Diversity oriented heterocyclizations of pyruvic acids, aldehydes and 5-amino-N-aryl-1H-pyrazole-4-carboxamides: catalytic and temperature control of chemoselectivity

Abstract

Heterocyclization reactions of pyruvic acids, aromatic aldehydes and 5-amino-N-aryl-1H-pyrazole-4-carboxamides yielding four different types of final compounds are described. The reactions involving arylidenpyruvic acids lead with high degree of selectivity to either 4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acids or 5-[(2-oxo-2,5-dihydrofuran-3-yl)amino]-1H-pyrazoles, depending on the catalyst type or temperature regime. The interactions based on arylpyruvic acids can take place under kinetic or thermodynamic control producing 7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic acids or 3-hydroxy-1-(1H-pyrazol-5-yl)-1,5-dihydro-2H-pyrrol-2-ones, respectively.

Features of the behavior of 4-amino-5-carboxamido-1,2,3-triazole in multicomponent heterocyclizations with carbonyl compounds

“…Changing these parameters gives us the opportunity to synthesize different types of heterocyclic systems, with a high level of selectivity, from the same starting materials. For example, MCRs or 5-aminopyrazoles containing several nonequivalent nucleophilic reaction centers with aromatic aldehydes and derivatives of 1,3-cyclohexanedione [10–11] or pyruvic acids [12–14] can be selectively directed to the formation of one of the compounds I – III or IV – VI (Fig. 1).…”

A Rapid Synthesis of 4‐Oxazolidinones: Total Synthesis of Synoxazolidinones A and B

“…Coupling agents such as DCC or cyanuric chloride provided the undesired carbon addition product 9 exclusively in up to 57 % yield. We cannot rule out an intermolecular imine addition process analogous to that reported; [11] however, that mechanism appears unlikely under the conditions employed. By contrast, the acid chloride generated from oxalyl chloride/DMF provided the desired 4-oxazolidinone 10 as the major product from the reaction mixture (24-40 % yield of isolated product).…”

“…[15] The imine acylation/enol addition provides a mild method to generate these heterocycles and provides compatibility with alkyl substituents that is not possible with current methods. [11] With a route to the core heterocycle in hand, we turned our attention to the incorporation of the functional groups required for the synoxazolidinones. Being the simplest member of the family, synoxazolidinone B (2) was initially targeted for synthesis (Scheme 3 A).…”

“…Being the simplest member of the family, synoxazolidinone B (2) was initially targeted for synthesis (Scheme 3 A). The treatment of 4-aminobutanol (11) with N,N'-bis(tert-butoxycarbonyl)-Smethylisothiourea provided a Boc-protected guanidine alcohol that was oxidized under Swern conditions to yield aldehyde 12 in 88 % yield over the two steps. Conversion of the aldehyde to the requisite benzylimine was accomplished by treatment with 2,4-dimethoxybenzyl amine (13) and MgSO 4 , and the crude imine was directly subjected to the aforementioned acylation/cyclization cascade with acid chloride 14 to provide the fully functionalized synoxazolidinone B scaffold in 30 % yield over two steps.…”

“…[10] Furthermore, intermolecular addition of phenylpyruvic acids to imines has been reported to prepare the biologically active but undesired 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones (5, Scheme 1 a) through an addition/cyclization/dehydration sequence. [11] Unlike these previously developed methods, the proposed reaction requires the formation of an activated enolizable a-keto carboxylic acid, subsequent reaction with an enolizable achloroimine [12] to generate an acyliminium ion, and finally cyclization through the oxygen atom (as opposed to the carbon atom) of the enol to generate 4-oxazolidinone 6.…”