Synthesis of functionalized spiroindolines via palladium-catalyzed methine C-H arylation

Article abstract of DOI:10.1021/ol400380y

The synthesis of cyclopropyl spiroindolines is described using an intramolecular palladium(0)-catalyzed C-H functionalization of a methine C(sp³)-H bond. This transformation can be coupled with intermolecular Suzuki couplings or direct arylations of heteroaromatics to access functionalized indoline scaffolds in a single step.

Full text of DOI:10.1021/ol400380y

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1354–1357
Synthesis of Functionalized
Spiroindolines via Palladium-Catalyzed
Methine CÀH Arylation
Tanguy Saget, David Perez, and Nicolai Cramer*
Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and
ꢀ ꢀ
Engineering, Ecole Polytechnique Federale de Lausanne, EPFL SB ISIC LCSA,
BCH 4305, CH-1015 Lausanne, Switzerland
nicolai.cramer@epfl.ch
Received February 7, 2013
ABSTRACT
The synthesis of cyclopropyl spiroindolines is described using an intramolecular palladium(0)-catalyzed CÀH functionalization of a methine
C(sp3)ÀH bond. This transformation can be coupled with intermolecular Suzuki couplings or direct arylations of heteroaromatics to access
functionalized indoline scaffolds in a single step.
The indoline scaffold is a ubiquitous structural motif
found in many alkaloid natural products and bioactive
molecules.1 Cyclopropanes and spirocyclopropanes are
design elements in medicinal chemistry due to their in-
creased metabolic stability and their favorable properties
to constrain molecular conformation rigidifying structural
scaffolds.2 In particular, compounds with a spirocyclo-
propyl oxindole motif display interesting biological prop-
erties (Figure 1).3 Furthermore, they serve as substrates for
ring-expansion reactions to oxindole alkaloids.4 However,
the corresponding and chemically more stable cyclopropyl
spiroindolines remain less explored despite their applica-
tion potential. By and large, they are synthetically accessed
by the reduction of oxindole precursors.
Among others,5 most methods for indoline synthesis are
based on CÀN bond formation.6 Complementary strate-
gies toaccess indolines by constructing of CÀC bonds were
reported.7 In particular, these methods are based on
palladium(0)-catalyzed direct functionalization of C(sp3)ÀH
bonds8 occurring via a concerted metalationÀdeprotonation
(5) (a) Lui, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975. (b)
Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447.
(6) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1995, 34, 1348. (b) Klapars, A.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421. (c) Omar-Amrani, R.; Thomas, A.;
Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311. (d) Li, J.-J.;
Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452. (e)
Neumann, J. J.; Rakshit, S.; Droge, T.; Glorius, F. Angew. Chem., Int.
Ed. 2009, 48, 6892. (f) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc.
2009, 131, 10806. (g) Haffemayer, B.; Gulias, M.; Gaunt, M. J. Chem.
Sci. 2011, 2, 312. (h) Nguyen, Q.; Sun, K.; Driver, T. G. J. Am. Chem.
Soc. 2012, 134, 7262. (i) He, G.; Lu, C.; Zhao, Y.; Nack, W. A.; Chen, G.
Org. Lett. 2012, 14, 2944.
(7) (a) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008,
10, 1759. (b) Nakanishi, M.; Katayev, D.; Besnard, C.; Kundig, E. P.
Angew. Chem., Int. Ed. 2011, 50, 7438. (c) Anas, S.; Cordi, A.; Kagan,
H. B. Chem. Commun. 2011, 47, 11483. (d) Saget, T.; Lemouzy, S. J.;
Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 2238. (e) Katayev, D.;
(1) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003.
(2) (a) Armstrong, P. D.; Cannon, G. J.; Long, J. P. Nature 1968, 220,
65. (b) Stammer, S. H. Tetrahedron 1990, 46, 2231. (c) Shimamoto, K.;
Ofune, Y. J. Med. Chem. 1996, 39, 407. (d) Sekiyama, T.; Hatsuya, S.;
Tanaka, Y.; Uchiyama, M.; Ono, N.; Iwayama, S.; Oikawa, M.; Suzuki,
K.; Okunishi, M.; Tsuji, T. J. Med. Chem. 1998, 41, 1284. (e) Martin,
S. F.; Dwyer, M. P.; Hartmann, B.; Knight, K. S. J. Org. Chem. 2000, 65,
1305.
(3) (a) Schwartz, R. E.; Hirsch, C. F.; Springer, J. P.; Pettibone, D. J.;
Zink, D. L. J. Org. Chem. 1987, 52, 3704. (b) Jiang, T.; Kuhen, K. L.;
Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Tuntlan, T.;
Zhang, K.; Karanewsky, D.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
2109. (c) Pan, G.; Mason, J. M.; Wei, X.; Fher, M. WO 201200103, 2012.
(d) Cao, Z.-Y.; Zhou, F.; Yu, Y.-H.; Zhou, J. Org. Lett. 2013, 15, 42.
(4) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira,
E. M. Angew. Chem., Int. Ed. 1999, 38, 3186. (b) Lerchner, A.; Carreira,
E. M. J. Am. Chem. Soc. 2002, 124, 14826. (c) Marti, C.; Carreira, E. M.
J. Am. Chem. Soc. 2005, 127, 11505.
€
€
Nakanishi, M.; Burgi, T.; Kundig, E. P. Chem. Sci 2012, 3, 1422. (f)
Guyonnet, M.; Baudoin, O. Org. Lett. 2012, 14, 398. (g) Donets, P. A.;
Saget, T.; Cramer, N. Organometallics 2012, 31, 8040.
r
10.1021/ol400380y
Published on Web 03/01/2013
2013 American Chemical Society

