Air-stable secondary phosphine oxide as preligand for palladium-catalyzed intramolecular a-arylations with chloroarenes

Article abstract of DOI:10.1021/ol901597d

A palladium catalyst derived from air-stable secondary phosphlne oxide (1-Ad)₂P(O)H enabled efficient Intramolecular a-arylations of amides with aryl chlorides, which allowed for the synthesis of diversely substituted (aza)oxindoles.

Full text of DOI:10.1021/ol901597d

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4274-4276
Air-Stable Secondary Phosphine Oxide
as Preligand for Palladium-Catalyzed
Intramolecular r-Arylations with
Chloroarenes
Lutz Ackermann,* Rube´n Vicente, and Nora Hofmann
Institut fuer Organische und Biomolekulare Chemie, Georg-August-UniVersitaet,
Tammannstrasse 2, 37077 Goettingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received July 13, 2009
ABSTRACT
A palladium catalyst derived from air-stable secondary phosphine oxide (1-Ad)2P(O)H enabled efficient intramolecular r-arylations of amides
with aryl chlorides, which allowed for the synthesis of diversely substituted (aza)oxindoles.
Oxindoles constitute an important structural motif in various
natural products and biologically active compounds.1,2 While
traditional methodologies are available to access this valuable
heterocyclic moiety,1,3 significant progress was represented
by the development of complementary transition metal-
catalyzed syntheses.1,2 Particularly, pioneering studies by
Miura,4 Buchwald,5 and Hartwig6 set the stage for broadly
applicable protocols for arylations of R-C-H acidic com-
pounds,7,8 which were shown to be applicable to intramo-
lecular9 arylations of amides.10 While these efforts provided
a modular access to substituted oxindoles, palladium-
(7) For early examples, see: (a) Semmelhack, M. F.; Stauffer, R. D.;
Rogerson, T. D. Tetrahedron Lett. 1973, 45, 4519–4522. (b) Semmelhack,
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10.1021/ol901597d CCC: $40.75
Published on Web 08/31/2009
 2009 American Chemical Society

