Palladium-Catalyzed Cross-Coupling of Stereospecific Potassium Cyclopropyl Trifluoroborates with Aryl Bromides

Article abstract of DOI:10.1021/ol036184e

(Matrix presented) Stereospecific cyclopropanation of alkenylboronic esters of pinacol followed by in situ treatment with excess KHF₂ afforded the corresponding potassium cyclopropyl trifluoroborates in high yields, which then underwent Suzuki-

Full text of DOI:10.1021/ol036184e

ORGANIC
LETTERS
2004
Vol. 6, No. 3
357-360
Palladium-Catalyzed Cross-Coupling of
Stereospecific Potassium Cyclopropyl
Trifluoroborates with Aryl Bromides
Guo-Hua Fang, Zheng-Jun Yan, and Min-Zhi Deng*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P.R. China
dengmz@pub.sioc.ac.cn
Received November 7, 2003
ABSTRACT
Stereospecific cyclopropanation of alkenylboronic esters of pinacol followed by in situ treatment with excess KHF2 afforded the corresponding
potassium cyclopropyl trifluoroborates in high yields, which then underwent Suzuki−Miyaura cross-coupling reactions with aryl bromides to
give cyclopropyl-substituted arenes in good yields with retention of configuration. This promises to be a useful method for the synthesis of
enantiomerically pure cyclopropanes.
A growing number of cyclopropyl-containing natural prod-
ucts have been isolated and synthesized.1 Cyclopropanes are
also increasingly incorporated into pharmaceuticals due to
their well-defined three-dimensional structure.2 Therefore,
the stereocontrolled synthesis of cyclopropane derivatives
has attracted considerable interest in recent years.
Alkenylmetal compounds (B, Al, Si, Sn) are versatile
intermediates because after cyclopropanation they can po-
tentially react with a variety of electrophiles.
selective and tolerant of a broad range of functional groups.
In the studies on Suzuki-Miyaura coupling reactions, various
organoboranes,4 boronic acids,5 and boronic esters6 were most
often employed. Although boronic acids and esters have often
been widely utilized in cross-coupling reaction, much atten-
tion has been focused on the preparation of various orga-
noboron derivatives. Compared with commonly used orga-
noboron compounds, organotrifluoroborates have distinguishing
features: greater nucleophilicity, ready accessibility, and re-
Among the powerful palladium-catalyzed cross-coupling
of electrophiles with organometallic reagents, the Suzuki-
Miyaura cross-coupling reaction of organoboron compounds
has especially attracted chemists’ attention.3 The organoboron
reagents are less toxic and more easily accessed by a variety
of routes. The conditions are mild, and the reaction is highly
(2) (a) Patai, S., Rappoport, Z., Eds. The Chemistry of the Cyclopropyl
Group; Wiley: New York, 1987. (b) Wong, H. N. C.; Hon, M.-Y.; Tse,
C.-W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165-
198. (c) De Meijere, A., Ed. Houben-Weyl, Methods in Organic Chemistry,
4th ed.; Georg Thieme Verlag: Stuttgart, 1997; Vol. E17c. (d) Reissig,
H.-U. Top. Curr. Chem. 1988, 144, 73-135.
(3) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (c) Suzuki, A. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
VCH: Weinheim, 1998; pp 49-97.
(4) (a) Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437-3440.
(b) Miyaura, N.; Yamada, K.; Suzuki, A. J. Am. Chem. Soc. 1985, 107,
972-980.
(5) (a) Miyaura, N.; Suginome, H.; Suzuki, A. Tetrahedron 1983, 39,
3271-3277. (b) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513-519. (c) Littke, A. F.; Dai, C.-Y.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020-4028. (d) Wang, X.-Z.; Deng, M.-Z. J. Chem. Soc., Perkin
Trans. 1 1996, 4, 2663-2664.
(6) (a) Soderquist, J. A.; Santiago, B. Tetrahedron Lett. 1990, 31, 5541-
5542. (b) Moore, W. R.; Schatzman, G. L.; Jarvi, E. T.; Gross, R. S.;
McCarthy, J. R. J. Am. Chem. Soc. 1992, 114, 360-361. (c) Hilderbrand,
J. P.; Marsden, S. P. Synlett 1996, 893-894.
* To whom correspondence should be addressed. Fax: 86-21-64166128.
(1) (a) Gerwick, W. H. Chem. ReV. 1993, 93, 1807-1823. (b) Barrett,
A. G. M.; Hamprecht, D.; White, A. J. P.; Williams, D. J. J. Am. Chem.
Soc. 1996, 118, 7863-7864. (c) McDonald, W. S.; Verbicky, C. A.; Zercher,
C. K. J. Org. Chem. 1997, 62, 1215-1222. (d) Barloy-Da Silva, C.; Pale,
P. Tetrahedron: Asymmetry 1998, 9, 3951-3954. (e) Nagle, D. G.; Gerwick,
W. H. J. Org. Chem. 1994, 59, 7227-7237. (f) Charette, A. B.; Lebel, H.
J. Am. Chem. Soc. 1996, 118, 10327-10328. (g) White, J. D.; Jensen, M.
S. J. Am. Chem. Soc. 1993, 115, 2970-2971. (f) Barrett, A. G. M.; Kasdorf,
K. Chem. Commun. 1996, 325-326. (h) Salaun, J. Top. Curr. Chem. 2000,
201, 1-67. (i) Suckling, C. J. Angew. Chem. 1988, 100, 555-570; Angew.
Chem., Int. Ed. Engl. 1988, 27, 537. (j) Miyaoka, H.; Shigemoto, T.;
Yamada, Y. Tetrahedron Lett. 1996, 37, 7407-7408. (k) Miyaoka, H.;
Shigemoto, T.; Yamada, Y. Heterocycles 1998, 47, 415-428.
10.1021/ol036184e CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/03/2004

