Silver-promoted, palladium-catalyzed direct arylation of cyclopropanes: Facile access to spiro 3,3′-cyclopropyl oxindoles

Article abstract of DOI:10.1021/ol4003338

The Pd-catalyzed, Ag(I)-mediated intramolecular direct arylation of cyclopropane C-H bonds is described. Various spiro 3,3′-cyclopropyl oxindoles can be obtained in good to excellent yields from easily accessible 2-bromoanilides. The kinetic isotope effect was determined and epimerization studies were conducted, suggesting that the formation of a putative Pd-enolate is not operative and that the reaction proceeds via a C-H arylation pathway.

Full text of DOI:10.1021/ol4003338

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1350–1353
Silver-Promoted, Palladium-Catalyzed
Direct Arylation of Cyclopropanes:
Facile Access to Spiro 3,30-Cyclopropyl
Oxindoles
ꢀ
Carolyn L. Ladd, Daniela Sustac Roman, and Andre B. Charette*
ꢀ
Centre in Green Chemistry and Catalysis, Department of Chemistry, Universite de
Montreal, P.O. Box 6128 Station Downtown, Montreal, Quebec, H3C 3J7, Canada
ꢀ
ꢀ
ꢀ
andre.charette@umontreal.ca
Received February 4, 2013
ABSTRACT
The Pd-catalyzed, Ag(I)-mediated intramolecular direct arylation of cyclopropane CꢀH bonds is described. Various spiro 3,30-cyclopropyl
oxindoles can be obtained in good to excellent yields from easily accessible 2-bromoanilides. The kinetic isotope effect was determined and
epimerization studies were conducted, suggesting that the formation of a putative Pd-enolate is not operative and that the reaction proceeds via a
CꢀH arylation pathway.
The spiro 3,30-cyclopropyl oxindole core is a recurring
structural motif present in several agrochemically and
pharmaceutically active compounds,1 including herbici-
des,2 inhibitors, and antagonistsfor treatingcancer,3 mood
disorders,4 and HIV.5 In addition, spiro 3,30-cyclopropyl
oxindoles have demonstrated synthetic utility as inter-
mediates toward accessing relevant oxindole alkaloids.6
Given the biological and synthetic potential of these
compounds, it is not surprising that the number of reports
regarding spirooxindole synthesis has increased over the
past decade, suggesting a demand for novel and more
efficient routes for preparing these architectures.7
Common routes to obtain spiro 3,30-cyclopropyl oxi-
ndoles involve functionalization of enolizable 2-oxindoles
via alkylation strategies such as Michael-initiated ring
closure (Scheme 1).8 3-Alkylidene oxindoles can also be
functionlized via the addition of sulfur9 or phosphorus
ylides.10 Other disclosed methods involve Rh(II)-catalyzed
decomposition of carbene precursors such as diazo species
and subsequent formal [2 þ 1] cycloaddition with alkenes
to form cyclopropanes.11,12 Some drawbacks to these
(1) Pesciaioli, F.; Righi, P.; Mazzanti, A.; Bartoli, G.; Bencivenni, G.
Chem.;Eur. J. 2011, 17, 2842.
(2) Condon, M.; Karp, G. EP 0 549 892 A1, 1993.
(3) Wurster, J. WO 2007/008664 A1, 2007.
(4) (a) Atkinson, B.; Beattie, D.; Culshaw, A.; Dale, J.; Devereux, N.;
McKenna, J. WO 2011/092293 A2, 2011. (b) Schmidt, C.; Sobolov-Jaynes,
S. EP 1 186 318 A2, 2002.
(5) (a) He, Y.; Jiang, T.; Kuhen, K.; Ellis, D.; Wu, B.; Wu, T.;
Bursulaya, B. WO 2004/037247 A1, 2004. (b) Jiang, T.; Kuhen, K. L.;
Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu, T. Y.; He, Y.
Bioorg. Med. Chem. Lett. 2006, 16, 2105. (c) Jiang, T.; Kuhen, K. L.;
Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Tuntland, T.;
Zhang, K.; Karanewsky, D.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
2109.
(6) (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
(b) Meyers, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 694.
(c) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 1498.
(d) Lerchner, A.; Carreira, E. M. Chem.;Eur. J. 2006, 12, 8208. (e)
Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc. 2002, 124, 14826. (f)
Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta 2000, 83, 1175.
(7) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem.
2012, 10, 5165.
(8) (a) Stevens, F. C.; Bloomquist, W. E.; Borel, A. G.; Cohen, M. L.;
Droste, C. A.; Heiman, M. L.; Kriauciunas, A.; Sall, D. J.; Tinsley, F. C.;
Jesudason, C. D. Bioorg. Med. Chem. Lett. 2007, 17, 6270. (b) Jaegli, S.;
Vors, J.-P.; Neuville, L.; Zhu, J. Tetrahedron 2010, 66, 8911. (c)
Pesciaioli, F.; Righi, P.; Mazzanti, A.; Bartoli, G.; Bencivenni, G.
Chem.;Eur. J. 2011, 17, 2842.
(9) Forrest, G.; Hamilton, H. WO 2004/037820 A1, 2004.
(10) Eberle, M. K.; Kahle, G. G.; Shapiro, M. J. J. Org. Chem. 1982,
47, 2210.
(11) He, Y.; Jiang, T.; Kuhen, K.; Ellis, D.; Wu, B.; Wu, T.;
Bursulaya, B.WO 2004/037247 A1, 2004.
r
10.1021/ol4003338
Published on Web 03/01/2013
2013 American Chemical Society

