- Iodine-catalyzed oxidative functionalization of purines with (thio)ethers or methylarenes for the synthesis of purin-8-one analogues
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An efficient oxidative functionalization of purine-like substrates with (thio)ethers or methylarenes under mild conditions is described. Using I2as the catalyst, and TBHP as the oxidant, this protocol provides a valuable synthetic tool for the assembly of a wide range of 9-alkyl(benzyl)purin-8-one derivatives with high atom- and step-economy and exceptional functional group tolerance.
- Zhuge, Juanping,Jiang, Ziyang,Jiang, Wei,Histand, Gary,Lin, Dongen
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supporting information
p. 5121 - 5126
(2021/06/21)
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- Regioselective alkylation reaction of purines under microwave irradiation
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The alkylation of purines which is generally carried out after anion formation by treatment with a base and alkyl halide is complicated and in the best cases, mixtures of N-alkylated compounds are obtained. Purine derivatives can be acquired from alkylati
- Ginard, Jaume,Jahani, Daniel,Mur, Nuria,Pujol, Maria Dolors,Vi?as, Miquel,Vinuesa, Arturo
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- METHOD FOR SYNTHESIZING DIVERSELY SUBSTITUTED PURINES
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The present invention relates to a method for synthesizing diversely substituted purines starting from a pyrimidine. Formula (I). The method comprises the formation of an amidine group on the pyrimidine by implementing a Vilsmeier type reagent, the functi
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Page/Page column 34
(2018/12/03)
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- A One-Pot Synthesis of Highly Functionalized Purines
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Highly substituted purines were synthesized in good to high yields through a one-pot straightforward metal-free scalable method, using the Traube synthesis adapted to Vilsmeier-type reagents. From 5-amino-4-chloropyrimidines, new 9-aryl-substituted chloropurines and intermediates for peptide nucleic acid synthesis were prepared. Variant procedures allowing a rapid synthesis of ribonucleosides and 7-benzylpurine from 5-amidino-6-aminopyrimidines are also reported to illustrate the high potential of this versatile toolbox. This route appears to be particularly interesting in the field of nucleic acids for a direct and rapid access to various new 8-alkylpurine nucleosides.
- Zelli, Renaud,Zeinyeh, Wa?l,Haudecoeur, Romain,Alliot, Julien,Boucherle, Benjamin,Callebaut, Isabelle,Décout, Jean-Luc
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supporting information
p. 6360 - 6363
(2017/12/08)
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- Direct, Regioselective N-Alkylation of 1,3-Azoles
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Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases to affect regioselective alkylation of various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 to 95%.
- Chen, Shuai,Graceffa, Russell F.,Boezio, Alessandro A.
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supporting information
p. 16 - 19
(2016/01/15)
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- Regioselective and facile synthesis of 7,9-dialkyl-8-oxopurines from 7,9-dialkyl-7,8-dihydropurines: Total synthesis of heteromines i and J
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A novel protocol for the synthesis of 6-halo-8-oxo-7,8-dihydro-9H-purines based on the oxidation of 7,9-dialkyl-7,8-dihydro-9H-purines has been developed. The presented methodology was used as a key step in the synthesis of heteromines I and J. Georg Thie
- Tobrman, Tomá?,Dvo?ák, Dalimil
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p. 660 - 668
(2014/03/21)
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- Highly efficient and broad-scope protocol for the preparation of 7-substituted 6-halopurines via N 9-Boc-protected 7,8-dihydropurines
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9-Boc-6-chloropurine, which can be obtained in high yield, is nearly quantitatively reduced with the THFBH3 complex. The obtained 9-Boc-7,8-dihydropurine derivative is more stable compared to the corresponding 9-tritylpurine and can be smoothly
- Kotek, Vladislav,Tobrman, Toma,Dvoak, Dalimil
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p. 610 - 618
(2012/04/04)
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- Selective synthesis of 7-substituted purines via 7,8-dihydropurines
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A simple and efficient protocol for the preparation of 7-substituted purines is described. 6- and 2,6-Dihalopurines were N9-tritylated and then transformed to 7,8-dihydropurines by DIBAL-H. Subsequent N 7-alkylation followed by N9-trityl deprotection with trifluoroacetic acid was accompanied by spontaneous reoxidation, which led to the 7-substituted purines at 55 - 88% overall isolated yields.
- Kotek, Vladislav,Chudikova, Nadezda,Tobrman, Tomas,Dvorak, Dalimil
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p. 5724 - 5727
(2011/03/19)
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- Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors
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On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
- Laufer, Stefan A.,Domeyer, David M.,Scior, Thomas R. F.,Albrecht, Wolfgang,Hauser, Dominik R. J.