markable stability in air. Palladium-catalyzed cross-coupling
reactions of potassium organotrifluoroborates have been
reported by Genet, Molander, and others.7
Scheme 1
It was well-known that boronic esters allow for the
introduction of chiral auxiliaries, thus enabling diastereo-
selective cyclopropanations of alkenylboronic esters.8 Fur-
thermore, the alkenylboronic esters are conveniently cyclo-
propanated by the Pd-catalyzed decomposition of diazo-
methane to furnish cyclopropylboronic esters. But there were
few reports concerning the preparation of stereospecifically
chiral cis-cyclopropanes.
In our previous work, we have reported that trans-
alkenylboronic acids could be condensed with chiral diols
under reflux for a long period of time,8c but it was found
that these conditions caused the isomerization of cis-
alkenylboronic acid. Pietruszka’s chiral diol could be con-
densed with alkenylboronic acids smoothly under mild
conditions,9 but cyclopropylboronic esters of chiral diols are
reluctant to take part in cross-coupling reactions8d,10 and are
difficult to hydrolyze,11 so it was necessary to first reduce
using an excess of LiAlH4 and then hydrolyze to obtain
cyclopropylboronic acids before further transformation was
possible.
The results obtained are shown in Table 1. As evidenced
by 2D NOESY spectra, the cyclopropyl trifluoroborates
generated from (E)-alkenylboronic acids have trans configu-
rations, while the ones obtained from (Z)-alkenylboronic
Table 1. Stereospecific Preparation of Potassium Cyclopropyl
Trifluoroboratesa
With our ongoing interest in the synthesis of enantiomeri-
cally pure cyclopropanes, we attempted to find a new way
to obtain enantiomerically pure cyclopropanes including the
cis isomers. Recently, we studied the stereodefined prepara-
tion of racemic potassium cyclopropyl trifluoroborates gener-
ated from cyclopropylboronic esters of pinacol and their
cross-coupling reactions with aryl bromides as an array of
model experiments, because pinacol can also be condensed
with boronic acids smoothly. Herein we report our prelimi-
nary results.
Alkenylboronic acids 1 were easily condensed with pinacol
at room temperature to give the corresponding esters in
quantitative yield. Cyclopropanation of the esters via pal-
ladium-catalyzed decomposition of CH2N212 followed by in
7a,13
situ treatment with excess KHF2
afforded the stereo-
defined potassium cyclopropyl trifluoroborates in good to
excellent yield (Scheme 1).
(7) (a) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393-396. (b)
Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107-109. (c) Molander,
G. A.; Biolatto, B. Org. Lett. 2002, 4, 1867-1870. (d) Molander, G. A.;
Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67, 8416-8423. (e)
Darses, S.; Genet, J. P.; Brayer, J.-L.; Demoute, J.-P. Tetrahedron Lett.
1997, 38, 4393-4395. (f) Darses, S.; Michaud, G.; Genet, J. P. Tetrahedron
Lett. 1998, 39, 5045-5048. (g) Darses, S.; Michaud, G.; Genet, J. P. Eur.
J. Org. Chem. 1999, 1875-1883. (h) Molander, G. A.; Biolatto, B. J. Org.
Chem. 2003, 68, 4302-4314. (i) Molander, G. A.; Yun, C.-S.; Ribagorda,
M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534-5539. (j) Batey, R. A.;
Quach, T. D. Tetrahedron Lett. 2001, 42, 9099-9103. (k) Kabalka, G. W.;
Venkataiah, B.; Dong, G. Org. Lett. 2003, 5, 3803-3805.
(8) (a) Imai, H. Mineta, S. Nishida, J. Org. Chem. 1990, 55, 4986-
4988. (b) Pietruszka, J.; Widenmeyer, M. Synlett 1997, 977-979. (c) Zhou,
S.-M.; Deng, M.-Z.; Xia, L.-J.; Tang, M.-H. Angew. Chem. 1998, 110,
3061-3063; Angew. Chem., Int. Ed. 1998, 37, 2845-2847. (d) Luithle, J.
E. A.; Pietruszka, J. J. Org. Chem. 1999, 64, 8287-8297.
(9) (a) Luithle, J. E. A.; Pietruszka, J. Liebigs Ann./Recueil 1997, 2297-
2302. (b) Luithle, J. E. A.; Pietruszka, J.; Witt, A. Chem. Commun. 1998,
2651-2652.
a (1) The mixture of alkenylboronic acid (10 mmol), pinacol (10.5 mmol),
20 mL of Et2O, and 0.6 g of MgSO4 was stirred for 1 h at room temperature.
(2) To the mixture of alkenylboronic esters (10 mmol), Pd(OAc)2 (122 mg)
in 50 mL of Et2O, was added a 2 M solution of CH2N2 in 100 mL of Et2O
at 0 °C for 1 h and then for additional 1 h at room temperature. (3) The
mixture of KHF2 (70 mmol), cyclopropylboronic esters, 35 mL of methanol,
and 7 mL of water was stirred for 4 h at room temperature. b Isolated yields
based on alkenylboronic acids used.
(10) Chen, H.; Deng, M.-Z. J. Chem. Soc., Perkin Trans. 1 2000, 1609-
1613.
(11) (a) Matteson, D. S.; Man, H.-W. J. Org. Chem. 1996, 61, 6047-
6051. (b) Hiscox, W. C.; Matteson, D. S. J. Org. Chem. 1996, 61, 8315-
8316.
358
Org. Lett., Vol. 6, No. 3, 2004

