N-alkylation of unsymmetrical 1,6-dihydro-1,2,4,5-tetrazine under alkali condition

Article abstract of DOI:10.1080/00397911.2010.518272

6-Methyl-3-phenyl-1,6-dihydro-1,2,4,5-tetrazine was stable in alkali solution at room temperature and decomposed gradually to form 1,2-dibenzylidenehydrazine. The plausible mechanism of the reaction is discussed. Because it was stable for a period of time, a convenient and effective method for synthesis of 1-alkyl-1,6-dihydro-1,2,4,5-tetrazines has been developed. The starting 1,6-dihydro-1,2,4,5-tetrazine can be alkylated with alkyl halides in methanol and lithium hydroxide monohydrate as a base at room temperature.

Full text of DOI:10.1080/00397911.2010.518272

This article was downloaded by: [University of New Brunswick]
On: 18 June 2014, At: 05:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
N-Alkylation of Unsymmetrical 1,6-
Dihydro-1,2,4,5-tetrazine Under Alkali
Condition
Feng Xu a , Zhen-Zhen Yang a , Shi-Jie Zhang b & Wei-Xiao Hu b
a Biological and Chemical Engineering Department , Taizhou
Vocational and Technical College , Taizhou , China
b College of Pharmaceutical Science , Zhejiang University of
Technology , Hangzhou , China
Published online: 26 Jul 2011.
To cite this article: Feng Xu , Zhen-Zhen Yang , Shi-Jie Zhang & Wei-Xiao Hu (2011) N-Alkylation of
Unsymmetrical 1,6-Dihydro-1,2,4,5-tetrazine Under Alkali Condition, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:22, 3367-3375,
DOI: 10.1080/00397911.2010.518272
To link to this article: http://dx.doi.org/10.1080/00397911.2010.518272
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 41: 3367–3375, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518272
N-ALKYLATION OF UNSYMMETRICAL 1,6-DIHYDRO-
1,2,4,5-TETRAZINE UNDER ALKALI CONDITION
Feng Xu,1 Zhen-Zhen Yang,1 Shi-Jie Zhang,2 and Wei-Xiao Hu2
1Biological and Chemical Engineering Department, Taizhou Vocational and
Technical College, Taizhou, China
2College of Pharmaceutical Science, Zhejiang University of Technology,
Hangzhou, China
GRAPHICAL ABSTRACT
Abstract 6-Methyl-3-phenyl-1,6-dihydro-1,2,4,5-tetrazine was stable in alkali solution at
room temperature and decomposed gradually to form 1,2-dibenzylidenehydrazine. The plaus-
ible mechanism of the reaction is discussed. Because it was stable for a period of time, a con-
venient and effective method for synthesis of 1-alkyl-1,6-dihydro-1,2,4,5-tetrazines has been
developed. The starting 1,6-dihydro-1,2,4,5-tetrazine can be alkylated with alkyl halides in
methanol and lithium hydroxide monohydrate as a base at room temperature.
Keywords Alkyl halides; N-alkylation; 1,6-dihydro-1,2,4,5-tetrazine; lithium hydroxide;
unsymmetrical
INTRODUCTION
1,6-Dihydro-1,2,4,5-tetrazine is an important compound for the synthesis of
some 1,2,4,5-tetrazine derivatives, which have been found to show strong antitumor
activity.[1] So far, a few reports have been published for 1,6-dihydro-1,2,4,5-
tetrazines and their derivatives.[2,3] The only method described in the literature[3a]
to synthesize 1-alkyl-3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazines 2 consists of the
N-alkylation reaction between 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine 1 and alkyl
halides in acetone in the presence of potassium carbonate (Scheme 1). This reaction
needs longer reaction time (12 h) and gives lower yields because the products were
always a mixture of the desired tertiary amine 2 and starting material 1.
Received April 30, 2009.
Address correspondence to Feng Xu, Biological and Chemical Engineering Department, Industry
Analysis and Examination Staff Room, Taizhou Vocational and Technical College, Taizhou 18000,
China. E-mail: xufeng901@126.com
3367

3368
F. XU ET AL.
Scheme 1. Synthesis of 1-alkyl-3,6-dimethyl-1,2,4,5-tetrazine.
