Domino palladium-catalyzed heck-intermolecular direct arylation reactions

Article abstract of DOI:10.1021/ol901799p

A domino palladium-catalyzed Heck-intermolecular direct arylation reaction has been developed, giving access to a variety of dihydrobenzofurans, indolines, and oxindoles. A variety of sulfur-containing heterocycles such as thiazoles, thiophenes, and benzo

Full text of DOI:10.1021/ol901799p

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4560-4563
Domino Palladium-Catalyzed
Heck-Intermolecular Direct Arylation
Reactions
Olivier Rene´, David Lapointe, and Keith Fagnou*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, ON K1N 6N5, Canada
keith.fagnou@uottawa.ca
Received August 4, 2009
ABSTRACT
A domino palladium-catalyzed Heck-intermolecular direct arylation reaction has been developed, giving access to a variety of dihydrobenzofurans,
indolines, and oxindoles. A variety of sulfur-containing heterocycles such as thiazoles, thiophenes, and benzothiophene can be employed as
the direct arylation coupling partner in yields up to 99%.
Although the use of aryl halide and organometallic coupling
partners is the norm in metal-catalyzed cross-coupling
reactions,1 more efficient processes that can replace the aryl
organometallic with a simple arene are emerging as valuable
alternatives.2 The majority of studies done in the past decade
have focused on the formation of Csp2-Csp2 bonds.2
Recently, however, important steps have been made dealing
with the formation of Csp3-Csp2 (alkane-arene) bonds.
Building on the first reports that validated this reactivity in
intramolecular processes,3 new intermolecular reactions have
been realized with aliphatic and benzylic halides with Pd(0)
catalysts4 as well as with aliphatic halides and Pd(II)5 or
Ru(II) catalysts.6
An alternative to the use of aliphatic halides as a means
of accessing the alkylpalladium(II) intermediates is to employ
a Heck coupling of an aryl halide with an alkene in a domino
sequence with a direct arylation step.7 This strategy has been
successfully employed in the preparation of complex organic
(3) (a) Song, Z. Z.; Wong, H. N. C. J. Org. Chem. 1994, 59, 33. (b)
Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130, 16158.
(4) (a) Verrier, C.; Hoarau, C.; Marsais, F. Org. Biomol. Chem. 2009,
7, 647. (b) Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4160.
(5) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 6097.
(1) For reviews on traditional cross-coupling reactions, see: (a) Diederich,
F., Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: New York, 1998. (b) Hassan, J.; Gvignon, M. S.; Gozzi, C.; Shulz,
E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (c) Baudoin, O. Eur. J. Org.
Chem. 2005, 20, 4223.
(6) Ackermann, L.; Nova´k, P.; Vicente, R.; Hofmann, N. Angew. Chem.,
Int. Ed. 2009, 48, 6045.
(7) For reviews on domino palladium-catalyzed reactions, see: (a) Patil,
N. T.; Yamamoto, Y. Top. Organomet. Chem. 2006, 19, 91. (b) Balme, G.;
Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 21, 4101. (c) De
Meijere, A.; Von Zezschwitz, P.; Bra¨se, S. Acc. Chem. Res. 2005, 38, 412.
(d) Patil, N. T.; Yamamoto, Y. Synlett 2007, 13, 1994.
(2) For reviews on direct arylation, see: (a) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (b) Campeau, L.-C.; Stuart, D. R.;
Fagnou, K. Aldrichim. Acta 2007, 40, 35. (c) Campeau, L.-C.; Fagnou, K.
Chem. Commun. 2006, 1253. (d) Satoh, T.; Miura, M. Chem. Lett. 2007,
36, 200. (e) Lewis, J. C.; Bergman, R. C.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013. (f) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (g)
Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.; Lazareva, A.
Synlett 2006, 3382. (h) Pascual, S.; de Mendoza, P.; Echavarren, A. M.
Org. Biomol. Chem. 2007, 5, 2727. (i) Catellani, M.; Motti, E.; Della Ca’,
N.; Ferraccioli, R. Eur. J. Org. Chem. 2007, 4153. (j) McGlacken, G. P.;
Bateman, L. M. Chem. Soc. ReV. 2009, 38, 2447.
(8) For selected examples, see: (a) Grigg, R.; Sridharan, W.; Zhang, J.
Tetrahedron Lett. 1999, 40, 8227. (b) Grigg, R.; Sansano, J. M.; Santha-
kumar, V.; Sridharan, V.; Thangavelanthum, R.; Thornton-Pett, M.; Wilson,
D. Tetrahedron 1997, 53, 34, 11803. (c) Sukanthini, S.; Wilson, D.; Redpath,
J. Tetrahedron 2000, 38, 7525. (d) Lee, C.-W.; Oh, K. S.; Kim, K. S.;
Ahn, K. H. Org. Lett. 2000, 2, 1213. (e) Arthuis, M.; Pontikis, R.; Florent,
J.-C. Tetrahedron Lett. 2007, 48, 6397. (f) Ishikura, M.; Takahashi, N.;
Yamada, K.; Yanada, R. Tetrahedron 2006, 62, 11580.
10.1021/ol901799p CCC: $40.75
Published on Web 09/22/2009
 2009 American Chemical Society

