Synthesis and reactivity of solid-supported organotrifluoroborates in suzuki cross-coupling

Article abstract of DOI:10.1021/ol300215p

Solid-supported organotrifluoroborates were prepared in high yields by ion exchange with Amberlyst resins. The reactivity of solid supported aryltrifluoroborates was evaluated in Suzuki-Miyaura couplings with numerous aryl bromide partners. Electron-rich

Full text of DOI:10.1021/ol300215p

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1680–1683
Synthesis and Reactivity of Solid-
Supported Organotrifluoroborates in
Suzuki Cross-Coupling
Virginie Colombel,† Marc Presset,‡ Daniel Oehlrich,† Frederik Rombouts,*,† and
Gary A. Molander*,‡
Neuroscience Medicinal Chemistry, Research & Development, Janssen Pharmaceutica,
Turnhoutseweg 30, 2340 Beerse, Belgium, and Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania
19104-6323, United States
FROMBOUT@its.jnj.com; gmolandr@sas.upenn.edu
Received January 26, 2012
ABSTRACT
Solid-supported organotrifluoroborates were prepared in high yields by ion exchange with Amberlyst resins. The reactivity of solid supported
aryltrifluoroborates was evaluated in SuzukiꢀMiyaura couplings with numerous aryl bromide partners. Electron-rich and -poor substituents were
tolerated on both substrates, providing yields up to 90%. Examples of alkyl-, alkenyl-, alkynyl-, and heteroaryltrifluoborates were also successfully
cross-coupled to aryl halides.
In conjunction with the increased use of organoboron
compounds in the SuzukiꢀMiyaura cross-coupling, their
use in solid-phase chemistry has received attention in the
past decade for both purification and synthesis purposes.
Arylboronic acids have been captured as alkyl- or arylbo-
ronate species. Previousworkdescribed threetypesofalkyl
diol resins. One type is a macroporous polymer-supported
1,3-diol, but its application requires high temperature and
an excess of boronic acid to optimize the catch phase.1
Alternatively, a fluorinated 1,2-diol resin2 as well as a
DiEthanolAminoMethyl polystyrene (DEAM-PS) resin
can be used, providing immobilization under milder
conditions.3 In all cases, the release procedure can provide
access not only to the free and pure arylboronic acids but
also to the corresponding arenes or phenol derivatives.
Finally, boronic acids can be caught as catecholborane
derivatives using the Merrifield resin.4
An alternative method for the formation of solid-
supported pinacolboronate ester derivatives starts directly
from the free boronate esters. Wilson and co-workers
applied this strategy with the MBHA resin in a solid-
supported boronic acid synthesis.5
Solid-phase arylꢀaryl SuzukiꢀMiyaura cross-couplings
are usually performed between a boronic acid and a resin-
bound aryl halide.6 Aryl bromides7 and iodides8 are the
most utilized electrophiles, but aryl triflates can also be
used.9 However, only a few examples describe the reaction
† Janssen Pharmaceutica.
‡ University of Pennsylvania.
(1) (a) Carboni, B.; Pourbaix, C.; Carreaux, F.; Deleuze, H.;
Maillard, B. Tetrahedron Lett. 1999, 40, 7979–7983. (b) Carboni, B.;
Pourbaix, C.; Carreaux, F.; Deleuze, H. Chem. Commun. 2000, 1275–1276.
(2) Chen, D.; Qing, F.-L; Huang, Y. Org. Lett. 2002, 4, 1003–1005.
(3) (a) Hall, D. G.; Tailor, J.; Gravel, M. Angew. Chem., Int. Ed. 1999,
38, 3064–3067. (b) Gravel, M.; Thompson, K. A.; Zak, M.; Berube, C.;
Hall, D. G. J. Org. Chem. 2002, 67, 3–15. (c) Arimori, S.; Hartley, J. H.;
Bell, M. L.; Oh, C. S.; James, T. D. Tetrahedron Lett. 2000, 41, 10291–
10294.
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2002, 43, 6339–6342.
