unactivated alkanes and a peroxide in the absence of a transition
metal (eq 1).11 Under similar conditions, however, unactivated
pyridines or quinolines did not react with simple alkanes even
when increasing the tert-butyl peroxide to 3 equiv (eq 2).
Alternatively, we rationalized that it may be possible to increase
the acidity of the C(2)-H bond on these heteroaromatic rings
by using a Lewis acid (LA) catalyst and, thus, to increase the
reactivity of pyridine derivatives similar to the use of pyridine
N-oxide substrates. In a previous mechanistic study, Minisci
found that direct alkylation of pyridine could be achieved in a
very low yield by using iron catalyst (the yield based on pyridine
is only 0.88%).12 Obviously, an alternative catalyst is necessary
to make the direct alkylation of pyridine derivatives more
efficient.
Table 1. Optimization of Reaction Conditionsa
We used quinoline as the standard substrate to look for an
efficient catalyst. No desired product (4a) was observed when
quinoline was reacted with cyclooctane together with 3a in the
absense of Lewis acid catalyst (Table 1, entry 1). Then, we
tested various silver salts as Lewis acid catalysts for the reaction
and are pleased to find that the bisalkylation product was
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a Conditions: 1a (0.5 mmol), 2a (7.45 mmol, 1.0 mL), 3 (1.0 mmol),
135 °C, 16 h, under air unless otherwise noted. Determined by H NMR
using 1,2-dichloroethane as an internal standard; yields based on quinoline
utilized. c Reaction was carried out at 120 °C. d 5 equiv of 2a was used.
b
1
obtained in 22% yield when adding 10 mol % silver fluoride
(entry 2). Other silver salts such as AgBF4, AgPF6, and AgOTf
are more efficient for this reaction, and the bisalkylation product
was achieved in 66%, 77%, and 73% yields, respectively.
Subsequently, various Lewis acid metal complexes were
investigated under similar conditions and all showed catalytic
activity in various efficiencies (entries 6-10). Among the Lewis
acids tested, Sc(OTf)3 showed the best catalytic activity, which
gave 91% yield of the bisalkylation product with 10 mol %
Sc(OTf)3 as catalyst (entry 10).
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Org. Lett., Vol. 11, No. 5, 2009