recent modification of the latter method, popularized by
Wong,12 has found numerous applications,13 due to the high
yields and relatively mild conditions of the adapted proce-
dure. However, the synthesis of aryl azides relies upon a
more limited selection of transformations.1b They are com-
monly prepared from the corresponding amines via their
diazonium salts,14 which may sometimes be problematic with
respect to the presence of incompatible functional groups.
Alternative methods have been investigated, for example,
reactions of organometallic aryls (derived from the corre-
sponding aryl halide) with p-tosyl azide.15 More recently,
Liu and Tor have applied Wong’s (TfN3) methodology
toward the efficient preparation of aryl azides.16 Although
powerful, this procedure presents some drawbacks. First,
toxic and potentially explosive NaN3, and the highly reactive
Tf2O are used in excess. Second, TfN3 has been reported to
be explosive when not in solvent, thus presenting further
potential hazards.17 Recently, Das et al. reported the use of
tert-butyl nitrite (t-BuONO) in combination with NaN3 in
the synthesis of aromatic azides.18 This procedure requires
a large excess of reagents (12 equiv of t-BuONO, 3 equiv
of NaN3), which is undesirable considering the hazards
associated with NaN3.
equiv) and TMSN3 (1.2 equiv) at 0 °C, with warming to
room temperature.20 The reaction proceeds smoothly and
rapidly to afford azidobenzene 1 in 93% isolated yield.20
To explore the scope of this reaction, a range of aromatic
amines (2-18) were reacted under the optimized conditions.
Table 1 summarizes the results. Simple anilines containing
inert substituents reacted smoothly to afford the desired
product in high yield (e.g., entry 2). Electron-rich (e.g.,
entries 5 and 6) as well as sterically demanding (e.g., entry
3) anilines also react effectively. In contrast to the related
TfN3 procedure,16 anilines substituted with strong electron-
withdrawing groups react rapidly and with high yields (e.g.,
entries 7, 9, and 10). Interestingly, several aminobenzoic acid
derivatives afforded the desired azides in good yields and
did not require purification (e.g., entries 12-18) (Table 1
and the Supporting Information).
Although organic azides are stable against most reaction
conditions, compounds of low molecular weight tend to be
explosive and are difficult to handle.1 Thus, in the context
of the “click reaction”, procedures which generate azides in
situ, followed by azide-alkyne cycloaddition have become
an attractive option.21
We considered whether our described procedure could be
adapted toward a convenient one-pot synthesis of triazole
linked structures starting from aromatic amines, thus avoiding
the isolation of the azide intermediates. The key to this
procedure was the generation of Cu(I) required for the azide-
alkyne cycloaddition, which was achieved by adding Cu(II)
and a reducing agent after complete diazo transfer.5b
The reaction conditions for a sequential one-pot procedure
were optimized by using aniline as the chosen substrate
(Scheme 2).22 First, the azide transfer was performed as
In this contribution, we disclose a less hazardous and
practical synthesis of aromatic azides from their correspond-
ing amines using stable and non-explosive reagents: tert-
butyl nitrite (t-BuONO) and azidotrimethylsilane (TMSN3).19
Mild reaction conditions and very high yields make this
transformation an attractive option for the straightforward
preparation of numerous aromatic azides.
Scheme 1
Scheme 2
In a typical reaction (Scheme 1), aniline was dissolved in
acetonitrile and reacted in the presence of t-BuONO (1.5
outlined above. After complete consumption of starting
material (TLC), catalytic amount sof CuSO4 (7 mol %),
(12) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 6029-6032.
(13) For example see: (a) Ding, Y.; Swayze, E. E.; Hofstadler, S. A.;
Griffey, R. H. Tetrahedron Lett. 2000, 41, 4049-4052. (b) Greenberg, W.
A.; Priestley, E. S.; Sears, P. S.; Alper, P. B.; Rosenbohm, C.; Hendrix,
M.; Hung, S.-C.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 6527-6541.
(14) For a review see: Biffin, M. E. C.; Miller, J.; Paul, D. B. In The
Chemistry of the Azido Group; Patai, S., Ed.; Wiley: New York, 1971; pp
147-176. See also: (b) Takahashi, M.; Suga, D. Synthesis 1998, 7, 986-
990.
(20) Aniline (200 mg, 2.14 mmol) was dissolved in CH3CN (4 mL) in
a 25 mL round-bottomed flask and cooled to 0°C in an ice bath. To this
stirred mixture was added t-BuONO (331 mg, 380 µL, 3.21 mmol) followed
by TMSN3 (300 mg, 340 µL, 2.56 mmol) dropwise. The resulting solution
was stirred at room temperature for 1 h. The reaction mixture was
concentrated under vacuum and the crude product was purified by silica
gel chromatography (hexane) to give the product, 1, as a pale yellow oil
(236 mg, 93%). IR (film) 3062.99, 2124.35, 2093.43, 1593.63, 1491.52,
(15) For example see: (a) Smith, P. A. S.; Rowe, C. D.; Bruner, L. B.
J. Org. Chem. 1969, 34, 3430-3433. (b) Gavenonis, J.; Tilley, T. D.
Organometallics 2002, 21, 5549-5563.
1
1294.58 cm-1. H NMR (CDCl3, 400 MHz) δ 6.96 (dd, J ) 7.6 and 0.7
Hz, 2H), 7.06 (td, J ) 7.6 and 0.7 Hz, 1H), 7.27 (t, J ) 7.6 Hz, 2H). 13C
NMR (CDCl3, 100 MHz) δ 119.0, 124. 9, 129.8, 140. 0. EA calcd for
C6H5N3: C, 60.50; H, 4.23; N, 35.27. Found: C, 60.48; H, 4.27; N, 35.25.
(21) For example see: (a) Beckmann, H. S. G.; Wittmann, V. Org. Lett.
2007, 9, 1-4. (b) Titz, A.; Radic, Z.; Schwardt, O.; Ernst, B. Tetrahedron
Lett. 2006, 47, 2383-2385. (c) Yan, R.-B.; Yang, F.; Wu, Y.; Zhang, L.-
H.; Ye, X.-S. Tetrahedron Lett. 2005, 46, 8993-8995. (d) Chittaboina, S.;
Xie, F.; Wang, Q. Tetrahedron Lett. 2005, 46, 2331-2336. (e) Feldman,
A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6, 3897-3899. (f)
Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E. Org. Lett.
2004, 6, 4223-4225.
(16) Liu, Q.; Tor, Y. Org. Lett. 2003, 5, 2571-2572.
(17) Zaloom, J.; Roberts, D. C. J. Org. Chem. 1981, 46, 5173-5176.
(18) Das, J.; Patil, S. N.; Awasthi, R.; Narasimhulu, C. P.; Trehan, S.
Synthesis 2005, 11, 1801-1806.
(19) This combination of reagents has been previously used in large
excess in the synthesis of 2-azidodeoxyadenosine, see: (a) Higashiya, S.;
Kaibara, C.; Fukuoka, K.; Suda, F.; Ishikawa, M.; Yoshida, M.; Hata, T.
Bioorg. Med. Chem. Lett. 1996, 6, 39-42. (b) Wada, T.; Mochizuki, A.;
Higashiya, S.; Tsuruoka, H.; Kawahara, S.-I.; Ishikawa, M.; Sekine, M.
Tetrahedron Lett. 2001, 42, 9215-9219.
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