Suzuki-miyaura cross-coupling reactions of primary alkyltrifluoroborates with aryl chlorides

Article abstract of DOI:10.1021/jo900152n

(Chemical Equation Presented) Parallel microscale experimentation was used to develop general conditions for the Suzuki-Miyaura cross-coupling of diversely functionalized primary alkyltrifluoroborates with a variety of aryl chlorides. These conditions wer

Full text of DOI:10.1021/jo900152n

Suzuki-Miyaura Cross-Coupling Reactions of Primary
Alkyltrifluoroborates with Aryl Chlorides
Spencer D. Dreher,*,† Siang-Ee Lim,‡ Deidre L. Sandrock,‡ and Gary A. Molander*,‡
Department of Process Research and the Catalytic Reactions DiscoVery and DeVelopment Laboratory,
Merck and Co., Inc., Rahway, New Jersey, and Department of Chemistry, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
spencer_dreher@merck.com; gmolandr@sas.upenn.edu
ReceiVed January 23, 2009
Parallel microscale experimentation was used to develop general conditions for the Suzuki-Miyaura
cross-coupling of diversely functionalized primary alkyltrifluoroborates with a variety of aryl chlorides.
These conditions were found to be amenable to coupling with aryl bromides, iodides, and triflates as
well. The conditions that were previously identified through similar techniques to promote the cross-
coupling of secondary alkyltrifluoroborates with aryl chlorides were not optimal for the primary
alkyltrifluoroborates, thus demonstrating the value of parallel experimentation to develop novel, substrate
specific results.
Introduction
Suzuki-Miyaura reaction often make organoboron reagents the
preferred nucleophilic partners.
The Suzuki-Miyaura cross-coupling reaction has emerged
as one of the most powerful platforms for carbon-carbon bond
formation because of its mild reaction conditions and its
compatibility with a broad range of functional groups.1 The
organoboron compounds employed in this reaction offer a
variety of advantages, including ready accessibility, ease of
incorporation of nontransferable boron ligands, and the relative
nontoxicity of the byproducts generated upon cross-coupling.
Trialkylboranes have been most often employed in the
Suzuki-Miyaura reaction because they are easily accessed via
hydroboration of alkenes with 9-BBN.4 Although many effective
protocols have been established and optimized for this cross-
(2) (a) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem.
Soc. 2002, 124, 14983. (b) Chappell, M. D.; Harris, C. R.; Kuduk, S. D.; Balog,
A.; Wu, Z.; Zhang, F.; Lee, C. B.; Stachel, S. J.; Danishefsky, S. J.; Chou, T.-
C.; Guan, Y. J. Org. Chem. 2002, 67, 7730. (c) Altmann, K.-H.; Bold, G.;
Caravatti, G.; Denni, D.; Florsheimer, A.; Schmidt, A.; Rihs, G.; Wartmann, M.
HelV. Chim. Acta 2002, 85, 4086. (d) Gagnon, A.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2002, 41, 1581. (e) Trost, B. M.; Lee, C. J. Am. Chem. Soc.
2001, 123, 12191. (f) Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K. Org.
Lett. 2002, 4, 2771. (g) Mohr, P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003,
125, 1712. (h) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442.
Strategies utilizing the B-alkyl Suzuki-Miyaura cross-
coupling reaction have emerged in syntheses of various natural
products and biologically significant analogues.2 Although other
alkylmetal cross-coupling reactions have been successfully
employed in this context,3 the advantages associated with the
(3) (a) Tamao, K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3. (b) Terao, J.; Watanabe,
H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222. (c)
Kobayashi, M.; Negishi, E.-i J. Org. Chem. 1980, 45, 5223. (d) Negishi, E.-i.;
Owczarczyk, Z Tetrahedron Lett. 1991, 32, 6683. (e) Negishi, E.-i; Ay, M.;
Gulevich, Y. V.; Noda, Y Tetrahedron Lett. 1993, 34, 1437. (f) Giovannini, R.;
Stu¨demann, T.; Dussin, G.; Knochel, P. Angew. Chem., Int. Ed. 1998, 37, 2387.
(g) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79. (h) Moore, W. R.;
Schatzman, G. L.; Jarvi, E. T.; Gross, R. S.; McCarthy, J. R. J. Am. Chem. Soc.
