Convenient preparation of 3,6-dialkyl-1,6-dihydro-s-tetrazines

Article abstract of DOI:10.1081/SCC-120022164

1,6-Dihydro-s-tetrazines such as 1, with a large variety of substituents in the 3- and 6-position of the heterocycle, have been synthesized, and due to their homoaromaticities and their potential reactivities, have aroused more and more interests (Sauer, J. 1,2,4,5-Tetrazines. In Comprehensive Heterocyclic Chemistry II; Boultou, A.J., Ed.; Elsevier: Oxford, UK, 1996; Vol. 6, 901; Neunhoeffer, H. In Comprehensive Heterocyclic Chemistry I; Katritzky, A., Ed.; Pergamon Press Ltd.: Federal Republic of Germany, 1984; Vol. 3, 545).

Full text of DOI:10.1081/SCC-120022164

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Convenient Preparation of 3,6-Dialkyl-1,6-dihydro-s-
tetrazines
Yaquan Sun a , Weixiao Hu a & Qing Yuan a
a Institute of Pharmaceutical Engineering , Zhejiang University of Technology , Hangzhou,
P.R. China
Published online: 19 Aug 2006.
To cite this article: Yaquan Sun , Weixiao Hu & Qing Yuan (2003) Convenient Preparation of 3,6-Dialkyl-1,6-dihydro-s-
tetrazines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:16, 2769-2775, DOI: 10.1081/SCC-120022164
To link to this article: http://dx.doi.org/10.1081/SCC-120022164
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 16, pp. 2769–2775, 2003
Convenient Preparation of
3,6-Dialkyl-1,6-dihydro-s-tetrazines
*
Yaquan Sun, Weixiao Hu, and Qing Yuan
Institute of Pharmaceutical Engineering, Zhejiang
University of Technology, Hangzhou, P.R. China
ABSTRACT
1,6-Dihydro-s-tetrazines such as 1, with a large variety of substi-
tuents in the 3- and 6-position of the heterocycle, have been synthe-
sized, and due to their homoaromaticities and their potential
reactivities, have aroused more and more interests (Sauer, J. 1,2,4,5-
Tetrazines. In Comprehensive Heterocyclic Chemistry II; Boultou,
A.J., Ed.; Elsevier: Oxford, UK, 1996; Vol. 6, 901; Neunhoeffer, H.
In Comprehensive Heterocyclic Chemistry I; Katritzky, A., Ed.;
Pergamon Press Ltd.: Federal Republic of Germany, 1984;
Vol. 3, 545).
*Correspondence: Weixiao Hu, Institute of Pharmaceutical Engineering,
Zhejiang University of Technology, Hangzhou 310014, P.R. China; Fax:
86-571-851331999; E-mail: Huyang@mail.Hz.Zj.cn.
2769
DOI: 10.1081/SCC-120022164
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2770
Sun, Hu, and Yuan
R
R
R
R
H
(5)
N
NH
N
N
N
NH
NH
N
NH
NH
N
HN
P
t
O
2
/
O
R
H
O
g
(3)
O
aN
N
R
H
2
2
R
R
R
H
R
H
HNO2
HN
HN
NH
NH
N
NH
N
N
N
N
N
N
PtO2/O2
NaBH4
R
H
(1)
(2)
(4)
R
Figure 1. The formation of 1,6-dihydro-s-tetrazine.
In the Lit.,[1–8] 1,6-dihydro-s-tetrazines can be obtained as follows
(Fig. 1).
However, as is also known for many other heterocycles, the prepara-
tion of the parent compound such as 5, is often accompanied by various
synthetic obstacles.[1] So the method (A), which 5 is the starting materials,
is inconvenient, because these compounds can be obtained by a multistep
procedure involving some low-yielding steps. But another method (B), in
which the starting materials is (2) or (3), is also impractical, because PtO2
is very expensive. Compared with method A, the procedure of the
method B is shorter. It will be better if a new and cheaper catalyst
would be adopted in place of PtO2.
Using 3,6-dimethyl-1,6-dihydro-s-tetrazine as starting material in our
laboratory, 3,6-dimethyl-1,4-dihydro-s-tetrazine derivatives which have
strong anticancer activities have been prepared.[9] So it was expected to
prepare the 3,6-dialkyl-1,6-dihydro-s-tetrazinein large quantity with
cheaper and convenient method.
To our knowledge, Pd/C is often used as hydrogenation catalyst and
seldom used in dehydrogenation process. According to the theory of
microscopic reversibility, Pd/C may catalyze the dehydrogenation process.
Herein we wish to report that Pd/C, which is in place of PtO2, can
catalyze the dehydrogenation of (2) or (3) to yield 1,6-dihydro-s-tetra-
zines. The following procedure (Fig. 2) is adapted.
RESULTS AND DISCUSSION
Synthesis of 3,6-Dialkyl-hexahydro-s-tetrazines (2)
3,6-Dialkyl-hexahydro-s-tetrazines (2) can be synthesized from
commercially available starting materials aldehyde and hydrazine

