A highly efficient palladium/copper cocatalytic system for direct arylation of heteroarenes: An unexpected effect of Cu(xantphos)I

Article abstract of DOI:10.1021/ja100354j

"Chemical equation presented" Heteroarenes are important structural moieties in many chemical industry fields. A highly efficient Pd/Cu-catalyzed C-H arylation method for a range of heterocycles has been discovered. It was found that the key to the success of this transformation is a combination of a palladium catalyst and a well-defined copper cocatalyst. The efficiency and low loadings of catalyst (0.25 mol %) and cocatalyst (1 mol %) together with the mild reaction conditions demonstrate this method to be practically useful and mechanistically interesting.

Full text of DOI:10.1021/ja100354j

Published on Web 02/24/2010
A Highly Efficient Palladium/Copper Cocatalytic System for Direct Arylation of
Heteroarenes: An Unexpected Effect of Cu(Xantphos)I
Jinkun Huang,* Johann Chan, Ying Chen, Christopher J. Borths, Kyle D. Baucom, Robert D. Larsen,
and Margaret M. Faul
Chemical Process Research and DeVelopment, Amgen Inc., Thousand Oaks, California 91320
Received January 20, 2010; E-mail: jhuang@amgen.com
There is a continuing interest in the development of general
methods for providing diverse scaffolds of pharmaceutically active
compounds. Driven by the need for the synthesis of 2-aryl-
substituted benzoazoles, we became interested in the direct arylation
of heteroarenes. While numerous methods to construct this motif
have been reported in the literature,1 transition-metal-catalyzed
direct C-H arylation to effect this tranformation has only recently
been popularized.2 However, its application remains challenging,
in part because of the high catalyst loadings, use of strong bases,
and drastic reaction conditions.3 Certain heteroarenes must be
functionalized at the adjacent nitrogen.4 Herein we report our
discovery of a highly efficient catalyst system utilizing a Pd/Cu
cocatalyst that addresses these issues and enables a practical direct
C-H arylation process.5
Figure 1. ORTEP views (50% probability) of the crystal structures of
Cu(Xantphos)I (2) and Cu(Xantphos)(benzothiazole)I (3).
This new catalytic system has been found to be general for the
coupling of a broad range of heteroarenes with a variety of aryl
halides (Table 2). Electron-poor or -rich aryl bromides containing
functionalities such as nitrile, trifluoromethyl, vinyl, ester, or
aldehyde as well as pyridinyl rings are well-tolerated. Activated
aryl chlorides (entries 3 and 9) are compatible, providing excellent
conversion to the desired products. Phenyl triflate shows good
reactivity, but the corresponding reaction with iodobenzene is
sluggish, affording only a moderate yield (entry 1).10 Electron-
rich benzothiazoles (entries 11 and 13) are more reactive than their
electron-poor counterparts (entry 12; see below). Benzoxazole is
an excellent coupling partner (entry 15), while N-methylbenzoimi-
dazole is much less reactive (entry 16).
The optimization of the C-H arylation was first examined using
benzothiazole and 4-tolyl bromide as coupling partners (Table 1).
Low yields of the heteroarene coupling product were observed,
except under conditions utilizing phosphorus or nitrogen ligands
bound to copper(I). After extensive screening, we discovered that
the commercially available, air-stable PXPd complex (1)6 in
combination with Cu(Xantphos)I (2, Figure 1)7 forms an excellent
cocatalyst system.8 Specifically, the combination of 1 (0.25 mol
%) and 2 (1 mol %) gave 97% yield of the desired arylation product
in 18 h (entry 11) at 100 °C. At the same loading, neither 1 nor 2
indiVidually can catalyze the C-H arylation reaction (entries 4
and 12). Interestingly, the similar bidentate complex Cu(dppf)I is
less effective in catalyzing the reaction (entry 10), and the bulky
monodentate complex Cu(IPr)I9 shows no activity.
While the unprecedented high efficiency of the current catalytic
system is not well understood, it is believed to stem from the
introduction of Cu(Xantphos)I (2). Accordingly, we focused our
attention on elucidating its role in the reaction. To probe its function,
an equimolar mixture of 2 and benzothiazole was dissolved in
CH2Cl2 at room temperature, from which a 1:1 complex (3) was
cleanly formed to afford X-ray-quality crystals (Figure 1).
The lone pair on the nitrogen atom in benzothiazole binds to
the copper center to form tetrahedral complex 3. This solid-state
Table 1. Optimization of the Direct Arylation of Benzothiazole
Entry
PXPda (mol %)
Additive
Cu(I) (mol %)
Yieldb
1
structure correlates well with H NMR data, wherein the proton
1
2
3
4
5
6
7
8
9
2.5
1
1
none
none
Cu
0
0
4
0
1
1
1
1
1
1
1
1
30
16
32
<5
<5
<5
31
63
52
65
97
0
chemical shift of the 2-position shifts downfield from 9.00 ppm in
benzothiazole to 9.19 ppm in 3. We postulate that the effect of this
coordination lowers the pKa of the adjacent C-H bond, allowing
for facile deprotonation.11
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0
none
CuXc
CuTcd
On the basis of the experimental observations, we propose a
mechanism in which the copper complex takes part in the critical
transmetalation step in the Pd/Cu double-cocatalytic cycles (Scheme
1). Formation of 3 and its subsequent deprotonation12/re-
arrangement would afford 4.13 Transmetalation of the 2-benzo-
thiazole-copper species 4 to palladium(II) followed by reductive
elimination would give the desired product and release both the copper
and palladium catalysts.14 The presumed presence of such organo-
copper intermediates is in agreement with the function of copper(I)