Scheme 1
.
Precedent in Domino Heck-Direct Arylation Involving Alkylpalladium(II) Intermediates and the Formation of New
Csp3-Csp2 Bonds
molecules using traditional techniques,8 and the first ex-
amples of successful Heck-intramolecular direct arylation
involving alkyl palladium(II) intermediates have recently
been described (Scheme 1).9 To our knowledge, no reports
have appeared where a challenging intermolecular direct
arylation-terminating step has been used. For this reaction
class to function, the catalyst must undergo selective
intermolecular direct arylation in the presence of unreacted
alkene that may participate in a competitive intermolecular
Heck-type addition to give unwanted byproduct. By building
on previous advances in catalyst design in palladium-
catalyzed direct arylation, our hope was that intermolecular
direct arylation at an alkylpalladium(II) intermediate may
become a favored process. Herein, we describe several
examples demonstrating that such reactivity is indeed pos-
sible, providing rapid access to highly functionalized het-
erocyclic compounds. These results build on past success
and should further inspire confidence in the use of direct
arylation techniques as a viable alternative to the use of
stoichiometric organometallic reagents in an ever widening
range of commonly employed palladium(0)-catalyzed organic
transformations.
ment was observed with K2CO3, giving rise to product 3a
in 21% yield with low regioselectivity (Table 1, entry 3).
Table 1. Optimization of the Reaction with 4-Methylthiazolea
entry
base
ligand
equiv. HetAr yield (%) (3a/3b)b
1
2
3
4
5
6
7
Cs2CO3 DavePhos
K3PO4 DavePhos
K2CO3 DavePhos
K2CO3 JohnPhos
K2CO3 PtBu3·HBF4
K2CO3 X-Phos
2.0
2.0
2.0
2.0
2.0
2.0
4.0
2:2
4:1
21:9
22:6
10:31
33:4
57:5
Initial reaction development and optimization was per-
formed with bromoarene 1 and 4-methylthiazole 2. Two
factors were found to exert a dramatic influence on both the
yield and the regioselectivity of arylation: the base and the
ligand.
For example, with DavePhos, the use of Cs2CO3 or K3PO4
as the base did not yield significant amounts of desired
product (Table 1, entries 1 and 2). A noteworthy improve-
K2CO3 X-Phos
a Reaction conditions: aryl bromide (1.0 equiv), heterocycle (2 or 4
equiv), Pd(OAc)2 (5 mol %), ligand (5 mol %), PivOH (30 mol %), base
(2.0 equiv), dimethylacetamide (0.3 M), 110 °C, 16 h. b Determined by
GC analysis relative to tetradecane as an internal standard.
While the use of JohnPhos did not provide any notable
change on the reaction outcome (Table 1, entry 4), the use
of tri-tert-butylphosphine gave an inversion in direct arylation
regioselectivity at the thiazole, providing regioisomer 3b in
31% yield with a 3:1 regioisomeric ratio (Table 1, entry 5).
X-Phos, on the other hand, gave a slightly improved yield
(9) (a) Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin, M.; Kandur,
W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4711. (b)
Satyanarayana, G.; Maichle-Mo¨ssmer, C.; Maier, M. E. Chem. Commun.
2009, 12, 1571. (c) Hu, Y.; Yu, C.; Ren, D.; Hu, Q.; Zhang, L.; Cheng, D.
Angew. Chem., Int. Ed. 2009, 48, 5448. (d) For a slightly different variant
of this process where the direct arylation occurs at the aryl halide fragment,
see: Beaudoin, M.; Wolfe, J. P. Org. Lett. 2007, 9, 3073.
Org. Lett., Vol. 11, No. 20, 2009
4561

