Palladium-catalyzed reductive N-heterocyclization of alkenyl-substituted nitroarenes as a viable method for the preparation of bicyclic pyrrolo-fused heteroaromatic compounds

Palladium-catalyzed, carbon monoxide-mediated reductive N-heterocyclization of nitro-heteroaromatic compounds having an alkene adjacent to the nitro-group affords bicyclic pyrrolo-fused heteroaromatic molecules. This type of reaction was used to prepare the fused bicyclo[3.3.0] ring-system: thieno[3,2-b]pyrrole, thieno[2,3-b]pyrrole, furo[2,3-b]pyrrole, pyrrolo[3,2-d]thiazole, and pyrrolo[2,3-d]imidazole and the bicyclo[4.3.0] ring-systems: pyrrolo[3,2-b]pyridine, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridazine, and pyrrolo[3,2-d]pyrimidine in 32-94% yield.     

Imidazo- und Diazino-Anellierungen an das [1]Benzothieno[2,3—d]pyrimidin-System

Derivatives of the following six ring systems were synthesized:

1. 3,10-Dihydro-[1]benzothieno[2,3-d]imidazo[1,5-a]-pyrimidine (I)
2. 6H-[1]Benzothieno[2,3-d]pyrazino[1,2-a]pyrimidine (II)
3. 1,5-Dihydro-[1]benzothieno[2,3-d]imidazo[1,2-a]-pyrimidine (III)
4. 6H-[1]Benzothieno[2,3-d]pyrimido[1,2-a]pyrimidine (IV)
5. 1,5-Dihydro-imidazo[1,2-a]thieno[2,3-d]pyrimidine (V)
6. 4H-Pyrimido[1,2-a]thieno[2,3-d]pyrimidine (VI)

The first four types are new heterocyclic systems. 2-Aminomethyl-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (5), which was used as intermediate for typesI andII, was synthesized by various methods. TypesIII andIV were prepared from 2-methylthio-5,6,7,8-tetrahydro-[1]-benzothieno[2,3-d]pyrimidin-4(3H)-one via the corresponding 2-benzylamino derivatives, followed by ring closure.     

Synthesis of new thiazolo[2,3-b]pyrimidine derivatives of pharmaceutical interest

2H-5-Amino-6-cyano-3,7-dioxothiazolo[2,3-b]pyrimidine was subjected to ring formation affording thiazolo[2,3-b]pyrimidine derivatives. 2H-5-Amino-6-cyano-3,7-dioxo-2-phenylmethylenethiazolo[2,3-b]pyrimidine was also subjected to ring formation affording pyrimido[4,5-d]-, pyrano[2,3-d]-, and pyrido[2,3-d]thiazolo[2,3-b]pyrimidine derivatives. 2-Anilinothiocarbonyl-3,9-dioxo-8-imino-7-phenyl-6-thioxothiazolo[2,3-b]pyrimido[4,5-d]pyrimidine and 8-amino-3,9-dioxo-6-thioxothiazolo[2,3-b]pyrimido[4,5-d]pyrimidine reacted with α-haloactive-methylene compounds to afford heterocyclic compounds containing two, fused and isolated, thiazole moieties, respectively.     

Synthesis and photophysical properties of oligoarylenes with a pyrrolo[2,3-d]pyrimidine core

The palladium-catalyzed Suzuki-Miyaura reaction of 2,4-dichloropyrrolo[2,3-d]pyrimidine with aryl boronic acids has been studied. Pd(OAc)₂/dicyclohexyl(2-biphenyl)phosphine/K₃PO₄ was found to be an efficient catalyst system to prepare 4-aryl-2-chloro- and 2,4-diarylpyrrolo[2,3-d]pyrimidines. Novel non-linear molecules consisting of a pyrrolo[2,3-d]pyrimidine core and aryl branches have been elucidated as blue light-emitters with fluorescence quantum yields ranging from 4% to 67% in THF solution. The impact of an electron-withdrawing t-BuOCO group attached to the pyrrole ring of pyrrolopyrimidine derivatives on optical properties is discussed.     

Pyrrolopyrimidine nucleosides. VI. Synthesis of 1,3 and 7-β-D-ribofuranosylpyrrolo[2.3-d] pyrimidines via silylated intermediates

The ribosylation of several silylated pyrrolo[2,3-d]pyrimidines by the Wittenberg procedure has produced 1,3 and 7-ribosylpyrrolo[2,3-d]pyrimidine derivatives in high yield. Structure assignments have been made on the basis of the ultraviolet spectra of model compounds and further confirmed by chemical conversion to derivatives of established structure. A convenient ribosylation procedure utilizing silver oxide, a halosugar, and a silylated pyrrolo[2,3-d]pyrimidine derivative in acetonitrile has been described.     

