Parallel solution-phase synthesis of 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines

A simple and straightforward methodology for the parallel, solution-phase synthesis of novel 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines 9a-j has been developed. Starting from 2-methylthio-6-[2-(p-toluensulfonyloxy)ethan-1-yl]-4(3H)-pyrimidinone (6), a three-step procedure (namely, tosylate substitution by amines, base-catalyzed rearrangement, and sulfide to sulfone oxidation) using a Buchi Sincore synthesizer gave the final products in high yield after simple ethyl acetate extraction and without further purification. Interestingly, when the final oxidation step was performed on 4-arylpiperazine derivatives 8g-j, the corresponding highly polar piperazine N-oxides 9g-j were obtained, which conversely needed chromatographic purification in order to give the pure products.     

Parallel solution-phase synthesis of a 2-aminothiazole library including fully automated work-up

A straightforward and effective procedure for the solution phase preparation of a 2-aminothiazole combinatorial library is described. Reaction, work-up and isolation of the title compounds as free bases was accomplished in a fully automated fashion using the Chemspeed ASW 2000 automated synthesizer. The compounds were obtained in good yields and excellent purities without any further purification procedure.     

Parallel solution-phase synthesis of a 2,6,8,9-tetrasubstituted purine library via a sulfur intermediate

Purine analogues exhibiting a wide range of pharmacological activities have been considered a privileged structure in medicinal chemistry. In addition, the purine core consisting of four points of structural diversity is a well-sought scaffold in combinatorial chemistry. Although most of the efforts have been focused on 2,6,9-, 6,8,9-, or 2,8,9-trisubstituted purines, syntheses of 2,6,8,9-tetrasubstituted purines are rare. This paper presents a parallel solution phase approach for the synthesis of fully substituted purines via a 6-sulfur-substituted pyrimidine as the key intermediate. This strategy combining construction and modification of the purine ring thus increases the structural diversity of the final products. Sequential substitution of chlorines in 4,6-dichloro-2-methyl-5-nitropyrimidine with primary amine and benzylmercaptan afforded the 4-(substituted)amino-6-benzylthio-5-nitropyrimidine, which was readily converted to its diaminopyrimidine analogue by reduction of the nitro group. The diaminopyrimidine intermediate was cyclized to construct the purine ring with a C-8 substituent. Eventual oxidation of sulfur to sulfone and subsequent displacement by a primary or secondary amine provided the desired 2,6,8,9-tetrasubstituted purine analogues. This synthetic methodology was validated with the synthesis of a 216-member purine library.     

Parallel solution-phase synthesis of substituted 2-(1,2,4-triazol-3-yl)benzimidazoles

A solution-phase synthesis for the preparation of substituted 2-(1,2,4-triazol-3-yl)benzimidazoles from triazole aldehydes and ortho-phenylenediamines has been developed for the purpose of producing diverse lead generation libraries. Crude products were obtained and further purified by mass-guided preparative HPLC.     

Natural products as scaffolds for chemical diversification: solution-phase parallel synthesis of a series of naringin analogues

The flavanone glycoside naringin hydrate is widely abundant in various citrus plants. As an ongoing effort toward the exploitation of natural products as scaffolds for chemical diversification at readily accessible positions, we have prepared a series of analogues of naringin in which the 6-hydroxyl group of the beta-d-glucopyranosyl subunit was converted to sulfonamides, amides, urethanes, and secondary and tertiary amines via the corresponding 6-amino derivative using a solution-phase parallel array protocol.     

Recent application of acidic 1,3-azolium salts as promoters in the solution-phase synthesis of nucleosides and nucleotides

Acidic 1,3-azolium salts are prepared from Brønsted acids and 1,3-azoles such as imidazole, thiazole, and oxazole. Acidic imidazolium salts are frequently employed as promoters for the synthesis of nucleotides using the phosphoramidite method in a solution phase. Recently, it was revealed that thiazolium and oxazolium salts catalyzed Vorbrüggen-type N-glycosylation reactions to give nucleosides. These reactivities are attributed to the stronger Brønsted acidities of the thiazolium and oxazolium salts relative to those of the imidazolium salts. This digest focuses on recent progress in the applicability of acidic 1,3-azolium salts as promoters in the solution-phase synthesis of nucleosides and nucleotides.     

Toward solution-phase automated iterative synthesis: fluorous-tag assisted solution-phase synthesis of linear and branched mannose oligomers

We report herein the first synthesis of linear and branched mannose oligosaccharides using fluorous-tag assistance with reagents and FSPE protocols that are amenable to automation. The particular fluorous linker proved to maintain solubility of the growing oligosaccharide chain such that identical reaction solvent conditions and purification protocols could be used between glycosylation and deprotection reactions, thereby rendering the procedures amenable to automation.     

Parallel solution-phase synthesis of 2-alkylthio-5-arylidene-3,5-dihydro-4H-imidazol-4-one by one-pot three-component domino reaction

A practical protocol for the preparation of a parallel solution-phase library of 5-arylidene imidazolone is reported. Target compounds were obtained in good yield, stereoselectively, and purity by one-pot domino reaction from various thiohydantoines, arylaldimines, and halogenoalkanes. Purification of the final products by recrystallization with a mixture of pentane/ethanol allowed simple isolation of the 17 components of the array.     