When we attempt to perform the N-alkylation reaction between 6-methyl-3-
phenyl-1,6-dihydro-1,2,4,5-tetrazine 3[2g] and benzyl bromide 4a under the conditions
employed by Jennison et al., no product 5a formed after 42h. In contrast, we got an
unexpected product, which was identified as 1,2-dibenzylidene hydrazine 6 with 32%
yield (entry 1, Table 1). This phenomena may result from the instability of 1,6-
dihydro-1,2,4,5-tetrazine under alkali conditions. To explain the phenomena, a blank
experiment was executed between 3 and NaOH as the base in methanol at room
temperature. The relationship between reaction time and residual contents of 3 and
6 analyzed by high-performance liquid chromatography (HPLC) is shown in Fig. 1.
From the figure, it is obvious that 1,6-dihydro-1,2,4,5-tetrazine 3 was almost stable
for a period of time (0–8 hours) under alkali conditions. After that time, 3 decomposed
quickly to form 1,2-dibenzylidenehydrazine 6. We also changed the base to LiOH ꢀ H2O
and Et3N and found similar results. The plausible mechanism for the formation of 6 is
outlined in Scheme 2. Initially, on the effect of base, 3 deprotonates to form the anion 7,
which could be considered a homoaromatic anion,[2e–2f] 7 attacks the C3 position of 3
to form 8 via intramolecular decyclization,[4] which gives intermediate 9 after a
1,3-hydrogen shift and extrusion of molecular nitrogen.[5] Then, 9 gives 10 via elimin-
ation of 3-methyl-3H-diazirin; charge delocalization induces ring opening and leads to
the generation of 11. Finally, elimination of 3-methyl-3H-diazirin from 11 leads to the
formation of 12, which gets a proton from water to form the product 6.
Once we have known where 6 came from, optimization was carried out to find
favorable conditions for the N-alkylation of 3 with alkyl halides. The study was
executed taking benzyl bromide 4a as the standard alkyl halide to react
with1,6-dihydro-1,2,4,5-tetrazine 3. The influence of the base and solvent was inves-
tigated (Table 1).
As shown in Table 1, it is obvious that strong inorganic bases, such as NaOH
or LiOH ꢀ H2O, were the most appropriate bases to carry out the N-alkylation
reaction, affording the desired product 5a in good yields. When increasing the
equivalence of LiOH ꢀ H2O from 1.0 to 2.0, the yields of 5a decreased from 82%
to 30% (entries 6 and 7), which may be caused by the side reaction between exce-
ssive alkali and 4a.[6] The solvent also plays a crucial role, with methanol being the
best for good conversions (entries 6, and 8–10, Table 1). Nonpolar solvents were
not suitable.
Once the optimal conditions for the N-alkylation reaction between 3-phenyl-6-
methyl-1,6-dihydro-1,2,4,5-tetrazine 3 and benzyl bromide 4a had been found (entry
5, Table 1), the scope of this reaction was explored with a set of alkyl halides.

N-ALKYLATION OF 1,6-DIHYDRO-1,2,4,5-TETRAZINE
3369
Table 1. N-Alkylation of 3 with 4a under various conditionsa
Yield (%)b
Entry
Base (equiv)
Solvent
Time (h)
5a
6
1c
2c
3c
4
K2CO3 (7.0)
Et3N (1.0)
Acetone
Acetone
Acetone
MeOH
MeOH
MeOH
MeOH
MeCN
THF
42
42
42
42
5
—
10
12
55
76
82
30
75
65
—
32
45
35
30
—
—
—
—
—
6
DMAP (1.0)
DMAP (1.0)
NaOH (1.0)
5
6
LiOH ꢀ H2O (1.0)
LiOH ꢀ H2O (2.0)
LiOH ꢀ H2O (1.0)
LiOH ꢀ H2O (1.0)
LiOH ꢀ H2O (1.0)
5
7c
8
5
5
9
10c
5
Toluene
5
aReactions conditions: 3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine 3 (1.0 mmol, 1.0 equiv), benzyl
bromide 4a (1.0 equiv), base in corresponding solvent (20 ml) at room temperature.
bIsolated yields.
cThese reactions retrieved 3 with yields of 50% (entry 1), 32% (entry 2), 35% (entry 3), 42% (entry 7), and
85% (entry 10), respectively.
Figure 1. Decomposition 3 to form 6 under alkali condition.

