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Synlett 2007(2): 0204-0210  
DOI: 10.1055/s-2007-967991
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Palladium-Catalyzed Synthesis of Unsymmetrical (Het)aryl­tetrazines

Nicolas Lecontea, Anne Keromnes-Wuillaumeb, Franck Suzenet*a, Gérald Guillaumeta
a Institut de Chimie Organique et Analytique, UMR 6005, Université d’Orléans, BP 6759, 45067 Orléans, France
b CEA Le Ripault, BP 16, 37260 Monts, France
Fax: +33(2)38417281; e-Mail: franck.suzenet@univ-orleans.fr;
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Publication History

Received 27 July 2006
Publication Date:
24 January 2007 (online)

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Abstract

Palladium-catalyzed copper(I)-mediated cross-coupling reaction of 3-methylthio-6-(morpholin-4-yl)-1,2,4,5-tetrazine with a wide range of boronic acids and organotin derivatives led to new unsymmetrical aryl- and hetaryl-substituted tetrazines in moderate to good yields. These results represent the first cross-coupling reactions of readily available 3-methylthiotetrazine under Suzuki-like and Stille-like conditions and could extend the scope of tetrazine chemistry.

Key words

3-methylthio-1,2,4,5-tetrazine - Pd-catalyzed - Cu(I)-assisted - Suzuki-like reactions - Stille-like reactions

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(17) 3-Methylthio-6-(morpholin-4-yl)-1,2,4,5-tetrazine (1): To a suspension of 3,6-bis(methylthio)-1,2,4,5-tetrazine (1.08 g, 6.2 mmol) in EtOH (20 mL) at 25 °C, morpholine (660 µL, 7.5 mmol) was added. After the mixture was refluxed for 15 h, it was allowed to cool to r.t. and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane-EtOAc = 95:5 to 8:2). 3-Methylthiotetrazine 1 (1.24 g, 94%) was obtained as a red solid; mp 131-132 °C. MS (Ionspray®): m/z = 214 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 3.94 (dt, J = 1.0, 4.8 Hz, 4 H), 3.84 (dt, J = 1.0, 4.8 Hz, 4 H), 2.67 (s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ = 166.6 (C), 160.5 (C), 66.5 (CH2), 43.9 (CH2), 13.7 (CH3). IR: 2965, 2908, 1524, 1441, 1267, 1113, 920, 847, 791 cm-1. HRMS: m/z [M+·] calcd for C7H11N5OS: 213.0684; found: 213.0687.

