Metal-free carbon-nitrogen bond-forming coupling reaction between arylboronic acids and organic azides

Article abstract of DOI:10.1016/j.tetlet.2010.11.103

A novel and efficient metal-free carbon-nitrogen bond-forming coupling reaction between arylboronic acids and organic azides is reported. The reaction is fairly general for the preparation of secondary aromatic amines. Furthermore, the reaction is very functional-group tolerant. A possible mechanism is also proposed.

Full text of DOI:10.1016/j.tetlet.2010.11.103

Tetrahedron Letters 52 (2011) 1430–1431
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free carbon–nitrogen bond-forming coupling reaction between
arylboronic acids and organic azides
Lili Ou a, Jiaan Shao a, Guolin Zhang a, , Yongping Yu a,b,
⇑
⇑
a College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China
b Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient metal-free carbon–nitrogen bond-forming coupling reaction between arylboronic
acids and organic azides is reported. The reaction is fairly general for the preparation of secondary aro-
matic amines. Furthermore, the reaction is very functional-group tolerant. A possible mechanism is also
proposed.
Received 15 September 2010
Revised 10 November 2010
Accepted 19 November 2010
Available online 24 November 2010
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
C–N formation
Arylboronic acids
Organic azides
Metal-free
The selective formation of carbon–nitrogen bonds is a funda-
mental transformation in organic synthesis. Although enormous
approaches are available, the development of methods which are
advantageous in the aspects of simplicity, selectivity, functional-
group tolerance, and availability of starting materials would be
valued in organic synthesis. Over the past decades, transi-
tion-metal-catalyzed aromatic C–N bond-forming reactions have
been intensively studied due to the importance of aromatic amines
in chemistry related fields.1 The most well-known method is palla-
dium-, nickel-, or copper-catalyzed coupling reactions between
aryl halides and amines,2 arylboronic acids and amines.3 The aryl-
boronic acids are popular owing to their advantages in terms of
stability, low toxicity, and commercial availability. To the best of
our knowledge, all the arylboronic acid mediated C–N bond-
forming coupling reactions need metal catalysts. It will be benefi-
cial if metal-free C–N bond formation coupling reactions can be
developed because it will eliminate the necessity for disposing
the catalysts from the reaction residues and separating the
traceless metal from the products.
methodology for a metal-free carbon–nitrogen bond-forming cou-
pling reaction between arylboronic acids and organic azides.
Initially, the reaction conditions were optimized using phenyl-
boronic acid (1a) and benzyl azides (2a) as starting substrates
(Table 1). When the reaction was carried out in ethanol, THF,
1,4-dioxane, xylene, DMF at 80 °C for 24 h, no reaction occurred
(entries 1–5). When the temperature was increased to 100 °C,
there was still no reaction in DMF (entry 6), but it gave relatively
Table 1
Optimization of reaction conditionsa
Entry
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ethanol
THF
1,4-Dioxane
Xylene
DMF
80
80
80
80
24
24
24
24
24
24
24
24
24
24
24
48
0
0
0
0
0
0
15
20
32
55
53
82
Organic azides are versatile synthetic intermediates that partic-
ipate in various important organic reactions, such as Huisgen reac-
tion, Staudinger reaction, Schmidt rearrangement, and aza-Wittig
reaction.4 Recently, it was reported that diazo compounds could
be coupled with arylboronic acids to form C–C bonds without the
use of metal catalysts.5 Thus, we herein wish to report a novel
80
DMF
100
100
100
120
140
Reflux
140
1,4-Dioxane
Xylene
Xylene
Xylene
Xylene
Xylene
10
11
12
⇑
Corresponding authors. Tel.: +86 571 88208450 (G.Z.), +86 571 88208452 (Y.Y.).
E-mail addresses: guolinzhang@zju.edu.cn (G. Zhang), yyongping@tpims.org (Y.
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), xylene (5 ml), N2.
The yield of the isolated product.
b
Yu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.103

