N-Nitration of Secondary Amines with 4-Chloro-5-methoxy-2-nitropyridazin-3-one

Article abstract of DOI:10.1021/jo0301503

N-Nitration of 4-chloro-5-substituted-pyridazin-3-one with copper nitrate trihydrate in acetic anhydride gave the corresponding 4-chloro-2-nitro-5-substituted-pyridazin-3-one. 4-Chloro-5-alkoxy-2-nitropyridazin-3-ones such as 5-methoxy (2b) and 5-ethoxy (2d) derivatives showed excellent nitro group transfer potentiality. N-Nitration of some secondary amines with 2b gave the corresponding N-nitramines under mild neutral condition in good yields.

Full text of DOI:10.1021/jo0301503

TABLE 1. 2-Nitr op yr id a zin -3-on es P r ep a r ed
N-Nitr a tion of Secon d a r y Am in es w ith
yieldb of
2 (%)
4-Ch lor o-5-m eth oxy-2-n itr op yr id a zin -3-on e
entry substrate
conditionsa
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
Cu(NO3)2‚3H2O, Ac2O, rt, 2 h
NH4NO3, (CF3CO)2O, CH2Cl2, rt, 2 h 2a (80)
TBAN, (CF3CO)2O, CH2Cl2, 0 °C, 3 h 2a (60)
2a (90)
Young-Dae Park,† Ho-Kyun Kim,† J eum-J ong Kim,†
Su-Dong Cho,‡ Sung-Kyu Kim,§ Motoo Shiro, and
Yong-J in Yoon*,†
concd H2SO4, concd HNO3
2a (0)
1b11d
1c11d
1d 11d
1e11d
1f
Cu(NO3)2‚3H2O, Ac2O, rt, 1.5 h
Cu(NO3)2‚3H2O, Ac2O, rt, 1 h
Cu(NO3)2‚3H2O, Ac2O, rt, 1.5 h
Cu(NO3)2‚3H2O, Ac2O, rt, 2 h
Cu(NO3)2‚3H2O, Ac2O, rt, 2 h
2b (85)
2c (81)
2d (80)
2e (85)
2f (88)
Department of Chemistry and Research Institute of Natural
Sciences, Gyeongsang National University,
Chinju 660-701, Korea, Department of Chemistry and
Biology, Research Institute of Natural Science, Changwon
National University, Changwon 641-773, Korea,
Department of Sciece Education, Chinju National University
of Education, Chinju 660-756, Korea, and
a
rt ) room temperature. TBAN ) tetrabutylammonium nitrate.
b
Isolated yield.
Rigaku Corporation, 3-9-12 Matsubara-cho,
Akishima-shi, Tokyo 196-8666, J apan
of secondary arylamines into corresponding nitramines
by acting n-butyl nitrate with organomagnesium bro-
mide. These methods suffer the inconvenience of han-
dling, low yield, or potential explosion hazard because
of the requirements of special preparation.10 Thus, we
were interested in finding a mild and stable reagent for
the N-nitration of secondary amines. As we continued our
research on the synthesis and the application of 2-sub-
stituted pyridazin-3-ones containing a useful functional
group at the 2-position on the pyridazin-3-one ring,11 we
found that 2-acyl or 2-benzenesulfonyl-4,5-dichloro-
pyridazin-3-ones serve as excellent N-acylating or N-
benzenesulfonylating reagents for amines under neutral
conditions. 4,5-Dichloropyridazin-3-one also is a good
leaving group. Thus, we have investigated the synthesis
and N-nitro transfer potentiality of 2-nitropyridazin-3-
ones to secondary amines. This paper reports on a simple
and convenient method using a new reagent for effective
N-nitration of secondary amines (3) to their correspond-
ing N-nitro derivatives (4) under mild conditions.
