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SCHEME 1. Cross-Coupling Reactions of 2-Heterocyclic
Organometallic Reagents with Aryl Halides
A Mild Negishi Cross-Coupling of 2-Heterocyclic
Organozinc Reagents and Aryl Chlorides
Michael R. Luzung,* Jigar S. Patel, and Jingjun Yin*
Department of Process Research,
Merck Research Laboratories, P.O. Box 2000 Rahway,
New Jersey 07065, United States
Received September 23, 2010
on aryl bromides, iodides, or activated chlorides. 2-Pyridyl
borates can be synthesized, but they often require a cryogenic
lithium-halogen exchange before subsequent trapping with
a boron source, which is followed by alcohol metathesis at
refluxing temperatures for isolation.2f,3
An attractive alternative to the Suzuki reaction for this
transformation is the Negishi cross-coupling, for which numer-
ous reports have recently described using aryl bromides or
iodides.4 This note addresses the Negishi cross-coupling of
2-heterocyclic organozinc reagents with aryl and heteroaryl
chlorides (Scheme 1). Aryl chlorides5 may be more useful
due to their low cost and higher availability relative to
the corresponding bromides and iodides. Organozinc re-
agents have typically been synthesized using either lithium-
halogen exchange6a or highly reactive Rieke zinc.7 This note
also addresses the synthesis of 2-heterocyclic organozinc
reagents using Knochel conditions8 at ambient temperature.
A mild Negishi cross-coupling of 2-heterocyclic organozinc
reagents and aryl chlorides is described. The use of Pd2(dba)3
and X-Phos as a ligand provides high yields for many
examples. An efficient method to generate the organozinc
reagents at room temperature is also demonstrated.
The coupling of 2-heterocyclic organometallic reagents
with aryl halides is a transformation used by many in the
chemical community to produce coupled products prevalent
in pharmaceuticals, ligands, and materials. Extensive re-
search has focused on a variety of ways to form this C-C
bond using Pd catalysis.1 The Suzuki reaction has been the
focus of many groups for this transformation (Scheme 1).2
2-Pyridyl couplings have been of particular interest to our
drug discovery efforts.2b,c Commercially available 2-pyridyl-
boronic esters can couple with aryl bromides and iodides
using palladium phosphine oxide or chloride catalysts2b or
utilizing CuCl2c,d to facilitate the transmetalation of these
electron-deficient nucleophiles. While these methods show
versatility in substrate scope, the reactions are performed at
high temperatures in moderate yields, require stoichiometric
Cu, or require substitution at the 6-position of the pyridyl
reagent. Unactivated aryl chlorides have been relatively
difficult to couple,2g as such research has mainly focused
(3) (a) Yamamoto, Y; Takizawa, M.; Yu, X. Q.; Miuaura, N. Angew.
Chem., Int. Ed. 2008, 47, 928–931. (b) Dick, G. R.; Knapp, D. M.; Gillis,
E. P.; Burke, M. D. Org. Lett. 2010, 12, 2314–2317.
(4) For selected 2-pyridylzinc Negishi cross-couplings, see: (a) Kim,
S.-H.; Rieke, R. D. Tetrahedron 2010, 66, 3135–3146. (b) Kim, S.-H.; Rieke,
R. D. Tetrahedron Lett. 2010, 51, 2657–2659. (c) Coleridge, B. M.; Bello,
C. S.; Ellenberger, D. H.; Leitner, A. Tetrahedron Lett. 2010, 51, 357–359.
€
(d) Kiehne, U.; Bunzen, J.; Staats, H.; Lutzen, A. Synthesis 2007, 7, 1061–
1069. (e) Lutzen, A.; Hapke, M.; Staats, H.; Bunzen, J. Eur. J. Org. Chem.
€
2003, 20, 3948–3957. (f) Fang, Y.-Q.; Hanan, G. S. Synlett 2003, 6, 852–854.
(g) Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem. 1998, 63, 10048–
10051. For selected 2-furyl and 2-thienyl zinc Negishi reactions, see:
(h) Mignani, G.; Leising, F.; Meyrueix, R.; Samson, H. Tetrahedron Lett.
1990, 31, 4743–4746. (i) Pelter, A.; Rowlands, M.; Jenkins, I. H. Tetrahedron
Lett. 1987, 28, 5213–5216. (j) Pelter, A.; Rowlands, M.; Clements, G.
Synthesis 1987, 1, 51–53.
(5) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–
4211. (b) For two examples of microwave-assisted Ni-catalyzed Negishi
cross-coupling of 2-pyridylzinc chloride, see: Walla, P.; Kappe, C. O. Chem.
Commun. 2004, 564–565.
(1) For a review on 2-pyridyl cross-couplings, see: Campeau, L.-C.;
Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058–1068.
(2) For selected heterocyclic Suzuki reactions, see: (a) Guetz, G.; Luetzen,
A. Synthesis 2010, 1, 85–90. (b) Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.;
Li, G. Y.;Shen, H. C.Org.Lett. 2009, 11, 381–384.(c) 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, 345–347. (d) Knapp, D. M.; Gillis, E. P.;
Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961–6963. (e) Ackermann, L.;
Potukuchi, H. K. Synlett 2009, 17, 2852–2856. (f) Billingsley, K. L.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 4695–4698. (g) Billingsley, K.; Buchwald,
S. L. J. Am. Chem. Soc. 2007, 129, 3358–3366. (h) Hodgson, P. B.; Salingue,
F. H. Tetrahedron Lett. 2004, 45, 685–687. (i) Bouillon, A.; Lancelot, J.-C.;
Sopkova de Oliveira Santos, J.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
2003, 59, 10043–10049. (j) Deshayes, K.; Broene, R. D.; Chao, I.; Knobler,
C. B.; Diederich, F. J. Org. Chem. 1991, 56, 6787–6795.
(6) (a) For organozinc synthesis and RuPhos, see: Milne, J. E.; Buchwald,
S. L. J. Am. Chem. Soc. 2004, 126, 13028–13032. (b) S-Phos: Walker, S. D.;
Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004,
43, 1871–1876. (c) For S-Phos and Negishi, see: Manoliakakes, G.; Schade,
M. A.; Hernandez, C. M.; Mayr, H.; Knochel, P. Org. Lett. 2008, 10, 2765–
2768. (d) JohnPhos: Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158–1174.
(7) (a) Wu, X.; Rieke, R. D. J. Org. Chem. 1995, 60, 6658–6659. (b) Rieke,
R. D. Science 1989, 246, 1260–1264.
(8) (a) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V. A.;
Knochel, P. Synthesis 2002, 4, 565–569. (b) For synthesis of 2-pyridylboronic
acids using Knochel conditions, see: Matondo, H.; Souirti, S.; Baboulene,
M. Synth. Commun. 2003, 33, 795–800.
8330 J. Org. Chem. 2010, 75, 8330–8332
Published on Web 11/03/2010
DOI: 10.1021/jo1018798
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2010 American Chemical Society