1992, 114, 360.
† Merck and Co., Inc.
‡ University of Pennsylvania.
(1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001,
40, 4544. (c) Suzuki, A.; Brown, H. C. Organic Syntheses Via Boranes; Aldrich
Chemical Co., Inc.: Milwaukee, 2002; Vol. 3. (d) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633. (e) Bellina, F.; Carpita, A.; Rossi, R. Synthesis
2004, 2419.
3626 J. Org. Chem. 2009, 74, 3626–3631
10.1021/jo900152n CCC: $40.75 2009 American Chemical Society
Published on Web 03/09/2009

Suzuki-Miyaura Cross-Coupling Reactions
coupling, the scope of the reactions is limited by the incompat-
ibility of dialkylborane hydroborating agents with a variety of
functional groups. The air sensitivity of the trialkylboranes
requires them to be prepared and used in situ, making optimiza-
tion on small-scale onerous and thus limiting their use in
synthetic sequences.
Alkylboronic acids and alkylboronate esters can also be easily
prepared and employed as coupling partners in this reaction.
However, the cross-coupling of alkylboronic acids is compli-
cated by competitive protodeboronation, and as a result sig-
nificant excesses of the boronic acids are employed to ensure
complete consumption of the electrophiles.5 The corresponding
esters can be employed as the boron reagents, but the use of
these compounds leads to low yields unless highly toxic thallium
bases (TlOH or Tl2CO3) are employed.6 A single example
demonstrates the cross-coupling of alkylboronate esters in good
yields without the use of these toxic bases, but treatment in
situ with sec-butyllithium was required to generate the active
lithium n-alkylborate reagents.7
The first 25 years of research devoted to the Suzuki-Miyaura
cross-coupling reaction focused largely on optimization of the
metal/ligand catalyst systems using the standard set of orga-
noboron reagents outlined above.5c,8 Expensive additives were
also employed to facilitate product formation.9 Although
important contributions have been made through these efforts,
little consideration had been given to improving the organoboron
coupling partner of the reaction, which might also lead to
enhancements in the overall process.
Throughout the past decade, organotrifluoroborates have
emerged as alternative nucleophilic partners in Suzuki-Miyaura
cross-coupling.10 Fortified by their strong boron-fluorine bonds
and tetracoordinate nature, organotrifluoroborates act as pro-
tected forms of boronic acids that are readily unmasked under
conditions required for cross-coupling. The ease with which
alkyltrifluoroborate compounds can be prepared [e.g., via
hydroboration of the corresponding alkenes,11 transmetalation
from other organometallics,12 or metalation reactions13 followed
by treatment with inexpensive potassium hydrogen fluoride
(KHF2)], partnered with their air and moisture stability, reinforce
their value as appealing alkylboron reagents for this reaction.
In previous contributions, the cross-coupling of substituted
potassium alkyltrifluoroborates with aryl bromides and triflates
has been described.14 The cross-coupling of several specialized
alkyltrifluoroborates (e.g., aminomethyltrifluoroborates,15 alkoxy-
methyltrifluoroborates,16 cyclopropyltrifluoroborates,17 and ꢀ-
boratohomoenolates18) with aryl chlorides has also been com-
municated. Although these previous contributions represent
important developments, a general protocol for the cross-
coupling of primary alkyltrifluoroborates with aryl chlorides has
yet to be revealed.
Even outside of the alkyltrifluoroborate arena, although
numerous publications have appeared outlining the cross-
coupling of alkylboron species with aryl chlorides, in all of
these examples only straight-chain alkylboronic acids void
of embedded functional groups were used. In none of these
contributions has there been significant development toward
a universal cross-coupling protocol for both aryl and het-
eroaryl chlorides.5d,e,19
In a recent communication, we disclosed conditions for the
cross-coupling of secondary alkyltrifluoroborates with aryl
chlorides.20 In that case, the choice of catalyst ligand was
dictated by the difficult transmetalation and the interference of
ꢀ-hydride elimination that are problematic steps with use of
secondary organoborons. These mechanistic issues are mini-
mized for primary alkyltrifluoroborates, and indeed, using
parallel miscroscale experimentation, we discovered alternate
conditions that are more suitable for primary alkyl trifluorobo-
rates than the conditions used for the secondary reagents.
