A highly efficient Ga(OTf)3/KI-catalysed transformation of aryl azides to aryl amines using low catalyst loading

Article abstract of DOI:10.3184/174751918X15404076150031

A highly proficient transformation of aryl azides to aryl amines under Ga(OTf)₃/KI catalysis is described.

Full text of DOI:10.3184/174751918X15404076150031

572 RESEARCH PAPER
VOL. 42 NOVEMBER, 572–574
JOURNAL OF CHEMICAL RESEARCH 2018
A highly efficient Ga(OTf)3/KI-catalysed transformation of aryl azides to aryl
amines using low catalyst loading
Hani Mutlak A. Hassan*
King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, Jeddah 21589, Kingdom of Saudi Arabia
A highly proficient transformation of aryl azides to aryl amines under Ga(OTf)3/KI catalysis is described.
Keywords: gallium triflate, azides, amines, reduction of aromatic azides
The amino functional group is one of the most important
functional groups in organic chemistry. Amine compounds
are important building blocks in organic synthesis as they are
employed as precursors for the synthesis of other functional
groups such as amides, ureas/thioureas, and imines. They are
also highly useful synthetic intermediates for the synthesis of a
variety of biologically active pharmaceutical molecules.1 On the
other hand, the azide functional group is very useful, particularly
for the synthesis of triazoles via Huisgen cycloaddition (click)
reactions2–4 which have found extensive utility in medicinal
chemistry.5 One of the most effective and reliable methods for
the preparation of amines is through the reduction of the easily
accessible azides.6 There are a variety of synthetic methods
reported in the literature for the reduction of azides to their
corresponding amines.7–17 Although the available methods are
generally valuable, some of them have limitations such as harsh
reaction conditions, toxicity of reagents, poor chemoselectivity,
high catalyst loading, and convenience. Thus, there is a
continuous need to explore new methods that can overcome these
drawbacks and effectively achieve this reductive transformation.
Previous studies have reported the reduction of azides to amines
using Lewis acid catalysts such as FeCl3/NaI18 and CeCl3·7H2O/
NaI.19 Since the use of water-labile Lewis acids in the reduction
of azides could hamper the Lewis acids’ activity, metal triflates
[M(OTf)3] offer a distinct alternative because they are water-
stable, environmentally benign, and are very efficient. The
reduction of azides using metal triflates is very limited and
less explored. To the best of our knowledge, there is only one
report describing the use of metal triflates such as Al(OTf)3 and
Gd(OTf)3 in combination with NaI for the reduction of azides to
amines.20 Although efficient, the use of relatively high catalyst
loading (20 mol%) is not appreciated when it comes to cost
efficiency of this transformation. Gallium triflate [Ga(OTf)3] is a
versatile, water-tolerant, stable, and highly chemoselective Lewis
acid that often requires low catalyst loading to effect various
transformations in organic synthesis.21 Herein, we report the use
of Ga(OTf)3/KI catalytic system for the effective reduction of
aromatic azides to their corresponding aromatic amines with
gallium triflate as the Lewis acid promoter.
yield (Table 1, entry 2). Increasing the amount of KI to 4 equiv.
gave 2a in virtually quantitative yield of 94% (Table 1, entry
3; Table 3, entry 1). We then tested this catalytic system using
other popular solvents such as DMF, DMSO, and THF, which
afforded 2a in lower yields of 62%, 67%, and 55%, respectively
(Table 1, entries 4–6), indicating that CH3CN is the superior
solvent for the reaction to proceed in high yield.
We then investigated the effect of catalyst loading [i.e.
loading of Ga(OTf)3] of this catalytic system. The Ga(OTf)3/KI
system is highly efficient as the product 2a was easily formed
even with catalyst loading as low as 2 mol% to provide amino
product 2a in 72% yield (Table 2, entry 1). When we carried
out the reaction with 10 mol% catalyst loading, 2a was formed
in 94% yield which was the same yield when the reaction was
conducted with 5 mol% catalyst loading (Table 2, entries 2 and
3). This indicates that Ga(OTf)3 is a very efficient Lewis acid
promoter as 5 mol% Ga(OTf)3 was sufficient for the reaction
to form the amino product 2a in quantitative yield without the
need to use any higher catalyst loading.
Table 1 Optimisation of the azide reduction reaction
N3
NH2
Ga(OTf)3 [5 mol%]
(conditions)
N
O2
N
O2
1a
2a
Entry Temperature (°C) Solvent
KI (equiv.)
Yield (%)a
1
2
3
4
5
6
23 (rt)
60
60
60
60
CH3CN
CH3CN
CH3CN
DMF
DMSO
THF
2
3
4
4
4
4
No reaction
86
94
62
67
55
60
aThe reaction was performed using azide substrate 1a (1 mmol), Ga(OTf)3 (5 mol%), KI
(equiv.), using different temperatures, and solvents for 1 h.
Table 2 Effect of Ga(OTf)3 catalyst loading on the efficiency of the
reductive reaction
Results and discussion
We began by studying the reduction of azides to their
corresponding amines with 1-azido-4-nitrobenzene 1a as
the model substrate. We were interested to explore the use
of Ga(OTf)3 with KI as the iodide source because it has the
advantage of being less hygroscopic than NaI. At the beginning
of our investigation, we performed a reaction using 5 mol%
Ga(OTf)3 in the presence of KI (2 equiv.) in CH3CN at room
temperature which failed to provide the desired amino product
2a (Table 1, entry 1). We then increased the KI to 3 equiv. and
performed the reaction at 60 °C which provided 2a in 86%
Entry
Ga(OTf)3 (mol%)
Yield (%)a
1
2
3
2
5
10
72
94
94
aThe reaction was performed using azide substrate 1a (1 mmol), Ga(OTf)3 (mol%, see
table), KI (4 mmol) in CH3CN at 60 °C for 1 h.
* Correspondent. E-mail: hmahassan@kau.edu.sa

