M. José Alves

Synthesis of 5-amino-4-(cyanoformimidoyl)-1H-imidazole: a reactive intermediate for the synthesis of 6-carbamoyl-1,2-dihydropurines and 6-carbamoylpurines

5-Amino-4-(cyanoformimidoyl)-1H-imidazole (3) has been prepared in good yield by the base-catalysed cyclisation of (Z)-N-(2-amino-1,2-dicyanovinyl)formamidine. Compound (3) reacts with ketones, R1COR2[R1= R2= Et, Me, Bu, –(CH2)5–, PhCH2; R1= Me, R2= Ph] togive2,2-disubstituted-6-carbamoyl-1,2-dihydropurines as the major products, together with minor amounts of compounds believed to be novel 7-amino-1-carbamoyl-3,3-disubstituted 3H-imidazo[1,5-c]imidazole derivatives, which have been isolated when R1= R2= Et, Bu, and PhCH2; when R1= R2= Ph the only product isolated is tentatively assigned the imidazo[1,5-c]imidazole structure. In the reaction with acetylacetone the 1,2-dihydropurine intermediate is unstable and loses acetone to give 2-methyl-6-carbamoylpurine. The aldehydes RCHO [R = Me, Et, (E)-MeCHCH–, c-C4H4O] also react readily with (3) at room temperature to give the corresponding 6-carbamoyl-1,2-dihydropurine derivatives, which can be isolated when R = Me or Et; these oxidise in solution to afford the corresponding 6-carbamoylpurines.

Diastereoselective synthesis of aziridines from (1R)-10-(N,N-dialkylsulfamoyl)isobornyl 2H-azirine-3-carboxylates

Reaction of the chiral azirine 1a with nucleophiles and dienes is described. Thiols, heteroaromatic nitrogen compounds and phenylmagnesium bromide add to the azirine 1a to give functionalised aziridines 2/3a–h. X-Ray crystal structures for the products 3e and 3g have been obtained. Diastereodifferentiation of the two faces of the azirine 1a is observed in most cases, but only thiophenol gives a single diastereomer (2a). Most mixtures of diastereomers were separated by dry flash chromatography. Benzylamine produced a dimer of the original azirine 1a, compound 9. Representative conjugated dienes (cyclopentadiene, furan and open chain dienes) were added to the chiral azirine 1a. Only poor selectivities were observed. The selectivity was not significantly enhanced in the cycloaddition of cyclopentadiene to the more bulky azirine 1b.

(Z)-N3-(2-amino-1,2-dicyanovinyl)formamidrazone: a precursor in the synthesis of 1,5-diaminoimidazoles and 6-carbamoyl-1,2-dihydropurines

The reaction of ethyl (Z)-N-(2-amino-1,2-dicyanovinyl)formimidate with hydrazine monohydrate leads to (Z)-N3-(2-amino-1,2-dicyanovinyl)formamidrazone in almost quantitative yield. This compound proved to be an important starting material for the synthesis of the corresponding N1-isopropylidene-and N1-acetyl-formamidrazones.The amidrazones prepared promptly cyclize in the presence of base to give a 1,5-diamino-4-cyanoimidazole or a 1,5-diamino-4-(cyanoformimidoyl)imidazole, depending on the reaction conditions and mainly on the nature of the base used to induce cyclization.1,5-Diamino-4-(cyanoformimidoyl)imidazole was treated with carbonyl compounds and the 1,2-dihydropurines thus isolated indicated that the amino group in position 5 is more reactive than that in position 1.

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron rich 2-azadienes

Abstract tert -Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2 H -azirine 3 leading to Diels–Alder cycloadducts in moderate yields. The reactions are endo - and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b , 4b . There are two isomers ( 4 and 5 ) from 1a , 1c and 1d . A different result was obtained with the diene 1e . Diene 1e formed products 4e and 8 . Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7 . Compound 8 gave aziridine 9 .

Optically active aziridine esters by nucleophilic addition of nitrogen heterocycles to a chiral 2H-azirine-2-carboxylic ester

Chiral enriched ethyl 3-methyl-2H-azirine-2-carboxylate acts as an efficient alkylating agent for a variety of five-membered aromatic nitrogen heterocycles.

Advances in the synthesis of homochiral (-)-1-azafagomine and (+)-5-epi-1-azafagomine. 1-N-phenyl carboxamide derivatives of both enantiomers of 1-azafagomine: Leads for the synthesis of active α-glycosidase inhibitors.

