Chemoselective nitro reduction and hydroamination using a single iron catalyst

Article abstract of DOI:10.1039/c5sc04471e

The reduction and reductive addition (formal hydroamination) of functionalised nitroarenes is reported using a simple and bench-stable iron(iii) catalyst and silane. The reduction is chemoselective for nitro groups over an array of reactive functionalities (ketone, ester, amide, nitrile, sulfonyl and aryl halide). The high activity of this earth-abundant metal catalyst also facilitates a follow-on reaction in the reductive addition of nitroarenes to alkenes, giving efficient formal hydroamination of olefins under mild conditions. Both reactions offer significant improvements in catalytic activity and chemoselectivity and the utility of these catalysts in facilitating two challenging reactions supports an important mechanistic overlap.

Full text of DOI:10.1039/c5sc04471e

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Chemoselective nitro reduction and
hydroamination using a single iron catalyst†
Cite this: DOI: 10.1039/c5sc04471e
*
*
Kailong Zhu, Michael P. Shaver and Stephen P. Thomas
The reduction and reductive addition (formal hydroamination) of functionalised nitroarenes is reported
using a simple and bench-stable iron(III) catalyst and silane. The reduction is chemoselective for nitro
groups over an array of reactive functionalities (ketone, ester, amide, nitrile, sulfonyl and aryl halide). The
high activity of this earth-abundant metal catalyst also facilitates a follow-on reaction in the reductive
addition of nitroarenes to alkenes, giving efficient formal hydroamination of olefins under mild
conditions. Both reactions offer significant improvements in catalytic activity and chemoselectivity and
the utility of these catalysts in facilitating two challenging reactions supports an important mechanistic
overlap.
Received 20th November 2015
Accepted 24th January 2016
DOI: 10.1039/c5sc04471e
www.rsc.org/chemicalscience
they also showed excellent activity and chemoselectivity for the
hydrosilylation of aldehydes and ketones over a wide range of
Introduction
other functionalities.
The chemoselective production of aniline and aniline deriva-
tives is a cornerstone of modern industrial chemistry. The
global aniline market was valued at £6.25 billion in 2013 and
will reach a gross market value of £10.17 billion by 2020.1
Aniline and aniline derivatives nd use in polymers and mate-
rials (e.g. polyurethane and rubber), herbicides, bulk chemicals
and dyes and pigments (e.g. indigo).2 Current preparation
methods rely on the precious metal-catalysed reduction of
nitroarenes using high pressures of hydrogen gas, and suffer
from low chemoselectivity.3 Silanes have emerged as a hydrogen
gas alternative.4
Inspired by this ability of the amine-bis(phenolate) catalyst
to mediate both radical and reduction events we sought to
extend this reaction manifold to the reduction and reductive
functionalisation of nitroarenes. If the chemoselectivity and
high catalyst activity observed in the carbonyl reductions could
be transferred to nitroarene reductions, the amine-bis(pheno-
late) system would represent a clear advance of the current iron-
based reduction manifolds. Moreover, if nitro reduction is
combined with radical hydrogen-atom transfer (HAT) to an
alkene,9 a formal hydroamination would be possible. As
Earth abundant metal catalysis is at the fore of academic and
industrial research due to the inherent availability, sustain-
ability, low cost and low toxicity of these metals. Iron holds
a unique position, offering the lowest environmental and soci-
etal impact as it is the most abundant transition metal, non-
toxic and environmentally benign. Although great strides have
been made in the use of iron catalysts in organic synthesis,5 the
reduction of nitro groups has received relatively little attention.6
The current state-of-the-art methods oen require high catalyst
loadings and long reaction times to transform a limited scope of
substrates with low chemoselectivity.
We recently reported the reduction of carbonyl compounds
using an iron(III)-amine-bis(phenolate) catalyst 4b and silane as
the stoichiometric reductant (Scheme 1a).7 While these
complexes were originally used as mediators of controlled
radical polymerisations,8 (Scheme 1b) we were surprised that
School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster
Road, Edinburgh, EH9 3FJ, UK. E-mail: michael.shaver@ed.ac.uk; stephen.thomas@
ed.ac.uk
Scheme 1 Iron-catalysed reduction and radical reactions supported
by Fe(III) amine-bis(phenolate) catalysts and the extension of these
reactions to the reduction and reductive addition of nitroarenes.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5sc04471e
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recently reported,9 the iron-catalysed formal hydroamination of donating group gave both high reactivity and chemoselectivity
alkenes is an extremely powerful reaction accessible with high for amine 2a (entry 2). Solvent had a signicant inuence on
iron catalyst loadings (>30 mol%) and elevated reaction the reaction in terms of both reactivity and selectivity.
temperatures (60 ꢀC) to achieve moderate yields. We postulated Replacing MeCN with toluene gave a signicant drop in both
that increasing the rate of nitroarene reduction, and thus conversion and chemoselectivity (entry 3). Using THF gave an
increasing the concentration of the intermediate nitrosoarene, even lower conversion and reduction of the carbonyl group
the overall efficiency of this process could be increased and the was observed (entry 4). Ethyl acetate gave a similar result to
catalyst loading lowered signicantly.