Results and Discussion
To find optimal cross-coupling conditions for primary alkyl-
trifluoroborates with both aryl and heteroaryl chlorides, we
employed parallel microscale experimentation. We have previ-
ously shown in several studies that a toluene/H2O solvent
combination was superior to a THF/H2O or a CPME (cyclo-
pentyl methyl ether)/H2O system for the cross-coupling of
potassium alkyltrifluoroborates.20 As a result, toluene/H2O was
employed as a starting point for exploration of the primary
alkyltrifluoroborate system. 2-Chloroanisole 2 (electron-rich and
sterically hindered) and 3-chloropyridine 3 were chosen as
challenging aryl and heteroaryl electrophilic models, respec-
tively, while potassium phenethyltrifluoroborate 1 was selected
as the nucleophilic partner (Scheme 1).
(4) (a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 6369. (b) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.;
Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (c) Old, D. W.; Wolfe,
J. P.; Buchwald, S. L.; High, A. J. Am. Chem. Soc. 1998, 120, 9722. (d) Wolfe,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550.
(5) (a) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553. (b) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2004, 43, 1871. (c) Botella, L; Najera, C. Angew.
Chem., Int. Ed 2002, 41, 179. (d) Kondolff, I.; Doucet, H.; Santelli, M.
Tetrahedron 2004, 60, 3813. (e) Kwong, F. Y.; Lam, W. H.; Yeung, C. H.;
Chan, K. S.; Chan, A. S. C. Chem. Commun. 2004, 1922.
(6) Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405.
(7) Zou, G.; Falck, J. R. Tetrahedron Lett. 2001, 42, 5817.
The parallel experimentation used in this study was ac-
complished using a 96-well-plate reactor with 1 mL reaction
vials [10 µmol of substrate per reaction, 100 µL of solvent, 10
mol % of Pd(OAc)2, and 20 mol % of ligand]. For each
(8) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 37, 3387. (b)
Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64,
3804. (c) Littke, A. F.; Chaoyang, D.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020. (d) Netherton, M. R.; Dai, D.; Neuschu¨tze, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 10099. (e) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001,
1540. (f) Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
1945. (g) Gsto¨ttmayr, C. W. K.; Bo¨hm, V. P. W.; Herdtweck, E.; Grosche, M.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1363. (h) Kirchhoff, J. H.;
Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662.
(9) Zou, G.; Reddy, K.; Falck, J. R. Tetrahedron Lett. 2001, 42, 7213.
(10) (a) Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49. (b)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (c) Stefani, H. A.;
Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623. (d) Darses, S.; Genet, J. P.
Chem. ReV. 2008, 108, 288.
(13) Hartwig, J. F.; Lawrence, J. D.; Takahashi, M.; Bae, C. J. Am. Chem.
Soc. 2004, 126, 15334.
(14) (a) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393. (b) Molander, G. A.;
Yun, C.-S.; Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534.
(15) Molander, G. A; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem. 2008,
73, 2052.
(16) Molander, G. A.; Canturk, B. Org. Lett. 2008, 10, 2135.
(17) Molander, G. A.; Gormisky, P. E. J. Org. Chem. 2008, 73, 7481.
(18) Molander, G. A.; Petrillo, D. E. Org. Lett. 2008, 10, 1795.
(19) (a) So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2007, 9, 2795. (b)
Na´jera, C.; Gil-Molto´, J.; Karlstro¨m, S. AdV. Synth. Catal. 2004, 346, 1798. (c)
Kwong, F. Y.; Chan, K. S.; Yeung, C. H.; Chan, A. S. C. Chem. Commun.
2004, 2336.
(11) (a) Snieckus, V.; Kalinin, A. V.; Scherer, S. Angew. Chem., Int. Ed.
2003, 42, 3399. (b) Vedejs, E.; Clay, J. M. J. Am. Chem. Soc. 2005, 127, 5766.
(c) Miyaura, N.; Ohmura, T.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 4990.
(d) Miyaura, N.; Yamamoto, Y.; Fujikawa, R.; Umemoto, T. Tetrahedron 2004,
60, 10695.
(20) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257.
(12) Matteson, D. S. Tetrahedron 1989, 45, 1859.
J. Org. Chem. Vol. 74, No. 10, 2009 3627

Dreher et al.
