Microwave-assisted traceless synthesis of benzimidazolones

We have developed a microwave-assisted traceless rapid synthesis of benzimidazolones on polymeric supports. The key step in our approach involves an arylation of benzylammonia followed by treatment with N-chlorosulfonyl isocyanate and by subsequent hydrolysis to yield the corresponding primary ureas. Intramolecular cyclization of the resin-bound primary ureas under Pd-catalyzed condition followed by cleavage with TFA-H₂O provided the desired benzimidazolones with excellent yields and high purities. Except for step 4, the other reactions involved were performed completely within a few minutes under microwave exposure.     

Microwave-assisted traceless synthesis of thiohydantoin

An efficient, microwave-assisted method for the liquid-phase combinatorial synthesis of 3,5-disubstituted-thiohydantoin has been developed. Fmoc-protected amino acids were coupled with HO-PEG-OH and after deprotection, reacted with various isothiocyanates in microwave cavity. The PEG bound thiourea compounds underwent base mediated cyclization/cleavage step by microwave flash heating. The desired products were then liberated from the soluble matrix in good yield and purity under microwave exposure.     

A traceless solid-phase synthesis of pteridines

The linking of pyrimidines to polystyrene supports via either a 2- or 4-thioether provides access to pteridines through solid-phase synthesis. Oxidative cleavage (dimethyldioxirane) followed by nucleophilic substitution by amines, azide, or water completes a traceless synthesis of pteridines.     

Microwave-assisted traceless synthesis of hydantion-fused β-carboline scaffold

Multistep microwave-assisted reactions toward the synthesis of hydantoin-fused tricyclic tetrahydro-β-carbolines on the soluble polymer support have been developed. Polymer-bound tryptophan with various aldehydes has been subjected to Pictet-Spengler reaction to obtain tricyclic β-carboline conjugates. The terminal hydantoinyl moiety is constructed across polymer-bound β-carbolines by the reaction with various isocyanates under microwave irradiation to form urea intermediate. Simultaneous intramolecular cyclization of urea followed by cleavage of the polymer support leads to a traceless synthesis of tetracyclic scaffolds in high yield and high purity.     

Fluorous and traceless synthesis of substituted indole alkaloids

The fluorous traceless synthesis of substituted indole alkaloids is carried out first by attaching the 3-(perfluorooctyl)propanol with Boc protected L-tryptophan. The reaction of perfluoroalkyl (Rfh)-tagged tryptophan esters with various aldehydes undergoes Pictet-Spengler reaction to give cis and trans stereoisomers of tetrahydro-beta-carbolines. The nucleophilic addition of the piperidine nitrogen across various isocyanates is followed by the cyclization of ureas and simultaneous rupture of the fluorous tag to afford the hydantoin ring fused tetrahydro-beta-carbolines. All the fluorous-tag compounds are purified by solid-phase extraction (SPE) through Fluoro Flash cartridges.     

A traceless solid-supported synthesis of novel pyrazinediazepinedione derivatives

A simple, convenient, six-step synthesis of novel, tricyclic pyrazinebenzodiazepinedione derivatives has been described. The strategy is based on the use of the orthogonally-protected, optically pure, (S)-piperazine-2-carboxylic acid, in a Petasis reaction, followed by coupling with anthranilic acid and finally cyclizing cleavage. The investigated method was applied for the synthesis of novel bicyclic pyrazinediazepinedione derivatives. This traceless, solid-supported approach allows the preparation of a wide variety of compounds in moderate yields from commercially available or easily obtainable reagents.     

Development of the traceless phenylhydrazide linker for solid-phase synthesis

The hydrazide group is a new oxidatively cleavable traceless linker for solid-phase chemistry. It can be readily introduced by hydrazide formation between a carboxy-functionalized resin and different substituted hydrazines. In order to achieve high yields in this step, new carboxylic acid resins were developed that are not prone to undesired imide formation upon activation of the carboxylic acid. The polymer-bound acyl hydrazides were successfully employed in various transformations, namely Heck, Suzuki, Sonogashira, and Stille couplings, as well as Wittig and Grignard reactions. Traceless release of the coupling products from the solid support is achieved selectively under mild conditions and in high purity by oxidation of the aryl hydrazides to acyl diazenes with Cu(II) salts or N-bromosuccinimide (NBS) and subsequent nucleophilic attack of the acyl diazene intermediates. Traceless cleavage by oxidation with NBS can be carried out as a two-step process in which stable acyl diazenes are first generated by treatment with NBS in the absence of a nucleophile. After removal of the reagents by simple resin washing, the traceless release is effected by the addition of methanol, which leads to products of high purity without any additional separation steps.     