Direct N-nitration of 4,5-dichloropyridazin-3-one (1a )
was performed with some nitrating reagents such as Cu-
(NO3)2/Ac2O, NH4NO3/(CF3CO)2O in methylene chloride,
tetrabutylammonium nitrate/(CF3CO)2O in methylene
chloride, and concd H2SO4/concd HNO3 (Table 1). Our
experimental results demonstrated that Cu(NO3)2 is the
best reagent for N-nitration of 1a to 2a . Thus, N-nitration
of some pyridazin-3-ones 1b-f with Cu(NO3)2 in acetic
anhydride at room temperature afforded the correspond-
ing N-nitro derivatives 2b-f in good yields.
yjyoon@nongae.gsnu.ac.kr
Received May 2, 2003
Abstr a ct: N-Nitration of 4-chloro-5-substituted-pyridazin-
3-one with copper nitrate trihydrate in acetic anhydride gave
the corresponding 4-chloro-2-nitro-5-substituted-pyridazin-
3-one. 4-Chloro-5-alkoxy-2-nitropyridazin-3-ones such as
5-methoxy (2b) and 5-ethoxy (2d ) derivatives showed excel-
lent nitro group transfer potentiality. N-Nitration of some
secondary amines with 2b gave the corresponding N-
nitramines under mild neutral condition in good yields.
Many N-nitramines have been produced over the years
because of their importance as energetic materials1 and
biologically active nucleosides.2
The most common method of preparing N-nitramines
is by direct nitration of amino derivatives with acetone
cyanohydrin nitrate,3 CF3CMe2ONO2,4 N2O5,1i,5 HNO3,1j,6
7
or NH4NO3 in trifluoroacetic anhydride and NO2OSO2-
CF3.8 Also Daszkiewicz et al.9 reported on the conversion
* Address correspondence to this author at Gyeongsang National
University. Phone: 082-055-751-6019. Fax: 082-0550761-0244.
† Gyeongsang National University.
‡ Changwon National University.
§ Chinju National University of Education.
Rigaku Corporation.
(1) (a) Brill, T. B.; Russell, T. P.; Tao, W. C.; Wardle, R. B.
Decomposition, Combustion and Detonation Chemistry of Energetic
Materials; Materials Research Society Symposium Proceedings Vol.
418; Material Research Society: Pittsburgh, PA, 1996. (b) Fischer, J .
W.; Atkins, R, L. Org. Prep. Proced. Int. 1986, 18, 281. (c) Muller, D.
Propellants, Explos., Pyrotech. 1999, 24, 176. (d) Chung, K. H.; Kil, H.
S.; Choi, I. Y.; Chu, C. K.; Lee, I. M. J . Heterocycl. Chem. 2000, 37,
1647. (e) Axenrod, T.; Watnick, C.; Yazdekhasti, H. Tetrahedron Lett.
1993, 34, 6677. (f) Agrawal, J . P. Prog. Energy Combust. Sci. 1998,
24, 1. (g) Chafin, A.; Merwin, L. J . Org. Chem. 2000, 65, 4743. (h)
Agrawal, J . P.; Surve, R. N.; Sonawane, M. S. H. J . Hazard. Mater.
2000, A77, 11. (i) Willer, R. L.; Atkins, R. L. J . Org. Chem. 1984, 49,
5147. (j) Willer, R. L. J . Org. Chem. 1984, 49, 5150.
(2) (a) Giziewicz, J .; Wnuk, S. F.; Robins, M. J . J . Org. Chem. 1999,
64, 2149. (b) Gorchs, O.; Hernandez, M.; Garriga, L.; Pedroso, E.;
Grandas, A.; Farras, J . Org. Lett. 2002, 4, 1827.
(3) Emmons, W. D.; Freeman, J . P. J . Am. Chem. Soc. 1955, 77,
4387.
(4) Bottaro, J . C.; Schmitt, R. J .; Bedford, C. D. J . Org. Chem. 1987,
52, 2292.
(5) (a) Emmons, W. D.; Pargano, A. S.; Stevens, T. E. J . Org. Chem.
1958, 23, 311. (b) Golding, P.; Millar, R. W.; Paul, N. C.; Richards, D.