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3,6-Dialkyl-1,6-dihydro-s-tetrazines
2771
R
H
H
R
N
N H
H N
H N
N H
N H
N H 2N H 2 H 2
O
O 2
R C H O
N
N
Pd/C
H
R
(1)
R
(2)
Figure 2. The route to prepare 1,6-dihydro-s-tetrazine (1).
H
R
R
N H 2N H 2 H 2
O
N
C
N H 2N H 2 H 2
O
H
H N
H N
N H
N H
R C H O
H
C
N
R
H
R
Figure 3. The mechanism of forming 3,6-dialkyl-hexahydro-s-tetrazines.
hydrate. The procedure had been published by Skorianetz and
Kovats.[4–6] The formation of the hexahydro-s-tetrazine ring system
accompanying a few side-reaction involves several condensation and
cycloaddition steps. As to the mechanism, there is a dispute. It was
supposed that hydrazone is the intermediate in the reaction. Using
13C NMR, the mechanistic investigations of the reaction between acet-
ylaldehyde and hydrazine hydrate were undertaken by Chudek et al.,[10]
the mainly intermediate formation of azine is beyond doubt. The reac-
tion between butyraldehyde and hydrazine hydrate was traced by
HPLC in this work. When hydrazine hydrate was dropwised into butyr-
aldehyde, it appears a new peak at 10.5 min, just the same position as
azine, which is prepared referring to Chudek et al.[10] This peak grew
the main until the molar ratio of hydrazine hydrate and butyraldehyde
is 1:2. When hydrazine hydrate was continually added, the peak at
10.5 min become smaller and smaller and till disappear. Meanwhile a
new peak, stands for hexahydro-s-tetrazine, appears at 3.8 min and
becomes bigger and bigger. So the mechanism can be described as
follows (Fig. 3).
This correspondence to the results reported by Chudek et al.[10]
In order to raise the yields, keeping the reaction mixture in
low temperature for long time is accessible. Because hydrazone
is one kind of by-products, it could be converted into hexahydro-s-
tetrazine in low temperature. The results of the reaction are described
in Table 1.
In addition, it was found that 3,6-diaryl-hexahydro-s-tetrazines
cannot be synthesized according to this method.

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2772
Sun, Hu, and Yuan

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3,6-Dialkyl-1,6-dihydro-s-tetrazines
Table 2. The results of 1,6-dihydro-s-tetrazines.
2773
Entry
R
Yielda (%) (lit.[5]
)
Time (h)
M.p. (ꢀC) (lit.[5]
)
1a
1b
1c
Me
Et
35 (65)
48.6 (54)
43.6 (77)
40
42
42
107–108 (107–108)
41–43 (43–44)
71–72 (73–74)
n-Pr
aIsolated yield according to hexahydro-s-tetrazine.
Oxidation of Hexahydro-s-tetrazines (2)
to 1,6-Dihydro-s-tetrazines (1)
Using 5% Pd/C replacing PtO2 as oxidation catalyst, it is an avail-
able access to obtain the compounds (1) in moderate yields. The results of
oxidation are listed in Table 2.
Although the yields are comparatively lower than those in literature,
we still propose that this method is very useful because the price of Pd/C
is very cheaper than the one of PtO2. So it can be affirmed that this
optimized procedure allows the preparation of 1,6-dihydro-s-tetrazines
in low expensive. In the present work, three compounds of 1,6-dihy-
dro-s-tetrazine can be obtained. Attempted oxidation of 3,6-di-n-butyl-
hexahydro-s-tetrazine in the above method failed to give detectable
amounts of 3,6-di-n-butyl-1,6-dihydro-s-tetrazine. The possible reason
may lie in which 3,6-di-n-butyl-hexahydro-s-tetrazine is not able to
dissolve in sodium hydroxide solution. In the process of the oxidation
reaction, the optimized temperature is 5–10ꢀC. The mechanism of this
reaction is still being studied.
EXPERIMENTAL SECTION
General Remarks
Infrared spectra were recorded from KBr dics on a NicolexFI-IR-170
1
instrument. H NMR spectra were run on a Brucker AC 400 (400 MHz)
spectrometer using TMS as internal standard and CDCl3 as the solvent.
Mass spectra were obtained on a HP5989A spectrometer at an ionizing
voltage of 70 eV by electron impact. Melting points were carried on
XRC-1 apparatus and uncorrected. The reactions are traced by HPLC
(CLASS-LC10), which the operation conditions are followed as: C18

