Addition of aryl cuprates to azides: a novel approach for the synthesis of unsymmetrical diaryl amines

Article abstract of DOI:10.1016/j.tetlet.2009.09.056

Aryl and benzyl azides react smoothly with aryl cuprates, generated in situ from aryl magnesium bromide and CuCN in THF to furnish a variety of unsymmetrical diaryl amines in good yields. This is the first report on the synthesis of diarylamines from aryl

Full text of DOI:10.1016/j.tetlet.2009.09.056

Tetrahedron Letters 50 (2009) 6642–6645
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Tetrahedron Letters
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Addition of aryl cuprates to azides: a novel approach for the synthesis
of unsymmetrical diaryl amines
*
J. S. Yadav , B. V. Subba Reddy, Prashant Borkar, P. Janardhan 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:
Received 20 July 2009
Revised 7 September 2009
Accepted 10 September 2009
Available online 15 September 2009
Aryl and benzyl azides react smoothly with aryl cuprates, generated in situ from aryl magnesium bro-
mide and CuCN in THF to furnish a variety of unsymmetrical diaryl amines in good yields. This is the first
report on the synthesis of diarylamines from aryl azides and aryl bromides via an organometallic
approach.
Ó 2009 Published by Elsevier Ltd.
Keywords:
Aryl azides
Grignard reaction
Aryl cuprates
Diaryl amines
Diaryl amines are important industrial intermediates and are
frequently found in a variety of biologically active molecules such
as natural products,1 agrochemicals,2 and HIV-1 protease inhibi-
tors.3 They are also widely used as stabilizers and antioxidants
for rubber and polymers, stabilizers for explosives, as polymeriza-
tion and corrosion inhibitors, and in dye preparation.4 Tradition-
ally, the N-arylation of amines has been carried out under
copper-mediated Ullmann-type conditions involving the coupling
of amines with aryl halides.5 Although these copper-promoted
reactions are useful, they usually require harsh reaction conditions
and stoichiometric amounts of copper, and the yields are not
reproducible.6 Recently, various diaryl amines have been prepared
by palladium-catalyzed cross-coupling reactions of amines with
aryl halides.7 Other transition metals such as copper8 and nickel9
have also been used for C–N bond-formation reactions. Oxidative
coupling procedures between arylboronic acids and aromatic or
heterocyclic amines mediated by Cu(II) salts are also effective.10
Addition of aromatic Grignard reagents to nitroarenes has also
been reported for the synthesis of diaryl amines.11 Despite these
significant recent improvements, there are still limitations such
as the use of expensive catalysts and ligands in the present N-ary-
lation methods. Furthermore, there have been no reports on the
synthesis of unsymmetrical diaryl amines via aryl cuprate addi-
tions to organic azides.
cuprates to azides. Initially, we attempted arylation of phenyl azide
(1) with phenyl magnesium bromide (2) in THF at 0 °C. To our sur-
prise, no desired diphenyl amine was obtained using phenylmag-
nesium bromide alone. However, the corresponding diphenyl
amine 3a was obtained in 65% by phenyl cuprate generated
in situ from phenyl magnesium bromide and CuCN (Scheme 1).
Next, we examined the reactivity of various azides and aryl ha-
lides. Interestingly, several aryl azides reacted readily with aryl
cuprates to produce a wide range of diaryl amines (Table 1). This
method worked well with aryl and benzyl azides. Though alkyl
azides failed to react with aryl cuprates, benzyl azide reacted well
with phenyl cuprate because of its high reactivity compared to al-
kyl azides. Furthermore, this method is highly selective for the
monoarylation of azides, whereas Pd(II)/base-promoted arylation
of amines produce a mixture of products. The reaction conditions
are compatible with various functionalities such as chloro, nitro,
and aryl ethers (Table 1). The steric and electronic factors had
shown some effect on the conversion. In general, electron-rich
azides gave higher conversion than electron-deficient counterpart
(Table 1, entries d–f). Similarly, sterically hindered azides gave
lower yields compared to simple aromatic azides (Table 1, entries
i and l).
In continuation of our work on metal-mediated reactions of or-
ganic azides,12 we herein report a novel procedure for the prepara-
tion of unsymmetrical diaryl amines by means of addition of aryl
H
N3
Br
N
Mg
+
°
CuCN,THF, 0 C
1
2
3a
* Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512.
E-mail address: yadav@iict.res.in (J.S. Yadav).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.09.056