A new expeditious preparation of homochiral (-)-1-azafagomine and (+)-5-epi-1-azafagomine has been devised. Stoodleys diastereoselective cycloaddition of dienes bearing a 2,3,4,6-tetraacetyl glucosyl chiral auxiliary to 4-phenyl-1,2,4-triazole-3,5-dione was merged with Bolss protocol for functionalizing alkenes into molecules bearing a glucosyl framework. Homochiral (+)-5-epi-1-azafagomine was synthetized for the first time. Partial reductive cleavage of the phenyltriazolidinone moiety afforded new homochiral 1-N-phenyl carboxamide derivatives of 1-azafagomine. Both enantiomers of these derivatives were synthetized and tested, displaying a very good enzymatic inhibition toward bakers yeast α-glucosidase. The molecular recognition mechanism of the 1-N-phenyl carboxamide derivative of 1-azafagomine by α-glucosidase from bakers yeast was studied by molecular modeling. The efficient packing of the aromatic ring of the 1-N-phenyl carboxamide moiety into a hydrophobic subsite (pocket) in the enzymes active site seems to be responsible for the improved binding affinity in relation to underivatized (-)-1-azafagomine and (+)-1-azafagomine.

Novel 4-substituted 4,5-dihydro-3H-(8-amino-6-oxo)pyrrolo[3,4-f][1,3,5]triazepines from(Z)-N2-(2-amino-1,2-dicyano)formamidine and carbonyl compounds

The title formamidicine reacts with ArCHO (where Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-FC6H4) and acetone in the presence of a base to give products, shown by X-ray crystallography (Ar = Ph), to be the title compounds 4a–e

Synthesis of 1,3,8,8a-tetrahydro-3,8-epoxyazirino[1,2-b]isoquinolines and their reactions with oxygen nucleophiles

Cycloadditions of 2H-azirines to isobenzofurans is described. The endo and exo products were obtained and were reacted with oxygen nucleophiles. Tetrahydroquinolines or benzofuranols were obtained, usually in excellent yields. Cycloaddition of the less electrophilic azirine (14) was performed at room temperature in the presence of ZnCl 2 . The cycloadduct was hydrolysed in the reaction conditions, but dehydration to give back the original cycloadduct was obtained in the presence of 4A molecular sieves. The structure assigned in the literature to the product of hydrolysis of the cycloadduct (10) was rectified.

Synthesis of 9-aryl-6-carbamoyl-1,2-dihydropurines and a study of their tautomerism

The title compounds have been prepared in high yield by reaction of the corresponding 4-(cyanoformimidoyl)-1 -arylimidazol-5-amines with the carbonyl compounds R1R2CO (R1= R2= Me, Et; R1= H, R2= Ph). The same 9-aryl-6-carbamoyl-1,2-dihydropurines (R1= R2= Me) have also been isolated from the corresponding (Z)-N1-(2-amino-1,2-dicyanovinyl)-N2-arylformamidines by reaction with acetone in the presence of a base. In these cases the initially formed products are off-white solids, believed to be the oxazolidine derivatives 4, which in solution rapidly undergo conversion into the respective 1,2-dihydropurines. The two tautomers of the dihydropurines have been fully characterised by 1H and 13C NMR spectroscopy and single-crystal X-ray structures have been obtained for both the orange and yellow tautomers of the dihydropurine derivative where Ar = Ph, R1= R2= Me. In [2H6]Me2SO solution the presence of an ortho-substituent on the N-aryl ring causes an increase in the equilibrium concentration of the yellow tautomer. A single-crystal X-ray structure determination on the dihydropurine where Ar = 2,4-(MeO)2C6H3; R1= R2= Me has shown that in the solid state the aryl ring is twisted at 73.1 (9)° to the plane of the heterocyclic ring and this may explain the observed behaviour in solution.

Synthesis of 4-substituted 8-amino-4,5-dihydro-3H-pyrrolo[3,4-f]-1,3,5-triazepin-6-ones and 5-amino-2-aryl-4-(1-aryl-5-alkylideneaminoimidazol-4-yl)1,3-oxazoles

The title compounds have been prepared from (Z)-N2-(2-amino-1, 2-dicyanovinyl)formimidamide by reaction of an excess of an aldehyde or ketone in the presence of a base. The triazepine 1e can also be obtained by the reaction of ethyl (Z)-N-(2-carbamoyl-1-cyano-2-isopropylideneaminovinyl)formimidate 7a with ammonia and a catalytic amount of anilinium hydrochloride. Under similar conditions the 2-benzylideneamino derivative 7b affords the corresponding amidine 6, and only a low yield of the triazepine. In this last reaction aminolysis of the alkylideneamino bond competes with amidine formation to give compound 8, and reaction between the formimidate 7c and p- anisidine resulted only in the formation of ethyl (Z)-N-(2-amino-2-carbamoyl-1-cyanovinyl)formimidate 8. Reactions between N2-aryl-(Z)-N1-(2-amino-1,2-dicyanovinyl)formimidamides and aldehydes in the presence of a base do not give 1, 3, 5-triazepines, but instead afford novel 5-amino-2-aryl-4-(1aryl-5-alkylideneaminoimidazol-4-yl)-1, 3-oxazoles 11 together with the known 9-aryl-6carbamoyl-1, 2-dihydropurines, the corresponding purines and other products.