of 33% but favored the formation of regioisomer 3a in an
8:1 ratio (Table 1, entry 6). We also found that by using 4
equiv of the heterocyclic coupling partner,10 the isolated yield
of 3a could be further improved to 57% with an 11:1
regioselectivity (Table 1, entry 7).
beneficial effect of pivalic acid is even more marked in the
preparation of indolines 9a and 9b where yields of 84% and
75% are reduced to 40% and 48% when the use of pivalic
acid is omitted (Table 3, entries 1 and 2). While the addition
Pivalic acid, which has previously been shown to be a
beneficial additive in palladium-catalyzed direct arylation,11
also results in increased yields and reproducibility in these
reactions. For example, dihydrobenzofurans 5a and 5b (Table
2, entries 1 and 2) are obtained in 76% and 72% yields in
Table 3. Scope of the Reaction for the Formation of Indolines
and Oxindolesa
Table 2. Scope of the Reaction for the Formation of
Dihydrobenzofuransa
a Reaction conditions: aryl bromide (1.0 equiv), heterocycle (4.0 equiv),
Pd(OAc)2 (5 mol %), X-Phos (5 mol %), PivOH (30 mol %), K2CO3 (2.0
equiv), dimethylacetamide (0.3 M), 110 °C, 16 h. b Yield of isolated product.
c No PivOH added.
of pivalic acid is not a crucial prerequisite for product
formation, given the improved outcomes associated with its
use, we adopted the addition of 30 mol % of pivalic acid as
a standard procedure in the evaluation of scope. The role of
the potassium pivalate, generated in situ from the stoichio-
metric potassium carbonate base, is plausibly that of a ligand
on the palladium metal that is involved in the transition state
for heterocycle C-H bond cleavage.11a
a Reaction conditions: aryl bromide (1.0 equiv), heterocycle (4.0 equiv),
Pd(OAc)2 (5 mol %), X-Phos (5 mol %), PivOH (30 mol %), K2CO3 (2.0
equiv), dimethylacetamide (0.3 M), 110 °C, 16 h. b Yield of isolated product.
c No PivOH added.
the presence of 30 mol % of PivOH, while 66% and 50%
yields, respectively, are observed in its absence. The
llustrative examples of the scope are shown in Tables 2
and 3. Using aryl bromides 4 and 6, the reaction affords 3,3-
disubstituted dihydrobenzofurans with a variety of sulfur-
containing heterocycles in yields up to 92% (Table 2). The
transformation is compatible with benzothiophene (Table 2,
entry 1), alkyl-substituted thiazoles at the 2 or 4 positions
(Table 2, entries 2 and 3), and 2-propylthiophene (Table 2,
entry 4) producing the dihydrobenzofuran products in good
yields ranging from 58% to 76%. Chlorothiophene 15 is also
an excellent substrate resulting in a 92% yield (Table 2, entry
5). Electron-withdrawing substituents on the thiophene such
(10) The excess heterocycle remains unreacted and can be recovered in
the purification process.
(11) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(b) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
14570. (c) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64,
6015. (d) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10,
1759. (e) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10,
2299. (f) Lie´gault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J.
Org. Chem. 2009, 74, 1826. (g) Huestis, M. P.; Fagnou, K. Org. Lett. 2009,
11, 1357. (h) Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc.
2009, 131, 3042. (i) Ackermann has found that other carboxylic acid
additives improve outcomes in Ru-catalyzed direct arylation; see: Acker-
mann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int. Ed. 2009, 48,
201.
4562
Org. Lett., Vol. 11, No. 20, 2009

