Chloromethyl with carboxylates

Polystyrene-bound benzhydryl- or trityl halides react much more rapidly with carboxylates than chloromethyl polystyrene, and the base used to form the carboxylate no longer plays a decisive role in these reactions (see Experimental Procedure 13.7). Support-bound phenyldiazomethanes have been used to prepare esters directly from carboxylic acids under mild reaction conditions. Unfortunately, the diazomethanes required are not easy to prepare, and have not yet found widespread application. 

When aminomethyl polystyrene is reacted with dialkylcarbodiimides, the corresponding polyguanidines are obtained which exhibit high selectivity towards Au(CN)2 ions. Also, reaction of chloromethyl polystyrene with EDC affords the polymeric EDC hydrochloride 28. This polymer is used in the coupling of amino acids with carboxylic acids (yield 72-100 %). ... 

Another ether of 9 used as auxiliary is the methoxymethyl (MOM) ether 12 which forms amides with carboxylic acids for sigmatropic rearrangements (Section D. 1.6.3.2.) or enantiose-lective Birch reduction/alkylation (Section D. 1.1.1.3.1.). The ether is obtained by an analogous alkylation procedure with chloromethyl methyl ether15 6. 

To illustrate the specific operations involved, the scheme below shows the first steps and the final detachment reaction of a peptide synthesis starting from the carboxyl terminal. N-Boc-glycine is attached to chloromethylated styrene-divinylbenzene copolymer resin. This polymer swells in organic solvents but is completely insoluble. ) Treatment with HCl in acetic acid removes the fert-butoxycarbonyl (Boc) group as isobutene and carbon dioxide. The resulting amine hydrochloride is neutralized with triethylamine in DMF. 

The actual process of solid phase peptide synthesis outlined m Figure 27 15 begins with the attachment of the C terminal ammo acid to the chloromethylated polymer m step 1 Nucleophilic substitution by the carboxylate anion of an N Boc protected C terminal... 

Chloromethylation of the aromatic nucleus occurs readily with alkyl and alkoxy substituents accelerating the reaction and halo, chloromethyl, carboxyl, and nitro groups retarding it. 

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

The hydroxy group of ethyl 9-hydroxy-4-oxo-4//-pyrido[l,2-u]pyrimi-dine-3-carboxylate was O-alkylated with 2-chloromethyl-4-isopropyl-l,... 

The above methods occurred in 3 steps, therefore, these methods are not preferred. For instance, in the first step, o-, m-, and p-bromostyrene and its copolymer are synthesized. In the second step, Li-PS is synthesized from the reaction of copolymers with an organic compound containing LI. The abovementioned reactions are made with different compounds of Li-PS in the third step. These methods were also investigated by Ayres and Mann [34], who used the synthesis of PS containing chloro groups with chloromethylated PS as the first step. In the second step, formil resin was obtained by oxidation of chlorometylated PS. In the third step, carboxyl-ated PS was obtained by the oxidation of formol resin with acetic acid at 20°C for 48 h. There are some disad-... 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Several aryl esters of 6-chloromethyl-2-oxo-2//-l -benzopyran-3-carboxylic acid act as human Lon protease inhibitors (alternate substrate inhibitors)46 without having any effect on the 20S proteasome. Proteasomes are the major agents of protein turnover and the breakdown of oxidized proteins in the cytosol and nucleus of eukaryotic cells,47 whereas Lon protease seems to play a major role in the elimination of oxidatively modified proteins in the mitochondrial matrix. The coumarin derivatives are potentially useful tools for investigating the various biological roles of Lon protease without interfering with the proteasome inhibition. 

Bromobenzyl groups were introduced into PPO by radical bromination of the methyl groups. The PPO bromobenzyl groups and PECH chloromethyl groups were then esterified under phase-transfer-catalyzed reaction conditions with the potassium carboxylates just described. This procedure has been described previously (29). The sodium salt of 4-methoxy-4 -hydroxybiphenyl was also reacted with PECH (no spacer). 

In a similar way, piperazinone derivatives can be prepared by either addition of the formed amine to a carboxylate moiety or by an intramolecular alkylation with a chloromethyl group present in the substrate [485]. 

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

An interesting preparation of alkyl carboxylates in high yield (Table 3.14) from the sodium salt of the carboxylic acids under mild phase-transfer catalytic conditions involves their reaction with alkyl chlorosulphate [50] and has been used with success in the preparation of alkyl esters derived from p-lactam antibiotics. The procedure is also excellent for the production of chloromethyl esters, particularly where the carboxylic acids will not withstand the classical Lewis acid-catalysed procedure using an acid chloride and formaldehyde, or where the use of iodochloromethane [51] results in the formation of the bis(acyloxy)methane. The procedure has been applied with some success to the synthesis of chloromethyl A-protected a-amino carboxylates [52],... 

Primary and secondary alcohols are oxidized slowly at low temperatures by benzyltriethylammonium permanganate in dichloromethane primary alcohols produce methylene esters (60-70%), resulting from reaction of the initially formed carboxylate anion with the solvent, with minor amounts of the chloromethyl esters and the carboxylic acids. Secondary alcohols are oxidized (75-95%) to ketones [34] the yields compare favourably with those obtained using potassium permanganate on a solid support. 1,5-Diols are oxidized by potassium permanganate under phase-transfer catalytic conditions to yield 8,8-disubstituted-8-valerolactones [35] (Scheme 10.1). 

In the initial step, the first BOC-protected amino acid is bound to the polymer, e.g. polystyrene in which a proportion of the phenyl rings have chloromethyl substitution. Attachment to these residues is through the carboxyl via an ester linkage. This involves a simple nucleophilic substitution reaction, with the carboxylate as nucleophile and chloride as leaving group (see Section 6.3.2). After each stage, the insoluble polymer-product combination is washed free of impurities. 

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