Cross-coupling of cyclopropyl- and cyclobutyltrifluoroborates with aryl and heteroaryl chlorides

Article abstract of DOI:10.1021/jo801269m

(Chemical Equation Presented) Suitable conditions were found for the Suzuki-Miyaura cross-coupling reaction of potassium cyclopropyl-and cyclobutyltrifluoroborates with aryl chlorides. Both of these secondary alkyl trifluoroborates coupled in moderate to excellent yield with electron-rich, electron-poor, and hindered aryl chlorides to give a variety of substituted aryl cyclopropanes and cyclobutanes.

Full text of DOI:10.1021/jo801269m

Cross-Coupling of Cyclopropyl- and Cyclobutyltrifluoroborates with
Aryl and Heteroaryl Chlorides
Gary A. Molander* and Paul E. Gormisky
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed June 13, 2008
Suitable conditions were found for the Suzuki-Miyaura cross-coupling reaction of potassium cyclopropyl-
and cyclobutyltrifluoroborates with aryl chlorides. Both of these secondary alkyl trifluoroborates coupled
in moderate to excellent yield with electron-rich, electron-poor, and hindered aryl chlorides to give a
variety of substituted aryl cyclopropanes and cyclobutanes.
Introduction
The few examples using aryl chlorides are limited to activated,
electron-poor arenes,4a,5 and although a number of heteroaryl
triflates have been successfully cross-coupled with cyclopro-
pylboronic acid,6 only one example of a heteroaryl chloride
exists in the literature.4a Furthermore, boronic acids themselves
suffer from several notable drawbacks. Most significantly, the
propensity of cyclopropylboronic acid to protodeboronate
renders it unstable and unsafe upon prolonged storage and
requires the use of between 10% and 200% excess4 in cross-
coupling reactions. Consequently, a significant quantity of the
key reagent is wasted.
The development of mild methods for the incorporation of
the cyclopropyl group into complex molecules is becoming
increasingly important as a result of the prevalence of cyclo-
propanes in natural products1 as well as in pharmaceutical
targets, where the group’s distinctive steric and electronic
properties create unique opportunities for interrogating biological
receptors.2 The ease of access to cyclopropylborons, combined
with the mild reaction conditions and tolerance of diverse
functional groups, make the Suzuki-Miyaura cross-coupling3
an extremely attractive method for the installation of the
cyclopropyl group into aromatic and heteroaromatic systems.
To date, the majority of investigations employing the Suzuki-
Miyaura reaction in this endeavor have focused on the use of
cyclopropylboronic acid.4 Most of these reports feature aryl
bromide or iodide electrophiles as opposed to the less expensive
and more readily available (albeit less reactive) aryl chlorides.
Potassium organotrifluoroborates7 have proven to be a
particularly useful class of boron reagents that are air- and
moisture-stable, atom economical, and resistant to protodebo-
ronation,8 thereby allowing essentially stoichiometric quantities
of reagent to be used in cross-coupling protocols. Organotri-
(4) (a) Lemhadri, M.; Doucet, H.; Santelli, M. Synth. Commun. 2006, 121–
128. (b) Wallace, D.; Chen, C. Tetrahedron Lett. 2002, 43, 6987–6990. (c) Zhou,
S.-M.; Deng, M.-Z.; Xia, L.-J.; Tang, M.-H. Angew. Chem., Int. Ed. 1998, 37,
2845–2847. (d) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 12634–12635.
(1) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. ReV. 2003, 103,
1625–1648.
(2) (a) The Chemistry of the Cyclopropyl Group; Patai, S., Rappoport, Z.,
Eds.; John Wiley & Sons: New York, 1987. (b) Gagnon, A.; St-Onge, M.; Little,
K.; Duplessis, M.; Barabe, F. J. Am. Chem. Soc. 2007, 129, 44–45.
(3) For reviews, see:(a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–
2483. (b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4544–4568. (c) Suzuki, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998. (d)
Suzuki, A.; Brown, H. C. Organic Syntheses Via Boranes; Aldrich Chemical
Co., Inc.: Milwaukee, WI, 2002; Vol. 3.
(5) Fu¨rstner, A.; Leitner, A. Synlett 2001, 290–292.
