Showing papers by "Branko Stanovnik published in 2009"

Bis-enaminone based parallel solution-phase synthesis of 1,4-dihydropyridine derivatives.

Abstract: Two variations of a parallel solution-phase synthesis of N-substituted dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates 4 and methyl 3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylates 9 from dimethyl acetone-1,3-dicarboxylate (1) were developed. The first synthetic method comprises preparation of the bis-enaminone reagents 2 and 8 and their cyclization with primary amines 3 via double substitution of both dimethylamino groups to give dihydropyridines (DHPs) 4 and 9, respectively. Another variation consists of preparation of the monoenaminone reagents 5 and 10, followed by substitution of the dimethylamino group with primary amines 3, and cyclization of the so formed intermediates 6 with N,N-dimethylformamide dimethylacetal (DMFDMA). In this manner, a library of 46 analytically pure compounds, 24 intermediates 6, 11, and 13, and 22 final dihydropyridines 4 and 9 was obtained employing just a simple filtration workup.

1,3-Dipolar cycloadditions of 5-(4-methoxyphenyl)- and 5-(1H-indol-3-yl)-substituted (1Z,4R*,5R*)-1-(arylmethylidene)-4-benzamido-3-oxopyrazolidin-1-ium-2-ides to olefinic dipolarophiles

Abstract: 1,3-Dipolar cycloadditions of (1 Z ,4 R *,5 R *)-1-(arylmethylidene)-4-benzamido-5-(4-methoxyphenyl)-3-oxopyrazolidin-1-ium-2-ides 6a – 6f and their 5-(1 H -indol-3-yl) analogues 6g – 6j to olefinic dipolarophiles 7 – 9 were studied. Stereochemistry was controlled by the structure of dipoles 6 and dipolarophiles 7 – 9 . Reactions of ortho -unsubstituted dipoles 6a – 6c , 6g gave the major isomers 10 and 14 with syn -oriented protons H-3 and H-5, whilst ortho -disubstituted dipoles 6d , 6e , 6j gave cycloadducts 11 and 12 with anti -oriented protons H-3 and H-5. In comparison with their 5-phenyl-substituted analogues, dipoles 6a – 6e , 6g , 6j were less reactive in cycloadditions to olefinic dipolarophiles 7 – 9 . This was reflected in longer reaction times, lower yields, and sometimes in lower selectivity as well. The relative configurations of cycloadducts were determined by NMR.

TRANSFORMATIONS OF DIETHYL 2-[(DIMETHYLAMINO)METHYLENE]-3-OXOPENTANEDIOATE. A SIMPLE SYNTHESIS OF SUBSTITUTED 2-AMINO-5-OXO-5,6-DIHYDROPYRIDO[4,3-d]PYRIMIDINE-8-CARBOXYLATES

Abstract: Diethyl 2-[(dimethylamino)methylene]-3-oxopentanedioate (2), prepared from acetone- 1,3-dicarboxylates (1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) was, without isolation, transformed by treatment with guanidine hydrochloride into ethyl 2-amino-4-(2-ethoxycarbonylmethyl)-pyrimidine-5-carboxylate (3). Compound 3 was transformed with DMFDMA first into intermediate 4 and with an excess of DMFDMA into ethyl 4-[l-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyle neamino]pyrimidine-5-carboxylate (5). By treatment of compound 5 with ammonia, primary amines, hydrazine or hydroxylamine intermediates 6a-j were formed, which cyclized into 6-substituted 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyridine-8- carboxylates (7a-j).

A Simple Synthesis of 1-Substituted Diethyl Pyrrole-3,4-dicarboxylates

Abstract: Pyrrole is an important heterocycle because its structure is incorporated in a variety of biologically important compounds, such as heme, chlorophyll, vitamin B12, and bile pigments. Besides, pyrrole and pyrrolidine partial structures occur in numerous natural products and synthetically important compounds [1]. Among numerous syntheses of pyrroles reported so far in the literature, three general methods have to be outlined: a) the Paal-Knorr synthesis of pyrroles from 1,4-dicarbonyl compounds and primary amines (5+1 cyclocondensation approach), b) the Knorr pyrrole synthesis from α-amino ketones and 1,3-dicarbonyl compounds (3+2 cyclocondensation approach), and c) the van Leusen synthesis of pyrroles from tosylmethyl isocyanide (Tosmic) and α ,β -unsaturated carbonyl compounds (3+2 cycloaddition approach) [1]. 2-Substituted alkyl 3-(dimethylamino)prop-2enoates and related enaminones are a group of enamino-masked alkyl α-formylacetates, which are easily available and are versatile reagents in heterocyclic synthesis [2]. In addition to their extensive use in the synthesis of various heterocyclic systems, recent applications of enaminones are mostly oriented towards the preparation of functionalised heterocyclic compounds including natural product analogues [2 – 4] and in combinatorial synthesis of functionalized heterocycles [5]. In this context, pyrrole derivatives have been prepared by intramolecular cyclisation of 2-(2-cyano-vinyl)amino-3-(dimethylamino)

A Simple Synthesis of 1‐Substituted Diethyl Pyrrole‐3,4‐dicarboxylates.

