacuo, and the crude product was
purified by silica gel column chromatography (eluting with n-pen-
tane/ether ) 100:1) to yield diphenylmethane (70.56 mg, 84%):
Supporting Information Available: Experimental procedures
and characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO061699F
9202 J. Org. Chem., Vol. 71, No. 24, 2006