H. Tetrahedron Lett. 1988, 29, 2735.
To evaluate their N-nitro transfer potentiality, N-
nitration of N-methylbenzylamine (3a ) as a secondary
amine with 2a -f was conducted in dichloromethane at
room temperature. The results are shown in Table 2
(entries 1-6). Among six N-nitropyridazin-3-ones, 5-alkoxy
(8) Adams, C. M.; Sharts, C. M.; Shackelford, S. A. Tetrahedron Lett.
1993, 34, 6669.
(9) Daszkiewicz, Z.; Domanski, A.; Kyziol, J . B. Org. Prep. Proced.
Int. 1994, 26, 337.
(10) Bedford, C. D. Chem. Eng. News 1980, 58 (35), 33.
(11) (a) Kang, Y. J .; Chung, H. A.; Kim, J . J .; Yoon, Y. J . Synthesis
2002, 733. (b) Park, Y. D.; Kim, J . J .; Chung, H. A.; Kweon, D. H.;
Cho, S. D.; Lee, S. G.; Yoon, Y. J . Synthesis 2003, 560. (c) Kweon, D.
H.; Kim, H. K.; Kim, J . J .; Chung, H. A.; Lee, W. S.; Kim, S. K.; Yoon,
Y. J . J . Heterocycl. Chem. 2002, 39, 203. (d) Chung, H. A.; Kweon, D.
H.; Kang, Y. J .; Park, J . W.; Yoon, Y. J . J . Heterocycl. Chem. 1999, 36,
905.
(6) Robson, J . H.; Reinhart, J . J . Am. Chem. Soc. 1955, 77, 2453.
(7) Suri, S. C.; Chapman, R. D. Synthesis 1988, 743.
(12) Wagner, U. G.; Kratky, C.; Kappe, T. Monatsh. Chem. 1989,
120, 329.
10.1021/jo0301503 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/16/2003
J . Org. Chem. 2003, 68, 9113-9115
9113

SCHEME 1
TABLE 2. N-Nitr a tion of N-Meth ylben zyla m in e w ith
2-Nitr o-p yr id a zin -3-on es 2a -c, 2e, a n d 2g
F IGURE 1. ORTEP of N-nitrosodicyclohexylamine (4k ).
conditionsa
yieldb of 4a (%)
SCHEME 2
entry
2
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2b
2b
2b
2b
2b
2b
CH2Cl2, rt, 4 h
CH2Cl2, rt, 1 h
CH2Cl2, rt, 0.5 h
CH2Cl2, rt, 2.5 h
CH2Cl2, rt, 3 h
CH2Cl2, rt, 5 h
n-hexane, rt, 5 h
AcOEt, rt, 1 h
THF, rt, 8 h
tracec
95
18c
92
44c
10c
70
90
84
87
55
88
10
11
12
Et2O, rt, 2 h
MeOH, rt, 10 h
CH3CN, rt, 1 h
a
b
rt ) room temperature. Isolated yield. 4-Chloro-5-methoxy-
pyridazin-3-one was also recovered in good yield in entries 2, 7,
and 9. c Several unknown products were also detected on TLC.
TABLE 3. N-Nitr a tion of Som e Secon d a r y Am in es 3
w ith 2b in CH2Cl2 a t Room Tem p er a tu r e
entry
secondary amine 3
time (h) yielda of 4 (%)
1
2
3
4
5
6
7
8
9
N-isopropylbenzylamine (3b)
diethylamine (3c)
8
1
49
2.5
3
4b (86)
4c (90)
4d (28)
4e (92)
4f (74)
4g (82)
4h (86)
4i (79)
4j (92)
dicyclohexylamine (3d )b
morpholine (3e)
2,6-dimethylmorpholine (3f)
3-pyrroline (3g)
3
homopiperazine (3h )c
2-methylpiperazine (3i)
decahydroquinoline (3j)
0.5
3.5
4
(Figure 1). According to TLC monitoring, compound 4d
changed slowly to the corresponding N-nitroso derivative
4k under the reaction condition.
