Bio-inspired domino reduction of nitroarenes by acrolein-amine conjugates in one-pot operation

Article abstract of DOI:10.1246/cl.170175

Biologically relevant amines react with acrolein to provide 3-formyl-3,4-dehydropiperidine (FDP) as the oxidative stress product, which has reduction potential via hydrogen transfer. This biogenic process was applied to the domino reduction of electron-deficient nitroarenes in one-pot operation, by simply mixing primary amine, acrolein, nitroarene, and calcium chloride. The reaction can be performed in a gram-scale without the use of hazardous metals.

Full text of DOI:10.1246/cl.170175

Advance Publication Cover Page
Bio-inspired Domino Reduction of Nitroarenes by Acrolein-amine Conjugates in
One-pot Operation
Masayuki Takamatsu, Koichi Fukase, and Katsunori Tanaka*
Advance Publication on the web March 15, 2017
doi:10.1246/cl.170175
© 2017 The Chemical Society of Japan
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1
Bio-inspired Domino Reduction of Nitroarenes by Acrolein-amine Conjugates in One-pot
Operation
Masayuki Takamatsu,1,2 Koichi Fukase,2 and Katsunori Tanaka*1,3,4
1Biofunctional Synthetic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
2Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
3Biofunctional Chemistry Laboratory, A. Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya street, Kazan
420008, Russia
4Japan Science and Technology Agency-PRESTO, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
E-mail: kotzenori@riken.jp
Biologically relevant amines react with acrolein to
could easily be reduced through domino process and in one-
pot operation by simply mixing primary amine, acrolein,
nitroarene, and calcium chloride, without using pre-
synthesized FDP (Figure 1c). In this Letter, we wish to report
a bio-inspired “eco-friendly” and “gram-scale” procedure for
reduction of nitroarenes without use of hazardous metals.
provide 3-formyl-3,4-dehydropiperidine (FDP) as the
oxidative stress product, which has reduction potential via
hydrogen-transfer. This biogenic process was applied to
domino reduction of electron deficient nitroarenes in one-pot
operation, by simply mixing primary amine, acrolein,
nitroarene, and calcium chloride. The reaction can be
performed in a gram-scale without use of hazardous metals.
our previous work:
a. biogenic formation of FDP from acrolein and amine
R
N
3‒Formyl‒3,4-dehydropiperidine (FDP) is produced
from acrolein and biologically relevant amines, e.g., lysines,
sphingosine, or polyamines, under oxidatively stressed
X
O
R-NH2
8
N
[4+4]
cyclization
H
R
CHO
X
N
acrolein
FDP
conditions.1-3
This
non-enzymatic
post-translational
R
X = amino or alkoxy group
modification product has widely been used as marker of
various disease associated with oxidative stress.4 As one the
possible mechanisms of FDP formation, we recently found
that 1,5-diazacyclooctane derivatives, as the initial “formal”
imino [4+4] cycloaddtion products of acrolein Schiff base,5-10
are gradually transformed into FDP (Figure 1a).11,12
Alternatively, we found that FDP has a reduction potential
through hydrogen-transfer process (Figure 1b).13 Namely,
dehydropiperidine of FDP is oxidized to pyridinium ring,
while reducing compounds containing hydrogen acceptors.
For examples, various electron deficient nitroarenes could be
smoothly reduced by FDP at 100 ºC in the presence of
calcium chloride (Figure 1b; effects of calcium chloride,
optimized conditions, i.e., temperature and equivalents, and
scope of nitroarene substrates were described in details in ref.
13). While NAD(P)H as representative biological reducing
agent of “organic molecule” can reduce various carbonyl
compounds,14 reduction of nitroarenes with organic
molecules without using more than equimolar amount of
hazardous Lewis acids, e.g., Al, Sn, or Ti, is very limited.15-17
In fact, recently reported metal-free hydrogenation of
nitroarenes by natural product, vasicine, is notable example
in this aspect.18 We have so far applied such reduction
potential of FDP to “chemistry-driven” diagnostic tool, in
order to analyze the oxidative stress levels in mouse or even
human samples.13
b. reduction of nitroarene by FDPꢀ
O
ꢁꢁꢁꢀ
O
O
H+
CHO
CHO
O
Br
NH2
N
N
O
R
base
R
R
O
R'
R'
NO2
NH2
CaCl2
N
N
R
CHO
R
CHO
R’ = electron withdrawing groups
this work:
c. bio-inspired domino reduction of nitroarenes
- without hazardous metals
- simple operation
- large scale
R'
O
H
R
CaCl2
NH2
NO2
R'
DMF, 100 oC
NH2
Although FDP as a new organic reductant is promising
finding for “eco-friendly” process of nitroarene reduction,
we previously prepared the benzyl FDP (Figure 1b, R =
benzyl)13 as a reducing agent from benzylamine through
tedious steps.19 Here, hinted by the fact that FDP could
biologically be generated from acrolein and amines through
[4+4] process (Figure 1a), we envisioned that nitroarenes
Figure 1. [a] Production mechanism of FDP as oxidative stress product
from biologically relevant acrolein and amine. [b] Reduction potential of
FDP against nitroarenes through hydrogen-transfer process. [c] Bio-
inspired domino reduction of nitroarenes in one-pot operation, by
simultaneously mixing amine, acrolein, nitroarenes and calcium chloride,
described in this Letter.

