Reliable and diverse synthesis of aryl azides through copper-catalyzed coupling of boronic acids or esters with TMSN3

Article abstract of DOI:10.1002/chem.201000971

(Figure Presented) Aryl azide formation: The copper-catalyzed coupling reaction of boronic esters and acids with TMSN₃ have been presented as a highly efficient, simple, broadly applicable, and less hazardous methodology for the practi cal synthesis of aryl azides with structural diversity (see scheme).

Full text of DOI:10.1002/chem.201000971

COMMUNICATION
DOI: 10.1002/chem.201000971
Reliable and Diverse Synthesis of Aryl Azides through Copper-Catalyzed
Coupling of Boronic Acids or Esters with TMSN3
Yu Li,[a, b] Lian-Xun Gao,[a] and Fu-She Han*[a]
Organic azides are versatile compounds in a wide spec-
trum of areas. They are commonly used as photoaffinity la-
beling reagents for biomolecules,[1] and they also serve as a
latent group for accessing a rich variety of functional groups
including amines, amides, and carbamates, as well as aziri-
dines, the ring-opening and expansion reactions of which are
extremely attractive for constructing numerous N-containing
structural motifs.[2] Particularly, with the recent advent of
the click chemistry of azides and alkynes for accessing tri-
present a less hazardous, simple, and highly efficient proto-
col for the diverse synthesis of aryl azides through copper-
catalyzed coupling of boronic acids or esters with TMSN3.
Although TMSN3 is a more reliable azide source,[9b] its use
in metal-catalyzed organic azide formation is virtually un-
known.
In the initial studies, coupling of 4-methoxylphenylboronic
acid (1) with TMSN3 was carried out to optimize the reac-
tion conditions. As shown in Table 1, either in the absence
or in the presence of tetrabutylammonium fluoride (TBAF),
the CuI-catalyzed coupling was inefficient in MeOH at
room temperature (Table 1, entries 1 and 2). The reaction
was also sluggish by heating under reflux without using
TBAF (Table 1, entry 3). Pleasingly, when TBAF was added
under reflux conditions, the desired coupling reaction oc-
curred quite smoothly to give the 4-methoxylphenyl azide
(2) in 89% yield (Table 1, entry 4). The control experiment
showed that no reaction occurred in the absence of CuI
(Table 1, entry 5).[15] It is thus evident that in addition to the
catalyst, the use of TBAF as an additive coupled with an
elevated reaction temperature plays a pivotal role in effect-
ing the reaction. Here, TBAF is assumed to promote the
ACHTUNGTRENNUNG
azoles,[3] and the [3+2] cycloaddition of azides and cyanides
for the construction of structurally more interesting tetra-
zoles,[4] azides have found widespread applications in drug
discovery,[5] biochemistry,[6] materials science,[7] and supra-
molecular chemistry.[8]
Thus, practical routes to access various azides are re-
quired. Although a myriad of approaches for the synthesis
of aliphatic azides are available,[9] methods for the prepara-
tion of aryl azides are rather limited, with the conversion of
amines to the azides through their diazonium salts[9,10] or the
reactions of organometallic aryls with p-tosyl azide[11] being
the major choice. However, general use of these processes is
restricted owing to the poor functional-group compatibility
and harsh reaction conditions. Recently, copper-catalyzed
À
cleavage of the N Si bond in TMSN3 to form a more nucle-
ophilic N3 anion.
À
couplings of aryl amines,[12] halides,[13] and boronic acids[14]
[12a]
with an azide source such as TfN3
and NaN3,[13,14] have
With these preliminary results in hand, we investigated
further the effect of catalysts, additives, and solvents on this
transformation. A survey of the catalysts revealed that al-
though FeCl2 was inefficient (Table 1, entry 6), rapid conver-
sion as well as excellent yields were observed for various
copper catalysts that have different redox states (e.g., CuI
and CuII) and counter ions (Table 1, entries 7–11), and CuCl
appeared to be the most appealing catalyst in terms of the
yield and reaction time (Table 1, entry 7). Thus, by using
CuCl as the catalyst, the effect of additives was then evalu-
ated. The results showed that TBAF was more effective
than KF, CsF, and NH4F as shown by a comparison of the
corresponding results (Table 1, entry 7 vs. entries 12–14).
More interestingly, we observed a strong dependence of the
reaction efficiency on the nature of solvents. Namely, the re-
action was completely suppressed when aprotic solvents
been reported. Although powerful, the generality of these
methods remains to be determined. More significantly, haz-
ards associated with the azide sources[12–14] and tBuONO[10]
are important deterrents to their practical use. Herein, we
[a] Y. Li, Prof. Dr. L.-X. Gao, Prof. Dr. F.-S. Han
Changchun Institute of Applied Chemistry
Chinese Academy of Sciences, 5625 Renmin Street
Changchun 130022, Jilin (China)
Tel : (+86)431-85262936
E-mail: fshan@ciac.jl.cn
[b] Y. Li
Graduate School of Chinese Academy of Sciences
Beijing, 100864 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000971.
