A Simple Setup for Transfer Hydrogenations in Flow Chemistry

Article abstract of DOI:10.1055/s-0035-1561624

By using a packed-bed reactor with a palladium/charcoal catalyst and ammonium formate or triethylsilane as hydrogen/hydride source, various functional groups including nitro groups, azides and alkenes can be efficiently reduced by a transfer hydrogenation process under mild conditions in a simple flow system.

Full text of DOI:10.1055/s-0035-1561624

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©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
A
letter
Synlett
M. Hutchings, T. Wirth
Letter
A Simple Setup for Transfer Hydrogenations in Flow Chemistry
Matthew Hutchings
Thomas Wirth*
packed bed reactor
Pd/C, Celite
2.17 mL
hydrogen
source
+
R – NO2
MeOH
School of Chemistry, Cardiff University,
Cardiff CF10 3AT, UK
wirth@cf.ac.uk
peristaltic
or
syringe pump
40 psi
BPR
2
0 min
0 °C
4
R – NH2
Received: 01.02.2016
Accepted after revision: 29.03.2016
Published online: 18.04.2016
Metal-catalysed hydrogenations without elemental hy-
drogen are already known, and transfer hydrogenations
have been investigated in batch chemistry. Some examples
have also been reported in flow chemistry, such as the use
DOI: 10.1055/s-0035-1561624; Art ID: st-2016-d0074-l
Abstract By using a packed-bed reactor with a palladium/charcoal
catalyst and ammonium formate or triethylsilane as hydrogen/hydride
source, various functional groups including nitro groups, azides and
alkenes can be efficiently reduced by a transfer hydrogenation process
under mild conditions in a simple flow system.
17
of aqueous zirconia. Means et al. described a similar
18
method using palladium for the reduction of alkenes.
A
column was filled with palladium black and gravity was
used to flow a solution containing the substrate and formic
acid through the column. A stop clock was adjusted to con-
trol residence times. Very good yields were obtained in a
short reaction time. Although this method was highly suc-
cessful, 5.6 mmol of Pd for 1 mmol of alkene was used. We
report herein the development of a simple flow system
with a fixed bed catalyst that can be used to perform cata-
lytic hydrogenation reactions. We mainly investigated the
reduction of nitro compounds to the corresponding amines,
as shown in the general setup in Figure 1. The substrate (0.5
M in MeOH) and reagent were premixed and introduced by
using a single syringe. The hydrogen source was used in
five-fold excess relative to the substrate and the stream was
then fed into the catalyst-containing glass column connect-
ed through Teflon tubing and connectors. To allow for a
steady stream, the system was connected to a backpressure
regulator (BPR) of 40 psi. This allows for a homogeneous
flow regime in the column without the formation of hydro-
gen gas influencing the flow rate.
Key words alkenes, flow chemistry, nitro compounds, packed bed re-
actor, transfer hydrogenation
Microreactors are nowadays common in many organic
synthesis laboratories in both academia and industry. They
have gained acceptance because they have been shown to
run chemical transformations more efficiently, more selec-
tively, and with a much higher degree of safety. Reduc-
tion chemistry is well suited to flow chemistry given the in-
herent risks involved in such transformations. Using hy-
drogen gas in industrial applications in large-scale batch
reactors is undesirable and specialist equipment has to be
used. Similar risks, although on a smaller scale, are appar-
ent in synthetic laboratories, and equipment for flow hy-
drogenations with the generation of small amounts of hy-
1
2–9
10
11
drogen are commercially available. Although this is an es-
tablished and reliable technique, it does come with a large
price tag. Many groups have sought to find methods to per-
form hydrogenations and reductions by using simple
equipment designs such as tube-in-tube reactors using hy-
Initially, the potential of the simple reactor in hydroge-
nation reactions was assessed with the hydrogenation of 2-
nitro-1-(p-tolyl)ethan-1-ol (1). This compound is easily ac-
cessible by the Henry reaction using p-tolualdehyde and ni-
12–15
drogen gas
and even supported-reagent-based car-
16
19
tridge systems using sodium borohydride. Herein, we re-
port flow hydrogenations conducted by using a convention-
al multipurpose setup. This allows easy operation without
the need to purchase specialist equipment and thereby pro-
vides access to hydrogenation facilities for a wide range of
laboratories.
