STUDIES ON HETEROCYCLIC COMPOUNDS VI: Synthesis of Thiophene Isosters of Protoberberine Alkaloids1

Abstract

Synthesis of thiophene isosters of protoberberine alkaloids (6, 12, 19) is described. The Mannich type reaction of the tetrahydroisoquinolines (5, 11) and the thienopyridine (18) with formaldehyde in glacial acetic acid afforded the title compounds. Cyclization of the tetrahydroisoquinoline derivative (23) failed to furnish the D-ring protoberberine isoster (25), but gave an unexpected product, the oxazepinoisoquinoline derivative (24). The conversion of the compound (24) to the 2-substituted isoquinoline (27) is also described.     

Synthesis of pyrrolo[2,1-c][1,4]benzoxazepines. 1. A novel heterocyclic ring system

The synthesis of a novel pyrrolo[2,1-c][1,4]benzoxazepine ring system (II) by a nucleophilic aromatic fluoride displacement-cyclization is described. Aminoalkyl derivatives were prepared by either the Mannich reaction, or Vilsmeier formylation to provide the 3-formyl derivative which was further elaborated.     

An application of the mannich reaction using hydroxylamine and some of its derivatives. 6-Substituted-2,4-diamino-5,6,7,8-tetrahydropyrimido[4,5-dpyrimidines

Hydroxylamine and some of its O -substituted derivatives ( 2 ) have been used as the amine component in Mannich reactions with 2,4,6-triaminopyrimidine ( 1 ). The resulting 6-substituted tetrahydropyrimido[4,5-d]-pyrimidines ( 3 ) contain an N-0 bond linking the substituent to the ring. These results extend the utility of this modified Mannich reaction to otherwise inaccessible substituents. Reaction conditions, spectral data and certain limitations of the reaction are discussed.     

Studies on pyrrolidinones. Synthesis of 1-[(N-acetylarylamino)methyl]pyroglutamic acid derivatives

Pyroglutamic acid was transformed into 1-[(N-Acetylarylamino)methyl]pyroglutamic acid derivatives by using trimethylsilyl variations of the Mannich reaction.     

Some reactions of 4-aryl-1 (2H)-phthalazinones

The behaviors of 4-aryl-1 (2H)-phthalazinones (1a–c) toward carbon nucleophiles (Grignard reagents) and secondary amine under Mannich conditions as well as the nucleophilic substitution reaction on chlorophthalazine derivatives have been studied.     

Studies on the syntheses of heterocyclic compounds. Part DLIV. A total synthesis of (±)-coreximine by thermolysis

Thermolysis of the dibenzyloxy-substituted benzocyclobutene IXc effected cyclization and mono-O-debenzylation to provide a facile route to the total synthesis of the protoberberine isoquinoline (±)-coreximine (XIII).     

Naphthoindoles. 8. Electrophilic substitution reactions of 4,11-dimethyxynaphtho[2,3-f]indole-5,10-dione

Some electrophilic substitution reactions characteristic of indole derivatives have been investigated for 4,11-dimethoxynaphtho[2,3-f]indole-5,10-dione. The corresponding 3 derivatives were obtained as a result of Vilsmeier, Mannich, and acylation reactions.See [1] for Part 7.Russian Chemico-Technological University, Moscow 125190. Center for Drug Chemistry, All-Russian Chemical and Pharmaceutical Research Institute, Moscow 119815. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 939–941, July, 1998.     

Potential anticonvulsants. VII. Synthesis of 5′-methylspiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)-diones

The title compounds have been prepared, by the cyclocondensation of thiolactic acid with isatin-3-imines. 5′-Methyl-3′-phenyl-spiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)-dione has been subjected to the Mannich condensation to give 1-substituted derivatives. With one exception, all of the products were inactive in an anticonvulsant screen.     

Synthesis of novel Mannich bases and hybrid Mannich bases related to isoindolin-1,3-dione

Treatment of isoindolin-1,3-dione ( 1 ) with formalin and the appropriate amine or diamine afforded new N-Mannich bases and bis-(Mannich bases) 2 to 6 . The use of the appropriate hydrazide or dihydrazide as the amine component in the Mannich reaction with 1 led to Mannich bases and bis-(Mannich bases) incorporating a hydrazide moiety. The synthetic potential of sec-Mannich bases as precursors in synthesis of hybrid Mannich bases incorporating 1 was described. The N-alkylation of 1 with ketonic Mannich bases was investigated.     

