Mannich-type reaction for synthesis of 3-methyl-4-nitroimino-tetrahydro-1, 3,5-oxadiazine

Article abstract of DOI:10.1080/00397911.2010.550705

The reaction of N-methyl-N-nitroguanidine with 3-methyl-4-nitroimino- tetrahydro-1,3,5-oxadiazine is a Mannich-type reaction. The reaction was catalyzed by several organic and inorganic bases at different reaction times and temperatures. Three inorganic base catalysts [potassium carbonate (K ₂CO₃), sodium hydrogen carbonate (NaHCO₃), and sodium hydroxide (NaOH)] and several organic bases (methylamine, ethamine, iso-propylamine, and n-butylamine) have been studied. The results showed that both the inorganic and organic base catalysts can be used as catalysts, with the organic bases performing better. N-Methyl-N′-nitroguanidine reacts to give the title compound 2 and is catalyzed by both acids and bases. The intensity of inorganic base catalysts, reaction temperature, and reaction time had significant effects on the products.

Full text of DOI:10.1080/00397911.2010.550705

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Mannich-Type Reaction for Synthesis of
3-Methyl-4-nitroimino-tetrahydro-1,3,5-
oxadiazine
a
a
a
a
Wen-Yan Qu , Dong-Mei She , Jian Zhao , De-Jie Lin , Qi-Liang
a
a
Huang & Feng-Min Li
a
Key Laboratory of Pesticide Chemistry and Application, MOA, Plant
Protection Institute of Chinese Academy of Agricultural Sciences,
Beijing, China
Accepted author version posted online: 27 Oct 2011.Version of
record first published: 26 Mar 2012.
To cite this article: Wen-Yan Qu, Dong-Mei She, Jian Zhao, De-Jie Lin, Qi-Liang Huang & Feng-Min Li
(2012): Mannich-Type Reaction for Synthesis of 3-Methyl-4-nitroimino-tetrahydro-1,3,5-oxadiazine,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:13, 1950-1958
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1
Synthetic Communications , 42: 1950–1958, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.550705
MANNICH-TYPE REACTION FOR SYNTHESIS OF
-METHYL-4-NITROIMINO-TETRAHYDRO-1,3,5-
OXADIAZINE
3
Wen-Yan Qu, Dong-Mei She, Jian Zhao, De-Jie Lin,
Qi-Liang Huang, and Feng-Min Li
Key Laboratory of Pesticide Chemistry and Application, MOA, Plant
Protection Institute of Chinese Academy of Agricultural Sciences,
Beijing, China
GRAPHICAL ABSTRACT
0
Abstract The reaction of N-methyl-N -nitroguanidine with 3-methyl-4-nitroimino-
tetrahydro-1,3,5-oxadiazine is a Mannich-type reaction. The reaction was catalyzed
by several organic and inorganic bases at different reaction times and temperatures. Three
2 3
inorganic base catalysts [potassium carbonate (K CO ), sodium hydrogen carbonate
(
ethamine, iso-propylamine, and n-butylamine) have been studied. The results showed that
NaHCO ), and sodium hydroxide (NaOH)] and several organic bases (methylamine,
3
both the inorganic and organic base catalysts can be used as catalysts, with the organic
0
bases performing better. N-Methyl-N -nitroguanidine reacts to give the title compound 2
and is catalyzed by both acids and bases. The intensity of inorganic base catalysts, reaction
temperature, and reaction time had significant effects on the products.
Keywords Formaldehyde; Mannich reaction; 3-methyl-4-nitroimino-tetrahydro-1,3,5-
oxadiazine; N-(1,5-dimethyl-1,3,5-triazinan-2-ylidene)nitramide; N-(5-ethyl-1-methyl-
0
1
,3,5-triazinan-2-ylidene)nitramide; N-methyl-N -nitroguanidine
Received September 11, 2010.
Address correspondence to Dong-Mei She, Key Laboratory of Pesticide Chemistry and
Application, MOA, Plant Protection Institute of Chinese Academy of Agricultural Sciences,
Yuanmingyuan West Road No. 2, Beijing 100193, China. E-mail: dmshe2000@yahoo.com.cn
1
950

