Selective reduction of N-nitroso aza-aliphatic cyclic compounds to the corresponding N-amino products using zinc dust in CO2–H2O medium

Article abstract of DOI:10.1007/s10593-018-2349-0

[Figure not available: see fulltext.] A new method for reduction of N-nitroso aza-aliphatic cyclic compounds employing zinc in pressurized CO₂–H₂O medium has been developed. H₂O and NH₄Cl were used as hydrogen donors, and reduction was performed under environmentally benign conditions. The presented approach allowed to obtain the respective N-amino products selectively and in excellent yields (up to 97%).

Full text of DOI:10.1007/s10593-018-2349-0

DOI 10.1007/s10593-018-2349-0
Chemistry of Heterocyclic Compounds 2018, 54(8), 780–783
Selective reduction of N-nitroso aza-aliphatic cyclic compounds
to the corresponding N-amino products
using zinc dust in CO2–H2O medium
Weiqing Yang1, Xiang Lu1, Tingting Zhou1, Yongjing Cao1,
Yuanyuan Zhang1,2, Menglin Ma1*
1 School of Science, Xihua University,
999 Jin Zhou Rd., Jin niu District, Chengdu 610039, China
2 Key Laboratory of Green Chemistry and Technology,
Faculty of Chemistry, Sichuan University,
24 South Section 1 Yihuan Rd., Chengdu 610064, China; е-mail: mmlchem@163.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(8), 780–783
Submitted June 15, 2018
Accepted August 3, 2018
R2
R2
N
i
R1
X
N
N
O
R1
X
NH2
R2
R2
i: Zn, NH4Cl, CO2 H2O
35°C, 1.5 h (87 97%)
8 examples
N
N
O
N
NH2
i
i
R3
R3
R1 = H, Me, cyclopentyl, Ph
R2 = H, Me
N
R3 = H, CH2OMe
X = C, N
N
NH2
N O
A new method for reduction of N-nitroso aza-aliphatic cyclic compounds employing zinc in pressurized CO2–H2O medium has been
developed. H2O and NH4Cl were used as hydrogen donors, and reduction was performed under environmentally benign conditions. The
presented approach allowed to obtain the respective N-amino products selectively and in excellent yields (up to 97%).
Keywords: zinc, N-amino group, aza-aliphatic cycle, N-nitroso group, system carbon dioxide – water, reduction.
N-Amino aza-aliphatic cyclic compounds are useful
intermediates in the synthesis of pharmaceutical and agri-
cultural chemicals.1 Such compounds have been previously
obtained by reduction of the corresponding N-nitroso
derivatives using LiAlH4 in Et2O or THF2 and TiCl3 in
H2O.3 Catalytic hydrogenation using molecular hydrogen is
a straightforward and convenient method.4 However, this
synthetic approach has been rarely exploited for reduction
of N-nitroso group,5 since the hydrazine N–N bond may be
further cleaved under the reaction conditions.6 Therefore,
development of selective method for reduction of N-nitroso
group is still required.
Zinc is a readily available and inexpensive reducing reagent,
commonly used for the reduction of nitro or nitroso com-
pounds. Beneficially, it can tolerate a variety of reducible
functionalities. The reduction of N-nitroso group with zinc
usually has been performed in combination with HCl3b,7 or
AcOH.8 According to these procedures, subsequent
neutralization of the mixture with a base leads to inevitable
salt formation in the aqueous solution. Hence, finding
alternatives to conventional acids is of great importance.
In recent years, public health and environment protec-
tion have attracted increased attention. Therefore, elabora-
tion of environmentally friendly reagents and chemical
processes in organic synthesis is highly desirable.9 In this
regard, CO2–H2O system has been demonstrated as an
environmentally benign alternative to conventional acids.10
At high pressure conditions, pH values of the CO2–H2O
system can decrease as low as to 3.1.11 However, pressure
reduction promotes the release of CO2 and self-
neutralization of the reaction medium. Under such
conditions, zinc powder has been successfully used for
selective reduction of nitroarenes bearing a variety of other
reducible functional groups.10f,g,12
Herein, reduction of N-nitroso aza-aliphatic cyclic com-
pounds employing zinc in pressurized CO2–H2O medium
0009-3122/18/54(8)-0780©2018 Springer Science+Business Media, LLC
780

Chemistry of Heterocyclic Compounds 2018, 54(8), 780–783
Table 1. Effect of the reaction temperature and CO2 pressure
piperazin-1-amine (2a) was decreased (entry 4). In
addition, the reaction at 5°C afforded trace amounts of
hydrazine 2a (entry 8). Overall, the highest selectivity of
4-methylpiperazin-1-amine (2a) was observed when CO2
was applied at 0.2 MPa pressure and the reduction was
conducted at 35°C (entries 3, 5–8).