Abstract: Pyrrole is an important heterocycle because its structure is incorporated in a variety of biologically important compounds, such as heme, chlorophyll, vitamin B12, and bile pigments. Besides, pyrrole and pyrrolidine partial structures occur in numerous natural products and synthetically important compounds [1]. Among numerous syntheses of pyrroles reported so far in the literature, three general methods have to be outlined: a) the Paal-Knorr synthesis of pyrroles from 1,4-dicarbonyl compounds and primary amines (5+1 cyclocondensation approach), b) the Knorr pyrrole synthesis from α-amino ketones and 1,3-dicarbonyl compounds (3+2 cyclocondensation approach), and c) the van Leusen synthesis of pyrroles from tosylmethyl isocyanide (Tosmic) and α ,β -unsaturated carbonyl compounds (3+2 cycloaddition approach) [1]. 2-Substituted alkyl 3-(dimethylamino)prop-2enoates and related enaminones are a group of enamino-masked alkyl α-formylacetates, which are easily available and are versatile reagents in heterocyclic synthesis [2]. In addition to their extensive use in the synthesis of various heterocyclic systems, recent applications of enaminones are mostly oriented towards the preparation of functionalised heterocyclic compounds including natural product analogues [2 – 4] and in combinatorial synthesis of functionalized heterocycles [5]. In this context, pyrrole derivatives have been prepared by intramolecular cyclisation of 2-(2-cyano-vinyl)amino-3-(dimethylamino)

1,3-Dipolar Cycloadditions of 5-(4-Methoxyphenyl)- and 5-(1H-Indol-3-yl)-Substituted (1Z,4R*,5R*)-1- (arylmethylidene)-4-benzamido-3-oxopyrazolidin-1-ium-2-ides to Olefinic Dipolarophiles

Abstract: 1,3-Dipolar cycloadditions of (1 Z ,4 R *,5 R *)-1-(arylmethylidene)-4-benzamido-5-(4-methoxyphenyl)-3-oxopyrazolidin-1-ium-2-ides 6a – 6f and their 5-(1 H -indol-3-yl) analogues 6g – 6j to olefinic dipolarophiles 7 – 9 were studied. Stereochemistry was controlled by the structure of dipoles 6 and dipolarophiles 7 – 9 . Reactions of ortho -unsubstituted dipoles 6a – 6c , 6g gave the major isomers 10 and 14 with syn -oriented protons H-3 and H-5, whilst ortho -disubstituted dipoles 6d , 6e , 6j gave cycloadducts 11 and 12 with anti -oriented protons H-3 and H-5. In comparison with their 5-phenyl-substituted analogues, dipoles 6a – 6e , 6g , 6j were less reactive in cycloadditions to olefinic dipolarophiles 7 – 9 . This was reflected in longer reaction times, lower yields, and sometimes in lower selectivity as well. The relative configurations of cycloadducts were determined by NMR.

Bis-enaminone Based Parallel Solution-Phase Synthesis of 1,4-Dihydropyridine Derivatives.

Abstract: Two variations of a parallel solution-phase synthesis of N-substituted dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates 4 and methyl 3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylates 9 from dimethyl acetone-1,3-dicarboxylate (1) were developed. The first synthetic method comprises preparation of the bis-enaminone reagents 2 and 8 and their cyclization with primary amines 3 via double substitution of both dimethylamino groups to give dihydropyridines (DHPs) 4 and 9, respectively. Another variation consists of preparation of the monoenaminone reagents 5 and 10, followed by substitution of the dimethylamino group with primary amines 3, and cyclization of the so formed intermediates 6 with N,N-dimethylformamide dimethylacetal (DMFDMA). In this manner, a library of 46 analytically pure compounds, 24 intermediates 6, 11, and 13, and 22 final dihydropyridines 4 and 9 was obtained employing just a simple filtration workup.

Transformations of Diethyl 2‐[(Dimethylamino)methylene]‐3‐oxopentanedioate. A Simple Synthesis of Substituted 2‐Amino‐5‐oxo‐5,6‐dihydropyrido[4,3‐d]pyrimidine‐8‐carboxylates.

Abstract: Diethyl 2-[(dimethylamino)methylene]-3-oxopentanedioate (2), prepared from acetone- 1,3-dicarboxylates (1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) was, without isolation, transformed by treatment with guanidine hydrochloride into ethyl 2-amino-4-(2-ethoxycarbonylmethyl)-pyrimidine-5-carboxylate (3). Compound 3 was transformed with DMFDMA first into intermediate 4 and with an excess of DMFDMA into ethyl 4-[l-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyle neamino]pyrimidine-5-carboxylate (5). By treatment of compound 5 with ammonia, primary amines, hydrazine or hydroxylamine intermediates 6a-j were formed, which cyclized into 6-substituted 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyridine-8- carboxylates (7a-j).

Transformations of (1E,3E)-1-(Benzoylamino)-4- (dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates into Pyridine and Pyrrole Derivatives.

Abstract: New, highly functionalised (1 E ,3 E )-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates proved to be useful and versatile reagents in the formation of highly substituted pyridine, N -aminopyridine, pyrrole and pyrido[3,4- c ]pyridazine derivatives. The formation of the particular type heterocyclic system is dependent on the starting (1 E ,3 E )-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylate. By an appropriate choice of different ester groups it is possible to drive the reactions towards the formation of either pyridine or pyrrole derivatives.