Reagents and methods for tetrazine synthesis

A compound according to the following structure:

• wherein R is hydrogen, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group;
• wherein R2 is hydrogen, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, or a substituted heterocyclic group;
• wherein R3 and R4 are independently H, an alkyl group, a cycloalkyl group, or a heterocyclic group;
• wherein a substituent for the substituted alkyl group and the substituted aryl group comprises an alkyl group, a halogen, a cycloalkyl group, a heterocyclic group, an aryl group, and/or a heteroaryl group;
• wherein the alkyl group has 1-20 carbon atoms, the cycloalkyl group has 3-20 carbon atoms, the aryl group has 6-40 carbon atoms, the aryl group has 6-40 carbon atoms;
• wherein the heteroaryl group is pyridyl group, a furanyl group, a thiophenyl group, a quinolinyl group, an isoquinolinyl group, a pyrazinyl group, a pyrimidyl group, a pyridazinyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an indazolyl group, a benzofuranyl group, a benzothiophenyl or a triazinyl group;
• and
• wherein the heterocyclic group is a piperazine ring, a pyrrolidine ring, a pyrrolidone ring, an azetidine ring, a morpholine ring, a dioxane ring, a tetrahydrofuran ring, an oxirane ring, a pyran ring, a piperidine ring, or a cyclic amide.

A compound according to the following structure:

• wherein R1 is an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group;
• wherein R is hydrogen, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group;
• wherein a substituent for the substituted alkyl group and the substituted aryl group comprises an alkyl group, a halogen, a cycloalkyl group, a heterocyclic group, an aryl group, and/or a heteroaryl group;
• wherein the alkyl group has 1-20 carbon atoms, the cycloalkyl group has 3-20 carbon atoms, the aryl group has 6-40 carbon atoms, the aryl group has 6-40 carbon atoms;
• wherein the heteroaryl group is pyridyl group, a furanyl group, a thiophenyl group, a quinolinyl group, an isoquinolinyl group, a pyrazinyl group, a pyrimidyl group, a pyridazinyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an indazolyl group, a benzofuranyl group, a benzothiophenyl or a triazinyl group;
• and
• wherein the heterocyclic group is a piperazine ring, a pyrrolidine ring, a pyrrolidone ring, an azetidine ring, a morpholine ring, a dioxane ring, a tetrahydrofuran ring, an oxirane ring, a pyran ring, a piperidine ring, or a cyclic amide.

A method for converting an oxetanyl ester 15 to a thio-substituted tetrazine 30,

• the method comprising:
• contacting the oxetanyl ester 15 with a Lewis base and a 5-isothiocarbonohydrazidium salt 20 to form a thio-substituted tetrazine 30, as shown below in reaction scheme (3):
• wherein R is hydrogen, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group;
• wherein R1 is an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group;
• wherein a substituent for the substituted alkyl group and the substituted aryl group comprises an alkyl group, a halogen, a cycloalkyl group, a heterocyclic group, an aryl group, and/or a heteroaryl group,
• wherein the alkyl group has 1-20 carbon atoms, the cycloalkyl group has 3-20 carbon atoms, the aryl group has 6-40 carbon atoms, the aryl group has 6-40 carbon atoms,
• wherein the heteroaryl group is pyridyl group, a furanyl group, a thiophenyl group, a quinolinyl group, an isoquinolinyl group, a pyrazinyl group, a pyrimidyl group, a pyridazinyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an indazolyl group, a benzofuranyl group, a benzothiophenyl or a triazinyl group, and
• wherein the heterocyclic group is a piperazine ring, a pyrrolidine ring, a pyrrolidone ring, an azetidine ring, a morpholine ring, a dioxane ring, a tetrahydrofuran ring, an oxirane ring, a pyran ring, a piperidine ring, or a cyclic amide.