as a methyl ester and an aldehyde are also tolerated, albeit
in more modest yields of 47% and 41%, respectively (Table
2, entries 6 and 7). Entries 8 and 9 show that dihydroben-
zofurans can also be substituted by an ester at the 3 position
in yields ranging from 55% to 61% using 2-chlorothiophene
and benzothiophene as the second coupling partner.
isolated yield for the mixture. This outcome is most likely
the result of palladium migration from the alkyl group to
the adjacent aromatic ring. As shown in Scheme 2, inter-
mediate 22, produced after the intramolecular Heck reaction
may undergo two competitive processes: intermolecular
direct arylation to give product 20 or migration to the
neighboring aromatic ring to form a new arylpalladium(II)
intermediate 23. Once formed, 23 may then participate in
an arylation process with the thiophene coupling partner to
give regioisomer 21. Larock and co-workers have demon-
strated that such migratory processes can occur when the
alkylpalladium intermediate and the adjacent C-H bond on
the aromatic ring are in a favorable geometry.13
In conclusion, we have developed a domino Heck-
intermolecular direct arylation to furnish a variety of dihy-
drobenzofurans, indolines, and oxindoles. The reaction
conditions are general for a variety of sulfur-containing
heterocycles as the direct arylation coupling partner and
excellent yields can be obtained. In addition to synthetic
utility, the demonstrated ability to combine direct arylation
into this class of tandem process should raise confidence in
the viability of other domino processes involving alkylpal-
ladium(II) reactive intermediates.
Indolines and oxindoles are prevalent in natural products
and medicinal compounds;12 therefore, the establishment of
methods enabling their rapid access remains an important
goal. We were pleased to find that the domino Heck-direct
arylation reaction may be used to access a variety of 3,3-
disubstituted indoline and oxindole compounds (Table 3).
For the formation of indolines, the reaction is compatible
with benzothiophene (Table 3, entry 1), alkyl-substituted
thiazoles (Table 3, entries 2 and 3), and 2-propylthiophene
(Table 3, entry 4) with yields ranging from 64% to 84%.
2-Chlorothiophene is an ideal coupling partner, providing
the desired indoline product in 99% yield (Table 3, entry
5). The formation of oxindoles is also possible with yields
ranging from 47% with 2-propylthiophene (Table 3, entry
6) to 82% with 2-chlorothiophene (Table 3, entry 7).
Benzothiophene 12 and thiazole 13 both gave product in 67%
yield (Table 3, entries 8 and 9).
The formation of isochroman heterocycles was also
investigated by the homologation of the phenyl ether to
benzyl ether 19. In this case, the formation of the two
regioisomers 20 and 21 in a 1.7:1 ratio was obtained in 65%
Acknowledgment. We thank NSERC, the University of
Ottawa, Eli Lilly, Amgen, Astra Zeneca, and the Sloan
Foundation (fellowship, K.F.). O.R. thanks OGS and FQRNT
for graduate student scholarships. D.L. thanks NSERC for a
graduate student scholarship.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 2. Regioselectivity of the Formation of Isochromans
OL901799P
(12) For selected examples of 3,3-disubstituted indolines in natural
products, see: (a) Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007,
9, 279. (b) Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett 2000, 883. (c)
Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137. For
selected examples of 3,3-disubstituted oxindoles in natural products, see:
(d) Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org.
Chem. 1991, 56, 6527. (e) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot.
1996, 49, 832. (f) Pellegrini, C.; Weber, M.; Borschberg, H. J. HelV. Chim.
Acta 1996, 79, 151.
(13) (a) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C.
J. Am. Chem. Soc. 2004, 126, 7460. (b) Kesharwani, T.; Larock, R. C.
Tetrahedron 2008, 64, 5963.
Org. Lett., Vol. 11, No. 20, 2009
4563