on the reduction of 1-methyl-4-nitrosopiperazine (1a)
with zinc in CO2–H2O*
As reported previously, acidic medium (pH <5) may be
present in a pressurized CO2–H2O system, since CO2 and
H2O exist in equilibrium with H2CO3.12,13 However, H2CO3
is a weak acid, therefore NH4Cl was evaluated as an
additive for the zinc-mediated reduction of 1-methyl-
4-nitrosopiperazine (1a). Effect of different amounts of
NH4Cl on conversion of starting material 1a and selectivity
of product 2a was investigated (Table 2).
Without NH4Cl, low conversion of 1-methyl-4-nitroso-
piperazine (1a) and selectivity of 4-methylpiperazin-
1-amine (2a) were observed. Increasing the ratio of NH4Cl
and starting material 1a from 0 to 0.10 mol allowed to
improve the conversion and selectivity up to >99 and 94%,
respectively (Table 2, entries 1–5). Addition of 0.10 mol
NH4Cl provided acidic reaction medium with initial
pH 5.21, which was beneficial for the investigated
reduction. However, with a further increase in the amount
of NH4Cl up to 1.00 mol, the initial pH of the solution
changed from 5.21 to 4.49 and the selectivity of 4-methyl-
piperazin-1-amine (2a) decreased gradually (entries 6–8).
The importance of both NH4Cl and CO2 in providing acidic
conditions for the reaction was demonstrated in a control
experiment. When the reduction was performed in the
presence of 0.10 mol NH4Cl and without CO2, the
conversion of starting material 1a was only 14% and the
reaction did not proceed further under the conditions with
final pH 6.79, observed after consumption of NH4Cl
protons (entry 9).
Conversion of
Selectivity of
CO2 pressure, Temperature,
Entry
compound 1a**, hydrazine 2a**,
MPa
°C
%
Trace
73
%
Trace
34
1
2
3
4
5
6
7
8
–***
0.1
0.2
0.5
0.2
0.2
0.2
0.2
60
60
60
60
45
35
25
5
99
>99
64
32
12
37
19
58
6
58
Trace
Trace
* Reaction conditions: 1-methyl-4-nitrosopiperazine (1a) (129 g, 1.0 mol),
zinc dust (163 g, 2.5 mol), H2O (250 ml, 14.3 mol), 1.5 h.
** Determined by GC using area normalization method.
*** Reaction was performed without CO2.
has been studied. The reduction of 1-methyl-4-nitroso-
piperazine (1a) was selected as a model reaction in order to
demonstrate the reactivity of N-nitroso group and the selec-
tivity toward formation of 4-methylpiperazin-1-amine (2a)
(Table 1). First of all, the role of CO2 was examined
because pressure and thereby content of CO2 are the key
factors for evaluation of the system acidity.
In the absence of CO2, only trace amounts of product 2a
were detected (Table 1, entry 1). However, the reaction could
be accelerated significantly with the charge of 0.1 MPa
CO2 thus indicating the crucial role of CO2 (entry 2). When
the reduction was performed at 60°C with a CO2 pressure
of 0.2 MPa, the conversion of 1-methyl-4-nitrosopiperazine
(1a) reached 99% (entry 3). With a further increase in CO2
pressure, formation of 1-methylpiperazine (3a), the side
product resulting from a complete reduction of starting
material 1a, was promoted and selectivity toward 4-methyl-
Effect of the amount of zinc and substitution of zinc
with iron on the reaction was also evaluated (Table 3).
