Improved synthesis of an energetic material, 1,3,3-trinitroazetidine exploiting 1-azabicyclo [1.1.0]Butane

Article abstract of DOI:10.3987/com-99-8791

Expeditious synthesis of 1-nitroso-3-nitroazetidine (6), a useful key intermediate for the synthesis of 1,3,3-trinitroazetidine (4), was investigated by using 1-azabicyclo[1.1.0]butane (3) and NaNO₂ in the presence of some acids. The most efficient method was achieved in 26% yield by treatment of 3 with NaNO₂ in the presence of H₂SO₄. Conversion of 6 into 4 was also carried out.

Full text of DOI:10.3987/com-99-8791

HETEROCYCLES, Vol. 53, No. 2, 2000, pp. 447 - 452, Received, 25th October, 1999
IMPROVED SYNTHESIS OF AN ENERGETIC
MATERIAL, 1,3,3-TRINITROAZETIDINE
EXPLOITING 1-AZABICYCLO[1.1.0]BUTANE
†
,‡
‡
,†
Kazuhiko Hayashi,
Toshio Kumagai, and Yoshimitsu Nagao*
†
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi,
Tokushima 770-8505, Japan
‡
The Medical Research Laboratories, Wyeth Lederle Japan, Ltd., Kashiwa-cho,
Shiki, Saitama 353-8511, Japan
Abstract- Expeditious synthesis of 1-nitroso-3-nitroazetidine (6), a useful key
intermediate for the synthesis of 1,3,3-trinitroazetidine (4), was investigated by
using 1-azabicyclo[1.1.0]butane (3) and NaNO in the presence of some acids.
2
The most efficient method was achieved in 26% yield by treatment of 3 with
2 2 4
NaNO in the presence of H SO . Conversion of 6 into 4 was also carried out.
1
1
-Azabicyclo[1.1.0]butanes have been characterized to be highly strained bicyclic structures. Since the
first report of the synthesis and reactivity of these compounds, little attention has been paid to the unusual
2
ring system. Specifically, the synthetic utility of 1-azabicyclo[1.1.0]butane (3), which must be expected
to be useful for the preparation of various 1,3-disubstituted and 3-monosubstituted azetidines, has
1
-3
scarcely reported because of its synthetic difficulty due to the remarkably strained structure. In the
meantime, the usefulness of the compound (3) and its related compound as a key intermediate in the
4
synthesis of a particular compound, 1,3,3-trinitroazetidine (TNAZ, 4) was reported. TNAZ (4) has been
noteworthy from the viewpoint of a new important energetic material involving numerous applications to
5
the explosive and propellant technology. Hence, efficient and environmentally benign methods for the
6
large-scale synthesis of TNAZ (4) have been required. Although there have been several reports for the
synthesis of TNAZ (4), its preparation exploiting a highly strained molecule (3) seems to be a quite
4
,7
elegant method. However, the earlier methods using 3 resulted in the very poor yields of TNAZ (4) or
4
of its synthetic intermediate. Recently, we have developed a new efficient procedure for the synthesis of

3
starting from an inexpensive compound, allylamine (1) via its bromination followed by treatment of the
8
resultant dibromide 2 with n-BuLi, as shown in Scheme 1. We describe here an expeditious synthesis of
TNAZ (4) by exploiting 1-azabicyclo[1.1.0]butane (3).
Scheme 1
O N NO2
1
) n-BuLi, THF
2
Br2
EtOH
Br
-78 °C
+
NH2
Br
NH
-3 2) codistillation
with THF
rt
N
N
THF
Br
9
5%
NO2
4
1
2
3
2
First of all, preparation of a key intermediate (6) was investigated by treatment of 3 with NaNO in the
presence of some mineral acids. All experimental results are summarized in Scheme 2. A THF solution
Scheme 2
aq. NaNO , 1N HCl
2
rt
Cl
N NO + O N
N NO
2
5
7
21% from 2
6 12% from 2
aq. NaNO , conc. HNO ,
2
3
rt
O NO
N NO
2
13% from 2
aq. NaNO , 1N H SO
N
2
2
4
THF
-10 °C
3
6 26% from 2
aq. NaNO , 70% HClO4
2
rt
inseparable products
of 3, obtained from the reaction of 2 with n-BuLi in THF at -78°C for 1 h followed by codistillation
along with THF, was treated with an aqueous solution of NaNO in the presence of 1N HCl at room
2
temperature for 3 h to give 3-chloro-1-nitrosoazetidine (5) and 3-nitro-1-nitrosoazetidine (6) in 21% and
9
1
2% yields from 2, respectively. Similar treatment of the THF solution of 3 with aqueous NaNO
2
- conc.
3
HNO afforded only 3-nitrooxy-1-nitrosoazetidine (7) in 13% yield from 2. It was presumed that the
reactions described above might be promoted by concomitant N1-nitrosation with nucleophilic addition
-
-
of X (X = Cl, ONO
2 2
) or nitrite anion (NO ) involving cleavage of the strained C3-N bond in the
molecule (3), as shown in Scheme 3.

