Solid acids amide formation

Peptide synthesis requires the use of selective protecting groups. An N-protected amino acid with a free carboxyl group is coupled to an O-protected amino acid with a free amino group in the presence of dicydohexvlcarbodi-imide (DCC). Amide formation occurs, the protecting groups are removed, and the sequence is repeated. Amines are usually protected as their teit-butoxy-carbonyl (Boc) derivatives, and acids are protected as esters. This synthetic sequence is often carried out by the Merrifield solid-phase method, in which the peptide is esterified to an insoluble polymeric support. 

Hajek et al. [173] have reported a detailed kinetic study of the solid phase decomposition of the ammonium salts of terephthalic and iso-phthalic acids in an inert-gas fluidized bed (373—473 K). Simultaneous release of both NH3 molecules occurred in the diammonium salts, without dehydration or amide formation. Reactant crystallites maintained their external shape and size during decomposition, the rate obeying the contracting volume equation [eqn. (7), n = 3]. For reaction at 423 K of material having particle sizes 0.25—0.40 mm, the rate coefficients for decompositions of diammonium terephthalate, monoammonium tere-phthalate and diammonium isophthalate were in the ratio 7.4 1.0 134 and values of E (in the same sequence) were 87,108 and 99 kJ mole-1. 

Rare-earth exchanged [Ce ", La ", Sm"" and RE (RE = La/Ce/Pr/Nd)] Na-Y zeolites, K-10 montmorillonite clay and amorphous silica-alumina have also been employed as solid acid catalysts for the vapour-phase Beckmann rearrangement of salicylaldoxime 245 to benzoxazole 248 (equation 74) and of cinnamaldoxime to isoquinoline . Under appropriate reaction conditions on zeolites, salicyl aldoxime 245 undergoes E-Z isomerization followed by Beckmann rearrangement and leads to the formation of benzoxazole 248 as the major product. Fragmentation product 247 and primary amide 246 are formed as minor compounds. When catalysts with both Br0nsted and Lewis acidity were used, a correlation between the amount of Br0nsted acid sites and benzoxazole 248 yields was observed. 

A solid-phase synthesis of furo[3,2-3]pyran derivatives utilizing highly functionalized sugar templates has been reported <2003JOC9406>. After incorporation of alkenes within the sugar template, such as compound 95, the solid support is introduced via formation of the acid amide. This immobilized system then allows a ruthenium-catalyzed ring-closing metathesis that leads to the formation of the fused oxacycles. 

Conditions for the efficient use of Fmoc-protected amino acid chlorides in stepwise peptide synthesis have been delineated. The acid chlorides are reasonably stable solids that are readily aminolyzed if a base is added to neutralize the hydrogen chloride liberated in the reaction. They form the corresponding oxazol-5(4//)-ones and undergo stereomutation if left in the presence of tertiary amines, however, amide formation without stereomutation can be obtained under appropriate conditions. The acid chlorides are advantageously applied to acylate weak nucleophiles and sterically hindered amino components, but their application may be limited by the lack of stability of tert-butyl-type side-chain protecting groups toward conditions of acid chloride preparation. 

Some work has been directed toward the surface film and association in it. Alexander (16, 17) studied acids, amides, and esters, and showed that H bonding, both within the layer and with the substrate, is important it influences the formation and stability of the layer, and is a major factor in the area occupied by each molecule. Two dimensional solid films were obtained only when either long, close-packed chains of atoms were present or when H bonding was present. Such findings are clearly of interest in detergency work. These tests were made in the usual way with a water substrate. In fact, there are essentially no measurements on other liquids, so the H bonding ability of water may be an important part of the observed behavior. 

DECP is an efficient and valuable reagent for amide formation, and both aliphatic and aromatic acids react with aliphatic and aromatic amines. In combination with EtjN, DECP is a coupling reagent for the racemization-free peptide synthesis in DMP, CH2CI2, or THE with excellent yields.359-378 -dso useful for solid-phase peptide synthesis in both the stepwise and fragment-... 

