Published on Web 10/14/2009
Zn-Mediated, Pd-Catalyzed Cross-Couplings in Water at Room Temperature
Without Prior Formation of Organozinc Reagents
Arkady Krasovskiy, Christophe Duplais, and Bruce H. Lipshutz*
Department of Chemistry & Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received August 11, 2009; E-mail: lipshutz@chem.ucsb.edu
Palladium-catalyzed cross-couplings of organozinc reagents with
aryl halides and pseudohalides (Ar-X) are considered fundamental
transition metal mediated C-C bond forming reactions. Such couplings
continue to offer a highly valued entry to alkylated aromatic rings
(Scheme 1).1 Without exception, preformation of an organozinc halide
(e.g., RZnI) is required, frequently relying on insertion of zinc(0) into
an alkyl iodide precursor (R-I).2 Typically, a coupling partner Ar-X
and a group 10 metal catalyst (e.g., ligated palladium, LnPd) are
subsequently introduced. Although alkylzinc halides as nucleophiles
are commonly regarded as the most reactive of partners and yet
especially functional group tolerant, the conditions of their use in Pd
catalysis are rigorously aprotic and not forgiving.3 Hence, prospects
for effecting such reactions to any synthetically meaningful degree in
the presence of moisture would typically be viewed as dim.4-7
cross-coupling of an unactivated aryl bromide could be effected at rt
in the presence of excess, albeit variable amounts of N,N,N′,N′-
tetramethylethylenediamine (TMEDA; Table S1); no homocoupling
of the bromide is observed. The crucial role of the diamine is likely to
involve both activation of the Zn surface toward insertion into an alkyl
halide and stabilization of the organozinc species. In its absence, there
is no insertion and, hence, no subsequent coupling. Of several catalysts
surveyed, only catalyst 1 was useful (Table S2). Even the parent ligand
in this series (2) gave significantly inferior results, although the
explanation to account for these unexpected variations remains unclear.
Other species, including more active catalysts containing Pd(0) were
surprisingly ineffective.
Table 1 illustrates a number of representative aryl bromides that
have been alkylated. Both simple alkyl (entries 1-9) and several
functionalized primary alkyl iodides (entries 10-15) led to good
isolated yields, indicative of considerable generality. Noteworthy
among these are aryl bromides bearing sensitive groups (e.g., ketone
or aldehyde) that remain intact under these conditions (entries 5, 6,
respectively). Also included are educts bearing ester residues (entries
11, 13), an amide (entry 14), and a highly adorned aromatic ring (entry
16). Prospects for alkyl bromides under related conditions look
promising (entries 1, 11).
Scheme 1. Zn-Mediated, Pd-Catalyzed Cross-Couplings with Aryl
Bromides
Secondary iodides, typified by iodocyclohexane, were found to be
far more reactive toward insertion of Zn than that seen with primary
systems. Attempts to apply our standard conditions (TMEDA, 2% PTS/
H2O, cat. LnPd, rt) to the coupling of this halide with m-bromoanisole
afforded low conversion (<20%) of the starting aryl bromide, albeit
with complete consumption of the excess iodide present (path A,
Scheme 2). The rate at which (cyclohexyl)ZnI•diamine is presumably
formed on the zinc surface could be controlled by simply increasing
the steric bulk of the alkyl groups on nitrogen in the ethylenediamine
ligand. While both the unsymmetrical diamine homologue 22 and
symmetrical version 23 gave results similar to those seen with
TMEDA, the tetraethyl derivative (TEEDA, 24) increased the overall
conversion dramatically to 78%. Curiously, in the case of a p-
bromobenzoate (path B), diamine 22 was found to give the highest
levels of conversion (72%). Applications of these diamine-modified
conditions to other secondary iodide-derived products 25 and 26 further
demonstrate the potential for these cross-couplings in water. Notably,
by contrast to recent studies using acyclic secondary zinc halides,10
there was no observed rearrangement in the coupling of s-butyl iodide
to give alkylated aromatic 26.
Hints that such reactions might be possible come from a limited
number of tangential literature reports describing the use of Zn metal
in protic media. Early studies by Wolinsky5a and Luche5b demonstrated
that allylic residues could be trapped by aldehydes in a Barbier-type
sense.5 An amalgam of Zn/Cu has been shown to lead to conjugate
additions with enones and enals following insertion of Zn into a
carbon-halogen bond.6 Most recently, Fleming, likewise, has used a
Zn/Cu couple (mainly on silica) to add alkyl residues to unsaturated
nitriles in water.6e The closest literature analogy is the very recent
method reported by von Wangelin and co-workers,8 which uses Fe to
catalyze cross-couplings with in situ generated Grignard reagents.
Given the nature of the organometallic, however, there is very limited
tolerance for functionality in either reaction partner, and these couplings
must be conducted with cooling under strictly anhydrous conditions.
We now describe new technology that allows Pd-catalyzed Zn-
mediated cross-couplings to be conducted without organic solvents,
i.e. in water and at room temperature. This discovery also obviates
prior stoichiometric formation of RZnI; i.e., there is no need to preform
any organometallic. Our approach utilizes homogeneous micellar
catalysis within catalytic nanoreactors formed spontaneously upon
dissolution in water of the commercially available amphiphile PTS.9
Other nonionic surfactants (e.g., TPGS, Brij 30, and Solutol) can also
be used with roughly comparable efficiencies.
A tertiary halide (e.g., tert-butyl iodide), on the other hand, reacted
far too rapidly with zinc regardless of the diamine present. The trend,
therefore, suggests involvement of an initial single electron transfer
(SET) ultimately leading to an organozinc halide after a second, rapid
SET event, as homocoupling was not a major competing process.
Additional control experiments confirmed the enabling role of PTS
(Table S3), as cross-couplings in its absence (i.e., “on water”)11 led to
highly variable levels of conversion based on the limiting aryl bromide
and longer reaction times (entries 1 and 7 vs entries 2 and 8, Table
S3). Use of dry THF as the only solvent (0.25 M) for this same reaction
(i.e., no PTS/H2O; entries 3 and 4, Table S3), run at ambient
The scope of this experimentally simple process has been studied
with regard to the nature of both the alkyl halide (1°, 2°, 3°) and the
aryl bromide. Initially, the combination of excess n-heptyl iodide and
m-bromoanisole (as limiting reagent) in the presence of fresh Zn
powder (or dust) and a Pd catalyst was examined as a model system,
with 2 wt % PTS/H2O as medium (entry 1, Table 1). Remarkably, the
9
15592 J. AM. CHEM. SOC. 2009, 131, 15592–15593
10.1021/ja906803t CCC: $40.75 2009 American Chemical Society