Synthesis of Novel Classes of Pyrido[2,3‐d]‐pyrimidines,Pyrano[2,3‐d]pyrimidines,and Pteridines

6‐Amino‐5‐formyluracils 1 and 5‐formyl‐6‐hydroxyuracils 4 react with Meldrum's acid 2 in the presence of piperidine as catalyst under thermolytic conditions to afford 6‐carboxy‐2,4,7‐trioxopyrido[2,3‐d]pyrimidines 3 and 6‐carboxy‐2,4,7‐trioxopyrano[2,3‐d]pyrimidines 5 in good yield. Under identical conditions, 6‐amino‐5‐nitrosouracils 6 react with 2 to afford pteridine‐6‐carboxylic acids 7 in good yields.     

Synthesis of [125I]‐, [2H]‐, and [3H]‐Labeled 3‐Iodothyronamine (T1AM)

3‐Iodothyronamine (T₁AM) is a novel metabolite of thyroid hormone. In HEK‐293 cells expressing an orphan G‐protein coupled receptor, the trace amine receptor, T₁AM, potently increased cAMP accumulation. In mice, T₁AM rapidly induced hypothermia and bradycardia within minutes of administration. These results suggest the existence of a new signaling pathway, the stimulation of which leads to rapid physiological and behavioral consequences. Isotope‐labeled T₁AM derivatives would be useful to study the biology and pharmacology of T₁AM. Herein we describe efficient syntheses of [¹²⁵I]‐, [²H]‐, and [³H]‐T₁AM.     

Synthesis of some sulfur-containing pyrido[1,2-α]pyrimidines

4-Methylthiopyrido[1,2-α]pyrimidin-2-one and 2-hydroxypyrido[1,2-α]pyrimidine-4-thione derivatives were synthesized by the addition ofN-(4-R-pyrid-2-yl)acetoacetamides (R = H, Me) to CS₂ under phase-transfer conditions followed by the alkylation of the reaction products with Mel. The molecular structure of 3-acetyl-4-methylthiopyrido[1,2-α]pyrimidin-2-one is established by X-ray analysis.     

Glycosylation of 4‐Aryl‐1‐thioxo[1,2,4] triazolo[4,3‐a] quinazolin‐5(4H)‐one

Reaction of 4‐aryl‐1‐thioxo [1,2,4] triazolo [4,3‐a] quinazolin‐5 (4H)‐ones (2a,b) with acetylated glycosyl bromides 3a–c under alkaline conditions afforded the corresponding S‐glycoside derivatives 4, 5 and N‐glycoside derivatives 6, 7. Oxidation of S‐glycosyl derivatives 4, 5 with m‐chloroperbenzoic acid yielded the corresponding sulphones 8, 9, whereas the N‐glycosyl derivatives 6, 7 yielded 1‐oxo derivatives 10, 11. However their O‐deacetylation with sodium methoxide in methanol caused cleavage of the S‐glycosyl residue and gave N ²‐glycosylated analogues 12, 13, 14 and 15.     

Synthesis of novel spiro-fused pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines

New pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidines, with an associated spiro-3,3′-oxindole attachment, were prepared by three-component combinations of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione with a pair of reactants chosen from a pyrazol-5-one, a pyrazole-5-amine, a barbituric acid, or a 6-aminouracil.     

Synthesis of Some Novel 2,3,4,8,9‐Pentahydro‐7‐(4‐haloaryl)‐pyrazolo[5,1‐e]benzo[1,5]oxazocines and 2,3(erythro), 7,8‐Tetrahydro‐2‐aryl‐3‐(4‐fluoro‐3‐methylbenzoyl)‐6‐(4‐haloaryl)pyrazolo[5,1‐d] Benzo[1,4]oxazepines via Solid–Liquid PTC