catalyzed intramolecular arylations of amides with inexpen-
sive aryl chlorides11 were thus far only accomplished with
palladium complexes derived from either electron-rich N-
heterocyclic carbenes or phosphine PCy3, as developed by
Hartwig.12
At the outset of our studies we probed representative air-
stable SPO preligands in the palladium-catalyzed intramo-
lecular R-arylation of amide 1a (Table 1).
In recent years, secondary phosphine oxides (SPO) were
introduced as air-stable preligands for transition metal-
catalyzed cross-coupling reactions (Scheme 1).13,14 During
Table 1. Air-Stable Secondary Phosphine Oxide Preligands 3
for the R-Arylation of Amide 1aa
Scheme 1. Tautomerization and Complex Formation of
Secondary Phosphine Oxide (SPO) Preligands
our studies on the development of heteroatom-substituted
secondary phosphine oxide (HASPO) preligands for catalytic
cross-coupling chemistry,15,16 we observed that SPOs17 can
be employed as preligands for palladium-catalyzed R-ary-
lations. Herein, we wish to report on these findings, which
involve intramolecular arylations of amides with unactivated
aryl chlorides for the synthesis of substituted (aza)oxindoles.
(10) (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1998, 63, 6546–6553. (b) For a recent application to a catalytic
reaction sequence, see: Millemaggi, A.; Perry, A.; Whitwood, A. C.; Taylor,
R. J. K. Eur. J. Org. Chem. 2009, 2947–2952.
a Reaction conditions: 1a (0.50 mmol), Pd(OAc)2 (5.0 mol %), preligand
(10 mol %), NaOt-Bu (1.2 mmol), 1,4-dioxane (2.0 mL), 18 h; yields of
isolated product. b GC-conversion. c PhMe (2.0 mL) as solvent. d 20 mmol
scale.
(11) (a) Littke, A. F. In Modern Arylation Methods; Ackermann, L.,
Ed.; Wiley-VCH: Weinheim, Germany, 2009; pp 25-68. (b) Bedford, R. B.;
Cazin, C. S. J.; Holder, D. Coord. Chem. ReV. 2004, 248, 2283–2321.
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See also: (b) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193–
195. (c) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem.
Commun. 2002, 2704–2705. (d) Ku¨ndig, E. P.; Seidel, T. M.; Jia, Y.-X.;
Bernardinelli, G. Angew. Chem., Int. Ed. 2007, 46, 8484–8487. (e) Luan,
X.; Mariz, R.; Robert, C.; Gatti, M.; Blumentritt, S.; Linden, A.; Dorta, R.
Org. Lett. 2008, 10, 5569–5572, and references cited therein.
Unfortunately, aryl-substituted SPOs 3a and 3b provided
unsatisfactory results, even when bearing sterically demand-
ing substituents (entries 2, and 3). Catalysts generated in situ
from sterically hindered alkyl-substituted SPOs 3c and 3d
displayed significantly improved activities, with (1-
Ad)2P(O)H (3d)18 providing superior results (entries 4 and
5). A comparable catalytic efficacy was observed when
conducting reactions in toluene as solvent (entry 6). Likewise,
a reaction performed on larger scale proceeded efficiently
(entry 7). It is noteworthy that a valuable asset of preligand
3d is represented by its nonhygroscopic nature, which renders
its handling more convenient, when being compared with
preligand 3c.
(13) For reviews, see: (a) Ackermann, L. Synthesis 2006, 1557–1571.
(b) Ackermann, L.; Born, R.; Spatz, J. H.; Althammer, A.; Gschrei, C. J.
Pure Appl. Chem. 2006, 78, 209–214. (c) Ackermann, L. In TriValent
Phosphorus Compounds in Asymmetric Catalysis, Synthesis and Applica-
tions; Bo¨rner, A., Ed.; Wiley-VCH: Weinheim, Germany, 2008; pp
831-847. (d) Ackermann, L.; Althammer, A. Chem. Unserer Zeit 2009,
43, 74–83
.
(14) For representative examples of SPO preligands in catalytic cross-
coupling reactions, see: (a) Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.;
Li, G. Y.; Shen, H. C. Org. Lett. 2009, 11, 381–384. (b) Xu, H.; Ekoue-
Kovi, K.; Wolf, C. J. Org. Chem. 2008, 73, 7638–7650. (c) Wolf, C.; Xu,
H. J. Org. Chem. 2008, 73, 162–167. (d) Billingsley, K. L.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 4695–4698. (e) Zhang, Z.; Hu, Z.;
Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48,
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Lerebours, R.; Wolf, C. J. Am. Chem. Soc. 2006, 128, 13052–13053. (h)
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With an optimized catalytic system in hand, we explored
its scope in the R-arylation of differently substituted amides
1 (Table 2). Notably, a variety of intramolecular arylations
were achieved with chlorides as electrophiles, giving access
to substituted oxindoles 2 (entries 1-13). Notably, the use
of less expensive PdCl2 as palladium precursor gave rise to
a comparable isolated yield of oxindole 2i (entries 9 and
10). Further, preligand 3d enabled the palladium-catalyzed
R-arylation with chloride 1m (entry 14) yielding a 3-alkoxy-
substituted oxindole, which constitutes an indispensable core
structure of a wide range of biologically active compounds.2
Int. Ed. 2001, 40, 1513–1516
.
(15) Ackermann, L. Synlett 2007, 507–526
.
(16) For selected examples, see: (a) Ackermann, L.; Barfu¨ꢀer, S. Synlett
2009, 808–812. (b) Ackermann, L.; Althammer, A. Org. Lett. 2006, 8, 3457–
3460. (c) Ackermann, L.; Gschrei, C. J.; Althammer, A.; Riederer, M. Chem.
Commun. 2006, 1419–1421. (d) Ackermann, L.; Althammer, A.; Born, R.
Angew. Chem., Int. Ed. 2006, 45, 2619–2622. (e) Ackermann, L.; Born,
R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216–7219.
(f) Ackermann, L.; Born, R. Angew. Chem., Int. Ed. 2005, 44, 2444–2447
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(17) For the use of a diaminochlorophosphine for palladium-catalyzed
R-arylations, see: Ackermann, L.; Spatz, J. H.; Gschrei, C. J.; Born, R.;
Althammer, A. Angew. Chem., Int. Ed. 2006, 45, 7627–7630.
Org. Lett., Vol. 11, No. 19, 2009
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a 3-alkoxyoxindole synthesis through catalytic intramolecular
R-arylation with an aryl chloride19 as electrophile.
Table 2. Scope of Palladium-Catalyzed Oxindole Synthesisa
Finally, we explored the unprecedented use of intramo-
lecular palladium-catalyzed R-arylations for the preparation
of azaoxindoles. Thus, we were delighted to observe that
2-chloropyridines 1 proved to be viable precursors for
4-azaoxindoles 2n-p under our optimized reaction condi-
tions (Scheme 2).
Scheme 2. Palladium-Catalyzed Syntheses of Azaoxindoles 2
In summary, we reported on the first use of air-stable
secondary phosphine oxides (SPO) for catalyzed arylation
reactions of R-C-H acidic compounds, which turned out to
be applicable to intramolecular transformations of various
amides with aryl chlorides, and enabled the synthesis of
azaoxindoles among others.
Acknowledgment. Support by the DFG, the GIF, and the
Alexander-von-Humboldt foundation (fellowship to R.V.) is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL901597D
(18) For catalytic direct C-H bond arylations with preligand (1-
Ad)2P(O)H (3d), see: (a) Ackermann, L.; Vicente, R.; Althammer, A. Org.
a Reaction conditions: 1 (0.50 mmol), Pd(OAc)2 (5.0 mol %), 3d (10 mol
%), NaOt-Bu (1.2 mmol), 1,4-dioxane (2.0 mL), 18 h; yields of isolated product.
b Using the corresponding bromoarene. c PdCl2 (5.0 mol %) as precatalyst.
´
Lett. 2008, 10, 2299–2302. (b) Ackermann, L.; Born, R.; Alvarez-Bercedo,
P. Angew. Chem., Int. Ed. 2007, 46, 6364–6367. (c) Ackermann, L. Org.
Lett. 2005, 7, 3123–3125.
(19) For the use of aryl bromides, see: (a) Jia, Y.-X.; Hillgren, J. M.;
Watson, E. L.; Marsden, S. P.; Ku¨ndig, E. P. Chem. Commun. 2008, 4040–
4042. (b) Hillgren, J. M.; Marsden, S. P. J. Org. Chem. 2008, 73, 6459–
6461.
While this transformation proceeded less efficiently, it
represents, to the best of our knowledge, a first example of
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