Journal of the American Chemical Society
Communication
can be inferred that, although both KOAc and K2CO3 could
promote the C−H activation of the methoxy groups and the
arenes, only KOAc could enable the last C(sp3)−H activation
of the methyl group by the C(sp3)−PdII species. As a
consequence, the use of KOAc led to triple C−H activation
and the formation of 2,3-dihydrobenzofuran, and K2CO3 only
gave dimethylated products. The detailed mode of action of
these two bases in the reactions remains to be investigated.
Notably, the Baudoin group found very recently that pivalate
could promote C(sp3)−H activation by alkylpalladium
species.96 Furthermore, it has been reported that carboxylates
could promote Pd-catalyzed C−H functionalization reactions
of aryl halides more efficiently than carbonates.97−101
Based on the above results, a plausible mechanism is
proposed in Figure 4. Palladacycle B is formed by C(sp3)−H
activation. B undergoes oxidative addition with methyl halides
that are generated from DMC, affording C. The reductive
elimination of C gives D, which then cleaves the aryl C−H
bond to form a second palladacycle, E. E undergoes the same
process as that for the formation of D to introduce a second
methyl group and gives G. Using K2CO3, G is protonated by
DMAc or CH3OH that is generated from DMC, delivering
dimethylated product 3b. DMC not only should act as the
methyl source but also could release CH3OH to reduce PdII
species. Using KOAc, the third activation of methyl C−H
bonds occurs to form palladacycle H. The reductive
elimination of H yields 4b and releases Pd0 species.
In summary, we have developed innovative Pd-catalyzed C−
H methylation reactions of ortho-substituted iodoarenes by
using dimethyl carbonate as a methyl source. It is the first time
for DMC to be used as a methyl source in transition-metal-
catalyzed cross-coupling reactions. By using K2CO3 as a base,
iodoarenes are dimethylated at the ipso- and meta-positions of
the iodo group, yielding 2,6-dimethylated arenes. The reaction
represents a novel strategy for meta-C−H methylation. By
using KOAc, dihydrobenzofurans or indanes are formed
through cascade triple C−H activation. The methylation of
complex molecules and trideuteriomethylation have been
demonstrated. Further studies aimed at developing other
DMC-based methylation reactions and elucidating the detailed
mechanism, in particular the roles of inorganic bases, are
underway.
Figure 4. Plausible mechanism.
4ah, respectively (Figure 3d). 9 and 10 are the synthetic
intermediates of an endopeptidase inhibitor86 and an IDO1
inhibitor,87 respectively. The 2-iodoanisole substrate in the
synthesis of 4ah was readily prepared from cheap vanillic acid.
The reactions also allow for the methylation of molecules with
structural complexity or intriguing properties (Figure 3e). For
example, the estradiol-derived iodide and Mecarbinate88 could
be dimethylated (11 and 12). The dimethylation reaction also
provides an easy access to a precursor for the synthesis of a
liquid crystal with composition 1389,90 and bioactive
compound 14.91−93 The tyrosine-derived iodide was also
transformed to compound 15. All the 2-iodoanisole substrates
in the syntheses of 11−15 were readily prepared (see
Preliminary mechanistic studies were conducted (see
from 2-iodoanisole did not react with DMC in the absence of a
halide source, the dimethylated product was formed in the
presence of n-Bu4NBr, albeit in a low yield. On the other hand,
when CH3I was used instead of DMC in the reaction of 1a,
only a trace amount of the dimethylated product was observed.
However, MeI could dimethylate the palladacycle in 10% yield.
Therefore, MeBr could be the actual methylating reagent, and
DMC may be a methyl source. However, MeI could not be
ruled out as the methylating reagent. n-Bu4NBr acted as the
bromide source in the reaction. Furthermore, n-Bu4NBr may
also promote the reaction by stabilizing palladium catalyst.94,95
It should be mentioned that the use of MeBr is not desirable
due to its high toxicity and the difficult handling of a gas, which
is evidenced by the fact that MeBr is much less frequently used
as a methylating reagent than MeI. Therefore, DMC is still an
ideal or even necessary methyl source. Furthermore, Me2SO4,
PO(OMe)3, and MeOTs were also competent methylating
reagents in the dimethylation reaction, but the reactions were
low-yielding. However, the 2,3-dihydrobenzofuran product was
not observed using PO(OMe)3 as the methylating reagent.
When the dimethylation reactions were carried out in the
presence of deuterated reagents, the methoxy group was
deuterated by CD3OD and d7-DMF, and the deuteration
almost failed to occur in the presence of D2O (see Supporting
Information). These outcomes indicate that the alkylPdII
species were reduced primarily by CD3OD or d7-DMF instead
of protonated by a free proton. It is noted that the two ortho-
methyl groups were not deuterated, which implies that C−H
bonds of the methyl groups were not activated. Therefore, it
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
Experimental details, characterization data, and NMR
AUTHOR INFORMATION
Corresponding Author
■
Yanghui Zhang − School of Chemical Science and Engineering,
Shanghai Key Laboratory of Chemical Assessment and
Sustainability, Tongji University, Shanghai 200092, China;
Authors
Zhuo Wu − School of Chemical Science and Engineering,
Shanghai Key Laboratory of Chemical Assessment and
Sustainability, Tongji University, Shanghai 200092, China
4527
J. Am. Chem. Soc. 2021, 143, 4524−4530