acids have cis configurations. The model experiments may
open the door to prepare various chiral potassium cyclopropyl
trifluoroborates involving chiral cis-cyclopropyl trifluoro-
borates in particular from the corresponding alkenylboronic
ester of the chiral diols.
With various potassium cyclopropyl trifluoroborates 2 in
hand, we then investigated Suzuki-Miyaura cross-coupling
reactions of 2 with aryl bromides. The conditions for carrying
out the Suzuki-Miyaura coupling reaction were optimized
by using potassium trans-2-pentylcyclopropyl-trifluoroborate
(2f) and 4-bromoacetophenone as the substrates. The results
are indicated in Table 2.
furnished the products (3h) in satisfactory yields (Table 2,
entries 5 and 6).
The conditions (Table 2, entry 6) were subsequently
applied to study the cross-coupling reaction of various
stereodefined potassium cyclopropyl trifluoroborates with
aryl bromides, considering Pd(PPh3)4 and K3PO4‚3H2O are
easily obtained and cheap. The results are summarized in
Table 3.
As outlined in Table 3, both cis- and trans-cyclopropyl
trifluoroborates readily reacted not only with the aryl
Table 3. Cross-Coupling Reaction of Potassium Cyclopropyl
Trifluoroborates with Aryl Bromidesa
Table 2. Effects of Ligands and Solvents on the Coupling
Reaction of Potassium trans-2-Pentylcyclopropyl
Trifluoroborates with 4-Bromoacetophenonea
entry
coupling conditions
yieldb (%)
1
2
3
4
5
6
PdCl2(dppf), t-BuNH2, H2O, i-PrOH
PdCl2(dppf), Et3N, n-PrOH
PdCl2(dppf), Cs2CO3, THF, H2O
PdCl2(dppf), K3PO4‚3H2O, toluene, H2O
Pd(OAc)2, ligand,c K3PO4‚3H2O, toluene, H2O
Pd(PPh3)4, K3PO4‚3H2O, toluene, H2O
NR
NR
91
86
89
87
a The mixture of potassium trans-2-pentylcyclopropyl trifluoro borates
(1.2 mmol), 4-bromoacetophenone (1 mmol), 2 mol % of catalyst, 3 mmol
of base in various organic solvents (3 mL), and water (1 mL) was refluxed
for 20 h under N2 atmosphere. b Isolated yields based on 4-bromoacetophe-
none. c Ligand is 4 mol % of 2-biphenyldicyclohexylphosphine.
Molander reported that with i-PrOH-H2O as cosolvents
and t-BuNH2 or NEt3 as base, the palladium-catalyzed cross-
coupling reactions of potassium alkenyltrifluoro-borates with
aryl bromides can proceed smoothly.7b However, the condi-
tions mentioned above were not effective in our case (Table
2, entries 1 and 2). Using another method7b developed by
Molander, which was slightly modified by us (decreasing
the amount of palladium catalyst), we obtained the desired
cross-coupling product in high yield (Table 2, entry 3). To
avoid employing expensive Cs2CO3, we reinvestigated the
coupling conditions and found that using cheaper K3PO4‚
3H2O as base instead of Cs2CO3 and toluene in place of THF,
we also obtained the desired coupling products in satisfactory
yield (Table 2, entry 4). Further studies illustrated that the
combination of Pd(OAc)2 and 2-biphenyldicyclohexylphos-
phine or Pd(PPh3)4 rather than PdCl2(dppf) as catalyst also
(12) (a) Fontain, P.; Carboni, B.; Vaultier, M.; Carri_, R. Tetrahedron
Lett. 1989, 30, 4815-4818. (b) Fontain, P.; Carboni, B.; Vaultier, M.; Maas,
G. Synthesis 1991, 605-609.
(13) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020-3027. (b) Matteson, D. S.; Kim, G.
Y. Org. Lett. 2002, 4, 2153-2155.
a 1.2 mmol of potassium cyclopropyl trifluoroborate, 1.0 mmol of aryl
bromides, 2 mol % of Pd(PPh3)4, 3.0 equiv of K3PO4‚3H2O, 4.0 mL of
toluene-water (3:1, v: v), reflux for 20 h. b Isolated yields based on aryl
bromides used.
Org. Lett., Vol. 6, No. 3, 2004
359