Structural study of 8-azole derivatives of protoberberine alkaloids: experimental and quantum chemical approach

New derivatives of protoberberine alkaloids were prepared by nucleophilic addition of some azoles (differing in bulkiness) to the iminium functionality of the quaternary protoberberine alkaloids. Compounds were structurally characterized mainly by ¹H and ¹³C NMR spectroscopy, and the structure of 8-carbazol-1-yl-7,8-dihydroberberine was determined using single-crystal X-ray diffraction. Additionally, conformational behaviors of five derivatives varying in bulkiness of the azole moiety have been investigated by low temperature NMR spectroscopy and quantum chemical calculations. Ring current effects of pyrrole and carbazole moieties on selected ¹H NMR resonances have been characterized, visualized, and discussed.     

3-Azabicyclo[3.3.1]nonane Derivatives: III. Synthesis of 3-Substituted 9-Acetonyl-1,5-dinitro-3-azabicyclo[3.3.1]-non-6-en-8-ones by Mannich Condensation of the Janovsky σ-Adduct of 2,4-Dinitrophenol with Acetonide Ion

A number of 9-acetonyl-1,5-dinitro-3-azabicyclo[3.3.1]non-6-en-8-one derivatives were synthesized by Mannich condensation of 3-acetonyl-2,4-bis(aci-nitro)cyclohex-5-en-1-one disodium salt with formaldehyde and primary amines.     

Arylindoles. III. Mannich reaction of 1-arylindoles

1-Phenyl-, and 1-nitrophenylindoles when subjected to Mannich reaction conditions gave the corresponding 3-dialkylaminomethyl derivatives ( IIc-IIk ) in good yields.     

Transition-Metal Acetate-Promoted Intramolecular Nitrene Insertion to Vinylogous Carbonates for Divergent Synthesis of Azirinobenzoxazoles and Benzoxazines

Synthesis and isolation of highly unstable azirinobenzoxazole and benzoxazines in a chemodivergent fashion from aryl azido vinylogous carbonates by simple change in transition metal acetate is described. Thermal or rhodium(II) acetate-mediated decomposition of these azides gave dihydroazirino benzoxazole. Their nickel(II) acetate-promoted reaction gave 4-dihydro-2H-benzoxazines, whereas copper(II) acetate led to the corresponding oxidized imine derivatives. Benzaoxazine derivative could be kinetically resolved using a proline-catalyzed Mannich reaction. The benzoxazines were rapidly elaborated to angularly fused tetracyclic systems and coumarin-fused derivatives in a “one pot” fashion.     

Synthesis of Novel Coumarin-7,8-cyclophosphoramide Analogs

Coumarin-7,8-cyclophosphoramide derivatives were conveniently prepared by a facile method. 7-Hydroxycoumarin was aminomethylated regioselectively at the 8-C position using the Mannich reaction. The newly formed 8-(N-alkylaminomethyl) coumarins were then coupled with bis-β-chloroethyl dichlorophosphamide to form coumarin-7,8-cyclophosphoramide analogs. An efficient, highly regioselective method to synthesize coumarin-7,8-cyclophosphoramide derivatives is provided, and the approach has the merits of mild reaction conditions.     

Reactions of nitrogenous derivatives of substituted salicylaldehydes with cyclic ketones and enamines

The reactions of aminals, the Mannich bases, and azomethines derived from substituted salicylaldehydes were studied. Derivatives of tetrahydrocyclopenta[b]- and hexahydrocyclohepta[b]chromenes and substituted 2,2"-spirobichromenes were prepared from aminals, and substituted hexahydroxanthenes were synthesized from the Mannich bases. Azomethine derivatives of 5-nitrosalicylaldehyde and aliphatic amines react with cyclohexanone to form 4a-amino-7-nitro-2,3,4,4a-tetrahydro-1H-xanthenes. 4a-Morpholino-7-nitro-9-phenylethynyl-1,2,3,4,9,9a-hexahydroxanthene was studied by X-ray diffraction analysis.     