that of toluene with regard to conversion and selectivity (entry
In the context of the catalytic exibility of the Fe(III) amine- 5). The use of PhSiH3 or Ph2SiH2 as the reducing agent,
bis(phenolate) framework, there is an obvious opportunity to signicantly reduced conversion and chemoselectivity (entries
develop a single catalytic system that is able to both reduce nitro 6 and 7). The sterically bulky silanes Ph2MeSiH and (Me3-
compounds under mild conditions with high chemoselectivity SiO)2MeSiH showed no reactivity towards either the nitro or
and access a formal hydroamination of olens at low catalyst carbonyl groups (entries 8 and 9). Reducing the amount of
loadings and temperatures (Scheme 1c).
silane from 4.0 equivalents to 3.0 equivalents led to a longer
reaction time of 8 h in order to obtain comparable reduction
(entry 10). Using diethoxymethylsilane, a widely used surro-
gate for triethoxysilane with greater thermal stability, gave
product 2a in 90% yield together with 5% of 3a using 5 mol%
catalyst (entry 11).
Results and discussion
Our investigations began with the development of the che-
moselective nitro reduction of 4-nitroacetophenone 1a (Table
1). Triethoxysilane was selected as the stoichiometric reduc-
tant due to its low cost, ease of handling and wide avail-
ability.10 Amine-bis(phenolate) iron(III) catalysts 4a gave amine
2a in 79% yield with 7% reduction of the ketone to give alcohol
3a (entry 1). Catalyst 4b, bearing the tetrahydro-2-furanyl
The substrate scope of this newly developed catalytic
system was investigated using the optimised reaction
conditions of 2 mol% catalyst 4b, 4.0 equivalents of trie-
ꢀ
thoxysilane in MeCN (1.0 M) at 80 C (Table 2). In all cases,
good to excellent yield and chemoselectivity were obtained,
demonstrating the utility of this methodology in synthesis.
Industrially important aniline could be prepared from
nitrobenzene in 84% isolated yield (entry 1). o-Methyl, m-
methyl and, in contrast to other methods,6 even the sterically
hindered 2,6-dimethyl nitrobenzene were all successfully
reduced in good yields (entries 2, 3 and 4). p-(Methylthio)
aniline 2f was produced from the corresponding nitroarene
in excellent yield, although an 8 hour reaction time was
needed (entry 5). The selective reduction of the nitro group in
the presence of an ester functionality proceeded smoothly in
all cases with excellent yields (entries 6, 7, 8, and 9), indi-
cating the complete chemoselectivity and reactivity of the
developed system for these challenging substrates.11 Meth-
ylsulfonyl substituted nitrobenzene 1k was also reduced with
excellent chemoselectivity for the NO2 group (entry 10). In the
case of 4-nitrobenzonitrile, 65% yield of amine 2l was ob-
tained; however, 30% of the starting material was recovered,
once again demonstrating the high chemoselectivity of the
catalyst for the nitro group over nitrile (entry 11). The low
yield in the reaction of 4-nitrobenzonitrile is attributed to the
strong coordination of the nitrile group to the catalyst which
inhibits catalyst activity. To demonstrate this, a standard
reduction of ethyl 4-nitrobenzoate was doped with 4-nitro-
benzonitrile (1 : 1) and the yield of nitro reduction at ethyl 4-
nitrobenzoate 1h dropped from 98% to 30%.12 Halogenated
nitrobenzene derivatives were also reduced chemoselectively
and in good yield without any protodehalogenation13 or
homocoupling14 observed (entries 12, 13 and 14). Nitroarenes
1p and 1q, bearing the strongly electron-withdrawing CF3
Table 1 Optimisation of reaction conditiona
Entry Cat. Solvent Silane
SMb (%) 2ab (%) 3ab (%)
1
2
3
4
5
6
7
8
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
MeCN
MeCN
PhMe
THF
EtOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
HSi(OEt)3
HSi(OEt)3
HSi(OEt)3
HSi(OEt)3
HSi(OEt)3
PhSiH3
Ph2SiH2
Ph2MeSiH
(Me3SiO)2MeSiH >95
HSi(OEt)3
7
79
7
Trace
46
84
51
22
>95(91)c Trace
40
14
35
60
26
0
0
>95
90
14
2
14
11
10
0
55
>95
9
0
10d
11e
Trace
Trace
Trace
5
HSiMe(OEt)2
a
Unless otherwise noted, all reactions were carried out using 4.0 eq. of
hydrosilane (1.20 mmol), 1.0 eq. of 4-nitroacetophenone (0.3 mmol),
0.02 eq. of catalyst 4 (0.006 mmol) in 0.3 mL solvent at 80 ꢀC for 4 h. group, were reduced to the corresponding anilines, 2p and
b
Determined by 1H NMR using 1,3,5-trimethoxybenzene as internal
2q, in 90% and 85% yield, respectively (entries 15 and 16).
Nitro-substituted benzoxazole 1r was selectively reduced to
corresponding amine 2r in 88% yield without any ring-
c
d
standard. Isolated yield. 3.0 eq. of triethoxysilane was used, 8 h.
e
0.05 eq. of catalyst was used.