(6) Yao, M.-L.; Deng, M.-Z. New J. Chem. 2000, 24, 425–428.
(7) For reviews on organotrifluoroborate salts, see: (a) Molander, G. A.;
Figueroa, R. Aldrichimica Acta 2005, 38, 49–56. (b) Molander, G. A.; Ellis, N.
Acc. Chem. Res. 2007, 40, 275–286. (c) Stefani, H. A.; Cella, R.; Adriano, S.
Tetrahedron 2007, 63, 3623–3658. (d) Darses, S.; Geneˆt, J. P. Chem. ReV. 2008,
108, 288–305.
(8) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302–4314.
10.1021/jo801269m CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7481–7485 7481

Molander and Gormisky
TABLE 1. Optimization of Reaction Conditions for Aryl Chlorides
entry
catalyst/ligand (mol %)
R
base
solvent (°C)
ratio P/SMa
1
2
3
4
5
6
PdCl2(dppf)·CH2Cl2 (3)
Pd(OAc)2/XPhos (3/6)
Pd(OAc)2/XPhos (3/6)
Pd(OAc)2/XPhos (3/6)
Pd(OAc)2/XPhos (3/6)
Pd(OAc)2/1,1,3,3-
4-CN
4-CN
4-CN
4-OMe
4-OMe
4-OMe
Cs2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
THF/H2O (80)
THF/H2O (80)
THF/H2O (80)
THF/H2O (80)
THF/H2O (80)
THF/H2O (80)
5/95
99/1
100/0
78/22
83/17
4/94
tetramethylbutylisocyanide (3/6)
7
Pd(OAc)2/XPhos (3/6)
4-OMe
K2CO3
CPME/H2O (100)
100/0
a Ratio of product/starting material as determined by GC-MS assay.
Results and Discussion
Our study began with optimization of reaction conditions for
the cross-coupling of aryl chlorides with commercially available
potassium cyclopropyltrifluoroborate. Previous cross-coupling
studies of cyclopropyltrifluoroborates with aryl bromides by
Deng and co-workers9a utilized traditional catalyst systems such
as PdCl2(dppf) or Pd(PPh3)4 to good effect (eq 1).
FIGURE 1. Ligands for cross-coupling.
However, the former conditions proved unsuccessful in our
case owing to the increased difficulty of oxidative addition to
aryl chlorides.13 Table 1 summarizes our studies toward
optimizing reaction conditions for this reaction. Previous success
with dialkylbiaryl phosphine ligands in challenging systems7,13b
led us quickly to examine the Buchwald palette of phosphines.
A hindered isonitrile was examined as a unique potential
alternative.
Among the suite of Buchwald and other ligands examined
in initial screens (Figure 1), reaction conditions developed
previously in our group for the cross-coupling of aryl chlorides
and bromides with aminomethyltrifluoroborates14 proved the
most efficacious for cyclopropyltrifluoroborate (entries 2-5 and
7). Thus, it was determined that 3% Pd(OAc)2 with 6%
2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos)15
as the catalyst system in the presence of a base in a 10:1 mixture
of cyclopentyl methyl ether (CMPE) and H2O (0.25 M) at 100
°C proved suitable for this reaction. In contrast to our previous
fluoroborates are readily accessible from diverse organoboron
precursors, and in accord with this, numerous methods have
been developed for their synthesis, including cyclopropanation
of alkenylboronic acids or -boronate esters,9 transmetalation
from cyclopropylzinc reagents,10 and hydroboration of cyclo-
propenes.11 Furthermore, the use of chiral boronates9b or
catalytic asymmetric hydroboration11 generates enantioenriched
cyclopropyl boron reagents that undergo cross-coupling with
retention of configuration9-11 to allow facile, stereospecific
incorporation of substituted cyclopropanes into complex mol-
ecules. Various cyclopropyltrifluoroborates have been demon-
strated to cross-couple stereospecifically to aryl bromides or
iodides,9a,10 but the use of trifluoroborates with aryl chlorides
has not been investigated. The current contribution represents
an expansion of the utility of the Suzuki-Miyaura reaction for
the installation of the cyclopropyl unit into a wide variety of
aromatic substrates using potassium organotrifluoroborates,
employing both aryl and heteroaryl chlorides.
