Solution-phase synthesis of an aminomethyl-substituted biaryl library via sequential amine N-alkylation and Suzuki cross-coupling

Described herein is the semiautomated preparation of a 20-member aminomethyl-substituted biaryl library. The two-step solution-phase synthesis was achieved via sequential N-alkylation of various amines with either 3- or 4-bromobenzyl bromide and Suzuki cross-coupling of the resultant aryl bromides with various boronic acids.     

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.     

Heterocyclization of carboxy- and sulfonamides in the course of oxidative addition to unsaturated substrates

Formation of heterocyclic compounds in the course of oxidative addition of carboxamides and sulfonamides to alkenes and dienes is reviewed. Main attention is focused on reactions proceeding in the presence of halo-containing oxidative systems and reagents. Features of behavior of fluorine-substituted sulfonamides and carboxamides are discussed.     

Metal-free synthesis of allylic amines by cross-dehydrogenative-coupling of 1,3-diarylpropenes with anilines and amides under mild conditions

Dehydrogenative cross-coupling reaction of primary anilines, secondary anilines, carboxamides, and sulfonamides with 1,3-diarylpropenes to form a series of allylic amines promoted by DDQ have been realized. Both monoallylation and diallylation products can be selectively synthesized when primary anilines are used as the starting materials. The method may provide a wide scope of allylamines in scientific research including biologically active compound library construction.     

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.     

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].     

5-(hydroxymethyl)oxazoles: versatile scaffolds for combinatorial solid-phase synthesis of 5-substituted oxazoles

A scheme combining the preparation of building blocks in solution followed by solid-phase combinatorial chemistry has been developed to side-chain diversify 5-(hydroxymethyl)oxazole scaffold (1) into aryl ethers, thioethers, sulfones, sulfonamides, and carboxamides. Protected heterocyclic scaffolds 2 were linked to the solid phase and N-terminal derivatized using active ester chemistry, providing chemset 4?1-4,1-4?. The free side-chain hydroxyl of 4 was smoothly converted to aryl ethers 6 under Mitsunobu conditions, with a broad range of substituted phenols. Alternatively, quantitative conversion of hydroxyl to bromide followed by displacement with alkyl and aryl thiols gave thioethers 8. Thioethers were optionally oxidized to sulfones 9. Bromide displacement by azide, followed by reduction to amine and acylation with a range of carboxylic acids and sulfonyl chlorides gave carboxamides 11 and sulfonamides 13, respectively. Crude purity at typically >90% was observed for each of the five modifications detailed. A series of 20 compounds, exemplifying each modification, was reprepared, purified, and fully characterized.     

Minimisation of palladium content in Suzuki cross-coupling reactions

A protocol for conducting Suzuki reactions in a plate format amenable to use in library synthesis of biaryl compounds has been developed. A key objective was to determine reaction conditions which give biaryl products containing <10 ppm of Pd for a wide variety of building blocks. A Design of Experiments (DoE) approach for the identification of an optimised set of reaction conditions was successfully applied. The utility of the protocol developed has been demonstrated by preparation of an array of 96 biaryl compounds in a parallel fashion.     

Practical solid-phase parallel synthesis of Delta(5)-2-oxopiperazines via N-acyliminium ion cyclization

A practical solid-phase strategy for the synthesis of Delta(5)-2-oxopiperazines via N-acyliminium ion cyclization has been developed. A key step in the library synthesis is tandem acidolytic cleavage with subsequent in situ iminium formation, followed by stable enamide transformation. This approach is exemplified by the preparation of a 192-member pilot library using bromoacetal resins without further purification.     

Copper‐Catalyzed Remote C(sp3)−H Trifluoromethylation of Carboxamides and Sulfonamides

Reported herein is an unprecedented protocol for trifluoromethylation of unactivated aliphatic C(sp³)?H bonds. With Cu(OTf)₂ as the catalyst, the reaction of N‐fluoro‐substituted carboxamides (or sulfonamides) with Zn(CF₃)₂ complexes provides the corresponding δ‐trifluoromethylated carboxamides (or sulfonamides) in satisfactory yields under mild reaction conditions. A radical mechanism involving 1,5‐hydrogen atom transfer of N‐radicals followed by CF₃‐transfer from Cu^II?CF₃ complexes to the thus formed alkyl radicals is proposed.     

Solution-phase synthesis of a 1,5-dialkylamino-2,4-dinitrobenzene library and the identification of novel antibacterial compounds from this library

In this report we demonstrate that a 1,5-dialkylamino-2,4-dinitrobenzene small molecule library can be generated by a highly efficient solution-phase synthesis method. From this 2485-member library, a series of novel compounds with antibacterial activity were isolated. The significance of this report is that the synthetic scheme is extremely simple, with minimal number of liquid handling steps, and the solvents and reagents left in the final library preparation are fully compatible with cell-based assays.     

