Simple and efficient synthesis of N -nitroethylenediamine derivatives

Article abstract of DOI:10.1055/s-0030-1259935

A simple and efficient synthesis of N-nitroethylenediamine derivatives was carried out by reaction of 1-nitroimidazolidin-2-one with various nitrogen-, oxygen-, and sulfur-containing nucleophiles. The reactivity of primary and secondary amines, amino alco

Full text of DOI:10.1055/s-0030-1259935

1168
LETTER
Simple and Efficient Synthesis of N-Nitroethylenediamine Derivatives
S
ynthesis of
N
-
N
u
itroethylene
b
diamine
D
er
o
ivatives mír Kvapil,a Adam Šimáček,b Martin Grepl,a Tomáš Gucký,c Tomáš Pospíšil,c Pavel Hradil*a,b
a
Farmak a.s., 771 17 Olomouc, Czech Republic
Fax +420585634465; E-mail: ph.1@tiscali.cz
b
c
Department of Organic Chemistry, Palacky University, Tr. 17. Listopadu 12, 771 46 Olomouc, Czech Republic
Laboratory of Growth Regulators, Palacky University, Slechtitelu 11, 783 71 Olomouc, Czech Republic
Received 13 December 2010
5 (Scheme 1).11 These results encouraged us to test the re-
action of 4 with various nucleophiles (Table 1). Reaction
of compound 4 with primary and secondary amines in
methanolic solution was carried out initially and com-
Abstract: A simple and efficient synthesis of N-nitroethylenedi-
amine derivatives was carried out by reaction of 1-nitroimidazoli-
din-2-one with various nitrogen-, oxygen-, and sulfur-containing
nucleophiles. The reactivity of primary and secondary amines, ami-
no alcohols, hydrazines, amino acids, alcohols, and thiophenol was pounds 6–30 were prepared in high yields. Reaction pro-
tested.
ceeded similarly with amino alcohols and hydrazines thus
forming the corresponding products 31–40. On the other
hand, the reaction with guanidine and hydroxylamine re-
sulted in formation of inseparable complex mixtures;
whilst, in the case of anilines containing electron-with-
drawing groups, the reaction failed completely. Alcohols
reacted with 4 very slowly on heating but, in the presence
of alkali, bases 41 and 42 formed in good yield and after
short reaction time. Similarly, reaction with tertiary
amines (e.g., triethylamine) or amides (e.g., acetamide)
led to formation of 41 on prolonged heating in methanol.
Thiophenol formed 43 in the presence of triethylamine.12
Key words: nucleophiles, ring opening, N-nitroethylenediamine
derivatives, nitroamines
Ethylenediamines are an important class of organic com-
pounds with many applications in industry and with ex-
tensive occurrence in nature.1 They also serve as selective
ligands in organic synthesis2 and as synthons for hetero-
cyclic compounds.3 Relatively little attention has been
paid to N-nitroethylenediamine (1) and its derivatives
(Figure 1). These compounds belong to the nitroamine
family that have importance as industrial and military ex-
plosives.4,5 There are not many naturally occurring ni-
troamines, but N-nitroethylenediamine (1) and its
derivative b-nitroaminoalanine (2) have been identified as
metabolic products from mushroom Agaricus silvaticus.6
H2O, pH 7
1
HN
N
NO2
H
H
H2O, OH–
N
N
O
N-Nitroglycine (3), a metabolic product from the bacteria
Streptomyces noursei, inhibits growing of Escherichia
coli, Pseudomonas tabaci, and Mycobacterium phlei.7 In
the literature several rather complicated routes for the syn-
theses of N-nitroethylenediamine derivatives have been
described.6,8
O2NHN
NHNO2
4
O
5
Scheme 1 Hydrolysis of compound 4 in neutral and alkaline soluti-
on
Aci–nitro tautomerism was proved by methylation of 30
using diazomethane; both N- and O-methylated products
were isolated in a 1:2 ratio, respectively. Based on the
above results and previous experience, we proposee that
reaction begins with nucleophilic attack on the carbonyl
group followed by ring opening.
H2N
H2N
NHNO2
NHNO2
HOOC
NHNO2
COOH
1
2
3
Figure 1
In summary, the course of hydrolysis of 1-nitroimidazoli-
din-2-one with water described earlier was reinvestigated,
and we have prepared a number of N-nitroethylene-
diamine derivatives by simple reaction of an appropriate
nucleophile with 1-nitroimidazolidin-2-one. Aci–nitro
tautomerism has been proven by methylation.
Our research is aimed at accessing intermediates for pyra-
zole-based cytostatics.9 First, we reproduced the reaction
of 1-nitroimidazolidin-2-one (4) with neutral water de-
scribed previously.10 N-Nitroethylenediamine (1) and an
unknown compound were isolated, the latter being identi-
fied as 5. Subsequently, we found that the same reaction
carried out in alkaline aqueous solution led exclusively to
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
SYNLETT 2011, No. 8, pp 1168–1170
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.04.2011
DOI: 10.1055/s-0030-1259935; Art ID: D32010ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of N-Nitroethylenediamine Derivatives
1169
Table 1 Reaction of Compound 4 with Various Nucleophiles12
Table 1 Reaction of Compound 4 with Various Nucleophiles12
(continued)
H
H
Nu
N
NO2
HN
N
Nu
N
NO2
NuH
HN
N
NuH
NO2
N
NO2
N
H
H
O
O
O
O
6–43
4
6–43
4
Compd
Nu
mp (°C)
97–99
Yield (%)
Compd
Nu
mp (°C)
151–153
Yield (%)
6
7
NH2
80
75
81
88
77
25
76
59
83
80
77
N
n-BuNH
t-BuNH
79–81
26
27
28
29
103.5–105
95–97
8
117.5–119
70–72
N
9
CH3(CH2)7NH
CH3(CH2)8NH
O
N
10
88–90
133–135
168–170
H
N
EtOOC
EtOOC
N
N
11
12
120–122
204–206
80
75
H
N
N
Me
N
H
N
30
124–125
81
13
14
147–149
92–94
77
74
31
32
HOCH2CH2NH
101–103
80–82
81
80
N
H
HOCH2CH2CH2NH
H
N
HO
HN
15
16
153–155
124–126
67
74
33
98–100
85
N
HO
COOEt
NH
34
35
36
NH2NH
129–131
153–155
149.5–152
55
68
78
MeNHNH
PhNHNH
H
N
17
18
159–160
139–141
73
71
O2N
NHNH—
NO2
H
37
191–193
77
Et
N
H
N
38
39
40
41
42
43
AcNHNH
157–159
99–101
132–134
86–87.5
90–92
72
75
71
77
53
51
19
20
21
148–150
146–148
167–169
68
83
79
MeOCONHNH
t-BuOCONHNH
MeO
OMe
H
MeO
N
H
N
t-BuO
PhS
109–111
Cl
H
N
22
23
186–188
90.5–93
74
51
Cl
Acknowledgment
Et
N
This project was supported in part by the Ministry of Education,
Youth and Sport of the Czech Republic (grants MSM6198959216
and ME09057).
Et
i-Pr
24
120–122
48
N
i-Pr
References and Notes
(1) Saibabu Koti, S. R. S.; Timmons, C.; Li, G. Chem. Biol.
Drug Des. 2006, 67, 101.
Synlett 2011, No. 8, 1168–1170 © Thieme Stuttgart · New York

