Palladium-Catalyzed Suzuki-Type Cross-Couplings of lodocyclopropanes with Boronic Acids: Synthesis of trans-1,2-Dicyclopropyl Alkenes

Full text of DOI:10.1021/jo9614654

8718
J . Org. Chem. 1996, 61, 8718-8719
Ta ble 1. Effect of Solven t a n d Ba se on th e
Cr oss-Cou p lin g Rea ction
P a lla d iu m -Ca ta lyzed Su zu k i-Typ e
Cr oss-Cou p lin gs of Iod ocyclop r op a n es w ith
Bor on ic Acid s: Syn th esis of
tr a n s-1,2-Dicyclop r op yl Alk en es
Andre´ B. Charette* and Andre´ Giroux
De´partement de Chimie, Universite´ de Montre´al,
Que´bec H3C 3J 7, Canada
Received J uly 31, 1996
The palladium-catalyzed coupling reaction between
boronic acids and alkenyl and aryl iodides is a powerful
and general method for the formation of carbon-carbon
bonds.1 The availability of the reagents and the mild
reaction conditions all contribute to the versatility of this
reaction. The Suzuki coupling offers several additional
advantages, such as being largely unaffected by the
presence of water and having a broad range of functional
groups. Consequently, the coupling reaction has been
used extensively in the synthesis of natural products,
nucleoside analogs, and pharmaceutical compounds.
Although the Suzuki method has been extensively used
for the coupling of two sp2 carbon atoms,2 it also allows
the coupling of carbon atoms of other hybridization.3 We
were interested in extending the Suzuki cross-coupling
reaction to cyclopropyl iodides to synthesize more com-
plex cyclopropanes.4-6 To the best of our knowledge,
there is no literature precedent for the oxidative insertion
of palladium(0) into a cyclopropyl iodide bond; however,
we felt that this process was feasible since cyclopropanes
are known to have some sp2 character.5 Cross-coupling
of vinyl halides and cyclopropylzincs7 under Negishi’s
conditions are known, but these reactions rely on the
insertion of palladium(0) into the sp2 vinyl halide bond
in the oxidative insertion step of the catalytic cycle.
Herein, we report the first palladium-catalyzed cross-
couplings of iodocyclopropanes with vinyl boronate esters
and aryl boronic acids under Suzuki-type conditions.
For our initial studies, we examined the reaction
between iodocyclopropane 18 and vinylboronate ester 29
a
Reactions were carried out at 90 °C for 20 h using a mixture
of iodocyclopropane 1 (0.10 mmol), boronate ester 2 (0.15 mmol),
Pd(OAc)2 (0.01 mmol), PPh3 (0.05 mmol), and the additive (0.30
mmol). Conversions were determined by 1H NMR analysis and
b
are based on the remaining iodocyclopropane 1. c In this case, 0.02
mmol of Pd(OAc)2 is used with 0.10 mmol of PPh3.
(Table 1). A satisfying 25% conversion to the cross-
coupled product 3 was observed when the precursors 1
and 2 were first submitted to standard Suzuki conditions
(entry 1) using sodium carbonate as the base in benzene-
water. Increasing the solubility of the base in the organic
phase slightly improved the conversion10 (entries 2 and
3), but the overall yield was still at an impractical level.
In order to further increase the solubility of the base in
the organic phase, a phase-transfer catalyst was used as
an additive. The addition of tetrabutylammonium chlo-
ride with cesium carbonate improved the conversion to
50% in both benzene-H2O or DME-H2O mixtures
(entries 4 and 5). Conversely, using 20% palladium(0)
catalyst in benzene-H2O gave an 80% conversion (entry
6). Many other conditions were surveyed using different
bases, solvents, and catalysts in order to optimize the
conditions for the coupling. Gratifyingly, quantitative
conversion of iodocyclopropane 1 to the desired coupling
product 3 was obtained in DMF-H2O at 90 °C using K2-
CO3 as the base and Bu4NCl as an additive (entry 7).11
The cross-coupling reaction of a variety of vinyl bor-
onate esters with cis- or trans-3-iodocyclopropylmethanol
derivatives 1, 4, and 6 were then carried out using these
optimized conditions (Table 2).