Carbodiimides are traditionally one of the most frequently employed dehydrating reagents for the creation of the ester or amide bond, despite known problems related to difficulties in removing the corresponding generated urea or unreactive acylurea by-products [2]. Therefore, the use of polymer-supported carbodiimides is quite appropriate for the easy elimination of these by-products from the reaction medium by simple filtration, as they will remain anchored to the solid phase. In addition, if an ester or amide formation is intended an excess of acid can be used, as the remainder will also stay anchored as the corresponding isourea. 

This study looks at the rearrangement of a range of ketoximes and aldoximes over zeolite and alumina based solid acid catalysts with a view to elucidating the factors which determine the reactivity of the various oximes and the selectivity to the amide products. Another factor to be addressed is the mechanism of coke formation, in particular the role of acidic and basic surface sites in this process) 16]. 

Protein synthesis implies only one reaction, namely amide formation by condensation of a carboxylic acid with an amine group of two different a-amino acids. The amino group of the carboxyl component and the carboxyl group of the amino component as well as reactive side chains must be protected. Condensation as well as deprotection conditions must be mild, since the a-carbon chiral center has a strong tendency toward racemization. Nowadays solid-phase machines or biotechnological techniques are applied and trace amounts of thousands of different peptides are simultaneously synthesized by combinatorial synthesis methodologies. 

Synthesis of thiazolidinones [PEG -RMIM]X ionic liquids have been used for rapid synthesis of a small library of amido 4-thiazolidinones from amine, aldehyde, and mercaptoacid components (Scheme 7.22) [74]. In an initial feasibility study, acid-functionalized benzaldehydes were first coupled to the [PEG -RMIM]X ionic liquids. Imines were formed by reaction of the supported aldehydes with primary amines. The reactions were run in open vessels. Optimum results were obtained by irradiating the reaction mixture with low power at 100 °C for 20 min. The imines were then condensed with mercaptoacids to give the desired thiazolidinones which were then cleaved from the ionic liquid support by amide formation. Microwave irradiation was again used in this cleavage step. The procedure entailed addition of a small amount of solid potassium tert-butoxide to a premixed mixture of the amine and supported thiazolidinone and microwave exposure for 10-20 min at 100 or 150 °G depending on the amine used. In another study, a series of one-... 

Dressman et a/. described an alternative solid-phase synthesis in which the amino acids were N-terminally linked to a hydroxymethyl resin through a carbamate linker. Amide formation gave products 273 which, after treatment with base cyclised to yield hydantoins of typ>e 274 Scheme 4.4.6). 

The sugar moiety is blocked at C5 as a dimethoxytrityl [di(4-methoxyphenyl)phenylmethyl, DMT] ether, readily cleaved by mild acid through an SnI mechanism (Section 22-1 and Problem 40 of Chapter 22), much like 1,1-dimethylethyl (tcrt-butyl) ethers (Section 9-8, Real Life 9-2). To anchor the first protected nucleoside on the solid support, the C3 -OH is attached to an activated linker, a diester. Unlike the Merrifield medium of polystyrene, the solid used in oligonucleotide synthesis is surface-functionalized silica (Si02) bearing an amino substituent as a hook. Coupling to the anchor nucleoside is by amide formation. 

Besides the alkylation reactions in polyamine synthesis, the reductive am-ination approach found broad entry in solid phase chemistry in the backbone amide hnker (BAL) strategy [202] (Scheme 2). Thereby, amino acids are bound to a linker via imine reduction bearing a secondary amine, which can be further acylated to obtain peptides with a variety of C-terminal function-ahties. Besides the effective synthesis of C-modified peptides, this also opens access to amide formation in peptides if C- and N-terminal residues are de-protected, commonly leading to cychc peptides [ 177]. Cleavage from the resin... 

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