Pd/C-catalyzed transfer hydrogenation of aromatic nitro compounds using methanol as a hydrogen source

Article abstract of DOI:10.1016/j.jics.2021.100014

We describe the selective transfer hydrogenation of aromatic nitro compounds to anilines using Pd/C as a heterogeneous catalyst with methanol as a green reductant. Nitroarenes bearing both electron-releasing and electron-deficient groups are amenable to this method and enable the synthesis of corresponding arylamines in moderate to good selectivities including the synthesis of butamben, a local anesthictic drug molecule. This new concise protocol is simple, ligand-free and does not require the supply of external molecular hydrogen.

Full text of DOI:10.1016/j.jics.2021.100014

Journal of the Indian Chemical Society 98 (2021) 100014
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Pd/C-catalyzed transfer hydrogenation of aromatic nitro compounds using
methanol as a hydrogen source
Vishakha Goyal a,c, Naina Sarki a c, Kishore Natte a c, Anjan Ray b
,
,
,c,*
a
Chemical and Material Sciences Division, CSIR-Indian Institute of Petroleum, Haridwar Road, Mohkampur, Dehradun, 248 005, India
Analytical Sciences Division, CSIR-Indian Institute of Petroleum, Haridwar Road, Mohkampur, Dehradun, 248 005, India
Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Joggers Road, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201 002, India
b
c
A B S T R A C T
We describe the selective transfer hydrogenation of aromatic nitro compounds to anilines using Pd/C as a heterogeneous catalyst with methanol as a green reductant.
Nitroarenes bearing both electron-releasing and electron-deficient groups are amenable to this method and enable the synthesis of corresponding arylamines in
moderate to good selectivities including the synthesis of butamben, a local anesthictic drug molecule. This new concise protocol is simple, ligand-free and does not
require the supply of external molecular hydrogen.
1
. Introduction
direct hydrogenation process, catalytic transfer hydrogenation could be
very interesting in both lab-scale and industrial usage if environmental
and sustainability are shown to be superior to the status quo.
Transfer hydrogenation has been regarded as one of the most
attractive chemical transformations in organic synthesis. This is due to its
inherent advantages, such as ready availability of hydrogen donors, ease
of handling and avoidance of high-pressure equipment [1,2]. Also, the
transportation and distribution of molecular hydrogen cylinders might
sometimes result in increase of costs for small-scale industries and
research laboratories [3]. Considering safety obstacles and easy opera-
bility, a variety of transfer hydrogen sources were identified on labora-
tory scale [1]. For instance, formic acid [4], hydrazine hydrate [5],
formates [6], silanes [7], ammonia borane [8], and many other common
hydrogen donors that can supply hydrogen atom(s) to reduce various
suitable functional moieties [1]. However, these hydrogen donors are
relatively expensive and also generates significant waste or by products.
In the last two years, alcohols [9,10], especially simple methanol have
evolved as an attractive transfer hydrogen source [11–13]. Methanol is
produced abundantly from both fossil and renewable sources and serves
Due to the presence of high hydrogen content in methanol i.e., 12.5
wt% [22–24], the utilization of methanol as a hydrogen source for
organic reactions has become the subject of intense research as well.
Quite recently, Rueping [25], Li [11], Xiao [12], and Sunderraju [13]
have developed interesting methodologies for the reduction of various
functional groups using methanol as hydrogen donor. However,
catalytic-transfer hydrogenation of nitroarenes using methanol is still
underdeveloped [26,27].
Palladium is among the most active and versatile catalytic element for
a variety of organic reactions such as cross-coupling, hydrogenolysis,
hydrogenation, hydrodehalogenation and C–H activation reactions [28,
29]. Among various palladium catalysts, Pd/C is simple, ligand-free and
commercially available in ample quantities [30,31]. Indeed, Pd/C is a
promising catalyst for the transfer hydrogenation of nitroarenes and a
few reports are available with sodium formate and hydrazine hydrate as
hydrogen donors [6,32]. However, methanol as a hydrogen source is
seldom reported [26,27]. In this paper, we report our new results on
Pd/C-catalyzed transfer hydrogenation of nitroarenes using methanol as
a green hydrogen source. The desired anilines were obtained in good to
excellent selectivities. Additionally, local anesthictic drug molecule
butamben and a key oxazolidinone antibiotic intermediate of Linezolid
were successfully synthesized.
1
as an outstanding C building block for the manufacture of important
bulk and fine chemicals [14–17]. Also, methanol can be utilized as an
excellent liquid organic hydrogen carrier (LOHC) for fuel cell applica-
tions [18].
Aniline bearing functional compounds are extensively used as key
industrial intermediates in chemical sector [19]. The majority of aniline
derivatives are produced on industrial-scale via direct hydrogenation of
nitroarenes [3], especially in the fields like pharmaceuticals, agricultural
products, fragrances, and polymers (Fig. 1) [19–21]. In comparison to the
*
Corresponding author. Analytical Sciences Division, CSIR-Indian Institute of Petroleum, Haridwar Road, Mohkampur, Dehradun, 248 005, India.
E-mail address: anjan.ray@iip.res.in (A. Ray).
https://doi.org/10.1016/j.jics.2021.100014
Received 14 December 2020; Received in revised form 19 January 2021; Accepted 29 January 2021
0019-4522/© 2021 Indian Chemical Society. Published by Elsevier B.V. All rights reserved.