JOURNAL OF CHEMICAL RESEARCH 2018 573
Table 3 Reduction of various azide substrates under Ga(OTf)3/KI
solution of sodium thiosulphate was added. The crude product was
then extracted with EtOAc (three times) and the combined organic
extracts were washed with saturated aqueous solution of NaHCO3 and
brine, dried over anhydrous Na2SO4, filtered, and evaporated in vacuo.
Purification by silica gel column chromatography afforded the amino
products. Aryl amines 2a–h are known and commercially available
compounds.
catalysis
4-Nitroaniline (2a):22 Yellow solid; m.p. 145–147 °C (lit.
Entry
Compound
R (group)
NO2
Yield (%)
94
1
146–149 °C); H NMR (400 MHz, CDCl3): 8.07 (d, J = 8.7 Hz, 2H),
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
6.63 (d, J = 8.7 Hz, 2H), 4.42 (br s, 2H); 13C NMR (100 MHz, CDCl3):
152.5, 139.1, 126.3, 113.4. Anal. calcd for C6H6N2O2: C, 52.17; H, 4.38;
N, 20.28; found: C, 52.28; H, 4.32; N, 20.13%.
Br
96
OH
93
OCH3
CO2CH2CH3
COCH3
CN
94
88
87
91
4-Bromoaniline (2b):23 Yellow solid; m.p. 62–64 °C (lit. 62–64
°C); 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 8.7 Hz, 2H), 6.57 (d,
J = 8.7 Hz, 2H), 3.66 (br s, 2H); 13C NMR (100 MHz, CDCl3): δ 145.4,
132.0, 116.7, 110.2. Anal. calcd for C6H6BrN: C, 41.89; H, 3.52; N, 8.14;
found: C, 41.66; H, 3.45; N, 7.98%.
2g
2h
NH2
89
4-Aminophenol (2c):24 White solid; m.p. 186–188 °C (lit.
1
186–190 °C); H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 6.46 (d,
J = 8.7 Hz, 2H), 6.40 (d, J = 8.7 Hz, 2H), 4.35 (br s, 2H); 13C NMR (100
MHz, DMSO-d6) δ 148.2, 140.6, 115.5, 115.3. Anal. calcd for C6H7NO:
C, 66.04; H, 6.47; N, 12.84; found: C, 65.91; H, 6.33; N, 12.64%.
4-Methoxyaniline (2d):25 White solid; m.p. 57–58 °C (lit. 56–59 °C);
1H NMR (400 MHz, CDCl3): δ 6.74 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.9
Hz, 2H), 3.74 (s, 3H), 3.40 (br. s, 2H); 13C NMR (100 MHz, CDCl3): δ
152.7, 139.9, 116.3, 114.7, 55.6. Anal. calcd for C7H9NO: C, 68.27; H,
7.37; N, 11.37; found: C, 68.11; H, 7.24; N, 11.21%.
The scope of the reduction of azides to amines under the
optimised reaction conditions was then examined using azide
substrates with various functional groups (1b–h). The use of
Ga(OTf)3/KI catalytic system afforded the desired amino
products (2b–h) in yields ranging from 87–96% (Table 3,
entries 2–7). Interestingly, the 1,4-diazidobenzene substrate 1h
underwent simultaneous reduction of both azido groups under
the standard reaction conditions employed for mono-azide
reduction to provide 2h in high yield (89%) (Table 3, entry 8).
This method displays high efficiency for the chemoselective
reduction of aromatic azides through the use of low catalyst
loading and therefore would be a valuable protocol for this
important transformation.
Ethyl 4-aminobenzoate (2e):26 White solid; m.p. 89–91 °C (lit.
1
88–90 °C); H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.7 Hz, 2H),
6.64 (d, J = 8.7 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 4.04 (b s, 2H), 1.36
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.8, 150.9, 131.6,
