Rapid reduction of heteroaromatic nitro groups using catalytic transfer hydrogenation with microwave heating

Article abstract of DOI:10.1016/j.tetlet.2009.12.005

A method for the rapid, safe reduction of heteroaromatic and aromatic nitro groups to amines is described using catalytic transfer hydrogenation under microwave heating conditions. Commonly available Pd/C or Pt/C catalyst is extremely effective with 1,4-cyclohexadiene as the hydrogen transfer source. In the case of substrates containing potentially labile aromatic halogens, Pt/C is effective and results in little or no dehalogenation. In general, the reactions are complete within 5 min at 120 °C.

Full text of DOI:10.1016/j.tetlet.2009.12.005

Tetrahedron Letters 51 (2010) 786–789
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid reduction of heteroaromatic nitro groups using catalytic transfer
hydrogenation with microwave heating
*
John F. Quinn , Cole E. Bryant, Kathryn C. Golden, Brian T. Gregg
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the rapid, safe reduction of heteroaromatic and aromatic nitro groups to amines is
described using catalytic transfer hydrogenation under microwave heating conditions. Commonly avail-
able Pd/C or Pt/C catalyst is extremely effective with 1,4-cyclohexadiene as the hydrogen transfer source.
In the case of substrates containing potentially labile aromatic halogens, Pt/C is effective and results in
little or no dehalogenation. In general, the reactions are complete within 5 min at 120 °C.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 November 2009
Revised 30 November 2009
Accepted 1 December 2009
Available online 4 December 2009
Aryl amines are important synthetic targets and intermediates.
They are frequently encountered during the synthesis and optimi-
zation of biologically relevant molecules. One of the most frequent
methods for the synthesis of aryl amines is by the reduction of aryl
nitro groups which are obtained by the nitration of aromatic com-
pounds.1 Common methods for the reduction of nitro groups to
amines include Zn,2 Sn,3 and Fe4 in the presence of acid, Sn(II)Cl2,5
TiCl3,6 Raney Ni—hydrazine,7 and catalytic hydrogenation.8 Of
these, catalytic hydrogenation is, perhaps, the most desirable pro-
cedure. Its main drawbacks are the requirement for handling and
containing highly flammable hydrogen gas9 and chemoselectivity
in the presence of easily reduced functional groups such as
halogens.
EtOAc, Pd/C
O
O
1,4-cyclohexadiene
OH
OH
R
R
100 °C, MW, 5 min
Scheme 1. Transfer hydrogenation of alkenes with microwave heating.
Optimization of this reaction was performed on 4-fluoronitro-
benzene as a test substrate (Table 1). We initially choose reaction
conditions that worked well in our alkene hydrogenation case;
specifically methanol as solvent, 2 mol % Pd16, and 6 equiv of 1,4-
cyclohexadiene (2) with microwave heating at 100 °C for 5 min.
These reaction conditions only resulted in a 23% conversion to 3
Microwave heating technology10 enables safe access to high
temperatures and pressures that can dramatically shorten reaction
times.11 Recently there have been a number of reports utilizing
microwave heating and hydrogen transfer conditions12 as an alter-
native to conventional hydrogenation using hydrogen gas.13 The
majority of these procedures use formate as a hydrogen transfer
source which has the drawback that its reaction byproduct is CO2
and may result in unsafe pressure in the microwave vial upon reac-
tion completion. We have recently reported a new, microwave-en-
hanced procedure for the rapid and safe hydrogenation of alkenes
under catalytic hydrogen transfer conditions (Scheme 1).14
The key discovery in our previous work was that in the presence
of a Pd/C catalyst, 1,4-cyclohexadiene acts as a highly active hydro-
gen donor,15 generating only easily removable benzene as a reac-
tion byproduct. Herein we report the extension of this
hydrogenation methodology to the reduction of heteroaromatic
and aromatic nitro groups.
Table 1
Reduction of 4-fluoronitrobenzene with Pd/C—cyclohexadiene and microwave
heatinga
NO2
NH2
Pd/C
+
see Table
F
F
1
2
3
Entry Mol % Pd Equiv 2 Solvent Temp (°C) Time (min) % Conv.b
1
2
3
4
5
6
7
8
9
2
5
2
3
2
5
5
5
6
2
6
6
3
19
6
6
6
6
6
6
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOAc
CH3CN
THF
100
100
100
100
100
120
120
120
120
120
5
5
5
5
20
5
5
5
5
5
23
64
12
28
98
>99
10
28
19
>99
10
MeOH
a
All reactions performed in methanol (2 mL), 0.50 mmol substrate, heated under
microwave conditions.
* Corresponding author. Tel.: +1 518 512 2377; fax: +1 518 512 2079.
E-mail address: john.quinn@amriglobal.com (J.F. Quinn).
b
All % conversions determined by HPLC (AUC) at 254 nm.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.005

