Parallel synthesis of 2,4,5-trisubstituted thiophene-3-carbonitrile derivatives on traceless solid support

A parallel solid-phase synthesis of 2,4,5-trisubstituted thiophene-3-carbonitrile derivatives was developed. The polymer-supported synthetic route progressed using the sulfide linker via a traceless strategy. The initial synthesis utilized the Thorpe–Ziegler type cyclization of α-haloketone and polymer-supported 2,2-dicyanoethene-1,1-bis(thiolate), which was derived from the Merrifield resin. The resulting thiophene resin was introduced to one substitution by N-arylation. After oxidation of sulfides to sulfones in the thiophene resins for subsequent cleavage, nucleophilic desulfonative substitution with amines and thiols afforded the desired thiophene-3-carbonitrile derivatives in good overall yields.     

Soluble polymer-supported synthesis of 5-arylidene thiazolidinones and pyrimidinones using a novel traceless linker strategy

An efficient method for the soluble polymer-supported synthesis of 5-arylidene thiazolidinones and pyrimidinones using aniline as a traceless linker was described. Aldehyde substrates were attached to the polyethylene glycol (PEG)-bound aniline via an imine linkage, and after the subsequent PEG-promoted Suzuki coupling reaction for the diversification, Knoevenagel condensation was readily employed as the cleavage strategy.     

Synthesis of a polymer-supported oxazolidine aldehyde for asymmetric chemistry

An expedient synthesis of the polymer-supported aldehyde 3, as a Garner aldehyde equivalent, is described. Oxazolidine 3 may be obtained through preformation of aldehyde linker 4 in solution and loaded onto amine-terminating resin under peptide-coupling conditions, or alternatively via oxidation of polymer-bound alcohol 14. The integrity of the serine-derived stereocenter is maintained through all steps of the synthesis.     

Reductive cleavage of N-O bonds using Samarium(II) iodide in a traceless release strategy for solid-phase synthesis

A strategy for making amides and ureas using a polymer-supported hydroxylamine resin as a traceless linker is described. The cleavage of the linker by samarium(II) iodide is reported for the first time.     

Dual linker with a reference cleavage site for information rich analysis of polymer-supported transformations

Two dual linker systems with specific reference cleavage sites were designed and synthesized to accelerate and simplify development and optimization of reaction conditions for solid-phase synthesis. The dual linker allows simple evaluation of cleavage rate of polymer-supported compounds from the linker and, at the same time, ensures that all resin-bound components are cleaved from the solid support. The dual linker 4 was assembled from two Wang linkers connected by a three carbon spacer. The linker 9 was synthesized using the PAL and HMPB linkers.     

Reaction of N‐Heterocyclic Silylenes with Thioketone: Formation of Silicon–Sulfur Three (Si‐C‐S)‐ and Five (Si‐C‐C‐C‐S)‐Membered Ring Systems

Three‐ and five‐membered rings that bear the (Si‐C‐S ) and (Si‐C‐C‐C‐S ) unit have been synthesized by the reactions of L SiCl ( 1 ; L =PhC(NtBu)₂) and L′ Si ( 2 ; L′ =CH{(C?CH₂)(CMe)(2,6‐iPr₂C₆H₃N)₂}) with the thioketone 4,4′‐bis(dimethylamino)thiobenzophenone. Treatment of 4,4′‐bis(dimethylamino)thiobenzophenone with L SiCl at room temperature furnished the [1+2]‐cycloaddition product silathiacyclopropane 3 . However, reaction of 4,4′‐bis(dimethylamino)thiobenzophenone with L′ Si at low temperature afforded a [1+4]‐cycloaddition to yield the five‐membered ring product 4 . Compounds 3 and 4 were characterized by NMR spectroscopy, EIMS, and elemental analysis. The molecular structures of 3 and 4 were unambiguously established by single‐crystal X‐ray structural analysis. The room‐temperature reaction of 4,4′‐bis(dimethylamino)thiobenzophenone with L′ Si resulted in products 4 and 5 , in which 4 is the dearomatized product and 5 is formed under the 1,3‐migration of a hydrogen atom from the aromatic phenyl ring to the carbon atom of the C? S unit. Furthermore, the optimized structures of probable products were investigated by using DFT calculations.     

Novel polymer-supported 2-(diphenylmethylsilyl)ethoxymethyl chloride (DSEM-Cl) linker

A synthetic method to prepare a novel polymer-supported 2-(diphenylmethylsilyl)ethoxymethyl chloride (DSEM-Cl) linker and its applications are described.     

