Synthesis of Highly Substituted Pyridazines through Alkynyl Boronic Ester Cycloaddition Reactions

Abstract

A highly regioselective transformation of tetrazines through a cycloaddition reaction with alkynyl boronic esters provides highly substituted pyridazine boronic esters as intermediates for CO and CC bond‐forming reactions (see scheme). Functionalization reactions of the CB bond, such as oxidation and the Suzuki cross‐coupling, show the versatility of these species.

Six‐Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

“…Inverse electron demand Diels-Alder reaction of 1,2,4,5-tetrazines are well known in the literature. Cycloadditions with electron-rich alkynes [759,762,774,776,[781][782][783][784][785][786][787][788] or alkenes [602,762,772,773,781,784,[789][790][791][792] Zhou et al have described an alternative Diels-Alder route to the well-known C,C cycloaddition (Carboni-Lindsey reaction). Quantum mechanical calculations showed that N,N cycloaddition of alkenes and alkynes to s-tetrazines is possible.…”

Metalated heterocycles in organic synthesis: Recent applications

“…255 An example of this methodology is the cycloaddition of the tetrazine 132 with the alkynylboronate 133 to give the boronic ester 134 after nitrogen extrusion (Scheme 40). Subsequent palladium-catalyzed crosscoupling with phenyl iodide gave the pyridazine 135.…”

“…When the pyridazine boronic ester is treated with hydrogen peroxide, an oxidation to the 1H-pyridazin-4-ones takes place. 255 In addition, 5-pyrimidylboronic acid and 2-methoxy-5-pyrimidylboronic acid, prepared by the typical halogen-lithium-boron exchange process, has been used for the synthesis of heteroarylpyrimidine derivatives via Suzuki-Miyaura cross-coupling reactions. …”

Metalated Heterocycles in Organic Synthesis: Recent Applications

“…When the pyridazine boronic ester is treated with hydrogen peroxide, an oxidation to the 1H-pyridazin-4-ones takes place. 255 In addition, 5-pyrimidylboronic acid and 2-methoxy-5-pyrimidylboronic acid, prepared by the typical halogen-lithium-boron exchange process, has been used for the synthesis of heteroarylpyrimidine derivatives via Suzuki-Miyaura cross-coupling reactions. 256 257 An example is shown in Scheme X, for the reaction of the vinylboronate 136 and N-benzylated glycine in the presence of formaldehyde, to give the 3-boronic ester pyrrolidine 137 (Scheme 41).…”