Efficient Preparation of 2-Substituted Pyridazino[4,3-h]psoralen Derivatives

Abstract

An efficient synthesis of 2-chloro-6-methoxypyridazino[4,3-h]psoralen was achieved by Diels-Alder reaction of 3,6-dichloro-1,2,4,5-tetrazine and 8-methoxy-psoralen (8-MOP) in a one-pot procedure. The convenient transformation of this intermediate into the 2-triflate derivative allowed efficient palladium-catalyzed reduction, methoxycarbonylation , and Sonogashira cross-coupling reactions at C₂.

Key words

Diels-Alder - catalysis - DNA - palladium - polycycles

References

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  In our preparation the yield of tetrazine 2 was 68% (1.02 g) from 3,6-bisthiomethyltetrazine (1.74 g).

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11

The Hünig base was also added before heating the reaction mixture, but decomposition of tetrazine 2 and formation of a black tar was observed. Compound 4: mp 323-324 ºC. ¹H NMR (300 MHz, DMSO-d ₆ ): δ = 8.79 (s, 1 H, H₁), 8.35 (s, 1 H, H₁₁), 8.26 (d, J = 9.70 Hz, 1 H, H₁₀), 6.60 (d, J = 9.70 Hz, 1 H, H₉), 4.27 (s, 3 H, OMe). HRMS: m/z calcd for C₁₄H₈N₂O₄Cl (M + 1): 305.0143 (³⁷Cl)/303.0173 (³⁵Cl). Found: 305.0153/303.0180.

12

Aldrich: 5-Methoxypsoralen, 99% (27,572-7, 1 g, $201).

28

Compounds 5, 6, 7, 8, 9 and 10 gave satisfactory analytical and spectroscopic data.