1170
L. Kvapil et al.
LETTER
Starting material 4 (1.0 g, 7.63 mmol) was dissolved in
(2) For recent examples, see: (a) Diaz-Valenzuela, M. B.;
Philips, S. D.; France, M. B.; Gunn, M. E.; Clarke, M. L.
Chem. Eur. J. 2009, 15, 1227. (b) Uchida, T.; Katsuki, T.
Tetrahedron Lett. 2009, 50, 4741. (c) Fu, X.; Loh, W.-T.;
Zhang, Y.; Chen, T.; Ma, T.; Liu, H.; Wang, J.; Tan, C.-H.
Angew. Chem. Int. Ed. 2009, 48, 7387. (d) Yang, X.; Liu,
H.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Synlett 2010, 101.
(3) For recent examples, see: (a) Sriramurthy, V.; Barcan,
G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 1298.
(b) Murai, K.; Takaichi, N.; Takahara, Y.; Fukushima, S.;
Fujioka, H. Synthesis 2010, 520. (c) Hari, G. S.; Lee, Y. R.
Synthesis 2010, 453.
MeOH (30 mL) and 2-aminoethanol (0.5 g, 8.18 mmol, 1.07
equiv) was added. The reaction mixture was heated to
boiling and periodically analyzed using TLC (mobile phase:
EtOAc). After 2 h the spot corresponding to 4 disappeared,
the reaction mixture was concentrated to crystallization, and
the crude product was filtered. Recrystallization from i-
PrOH–toluene afforded 31 as colourless crystals (1.18 g,
81%). C5H12N4O4 (192.17); mp 101–103 °C. MS: m/z (%) =
131.0(16) [HO(CH2)2NHCONHCH2CH2]+. 1H NMR (300
MHz, DMSO-d6): d = 3.03 (q, 2 H, J = 5.6 Hz, H-8), 3.15 (q,
2 H, J = 5.8 Hz, H-4), 3.17–3.40 (m, 4 H, H-3, H-9), 4.73 (br
s, 1 H, OH), 6.03 (t, 1 H, J = 5.6 Hz, NH-7), 6.14 (t, 1 H,
J = 5.8 Hz, NH-5), 11.0 (s, 1 H, NH-2). 13C NMR, (75 MHz,
DMSO-d6): d = 36.5, 42.0, 46.6, 61.1, 158.
(4) Agrawal, J. P.; Hodgson, R. D. Organic Chemistry of
Explosives; Wiley: New York, 2007.
(5) Ledgard, J. B. The Preparatory Manual of Explosives, 3rd
ed.; Jared Ledgard: Washington, 2007.
Spectroscopic Data for Selected Products
(6) Chilton, W. S.; Hsu, Ch. P. Phytochemistry 1975, 14, 2291.
(7) Miyazaki, Y.; Kono, Y.; Shimazu, A.; Takeuchi, S.;
Yonehara, H. J. Antibiot. 1968, 21, 279.
(8) Bachmann, W. E.; Horton, W. J.; Jenner, E. L.;
MacNaughton, N. W.; Maxwell, C. E. J. Am. Chem. Soc.
1950, 72, 3132.
(9) Krapcho, A. P.; Menta, E.; Oliva, A.; Spinelli, S.
US 5519029, 1996; Chem. Abstr. 1994, 121, 157651.
(10) Astakhov, M.; Stepanov, R. S.; Kruglyakova, L. A.; Kekin,
Y. V. Russ. J. Org. Chem. 2000, 36, 575.
(11) Procedure for the Preparation of 1,3-Bis[2-(nitroamino)-