J. F. Quinn et al. / Tetrahedron Letters 51 (2010) 786–789
787
Table 2
(Table 1, entry 1). HPLC analysis indicated that the transformation
was extremely clean. The only compounds formed in the reaction
were aniline 3 and benzene (from the concomitant dehydrogena-
tion of the cyclohexadiene). Increasing the catalyst loading to
5 mol % led to a 64% conversion (Table 1, entry 2).
We next investigated the effect of the number of equivalents of
1,4-cyclohexadiene (Table 1, entries 3–4). Reducing from 6 to
3 equiv led to a 50% decrease in conversion from 23% to 12%. How-
ever, increasing from 6 to 19 equiv only led to a very modest in-
crease from 23% to 28% conversion. The heating time and
temperature had a much more pronounced effect on substrate con-
version. Increasing the heating time from 5 min at 100 °C to 20 min
resulted in a 98% conversion to 3 (Table 1, entry 5). Increasing the
reaction temperature from 100 to 120 °C resulted in a >99% con-
version to product in 5 min (Table 1, entry 6).
Methanol gives a 99% conversion at 120 °C within 5 min (Ta-
ble 1, entry 6), while ethyl acetate, acetonitrile, and THF give,
respectively, 10%, 28%, and 19% conversions under identical reac-
tion conditions (Table 1, entries 7–9). Finally, reducing the catalyst
loading in methanol from 5% to 2% while maintaining the reaction
time and temperature at 5 min and 120 °C also results in a >99%
conversion to 3 (Table 1 entry 10). These results led to a standard
set of conditions for the remainder of the study namely 6 equiv of
2, 5 mol % of catalyst, substrate 0.25 M in methanol, and micro-
wave heating at 120 °C for 5 min. For scale-up the reaction concen-
tration can be increased to 0.50 M with no adverse effect on
reaction conversion or yield.17
We next turned our attention to expanding the substrate scope
of the reduction reaction to nitro-pyridines and other nitro-hetero-
cycles (Table 2). Utilizing our standard protocol, we observed
essentially quantitative conversion of the nitro-heterocycles to
the corresponding amino heterocycles. Pyridines 4 and 6 gave
aminopyridines 5 and 7 in quantitative yields (Table 2, entries 1–
2). Similarly, nitropyrazole 13 and nitroindazole 15 gave the corre-
sponding amine compounds in quantitative yield (Table 2, entries
6–7). Reduction of 4-nitro-pyridine-N-oxide 11 gave a 90% yield
of 4-aminopyridine 12 along with 10% of 4-aminopyridine-N-oxide
(Table 2, entry 5). Surprisingly, increasing the equivalents of 2 from
6 to 8 and increasing the heating time from 5 to 10 min did not re-
sult in complete conversion to 12. Reduction of chlorine-containing
pyridines 8 and 10 gave exclusively the de-chlorinated amine 9 (Ta-
ble 2, entries 3–4). As expected, hydrogenation of nitro-isoxazole 17
resulted in ring-opening N–O hydrogenolysis. However, there was
no evidence for the further reduction of nitro-eneone 18 (Table 2,
entry 8). It is worth noting that the highly polar and water soluble
amino pyridines and pyrazines may be isolated in high yield and in
a high state of purity with this method. Potentially troublesome
aqueous workups and chromatography are avoided.
Catalytic reduction of nitro-heterocycles with cyclohexadiene and microwave
heatinga
Entry
1
Substrate
Product
% Conv.b (yield)
>99 (>99)
CH3
CH3
NO2
NH2
N
N
5
4
NO2
NH2
2
3
4
5
>99 (>99)
>99 (>99)
>99 (>99)
>99 (90)c
H3CO
N
N
H3CO
N
6
7
NO2
NH2
Cl
N
N
9
NH2
8
NO2
Cl
N
9
10
O2N
H2N
N
N
O
12
11
H
N
H
N
N
N
6
>99 (>99)
NO2
13
NH2
14
N
N
N
N
O2N
H2N
H3C
7
8
>99 (>99)
>99 (89)
H
H
15
16
O
O
NH2
CH3
H3C
N
CH3
O2N
NO2
17
18
a
All reactions performed in methanol (2 mL), 0.5 mmol substrate, 6 equiv 1,4-
cyclohexadiene, heated under microwave conditions at 120 °C for 5 min.
b
Isolated yields.
10% of the N-oxide obtained.
c
Table 3
Reduction of 2-chloro-3-nitropyridinea
H
N
NO2
Cl
NH2
NH2
Cl
2, catalyst
OH
MeOH, MW
Cl
N
N
N
N
Since the use of Pd/C resulted in the complete de-chlorination of
pyridines 8 and 10, we explored alternative reaction conditions to
provide the desired amino-chloropyridines (Table 3). Simply
switching to 5 mol % Pt/C17 gave a 71:29 ratio of 19/9 (Table 3, en-
try 1). In an attempt to improve selectivity we reduced the catalyst
loading (Table 3, entries 2–4), reduced the equivalents of 2 (Table 3,
entries 5–7), and lowered the reaction temperature (Table 3, en-
tries 8–11). As can be seen lowering the catalyst loading or the
reaction temperature results in incomplete conversions even with
extended reaction heating. Additionally, significant amounts of
oxime 20 are present in the product mixtures. Our best result
was obtained by reducing 2 to 5 equiv while extending the reaction
time to 8 min (Table 3, entry 7) giving a 79% yield of the desired 3-
amino-2-chloropyridine 19 along with 2% of oxime 20 and 19% de-
chlorinated pyridine 9.
8
19
20
9
Entry
Equiv 2
Temp (°C)/time (min)
Catalyst (mol %)
8:19:20:9
1
2
3
4
5
6
7
8
9
6
6
6
6
4
5
5
5
5
5
5
120, 5
120, 5
120, 15
120, 30
120, 5
120, 5
120, 8
100, 10
100, 20
100, 30
100, 90
Pt, 5
Pt, 1
Pt, 1
Pt, 1
Pt, 5
Pt, 5
Pt, 5
Pt, 4
Pt, 4
Pt, 4
Pt, 4
0:71:0:29
33:12:53:1
12:36:50:2
8:58:32:2
4:49:44:3
0:75:8:18
0:79:2:19
22:25:53:0
12:45:42:1
7:60:32:1
0:75:0:25
10
11
a
All reactions performed in methanol (2 mL), 0.50 mmol substrate, heated under
microwave conditions.
We next turned our attention to general nitro-aromatic com-
pounds (Table 4) with a particular interest in investigating the che-
moselectivity of halogenated aromatics. Both electron-rich
(Table 4, entry 3) and electron-poor (Table 4, entries 4–7) sub-
strates gave essentially quantitative conversion. Of particular note