CÀH activation dominates methylene activation completely.
With a range of conditions and as low as a 2 mol % cata-
lyst loading, the reaction provides reliably excellent yields
of 2a(Scheme 1). The enhanced reactivity can be attributed
to the enhanced s-character and acidity of the cyclo-
propane CÀH bonds14 rendering them attractive for
functionalizations.15
Figure 1. Natural products and pharmaceuticals comprising a
spirocyclopropane indoline motif.
Scheme 1. Selective Methine CÀH Functionalization for the
Synthesis of Spiroindoline 2a
(CMD) pathway.9 Whereas the activation of aromatic,
methyl, and methylene CÀH bonds recently underwent
significant progress,8,10 tertiary C(sp3)ÀH bond func-
tionalizations with palladium catalysis remain largely
elusive.11 The increased steric shielding and the decreased
acidity of the methine CÀH bond are key factors render-
ing functionalization reactions by discrete CÀPd inter-
mediates inherently difficult (Figure 2).
We then explored the potential and generality of this
activation (Scheme 2). Common electron-donating and
-withdrawing groups are well tolerated in the ortho-, meta-,
and para-position. Aryl chlorides can be employed as well,
though slightly higher reaction temperatures are required
(2a). The N-triflyl group of the indolines is readily removed
withRed-Al (eq 1). Alternatively, the process works as well
for substrates with a carbamate group, e.g. 1n with a methyl
carbamate.
Figure 2. Reactivity trends in palladium-catalyzed CÀH func-
tionalization.
During the development of enantioselective CÀH func-
tionalizations,12 we discovered a very rare Pd-catalyzed
methine CÀH arylationgiving spiroindoline2aratherthan
the expected product 3 (Scheme 1).13 Although formation
of 2a is favored by a smaller palladacycle (six-membered
over seven-membered), we were surprised that methine
However, with the current set of conditions, the unsub-
stituted oxygen analog 1p did not undergo cyclization. In
contrast, the carbon analog 1o with a malonyl group gives
rise to the congested dihydroindene 2o. More sterically
demanding substituted cyclopropanes are also smoothly
activated and cyclized. Noteworthy, the stereochem-
istry of both cis- and trans-cyclopropanes is completely
transferred to the indolines. As shown for 2l and 2m,
this reaction characteristic allows substituted spiro-
indolines to be prepared in a stereodefined and pro-
grammed manner.
(8) For reviews about metal-catalyzed C(sp3)ÀH functionalizations,
see: (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack- Kreutzer, J.;
Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (b) Baudoin, O. Chem.
Soc. Rev. 2011, 40, 4902.
(9) (a) Garcia-Cuadrado, D.; Braga, A.; Maseras, F.; Echavarren,
A. M. J. Am. Chem. Soc. 2006, 128, 1066. (b) Lapointe, D.; Fagnou, K.
Chem. Lett. 2010, 39, 1118.
(10) For selected reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. Rev. 2007, 107, 174. (b) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (c) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (d) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
2,6-Dibromoaniline 1k was not a competent substrate,
and most of the starting material was recovered after the
reaction. Presumably, after indoline formation, oxidative
(11) For two isolated examples with Pd-catalysis, see: (a) Rousseaux,
ꢀ
S.; Liegault, B.; Fagnou, K. Chem. Sci. 2012, 3, 244. (b) Ren, Z.; Mo, F.;
Dong, G. J. Am. Chem. Soc. 2012, 134, 16991.
(12) (a) Albicker, M. R.; Cramer, N. Angew. Chem., Int. Ed. 2009, 48,
9139. (b) Seiser, T.; Roth, O. A.; Cramer, N. Angew. Chem., Int. Ed.
2009, 48, 6320. (c) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011,
50, 11098. (d) Ye, B.; Cramer, N. Science 2012, 338, 504. (e) Ye, B.;
Cramer, N. J. Am. Chem. Soc. 2013, 135, 636.
(14) (a) de Meijere, A. Angew. Chem., Int. Ed. 1979, 18, 809. (b)
Exner, K.; Schleyer, P. V. R. J. Phys. Chem. A 2001, 105, 3407.
(15) (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
2112. (b) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q.
J. Am. Chem. Soc. 2011, 133, 19598. (c) Kubota, A.; Sanford, M. S.
Synthesis 2011, 2579.
(13) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 12842.
Org. Lett., Vol. 15, No. 6, 2013
1355