2
We optimized one-pot domino reduction by using p-
sulfonyl nitroarene 1a as a model substrate, based on the
previously established conditions for FDP-production and
reduction (Table 1).13 One-pot operation is quite simple; 5
equiv of amine (against nitroarene substrate) was
simultaneously mixed with acrolein (5 equiv), nitroarene,
and calcium chloride (5 equiv) in N,N-dimethylformamide
(DMF) at room temperature, and the mixture was then heated
at 100 ºC for 5 hours. Although reduction did not proceed
without adding neither amine or acrolein (entries 1 and 3),
nitroarene 1a was smoothly converted in the presence of
benzylamine to corresponding aniline 2a in 61% yield (entry
2). Gratified to find that FDP production and reduction could
proceed through domino process, we tried to use n-
propylamine as an amine source, because it is available at
reasonable cost (especially in applying to large scale
synthesis, vide infra), and excess of this volatile amine could
simply be removed by evaporation after completion of the
reaction. Surprisingly, when using propylamine, the
reduction preceded more efficiently in 86% yield, which is
compatible to that using pre-synthesized FDP (entry 4, also
see Table 2, entry 1). Most probably, use of nucleophilically
more reactive n-propylamine could accelerate the formation
of FDP from intermediary 1,5-diazacyclooctane, hence the
reduction efficiency could be maximized in domino process.
Although use of excess reagents, i.e., 5 equiv of amine,
acrolein and CaCl2, is necessary for efficient reduction of
nitroarene, the established conditions in entry 4 could also be
applicable to large-scale reduction without affecting the
efficiency. Thus, 1.5 gram of aniline 2a was obtained in 84%
(entry 5).
The optimized conditions for domino process were then
applied to other nitroarenes with various electron
withdrawing groups (Table 2). All reactions were performed
using 1.5 gram of nitroarene substrates. As for the reduction
achieved for sulfonyl nitrobenzene 1a (entry 1), p-
nitrobenzoic acid derivatives 1b and 1c could also be
efficiently reduced to the anilines 2b and 2c in 74% and 57%
yield, respectively (entries 2 and 3). Although product yields
were slightly reduced, p-nitroacetophenone 1d, p-
nitrobenzonitrile 1e, and p-nitrophthalonitrile 1f, could
similarly be reduced in gram-scale, yielding the
corresponding anilines 2d-f in around 60% yields (entries 4-
6). Thus, (1) operationally simple procedure (mixing, heating,
evaporating, and then purifying), (2) the use of inexpensive
and less hazardous reagents, and hence (3) applicability to
“eco-friendly” (at least unnecessary for toxic metals) and
“safe” scaled-up reduction, highlight the established domino
reduction of nitroarenes in one-pot operation.
1a-f
(1 eq)
O
(5 eq)
R
CaCl2
(5 eq)ꢀ
H
NH2
(5 eq)
NO2
R
2a-f
NH2
o
DMF, 100 C
yield
yield
entry nitroarenea
product
R
by N-Bn FDPb by one-pot
O
O
1
1a
2a
ρ- Sꢀ
N
89%
84%
O
2
3
4
5
1b
1c
1d
1e
2b
2c
2d
2e
ρ-CO2Me
ρ-CO2H
ρ-COMe
ρ-CN
69%
61%
88%
82%
74%
57%
60%
60%
O
N
1a
(1 eq)
S
O
(5 eq)
H
6
1f
2f
m, ρ-(CN)2
78%
61%
O
S
CaCl2
(5 eq)ꢀ
NH2
(5 eq)
R
O
N
NO2
Table 2. Bio-inspired domino reduction of various nitroarenes with
electron withdrawing substituents in one-pot operation. [a] 1.5 Gram of
nitroarene 1a-f (7.0 mmol) was used. [b] Reduction performed by using
pre-synthesized benzyl FDP.
2a
o
DMF, 100 C
NH2
In conclusion, we developed bio-inspired domino
reduction of nitroarenes using “organic molecules”. One-pot
operation incudes simply heating a mixture of acrolein,
amines, nitroarenes, and calcium chloride, and then
evaporated the excess reagents for purification. The reaction
can easily be performed in a gram-scale, hence providing an
alternative to metal-mediated reaction. The method is
currently limited to the nitroarenes with electron
withdrawing substituents,20 but the research directed to
expanding applicability is now ongoing in our laboratory.
entry
R-NH2
yield of 2a
no reaction
61%ꢀ
1
-
2
3a
4
no reactionꢀ
86%
NH2
NH2
5b
84%
Acknowledgments
Table 1. Domino reduction of nitroarene 1a in one-pot operation from
amine, acrolein, nitroarene, and calcium chloride. [a] Reaction was
performed without acrolein. [b] 1.7 Gram of nitroarene 1a (7.0 mmol)
was used.
This work was supported by JSPS KAKENHI Grant
Numbers JP16H03287, JP16K13104 and JP15H05843 in
Middle Molecular Strategy, RIKEN Junior Research