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Table 2 Substrate scope of nitroarene reductiona
Table 2 (Contd.)
Yieldb
90%
Entry
1
Substrate
Product
Time
4 h
Yieldb
84%
Entry
15
Substrate
Product
Time
3 h
2
3
4
5
6 h
6 h
6 h
8 h
84%
70%
82%
93%
16
17
3 h
6 h
85%
88%
18f
4 h
6 h
98%
55%
19
6
7
8
9
5 h
5 h
5 h
5 h
91%
a
Unless otherwise noted, all reactions were carried out using 4.0 eq. of
triethoxysilane (2.40 mmol), 1.0 eq. of nitro substrate (0.6 mmol), 0.02
b
eq. of catalyst (0.012 mmol) in 0.6 mL MeCN at 80 ꢀC. Isolated yield.
c
d
Using 4.0 eq. of HSiMe(OEt)2, 0.05 eq. of 4b, 5 h. Starting material
98%(85%)c
94%
e
recovered.
Yield determined by 1H NMR using 1,3,5-
f
trimethoxybenzene as internal standard. 0.04 eq of catalyst was used.
opening or arene hydrogenation observed (entry 17).15
Nitrobenzene 1s, bearing an amide functionality, was also
well tolerated to give the product in excellent yield (entry 18).
When a substrate bearing a free alcohol was used, decreased
catalytic activity was observed (entry 19).
93%
To showcase the applicability of the developed nitro reduc-
tion, we explored the reduction of academically- and industri-
ally-relevant targets. Bis(2-aminophenyl)amine 2u, which is
widely used in the synthesis of N,N,N-type pincer16 or triamido17
ligands, was obtained in 80% isolated yield. This was directly
comparable to the yield reported using palladium-catalysed
reduction with H2.16 Drug precursor 1v was chemoselectively
reduced to amine 2v in 90% yield. This late stage reduction with
a non-toxic metal greatly simplies purication and trace metal
removal, so making the developed method ideal for targets to be
tested in vivo.18 Amidation of 2v would give 4-(pyrazole-1-yl)
carboxanilides, a family of drugs that tune the activity of
canonical transient receptor potential channels (TRPC) and
thus control the inux of intracellular Ca2+ into a plethora of
mammalian cell types (Scheme 2).19
10
11
12
13
14
4 h
6 h
5 h
8 h
5 h
80%(15%)d
65%(30%)d
82%
87%e
90%
Having successfully developed a highly efficient silane-
mediated reduction of nitroarenes, we were keen to explore if
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Scheme 2 Selective nitro reduction in the synthesis of ‘real-world’
targets. [a] Reactions were carried out using 0.6 mmol of nitro
compounds. [b] Isolated yield.
this could be combined with radical HAT for a formal hydro-
amination.9,20 We hypothesised that the high reactivity of 4b
for nitroarene reduction would increased rates of reactions
with alkenes. Strikingly, application of catalyst 4b in the
formal hydroamination of alkenes using nitroarene 1w and
alkene 5a gave amine 6a in 75% isolated yield aer Zn/HCl
work-up21 using just 2.0 mol% catalyst, a 15-fold reduction in
catalyst loading compared to the previous system.20 Addi-
tionally, the starting nitro substrate was fully consumed at
room temperature in just 2 h. 1-Chloro-2-nitrobenzene 1n gave
the corresponding amine product 6b in relatively lower yield,
potentially due to the halogenophilicity of the parent Fe
complexes.8 A methyl substituted nitroarene 1c was well
tolerated to give the formal hydroamination product 6c while
nitroarene 1f, bearing a methyl thioester group, gave the cor-
responding amine 6d, both in good yields. Nitroarene 1x with
a free carbonyl group was also well tolerated to give the
product 6e in lower yield but with the carbonyl functionality
unchanged. Importantly, the formal hydroamination of olen
5d could be further extended under the same reaction condi-
tions. Reaction with 4-nitroanisole 1y followed by an intra-
molecular reductive amination gave the N-arylpiperidine 7a in
45% yield, indicating the potential application of this method
in the preparation of N-heterocycles (Scheme 3). Deprotection
of the para-methoxyphenyl (PMP) group of 7a would give 2,2,6-
trimethyl piperidine which is a useful reagent for the a-alkyl-
ation of aldehydes.22
Scheme 3 Formal hydroamination of olefins with catalyst 4b. [a]
Reactions were carried out using 0.3 mmol of nitro compounds and
0.9 mmol of alkene. [b] 2.0 equiv. of silane, 2 h. [c] 1.0 equiv. of silane, 1
h. Isolated yield are shown in parentheses together with the donor
olefin used.
Acknowledgements
MPS and SPT thank the University of Edinburgh for Chancel-
lor's Fellowships and the School of Chemistry for continued
support. MPS thanks the Framework Program 7 for a Marie
Curie Career Integration Grant. SPT thanks the Royal Society for
a University Research Fellowship and a Research Grant. KZ
thanks the China Scholarship Council and the University of
Edinburgh for an academic scholarship. The authors thank
Prof. Jason Love and AJ MacNair for useful discussions.
Notes and references
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