(9) (a) Fang, G.-H.; Yan, Z.-J.; Deng, M.-Z. Org. Lett. 2004, 6, 357–360.
(b) Hohn, E.; Pietruszka, J.; Solduga, G. Synlett 2006, 1531–1534. (c) Hildebrand,
J. P.; Marsden, S. P. Synlett 1996, 893–894. (d) Zhou, S.-M.; Deng, M.-Z.; Xia,
L.-J.; Tang, M.-H. Angew. Chem., Int. Ed. 1998, 37, 2845–2847.
(10) Charette, A. B.; Mathieu, S.; Fournier, J.-F. Synlett 2005, 1779–1782.
(11) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125,
7198–7199.
The increased sp3 character in the carbon-boron bond of
cyclobutyl organometallics, combined with the potential intru-
sion of a ꢀ-hydride elimination from the diorganopalladium
intermediate, makes the use of cyclobutyl derivatives in cross-
coupling reactions significantly more challenging than that of
their cyclopropyl counterparts. In a continued effort to expand
the feasibility of secondary alkyl cross-coupling reactions with
potassium organotrifluoroborates,12 we synthesized cyclobutyl-
trifluoroborate and examined its reaction with various aryl
chlorides and report what is, to the best of our knowledge, the
first example of a cross-coupling reaction using a cyclobutyl
organometallic coupling partner.
(12) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257–9259.
(13) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685–4696. (b) Martin, R.; Buchwald, S. L. Acc. Chem.
Res. 2008, published ASAP ahead of print; DOI 10.1021/ar800036s.
(14) Molander, G. A.; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem. 2008,
73, 2052–2057. (b) Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597–
1600.
(15) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028–
13032.
7482 J. Org. Chem. Vol. 73, No. 19, 2008

Cross-Coupling of Cyclopropyl- and Cyclobutyltrifluoroborates
TABLE 2. Cross-Coupling of Potassium
TABLE 3. Optimization of Reaction Conditions for Heteroaryl
Chloridesa
Cyclopropyltrifluoroborate with Various Aryl Chloridesa
ratio
entry catalyst/ligand (mol %)
base
solvent (°C)
4a/3aa
1
2
3
4
5
6
7
8
Pd(OAc)2/XPhos (3/6)
Pd(OAc)2/XPhos (3/6)
Pd(OAc)2/RuPhos (3/6)
Pd(OAc)2/DavePhos (3/6) Cs2CO3 THF/H2O (80)
Pd(OAc)2/SPhos (3/6) Cs2CO3 THF/H2O (80)
Pd(OAc)2/XantPhos (3/6) Cs2CO3 THF/H2O (80)
Pd(OAc)2/(S)-BINAP (3/6) Cs2CO3 THF/H2O (80)
Pd(OAc)2/n-BuPAd2 (2/3) Cs2CO3 Toluene/ H2O (100) 100/0
K2CO3 THF/H2O (80)
K2CO3 CPME/H2O (100)
Cs2CO3 THF/H2O (80)
72/28
77/23
46/54
0/100
0/100
90/10
0/100
a Ratio of product/starting material as determined by GC-MS assay.
We next demonstrated the substrate scope of this method.
Table 2 shows the reaction of potassium cyclopropyltrifluo-
roborate with various aryl chlorides. Electron-rich, electron-
poor, and hindered aryl chlorides proved amenable to the
reaction conditions, which tolerated numerous functional groups
such as ketones, nitriles, and esters. However, reduction of the
nitro group to the corresponding aniline resulted when 4-chloro-
1-nitrobenzene was used. This phenomenon has been observed
previously in cross-coupling of organoborons with nitro-
containing aryl halides.16 Highlighting the advantages of orga-
notrifluoroborates over boronic acids and their derivatives,4 only
1% excess of the trifluoroborate was used in all cases.
We next extended the method to heteroaryl chlorides, a class
of electrophiles only minimally explored for the Suzuki-Miyaura
reaction of cyclopropylborons.4a Unfortunately, the reaction
conditions used for aryl chlorides and several other catalyst
systems (Table 3, entries 1-7) failed to afford the cross-coupled
product in useful yields.