Scheme 3
NaNO + HX
2
-
+
-
O
O
O Na
X
-
N
+
O + O
N
(
H )
X
N
HNO2
and / or
N
N
N
NO
5
NO
6
3
HO N
X = Cl, ONO2
Based on this assumption, the use of the acid composed of a weak nucleophilic counter anion was
predicted to afford the desired compound (6) selectively. Thus, 3 was treated with aqueous NaNO
2
- 1N
9
H
2
SO
HClO
Finally, conversion of 6 into TNAZ (4) was performed according to the known reaction route
represented in Scheme 4. Oxidation of the NO group of 6 with 90% HNO - (CF CO) O gave 1,3-
dinitroazetidine (8) (79% yield), whose sodium nitronate was subjected to the oxidative nitration with
NaNO - K Fe(CN) to obtain TNAZ (4) in 28% yield. We have achieved an improved synthetic method
4
, and 6 was obtained in 26% yield from 2. However, the reaction of 3 with aqueous NaNO
2
- 70%
4
gave inseparable many products.
4
a
3
3
2
2
3
3
for the TNAZ exploiting 1-azabicyclo[1.1.0]butane (3), which must be fairly better than the earlier
procedure.
Scheme 4
NO2
9
0% HNO3
O N
NO2
1) NaOH, 40% MeOH
rt
2
(CF CO) O
3
2
6
CH Cl , rt
2) NaNO , K Fe(CN)
3
N
2
2
N
2
3
Et O-H O (5 : 1)
2
2
NO2
NO2
7
9%
28%
rt
TNAZ
4
8
EXPERIMENTAL
All melting points were measured using a Yanagimoto apparatus and are uncorrected. IR spectra were
1
recorded on a Perkin-Elmer 1720 infrared Fourier transform spectrophotometer. H NMR (200 MHz, 400
1
3
MHz) and C NMR (100 MHz) spectra were taken on a JEOL JNM-FX 200 or JEOL JNM-GSX 400
spectrometer with tetramethylsilane as an internal standard, and chemical shifts are recorded in δ values.
HR-MS (FAB and EI) was measured on a JEOL JMS SX-102A mass spectrometer using a direct inlet
system. Combustion analyses were performed by a Yanagimoto CHN Corder.

1
-Amino-2,3-dibromopropane hydrobromide (2)
To an EtOH (100 mL) solution of Br (40 mL, 785 mmol) was added dropwise allylamine (1) (28 mL,
74 mmol) at 0 °C, and the mixture was stirred at rt for 18 h. The resulting precipitate was filtered off,
2
3
washed with ether, and recrystallized from MeOH. Compound (2) (106 g, 95%) was obtained as colorless
1
prisms. mp 176-180 °C. H NMR (200 MHz, CD OD) δ 3.38 (1H, dd, J = 9.5 and 13.9 Hz), 3.70 (1H, dd,
3
J = 3.2 and 13.9 Hz), 3.94 (1H, dd, J = 8.3 and 11.0 Hz), 4.01 (1H, dd, J = 4.6 and 11.0 Hz), 4.5-4.7 (1H,
-1
3 7 2
m); IR (KBr) 1978, 1591, 1430, 1393, 1225, 1170, 1094, 1054 cm ; HRMS (FAB): Calcd for C H NBr :
+
2
15.9023, Found m/z: 215.9041 ((M+1) ); Anal. Calcd for C
3
H
8
NBr
3
: C, 12.10; H, 2.71; N, 4.70. Found:
C, 12.20; H, 2.67; N, 4.57.
8
THF solution of 1-azabicyclo[1.1.0]butane (3)
A hexane solution of n-BuLi (50.4 mmol) was added dropwise to a suspension of 2 (5.00 g, 16.8 mmol) in
anhydrous THF (50 mL) at -78 °C under argon, and the mixture was stirred at -78 °C for 1 h. Then the
reaction was quenched with 50% KOH and distilled at 80 °C. The resulting THF solution was dried over
K
2
CO
in next reaction. H NMR (400 MHz, THF-d
MHz, THF-d ) δ 17.2, 51.1.
-Chloro-1-nitrosoazetidine (5) and 3-nitro-1-nitrosoazetidine (6)
To a water (3 mL) solution of NaNO (2.0 g, 29.0 mmol) was added a THF solution of 3 (20 mL), and the
3
and filtered. The filtrate was adjusted to the 100 mL volume with THF. This THF solution was used
1
13
8
) δ 0.85 (2H, m), 2.07 (2H, m), 2.29 (1H, m); C NMR (100
8
3
2
mixture was stirred at rt for 20 min. Then, 1N HCl (77 mL, 77 mmol) was added dropwise, and the
mixture was stirred at rt for 3 h. The reaction mixture was extracted with AcOEt, and the extract was
3 4
washed with saturated NaHCO and brine. The organic layer was dried over MgSO and filtered, and the
filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel by
elution with CHCl
3
- acetone (95 : 5). The first chromatography fraction afforded 5 (93 mg, 21% yield
1
based on 2) as a yellow oil. H NMR (200 MHz, CDCl
3
) δ 4.1-4.3 (1H, m), 4.6-4.8 (1H, m), 4.8-5.0 (2H,
3
b 1
m), 5.3-5.5 (1H, m) [lit., H NMR (CDCl
.23-5.34 (1H, m)].
Further elution of the column with CHCl
a pale yellow crystalline solid. mp 77-79 °C (lit., mp 77-78 °C). H NMR (200 MHz, CDCl
2H, d, J = 3.9 Hz), 5.3-5.5 (3H, m).
-Nitrooxy-1-nitrosoazetidine (7)
To a water (3 mL) solution of NaNO
the resulting mixture was stirred at rt for 20 min. Then, concentrated aqueous HNO
was added dropwise, and the mixture was stirred at rt for 3.5 h. The reaction mixture was extracted with
3
) δ 4.07-4.20 (1H, m), 4.50-4.73 (1H, m), 4.78-4.88 (2H, m),
5
3
- acetone (95 : 5) afforded 6 (54 mg, 12% yield based on 2) as
3
a
1
3
) δ 4.59
(
3
2
(2.0 g, 29.0 mmol) was added a THF solution of 3 (20 mL), and
(2.65 mL, 29 mmol)
3

