Dicyclohexyl carbodiimide, synthesis

Saponification next frees the carboxy group for condensation with -butyl 7-aminocephalosporinate mediated by dicyclohexyl-carbodiimide and 1-hydroxybenzotriazole. The synthesis is... 

The reaction between acyl halides and diazomethane is of wide scope and is the best way to prepare diazo ketones. Diazomethane must be present in excess or the HX produced will react with the diazo ketone (10-74). This reaction is the first step of the Amdt-Eistert synthesis (18-8). Diazo ketones can also be prepared directly from a carboxylic acid and diazomethane or diazoethane in the presence of dicyclohexyl-carbodiimide. ... 

Dicyclohexyl carbodiimide (DCC) is one of the most frequently used coupling agents, especially in organic synthesis applications. It has been used for peptide synthesis since... 

C-(w-propyl)-N-phenylnitrone to N-phenylmaleimide, 46, 96 semicarbazide hydrochloride to ami-noacetone hydrochloride, 45,1 tetraphenylcyclopentadienone to diphenyl acetylene, 46, 44 Alcohols, synthesis of equatorial, 47, 19 Aldehydes, aromatic, synthesis of, 47,1 /8-chloro-og3-unsaturated, from ketones and dimethylformamide-phosphorus oxychloride, 46, 20 from alkyl halides, 47, 97 from oxidation of alcohols with dimethyl sulfoxide, dicyclohexyl carbodiimide, and pyridinium trifluoroacetate, 47, 27 Alkylation, of 2-carbomethoxycyclo-pentanone with benzyl chloride, 45, 7... 

As the last example of an SN reaction at the carboxyl carbon of a carbonic acid derivative, consider the synthesis of dicyclohexylurea in Figure 6.30. In this synthesis two equivalents of cyclohexylamine replace the two methoxy groups of dimethyl carbonate. Dicyclohexylurea can be converted into the carbodhmide dicyclohexyl-carbodiimide (DCC) by treatment with tosyl chloride and triethylamine. Thereby, the urea is effectively dehydrated. The mechanism of this reaction is identical to the mechanism that is presented in Figure 7.5 for the similar preparation of a different carbodiimide. 

Although there are many methods available, there are two main routes for the synthesis of nucleoside monophosphates. These involve either the reaction of the nucleoside with 2-cyanoethylphosphate in the presence of a condensing agent such as dicyclohexyl carbodiimide (DCC)2,3 or phosphorylation of the nucleoside... 

Figure 3-2 Merrifield synthesis on a polymer bead support. The growing peptide chain is attached to a polymer support, usually in the form of small beads. The next amino acid (bearing R2) IS attached, and its protecting group (BOO is removed with acid ase treatment. flOC. butyl-oxycarbonyl, DCC, dicyclohexyl-carbodiimide.

The procedures used for the synthesis of nucleotides of 2 -deoxycytidine were successfully applied to the preparation of their ptirine counterparts. 2 -Deoxyadenosine was fully benzoylated and then converted with alkali into the A -benzoyl derivative. Tritylation with (119) yielded (125), which was converted by the 2-cyanoethyl phosphate-iV,iV -dicyclohexyl-carbodiimide method, followed by removal of the protecting groups, into 2 -deoxyadenosine 3 -phosphate (126). With 2 -deoxyguanosine, direct tritylation with (119) gave (127), from which 2 -deoxyguanosine 3 -phos-phate (128) was obtained. ... 

Scheme 8.2. Synthesis of reveromycin (DCC = dicyclohexyl-carbodiimide, DMAP = N,N-d/methy/-p-aminopyridine).

Fig. 15 PAA-g/c-PVA cryogel synthesis. The reaction requires the use of equimolar amounts of PAA, PVA, and 4-dimethyl aminopyridine (DMAP) and an excess of 1,3-dicyclohexyl carbodiimide DCC). Reprinted from [111] with permission. Copyright 2011 Wiley Periodicals...

In another synthesis, the disilver salt of adenosine-5 -phosphate was treated directly with an excess of dibenzylphosphorochloridate, and this was followed by hydrogenolysis and hydrolysis (10.104). In a later method, ATP was obtained directly from adenosine monophosphate using ortho-phosphoric add and dicyclohexyl-carbodiimide [84,85]. 

Some examples of common additives are given which may be used as drugs themselves (such as benzoyl peroxide for acne), in the synthesis of drugs (dicyclohexyl carbodiimide) or as antioxidants in final products. Ethylene diamine is present in topical drugs and in aminophylline and is the allergen in the latter compound. Several cases of occupational contact dermatitis have been reported (Corazza et al. 