(1) (a) Suzuki, A.; Miyaura, N. Chem. Rev. 1995, 95, 2457-2483.
(b) Suzuki, A.; Miyaura, N.; Suginome, H. Bull. Chem. Soc. J pn. 1982,
55, 2221-2223.
(2) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513-519.
(3) For examples see: (a) Moreno-Manas, M.; Pajuelo, F.; Pleixats,
R. J . Org. Chem. 1995, 60, 2396-2397. (b) Ishiyama, T.; Abe, S.;
Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691-694. (c) Moriya, T.;
Furuuchi, T.; Miyaura, N.; Suzuki, A. Tetrahedron 1994, 50, 7961-
7968. (d) Miyaura, N.; Maeda, K.; Suginome, H.; Suzuki, A. J . Org.
Chem. 1982, 47, 2117-2120.
(4) For examples of coupling reactions involving cyclopropanes,
see: (a) Corey, E. J .; Eckrich, T. M. Tetrahedron Lett. 1984, 25, 2415-
2418. (b) Hildebrand, J . P.; Marsden, S. P. Synlett 1996, 893-894. (c)
Piers, E.; J ean, M.; Marrs, P. S. Tetrahedron Lett. 1987, 28, 5075-
5078.
High yields of the cross-coupling products were usually
obtained with alkyl-substituted vinylboronate esters. In
most cases, the reaction was completed in less than 6 h.
However, moderate yields and lower reactivities were
obtained when the vinyl boronate ester moiety contained
an oxygen (entries 4 and 5). The cross-coupling reaction
is also applicable to cis-iodocyclopropane 6 (entry 3), and
it tolerates an unprotected hydroxyl group such as that
in 4 (entry 2).
(5) For reactivity studies and molecular orbital calculations of
cyclopropanes see: (a) Wiberg, K. B. Acc. Chem. Res. 1996, 29, 229-
234.
(6) (a) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.;
Shigematsu, N.; Okuhara, M.; Kohsaka, M.; Horikoshi, K. J . Antibiot.
1990, 43, 748-754. (b) Kuo, M. S.; Zielinski, R. J .; Cialdella, J . I.;
Marschke, C. K.; Dupuis, M. J .; Li, G. P.; Kloosterman, D. A.; Spilman,
C. H.; Marshall, V. P. J . Am. Chem. Soc. 1995, 117, 10629-10634.
(7) (a) Piers, E.; J ean, M.; Marrs, P. S. Tetrahedron Lett. 1987, 28,
5075-5078. (b) Harada, T.; Katsuhira, T.; Hattori, K.; Oku, A. J . Org.
Chem. 1993, 58, 2958-2965.
With these results in hand, we next carried out the
Suzuki cross-coupling reaction on a variety of aryl- and
(10) It was shown previously that the addition of a base greatly
facilitates the cross-coupling of organoboron reagents with electrophiles
by accelerating the rate of the transmetalation step; for examples,
see: (a) Takayuki, O.; Miyaura, N.; Suzuki, A. J Org. Chem. 1993, 58,
2201-2208. (b) Suzuki, A. Pure Appl. Chem. 1991, 63, 419-422.
(11) The coupling yield drops significantly if the addition of Bu4-
NCl is omitted. For a detailed discussion of the cross-coupling catalytic
cycle, see: (a) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749-1758. (b)
Moreno-Manas, M.; Pe´rez, M.; Pleixats, R. J . Org. Chem. 1996, 61,
2346-2351 and references cited therein.
(8) (()-Iodocyclopropane 1 was prepared by known procedures: (a)
J ung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851-3854. (b)
Piers, E.; Coish, P. D. Synthesis 1995, 47-55.
(9) Boronate ester 2 was prepared in five steps from cinnamyl
alcohol (1. ZnEt2, CH2I2; 2. DMSO, (COCl)2, Et3N; 3. CBr4, PPh3; 4.
BuLi; 5. catecholborane). See the Supporting Information for details.