tromethane in combination with sodium hydroxide. In
the reduction, different catalysts/reagents were used in the
fixed bed reactor together with a range of hydrogen sourc-
es, as shown in Table 1.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
Synlett
M. Hutchings, T. Wirth
Letter
hydrogen
source
+
R – NO2
Pd/C, Celite
MeOH
packed bed reactor
40 psi
BPR
R – NH2
Figure 1 Flow setup for the reduction of nitro compounds using a packed-bed reactor in flow
The initial reaction was carried out at 20 °C (Table 1, en-
try 1), using conditions similar to previously reported pro-
cedures. The flow rate of 0.108 mL/min corresponded to a
residence time of 20 min within the reactor cartridge. Upon
collection, it was shown that a conversion of 66% was
when moving to substrates with other functional groups.
This would also be the case using tin and hydrochloric acid
(entry 7). A slightly milder method is the combination of
zinc and ammonium chloride (entry 6). This method al-
lowed for conversion of 1 into 2, but was still not as high as
with Pd/C. This clearly shows the superiority of the palladi-
um on charcoal catalyst for the reduction of the nitro func-
tionality.
1
achieved, as shown by H NMR spectroscopic analysis.
When the temperature of the reaction was increased to
40 °C, the conversion increased to 91% (entry 2). Decreasing
the number of equivalents of ammonium formate to 2.5 re-
sulted in a drop in conversion to 71% (entry 3); whereas a
larger number of equivalents of ammonium formate was
not soluble. Furthermore, when the flow rate was increased
to 0.216 mL/min the conversion decreased substantially.
For comparison, Raney nickel and further metallic reagents
were also investigated for the reduction of 1. As shown in
Table 1, the use of Raney nickel (entry 4) resulted in a lower
conversion rate compared with Pd/C under the same reac-
tion conditions. For further comparison, non-catalytic
methods were used to demonstrate the mild and efficient
nature of this method. The combination of iron and acetic
acid at 70 °C showed reasonable conversions in the reduc-
tion of 1, but under considerably harsher reaction condi-
tions. The strongly acidic conditions may cause problems
After the initial optimisation, the substrate scope of this
procedure was investigated (Table 2). Phenylnitromethane
(3) could be cleanly reduced to benzylamine (4). Ben-
zylazide (5) was reduced with similar efficiency, providing
benzylamine (4) in 95% yield. Aromatic nitro groups were
also easily reduced to the corresponding aniline derivatives.
2-Nitrobenzoic acid (6) was efficiently reduced to anthra-
Table 2 Substrate Scope for the Reduction of Nitro Compounds Using
Flow Conditionsa
Entry
1
Starting material
Product
Yield (%)
85
OH
OH
NO2
NH2
1
2
Table 1 Catalysts and Reagents for the Reduction of 1 in Methanola
NO2
NH2
2
3
98
95
OH
catalyst/reagent
hydrogen source
OH
NO2
NH2
3
4
4
MeOH
N3
1
2
5
Entry
Catalyst/reagent Hydrogen source Temp (°C)
Conv. (%)b
NO2
NH2
1
2
3
4
5
6
Pd/C
Pd/C
Pd/C
Raney Ni
Fe
HCO
HCO
HCO
HCO
2
2
2
2
NH
NH
NH
NH
4
4
4
4
20
40
40
40
70
40
20
66
91
71d
86
60
85
45
4
5
90
CO2H
CO2H
6
7
NO2
NH2
98
AcOHc
NH Cl
HCl
8
9
Zn
4
NO2
NH2
6
78b
7
Sn
a
Reaction conditions: 1 (1 equiv), hydrogen source (5 equiv), MeOH (0.5
10
11
M).
a
b
c
1
Reaction conditions: nitro compound (1 equiv), ammonium formate
(5 equiv), MeOH (0.5 M).
