Palladium-catalyzed cross-coupling of cyclopropanol-derived ketone homoenolates with aryl bromides

Article abstract of DOI:10.1039/c3cc42080a

The cross-coupling reaction of cyclopropanol-derived ketone homoenolates bearing β-hydrogens with aryl and hetaryl bromides has been achieved for the first time. This reaction is high yielding, is broad in scope and uses a simple catalytic system. Notably, the proposed palladium homoenolates do not undergo β-hydride elimination to the corresponding α,β- unsaturated ketones.

Full text of DOI:10.1039/c3cc42080a

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Palladium-catalyzed cross-coupling of cyclopropanol-
derived ketone homoenolates with aryl bromides†
Cite this: DOI: 10.1039/c3cc42080a
David Rosa and Arturo Orellana*
Received 21st March 2013,
Accepted 22nd April 2013
DOI: 10.1039/c3cc42080a
www.rsc.org/chemcomm
The cross-coupling reaction of cyclopropanol-derived ketone direct approaches to this transformation. Unfortunately, these cataly-
homoenolates bearing b-hydrogens with aryl and hetaryl bromides tic methods are restricted to the use of amides or esters, and can suffer
has been achieved for the first time. This reaction is high yielding, is from the generation of product mixtures.
broad in scope and uses a simple catalytic system. Notably, the
In the 1970s Kuwajima recognized the potential of the cyclo-
proposed palladium homoenolates do not undergo b-hydride propanol ring to act as a homoenolate precursor (Fig. 1), and
elimination to the corresponding a,b-unsaturated ketones.
subsequently developed a number of related synthetic methods,10
including the first palladium-catalyzed cross-coupling reaction
Homoenolates constitute an important class of umpolung1 synthons of cyclopropanol derivatives.11 These cross-coupling reactions, how-
that bear a charge affinity pattern complementary to that of enolate ever, were severely limited in scope and required very electron-rich
anions (Fig. 1). Owing to their synthetic potential and the difficulties cyclopropane acetals, very electron-poor palladium intermediates
associated with their direct preparation from ketones,2 significant (derived from oxidative addition of Pd(0) to aryl triflates or acyl
effort has been devoted to the development of new methods to access halides), or both. In addition, the preparation of the cyclopropanol
and use homoenolates and homoenolate equivalents over the years.3,4 derivatives was not straightforward. Since then, the development of
N-Heterocyclic carbenes have enabled the catalytic generation of the Kulinkovich reaction12 has made cyclopropanols readily avail-
homoenolates from a,b-unsaturated aldehydes.5 These reactions, able. In this light, it is surprising that little work related to the
however, are not amenable to forging C–C bonds between homo- catalytic cross-coupling reactions of cyclopropanol-derived homo-
enolates and aryl electrophiles (i.e. aryl halides). One approach to this enolates with aryl electrophiles has been performed. This is
transformation involves the palladium-catalyzed cross-coupling reac- perhaps due to limitations shown in Kuwajima’s early work,
tion of preformed homoenolates6 with aryl electrophiles. These reac- and to the propensity of palladium homoenolates to undergo
tions, however, suffer from the need to synthesize these homoenolates decomposition to the corresponding a,b-unsaturated ketones via
by activation of simpler substrates, which often requires multiple b-hydride elimination.13 Our group reported the first palladium-
steps.7 The catalytic formation and cross-coupling of ester homoeno- catalyzed cross-coupling of aryl halides with cyclopropanol-derived
lates with aryl electrophiles developed by Baudoin et al.,8 and the homoenolates,14 and the first direct arylation reaction using cyclo-
formation and cross-coupling of amide homoenolates using Pd(0)/ propanol-derived homoenolates.15 These reactions were limited by
Pd(II) and Pd(II)/Pd(IV) catalysis developed by Yu et al.9 represent more the need to use homoenolates that were incapable of undergoing
b-hydride elimination. Here we report the first palladium-catalyzed
cross-coupling reaction of aryl bromides with catalytically generated
ketone homoenolates bearing b-hydrogens.