Simultaneously in our group, reaction conditions for the cross-
coupling of secondary alkyltrifluoroborates, such as cyclopen-
tyltrifluoroborate, were developed (entry 8).12 Using these
conditions [2% Pd(OAc)2, 3% n-BuPAd2, 3.0 equiv of Cs2CO3
in 10:1 toluene/H2O at 100 °C], an 85% yield of 5-cyclopropyl-
2-methoxypyridine (4a) was obtained from the reaction of
5-chloro-2-methoxypyridine with potassium cyclopropyltrifluo-
roborate. The scope of this reaction proved to be quite broad with
respect to a wide variety of heteroaryl chlorides (Table 4).
Various substitution patterns and functional groups were well
tolerated. Of particular interest are the 2-substituted nitrogen
heterocycles, such as 2-chloroquinoline (4e) and 2-chloroqui-
noxaline (4d), which are sometimes difficult to couple owing
to catalyst deactivation via complexation to the palladium
catalyst17 but are nevertheless desirable as substructures embed-
ded within pharmacologically active materials.18 Notably,
4-chlorobenzonitrile and 3-chloro-4,5-dimethoxybenzonitrile
failed to react and afforded only starting material after 48 h by
GC-MS analysis. We postulate that some interaction between
the nitrile and the metal center causes the catalysts to be
inactivated because the effect seems to be ligand dependent.
a All reactions used 0.5 mmol of the aryl chloride and 0.505 mmol of
potassium cyclopropyltrifluoroborate. b 10:1 THF/H2O was used as the
solvent, 80 °C. c Reaction time was 48 h.
reports,14 which required cesium carbonate to be used as the
base, the less expensive potassium carbonate was effective in
this case (entries 3 and 7). Using these reaction conditions a
75% yield of the cross-coupled product (2a) was obtained from
the reaction of potassium cyclopropyltrifluoroborate with 4-chlo-
roanisole.
(16) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221–223.
(17) Buchmeiser, M. R.; Schareina, T.; Kempe, R.; Wurst, K. J. Organomet.
Chem. 2001, 634, 39–46.
(18) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893–930.
J. Org. Chem. Vol. 73, No. 19, 2008 7483

Molander and Gormisky
TABLE 4. Cross-Coupling of Potassium
TABLE 5. Cross-Coupling of Potassium Cyclobutyltrifluoroborate
with Various Aryl and Heteroaryl Chloridesa
Cyclopropyltrifluoroborate with Various Heteroaryl Chloridesa
a All reactions used 0.5 mmol of the aryl or heteroaryl chloride and
0.505 mmol of potassium cyclobutyltrifluoroborate.
yields. Unfortunately, the reaction failed to reach completion
with several substrates (4-chlorobenzophenone, 5-chloro-2-
thiophenecarboxaldehyde and 1-chloro-4-methoxy-2,6-dimeth-
ylbenzene). The similar physicochemical characteristics of the
aryl chloride and cross-coupled products in these particular cases
made effective separation by silica gel column chromatography
difficult, and the desired products could not be readily isolated
in pure form.
Conclusion
We have demonstrated that the palladium-catalyzed Suzuki-
Miyaura cross-coupling reaction can be effectively applied to
the cyclopropanation of aryl chlorides. The reaction accom-
modates aryl as well as heteroaryl chlorides with diverse
functional groups (esters, ketones, aldehydes, nitriles) and
substitution patterns. This method, in conjunction with previ-
ously developed methods for the syntheses of stereodefined
cyclopropyltrifluoroborates, should find utility for the installation
of cyclopropanes into a variety of functionalized aryl and
heteroaryl target molecules. Finally, suitable conditions were
found for the cross-coupling of potassium cyclobutyltrifluo-
a All reactions used 0.5 mmol of the heteroaryl chloride and 0.505
mmol of potassium cyclopropyltrifluoroborate.
Finally, in an effort to expand the utility of this method for
the installation of small rings into complex molecules, we
synthesized cyclobutyltrifluoroborate (5) (eq 2) and subjected
it to our optimized reaction conditions for cross-coupling with
heteroaryl chlorides (Table 5).
roborate with aryl chlorides, representing an unprecedented
mode of cross-coupling reactivity.