V. Goyal et al.
Journal of the Indian Chemical Society 98 (2021) 100014
Fig. 1. Selected primary anilines in commercial pharmaceuticals and agrochemicals. *Reference 21.
2
. Experimental section
catalyst was separated from the reaction mixture by filtration through
filter paper and washed with 3 mL of ethyl acetate. After evaporating
the solvent through rotary evaporator, the crude was submitted for
GCMS analysis.
General Information. All chemicals were purchased from Sigma-
Aldrich or TCI and were used as received unless stated otherwise. 5%
Pd/C was procured from Sigma-Aldrich (product number 75992-10G).
The reactions were monitored by thin-layer chromatography (TLC)
using silica gel plates (TLC Silica gel 60 F254) and compounds were
monitored/visualized with UV light. Gas chromatography mass spec-
trometry (GCMS) analysis was performed using 5977A MSD attached to a
3. Results and discussions
Very recently, Natte and co-workers reported Pd/C-catalyzed N-
methylation of nitroarenes using methanol as both one-carbon and
hydrogen source [33]. During the course of this reaction, very low
amounts of anilines as byproduct was observed. This result motivated us
to explore selective transfer hydrogenation of nitroarenes using meth-
anol as hydrogen donor by employing 5% Pd/C as a catalyst. Initially,
we have chosen simple nitrobenzene (1a) as a benchmark reaction with
methanol as both reductant and solvent by employing commercially
available 5% Pd/C (1.87 mol%) as catalyst, 2.0 equivalents of KOtBu at
7
0
890B, an Agilent GC system equipped with a 30 m  0.32 mm id and
.25 me mid-polarity capillary column (DB35MS, 35% phenyl/65%
dimethylpolysiloxane).
General procedure for transfer hydrogenation of nitroarenes.
An oven dried 20 mL ACE® pressure tube was charged with 5% Pd/C
(
1.87 mol%), KOtBu (2 equiv., 112 mg), nitroarene (0.5 mmol), and
MeOH (2 mL). The pressure tube was then sealed and allowed to stir at
ꢀ
ꢀ
1
00 C in oil bath for 24 h. After completion of the reaction, the pressure
100 C and 24 h: these reaction conditions enabled the desired aniline
tube was cooled to room temperature, and then the pressure build-up in
the tube has been released slowly by losing the screw cap. The solid
(1b) in 90% GCMS selectivity (Table 1, entry 1). We also examined
various bases (entries 2–4), nevertheless K PO , K CO , NaOH and KOH
3 4 2 3
Table 1
Reaction
optimization
for
transfer
hydrogenation
of
nitroarenes
using
MeOH
as
hydrogen
donora.
.
Entry
Base
Catalyst
Selectivity of 1b (%)
1
2
3
4
5
6
7
8
9
KOtBu
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Ru/C
Pd(OAc)
Pd/C
.
90
59
68
70
69
45
33
–
K
K
3
PO
CO
4
2
3
NaOH
KOH
KOtBu
KOtBu
.
2
KOtBu
–
a
ꢀ
Reaction conditions: nitrobenzene 1a (0.5 mmol), 5% Pd/C (1.87 mol%), base (2 equiv.), MeOH (2 mL), 100 C, 24 h. Selectivity of 1b (major compound) was
determined using GCMS.
2