Reaction conducted on 10 mmol scale.
Determined by H NMR spectroscopic analysis.
Acetic acid was used as a co-solvent in a 1:1 ratio with methanol.
HCO NH (3 equiv) was used.
2 4
b
d
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Synlett
M. Hutchings, T. Wirth
Letter
Table 3 Substrate Scope of Reductions of Olefinic Compounds Using Flow Conditionsa
packed bed reactor
hydrogen
source
R
+
Ph
Pd/C, Celite
MeOH
2
2
2
.17 mL
0 min
0 °C
40 psi
BPR
R
Ph
Entry
1
Starting material
Product
Hydrogen source
Yield (%)
42
CO2Me
CO2Me
HCO
2
NH
4
4
1
2
13
13
13
2
3
12
12
HCO
2
NH
20b
97
Et
3
SiH
SiH
CN
CN
4
Et
3
80
1
4
15
a
Reaction conditions: substrate (1 equiv), hydrogen source (5 equiv), MeOH (0.5 M), 20 °C.
Reaction carried out at 60 °C.
b
nilic acid (7) under the reaction conditions, leaving the acid
group intact. Interestingly, when 3-nitrostyrene (8) was
substrate (entry 3). The mild conditions did not affect the
ester functionality, resulting in 97% yield of the reduction
product 13.
used as substrate, both the nitro group and the double bond
20
were reduced in almost quantitative yield.
The results shown here demonstrate a rapid, versatile
and selective reducing system for a variety of functional
groups. The method can also be used in the presence of oth-
er functional groups such as esters, carboxylic acids and ni-
triles. The use of ammonium formate as reductant has the
advantages of being readily available, inexpensive, stable
and non-toxic, and can be used in conjunction with either
Pd/C or Raney-Ni catalysts. Triethylsilane proved to be a su-
perior hydrogen donor for double bonds, allowing the
scope of substrates to be extended to α,β-unsaturated com-
pounds.
To gain further insight into the usefulness of this pro-
cess, a larger scale reaction was carried out. By using 10
mmol nitrobenzene (10) dissolved in methanol in combina-
tion with ammonium formate, the reaction was run contin-
uously for 100 minutes, leading to the isolation of 0.73
grams of aniline (11; 78%). To investigate possible leaching
of the palladium catalyst, a simple experiment was devised.
Nitrobenzene, ammonium formate and methanol were
placed into a collection flask and a flow of further methanol
was pumped into the flask, passing through the column
into a collection flask. This was then stirred for 4 hours and
1
characterised by H NMR spectroscopic analysis. From the
Acknowledgment
acquired spectra there was no evidence of the formation of
aniline, therefore it can be concluded that no or very little
palladium was leached from the column into the collection
flask.
Support from the School of Chemistry, Cardiff University, is gratefully
acknowledged.
The reduction of the double bond in addition to the ni-
tro functionality allowed an extension of the methodology
to other substrates. Application of this method for the re-
duction of methyl cinnamate (12) proved to be only slightly
successful, with some conversion within the 20 minutes of
residence time. Even an increase of the reaction tempera-
ture to 60 °C had little effect (Table 3, entry 2). However,
changing the hydrogen source from ammonium formate to
triethylsilane led to almost full conversion of the olefinic
References and Notes
(1) Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.;
Wiley-VCH: Weinheim, 2013.
(2) Watts, P.; Haswell, S. J. Chem. Soc. Rev. 2005, 34, 235.
(
3) Geyer, K.; Codée, J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12,
434.
4) Ahmed-Omer, B.; Brandt, J. C.; Wirth, T. Org. Biomol. Chem.
007, 5, 733.
8
(
2
(
(
5) Yoshida, J.; Nagaki, A.; Yamada, T. Chem. Eur. J. 2008, 14, 7450.
6) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
Synlett
M. Hutchings, T. Wirth
Letter
(
(
(
7) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem. Int.
Ed. 2011, 50, 7502.
8) Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354,
water (20 mL), and extracted with diethyl ether or dichloro-
methane (3 × 15 mL). The combined organic phases were dried
over MgSO , filtered, and the solvent was removed in vacuo.
4
1
7.
9) Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem. Int. Ed.
015, 54, 6688.
10) Irfan, M.; Glasnov, T. N.; Kappe, C. O. ChemSusChem 2011, 4,
00.
2-Amino-1-(p-tolyl)ethan-1-ol (2): Yield: 138 mg (0.92 mmol,
1
85%); colourless solid; mp 139–140 °C. H NMR (CDCl , 400
3
2
MHz): δ = 7.18 (d, J = 7.9 Hz, 2 H), 7.08 (d, J = 7.8 Hz, 2 H), 4.70
(dd, J = 8.4, 2.8 Hz, 1 H), 3.57 (br s, 3 H), 2.99 (dd, J = 12.7, 3.4 Hz,
1 H), 2.84 (dd, J = 12.6, 8.8 Hz, 1 H), 2.30 (s, 3 H); in agreement
(
(
(
(
(
(
(
(
(
(
3
21a
11) Bryan, M. C.; Wernick, D.; Hein, C. D.; Petersen, J. V.; Eschelbach,
J. W.; Doherty, E. M. Beilstein J. Org. Chem. 2011, 7, 1141.
12) O’Brien, M.; Taylor, N.; Polyzos, A.; Baxendale, I. R.; Ley, S. V.
Chem. Sci. 2011, 2, 1250.
13) Newton, S.; Ley, S. V.; Casas Arcé, E.; Grainger, D. M. Adv. Synth.
Catal. 2012, 354, 1805.
with reported literature data.
Benzylamine (4): Yield: 113 mg (1.06 mmol, 98%); colourless
1
liquid; H NMR (CDCl , 400 MHz): δ = 7.18–7.31 (5 H, m), 3.81
3
13
(2 H, s); C NMR (CDCl , 100 MHz): δ = 143.3, 128.6, 127.1,
3
126.8, 46.2; in agreement with reported literature data.2
1b
Anthranilic acid (7): Yield: 133 mg (0.98 mmol, 90%); off-white
1
14) Ouchi, T.; Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Org. Process
Res. Dev. 2014, 18, 1560.
solid; mp 147–150 °C; H NMR (CDCl , 400 MHz): δ = 7.93 (d, J =
3
8.1 Hz, 1 H), 7.32 (t, J = 7.7 Hz, 1 H), 6.67 (d, J = 7.2 Hz, 2 H); 13
C
15) Baumann, M.; Baxendale, I. R.; Hornung, C. H.; Ley, S. V.; Rojo,
M. V.; Roper, K. A. Molecules 2014, 19, 9736.
16) Gilmore, K.; Vukelić, S.; McQuade, D. T.; Koksch, B.; Seeberger, P.
H. Org. Process Res. Dev. 2014, 18, 1771.
NMR (CDCl , 100 MHz): δ = 173.6, 151.6, 135.6, 132.6, 117.2,
3
116.9, 109.9; in agreement with reported literature data.2
1c
3-Ethylaniline (9): Yield: 128 mg (1.06 mmol, 98%); pale-
1
yellow liquid; H NMR (CDCl , 400 MHz): δ = 7.08 (t, J = 7.7 Hz,
3
17) Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Org. Lett. 2013, 15,
1 H), 6.62 (d, J = 7.5 Hz, 1 H), 6.57–6.50 (m, 2 H), 3.25 (br. s,
2
278.
18) Elamin, B.; Park, J.-W.; Means, G. E. Tetrahedron Lett. 1988, 29,
599.
