Cross-couplings between benzylic and aryl halides on water : Synthesis of diarylmethanes

Article abstract of DOI:10.1039/b922280d

A remarkably simple entry to unsymmetrical diarylmethanes has been developed that relies on an in situ organozinc-mediated, palladium-catalyzed cross-coupling. Thus, by mixing a benzyl and aryl halide together in the presence of Zn metal and a Pd catalyst, diarylmethanes are formed at room temperature without assistance by a surfactant; hence, on water .

Full text of DOI:10.1039/b922280d

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Cross-couplings between benzylic and aryl halides ‘‘on water’’: synthesis
of diarylmethaneswz
Christophe Duplais, Arkady Krasovskiy, Alina Wattenberg and Bruce H. Lipshutz*
Received (in Cambridge, UK) 26th October 2009, Accepted 30th November 2009
First published as an Advance Article on the web 9th December 2009
DOI: 10.1039/b922280d
A remarkably simple entry to unsymmetrical diarylmethanes has
been developed that relies on an in situ organozinc-mediated,
palladium-catalyzed cross-coupling. Thus, by mixing a benzyl
and aryl halide together in the presence of Zn metal and a Pd
catalyst, diarylmethanes are formed at room temperature
without assistance by a surfactant; hence, ‘‘on water’’.
reactive 3-chlorobenzyl chloride, even less TMEDA (e.g., 25
mol%) is required to realize a high yield of 2 (entry 3). In fact,
if too much TMEDA is present, zinc insertion is uncontroll-
able and the product from protio-quenching, rather than 2, is
formed (entries 1 and 2).15
It is assumed that TMEDA is stabilizing the organozinc
species by chelation, in water, rather than solely acting as a
surface-cleaning and/or activating agent. Without TMEDA
(entries 4 and 8), lower yields are obtained notwithstanding
complete consumption of the starting benzyl chloride. Thus,
the empirically-determined, optimized amount of TMEDA
shown reflects a balance between stabilization and activation.
In changing to zinc powder, the same trend was observed for
both starting benzyl chlorides that ultimately led to products 1
and 2. These were obtained in excellent isolated yields
(94% and 96%, respectively) employing only 25 mol% of
TMEDA. However, in the case of electron-poor benzylic
chlorides, zinc powder (rather than zinc dust) is the preferred
precursor of this coupling partner.
Diarylmethanes have recently come into focus given the
presence of this subunit in a substantial number of biologically
active molecules.1 The majority of approaches to this
functional group array rely on cross-couplings; e.g., reactions
using organoboron derivatives, catalyzed by palladium,2 or
Grignards catalyzed by copper,3 nickel,4 or iron5 salts.
Organozinc reagents are very attractive for this purpose given
their low cost of preparation, high functional tolerance, and
their low toxicity. Surprisingly, since the original work of
Negishi et al.,6 few studies have been reported on the synthesis
of diarylmethanes based on organozinc reagents with catalysis
by palladium,7 rhodium,8 nickel,9 or cobalt.10 Nonetheless,
organozinc reagents are routinely used stoichiometrically and
hence, need to be prepared in a separate step.11 Recently, we
have described a new process for effecting cross-coupling
reactions that avoid entirely the prior preparation of organo-
zinc reagents.12 Thus, zinc-mediated, palladium-catalyzed
couplings are now possible between two organic halides, all
of which takes place selectively (including insertion by zinc
metal and Pd catalysis) using nanomicelles in water at room
temperature.13 In this report, we describe an alternative
approach: that is, an ‘‘on water’’ phenomenon (and hence,
in the absence of a surfactant) that leads directly to unsymme-
trical diarylmethanes.
Table 1 Optimization of the reaction between substituted benzyl
chlorides and ethyl 4-bromobenzoatea
This investigation was initiated by treatment of 3-methoxy-
benzyl chloride (2 equiv.) and ethyl 4-bromobenzoate in pure
water (Table 1) with zinc dust and a Pd catalyst (0.5 mol%
PdCl2(Amphos)2).14 In the presence of TMEDA as the
additive of choice,12 product 1 (R = OMe) is formed in high
yields (entries 1–3) compared to that obtained in its absence
(entry 4). Interestingly, the use of a surfactant for micellar
catalysis in this reaction type does not enhance the reaction
rate, or improve the yield of the coupling. Using the more
TMEDA
(n equiv.)
Isolated yield
of 1 (%)
Isolated yield
of 2 (%)
Entry
Type of zinc
1
2
3
4
5
6
7
8
Dust
Dust
Dust
Dust
Powder
Powder
Powder
Powder
1
92
96
95
53
84
82
94
76
52
66
92
65
62
86
96
74
0.5
0.25
0
Department of Chemistry & Biochemistry, University of California,
Santa Barbara, CA 93106, USA. E-mail: lipshutz@chem.ucsb.edu;
Fax: +1 805 893 8265; Tel: +1 805 893 2521
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/b922280d
1
0.5
0.25
0
a
Conditions: benzyl chloride (4 mmol), ethyl 4-bromobenzoate
(2 mmol), zinc (6 mmol), PdCl2(Amphos)2 (0.01 mmol), degassed
water (5 mL).
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562 | Chem. Commun., 2010, 46, 562–564

