Selective Synthesis of 7-Substituted Purines via 7,8-Dihydropurines

N‐9‐ and N‐7‐alkenylpurines have been synthesized by rearrangement of the corresponding N‐allyl derivatives, often in good yields and with high stereoselectivity. Base promoted and transition metal mediated rearrangements have been studied. Simple allylpurines were easily rearranged with catalytic amounts of RuClH(CO)(PPh3)3. The efficiency of base promoted rearrangement was highly dependent on the detailed structure of the starting material, but this reaction often occurred with surprisingly high Z‐selectivity.

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“…Yield 242 mg (28 %), yellow oil. The spectroscopic data were in good agreement with those reported before 28…”

Section: Methodssupporting

confidence: 91%

Synthesis of N‐Alkenylpurines by Rearrangements of the Corresponding N‐Allyl Isomers: Scopes and Limitations

Kania

Gundersen

2013

Eur J Org Chem

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“…The syntheses of compounds 1–4 and 6–7 have been described previously . For the selective preparation of 7‐substituted purines, an alternative synthetic approach could be used . The preparation of compounds 5 , 9 and 10 will be described in a separate paper with the description of their biological activities.…”

Section: Methodsmentioning

confidence: 99%

Long‐range heteronuclear coupling constants in 2,6‐disubstituted purine derivatives

Procházková

Čechová

Jansa

et al. 2012

Magnetic Reson in Chemistry

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Four- and five-bond heteronuclear J-couplings between the hydrogen H-8 and carbons C-6 and C-2 in a series of 7- and 9-benzyl substituted purine derivaties with variuous substituents in positions 2 and 6 were studied by coupled (13) C NMR and H,C-HMBC experiments and by DFT calculations. We have found that for some of the derivatives, the five-bond coupling H8-C2 is higher than the four-bond H8-C6 coupling, which is also evidenced by a stronger crosspeak in the HMBC. This finding contradicts the generally accepted opinion that only strong three-bond crosspeaks and one weak four-bond H8-C6 crosspeak can be observed in the HMBC spectra of purine derivatives. The misinterpretation of HMBC spectra may lead to an incorrect determination of the purine derivatives' structure.

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“…9 Recently, as a part of our ongoing project to develop a new selective synthesis of C-and N 7 -substituted pu-rines, 9,10 we have developed a new practical route to the synthesis of N 7 -alkyl-6-halo and N 7 -alkyl-2,6-dihalopurines based on the reaction of 9-tritylated-7,8-dihydropurines with alkyl halide in the presence of a base. 11 One complication of the reported procedure is that the solutions of 9-benzyl-6-chloro-7,8-dihydropurine and 6-chloro-9-trityl-7,8-dihydropurine turned out to be prone to spontaneous oxidation to the corresponding purines in the presence of air. Since the 7,8-dihydropurines bearing electron-withdrawing substituents at the 2-, 6-, or 8-positions were reported to be more stable to oxidation, 12 we envisioned that the introduction of an electron-withdrawing group to the N 9 -position of 7,8-dihydropurines could lower the electron density and thus increase the overall stability of 7,8-dihydropurines to the oxidation as well.…”

mentioning

confidence: 99%

“…Thus, dihydropurines 2a,b can be obtained accordingly in 92% isolated yield in two steps starting from 6chloro or 6-iodopurine. Since the previous study 11 revealed that the reactivity of 6-iodopurines was very similar to that of 6-chloro derivatives, the easier accessible 6chloro derivative 2a was used in the reactions mentioned here. 14 The ability of 2a to undergo spontaneous oxidation in solution was also tested.…”

mentioning

confidence: 99%

Highly Efficient and Broad-Scope Protocol for the Preparation of 7-Substituted 6-Halopurines via N9-Boc-Protected 7,8-Dihydropurines

Kotek¹,

Tobrman²,

Dvořák³

2012

Synthesis

Self Cite

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9-Boc-6-chloropurine, which can be obtained in high yield, is nearly quantitatively reduced with the THF·BH 3 complex. The obtained 9-Boc-7,8-dihydropurine derivative is more stable compared to the corresponding 9-tritylpurine and can be smoothly N 7 -alkylated, acylated, or it can serve as an N-nucleophile in conjugate additions. Deprotection with trifluoroacetic acid followed by MnO 2 oxidation affords the N 7 -substituted purines in high yields. The whole sequence of alkylation, deprotection, and oxidation can be done with crude intermediates using chromatography only for the purification of the final N 7 -substituted purine.Due to the wide occurrence of purine scaffolds in biological systems, many substituted purines are biologically active compounds. A vast number of purine derivatives have therefore been synthesised, and a number of them have been found to be biologically active. 1 Many synthetic methodologies, including C-C cross coupling reactions at the 2-, 6-and 8-positions, substitution of halogens by nucleophiles or N 9 -alkylation, and arylation have been developed for the synthesis of purine derivatives. 2 However, a simple and reliable methodology for the synthesis of N 7 -substituted purines, despite their reported biological activity, 3 was absent until very recently. Direct alkylation of purine bases usually leads to the formation of both N 7 and N 9 isomers of which, with the exception of a few 2-and 6-aminopurines, 4 the latter predominates. Thus, N 7 -substituted purines were mostly prepared by laboured cyclisation of diaminopyrimidine derivatives. 5 A more convenient method has been recently described involving cyclisation of N-substituted 5-amido-4-iodo-6-benzylsulfanylpyrimidines, which is based on coppercatalysed amidation. 6 Additionally, methodology using Co-complexes of chloropurines 7 and temporary protection of the N 9 -position by reversible Michael addition of acrylonitrile in the synthesis of asmarines 8 have also been used for the N 7 -alkylation of purines. Solvent dependent, preferential N 7 -arylation was also observed in the arylation of N 2 -[(dimethylamino)methylene]guanine and N 6 -[(dimethylamino)methylene]adenine. 9 Recently, as a part of our ongoing project to develop a new selective synthesis of C-and N 7 -substituted purines, 9,10 we have developed a new practical route to the synthesis of N 7 -alkyl-6-halo and N 7 -alkyl-2,6-dihalopurines based on the reaction of 9-tritylated-7,8-dihydropurines with alkyl halide in the presence of a base. 11 One complication of the reported procedure is that the solutions of 9-benzyl-6-chloro-7,8-dihydropurine and 6-chloro-9-trityl-7,8-dihydropurine turned out to be prone to spontaneous oxidation to the corresponding purines in the presence of air. Since the 7,8-dihydropurines bearing electron-withdrawing substituents at the 2-, 6-, or 8-positions were reported to be more stable to oxidation, 12 we envisioned that the introduction of an electron-withdrawing group to the N 9 -position of 7,8-dihydropurines could lower the electron den...

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Selective Synthesis of 7-Substituted Purines via 7,8-Dihydropurines

Cited by 30 publications

References 32 publications

Synthesis of N‐Alkenylpurines by Rearrangements of the Corresponding N‐Allyl Isomers: Scopes and Limitations

Synthesis of N‐Alkenylpurines by Rearrangements of the Corresponding N‐Allyl Isomers: Scopes and Limitations

Long‐range heteronuclear coupling constants in 2,6‐disubstituted purine derivatives

Highly Efficient and Broad-Scope Protocol for the Preparation of 7-Substituted 6-Halopurines via N9-Boc-Protected 7,8-Dihydropurines

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