Scheme 2. Scope of the Indoline 2 by Methine CÀH Arylationa
Scheme 3. Tandem Strategy to Access More Complex Indolines
Scheme 4. Domino Methine CÀH Arylation and
Intermolecular Suzuki Couplinga
a Reaction conditions: 1 (0.10 mmol), PivOH (50.0 μmol), Cs2CO3
(0.20 mmol), Pd(OAc)2 (5.00 μmol), PCy3 HBF4 (15.0 μmol), 0.30 M in
3
b
toluene at 110 °C for 12 h; yield of isolated product 2. From ArÀCl
instead of ArÀBr, in p-xylene at 130 °C. c In mesitylene at 130 °C. d With
PPh3 (15.0 μmol).
a Reaction conditions: 1 (0.10 mmol), PivOH (50.0 μmol), Cs2CO3
(0.35 mmol), Bu4NBr (0.15 mmol), Pd(OAc)2 (10.0 μmol), PCy3•HBF4
(30.0 μmol), 0.10 M in toluene at 110 °C for 12 h; isolated yields.
addition of the remaining aryl bromide irreversibly forms
aryl Pd(II) intermediate 5 hence sequestering the palla-
dium catalyst (Scheme 3).16 This results in an open cata-
lytic cycle, deteriorating over time all of the palladium
catalyst. We reasoned that a suitable coupling partner for 5
would allow the catalytic cycle to be closed. In this respect,
one could exploit the dual functionality of 1k to induce
versatile complexity in tandem processes. We chose Suzuki
cross-couplings and intermolecular CÀH functionaliza-
tions of heteroaromatics as two promising reactions. Both
are known to proceed under very similar conditions as
required for the methine functionalization.17
that the intramolecular CÀH functionalization is faster
than the intermolecular transmetalation.
Replacing the stoichiometric aryl boronic acids with
cheap and widely available heteroarenes, we aimed for
an intramolecular methine C(sp3)ÀH/intermolecular arene
C(sp2)ÀH functionalization tandem.19 As the utilized
Scheme 5. Domino Methine CÀH and Intermolecular CÀH
Arylationa
At first, we tried to combine our methine CÀH arylation
with Suzuki couplings (Scheme 4). The addition of
Bu4NBr18 was critical for the reaction success. Both
electron-rich and -poor arylboronic acids react well
and provide arylated indolines 6aÀ6d. Vinylated prod-
uct 6e is obtained in good yield with (E)-styrylboronic
acid as the coupling partner. No trace of product arising
from a double Suzuki coupling was observed, suggesting
(16) (a) Lautens, M.; Fang, Y.-Q. Org. Lett. 2003, 5, 3679. (b)
ꢀ
Leclerc, J.-P.; Andre, M.; Fagnou, K. J. Org. Chem. 2006, 71, 1711.
(17) (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020. (b) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826.
(18) Nicolaus, N.; Franke, P. T.; Lautens, M. Org. Lett. 2011, 13,
4236.
a Reaction conditions: 1 (0.10 mmol), PivOH (50.0 μmol), Cs2CO3
(0.35 mmol), HetAr (0.20 mmol), Pd(OAc)2 (5.00 μmol), PCy3 HBF4
3
(15.0 μmol), 0.30 M in p-xylene at 120 °C for 12 h; isolated yields.
1356
Org. Lett., Vol. 15, No. 6, 2013

conditions are similar to Fagnou’s general protocol for the
arylation of heteroaromatics,14b we first evaluated thio-
phenes for this tandem process (Scheme 5). The reaction
afforded indolines 7a and 7b in high yields. Thiazoles and
furanes are also competent coupling partners providing
indolines 7c and 7d in a regioselective manner.
In conclusion, we have reported an intramolecular
palladium(0)-catalyzed methine CÀH arylation which
provided a convenient access to conformationally con-
strained spiroindolines. The employed reaction condi-
tions are well suited for consecutive Suzuki couplings or
intermolecular CÀH arylations to give well functionalized
indoline scaffolds.
Supporting Information Available. Experimental pro-
cedures, analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work is supported by the
European Research Council under the European Commu-
nity’s Seventh Framework Program (FP7 2007À2013)/
ERC Grant Agreement No. 257891 and the EPFL.
(19) For a related tandem sequence, see: Pierre, C.; Baudoin, O. Org.
Lett. 2011, 13, 1816.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
1357