In this communication, a simple and straightforward procedure for the heterocyclization of 1H‐4,5‐dihydro‐3‐(4‐haloaryl)‐5‐substituted phenylpyrazoles (4) with 1‐bromo‐3‐chloropropane and 2,3‐dibromo‐1‐(4‐fluoro‐3‐methylphenyl)‐3‐phe‐ nylpropanone affording 2,3,4,8,9‐pentahydro‐7‐(4‐haloaryl)pyrazolo[5,1‐e]benzo[1,5] oxazocines 5 and regioselective synthesis of 2,3(erythro),7,8‐tetrahydro‐2‐ aryl‐3‐(4‐fluoro‐3‐methylbenzoyl)‐6‐(4‐halophenyl)pyrazolo[5,1‐d]benzo[1,4]oxa‐ zepines 6, respectively, via solid–liquid PTC is reported. All the synthesized compounds have been characterized on the basis of their spectral studies (IR, PMR, and MS) and analytical data.     

Synthesis and Cytotoxicity of 9‐Substituted Benzo[de]chromene‐7,8‐dione and 5‐Benzyl‐9‐substituted Benzo[de]chromene‐7,8‐dione

New Mansonone analogues of 9‐substitued benzo[de]chromene‐7,8‐dione 5b–e and 5‐benzyl‐9‐substitued benzo[de]chromene‐7,8‐dione 6a–e were prepared through a modified route. The first step involved a bulky base t‐butylamine mediated regioselective deacetylation of 2‐substituted‐1,4‐naphth‐diyl diacetate, resulting in obtaining of monoacetate 4‐acetate 2 in high yield. The mechanism of cyclization, debenzylation, and oxidation for the formation of 5a–e and 6a–e were discussed. The cytotoxicity of the prepared compounds 5 and 6 were comparable with naturally occurring Mansonone F.     

Synthesis of 2‐Spironaphtho[2,3‐b]pyranoquinones

A convenient procedure for the synthesis of 2‐spirobenzopyranoquinone 5 and its application to the preparation of spironaphtho[2,3‐b]pyranoquinones 6 and 7 is described.     

Design and Syntheses of Novel Calix[4]crown: Calix[4]‐Dixanthates‐Crowns

Abstract

A series of novel calix[4]‐dixanthates‐crowns were designed and synthesized by the “1 + 1 condensation” of reacting calix[4]‐1,3‐dixanthate salts derivative (4) with polyethylene glycol ditosylates in 40–60% yields. It was found that the new calixcrowns showed outstanding complexation abilities towards soft cations. Calix[4]‐dixanthate‐crown‐4 (5b) exhibited high complexation selectivity towards Ni²⁺.     

Synthesis of Ethyl 8‐Aryl‐8‐hydroxy‐3‐oxo‐8H[1,2,4]oxadiazolo‐[3,4‐c][1,4]thiazine‐5‐carboxylates by Ring‐Expansion Rearrangement

The title compounds were prepared by the ring–ring interconversion of ethyl 5‐nitroso‐6‐arylimidazo[2,1‐b]thiazole‐3‐carboxylates with hydrochloric acid. The effect of electron‐withdrawing substituent in the thiazole ring on the general applicability of the ring–ring interconversion has been also evaluated.     

Synthesis and interconversion of isomeric pyrrolotriazolopyrimidines

4‐Hydrazino‐7H‐pyrrolo[2,3‐d]pyrimidines 4 were cyclocondensed with formic acid or triethyl orthoformate to give 7H‐pyrrolo[3,2‐e][1,2,4]triazolo[1,5‐c]pyrimidines 6 and 7H‐pyrrolo[3,2‐e][1,2,4]triazolo[4,3‐c]pyrimidines 7 , respectively. The [4,3‐c] isomers 7 were rearranged into thermodynamically more stable [1,5‐c] isomers 6 . The identical compounds 6 were prepared using another route by reacting 3‐amino‐4‐imino‐7H‐pyrrolo[2,3‐d]pyrimidines 3 with formic acid or triethyl orthoformate. The reaction of 2‐amino‐3‐cyanopyrroles 1 with triethyl orthoformate gave N‐ethoxymethylene‐2‐amino‐3‐cyanopyrroles 2 . Further reaction with an equivalent of hydrazine hydrate provided 3‐amino‐4‐imino‐7H‐pyrrolo[2,3‐d]pyrimidines 3 , whereas treatment with excess of hydrazine hydrate, 3 rearranged to 4‐hydrazino‐7H‐pyrrolo[2,3‐d]pyrimidines 4 . Compounds 4 were also obtained by the treatment of N‐ethoxymethylene‐2‐amino‐3‐cyanopyrroles 2 in excess of hydrazine hydrate. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:265–273, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20295     

