Polystyrene carbodiimide

Sauer and coworkers have presented the use of polystyrene-bound carbodiimide for convenient and rapid amide synthesis [124], An equimolar mixture of 1-methy-lindole-3-carboxylate, the requisite amine, and 1-hydroxybenzotriazole (HOBt) in... 

The earliest published example of microwave-assisted SPOS involved diisopropyl-carbodiimide (DlC)-mediated solid-phase peptide couplings [24], Numerous Fmoc-protected amino acids and peptide fragments were coupled with glycine-preloaded polystyrene Wang resin (PS-Wang) in DMF, using either the symmetric anhydride or preformed N-hydroxybenzotriazole active esters (HOBt) as precursors (Scheme 12.1). 

The present procedure2 describes the conversion of resin-bound, primary aliphatic amines into isothiocyanates and the conversion of the latter into 3-aminothiophenes. The generation of isothiocyanates is related to known procedures,3 in which amines are first treated with carbon disulfide and the resulting dithiocarba-mates are desulfurized by treatment with a condensing agent (alkyl chloroformates, carbodiimides, lead or mercury salts, etc.). The presence of resin-bound isothiocyanates on the polystyrene support could be qualitatively ascertained by infrared spectroscopy (KBr-pellet strong absorption at 2091 cm-1). 

The immobilization proceeded as follows horseradish peroxidase (HRP) was biotinilated with biotinamidocaproate AT-hydroxysuccinimide ester to obtain biotinylated HRP with two biotin molecules per enzyme molecule. Avidin was immobilized on polystyrene support beads using the carbodiimide method. This procedure was followed by an attachment of the disubstituted biotinylated HRP... 

A carbodiimide-grafted polystyrene resin was reacted with tetramethyl-guanidine to give an interesting biguanide structure (Scheme 13). This was assayed as a catalyst for a transesterification reaction.33 Incidentally, resin-bound guanidines are useful bases for processes involving resin capture.34... 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

Figure 8 Chemiluminescent (A and B) and bioluminescent (C) detections for immobilized hybridizations of PCR product. Dg, digoxigenin Bt, biotin Ad, avidin. Procedure A [30] Biotin moiety is incorporated into PCR products during the amplification reaction, using one 5 -biotinylated primer. The product is hybridized with a Dg-labeled probe and is immobilized on streptavidin-coated magnetic beads. This capture reaction is carried out for 30 min at 37°C. A permanent magnet is used to sediment the beads during washing to remove unbound DNA. By incubation with the washed beads for 45 min at 37°C, anti-Dg antibody conjugated to HRP enzyme is bound to the Dg-labeled probe, and luminol reaction is performed for CL detection. Procedure B [31] Wells of a polystyrene microtiter plate are activated with l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, and then coated with a labeled cDNA probe complementary to an internal region of the target DNA.

Andres and coworkers demonstrated the iCP of densely packed alkanethiolate-functionalized Au nanoparticle arrays in monolayer and multilayer structures.81,82 Dense and hexagonally packed monolayers of nanoparticles were first assembled on a water surface. By using the Langmuir-Schafer technique, the Au nanoparticle monolayer was transferred to a PDMS stamp, and printed onto a substrate. Multilayers were prepared by repeating the printing process in an LbL scheme, in which subsequent particle layers may be made up of the same or different types of particles. Similarly, the assembly of irregular, densely packed monolayers of polystyrene nanoparticles on iCP substrates via carbodiimide coupling was reported.83 The conformal contact of the carbodiimide-functionalized polystyrene particles resulted in the covalent attachment of the nanoparticles at a carboxylate-functionalized surface. 

To a slurry of the product from Step 5 (1.4 mmol) was added 1-hydroxybenzotriazole (1.4 mmol), Cbz-4-amidinobenzylamine (1.6 mmol), polystyrene-graft-carbodiimide (0.42 g 1.4 mmol), N-methylmorpholine (5.6 mmol) and CH2Cl2/N,N-dimethylformamide,... 

Polystyrene-graft-carbodiimide, (I), is used to facilitate amide formation its preparation and use are described (1). Polystyrene-g-amine and -aldehyde were used to remove excess acid and amine reagents, respectively. 