A traceless solid phase synthesis of thiomorpholin-3-ones

A novel synthesis of thiomorpholin-3-ones using a traceless solid phase approach is described, in which many kinds of thiomorpholin-3-ones were efficiently obtained in high purity based on an intramolecular alkylation of sulfides followed by an elimination of desired thiomorpholin-3-ones from the generated sulfonium salts.     

A direct synthesis of allenes by a traceless Petasis reaction

A one-pot synthesis of allenes by the 2-nitrobenzenesulfonylhydrazide-mediated coupling of hydroxyaldehydes or ketones with alkynyl trifluoroborate salts is reported. This mild process involves in situ formation of a sulfonylhydrazone that reacts with alkynyl trifluoroborates to generate a transient propargylic hydrazide species. Decomposition of this unstable hydrazide via an intermediate monoalkyldiazine produces the allene products through an alkene walk mechanism.     

Solid-phase organic synthesis of polyisoprenoid alcohols with traceless sulfone linker

Solid-phase organic synthesis of polyprenols with a traceless sulfone linker is described. The polymer-bound benezenesulfinate is first linked with the "tail" building blocks of isoprenyl chlorides via S-alkylation. With use of dimsyl anion as an appropriate base, the polymer-bound alpha-sulfonyl carbanion is generated and coupled with other "body" building blocks in an efficient manner. After repeated processes and a global palladium-catalyzed desulfonation with LiEt 3BH as the reducing agent, the desired polyprenols with various chain lengths and geometrical configurations are obtained in 32-59% overall yields. The solid-phase synthesis offers the advantage in facile isolation of polyprenols without tedious operation or time-consuming purification.     

Light fluorous-tagged traceless one-pot synthesis of benzimidazoles facilitated by microwave irradiation

A novel protocol for rapid assemble of benzimidazole framework has been demonstrated. This method incorporated with light fluorous-tag provides a convenient method for diversification of benzimidazoles and for easy purification via fluorous solid-phase extraction (F-SPE) in a parallel manner. The key transformation of this study involves in situ reduction of aromatic nitro compound, amide formation, cyclization and aromatization promoted by microwave irradiation in a one-pot fashion. The strategy is envisaged to be applied for the establishment of drug-like small molecule libraries for high throughput screening.     

Enantioselective synthesis of biphenols from 1,4-diketones by traceless central-to-axial chirality exchange

A method for the enantioselective synthesis of biphenols from readily prepared 1,4-diketones is reported. Key to the success of this method is the highly selective transfer of central to axial chirality during a double aromatization event triggered by BF(3)·OEt(2). On the basis of X-ray crystallographic data, a stereochemical model for this chirality exchange process is put forth.     

1,3,4-Oxadiazole formation as traceless release in solid phase organic synthesis

Oxadiazoles were generated upon a dehydrative cyclization reaction with 2-acyl hydrazides bound to the polymeric support via one of their N atoms using TFAA as a dehydration agent.     

3-Mercaptopropanol as a traceless linker for chemical and enzymatic synthesis of oligosaccharides

The reducing end of protected carbohydrates can be equipped with a series of aglycones via the photochemical installation of a 3-mercaptoethanol linker. This linker is stable during chemical and enzymatic glycosylation reactions but can be activated readily and efficiently to couple oligosaccharides with different nucleophiles. This approach provides straightforward access to a range of molecules that serve as probes for carbohydrate modifying enzymes. [reaction: see text].     

Solid-phase synthesis of traceless 1,3-diketones

A traceless synthesis of 1,3-diketones has been achieved through enamine methodology from solid-phase organic synthesis. Thus, piperazine served as a linker for this traceless cleavage of β-diketones from solid support.