56107-91-6

Upstream product

• 5720-07-0 4-methoxyphenylboronic acid 
• 100-09-4 4-methoxybenzoic acid 
• 497870-31-2 (3-methyloxetan-3-yl)methyl 4-methoxybenzoate 
• 72116-54-2 3-(4-methoxyphenyl)-6-(methylthio)-1,2,4,5-tetrazine 
• 76109-86-9 1-(4-methoxyphenyl)-2,6,7-trioxabicyclo<2.2.2>octane 

Downstream Products

• 96859-87-9 3-(4-Methoxy-phenyl)-5-nitro-pyridazine 
• 72115-80-1 6-amino-3-(p-methoxy-phenyl)-1,2,4,5-tetrazine 
• 78199-57-2 3-(p-methoxy-phenyl)-1,6-dihydro-1,2,4,5-tetrazine 

Relevant academic research and scientific papers

REAGENTS AND METHODS FOR TETRAZINE SYNTHESIS

Disclosed herein are mono- and di-substituted tetrazines and methods of their preparation and converting an oxetanyl ester to a thio-substituted tetrazine, which is then converted to a mono-substituted tetrazine, a di-substituted tetrazine, or a vinylether disubstituted tetrazine.

Cross-Coupling Reactions of Monosubstituted Tetrazines

A Ag-mediated Pd-catalyzed cross-coupling method for 3-bromo-1,2,4,5-tetrazine with boronic acids is presented. Electronic modification of the 1,1′-bis(diphenylphosphine)ferrocene (dppf) ligand was found to be crucial for good turnover. Using this fast method, a variety of alkyl-, heteroatom-, and halide-substituted aryl- and heteroaryl-tetrazines were prepared (29 examples, up to 87% yield).

Nucleophilic Attack on Nitrogen in Tetrazines by Silyl-Enol Ethers

The nucleophilic addition of silyl-enol ethers to nitrogen in 3-monosubstituted s-tetrazines mediated by BF3 is reported. The preference for this azaphilic addition over the usually observed inverse electron demand Diels-Alder reactions was evaluated theoretically and corroborated by experiments. The substrate dependency of this unusual reaction was rationalized by determination of the activation barriers and on the basis of the activation strain model by employing density functional theory.

Boron Trifluoride-Mediated Cycloaddition of 3-Bromotetrazine and Silyl Enol Ethers: Synthesis of 3-Bromo-pyridazines

Pyridazines are important scaffolds for medicinal chemistry or crop protection agents, yet the selective preparation of 3-bromo-pyridazines with high regiocontrol remains difficult. We achieved the Lewis acid-mediated inverse electron demand Diels-Alder reaction between 3-monosubstituted s-tetrazine and silyl enol ethers and obtained functionalized pyridazines. In the case of 1-monosubstituted silyl enol ethers, exclusive regioselectivity was observed. Downstream functionalization of the resulting 3-bromo-pyridazines was demonstrated utilizing several cross-coupling protocols to synthesize 3,4-disubstituted pyridazines with excellent control over the substitution pattern.

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6-Disubstituted Tetrazines from Carboxylic Ester Precursors

Since tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3-monosubstituted tetrazines. Described here is a general, one-pot method for converting (3-methyloxetan-3-yl)methyl carboxylic esters into 3-thiomethyltetrazines. These versatile intermediates were applied to the synthesis of unsymmetrical tetrazines through Pd-catalyzed cross-coupling and in the first catalytic thioether reduction to access monosubstituted tetrazines. This method enables the development of new tetrazine compounds possessing a favorable combination of kinetics, small size, and hydrophilicity. It was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied to the labeling of endogenous MAGL in live cells.