Novel synthesis of unsymmetrically substituted s‐tetrazines

Abstract

The synthesis of unsymmetrical 3‐aryl and 3‐heterocyclic s‐tetrazines has been examined and the scope of the reaction and the product distribution is discussed. The products included unsymmetrical and symmetrical s‐tetrazines, hydrazines, diimides, tetrazoles and triazoles with the composition of the mixtures with respect to structural type varying with the individual reactions. Some transformations with the system are discussed.

Metal‐Catalyzed One‐Pot Synthesis of Tetrazines Directly from Aliphatic Nitriles and Hydrazine

“…[19][20][21] There have been several reported methods to access dialkyl tetrazines from alternative precursors, such as imidates, amidine salts, and aldehydes, but these methods suffer from low yields, limited substrate scope, and the requirement of additional synthetic steps. [22][23][24] For these reasons, a general and robust method to prepare symmetric and asymmetric 1,2,4,5-tetrazines directly from unactivated nitriles would be highly desirable.…”

“…[6,35] 6-Methyl-terminated tetrazines were previously only accessible from reactive precursors such as imidates and amidine salts and in lower yield. [23,35] Dialkyl asymmetric tetrazines with bulkier substituents are extremely difficult to isolate, even from imidates and amidines. In contrast, we were able to isolate 3-benzyl-6pentyl-1,2,4,5-tetrazine (entry 15) from benzyl cyanide and excess hexanenitrile, albeit in lower yield (12 %).…”

A new synthesis of 6‐(alkyl)amino‐3‐aryl(alkyl)‐1,2,4,5‐tetrazines

“…This compound was prepared according to the synthesis described by Lang, Johnson and Cohen (11). We modified the oxidation step by using air or oxygen instead of bromine in acetic acid.…”

Development of a 18F‐Labeled Tetrazine with Favorable Pharmacokinetics for Bioorthogonal PET Imaging

“…Quantum chemical calculations on the basis of a recently reported computational approach (DFT, M06-2X/6-31G(d,p), Gaussian 09) [18] were applied to estimate the reaction kinetics (Table 1) of 1 in comparison to that of phenyl-substituted tetrazines (e.g. 2), [19] which are commonly used in combination with TCO tags for various bioorthogonal ligation applications. [20] As expected, modeling of IEDDA reactions with trans-cyclooctene (3) showed an increased activation free energy for 1 (18.8 kcal mol À1 ) relative to that for 2 (15.0 kcal mol À1 ), but this difference is compensated when s-TCO 4 is used for cycloaddition with 1 (15.3 kcal mol À1 ).…”