Multicomponent Synthesis of Dihydropyrimidines and Thiazines

Abstract

A broad range of differently substituted dihydropyrimidines and thiazines can be efficiently prepared by using a four-component reaction between phosphonates, nitriles, aldehydes, and iso(thio)cyanates. The scope and limitations of this multicomponent reaction are fully described. Variation of all four components has been investigated. The nitrile and aldehyde inputs can be varied extensively, but variation of the phosphonate input remains limited. An interesting rearrangement leading to phosphoramidates has been observed. Furthermore, the multicomponent reaction seems to be restricted to the use of isocyanates with strongly electron-withdrawing substituents, but an interesting additional exchange reaction under microwave conditions leads to dihydropyrimidines with less electron-withdrawing substituents at N3. In addition, a diastereoselective formation of dihydropyrimidines has been observed when using a chiral aldehyde as the input. Finally, by changing the isocyanate component to an isothiocyanate, thiazines are efficiently formed instead of the corresponding thio-dihydropyrimidines.

Triethylamine‐Catalyzed Domino Reactions of 1,3‐Thiazolidinedione: A Facile Access to Functionalized Dihydrothiophenes

“…[1,2] In recent years MCRs have attracted considerable attention due to their rapid elaboration of complex structures in a highly efficient and modular manner, and the formation of several bonds in a single step is highly compatible with the goals of "green chemistry" and atom economy. [3,4] The application of this strategy in the synthesis of heterocycles has recently become an attractive field because of the important role of these targets in natural products, pharmaceuticals, and functional materials. [5,6] The synthesis of heterocycles by multicomponent reactions often involves classic carbonyl condensation chemistry.…”

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

“…The Yi [192] example follows the traditional coupling using a nitrile instead of a urea precursor, which ultimately leads to a heterocyclic ring that contains only one nitrogen atom instead of two. Scheme 12 shows a novel [2 + 2 + 1 + 1] four-component strategy by Orru [193–194]. Since the Biginelli adduct is an even-membered ring with alternating nucleophilic and electrophilic centres, all but two of the cited examples do not involve redox chemistry and are simply characterized as condensation or coupling reactions.…”

Microwave‐Assisted Dimroth Rearrangement of Thiazines to Dihydropyrimidinethiones: Synthetic and Mechanistic Aspects

“…In the context of our recent multicomponent syntheses of functionalized 2-amino-1,3-thiazines 1 [8,9] we became interested in exploring this underutilized type of Dimroth rearrangement in more detail and to investigate its scope as preparative route to otherwise difficult to prepare N3-substituted dihydropyrimidine-2-thiones 2 (DHPMs, see Scheme 2) [9a, 10]. Dihydropyrimidines of this structural type are privileged heterocyclic scaffolds that exhibit a variety of different biological activities [11].…”