A cleavable linker strategy for optimising enolate alkylation reactions of a polymer-supported Evans' oxazolidin-2-one

A cleavable linker strategy has been used to optimise the enolate alkylation reactions of a recyclable L-tyrosine derived polymer-supported oxazolidin-2-one for the asymmetric synthesis of a series of chiral alpha-alkyl acids.     

Poly(ethylene glycol)-supported nitroxyls: branched catalysts for the selective oxidation of alcohols

Nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) are highly selective oxidation catalysts for the conversion of primary alcohols into the corresponding aldehydes. In this study, direct tethering of TEMPO units onto linear poly(ethylene glycol) (PEG) has afforded macromolecular catalysts that exhibit solubility in both aqueous and organic solvents. Recovery of the dissolved polymer-supported catalyst has been carried out by precipitation with a suitable solvent such as diethyl ether. The high catalyst activities and selectivities associated traditionally with nitroxyl-mediated oxidations of alcohols are retained by the series of "linker-less" linear PEG-TEMPO catalysts in which the TEMPO moiety is coupled directly to the PEG support. Although the selectivity remains unaltered, upon recycling of the linker-less polymer-supported catalysts, extended reaction times are required to maintain high yields of the desired carbonyl compounds. Alternatively, attachment of two nitroxyl radicals onto each functionalized PEG chain terminus via a 5-hydroxyisophthalic acid linker affords branched polymer-supported catalysts. In stark contrast to the linker-less catalysts, these branched nitroxyls exhibit catalytic activities up to five times greater than 4-methoxy-TEMPO alone under similar conditions. In addition, minimal decrease in catalytic activity is observed upon recycling of these branched macromolecular catalysts via solvent-induced precipitation. The high catalytic activities and preservation of activity upon recycling of these branched systems is attributed to enhanced regeneration of the nitroxyl species as a result of intramolecular syn-proportionation.     

Chemoenzymatic polymer-supported liquid phase synthesis of glucose γ-aminobutyric ester

A concise, polymer-supported solution synthesis of 6-O-(γ-aminobutyryl)-d-glucose has been achieved. Glucose was attached to polyethylene glycol monomethyl ether (MPEG) through an α,α′-dioxyxylyl diether linker, and, subsequently, the HO-6 hydroxyl of the glucose was regioselectively esterified with γ-aminobutyric acid by a lipase-catalyzed reaction.     

General methodology for solid-phase synthesis of N-alkyl hydroxamic acids

Polymer-supported N-benzyloxy-2-nitrobenzenesulfonamides 1 were N-alkylated using three different routes: via Fukuyama reaction with alcohols, by N-alkylation with alkylbromides, and by Michael addition reaction with α,β-unsaturated carbonyl compounds. The N-alkylated products prepared on the linker 1b were obtained in excellent purity and yield. The 2-nitrobenzenesulfonyl (Nos) group was cleaved under mild conditions to yield polymer-supported N-alkylated benzyloxyamines. Acylation by carboxylic acids and cleavage with TFA yielded N-alkyl hydroxamic acids.     

Combinatorial synthesis of RGD model cyclic peptides utilizing a palladium-catalyzed carbonylative macrolactamization on a polymer support

A combinatorial synthesis of 24-member RGD models was accomplished on polymer-support. Ortho-, meta-, and para-iodobenzylamines loaded on an aldehyde linker by reductive amination were coupled with RGD sequences and various omega-amino acids by a split-and-pool method. Palladium-catalyzed carbonylative macrolactamization of the polymer-supported cyclization precursors, followed by acid cleavage, provided conformationally restricted RGD model cyclic peptides.     

C-acylations of polymeric phosphoranylidene acetates for C-terminal variation of peptide carboxylic acids

C-Acylations of polymer-supported 2-phosphoranylidene acetates ("linker reagents") with protected amino acids yielded 2-acyl-2-phosphoranylidene acetates as flexible intermediates for the C-terminal variation of carboxylic acids: peptidyl-2,3-diketoesters, peptidyl vinyl ketones, peptidyl-2-ketoaldehydes, and 1,3-diamino-2-hydroxy-propanes were obtained as products. [reaction: see text]     

Strategy for the synthesis of polymeric supports with hydrazone linkers for solid-phase alkylation of ketones and aldehydes

A new approach to polymeric supports useful for the immobilization of aldehydes and ketones via hydrazone linkers is reported. The new strategy gives supports with better properties and is effective for the synthesis of all supports previously used for the alkylation of ketones anchored as hydrazones. In contrast to other approaches, the new strategy also provided a polymer with an economical C2 spacer linker. The supports were used for immobilization of ketones 3-pentanone, acetone, N-benzylpiperidone, and aldehydes hexanal and 3-phenylpropanal in the form of their hydrazones. The polymer-supported hydrazones were subjected to alpha-alkylation (LDA/RX) followed by acidic, reductive, or oxidative cleavage/workup procedures to provide alpha-alkylated aldehydes or ketones as well as corresponding primary amines, alcohols, nitriles or acids.     