reported recently in a Suzuki coupling15 and the well-known Sono-
CuI/Phene
Cu(PPh3)(Phen)Bre
Cu(PPh3)3Br
10
11
12
Cu(dppf)I
Cu(Xantphos)If
Cu(Xantphos)If
a PXPd ) dichlorobis(chloro-di-tert-butylphosphine)palladium. b Yield
determined by HPLC based on a purified standard. c X ) I, Br, Cl, OTf.
d CuTc ) copper(I) thiophene-2-carboxylate. e Phen ) 1,10-phenanthroline.
f Xantphos ) 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene.
9
3674 J. AM. CHEM. SOC. 2010, 132, 3674–3675
10.1021/ja100354j  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of PXPd/Cu(Xantphos)I-Catalyzed C-H Arylation
Scheme 1. Proposed Mechanism for the Direct C-H Arylation
King, and Jerry A. Murry and Prof. Steve L. Buchwald for their
insightful suggestions. We are grateful to Drs. Tsang-Lin Hwang,
Bo Shen, and Richard Staples for structural analysis assistance.
Supporting Information Available: Detailed experimental proce-
dures, analytical data for compounds, and CIF files for 2 and 3. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, Germany, 1998. (b) Modern Arylation
Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim, Germany, 2009.
(2) Reviews: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (c)
Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269.
(3) Selected examples: Pd (or with Cu): (a) Ackermann., L.; Althammer, A.;
Fenner, S. Angew. Chem., Int. Ed. 2009, 48, 201. (b) Do, H.-Q.; Kashif
Khan, R. M.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185. (c) Chiong,
H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (d) Nandurkar, N. S.; Bhanushali,
M. J.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett. 2008, 49, 1045. (e)
Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63,
1970. (f) Yokooji, A.; Okazawa, T.; Tetsuya, S.; Miura, M.; Nomura, M.
Tetrahedron 2003, 59, 5685. (g) Pivsa-Art, S.; Satoh, Kawamura, Y.; Miura,
M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. Rh: (h) Wang, X.;
Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (i) Lewis, L. C.;
Wu, J. Y.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130,
2493. Cu: (j) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You,
J. Angew. Chem., Int. Ed. 2009, 48, 3296. (k) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 12404. (l) Ackermann, L.; Potukuchi, H. K.;
Landsberg, D.; Vincente, R. Org. Lett. 2008, 10, 3081. Ni: (m) Hachiya, H.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737. (n) Canivet, J.;
Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733.
(4) (a) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.;
Villermure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou,
K. J. Am. Chem. Soc. 2009, 131, 3291. (b) Larivee, A.; Mousseau, J. J.;
Charette, A. B. J. Am. Chem. Soc. 2008, 130, 52.
(5) A multikilogram process based on this system was run successfully.
(6) 1 is commercially available from Combiphos. For examples in coupling
reactions, see: Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513. Other
ligands such as PtBu3, Xantphos, and some biphenyl phosphines with
[Pd(allyl)Cl]2 are competent palladium catalyst partners.
(7) 2 is an air-stable white solid that can be conveniently prepared in quantitative
yield from an equimolar ratio of CuI and Xantphos in CH2Cl2 or CH3CN.
(8) The coupling experiment using 0.25 mol % Pd and Xantphos in the absence
of 1 gave <5% product.
a Isolated yield. The reactions were monitored by LC-MS.
b Reaction conducted with 0.5 mol % 1 and 2 mol % 2.
(9) IPr ) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
(10) Similar controversial poor reactivity of aryl iodides in C-H arylation has
recently been observed: Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 581.
gashira reaction,16 but other mechanisms,1b including aromatic elec-
trophilic substitution as proposed by others,3c,g cannot be excluded.
In summary, we have disclosed a mild and efficient catalytic
system for direct arylation of heteroarenes. This new catalytic
system has been demonstrated to be suitable for the couplings of a
broad range of substrates. Notable features of this system include
the unprecedented high efficiency achieved by very low metal
loadings, which is attributed to the unique role of Cu(Xantphos)I.
Further applications to other substrates as well additional data on
the reaction mechanism will be reported in due course.
(11) The electron-rich 6-piperidinylbenzothiazole (Table 2, entry 13) is a superior
substrate in comparison with its 6-nitrile analogue (<5% conversion). 1H NMR
studies showed strong binding of 2 with the former to form the corresponding
complex, but the analogous interaction was not observed with the latter. A
similar explanation has been proposed in N-oxide C-H arylations. See:
Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848.
(12) The isotope effect (kH/kD ) 1.3) indicates that deprotonation is unlikely to be
the rate-determining step.
(13) The Xantphos bite angle may play a crucial role: Kamer, P. C.; Van
Leeuwen, P. W. N. M.; Reek, J. N. H. Acc. Chem. Res. 2001, 34, 895.
(14) A similar mechanism was proposed in Pd/Cu-catalyzed decarboxylative
coupling: Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(15) Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara, H.; Dreher, S. D.;
Weissman, S. A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11, 345.
(16) Osakada, K.; Sakata, R.; Yamamoto, T. Organometallics 1997, 16, 5354.
Acknowledgment. This work is dedicated to the memory of
Prof. Keith Fagnou. We also thank Drs. Xiang Wang, Anthony O.
JA100354J
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