V. Goyal et al.
Journal of the Indian Chemical Society 98 (2021) 100014
gave moderate selectivities (entries 2–5). Next, Ru/C and homogeneous
Pd(OAc) catalysts known for transfer hydrogenation reactions did not
2
show any major improvements in the selectivities (entries 6–7). Control
experiments revealed that the reaction does not proceed in the absence
of a base or catalyst (entries 8–9).
After having optimal conditions in hand, we investigated substrate
scope with various nitro derivatives (Scheme 1). Nitroarenes
substituted with electron-donating groups like, -Me, -OMe, and –SMe
furnished desired anilines in moderate to good selectivities (entries
1
–3). However, when 1-chloro-4-nitrobenzene and 1-bromo-4-nitro-
benzene were applied, removal of halogens (chloro and bromo) or
various side reactions occurred. This may be due to the oxidative
addition of aryl halides with palladium [34]. Notably, 4-(2-Fluo-
ro-4-nitrophenyl)morpholine was transfer hydrogenated to its corre-
sponding 3-Fluoro-4-morpholinoaniline in good selectivity by keeping
the fluorine group intact (entry 4). Interestingly, the obtained product is
a key intermediate for the production of antibacterial drug linezolid
[
20,35]. Then, nitroarenes substituted with electron-withdrawing
groups such as ketone, ester and amide gave corresponding anilines
in low to good selectivities (entries 5–7). Delightfully, we directly
synthesized pain-killer drug molecule butamben in 85% selectivity
from the corresponding starting material (entry 8). Remarkably,
nitropyridines also underwent transfer hydrogenation in low to good
selectivities (entries 9–10). These results indicate the robustness of
Pd/C as a catalyst and methanol as a green hydrogen source to access
functional anilines that are widely useful in drug discovery and agro-
chemical industries. A few of the nitroarenes showed reduced conver-
sion to anilines. This may be attributed to kinetic reaction control and
competition between transfer hydrogenation of nitroarene and
N-methylation of aniline.
Next, based on the literature [33], a plausible catalytic cycle was
proposed and shown in Scheme 2. Initially, methanol undergoes dehy-
drogenation to release dihydrogen and formaldehyde in presence of Pd/C
2
and base. Next, Pd abstracts hydrogen and produces Pd–H species,
which participates in hydrogenation of nitroarene to yield the desired
corresponding aniline (Scheme 2).
4
. Conclusions
We have developed an operationally simple and environmentally
friendly palladium-catalyzed transfer hydrogenation of nitroarenes
using methanol as green reductant. This concise catalytic protocol
features the use of commercially available Pd/C as catalyst and does not
require the use of ligands. Various nitroarene bearing functional groups
have been tolerated and gave selectivites up to 90%. Notably, the
developed approach is also applicable for the synthesis of butamben, a
local anesthictic drug molecule and a key pharmaceutical intermediate
of linezolid.
Scheme 1. Transfer hydrogenation of various nitroarenes using MeOH as
hydrogen donor.a
[
a] Reaction conditions: nitroarene (0.5 mmol), 5% Pd/C (1.87 mol%), KOtBu
ꢀ
(2 equiv.), MeOH (2 mL), 100 C, 24 h, GCMS selectivity with respect to major
ꢀ
compound; [b] 120 C; Compound 4: Key intermediate of linezolid; Compound
8: butamben.
Scheme 2. Plausible catalytic cycle for Pd/C-catalyzed transfer hydrogenation of nitroarenes.
3

V. Goyal et al.
Journal of the Indian Chemical Society 98 (2021) 100014
Declaration of competing interest
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the work reported in this paper.
2
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Acknowledgements
1
2
KN acknowledges Department of Science and Technology, Science
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