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Table 1. Optimization studies for the copper-catalyzed cross-coupling of
the data are listed in Table 2. Simple boronic acids with
inert methyl substituents underwent smooth coupling to
afford the desired products in excellent yields (Table 2, en-
tries 1 and 2). The reaction was also tolerant of a rich varie-
ty of substituents with a strong electron-donating (Table 2,
entries 3-5) and electron-withdrawing nature (Table 2, en-
tries 6-13). In addition, the mild and simple reaction condi-
tions permit the synthesis of aryl azides containing various
reactive groups such as acid or base-labile Boc, ester, and
cyano groups (Table 2, entries 9-11), as well as electrophilic
ketone and aldehyde groups (Table 2, entries 12 and 13).
Moreover, the sterically congested 2,6-disubstituted sub-
strates could also be coupled efficiently under the optimized
4-methoxylphenylboronic acid (1) and TMSN3.[a]
Entry Catalyst
Additive Solvent
T
[8C]
t
Yield
[%][b]
[h]
[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
CuI
CuI
CuI
CuI
–
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
RT
RT
reflux 25
reflux
reflux 22
reflux 22
reflux
reflux
reflux
reflux
reflux
reflux
reflux 17
reflux 22.5 74
reflux
70
70
reflux
RT
RT
10
5
NR[d]
NR
TBAF[e]
[c]
–
trace[f]
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
4.5 89
[g]
–
NR
NR
FeCl2
CuCl
CuBr
CuCl2·H2O
4.5 94
5.5 93
7
4
6
8
85
90
92
83
76
Table 2. Cross-coupling of various boronic acids with TMSN3 under opti-
mized conditions.[a]
CuACHTUNGTRENNUNG(OAc)2
CuSO4·5H2O TBAF
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl[h]
CuCl[h]
CuCl[h]
CuCl
KF
CsF
NH4F
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
8
11
11
4
trace
trace
trace
93
Entry ArB(OH)2
1
t [h] ArN3
Yield [%][b]
83[c]
dioxane
DMF
THF
DMF
dioxane
4.5
10
74
22.5 72
MeOH/THF reflux 15.5 79
2
5.0
97
(v/v=1:1.6)
22
23
CuCl
CuCl
TBAF
TBAF
MeOH/THF reflux
(v/v=1:1)
MeOH/THF reflux
(v/v=2:1)
7
6
87
96
AHCTUNGTRENNUNG
3
4
4.5
4.5
100
94
AHCTUNGTRENNUNG
[a] Reaction conditions: 4-methoxylphenylboronic acid (1 mmol), TMSN3
(1.1 mmol for entries 1–3, and 1.2 mmol for entries 4–23), copper catalyst
(10 mol%), additives (1.2 mmol), solvent (4 mL). [b] Isolated yields.
[c] No additives were used. [d] NR=No reaction. [e] Tetrabutylammoni-
um fluoride (1 molLÀ1 solution in THF). [f] Monitored by TLC. [g] No
CuI catalyst. [h] CuCl (1.0 equiv) was used.
5
1.5
77
6
7
4
90
86
22.5
such as THF, DMF, and dioxane were used instead of protic
MeOH (Table 1, entries 15–17). Further investigation
showed that effective conversion in these aprotic media re-
quires at least a stoichiometric amount of catalyst (Table 1,
entries 18–20). Such a marked solvent effect was further
confirmed by executing the reaction in a THF/MeOH mixed
solvent. In such a solvent system both the reaction rate and
the yield were increased gradually as the proportion of
MeOH increased (Table 1, entries 21–23), indicating that the
choice of protic solvent is crucial for this transformation.
The role of MeOH in promoting the coupling reaction is not
clear at this stage and deserves a further detailed investiga-
tion.
Thus, extensive survey of various reaction parameters that
include catalyst, additive, solvent, and temperature led to
the identification of an optimal reaction system, that is,
CuCl (10 mol%) and TBAF (1.2 equiv) at reflux in MeOH.
By applying the optimized conditions, we then defined the
scope and functional-group tolerance of this transformation.
Accordingly, a variety of boronic acids were examined and
8
4.5
93
9
10
11
12
5
7
5
4
92
100
80
82
13
14
4
7
83
73
[a] Reaction conditions: Arylboronic acid (1 mmol), TMSN3 (1.2 mmol),
CuCl (10 mol%), TBAF (1.2 mmol; 1 molLÀ1 solution in THF), MeOH
(4 mL) under reflux. [b] Isolated yields. [c] Part of the product was lost
during evaporation and drying under reduced pressure owing to the
rather volatile property of the product.
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Synthesis of Aryl Azides
COMMUNICATION
Table 3. Cross-coupling of various boronic esters with TMSN3 under opti-
mized conditions.[a]
conditions (Table 2, entries 2 and 5). Finally, a heteroaro-
matic boronic acid proved to be a competent substrate, pro-
viding the corresponding heteroaromatic azide in 73% yield
(Table 2, entry 14).
Note that to compare with the reported procedures, the
methodology presented here is compatible with a broader
range of functional groups. For instance, boronic acids that
are substituted with a strong electron-withdrawing group
such as 4-cyano or 4-acetyl group are weak nucleophiles but
could be converted to the desired cyano and acetylphenyl
azides in high yields of over 80% (Table 2, entries 11 and
12). In sharp contrast, we noted that attempts to realize the
same products through the CuSO4-catalyzed cross-coupling
of the aniline derivatives with TfN3 was less efficient, pro-
ducing the desired products only in 7% and 15% yields, re-
spectively.[12a] Consequently, the high reaction efficiency,
simplified operation, broad applicability, and the less haz-