In vitro antiproliferative activity of glabridin derivatives and their in silico target identification

Abstract

Novel Mannich base derivatives of glabridin were synthesized and their antiproliferative activity were performed along with our previously reported glabridin-chalcone hybrids molecules (GCHMs) against various human cell lines MDA-MB-231 (breast adenocarcinoma), HEK-293 (embryonic kidney cell line), K562 (leukemia), MCF-7 (breast adenocarcinoma), HeLa (cervix adenocarcinoma), HepG2 (hepatocellular carcinoma) and WRL-68 (hepatic carcinoma). The result showed that the glabridin significantly reduced cell proliferation with IC₅₀ ranges from 3.67 to 58.30?µM against all the tested cell lines. The remarkable reduction in antiproliferative activity 2’,4’-dimethoxyglabridin and GCHMs compounds with phenolic OH groups protected by methoxy (OCH₃) groups suggested that the free OH groups are essential factor for the antiproliferative activity of glabridin and its derivatives. The Mannich base derivatives of glabridin showed moderate activity IC₅₀ (2.20–>95.78?µM). Furthermore, in silico target identification analysis revealed that AKT1, DECR1 and NOS1 are the potential targets for glabridin and their derivatives.     

Synthesis of New Fused and Spiro Heterocyclic Systems from 3,5‐Pyrazolidinediones

4‐Bromo‐1‐phenyl‐3,5‐pyrazolidinedione 2 reacted with different nucleophilic reagents to give the corresponding 4‐substituted derivatives 3–8 . The cyclized compounds 9–11 were achieved on refluxing compounds 3 , 4 or 6_a in glacial acetic acid or diphenyl ether. 4,4‐Dibromo‐1‐phenyl‐3,5‐pyrazolidinedione 12 reacted with the proper bidentates to give the corresponding spiro 3,5‐pyrazolidinediones 13–15 , respectively. The 4‐aralkylidine derivatives 16_a‐c , were subjected to Mannich reaction to give Mannich bases 17_a‐c‐22_a‐c , respectively. 4‐(p‐Methylphenylaminomethylidine)‐1‐phenyl‐3,5‐pyrazolidinedione 23 or 4‐(p‐methylphenylazo)‐1‐phenyl‐3,5‐pyrazolidinedione 29 were prepared and reacted with active nitriles, cyclic ketones and N,S‐acetals to give pyrano[2,3‐c]pyrazole, pyrazolo[4′,3′:5,6]pyrano[2,3‐c]pyrazole, spiropyrazole‐4,3′‐pyrazole and spiropyrazole‐4,3′‐[1,2,4]triazolane derivatives 24–34 , respectively.     

Diastereo- and Enantioselective Mannich/Cyclization Cascade Reaction Access to Chiral Benzothiazolopyrimidine Derivatives

An efficient asymmetric Mannich/cyclization cascade strategy was established from 2-benzothiazolimines with N-acylpyrazoles to provide optical active benzothiazolopyrimidine derivatives using a copper-based complex. The mild cascade process constructed various structurally diverse products with broad scope of substrates together with excellent enantioselectivities (up to 99 % ee) and diastereoselectivities (up to 99:1 d.r.).     

Acetylenic derivatives of betulonic acid amide as a new type of compounds possessing spasmolytic activity

Efficient and versatile synthetic procedures towards novel derivatives of betulonic acid via Mannich reaction, Sonogashira cross-coupling, and copper(i)-catalyzed 1,3-dipolar cyclo-additions were developed. Introduction of secondary amines (Mannich reaction) into betulonic acid amides led to derivatives possessing marked spasmolytic activity, which is not characteristic of the triterpene fragment.     

Convenient synthesis of 2,3,9,10-tetraoxygenated protoberberine alkaloids and their 13-methyl alkaloids

New and convenient synthesis of 2,3,9,10-tetraoxygenated protoberberine alkaloids and their 13-methyl alkaloids through the same intermediates was developed. Acylation of the brominated benzylphenethylamine (13) with alpha-chloro-alpha-(methylthio)acetyl chloride, followed by cyclization with stannic chloride, furnished the key intermediates 4-methylthio-3-phenethylisoquinolin-3-ones (14), which were methylated to provide their methyl derivatives (17). Both isoquinolin-3-ones (14, 17) were easily transformed into protoberberine alkaloids (16) and their 13-methyl alkaloids (21) in good yield.