Nucleophilic Attack on Nitrogen in Tetrazines by Silyl-Enol Ethers

Abstract

<div><div><div><p>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.</p></div></div></div>

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

“…Based on the experimental observations and our previous work, 11 we propose the following mechanism for the reaction. BF 3 •OEt 2 prefers binding to N-1 over N-2 (Scheme 6) due to the lower steric interaction with the Br-substituent, thereby lowering the LUMO energy and leading to a stronger overlap with the HOMO of the silyl enol ether.…”

“…Acetonitrile as a solvent led only to traces of product (Table 1, entry 5). To further improve the yield of the reaction, the use of BF As a coordination of the Lewis acid to the tetrazine core was hypothesized as the first step of the reaction, 11 prestirring BF 3 • OEt 2 with Br-Tet for 5 min prior to addition of the silyl enol ether was tested. The yield of 2a, however, turned out to be diminished (19%; Table 1, entry 7), probably due to decomposition of tetrazine 1.…”

“…BF 3 •OEt 2 prefers binding to N-1 over N-2 (Scheme 6) due to the lower steric interaction with the Br-substituent, thereby lowering the LUMO energy and leading to a stronger overlap with the HOMO of the silyl enol ether. 11 Activation of the tetrazine core by BF 3 •OEt 2 at N-1 is followed by the selective formation of intermediate C, which rapidly loses nitrogen. Rearomatization via the loss of TBSOH then affords the product pyridazine.…”

“…Rearomatization via the loss of TBSOH then affords the product pyridazine. 11,16 In contrast, the formation of intermediate C is sterically unfavorable for terminally substituted silyl enol ethers, leading to a completely different reaction pathway. As was demonstrated by the active strain model, the energy required to transform the terminally substituted silyl enol ether into the planar transition state renders the iEDDA reaction unfavorable.…”

“…10 A one-pot procedure to obtain a pyridazine-coordinated airstable variant of the catalyst was also disclosed; however, here too, strictly inert conditions and hazardous reagents have to utilized to synthesis this compound. 10 In contrast to our recently reported azaphilic addition of terminally substituted silyl enol ethers (Scheme 1C), 11 which delivers dearomatized dihydrotetrazines and in some cases pyridazines as minor byproducts in low yields, we envisioned using terminally unsubstituted silyl enol ethers to selectively undergo iEDDA reactions (Scheme 1D).…”