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Palladium-Catalyzed Cross-Coupling Reaction of Compound 1 with Boronic Acids 2a-i; General Procedure: 3-Methylthio-6-(morpholin-4-yl)-1,2,4,5-tetrazine (1; 100 mg, 0.5 mmol), boronic acid (1.1 mmol) and CuTC (197 mg, 1.1 mmol) were dissolved in anhyd DME (5 mL) in a sealed reaction vessel under argon. After the mixture was degassed, Pd(PPh3)4 (27 mg, 0.025 mmol) was added and the reaction mixture was stirred under microwave irradiation at 200 °C (14-16 bars) for 2 h. The reaction mixture was then allowed to cool to r.t., poured into sat. aq Na2CO3 and extracted with CH2Cl2. The organic phases were collected, dried over MgSO4 and the solvent was removed under reduced pressure. Desired compounds were purified by chromatography on silica gel (PE-EtOAc = 95:5 to 7:3).
3-(Morpholin-4-yl)-6-(4-methoxyphenyl)-1,2,4,5-tetrazine ( 3a): 4-Methoxyphenylboronic acid (2a; yield: 71%) and 1-methoxy-4-tributylstannylbenzene (4a; yield: 49%) were used as the boronic acid and the organostannane derivatives, respectively; red solid; mp 176-178 °C. MS (Ionspray®): m/z = 274 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.34 (d, J = 9.0 Hz, 2 H), 7.05 (d, J = 9.0 Hz, 2 H), 4.04 (t, J = 4.5 Hz, 4 H), 3.89 (s, 3 H), 3.87 (t, J = 4.5 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 162.0 (C), 160.6 (C), 159.5 (C), 128.0 (CH), 125.3 (C), 114.6 (CH), 66.6 (CH2), 55.6 (CH3), 43.9 (CH2). IR: 2917, 1607, 1512, 1438, 1244, 1116, 1034, 936, 837 cm-1. Anal. Calcd for C13H15N6O2 (273): C, 57.13; H, 5.53; N, 25.63. Found: C, 57.34; H, 5.52; N, 24.48.
3-(Morpholin-4-yl)-6-(3-methoxyphenyl)-1,2,4,5-tetrazine ( 3b): 3-Methoxyphenylboronic acid (2b) was used as the boronic acid derivative; yield: 67%; red solid; mp 140-142 °C. MS (Ionspray®): m/z = 274 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 7.99 (dt, J = 1.0, 8.0 Hz, 1 H), 7.93 (dd, J = 1.0, 2.6 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.05 (ddd, J = 1.0, 2.6, 8.0 Hz, 1 H), 4.05 (t, J = 4.5 Hz, 4 H), 3.89 (s, 3 H), 3.87 (t, J = 4.5 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.5 (C), 160.2 (C), 159.3 (C), 134.0 (C), 130.1 (CH), 118.8 (CH), 117.4 (CH), 110.7 (CH), 66.5 (CH2), 55.5 (CH3), 43.8 (CH2). IR: 2927, 2857, 1598, 1522, 1448, 1262, 1229, 1119, 963, 786 cm-1. HRMS: m/z [M+·] calcd for C13H15N5O2: 273.1226; found: 273.1220.
3-(Morpholin-4-yl)-6-(3-methylphenyl)-1,2,4,5-tetrazine ( 3c): 3-Methylphenylboronic acid (2c) was used as the boronic acid derivative; yield 58%; red solid; mp 127-129 °C. MS (Ionspray®): m/z = 258.5 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.22 (s, 1 H), 8.20 (d, J = 7.8 Hz, 1 H), 7.42 (t, J = 7.8 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 4.06 (t, J = 4.7 Hz, 4 H), 3.88 (t, J = 4.7 Hz, 4 H), 2.46 (s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.6 (C), 159.7 (C), 139.9 (C), 132.6 (C), 131.6 (CH), 129.1 (CH), 127.1 (CH), 123.6 (CH), 66.6 (CH2), 43.9 (CH2), 21.7 (CH3). IR: 2965, 2860, 2362, 2338, 1521, 1451, 1252, 1116, 941, 784 cm-1. HRMS: m/z [M+·] calcd for C13H15N5O: 257.1277; found: 257.1288.
3-(Morpholin-4-yl)-6-(3-acetylphenyl)-1,2,4,5-tetrazine ( 3d): 3-Acetylphenylboronic acid (2d) was used as the boronic acid derivative; yield: 56%; red solid; mp 174-176 °C. MS (Ionspray®): m/z = 286 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.98 (s, 1 H), 8.60 (d, J = 7.9 Hz, 1 H), 8.12 (d, J = 7.9 Hz, 1 H), 7.65 (t, J = 7.9 Hz, 1 H), 4.09 (t, J = 4.4 Hz, 4 H), 3.89 (t, J = 4.4 Hz, 4 H), 2.70 (s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ = 197.7 (C), 160.5 (C), 158.7 (C), 137.9 (C), 133.2 (C), 130.5 (CH), 130.1 (CH), 129.5 (CH), 126.4 (CH), 66.5 (CH2), 43.8 (CH2), 26.9 (CH3). IR: 2981, 2906, 2359, 2340, 1692, 1536, 1262, 1111, 967, 946 cm-1. HRMS: m/z [M+·] calcd for C14H15N5O2: 285.1226; found: 285.1213.
