COMMUNICATIONS
DOI: 10.1002/adsc.200505405
User-Friendly Methylation of Aryl and Vinyl Halides and
Pseudohalides with DABAL-Me3
a
a
b
b
Thea Cooper, Andrew Novak, Luke D. Humphreys, Matthew D. Walker,
a,
Simon Woodward *
School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK
a
Fax: (þ44)-155-951-3564, e-mail: simon.woodward@nottingham.ac.uk
b
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
Fax: (þ44)-143-876-4869, e-mail: luke.d.humphreys@gsk.com
Received: October 14, 2005; Accepted: February 14, 2006
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
[
6]
Abstract: An extremely technically simple cross-
methylation of aryl and vinyl halides and pseudoha-
lides using an air-stable adduct of trimethylalumini-
um with a Pd(0) catalyst supported by commercially
available biarylphosphines gives excellent yields of
methylated products (mainly >95%). Reactions
can be run with either 0.5 mol % catalyst or without
requiring the exclusion of atmospheric oxygen or the
drying of solvents in some cases. A wide variety of
functional groups is tolerated including CN, OH,
CO R, CHO and NO .
clo[2.2.2]octane) (1), which we call DABAL-Me3,
could be applied to the asymmetric methylation of alde-
[
7]
hydes. DABAL-Me (1), formed in one step from
DABCO and neat AlMe , although somewhat moisture
sensitive can be easily handled without the need for an
inert atmosphere. In comparison to the Schumann–
Blum reagents 2 and 3 DABAL-Me (1) is prepared di-
rectly from inexpensive, commercially available materi-
als and is an extremely convenient source of methyl car-
banions. Herein we report a convenient, robust and near
quantitative method for the Pd-catalysed cross-methyl-
ation of aryl and vinyl halides or pseudohalides which
utilises the reagent 1.
3
3
3
2
2
Keywords: alkylation; aluminium; aryl halides; cross-
coupling; palladium; vinyl halides
Preliminary work demonstrated that in the presence
of 3 mol % Pd(PPh ) , in anhydrous THF at reflux and
3
4
under an inert atmosphere, synthetically useful yields
of methylated products are attained from the cross-alky-
lation of DABAL-Me (1) using unfunctionalised aryl
3
Palladium- and nickel-catalysed cross-alkylation of aryl bromides and iodides (50–96%). However, in practice
and vinyl halides or pseudohalides with organometallic separation of the starting halides from their methylated
reagents represents an extremely powerful method of products is not easily attained in preparative procedures
[
1]
CÀC bond formation. A major drawback of this chem- and we sought to attain a process resulting in complete
istry is often the air-sensitive nature of the organometal- conversions and near quantitative yields under mild
lic reagents used. While tremendous developments have conditions. Simple in situ generation of the catalyst al-
[
2]
taken place in the use of organoboron and organosili- lowed the screening of the commercially available 1,1’-
[3]
con reagents, the utility of air-stable organometallic re- biphenylphosphines L1–L4. Primarily developed for
3
agents capable of transferring alkyl C(sp ) nucleophiles, the use in the Buchwald/Hartwig-type amination reac-
especially a simple CH group, is relatively unexplored. tions, the electron-rich phosphines L1–L4 have been
3
Attempts to realise stabilised reagents derived from tri- shown to be highly effective for Pd(0)-catalysed cross-
[
8]
methylaluminium through the formation of Lewis acid/ couplings. A brief ligand optimisation study, using
base pairs have been reported by Schumann, Blum and Pd (dba) as the Pd(0) source revealed that Xphos L3
2
3
co-workers leading to the reagents 2 and 3 (among oth- was the best ligand for the chosen substrates, allowing
[4]
ers). While the use of 2 and 3 under nickel or palladium complete conversion, and delivering the desired prod-
catalysis gives synthetically viable yields of the methy- ucts in near quantitative yields (Table 1).
lated products, starting from aryl halides, both 2 and 3
The Pd(0)/L3 system is known to be a potent activator
[
5]
must be handled under inert atmospheres. Recently, of ArÀX bonds. In line with this behaviour, highly effec-
we demonstrated that the remarkably air-stable AlMe3 tive methylation of a wide range of aryl and vinyl bro-
adduct (AlMe ) ·DABCO (DABCO¼1,4-diazobicy- mides, chlorides and triflates could be attained (Ta-
3
2
686
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 686 – 690