Rapid synthesis of aryl azides from aryl halides under mild conditions

Article abstract of DOI:10.1055/s-2005-872248

A rapid synthesis of aryl azides from the corresponding aryl halides catalyzed by CuI/diamine is described. Sodium ascorbate was found to have a positive effect on stabilization of the catalyst system. The reactions were performed under very mild conditions generally with high yields. In the case of aryl iodides, the transformation could be carried out at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872248

LETTER
2209
Rapid Synthesis of Aryl Azides from Aryl Halides under Mild Conditions
a
b
a
a
R
J
apid Syn
a
thesis of
A
c
ryl
A
zides ob Andersen, Ulf Madsen, Fredrik Björkling, Xifu Liang*
a
Department of Medicinal Chemistry, LEO Pharma, Industriparken 55, 2750 Ballerup, Denmark
Fax +45(7226)3320; E-mail: xifu.liang@leo-pharma.com
b
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2100 Copenhagen, Denmark
Received 25 June 2005
We chose 5-bromo-2-methylaniline and sodium azide as
a prototype reaction to discover suitable conditions using
microwave irradiation. A set of five ligands was examined
for the azidonation of 5-bromo-2-methylaniline
Abstract: A rapid synthesis of aryl azides from the corresponding
aryl halides catalyzed by CuI/diamine is described. Sodium ascor-
bate was found to have a positive effect on stabilization of the cata-
lyst system. The reactions were performed under very mild
conditions generally with high yields. In the case of aryl iodides, the (Scheme 1). Two diamine ligands d and e efficiently
transformation could be carried out at room temperature.
accelerated this reaction. Thus, the reaction was complete
in 30 minutes by using either ligand d or ligand e. Both
ligands have been successfully used for other C–N bond
formations. Ligands a, b, and c proved to be less effec-
tive. Proline (a) did not show any substantial improve-
ment as compared to ligands b and c. In the absence of a
ligand, only 13% conversion was achieved. In the follow-
ing experiments, both ligand d and e were used.
Key words: copper, aryl azides, aryl halides, ligands, azidonation
1
2
Aryl azides are used increasingly in organic synthesis, be-
cause of versatile transformations of the azide functional
1
group. For example, they can be used for generating
1
anilines and nitrenes, and for the preparation of a variety
2
of hetereocycles. Moreover, aryl azides have found wide
utility as photoaffinity probes/labels due to their ability to
be made radioactive with high specific activities.3
In one of our ongoing medicinal chemistry projects, we
need a variety of aryl azides to construct a heterocyclic
compound library. In contrast to the preparation of alkyl
azides, there exist few methods for the preparation of aryl
1
azides. Generally, they can be prepared by diazotization
of aryl amines and subsequent treatment with sodium
4
azide. However, sometimes, this method proves to be
problematic because of compatability of functional
groups. For this reason, some alternatives have been de-
5
–7
veloped. Recently, an efficient synthesis of aryl azides
from the corresponding amines using triflyl azide was re-
8
ported. The reaction proceeds under mild conditions,
normally giving high yields. One drawback of this method
is that triflyl azide is not commercially available and
needs to be freshly prepared. Another method for prepara-
tion of aryl azides is the Ullmann-type conversion of aryl
9
halides using CuI as catalyst. This transformation can be
1
0
accelerated by addition of proline. However, like some
1
1
other Ullmann-type reactions, the method still suffers
from high reaction temperature and low reaction rate. It is
known that several factors, such as ligand and solvent sys-
tem, play a crucial role in the reaction rate. Careful choice
of the reaction conditions should allow the reaction to pro-
ceed at relatively low temperature and in a short time.
Herein we report our findings through microwave-assist-
ed optimization of these reaction conditions, and their use
for the preparation of different aryl azides from the corre-
sponding aryl halides by conventional heating.
Scheme 1 Ligand screening
Next, we examined solvent systems using ligand e. When
1
,4-dioxane was used as solvent, no conversion was ob-
served (Table 1, entry 1). Acetonitrile proved to be fairly
ineffective – only 13% conversion (Table 1, entry 2). In-
terestingly, in contrast to Ma’s work, in which only trace
SYNLETT 2005, No. 14, pp 2209–2213
Advanced online publication: 26.07.2005
DOI: 10.1055/s-2005-872248; Art ID: D17405ST
0
2
.0
9
.2
0
0
5
©
Georg Thieme Verlag Stuttgart · New York