3370
F. XU ET AL.
Table 2. Preparation of 5a–ka
RX (R ¼ Benzyl or
Entry
1
alkyl, X ¼ Cl or Br)
Time (min)
5
Yield (%)b
5a (82)
2
3
4
4
5b (85)
5c (76)
4
5
4
4
5d (68)
5e (90)
6
5
5f (74)
7
8
5
5
5g (65)
5h (62)
9
10
11
CH2 ¼ CHCH2Br 4i
CH3I 4j
CH3CH2I 4k
7
8
5i (65)
5j (55)
5k (48)
10
12c
13c
10
10
5a (15)
5m (0)
aReactions conditions: 3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine 3 (1.0 mmol, 1.0 equiv), alkyl
halides (1.0 equiv), and base (1.0 equiv) in methanol (20 ml) at room temperature.
bIsolated yields.
cThese reactions retrieved 3 with yields of 65% (entry 12) and 85% (entry 13), respectively.

N-ALKYLATION OF 1,6-DIHYDRO-1,2,4,5-TETRAZINE
3371
Scheme 2. Plausible mechanism to form 6.
As can be see in Table 2, 1,6-dihydro-1,2,4,5-tetrazine 3 can be effectively
alkylated with different alkyl halides 4 in moderate to good yields. As shown in
4a–h, a variety of substituents were tolerated in ortho, meta, and para positions,
and substrates with electron-donating groups showed a little more reactivity than
those with electron-withdrawing groups (entries 2–5 and 6–8, respectively); no
desired product 5m was detected when 4-nitrobenzyl bromide 4m reacted with 3
(entry 13). On the other hand, 4i–k showed much less reactivity than 4a–h; it
afforded 5a–h within 5 h, but it required a much longer reaction time (7–10 h) to
afford 5i–k. Benzyl chloride 4l showed very low reactivity in this reaction.
CONCLUSION
In summary, it was found that 1,6-dihydro-1,2,4,5-tetrazine 3 was relatively
stable for 8 h under alkali conditions, and because of this a convenient and efficient
method for N-alkylation of 1,6-dihydro-1,2,4,5-tetrazines was developed via reaction
of 3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine 3 with alkyl halides 4 under
LiOH ꢀ H2O and methanol in moderate to good yields.
EXPERIMENTAL
Compounds 4b–h and 4m were synthesized according to literature.[7] Other
solvents and reagents were commercially available and used without further purifi-
cation or purified by standard methods prior to use.
Melting points were carried on a XRC-1 apparatus and uncorrected. Infrared
(IR) spectra were recorded from KBr discs on a Nicolex Fourier transform

3372
F. XU ET AL.
(FT)–IR-170 instrument. 1H NMR spectra were run on a Bruker AC400 (400-MHz)
spectrometer using tetramethylsilane (TMS) as internal standard and CDCl3 as the
solvent. High-resolution mass spectra (HRMS) were obtained on an Agilent 6210
turnover frequency (TOF) liquid chromatograph=mass spectrography (LC=MS).
Thin-layer chromatography (TLC) was carried out on silica-gel UV-254 plates in
the dichloromethane system.
General Procedure for the Preparation of 5
3-Phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine 3 (174 mg,1.0 mmol), LiOH ꢀ
H2O (42 mg, 1.0 mmol), and methanol (10 ml) were mixed. Alkyl halides (1.0 mmol)
in methanol (10 ml) were added dropwise with stirring at room temperature. After
the start 1,6-dihydro-1,2,4,5-tetrazine 3 was completely consumed (the reaction
courses was monitored by TLC in the dichloromethane system), methanol was
evaporated, and crude 1-alkyl-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine 5
was obtained and purified by preparative TLC over silica gel PF254 (2 mm) (dichlor-
omethane–petroleum ether 9:1). These products 5 easily decomposed gradually at
room temperature and should be stored at ꢁ20 ꢂC.
1-Benzyl-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5a)
Mp: 101–103 ꢂC. IR (KBr, cmꢁ1): 3064, 2986, 1636, 1455, 1406, 1356, 1161,
1
1071, 764, 736, 695. H NMR (400 MHz, CDCl3) d ppm: 7.98 (d, 2H, J ¼ 7.6 Hz),
7.44 (t, 2H, J ¼ 7.8 Hz), 7.30–7.37 (m, 4H, ArH), 7.17 (d, 2H, J ¼ 6.8 Hz), 4.84 (s,
2H), 2.95 (q, 1H, J ¼ 6.1 Hz), 1.84 (d, 3H, J ¼ 6.4 Hz). MS (m=z, %): 236
[M-28(N2), 3], 133 (8), 118 (7), 103 (15), 91 (100), 77 (10). Anal. calcd. for
C16H16N4 (264.14): C, 72.70; H, 6.10; N, 21.20. Found: C, 72.40; H, 6.05; N, 21.45.