Synthesis of 10,10-Dioxo-10H-10λ6-phenoxathiine-2,8-dicarboxamides

Russian Journal of Organic Chemistry - New carboxamides and sulfonamides containing alkyl and heterocyclic fragments were synthesized on the basis of 2-arylaminopyrimidine derivatives,...     

Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce–Smiles Rearrangement

A new benzyne transformation is described that affords versatile biaryl structures without recourse to transition‐metal catalysis or stoichiometric amounts of organometallic building blocks. Aryl sulfonamides add to benzyne upon fluoride activation, and then undergo an aryl Truce–Smiles rearrangement to afford biaryls with sulfur dioxide extrusion. The reaction proceeds under simple reaction conditions and has excellent scope for the synthesis of sterically hindered atropisomeric biaryl amines.     

Copper-catalyzed amidation of 2-phenylpyridine with oxygen as the terminal oxidant

The Cu(OAc)(2)-catalyzed, O(2)-mediated amidation of 2-phenylpyridine via C-H bond activation is reported. A variety of nitrogen reagents including sulfonamides, carboxamides, and anilines participate in the reaction in moderate to good yields.     

An unusual conformational similarity of two peptide folds featuring sulfonamide and carboxamide on the backbone

Two folded peptides featuring carboxamide and sulfonamide at the core of the peptide fold have been shown to possess almost similar conformational features, despite the well-known fact that carboxamides and sulfonamides have strikingly different hydrogen-bonding and geometrical preferences.     

Asymmetric Stepwise Reductive Amination of Sulfonamides,Sulfamates, and a Phosphinamide by Nickel Catalysis

Asymmetric reductive amination of poorly nucleophilic sulfonamides was realized in the presence of nickel catalysts and titanium alkoxide. A wide range of ketones, including enolizable ketones and some biaryl ones, were converted into sulfonamides in excellent enantiomeric excess. The cyclization of sulfamates and intermolecular reductive amination of a diarylphosphinamide were also successful. Formic acid was used as a safe and economic surrogate of high‐pressure hydrogen gas.     

Asymmetric Stepwise Reductive Amination of Sulfonamides,Sulfamates, and a Phosphinamide by Nickel Catalysis

Asymmetric reductive amination of poorly nucleophilic sulfonamides was realized in the presence of nickel catalysts and titanium alkoxide. A wide range of ketones, including enolizable ketones and some biaryl ones, were converted into sulfonamides in excellent enantiomeric excess. The cyclization of sulfamates and intermolecular reductive amination of a diarylphosphinamide were also successful. Formic acid was used as a safe and economic surrogate of high‐pressure hydrogen gas.     

A reversible safety-catch method for the hydrogenolysis of N-benzyl moieties

The benzyl groups of β-hydroxy-N-benzyl sulfonamides are labile toward hydrogenolysis-unlike N-benzyl sulfonamides lacking the β-hydroxy moiety. We find that N-acyl-N-benzyl sulfonamides undergo hydrogenolysis under very mild conditions. Based upon these observations, we developed a reversible safety-catch method using tert-butoxycarbonyl moieties to activate N-benzyl sulfonamides toward hydrogenolysis. We also explored the utility of the safety-catch activation method for other nitrogen-based functionality such as N-benzyl carboxamides, imides, and related functionality.     

Application of divergent multi-component reactions in the synthesis of a library of peptidomimetics based on γ-amino-α,β-cyclopropyl acids

The multi-component condensation of organozirconocene, aldimine and zinc carbenoid was applied to the stereoselective synthesis of cyclopropane amino acid derivatives. These compounds served as scaffolds for the preparation of a 46-member library. The C- and N-termini of the cyclopropane amino acid derivatives were diversified by condensations with ten amines and ten acylating agents, respectively. To improve yields and accelerate library synthesis, most products were prepared under microwave irradiation and purified by polymer-bound scavengers and SPE methodology. All compounds were analyzed by LC-MS and a representative selection was fully characterized.     

Efficient dehydrative C-N bond formation using alcohols and amides in the presence of silica supported perchloric acid as a heterogeneous catalyst

Silica supported perchloric acid has been utilized as an efficient heterogeneous recyclable catalyst for N-alkylation of amides (sulfonamides and carboxamides) using alcohols (primary and secondary aliphatic as well as benzylic). The products are formed in high yields within 2-3 h.