Palladium-catalyzed cross-coupling of cyclopropanols with aryl halides under mild conditions

Article abstract of DOI:10.1021/ol1026409

Intra- and intermolecular palladium-catalyzed cross-coupling of cyclopropanols with aryl halides can be achieved in good yields under mild conditions.

Full text of DOI:10.1021/ol1026409

ORGANIC
LETTERS
2011
Vol. 13, No. 1
110-113
Palladium-Catalyzed Cross-Coupling of
Cyclopropanols with Aryl Halides Under
Mild Conditions
David Rosa and Arturo Orellana*
Department of Chemistry, York UniVersity, 4700 Keele Street,
Toronto, ON, Canada M3J 1P3
aorellan@yorku.ca
Received October 31, 2010
ABSTRACT
Intra- and intermolecular palladium-catalyzed cross-coupling of cyclopropanols with aryl halides can be achieved in good yields under mild
conditions.
Reactivity umpolung is a powerful concept that often
facilitates unusual or nonintuitive disconnections in synthetic
planning. Homoenolates1 represent an important class of
umpolung synthons that display a charge affinity pattern
opposite to that of an R,ꢀ-unsaturated ketone. While it is
possible to deprotonate ketones directly to yield homoeno-
lates in some cases, these reactions are not general or
practical.2 Consequently, significant effort has been spent
seeking alternative means for the generation of homoenolates.
The metal-catalyzed rearrangement of siloxycyclopropanes
to nucleophilic homoenolates has received significant atten-
tion since Kuwajima’s seminal report.3 More recently, the
palladium(II)-catalyzed formation of palladium homoenolates
incapable of ꢀ-hydride elimination via directed C(sp3)-H
activation has been reported.4 In addition, recent work with
N-heterocyclic carbenes as organocatalysts has provided new
avenues for the generation and use of homoenolate equiva-
lents.5
The rearrangement of siloxycyclopropanes to homoeno-
lates can be achieved by using a variety of metals, and in
some cases the resulting homoenolates can be used in
palladium-catalyzed cross-coupling reactions.6 The pal-
ladium-catalyzed rearrangement of siloxycyclopropanes is
of particular interest since it obviates the use of a second
metal in the reaction mixture, and thus allows their direct
use in cross-coupling reactions.7 Although very useful, this
method is not without limitations. The cross-coupling reac-
tion of cyclopropane acetals with aryl triflates generally
proceeds in good yield as a result of the enhanced nucleo-
philicity of the cyclopropane ring and a sufficiently electro-
philic arylpalladium(II) intermediate. In contrast, the use of
aryl halides results in no reaction (eq 1). Furthermore, when
aryl triflates are utilized in the presence of LiCl the reaction
(5) Nair, V.; Vellalath, S.; Babu, N. P. Chem. Soc. ReV. 2008, 37, 2691.
(6) Reviews: (a) Kuwajima, I.; Nakamura, E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991;
Vol. 2, p 441. (b) Kuwajima, I.; Nakamura, E. In Topics in Current
Chemistry; Springer-Verlag: Berlin, Germany, 1990; Vol. 155, p 1. (c)
Kuwajima, I. Pure Appl. Chem. 1988, 60, 115.
(1) For a good entry into the homoenolate literature see: Molander, G. A.;
Jean-Ge´rard, L. J. Org. Chem. 2009, 74, 1297.
(2) (a) Nickon, A.; Lambert, J. L. J. Am. Chem. Soc. 1962, 84, 4004.
(b) Shiner, C. S.; Berks, A. H.; Fisher, A. M. J. Am. Chem. Soc. 1988, 110,
957.
(7) (a) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I. J. Am. Chem.
Soc. 1988, 110, 3296. (b) Aoki, S.; Nakamura, E.; Kuwajima, I. Tetrahedron
Lett. 1988, 29, 1541. (c) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima,
I. Tetrahedron Lett. 1989, 30, 6541. (d) Aoki, S.; Nakamura, E. Synlett
1990, 741. (e) Fujimura, T.; Aoki, S.; Nakamura, E. J. Org. Chem. 1991,
56, 2809. (f) Kang, F.-K.; Yamaguchi, T.; Ho, P.-S.; Kim, W.-Y.; Yoon,
S.-K. Tetrahedron Lett. 1997, 38, 1947.
(3) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1977, 99, 7360.
(4) (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazanno, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (b) Wang,
D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(c) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886.
10.1021/ol1026409  2011 American Chemical Society
Published on Web 12/01/2010

