Solid-phase synthesis of urea and amide libraries using the T2 triazene linker

Starting from Merrifield resin, primary amines were immobilized in two steps by triazene linkage (T2-linker). While reaction with isocyanates gave rise to resin-bound urea derivatives, acylation by acid chlorides or anhydrides furnished amides bound to solid support via the nitrogen atom, therefore representing a novel backbone amide linker. Cleavage from the resin was conducted using dilute trimethylsilyl chloride or trifluoroacetic acid, respectively, to yield ureas and amines/amides in a library format (altogether 60 examples; manual synthesis: 17 ureas, 6 mono-alkylated ureas [including dihydroxylation and ozonolysis/Wittig reaction]; automated synthesis: 15 ureas, 15 amides) in high purities and good overall yields. The synthesis of a small library (4 x 4 member) was successfully conducted on a Bohdan Neptune synthesizer.     

Achieving functional group diversity in parallel synthesis: solution-phase synthesis of a library of ureas, carbamates, thiocarbamates, and amides using carbamoylimidazolium salts

A convenient protocol for the parallel solution-phase synthesis of a library of thiocarbamates, ureas, carbamates, and amides from carbamoylimidazolium salts has been developed. The crystalline carbamoylimidazolium salts are readily synthesized from secondary amines, CDI and iodomethane, and act as stable carbamoylation reagents. A common set of reaction conditions and a straightforward non-chromatographic liquid-liquid extraction purification protocol were developed for reactions with thiols, amines, phenols, and carboxylic acids, giving the products with high purities and yields. The resultant library incorporates diversity arising from the choice of reaction partners and the functional group linkage generated in the couplings.     

Combinatorial approach to N-substituted aminocyclitol libraries by solution-phase parallel synthesis and preliminary evaluation as glucocerebrosidase inhibitors

Libraries of N-substituted aminocyclitol derivatives of the scyllo and racemic chiro series by means of parallel solution-phase methodology with the help of robotic technology are described. Chemical diversity has been introduced by reaction of selected scaffolds with a set of aldehydes, acyl chlorides, sulfonyl chlorides, chloroformates, and amines to afford the corresponding amines, amides, sulfonamides, carbamates and ureas, respectively. The optimized methodology has proven excellent, in terms of overall purities of the resulting libraries, for the production of amides. Sulfonamides and carbamates have been obtained in slightly lower purities, while amines afforded modest results. Selected library members have been evaluated as inhibitors of recombinant glucocerebrosidase with K(i) values ranging in the low micromolar scale for the most active members.     

Fully automated flow-through synthesis of secondary sulfonamides in a binary reactor system

A fully automated flow-through process for the production of secondary sulfonamides is presented. Primary sulfonamides were monoalkylated using a two-step "catch and release" protocol to generate library products of high purity. The automated flow synthesis platform incorporates four independent reactor columns and is able to perform automated column regeneration. A 48-member sulfonamide library was prepared as two 24-member sublibraries, affording library compounds in good yields and high purities without the need for further column chromatographic purification.     

A Practical,Water‐Soluble,Ionic Scavenger for the Solution‐Phase Syntheses of Amides

A new ionic, water‐soluble scavenger for acyl chlorides, 1‐(2‐aminoethyl)pyridinium bromide ( 1 ), has been investigated. Compound 1 was used for the rapid and simple purification of a series of benzamides and sulfonamides (Table) obtained by solution‐phase synthesis from the corresponding amines (Scheme). The inexpensive scavenger, which can be prepared on large scale, was shown to readily ‘eliminate’ excess acyl chlorides (reagent) by simple aqueous extraction. The amides purified in this way were obtained in excellent yields and purities (Table), which makes 1 a versatile new reagent, especially for the combinatorial solution‐phase synthesis of amide libraries.     

A highly automated, polymer-assisted strategy for the preparation of 2-alkylthiobenzimidazoles and N,N'-dialkylbenzimidazolin-2-ones

A multistep, polymer-assisted solution phase strategy for the highly automated (auto-PASP) synthesis of 2-alkylthiobenzimidazole and N,N'-dialkylbenzimidazolin-2-one libraries is presented. The approach incorporates in-line purification techniques to afford library products directly with high purities and is exemplified by the preparation of a 96-member 2-alkylthiobenzimidazoline library 1[1-12,1-8] and a 72-member N,N'-dialkylbenzimidazolin-2-one library 9[1-12,1-6].     

Parallel synthesis of tri- and tetrasubstituted ureas from carbamoyl imidazolium salts

A method for producing tri- and tetrasubstituted ureas from carbamoyl imidazolium salts is presented. Carbamoyl imidazolium salts are prepared from the reaction of N,N carbonyldiimidazole (CDI) with secondary amines, followed by alkylation with iodomethane. These stable salts can be stored for extended periods and are effective electrophilic carbamoylation reagents. Primary and secondary amines add to carbamoyl imidazolium salts at room temperature to give tri- and tetrasubstituted ureas in excellent yields. This reaction was used to synthesize ureas using both liquid-liquid extraction and solid-phase extraction (cation exchange) purification techniques. Liquid-liquid extraction affords the product ureas more cleanly than cationic exchange. A series of urea compounds were synthesized using parallel synthesis techniques in high yields and with suitable purity for routine in vitro biological tests. These studies validate the utility of carbamoyl imidazolium salts as useful building blocks for combinatorial library synthesis.     

