Evaluation of New Dihydrophthalazine-Appended 2,4-Diaminopyrimidines against Bacillus anthracis: Improved Syntheses Using a New Pincer Complex

Abstract

The synthesis and evaluation of ten new dihydrophthalazine-appended 2,4-diaminopyrimidines as potential drugs to treat Bacillus anthracis is reported. An improved synthesis utilizing a new pincer catalyst, dichlorobis[1-(dicyclohexylphosphanyl)-piperidine]palladium(II), allows the final Heck coupling to be performed at 90 °C using triethylamine as the base. These milder conditions have been used to achieve improved yields for new and previously reported substrates with functional groups that degrade or react at the normal 140 °C reaction temperature. An analytical protocol for separating the S and R enantiomers of two of the most active compounds is also disclosed. Finally, the X-ray structure for the most active enantiomer of the lead compound, (S)-RAB1, is given.

Thermal Stability and Utility of Dienes as Protecting Groups for Acrylamides

“…There is a large body of literature precedent for the protection of electron deficient alkenes, such as maleimides, α,β-unsaturated ketones, and α,β-unsaturated esters, as thermally reversible retro-Diels–Alder (DA) adducts. , There are fewer examples of such a strategy being used to mask α,β-unsaturated amides. − Though less reactive than their keto or ester counterparts, acrylamides can react via undesired pathways depending on the reaction conditions as well as their electronic and steric environments. Basic and/or nucleophilic conditions such as those in nucleophilic aromatic substitution or palladium mediated cross couplings can be particularly problematic for acrylamides. − Most often, this motif is installed at the end of a synthetic sequence to avoid these problems. Notably, there are several examples where a β-chloro or sulfonyl propionamide 4 serves as a masked acrylamide, and the olefin 5 is generated by treatment with strong base (Figure A). , To our knowledge, there is a single report disclosing a Diels–Alder adduct as a masked acrylamide in a medicinal chemistry setting .…”