Scheme 4-17. Template synthesis of [Fe(L1019)] (a) C6H5CH2CI, KI, K2CO3, acetone reflux, 72 h, 85% (b) NaOH, DMF/H2O, reflux, 9 h, 94% (c) 7V-hydroxysuccinimide, dicyclohexyl-carbodiimide, dioxan, 72% (d) H2/5% Pd-C, ethyl acetate, room temperature, 1 h, 100% (e) FeCla, (C2Hs)3N, DMF or DMSO, not isolated (f) tris(2-aminoethyl)amine (2 equivalents), room temperature, 14 h (g) 4-(dimethylaniino)-pyridine, 65°C, 5 days, 70%.

DCC (dicyclohexyl carbodiimide) has been used as a dehydrating agent for converting amide to cyanide in the synthesis of an end-group modified retro-inverso Bombesin C-terminal nonapeptide. Using DCC, the amino add asparagine 1500 was converted into 3-cyanoalanine 1501 in 63% yield [1135]. 

A general method for the synthesis of carbodiimides, isonitriles, ketimines, and aldehydes using triphenylphosphine dibromide has been developed. Diphenyl and dicyclohexyl carbodiimides are formed from N,N -disubstituted ureas in the presence of triethylamine at 80 °C in 90 min in yields of 66-75% [1257]. 

Synthesis of Bromoacetyl-N-hydroxysucdnimide See Fig. 1). Bromo-acetic acid (0.5 mmole, 66 mg) is dissolved in 0.6 ml of dry dioxane and 0.2 ml of dry ethyl acetate. iV-Hydroxysuccinimide, 0.6 mmole, is added, and the mixture is cooled to 4° in an ice-water bath. Dicyclohexyl-carbodiimide, 0.5 mmole, dissolved in 0.5 ml of dry dioxane at 0°, is then added to the mixture. The reaction is stirred for 1 hr in an ice-water... 

Synthesis of a,a -Dibromo-[2- C]acetic Anhydride. Bromo-[2- C] acetic acid ( 5 /nmoles, 22.6 Ci/mole) is dissolved in 50 /nl of dry dioxane. A, iV -dicyclohexyl carbodiimide, 2.5 /nmoles, dissolved in 50 /nl of dioxane, is added. After 1 hr in the dark at room temperature, the precipitated dicyclohexyl urea is removed by centrifugation. The supernatant liquid contains the anhydride and can be used directly in acetylation reactions. The dioxane used in these reactions should be absolutely free of peroxides. 

The more classical chemical procedures of degradation and total synthesis also developed apace with the use of newer reagents and synthetic methods. For instance, the use of condensing reagents trifluoroacetic anhydride and dicyclohexyl-carbodiimide makes the preparation of lichen depsides a relatively straightforward procedure, so that total synthesis is now a common means of strucmral confirmation. 

This chapter describes an optimized synthesis of polyamides based on Boc protection and azabenzotriazole (OAt) activation that solves the problems of sluggish reactions and difficult purification (Fig. 1). It is divided into two sections (1) the solid-phase synthesis of polyamides, and (2) resin aminolysis, purification, and characterization of the final product. Section 1 details the OAt-mediated couplings using either 0-(7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATH) or dicyclohexyl-carbodiimide (DCC)/l-hydroxy-7-azabenzotriazole (HOAt) (24-28). Diisopropylethylamine (DIEA) is used both to catalyze the formation of the OAt ester when employing HATH and to deprotonate the amine-trifluoroacetate salt formed after Boc deprotection. With OAt activation, coupling time is reduced to 20 min per step, making nine residue polya-... 

Peptide synthesis requires the use of selective protecting groups. An N-protected amino acid with a free carboxyl group is coupled to an 0-pro-tected amino acid with a free amino group in the presence of dicyclohexyl-carbodiimide (DCC). Amide formation occurs, the protecting groups are removed, and the sequence is repeated. Amines are often protected as their ferf-butyloxycarbonyl (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. 

Once the stmcture of a peptide is known, its synthesis can then he undertaken— perhaps to obtain a larger amount for biological evaluation. A simple amide might be formed by treating an amine and a carboxylic acid with dicyclohexyl-carbodiimide (DCC Section 21.7), but peptide synthesis is a more difficult problem because many different amide bonds must be formed in a specific order rather than at random. 

Polypeptide synthesis requires end-protected amino acids that are coupled by dicyclohexyl-carbodiimide. The product can be selectively deprotected at either end to allow for fvuther extension of the chain. The use of solid supports, as in the Merrifield synthesis, can be automated. 

Bonsignore, L. Cottiglia, F. Maccioni, A. M. Secci, D. Lavagna, S. M. Synthesis of coumarin-3-O-acylisoureas by dicyclohexyl-carbodiimide. J. Heterocycl. Chem. 1995, 32, 573-577. 

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