fails. The related cross-coupling of the less nucleophilic
ketone-derived cyclopropanols is also limited to the use of
aryl triflates and acyl halides (eq 2).
PdL2, would undergo a ligand exchange with the cyclopro-
panol (Scheme 1, I to II). Subsequent cyclopropanol rear-
Scheme 1
. Proposed Catalytic Cycle for the Cross-Coupling of
Palladium Homoenolates with Aryl Halides
Mechanistic studies by Nakamura point to C-C bond
cleavage of the siloxycyclopropane through a “corner attack”
by an electrophilic palladium intermediate as a key step in
the mechanism of these reactions. In 2000, Cha8 developed
palladium-catalyzed oxidative rearrangement of unprotected
cyclopropanols to R,ꢀ-unsaturated ketones,9,10 and invoked
a mechanism involving coordination of the cyclopropanol
oxygen to a Pd(II) species prior to C-C bond cleavage11
(Figure 1).
rangement (II to III) and reductive elimination would result
in the desired cross-coupled product (Scheme 1).
Substrates for this study were readily prepared from the
corresponding ketones by formation of the thermodynamic silyl
enol ether12 followed by cyclopropanation using the Furukawa13
modification of the Simmons-Smith reaction14 (eq 3).
We began our reaction development studies by attempting
the cross-coupling reaction of an unprotected cyclopropanol
with a tethered aryl bromide. We were happy to observe that
treatment of the free cyclopropanol with a simple catalyst system
consisting of Pd(OAc)2 and Ph3P provided the desired spiro-
cyclic ketone in 60% isolated yield (eq 4). We speculated that
the moderate yield was perhaps due to decomposition of the
cyclopropanol under the reaction conditions, and that in situ
deprotection might have a salubrious effect on the reaction.
Parenthetically, it is worth noting that this intramolecular process
could serve as a valuable alternative to the double alkylation
of ketone enolates to prepare spirocyclic ketones.
Figure 1. Mechanistic proposals for the palladium-catalyzed
rearrangement of 1-alkoxy-1-siloxycyclopropanes (Nakamura) and
cyclopropanols (Cha).
Given that the palladium-catalyzed rearrangement of
unprotected cyclopropanols likely proceeds through a dif-
ferent mechanism than that established by Nakamura for the
reaction of siloxycyclopropanes, it seemed plausible that this
alternative route to palladium-homoenolates could facilitate
their cross-coupling with aryl halides. We envisioned a
mechanistic scenario wherein an arylpalladium(II) intermedi-
ate, resulting from oxidative addition of an aryl halide to
(8) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2, 147.
The results of our optimization studies are summarized in
Table 1. Before screening fluoride sources for in situ
(9) For a similar report see: Okumoto, H.; Jinnai, T.; Shimizu, H.;
Harada, Y.; Mishima, H.; Suzuki, A. Synlett 2000, 629
.
(10) (a) Shan, M.; O’Doherty, G. A. Org. Lett. 2008, 10, 3381. (b) Shan,
M.; O’Doherty, G. A. Synthesis 2008, 3171. For a related iridium catalyzed
transformation, see: (c) Ziegler, D. T.; Steffens, A. M.; Funk, T. W.
(12) Miller, R. D.; McKean, D. R. Synthesis 1979, 730.
(13) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett.
1966, 7, 3353. (b) Furukawa, J.; Kawabata; Nishimura, J. Tetrahedron 1968,
24, 53.
Tetrahedron Lett. 2010, 51, 6726
.
(11) Terao, Y.; Wakui, H.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura,
M. J. Org. Chem. 2003, 68, 5236.
(14) See the Supporting Information for details.
Org. Lett., Vol. 13, No. 1, 2011
111

