Substituent Effects in Carboni-Lindsey Reactions of 1,2,4,5-Tetrazines and Aryl-Substituted Alkynylboronates

Matthew D. Helm; Andrew Plant; Joseph P. A. Harrity

doi:10.1055/s-2007-991064

LETTER

Substituent Effects in Carboni-Lindsey Reactions of 1,2,4,5-Tetrazines and Aryl-Substituted Alkynylboronates

Matthew D. Helm^a, Andrew Plant^b, Joseph P. A. Harrity*^a
^a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
^b Research Chemistry, Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK
Fax: +44(114)2229346; e-Mail: j.harrity@shef.ac.uk;

Abstract

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Abstract

Evidence for an inverse-electron-demand cycloaddition of tetrazines with alkynylboronates is presented by the reaction of 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine with arylalkynylboronate substrates bearing various para substituents.

Key words

cycloaddition - Carboni-Lindsey reaction - 1,2,4,5-tetrazine - pyridazine - boronic ester

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References

References and Notes

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<A NAME="RD27607ST-3D">3d</A> Gandon V. Leboeuf D. Amslinger S. Vollhardt KPC. Malacria M. Aubert C. Angew. Chem. Int. Ed. 2005, 44: 7114

<A NAME="RD27607ST-3E">3e</A> Hilt G. Smolko KI. Angew. Chem. Int. Ed. 2003, 42: 2795

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<A NAME="RD27607ST-4A">4a</A> Moore JE. Davies MW. Goodenough KM. Wybrow RAJ. York M. Johnson CN. Harrity JPA. Tetrahedron 2005, 61: 6707

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Representative Experimental Procedure for Alkynylboronate Cycloaddition Reactions; Synthesis of 3,6-Bis(3,5-dimethyl-1 H -pyrazol-1-yl)-4-(4-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine ( 3b): 3,6-Bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (1; 131 mg, 0.486 mmol) and 2b (125 mg, 0.486 mmol) were dissolved in nitrobenzene (2 mL) and heated at 140 °C until the red colour of the tetrazine had faded. The nitrobenzene was then removed by bulb-to-bulb distillation under reduced pressure and the residue was purified by chromatography on silica gel to give the title compound as a light yellow solid (202 mg, yield: 83%); mp 169.3-170.2 °C. ¹H NMR (250 MHz, CDCl₃): δ = 1.03 (s, 12 H, Me), 1.92 (s, 3 H, Me), 2.09 (s, 3 H, Me), 2.29 (s, 3 H, Me), 2.72 (s, 3 H, Me), 3.74 (s, 3 H, Me), 5.72 (s, 1 H, CH), 6.04 (s, 1 H, CH), 6.71-6.80 (m, 2 H, CH), 7.10-7.20 (m, 2 H, CH). ¹³C NMR (69.2 MHz, CDCl₃): δ = 11.2, 13.4, 13.9, 14.8, 25.2, 55.3, 84.3, 106.0, 111.1, 113.0, 126.0, 130.9, 141.0, 142.4, 145.5, 149.5, 150.4, 152.6, 157.7, 160.0. FTIR: 2977 (m), 2930 (m), 2837 (w), 1611 (m), 1576 (m), 1536 (w), 1507 (s), 1498 (s), 1421 (s), 1402 (s), 1370 (s), 1302 (m), 1251 (s), 1179 (m), 1140 (m), 1124 (m) cm^-1. HRMS: m/z [M + H⁺] calcd for C₂₇H₃₄BN₆O₃: 501.2785; found: 501.2800.

Characterisation Data for Compounds 3c-e: 3c: isolated as a light yellow solid; mp >184 °C (dec.). ¹H NMR (250 MHz, CDCl₃): δ = 0.99 (s, 12 H, Me), 1.97 (s, 3 H, Me), 2.01 (s, 3 H, Me), 2.27 (s, 3 H, Me), 2.70 (s, 3 H, Me), 5.70 (s, 1 H, CH), 6.02 (s, 1 H, CH), 6.85-6.95 (m, 2 H, CH), 7.12-7.22 (m, 2 H, CH). ¹³C NMR (62.9 MHz, CDCl₃): δ = 11.3, 13.3, 13.9, 14.9, 25.3, 84.3, 106.2, 111.3, 114.6 (d, J = 22.0 Hz), 129.8, 131.4 (d, J = 8.5 Hz), 141.2, 142.5, 144.7, 149.7, 150.5, 152.4, 157.6, 162.9 (d, J = 249.0 Hz). FTIR: 2980 (m), 2922 (w), 1604 (w), 1579 (m), 1535 (w), 1505 (s), 1475 (s), 1422 (s), 1402 (s), 1341 (s), 1234 (m), 1162 (w), 1142 (m), 1123 (m) cm^-1. HRMS: m/z [M + H⁺] calcd for C₂₆H₃₁BN₆O₂F: 489.2586; found: 489.2581. 3d: isolated as a light yellow solid; mp 191.9-193.4 °C. ¹H NMR (250 MHz, CDCl₃): δ = 0.98 (s, 12 H, Me), 1.98 (s, 3 H, Me), 2.01 (s, 3 H, Me), 2.26 (s, 3 H, Me), 2.70 (s, 3 H, Me), 5.71 (s, 1 H, CH), 6.01 (s, 1 H, CH), 7.09-7.22 (m, 4 H, CH). ¹³C NMR (62.9 MHz, CDCl₃): δ = 11.3, 13.3, 13.9, 14.9, 25.3, 84.4, 106.3, 111.3, 127.7, 130.9, 132.3, 134.8, 141.2, 142.5, 144.5, 149.8, 150.6, 152.1, 157.5. FTIR: 2980 (m), 2929 (m), 1600 (w), 1579 (m), 1560 (m), 1532 (m), 1493 (s), 1475 (s), 1448 (m), 1421 (s), 1356 (s), 1140 (s) cm^-1. HRMS: m/z [M + H⁺] calcd for C₂₆H₃₁BN₆O₂Cl: 505.2290; found: 505.2310. 3e: isolated as a light yellow solid; mp 215.3-217.0 °C. ¹H NMR (250 MHz, CDCl₃): δ = 1.00 (s, 12 H, Me), 1.97 (s, 3 H, Me), 2.14 (s, 3 H, Me), 2.32 (s, 3 H, Me), 2.76 (s, 3 H, Me), 5.77 (s, 1 H, CH), 6.08 (s, 1 H, CH), 7.30-7.38 (m, 2 H, CH), 7.52-7.61 (m, 2 H, CH). ¹³C NMR (62.9 MHz, CDCl₃): δ = 11.5, 13.2, 13.9, 14.9, 25.3, 84.4, 106.6, 111.6, 112.2, 118.4, 130.3, 131.2, 138.9, 141.4, 142.5, 143.4, 149.9, 150.7, 151.5, 157.4. FTIR: 2992 (m), 2925 (w), 1857 (w), 2232 (m), 1579 (m), 1534 (m), 1503 (m), 1469 (s), 1419 (s), 1369 (m), 1141 (m) cm^-1. HRMS: m/z [M + H⁺] calcd for C₂₇H₃₁N₇O₂B: 496.2632; found: 496.2608.

Unfortunately, the relative rates depicted in Table 4 did not provide a good linear slope when a Hammett plot was drawn up.