Pyrrolopyrimidine nucleosides. IV. The synthesis of certain 4,5-disubstituted-7-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines related to the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics

The treatment of 4-chloro-7-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 4 ) with N-bromoacetamide in methylene chloride has furnished the 5-bromo derivative of 4 which on subsequent deacetylation provided a good yield of 5-bromo-4-chloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d] pyrimidine ( 6 ). Assignment of the halogen substituent to position 5 was made on the basis of pmr studies. Treatment of 6 with methanolic ammonia afforded 4-amino-5-bromo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d ]pyrimidine ( 8 , 5-bromotubercidin) and a subsequent study has revealed that the 4-chloro group of 6 was replaced preferentially in a series of nucleophilic displacement reactions. The analogous synthesis of 4,5-dichloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d]pyrimidine ( 13b ) and 4-chloro-5-iodo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 13a ) from 4 furnished 5-chlorotubercidin ( 15 ) and 5-iodotubercidin ( 14 ), respectively, on treatment of 13b and 13a with methanolic ammonia. The possible biochemical significance of these tubercidin derivatives is discussed.     

A short, concise synthesis of queuine

A short, concise synthesis of queuine was accomplished in a 36% overall yield through a convergent scheme utilizing a reductive amination as the penultimate step. The synthesis demonstrates the utility of silylation to facilitate reactions of various pyrrolo[2,3-d]pyrimidine intermediates, and offers the possibility of easily accessing related pyrrolo[2,3-d]pyrimidines as well as making additional analogues of queuine.     

Synthesis and properties of a novel nucleoside derivative possessing a 2,3,5,6-tetraazabenzo[cd]azulene skeleton

We describe herein the synthesis and properties of the novel nucleoside derivative, 4,7-diamino-2-(2-deoxy-β-d-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene (1). The palladium catalyzed cross-coupling reaction of 2,4-diamino-5-iodo-7-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (9) with acrylonitrile afforded 2,4-diamino-5-[(E)-1-cyano-2-ethenyl]-7-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (10) in 77% yield, which was treated with NaOMe in MeOH in the presence of NaSPh to give the desired 1 in 64% yield. Whereas 1 was stable in concentrated ammonia at room temperature, it was gradually hydrolyzed in water to give 4-amino-2-(2-deoxy-β-d-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulen-7-one (12). Density functional calculations indicated that 12 was 20 kcal/mol more thermodynamically stable than 1 in a model study.     

A one-pot synthesis of 3-methyl-5-aryl-4H-pyrrolo[2,3-d]-isoxazoles

Sharpless epoxidation of 4-amino-3-methyl-5-styrylisoxazoles 1 resulted in the formation of 3-methyl-5-aryl-4H-pyrrolo[2,3-d]-isoxazoles 4 in a one-step reaction. The reaction initially involves epoxide formation, followed by ring-opening and cyclization. Finally dehydration leads to the title compounds. The pyrrolo[2,3-d]-isoxazoles 4 were also synthesized via an alternative procedure.     

Synthesis,cytotoxicity and antiviral activity studies of the conjugates of cobalt bis(1,2-dicarbollide)(-I) with 5-ethynyl-2′-deoxyuridine and its cyclic derivatives

A series of novel conjugates of cobalt bis(1,2-dicarbollide)(-I) with 5-ethynyl-2′-deoxyuridine and its cyclic derivatives were synthesized. Conjugates with 5-ethynyl-2-deoxyuridine were prepared by the direct Sonogashira coupling of a series of cobalt bis(1,2-dicarbollide)(-I) terminal alkynes and 5-iodo-2′-deoxyuridine. Their furo[2,3-d]pyrimidin-2(3H)-one isomers were obtained either by intermolecular cyclization of the above conjugates or by Sonogashira coupling using Pd/C as a catalyst. Action of ammonia on these furo[2,3-d]pyrimidin-2(3H)-one conjugates resulted in pyrrolo[2,3-d]pyrimidin-2(3H)-one conjugates. Most of the designed compounds have shown low cytotoxicity in several cell lines. Some 5-ethynyl-2-deoxyuridine and furo[2,3-d]pyrimidin-2(3H)-one conjugates have also presented antiviral activity.     

Synthesis and Properties of 6-Amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

We have established that when 5-chloro-6-[cyano(2,3-dihydro-1-R-benzo[d]azol-2-yl)methyl]-2,3-pyrazinedicarbonitriles are reacted with nucleophilic reagents (aliphatic and aromatic amines, hydrogen sulfide), annelation of the five-membered ring occurs on the [b] face of the pyrazine with formation of 6-amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles and 6-amino-7-(1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyrazine-2,3-dicarbonitrile respectively. Further heating with excess of acylating reagent leads to formation of a novel heterocyclic system 1H-benzo[4,5]imidazo[1,2-c]pyrazino[2',3':4,5]pyrrolo[3,2-e]pyrimidine. Reaction of vicinal dinitriles with hydrazine hydrate leads to the novel system 1H-pyrrolo[2',3':5,6]pyrazino[2,3-d]pyridazine.     

