Carbodiimides chlorides

Finally, attachment of a rather complex side chain to the para position of the benzene ring on the sulfonamide leads to the very potent, long-acting oral antidiabetic agent, glyburide (215). Preparation of this compound starts with the chlorosul-fonation of the acetamide of 3-phenethylamine (209). The resulting sulfonyl chloride (210) is then converted to the sulfonamide (211) and deacylated (212). Reaction with the salicylic acid derivative, 213, in the presence of carbodiimide affords the amide, 214. Condensation of that with cyclohexylisocyanate affords glyburide (215). ... 

Carbodiimides have been prepared by desulfurization of thioureas by metal oxides, by sodium hypochlorite,4 or by ethyl chloroformate in the presence of a tertiary amine by halogena-tion of ureas or thioureas followed by dehydrohalogenation of the N,N -disubstituted carbamic chloride 8 and by dehydration of disubstituted ureas using -toluenesulfonyl chloride and pyridine.7 The method described above is a modification of that of Campbell and Verbanc. ... 

Activating agents, such as trifluoroacetic anhydride 1,1 -carbonyldiimidazolc carbodiimides sulfonyl, tosyl, and picryl chlorides and a range of phosphorus derivatives can promote direct solution reactions between dicarboxylic acids and diols or diphenols in mild conditions. The activating agents are consumed during the reaction and, therefore, do not act as catalysts. These so-called direct polycondensation or activation polycondensation reactions proceed via the in situ transformation of one of the reactants, generally the carboxylic acid, into a more... 

Poly (ethylene oxide) macromonomers72 761 are made in a similar way, as the alkoxide end group is reactive enough towards benzylic halides. With methacryloyl chloride, side reactions are involved. It is better to first protonate the PEO, and then to have it react with methacryloyl chloride in the presence of some triethyl amine. One can also react co-hydroxy polyethylene oxide) with methacryloyl imidazole, or with methacrylic acid in the presence of dicyclohexyl carbodiimide (DCCf)77). 

Amidines and cyclic amidines are also converted into 1,2,4-thiadiazoles by reaction with isothiocyanates, imino-sulfenyl chlorides, di- and trichloromethyl sulfenyl chlorides, and carbon disulfide in the presence of sulfur. Ureas, thioureas, guanidines, carbodiimides, and cyanimides react with chlorocarbonylsulfenyl chloride to produce 1,2,4-thiadiazol-5-one derivatives in another example of a type B synthesis <1996CHEC-II(4)307>. 

Chloro-l,2,4-thiadiazolin-5-ones can be prepared by reacting chlorocarbonylsulfenyl chloride with carbodiimides or cyanamides (see Section 5.08.9.3). 

Carbodiimides are, in general, useful compounds for effecting certain dehydrative condensations, e.g., in the formation of amides, esters, and anhydrides. These two crystalline water-soluble carbodiimides are especially useful in the synthesis of peptides and in the modification of proteins. The excess of reagent and the co-product (the corresponding urea) are easily separated from products with limited solubility in water. The hydrochloride is best employed in nonaqueous solvents (methylene chloride, acetonitrile, dimethylformamide). The methiodide is relatively stable in neutral aqueous systems, and thus is recommended for those media. 

This procedure for the preparation of l-ethyl-3-(3-dimethyl-amino)propylcarbodiimide and its salts is a modification of one that has been published.4 Unsymmetrical carbodiimides have also been prepared by desulfurization of the corresponding thioureas with mercuric oxide3 or by dehydration of the corresponding ureas with -toluenesulfonyl chloride in pyridine.4 Unsymmetrical 1,3-disubstituted ureas are best prepared by the reaction... 

Carbodiimide peptide synthesis. 1 -Hydroxybenzotriazole (HOBt) is frequently used to suppress racemization in peptide syntheses using carbodiimides. Copper(II) chloride decreases racemization, but also depresses the yield markedly. By judicious use of both additives, racemization can be prevented with only slight effect on the yield. 

In an extension beyond hetaryl onium salt promoted hemiacetal activation, Ishido and coworkers have reported the carbodiimide activation of hemiacetals [141]. In the method (Scheme 3.13), the hemiacetal donor 1 is treated with a carbodiimide electrophile 83 and copper(I) chloride to provide glycosyl isourea intermediate 85. Highly susceptible to hydrolysis, the isourea 85 was not isolated but could be detected by 13C NMR and IR spectroscopy [142,143], Accordingly, the reaction between intermediate 85 and the glycosyl acceptor (NuH) provides glycoside product 3, along with urea by-product 84. 

A typical procedure calls for reaction of the hemiacetal donor with dicydohexyl carbodiimide and copper(I) chloride (0.1 equiv) at 80 °C, followed by an addition of the acceptor and continued heating. As an early demonstration of this protocol, oc-riboside 86 was prepared in moderate yield but with exclusive stereoselectivity [141]. Further measures were required for the glycosylation of monosaccharide acceptors, such as addition of p-toluenesulfonic add (0.1 equiv) to promote the formation of disaccharide 87 [144]. The method was more suitably applied to the synthesis of O-acyl glycopeptides, as evidenced by the formation of 88 in 60% yield [143,144]. Various peptides with non-nudeophilic side chains were found to be amenable to this stereoselective reaction. The [3-selectivity was suggested to arise from a preponderance of the a-isourea intermediate 85 in the activation step. 

T Miyazawa, T Otomatsu, Y Fukui, T Yamada, S Kuwata. Racemization-free and efficient peptide synthesis by the carbodiimide method using 1-hydroxybenzotriazole and copper(II) chloride simultaneously as additives. J Chem Soc Chem Commun 419, 1988. 

The aroyl chloride (10 mmol) in PhMe (10 ml) is added dropwise to the carbodiimide (10 mmol), NaN (975 mg, 15 mmol) and TBA-Cl (0.28 g, l mmol) in PhMe (40 ml) at room temperature under N2. After ca. 3-4 h, the mixture is heated to 95 °C for 30 min. The cooled mixture is filtered and evaporated under reduced pressure to yield the tetra-zole, which is purified by chromatography from silica [e.g. 64% from PhN=C=NPh and PhCOCl 55% from TolN=C=NTol and PhCOCl 70% from PhN=C=NPh and TolCOCI],... 

Dehydration of /V./V -disubstitutcd ureas with 4-tosyI chloride under soliddiquid two-phase conditions to produce carbodiimides is aided by the addition of benzyltri-ethylammonium chloride [45,46]. 

AT-Acyl-L-HSL can be conveniently prepared in excellent yields by the acylation of l-HSL either with the corresponding carboxylic acids activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) in a water/ 1,4-dioxane (1 1) solvent system or with the corresponding acid chlorides in dichloromethane (DCM) in the presence of triethylamine (Scheme 4) [15,16, 37,53]. 

The carboxylic functionalities inserted onto the tubes can be used as platforms to obtain further transformations (Fig. 3.5). A commonly utilized route is the reaction of carboxylic groups with thionyl chloride or oxalyl chloride to prepare the corresponding acyl chlorides, which are useful intermediates for amidation or esterification reactions. Amides can also be prepared directly from the acids by means of standard solution chemistry conditions, using carbodiimide derivatives in the presence of the selected amine. 

Although this procedure offers no advantage over that of Hiinig, Lehmann, and Grimmer, it effectively illustrates a new method for the synthesis of symmetrical and unsymmetrical carbodiimides. The generality of this procedure is limited only by the number of substituted benzohydroxamoyl chlorides that can be made without difficulty, as a variety of N-sulfinylamines is easily accessible. ... 

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