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

Abstract

Pyridazines are important scaffolds for medicinal chemistry or crop protection agents, yet the selective preparation of 3bromo-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.

Preparation of 3‐Bromo‐1,2,4,5‐tetrazine

“…3‐Bromotetrazine 7 was shown to be susceptible to nucleophilic attack on nitrogen, [15] leading to unusual alkyl‐hydro‐tetrazines through an interesting mechanism, [15,16] and the products were further converted to novel heterocycles [15] . 3‐Bromo pyridazines could be accessed from this building block 7 , as subsequent downstream products [17] . 3‐Bromotetrazine 7 was further diversified by cross‐coupling reactions, [18] and a data science‐guided computational approach [19] led to the improvement of catalyst systems and broadening of substrate scope, [20] even extending into 1,2,3‐triazines [21] .…”

Examining the Scope of Deriving β-Aryl Enones from Enol Silanes as Ketone Equivalents via Pd(II)-Mediated Sequential Dehydrosilylation and Arylation

“…The arylboronic acid starting materials 2a – 2z and aryl halide starting materials 9a – 9k are available commercially. All silyl enol ether starting materials ( 1a , 6a , 6b , 6c , 6d , 6e , 6f , and 10a ) have been known in the literature and were prepared as per the literature protocols.…”

Synthetic Access to α-Oxoketene Aminals by the Nucleophilic Addition of Enol Silane-Derived Palladium(II) Enolates to Carbodiimides

“…Trimethyl((1-phenylvinyl)oxy)silane ( 2a ), trimethyl((1-( p -tolyl)vinyl)oxy)silane ( 2b ), ((1-(4-methoxyphenyl)vinyl)oxy)trimethylsilane ( 2c ), ((1-(benzo[ d ][1,3]dioxol-5-yl)vinyl)oxy)trimethylsilane ( 2d ), ((1-(3-methoxyphenyl)vinyl)oxy)trimethylsilane ( 2e ), trimethyl((1-(4-(trifluoromethyl)phenyl)vinyl)oxy)silane ( 2f ), methyl 3-(1-((trimethylsilyl)oxy)vinyl)benzoate ( 2g ), 4-(1-((trimethylsilyl)oxy)vinyl)benzonitrile ( 2h ), trimethyl((1-(4-nitrophenyl)vinyl)oxy)silane ( 2i ), ((1-(4-fluorophenyl)vinyl)oxy)trimethylsilane ( 2j ), ((1-(4-chlorophenyl)vinyl)oxy)trimethylsilane ( 2k ), ((1-(4-bromophenyl)vinyl)oxy)trimethylsilane ( 2l ), ((1-(4-iodophenyl)vinyl)oxy)trimethylsilane ( 2m ), ((1-(2-chlorophenyl)vinyl)oxy)trimethylsilane ( 2n ), trimethyl((1-(naphthalen-1-yl)vinyl)oxy)silane ( 2o ), trimethyl((4-phenylbuta-1,3-dien-2-yl)oxy)silane ( 2p ), trimethyl((4-( p -tolyl)buta-1,3-dien-2-yl)oxy)silane ( 2q ), trimethyl((1-(1-methylcyclopropyl)vinyl)oxy)silane ( 2r ), ((3,3-dimethylbut-1-en-2-yl)oxy)trimethylsilane ( 2s ), (cyclopent-1-en-1-yloxy)trimethylsilane ( 2t ), and ethyl 2-oxo-3-((trimethylsilyl)oxy)but-3-enoate ( 2u ) …”