3-(Morpholin-4-yl)-6-(4-acetylphenyl)-1,2,4,5-tetrazine ( 3e): 4-Acetylphenylboronic acid(2e) was used as the boronic acid derivative; yield: 54%; red solid; mp 194-197 °C. MS (Ionspray®): m/z = 286 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.49 (d, J = 8.8 Hz, 2 H), 8.11 (d, J = 8.8 Hz, 2 H), 4.09 (t, J = 4.6 Hz, 4 H), 3.89 (t, J = 4.6 Hz, 4 H), 2.41 (s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ = 197.7 (C), 160.2 (C), 158.7 (C), 138.6 (C), 136.9 (C), 129.1 (CH), 126.4 (CH), 66.6 (CH2), 43.9 (CH2), 26.9 (CH3). IR: 2975, 2874, 2324, 1676, 1536, 1269, 1114, 943, 849 cm-1. HRMS: m/z [M+·] calcd for C14H15N5O2: 285.1226; found: 285.1216.
3-(Morpholin-4-yl)-6-(3-cyanophenyl)-1,2,4,5-tetrazine ( 3f): 3-Cyanophenylboronic acid (2f) was used as the boronic acid derivative; yield: 28%; red solid; mp 197-198 °C. MS (Ionspray®): m/z = 269 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.71 (dt, J = 0.5, 1.5 Hz, 1 H), 8.63 (dt, J = 1.5, 8.0 Hz, 1 H), 7.79 (dt, J = 1.5, 8.0 Hz, 1 H), 7.65 (dt, J = 0.5, 8.0 Hz, 1 H), 4.09 (t, J = 4.7 Hz, 4 H), 3.89 (t, J = 4.7 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.4 (C), 157.8 (C), 134.1 (C), 133.8 (CH), 130.1 (CH), 130.0 (CH), 129.8 (CH), 118.5 (C), 113.5 (C), 66.5 (CH2), 43.9 (CH2). IR: 2872, 2235, 1536, 1446, 1255, 1117, 1034, 966 cm-1. HRMS: m/z [M+·] calcd for C13H12N6O: 268.1073; found: 268.1079.
3-(Morpholin-4-yl)-6-(3-trifluoromethylphenyl)-1,2,4,5-tetrazine ( 3g): 3-Trifluoromethylphenylboronic acid (2g) was used as the boronic acid derivative; yield: 31%; red solid; mp 144 °C. MS (Ionspray®): m/z = 311.5 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.69 (s, 1 H), 8.58 (d, J = 7.8 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1 H), 4.08 (t, J = 4.5 Hz, 4 H), 3.89 (t, J = 4.5 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.5 (C), 158.4 (C), 133.6 (C), 131.6 (2 J C-F = 33 Hz, C), 129.7 (CH), 129.3 (CH), 127.3 (3 J C-F = 4 Hz, CH), 124.1 (1 J C-F = 271 Hz, C), 123.2 (3 J C-F = 4 Hz, CH), 66.5 (CH2), 43.9 (CH2). IR: 2917, 2850, 1530, 1446, 1302, 1268, 1166, 1120, 1066, 1034, 963, 945, 695 cm-1. HRMS: m/z [M+·] calcd for C13H12N5OF3: 311.0994; found: 311.0991.
3-(Morpholin-4-yl)-6-(3-bromophenyl)-1,2,4,5-tetrazine ( 3h): 3-Bromophenylboronic acid (2h) was used as the boronic acid derivative; yield: 42%; red solid; mp 141-142 °C. 1H NMR (250 MHz, CDCl3): δ = 8.56 (t, J = 1.5 Hz, 1 H), 8.33 (ddd, J = 1.0, 1.5, 8.0 Hz, 1 H), 7.64 (ddd, J = 1.0, 1.5, 8.0 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 4.07 (t, J = 4.4 Hz, 4 H), 3.88 (t, J = 4.4 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.5 (C), 158.4 (C), 134.8 (C), 133.7 (CH), 130.6 (CH), 129.4 (CH), 124.8 (CH), 123.4 (C), 66.6 (CH2), 43.9 (CH2). IR: 2361, 2337, 1530, 1447, 1254, 1123, 1031, 944, 780, 733 cm-1. HRMS: m/z [M+·] calcd for C12H12N5O79Br: 321.0225; found: 321.0211.
3-(Morpholin-4-yl)-6-(naphtalen-2-yl)-1,2,4,5-tetrazine ( 3i): Naphthalen-2-ylboronic acid (2i) was used as boronic acid derivative; yield: 60%; red solid; mp 172-173 °C. MS (Ionspray®): m/z = 294 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.93 (s, 1 H), 8.48 (dd, J = 1.8, 8.5 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 2 H), 7.89 (t, J = 5.0 Hz, 1 H), 7.54 (m, 2 H), 4.08 (t, J = 4.5 Hz, 4 H), 3.89 (t, J = 4.5 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.5 (C), 159.7 (C), 134.7 (C), 133.5 (C), 130.0 (C), 129.2 (CH), 129.0 (CH), 128.0 (CH), 127.4 (CH), 126.8 (CH), 126.5 (CH), 123.3 (CH), 66.6 (CH2), 43.9 (CH2). IR: 2960, 2869, 2359, 1522, 1451, 1336, 1262, 1119, 953 cm-1. Anal. Calcd for C16H15N5O(293): C, 65.52; H, 5.15; N, 23.88. Found: C, 65.64; H, 5.07; N, 23.26.

