Angewandte
Chemie
took place at one methyl group, giving the corresponding
monoamides in all cases. Notably, the amidation of 2,5-
lutidine (1r) mostly took place on the methyl group at
2 position, which is most likely due to the coordination of the
pyridine group on active sites (or their neighbor).[7h]
To show the usefulness of the present MnO2-catalyzed
amidation of methylarenes, the larger-scale synthesis of 5-
methylnicotinamide (2q) was carried out. Compound 2q is
very useful as an inhibitor of poly(ADP-ribose) synthetase,[15]
and have generally been synthesized by the step-by-step
procedure form 1q; for example: 1) oxygenation of 1q with
KMnO4 to the corresponding monocarboxylic acid; 2) reac-
tion of the monocarboxylic acid with SOCl2 to form the
corresponding acid chloride; and 3) ammonolysis of the acid
chloride (Scheme 1a).[16] Without any decrease in the perfor-
hardly produced, suggesting that the present amidation does
not proceed through condensation (direct ammonolysis) of
carboxylic acid with ammonia (that is, benzoic acid is
a byproduct). Therefore, the present MnO2-catalyzed amida-
tion possibly proceeds through the sequence of ammoxidation
of methylarenes to nitriles (via aldehydes), followed by
hydration to form the corresponding primary amides
(Scheme 2).
Scheme 2. Possible reaction path for amidation of methylarenes.
In summary, we have successfully developed a novel
procedure for synthesis of primary amides by the MnO2-
catalyzed aerobic oxidative amidation of methylarenes with
ammonia surrogates. A wide range of methylarenes could
selectively be converted into the corresponding monoamides
(or nitriles) even in the case of methylarenes with two or more
methyl groups. The observed catalysis for the present
amidation was truly heterogeneous, the product isolation
was very easy, unreacted substrates could easily be recovered
and recycled, rather inexpensive manganese-based oxides
could be utilized, and the MnO2 catalyst could be reused
without an appreciable loss of its high performance.
Scheme 1. Synthesis of 5-methylnicotinamide (2q) from 3,5-lutidine
(1q): a) General step-by-step procedure and b) MnO2-catalyzed amida-
tion (this study; 80% yield of isolated product). Reaction conditions
for amidation: 1q (30 mL), amorphous MnO2 (2 g), urea (2.5 mmol),
1508C (bath temperature), O2 (5 atm), 4 h.
Received: April 23, 2012
Revised: May 10, 2012
Published online: && &&, &&&&
mance in comparison with the small-scale transformation in
Table 2, the MnO2-catalyzed larger scale amidation of 1q also
efficiently carried out. After the amidation was completed,
the spent MnO2 catalyst was separated by filtration and
washed with ethanol and acetone. Ethanol and acetone were
first removed by evaporation, and then the remaining
substrate 1q was recovered by distillation under reduced
pressure (> 90% recovery).[12] The solid residue was rinsed
with diethyl ether, giving analytically pure 2q (0.54 g, 80%
yield of isolated product based on ammonia, > 98% purity;
Scheme 1b).
The reaction profile for the amidation of 1a showed that
the formation of not only the corresponding amide 2a but also
3a, benzaldehyde, and benzoic acid during the transformation
(Supporting Information, Figure S1). When the transforma-
tion of 1a was carried out in the presence of amorphous MnO2
(without ammonia surrogates), toluene was oxidized to
benzaldehyde and benzoic acid (Supporting Information,
Scheme S1). We confirmed that amorphous MnO2 showed
high catalytic activities for the amidation of benzaldehyde
with urea (Supporting Information, Scheme S2).[11] The
reaction profile for the amidation of benzaldehyde showed
that 3a was initially formed followed by the formation of 2a.
Furthermore, amorphous MnO2 showed high catalytic activ-
ities for the hydration of 3a (Supporting Information,
Scheme S2). When the transformation of benzoic acid with
urea was carried out under the conditions described in Table 2
(in 1,4-dioxane), the corresponding primary amide 2a was
Keywords: ammonia · heterogeneous catalysis ·
.
manganese oxide · methylarenes · primary amides
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Organic Compounds, Academic Press, New York, 1981; b) C. L.
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Oxidations in Organic Chemistry, ACS Monograph Series,
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[4] a) C. E. Mabermann in Encyclopedia of Chemical Technology,
Vol. 1 (Eds.: J. I. Kroschwitz), Wiley, New York, 1991, pp. 251 –
266; b) D. Lipp in Encyclopedia of Chemical Technology, Vol. 1
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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