Parallel solution-phase synthesis of (Z)-3-(arylamino)-2,3-dehydroalanine derivatives and solid-phase synthesis of fused pyrimidones

N-Protected (Z)-3-(arylamino)-2,3-dehydroalanine esters 5 and 10 were prepared in one step from methyl (Z)-2-acylamino-3-(dimethylamino)prop-2-enoates 3 and 9 and anilines 4 employing a parallel solution-phase synthetic approach. In most cases, analytically pure products 5 and 10 were obtained. On the other hand, a three-step parallel solid-phase synthesis of 2-acetylamino-4H-azino[1,2-x]pyrimidin-4-ones 15 via the polymer-bound methyl (Z)-2-acetylamino-3-(dimethylamino)prop-2-enoate (12) was also developed.     

Application of an automated synthesis suite to parallel solution-phase peptide synthesis

An in-house developed automated synthesis suite was used to prepare a library of 72 tetrapeptide derivatives, the starting materials for pharmaceutically attractive pentapeptides, employing a convergent strategy. An initial set of 18 dipeptides were synthesized on a large-scale (100-1000 g) using automated synthesis workstations, and then 72 tetrapeptides were synthesized on a medium scale (5-10 g) using an automated system. Each di- or tetrapeptide was prepared in a single operating cycle using a modified methanesulfonic acid method, then a sub-library of 56 pentapeptides were synthesized in parallel, on a small-scale (100 mg-1 g) using a robotic workstation.     

Low-temperature solution-phase synthesis of quantum well structured CdSe nanoribbons

Quantum well structured CdSe nanoribbons with uniform and ultrathin thickness of 1.4 nm were synthesized from the low-temperature reaction of CdCl2 and ammonium selenocarbamate. The CdSe nanoribbons exhibited an extremely narrow photoluminescence band with fwhm of 70 meV.     

Iron carbonyl-mediated parallel solution-phase synthesis of cyclohexadienoic acid amides

Iron carbonyl-stabilized cations have been employed to develop methodology for carbon-carbon and carbon-heteroatom formation suitable for the preparation of combinatorial libraries. Different nucleophiles were added to tricarbonyl(cyclohexa-1,3-dienylcarboxylic acid 4-nitro-phenyl ester)iron hexafluorophosphate. Aminolysis, followed by decomplexation, yielded substituted cyclohexadienyl amides of high purity. Carbon, oxygen, and sulfur nucleophiles gave good results, while amine nucleophiles gave products of somewhat lower purity.     

Total synthesis of the fumiquinazoline alkaloids: solution-phase studies

Biomimetic total syntheses of glyantrypine, fumiquinazoline F, fumiquinazoline G, and fiscalin B were achieved in four steps from tryptophan methyl ester. In the key step, the anthranilamide residue in a linear tripeptide is dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine, and a tertiary amine. The benzoxazines subsequently undergo rearrangement to the natural products via an amidine intermediate. This dehydrative oxazine to quinazoline route is applicable to a broad range of N-acylanthranilamides, including sterically hindered cases.     

Parallel approach for solution-phase synthesis of 2-quinoxalinol analogues and their inhibition of LPS-induced TNF-alpha release on mouse macrophages in vitro

A parallel solution-phase synthesis of 2-quinoxalinol analogues is described. The key step-simultaneous reductions of m-Ar(NO(2))(2) to m-Ar(NH(2))(2) was investigated extensively. We obtained preliminary pharmacological activity of those analogues for the inhibition of LPS-induced TNF-alpha release on mouse macrophage in vitro. Two compounds revealed inhibitory activity, with IC(50) values of 0.40 microM (7-amino-6-[(3-methoxypropyl)amino]-3-methyl-2-quinoxalinol) and 2.2 microM (7-amino-6-[(3-butoxypropyl)amino]-3-methyl-2-quinoxalinol), respectively.     

A two-step sulfurization for efficient solution-phase synthesis of phosphorothioate oligonucleotides

A solution-phase approach for the synthesis of phosphorothioate oligonucleotides that circumvents the use of chromatographic purifications of protected phosphorothioate intermediates was developed. Implementation of a two-step sulfurization protocol in the phosphoramidite method allows efficient isolation of the intermediate phosphorothioates by extractions. The viability of this approach is demonstrated by the synthesis of a hexameric phosphorothioate oligonucleotide fragment.     

A solution-phase combinatorial synthesis of selective dopamine D4 ligands

Utilizing combinatorial synthesis and a preparative LC-MS automated chromatography system we have prepared and purified a library of 4-[2-(1,2,4-oxadiazolyl)]piperidines that were designed to be novel and selective dopamine D4 ligands. In one round of synthesis we identified N-4-chlorobenzyl-4-[2-(3-(2-thienyl)-1,2, 4-oxadiazolyl)]piperidine with a Kd of 5 nM for the human D4 receptor.     

Solid-phase and solution-phase parallel synthesis of tetrahydro-isoquinolines via Pictet-Spengler reaction

An efficient parallel synthesis of 6,7-dimethoxytetrahydroisoquinolines is reported. The key reaction step is 3,4-dimethoxyphenethylimines reacting with acid chlorides to form an N-acyliminium ion intermediate, which undergoes Pictet-Spengler condensation to give the desired products in >80% yield. Both solution-phase and solid-phase synthesis of 6,7-dimethoxytetrahydroisoquinolines are described.     

Facile solution-phase synthesis of γ-Mn3O4 hierarchical structures

Background  

A lot of effort has been focused on the integration of nanorods/nanowire as building blocks into three-dimensional (3D) complex superstructures. But, the development of simple and effective methods for creating novel assemblies of self-supported patterns of hierarchical architectures to designed materials using a suitable chemical method is important to technology and remains an attractive, but elusive goal.