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 6642–6645
6643
Table 1
Preparation of diaryl amines via the addition of aryl cuprates to azides
Entry
Azide
Aryl halide
Diaryl aminea
Time (h)
1.5
Yieldb,c (%)
H
N
N3
N3
N3
Br
a
65
62
58
56
54
61
70
63
60
67
OMe
I
H
N
b
c
d
e
f
2.0
2.0
2.5
2.5
2.0
1.5
1.5
2.0
2.0
OMe
H
N
I
I
Me
Me
Me
H
N
N3
N3
O2N
O2N
Me
I
H
N
O2N
O2N
O2N
O2N
H
N
Br
Br
Br
Br
Br
N3
Br
N3
Br
H
N
g
h
i
H
N3
N
Cl
Cl
Me
N3
Me
H
N3
N
Me
Me
Me
Me
H
N
j
H
N
N3
Br
O
O
O
O
k
l
1.5
3.0
1.5
75
57
60
Me
OMe
H
N
N3
OMe
I
Br
Me
Br
Br
N3
m
N
H
a
b
c
The products were characterized by 1H NMR, IR, and mass spectrometry.
Yield refers to pure products after chromatography.
The reactions were performed in 1 mmol scale at 0 °C.

6644
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 6642–6645
Table 2
Effect of various Cu(I) salts in the preparation of 3a
Entry
Cu(I) salt
Quantitya (mmol)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuI
CuI
0.2
1.2
0.2
1.2
0.2
1
1.2
2
3
10
32
8
24
15
60
65
65
65
CuBr
CuBr
CuCN
CuCN
CuCN
CuCN
CuCN
a
The reaction was carried out with phenyl azide (1 mmol), bromobenzene (1.2 mmol), and magnesium (2.5 mmol).
Yield refers to pure products after chromatography.
b
Mg
Br
MgBr
Cu
CuCN
-
+
N
N
N
°
THF, 0
C
°
THF, 0
C
Cu(I)
H
N
-
NH4Cl
-N2
N
N
N
Scheme 2.
The products were characterized by 1H NMR, IR, and mass spec-
References and notes
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ing the reaction time or by increasing the amount of copper(I) salt.
In the absence of CuCN, 1,4-diaryl triazene was formed from aryl-
magnesium halide and azide, which was unstable and decomposed
rapidly to give the respective orange-red diazo compound. The
reaction was successful only with aryl cuprates. The scope and
generality of this procedure is illustrated with respect to various
organic azides and aryl halides and the results are presented in Ta-
ble 1.13
The effect of various Cu(I) salts such as CuI, CuBr and CuCN,
CuCN was studied in the reaction of phenyl azide (1 mmol), bro-
mobenzene (1.2 mmol), and magnesium (2.5 mmol). Low yields
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tives. The use of catalytic amount of CuCN (0.2 equiv) gave the de-
sired product 3a in 15% yield. Under optimized conditions,
1.2 equiv of CuCN is essential to achieve high conversion. No in-
crease in the yield was observed even by increasing the quantity
of the CuCN (Table 2).
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Acknowledgment
P.B. and P.J.R. thank CSIR, New Delhi, for the award of
fellowships.
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6645
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J = 7.5 Hz, 1H), 6.69–6.61 (m, 2H), 6.48 (dd, J = 8.3 and 2.2 Hz, 1H), 5.88 (s, 2H),