ardous properties of the process presented herein by em-
ploying boronic acids and TMSN3 as substrates appeared to
be a more attractive option for the synthesis of aryl azides
with structural diversity.
Having established a robust protocol for the synthesis of
various aryl azides through the CuCl-catalyzed coupling of
aryl boronic acids and TMSN3, we then became interested
in extending this method to boronic esters because this class
of substrate can now be accessed very readily through the
Suzuki–Miyaura approach, either from aryl halides or from
phenol derivatives.[16] More significantly, utilizing boronic
esters as substrates would omit the acidic hydrolysis step for
converting boronic esters to the corresponding acids, which
not only makes the pathway for accessing aryl azides more
straightforward but also enlarges the scope of the coupling
substrates. It should also be mentioned that although direct
azidation of aryl halides (I and Br) and NaN3 catalyzed by
CuI has been reported,[13] practical application of this tech-
nology was limited owing to the relatively harsh reaction
conditions such as the utilization of NaOH base under ele-
vated temperature, inert gas atmosphere, and the explosive
NaN3.
To examine the feasibility and general applicability of this
transformation, a number of boronic esters were subjected
to treatment with TMSN3 by employing identical conditions
to those of boronic acids (Table 3). The results showed that
this procedure exhibits not only high efficiency but also
broad applicability to various aryl boronic esters that are
substituted by electron-neutral (Table 3, entry 1), electron-
donating (Table 3, entry 2), and electron-withdrawing
groups (Table 3, entries 3–10). More interestingly, substrates
with rather a strong electron-withdrawing nature such as
NO2 and carbonyl groups (Table 3, entries 6–8) were also ef-
fective. In addition, substrates with a Br group, which has
been shown to be a prominent leaving group in numerous
transition-metal-catalyzed cross-couplings,[17] also underwent
smooth coupling to afford the desired azide in high yield
(Table 3, entry 10). Equally interesting is the fact that the
high coupling efficiency was also observed for biaryl and
fused aromatic substrates (Table 3, entries 11 and 12).
Entry ArBPinacol
1
t [h] ArN3
Yield [%][b]
79[c]
11
2
3
9.5
8
91
95
4
5
6
8
86
77
67
4.5
9
7
8
7.5
10
7
86
78
84
75
96
9
10
11
7.5
8
12
6.5
95
[a] Reaction conditions: Arylboronic ester (1 mmol), TMSN3 (1.2 mmol),
CuCl (10 mol%), TBAF (1.2 mmol, 1 molLÀ1 solution in THF), MeOH
(4 mL) under reflux. [b] Isolated yields. [c] Part of the product was lost
during evaporation and drying under reduced pressure owing to the rather
volatile property of the product.
In summary, we have developed a reliable and highly effi-
cient methodology for the diverse synthesis of aryl azides
through copper-catalyzed coupling reactions of aryl boronic
acids or esters with TMSN3. This procedure offers several
advantages over the available methods that include an in-
creased safeness and a broadened functional group compati-
bility. These points are of crucial importance for large-scale
azide production. Most importantly, we demonstrated that
boronic esters are also viable substrates, providing a more
practical pathway to access a rich range of aryl azides. Con-
sequently, the method presented in this work would provide
an important advance in the synthetic chemistry of aryl
azides, and thereby serve as a more powerful tool to offer
structurally more abundant materials for the downstream
fields related to organic azides. Further efforts towards the
clarification of the solvent effect on this transformation, and
the applications of our azides to the diverse construction of
biologically important compounds that contain tetrazole
skeletons such as valsartan and olmesartan derivatives are
currently underway.
Chem. Eur. J. 2010, 16, 7969 – 7972
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7971

F.-S. Han et al.
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Experimental Section
Typical procedure for copper-catalyzed coupling of aryl boronic acids (or
esters) with TMSN3: TBAF (1.2 mmol), TMSN3 (1.2 mmol), and CuCl
(10 mol%) were sequentially added to a solution of the boronic acid (or
ester; 1 mmol) in MeOH (4 mL). The resulting solution was then stirred
under reflux until the starting material had disappeared as monitored by
TLC. The reaction mixture was concentrated under reduced pressure and
the crude product was purified by silica-gel chromatography to give the
desired products (a mixture of EtOAc and petroleum ether was used as
the eluent, and the ratio of EtOAc to petroleum ether was adjusted
based on the solubility and polarity of the products).
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Keywords: aryl azides · boronic acids · boronic esters ·
copper · cross-coupling
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Received: April 15, 2010
Published online: June 16, 2010
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Chem. Eur. J. 2010, 16, 7969 – 7972