Efficient conversion of 6-cyanopurines into 6-alkoxyformimidoylpurines

Carvalho, M. Alice; Esteves, Teresa; Proença, M. Fernanda; Booth, Brian L.

doi:10.1039/b400171k

Cited by 20 publications

(9 citation statements)

References 24 publications

(16 reference statements)

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“…The 6-amidinopurines 2c and 2e were actually prepared by an alternative synthetic method, based on the reactions between the 6-alkoxyformimidoylpurine 3 [24] and either hydrazine hydrate or ammonium acetate, respectively (Scheme 1). The reactions occurred smoothly in the presence of acid and the products were isolated in very good yield.…”

Section: Resultsmentioning

confidence: 99%

“…In both cases the product is formed by a Dimroth rearrangement of the precursor 7,8-dihydropyrimido [5,4- nopurines and substituted amines are confusing and somewhat contradictory. Higashino [23] reported the formation of 6-amidinopurines 2 (Scheme 1) when 9-phenyl-6-cyanopurine (1a) was treated with n-butylamine, piperidine, hydrazine and hydroxylamine, in methanol or ethanol as solvent, whilst our previous results on the reaction behaviour of 6-cyanopurines in methanol in the presence of DBU [24] showed nucleophilic attack of the solvent on the cyano carbon atom to be the major pathway, resulting in a 6-imidatopurine 3 (Scheme 1). Imidates are useful precursors of amidines, and compound 3 was efficiently transformed into a 6-amidinopurine 2 on treatment with methylammonium chloride.…”

Section: Introductionmentioning

confidence: 96%

“…Imidates are useful precursors of amidines, and compound 3 was efficiently transformed into a 6-amidinopurine 2 on treatment with methylammonium chloride. [24] Currently available information on the reactivity of 6-cyanopurines with amine nucleophiles indicates that the reaction can follow two different pathways, affording either pyrimido [5,4-d]pyrimidines [22] or 6-amidinopurines, [23,24] depending on a delicate balance of the reaction conditions.…”

Section: Introductionmentioning

confidence: 99%

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An Efficient Synthesis of 7,8‐Dihydropyrimido[5,4‐d]pyrimidines

et al. 2007

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Keywords: Cyanopurines / Amines / Rearrangement / Pyrimido [5,4-d]pyrimidines 7,pyrimidines 4 were isolated in very good yields by treatment of 9-aryl-6-cyanopurines 1 with primary amines. Nucleophilic attack of the amine on C8 of the purine ring was followed by ring-opening of the imidazole unit, and subsequent intramolecular cyclization involving the newly formed amidine group and the cyano substituent in the pyrimidine ring produced the 7,8-dihydropyrimido[5,4-d]pyrimidine structure 4. When ammonia was used instead of primary amines, compound 4 rapidly reacted further to afford the more stable pyrimido [5,4-d]pyrimidine 6 as

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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An Efficient Synthesis of 7,8‐Dihydropyrimido[5,4‐d]pyrimidines

et al. 2007

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“…[14,15,21,24] NMR spectra were recorded with a Varian Unity Plus, including the 1 H-13 C correlation spectra (HMQC and HMBC). IR spectra were recorded with a FT-IR Bomem MB 104 by using nujol mulls and NaCl cells.…”

Section: Methodsmentioning

confidence: 99%

A New Approach to the Synthesis of N,N‐Dialkyladenine Derivatives

Alves

Carvalho

et al. 2007

Eur J Org Chem

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N,N‐Dialkyladenine derivatives were prepared by two different reaction sequences starting from 5‐amino‐4‐cyanoformimidoylimidazoles. When these imidazoles were treated with dimethylformamide diethyl acetal, a 5‐aminomethyleneamino‐4‐cyanoformimidoylimidazole was isolated and evolved to the N,N‐dialkyladenine in the presence of a secondary alkylamine. The same purine structure was isolated when the 5‐amino‐4‐cyanoformimidoylimidazole was first treated with a secondary amine to give a stable 4‐amidino‐5‐aminoimidazole. The desired product was generated when the 4‐amidino‐5‐aminoimidazole was combined with dimethylformamide diethyl acetal, at room temperature. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