S0022-3263(96)01465-X CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 25, 1996 8719
Ta ble 2. Cr oss-Cou p lin g Rea ction s of Vin yl Bor on a te Ester s w ith Iod ocyclop r op a n es
a
All the reactions were carried out at 90 °C in DMF-H2O (4:1) using a mixture of the iodocyclopropane (0.40 mmol), the boronate
b
ester (0.60 mmol), Pd(OAc)2 (0.04 mmol), PPh3 (0.20 mmol), K2CO3 (1.20 mmol), and Bu4NCl (0.80 mmol). Isolated yields.
Ta ble 3. Cr oss-Cou p lin g Rea ction s of Ar ylbor on ic
Acid sa
process via the possible formation of a stable trifluorobo-
rate intermediate in the transmetalation step.14 In our
case, the addition of CsF afforded the o-methylphenyl-
substituted cyclopropane product 22 in 80% isolated yield
(entry 5). Attempts to cross-couple heterocyclic-derived
boronic acids such as 2-thienylboronic acid under the
initial conditions (K2CO3, Bu4NCl) completely failed and
resulted in the exclusive formation of the deboronation
product.15 Gronowitz16 has shown that the use of DME
as the solvent was another means of preventing the
formation of the deboronation product. The desired
coupled products 24 and 26 were obtained in moderate
yields when DME was used as the solvent. The DMF-
CsF combination again produced the best results, afford-
ing the desired coupled products in 70 and 78% isolated
yield (entries 6 and 7).
In conclusion, we have reported the first cross-coupling
reaction of substituted cyclopropyl iodides with boronic
acids. This methodology represents the first insertion
of palladium(0) in a cyclopropyl halide bond, and it opens
the door to other palladium-catalyzed coupling reactions
involving cyclopropyl iodides.
Ack n ow led gm en t. This research was supported by
the Natural Science and Engineering Research Council
(NSERC) of Canada, Merck Frosst Canada, F.C.A.R.
(Que´bec), Eli Lilly, and the Universite´ de Montre´al. An
Ontario Graduate Scholarship to A.G. is also gratefully
acknowledged. We also thank P. Chua for useful
discussions.
a
Coupling reactions were conducted at 90 °C for 4-20 h using
the iodocyclopropane (0.40 mmol), the boronic acid (0.60 mmol),
Pd(OAc)2 (0.04 mmol), and PPh3 (0.20 mmol). Conditions used
are as follows. Procedure A: K2CO3 (1.20 mmol), Bu4NCl (0.80
mmol) in DMF-H2O (4:1). Procedure B: K2CO3 (1.20 mmol),
Bu4NCl (0.80 mmol) in DME-H2O (4:1). Procedure C: CsF (1.80
mmol) in anhyd DMF. c Isolated yield.
b
Su p p or tin g In for m a tion Ava ila ble: General experimen-
heterocyclic-derived boronic acids (Table 3).12 Phenyl-
boronic acid (14) gave very good coupling yields with both
the trans- and cis-iodocyclopropane 1 and 6 (entries 1 and
2). p-Substituted arylboronic acids were also smoothly
converted into the coupling products in high yields
(entries 3 and 4). One limitation of the coupling reaction
under these conditions surfaced when we attempted to
use o-substituted arylboronic acids. For example, the
coupling reaction using 2-methylphenylboronic acid gave
the desired compound in only 15% yield.13 The addition
of fluoride ion is known to facilitate the cross-coupling
tal procedures, characterization data for all compounds, and
1
copies of the H and 13C NMR spectra of the reaction products
(50 pages).
J O9614654
(13) For examples of cross-coupling studies of o-substituted phenyl-
boronic acids see: (a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett
1992, 207-210. (b) Anderson, J . C.; Namli, H. Synlett 1995, 765-766.
(c) Zhang, H.; Chan, K. S. Tetrahedron Lett. 1996, 7, 1043-1044.
(14) Wright, S. W.; Hageman, D. L.; McClure, L. D. J . Org. Chem.
1994, 59, 6095-6097.
(15) Minor amounts of thiophene could be detected in the crude
NMR of the reaction mixture.
(12) For the preparation of arylboronic acids see: Thompson, W.;
Gaudino, J . J . Org. Chem. 1984, 49, 5237-5243.
(16) Gronowitz, W. J .; Bobosic, V.; Lawitz, K. Chem. Scripta 1984,
23, 120-125.-