Polymeric catalysts are also developed. For example, phospholene oxide modified divinylbenzene/styrene copolymers, as well as a polystyrene anchored triph-enylarsine oxide catalyst were prepared. The solid phase catalysts can be removed by filtration after partial conversion of an isocyanate to the carbodiimide. Such a catalyst is useful for the preparation of carbodiimide modified liquid MDl (4,4 -diisocyanatodiphenylmethane) products, which are of considerable commercial interest. 

Polymers with pendant carbodiimide groups are also synthesized from crosslinked polystyrene. In this synthetic route crosslinked polystyrene beads are chloromethylated... 

In the reaction of acylhydrazines with isothiocyanates, N-substituted thiourea derivatives 14 are formed, which react with a polystyrene based polymeric carbodiimide (PCD) to generate the nitrogen substituted carbodiimide 15, which cyclizes to form 2-amino-1,3,4-oxazoles 16. ... 

Polymers with pendant carbodiimide groups 27 are also synthesized from crossUnked polystyrene. In this synthetic route crossUnked polystyrene beads are chloromethylated and converted to the amines. Reaction with isopropyl isocyanate gives the corresponding ureas, which are treated with tosyl chloride and triethylamine to produce the crossUnked polycarbodiimides. This polymer is used in the polymer supported Moffatt oxidation of alcohols into aldehydes or ketones using benzene/DMSO. ... 

Also, reaction of the aminomethyl polystyrene with cyclohexylisocyanate affords a polymer bound urea, which is converted into the carbodiimide using Ph3PBr2. Reaction of the polycarbodiimide with methanol affords an 0-alkylisourea which is used in the 0-alkylation of carboxylic acids. ... 

Reactions are carried out at room temperature in dichloromethane which is an excellent swelling agent for polystyrene supports. Dimethylformamide can be added to increase the solubility of some amino acid derivatives e.g. Boc-Arg(N02), Boc-Arg(Tos), Boc-His(Tos), Boc-Trp, and Boc-Asn(Xan), but it increases the rate of undesirable rearrangement of O-acylisourea to A-acylurea which is not reactive.P The principal limitations in using car-bodiimides are racemization, rearrangement of O-acylisourea to A-acylurea 5, and dehydration of Asn and Gin side-chain carboxamide groups. Fortunately this dehydration problem is completely avoided by the use of additives such as A-hydroxysuccinimide (HOSu) and 1,2,3-benzotriazol-l-ol (HOBt). Additives also reduce racemization and A-acyl-urea formation. Other carbodiimides have also been used in SPPS such as or N-tert-... 

Quinazolines have also been prepared by the reaction of a polystyrene-bound phosphoranimine and isocyanates, followed by an intramolecular cyclization of the carbodiimide intermediate 4-Ferrocenylidene-l-aminoimidazolone derivatives have been obtained from p-ferrocenyl-a-azidoacrylates and isocyanates followed by condensation of the resulting carbodiimidoester with hydrazines " In a Staudinger/ aza-Wittig process and in the presence of PPh3, bimetallic ferrocenyl oxazole derivatives (23) - (26) have been formed by the reaction of a-... 

Fig. 13.3. Modified polystyrene beads for covalent binding of proteins. Proteins can be linked to hydrazide beads (a) with glutaraldehyde or to beads derivatized with alkylamine using succinic anhydride and carbodiimide or Sanger s reagent (Pierce Chemical Co. Technical Information).

However, more frequently employed has been the commercial polystyrene-supported carbodiimide 5 (0.9-1.4mmolg 1), another bound variant of DCC, although showing similar reactivity. In this supported reagent the tether to the polystyrene backbone has greater activity than the N-methylene linkage present in reagent 2 (R = Cy). 

Polystyrene-supported tethered l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (PS-EDC or PS-EDCI, 11) is also a commercially available, frequently used resin-supported carbodiimide [25], which is highly effective in the coupling of carboxylic acids and amines, in the absence of any additive the use of chloroform as solvent is essential. 

Miller, M.M. and Boger, D.S. (2005) Polystyrene-1-ethyl-3-(3 -dimethylaminopropanej-carbodiimide Hydrochloride (PS-EDCI), in Handbook of Reagents for Organic Synthesis, Reagents for Glycoside, Nucleotide and Peptide Synthesis (ed. D. Crich), John Wiley Sons Ltd, Chichester, pp. 529-33. 

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