L. Ou et al. / Tetrahedron Letters 52 (2011) 1430–1431
1431
Table 2
Coupling reaction between arylboronic acids and organic azidesa
Entry
Ar
R
Product
Yieldb (%)
1
2
3
Ph
Ph
Ph
Ph
Benzyl
CH3(CH2)6CH2
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
82
35
36
67
48
60
60
85
75
58
44
85
75
46
58
40
74
0
4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
CH3(CH2)6CH2
4-MeOC6H4
4-MeC6H4
2-BrC6H4
4-NO2C6H4
Benzyl
4-MeOC6H4
4-ClC6H4
Benzyl
4-MeC6H4
Benzyl
4-MeOC6H4
4-MeOC6H4
5
Ph
Scheme 1. Possible mechanism for coupling reactions between arylboronic acids
and organic azides.
6c
7
3-CHOC6H4
3,4,5-tri-F-C6H2
3,4,5-tri-F-C6H2
3,4,5-tri-F-C6H2
3,4,5-tri-F-C6H2
3,4,5-tri-F-C6H2
3-F-C6H4
3-F-C6H4
3-F-C6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-Pyridyl
2-Thienyl
8
9
amines were found (entries 18 and 19). Instead, the self-coupled
product, 1,2-bis (4-methoxyphenyl) diazene was obtained.
The mechanism of this coupling reaction between arylboronic
acids and organic azides was considered to be similar to the
reaction between arylboronic acids with diazo compounds
(Scheme 1).5 The reaction is proposed to be initiated by the nucle-
ophilic attack of azide nitrogen to arylboronic acid to form the
reversible intermediate A, followed by 1,2-migration of aromatic
rings with the loss of nitrogen. Finally, the generated intermediate
B is converted to product 3 upon protodeboronation.
In conclusion, we have developed a novel, efficient, and metal-
free reaction for carbon–nitrogen bond formation via arylboronic
acids and organic azides. This reaction is fairly general and func-
tional-group tolerant. Thus, we believe it will be widely applied
in organic synthesis.
10
11
12
13
14
15
16
17
18
19
3s
0
a
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), xylene (5 ml), N2, 140 °C, 24–
48 h.
b
The yield of the isolated product.
Reaction temperature is 120 °C.
c
low yields in 1,4-dioxane compared to that in xylene (entries 7 and
8, respectively). With the temperature increasing, the yield of the
reaction was improved (entries 8–10), but at reflux the yield was
not further improved (entry 11). It was also found that the yield
was increased when prolonging the reaction time (entry 12 com-
pared to 10). Thus, the optimized condition for this reaction was
achieved in xylene at 140 °C for 48 h.
Acknowledgments
We thank the National Natural Science Foundation of China
(Nos. 30772652 and 90813026) and National key Tech project for
Major Creation of New Drugs (No. 2009ZX09501-010) for financial
support.
With the optimized reaction conditions in hand, the generality
of this reaction was studied using a set of arylboronic acids 1
and organic azides 2 (Table 2). The alkyl azides were readily pre-
pared from alkyl bromides by the nucleophilic substitution of bro-
mide with sodium azide,6 while aromatic azides are commonly
prepared from the corresponding aromatic amines via their diazo-
nium salts.7 The coupling reaction was conducted over a broad
range of reagents. Both alkyl azides and aromatic azides were cou-
pled with various arylboronic acids in moderate to good isolated
yields. When compared to octyl azide, benzyl azide showed better
reaction activity (entries 1 and 2). In addition, when arylboronic
acids were coupled with benzyl azides, electron-withdrawing sub-
stitution gave satisfactory coupling (entry 12), but the yields
dropped off with electron-donating substitution (entries 15 and
17). Furthermore, the coupling of arylboronic acids with a series
of aryl azides was investigated. Arylboronic acids containing elec-
tron-withdrawing groups provided higher yields than those with
electron-donating groups (entries 5, 9, and 16). While the results
with the aryl azides were the opposite (entries 3–5). Especially
the aryl azides with strong electron-withdrawing groups such as
–NO2, these hardly reacted with phenylboronic acid, but did re-
acted with 3,4,5-trifluorophenylboronic acid in moderate yield
(entry 11). To our delight, the functional-group tolerance of the
reaction was evident. The reaction was performed successfully in
the presence of unprotected aldehydes (entry 6). The coupling
was also conducted successfully with halogen substituted aromatic
rings (entries 5, 7–14). However, with regard to heterocyclic boro-
nic acids such as pyridine-4-boronic acid and thiophene-2-boronic
acid reacting with 4-methoxylphenyl azide, no desired secondary
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data, and copies of 1H and 13C NMR spectra for all products)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.11.103.
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