Nucleophilic substitution with amines: dihydro-1,2,4,5-tetrazines are more useful precursors than 1,2,4,5-tetrazines

Article abstract of DOI:10.1016/j.tetlet.2008.02.145

A one step synthesis of (di)alkylamino-substituted 1,2,4,5-tetrazines direct from 3,6-disubstituted-1,2-dihydro-1,2,4,5-tetrazine precursors is described. A comparative study revealed that the described method not only avoids the up-to-now required oxidat

Full text of DOI:10.1016/j.tetlet.2008.02.145

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2748–2751
Nucleophilic substitution with amines: dihydro-1,2,4,5-tetrazines
are more useful precursors than 1,2,4,5-tetrazines
Arnaud Cutivet, Emmanuel Leroy, Eric Pasquinet *, Didier Poullain
`
Commissariat a l’Energie Atomique, BP 16, 37260 Monts, France
Received 13 July 2007; revised 22 February 2008; accepted 27 February 2008
Available online 4 March 2008
Abstract
A one step synthesis of (di)alkylamino-substituted 1,2,4,5-tetrazines direct from 3,6-disubstituted-1,2-dihydro-1,2,4,5-tetrazine
precursors is described. A comparative study revealed that the described method not only avoids the up-to-now required oxidation step
but also lower reaction times and/or temperatures compared to usual protocols. The efficiency of the reaction was highlighted by a
practical synthesis of 3,6-bis(methylamino)-1,2,4,5-tetrazine using aqueous methylamine. Other primary and secondary amines were also
found to give disubstitution products when reacted with 3,6-bis(methylsulfanyl)-1,2,4,5-dihydrotetrazine.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Dihydrotetrazines; Tetrazines; Nucleophilic substitution; Methylamine; Oxidation
Due to their large scope of applications, tetrazine-based
compounds have been the subject of numerous studies.1
Tetrazines are widely known to react in inverse demand
Diels–Alder reactions2–6 and exhibit energetic,7–11 dye,12
insecticide,13 optical,14,15 electrochemical16 and biomedi-
cal17,18 properties. The electron deficient tetrazine ring
leads to an increased reactivity towards nucleophiles.
Therefore, nucleophilic aromatic substitution of 3,6-disub-
stituted-1,2,4,5-tetrazines was widely employed to synthe-
size new unsymmetrical or symmetrical tetrazines,
unavailable by other synthetic methods. A wide range of
nitrogen, oxygen and sulfur nucleophiles was used in such
processes.19–27 Commonly, the first leaving group was rap-
idly displaced, with the second displacement requiring
more drastic conditions.
aromatic 1,2,4,5-tetrazines obtained by the oxidation of
the corresponding dihydro-1,2,4,5-tetrazines.
Herein, we report the synthesis of (di)alkylamino-substi-
tuted 1,2,4,5-tetrazines which were obtained, contrary to
the usual pattern, directly from a dihydrotetrazine com-
pound rather than from an aromatic tetrazine. This is of
practical significance, since the oxidation step may be
somewhat cumbersome. For example, 3,6-bis(3,5-di-
methylpyrazol-1-yl)-dihydro-1,2,4,5-tetrazine 2b is converted
to 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine 1b
using N2O4,20 a highly toxic and corrosive gas. To the best
of our knowledge, there is only one example of substitution
on a dihydro-1,2,4,5-tetrazine (2b, hydrazine as the nucleo-
phile).30 Yield, detailed experimental conditions and com-
parison with the usual reaction on the corresponding
1,2,4,5-tetrazine31 were not specified.
In particular, we addressed the synthesis of 3,6-
bis(methylamino)-1,2,4,5-tetrazine 4 (Scheme 1). This com-
pound was claimed to exhibit herbicide properties32 and
stimulated the curiosity of different groups of physical
chemists.21,22,33 In the only reported synthesis of 4,21 3,6-
bis(methylsulfanyl)-1,2,4,5-tetrazine 1a underwent nucleo-
philic substitution by gaseous methylamine.