Experimental Section
General Experimental Procedure for the Suzuki-Miyaura
Cross-Coupling Reactions of Cyclopropyltrifluoroborate with
Aryl Chlorides. Preparation of 1-Cyclopropyl-4-methoxyben-
The reaction proved to be somewhat substrate dependent;
however, it afforded aryl cyclobutanes in moderate to good
7484 J. Org. Chem. Vol. 73, No. 19, 2008

Cross-Coupling of Cyclopropyl- and Cyclobutyltrifluoroborates
zene (2a). A Biotage microwave vial was charged with Pd(OAc)2
(3.3 mg, 0.015 mmol), XPhos (14.3 mg, 0.03 mmol), potassium
cyclopropyltrifluoroborate (74.7 mg, 0.505 mmol), and K2CO3 (210
mg, 1.5 mmol). The tube was sealed with a cap lined with a
disposable Teflon septum, evacuated under vacuum, and purged
with N2 three times. 4-Chloroanisole (71.3 mg, 0.5 mmol) and
CPME/H2O (10:1) (2 mL) were added by syringe, and the reaction
was stirred at 100 °C for 24 h, cooled to room temperature, and
diluted with H2O (1.5 mL). The reaction mixture was extracted
with CH2Cl2 (3 × 5 mL). The organic layer was dried (Na2SO4).
The solvent was removed in vacuo, and the crude product was
purified by silica gel column chromatography (elution with hexane/
EtOAc 99:1; Rf 0.31) to yield the product as a light yellow oil in
75% yield (55.7 mg, 0.37 mmol). The spectral data match those
reported in the literature.19 1H NMR (500 MHz, CDCl3) δ: 7.01
(d, J ) 8.7 Hz, 2H), 6.80 (d, J ) 8.7 Hz, 2H), 3.77 (s, 3H),
1.82-1.86 (m, 1H), 0.86-0.89 (m, 2H), 0.60-0.62 (m, 2H). 13C
NMR (125.8 MHz, CDCl3) δ: 157.9, 136.1, 127.1, 114.0, 55.5,
14.8, 8.6.
General Experimental Procedure for the Suzuki-Miyaura
Cross-Coupling Reactions of Heteroaryl Chlorides with Potas-
sium Cyclopropyltrifluoroborate. Preparation of 5-Cyclopropyl-
2-methoxypyridine (4a). In the glovebox, a Biotage microwave vial
was charged with Pd(OAc)2 (2.2 mg, 0.01 mmol), n-BuPAd2 (5.3
mg, 0.015 mmol), potassium cyclopropyltrifluoroborate (74.7 mg,
0.505 mmol), and Cs2CO3 (480 mg, 1.5 mmol). The tube was sealed
with a cap lined with a disposable Teflon septum and removed from
the glove box. 5-Chloro-2-methoxypyridine (71.7 mg, 0.5 mmol)
and toluene/H2O (10:1) (2 mL) were added by syringe, and the
reaction was stirred at 100 °C for 24 h, cooled to room temperature,
and diluted with H2O (1.5 mL). The reaction mixture was extracted
with CH2Cl2 (3 × 5 mL). The organic layer was dried (Na2SO4).
The solvent was removed in vacuo, and the crude product was
purified by silica gel column chromatography (elution with hexane/
EtOAc 99:1; Rf 0.22) to yield the product as a light yellow oil in
85% yield (65.3 mg, 0.44 mmol). 1H NMR (500 MHz, CDCl3) δ:
7.97 (s, 1H), 7.24 (dd, J ) 8.5 Hz, 1H), 6.63 (d, J ) 8.5 Hz, 1H),
3.90 (s, 3H), 1.81-1.85 (m, 1H), 0.90-0.93 (m, 2H), 0.59-0.63
(m, 2H). 13C NMR (125.8 MHz, CDCl3) δ: 162.8, 145.1, 136.6,
131.8, 110.5, 53.5, 12.4, 8.0. IR (neat) ) 3006, 1608, 1495, 1286,
1025 cm-1. HRMS (CI) calcd for C9H12NO (MH+) 150.0919, found
150.0926.
dried under vacuum. Mp 200 °C (dec). 1H NMR (500 MHz,
acetone-d6) δ: 1.77-1.84 (m, 6H), 1.38 (br s, 1H). 13C NMR (125.8
MHz, DMSO-d6) δ: 23.7, 12.4. 19F NMR (471 MHz, DMSO-d6)
δ: -144.64. 11B NMR (128.37 MHz, acetone-d6) δ: 4.28. IR (KBr)
) 2967, 1316, 1121, 924 cm-1
.