(5) MHBA Resin: 4-Methylbenzhydrylamine Hydrochloride Salt
Resin. Dunsdon, R. M.; Greening, J. R.; Jones, P. S.; Jordan, S.; Wilson,
F. X. Bioorg. Med. Chem. Lett. 2000, 10, 1577–1579.
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ꢀ
ꢀ
r
10.1021/ol300215p
Published on Web 03/09/2012
2012 American Chemical Society

Table 1. Optimization of Solid-Supported Phenyltrifluorobo-
rate Formation
Table 2. Scope of Solid-Supported Aryltrifluoroboratesa
entry
X
equivalents
time (h)
conversion (%)a
1
2
3
F
1.1
4
0.5
4
100
100
100
Cl
Br
8
24
a Conversion determined by LCMS analysis using mesitylene or
toluene as an internal standard.
between solid-phase boronate esters and aryl halides. Suzu-
kiꢀMiyaura cross-couplings have been achieved between
polystyrene-supported arylboronic acids [PS-R-B(OH)2]
and iodo- or bromoarenes in good yields,10 as well as solid-
phase boronate esters [R-B(OR)OR0-PS] and iodoaryls.2,11
Arylboronic acids have also been captured as ammo-
nium trihydroxyborate salts on ammonium hydroxide
form Dowex ion exchange resins and directly cross-
coupled under palladium-catalyzed SuzukiꢀMiyaura con-
ditions to form biaryls as well as macroheterocycles.12
Because of their increased stability, organotrifluorobo-
rates represent an attractive alternative to boronic acids in
(7) (a) Lago, M. A.; Nguyen, T. T.; Bhatnagar, P. Tetrahedron Lett.
1998, 39, 3885–3888. (b) Chamoin, S.; Houldsworth, S.; Kruse, C. G.;
Kruse, C. G.; Bakker, W. I.; Snieckus, V. Tetrahedron Lett. 1998, 39,
4179–4182. (c) Xiong, Y.; Klopp, J.; Chapman, K. T. Tetrahedron Lett.
2001, 42, 8423–8427. (d) Chhabra, S. R.; Mahajan, A.; Chan, W. C.
J. Org. Chem. 2002, 67, 4017–4029. (e) Ohnmacht, S. A.; Brenstrum, T.;
Bleicher, K. H.; McNulty, J.; Capretta, A. Tetrahedron Lett. 2004, 45,
5661–5663. (f) Zhu, J.; Pottorf, R. S.; Player, M. R. Tetrahedron Lett.
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2006, 47, 7267–7270. (g) Cousaert, N.; Willand, N.; Gesquiere, J.-C.;
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Tartar, A.; Deprez, B.; Deprez-Poulain, R. Tetrahedron Lett. 2008, 49,
2743–2747.
(8) (a) Guiles, J. W.; Johnson, S. G.; Murray, W. V. J. Org. Chem.
1996, 61, 5169–5171. (b) Ruhland, B.; Bombru, A.; Gallop, M. A. J. Org.
Chem. 1997, 62, 7820–7826. (c) Wendeborn, S.; Berteina, S.; Brill,
W. K.-D.; De Mesmaeker, A. Synlett 1998, 671–675. (d) Blettner,
a Conditions: Potassium aryltrifluoroborate (1.0 mmol), resin (1.1
mmol), solvent, 20 °C, time. b Reaction performed in MeOH. c Reaction
performed in acetone. d Reaction performed in a mixture of MeOH/
MeCN (1:1).
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C. G.; Konig, W. A.; Ruhter, G.; Stenzel, W.; Schotten, T. Synlett
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Lett. 2002, 4, 3071–3073. Lepore, S. D.; Wiley, M. R. Org. Lett. 2003, 5,
7–10. (g) Sunami, S.; Ohkudo, M. Tetrahedron 2009, 65, 638–643.
(9) Lutz, C.; Bleicher, K. H. Tetrahedron Lett. 2002, 43, 2211–2214.
(10) (a) Piettre, S. R.; Baltzer, S. Tetrahedron Lett. 1997, 38, 1197–
1200. (b) Main, C. A.; Petersson, H. M.; Rahman, S. S.; Hartley, R. C.
Tetrahedron 2008, 64, 901–914.
these contexts.13 Over the past 10 years, potassium aryltri-
fluoroborateshave been shown tobeveryefficient partners
in SuzukiꢀMiyaura cross-couplings14 with various aryl
halides.15
In addition to the more common potassium salts, ammo-
nium16 organotrifluoroborates can also be synthesized.17
Batey et al. initially investigated the cross-coupling between
n-tetrabutylammonium phenyltrifluoroborate and iodo- or
bromoarenes.17 Recently, our group has also reported
cross-coupling reactions using n-tetrabutylammonium18 or
(11) (a) Li, W.; Burgess, K. Tetrahedron Lett. 1999, 40, 6527–6530.
