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Synlett 2009(5): 731-734  
DOI: 10.1055/s-0028-1087818
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 3,6-Divinyl-1,2,4,5-Tetrazine, the First Member of the Elusive Vinyltetrazine Family

Stéphanie Picana, Vincent Lapintea,c, Jean-François Pilard*a, Eric Pasquinetb, Lionel Bellerb, Laurent Fontainea, Didier Poullainb
a UCO2M - Chimie des Polymères, UMR6011 CNRS, Université du Maine, Avenue O. Messiaen, 72085 Le Mans Cedex 09, France
Fax: +33(0)24833754; e-Mail: jean-francois.pilard@univ-lemans.fr;
b CEA, DAM, LE RIPAULT, 37260 Monts, France
c Institut Charles Gerhardt Montpellier, UMR5253 CNRS, IAM, Université Montpellier II, Place E. Bataillon, 34095 Montpellier Cedex 5, France
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Publication History

Received 17 November 2008
Publication Date:
16 February 2009 (online)

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Abstract

The synthesis of the first vinyltetrazine derivative is ­described. 3,6-Divinyl-1,2,4,5-tetrazine was obtained following a methodology involving cyclization from an imidate and use of 2-phenylsulfonylethyl groups as masked vinyl entities. The first properties of this unique compound are reported.