3
-METHYL-4-NITROIMINO-TETRAHYDRO-1,3,5-OXADIAZINE
1951
INTRODUCTION
The Mannich reaction, which was developed early last century, is also known
[
1,2]
as the amine methylation reaction (aminomethlylation)
and been widely used in
the synthesis of alkaloids (e.g., tropinone) and medicine (e.g., fluxetine, tramadol,
and tolmetin). Commonly, the Mannich reaction has three components: amine, for-
maldehyde, and compound with least one active hydrogen for the condensation pro-
cess (Scheme 1). Different from the general Mannich reaction, the reaction of
0
N-methyl- N -nitroguanidine (compound 1) with 3-methyl-4-nitroimino-
tetrahydro-1,3,5-oxadiazine (compound 2) is a two-component process; the formal-
dehyde is played as aldehyde and compound 1 is played as an active hydrogen com-
pound (Scheme 2).
[
3–6]
The Mannich reaction can be catalyzed either by acid or alkali.
The
acid-catalyzed reaction usually utilizes protic solvents such as methanol, water, and
acetic acid. The Mannich reaction of N-methyl-N’-nitroguanidine (compound 1) has
been widely used in pharmaceuticals, pesticides, military applications, and other
[
7]
synthetic fields, especially in the synthesis of agrochemicals.
-Methyl-4-nitroimino-tetrahydro-1,3,5-oxadiazine (compound 2), N-(1,5-
3
dimethyl-1,3,5-triazinan-2-ylidene)nitramide (compound 3a), and N-(5-ethyl-1-
methyl-1,3,5-triazinan-2-ylidene)nitramide (compound 3b) are the major products
of the Mannich reaction of 1, in which compound 2 is one of the most important
intermediates in synthetic pesticides. In many reports, the major catalysts used for
the transformation were acids, for example hydrochloric acid, trifluoroacetic acid,
glacial acetic acid, and formic acid, which have been studied by Maienfisch
[
7–9]
[10]
[11]
[12]
[13]
[14]
et al.,
Gobel et al., Fan et al.,
Kang et al.,
Zhou et al.,
Tao et al.,
Scheme 1. Mannich reaction general formula.
0
Scheme 2. Mannich reaction of N-methyl-N -nitroguanidine in organic and inorganic bases.

1952
W.-Y. QU ET AL.
[
15]
[16]
Yang et al., and Metelkina. They also discovered that the reaction catalyzed by
formic acid gave the most satisfactory results. The reaction of N-methyl-
0
N -nitroguanidine (compound 1) and formaldehyde in amine solution was men-
tioned by Maienfisch et al.
[17]
However, these data were not reported by our labratory. Potassium carbonate
K CO ), sodium bicarbonate (NaHCO ), and sodium hydroxide (NaOH) have not
(
2
3
3
been employed as catalysts for the Mannich reaction of 1. In this communication, we
report the synthesis of 2 using the three inorganic basic catalysts mentioned pre-
viously for the first time and the synthesis of 3 in methylamine, ethamine, isopropy-
lamine, and n-butylamine aqueous solution. We also explored the formation of
products at the different reaction temperatures and times under the inorganic base
catalyst conditions.
RESULTS AND DISCUSSION
Product of reaction of 1 with formaldehyde is different when using different
catalysts. For example, when using NaOH, only compound 3a was detected, but
both compound 2 and compound 3a were formed when NaHCO and K CO were
3
2
3
used (Scheme 3). This phenomenon may due to the intensity of base catalysts. When
the inorganic bases were not added to the reaction mixture, compounds 2 and 3a
were not detected. The appearance of 3a after the inorganic bases were added to
the reaction mixtures may be result from the decomposition of 1 in the alkali con-
ditions, especially in the high-intensity alkali conditions. The synthesis of 2 may
be more suitable in an appropriate alkali condition, and the detailed mechanism is
shown in Scheme 4.
0
ꢀ
Scheme 3. Reaction of N-methyl-N -nitroguanidine in different catalysts under 60 C condition.

