Organic Superbases in Annulation with Propargylic Alcohols: Straightforward Synthesis of the Functionalized Oxazolopyrrolohexahydropyrimidine and Oxazolohexahydropyrimidoazepine Scaffolds

Abstract

The popular organic superbases 1,5‐diazabicyclo[4.3.0]non‐5‐ene (DBN) and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) underwent annulation with electron‐deficient propargylic alcohols [EWG = CN, C(O)Ph, CO2Me] to afford functionalized condensed hexahydropyrimidine systems, [1,3]oxazolo[3,2‐a]pyrrolo[2,1‐b]hexahydropyrimidines and [1,3]oxazolo[3′,2′:3,4] hexahydropyrimido[1,2‐a]azepines, in good to high yields. The reactions proceeded regioselectively and, in most cases, stereoselectively under mild conditions (without catalyst, 20–25 °C). The synthesized compounds, owing to their potential rich chemistry, are novel promising precursors for pyrimidine‐based pharmaceuticals.

DBU: A Reaction Product Component

“…A large excess of water was required for the amidation of alkyl 4hydroxybut-2-ynoates (Scheme 22a), low amounts leading to addition/cyclization reactions (see Chapter 5, Scheme 32). [50] In 1996, Dolphin and Ma disclosed the synthesis of the amidolactame depicted in Scheme 23a from TMSOTf-promoted reaction of DBU with pheophorbide a. [51] A plausible mechanism which somewhat differs from that proposed by the authors involves activation of the β-ketoester unit with TMSOTf to mediate addition of DBU, leading to 23A (Scheme 23b).…”

“…[49] Similar annulation reactions occurred from the corresponding keto-and cyano-compounds (Scheme 32a). [50,60] The products would arise via Michael-type addition intermediates 32A (Scheme 32b). As depicted in Chapter 3, Shi and co-workers reported a different addition/cyclization process from -methyl alkynoates (Scheme 18a).…”

“…Indeed, DBN display properties similar to those of DBU, [8] and reports describing similar results are already available. [13,18,20,30,34,40,43,44,46,49,50,51,55,62,70,73,[75][76][77][78]…”

Tandem Reactions of Ynones: via Conjugate Addition of Nitrogen‐, Carbon‐, Oxygen‐, Boron‐, Silicon‐, Phosphorus‐, and Sulfur‐Containing Nucleophiles

“…In this decade, R 2 N–E substrates were frequently applied in cyclization reactions. The electrophilic moiety could be ketone, or imine etc. Usually, the mechanism included a conjugate addition and an intramolecular nucleophilic addition (Scheme ).…”

“…Commercial reagents like 1,5‐diazabicyclo[4.3.0]non‐5‐ene (DBN) and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) can be applied in the R 2 N–E strategy [Eq. (27‐1)].…”