Interestingly, increase in the amount of zinc up to 5.0 mol
did not influence the selectivity of reduction. On the other
hand, conversion of starting material 1a was increased
significantly up to >99% (entries 2–5). The experimental
Table 2. Effect of NH4Cl on the reduction of 1-methyl-4-nitrosopiperazine (1a) with zinc in CO2–H2O*
Amount of NH4Cl
and compound 1a, mol
Initial pH
of the system
Final pH
of the system
Conversion
of compound 1a**, %
Selectivity
of hydrazine 2a**, %
Entry
CO2 pressure, MPa
1
2
3
4
5
6
7
8
9
0.2
0.2
–
6.94
6.50
6.07
5.68
5.21
4.99
4.92
4.49
5.21
4.14
4.13
4.11
4.10
4.09
4.09
4.07
4.02
6.79
19
42
58
89
92
94
94
90
85
81
44
0.01
0.025
0.05
0.10
0.25
0.50
1.00
0.10
0.2
64
0.2
89
0.2
>99
>99
>99
>99
14
0.2
0.2
0.2
–***
* Reaction conditions: 1-methyl-4-nitrosopiperazine (1a) (129 g, 1.0 mol), zinc dust (163 g, 2.5 mol), H2O (250 ml, 14.3 mol), 35°C, 1.5 h.
** Determined by GC using area normalization method.
*** Reaction was performed without CO2.
781

Chemistry of Heterocyclic Compounds 2018, 54(8), 780–783
Table 3. Effect of metal on the reduction
of 1-methyl-4-nitrosopiperazine (1a) in CO2–H2O*
Table 4. Reduction of N-nitroso aza-aliphatic cyclic compounds
1a–c, 4a,b, 6a,b, and 8 under optimized reaction conditions*
Conversion of Selectivity of
Conversion of
Selectivity of
Molar ratio of metal
Substrate
Product
substrate**,
%
product**,
%
Entry Metal
compound 1a**, hydrazine 2a**,
and compound 1a
%
0
46
%
0
1
2
3
4
5
6
Zn
Zn
Zn
Zn
Zn
Fe
–
>99
94
1a
2a
0.5
1.0
2.5
5.0
2.5
96
96
94
90
6
68
99
91
>99
>99
13
* Reaction conditions: 1-methyl-4-nitrosopiperazine (1a) (129 g, 1.0 mol),
NH4Cl (5.35 g, 0.1 mol), H2O (250 ml, 14.3 mol), CO2 pressure 0.2 MPa,
35°C, 1.5 h.
99
96
96
95
** Determined by GC using area normalization method.
results also confirmed that iron is not applicable to this
reaction system (entry 6).
On the basis of the optimized reaction conditions,
reduction of other N-nitroso aza-aliphatic cyclic com-
pounds 1b,c, 4a,b, 6a,b, and 8 was further investigated
using zinc dust in CO2–H2O system (Table 4). It is well
established that amines and hydrazine in CO2–H2O system
may easily capture CO2 in the form of carbamates or
bicarbonates.14 Indeed, presence of unidentified impurities was
observed in 1H NMR spectra of almost all products
suggesting that the obtained hydrazines may possibly react
with CO2. However, the amount of these impurities was
negligible. In all cases, the reaction proceeded smoothly
with high conversion of starting materials (92–99%) and
selectivity of products (91–99%).
92
98
98
94
94
99
In summary, a series of N-nitroso aza-aliphatic cyclic
compounds has been reduced by zinc in pressurized CO2–H2O
medium containing NH4Cl. The N-nitroso group can be
converted into the corresponding amine with a selectivity
higher than 91%. The noteworthy selectivity and green
reaction conditions make the presented synthetic method
environmentally benign as well as suitable for scale-up and
preparation of other N-amino aza-aliphatic cyclic com-
pounds.
94
95
* Reaction conditions: N-nitroso aza-aliphatic cyclic compound 1a–c,
4a,b, 6a,b, or 8 (1.0 mol), zinc dust (163 g, 2.5 mol), NH4Cl (5.35 g,
0.1 mol), H2O (250 ml, 14.3 mol), CO2 pressure 0.2 MPa, 35°C, 1.5 h.