3
-METHYL-4-NITROIMINO-TETRAHYDRO-1,3,5-OXADIAZINE
1953
0
Scheme 4. Mechanism of compound 2 from N-methyl-N -nitroguanidine.
The reaction of 1 and formaldehyde in organic base aqueous solutions such as
methylamine, ethamine, isopropylamine, and n-butylamine also gave good yields
with high purities.
The reaction conditions, results, and the yields of compounds 2 and 3 are given
in Tables 1 and 2. In the inorganic base reaction, product was transformed into com-
pound 3a from the mixtures of 2 and 3a when the reaction time was kept for 8 h, and
ꢀ
the temperature was increased gradually from 40 to 90 C. This phenomena was also
ꢀ
observed when the reaction temperature was kept at 60 C but the reaction times
were changed from 2 to 12 h. The yields of compounds 2 and 3 under the conditions
described above are shown in Table 3. When HCl, HCOOH, CH COOH, and
3
F CCOOH and were employed in our work, no title compound was detected.
3
[
18,19]
The three-component Mannich reaction mechanism
and 6.
is given in Schemes 5
Through the three-component Mannich reaction mechanism, both acid and
alkaline catalysts can be used to promote reactions, and both formed enolase tran-
sition states (Schemes 5 and 6). In the two-component (1 and formaldehyde) Man-
nich reaction process, no enolate transition-state compound was found. No title
compound was detected in our laboratory when the acidic catalysts formic acid,
acetic acid, hydrochloric acid, and trifluoroacetate were added to the mixtures (pH
ꢀ
1
solution to pH 6–7. The results were different from the literature reports.
–5), reacted for several hours at 90 C, and neutralized with 10% sodium hydroxide
7–16]
[
Otherwise, when alkaline catalyst instead of acidic catalyst was added, the reaction
Table 1. Final compound affected by different temperature under the catalyst conditions
(reaction time 8 h)
ꢀ
Entry
Temperature ( C)
NaHCO
3
NaOH
2 3
K CO
a
b
1
2
3
4
5
6
40
50
60
70
80
90
3a þ 2
3a
3a þ 2
3a þ 2
3a þ 2
3a þ 2
3a
3a þ 2
3a þ 2
3a þ 2
3a
3a
3a
3a
3a
3a
3a
3a
a
Both compounds 3a and 2 were detected.
Only compound 3a was detected.
b

1954
W.-Y. QU ET AL.
Table 2. Final compound affected by different reaction times under the catalyst
ꢀ
conditions (temperature 60 C)
Entry
Reaction time
NaHCO
3
NaOH
2 3
K CO
a
b
1
2
3
4
5
6
7
8
2 h
4 h
3a þ 2
3a
3a þ 2
3a þ 2
3a þ 2
3a þ 2
3a þ 2
3a
3a þ 2
3a þ 2
3a þ 2
3a þ 2
3a
3a
3a
3a
3a
3a
3a
3a
6 h
8 h
10 h
12 h
15 h
20 h
3a
3a
3a
3a
a
Both compounds 3a and 2 were detected.
Only compound 3a was detected.
b
Table 3. Yields of title compounds
ꢀ
Entry
Base
Reaction time (h) Reaction temperature ( C) Yield (%)
a
b
b
1
2
3
4
5
6
7
NaHCO
NaOH
3
6
6
6
5
5
5
5
60
60
60
60
60
60
60
33.7, 37.8
a
53.2
48.3, 29.7
a
K
2
CO
NH
3
c
CH
3
2
92.7
c
C
(CH
2
H
5
NH
2
89.6
c
3
)
2
CH
2
NH
2
91.5
c
n-C
4
H
9
NH
2
87.3
a
Yield of isolated compound 3a.
Yield of isolated compound 2.
Yield of isolated compound 3.
b
c
proceed well. Meanwhile, the change of the products was also explored under the
conditions shown in Tables 1 and 2. The compound 2 disappeared as temperature
ꢀ
ꢀ
increased from 40 C to 90 C gradually and reaction time prolonged from 2 h to
0 h. Therefore, during the two-component (1 and formaldehyde) Mannich reaction,
the activity of H of compound 1 was decreased under acidic conditions and increased
2
Scheme 5. Mannich reaction under acidic conditions.