SCHEME 1
substrate, 72 structurally diverse ligands were screened, and
K2CO321 was employed as the base. The product from each of
the reactions was then analyzed against an internal standard of
4-isopropylbiphenyl using HPLC analysis. Four ligands (SPhos,
RuPhos, n-BuPAd2, and DTBPF, Figure 1) emerged as leads
for the optimization of this reaction.
FIGURE 1. Lead ligands from parallel microscale experimentation
study.
To investigate these hits further, an additional set of parallel,
microscale experiments was performed, screening both elec-
trophilic species with our model trifluoroborate at lower amounts
of catalyst and ligand used [1 and 2 mol % of Pd(OAc)2]. The
reactions were analyzed by HPLC, comparing the ratio of the
product generated to the amount of internal standard (4-
isopropylbiphenyl) observed (Figure 2). In a direct comparison
of catalyst/ligand loadings, an increased loading of 2 mol % of
Pd(OAc)2 and 4 mol % of the ligand provided the highest
product ratios. In all cases, SPhos and RuPhos generated the
highest ratios of product. However, RuPhos consistently gave
slightly better results. Interestingly, the use of Pd(OAc)2 and
n-BuPAd2 as a catalyst system, which proved to be optimally
effective for the cross-coupling of secondary alkyltrifluorobo-
rates, did not emerge as the most successful system for the
primary alkyltrifluoroborates, reinforcing the idea that unique
reaction conditions are required for each family of reaction
partners.
FIGURE 2. Optimization of conditions for Suzuki-Miyaura cross-
coupling of potassium alkyltrifluoroborates with aryl and heteroaryl
chlorides.
With these conditions in hand, the generality of the method
was explored with respect to the aryl chloride. To do this,
potassium 4-(benzoyloxy)butyltrifluoroborate (6) was employed,
which was prepared via hydroboration of the corresponding
alkene22 followed by addition of aqueous potassium hydrogen
fluoride (KHF2) (eq 1).
The reaction was not dependent on the electronics of the
electrophilic partner (Table 2), as alkyltrifluoroborate 6 cross-
coupled in good to excellent yields with electron-neutral
(entry 1) and electron-poor (entries 2-8) aryl chlorides. This
reaction was found to tolerate a variety of functional groups
including ketones, aldehydes, nitriles, and esters. Most
notably, the nitro group, which has a propensity to undergo
reduction during cross-coupling with alkylborane reagents,23
survives the current reaction conditions completely intact
(entry 3). Potassium 4-(benzoyloxy)butyltrifluoroborate also
reacted in excellent yield with a trifluoromethyl-substituted
derivative (entry 4).
The coupling conditions were then applied to a variety of
heteroaryl chloride substrates (Table 3). The model heteroaryl
electrophile, chloropyridine 3, reacted with potassium 4-(ben-
zoyloxy)butyltrifluoroborate in excellent yield, cleanly generat-
ing the cross-coupled product (entry 1). These conditions were
amenable to methoxy-, fluoro-, and aldehyde-substituted 3-chlo-
ropyridines as well (entries 2-4). A quinoline derivative also
cross-coupled in excellent yield (entry 5). In addition to these
nitrogen-based heteroaryl systems, a variety of thiophene and
furan derivatives were found to react under the optimized
conditions to generate the cross-coupled products in good yields
(entries 6-10).
We found that chloroanisole 2 could be cross-coupled with
potassium 4-(benzoyloxy)butyltrifluoroborate in 87% yield
(Table 1, entry 1). Other electron-rich electrophiles were found
to undergo reaction with alkyltrifluoroborate 6, generating the
cross-coupled products in good to excellent yields. Steric
hindrance did not affect the reaction, as 1-chloro-2,6-dimeth-
ylbenzene cross-coupled in excellent yield (Table 1, entry 5).
Additionally, an electron-rich, sterically hindered derivative also
cross-coupled very well under the optimized reaction conditions
(Table 1, entry 6) providing the product in 92% yield. The
reaction conditions also proved to be scalable, providing the
cross-coupled product in comparable yield when run on 5 mmol
scale (entry 2).
(21) The system was optimized with K2CO3 because it is inexpensive.
However, Cs2CO3 can also be used and is indeed preferred if yields are not
optimal with K2CO3.
(22) Brown, H. C.; Bhat, N. G.; Somayaji, V. Organometallics 1983, 2, 1311.