1-(2-Methylbenzyl)-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5b)
Yellow liquid. IR (KBr, cmꢁ1): 3063, 2981, 2820, 1697, 1602, 1460, 1406, 1350,
1
1160, 752, 744, 694. H NMR (400 MHz, CDCl3) d ppm: 7.95 (d, 2H, J ¼ 7.2 Hz),
7.42 (t, 2H, J ¼ 7.4 Hz), 7.33 (t, 1H, J ¼ 7.4 Hz), 7.16–7.22 (m, 3H, ArH), 7.01 (d,
1H, J ¼ 6.8 Hz), 4.89 (d, 1H, J ¼ 16.0 Hz), 4.77 (d, 1H, J ¼ 16.0 Hz), 3.27 (q, 1H,
J ¼ 6.3 Hz), 2.34 (s, 3H), 1.68 (d, 3H, J ¼ 6.0 Hz). MS (m=z, %): 250 [M-28(N2), 2],
146 (15), 132 (90), 105 (100), 91(5), 77 (32). HRMS (APCI): calcd. C17H19N4
(M þ Hþ) 279.1610; found 279.1603.
1-(3-Methylbenzyl)-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5c)
Yellow liquid. IR (KBr, cmꢁ1): 3027, 2922, 1607, 1447, 1404, 1384,1356, 1150,
1
761, 693. H NMR (400 MHz, CDCl3) d ppm: 7.98 (d, 2H, J ¼ 7.6 Hz), 7.43 (t, 2H,
J ¼ 7.4 Hz), 7.34 (t, 1H, J ¼ 7.4 Hz), 7.21 (t, 1H, J ¼ 7.6 Hz), 7.09 (d, 1H, J ¼ 7.6 Hz),
6.96–6.98 (m, 2H, ArH), 4.80 (s, 2H), 2.96 (q, 1H, J ¼ 6.2 Hz), 2.33 (s, 3H), 1.83 (d,
3H, J ¼ 6.4 Hz). MS (m=z, %): 250 [M-28(N2), 10], 224 (8), 147 (15), 132 (16), 106
(100), 91 (30), 77 (76). HRMS (APCI): calcd. C17H19N4 (M þ Hþ) 279.1610; found
279.1628.

N-ALKYLATION OF 1,6-DIHYDRO-1,2,4,5-TETRAZINE
3373
1-(4-Methylbenzyl)-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5d)
Mp: 81–83 ꢂC. IR (KBr, cmꢁ1): 3024, 2936, 2817, 1633, 1445, 1402, 1384, 1151,
1
1
780, 761, 692. H NMR (CDCl3) d ppm: H NMR (400 MHz, CDCl3) d ppm: 7.97
(d, 2H, J ¼ 7.2 Hz), 7.43 (t, 2H, J ¼ 7.8 Hz), 7.34 (t, 1H, J ¼ 7.0 Hz), 7.12 (d, 2H,
J ¼ 8.0 Hz), 7.06 (d, 2H, J ¼ 8.0 Hz), 4.78 (t, 2H, J ¼ 16.4 Hz), 2.96 (q, 1H,
J ¼ 6.1 Hz), 2.32 (s, 3H), 1.83 (d, 3H, J ¼ 6.0 Hz). MS (m=z, %): 250 [M-28(N2), 5],
147 (13), 132 (3), 105 (100), 91 (8), 77 (32). Anal. calcd. for C17H18N4 (278.15): C,
73.35; H, 6.52; N, 20.13. Found: C, 73.42; H, 6.31; N, 20.25.