3
-METHYL-4-NITROIMINO-TETRAHYDRO-1,3,5-OXADIAZINE
1955
Scheme 6. Mannich reaction under basic conditions.
under basic conditions, which makes it difficult to react in acidic solution and easy to
react in basic solution.
CONCLUSION
In conclusion, this work demonstrates a method for synthesizing 2, 3a, 3b, 3c,
and 3d under basic conditions. The Mannich reaction of 1 and formaldehyde
solution (or paraformaldehyde) can be catalyzed by alkaline catalyst but not acidic
catalyst. Both organic and inorganic bases worked well in this reaction, but organic
bases are better. The intensity of inorganic alkali, reaction time, and reaction tem-
perature have great effects on the final products; high temperatures or long reaction
times will cause compound 2 to be hydrolyzed.
EXPERIMENTAL
All purchased starting materials and reagents were used without further
1
purification. H NMR spectra were recorded on a DRX-300 FT-NMR Bruker
instrument. Chemical shifts are expressed in parts per million (ppm, d). Splitting pat-
terns describe apparent multiplicities and are designated as s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), or br s (broad singlet). Mass spectra (MS,
electrospray ionization positive) were recorded on an Apex IV FTMS Bruker instru-
ment. Infrared (IR) spectra were recorded on a Nicolet 6700 FT-IR Thermo instru-
ment. Ultraviolet (UV) spectra were recorded on an UV-1800 Shimadzu
spectrophotometer.
[20,21]
Preparation of N-Methyl-n’-nitroguanidine (Compound 1)
ꢀ
Nitroguanidine (40.2 g, 0.39 mol) was dissolved in water (50 ml) at 60 C, and
then methylamine aqueous solution (58.1 g, 0.47 mol, 25% in water) was added to
the solution over 30 min. The evolution of ammonia was observed, and the solutiion
was stirred for 20 min. At the end of this time, during which the reaction mixture was
ꢀ
stirred continuously, the clear solution was cooled in an ice-water bath to 4 C. The
white precipitation was filtered off, washed with cold water to neutral, and dried in
ꢀ
the vacuum oven at 60 C for 3 h to afford 38.6 g.
Data for Compound 1
N-Methyl-N’-nitroguanidine (1). Yield 84.6%; white solid; mp 155–
[22]
ꢀ
1
1
56 C.
MS m=z 118.1; H NMR (300 MHz, DMSO-d ) d 2.75 (d, J ¼ 6 Hz, 3H,
6

1956
W.-Y. QU ET AL.
CH ), 7.82 (br s, 2H, NH ), 8.57 (br s, 1H, NH); IR 3418.20, 3252.28, 3112.44,
3
2
ꢁ
1
642.68, 1605.35, 1294.01, 1142.08, 594.93 cm ; UV 267.80 nm.
1
Preparation of 3-Methyl-4-nitroimino-tetrahydro-1,3,5-oxadiazine
(Compound 2)
0
A mixture of N-methyl-N -nitroguanidine (4.58 g, 0.039 mol) and sodium
ꢀ
hydrogen carbonate (3.28 g, 0.039 mol) in 50 ml of water was stirred at 60 C. After
0
N-methyl-N -nitroguanidine was dissolved, formaldehyde aqueous solution (7.27 g,
ꢀ
0
.09 mol, 37% in water) was added. The mixture was stirred for 4–6 h at 60 C. After
this period, the reaction was extracted with dichloromethane, and the combined
organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated
followed by column chromatography (eluted with dichloromethane–acetonitrile
ꢀ
5
:2) to afford 2.35 g, dried in the vacuum oven at 60 C for 3 h.
ꢀ
1
Data for compound 2. Yield 37.8%; white solid; mp 143–144 C; MS m=z
[22]
1
(
61.06650 (M þ H), 183.04850 (M þ Na), 199.02246 (M þ K); H NMR
300 MHz, CDCl ) d 3.03 (s, 3H, CH ), 4.87 (s, 2H, CH ), 5.01 (d, J ¼ 3 Hz, 2H,
3
3
2
CH ), 9.70 (br s, 1H, NH); IR 3314.36, 2942.94, 2890.16, 1600.76, 1544.51,
2
ꢁ
1
300.80, 940.14, 625.21, 602.79 cm ; UV 273.4 nm.
1
Preparation of N-(5-Ethyl-1-methyl-1,3,5-triazinan-2-
ylidene)nitramide (Compound 3b)
0
N-Methyl-N -nitroguanidine (2.0 g, 0.017 mol) was dissolved in water (8 ml) at
0 C, and then formaldehyde aqueous solution (3.16 g, 0.039 mol, 37% in water) and
ꢀ
6
ethamine aqueous solution (1.25 g, 0.018 mol, 65% in water) were added to the
solution over 10 min. The mixture was stirred for 5 h at 60 C. After this period,
the reaction was extracted with dichloromethane, and the combined organic layers
ꢀ
were dried over anhydrous sodium sulfate, filtered, and evaporated to afford
ꢀ
2
.84 g, which were dried in the vacuum oven at 30 C for 3 h.
The compounds 3a, 3c, and 3d were synthesized according to the method of 3b.
Data for Compounds 3a–3d
N-(1,5-Dimethyl-1,3,5-triazinan-2-ylidene)nitramide
ꢀ
(compound
. Yield 92.7%; white solid; mp 127–128 C; MS m=z 174.09822 (M þ H),
[23–25]
3
1
3
a)
1
96.08013 (M þ Na), 212.05409 (M þ K); H NMR (300 MHz, CDCl ) d 2.62 (s,
3
H, CH ), 3.03 (s, 3H, CH ), 4.25 (s, 2H, CH ), 4.35 (s, 2H, CH ), 9.51 (br s, 1H,
2
3
3
2
NH); IR 3421.61, 3318.27, 3291.97, 2932.96, 1597.36, 1540.69, 1380.57, 996.52,
6
ꢁ
1
26.87 cm ; UV 273.8 nm.
N-(5-Ethyl-1-methyl-1,3,5-triazinan-2-ylidene)nitramide
ꢀ
(compound
[26]
3
2
b) . Yield 89.6%; white solid; mp 105–106 C; MS m=z 188.11383 (M þ H),
1
10.09579 (M þ Na), 226.06973 (M þ K); H NMR (300 MHz, CDCl ) d 1.07 (t,
3 2 3
3
J ¼ 3 Hz, 3H, CH ), 2.73 (q, J ¼ 9 Hz, 2H, CH ), 2.94 (s, 3H, CH ), 4.25 (s, 2H,
CH ), 4.35 (s, 2H, CH ), 9.36 (br s, 1H, NH); IR 3318.02, 2967.68, 2935.46,
2
2
ꢁ
1
875.62, 1599.91, 1540.73, 1361.59, 995.49, and 634.35 cm ; UV 274.4 nm.
2