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Cross-Coupling Reaction Followed by an Oxidative Treatment (Compounds 3g-j): Same procedure as in ref. 18 was used with an extra oxidative step, described as follows. The crude product was dissolved in CH2Cl2. After the temperature was adjusted to 5 °C with an ice bath, MCPBA (81 mg, 0.47 mmol) was added and the mixture was stirred for 30 min at 5 °C. The reaction was then hydrolyzed with sat. aq NaHCO3 and extracted with CH2Cl2. The organic phases were collected, dried over MgSO4 and the solvent was removed under reduced pressure. Desired compounds were purified by chromatography on silica gel (PE-EtOAc: 95:5 to 7:3).

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Palladium-Catalyzed Cross-Coupling Reaction of Compound 1 with Organostannanes 4a-d; General Procedure: Same procedure as in ref. 18 was used except that the reaction was carried out with organotin derivatives.
3-(Morpholin-4-yl)-6-[( E )-styryl]-1,2,4,5-tetrazine ( 3j): 3-[(E)-2-Phenylethenyl]tributyltin (4b) was used as the organostannane derivative; yield: 34%; red solid; mp 126 °C. MS (Ionspray®): m/z = 270 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 7.96 (d, J = 16.3 Hz, 1 H), 7.62 (dd, J = 1.5, 8.3 Hz, 2 H), 7.41 (m, 3 H), 7.35 (d, J = 16.3 Hz, 1 H), 4.03 (t, J = 4.5 Hz, 4 H), 3.86 (t, J = 4.5 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.1 (C), 160.0 (C), 136.0 (C), 135.7 (CH), 129.3 (CH), 129.0 (CH), 127.6 (CH), 121.1 (CH), 66.6 (CH2), 43.8 (CH2). IR: 2956, 2863, 1637, 1521, 1450, 1341, 1254, 1119, 1056, 949, 848, 751, 693 cm-1. HRMS: m/z [M+·] calcd for C14H15N5O: 269.1277; found: 269.1274.
3-(Morpholin-4-yl)-6-(thien-2-yl)-1,2,4,5-tetrazine ( 3k): 2-Tributylstannylthiophene (4c) was used as the organostannane derivative; yield: 42%; red solid; mp 187-191 °C. MS (Ionspray®): m/z = 250 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.00 (dd, J = 1.0, 3.8 Hz, 1 H), 7.50 (dd, J = 1.0, 5.0 Hz, 1 H), 7.19 (dd, J = 3.8, 5.0 Hz, 1 H), 4.03 (t, J = 4.4 Hz, 4 H), 3.87 (t, J = 4.4 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.4 (C), 157.8 (C), 136.7 (C), 129.2 (CH), 128.5 (CH), 127.6 (CH), 66.6 (CH2), 43.9 (CH2). IR: 2965, 2907, 2866, 2362, 2341, 1529, 1433, 1259, 1112, 941, 718 cm-1. HRMS: m/z [M+·] calcd for C10H11N5OS: 249.0684; found: 249.0693.
3-(Morpholin-4-yl)-6-(pyridin-4-yl)-1,2,4,5-tetrazine ( 3l): 4-Tributylstannylpyridine (4d) was used as the organostannane derivative; yield: 30%; red solid; mp 198-199 °C. MS (Ionspray®): m/z = 245.5 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.81 (br s, 2 H), 8.26 (d, J = 4.1 Hz, 2 H), 4.11 (t, J = 4.7 Hz, 4 H), 3.89 (t, J = 4.7 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): δ = 160.4 (C), 157.9 (C), 150.9 (C), 140.1 (CH), 66.6 (CH2), 43.9 (CH2); C9 was not observed. IR: 2989, 2902, 1593, 1520, 1443, 1340, 1250, 1117, 1037, 966, 942, 846 cm-1. Anal. Calcd for C11H12N6O(244): C, 54.09; H, 4.95; N, 34.41. Found: C, 54.41; H, 4.93; N, 34.55.

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For preparation of compound 4b, see ref. 15b.

24

The same experimental procedure as described in ref. 18 was used, except that the reaction was carried out in a 10 mL round-bottomed flask and stirred in refluxing DME for 48 h.

25

In refluxing DME after 48 hours, only traces of the cross-coupling product 6 were observed.
3-Methoxy-6-(4-methoxyphenyl)-1,2,4,5-tetrazine ( 6): 3-Methylthio-6-methoxy-1,2,4,5-tetrazine (5; 129 mg, 0.8 mmol), 4-methoxyphenylboronic acid (2a; 277 mg, 1.8 mmol) and CuTC (342 mg, 1.8 mmol) were dissolved in anhyd DME (6 mL) in a sealed reaction vessel under argon. After the mixture was degassed, Pd(PPh3)4 (47 mg, 0.04 mmol) was added and the reaction mixture was stirred under microwave irradiation at 200 °C for 2 h. The reaction mixture was then allowed to cool to r.t., poured into sat. Na2CO3 and extracted with CH2Cl2. The organic phases were collected, dried over MgSO4 and the solvent was removed under reduced pressure. Purification by chromatography on silica gel (PE-EtOAc: 1:0 to 9:1) afforded compound 7 (22 mg, 12%) as a red solid; mp 119-120 °C. MS (Ionspray®): m/z = 219 [M + H]+. 1H NMR (250 MHz, CDCl3): δ = 8.46 (d, J = 9.0 Hz, 2 H), 7.07 (d, J = 9.0 Hz, 2 H), 4.34 (s, 3 H), 3.91 (s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ = 166.8 (C), 163.1 (C), 162.9 (C), 129.3 (CH), 124.3 (C), 114.8 (CH), 56.6 (CH3), 55.6 (CH3). IR: 2923, 2854, 1602, 1488, 1453, 1376, 1249, 1179, 1117, 1041, 940, 848 cm-1. HRMS: m/z [M+·] calcd for C10H10N4O2: 218.0804; found: 218.0797.