methods involve hazardous reagents such as diazo com-
pounds and extra synthetic steps to access the required
precursors. Alternatively, an intramolecular arylation
strategy involving a direct functionalization of R-(sp3)-H
from cyclopropyl anilides would permit exploitation of
readily accessible, easier to handle starting materials, thus,
circumventing the use of the above-mentioned reagents.
Scheme 2. Effect of Aromatic Substitutiona
Scheme 1. Routes To Access Spiro 3,30-Cyclopropyl Oxindoles
a Reactions were performed on 0.5 mmol scale. Isolated yields.
preparation of numerous other relevant compounds.17
Cognizant of this, our group has been actively involved
in developing novel cyclopropanation methodologies.18
With this interest, in conjunction with our experience
in the direct arylation of C(sp3)ꢀH centers, we turned
our attention to developing methods for functionalizing
cyclopropane CꢀH bonds. The potential for direct func-
tionalization methods for cyclopropanes remains largely
untapped, despite the pseudo sp2 natureofthese bondsand
their pKa, which is highly suited for insertion.19 Herein,
we disclose a novel intramolecular Pd-catalyzed aryla-
tion of 2-bromoanilides, producing spiro 3,30-cyclopropyl
oxindoles in the presence of Ag(I) salts. Additionally,
mechanistic studies were performed to eliminate the possi-
bility of the arylation proceeding via enolate pathways,
supporting a direct arylation scaffold.
Progress within the field of direct CꢀH functionaliza-
tion has contributed new synthetic pathways, leading to
more streamlined chemical syntheses.13 Earlier work by
our group has focused on the direct functionalization of
various arenes, providing facile access to relevant hetero-
cyclic and nonheterocyclic compounds.14 For example, we
reported the direct benzylic arylation of N-iminopyridinium
ylides with aryl chlorides.15 Considering the prevalence
of C(sp3)ꢀH bonds, we directed our interests to targeting
other direct functionalizations involving these bonds.16
Cyclopropanes have been established as key alkene
isosteres in various pharmacologically active compounds.
They are also present in natural products and have been
applied as valuable synthetic precursors en route to the
Our initial optimization of the arylation of 2-bromoanilide
1a revealed that Pd(OAc)2 (5 mol %), PCy3 (5 mol%), and
K2CO3 (1.5 equiv) were optimal. Only 1 equiv of cationic
Ag was required, and this could also be delivered using
Ag3PO4.20,21 Aryl bromides proved optimal, as chloro
(12) Kumari, G.; Nutan; Modi, M.; Gupta, S. K.; Singh, R. K. Eur. J.
Med. Chem. 2011, 46, 1181.
(13) For selected reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. Rev. 2007, 107, 174. (b) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147. (c) Daugulis, O.; Do, H.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074.
(18) For recent examples: (a) Lindsay, V. N. G.; Nicolas, C.;
Charette, A. B. J. Am. Chem. Soc. 2011, 133, 8972. (b) Beaulieu, L. P.;
Zimmer, L. E.; Gagnon, A.; Charette, A. B. Chem.;Eur. J. 2012, 18,
14784. (c) Marcoux, D.; Azzi, S.; Charette, A. B. J. Am. Chem. Soc. 2009,
131, 6970. (d) Goudreau, S. R.; Charette, A. B. J. Am. Chem. Soc. 2009,
131, 15633.
(14) (a) Mousseau, J. J.; Charette, A. B. Acc. Chem. Res. 2013, 46,
412. (b) Mousseau, J. J.; Bull, J. A.; Charette, A. B. Angew. Chem., Int.
ꢀ
Ed. 2010, 49, 1115. (c) Larivee, A.; Mousseau, J. J.; Charette, A. B.
J. Am. Chem. Soc. 2008, 130, 52. (d) Mousseau, J. J.; Bull, J. A.; Ladd,
C. L.; Fortier, A.; Sustac Roman, D.; Charette, A. B. J. Org. Chem. 2011,
76, 8243.
(19) (a) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J. Q.
ꢀ
J. Am. Chem. Soc. 2011, 133, 19598. (b) Rousseaux, S.; Liegault, B.;
ꢀ
(15) Mousseau, J. J.; Larivee, A.; Charette, A. B. Org. Lett. 2008, 10,
1641.
Fagnou, K. Chem. Sci. 2012, 3, 244. (c) Saget, T.; Cramer, N. Angew.
Chem., Int. Ed. 2012, 51, 12842. (d) Kubota, A.; Sanford, M. S. Synthesis
2011, 2579. (e) Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem., Int. Ed. 2005,
44, 2112. (f) Ackermann, A.; Kozhushkov, S. I.; Yufit, D. S. Chem.;
Eur. J. 2012, 18, 12068.
(16) For selected reviews, see: (a) Li, H.; Li, B.-J.; Shi, Z.-J. Catal. Sci.
Technol. 2011, 1, 191. (b) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-
Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654.
(17) (a) Lebel, H.; Marcoux, J.; Molinaro, C.; Charette, A. B. Chem.
Rev. 2003, 103, 977. (b) Donaldson, W. A. Tetrahedron 2001, 57, 8589.
(20) The reaction was both hindered by the excess and lack of
1.0 equiv of cationic Ag.
Org. Lett., Vol. 15, No. 6, 2013
1351