bromides containing an electron-withdrawing group (Table
3, entries 2, 5, 7, and 8) but also with the ones bearing
electron-donating groups (Table 3, entries 1,3, 4, and 6). The
2D NOESY spectra of 3 showed that the products had the
same configurations as the potassium cyclopropyl trifluo-
roborates 2 used.
In summary, stereodefined potassium cyclopropyl trifluo-
roborates were prepared for the first time by the cyclopro-
panation of the alkenylboronic esters of pinacol generated
from the corresponding alkenylboronic acids and pinacol in
the presence of anhydrous MgSO4, followed by in situ
treatment with KHF2 in high yields. The first Suzuki-
Miyaura cross-coupling reaction of potassium cyclopropyl
trifluoroborates with aryl bromides under appropriate condi-
tions has also been achieved in satisfactory yields. In the
coupling reaction, the configurations of the cyclopropanes
were retained.
and handled. Thus, this work provides a new and facile
approach to synthesize various stereodefined cyclopropyl-
arenes, and it promises to be a potentially facile method for
the synthesis of enantiomerically pure cyclopropanes. Further
studies on the application of this method in the synthesis of
enantiomerically pure cyclopropanes are currently underway
in our laboratory.
Acknowledgment. We thank the NNSF of China and
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sci-
ences, for financial support.
Supporting Information Available: Experimental details
and spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
In addition, potassium cyclopropyl trifluoroborates are
monomeric and stable in air and are easily purified, stored,
OL036184E
360
Org. Lett., Vol. 6, No. 3, 2004