** Determined by GC using area normalization method.
Experimental
Synthesis of N-amino aza-aliphatic cyclic compounds
2a–c, 5a,b, 7a,b, and 9 (General method). A solution of
N-nitroso aza-aliphatic cyclic compound 1a–c, 4a,b, 6a,b,
or 8 (1.0 mol) in H2O (250 ml) was placed into a 1-l
autoclave equipped with a CO2 ventilation device, a gas
flow meter, and a barometer. NH4Cl (5.35 g, 0.1 mol) was
added to the solution and the system was charged with CO2
at a flow rate 30 l/h. After stirring for 20 min, the mixture
was heated to 35°C and zinc powder (163 g, 2.5 mol) was
added in portions (16.3 g every 6 min). The pressure in the
closed system was maintained at 0.2 MPa and temperature
at 35°C. After addition of all zinc (about 1 h), the reaction
mixture was stirred at 35°C for 0.5 h and then analyzed by
GC. The resulting ZnCO3 was filtered off and washed with
H2O (150 ml). The filtrate was transferred to a 1-l three-
neck round-bottom flask, H2O was removed under reduced
pressure, and vacuum distillation at 60–135°C (internal
temperature) was performed to afford products 2a–c, 5a,b,
7a,b, and 9.
1H NMR spectra (400 MHz) were recorded on a Bruker
DPX-400 FT NMR spectrometer in CDCl3 (compounds
2a,c, 5a,b, 7a,b, and 9) or D2O (compound 2b) solution
using TMS as internal standard. GC analyses were per-
formed on a Shanghai Precision Scientific Instruments Co.,
Ltd. GC1102N gas chromatograph equipped with an OV-17
capillary column (length 15 m, inner diameter 0.53 mm,
film thickness 0.6 μm) and a flame ionization detector.
Parameters for the analyses were as follows: column
temperature 80°C, sample injection temperature 290°C, He
flow rate 2 ml/min, detector temperature 200°C, H2 pres-
sure 0.1 MPa, air pressure 0.16 MPa, and precolumn
pressure 1.5 MPa. Mass spectra were obtained on a Varian
CH-5 instrument using EI method (70 eV). Melting points
were determined on a Shanghai inesa physical optics
instrument Co., Ltd. SGWX-4B melting point apparatus.
All reagents and solvents were purchased from commercial
suppliers and were used without further purification.
782

Chemistry of Heterocyclic Compounds 2018, 54(8), 780–783
4-Methylpiperazin-1-amine (2a).15 Yield 110 g (96%),
References
1
colorless liquid, bp 75–80°C (30–40 mmHg). H NMR
1. (a) Fang, Z.; Yang, Z.; Xu, J.-F.; Guo, K.; Wei, P. Org. Prep.
Proced. Int. 2012, 44, 164. (b) Xia, T.; Hu, Z.; Ji, W.; Zhang, S.;
Shi, H.; Liu, C.; Pang, B.; Liu, G.; Liao, X. Org. Chem. Front.
2018, 5, 850. (c) Eissa, S. I. Med. Chem. Res. 2017, 26, 2205.
2. (a) Lucarini, M.; Pedulli, G. F.; Lazzari, D. J. Org. Chem.
2000, 65, 2723. (b) Dhainaut, A.; Régnier, G.; Atassi, G.;
Pierré, A.; Léonce, S.; Kraus-Berthier, L.; Prost, J.-F. J. Med.
Chem. 1992, 35, 2481.
3. (a) Zhang, Y.; Tang, Q.; Luo, M. Org. Biomol. Chem. 2011,
9, 4977. (b) Lunn, G.; Sansone, E. B.; Keefer, L. K. J. Org.
Chem. 1984, 49, 3470.
4. (a) Orlandi, M.; Brenna, D.; Harms, R.; Jost, S.; Benaglia, M.
Org. Process Res. Dev. 2018, 22, 430. (b) Wang, D.; Astruc, D.
Chem. Rev. 2015, 115, 6621.
5. (a) Klager, K.; Wilson, E. M.; Helm-kamp, G. Ind. Eng.
Chem. 1960, 52, 119. (b) Tungler, A.; Szabados, E. Org.
Process Res. Dev. 2016, 20, 1246.
6. (a) Kelley, J. L.; Thompson, J. B.; Styles, V. L.; Soroko, F. E.;
Cooper, B. R. J. Heterocycl. Chem. 1995, 32, 1423.
