À
conversion to the desired products in moderate to good yields
as shown for the syntheses of 2i–l.
We next varied the benzoxazole core and reacted 4-, 5-,
and 6-methyl-substituted benzoxazoles with piperidine under
optimized conditions (Scheme 4).[27] For the 5- and 6-methyl-
substituted derivatives, excellent yields of the amination
tively oxidized to 2a upon treatment with TEMPO+BF4 at
room temperature within 1 min in the presence of 2,6-lutidine
or TEMP. Without added base, the reaction stopped at 50%
conversion. These experiments show that amidine 4 is likely
À
an intermediate in our C H amination. TEMPO and 3,3’,5,5’-
tetra-tert-butyldiphenoquinone[28] did not work as oxidants to
convert 4 into 2a, but 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ, 1 equiv) was also capable of oxidizing amidine 4 to 2a
(89%; base was not necessary in that case). Moreover,
reaction of 1 with piperidine in deuterated MeCN in the
1
presence of 2 mol% Sc(OTf)3 was monitored by H NMR
spectroscopy (see the Supporting Information). This experi-
ment revealed clean formation of 4 under the reaction
conditions. Along with benzoxazole, no other compound
was detected in the reaction mixture. Based on these experi-
ments we suggest the following mechanism. Benzoxazole is
first converted to 4. Single-electron transfer (SET) to
À
TEMPO+BF4 followed by deprotonation generates phe-
noxyl radical 5 which undergoes 5-endo cyclization to give
aminyl radical 6. Renewed SET and deprotonation finally
affords product 2a (Scheme 5).
Scheme 4. Substrate scope: Variation of the benzoxazole core.
products 3b and 3c were obtained. However, the 4-methyl
derivative delivered a significantly lower yield, probably for
steric reasons (3a). With benzoxazoles bearing electron-
donating or -withdrawing substituents amination was very
efficient and products 3d–g were isolated in excellent yields.
Arylated benzoxazoles turned out to be very good substrates
for direct amination (3h–j).
It is important to note that all reactions carried out gave
the aminated benzoxazoles in quantitative yield based on
recovered starting benzoxazole. No side products were
formed and the unreacted heterocycle can be reisolated
readily. Even more importantly, the reduced form of the
oxidant (the nitroxide) can be recovered in near quantitative
yield (see the Supporting Information) and the N-oxoammo-
nium salt can readily be regenerated by disproportionation of
the nitroxide upon treatment with HBF4 (see the Supporting
Information). The hydroxylamine formed along with the N-
oxoammonium salt during the disproportionation is readily
reoxidized to the nitroxide under basic aerobic atmosphere.
Therefore, dioxygen can be considered to be the terminal
oxidant in our oxidation protocol.
Scheme 5. Mechanistic studies.
To further demonstrate the synthetic potential of our
methodology, we used 1,3,4-oxadiazoles as substrates to gain
access to the corresponding bioactive 2-aminated hetero-
cycles.[29] To our delight, a variety of substituted 1,3,4-
oxadiazoles could be converted to the desired products 7a–
k. In contrast to the benzoxazole amination, higher temper-
atures, longer reaction times, and increased catalyst loadings
were necessary (Table 2). Piperidine as a cyclic amine
(Table 2, entries 1, 4, 6, and 9), morpholine as a heteroatom-
bearing cyclic amine (Table 2, entries 2, 7, and 10) and the
aliphatic N-methylbenzylamine (Table 2, entries 3, 5, 8, and
11) were successfully coupled to different arylated 1,3,4-
oxadiazoles in moderate to good yields.
Finally, we applied our method to the synthesis of racemic
MK-4305 (Scheme 6). Amine 9 was prepared according to a
literature procedure,[4b] and the key amination of the com-
mercially available chlorobenzoxazole 8 using the Sc(OTf)3
protocol proceeded with 84% yield. This example demon-
strates the great potential of our new method for late-stage
benzoxazole amination.
To shed light onto the reaction mechanism, we performed
NMR studies and conducted some preparative control
experiments. Stirring 1, piperidine, and TfOH (10 mol%) in
MeCN for 4 h at room temperature followed by basic workup
and chromatography provided amidine 4 in 86% yield (see
the Supporting Information). We found that 4 was quantita-
In summary, we have developed a metal-free protocol for
the highly efficient direct amination of nonactivated benzox-
azoles and 1,3,4-oxadiazoles with secondary amines using
Angew. Chem. Int. Ed. 2011, 50, 11511 –11515
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim