Grimes et al.
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The copper(II)-catalyzed synthesis of aryl azides from arylboronic acids is based on the Chan–
Lam coupling of arylboronic acids with N–H containing heteroarenes, anilines, phenols, and
amides that employs stoichiometric copper(II) acetate in aprotic solvents and requires a base
9,10
such as pyridine or triethylamine.
Since sodium azide is sparingly soluble in most aprotic
organic solvents, we examined protic solvents and discovered that in contrast to the Chan–Lam
coupling conditions, the azidation of 4-cyanophenylboronic acid (1q) proceeds efficiently in
water, methanol, and ethanol (Table 1). Additionally, we found removal of the obligate base
(pyridine or triethylamine) in the Chan–Lam coupling improved the yield (Table 1, entries 4
and 7). The ligands 2,2′-bipyridine (Bipy) and 1,10-phenanthroline (Phen) were also evaluated
as these have been shown to enhance copper(II)-catalyzed cross-coupling reactions; however,
these provided no major benefit in terms of isolated yield or enhancement in the reaction rate
(Table 1, entries 5 and 6). If the reaction was conducted under an aerobic atmosphere to
reoxidize Cu(0) back to Cu(II), then copper could be used catalytically (Table 1, entry 8). Our
standardized reaction conditions involved vigorously stirring a 0.2 M solution of arylboronic
acid in methanol with sodium azide (1.5 equiv) and copper(II) acetate (0.1 equiv) at 55 °C for
1–3 hours under air (Table 1, entry 9). The higher temperature used herein allow the reactions
to reach completion in 1–3 hours, but the reaction can also be performed at room temperature
if the reaction time is extended to 24 hours, which is preferred when working on scales larger
8
than several millimoles. The reaction was conveniently followed colorimetrically as the dark
brown solution turned light green as the reaction reached completion.
A systematic series of para-substituted phenylboronic acids was initially examined to explore
the influence of electron-donating and -withdrawing substituents on coupling efficiency (Table
2). Remarkably, all compounds underwent coupling providing 40–98% yields of the
corresponding aryl azides. While coupling efficiency did not correlate with electron-donating
11
ability as measured by the Hammett substituent constant σ , we observed that arylboronic
p
acids with strongly electron-withdrawing groups reacted more slowly, requiring three hours to
reach completion and compounds with electron-donating groups, such as methoxy, were
complete within one hour. In the case of volatile azides, such as phenyl azide (2e), 1-azido-4-
fluorobenzene (2g), and 1-azido-4-(trifluoromethyl)benzene (2p), low isolated yields were
obtained, therefore these were isolated as the corresponding triazole derivatives 3e, 3g, and
3p, respectively, by reacting the azides with methyl propiolate at room temperature. Overall,
the results highlight the functional group compatibility of this reaction. The impact of sterics
was examined with 2-(pivaloylamino)phenylboronic acid (1v) that provided 2v in 94% yield
while biphenyl-2- (1u), -3- (1t), and -4-boronic acid (1c) provided 2u, 2t, and 2c, respectively,
in yields ranging from 40–50% illustrating the relative lack of sensitivity to sterics (Table 2).
Next, arylboronic acid pinacol esters were evaluated. 4-Cyanophenylboronic acid pinacol ester
(4q) furnished azide 2q in 81% yield (Table 3, entry 1), while 2q was obtained in 98% yield
from the corresponding boronic acid derivative 1q (Table 2, entry 17). The successful coupling
of amino- and dimethylamino-substituted phenylboronic acid pinacol esters4w and 4x to afford
azides 2w and 2x further highlights the functional group compatibility of this reaction (Table
3). Examination of heterocyclic substrates revealed some limitations to this reaction as 4-
azidopyrazole 2y and 5-azidoindole 2z were isolated in only modest yields.
Heterocyclic boronic acids were also examined including pyridine, pyrimidine, quinoline, and
isoquinoline 5a–d and the corresponding azides 6a–d were isolated in yields ranging from 34–
3
42% (Table 4). Finally, several substrates containing B–C(sp ) bonds were examined including
cyclopropyl 5e, cyclohexyl 5f, and benzyl 5g; however, no coupling was observed with any of
these substrates demonstrating the limitations of the current method, which is restricted to
2
substrates with B–C(sp ) bonds.
Synthesis (Stuttg). Author manuscript; available in PMC 2010 November 1.