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 .     

Pyrrolopyrimidine nucleosides. XIII. Synthesis and chemical reactivity of certain selenopyrrolo[2,3-d]pyrimidine nucleosides

5-Cyano-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidin-4-selone ( 1 ) has been prepared via a reaction of the appropriate 4-chloro compound with sodium hydrogen selenide. Alkylation of 2 under basic conditions has provided certain 4-substitutedseleno-5-cyano-7-(β-D-ribofuranosyl)-pyrrolo[2,3-d]pyrimidines. 5-Cyano-4-methylseleno-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine was allowed to react with hydroxylamine and hydrazine. The products obtained and reaction course were compared to those obtained from identical reactions using the corresponding sulfur analog.     

Pyrrolopyrimidine nucleosides VII. A study on electrophilic and nucleophilic substitution at position six of certain pyrrolo[2,3-d] pyrimidine nucleosides

A study involving the reactivity of the pyrrolo[2,3-d] pyrimidine ring system at position 6 with another exocyclic group (CN or -NH₂) already residing at C5 has established that hydrogen and bromine are susceptible to electrophilic and acid-catalyzed nucleophilic substitution, respect-tively. In one instance a strong nucleophile (hydrazine) gave nucleophilic substitution at position 6 which was followed by a reaction with the o-nitrile group to afford the tricyclic nucleoside 4,5-diamino-8-(β-D-ribofuranosyl)pyrazolo[3′, 4′ :5,4] pyrrolo[2,3-d] pyrimidine (4).     

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.     

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.     

7-Deazapurines II. Syntheses and reactions of 5-aminopyrrolo[2,3-d] pyrimidine-6-carbonitrile and related compounds

The reaction of 4-chloro-2-phenyl-5-pyrimidinecarbonitrile (III) with N-methylglycinonitrile gave 4-[(eyanomethyl)methylamino]-2-phenyl-5-pyrimidinecarbonitrile (VIa), which upon cycli-zation under Dieckmann conditions afforded 5-amino-7-methyl-2-phenyl-7H-pyrrolo[2,3-d]-pyrimidine-6-carbonitrile (VIIa). Other examples (VIIb and VIIc) were prepared similarly from the reactions of III with glycinamide and ethyl glycinate, respectively. The preparation of simple 5-amino derivatives of the pyrrolo[2,3-d] pyrimidines thus synthesized is described. The alkyla-tion of VIIc with N-cyeloheptylchloroacetamide took place at the ring nitrogen, giving XII. The reaction of VIIa with formamide gave 4-amino-5-methyl-7-phenyl-5H-pyrrolo[2,3-d:4,5-d′ ]-dipyrimidine (XIII), the first member of a new ring system. Treatment of VIIa with carbon disulfide and pyridine afforded another example of this new ring system, 1,5-dihydro-5-methyl-7-phenyl-2H-pyrrolo[2,3-d:4,5-d′] dipyrimidine-2,4-(3H)dithione (XIV).     

Synthesis of pyrrolo[2,3-d]pyrimidines with 3-amino-2-hydroxypropyl substituents

A novel route has been found for the synthesis of pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazines. They are promising reagents for the preparation of pyrrolo[2,3-d]pyrimidine-6-carboxylic acid amides which contain a 3-amino-2-hydroxypropyl substituent in position 7 of the heterocyclic ring.     

Synthesis of Fused Tetrazolo[1,5‐c] pyrrolo[3,2‐e]pyrimidines and Their Reductive Conversion to New 4‐Aminopyrrolo[2,3‐d]pyrimidines

Some new 7,9‐substituted 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 1,4‐disubstituted 2‐amino‐3‐cyanopyrroles 1 with formic acid, which, on chlorination using phosphorus oxychloride, afforded 3. 2‐Amino‐3‐cyanopyrroles 1 were synthesized from the reaction between (2-bromo-1-(4-fluorophenyl) ethylidene) propanedinitrile and substituted aromatic amines under Gewald reaction conditions. 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 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     

Aromaticity in heterocyclic systems V. Bromination studies of certain purines,pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines

The bromination of certain selected purines, pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]-pyrimidines has been studied and the reactivity of these systems compared. Displacement of a carboxyl group by bromine was noted in the case of 6-carboxypyrrolo[3,2-d]-2,4-pyrimidinedione. In contrast to xanthine, 2,6-diethoxypurine readily brominated at position 8. Pyrazolo-[4,3-d]-7-pyrimidone was readily brominated at position 3.     

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.     

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.     