(23) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221.
3628 J. Org. Chem. Vol. 74, No. 10, 2009

Suzuki-Miyaura Cross-Coupling Reactions
TABLE 1. Suzuki-Miyaura Cross-Coupling of Potassium
4-(Benzoyloxy)butyltrifluoroborate with Various Electron-Rich Aryl
Chloridesa
TABLE 2. Suzuki-Miyaura Cross-Coupling of Potassium
4-(Benzoyloxy)butyltrifluoroborate with Various Electron-Poor and
Electron-Neutral Aryl Chloridesa
a General conditions: Pd(OAc)2 (2 mol %), RuPhos (4 mol %),
RBF3K (1.0 equiv), electrophile (1.0 equiv), K2CO3 (3.0 equiv), and
10:1 toluene/H2O (0.25 M), 24 h, 80 °C, 0.5 mmol scale. b Reaction
scaled to 5 mmol.
a General conditions: Pd(OAc)2 (2 mol %), RuPhos (4 mol %),
RBF3K (1.0 equiv), electrophile (1.0 equiv), K2CO3 (3.0 equiv), and
10:1 toluene/H2O (0.25 M), 24 h, 80 °C, 0.5 mmol scale.
The optimized reaction conditions were amenable to a variety
of alkyltrifluoroborates (Table 4). Straight-chain alkyltrifluo-
roborates (entries 1 and 2), a trimethylsilyl derivative (entry
3), and substrates with distal ketone, nitrile, and trimethylacety-
loxy moieties (entries 4, 6, and 8, respectively) all provided
their corresponding cross-coupled products when reacted with
4-chloroanisole. Of note is the tolerance of a silyl ether
derivative throughout the overall process (entry 9). Thus,
siloxyalkyltrifluoroborate substrate 7 was prepared via iridium-
catalyzed hydroboration of the corresponding alkene with
pinacolborane, followed by subsequent treatment with saturated
aqueous KHF2 (eq 2). The silyl group not only survives this
synthetic process (with exposure to a fluoride source) but also
the cross-coupling with a fluoride embedded within the trifluo-
roborate.
Sterically hindered trifluoroborate substrates (Table 4, entries
3 and 10) also generated the desired products in good yields.
However, each of these examples required a slightly longer time
to go to completion. Unfortunately, when alkyltrifluoroborates
containing alkyl iodides and thioethers were employed, no cross-
coupled products were observed (entries 11 and 12).
We also evaluated these conditions for the methylation of
aryl chlorides using potassium methyltrifluoroborate. Owing to
the low molecular weight and volatility of the corresponding
cross-coupled product with use of 4-chloroanisole, 1-(4-chlo-
rophenyl)-1H-pyrrole was employed as the electrophilic species
in this case. Under the standard conditions, desired product 9
was obtained in 72% yield (eq 4).
Potassium isobutyltrifluoroborate 8 was also prepared by the
addition of isobutylmagnesium bromide to trimethyl borate,
followed by the addition of KHF2 (eq 3).
J. Org. Chem. Vol. 74, No. 10, 2009 3629

Dreher et al.
TABLE 3. Suzuki-Miyaura Cross-Coupling of Potassium
4-(Benzoyloxy)butyltrifluoroborate with Various Heteroaryl
Chloridesa
TABLE 4. Cross-Coupling of Various Primary Alkyl
Trifluoroborates with 4-Chloroanisolea
a General conditions: Pd(OAc)2 (2 mol %), RuPhos (4 mol %),
RBF3K (1.0 equiv), electrophile (1.0 equiv), K2CO3 (3.0 equiv), and
10:1 toluene/H2O (0.25 M), 24 h, 80 °C, 0.5 mmol scale.
Finally, we investigated the compatibility of the optimized
cross-coupling conditions with a variety of electrophilic species
(Table 5). The aryl bromide and triflate both cross-coupled under
the reaction conditions (86% and 75%, respectively) albeit in
lower yield than that of the corresponding chloride. The aryl
iodide was transformed in 80% yield; however, the reaction
required Cs2CO3 as the base to go to completion.
a General conditions: Pd(OAc)2 (2 mol %), RuPhos (4 mol %),
RBF3K (1.0 equiv), electrophile (1.0 equiv), K2CO3 (3.0 equiv), and
10:1 toluene/H2O (0.25 M), 24 h, 80 °C, 0.5 mmol scale. b Reaction
required 36 h to go to completion.
of cross-coupling primary alkyltrifluoroborates with aryl iodides,
bromides, and triflates. Importantly, the ligand choice was found
to be different than that used for secondary alkyltrifluoroborates,
demonstrating the utility of parallel microscale experimentation
to find substrate specific cross-coupling conditions rapidly.