The electrophilic partners were mostly 3,6-bis(meth-
ylsulfanyl)-1,2,4,5-tetrazine 1a,28 3,6-bis(3,5-dimethylpyr-
azol-1-yl)-1,2,4,5-tetrazine 1b,20,29 3,6-bis(4-bromo-3,5-
dimethylpyrazol-1-yl)-1,2,4,5-tetrazine24,25 and 3,6-dichloro-
1,2,4,5-tetrazine.27,30 All of these are easily available
*
Corresponding author. Tel.: +33 0 247345694; fax: +33 0 247345142.
E-mail address: eric.pasquinet@cea.fr (E. Pasquinet).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.145

A. Cutivet et al. / Tetrahedron Letters 49 (2008) 2748–2751
2749
series, the disubstituted product 4 was almost the only
product detected when dihydrotetrazine precursor 2b was
used as the starting material, whereas the intermediate
monoaminated compound 3 was the major product in the
case of tetrazine 1b under the same conditions (entries 2,
6 and 3, 7).
NHMe
R
R
R
R
conditions
N
N
N
N
N
N
N
N
N
NH
NH
N
N
N
N
or
N
see Table 1
NHMe
4
R
1
NHMe
3
2
Scheme 1. Synthesis of methylamino-substituted 1,2,4,5-tetrazines from
(dihydro)-1,2,4,5-tetrazines bearing leaving groups.
This result is important from a mechanistic point of
view. As a matter of fact, one could have thought that
the first step of the process was oxidation of the dihydro-
tetrazine precursor to the corresponding tetrazine followed
by substitution on the aromatic product. However, this
hypothesis was ruled out since in this case the whole oxida-
tion/substitution process could not have been faster than
the substitution reaction on tetrazine as the starting mate-
rial. Thus, this clearly shows that methylamination is faster
on dihydrotetrazine precursors than on tetrazine counter-
parts. The reason for this could be that nucleophilic substi-
tution is expected to be easier on a non-aromatic
compound. A completely different pathway such as a
SN(ANRORC) process is also possible, since substituted
tetrazines are known to undergo such reactions.34 Methyl-
amine also has been involved in SN(ANRORC) pathways
in other aza-aromatic series.35,36
The final, spontaneous oxidation step is still not fully
understood. As a matter of fact, the reaction was carried
out in relatively concentrated solutions in a sealed vessel.
Under the same conditions, dissolved or atmospheric oxy-
gen would only partially account for oxidation. The deep
red colour which developed quickly when the reaction mix-
ture was exposed to ambient air suggested that oxidation
occurred spontaneously during treatment.
We investigated the methylamination reaction in detail,
using different methylamine reactants and two electrophilic
dihydro-1,2,4,5-tetrazine precursors. The corresponding
tetrazines in their aromatic form were also included for
comparison purpose (Table 1). Ethanolic methylamine
solutions or methylamine hydrochloride in the presence
of a base both lead to extensive degradation. Methylamine
in water or in THF was found more suitable and was used
throughout the study. As expected, mono- and disubstitu-
tion products were observed depending on the conditions.
Aqueous methylamine in acetonitrile always resulted in
a higher or faster conversion in 4 than MeNH2 in THF.
This is certainly because the medium was more polar using
the former conditions (entries 6, 7 and 2, 3). Concerning
the aromatic starting materials, we also noticed that 1b
was more prone to disubstitution than 1a using the THF
conditions, suggesting that the dimethylpyrazolyl moiety
was more easily displaced than the methylsulfanyl group
(entries 1 and 2).
