Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 817–819
Negishi-type coupling of bromoarenes with dimethylzinc
John M. Herbert*
Isotope Chemistry and Metabolite Synthesis Department, Sanofi-Syntheꢀlabo, Willowburn Avenue, Alnwick,
Northumberland NE66 2JH, UK
Received 28 August 2003; accepted 7 November 2003
Abstract—Treatment of bromoarenes with dimethylzinc in the presence of a palladium catalyst provides a high-yielding route to
methylarenes. The process accommodates a wide range of aromatic substituents and, in the majority of cases, is free of side
reactions.
Ó 2003 Elsevier Ltd. All rights reserved.
Nucleophilic displacement of an aromatic halogen is an
important technique in the construction of polysubsti-
tuted aromatic systems with defined regiochemistry. In
the course of a route development, aimed at the prepa-
ration of a multiply [13C]-labeled drug candidate for
human trial purposes, it was necessary to develop a
robust method to convert derivatives of 4-bromobenzoic
acid, or an ester thereof, into the corresponding 4-toluic
acids or esters. Classical methods, involving metal–halo-
gen exchange and exposure of the resulting anion to
methyl iodide or dimethyl sulfate, are prone to side
reactions where the substrate contains an electrophilic
group, as are methods involving the coupling of more
reactive organometallics such as Grignard reagents. In
addition, the Suzuki–Miyaura coupling using methyl-
boronic acid1 gave unsatisfactory results with the sub-
strates in question.
(dppf) or 1,2-bis(diphenylphosphino)ethane (dppe),
conversion into ethyl p-toluate proceeded smoothly and
without any indication of side reactions. Bis(triphenyl-
phosphine)palladium dibromide promoted the same
reaction, but in this case the desired process was
accompanied by reductive dehalogenation to give an
additional 5% of ethyl benzoate. Bis(triphenylphos-
phine)palladium dichloride and tetrakis(triphenylphos-
phine)palladium were ineffective. Nevertheless, in all
cases where the reaction proceeded, it was gratifying
to note that there was no indication of attack upon
the ester group (Table 1).
As shown in Table 2, identical conditions are suitable
for the conversion of a range of other bromoarenes 1
into methylarenes 2 (Scheme 2). Isolated yields are
generally in excess of 80% and often better than 90%.
The process is not adversely affected by the presence of
phenolic, amine or ether residues, or of unprotected
alcohol groups, and bromophenylacetic acids are con-
verted as effectively as bromobenzoic acids. The isolated
yield of p-toluidine (2j) was modest, although this was
improved by carrying out the reaction using the silyl-
protected substrate 1k. The process does, however,
appear to be impeded by steric congestion, with the very
hindered substrate 1q undergoing very slow conver-
sion to the methylated product, even in the presence of
the slightly more active catalyst, Pd(dppe)Cl2. Using
the slightly less active Pd(dppf)Cl2 catalyst, complete
selectivity was observed for the displacement of bro-
mide over chloride, with 2,4-dichlorotoluene (2m)
being uncontaminated by chloroxylene, which would
have resulted from the displacement of one of the
chlorines.
The Negishi coupling of organozinc halides with
haloarenes or aryl triflates is an effective means for
the attachment of a carbon chain to an arene.2 This
procedure normally uses organozinc halides,3 but the
possibility of adapting this methodology to use com-
paratively cheap dimethylzinc for the conversion of
derivatives of 4-bromobenzoic acid into the corre-
sponding p-toluic acid derivatives (Scheme 1) appeared
attractive. Indeed, when ethyl 4-bromobenzoate was
treated with dimethylzinc in the presence of the palla-
dium(II) catalysts 1,10-bis(diphenylphosphino)ferrocene
Keywords: Arene alkylation; Palladium; Negishi coupling.
* Tel.: +44-1665-608414; fax: +44-1665-608815; e-mail: john.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.018