2
210
J. Andersen et al.
LETTER
of coupling product was isolated,10a 55% conversion was reached 80–90% in ten minutes, the reaction rate dropped
observed when DMSO was used (Table 1, entry 3). drastically (Table 3, entry 1). Increased equivalents of so-
DMSO–H O (5:1) gave a slightly better result (68%; dium azide, CuI, and ligand could not push the reaction to
2
Table 1, entry 4). When toluene was used, 59% conver- completion. All the reactions were carried out in an atmo-
sion was observed (Table 1, entry 5). tert-Butanol–H O sphere of air until this point. The slow rate could be due to
2
(
2:1) turned out to be a good solvent system (73% con- the deterioration of Cu(I) under air atmosphere. However,
version; Table 1, entry 6). However, no solvent systems even when the reaction proceeded under argon, the same
tested were as good as EtOH–H O (7:3).
phenomenon was observed (Table 3, entry 2). We then
tried another Cu(I) source, obtained from in situ reduc-
2
2c
Table 1 Screening Solvent Systema
tion of CuSO with excess sodium ascorbate. Using this
4
Cu(I) source, azidonation of p-tolyl bromide was com-
plete within 40 minutes (Table 3, entry 3). We speculated
that excess of sodium ascorbate had some positive effect
on the catalyst stability. Indeed, as we retried the reac-
tion by using CuI, ligand e, and, additionally, five mol%
of sodium ascorbate, total conversion was observed in 45
minutes (Table 3, entry 4). By using ligand d, the reaction
time was even shorter (10 min) for full conversion
Entry
Solvent
Conversion (%)b
1
2
3
4
5
6
1,4-Dioxane
MeCN
0
13
13
DMSO
55
DMSO–H O (5:1)
68
2
(
Table 3, entry 5).
Toluene
59
We also performed the reaction under the same condi-
tions, but without ligand. It turned out that a large portion
of starting material was still left after several hours. This
experiment rules out the accelerating effect of ascorbate.
t-BuOH–H O (2:19
73
2
7
EtOH–H O (7:3)
100
2
a
Reagents and conditions: 5-bromo-2-methylaniline (1 mmol), NaN3
(
2 mmol), CuI, ligand e, EtOH–H O (7:3, 4 mL); microwave, 100 °C,
0 min.
Conversions were determined by LC-MS.
2
To lower the reaction temperature to the boiling point of
the solvent system, we tried the azidonation under reflux.
The reaction could be complete within ten minutes
3
b
(
Figure 1 and Table 3, entry 6). The reaction conditions
We also examined catalyst and ligand loadings in this re- thus far developed include reflux of an aryl bromide (2
action. Full conversion was achieved with ligand loading mmol), sodium azide (4 mmol), CuI (10 mol%), sodium
down to 15% (Table 2, entry 4).
ascorbate (5 mol%), and ligand d (15 mol%) in EtOH–
H O (7:3, 4 mL). A quantitative comparison of reactions
2
Table 2 Investigating the Loading of the Catalyst Systema
with and without sodium ascorbate under these conditions
is outlined in Figure 1 and show that ascorbate is essential
for 100% conversion.
Entry
CuI (mol%)
Ligand e (mol%)
Conversion (%)b
1
2
3
4
1
2
2
4
13
14
Table 3 Investigationg the Effect of Cu(I) Source and Sodium
Ascorbate on the Azidonation of p-Tolyl Bromide
NaN3 (2 equiv),
5
10
15
20
50
Br
CuI (10 mol%)
N3
10
10
100
100
ligand d or e (15 mol%)
EtOH/H2O (7:3), 100 °C ,
Ar
5
a
Reagents and conditions: 5-bromo-2-methylaniline (1 mmol), NaN3
Entry Cu source Ligand Sodium ascorbate Time Conversion
mol%)
(min) (%)a
(
2 mmol), CuI, ligand e, EtOH–H O (7:3, 4 mL); microwave, 100 °C,
0 min.
Conversions were determined by LC-MS.
2
(
3
b
1b
2
CuI
e
e
e
e
d
d
–
>60
45
40
45
10
10
90
92
CuI
–
We wondered whether the fast reaction could be ascribed
to the microwave effect. Therefore, the reaction times
were compared using microwave irradiation and conven-
tional heating. It turned out that conventional heating gave
full conversion within 40 minutes, suggesting that the
high reaction rate was not due to microwave effect. Simi-
lar reaction needs 24 hours for completion using proline
3
CuSO4
CuI
20
5
100
100
100
100
4
5
CuI
5
6c
CuI
5
1
0a
a
1
as ligand.
Conversions were determined by H NMR.
b
c
The reaction was performed in an atmosphere of air.
The reaction was carried out under reflux.
When we tried azidonation of p-tolyl bromide under the
optimized conditions, we observed a very high initial re-
action rate (Table 3). However, after the conversion had
Synlett 2005, No. 14, 2209–2213 © Thieme Stuttgart · New York