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“…Thus, efficient formation of pyrimido [5,4-d]pyrimidines 3 required an alternative approach and a new synthetic strategy was designed (Scheme 2). 6-Cyanopurines 1 had been previously used to generate 6-imidatopurines 6, 12 and reaction of these compounds with hydrazides was carried out in the presence of acid catalysis, aiming to prepare the 6-amidinopurines 4. Previous results on the reactivity of the purine ring, under basic conditions and in the presence of nucleophiles, indicated that attack on C8 was the major pathway, [8][9][10] leading to pyrimidopyrimidines 2.…”

Section: Figure 1 a New Class Of Antitubercular Agentsmentioning

confidence: 99%

6-Carbohydrazonamidepurines: Convenient Precursors for 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines

Rocha

Bacelar

Fernandes

et al. 2013

Synlett

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A series of 4-arylamino-8-(alkyl or aryl)hydrazidepyrimido [5,4-d]pyrimidines was obtained efficiently from 6-carbohydrazonamidepurines by reaction with piperidine. The 6-carbohydrazonamidepurines were generated selectively by the reaction of 6-imidatopurine with hydrazides under acidic conditions. Tuberculosis affects much of the world population and it is estimated that 9.2 million new cases appear each year, from which many lead to death. 1 The emergence of multidrug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) has added urgency to the search for new antitubercular agents 2 and, since the last decade of the 20 th century, the scientific community has undertaken intensive research in this area. 3 Recently, in our research group, the pyrimido[5,4-d]pyrimidines ( Figure 1) were identified as a promising new class of antitubercular agents. 4 The new compounds showed high potency that depends on the substituents R 1 and R 2 . Furthermore, the new compounds have no structural similarity to any other compounds active against Mycobacterium tuberculosis and may have a different mechanism of action in relation to drugs currently on the market. Therefore a research program was started in order to develop new methods for the efficient synthesis of new pyrimido [5,4-d]pyrimidines derivatives 3 (Scheme 1) for structureactivity relationship studies. Figure 1 A new class of antitubercular agentsIn the literature, the pyrimido[5,4-d]pyrimidine core structure has been prepared from a substituted pyrimidine, upon reaction with an appropriate electrophile or nucleophile. 5 Amino substituents are usually incorporated into the heteroaromatic ring by nucleophilic substitution of chlorine atoms by amines. 6 The 6-cyanopurines have also been used as precursors of substituted pyrimido [5,4-d]pyrimidines, as the reaction with amines leads to the desired structure by an ANRORC-type mechanism. 7 This approach has been used in our group for the efficient synthesis of compounds 2 (Scheme 1). 4,8-10 According to the literature, structure 2 can be used to generate the aromatic analogue 3 by Dimroth rearrangement, in the presence of acid or base catalysis. 11 Furthermore, our studies on the reactivity of the pyrimidopyrimidine derivatives 2 (R 2 = OBn) have proved that the conversion of 2 (R 2 = OBn) into 3 (R 2 = OBn) occurs efficiently under acid conditions although other products may also be formed (Scheme 1). 10 In the present work, compounds 2 were considered to be convenient precursors of the aromatic pyrimido[5,4-d]pyrimidines 3 (R 2 = NHCOR 3 ).Scheme 1 Synthesis of 2, its conversion into 3 (R 2 = OBn) and attempts to generate new derivatives 3 (R 1 = 4-NCC 6 H 4 , R 2 = NHCOR 3 ).Herein we report our attempts to convert pyrimido[5,4-d]pyrimidine 2 (R 2 = NHCOR 3 ) into 3 (R 2 = NHCOR 3 ) and the new synthetic strategy designed to generate derivatives 3 starting from 6-carbohydrazonamidepurines 4 that have proved to be valuable precursors for the target compounds 3. Compound 2 (R 1 = 4-NCC 6 H ...

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Efficient conversion of 6-cyanopurines into 6-alkoxyformimidoylpurines

Cited by 20 publications

References 24 publications

An Efficient Synthesis of 7,8‐Dihydropyrimido[5,4‐d]pyrimidines

An Efficient Synthesis of 7,8‐Dihydropyrimido[5,4‐d]pyrimidines

A New Approach to the Synthesis of N,N‐Dialkyladenine Derivatives

6-Carbohydrazonamidepurines: Convenient Precursors for 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines

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