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p. 710 - 722
(2007/10/03)
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- Design, synthesis and structure-activity relationships of a series of 9-substituted adenine derivatives as selective phosphodiesterase type-4 inhibitors
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Adenine derivatives substituted in position 9 have been demonstrated to have potent cyclic nucleotide phosphodiesterase (PDE) inhibition properties with high selectivity toward PDE-4. Starting from our initial lead compound 9-(2-fluorobenzyl)-N6-methyl-2-trifluoromethyladenine (4, NCS613), we designed and synthesized a new series of 9-substituted derivatives for developing structure-activity relationship studies. This new series of derivatives showed increased potencies and better selectivity profiles. Structural modifications were achieved in parallel on three different positions of the adenine ring, and led to the following observations: (i) introduction of a lipophilic substituent such as trifluoromethyl, n-propyl group or iodine in the C-2 position is favourable for both the PDE-4 inhibitory activity and the selectivity towards other isoenzymes; (ii) functionalization of the N9 benzyl group with a 2-methoxy substituent led to remarkably more active compounds; (iii) replacement of the N6-methylamino moiety by other amino groups is detrimental to the activity. Among all derivatives prepared, the 9-(2-methoxybenzyl)-N6-methyl-2-trifluoromethyladenine (9r), 9-(2-methoxybenzyl)-N6-methyl-2-n-propyladenine (9s), and the 2-iodo-9-(2-methoxybenzyl)-N6-methyladenine (13b) were found to be the most potent inhibitors within this series (PDE-4-IC50=1.4, 7.0, and 0.096 nM, respectively). Compared to our reference compound 4, which showed an IC50 of 42 nM, the derivative 13b was found 450-fold more potent. Moreover, 2-iodo-9-(2-methoxybenzyl)-N6-methyladenine (13b) and 9-(2-methoxybenzyl)-N6-methyl-2-trifluoromethyladenine (9r), were at least 50 000-150 000 times more selective for the PDE-4 than for the other PDE families. Additionally, these new derivatives showed improved efficiency in inhibiting the TNFα release from mononuclear cells from healthy subjects (e.g. adenines 7l, 9s and 13b). Thus, compounds 7l, 9r, 9s and 13b are among the most potent and selective PDE-4 inhibitors reported so far and represent very promising pharmacological tools for a better understanding of the signal transduction involving cyclic AMP within the cell: this pathway is implicated in the physiology and the pathophysiology of inflammation, asthma and autoimmune disorders.
- Raboisson, Pierre,Lugnier, Claire,Muller, Christian,Reimund, Jean-Marie,Schultz, Dominique,Pinna, Guillaume,Le Bec, Alain,Basaran, Helene,Desaubry, Laurent,Gaudiot, Francois,Seloum, Mohamed,Bourguignon, Jean-Jacques
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p. 199 - 214
(2007/10/03)
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- A Facile Synthesis of Trifluoromethylamines by Oxidative Desulfurization-Fluorination of Dithiocarbamates
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Trifluoromethylamines are easily synthesized from dithiocarbamates by a reagent system consisting of tetrabutylammonium dihydrogentrifluoride and an N-halo imide under mild conditions. When this reaction was applied to dithiocarbamates ArN(R)CS2Me at higher temperatures, the trifluoromethylation was accompanied by halogen substitution at the p-position of the Ar group. The synthesis of trifluoromethyl-substituted adenosine is also described.
- Kanie, Kiyoshi,Mizuno, Katsuya,Kuroboshi, Manabu,Hiyama, Tamejiro
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p. 1973 - 1991
(2007/10/03)
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- 6-Halopurines in palladium-catalyzed coupling with organotin and organozinc reagents
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N-9 and N-7 benzylated 6-halopurines readily participate in palladium catalyzed cross coupling reactions with organotin and organozinc derivatives. In most instances the 6-chloropurines can be used. Organostannanes are excellent reagents for the introduction of alkenyl and aryl substituents, but organozinc compounds are the reagents of choice for the introduction of alkyl groups.
- Gundersen,Bakkestuen,Aasen,Overas,Rise
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p. 9743 - 9756
(2007/10/02)
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- Mitsunobu reactions for the synthesis of carbocyclic analogues of nucleosides: Examintion of the regioselectivity
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In order to provide a general synthetic method for carbocyclic nucleosides, regioselectivities in Mitsunobu reaction of purine, pyrimidin-2-one and their substituted derivatives with a variety of alcohols with a variety of alcohols were examined and found to depend upon both substituents of the bases and kind of the alcohols.