LETTER
Rapid Synthesis of Aryl Azides
2211
Table 4 The Reaction of Aryl Bromides with Sodium Azide Using
Ligand d
NaN3 (2 equiv),
CuI (10 mol%)
R
R
Br
N3
ligand d (15 mol%)
sodium ascorbate (5 mol%)
EtOH/H2O (7:3), reflux, Ar
Entry
1
Product
Time (min)
10
Yield (%)a
89
N3
Figure 1 The effect of sodium ascorbate on the conversion of
p-tolyl bromide (both reactions were performed under an argon
atmosphere and the conversion was determined by H NMR)
2
3
MeO
N3
40
30
95
99
1
N3
This promising result encouraged us to explore the gener-
ality of this reaction. The results are provided in Table 4.
Azidonation of a wide variety of aryl bromides, present-
ing an assortment of functional groups, was conducted.
The reactions were generally fast and complete within one
hour. As previous reported, the reaction tolerates a variety
of common functional groups. Thus, aryl bromides con-
taining a phenolic OH, carboxylic acid, chloride, ketone
NH2
4
N3
20
60
96
82
5b
N3
HO2C
Cl
or an anilino NH , were efficiently converted to the
2
desired products.
6
7
N3
20
20
84
90
Finally, we explored the azidonation of aryl iodides, with
the intended goal to carry out this reaction at room tem-
perature. Our first azidonation of p-tolyl iodide was not
promising and the reaction was not complete after several
hours. When we changed the solvent system from EtOH–
H O (7:3) to DMSO–H O (5:1) to increase the solubility
N3
MeO
HO
8
9
N3
30
30
99
88
2
2
of reaction material, we observed a total conversion in 15
minutes (Table 5, entry 1). Several other phenyl azides
were obtained in good to excellent yield. Prolonged reac-
tion is prone to decompose 2-azidobenzoic acid, giving a
O
N3
N3
1
low yield according to the literature. But, by using our
1
0
40
99
standard method, 2-azidobenzoic acid was obtained in
8
4% yield (Table 5, entry 5). For the azidonation of 3-bro-
HO
mo-iodobenzene (Table 5, entry 7), only 1.05 equivalents
of sodium azide was used to circumvent the chemoselec-
tivity problem because azidonation of phenyl bromides
could be performed under the used conditions, albeit with
a low reaction rate.
a
Isolated yields.
b
1
Equiv of NaOH was used.
In conclusion, through optimizing the reaction conditions,
a remarkably fast reaction for the azidonation of aryl
halides catalyzed by Cu(I)/diamine was achieved under
extremely mild conditions. We also found that the addi-
General Procedure for Table 4
Aryl bromide (2 mmol), NaN (4 mmol), sodium ascorbate (0.1
3
mmol), CuI (0.2 mmol), ligand d (0.3 mmol), and 4 mL EtOH–H O
2
(
7:3) were introduced into a two-necked round-bottom flask
tion of sodium ascorbate has a stabilizing effect on the equipped with a stirring bar and a reflux condenser. After it was de-
catalyst. In addition, we have showed that microwave is a gassed, and then introduced under an argon atmosphere, the reac-
tion mixture was stirred under reflux and the progress of the
powerful tool to optimize reaction conditions though it
reaction was followed by TLC. When the aryl bromide was com-
turned out that the reaction can be complete in the same
pletely consumed, or when the progress of the reaction had stopped,
time period under conventional heating.
the reaction mixture was allowed to cool down to r.t., and the crude
mixture was purified either by extraction and/or flash chromatogra-
phy, giving the desired aryl azide.
Synlett 2005, No. 14, 2209–2213 © Thieme Stuttgart · New York