788
J. F. Quinn et al. / Tetrahedron Letters 51 (2010) 786–789
Table 4
Table 4 (continued)
Catalytic reduction of nitro-arenes with cyclohexadiene and microwave heatinga
Entry
Substrate
Product
NO2
% Conv. (yield)b
Entry
Substrate
NO2
Product
NH2
% Conv. (yield)b
NO2
12
>99d
Br
1
>99 (70)
41
39
21
23
22
24
a
Unless otherwise noted, all reactions performed in methanol (10 mL), 5 mmol
substrate, 6 equiv 1,4-cyclohexadiene, heated under microwave conditions at
NO2
NH2
120 °C for 5 min.
b
Isolated yields.
Catalyst is 5% Pt/C, 5 mol %.
H3C
H3C
c
2
3
4
5
6
>99 (94)
>99 (98)
>99 (82)
>99 (98)
>99 (68)
d
Reaction run on a 0.50 mmol scale in 2 mL methanol.
25% De-chlorinated aniline 22 obtained.
e
NO2
NH2
H3CO
25
H3CO
26
is the selective reduction of chlorine-containing 33 to 34 with Pd/C.
In the case of 2-bromo-1-nitrobenzene 35 a 91% yield of the 2-bro-
moaniline 36 is obtained using Pt/C (Table 4, entry 8). The 4-halo-
nitrobenzenes are more sensitive to dehalogenation than the 2-
halo isomers. Whereas the 2-chloro compound 33 cleanly gives
34 using 5 mol % Pd/C (Table 2, entry 7), the 4-chloro compound
37 gives a quantitative yield of aniline 22 (Table 4, entry 10). By
switching to a Pt/C catalyst, a 75:25 ratio of 38/22 is obtained (Ta-
ble 4, entry 9). In the case of 4-bromo-1-nitrobenzene 39, reduc-
NO2
NH2
F
F
F
F
27
28
tion using Pd/C unexpectedly gives
a quantitative yield of
NO2
CN
29
NH2
CN
30
nitrobenzene 41. Switching the catalyst to Pt/C also gives complete
consumption of the starting material. After filtration and concen-
tration, the desired 4-bromo-aniline 40 is the only isolated prod-
uct, albeit in low yield.13e This is perhaps due to unexpected
volatility of the product or any side products.
In conclusion, we have developed a convenient, rapid, and safe
procedure for the reduction of heteroaromatic and aryl nitro com-
pounds to the corresponding anilines. Given the greater chemose-
lectivity observed with Pt/C, it may be the reagent of choice for this
transformation. In analogy to traditional hydrogenation methods
involving hydrogen gas, all that is required in the way of work-
up and purification is a filtration to remove the spent catalyst
and concentration to remove the solvent, volatile reagents, and
byproducts. This is a significant advantage in cases of highly polar
amino pyridines and pyrazines.
NO2
NH2
CF3
31
CF3
32
Cl
Cl
NO2
NH2
7
>99 (89)
CF3
CF3
34
33
Acknowledgments
NO2
Br
NH2
Br
The authors wish to thank Drs. Keith Barnes and Bruce Molino
for their helpful discussions and suggestions.
8
>99 (91)c,d
>99 (75)c,d,e
>99d
35
36
References and notes
NO2
NH2
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Cl
Cl
Br
Cl
9
37
37
38
22
NO2
NO2
NH2
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1981, 29, 726.
10
11
7. Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214.
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Br
>99 (6.1)c,d
39
40