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2774
Sun, Hu, and Yuan
inverse phase column, CH3CN:H2O ¼ 9:1 as flow phase, the rate of flow
0.5 mL sꢁ1, UV detector maximum wave length 254 nm. Acetaldehyde
was depolymerizated from (CH3CHO)3 according to the published
procedure. The others are commercially available and were distilled
prior to use.
Hexahydro-s-tetrazine (2) (take 2a example). Acetaldehyde (53 mL,
0.9 mol) was placed in a 250 mL flask equipped with a mechanical stirrer,
pressure-equalizing dropping funnel, and a thermometer. At 0–5ꢀC, 85%
hydrazine hydrate (54 mL, 0.9 mol) and EtOH (15 mL) was then added
dropwise with stirring. The reaction mixture was allowed to keep at
ꢁ5–0ꢀC for 10 h after the mixture of hydrazine hydrate and EtOH was
added over. Then the mixture was filtered off with suction and the
product was dried in vacuum.
1,6-Dihydro-s-tetrazine (1) (take 1a example). 2a (R¼CH3) (0.5 mol)
were placed in a 500 mL four-inner flask equipped with a mechanical
stirrer, a thermometer, and two capillaries. The solution of sodium
hydroxide (300 mL, 3%) and 5% Pd/C (1.5 g) was added with stirring.
Oxygen was hubbled into the mixture for 40 h. The reaction mixture
was filtered off with suction, saturated with ammonium chloride, and
extracted with ether (5 Â 70 mL), and dried with Na2SO4. After removal
of the drying agent, the yellow solution was concentrated carefully
at atmosphere pressure to dryness and afforded 1a as bright yellow
crystals.
The Data of Compounds 1
1a. IR (KBr, cmꢁ1): 3135, 2975, 2950, 2915, 1536, 1451, 1393, 1349,
1
1329, 1222, 1136, 1078, 1042, 988, 949, 901, 748, 721, 678. H NMR
(CDCl3): 1.94 (d, 3H, J ¼ 6.0 Hz), 2.13 (q, 1H, J ¼ 6.0 Hz), 2.49 (s, 3H),
5.46 (b, 1H).
1b. IR (KBr, cmꢁ1): 3140, 2975, 2945, 2850, 1470, 1380, 1250, 1162,
1
1131, 1066, 1046, 980, 961, 880, 742, 682, 639, 540. HNMR (CDCl3):
1.25 (t, 3H, J ¼ 7.6 Hz), 1.31 (t, 3H, J ¼ 7.1 Hz), 1.99 (t, 1H, J ¼ 2.0 Hz),
2.28–2.32 (m, 2H), 2.85 (q, 2H, J ¼ 7.8 Hz), 4.43 (b, 1H). MS m/z (%):
141 (M þ 1, 11), 83 (7), 71 (4), 58 (18), 57 (20), 56 (100), 54 (11), 52 (4).
1c. IR (KBr, cmꢁ1): 3144, 2960, 2943, 2870, 1455, 1401, 1375, 1350,
1
1221, 1130, 1026, 972, 914, 749, 693, 638, 585, 522. H NMR (CDCl3):
0.97 (t, 3H, J ¼ 7.4 Hz), 1.09 (t, 3H, J ¼ 7.4 Hz), 1.67–1.72 (m, 2H),
1.77–1.82 (m, 2H), 2.03 (t, 1H, J ¼ 6.0 Hz), 2.21–2.27 (m, 2H), 2.80 (t,
2H, J ¼ 7.5 Hz), 4.57 (b, 1H). MS m/z (%): 169 (M þ 1, 4), 97 (13), 72
(11), 71 (11), 70 (82), 56 (100), 55 (8), 54 (10).

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3,6-Dialkyl-1,6-dihydro-s-tetrazines
ACKNOWLEDGMENT
2775
We are indebted to Zhejiang Province Natural Foundation (No.
200016), Zhejiang Province Science and Technology Bureau (011101937)
and National Natural Foundation (20272053) for financial support of
this research.
REFERENCES
1. Sauer, J. 1,2,4,5-Tetrazines. Comprehensive Heterocyclic Chemistry
II; Boultou, A.J., Ed.; Elsevier: Oxford, UK, 1996; Vol. 6, 901.
2. Neunhoeffer, H. Comprehensive Heterocyclic Chemistry I;
Katritzky, A., Ed.; Pergamon Press Ltd.: Federal Republic of
Germany, 1984; Vol. 3, 545.
3. Marcelis, A.T.M.; Ver der Plas, H.C. J. Heterocyclic Chem. 1987,
24, 545.
4. Skorianetz, W.; Kovats, E.S. Helv. Chim. Acta 1970, 53 (2), 251.
5. Skorianetz, W.; Kovats, E.S. Helv. Chim. Acta 1971, 54 (7), 1922.
6. Skorianetz, W.; Kovats, E.S. Helv. Chim. Acta 1972, 55 (5), 1404.
7. Sauer, J.; Heldmann, D.K.; Hetzenegger, J.; Krauthan, J.;
Sichert, H.; Schuster, J. Eur. J. Org. Chem. 1998, 2885.
8. Counotte-Potman, A.; Ver der Plas, H.C.; Van Veldhuizen, B.
J. Org. Chem. 1981, 46, 2138.
9. Cai, Z.-B.; Zhou, M.; Hu, W.-X; Yang, Z.-Y. Acta. Pharmaceutica
Sinic. 2000, 35 (10), 793 ( in Chinese).
10. Chudek, J.A.; Foster, R.; Young, D. J. Chem. Soc. Perkin Trans. II
1985, 1285.
Received in Japan September 21, 2002

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