The psuedo‐michael reaction of 2‐aminoimidazolines 2. Part 1. Synthesis and structure assignment of isomeric 5(1H)‐Oxo and 7(1H)‐Oxo‐2,3‐dihydroimidazo[1,2‐a]pyrimidine‐6‐carboxylates

Abstract

The pseudo-Michael reaction of 1-aryl-2-aminoimidazolines-2 with diethyl ethoxymethylenemalonate (DEEM) was investigated. Extensive structural studies were performed to confirm the reaction course. For derivatives with N1 aromatic substituents, it was found that the reaction course was temperature dependent. When the reaction temperature was held at -10 °C only the formation of 1-aryl-7(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates (4) was observed in contrast to earlier suggestions. Under the room temperature conditions, the same reaction yielded mixtures, with varying ratio, of isomeric 1-aryl-7(1H)-oxo-(4a-4f) and 1-aryl-5(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates (5a-5f). The molecular structure of selected isomers, 4b and 5c, was confirmed by X-ray crystallography. Frontal chromatography with delivery from the edge was applied for the separation of the isomeric esters. The isomer ratio of the reaction products depended on the character of the substituents on the phenyl ring. The 1-aryl-7(1H)-oxo-carboxylates (4a-4f) were preferably when the phenyl ring contained H, 4-CH 3 , 4-OCH 3 and 3,4-Cl 2 substituents. Chloro substitution at either position 3 or 4 in the phenyl ring favored the formation of isomers 5a-5f. The isomer ratios were confirmed both by 1 H NMR and chromatography. The reaction of the respective hydrobromides of 1-aryl-2-aminoimidazoline-2 with DEEM, in the presence of triethylamine, gave selectively 5(1H)-oxo-esters (5a-5f). J. Heterocyclic Chem., 40, 93 (2003).Diethyl ethoxymethylenemalonate (DEEM) is a wellknown reagent for heterocyclic annelation. Its reaction with 2-aminoazaheterocycles has been widely used to obtain fused pyrimidines bearing the β-oxo-acid moiety. To date, the formation of 4-oxo-pyrimidine-3-carboxylates has been reported [1]. Only Agata [2] and Koekoesi et al [3,4] suggested that the NH-C=NH system (e.g. present in cyclic amidines) can yield mixtures of isomeric products (2-or 4-oxo esters) when reacted with Michael reagents such as DEEM. Their results indicated that the isomer ratio depended only on the ring size. The main product was always a 4-oxo isomer, which suggested that reaction starts at the exo N6 nitrogen atom.At present the molecular geometry of three 5(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine derivatives are known; two with N8-phenyl [5,6] and one with N1-methyl [7] substitution. The 7(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine system has not been reported earlier.Differences in the structures of 1-aryl-2,3-dihydroimidazo[1,2-a]pyrimidine result from the location of the carbonyl group; in the 5-oxo compound, one of the guanidine N-atoms is part of the lactam group whereas in the case of the 7-oxo compound the carbonyl and the C5-C6 double bond give the pyrimidine ring a pseudo-quinoid character.Pharmacological activity of isomeric esters on the CNS of laboratory animals (mice, rats) was reported [8] and

The Pseudo‐Michael Reaction of 2‐Hydrazinylidene‐1‐Arylimidazolidines with Diethyl Ethoxymethylenemalonate

“…Compounds 2a , 2b , 2c , 2d , 2e were subjected to pseudo‐Michael reaction with DEEM in 96% ethyl alcohol, yielding chain adducts 3a , 3b , 3c , 3d , 3e . The isolation of chain derivatives was possible in this case, similarly as in our previously reported reaction of 1‐aryl‐4,5‐dihydro‐1 H ‐imidazol‐2‐amines with EMCA (Scheme ) and contrary to the earlier reported reaction of DEEM with 1‐aryl‐4,5‐dihydro‐1 H ‐imidazol‐2‐amines .…”

“…In our research on the pseudo‐Michael reaction, we have previously reported the reaction of 1‐aryl‐4,5‐dihydro‐1 H ‐imidazol‐2‐amines with DEEM (Scheme ) . The isolation of chain enamines was not possible in this case . This finding agrees with corresponding literature data .…”

“…It is used in synthesis of chain, cyclic, heterocyclic, and fused heterocyclic compounds. In our research on the pseudo‐Michael reaction, we have previously reported the reaction of 1‐aryl‐4,5‐dihydro‐1 H ‐imidazol‐2‐amines with DEEM (Scheme ) . The isolation of chain enamines was not possible in this case .…”

EMCA and DEEM as Michael Reagents Used in Organic Synthesis

“…(97). ( [274]. For the derivatives with N1 aromatic substituents, it was found that the reaction course was temperature dependent.…”

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate

“…We have previously reported the pseudo-Michael reaction of 4,5-dihydro-1 H -imidazol-2-amines with diethyl (methoxymethylidene)propanedioate (diethyl ethoxymethylenemalonate, DEEM, 2 ) (Scheme 1 ) [ 29 ]. The isolation of chain enamines was not possible for the adducts with DEEM [ 29 ] which is in agreement with corresponding literature data (for review see [ 1 ]). In the case of EMCA it is relatively easy to isolate the adducts which are the direct products of Michael reaction [ 1 ].…”