1-(4-Methoxybenzyl)-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-
tetrazine (5e)
Yellow liquid. IR (KBr, cmꢁ1): 3062, 2921, 2926, 2835, 1610, 1405, 1352, 1249,
1176, 762, 695. 1H NMR (400 MHz, CDCl3) d ppm: 7.97 (d, 2H, J ¼ 8.0 Hz), 7.43 (t,
2H, J ¼ 7.8 Hz), 7.34 (t, 1H, J ¼ 7.2 Hz), 7.11 (d, 2H, J ¼ 8.0 Hz), 6.85 (d, 2H,
J ¼ 8.0 Hz), 4.79 (d, 1H, J ¼ 16.0 Hz), 4.74 (d, 1H, J ¼ 14.4 Hz), 3.79 (s, 3H), 3.00
(q, 1H, J ¼ 6.3 Hz), 1.83 (d, 3H, J ¼ 6.0 Hz). MS (m=z, %): 266 [M-28(N2), 5], 163
(15), 136 (8), 121 (100), 103 (32), 91 (17), 77 (42). HRMS (APCI): calcd.
C17H19N4O (M þ Hþ) 295.1559; found 295.1562.
1-(2-Chlorobenzyl)-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5f)
Yellow liquid. IR (KBr, cmꢁ1): 3060, 2984, 2937, 1591, 1471, 1444, 1384, 1307,
1157, 1036, 752, 693, 652. 1H NMR (400 MHz, CDCl3) d ppm: 7.97 (d, 2H,
J ¼ 8.0 Hz), 7.42 (t, 2H, J ¼ 7.6 Hz), 7.36 (t, 2H, J ¼ 7.2 Hz), 6.98–7.25 (m, 2H,
ArH), 6.96–6.98 (m, 1H, ArH), 5.04 (d, 1H, J ¼ 16.8 Hz), 4.89 (d, 1H, J ¼ 16.4 Hz),
3.02 (q, 1H, J ¼ 6.3 Hz), 1.83 (d, 3H, J ¼ 6.4 Hz). MS (m=z, %): 298 (M, 1), 270
[M-28(N2), 10], 167 (45), 152 (14), 127 (100), 103 (52), 89 (55), 77 (32). HRMS
(APCI): calcd C16H16ClN4 (M þ Hþ) 299.1063; found 299.1062.
1-(3-Chlorobenzyl)-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5g)
Yellow liquid. IR (KBr, cmꢁ1): 3061, 2985, 2938, 1597, 1474, 1405, 1389, 1150,
1071, 762, 694. 1H NMR (400 MHz, CDCl3) d ppm: 7.97 (d, 2H, J ¼ 7.2 Hz), 7.43 (t,
2H, J ¼ 7.2 Hz), 7.35 (t, 1H, J ¼ 7.4 Hz), 7.24 (m, 2H, ArH), 7.18 (s, 1H), 7.00–7.14
(m, 1H, ArH), 4.81 (d, 1H, J ¼ 15.6 Hz), 4.76 (d, 1H, J ¼ 16.0 Hz), 2.91 (q, 1H,
J ¼ 6.1 Hz), 1.87 (d, 3H, J ¼ 6.4 Hz). MS (m=z, %): 270 [M-28(N2), 8], 166 (10),
125 (100), 103 (40), 91 (28), 76 (18). HRMS (APCI): calcd. C16H16ClN4 (M þ Hþ)
299.1063; found 299.1067.
1-(4-Chlorobenzyl)-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5h)
Mp: 88–90 ꢂC. IR (KBr, cmꢁ1): 3062, 2981, 2823, 1598, 1490, 1403, 1344, 1154,
1091, 1013, 780, 763, 694. 1H NMR (400 MHz, CDCl3) d ppm: 7.95 (d, 2H,
J ¼ 8.0 Hz), 7.43 (t, 2H, J ¼ 7.6 Hz), 7.35 (t, 1H, J ¼ 7.4 Hz), 7.26 (d, 2H, J ¼ 8.0 Hz),
7.07 (d, 2H, J ¼ 8.0 Hz), 4.82 (d, 1H, J1 ¼ 15.6 Hz), 4.75 (d, 1H, J ¼ 16.0 Hz), 2.91

3374
F. XU ET AL.
(q, 1H, J ¼ 6.3 Hz), 1.85 (d, 3H, J ¼ 6.4 Hz). MS (m=z, %): 298 (M, 2), 270 [M-28(N2),
15], 167 (40), 145 (15), 127 (100), 103 (65), 89 (60), 76 (33). Anal. calcd. for C16H15ClN4
(298.10): C, 64.32; H, 5.06; N, 18.75. Found: C, 64.58; H, 4.92; N, 18.65.