Key words

azo compounds - condensation - cyclizations - fused ring systems - heterocycles

    References and Notes

  • 1 Kizhnyaev VN. Vereshchagin LI. Russ. Chem. Rev.  2003,  72:  143 ; and references cited therein
    CrossrefGoogle Scholar
  • 2a Kizhnyaev VN. Pokatilov FA. Tsypina NA. Ratovskii GV. Vereshchagin LI. Smirnov AI. Russ. J. Org. Chem.  2002,  38:  1056 
    Google Scholar
  • 2b Wouters G. Smets G. Makromol. Chem.  1982,  183:  1861 
    Google Scholar
  • 2c Attaryan OS. Asratyan GV. Eliazyan GA. Darbinyan EG. Matsoyan SG. Arm. Khim. Zh.  1986,  39:  630 
    Google Scholar
  • 2d Toppet S. Wouters G. Smets G. J. Polym. Sci. Polym. Lett.  1976,  14:  389 
    Google Scholar
  • 3a inventors; GB  935787. American Cyanamid Company;
  • 3b Schaefer FC, and Peters GA. inventors; US  2845422. 
  • 3c Yuki Y. Kakurai T. Nogushi T. Hiramatsu N. Kobunshi Kugaku  1969,  26:  134 
    Google Scholar
  • 3d Yuki Y. Kakurai T. Nogushi T. Kobunshi Kugaku  1969,  26:  141 
    Google Scholar
  • 3e Overberger CG. Shapiro SL. J. Am. Chem. Soc.  1954,  76:  1061 
    Google Scholar
  • 3f Fukui K, Kitano H, Mizuta M, Osaka T, and Kanai K. inventors; JP  44025793. 
  • 4a Audebert P. Sadki S. Miomandre F. Clavier G. Electrochem. Commun.  2004,  6:  144 
    Google Scholar
  • 4b Topp KD. Grote M. React. Funct. Polym.  1996,  31:  117 
    Google Scholar
  • 4c Zhang BW. Fischer K. Bieniek D. Kettrup A. React. Funct. Polym.  1994,  24:  49 
    Google Scholar
  • 4d Stoicescu-Crivetz L. Mantaluta E. Neamtu G. Zugravescu I. J. Polym. Sci., Part C: Polym. Symp.  1969,  22:  761 
    Google Scholar
  • 4e Stoicescu-Crivetz L. Mantaluta E. Neamtu G. Zugravescu I. Rev. Roum. Chim.  1966,  11:  1127 
    Google Scholar
  • 4f Konishi K, Kobota J, Kotone A, and Nakane Y. inventors; JP  7234499. 
  • 5a Hamasaki A. Ducray R. Boger DL. J. Org. Chem.  2006,  71:  185 
    Google Scholar
  • 5b Soenen DR. Zimpleman JM. Boger DL. J. Org. Chem.  2003,  68:  3593 
    Google Scholar
  • 5c Wan ZK. Woo GHC. Snyder JK. Tetrahedron  2001,  57:  5497 
    Google Scholar
  • 5d Kotschy A. Novák Z. Vincze Z. Smith DM. Hajós G. Tetrahedron Lett.  1999,  40:  6313 
    Google Scholar
  • 5e Seitz G. Overheu W. Arch. Pharm.  1977,  310:  936 
    Google Scholar
  • 6a Chavez DE. Hiskey MA. Gilardi RD. Org. Lett.  2004,  6:  2889 
    Google Scholar
  • 6b Talawar MB. Sivabalan R. Senthilkumar N. Prabhu G. Asthana SN. J. Hazard. Mater.  2004,  113:  11 
    Google Scholar
  • 6c Pagoria PF. Lee GS. Mitchell AR. Schmidt RD. Thermochim. Acta  2002,  384:  187 
    Google Scholar
  • 6d Oxley JC. Smith JL. Chen H. Thermochim. Acta  2002,  384:  91 
    Google Scholar
  • 6e Chavez DE. Hiskey MA. Gilardi RD. Angew. Chem. Int. Ed.  2000,  39:  1791 
    Google Scholar
  • 7 Kotone A, and Hoda M. inventors; JP  24002. 
  • 8 Tsuda S, Manabe Y, and Tsuji K. inventors; JP  107254. 
  • 9 Audebert P. Sadki S. Miomandre F. Clavier G. Vernières M.-C. Saoud M. Hapiot P. New J. Chem.  2004,  28:  387 
    CrossrefGoogle Scholar
  • 10a Rao GW. Hu WX. Bioorg. Med. Chem. Lett.  2005,  15:  3174 
    Google Scholar
  • 10b Hu WX. Rao GW. Sun YQ. Bioorg. Med. Chem. Lett.  2004,  14:  1177 
    Google Scholar
  • 11 Boger DL. Coleman RS. Panek JS. J. Org. Chem.  1985,  50:  5377 
    CrossrefGoogle Scholar
  • 13 Alphonse FA. Suzenet F. Keromnes A. Lebret B. Guillaumet G. Org. Lett.  2003,  5:  803 
    CrossrefPubMedGoogle Scholar
  • 14 Sandstrom J. Acta Chem. Scand.  1961,  15:  1575 
    Google Scholar
  • 15 Lim CL. Pyo SH. Kim TY. Yim ES. Han BH. Bull. Korean Chem. Soc.  1995,  16:  374 
    Google Scholar
  • 16a Simpkins NS. In Sulfones in Organic Synthesis   Vol. 10:  Baldwin JE. Magnus PD. Tetrahedron Org. Chem. Series, Pergamon Press; Oxford: 1993. 
    Google Scholar
  • 16b Julia M. Arnould D. Bull. Soc. Chim. Fr.  1973,  2:  746 
    Google Scholar
  • 16c Colter AK. Miller RE. J. Org. Chem.  1971,  36:  1898 
    Google Scholar
  • 16d Hwang SH. Kurth MJ. Tetrahedron Lett.  2002,  43:  53 
    Google Scholar
  • 16e Giovannini R. Marcantoni E. Pietrini M. Tetrahedron Lett.  1998,  39:  5827 
    Google Scholar
  • 16f Baker-Glenn CAG. Barrett AGM. Gray AA. Procopiou PA. Ruston M. Tetrahedron Lett.  2005,  46:  7427 
    Google Scholar
  • 17 Renard M. Ghosez LA. Tetrahedron  2001,  57:  2597 
    CrossrefGoogle Scholar
  • 18 Sooducho J. Doskocz J. Cabaj J. Roszak S. Tetrahedron  2003,  59:  4761 
    CrossrefGoogle Scholar
  • 19a Weintraub L. Oles SR. Kalish N. J. Org. Chem.  1968,  33:  1679 
    Google Scholar
  • 19b Butler RCM. Chapleo CB. Myers PL. Welburn AP. J. Heterocycl. Chem.  1985,  22:  177 
    Google Scholar
  • 22 Comprehensive Heterocyclic Chemistry II   Vol. 6:  Katritzky AR. Rees CW. Scriven EFV. Pergamon Press; Oxford: 1996.  p.949 
    Google Scholar
  • 23 Panek JS. Zhu B. Tetrahedron Lett.  1996,  37:  8151 
    CrossrefGoogle Scholar
12

Lithium aluminium hydride, sodium borohydride, or diisobutylaluminium hydride led to major decomposition regardless of the conditions used.

