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

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

References and Notes

• 1 Boronic Acids   Hall DG. Wiley-VCH; Weinheim: 2005. 
• For recent overviews, see:
• 2a Hilt G. Bolze P. Synthesis  2005,  2091 
• 2b Gandon V. Aubert C. Malacria M. Chem. Commun.  2006,  2209 
• 3a Ester C. Maderna A. Pritzkow H. Siebert W. Eur. J. Inorg. Chem.  2000,  1177 
• 3b Davies MW. Johnson CN. Harrity JPA. J. Org. Chem.  2001,  66:  3525 
• 3c Gandon V. Leca D. Aechtner T. Vollhardt KPC. Malacria M. Aubert C. Org. Lett.  2004,  6:  3405 
• 3d Gandon V. Leboeuf D. Amslinger S. Vollhardt KPC. Malacria M. Aubert C. Angew. Chem. Int. Ed.  2005,  44:  7114 
• 3e Hilt G. Smolko KI. Angew. Chem. Int. Ed.  2003,  42:  2795 
• 3f Yamamoto Y. Ishii J.-I. Nishiyama H. Itoh K. J. Am. Chem. Soc.  2004,  126:  3712 
• 4a Moore JE. Davies MW. Goodenough KM. Wybrow RAJ. York M. Johnson CN. Harrity JPA. Tetrahedron  2005,  61:  6707 
• 4b Helm MD. Moore JE. Plant A. Harrity JPA. Angew. Chem. Int. Ed.  2005,  44:  3889 
• 4c Moore JE. York M. Harrity JPA. Synlett  2005,  860 
• 4d Delaney PM. Moore JE. Harrity JPA. Chem. Commun.  2006,  3323 
• 5 Gomez-Bengoa E. Helm MD. Plant A. Harrity JPA. J. Am. Chem. Soc.  2007,  129:  2691 
• 6 For related mechanistic studies of cycloadditions involving 1, see: Rusinov GL. Ishmetova RI. Latosh NI. Ganebnych IN. Chupakhin ON. Potemkin VA. Russ. Chem. Bull.  2000,  49:  355 
• 7 For an excellent overview of [4+2] cycloadditions of 1,2,4,5-tetrazines, see: Sauer J. Heldmann DK. Hetzenegger J. Krauthan J. Sichert H. Schuster J. Eur. J. Org. Chem.  1998,  2885 
• 8 Brown HC. Bhat NG. Srebnik M. Tetrahedron Lett.  1988,  29:  2631 
• 9a Carboni RA. Lindsey RV. J. Am. Chem. Soc.  1959,  81:  4342 
• 9b Boger DL. Chem. Rev.  1986,  86:  781 

10

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.

11

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.

12

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