1.5 H), 2.57 (q, J = 7.5 Hz, 2 H), 1.21 (t, J = 7.6 Hz, 3 H); 13C NMR
(CDCl , 100 MHz): δ = 146.4, 145.7, 129.2, 118.4, 115.0, 112.5,
3
28.9, 15.5; in agreement with reported literature data.2
1d
5
19) Ali, A.; Napolitano, J. M.; Deng, Q.; Lu, Z.; Sinclair, P. J.; Taylor, G.
E.; Thompson, C. F.; Quraishi, N.; Smith, C. J.; Hunt, J. A.; Dowst,
A. A.; Chen, Y.-H.; Li, H. PCT Int. Appl 2006014413, 2006.
Aniline (11): Yield: 0.73 g (7.85 mmol, 78%); pale-yellow liquid;
1
H NMR (CDCl , 400 MHz): δ = 7.17 (d, J = 7.5 Hz, 2 H), 6.77 (t, J
3
13
= 7.4 Hz, 1 H), 6.70 (t, J = 7.6 Hz, 2 H); C NMR (CDCl , 100
3
(20) Fixed Bed Column Preparation: Portions of Celite (1.45 g) and
MHz): δ = 146.5, 129.4, 118.7, 115.2.
5
% Pd/C (200 mg) were ground together with a mortar and
Methyl 3-phenylpropanoate (13): Yield: 172 mg (1.05 mmol,
1
pestle. After inserting the end-cap (with a 10–40 μm filter) into
a 150 mm Omni-Fit column (6.6 mm ID), the ground Celite/Pd/C
mixture was packed by tapping on the benchtop and priming
with solvent. The column was sealed with an end-cap. The
column was further packed by flowing MeOH through the
column at 0.5 mL/min until no air bubbles were observed. The
column volume, averaging 2.17 mL, was determined from the
difference between the anhydrous and wet weights divided by
the density of the solvent (MeOH).
97%); colourless oil; H NMR (400 MHz, CDCl ): δ = 7.25–7.30
3
(m, 2 H), 7.18–7.21 (m, 3 H), 3.66 (s, 3 H), 2.95 (t, J = 7.8 Hz,
13
2 H), 2.63 (t, J = 7.8 Hz, 2 H); C NMR (100 MHz, CDCl ): δ =
3
173.4, 140.5, 128.5, 128.3, 123.7, 51.7, 35.7, 30.9; in agreement
21a
with reported literature data.
3-Phenylpropanenitrile (15): Yield: 113 mg (0.86 mmol, 80%);
1
pale-yellow liquid; H NMR (CDCl , 400 MHz): δ = 7.25–7.31 (m,
3
5 H), 2.99 (t, J = 7.4 Hz, 2 H), 2.64 (t, J = 7.4 Hz, 2 H); 13C NMR
(CDCl , 100 MHz): δ = 138.3, 129.2, 128.6, 127.8, 119.5, 32.1,
3
19.6 ppm; in agreement with reported literature data.2
(21) (a) Shang, G.; Liu, D.; Allen, S. E.; Yang, Q.; Zhang, X. Chem. Eur. J.
2007, 13, 7780. (b) Hemantha, H. P.; Sureshbabu, V. V. Org.
Biomol. Chem. 2011, 9, 2597. (c) Regulska, E.; Samsonowicz, M.;
Świsłocka, R.; Lewandowski, W. J. Mol. Struct. 2009, 936, 162.
(d) Sharma, U.; Kumar, P.; Kumar, N.; Kumar, V.; Singh, B. Adv.
Synth. Catal. 2010, 352, 1834. (e) Mori, N.; Togo, H. Synlett 2005,
1456.
1e
General Procedure for Reductions: Nitro compound or olefin
(5 mmol) and hydrogen source (25 mmol) were dissolved in
MeOH (10 mL, 0.5 M). After flushing the column with MeOH,
the substrate/reagent solution was pumped through the
column at the specified temperature with a flow rate of 0.108
mL/min by using Vapourtec E-series equipment (with a peri-
staltic pump). Alternatively, a syringe pump can be used. The
first column volume was discarded, the second was collected.
The solvent was evaporated, the residue added to distilled
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D