3
AcOEt, and the extract was washed with saturated aqueous NaHCO and brine. The organic layer was
dried over MgSO and filtered, and the filtrate was concentrated in vacuo. The residue was purified by
4
column chromatography on silica gel with CHCl
3
- acetone (95 : 5). Compound (7) (148 mg, 13% yield
) δ 4.18 (1H, ddd, J = 2.2, 3.7
1
based on 2) was obtained as a pale yellow oil. H NMR (200 MHz, CDCl
3
and 13.9 Hz), 4.56 (1H, ddd, J = 2.2, 6.6 and 13.9 Hz), 4.92 (1H, ddd, J = 2.2, 3.7 and 12.2 Hz), 5.30 (1H,
-1
ddd, J = 2.2, 6.6 and 12.2 Hz), 5.5-5.7 (1H, m); IR (neat) 1402, 1376, 1354, 1309, 1121, 1069 cm ;
+
HRMS (EI): Calcd for C
-Nitro-1-nitrosoazetidine (6)
To a water (3 mL) solution of NaNO
the resulting mixture was stirred at rt for 20 min. Then, 1N H
dropwise at –10 °C, and the mixture was stirred for 30 min. The reaction mixture was extracted with
AcOEt, and the extract was washed with saturated NaHCO and brine. The organic layer was dried over
MgSO and filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on a
silica gel column with CHCl - acetone (95 : 5). Compound (6) (113 mg, 26% yield based on 2) was
obtained as a pale yellow crystalline solid.
,3-Dinitroazetidine (8)
To a mixture of trifluoroacetic anhydride (9.3 mL, 66 mmol) and 90% HNO
3
H
5
N
3
O
4
: 147.0280, Found m/e: 147.0285 (M ).
3
2
(2.0 g, 29.0 mmol) was added a THF solution of 3 (20 mL), and
SO (18.4 mL, 9.2 mmol) was added
2
4
3
4
3
1
3
(9.1 mL, 227 mmol) was
added 6 (448 mg, 3.32 mmol) in one portion with stirring at 0 °C. The mixture was stirred at rt for 22 h.
The reaction mixture then was poured over crushed ice, and the resulting aqueous suspension was
extracted with CH
dried over MgSO
silica gel column chromatography with hexane - AcOEt (75 : 25). Compound (8) (429 mg, 79%) was
2
Cl
. The extract was washed with saturated NaHCO and brine. The organic layer was
2 3
4
and filtered, and the filtrate was concentrated in vacuo. The residue was purified by
3
a
1
3
obtained as a white crystalline solid. mp 60-62 °C (lit., mp 62-63 °C). H NMR (200 MHz, CDCl )
δ 4.7-5.0 (4H, m), 5.1-5.3 (1H, m).
1
,3,3-Trinitroazetidine (4)
To a solution of NaOH (32 mg, 0.80 mmol) in 40% aqueous MeOH (9.0 mL) was added 8 (100 mg,
.613 mmol) with stirring, and the solution was stirred at rt for 30 min. This solution was added rapidly
with stirring to a mixture of K Fe(CN) (1.04 g, 3.16 mmol), NaNO (440 mg, 6.48 mmol), water (10
mL), and Et O (50 mL). After stirring at rt for 30 min, the organic layer was separated, and the aqueous
layer was extracted with CH Cl . The combined organic extract was washed with water and brine, and
dried over MgSO . After filtration, the filtrate was concentrated in vacuo to give an oily residue, which
was purified by preparative TLC with CH Cl . Pure compound (4) (35 mg, 28%) was obtained as
colorless needles. mp 95-97 °C (lit., mp 98-99 °C). H NMR (200 MHz, CDCl
0
3
6
2
2
2
2
4
2
2
3
a
1
3a
3
) δ 5.21 (4H, s) [lit.,

1
H NMR (CDCl ) δ 5.20 (4H, s)].
3
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4
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8
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4
a,b
. Earlier similar method for the preparation of 6 using 3 resulted in the 1% and 5.5% yield.