20

Ethyl 3-Phenylsulfanylpropionimido Ester Hydrochloride (2)
A steady stream of gaseous HCl was bubbled at r.t. for 10 h through a stirred EtOH solution (7.3 mL, 0.125 mol) of propionitrile 1 (2.02 g, 12.3 mmol). A white powder gradually precipitated. The solvent was removed under vacuum, and the crude precipitate was triturated three times with anhyd Et2O and finally filtered leading to compound 2 as a white powder (94% yield); mp 74-75 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 12.50 (s, 1 H), 11.60 (s, 1 H), 7.41-7.27 (m, 5 H), 4.56 (q, J = 6.9 Hz, 2 H), 3.30 (t, J = 6.6 Hz, 2 H), 3.06 (t, J = 6.6 Hz, 2 H), 1.44 (t, J = 6.9 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 177.0, 133.7, 130.9, 129.1, 126.4, 70.9, 33.4, 28.8, 13.4. IR (KBr): νmax = 3078, 2951, 1692, 1384, 975 cm-¹. LC-MS (AP+, MeCN-H2O, 80:20): 2.67 min, 246.7 [M + 1] and 210.3 [M - Cl]. HRMS (FI): m/z calcd for C11H15ONS [M - HCl]: 209.0874; found: 209.0875.

21

General Cyclization Procedure Imidoester hydrochloride 2 (6.17 g, 25.1 mmol) was dissolved in EtOH (0.16 M) under a nitrogen atmosphere, and the solution was brought to -10 ˚C. Then, Et3N and N2H4˙H2O (2.5 mL, 51.4 mmol) were successively added to the solution and the mixture was allowed to stir (conditions: see Table  [¹] ). The mixture was concentrated under vacuum, and the slightly pink crude solid obtained was further dissolved in EtOAc and washed with H2O. The aqueous layer was then extracted with EtOAc, and the resulting organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. Depending on reaction conditions the products could be obtained. Compound 5 was isolated after simple precipitation from cyclohexane, whereas 3, 4, and 6 were obtained after chromatography over SiO2 (cyclohexane-EtOAc, 7:1).
N′-[1-Amino-3-(phenylsulfanyl)propylid-1-ene]-3-(phenylthio)propanehydrazonamide (3)
Mp 75 ˚C (white crystals). ¹H NMR (400 MHz, CDCl3): δ = 7.88-7.15 (m, 10 H), 5.43 and 5.09 (br s, 4 H), 3.24 (t, J = 7.4 Hz, 4 H), 2.55 (t, J = 7.4 Hz, 4 H). ¹³C NMR (100 MHz, CDCl3): δ = 155.8, 135.5, 129.5, 129.0, 126.3, 32.9, 30.8. IR (KBr): νmax = 3450, 3337, 3060, 2960, 1633, 1583, 1482, 1444, 1356, 1287, 910 cm-¹. LC-MS (AP+, MeCN-H2O, 80:20): 3.40 min, 358.9.
3,6-Bis-(2-phenylsulfanylethyl)-1,2-dihydro-1,2,4,5-tetrazine (4) Mp 151 ˚C (white crystals); ¹H NMR (400 MHz, DMSO-d 6 ): δ = 7.96 (s, 2 H), 7.37-7.26 (m, 8 H), 7.24-7.12 (m, 2 H), 3.10 (t, J = 7.6 Hz, 4 H), 2.30 (t, J = 7.6 Hz, 4 H). ¹³C NMR (100 MHz, DMSO-d 6 ): δ = 148.5, 135.7, 129.1, 128.1, 125.7, 29.8, 28.2. IR: νmax = 3243, 3054, 1677, 1575, 1476, 1436, 1400, 1287, 1257, 1242, 1208, 1165, 1086, 1020 cm-¹. LC-MS (AP+, MeCN-H2O, 50:50): 7.15 min, 356.9.
4-Amino-3,5-bis(2-phenylsulfanylethyl)-1,2,4-triazole (5) Mp 80-82 ˚C (white crystals). ¹H NMR (400 MHz, DMSO-d 6 ): δ = 7.40-7.16 (m, 10 H), 5.63 (s, 2 H), 3.31 (t, J = 7.0 Hz, 4 H), 2.98 (t, J = 7.0 Hz, 4 H). ¹³C NMR (100 MHz, CDCl3): δ = 153.5, 134.9, 129.0, 128.9, 126.3, 31.4, 24.6.
IR (KBr): νmax = 3444, 3042, 2991, 1633, 1583, 1482, 1438, 1231, 1205, 790 cm-¹. LC-MS (AP+, MeCN-H2O, 80:20): 2.49 min, 356.6 [MH+]. Anal Calcd for C18H20N4S2: C, 60.64; H, 5.65; N, 15.72; S, 17.93. Found: C, 60.31; H, 5.81; N, 15.67; S, 17.71.
3,6-Bis(2-phenylsulfanylethyl)-1,2,4,5-tetrazine (6) Mp 55 ˚C (pink crystals). ¹H NMR (400 MHz, CDCl3): δ = 7.42-7.35 (m, 4 H), 7.32-7.25 (m, 4 H), 7.24-7.17 (m, 2 H), 3.60 (t, J = 6.8 Hz, 4 H), 3.52 (t, J = 6.8 Hz, 4 H). ¹³C NMR (100 MHz, CDCl3): δ = 168.4, 134.5, 130.5, 129.0, 126.7, 34.7, 31.8. IR (KBr): νmax = 3023, 2406, 1520, 1425, 1356, 1218, 1048, 929 cm-¹. LC-MS (AP+, MeCN-H2O, 80:20): 3.12 min, 355.2 [MH+]. HRMS (CI): m/z calcd for C18H19N4S2 [MH+]: 355.1051; found: 355.1043.