Our working mechanistic proposal for these cross-coupling
reactions invokes (i) oxidative addition of a Pd(0) catalyst to the
aryl halide, (ii) ligand exchange on palladium and deprotonation of
the cyclopropanol (not necessarily in that order), (iii) b-carbon
Fig. 1 Charge affinity patterns of enolates and homoenolates, and equilibrium
elimination leading to a palladium homoenolate, and (iv) reductive
elimination (Scheme 1). The development of this palladium-
catalyzed cross-coupling reaction must circumvent the propensity
of cyclopropanol rings to undergo base-mediated ring-opening to
the corresponding ketone,16 and the more problematic tendency of
palladium homoenolates to undergo facile b-hydride elimination17
to the corresponding a,b-unsaturated ketone. Therefore the choice
between a metal homoenolate and metallated cyclopropanol.
Department of Chemistry, York University, 4700 Keele Street, Toronto, ON M3J 1P3,
Canada. E-mail: aorellan@yorku.ca; Fax: +1 416 736 5936;
Tel: +1 416 736 2100 ext 70760
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectroscopic data. See DOI: 10.1039/c3cc42080a
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Table 2 Cross-coupling of cyclopropanol-derived homoenolates with various
(het)aryl bromidesa,b,c
Scheme 1 Mechanistic proposal for the cross-coupling of aryl halides with
ketone homoenolates and competing side reactions.
of base and catalyst system would be expected to have a significant
impact on the product distribution.
A 1,1-disubstituted cyclopropanol (1) and 4-bromoanisole were
chosen to optimize this reaction (Table 1). The use of monodentate
ligands provided the coupled product (1a) in modest yields along
with significant amounts of the ring-opened product (1b, entries 1
and 2). The use of monodentate biaryl phosphine ligands (Buchwald
ligands) resulted in increased product yields, however significant
amounts of ring-opened product were still observed (entries 3–5). A
further increase in yield was observed when bidentate ligands were
used (entries 6–10). Note that the yield of the coupled product does
not vary significantly with the bite angle or the nature of the
phosphine (trialkyl vs. alkyldiaryl vs. triaryl). These results suggest
that the increased yield of the reaction is due the bidentate
phosphine occupying two coordination sites on palladium, thereby
retarding b-hydride elimination relative to reductive elimination.18
Having developed satisfactory conditions for the cross-coupling of
cyclopropanol-derived homoenolates, we explored the scope of the
a
b
c
Isolated yields. Cs2CO3 was used instead of K3PO4. All reactions
were conducted using 0.24 mmol of cyclopropanol (0.1 M).
reaction with respect to the oxidative addition partner (Table 2). Aryl
halides bearing electron-withdrawing (entries 2–7) and electron-
donating (entries 8–12) functional groups provide the coupled
products in good yields. Aryl halides bearing one ortho-substituent
couple well (entry 8), however, a di-ortho-substituted aryl halide
provides a moderate yield of the product (entry 9). The latter result
likely reflects a difficult oxidative addition step. A selection of
electron-poor and electron-rich heterocycles was also shown to
couple effectively (entries 13–16). In some instances (entries 3, 6, 9,
11, 12, 14 and 16), the coupled product was obtained in lower
than expected yield and was sometimes (entries 3c, 9c and 11c)
accompanied by the corresponding a,b-unsaturated ketone.19,20
Fortunately, switching from K3PO4 to the weaker Cs2CO3 base
improved the yield of the coupled product, and prevented the
formation of the unsaturated ketone in all but one instance (entry 9).
We have also investigated the scope of the reaction with respect
to the cyclopropanol partner (Table 3). Monocyclic cyclopropanols
bearing alkyl (entries 17–19), allyl (entry 20), benzyl (entry 21)
and aryl (entry 22) substituents at the 1-position couple effec-
tively. Notably, monocyclic 1,2-disubstituted cyclopropanols
couple selectively, giving the product arising from cleavage of
Table 1 Reaction development (selected results)a,b
Entry
Base
Ligand
Yield (1a : 1b)c
1
2
3
4
5
6
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
PPh3
PtBu3
53 : 18
46 : 36
49 : 36
64 : 18
62 : 15
77 : 0
73 : 0
79 : 0
83 : 0
86 : 5
XPhosd
SPhosd
DavePhosd
dppf d
dpped
dpppd
dppbd
dcpbd
10
K3PO4
a
See ESI for complete optimization results. b All reactions were conducted the least substituted cyclopropane bond (entries 21 and 22).