An expedient microwave-assisted, solvent-free, solid-supported synthesis of pyrrolo[2,3-d]pyrimidine-pyrano[5,6-c]coumarin/[6,5-c]chromone derivatives by intramolecular hetero Diels-Alder reaction

A rapid synthesis of pyrrolo[2,3-d]pyrimidine annulated pyrano[5,6-c]coumarin/[6,5-c]chromone derivatives has been accomplished in good yields via an intramolecular domino hetero Diels-Alder reaction using microwave irradiation under solvent-free, solid-supported conditions.     

Synthesis and in vitro evaluation of some new pyrimidines and related condensed ring systems as potential anticancer agents

Several new pyrimidines 6–11, 18–20 , furo-, thieno-, and pyrrolo[2,3-d]pyrimidines 3, 8, 12 , triazolo-[4,3-a]pyrimidines 14, 15, 16 and tetrazolo[1,5-a]pyrimidine 17 were prepared from the known intermediate 5-(2-hydroxyethyl)-6-methyl-2-thiouracil ( 2 ). Compound 7 (4-chloro-5-(2-chloroethyl)-2-methylthio-6-methyl-pyrimidine) exhibited weak antitumor activity in vitro.     

Synthesis and Crystal Structures of Two 9‐(2‐Bromoethyl)‐Substituted 7‐Deazapurines

The 7‐(2‐bromoethyl) derivatives, 2a and 2b , of 4‐chloro‐7H‐pyrrolo[2,3‐d]pyrimidine ( 1a ) and 4‐chloro‐7H‐pyrrolo[2,3‐d]pyrimidin‐2‐amine ( 1b ) were synthesized by nucleobase anion alkylation (NaH, DMF) and crystallized. X‐Ray analyses of both compounds were performed, and they revealed significantly different positioning of the side chain relative to the heterocyclic ring, depending on the substituent (H or NH₂) at C(2).     

Reaction of 6-hydrazino-3,4-dimethyl-1H-pyrazolo[3,4-d]pyrimidine with pregnenolone derivatives

New androsteno[17,16-d]pyrazoles and -pyrazolines with pyrazolo[3,4-d]pyrimidine fragments were synthesized. A reaction of 3β-hydroxypregna-5,16-dien-20-one and its 3-O-acetyl derivative with 6-hydrazino-3,4-dimethyl-1H-pyrazolo[3,4-d]pyrimidine led to hydrazones at position 20 of the pregnenolone molecule, a possibility of their cyclization was studied. Upon melting, the hydrazones cyclize with the formation of pyrazoline ring annulated with ring D of the steroid at positions 16 and 17. Reflux of the hydrazones in mesitylene with AcOH leads to a mixture of two reaction products: androsteno[17,16-d]pyrazole and a dodecahydro-13H-phenanthro[1′,2′:5,6]pyrano[2,3-d]pyrazole derivative. Apparently, this transformation proceeds through the corresponding epoxide with subsequent rearrangement, which leads to the ring D expansion.     

Efficient synthesis of novel furo[2,3-d]pyrimidine derivatives under catalyst-free conditions

A series of furo[2,3-d]pyrimidine derivatives were synthesized via the [3+2] cyclization of pyrimidine-4,6-diol and a variety of nitroolefins at catalyst-free conditions. The reaction is easy to perform simply mixing inexpensive starting materials in water under conventional heating at 90 °C. The reaction proceeds at a fast speed within 1.5–2 h and gives the high biological and pharmacological active substituent furo[2,3-d]pyrimidine derivatives with good to high yields. Mechanism of formation of these furo[2,3-d]pyrimidine derivatives are also proposed.     

Synthesis of novel oxindolylpyrrolo[2,3-d]pyrimidines via a three-component sequential tandem reaction

A novel one-pot three-component reaction of 6-amino-uracil, isatin, and acetophenone was accomplished through a programmed pH variation for the synthesis of 5-(2-oxoindolin-3-yl)-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives. The reaction was conducted in a sequential tandem manner to give the oxindole substituted pyrrolo[2,3-d]pyrimidine products in good to excellent yields. Despite of timing all the processes were carried out in one pot. Most of these novel compounds show narrow to good spectrum of antimicrobial activities in vitro.     

The use of enamines in the synthesis of heterocycles

The reaction of the enamine N-styryl pyrrolidine with 4,6-dichloro-5-nitropyrimidine and 4-amino-6-chloro-5-nitropyrimidine was investigated. Reduction of resultant compounds was followed by spontaneous ring closure to the pyrrolo[3,2-d]pyrimidine ring system. This reaction sequence should provide a general method for the preparation of 4,7-disubstituted pyrrolo[3,2-d]-pyrimidines.     

Studies on uracils: synthesis of novel pyrido[2,3-d]pyrimidine oxides via ring transformation of isoxazolo[3,4-d]pyrimidine

The reaction of isoxazolo[3,4-d]pyrimidine 1 and cyanoolefins 2 in the presence of triethylamine (Et₃N) as a catalyst afforded an unprecedented one-pot synthesis of biologically important pyrido[2,3-d]pyrimidine oxides 3 in excellent yields.