But the more striking result of this study is that disubsti-
tution was a much more efficient process when dihydrotetr-
azine precursors were used instead of the usual tetrazine
counterparts. For example, in the bis(dimethylpyrazolyl)
Table 1
Methylamination conditions and results
Entry
Starting material
Conditions
Methylaminea
Ratio 3:4b (%)
Yield of 4c (%)
N N
MeS
SMe
1
THF, 40 °C, 24 h
2 M THF solution
100:0
—
N N
1a
N N
N
N
N
N
2
THF, 40 °C, 24 h
2 M THF solution
76:24
6
N N
1b
3
4
5
1b
MeCN, rt,d 12 h
MeCN, rt, 4 d
MeCN, rt, 24 h
40 wt % aqueous solution
40 wt % aqueous solution
Anhydrous
53:47
2:98
35
70
22
N N
MeS
SMe
HN NH
2a
2a
58:42
N N
N
N
N
6
THF, 40 °C, 24 h
2 M THF solution
4:96
45
24
N
HN NH
2b
7
2b
MeCN, rt, 12 h
40 wt % aqueous solution
0:100
a
In all cases, a large excess of methylamine was added (20 equiv).
b
c
Determined by integration of appropriate 1H NMR signals in the crude product.
Isolated yield of pure product.
d
rt: Room temperature.

2750
A. Cutivet et al. / Tetrahedron Letters 49 (2008) 2748–2751
As in the tetrazine series, the dihydro-1,2,4,5-tetrazine
hydrotetrazine precursors are more prone to substitution
than their tetrazine counterparts. The method was also
extended to other amines, thus highlighting the versatility
of this reaction.
bearing dimethylpyrazole as the leaving group was more
rapidly substituted by methylamine than the corresponding
bis(methylsulfanyl) derivative. However, chromatographic
removal of the dimethylpyrazole formed in the substitution
process was difficult, thus decreasing the yields of pure
3,6-bis(methylamino)-1,2,4,5-tetrazine 4 (entries 6 and 7).
Therefore, even if disubstitution required longer times,
3,6-bis(methylsulfanyl)-1,2-dihydro-1,2,4,5-tetrazine 2a was
our best choice of precursor since the by-product metha-
nethiol was pumped off with the solvent during work-up.
The isolated yield was 70%, a satisfying result considering
that the up-to-now required oxidation step was avoided
(entry 4).37
References and notes
1. (a) Saracoglu, N. Tetrahedron 2007, 63, 4199–4236; (b) Neunhoeffer,
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68, 3593–3598.
Interestingly, using liquefied gaseous methylamine with
our optimal conditions only resulted in a 22% yield due
to low conversion (mono- and disubstituted products were
formed in nearly equal amounts, entry 5).
4. Wan, Z. K.; Woo, G. H. C.; Snyder, J. K. Tetrahedron 2001, 57,
5497–5507.
´
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2000, 39, 1791–1793.
The substitution reaction on dihydro-1,2,4,5-tetrazine
2a was extended to other common amines (Scheme 2, Table
2).38 Ethylamine was as effective as methylamine and the
monosubstitution product was not detected when the reac-
tion was conducted at 50 °C. The expected disubstitution
product 6a was obtained in 89% yield. Surprisingly, the
other primary amine benzylamine reacted poorly. Even at
70 °C, only 17% of 3,6-bis(benzylamino)-1,2,4,5-tetrazine
6b was isolated along with 77% of the monosubstituted
product 5b. However, a secondary amine, pyrrolidine,
was also shown to give the corresponding disubstituted
product 6c in satisfactory yield (52%). The monosubsti-
tuted compound 5c was also observed (15% yield).
12. Kotone, A.; Hoda, M. (Sakai Chem. Int. Co. Ltd) Jpn. Pat. 24002,
1971.
13. Tsuda, S.; Manabe, Y.; Tsuji, K. (Sumitomo Chem. Co. Ltd) Jpn.
Pat. 107254, 1988.
`
´
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14, 1177–1181.
18. Rao, G.-W.; Hu, W.-X. Bioorg. Med. Chem. Lett. 2005, 15, 3174–
3176.
In conclusion, we have disclosed a convenient one step
methylamination of dihydro-1,2,4,5-tetrazines leading to
methylamino-substituted 1,2,4,5-tetrazines. This process
avoids both the oxidation step to obtain the usual tetrazine
precursor and the use of gaseous methylamine, thus
providing a practical synthesis of 3,6-bis(methylamino)-
1,2,4,5-tetrazine 4. A comparative study revealed that di-
`
19. Boger, D. L.; Zhang, M. J. J. Am. Chem. Soc. 1991, 113, 4230–4234.
20. Coburn, M. D.; Buntain, G. A.; Harris, B. W.; Hiskey, M. A.; Lee,
K.-Y.; Ott, O. G. J. Heterocycl. Chem. 1991, 28, 2049–2050.