Pyrimidines. 65. Synthesis of 6-substituted thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones

Several 6-substituted thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives were synthesized. 6-Ethoxycarbonyl derivatives 3 and 7 were prepared by treatment of 6-chloro-5-formyluracil 1 and 6-chloro-5-cyanouracil 6 with ethyl 2-mercaptoacetate in the presence of a base. Electrophilic substitution reactions (Vilsmeier-Haack reaction, bromination, and nitration) of 5,6-unsubstituted thieno[2,3-d]pyrimidine 9 , prepared by condensation of 6-mercaptouracil 8 with chloroacetaldehyde, afforded the corresponding 6-formyl-, 6-bromo-, and 6-nitrothieno[2,3-d]pyrimidines 10, 15 and 16 , respectively.     

Synthesis,Reactions, and Antimicrobial Evaluation of Some Polycondensed Thienopyrimidine Derivatives

Some novel indeno[2,1-b]thiophenes, indeno[1′,2′:4,5]thieno[2,3-d][1,2,3]triazines, indeno[1′,2′:4,5]thieno[2,3-d]pyrimidines, indeno[1′,2′:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidines, and indeno[1′,2′:4,5]thieno[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines 2–16 were prepared starting with 2-aminoindeno[2,1-b]thiophene-3-carboxylic acid amide ( 1 ). Furthermore, the antimicrobial evaluation of the prepared products showed that many of them revealed promising antimicrobial activity.     

2,4-Disubstituted Pyrrolo[2,3-d]pyrimidine α-D- and β-D-Ribofuranosides Related to 7-Deazaguanosine

Nucleobase-anion glycosylation (KOH, tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1), MeCN) of the pyrrolo[2,3-d]pyrimidines 4a – d with 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribo-furanosyl chloride ( 5 ) gave the protected β-D -nucleosides 6a – d stereoselectively (Scheme 1). Contrary, the β-D -halogenose 8 yielded the corresponding α-D -nucleosides ( 9a and 9b ) apart from minor amounts of the β-D -anomers. The deprotected nucleosides 10a and 11a were converted into 4-substituted 2-aminopyrrolo[2,3-d]-pyrimidine β-D -ribofuranosides 1 . 10c , 12 , 14 , and 16 and into their α-D -anomers, respectively (Scheme 2). From the reaction of 4b with 5 , the glycosylation product 7 was isolated, containing two nucleobase moieties.     

Synthesis of S-5-pyrrolo[2,3-b]pyridinemethyl and S-5- and S-6-pyrrolo[2,3-d]pyridinemethyl derivatives of 5′-deoxy-5′-thioadenosine

Reaction of 5-dimethylaminomethylpyrrolo[2,3-b]pyridine methiodide or 5-dimethylaminomethylpyrrolo[2,3-d]pyrimidin-4-one methiodide with 5′-deoxy-5′-S-thioacetyl-N⁶-formyl-2′,3′-O-isopropylideneadenosine in ethanolic sodium hydroxide solution, followed by deprotection of the resulting thioether in 80% formic acid, afforded 5′-deoxy-5′-(5-pyrrolo[2,3-b]pyridinemethylthio)adenosine or 5′-deoxy-5′-[5-(pyrrolo[2,3-d]pyrimidin-4-one)methylthio]adenosine, respectively. Similarly, the metiodide salt of the iso-gramine analog, 2-amino-6-dimethylaminomethylpyrrolo[2,3-d]pyrimidin-4-one afforded 5′-deoxy-5′-[6-(2-aminopyrrolo[2,3-d]pyrimidin-4-one)methylthio]adenosine.     

Synthesis and Ring Transformation of Pyrrolo[2,3-d][1,3]oxazine to Pyrrolo[2,3-d]Pyrimidines

A convenient route is reported for the synthesis of fused pyrrolo[2,3-d][1,3]oxazine and pyrrolo[2,3-d]-pyrimidine derivatives from 2-amino-1-benzyl-3-t-butoxycarbonyl]-4,5-dimethylpyrrole.     

Synthesis of derivatives of 3-acetyl-2-aminopyrrole and pyrolo[2,3-d]pyrimidine from monoacetylketene aminals

A new scheme for the synthesis of pyrrolo[2,3-d]pyrimidines from monoacetylketene animals was proposed. Reactions of monoacetylketeneN-benzoyl- andN-acetylaminals with -bromoacetophenone afforded the corresponding 3-acetyl-2-acylamino-5-phenyl- lH-pyr-roles, which underwent cyclization to 2,4,6-trisubstituted 7Hl-pyrrolo[2,3-d]pyrimidines under the action of ammonium acetate in boiling BuOH.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp, 1808–1811, July, 19W     

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.