(b) Pourbaix, C.; Carreaux, F.; Carboni, B. Org. Lett. 2001, 3, 803–805.
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Commun. 2001, 817–818.
(13) (a) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63,
3623–3658. (b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–
^
286. (c) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288–325.
(14) (a) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-
Jones, G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49, 5156–5160.
(b) Amatore, C.; Jutand, A.; Le Duc, G. Chem.;Eur. J. 2011, 17, 2492–
2503.
(16) (a) Molander, G. A.; Figueroa, R. J. Org. Chem. 2006, 71, 6135–
6140. (b) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2007, 72, 3558–
3560. (c) Prakash, G. K. S.; Pertusati, F.; Olah, G. A. Synthesis 2011,
292–302.
(15) (a) Molander, G. A.; Biolatto, B. Org. Lett. 2002, 4, 1867–1870.
(b) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302–4314. (c)
Kabalka, G. W.; Al-Masum, M. Tetrahedron Lett. 2005, 46, 6329–6331.
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Org. Lett., Vol. 14, No. 7, 2012
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Table 3. Release of Potassium Organotrifluoroboratesa
Table 4. Cross-Coupling of Solid-Supported Aryltrifluoroboratesa
a Solid-supported organotrifluoroborate (1.0 mmol), (1) aq 4.5 M
KOH (5.0 mmol), MeOH, 20 °C, 24 h; (2) sat. aq KHF2 (10.0 mmol),
MeOH, rt, 1 h.
cesium19 aryltrifluoroborates. In both cases, good yields
were obtained, showing no difference in comparison with
potassium salt analogs.
Herein, we report an efficient way to prepare solid-
supported organotrifluoroborates using an ion exchange
process with a quaternary ammonium salt functionalized
resin. Additionally, we describe the release of pure potas-
sium organotrifluoroborate salts and the first Suzukiꢀ
Miyaura cross-coupling involving solid-supported organo-
trifluoroborates.
We began our investigations with the study of the catch
phase. Because of the high stability of n-tetrabutylammo-
nium organotrifluoroborates, we turned our attention to
PS-trimethylammonium Amberlyst resins (Table 1).
In all cases, a complete immobilization of phenyltri-
fluoroborate on the solid support could be achieved. The
most efficient resin proved to be the one with a fluoride
counterion, as only 1.1 equiv of resin were needed for
complete conversion after 30 min.
A wide range of potassium aryltrifluoroborates were
immobilized in very good yields using fluoride on
Amberlyst A-26 resin (Table 2). Indeed, both electron-
rich (entries 2, 3, 6, 9ꢀ11) and electron-deficient (entries
4, 5, 7, 8, 12) solid-phase aryltrifluoroborates 1aꢀl were
obtained in less than 2 h. Methanol, acetone, or a
mixture of MeOH/CH3CN is alternatively used as a
solvent, depending on the solubility of each potassium
aryltrifluoroborate.
a 4-Bromobenzotrifluoride (1.0 mmol), aryltrifluoroborate on resin
(1.5 mmol), Pd(OAc)2 (0.025 mmol), SPhos (0.05 mmol), MeOH (0.25
M), 60 °C, time.
However, the isolation of the desired products was more
problematic than expected. We discovered that an addi-
tional acidic treatment was necessary following the basic
release, but the overall yield strongly depended on the
nature of the organotrifluoroborate (Table 3).
The second part of the study was focused on the cross-
coupling of numerous solid-supported aryltrifluorobo-
rates with 4-bromobenzotrifluoride. After optimizing the
conditions for the cross-coupling, yields between 31 and
90% were obtained (Table 4). Various electron-donating
groups are tolerated in the para, meta or ortho positions,
affording the corresponding desired biaryls in good to very
good yields (entries 2, 3, 5, 6, 8, and 9). The reaction is also
compatible with sterically hindered substrates, as evi-
denced by the successful cross-coupling of 2,6-dimethylphe-
nyltrifluoroborate (entry 8). Electron-deficient substituents
We then focused on the release phase to develop a
purification method for organotrifluoroborates. In this
case, the chloride form of the resin was chosen to make
this operation more cost-effective.20 Different potassium
salts were surveyed to release the potassium organotri-
fluoroborate. The use of excess aqueous KOH in methanol
1
allowed a quantitative release measured by H NMR.
