2
778
P. Belov et al. / Tetrahedron Letters 52 (2011) 2776–2779
Table 2 (continued)
Entry #
Substrate
Time (min)
60
Product
Yielda (%)
91
1
3
4
O
OH
O
O
1
60
69
O
OH
O
O
1
1
1
1
5
6
7
8
O
OH
60
30
30
30
O
O
90
92
78
98
F
F
F
F
O
OH
F
O
O
F
NC
O
OH
NC
O
O
OH
O
O
O
O
O
1
2
9b
0b
OH
30
60
O
89
84
HO
HO
O
O
OH
O
O
O
O
O
2
1b
30
81
N
a
Isolated yields are given.
b
4
equiv of DMF-DMA was used.
Early on we observed higher yields for phenolic derivatives the
acetal (DMF-DMA). Reactions were performed at 500 W for either
30 or 60 min depending on if there was an electron-withdrawing
or donating group attached, respectively. In addition, esterification
as well as enamine formation, was accomplished simultaneously
with methylation of phenols, if a carboxylic acid or ketone was
present.
electron-withdrawing functionality in the para position. We thus,
attempted methylation of these phenols for only 30 min of irradi-
ation at 500 W. Indeed, virtually identical yields were obtained un-
der these conditions. It is hypothesized that the accelerated rate of
a
the reaction is due to the decreased pK of the phenolic proton on
compounds possessing a para-substituted electron-withdrawing
group. This would allow for the increased production of the
alkoxyimmonium ion (4) intermediate (Scheme 2). Therefore, for
all the remaining compounds, we selected either 30 or 60 min of
irradiation depending on whether the phenol possessed an elec-
tron donating, or withdrawing group in the para position.
Acknowledgment
We thank Niagara University and the Niagara University Aca-
demic Center for Integrated Science for financial support.
Overall, yields of 67% (Table 2: entry 3) to 91% (Table 2: entry
References and notes
1
3), for phenolic compounds possessing para-substituted electron
1
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2
2
9
2
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3.
4.
5.
through double alkylation, with the former producing an ester.
The use of DMF-DMA, as well as other formamide acetals, has been
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effective under microwave irradiation conditions.23
1
In summary, we examined microwave-assisted methylation of
para-substituted phenols using N,N-dimethylformamide dimethyl-
2