3
Associate Program, and SUNBOR SCHOLARSHIP. This
work was also performed with the support of the Russian
Government Program for Competitive Growth granted to
Kazan Federal University.
Hz), 6.63 (dd, 2H, J = 6.8, 2.0 Hz), 6.26 (dd 2H, J = 2.3, 2.3 Hz),
4.21 (brs, NH2); 13C NMR (100 MHz, CDCl3) δ 151.6, 129.2(2C),
126.8, 120.6(2C), 114.1(2C), 113.1(2C); ESI-MS m/z calcd for
C10H10N2O2S
[M+H]+
223.1,
found
223.1.
Notes: All NMR and MS data of anilines 2a-f were in consistent
with those reported earlier.13
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14
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We could not observe imine formation between the oxidized
adduct of FDP and aromatic amine as reaction product under the
reaction conditions. The low reactivity of nitroarenes with
electron-donating groups is not due to such imine formation, but
due to lower reduction potential of nitroarenes. We have
examined this effects in details in our previous report.13
A general procedure for gram-scale reduction of nitroarenes.
To a solution of n-propylamine (2.7 mL, 35 mmol) in DMF (5.0
mL) was added acrolein (2.3 mL, 35 mmol), nitroarene 1a (1.7 g,
7.0 mmol) and CaCl2 (6.4 g, 34 mmol) at room temperature.
After 10 minutes, the solution was heated to 100 ºC and the
21
resulting mixture was stirred for
5 h. The mixture was
concentrated in vacuo to give a crude mixture as sticky gum.
After filtration, the crude residue was purified by
chromatography on silica gel (hexane:EtOAc = 2:1) to give the
aniline product 2a (1.3 g, 84% yield): 1H NMR (400 MHz,
CDCl3) δ 7.63 (dd, 2H, J = 6.8, 2.0 Hz), 7.13 (dd, 2H, J = 2.3, 2.3