using 0.24 mmol of cyclopropanol (0.1 M) and 20 mol% of bidentate or
Fused bicyclic cyclopropanols also couple selectively to give
40 mol% of monodentate ligand. c Isolated yields. d XPhos = 2-dicyclohexyl-
phosphino-20,40,60-triisopropyl-biphenyl, SPhos = 2-dicyclohexylphosphino-
the product arising from scission of the least substituted
cyclopropane bond (entries 23a, 24a and 25a/25c), however
appreciable amounts of the products arising from cleavage of
the ring fusion bonds are also observed in some instances
(entries 23d and 24d).
20,60-dimethoxybiphenyl, DavePhos
dimethylamino)biphenyl, dppf
dppe ethylenebis(diphenylphosphine), dppp
phino)propane, dppb 1,4-bis(diphenylphosphino)butane, dcpb
=
2-dicyclohexylphosphino-20-(N,N-
1,10-bis(diphenylphosphino)ferrocene,
1,3-bis(diphenylphos-
=
=
=
=
=
1,4-bis(dicyclohexylphosphino)butane.
c
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Table 3 Cross-coupling of various cyclopropanols with 4-bromoanisolea,b,c
Notes and references
1 D. Seebach, Angew. Chem., Int. Ed. Engl., 1979, 18, 239.
2 (a) A. Nickon and J. L. Lambert, J. Am. Chem. Soc., 1962, 84, 4004;
(b) C. S. Shiner, A. H. Berks and A. M. Fisher, J. Am. Chem. Soc., 1988,
110, 957.
3 For a concise overview see: R. B. Lettan II., C. V. Galliford,
C. C. Woodward and K. A. Scheidt, J. Am. Chem. Soc., 2009, 131, 8805.
4 Reviews on homoenolate chemistry: (a) N. H. Werstiuk, Tetrahedron,
1983, 39, 205; (b) I. Kuwajima, Pure Appl. Chem., 1988, 60, 115;
(c) D. Hoppe, T. Kramer, J.-R. Schwark and O. Zschage, Pure Appl.
Chem., 1990, 62, 1999; (d) M. T. Crimmins and P. G. Nantermet, Org.
Prep. Proced., 1993, 25, 41.
5 (a) V. Nair, S. Vellalath and N. P. Babu, Chem. Soc. Rev., 2008,
37, 2691; (b) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, R. R. Paul,
A. Jose and V. Sreekumar, Chem. Soc. Rev., 2011, 40, 5336;
(c) J. Izquierdo, G. E. Hutson, D. T. Cohen and K. A. Scheidt, Angew.
Chem., Int. Ed., 2012, 51, 11686.
6 (a) G. A. Molander and D. E. Petrillo, Org. Lett., 2008, 10, 1795;
´
(b) G. A. Molander and L. Jean-Gerard, J. Org. Chem., 2009, 74, 1297;
´
(c) G. A. Molander and L. Jean-Gerard, J. Org. Chem., 2009, 74, 5446–5450;
(d) Z.-L. Shen, K. K. K. Goh, H.-L. Cheong, C. H. A. Wong, Y.-C. Lai,
Y.-S. Yang and T.-P. Loh, J. Am. Chem. Soc., 2010, 132, 15852; (e) Z.-L. Shen,
Y.-C. Lai, C. H. A. Wong, K. K. K. Goh, Y.-S. Yang, H.-L. Cheong and
T.-P. Loh, Org. Lett., 2011, 13, 422; ( f ) Z.-L. Shen, K. K. K. Goh, C. H. A.
Wong, Y.-S. Yang, Y.-C. Lai, H.-L. Cheong and T.-P. Loh, Chem. Commun.,
2011, 47, 4778; (g) J. C. H. Lee, R. McDonald and D. G. Hall, Nat. Chem.,
´
2011, 3, 894; (h) D. L. Sandrock, L. Jean-Gerard, C. Chen, S. D. Dreher and
G. A. Molander, J. Am. Chem. Soc., 2012, 132, 17108.
7 See for example: G. A. Molander and S. A. McKee, Org. Lett., 2011,
13, 4684.