Conclusion
Using parallel microscale experimentation for reaction opti-
mization, reaction conditions were identified to accommodate
the cross-coupling of both aryl and heteroaryl chlorides with
primary alkyltrifluoroborates. These results represent an impor-
tant extension to methods described in the literature for aryl
bromides and triflates because less expensive aryl chlorides can
now be employed in this cross-coupling reaction. These condi-
tions have also proved to be compatible with a variety of
electrophilic partners, providing a metal/catalyst system capable
Experimental Section
Procedures for Preparation of Primary Potassium Alkyl-
trifluoroborates. Potassium 4-(Benzoyloxy)butyltrifluoro-
borate 6. A reaction flask was fitted with a reflux condenser, and
to it was added but-3-enyl benzoate (7.0 g, 40 mmol) in CH2Cl2
(20 mL).22 HBBr2-SMe2 (40 mL, 1 M in CH2Cl2, 40 mmol) was
3630 J. Org. Chem. Vol. 74, No. 10, 2009

Suzuki-Miyaura Cross-Coupling Reactions
TABLE 5. Electrophile Compatibility in the Cross-Coupling of
Potassium 4-(Benzoyloxy)butyltrifluoroborate
General Experimental Procedure for Suzuki-Miyaura
Cross-Coupling Reaction of Aryl and Heteroaryl Electro-
philes with Potassium 4-(Benzoyloxy)butyltrifluoroborate.
Preparation
of
4-(2-Methoxyphenyl)butyl
Benzoate.
4-(2-Methoxyphenyl)butyl Benzoate. A Biotage microwave vial
was charged with Pd(OAc)2 (2.3 mg, 0.01 mmol), RuPhos (9.3 mg,
0.02 mmol), 2-chloroanisole (71.3 mg, 0.50 mmol), potassium
4-(benzoyloxy)butyltrifluoroborate (142 mg, 0.50 mmol), and
K2CO3 (207 mg, 1.5 mmol). The test tube was sealed with a cap
lined with a disposable Teflon septum, evacuated, and purged with
N2 (×3). To the vial were added toluene (2.5 mL) and H2O (0.25
mL), and then the reaction was heated to 80 °C for 24 h. The
reaction mixture was allowed to cool to rt, and GC/MS analysis
showed complete conversion of the aryl chloride. The organic layer
was separated, and the aqueous layer was washed with EtOAc (3
× 1 mL). The resulting light yellow solution was concentrated and
purified by silica gel column chromatography (elution with hexane/
EtOAc 99:1) to yield the product as a clear, colorless oil in 87%
yield (124 mg, 0.44 mmol). 1H NMR (500 MHz, CDCl3):
7.98-7.99 (d, J ) 7.6 Hz, 2H), 7.48-7.50 (t, J ) 7.6 Hz, 1H),
7.36-7.39 (t, J ) 7.8 Hz, 2H), 7.08-7.12 (m, 2H), 6.78-6.83 (m,
2H), 4.28-4.31 (t, J ) 6.4 Hz, 2H), 3.75 (s, 3H), 2.62-2.65 (t, J
) 7.4 Hz, 2H), 1.68-1.78 (m, 4H). 13C NMR (125.8 MHz, CDCl3):
166.7, 132.7, 130.6, 130.5, 129.8, 129.5, 128.3, 127.0, 120.4, 110.3,
64.9, 55.2, 29.8, 28.5, 26.2. IR (neat) 3062, 2996, 2950, 2834, 1716,
a General conditions: Pd(OAc)2 (2 mol %), RuPhos (4 mol %),
RBF3K (1.0 equiv), electrophile (1.0 equiv), K2CO3 or Cs2CO3 (3.0
equiv), and 10:1 toluene/H2O (0.25 M), 24 h, 80 °C, 0.5 mmol scale.
1600, 1586, 1493, 1464, 1452, 1314, 1272, 1243, 1115 cm-1
.