Synthesis of isomeric triazolopyrrolopyrimidines

4‐Hydrazino‐7H‐pyrrolo[2,3‐d]pyrimidines ( 4 ) were cyclocondensed with formic acid or triethyl orthoformate to give 7H‐1,2,4‐triazolo[1,5‐c]pyrrolo[3,2‐e]pyrimidines ( 5 ) and 7H‐1,2,4‐triazolo[4,3‐c]pyrrolo‐[3,2‐e]pyrimidines ( 6 ) respectively. The [4,3‐c]‐isomers ( 6 ) were rearranged into thermodynamically more stable [1,5‐c]‐isomers ( 5 ). The identical compounds ( 5 ) were prepared using another route by reacting 3‐amino‐4‐imino‐7H‐pyrrolo[2,3‐d]pyrimidines ( 3 ) with formic acid or triethylorthoformate. Reaction of 2‐amino‐3‐cyanopyrroles ( 1 ) with triethyl orthoformate followed by hydrazinolysis afforded ( 3 ) via the formation of N‐ethoxymethylene‐2‐amino‐3‐cyanopyrroles ( 2 ).     

Synthesis of 7H-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines and their reductive ring cleavage to 4-aminopyrrolo[2,3-d]pyrimidines

Some new 7,9-disubstituted 7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 5 have been synthesized either by diazotization of 4-hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 4 obtained by hydrazinolysis of 4-chloro-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 3 or via a substitution reaction between 3 and sodium azide. 5,7-Disubstituted-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-ones 2 were obtained by cyclocondensation of 2-amino-3-cyano-1,4-disubstituted pyrroles 1 with formic acid which on chlorination using phosphorus oxychloride afforded 3 . A novel route for the synthesis of 4-amino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 6 by the reductive ring cleavage of 5 has been reported.     

Synthesis and reactions of fluoroaryl substituted 2-amino-3-cyanopyrroles and pyrrolo[2,3-d]pyrimidines

Some fluoroaryl substituted 2-amino-3-cyanopyrroles 2 were synthesized from the reaction between (2-bromo-1-arylalkylidene)propanedinitriles 1 and fluoroaryl substituted aromatic amines under Gewald reaction condition, which on reaction with formamide and formic acid gave 4-aminopyrrolo[2,3-d]pyrimidines 3 and pyrrolo[2,3-d]-pyrimidin-4(3H)-ones 4 respectively. 4-Chloropyrrolo[2,3-d]pyrimidines 5 were prepared by chlorination of 4 with phosphorus oxychloride, which on hydrazinolysis provided 4-hydrazinopyrrolo[2–3-d]pyrirnidines 6 .     

The gould‐jacob type of reaction for the synthesis of novel pyrimidopyrrolopyrimidines: A comparison of classical heating vs solvent free microwave irradiation

The Gould‐Jacob type of reaction for the synthesis of ethyl 4‐oxo‐8,10‐substituted‐4,8‐dihydropyrimido[1,2‐c]pyrrolo[3,2‐e]pyrimidine‐3‐carboxylates 5 has been carried out conventionally by the condensation between 4‐aminopyrrolo[2,3‐d]pyrimidines 2 and diethyl ethoxymethylenemalonate 3 via acyclic intermediates diethyl N‐[5,7‐substituted‐7H‐pyrrolo[2,3‐d]pyrimidin‐4‐yl]aminomethylenemalonates 4 and the results obtained were compared with single step microwave irradiation under solvent free conditions for the synthesis of 5 .     

