Indium/Cu(II)-mediated one-pot synthesis of unsymmetrical diaryl amines from aryl boronic acids and azides

Article abstract of DOI:10.1016/j.tetlet.2011.03.022

Aryl azides react smoothly with aryl boronic acids in the presence of indium metal in methanol to furnish a variety of unsymmetrical diaryl amines in good yields. This is the first report on the synthesis of diaryl amines from the cross coupling of aryl azides with aryl boronic acids via N-arylation.

Full text of DOI:10.1016/j.tetlet.2011.03.022

Tetrahedron Letters 52 (2011) 2547–2549
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium/Cu(II)-mediated one-pot synthesis of unsymmetrical diaryl amines
from aryl boronic acids and azides
⇑
B. V. Subba Reddy , N. Sivasankar Reddy, Y. Jayasudhan Reddy, Y. Vikram Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Aryl azides react smoothly with aryl boronic acids in the presence of indium metal in methanol to furnish
a variety of unsymmetrical diaryl amines in good yields. This is the first report on the synthesis of diaryl
amines from the cross coupling of aryl azides with aryl boronic acids via N-arylation.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 29 October 2010
Revised 1 March 2011
Accepted 4 March 2011
Available online 17 March 2011
Keywords:
N-Arylation
Indium metal
Aryl azides
Aryl boronic acids
Diaryl amines
The C–N bond formation via cross-coupling reactions is one of
the most widely used methods1 for the preparation of nitrogen-
containing compounds in pharmaceuticals, agrochemicals and
material sciences.2–5 Traditionally, N-arylation has been carried
out under Ullmann conditions via cross coupling reactions of
amines with aryl halides.6 The conventional copper-promoted
reactions normally require harsh reaction conditions and the yields
are not reproducible.7 Subsequently, palladium catalyzed C–N
cross-couplings of aryl halides with aliphatic, aromatic and hetero-
aromatic amines have been reported by Buchwald and Hartwig for
N-arylation.8,9
In particular, diaryl amines can easily be prepared by cross cou-
pling reactions of aryl boronic acids with aromatic amines using
Cu(II) salts in the presence of a base.10,11 Furthermore, diaryl
amines can also be synthesized via cross-coupling reactions of aryl
siloxanes with aromatic or heterocyclic amines using Cu(II) acetate
in the presence of TBAF/base.12 Recently, nitroarenes were found to
be effective for the synthesis of diaryl amines.13 In addition, aryl
azides have also been used for the one-pot synthesis of diaryl
amines.14 Though significant improvements have been achieved
in N-arylation, the use of expensive catalysts/ligands, moisture
sensitive organometallic reagents and strong basic conditions lim-
its their use in large scale synthesis.
be handled safely without any apparent toxicity. In addition, in-
dium exhibits low heterophilicity in organic reactions and thus
oxygen- and nitrogen-containing functional groups are usually
well tolerated by organoindium reagents.15 Moreover, indium-
assisted reactions display low nucleophilicity thus permitting
chemoselective transformations of groups of similar reactivity.16
However, there are no reports on the one-pot synthesis of diaryl
amines from aryl azides and aryl boronic acids.
In continuation of interest on organic azides,17 we, herein report
a direct method for the one-pot synthesis of unsymmetrical diaryl
amines from aryl azides and aryl boronic acids. Initially, we at-
tempted arylation of phenyl azide (1) with phenyl boronic acid
(2) in the presence of indium metal granule (1.5 equiv) in metha-
nol. The reaction proceeded smoothly at 70 °C and the correspond-
ing diphenyl amine 3a was obtained in 80% yield (Scheme 1).
No arylation was observed in absence of either indium metal or
copper(II) acetate. As solvent, methanol gave the best results. Un-
der these optimized conditions, we have examined the reactivity
of various azides and aryl boronic acids. Interestingly, several aryl
azides such as p-methoxy, p-ethyl, 2,4,6-trimethyl phenyl azides
reacted readily with aryl boronic acids to produce a wide range
Recently, indium has attracted significant interest in organic
synthesis as it possesses certain unique properties. Indium metal
is unaffected by air or oxygen at ambient temperatures and can
H
OH
B
N
Indium
N3
OH
+
Cu(OAc)2, MeOH, 70 0C
1
2
3a
⇑
Corresponding author. Tel.: 91 40 27193535; fax: +91 40 27160512
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
Scheme 1. Reaction between phenyl boronic acid and phenyl azide.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.022

