Carboxylic acid derivatives 4-dimethylaminopyridine

The coupling of the selone to racemic carboxylic acids with dicyclohexylcarbodiimide in dichloromethane with 4-dimethylaminopyridine at 0°C for 0.5-1 hour affords the acylated derivatives. Similar results are obtained using the acid chloride and triethyl amine. Figure 13 (upper part) shows the selenium spectrum for the diastereomeric. Y-acyl derivatives of the oxazo-lidine-2-selone with (A,A)-5-methylheptanoic acid. Clearly the shift difference of about (5 = 0.1 is sufficient for integration of the two singlets. The lower part of the figure shows the remarkably different 77Se resonances observed for four species derived from partially deuterated phenylacetic acid. The diastereomeric mixture of the monodeuteriated substance is easily detected (AS = 0.07, 5.0 Hz). 

Esterification.1 This reagent in combination with a catalytic amount of 4-dimethylaminopyridine (DMAP) is very effective for esterification of carboxylic acids with alcohols or thiols at room temperatures. However, reaction of aromatic and hindered acids requires several days at room temperature. French chemists report that only this method is useful for esterification of the protected baccatin III derivative (2) with (2R,3S)-N-benzoyl-0-(l-ethoxyethyl)-3-phenylisoserine (3) to provide the protected taxol derivative (4). A reaction conducted at 73° for 100 hours with 6 equiv. of 1 and 2 equiv. of DMAP produced 4 in 80% yield. Natural taxol, a cancer chemotherapeutic agent, is obtained by removal of the protective groups at C2 and C7 of 4. 

Preparation of Derivatives. Enoate derivatives are prepared from the corresponding chiral alcohol by treatment with acry-loyl chloride in the presence of Triethylamine and catalytic 4-Dimethylaminopyridine or the appropriate carboxylic acid chloride and Silveril) Cyanide. Alkynyl ethers are readily available from the potassium alkoxide by treating with Trichloroethylene, in situ dechlorination with n-Butyllithium, and electrophilic trapping. Trapping the intermediate anion with a proton source or lodomethane followed by Lindlar reduction of the alkynyl ether affords the corresponding vinyl and l-(Z)-propenyl ether, respectively, while reduction of the alkynyl ether with Lithium Aluminum Hydride affords the l-( )-propenyl ether. 

P-Keto esters (8, 313). Complete details are available for use of acyl derivatives of Meldrum s acid as precursors to fi-keto esters.1 A modification of this procedure has been used in a synthesis of thienamycin.2 The carboxylic acid group is activated by reaction with carbonyldiimidazole, and 4-dimethylaminopyridine is used as... 

Chlorocarbonylmethoxy)-4-melhylcoumarin is a reagent related to the above mentioned carbonyl azides [499]. It is prepared from 7-hydroxy-4-methylcoumarin and bromoacelic acid. The resulting carboxylic acid is transformed into the carbonyl chloride by refluxing with thionyl chloride. Derivatives (of prostaglandins and steroids) are formed in carefully dried methylene chloride containing 4-dimethylaminopyridine as catalyst. The esters formed are sufficiently stable for chromatographic separation. 

Ester and Thioester Formation. These reactions occur through the same O-acylurea or anhydride active intermediate as in the amide coupling reactions, and the discussion of associated problems applies here as well. In general, alkyl and (particularly) aryl thiols can be efficiently coupled to carboxylic acids using DCC. Reactions of primary and secondary alcohols proceed reliably, but require the presence of an acylation catalyst. This is usually 4-Dimethylaminopyridine (DMAP), " (see also 1,3-Dicyclohexylcarbodiimide—4-Dimethylaminopyridine), but others have been used including 4-pyrrolidinopyridine and pyridine (.solvent) with catalytic p-Toluenesulfonic Acid The acylation of more hindered alcohols often re.sults in reduced yields however, even f-butanol can be acylated, providing a useful route to t-butyl esters. Various other carbodiimide derivatives have also been used in the preparation of esters. As with amides, which are not limited to intermolecular reactions, a wide variety of lactones can also be synthesized. ... 

While the mixed anhydrides derived from the reaction of carboxylic acids with methyl chloroformate using EtsN as base are relatively stable, the addition of catalytic amounts of 4-Dimethylaminopyridine or A -methylmorpholine results in facile conversion to the corresponding methyl esters under very mild reaction conditions that are compatible with sensitive functionality. ... 

Carboxylic, and arylsulfonic acid halides react rapidly with pyridines generating 1-acyl- and 1-arylsulfonylpyridinium salts in solution, and in suitable cases some of these can even be isolated as crystalline solids. The solutions, generally in excess pyridine, are commonly used for the preparation of esters and sulfonates from alcohols and of amides and sulfonamides from amines. 4-Dimethylaminopyridine (DMAP) is widely used (in catalytic quantities) to activate anhydrides in a similar manner. The salt derived from DMAP and t-butyl chloroformate is stable even in aqueous solution at room temperature. " ... 

Ester Formation. Esters of iV-protected amino acids are prepared in high yield with EDC and 4-Dimethylaminopyridine (eq6). DMAP causes extensive racemization if not used in a catalytic amount. However, when esterifying the a-carboxyl of /3- and y-benzyl esters of aspartyl and glutamyl derivatives, extensive racemization was observed even with DMAP present in catalytic amounts. It is postulated that the side-chain esters contribute in some fashion to the lability of the cr-H. 

---