5.39 (br s, 1H); 13C NMR (75 MHz, CDCl3): d 148.1, 144.5, 137.1, 129.3, 121.3,
119.9, 116.1, 112.8, 108.5, 102.4, 101.0; ESI-MS: m/z: 214 (M+H); HRMS calcd
for C13H12NO2: 214.0868, found: 214.0860. Compound 3j. N-(1-Naphthyl)-N-
phenylamine: white solid, mp 132 °C, IR(neat): mmax 3391, 3051, 2922, 1595,
13. Typical procedure: a mixture of bromobenzene (188 mg, 1.2 mmol), activated
magnesium turnings (0.060 mg, 2.5 mmol), and a small iodine granule in
anhydrous THF (5 mL) was stirred under nitrogen atmosphere to generate
phenyl magnesium bromide. The thus-obtained aryl Grignard reagent was
added slowly to the solution of CuCN (128 mg, 1.5 mmol) in dry THF (4 ml) at
0 °C. After obtaining bluish-green colour, a solution of phenyl azide (119 mg,
1 mmol) in THF (1 mL) was added slowly in a dropwise manner. The resulting
mixture was stirred for 1 h at 0 °C. After the completion of the reaction, as
indicated by TLC, the mixture was quenched with saturated ammonium
chloride solution (5 mL) and filtered off under vacuo. The filtrate was extracted
with ethyl acetate (2 Â 10 mL), dried over Na2SO4. Removal of the solvent
followed by purification on silica gel (Merck, 100–200 mesh, ethyl acetate/
hexane, 2:98) afforded pure diphenyl amine (109 mg, 65% yield). In case of
substituted aryl iodides, the corresponding Grignard reagent was generated in
dry diethyl ether. Spectral data for selected products: compound 3k. N-(1,3-
Benzodioxol-5-yl)-N-phenylamine: white solid, mp 152 °C, IR (neat): mmax 3398,
1495, 1398, 1303, 774, 741, 691 cmÀ1 1H NMR (300 MHz, CDCl3): d 8.01–7.95
;
(m, 1H), 7.83–7.78 (m, 1H), 7.54–7.40 (m, 3H), 7.36–7.31 (m, 2H), 7.20 (t,
J = 7.5 Hz, 2H), 6.95 (d, J = 7.5 Hz, 2H), 6.85 (t, J = 7.5 Hz, 1H), 5.85 (br s, 1H); 13C
NMR (75 MHz, CDCl3): d 144.7, 138.7, 134.6, 129.3, 128.5, 127.7, 126.1, 125.9,
125.6, 122.9, 121.7, 120.4, 117.3, 115.8; ESI-MS: m/z: 220 (M+H); HRMS calcd
for C16H14N: 220.1126, found: 220.1125. Compound 3b. N-(2-Methoxyphenyl)-
N-phenylamine: White solid, mp 102 °C, IR (neat):
m
max 3413, 2959, 1593, 1517,
1238, 1026, 714, 694 cmÀ1
;
1H NMR (200 MHz, CDCl3): d 7.21–6.95 (m, 5H),
6.84–6.66 (m, 4H), 5.97 (br s, 1H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3): d
148.2, 142.6, 132.9, 129.2, 121.1, 120.7, 119.8, 118.5, 114.6, 110.4, 55.5; ESI-
MS: m/z: 200 (M+H); HRMS calculated for C13H14NO: 200.1075, found:
200.1069. Compound 3i. N-Mesityl-N-phenylamine: White solid, mp 52 °C IR
(neat): mmax 3390, 2919, 1600, 1495, 1311, 746, 692 cmÀ1 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; ESI-
MS: m/z: 212 (M+H); HRMS calcd for C15H18N: 212.1439, found: 212.1438.
2964, 2892, 1598, 1482, 1235, 1075, 930, 803, 747, 693 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d 7.15 (t, J = 7.5 Hz, 2H), 6.85 (d, J = 7.5 Hz, 2H), 6.78 (t,