derivatives gave no product and the more costly iodo
analogues furnished modest yields.22 A catalyst-to-ligand
ratio of 1:1 was identified, and good yields (80%) could
still be achieved upon decreasing the catalyst and ligand
loading from 5 to 2.5 mol %, although 5 mol % was
optimal for maximum yield. Finally, we found the process
to be rapid, as full conversion required only 3 h.
Using optimized conditions, we explored the effect of sub-
stitution on the aryl ring containing the halide (Scheme 2).
A range of functional groups were tolerated. Electron-
donating substituents furnished the desired products in
good yield (2bꢀ2d). Improved results were noted with
substrates bearing electron-withdrawing groups (2eꢀ2i),
presumably due to the increased ease of oxidative inser-
tion to the aryl halide bond. Notably, chloro-substituted
2i was also viable, allowing for further potential structural
modifications.
hindrance does not negatively impact the process. In
addition, para-substituted electron-donating (2lꢀ2m)
and electron-withdrawing substrates (2nꢀ2p) were both
tolerated, producing excellent yields, although electron-
donating groups gave slightly better diastereoselectivities.
Heterocyclic substitution (2qꢀ2r) could also be achieved.
The configuration for both diastereomers was confirmed
via X-ray crystallography (Scheme 4).
Scheme 4. X-ray Structures of Diastereomers
Scheme 3. Effect of Cyclopropane Substitutiona
To probe whether the cyclization proceeds via an
enolate-like mechanism or direct arylation scaffold, we
performed the reaction using enantioenriched 1sa and
1sb.23 In both cases, the reaction proceeded with little
erosion of % ee (Scheme 5), supporting the possibility of
a direct arylation mechanism.24 We also determined the
KIE to be 3.9, identifying CꢀH cleavage as the rate-
determining step, and providing further evidence against
enolate arylation where oxidative insertion is typically the
rate-limiting step.25,26
We next considered the role of CO32ꢀ, OAcꢀ, and Ag(I)
in the catalytic cycle. Unlike our previous accounts, OAcꢀ
is not required; PdBr2 still gave 2a in 81% yield.27 CO3
could then function as an external base, facilitating a
2ꢀ
(23) Trans-rac 1sa and 1sb gave isolated yields of 90% and 93%
respectively and diastereoselectivities of 6:1 and 1:5 respectively.
(24) See Supporting Information for more details.
(25) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. For a review
on Pd-R arylation methods, see: Bellini, F.; Rossi, R. Chem. Rev. 2010,
110, 1082.
a Reactions were performed on 0.5 mmol scale. Isolated yields. Major
diastereomer is shown. b Diastereomers were separated.
(26) (a) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012,
51, 3066. (b) Garcia-Cuadrado, D.; Braga, A.; Maseras, F.; Echavarren,
A. M. J. Am. Chem. Soc. 2006, 128, 1066. (c) Sun, H. Y.; Gorelsky, S. I.;
Stuart, D. R.; Campeau, L. C.; Fagnou, K. J. Org. Chem. 2010, 75, 8180.
Our next step was to investigate the effect of aromatic
substitution on the cyclopropane unit (Scheme 3). Ortho-
and meta-substitution provided the spiro 3,30-cyclopropyl
oxindole in high yield (2jꢀ2k), suggesting that steric
ꢀ
(27) Mousseau, J. J.; Vallee, F.; Lorion, M.; Charette, A. B. J. Am.
Chem. Soc. 2010, 132, 14412.
(28) No conversion occurs without both Ag(I) and base. This differs
from literature examples where modest yields are still achieved without
Ag(I). For examples, see: (a) Campeau, L. C.; Parisien, M.; Jean, A.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (b) Bryan, C.; Lautens, M.
Org. Lett. 2008, 10, 4633.
(21) See Supporting Information for full optimization.
(22) 48% yield was obtained for the aryl iodide substrate.
1352
Org. Lett., Vol. 15, No. 6, 2013