2548
B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 2547–2549
Table 1
Preparation of diaryl amines from aryl boronic acids and aryl azides
Entry
Azide
N3
Arylboronic acid
Diaryl aminea
Time (h)
3.0
Yieldb (%)
80
B(OH)2
H
N
a
N3
N3
B(OH)2
H
N
b
c
3.0
2.5
70
82
B(OH)2
H
O
O
N
O
O
N3
N3
B(OH)2
H
N
d
e
3.0
3.5
79
72
MeO
MeO
MeO
MeO
B(OH)2
H
N
N3
B(OH)2
H
N
f
3.5
3.5
4.0
4.5
2.5
76
68
73
65
70
N3
B(OH)2
H
N
g
h
i
B(OH)2
H
N
N3
B(OH)2
H
N
N3
N3
B(OH)2
H
N
j
S
S
N3
B(OH)2
H
N
k
3.0
72
S
S
a
The products were characterized by 1H NMR, IR and mass spectrometry.
Yield refers to pure products after chromatography.
b
patible with a halide substituted aryl azides. Furthermore, the
reactions with alkyl azides were sluggish and low yielding. It was
observed that aryl azides bearing electron donating groups are
more reactive than those with electron withdrawing groups.
The reaction works well even in the absence of metal activators
such as ammonium chloride or TMSCl. No arylation of azides was
observed with aryl halides. The reaction was successful only with
aryl boronic acids. The scope and generality of this procedure is
illustrated with various organic azides and aryl boronic acids and
the results are presented in Table 1.18
Mechanistically, the reaction proceeds by initial formation of
aryl amines from azides with indium metal. Then the mechanism
is similar to that postulated for N-arylation with boronic acids
(Scheme 2).10,11
In conclusion, we have demonstrated a one-pot bimetallic ap-
proach for the preparation of unsymmetrical diaryl amines by in-
dium mediated and copper catalyzed N-arylation. It is a direct
method to accomplish the synthesis of a variety of diaryl amines
from aryl azides and boronic acids.
L
L
Cu(OAc)2
Indium
MeOH
Ar-N3
Ar-NH2
CuII
ArNH
+
AcOH
Coordination
OAc
Ar'B(OH)2
Transmetallation
L
L
L
L
AcOB(OH)2
+
CuII
ArNH
CuIII
ArNH
O2 or Disproportionation
Ar'
Ar'
Reductive
elemination
-Cu 0
-Cu I
ArNHA '
Scheme 2. A plausible reaction mechanism.
Acknowledgment
of diaryl amines (Table 1). Next, we studied the reactivity of several
boronic acids such as naphthyl-2-boronic acid, 3,4-methylenedi-
oxyphenyl boronic acid and 3-thienyl boronic acid. This method
works well even with sterically hindered azides such as 2,4,6-tri-
methyl azide (entries h and i, Table 1). Similarly, bulky susbstrates
such as naphthyl-2-boronic acid also participated effectively in this
reaction (entries b, e, g and i, Table 1). 3-Thienyl boronic acid also
gave the desired product in good yields (entries j and k, Table 1).
Thus, a variety of diaryl amines were prepared using this proce-
dure. Furthermore, this method is highly selective for the mono-
arylation of azides. No diarylation of azide was observed under
the present reaction conditions. The reaction conditions are incom-
YJR thanks UGC, New Delhi for the award of a fellowship.
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18. Typical procedure: A mixture of phenyl azide (0.1 g, 1 mmol), phenyl boronic
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time (Table 1). After complete conversion as confirmed by TLC, the mixture
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7.18–7.28 (m, 3H), 7.04–7.17 (m, 3H), 6.90 (t, J = 7.3 Hz, 1H), 5.79 (br s, 1H). 13
NMR (75 MHz, CDCl3): d 142.7, 140.6, 134.5, 129.3, 129.1, 127.5, 126.4, 123.4,
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3388, 2923, 2853, 1593, 1494, 1300, 737 cmÀ1
C
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HRMS (ESI) [M+H] calcd for C16H14N:220.1126, found 220.1117; Compound
3d: 4-methoxy-N-phenylbenzenamine: white solid, mp 92–94 °C. 1H NMR
(300 MHz, CDCl3): d 7.15 (t, J = 7.5 Hz, 2H), 7.03 (d, J = 6.9 Hz, 2H), 6.70–6.90
(m, 5H), 5.41 (br s, 1H), 3.78 (s, 3H). 13C NMR (75 MHz, CDCl3): d 155.2, 145.1,
135.6, 129.2, 122.1, 119.5, 115.5, 114.6, 55.5; IR (KBr):
t
3392, 2924, 2854,
1597, 1512, 1244, 1028, 741 cmÀ1 EIMS [M+] 199; compound 3e: N-(4-
.
methoxyphenyl)naphthalen-2-amine: pale yellow solid, mp 218–220 °C. 1H
NMR (300 MHz, CDCl3): d 7.64 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.02–
7.35 (m, 6H), 6.84 (d, J = 8.8 Hz, 2H), 5.56 (br s, 1H), 3.80 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 155.9, 142.2, 135.3, 129.3, 128.8, 128.1, 126.9, 124.2, 124.1,
1228, 116.6, 114.2, 55.4.; IR (KBr):
t 3392, 3047, 2923, 1627, 1506, 1236, 1173,
1031, 816, 746 cmÀ1. HRMS (ESI) [M+H] calcd for C17H17NO: 250.1231, found
250.1235; compound 3h: 2,4,6-trimethyl-N-phenylbenzenamine: white solid,
mp 52 °C; 1H NMR (300 MHz, CDCl3): d 7.06 (t, J = 7.5 Hz, 2H), 6.87 (s, 2H), 6.65
(t, J = 7.5 Hz, 1H), 6.42 (d, J = 7.5 Hz, 2H), 5.00 (br s, 1H), 2.29 (s, 3H), 2.16 (s,
6H); 13C NMR (75 MHz, CDCl3): d 146.6, 135.9, 135.4, 135.3, 129.1, 127.0,
117.8, 113.2, 20.9, 18.2; IR (neat):
692 cmÀ1; ESIMS: m/z: 212 [M+H]; HRMS calcd for C15H18N: 212.1439, found:
212.1438. Compound 3k N-(4-ethylphenyl)thiophen-3-amine: colorless oil, 1
t 3390, 2919, 1600, 1495, 1311, 746,
H
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2H), 6.60–6.64 (m, 1H), 5.55 (br s, 1H), 2.57 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 144.3, 141.0, 129.2, 124.8, 123.2, 121.0,
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