R' R''
R' R''
SMe
N
N
21. Fisher, H.; Muller, T.; Umminger, I.; Neugebauer, F. A. J. Chem.
¨
R'R''NH / MeCN
50 or 70 °C / 4 d
N
N
NH
N
N
N
N
N
N
N
N
Soc., Perkin. Trans. 2 1988, 413–421.
22. Gleiter, R.; Schehlmann, V.; Spanget-Larsen, J. J. Org. Chem. 1988,
53, 5756–5762.
+
NH
SMe
N
SMe
R' R''
23. Gong, Y.-H.; Audebert, P.; Tang, J.; Miomandre, F.; Clavier, G.;
2a
6a-c
5a-c
´
Badre, S.; Meallet-Renault, R.; Marrot, J. J. Electroanal. Chem. 2006,
592, 147–152.
Scheme 2. Synthesis of (di)alkylamino-substituted 1,2,4,5-tetrazines.
24. Latosh, N. I.; Rusinov, G. L.; Ganebnykh, I. I.; Chupakhin, O. N.
Russ. J. Org. Chem. 1999, 35, 1363–1371.
25. Novak, Z.; Bostai, B.; Csekei, M.; Lorincz, K.; Kotschy, A.
Heterocycles 2003, 60, 2653–2668.
26. Rusinov, G. L.; Latosh, N. I.; Ganebnykh, I. I.; Ishmetova, R. I.;
Ignatenko, N. K.; Chupakhin, O. N. Russ. J. Org. Chem. 2006, 42,
757–765.
Table 2
Substitution of 2a with various amines: conditions and results
R0
R00
Temperature Monosubstitution Disubstitution
(°C)
product (isolated product (isolated
27. Schirmer, U.; Wuerzer, B.; Meyer, N.; Neugebauer, F. A.; Fisher, H.
DE Patent 3,508,214, 1986; Chem. Abstr. 1987, 106, 45718.
28. Sandstro¨m, J. J. Acta Chem. Scand. 1961, 15, 1575–1578.
29. Butler, R. N.; Scott, F. L.; Scott, R. D. J. Chem. Soc. 1970, 2510–
2512.
yield)
yield)
H
H
Et
Bn
50
70
50
—
5b (77%)
5c (15%)
6a (89%)
6b (17%)
6c (52%)
–(CH2)4–

A. Cutivet et al. / Tetrahedron Letters 49 (2008) 2748–2751
2751
30. Chavez, D. E.; Hiskey, M. A. J. Energy Mater. 1999, 17, 357–377.
31. Chavez, D. E.; Hiskey, M. A. J. Pyrotechnics 1998, 7, 11–14.
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1964; Chem. Abstr. 1965, 62, 1976.
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1978, 15, 445–448.
35. Oostven, E. A.; Van der Plas, H. C. Recl. Trav. Chim. Pays-Bas 1976,
95, 209–211.
38. 3,6-Bis(ethylamino)-1,2,4,5-tetrazine 6a: The compound was synthe-
sized as for 4, using 70 wt % aqueous ethylamine solution.