J. F. Quinn et al. / Tetrahedron Letters 51 (2010) 786–789
789
10. All microwave experiments were performed using
microwave synthesizer.
a
Biotage Initiator 2.0
14. Quinn, J. F.; Razzano, D. A.; Golden, K. C.; Gregg, B. T. Tetrahedron Lett. 2008, 49,
6137.
11. Microwave Methods in Organic Synthesis; Larhed, M., Olofsson, K., Eds.; Springer:
Berlin, 2006.
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J. Chem. Rev. 1974, 74, 567; (b) Johnstone, A. W.; Wilby, A. H.; Entwistle, I. D.
Chem. Rev. 1985, 85, 129.
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Quai, M.; Repetto, C.; Barbaglia, W.; Cereda, E. Tetrahedron Lett. 2007, 48, 1241;
(g) Baruwati, B.; Polshettiwar, V.; Varma, R. Tetrahedron Lett. 2009, 50, 1215;
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16. The catalysts used in this study were either 5 wt % Pd (dry basis) Degussa type
E101 O/W (ꢀ50 wt % H2O) or 10 wt % Pd (dry basis) Degussa type E101 NE/W
(ꢀ50 wt % H2O). The Pt catalyst was 5 wt % Pt (dry basis) Degussa type F101
KYA/W (ꢀ50 wt % H2O).
17. A procedure for the synthesis of p-toluidine (24) is as follows: A 20 mL Biotage
microwave process vial with
a stir bar was charged with 4-methyl-1-
nitrobenzene (685 mg, 5 mmol), 10 wt % Pd/C (50% wet, 532 mg, 0.25 mmol),
and methanol (10 mL). 1,4-Cyclohexadiene (3.00 mL, 32 mmol) was added and
the vessel was capped and heated under microwave conditions at 120 °C for
5 min. The reaction was filtered through Celite and was evaporated to give p-
toluidine (503 mg, 94%) as light brown crystals. This material had an identical
HPLC retention time, APCI MS spectra, and 1H NMR spectrum as authentic
material.