(18) Molander, G. A.; Petrillo, D. E. J. Am. Chem. Soc. 2006, 128,
9634–9635.
ꢀ
(19) Molander, G. A.; Fleury-Bregot, N.; Hiebel, M.-A. Org. Lett.
2011, 13, 1694–1697.
(20) In Sigma-Aldrich catalog: Amberlyst A-26 (fluoride), CAS #
39339-85-0, $445 for 50 g; Amberlite IRA-900 (chloride), CAS # 9050-
97-9, $60.80 for 500 g.
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Org. Lett., Vol. 14, No. 7, 2012

Table 5. Scope of Aryl Bromide Cross-Couplinga
Table 6. Cross-Coupling of Solid-Supported Alkyl-, Alkenyl-,
Alkynyl-, and Heteroaryltrifluoroboratesa
a All the reactions were performed on a 1.0 mmol scale of aryl halide.
b Pd(OAc)2 3 mol %, XPhos 6 mol %, K2CO3 3 equiv, THF/H2O (10:1),
100 °C. c Pd(OAc)2 1 mol %, RuPhos 2 mol %, Na2CO3 2 equiv, THF/
H2O (10:1), 100 °C. d PdCl2(dppf)•CH2Cl2, Cs2CO3, THF/H2O (20:1),
110 °C. e Pd(OAc)2 1 mol %, RuPhos 2 mol %, Na2CO3 2 equiv, EtOH,
85 °C.
fluoroborates, solid-supported cyclopropyl-, vinyl-, phenyl-
ethynyl-, and 5-methyl-2-thienyltrifluoroborate, respec-
tively, were selected. They all reacted according to the
literature reported conditions,21 giving unoptimized yields
of around 55%.
a Aryl bromide (1.0 mmol), solid-supported 2H-1,3-benzodioxol-5-
yltrifluoroborate (1.5 mmol), Pd(OAc)2 (0.025 mmol), SPhos (0.05
mmol), MeOH (0.25 M), 60 °C, time.
In summary, we have developed a general procedure for
the synthesis of solid-supported organotrifluoroborates.
These compounds can be released from the solid support,
providing a purification method for potassium organotri-
fluoroborates, or engaged in further reactions. We report
the first solid-phase Suzuki cross-coupling involving im-
mobilized aryltrifluoroborates. Numerous biaryls carrying
both electron-donating and -withdrawing substituents
were synthesized in yields up to 90%. The substrate scope
was successfully extended to solid-supported alkyl-, alkenyl-,
alkynyl-, and thienyltrifluoroborates.
were also tolerated (entries 4, 7) even though a lower yield of
31% was obtained for the biaryl 2g (entry 7).
The optimized conditions also proved to be efficient for
a wide range of substituted aryl bromides (Table 5). The
Suzuki cross-coupling was performed using solid-supported
2H-1,3-benzodioxol-5-yltrifluoroborate, resulting in
yields between 10 and 78%. Aryl bromides presenting
electron-rich (entries 1, 2, 5, and 7) and electron-with-
drawing groups (entries 3, 4, and 6) were alternatively
tested. Aswasthecaseinthesynthesisof2g (Table 4, entry 7),
a poor yield was obtained in the presence of a nitro sub-
stituent (entry 3), even though the analysis of the crude
mixture showed complete conversion.
Acknowledgment. We acknowledge the National Insti-
tutes of Health (R01 GM035249) and the Neuroscience
Medicinal Chemistry Department of Janssen Pharmaceu-
tica for their generous support of this work. Additionally,
ꢀ
we thank Dr. Andres Trabanco (Janssen Pharmaceutica)
for his helpful advice and suggestions.
The scope of solid-supported organotrifluoroborates
was then explored with nonaromatic substrates (Table 6).
To represent alkyl-, alkenyl-, alkynyl-, and heteroaryltri-
(21) ForSuzukicouplingswithpotassiumcyclopropyl-,vinyl-, alkynyl-,
and thienyltrifluoroborate, respectively, see: (a) Molander, G. A.;
Gormisky, P. E. J. Org. Chem. 2008, 73, 7481–7485. (b) Molander,
G. A.; Brown, A. R. J. Org. Chem. 2006, 71, 9681–9686. (c) Molander,
G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67, 8416–8423.
(d) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009,
74, 973–980.
Supporting Information Available. Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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