COMMUNICATION
Nickel-catalyzed cross-coupling reactions of benzylic zinc reagents with
aromatic bromides, chlorides and tosylatesw
Matthias A. Schade, Albrecht Metzger, Stephan Hug and Paul Knochel*
Received (in Cambridge, UK) 21st February 2008, Accepted 11th March 2008
First published as an Advance Article on the web 24th April 2008
DOI: 10.1039/b803072c
Benzylic zinc reagents prepared by direct insertion of zinc to
benzylic chlorides in the presence of LiCl undergo smooth cross-
coupling reactions with aromatic chlorides, bromides and
tosylates using Ni(acac)2 and PPh3 as a catalyst system.
Diarylmethanes are an important class of compounds with
pharmacological activity.1 So far, the most popular route to
diarylmethanes is the addition of organometallic reagents to
benzaldehydes and subsequent reduction.2 Recently, we have
Scheme 1
developed a general method for the preparation of highly
functionalized benzylic zinc reagents (1) derived from benzylic
chlorides (2) using zinc dust and LiCl (Scheme 1). Remark-
ably, this method tolerates the presence of important func-
tional groups such as an ester, a ketone and a cyanide.3
Herein, we wish to describe a new practical Ni-catalyzed
cross-coupling reaction4 of polyfunctionalized benzylic zinc
of type 1 with aryl halides (3) leading to functionalized
1c with 4-chloro-2,6-dimethoxypyrimidine (3f) in 98% yield
(entry 6).
Moreover, an electron poor benzylic zinc chloride bearing a
carbethoxy function (1d) in meta position undergoes a smooth
reaction with the protected uracil 3e to afford 4g in 84% yield
(entry 7). Its cross-coupling with 4-chlorobenzonitrile (3g)
leads to the diarylmethane 4h (60 1C, 30 min) in 91% yield
(entry 8). Various aromatic and heteroaromatic tosylates,
which are easily available from the corresponding phenoles,7
are efficient cross-coupling partners. Thus, the aryl tosylates
3h–j react with 3-carbethoxybenzylzinc chloride 1d to the
corresponding diarylmethanes 4i–k in yields up to 85%
(entries 9–11).
diarylmethanes of type
4 in good to excellent yields
(Scheme 1 and Table 1). Although, many ligands have been
tested, we have found as a highly efficient, cheap and con-
venient catalytic system PPh3 (2 mol%) combined with
Ni(acac)2 (0.5 mol%)5 in a mixture of THF and NMP. Under
these conditions, a broad range of aromatic and heteroaro-
matic halides (bromides and chlorides) and tosylates undergo
a smooth cross-coupling leading to polyfunctional diaryl-
methanes of type 4.
Remarkably, benzylzinc chlorides bearing keto groups in
meta position react as well. Thus, the reaction of 3-pentanoyl-
benzylzinc chloride (1e) with the chloropyridine 3k leads to the
nicotinic acid derivative 4l in 90% yield (Scheme 2, entry 12).
Also, the quinolyl tosylate 3l and the pyridyl tosylate 3m
undergo cross-coupling reactions with 1e, leading to the
desired products 4m and 4n (92% and 84%, entry 13 and 14).
Even the sensitive acetyl-substituted benzylic zinc reagent
1f, added over 30 min via a syringe pump, reacts with the
pyridyl chloride (3k) without significant enolization to the
nicotinic acid derivative 4o in 68% yield (entry 15).
Thus, the reaction of 3-cyanobenzylzinc chloride (1a, 1.2
equiv.) with 4-bromoacetophenone (3a) at 60 1C (0.5 h) using
Ni(acac)2 (0.5 mol%) and PPh3 (2 mol%) in THF : NMP (4 : 1
mixture) afforded the desired diarylmethane 4a in 75% yield
(entry 1). Also, aromatic chlorides such as 3b and 2-chloro-
pyrimidine (3c), react readily within 30 min to the correspond-
ing diarylmethanes (4b: 89%, 4c: 69%, entries 2 and 3).
The reaction of the secondary benzylic zinc chloride 1b with
4-bromo-benzoic acid ethyl ester (3d) affords within 12 h at
60 1C the 1,1-bisarylethane (4d, 95%, entry 4).
In summary, we have reported a highly efficient Ni-cata-
lyzed cross-coupling for preparing polyfunctionalized diaryl-
methanes. Remarkably, a broad range of polyfunctionalized
benzylic zinc reagents can be used, including keto substituted
The cross-coupling of an electron rich benzylic zinc chloride
such as 3,4,5-trimethoxybenzylzinc chloride (1c) with the
protected uracil 3e affords the uracile derivative 4e, a pre-
cursor of Trimethoprim,6 in 86% yield (entry 5). The isomeric
uracil derivative 4f was also prepared by the cross-coupling of
Department Chemie, Ludwig-Maximilians-Universitat Munchen,
¨
Butenandtstr. 5-13, Haus F, 81377 Munchen, Germany.
¨
¨
E-mail: Paul.Knochel@cup.uni-muenchen.de;
Fax: (+49)-89-2180-77680; Tel: (+49)-2180-77681
w Electronic supplementary information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/b803072c
Scheme 2
ꢀc
This journal is The Royal Society of Chemistry 2008
3046 | Chem. Commun., 2008, 3046–3048
Schade, Matthias A.