(b) Bellasio, E.; Campi, A.; Di Mola, N.; Baldoli, E. J. Med.
Chem. 1984, 27, 1077.
7. Manetti, D.; Di Cesare Mannelli, L.; Dei, S.; Galeotti, N.;
Ghelardini, C.; Romanelli, M. N.; Scapecchi, S.; Teodori, E.;
Pacini, A.; Bartolini, A.; Gualtieri, F. J. Med. Chem. 2005, 48,
6491.
8. (a) Waibel, M.; Hasserodt, J. J. Org. Chem. 2008, 73, 6119.
(b) Klein, J. T.; Davis, L.; Effland, R. C. J. Heterocycl. Chem.
1987, 24, 725.
9. (a) Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301.
(b) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437.
(c) Simon, M.-O.; Li, C.-J. Chem. Soc. Rev. 2012, 41, 1415.
10. (a) Pigaleva, M. A.; Elmanovich, I. V.; Kononevich, Y. N.;
Gallyamov, M. O.; Muzafarov, A. M. RSC Adv. 2015, 5,
103573. (b) Jiang, H.-F.; Huang, X.-Z. J. Supercrit. Fluids
2007, 43, 291. (c) Tundo, P.; Loris, A.; Selva, M. Green
Chem. 2007, 9, 777. (d) Li, G.; Jiang H.; Li, J. Green Chem.
2001, 3, 250. (e) Gao, G.; Tao, Y.; Jiang, J. Green Chem.
2008, 10, 439. (f) Liu, S.; Wang, Y.; Yang, X.; Jiang J. Res.
Chem. Intermed. 2012, 38, 2471. (g) Jiang, H.-F.; Dong, Y.-S.
Chin. J. Chem. 2008, 26, 1407.
11. (a) Gao, G.; Jiang, J.-Y. Comput. Appl. Chem. 2011, 28, 359
(In Chinese). (b) Roosen, C.; Ansorge-Schumacher, M.;
Mang, T.; Leitner, W.; Greiner, L. Green Chem. 2007, 9, 455.
12. Liu, S.; Wang, Y.; Jiang, J.; Jina, Z. Green Chem. 2009, 11, 1397.
13. Toews, K. L.; Shroll, R. M.; Wai, C. M.; Smart, N. G. Anal.
Chem. 1995, 67, 4040.
spectrum, δ, ppm: 3.11 (2H, s, NH2); 2.94–2.30 (8H, m,
CH2); 2.25 (3H, s, CH3). Mass spectrum, m/z (Irel, %): 115
[M]+ (100).
4-Phenylpiperazin-1-amine (2b).16 Yield 160 g (91%),
yellow solid, mp 53–55°C, bp 125–127°C (1–2 mmHg).
1H NMR spectrum, δ, ppm (J, Hz): 7.53–7.41 (5H, m,
H Ar); 3.82–3.53 (4H, m, CH2); 2.34 (2H, d, J = 13.9,
CH2); 2.16–2.00 (2H, m, CH2). Mass spectrum, m/z (Irel, %):
177 [M]+ (98), 161 [M–NH2]+ (100).
4-Cyclopentylpiperazin-1-amine (2c).16 Yield 161 g
(96%), yellow solid, mp 52–54°C, bp 106–114°C (5–
15 mmHg). 1H NMR spectrum, δ, ppm (J, Hz): 2.75 (4H, d,
J = 4.2, NCH2); 2.31 (5H, s, NCH2, NCH); 2.10 (2H, s, NH2);
1.69– 1.23 (8H, m, CH2). Mass spectrum, m/z (Irel, %): 169
[M]+ (100).
Pyrrolidin-1-amine (5a).17 Yield 79.0 g (92%), colorless
1
liquid, bp 60–65°C (30–40 mmHg). H NMR spectrum,
δ, ppm (J, Hz): 2.86 (4H, t, J = 5.8, CH2); 2.38 (2H, s,
NH2); 1.75–1.62 (4H, m, CH2). Mass spectrum, m/z (Irel, %):
86 [M]+ (97), 71 [M–NH2]+ (100).