1-Allyl-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5i)
Yellow liquid. IR (KBr, cmꢁ1) 3062, 2927, 1732, 1626, 1578, 1448, 1405, 1356,
1
1170, 1073, 761, 693. H NMR (400 MHz, CDCl3) d ppm: 7.94 (d, 2H, J ¼ 8.0 Hz),
=
7.42 (t, 2H, J ¼ 7.4 Hz), 7.34 (t, 1H, J ¼ 7.4 Hz), 5.68–5.72 (m, 1H, CH CH2), 5.13
=
(q, 2H, CH CH2), 4.25 (dd, 2H, J1 ¼ 24.4 Hz, J2 ¼ 6.0 Hz), 2.86 (q,1H, J ¼ 6.4 Hz),
1.94 (d, 3H, J ¼ 6.4 Hz). MS (m=z, %): 185 [Mþ-28(N2), 10], 178 (100), 161 (50), 134
(15), 118 (10), 89 (7). HRMS (APCI): calcd. C12H15N4 (M þ Hþ) 215.1297; found
215.1294.
1-Methyl-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5j)
Yellow liquid. IR (KBr, cmꢁ1): 3062, 2938, 1633, 1509, 1456, 1404, 1352, 1262,
1206, 1070, 799, 761, 695. 1H NMR (400 MHz, CDCl3) d ppm: 7.93 (d, 2H,
J ¼ 7.6 Hz), 7.43 (t, 2H, J ¼ 7.6 Hz), 7.34 (t, 1H, J ¼ 7.4 Hz), 3.40 (s, 3H), 2.51 (q,
1H, J ¼ 6.1 Hz), 2.07 (d, 3H, J ¼ 6.0 Hz). MS (m=z, %): 188 (M, 1), 160
[M-28(N2), 3], 103 (18), 76 (18), 63 (3), 57 (100). HRMS (APCI): calcd. C10H13N4
(M þ Hþ) 189.1140; found 189.1147.
1-Ethyl-3-phenyl-6-methyl-1,6-dihydro-1,2,4,5-tetrazine (5k)
Yellow liquid. IR (KBr, cmꢁ1): 3060, 2979, 2935, 1639, 1626, 1447, 1405, 1306,
1072, 755, 692. 1H NMR (400 MHz, CDCl3) d ppm: 7.85 (d, 2H, J ¼ 7.6 Hz), 7.43 (t,
2H, J ¼ 7.2 Hz), 7.34 (t, 1H, J ¼ 7.4 Hz), 3.73 (m, 1H), 3.58 (m, 1H), 2.75 (q, 1H,
J ¼ 6.3 Hz), 1.97 (d, 3H, J ¼ 6.8 Hz), 1.18 (t, 3H, J ¼ 7.4 Hz). MS (m=z, %): 201
(Mþ, 2), 173 (3), 131 (100), 104 (45), 89 (23), 77 (85). HRMS (APCI): calcd.
C11H15N4 (M þ Hþ) 203.1297; found 203.1307.
1,2-Dibenzylidene Hydrazine (6)
1
Mp: 92–94 ꢂC (lit.[8] 92 ꢂC). H NMR (400 MHz, CDCl3) d ppm: 8.68 (s, 2H),
7.85–7.87 (m, 4H, ArH), 7.46–7.48 (m, 6H, ArH). MS (m=z, %): 207 (Mþ, 60), 180
(35), 131 (100), 104 (36), 89 (20), 77 (75).
ACKNOWLEDGMENTS
We are indebted to the Science Foundation for Excellent Youth Scholars of the
Department of Education of Zhejiang Province and the Educational Commission of
Zhejiang Province for financial support (Y201018289).

N-ALKYLATION OF 1,6-DIHYDRO-1,2,4,5-TETRAZINE
3375
REFERENCES
1. (a) Hu, W. X.; Rao, G. W.; Sun, Y. Q. Synthesis and antitumor activity of s-tetrazine deri-
vatives. Bioorg. Med. Chem. Lett. 2004, 14, 1177–181; (b) Rao, G. W.; Hu, W. X. Synthesis,
x-ray crystallographic analysis, and antitumor activity of 1-acyl-3,6-disubstituted
phenyl-1,4-dihydro-1,2,4,5-tetrazines. Bioorg. Med. Chem. Lett. 2005, 15, 3174–3176.
