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

Iron-catalysed alkene and heteroarene H/D exchange by reversible protonation of iron-hydride intermediates

C–H functionalisation reactions offer a sustainable method for molecular construction and diversification. These reactions however remain dominated by precious metal catalysis. While significant interest in iron-catalysed C–H activation reactions has emerged, the isolation, characterisation and mechanistic understanding of these processes remain lacking. Herein the iron-catalysed C(sp(2))–H bond hydrogen/deuterium exchange reaction using CD(3)OD is reported for both heterocycles and, for the first time, alkenes (38 examples). Isolation and characterisation, including by single-crystal X-ray diffraction, of the key iron-aryl and iron-alkenyl C–H metallation intermediates provided evidence for a reversible protonation of the active iron hydride catalyst. Good chemoselectivity was observed for both substrate classes. The developed procedure is orthogonal to previous iron-catalysed H/D exchange methods which used C(6)D(6), D(2), or D(2)O as the deuterium source, and uses only bench-stable reagents, including the iron(ii) pre-catalyst. Further, a new mechanism of iron-hydride formation is reported in which β-hydride elimination from an alcohol generates the iron hydride. The ability to produce, isolate and characterise the organometallic products arising from C–H activation presents a basis for future discovery and development

Nucleophilic Attack on Nitrogen in Tetrazines by Silyl-Enol Ethers

The nucleophilic addition to nitrogen in 3-monosubstituted s-tetrazines under mild conditions is reported, by using silyl-enol ethers as the nucleophiles and mediated by BF3. The preference for this azaphilic addition over the usually observed inverse electron demand Diels-Alder reactions was determined experimentally and evaluated theoretically. In this regard, the influence of the effect of BF3-coordination to s-tetrazines was investigated thoroughly. 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. Lastly, the decomposition of the unstable adducts was examined and an interesting rearrangement to a triazine derived structure was observed.</div