Dicyclohexylcarbodiimide acid addition

Androst-4-ene-3,17-dione. Testosterone (0.58 g, 2 mmoles) is dissolved in a solution prepared from 3 ml of benzene, 3 ml of dimethyl sulfoxide, 0.16 ml (2 mmoles) of pyridine and 0.08 ml (1 mmole) of trifluoroacetic acid. After addition of 1.24 g (6 mmoles) of dicyclohexylcarbodiimide, the sealed reaction flask is kept overnight at room temperature. Ether (50 ml) is added followed by a solution of 0.54 g (6 mmoles) of oxalic acid in 5 ml of methanol. After gas evolution has ceased ( 30 min) 50 ml of water is added and the insoluble dicyclohexylurea is removed by filtration. The organic phase is then extracted twice with 5 % sodium bicarbonate and once with water, dried over sodium sulfate and evaporated to a crystalline residue (0.80 g) which still contains a little dicyclohexylurea. Direct crystallization from 5 ml of ethanol gives androst-4-ene-3,17-dione (0.53 g, 92%) in two crops, mp 169-170°. 

The first version of SPPS to be developed used the t-Boc group as the amino-protecting group. f-Boc can be cleaved with relatively mild acidic treatment and TFA is usually used. The original coupling reagents utilized for SPPS were carbodiimides. In addition to dicyclohexylcarbodiimide (DCCI), N, (V -diisopropylcarbodiimide (DIPCDI) is often used. The mechanism of peptide coupling by carbodiimides was... 

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

Activated esters of A-alkoxycarbonylamino acids are prepared by two approaches, activation of the acid followed by reaction with the hydroxy compound, and trans-esterification. Most of the products are stable enough to be purified by washing a solution of the ester in an organic solvent with aqueous solutions. A few that are not crystalline are purified by passage through a column of silica. The commonly used method for their preparation is addition of dicyclohexylcarbodiimide to a cold mixture of the reactants in dimethylformamide or ethyl acetate. The first Boc-amino acid nitrophenyl esters were obtained using pyridine as solvent. Pyridine generates the nitrophenoxide ion that is more reactive. For one type of ester, 2-hydroxypyridino... 

This can then be coupled to a second amino acid with a blocked amino group using dicyclohexylcarbodiimide (Eq. 3-10). The removal of the blocking group and addition of a new amino acid residue can then be repeated as often as desired. The completed peptide is removed from the polystyrene by action of a strong acid such as HF. 

Another in situ procedure for activating carboxylic acids utilizes earbodiimides, such as dicyclohexylcarbodiimide (DCC). DCC (19) plays an important role in peptide synthesis. Addition of a carboxylic acid to the C-N double bond leads to the activated species, an acyl isourea 20, which upon attack by a nucleophile (and alcohol or an amine) releases the corresponding ester or amide along with 21 (for the mechanism, see Chapter 5). However, in the conversion of 5 to 7 the DCC procedure gives poor results. 

The synthesis of various heterocyclic systems via 1,3-dipolar cycloaddition reactions of 1,3-oxazolium-5-oxides (32) with different dipolarophiles was reported. The cycloaddition reactions of mesoionic 5H,7H-thiazolo[3,4-c]oxazolium-l-oxides (32), which were prepared from in situ N-acyl-(/J)-thiazolidine-4-carboxyIic acids and N,N -dicyclohexylcarbodiimide, with imines, such as N-(phenylmethylene)aniline and N-(phenylmethylene)benzenesulfonamide, gave 7-thia-2,5-diazaspiro[3,4]octan-l-one derivatives (33) and lH,3H-imidazo[ 1,5-cJthiazole derivative (35). The nature of substituents on imines and on mesoionic compounds influenced the reaction. A spirocyclic p-lactam (33) may be derived from a two-step addition reaction. Alternatively, an imidazothiazole (35) may be obtained from a typical 1,3-dipolar cycloaddition via a tricyclic adduct (34) which loses carbon dioxide and benzenesulfinic acid. [95T9385]... 

The addition of carboxylic acids to dicyclohexylcarbodiimide was mentioned in the context of Figures 6.15 and 6.26, but there we looked at it only from the point of view of activating a carboxylic acid. This addition follows the proton-catalyzed mechanism of Figure 8.12. 

Esterification with alcohols in the presence of pyridine was used by Felder et al. [36]. Water produced in the reaction mixture is bound by the addition of N,N -dicyclohexyl-carbodiimide (Scheme 4.8). The acid (ca. 10 mequiv.) is dissolved in 25 ml of alcohol and 4 ml of pyridine and an excess of dicyclohexylcarbodiimide (12 mequiv.) are added (even more if the sample is not dry). The amount of pyridine can also be larger and it then acts as a solvent, e.g., if the alcohol used is solid (menthol). The mixture is then stirred at room temperature only with some higher alcohols or acids must the mixture be heated at 40—80°C for 30—120 min. If a precipitate of N,N -dicyclohexylurea is produced in the reaction, it is allowed to sediment and, after adding an internal standard,... 

A reactor was charged with ethyl-3-hydroxybutyrate (194.0 g), cyanoacetic acid (149.83 g), 4-dimethylaminopyridine (10.76 g), and 1500 ml of CH2CI2 and then treated with 75 ml of DMF. The solution was chilled in an ice-water bath and treated with dicyclohexylcarbodiimide (363.45 g) dissolved in 600ml of CH2CI2. A white precipitate formed within five minutes after the start of the addition, and the mixture was stirred overnight. The precipitate was then removed by filtration and the filtrate concentrated. The product was isolated in 73% yield after being distilled twice under vacuum, bp= 100-109°C/0.20-0.27mmHg. 

A carboxylic acid and an amine readily react to form an amide in the presence of an additional reagent, dicyclohexylcarbodiimide (DCC), which is converted to the by-product dicyclohexyl-urea in the course of the reaction. 

Peptide couplings with the sole use of carbodiimides and in the absence of a protic additive are usually restricted to carbamate- or Nps-protectedb l amino acids or to peptide fragments bearing a nonracemizing glycine or proline residue at the C-terminus. In these cases N,N dicyclohexylcarbodiimide (1, DCC) may be employed and is a very cheap reagent, which is also used on an industrial scale. 

Salts of dithiocarbamic acid can be prepared by the addition of primary or secondary amines to carbon disulfide." This reaction is similar to 16-10. Hydrogen sulfide can be eliminated from the product, directly or indirectly, to give isothiocyanates (RNCS). Isothiocyanates can be obtained directly by the reaction of primary amines and CS2 in pyridine in the presence of dicyclohexylcarbodiimide. Aniline derivatives react with CS2 and NaOH, and then ethyl chloroformate to give the aryl isothiocyanate." In the presence of diphenyl phosphite and pyridine, primary amines add to CO2 and to CS2 to give, respectively, symmetrically substituted ureas... 

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