24

3,6-Bis(2-phenylsulfonylethyl)-1,2,4,5-tetrazine (7) Tetrazine 6 (1.86 g, 5.25 mmol) was dissolved in CH2Cl2 (0.05 M), and the solution was cooled to -10 ˚C. A solution of MCPBA (5.38 g, 21.8 mmol) in CH2Cl2 (0.25 M) was added over a period of 1 h (the temperature was kept below 0 ˚C), after which TLC analysis indicated completion of the reaction [R f (6) = 0.37 (cyclohexane-EtOAc, 7:1), pink spot; R f (7) = 0 (cyclohexane-EtOAc, 7:1), pink spot]. The mixture was successively washed with a solution of NaHSO3 (10%) and a solution of NaHCO3 (10%). The organic layer was then washed with sat. NaCl solution, dried over MgSO4, and filtered. Product 7 was finally obtained as a pink powder (2.19 g, 100%) after concentration under vacuum; mp 183-185 ˚C. ¹H NMR (400 MHz, DMSO-d 6 ): δ = 7.92-7.88 (m, 4 H), 7.74-7.60 (m, 2 H), 7.71-7.62 (m, 4 H), 3.93 (t, J = 7.6 Hz, 4 H), 3.44 (t, J = 7.6 Hz, 4 H). ¹³C NMR (100 MHz, DMSO-d 6 ): δ = 167.0, 138.2, 134.1, 129.6, 127.9, 51.9, 28.1. IR (KBr): νmax = 3082, 2954, 1448, 1427, 1395, 1310, 1294, 1269, 1148, 1083, 1047, 1033, 996, 980, 906, 778, 745, 711 cm-¹. LC-MS (AP+, MeCN-H2O, 50:50): 5.72 min, 418.9 [MH+]. Anal. Calcd for C18H18N4S2O4: C, 51.66; H, 4.34; N, 13.39. Found: C, 51.98; H, 4.40; N, 13.55. HRMS (CI): m/z calcd for C18H19N4S2O4 [MH+]: 419.0848; found: 419.0854.

25

3,6-Divinyl-1,2,4,5-tetrazine (8) To a stirred solution of s-tetrazine 7 (600 mg, 1.43 mmol) in dry THF (120 mL) was added KOt-Bu (307 mg, 2.73 mmol) at -20 ˚C for 1.5 h. The reaction was followed by TLC analysis [R f (7) = 0.45 (cyclohexane-EtOAc, 4:6); R f (8) = 0.95 (cyclohexane-EtOAc, 4:6)]. The solution was finally diluted with 150 mL of cooled Et2O, filtered, and washed with a solution of NaHCO3 (10%, 2 × 100 mL). The organic layer was then washed with brine (150 mL), dried over MgSO4, and further concentrated under controlled vacuum because of its volatility. Product 8 was purified over a SiO2 column (pentane-Et2O, 80:20; R f  = 0.96), obtained as a dark pink oil (81 mg, 42% yield), and kept in the freezer. ¹H NMR (400 MHz, CD2Cl2): δ = 7.17 (dd, J = 10.8, 17.6 Hz, 2 H), 7.01 (dd, J = 1.2, 17.6 Hz, 2 H), 6.02 (dd, J = 1.2, 10.8 Hz, 2 H). ¹³C NMR (100 MHz, CD2Cl2): δ = 164.2, 131.0, 127.8. IR (KBr): νmax = 3041, 1632, 1434, 1364, 1343, 1259, 1075, 1032, 984, 950, 902, 711 cm-¹. LC-MS (AP+, MeOH): 0.04 min, 135.3 [MH+]; HRMS (FI): m/z calcd for C6H6N4 [M+]: 134.0592; found: 134.0590.