119.9, 113.8, 60.3, 14.4. Anal. calcd for C9H11NO2: C, 65.44; H, 6.71; N,
8.48; found: C, 65.23; H, 6.61; N, 8.39%.
1-(4-Aminophenyl)ethanone (2f):27 Yellow solid; m.p. 102–104 °C
(lit. 102–103 °C); 1H NMR (300 MHz, CDCl3): δ 7.79 (d, J = 8.6 Hz,
2H), 6.63 (d, J = 8.6 Hz, 2H), 4.11 (br s, 2H), 2.49 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ 196.6, 151.0, 130.8, 127.8, 113.7, 26.0. Anal. calcd
for C8H9NO: C, 71.09; H, 6.71; N, 10.36; found: C, 70.88; H, 6.55; N,
10.19%.
Conclusions
In summary, we have reported a green and efficient method
for the transformation of aryl azides to aryl amines under the
influence of Ga(OTf)3/KI. The reported reductive conversions
of azides to their corresponding amines required only 5 mol%
of catalyst loading to efficiently deliver the amino products in
high yields. This method is reliably efficient, showed impressive
catalytic activity, and could find wide applicability in organic
chemistry where the reduction of aromatic azides to aromatic
amines could conveniently be achieved.
4-Aminobenzonitrile (2g):28 Yellow solid; m.p. 82–84 °C (lit.
1
83–85 °C); H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.6 Hz, 2H),
6.65 (d, J = 8.6 Hz, 2H), 4.22 (br s, 2H); 13C NMR (100 MHz, CDCl3)
δ 150.4, 133.8, 120.2, 114.5, 100.1. Anal. calcd for C7H6N2: C, 71.17; H,
5.12; N, 23.71; found: C, 71.01; H, 5.04; N, 23.62%.
1,4-Benzenediamine (2h):29 Pale red solid; m.p. 140–142 °C (lit.
138–142 °C); 1H NMR (400 MHz, DMSO-d6) δ 6.35 (s, 4H), 4.18 (br
s, 4H); 13C NMR (100 MHz, DMSO-d6): δ 139.4, 115.7. Anal. calcd
for C6H8N2: C, 66.64; H, 7.46; N, 25.90; found: C, 66.44; H, 7.36; N,
25.72%.
Experimental
Melting points were determined using a Gallenkamp melting point
apparatus and are uncorrected. All reactions were performed in
pre-dried glassware under a nitrogen atmosphere and anhydrous
conditions. Reactions were monitored by thin layer chromatography
(TLC) carried out on silica gel plates (0.25 mm thickness) and
visualised using UV light and/or an aqueous potassium permanganate
solution followed by heating. Silica gel (60 Å, 200–425 mesh) was
used for flash column chromatography. NMR spectra were recorded
on a Bruker 300 or 400 MHz spectrometer in DMSO-d6 or CDCl3
as the solvent. Chemical shifts are reported in parts per million
(ppm) with reference to the hydrogenated residues of the deuterated
solvent. Coupling constants (J values) are recorded in Hertz (Hz)
and signal patterns are expressed as follows: singlet (s), broad singlet
(br s), doublet (d), triplet (t), quartet (q), and multiplet (m). Elemental
analyses were performed on a 2400 PerkinElmer Series II analyser.
Acknowledgement
This work was supported by the Deanship of Scientific
Research, King Abdulaziz University, under grant number
G-1436-141-167.
Received 12 September 2018; accepted 2 October 2018
Paper 1805627
https://doi.org/10.3184/174751918X15404076150031
Published online: 2 November 2018
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