Design,synthesis and biological evaluation of 2,4‐diamino‐6‐methyl‐5‐substitutedpyrrolo[2,3‐d]pyrimidines as dihydrofolate reductase inhibitors

Nine novel nonclassical 2,4‐diamino‐6‐methyl‐5‐mioarylsubstituted‐ 7H ‐pyrrolo[2,3‐d]pyrimidines 2‐10 were synthesized as potential inhibitors of dihydrofolate reductase and as antitumor agents. The analogues contain various electron donating and electron withdrawing substituents on the phenylsulfanyl ring of the side chains and were synthesized from the key intermediate 2,6‐diamino‐6‐methyl‐7H‐pyrrolo[2,3‐d]‐pyrimidine, 14 . Compound 14 , was in turn obtained by chlorination of 4‐position of 2‐amino‐6‐methylpyrrolo[2,3‐d]pyrimidin‐4(3H)‐one, 16 followed by displacement with ammonia. Appropriately substituted phenyl thiols were appended to the 5‐position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against rat liver, rat‐derived Pneumocystis, Mycobacterium avium and Toxoplasma gondii dihydrofolate reductase. The most potent and selective inhibitor, (2) has a 1‐naphthyl side chain. In this series of compounds electron‐withdrawing and bulky substituents in the side chain afford marginally active dihydrofolate reductase inhibitors. The single atom sulfur bridge in the side chain of these compounds is not conducive to potent dihydrofolate reductase inhibition.     

Synthesis of 5,7‐Disubstituted 7H‐Pyrrolo[2,3‐d]Pyrimidin‐4(3H)‐ones and Their N‐Alkylation's under Phase Transfer Conditions

5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 were synthesized by the cyclocondensation of 1,4‐disubstituted 2‐amino‐3‐cyanopyrrole 1 with formic acid. When comparative study of N versus O alkylation of ambident 5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 was carried out under liquid–liquid PTC, solid–liquid PTC, and solid–liquid solvent free conditions using various alkylating agents 3 , the N‐alkylated product 4 were obtained selectively and exclusively.     

Facile Methods for the Synthesis of 5‐Aryl and 5‐Iodo Pyrrolo[2,3‐d]pyrimidines

An efficient and environmentally benign one‐pot method has been developed for the synthesis of 4‐amino‐5‐arylpyrrolo[2,3‐d]pyrimidines. Phthalimido acetophenones were reacted with cyanoacetamide to give 2‐amino‐4‐phenyl‐1H‐pyrrole‐3‐carboxamides, which were further converted to 5‐aryl‐3H‐pyrrolo[2,3‐d]pyrimidin‐4‐ones. A novel method is also developed for the synthesis of 4‐amino‐5‐iodopyrrolo[2,3‐d]pyrimidines.     

Selective Synthesis of 1,2‐Diarylpyrrolo[3,4‐b]pyridine‐5,7‐diones via Cyclization Reaction of β‐Enamino Imides with Cinnamaldehydes

The novel 1,2‐diaryl substituted pyrrolo[3,4‐b]pyridine‐5,7‐diones were selectively synthesized in high yields by the base catalyzed cyclization reaction of 3‐arylamino‐1‐methyl‐1H‐pyrrole‐2,5‐diones with cinnamaldehyde and its derivatives in acetonitrile at room temperature. However, when piperidinium trifluoroacetate was employed as catalyst, the reaction afforded a mixture of 1,2‐diaryl and 1,4‐diaryl substituted pyrrolo[3,4‐b]pyridine‐5,7‐diones in comparable yields.     

Synthesis of Novel 5‐Trifluoromethyl‐2,4,7‐Trisubstituted Pyrido[2,3‐d]Pyrimidines

Abstract

Novel pyrido[2,3‐d]pyrimidines (2,4) were synthesized by reacting 2‐amino‐3‐cyano‐4‐trifluoromethyl‐6‐substituted pyridines (1) with Grignard reagent followed by condensation with anhydride/chloroacetylchloride/aromatic aldehyde.