- Toyota,Katagiri,Kaneko
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p. 1295 - 1305
(2007/10/02)
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- The alkylation of 6-chloropurine with alcohols by Mitsunobu reaction
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A general procedure has been developed for the preparation of 9-alkylated adenines by the Mitsunobu reaction between 6-chloropurine and several alcohols, followed by the replacement of the chlorine with ammonia. A lesser amount of the 7-alkylpurines was also obtained, irrespective of the alcohol used.
- Toyota,Katagiri,Kaneko
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p. 1039 - 1041
(2007/10/02)
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- ALKYLATION OF SOME 6-SUBSTITUTED PURINES UNDER INTERPHASE CATALYSIS CONDITIONS
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The mixture of 9-, 3-, and 7-benzyl-6-substituted purines is formed in almost quantitative yield by the alkylation of 6-benzylamino-, 6-furfurylamino-, 6-methylthio-, and 6-chloropurine with benzyhalides in the biphasic system of the liquid-liquid or liquid-solid type in the presence of interphase catalysts (quarternary ammonium salts, 18-crown-6).The catalytic activity of the quarternary ammonium salts increases with the inrease in the lipophilicity of the cation.Taking the alkylation of 6-benzylaminopurine as an example, the possibility of the application of ''triphasic catalysis'' in the alkylation reaction of purines is indicated.The alkylation of 6-substituted purines with isopropylbromide proceeds regioselectively under the conditions of the interphase catalysis with the formation of the corresponding 9-isopropylpurines.
- Ramzaeva, N. P.,Goncharova, L. N.,Lidak, M. Yu.,Gol'dberg, Yu. Sh.,Shimanskaya, M. V.
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- Heterocyclic Ambident Nucleophiles. III* The Alkylation of Sodium Adenide
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The alkylation of sodium adenide in HCONMe2 (30 deg) with various alkylating agents was analysed by 1H n.m.r. spectroscopy.Widely varying N3:N7:N9 alkylation patterns were observed, depending on the alkylating agent.These patterns are interpreted in terms of the electrostatic, thermodynamic and steric factors involved in the different SN2 transition states appropriate to each alkylating agent.Hydrogen bonding association between the 6-amino group and certain carbonyl containing alkylating agents is proposed to explain the enhancedN7-alkylation in some cases.Support for this latter proposal was obtain from a comparison of the adenine alkylation results with the corresponding alkylation patterns of 6-pivaloylamino- and 6-chloro-purine.
- Rasmussen, Malcolm,Hope, Janet M.
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p. 525 - 534
(2007/10/02)
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- Heterocyclic Ambident Nucleophiles. IV* The alkylation of Metal Salts of Adenine
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The N3:N7:N9 alkylation patterns for reactions of the lithium, sodium, and potassium salts of adenine with various alkylating agents in dimethyl sulfoxide were determined by 1H n.m.r. spectroscopy.Only for the Li+ salt was any significant effect of ionic association noticed.Of the alkylating agents used, only chloromethyl pivalate gave a concentration dependent alkylation pattern.The latter effect was most pronounced with the heterogenous alkylation conditions of anhydrous Na2CO3/HCONMe2, adenine, and chloromethyl pivalate; here, increasingconcentrations changed the main reaction from N7- to N9-alkylation.Solvent effects on the alkylation patterns were also studied.Within the common dipolar aprotic solvent group, (Me2N)3PO, HCONMe2 and Me2SO, effects were small; in protic solvents, particularly formamide, enhanced N3-alkylation was observed.
- Rasmussen, Malcolm,Hope, Janet M.
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p. 535 - 542
(2007/10/02)
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- Coupling of Diazopurines, a Curious Steric Effect in a Free Radical Reaction
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The reaction of adenine derivatives with nitrite esters in the presence of arenes was examined and found to give 6-arylpurines in good (83percent) to poor (11percent) yield.The arylated products consisted only of the meta and para isomers; none of the anticipated ortho isomers were found.The predominance of meta- and para-substituted products is attributed to steric effects.The evidence that the reaction proceeds via a purine radical includes light stimulation, relative insensitivity to electronic factors, and the facile reaction of the purine intermediate with pyridine N-oxide.Photolysis of 6-iodo-9-benzylpurine in the presence of anisole gave the same mixture of 6-(m-methoxyphenyl)- and 6-(p-methoxyphenyl)purine as did diazotization, suggesting that both reactions involve the same purine radical.
- McKenzie, Thomas C.,Epstein, Joseph W.
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p. 4881 - 4884
(2007/10/02)
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