pubs.acs.org/joc
of a copper catalyst.3,4 The heteroarene halides are typically
One-Step Conversion of Azine N-Oxides to
r-1,2,4-Triazolo-, 1,2,3-Triazolo, Imidazolo-,
and Pyrazoloheteroarenes
prepared through conversion of an R-hydroxyl group with
5
an oxyphilic halide source such as SOCl2 or POCl3,6
by halogenation of N-oxide precursors7 with subsequent
deoxygenation8-11 or deoxygenative halogenation,12 or by
direct metalation of an N-oxide followed by quenching with
an electrophilic halide source.13 In contrast, Katritzky in-
stalled benzotriazoles onto azine nuclei through activation of
N-oxide precursors,14 thus obviating the need for halide
intermediates. It is this latter approach that we felt could
be further developed to include other protic azoles.
John M. Keith*
Johnson & Johnson Pharmaceutical Research and
Development, L.L.C., San Diego, California
Received February 4, 2010
Pyridine, quinoline, isoquinoline, azaindole, and pyrim-
idine N-oxides were converted to their R-triazole and R-
diazole derivatives by treatment with the corresponding
p-toluenesulfonylazoles and Hunig’s base at elevated
temperatures.
FIGURE 1. Possible strategies for the activation and substitution
of N-oxides with azoles (Az) with potential side reactions shown.
With our continuing interest in the use of heteroaromatic
N-oxides as scaffolds onto which various nitrogenous frag-
ments may be appended,1 we elected to investigate the
possibility of introducing various triazoles and diazoles R
to heteroarene nitrogens. Typically, azoles are introduced to
electron-poor heteroarenes via substitution of a suitably
placed halide at elevated temperatures2 or through the use
Such deoxygenative substitution of N-oxides with azoles
could be approached in several ways (Figure 1): (1) the N-
oxide could be converted to a salt15,16 and then treated with a
nucleophilic azole or anionic azole salt; (2) the N-oxide could
be activated in situ17 and treated with an azole; or (3) the N-
oxide could be treated with an electrophile having an azole as
the labile substituent. There is literature precedent for each of
these approaches, but they have different potential propen-
sities to give side reactions. In eq 1a, the R0 group on the N-
oxide could be transferred to the azole, thus consuming both
the activating agent and nucleophile. In cases where R0 is a
monosubstituted methyl (R0 = YCH2-), the methylene can
be oxidized to an aldehyde and in the process consume the N-
oxide (Figure 1, eq 1b).18 In eq 2, the azole may attack the
electrophilic substituent on the N-oxide rather than the
R-position on the arene ring. The resultant azole/electrophile
complex could still be reactive, as in eq 3, though the reaction
is likely to proceed more slowly or require more forceful
(1) (a) Keith, J. M. J. Org. Chem. 2008, 73, 327–330. (b) Keith, J. M.
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Santocanale, C.; Martina, K.; Menichincheri, M. PCT Int. Appl. WO
2005013986, 2005, 65 pp.
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Published on Web 03/18/2010
DOI: 10.1021/jo1001017
r
2010 American Chemical Society