COMMUNICATION
DOI: 10.1002/asia.201100153
Synthesis of Unsymmetrical Arylheteroarylmethanes by Direct “On Water”
Cross-Coupling between Benzylic and Heteroaromatic Halides
Valeria Krasovskaya, Arkady Krasovskiy, and Bruce H. Lipshutz*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
Unsymmetrical arylheteroarylmethanes have been shown
to possess important biological and medicinal properties.[1]
These compounds also frequently appear as subunits in vari-
ous supramolecular structures.[2] One method for synthesiz-
ing arylheteroarylmethanes is the Friedel–Crafts alkylation
of aromatic compounds with benzylic halides.[3] Alternative-
ly, transition-metal-catalyzed cross-coupling reactions[4] have
been employed between heteroaryl halides and benzylic
metals.[5] Analogous reactions of heteroaryl metals with
benzyl halides/phosphates/carbonates are less-frequently
seen.[6] Nonetheless, in both cases, organometallic reagents
are necessary, and are prepared in separate steps. Avoiding
the preliminary formation of reactive organometallic species
not only saves one step, but also eliminates potential issues
associated with storage and handling. This advantage could
be important, especially for flammable Grignard reagents
(Kumada cross-coupling), and moisture-sensitive organozinc
reagents (Negishi cross-coupling). Consequently, there is in-
terest in developing cross-coupling reactions without the
pre-formation of organometallic reagents. During the course
[PdCl2ACTHNGUTERNNUG
(Amphos)2][10] as the catalyst (Table 1). We found that
1 efficiently afforded the coupled product within six hours,
on water, at room temperature, using 2 mol% [PdCl2
AHCTUNGTERG(NUNN Ampos)2], zinc dust (4 equiv), and N,N,N’,N’-tetramethyle-
thylenediamine (TMEDA; 1 equiv).[7,8]
Three equivalents of 1-(chloromethyl)-4-methylbenzene
were required to achieve full conversion along with a good
yield of isolated product (Table 1, entry 1). Using two equiv-
alents, competitive insertion of zinc metal into pyridine 1 oc-
curred, leading to protio-quenched product 2-methoxypyri-
dine (Table 1, entry 2). Unlike the case of cross-couplings of
aryl bromides,[8] one equivalent of TMEDA and 2 mol% of
the palladium catalyst were needed to reach full conversion
(Table 1, entries 3–5). Although the reaction was faster in
the presence of surfactant (complete within four hours;
Table 1, entries 7 and 8),[7,11] pure water alone was used for
reasons of simplicity.
Table 1. Optimization of the cross-coupling with bromide 1.[a]
3
2
[7]
À
of our work on direct sp sp cross-coupling reactions, we
reported a convenient approach for the synthesis of diaryl-
methanes.[8] Herein, we describe related couplings between
benzylic halides and heteroaromatic halides performed “on
water”[9] at room temperature, leading to valuable unsym-
metrical arylheteroarylmethanes in good to excellent yields.
Our initial attempts focused on optimization of the reac-
tion conditions for the coupling of representative 1-(chloro-
methyl)-4-methylbenzene with 2-methoxy-5-bromopyridine
(1) to afford unsymmetrical arylheteroarylmethane 2 using
Entry
Modification of original conditions
Conversion [%][b]
1
2
3
4
5
6
7
8
none
100 (88)[d]
2 equiv BnCl
TMEDA (0.50)
TMEDA (0.25)
1 mol% [PdCl
Zn powder
100[c] (79)[d]
90
81
92
(Amphos)2]
96 (83)[d]
100
[a] V. Krasovskaya, Dr. A. Krasovskiy, Prof. B. H. Lipshutz
Department of Chemistry & Biochemistry
University of California
2 wt% PTS/H2O, 4 h
2 wt% TPGS-750-M/H2O, 4 h
100
Santa Barbara, California 93106 (USA)
Fax : (+1)805-893-8265
[a] Conditions : 1-(chloromethyl)-4-methylbenzene (3 mmol), 2-methoxy-
5-bromo-pyridine (1 mmol), zinc dust (4 mmol), [PdCl2A(Amphos)2]
(0.02 mmol), degassed water (2 mL). [b] Determined by GC analysis.
[c] 10–15% of 2-methoxypyridine formed. [d] Yield of isolated product.
Bn=benzyl.
CTHUNGTRENNUNG
Supporting information for this article is available on the WWW
1974
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Chem. Asian J. 2011, 6, 1974 – 1976