2
Tetrahedron
were performed at various temperatures and reaction times in
toluene (Table 1, entries 3–9). Although the reaction did not
proceed at room temperature, the desired azide 2a was obtained as
reaction temperature was increased. As a result, azide 2a was
effectively formed in high yield by performing the reaction for 1h
at reflux (Table 1, entry 8). Yields were hardly improved by
adjusting the reagent amounts (Table 1, entries 10, 11). The use of
triethylamine (Et3N) or N,N-diisopropylethylamine (DIPEA) as a
base did not afford azide 2a (Table 1, entries 12, 13). The use of
inorganic bases such as K2CO3 and NaHCO3 also did not yield
azide 2a. As compared with toluene, the other solvents decreased
the yields (Table 1, entries 14–17.
Nucleophilic aromatic substitution (SNAr) is a substitution
reaction that occurs on an aromatic ring bearing electron-
withdrawing groups.1 Various functional groups can be introduced
into the aromatic ring via SNAr.2 In the case of phenols, it is
necessary to convert the hydroxyl group to the leaving group.2a, 3
Azide compounds are convenient intermediates in organic
synthesis since the azide group can be converted into a wide range
of substituents.4 Aryl azides are commonly synthesized via
SNAr,2c,3,4 diazo transfer,4,5 diazotization of hydrazine,4 cleavage
of triazene,4 Sandmeyer-type reactions,6 and coupling reactions.7
However, these reactions require toxic or explosive azide sources;
therefore, safer and more user-friendly methods for the synthesis
of aryl azides would be beneficial.
Encouraged by these results, the substrate scope of the SNAr
azidation was investigated with a variety of phenol derivatives, as
shown in Table 2. The phenol with a nitro group at the p-position
gave the desired product in high yield, whereas phenols with other
substituted groups drastically decreased yields (Table 2, 2a–h).
Furthermore, o-nitrophenol 1i did not afford the corresponding
azide 2i owing to the instability of the product against heat11 (Table
2, 2i). Therefore, we limited the substrate scope to nitrophenols
and expanded the reaction scope to a broad range of nitrophenols.
Diphenyl phosphorazidate (DPPA, (C6H5O)2P(O)N3))8 is a
less-explosive azidation reagent than other azidation reagents
owing to the stabilization of azide by the conjugated phosphorus
atom. Previously, it has been applied to the azidation of quinoline,
pyridine, and quinazoline-4-one derivatives9a as well as purine-6-
one derivatives.9b Only one reaction has been reported in which
DPPA was employed for azidation of a phenol; other phenols did
not afford the desired azide compounds under the same
conditions.10 Therefore, we attempted to develop an effective
azidation method for various phenols utilizing DPPA. Herein, we
report a concise SNAr azidation of phenol derivatives for the
synthesis of aryl azides using DPPA as not only the activator of
the hydroxyl group but also as the azide source.
Both nitrophenols with electron-donating and electron-
withdrawing groups gave the corresponding aryl azides (Table 2,
2j–t). In particular, the electron-poor substrates indicated high
We initially explored the optimum reaction conditions using p-
nitrophenol 1a as a model reaction. The reaction conditions were
explored by investigating various parameters including
temperature, reaction time, reagent equivalents, bases, and
solvents (Table 1).
The desired product 2a was not obtained under the reported
condition;10 however, at 110°C, the reaction did proceed to give
azide 2a in low yield (Table 1, entries 1, 2). To investigate the
effects of temperature and reaction time on reactivity, the reactions
Ishihara, Kotaro