deprotection we assessed the viability of the reaction using
the TMS-protected cyclopropanol. While the desired cross-
coupling product was observed, there was no improvement
in the yield and the extended reaction time was impractical
(entry 1).15
Table 1. Reaction Developmenta
Table 3. Intermolecular Cross-Coupling Reactionsa b
,
fluoride
source
temp yieldb
solvent
base
time
(°C)
(%)
1
2
3
toluene Cs2CO3 none
toluene Cs2CO3 CsF
16 h
10 h
110
90
60
68
56
toluene Cs2CO3 TBAF 1 M (THF) 45 min
90
TBAF·H2O +
4
5
6
7
8
9
toluene Cs2CO3
4 Å ms
45 min
4 h
90
90
90
90
90
90
65
90
80
80
80
27
45
68
59
50
59
56
61
56
78d
92
toluene Cs2CO3 TBATc
toluene Cs2CO3 TBAF·H2O
toluene Ag2CO3 CsF
45 min
16 h
toluene K2CO3
toluene Et3N
CsF
CsF
16 h
16 h
10 THF
11 DME
12 DMA
13 CH3CN Cs2CO3 TBAF·H2O
14 CH3CN none TBAF·H2O
Cs2CO3 TBAF·H2O
Cs2CO3 TBAF·H2O
Cs2CO3 TBAF·H2O
16 h
30 min
20 min
15 min
15 min
a All reactions were conducted with 0.15 mmol of substrate at 0.08 M
concentration, 10 mol % of Pd(OAc)2, and 30 mol % of Ph3P. b Isolated
yields of pure product after column chromatography on SiO2. c TBAT )
tetrabutylammonium difluorotriphenylsilicate. d Using these conditions, the
reaction was shown to be effective with reduced catalyst loading: 5 mol %
(75% yield), 2 mol % (71% yield). No reaction was observed with 1 mol
% catalyst. For convenience, a 10 mol % catalyst loading was used for all
subsequent reactions.
Table 2. Intramolecular Cross-Coupling Reactionsa b
,
a All reactions were conducted at 0.08 M concentration with respect to
the siloxycyclopropane with use of the optimized conditions in Table 1
and with 2 equiv of aryl halide. b Isolated yields after purification on SiO2.
The use of CsF resulted in an improved yield at lower
temperature; however, no reduction in reaction time was
observed, presumably due to the low solubility of the salt in
toluene (entry 2). The use of more soluble fluoride sources
under anhydrous conditions dramatically reduced the reaction
time; however, this was accompanied by a reduction in yield
(entries 3-5). Fortunately, the use of TBAF·H2O generated
the product in good yield after a short reaction time (entry
6). A concurrent screen of bases revealed Cs2CO3 to be
optimal (entries 7-9). A screen of ligands and palladium
salts did not improve the results. Finally, a screen of solvents
a All reactions were conducted at 0.08 M concentration with respect to
the siloxycyclopropane with the optimized conditions in Table 1. b Isolated
yields after purification on SiO2.
(15) Since arylpalladium(II) intermediates resulting from oxidative
addition to aryl halides have been shown to be incapable of ring opening
siloxycylopropanes, we suspect that the 60% yield observed in this reaction
is likely due to base-catalyzed deprotection of the siloxycyclopropane.
112
Org. Lett., Vol. 13, No. 1, 2011

revealed that the use of DMA, DME, and THF provided the
product in comparable yield (entries 10-12). In contrast,
the use of CH3CN resulted in a nearly 20% increase in yield
(entry 13). Finally, omission of the base furnished the desired
ketone in 92% yield (entry 14).
on the oxidative addition partner result in an increased yield
(entries 1-3 and 4-6).
In conclusion, we have shown that cyclopropanol-derived
palladium homoenolates can be cross-coupled with aryl
halides under mild conditions by using a simple catalyst
system. It is likely that this reaction proceeds through a
different mechanism than that previously established for the
cross-coupling of aryl triflates and acyl halides with siloxy-
clopropanes and 1-alkoxy-1-siloxycyclopropanes. The reac-
tion proceeds in excellent yield in intramolecular cases, and
moderate to good yield in intermolecular cases.
With a satisfactory protocol at hand we began to examine
the scope of this reaction (Table 2). Intramolecular cross-
coupling reactions result in uniformly high yields with
cyclopentanone-, cyclohexanone-, or cycloheptanone-derived
cyclopropanols (entries 1-4). Notably, we observed no
evidence of ring-expanded products resulting from cleavage
of the ring-fusion bond. The use of aryl iodides instead of
aryl bromides appears to have no effect on the reaction (entry
1).
Acknowledgment. This work was generously supported
by the Natural Science and Engineering Research Council
of Canada (NSERC), the York University Faculty of Science
and Engineering, and the York University Faculty Associa-
tion.
Next we explored the intermolecular variant of the cross-
coupling reaction using an excess of the aryl halide (Table
3). In general, a considerable drop in yield is observed for
these reactions. Cross-coupling reactions with cyclohex-
anone-derived cyclopropanols proceed in slightly higher yield
than those of cyclopentanone-derived cyclopropanols. In
addition, it is apparent that electron-withdrawing substituents
Supporting Information Available: Full experimental
1
details and H and 13C NMR data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL1026409
Org. Lett., Vol. 13, No. 1, 2011
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