Conditions and yield: see Scheme 2 and Table 2. IR (ATR): 3245,
2975, 2873, 1550, 1444, 1387, 1352 cmꢁ1 1H NMR (200 MHz,
a
;
CDCl3): d 1.30 (t, 6H, 3J = 7.2 Hz), 3.52 (dq, 4H, 3J = 7.2 Hz,
3J = 1.3 Hz), 5.01 (br s, 2H); 13C NMR (1050 MHz, CDCl3): d 14.8,
36.6, 160.6; HRMS (CI+) m/z: [M+H]+ calcd for C6H13N6, 169.1202;
found, 169.1200. 3,6-Bis(benzylamino)-1,2,4,5-tetrazine 6b: The com-
pound was synthesized as for 4. Conditions and yield: see Scheme 2
and Table 2. IR (ATR): 3247, 3028, 1558, 1455, 1426, 1352 cmꢁ1; 1H
NMR (200 MHz, CDCl3): d 4.69 (s, 4H), 5.51 (br s, 2H), 7.37 (m,
10H); 13C NMR (50 MHz, CDCl3): d 45.7, 127.6, 127.8, 128.7, 138.2,
160.6; HRMS (CI+) m/z: [M+H]+ calcd for C16H17N6, 293.1515;
found, 293.1523. The monosubstitution product was also isolated: 3-
benzylamino-6-methylsulfanyl-1,2,4,5-tetrazine 5b: IR (ATR): 3063,
36. Al-Azmi, A.; Booth, B. L.; Carpenter, R. A.; Carvalho, M. A.;
Marrelec, E.; Pritchard, R. G.; Proenßca, M. F. J. Chem. Soc., Perkin
Trans. 1 2001, 2532–2537.
37. 3,6-Bis(methylamino)-1,2,4,5-tetrazine 4:21 To a solution of 3,6-
bis(methylsulfanyl)-1,2-dihydro-1,2,4,5-tetrazine 2b (2.0 g, 11.3 mmol)
in MeCN (3 mL) was added a 40 wt % aqueous methylamine solution
(19.4 mL, 226 mmol). The mixture was stirred in a sealed vessel at
room temperature for 4 days. After completion, excess methylamine
was removed under vacuum. The aqueous phase was further extracted
with CH2Cl2 (3 ꢀ 60 mL). The organic extracts were combined, dried
on MgSO4 and then concentrated to give, after flash chromatography
(heptane–ethyl acetate, 7:3), 3,6-bis(methylamino)-1,2,4,5-tetrazine 4
1
2925, 1590, 1565, 1505, 1496, 1451, 1429 cmꢁ1; H NMR (200 MHz,
CDCl3): d 2.67 (s, 3H), 4.75 (d, 2H, 3J = 5.3 Hz), 5.94 (s, 1H), 7.38 (m,
5H); 13C NMR (50 MHz, CDCl3): d 13.6, 45.2, 127.8, 127.8, 128.8,
137.2, 160.8, 167.5; HRMS (CIꢁ) m/z: [M]ꢁ calcd for C10H11N5S,
233.0735; found, 233.0746. 3,6-Bis(pyrrolidino)-1,2,4,5-tetrazine 6c:21
The compound was synthesized as for 4. Conditions and yield: see
Scheme 2 and Table 2. IR (ATR): 2974, 2875, 1505, 1457 cmꢁ1 1H
;
as a red solid (1.105 g, 70%). IR (ATR): 3323, 2924, 1694, 1413 cmꢁ1
;
NMR (200 MHz, CDCl3): d 1.97 (m, 4H), 3.51 (m, 4H); 13C NMR
(50 MHz, CDCl3): d 24.9, 46.2, 158.2. The monosubstituted product
was also isolated: 3-methylsulfanyl-6-pyrrolidino-1,2,4,5-tetrazine 5c:22
1H NMR (200 MHz, CDCl3): d 3.10 (d, 6H, 3J = 5.0 Hz), 5.10 (s,
2H); 13C NMR (100 MHz, CDCl3): d 28.6, 161.1); 15N NMR
(40 MHz, CDCl3): d ꢁ39.2, ꢁ322.2; MS (CIꢁ, NH3): m/z (%) = 139
(100, [MÅꢁ]); Anal. Calcd for C4H8N6 (140.08): C, 34.28; H, 5.75; N,
59.97. Found: C, 34.71; H, 5.89; N, 58.07.
IR(ATR): 2979, 2927, 2878, 1538, 1455, 1428 cmꢁ1 1H NMR
;
(200 MHz, CDCl3): d 2.01 (m, 4H), 2.61 (s, 3H), 3.59 (m, 4H); 13C
NMR (50 MHz, CDCl3): d 13.2, 24.8, 46.3, 158.4, 164.1.