2
212
J. Andersen et al.
LETTER
+
Table 5 The Reaction of Aryl Iodides with Sodium Azide Using
Ligand d
126.7, 121.6, 116.4, 21.2. MS (EI+): m/z calcd for C H N O [M ]:
8
7
3
2
+
1
2
77; found (%): 177 (52), 149 (100) [M – N ]. IR (FTIR-ATR):
2
–
1
109 cm .
R
NaN3 (2 equiv), CuI (10 mol%)
R
I
N3
ligand d (15 mol%)
sodium ascorbate (5 mol%)
EtOH/H2O (7:3), reflux, Ar
-Azidophenol (Table 4, Entry 8)*14
3
1
Yield 99%; brown oil; R = 0.20 (PE–EtOAc, 10:1). H NMR (300
f
MHz, DMSO): d = 9.74 (s, 1 H), 7.19 (t, J = 8.01 Hz, 1 H), 6.60
(ddd, J = 8.01, 2.29, 0.76 Hz, 1 H), 6.54 (ddd, J = 8.01, 2.29, 0.76
Yield (%)a
Entry
1
Product
Time (min)
15
1
3
Hz, 1 H), 6.48 (t, J = 2.29 Hz, 1 H). C NMR (75.4 MHz, DMSO):
d = 158.7, 140.2, 130.7, 112.4, 109.6, 105.7. HRMS (EI): m/z calcd
N3
91
+
for C H N O [M ]: 135.0433; found: 135.0417. IR (FTIR-ATR):
107 cm .
6
5
–
3
1
2
2
N3
50
99
* No NMR data available in the literature.
4-Azido-2-methylbenzeneamine (Table 5, Entry 2)*15
H2N
1
Yield 99%, thick brown oil; R = 0.19 (PE–EtOAc, 3:1). H NMR
f
(
(
300 MHz, CDCl ): d = 6.76–6.61 (m, 3 H), 3.56 (br s, 2 H), 2.15
3
N3
35
60
60
99
99
84
3
1
3
s, 3 H). C NMR (75.4 MHz, CDCl ): d = 142.0, 130.0, 124.0,
3
+
HO
121.0, 117.6, 116.0, 17.4. MS (EI+): m/z calcd for C H N [M ]:
148; found (%): 148 (100). IR (FTIR-ATR): 2102 cm .
7
1
8
5
–
4b
HO C
2
N3
*
No NMR data available in the literature.
5b
16
CO H
2
3-Azido-1-bromobenzene (Table 5, Entry 7)*
Yield 77%; yellow oil; R = 0.39 (PE). H NMR (300 MHz, CDCl ):
f 3
1
N3
d = 7.26 (dt, J = 7.63, 1.15 Hz, 1 H), 7.22 (d, J = 7.63 Hz, 1 H), 7.18
t, J = 1.15 Hz, 1 H), 6.96 (dt, J = 7.63, 1.15 Hz, 1 H). 1 C NMR
3
(
6
CO Me
120
30
77
77
(75.4 MHz, CDCl ): d = 141.6, 130.9, 128.0, 123.3, 122.2, 117.8.
2
3
+
N3
GC-MS (EI+): m/z calcd for C H BrN [M ]: 197; found (%): 90
6
4
3
+
+
(
100) [M – N – Br]; no [M ] found. IR (FTIR-ATR): 2133, 2098
2
–
1
cm .
7c
* No NMR data available in the literature.
Br
N3
Acknowledgment
a
Isolated yields.
b
c
The Department of Spectroscopy at LEO Pharma is acknowledged
for their assistance in characterization of the compounds prepared
herein.
1
Equiv of NaOH was used.
1
.05 Equiv sodium azide was used.
General Procedure for Table 5
References
Aryl iodide (2 mmol), NaN (4 mmol), sodium ascorbate (0.1
3
mmol), CuI (0.2 mmol), ligand d (0.3 mmol) and 4 mL DMSO–H O
2
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5:1) were introduced into a two-necked round-bottom flask
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the aryl iodide was completely consumed, or when the progress of
the reaction had stopped, the crude reaction mixture was taken up in
a mixture of brine and EtOAc. The aqueous phase was extracted
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centrated in vacuo, and the residue was purified by filtration
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(
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(
Yield 99%; brown solid; mp 68–71 °C; R = 0.45 (PE–EtOAc, 4:1).
f
1
H NMR (300 MHz, CDCl ): d = 6.99 (d, J = 8.01 Hz, 1 H), 6.39
3
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(
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13
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3
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–1
7
4
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(
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(
4
-Azido-2-methylbenzoic Acid (Table 4, Entry 5)
1
Yield 82%; white solid; mp 159–162 °C; R = 0.28 (PE–EtOAc,
2
f
1
0:1 + 1% HOAc). H NMR (300 MHz, DMSO): d = 12.78 (br s, 1
(
H), 7.88 (dd, J = 7.63, 1.15 Hz, 1 H), 7.05–6.99 (m, 2 H), 2.53 (s, 3
1
H). 13C NMR (75.4 MHz, DMSO): d = 167.7, 142.6, 141.8, 132.4,
Synlett 2005, No. 14, 2209–2213 © Thieme Stuttgart · New York

LETTER
Rapid Synthesis of Aryl Azides
2213
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Synlett 2005, No. 14, 2209–2213 © Thieme Stuttgart · New York