General Experimental Procedure for the Suzuki-Miyaura
Cross-Coupling Reactions of Aryl and Heteroaryl Chlorides
with Potassium Cyclobutyltrifluoroborate. Preparation of 1-Cy-
clobutyl-3,5-dimethoxybenzene (7a). In the glovebox, a Biotage
microwave vial was charged with Pd(OAc)2 (2.2 mg, 0.01 mmol),
n-BuPAd2 (5.3 mg, 0.015 mmol), potassium cyclobutyltrifluorobo-
rate (81.8 mg, 0.505 mmol), and Cs2CO3 (480 mg, 1.5 mmol). The
tube was sealed with a cap lined with a disposable Teflon septum
and removed from the glove box. 5-Chloro-1,3-dimethoxybenzene
(86.3 mg, 0.5 mmol) and toluene/H2O (10:1) (2 mL) were added
by syringe, and the reaction was stirred at 100 °C for 24 h, cooled
to room temperature, and diluted with H2O (1.5 mL). The reaction
mixture was extracted with CH2Cl2 (3 × 5 mL). The organic layer
was dried (Na2SO4). The solvent was removed in vacuo, and the
crude product was purified by silica gel column chromatography
(elution with hexane/EtOAc 99:1; Rf 0.48) to yield the product as
1
a light yellow oil in 82% yield (81.0 mg, 0.42 mmol). H NMR
(500 MHz, CDCl3) δ: 6.28-6.51 (m, 3H), 3.78 (s, 6H), 3.46-3.50
(m, 1H), 2.29-2.33 (m, 2H), 2.10-2.15 (m, 2H), 1.97-1.99 (m,
1H), 1.84 (m, 1H). 13C NMR (125.8 MHz, CDCl3) δ: 161.0, 149.0,
107.2, 104.6, 99.5, 97.9, 55.7, 55.4, 40.8, 29.8, 18.3. IR (neat) )
2958, 1595, 1458, 1154 cm-1. HRMS (TOF) calcd for C12H17O2
(MH+) 193.1229, found 193.1235.
Acknowledgment. This work was generously supported by
the National Institutes of Health (GM035249), Amgen, and
Merck Research Laboratories. The authors also acknowledge
Deidre L. Sandrock (University of Pennsylvania) and Dr.
Spencer D. Dreher (Merck) for developing reaction conditions
for secondary alkyl trifluoroborates used in this paper. Aldrich
Chemical Co. is acknowledged for their generous donation of
cyclopropyltrifluoroborate and cyclobutylboronic acid. Frontier
Scientific and Johnson Matthey are acknowledged for a donation
of palladium catalysts. The authors also thank Professor Stephen
L. Buchwald (MIT) for a sample of phosphine ligands, Dr.
Rakesh Kohli (University of Pennsylvania) for obtaining high-
resolution mass spectra of new compounds, and the Zeon
Corporation for donation of cyclopentyl methyl ether (CPME).
Preparation of Potassium Cyclobutyltrifluoroborate (5). Cy-
clobutylboronic acid (909 mg, 9.1 mmol) was dissolved in methanol
(20 mL) at room temperature, and the solution was cooled to 0 °C
in an ice bath. A saturated aqueous solution of KHF2 (11.1 mL)
was added to the stirring solution dropwise at 0 °C. The reaction
was allowed to warm to room temperature and stirred for an
additional 3 h. The solvent was removed in vacuo and dried under
vacuum overnight. The resulting crude solid was extracted three
times by sonicating for 15 min and stirring for an additional 15
min in dry acetonitrile. The solvent was removed in vacuo. A
minimal amount of hot acetonitrile (∼50 mL) was added to dissolve
the crude product, and Et2O (∼150 mL) was added, leading to
precipitation of the product in 63% yield as a white crystalline solid
(929 mg, 5.7 mmol), which was collected by vacuum filtration and
Supporting Information Available: Experimental proce-
dures, spectral characterization, and copies of 1H, 13C, 11B, and
19F spectra for all compounds prepared by the method described.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801269M
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3719.
J. Org. Chem. Vol. 73, No. 19, 2008 7485