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Table 2 Representative benzyl–aryl cross-couplingsa
Entry
Benzyl halide
Aryl halide
Product
Yieldb (%)
1
2
3
X = Br
X = Cl
X = Cl
X = Br
X = Br
X = I
94c
95d
96d
4
X = Cl
92
5
6
X = Cl
X = Cl
X = I
X = Br
97d
98d
7
8
X = Br
X = Cl
70
95
9
10
X = Br
X = Cl
57e
96e
11
12
74
79e
13
78
14
15
80e
70
16
98f
a
Conditions: benzyl halide (5 mmol), aryl bromide (2 mmol), zinc dust (6 mmol), PdCl2(Amphos)2 (0.01 mmol), TMEDA (0.5 mmol), degassed
b
water (5 mL), rt, 8 h. Isolated yield. 10 mol % TMEDA. 2 equiv. BnCl. Zinc powder was used. 50 mol % TMEDA.
c
d
e
f
The reaction appears to be quite general, as reflected by the
examples illustrated in Table 2. Simple benzyl bromide and
benzyl chloride afford product 3 in high yields within a
reaction time of three hours (entries 1 and 2). Both electron-
rich or electron-poor benzyl bromides react very quickly with
zinc metal; hence, competitive quenching and/or homo-
coupling limit yields of desired cross-coupling products
(entries 7 and 9). Otherwise, high yields are routinely obtained
in all cases with relatively less reactive benzylic chlorides
(entries 8 and 10–16). Moreover, only small amounts of
homocoupling products are detected in these reaction
mixtures. With respect to the aryl halide partner, it is worthy
of note that aryl iodides also lead to high isolated yields of
diarylmethanes; i.e., they do not compete for zinc insertion
(entries 3 and 5). Steric effects do not appear to limit these
reactions (entries 4, 13 and 15). A vast array of functionalities
on both coupling partners are tolerated, including vinyl,
trifluoromethyl, ester, aldehyde, chloride, and nitrile
(entries 11–15). Finally 4-(1-chloroethyl)benzene leads to
product 13 in excellent isolated yield (98%), whereas no
product was detected using benzhydrylchloride.
In summary, a remarkably straightforward method for
preparing functionalized diarylmethanes, as described herein,
has been uncovered. An aryl and benzylic halide, in the presence
of inexpensive Zn and a Pd catalyst, combine in water alone at
room temperature to afford the targeted products in high yields.
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Chem. Commun., 2010, 46, 562–564 | 563

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We are grateful to the NIH for support (GM 86485), and
Johnson Matthey for generously supplying palladium catalyst
PdCl2(Amphos)2 (Pd-132, catalog #C4138).
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This journal is The Royal Society of Chemistry 2010
564 | Chem. Commun., 2010, 46, 562–564