tives. Here, we reveal a new type of site-selective cross
coupling in which complete ortho-selectivity was realized
even with a simple phosphine, tricyclohexylphosphine (PCy ).
3
Moreover, use of 1 or 2 further improved reactions of
dichlorophenol and dichloroaniline.
result is contrary to the reaction of dibromophenol, which
produced significant amounts of isomer and di (entry 1).4
Formation of diarylated compounds often are unavoidable
10
in cross-coupling reactions, and even in our previous ortho-
selective reactions of dibromobenzene derivatives using 1,4
complete suppression of diarylation could not be achieved.
Thus, the absence of di is worth noting. The complete ortho-
selectivity was also observed for compound 5 (entry 6). The
result is worth mentioning because cross-coupling occurred
at more electronically negative and more sterically hindered
carbons. Compound 6 was not reactive under these condi-
tions, probably because of the steric hindrance of o-Cl (entry
7). Not only the OH group but also other directing groups
The reaction of 2,4-dichlorophenol (4) with 4-methox-
9
yphenyl Grignard reagent was examined first. Remarkably,
such as CH
2 2
OH, NH , NHAc, and NHBoc worked well to
2 3 3
the catalyst generated from Pd (dba) and PCy afforded the
ortho-arylated compound in good yield (Table 1, entries 2
11
produce ortho-arylated products (entries 8-11).
The reaction of 2,4-dichloroanisole under the same condi-
tions did not give the cross-coupled products as shown in
eq 1. This result strongly suggests that the presence of a
Table 1. Ortho-Selective Cross-Coupling of Dihalobenzene
Derivatives
protic group in the substrates is essential for rate acceleration
at the ortho-position. The requirement of a protic group
seems counterintuitive, because the presence of an anionic
substituent formed by deprotonation with a Grignard reagent
should retard oxidative addition due to the strong electron-
1
2
donating ability. To explain the acceleration at the ortho-
position, we propose transition state A, in which Lewis acidic
a
At 25 °C with 4 equiv of the Grignard reagent. b 4 equiv. c Pd2(dba)3
Mg facilitates oxidative addition of the o-C-Cl bond to Pd.13
On the other hand, we cannot exclude the possibility that
(
2 mol %) and PCy3 (4.8 mol %) were used.
(10) (a) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka,
and 3). Neither the isomeric monoarylated compound
isomer) nor the diarylated compound (di) was obtained. This
A.; Kodama, S.-i.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc.
Jpn. 1976, 49, 1958. See also: (b) Sinclair, D. J.; Sherburn, M. S. J. Org.
Chem. 2005, 70, 3730. (c) Dong, C.-G.; Hu, Q.-S. J. Am. Chem. Soc. 2005,
(
1
27, 10006.
(7) In most of the reported examples, the reactions were mainly controlled
(11) Ortho-selective Suzuki-Miyaura coupling of these substrates was
by the electronic property of the substrates: the reactions occur preferentially
at less electronically negative carbons. For example, selective Sonogashira
coupling of dibromoanilines, which has an electron-donating NH2 group,
occurred preferentially at the meta-position over the ortho- or para-position.3a
See also: Fahey, D. R. J. Am. Chem. Soc. 1970, 92, 402.
not successful. For example, a reaction of 4 with 4-MeOC6H4B(OH)2 in
the presence of Pd2(dba)3 (2 mol%), PCy3 (4.8 mol%), and KF (3 equiv) in
THF at 70 °C for 21 h gave ortho (32%), isomer (14%), and di (12%).
For Suzuki-Miyaura coupling using these conditions, see: Littke, A. F.;
Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(12) Examples of cross-coupling of halophenols with Grignard re-
agents: (a) Jendralla, H.; Chen, L.-J. Synthesis 1990, 827. (b) Bumagin,
N. A.; Luzikova, E. V. J. Organomet. Chem. 1997, 532, 271. (c) Huang,
J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889. An example of Suzuki-
Miyaura coupling of 2-halophenols: (d) Wawrzyniak, P.; Heinicke, J.
Tetrahedron Lett. 2006, 47, 8921.
(8) Electron-withdrawn groups such as nitro and carboxylato groups are
known to facilitate cros- coupling at the ortho-position. This effect has been
attributed to coordination of these groups to Pd in the oxidative addition of
the o-C-X bond: (a) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125,
1
696. (b) Bahmanyar, S.; Borer, B. C.; Kim, Y. M.; Kurtz, D. M.; Yu, S.
Org. Lett. 2005, 75, 1011. (c) Widdowson, D. A.; Wilhelm, R. Chem.
Commun. 2003, 578. See also ref 3b.
(13) Activation of C-X bonds by coordination to Mg was reported by
Nakamura et al. in their Ni-catalyzed cross coupling of ArF or ArCl with
Grignard reagents: Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. Chem.
Soc. 2005, 127, 17978.
(
9) Reviews on cross-coupling with Grignard reagents: (a) Tsuji, J.
Palladium Reagents and Catalysts; John Wiley & Sons: West Sussex, 2004;
p 335. (b) Cepanec, I. Synthesis of Biaryls; Elesevier: Oxford, 2004, p 83.
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Org. Lett., Vol. 9, No. 26, 2007