Tetrazines and method of synthezising the same
View Patent ↗Provided herein, inter alia, are compositions and methods of synthesis and detection of tetrazines, e.g., a tetrazine of formula and diazonorcaradienes.
1. A method for synthesizing a 3,6-disubstituted 1,2,4,5-tetrazine compound of formula
said method comprising:
combining in a reaction vessel a first substituted nitrile having the formula
a second nitrile having the formula
hydrazine, and
a Lewis Acid catalyst;
thereby forming a tetrazine of formula
wherein
R 3 and R 4 are independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a detectable moiety, a water soluble moiety or a biomolecule; and
L 2A , L 2B , L 3A , and L 3B are independently a bond, —C(O)—, —O—, —S—, —NH—, —NR 5 —, —C(O)NR 6 —, —S(O) n —, —S(O)NR 7 —, —OP(O)(OR 8 )O—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein -L 2A -L 2B -R 3 and -L 3A -L 3B -R 4 are not hydrogen;
R 5 , R 6 , R 7 , R 8 are independently hydrogen, halogen, —N 3 , —NO 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —OCH 3 , —NHCNHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
n is 1 or 2; and
said Lewis Acid catalyst is a metal salt consisting of an anion in combination with a single metal atom selected from the group consisting of Zn, Mg, Cu, Mn, Co, Yb, Sc and Ni.
2. The method of claim 1 , wherein said first substituted nitrile or second substituted nitrile is acetonitrile.
3. The method of claim 1 , wherein said metal is Zn.
4. The method of claim 1 , wherein said metal is Ni.
5. The method of claim 1 , wherein said metal salt is a metal triflate.
6. The method of claim 1 , wherein said anion is Cl, Br or I.