2. For the synthesis of 1,6-dihydro-1,2,4,5-tetrazines, see (a) Sun, Y. Q.; Hu, W. X.; Yuan, Q.
Convenient Preparation of 3,6-Dialkyl-1,6-dihydro-s-tetrazines. Synth. Commun. 2003, 16,
2769–2775; (b) Hu, W. X.; Xu, F. Synthesis and x-ray crystallographic analysis of some
1,6-dihydro-1,2,4,5-tetrazines. J. Chem. Res. 2006, 12, 797–799; (c) Stam, C. H.; Counotte-
Potman, A. D.; Van der Plas, H. C. Crystal structure of ‘‘homoaromatic’’ 6-ethyl-3-phenyl-
1,6-dihydro-1,2,4,5-tetrazine. J. Org. Chem. 1981, 47, 2856–2858; (d) Skorianetz, W.;
Kovats, E. S. New synthesis of 3,6-dialkyl-1,2,4,5-tetrazines. Helv. Chim. Acta. 1971, 54,
1922–1939; (e) Counotte-Potman, A.; Van der Plas, H. C.; Van Veldhuizen, B.; Landheer,
C. A. Occurrence of the SN(ANRORC) mechanism in the hydrazination of 1,2,4,5-tetra-
zines. J. Org. Chem. 1981, 46, 5102–5109; (f) Counotte-Potman, A.; Van der Plas, H. C.;
Van Veldhuizen, B. Carbon-13 nuclear magnetic resonance iInvestigations of the anionic
homoaromatic r adducts formed between liquid ammonia and 1,2,4,5-tetrazine. J. Org.
Chem. 1981, 46, 3805–3810; (g) Counotte-Potman, A.; Van der Plas, H. C.; Van
Veldhuizen, B. 1,6-Dihydro-1,2,4,5-tetrazinea, Neutral homoaromatic system. J. Org.
Chem. 1981, 46, 2138–2141.
3. For the synthesis of 1-substituted-1,6-dihydro-1,2,4,5-tetrazines, see (a) Jennison, C. P. R.;
Mackay, D.; Watson, K. N.; Jaylor, N. J. The question of homoaromaticity in 1,6-dihydro-
l,2,4,5-tetrazines. J. Org. Chem. 1986, 51, 3043–3051; (b) Xu, F.; Hu, W. X. Reaction of
3-(substituted phenyl)-6-methyl-1,6-dihydro-1,2,4,5-tetrazine with aryl isocyanates, chloro-
formates, and acyl chlorides. J. Chem. Res. 2008, 4, 212–215; (c) Seccombe, R. C.; Kennard,
C. H. L. Bonding in 1,2,4-triazoles, part 6. Crystal structure of 6-mercapto-3-phenyl-s-
triazolo [4,3-b]-s-tetrazine pyridine adduct. J. Chem. Soc., Perkin Trans. 1973, 2, 11–14.
4. Counotte-Potman, A.; Van der Plas, H. C. SN(ANRORC) mechanism, 10: Degenerate ring
transformations in reactions of 1,2,4,5-tetrazines with hydrazine. J. Heterocycl. Chem.
1978, 15, 445–448.
5. Hunter, D.; Neilson, D. G. An investigation into the mechanism of formation of
oxadiazoles and arylidenehydrazides from the action of methanolic potassium hydroxide
on 1,4-dihydro-s-tetrazines. J. Chem. Soc., Perkin Trans. 1985, 1, 1081–1086.
6. Jin, C. H.; Lee, H. Y.; Lee, S. H.; Kim, I. S.; Jung, Y. H. Direct etherification of alkyl
halides by sodium hydride in the presence of N,N-dimethylformamide. Synlett 2007, 17,
2695–2698.
7. Zhang, W.; Go, M. L. Quinone reductase induction activity of methoxylated analogues of
resveratrol. Eur. J. Med. Chem. 2007, 42, 841–850.
8. (a) Aly, M. M. A.; El Sayed, B. A.; Hassan, A. M. Vibrational spectra of benzaldazine and
salicylaldazine complexes with Zn(II) and Fe(II) ions. Spectrosc. Lett. 2002, 35, 337–348;
(b) Mazzone, G.; Puglisi, G.; Bonina, F.; Corsaro, A. A new synthesis of symmetrical
2,5-diaryl-1,3,4-thiadiazoles. J. Heterocycl. Chem. 1983, 20, 1399–1401; (c) Fu, Y. Y.; Li,
H. X.; Hu, W. P. Small molecular chromogenic sensors for Hg2þ; a strong ‘‘push–pull’’
system exists after binding. Eur. J. Org. Chem. 2007, 15, 2459–2463.