Scheme 5. Epimerization Studiesa
Scheme 6. Proposed Mechanistic Pathway
a Enantiomeric excess determined via SFC. 1sb was inseparable via
SFC; % ee determined from its carboxylic acid precursor.
activation reactions targeting cyclopropanes. Work is
currently underway to determine the full extent of the
reaction and to deepen our mechanistic understanding.
concerted metalationꢀdeprotonation pathway. Ag(I) salts
are known halide sequestration agents.28 However, Ag(I)
can also mediate halide abstraction from Pd-complexes,
generating reactive cationic Pd-species with counterions
Acknowledgment. This work was supported by Uni-
3ꢀ 29
such as CO32ꢀ and PO4
.
ꢀ
ꢀ
versite de Montreal, the Natural Science and Engineering
Council of Canada (NSERC), the Centre in Green Chem-
istry and Catalysis, the Canada Research Chair Program,
and the Canada Foundation for Innovation. D.S.R.
would like to thank NSERC for a CGS-D scholarship.
Based on these findings, we propose the following
mechanism (Scheme 6). Oxidative addition of Pd(0) into
the ArꢀBr bond of 1a generates intermediate A. Ag(I)
2ꢀ
abstracts bromide, forming cationic Pd-species B. CO3
serves as the external base, resulting in irreversible depro-
tonation to form six-membered palladacycle D, which
undergoes reductive elimination to regenerate Pd(0) and
yield 2a.
ꢀ
ꢀ
ꢀ
We also thank Francine Belanger-Gariepy (Universite
de Montreal) for X-ray analysis. Dr. James J. Mousseau
ꢀ
ꢀ
(MIT), Guillaume Pelletier (Universite de Montreal), and
William S. Bechara (Universite de Montreal) are also
ꢀ
ꢀ
ꢀ
In conclusion, we report a novel example of the direct
arylation of cyclopropanes via a Pd-catalyzed, Ag-
mediated process. This methodology provides an efficient
process to access valuable spiro 3,30-cyclopropyl oxindoles
in excellent yields and enhances the collection of CꢀH
thanked for their comments on the manuscript.
Supporting Information Available. Experimental pro-
cedures, sample spectra, and compound characterization
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(29) (a) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130,
2926. (b) Hirabayashi, K.; Mori, A.; Kawashima, J.; Suguro, M.;
Nishihara, Y.; Hiyama, T. J. Org. Chem. 2010, 65, 5342.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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