Structure Based Library Approach to Photosynthesis Inhibitors:The Solid Phase Synthesis of Hydro-Uracils and Thiouracils

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Microwave-assisted "libraries from libraries" approach toward the synthesis of allyl- and C-cyclopropylalkylamides

Cascade reactions of internal and terminal alkynes, zirconocene hydrochloride, dimethylzinc, and phosphinoyl imines (prepared in one step from aldehydes and diphenylphosphinoyl amide) lead to allylic phosphinoyl amides after aqueous workup. Microwave acceleration allows the completion of this one-pot reaction sequence in 10 min. These allylic amides can be converted into a variety of derivatives, including carbamates and sulfonamides, or reacted prior to workup with diiodomethane to give novel C-cyclopropylalkylamides. A solution-phase "libraries from libraries" approach was used to generate an intermediate 20-member library which was subsequently expanded to a 100-member library by a series of N-functionalizations. The biological activity was evaluated in an assay for competitive binding to the estrogen receptor (ERalpha), revealing three potent lead compounds of a new structural type.     

Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine

Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80 seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p‐methoxybenzyl amines.     

Rapid access to 3-(N-substituted)-aminoquinolin-2(1H)-ones using palladium-catalyzed C-N bond coupling reaction

A series of 3-(N-substituted)-aminoquinolin-2(1H)-ones have been synthesized by the palladium-catalyzed C-N coupling reaction starting from 3-bromoquinolin-2-(1H)-ones. Various nucleophiles including amines, amides, sulfonamides, carbamates and ureas have been used successfully. In all the cases, the reactions take place rapidly in 1,4-dioxane and proceed in good to excellent yield using palladium acetate as a catalyst, Xantphos as a ligand and Cs₂CO₃ as a base.     

Solid-phase synthesis of trisubsituted guanidines

The solid-phase library synthesis of trisubstituted guanidines was accomplished. Amines were loaded onto the 4-formyl-3,5-dimethoxyphenoxymethyl linker via reductive amination. Subsequent acylation with Fmoc-4-aminomethylbenzoic acid followed by Fmoc deprotection gave solid-supported primary amines. Alternatively, sulfonylation of resin-bound secondary amines with 4-cyanobenzenesulfonyl chloride followed by borane reduction also gave solid-supported primary amines. Both resins were acylated with isocyanates to furnish solid-supported ureas. Dehydration of ureas with p-toluenesulfonyl chloride in pyridine gave solid-supported carbodiimides. Nucleophilic addition of amines to the carbodiimide bond followed by cleavage off the solid support gave trisubstituted guanidines.     

Parallel synthesis of an amide library based on the 6,8-dioxa-3-azabicyclo[3.2.1]octane scaffold by direct aminolysis of methyl esters

An efficient synthesis of unsubstituted and substituted amides based on the 6,8-dioxa-3-azabicyclo[3.2.1]octane scaffold is described. The reaction, carried out at 60 degrees C in the absence of solvent, is characterized by its mildness and ease of workup. A library of amides, was synthesized by combination of methyl esters 1-6 with various amines. In addition, the microwave-assisted automated synthesis of the library was compared with the above conventional parallel synthesis. Microwave synthesis significantly decreased the reaction time from hours to minutes.     

Carbamoylimidazolium salts as diversification reagents: an application to the synthesis of tertiary amides from carboxylic acids

An efficient method for the preparation of tertiary amides from carbamoylimidazolium salts and carboxylic acids is described. The transformation occurs at room temperature and under relatively mild conditions. The carbamoylimidazolium salts are obtained from the reaction of secondary amines with N,N′-carbonyldiimidazole, followed by methylation with methyl iodide. The utility of this reaction was demonstrated in the formation of Weinreb amides and in a short synthesis of fused bicyclic amides. The introduction of this reaction now permits carbamoylimidazolium salts to be utilized in the formation of tertiary amides, ureas, carbamates and thiocarbamates under a single set of conditions.     

Structure based library approach to photosynthesis inhibitors:Combinatorial synthesis of hydrouracil library

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Carbamates from alcohol diversity: a simple solution phase library method

A simple one-pot, solution phase method for the parallel synthesis of carbamates from amines and alcohols is described. The high-yielding method does not require support-bound reagents, extractions or resin washing steps and should be broadly applicable to the manual or automated generation of carbamate libraries.     

The use of polyhedral oligomeric silsesquioxane (POSS) as a soluble support for organic synthesis: A case study with a POSS-bound isocyanate scavenger reagent

The use of polyhedral oligomeric silsesquioxane (POSS) as a soluble support in organic synthesis is reported. A POSS-bound isocyanate was readily synthesised in one step from commercially available starting materials and was isolated in high yield and purity by simple filtration. It was found to perform well as a scavenger for excess amine in the solution phase synthesis of amides and sulfonamides, allowing product isolation in high yield and purity.     

Practical synthesis of amides from alkynyl bromides, amines, and water

A general and efficient method for the synthesis of a wide range of amides is described here. The reactions were conducted under convenient conditions and provided secondary and tertiary amides in moderate to excellent yields. A variety of amines and substituted alkynyl bromides were used to investigate the scope of the reactions.     

Efficient microwave access to polysubstituted amidines from imidoylbenzotriazoles

Microwave reactions of primary and secondary amines with imidoylbenzotriazoles 6a-w gave diversely substituted amidines 7a-Aa in 76-94% yields. Convenient preparations of a variety of amides 5a-Ab (87-96%) and imidoylbenzotriazoles 6a-w (56-95%) have also been developed using microwave irradiation under mild conditions and short reaction times. These results demonstrate further the advantages of microwave synthesis and introduce a new application of imidoylbenzotriazoles in the preparation of polysubstituted amidines.