HRMS (ESI): calcd for C18H20NaO3 [M + Na]+ 307.1310, found
307.1306.
added slowly, and the mixture was heated to reflux for 4 h. The
reaction was allowed to cool to rt and then cooled to 0 °C at which
point it was added via a double-ended needle to a 0 °C solution of
H2O (6 mL) in Et2O (20 mL). The resulting mixture was stirred
for 30 min, and then the organic layer was separated. The aqueous
layer was extracted with Et2O (2 × 50 mL). The organic extracts
were combined and washed with H2O (50 mL). The resulting crude
boronic acid was then dissolved in MeOH (100 mL) and cooled to
0 °C. To it was added saturated aqueous KHF2 (36 mL, 4.5 M)
dropwise, and then the reaction mixture was allowed to warm to
rt. After 30 min, the solution was concentrated in vacuo. The
resulting white solid was then subjected to high vacuum overnight.
The dried solids were triturated with hot acetone (3 × 20 mL) and
filtered to remove inorganic salts. The resulting solution was
concentrated until the trifluoroborate was minimally soluble in
acetone. Et2O (∼30 mL) was added to precipitate the product. The
pure compound was filtered and dried in vacuo and obtained as a
white crystalline solid in 80% yield (9.01 g, 31.7 mmol). Mp )
187-189 °C. 1H NMR (500 MHz, acetone-d6): 8.01-8.03 (d, J )
7.4 Hz, 2H), 7.59-763 (t, J ) 7.4 Hz, 1H), 7.48-7.51 (t, J ) 7.4
Hz, 2H), 4.25-4.28 (t, J ) 6.9 Hz, 2H), 1.70-1.74 (m, 2H),
1.39-1.43 (m, 2H), 0.18-0.22 (m, 2H). 13C NMR (125.8 MHz,
4-(Pyridin-3-yl)butyl Benzoate. According to the general
procedure described above using 3-chloropyridine on a 0.50 mmol
scale, the title compound was isolated in 93% yield (119 mg, 0.47
mmol) as a clear, colorless oil after silica gel column chromatog-
raphy (elution with hexane/EtOAc 3:2). 1H NMR (500 MHz,
CDCl3): 8.41-8.44 (m, 2H), 7.99-8.01 (d, J ) 7.6 Hz, 2H),
7.49-7.53 (t, J ) 7.6 Hz, 1H), 7.46-7.48 (d, J ) 7.8 Hz, 1H),
7.38-7.41 (t, J ) 7.6 Hz, 2H), 7.16-7.18 (m, 1H), 4.30-4.33 (t,
J ) 6.1 Hz, 2H), 2.64-2.67 (t, J ) 7.0 Hz, 2H), 1.71-1.82 (m,
4H). 13C NMR (125.8 MHz, CDCl3): 166.6, 150.0, 147.5, 137.2,
135.9, 133.0, 130.4, 129.6, 128.4, 123.4, 64.6, 32.6, 28.3, 27.6. IR
(neat): 3028, 2941, 2860, 1717, 1274, 1116 cm-1. HRMS (ESI):
calcd for C16H18NO2 [M + H]+ 256.1338, found 256.1327.
Acknowledgment. G.A.M. thanks the NIH General Medical
Sciences and Merck Research Laboratories for their generous
support of this research. The work was also generously
supported by a Novartis Summer Undergraduate Research
Fellowship to S.L. and a Novartis Graduate Research Fellowship
to D.L.S. Dr. Rakesh Kohli (University of Pennsylvania) is
acknowledged for obtaining HRMS data.
acetone-d6): 166.9, 133.6, 131.8, 130.1, 129.3, 66.4, 33.0, 22.8. 19
F
Supporting Information Available: Experimental details and
spectral data of all compounds synthesized. This material is
available free of charge via the Internet at http://pubs.acs.org.
NMR (470.8 MHz, acetone-d6): -141.6. 11B NMR (128.4 MHz,
acetone-d6): 5.93. IR (KBr): 3061, 2924, 2858, 1712, 1453, 1278,
1117, 1075 cm-1. HRMS (ESI): calcd for C11H13BF3O2 [M - K]-
245.0961, found 245.0950.
JO900152N
J. Org. Chem. Vol. 74, No. 10, 2009 3631