´
8 (a) A. Renaudat, L. Jean-Gerard, R. Jazzar, C. E. Kefalidis, E. Clot and
O. Baudoin, Angew. Chem., Int. Ed., 2010, 49, 7261; (b) P. Larini,
C. E. Kefalidis, R. Jazzar, A. Renaudat, E. Clot and O. Baudoin,
Chem.–Eur. J., 2012, 18, 1932.
9 (a) D. H. Wang, W. Masayuki, R. Giri and J.-Q. Yu, J. Am. Chem. Soc.,
2008, 130, 7190; (b) W. Masayuki, K. M. Engle and J.-Q. Yu, J. Am.
Chem. Soc., 2009, 131, 9886; (c) W. Masayuki and J.-Q. Yu, Tetra-
hedron, 2010, 66, 4811; (d) W. Masayuki, K. S. L. Chan, X.-G. Zhang,
J. He, M. Miura and J.-Q. Yu, J. Am. Chem. Soc., 2012, 134, 18570.
10 Reviews: (a) I. Kuwajima and E. Nakamura, Topics in Current Chemistry,
Springer-Verlag, Berlin, Germany, 1990, vol. 155, pp. 1–39; (b) I. Kuwajima
and E. Nakamura, in Comprehensive Organic Synthesis, ed. B. Trost and
I. Fleming, Pergamon, Oxford, UK, 1991, vol. 2, pp. 441–454.
11 (a) S. Aoki, T. Fujimura, E. Nakamura and I. Kuwajima, J. Am. Chem. Soc.,
1988, 110, 3296–3298. For mechanistic studies of this reaction see: (b) T.
Fujimura, S. Aoki and E. Nakamura, J. Org. Chem., 1991, 56, 2809–2821.
12 (a) O. Kulinkovich, Chem. Rev., 2003, 103, 2597; (b) O. Kulinkovich
and A. de Meijere, Chem. Rev., 2000, 100, 2789.
13 (a) S.-B. Park and J. K. Cha, Org. Lett., 2000, 2, 147; (b) H. Okumoto,
T. Jinnai, H. Shimizu, Y. Harada, H. Mishima and A. Suzuki, Synlett,
2000, 629.
14 D. Rosa and A. Orellana, Org. Lett., 2011, 13, 110.
15 D. Rosa and A. Orellana, Chem. Commun., 2012, 48, 1922.
16 D. H. Gibson and C. H. DePuy, Chem. Rev., 1974, 74, 605.
17 Reviews: (a) N. Kambe, T. Iwasaki and J. Terao, Chem. Soc. Rev.,
2011, 40, 4937; (b) R. Jana, T. P. Pathak and M. S. Sigman, Chem.
Rev., 2011, 111, 1417; (c) A. Rudolph and M. Lautens, Angew. Chem.,
Int. Ed., 2009, 48, 2656; (d) A. C. Frisch and M. Beller, Angew. Chem.,
Int. Ed., 2005, 44, 674; (e) M. R. Netherton and G. C. Fu, Top.
Organomet. Chem., 2005, 14, 85.
18 T. Hayashi, M. Konishi and M. Kumada, Tetrahedron Lett., 1979, 20, 1871.
19 Control experiments show that these a,b-unsaturated products arise
from the oxidation of the ketone obtained after cross-coupling, and
not through a Heck reaction of an a,b-unsaturated ketone with an
aryl bromide.
a
b
c
Isolated yields. Cs2CO3 was used instead of K3PO4. All reactions
were conducted using 0.24 mmol of cyclopropanol (0.1 M).
In conclusion, we have developed the first palladium-catalyzed
cross-coupling reaction of aryl bromides with cyclopropanol-
derived homoenolates capable of undergoing b-hydride elim-
ination. This reaction proceeds with good yields, uses a simple
catalyst system, and tolerates a wide range of aryl bromides and
cyclopropanols.
20 For a leading reference on the palladium-catalyzed oxidation of
similar ketones, see: Y. Shang, X. Jie, J. Zhou, P. Hu, S. Huang and
W. Su, Angew. Chem., Int. Ed., 2013, 52, 1299.
This work was supported by York University and the Natural
Science and Engineering Research Council (NSERC) of Canada.
c
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Chem. Commun.