N-Nitration of homopiperazine (3h ) with 2 equiv of 2b
at room temperature also yielded 1,4-dinitrohomopip-
erazine (4l) in 82% yield. On the other hand, N-nitration
of primary amine, amide, and aromatic secondary amines
was not achieved by using compound 2b.
a
Isolated yield. 4-Chloro-5-methoxypyridazin-3-one was also
b
isolated in good yields. N-Nitrsodicyclohexylamine (4k ) was also
isolated in 39% yield. c Reaction of 3h with 2b (2 equiv) in
refluxing acetonitrile gave 1,4-dinitrohomopiperazine (4l) in 82%
yield.
derivatives 2b and 2d showed excellent N-nitro transfer
potentiality to secondary amine. For easy preparation of
4-chloro-5-methoxypyridazin-3-one, we selected com-
pound 2b as a new nitrating reagent. The solvent effect
of this reaction was also examined, and the results are
shown in Table 2 (entries 2 and 7-12). Dichloromethane,
ethyl acetate, acetonitrile, and diethyl ether were good
solvents for our system. N-Nitration of some secondary
amines 3b-j with 2b as a nitrating agent at room
temperature in dichloromethane gave the corresponding
N-nitro derivatives 4b-c and 4e-j in good yield except
for 3d (Table 3). N-Nitration of dicyclohexylamine (3d )
with 2b in dichloromethane afforded 4d as the minor
product in 29% yield and N-nitrosodicyclohexylamine
(4k ) as the major product in 39% yield (Table 3, entry
3). The structure of 4k was established by X-ray analysis
In conclusion, our method for N-nitration of aliphatic
secondary amines using 2b is novel, practical, and
convenient. 2-Nitro-4-chloro-5-methoxypyridazin-3-one
(2b) can act as a stable, mild, and efficient reagent as a
source for the delivery of nitronium ion (NO2+) under
mild, neutral, and homogeneous conditions.
Exp er im en ta l Section
N-Nitr a tion of 4-Ch lor o-5-m eth oxyp yr id a zin -3-on e. A
mixture of Cu(NO3)2‚3H2O (5 g, 21.5 mmol) and acetic anhydride
(50 mL) was stirred for 1.2 h. After adding 4-chloro-5-methoxy-
pyridazin-3-one (3 g, 18.7 mmol), the resulting mixture was
stirred for an additional 2 h at room temperature. MeOH (150
mL) was added to the mixture, and the mixture was then stirred
for an additional 0.5 h. After the solvent was evaporated, water
(100 mL) was added. The solution was neutralized with an
9114 J . Org. Chem., Vol. 68, No. 23, 2003

aqueous saturated solution of sodium bicarbonate to pH 6. The
precipitate was filtered, washed with water (500 mL), and dried
in air to give 4-chloro-5-methoxy-2-nitropyridazin-3-one (2b) in
90% (3.4 g) yield.
corresponding N-nitramine. Reusable 4-chloro-5-methoxy-
pyridazin-3-one was also isolated in quantitative yield.
Ack n ow led gm en t. This work was supported by
Research Grant ADD-01-8-001 from the Agency for
Defense Development, Korea.
Gen er al P r ocedu r e for N-Nitr ation of Secon dar y Am in es
by Usin g 2b. A secondary amine (3.4 mmol) was dissolved in
methylene chloride (30 mL). After 2b (0.7 g, 3.7 mmol) was
added, the mixture was stirred and monitored by TLC until 2b
disappeared. The solvent was coevaporated with silica gel (2 g)
under reduced pressure. The resulting silica gel was applied to
the top of an open-bed silica gel column (2.5 × 7 cm). The column
was eluted with ethyl acetate/n-hexane (1:3, v/v). Fractions
containing N-nitramine were combined and the solvent was
evaporated under reduced pressure to give the analytically pure
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectral data, IR spectral data, CHN analyses, and melting
point for compounds 2 and 4; X-ray analytical data for
N-nitrosodicyclohexylamine (4k ). This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0301503
J . Org. Chem, Vol. 68, No. 23, 2003 9115