Effect of spacers on the activity of soluble polymer supported catalysts for the asymmetric addition of diethylzinc to aldehydes

A chiral Zn(II)-salen complex tethered with poly(ethylene glycol) (PEG) was synthesized. This soluble polymer-supported complex was found to catalyze the asymmetric addition of diethylzinc to a series of aromatic aldehydes in good yields and with good enantiomeric ratio (er). The PEG-supported catalyst could be recycled and reused up to three times. The reactivity and selectivity of the catalyst was dependent on the nature of the linker between the polymer and the complex.     

Polymerization of vinyl monomers by alkali metal–thiobenzophenone complexes

The polymerization of vinyl monomers by use of alkali metal (Li, Na, K)–thiobenzophenone complexes was studied. Monoalkali metal complexes of thiobenzophenone (thioketyls) induced the polymerization of vinyl monomers such as acrylonitrile (AN) and methyl methacrylate (MMA), and dialkali metal complexes of thiobenzophenone (dianion) induced the polymerization of styrene (St), butadiene (Bd), and isoprene (Ip) as well as AN and MMA. The polymerization of MMA with the dianion was initiated by both the mercaptide and the carbanion of the dianion, but that of styrene was initiated by the carbanion alone. In the case of polymerization of MMA by the thioketyl, the initial rate of polymerization depended on the catalyst concentration and the square of the monomer concentration. Similar results were obtained in the case of the dianion. The polymer yield increased with increasng polarity of sovents. In the copolymerization of AN with MMA, the copolymer obtained consisted almost of AN units. From these results, it was concluded that the polymerization proceeded by anionic mechanisms.     

Modular approach for the development of supported, monofunctionalized, salen catalysts

We report a modular approach toward polymer-supported, metalated, salen catalysts. This strategy is based on the synthesis of monofunctionalized Mn- and Co-salen complexes attached to a norbornene monomer via a stable phenylene-acetylene linker. The resulting functionalized monomers can be polymerized in a controlled fashion using ring-opening metathesis polymerization. This polymerization method allows for the synthesis of copolymers, resulting in an unprecedented control over the catalyst density and catalytic-site isolation. The obtained polymeric manganese and cobalt complexes were successfully used as supported catalysts for the asymmetric epoxidation of olefins and the hydrolytic kinetic resolution of epoxides. All polymeric catalysts showed outstanding catalytic activities and selectivities comparable to the original catalysts reported by Jacobsen. Moreover, the copolymer-supported catalysts are more active and selective than their homopolymer analogues, providing further proof that catalyst density and site isolation are key toward highly active and selective supported salen catalysts.     

A simple procedure for the polymer-supported N-heterocyclic carbene-rhodium complex via click chemistry: a recyclable catalyst for the addition of arylboronic acids to aldehydes

A novel polymer-supported carbene-rhodium complex was prepared using a simple procedure via click chemistry. This polymer-supported N-heterocyclic carbene-rhodium complex was characterized and used as a catalyst for the addition of arylboronic acids to aldehydes in good to excellent yields.     

Highly enantioselective Michael additions in water catalyzed by a PS-supported pyrrolidine

The development of a highly efficient, polymer-supported organocatalyst for the Michael addition of ketones to nitroolefins is described. A 1,2,3-triazole ring, constructed through a click 1,3-cycloaddition, plays the double role of grafting the chiral pyrrolidine monomer onto the polystyrene backbone and of providing a structural element, complementary to pyrrolidine, key to high catalytic activity and enantioselectivity. Optimal operation in water and full recyclability make the triazole linker attractive for the immobilization of organocatalysts.     

Polymer-supported (2,6-dichloro- 4-alkoxyphenyl)(2,4-dichlorophenyl)methanol: a new linker for solid-phase organic synthesis

An acid and base stable hydroxytetrachlorodiphenylmethyl (HTPM) linker is developed for polymer-supported organic synthesis. The linkers reported here are utilized for loading carboxylic acids, amines, alcohols, and phenols, and are stable to Br?nsted and Lewis acids, Br?nsted bases, and a wide variety of nucleophiles. However, the HTPM linkers can conveniently be cleaved by the solvolytic displacement reactions with 20% TFA. [structure: see text]