ethyl]urea (5)
1-[2-(Nitroamino)ethyl]urea (6)
C3H8N4O3 (148.12); mp 97–99 °C. MS: m/z (%) = 87.1 (100)
[NH2CONHCH2CH2]+. 1H NMR (300 MHz, DMSO-d6):
d = 3.14 (q, 2 H, J = 5.9 Hz, H-4), 3.41 (t, 2 H, J = 5.9 Hz,
H-3), 5.57 (s, 2 H, NH2), 6.10 (t, 1 H, J = 5.5 Hz, NH-5),
12.00 (s, 1 H, NH-2). 13C NMR (75 MHz, DMSO-d6):
d = 36.4, 45.7, 158.7.
N-[2-(Nitroamino)ethyl]hydrazinecarboxamide (34)
C3H9N5O3 (163.13); mp 129–131 °C. MS: m/z (%) = 163.9
(2) [M + H+], 102.0(100) [NH2NHCONHCH2CH2]+. 1H
NMR (300 MHz, DMSO-d6): d = 3.13–3.23 (m, 4 H, H-3,
H-4), 5.96 (br s, 3 H, NH2, NH-7), 6.46 (br s, 1 H, NH-5),
7.04 (s, 1 H, NH-2). 13C NMR (75 MHz, DMSO-d6):
d = 37.55, 50.01, 160.33.
Starting material 4 (2.0 g, 15.26 mmol) was suspended in
H2O (10 mL). To this suspension was added dropwise 10%
NaOH (10 mL); the starting material 4 dissolved. After 1 h
stirring at laboratory temperature the reaction mixture was
acidified with dilute HCl to pH 2. Product 5 crystallized
from this solution in 72% yield (1.3 g) as colorless crystals.
C5H12N6O5 (236.18); mp 161–163 °C. MS: m/z (rel.
abundance) = 175.1 (14)
Methyl [2-(Nitroamino)ethyl]carbamate (41)
C4H9N3O4 (163.13); mp 86–87.5 °C. MS: m/z (%) = 163.7
(4) [M + H]+, 102.1 (100) [CH3OCONHCH2CH2]+. 1H NMR
(300 MHz, DMSO-d6): d = 3.15 (q, 2 H, J = 5.98 Hz, H-4),
3.43 (t, 2 H, J = 6.00 Hz, H-3), 3.52 (s, 3 H, CH3), 7.25 (t, 1
H, J = 5.1 Hz, NH-5), 12.00 (s, 1 H, NH-2). 13C NMR (75
MHz, DMSO-d6): d = 37.57, 44.67, 51.36, 156.77.
S-Phenyl [2-(Nitroamino)ethyl]thiocarbamate (43)
C9H11N3O3S (241.26); mp 109–111 °C. MS: m/z (%): 180
(53) [C6H5SCONHCH2CH2]+. 1H NMR (300 MHz, DMSO-
d6): d = 3.30 (q, 2 H, J = 5.4 Hz, CH2), 3.47 (t, 2 H, J = 5.4
Hz, CH2), 7.36–7.47 (m, 5 H, ArH), 8.46 (t, 1 H, J = 5.4 Hz,
NH), 12.07 (br s, 1 H, NH). 13C NMR (300 MHz, DMSO-
d6): d = 33.9, 37.9, 127.1, 128.8, 129.4, 134.8, 164.3.
[NO2NHCH2CH2NHCONHCH2CH2]+. 1H NMR (300 MHz,
DMSO-d6): d = 3.16 (q, 4 H, J = 5.9 Hz, H4, H4¢), 3.42 (t, 4
H, J = 5.9 Hz, H3, H3¢), 6.19 (t, 2 H, J = 5.9 Hz, NH-5, NH-
5¢), 11.98 (br s, 2 H, NH-2, NH-2¢). 13C NMR (75 MHz,
DMSO-d6): d = 36.5, 45.5, 158.0.
(12) Representative Experimental Procedure for the
Preparation of 1-(2-Hydroxyethyl)-3-[2-(nitroamino)-
ethyl]urea (31)
Synlett 2011, No. 8, 1168–1170 © Thieme Stuttgart · New York

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