3
-METHYL-4-NITROIMINO-TETRAHYDRO-1,3,5-OXADIAZINE
1957
N-(5-Iso-propyl-1-methyl-1,3,5-triazinan-2-ylidene)nitramide (compound
ꢀ
[
27]
3
2
c) . Yield 91.5%; white solid; mp 152–153 C; MS m=z 202.12959 (M þ H),
1
24.11147 (M þ Na), 240.08532 (M þ K); H NMR (300 MHz, CDCl ) d 1.17 (d,
3 3 3
3
J ¼ 6 Hz, 6H, CH , CH ), 3.02 (s, 3H, CH ), 3.07–3.16 (m, H, CH), 4.38 (s, 2H,
CH ), 4.48 (d, J ¼ 1.2 Hz, 2H, CH ), 9.45 (br s, 1H, NH); IR 3341.29, 2980.33,
2
2
2927.98, 2878.12, 2843.21, 1604.43, 1552.59, 1378.08, 1336.27, 1176.15, 1049.45,
and 641.83 cm ; UV 274.3 nm.
ꢁ
1
N-(5-Butyl-1-methyl-1,3,5-triazinan-2-ylidene)nitramide
(compound
3
d). Yield 87.3%; yellow thick liquid; MS m=z 216.14522 (M þ H), 238.12707
1
(
3
M þ Na), 254.10109 (M þ K); H NMR (300 MHz, CDCl ) d 0.94 (t, J ¼ 6 Hz,
3
H, CH ), 1.34–1.45 (m, 2H, CH ), 1.46–1.54 (m, 2H, CH ), 2.73 (t, J ¼ 7 Hz, 2H,
2 3 2 2
3 2 2
CH ), 3.01 (s, 3H, CH ), 4.29 (s, 2H, CH ), 4.38 (d, J ¼ 1.2 Hz, 2H, CH ), 9.45 (br
s, 1H, NH); IR 3332.38, 2963.56, 2924.17, 2880.61, 2861.34, 2830.75, 1601.01,
1
ꢁ
1
554.19, 1378.90, 1331.46, 1190.30, 629.36 cm ; UV 274.6 nm.
ACKNOWLEDGMENT
We are grateful to the ‘‘Nonprofit Industry-Specific (Agriculture)’’ Technology
Support Project of China (No. 200903054) for financial support.
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