2-(Methoxymethyl)pyrrolidin-1-amine (5b).18 Yield
114 g (87%), slightly yellow liquid, bp 90–95°C (30–
1
40 mmHg). H NMR spectrum, δ, ppm: 4.93 (2H, s, NH2);
3.46–3.37 (2H, m, OCH2); 3.35 (3H, s, OCH3); 3.19–3.16
(1H, m, CH); 2.68–2.63 (2H, m, CH2); 2.04–1.96 (1H, m,
CH2); 1.82–1.71 (2H, m, CH2); 1.55–1.49 (1H, m, CH2).
Mass spectrum, m/z (Irel, %): 130 [M]+ (100).
Piperidin-1-amine (7a).17 Yield 92.0 g (92%), colorless
1
liquid, bp 71–76°C (30–40 mmHg). H NMR spectrum,
δ, ppm: 2.86 (2H, s, NH2); 2.66–2.17 (4H, m, NCH2); 1.38–
1.34 (4H, m, CH2); 1.08 (2H, s, CH2). Mass spectrum, m/z
(Irel, %): 100 [M]+ (100).
2,6-Dimethylpiperidin-1-amine (7b).19 Yield 124 g (97%),
slightly yellow liquid, bp 100–105°C (30–40 mmHg).
1H NMR spectrum, δ, ppm (J, Hz): 2.68 (2H, s, NH2); 1.72–
1.45 (6H, m, CH2); 1.38–1.28 (2H, m, CH); 1.09 (3H, d,
J = 8.0, CH3); 1.03 (3H, d, J = 8.0, CH3). Mass spectrum, m/z
(Irel, %): 128 [M]+ (95), 112 [M–NH2]+ (100).
3,4-Dihydroquinolin-1(2H)-amine (9).20 Yield 133 g
(90%), yellow solid, mp 52–54°C, bp 130–135°C (5–
1
15 mmHg). H NMR spectrum, δ, ppm (J, Hz): 7.10 (2H,
14. (a) Dutcher, B.; Fan, M.; Russell, A. G. ACS Appl. Mater.
Interfaces 2015, 7, 2137. (b) Lee, B.; Stowe, H. M.; Lee, K. H.;
Hur, N. H.; Hwang, S-J.; Paek, E.; Hwang, G. S. Phys. Chem.
Chem. Phys. 2017, 19, 24067.
15. Kushakova, P. M.; Kuznetsov, V. A.; Chernobroviy, A. N.;
Garabadgiu, A. V. Chem. Heterocycl. Compd. 2004, 40, 960.
[Khim. Geterotsikl. Soedin. 2004, 1111.]
dd, J = 10.2, J = 8.2, H Ar); 6.75 (1H, t, J = 7.4, H Ar);
6.58 (1H, d, J = 7.9, H Ar); 3.86 (2H, s, NH2); 3.43–3.36
(2H, m, NCH2); 2.89 (2H, t, J = 6.4, CH2); 2.12–2.01 (2H,
m, CH2). Mass spectrum, m/z (Irel, %): 148 [M]+ (100).
The Supplementary information file containing proce-
dure for the synthesis of starting materials 1a–c, 4a,b, 6a,b,
and 8 and 1H NMR spectral data of compounds 2a–c, 5a,b,
7a,b, and 9 is available at the journal website at http://
link.springer.com/journal/10593.
16. Mayer, N; Schweiger, M; Melcher, M.-C.; Fledelius, C.;
Zechner, R.; Zimmermann, R.; Breinbauer, R. Bioorg. Med.
Chem. 2015, 23, 2904.
17. Ilisson, M.; Tomson, K.; Selyutina, A.; Türk, S.; Mäeorg, U.
Synth. Commun. 2015, 45, 1367.
18. Lebrun, S; Couture, A; Deniau, E; Grandclaudon, P. Synthesis
2006, 3490.
The authors are grateful to the Ministry of Education,
''Chunhui Projects'' project Z2016163) and the Scientific
Research Foundation of the Education Department of
Sichuan Province (project 12ZB128) for financial support.
19. Shaaban, S.; Oh, J.; Maulide, N. Org. Lett. 2016, 18, 345.
20. Zhou, S.; Wang, J.; Zhang, F.; Song, C.; Zhu, J. Org. Lett.
2016, 18, 2427.
783