Esterification 4-dimethylaminopyridine

Dimethylaminopyridine [1122-58-3] (DMAP) (24) has emerged as the preferred catalyst for a variety of synthetic transformations under mild conditions, particularly acylations, alkylations, silylations, esterifications, polymeri2ations, and rearrangements (100). POLYDMAP resin [1122-58-3], a polymeric version of DMAP, is available, and is as effective as DMAP as a catalyst for acylation reactions. Furthermore, it can be recycled without regeneration more than 20 times with very Htde loss in activity. POLYDMAP is a trademark of Reilly Industries, Inc. 

However, this method is appHed only when esterification cannot be effected by the usual acid—alcohol reaction because of the higher cost of the anhydrides. The production of cellulose acetate (see Fibers, cellulose esters), phenyl acetate (used in acetaminophen production), and aspirin (acetylsahcyhc acid) (see Salicylic acid) are examples of the large-scale use of acetic anhydride. The speed of acylation is greatiy increased by the use of catalysts (68) such as sulfuric acid, perchloric acid, trifluoroacetic acid, phosphoms pentoxide, 2inc chloride, ferric chloride, sodium acetate, and tertiary amines, eg, 4-dimethylaminopyridine. 

AC2O, AcCl, Pyr, DMAP, 24-80°, 1-40 h, 72-95% yield. The use of DMAP increases the rate of acylation by a factor of 10. These conditions will acylate most alcohols, including tertiary alcohols. The use of DMAP (4-N,N-dimethylaminopyridine) as a catalyst to improve the rate of esterification is quite general and works for other esters as well. 

The second step, nucleophilic attack of an alcohol or phenol on the activated carboxylic acid RCOIm (carboxylic acid imidazolide), is usually slow (several hours), but it can be accelerated by heating[7] or by adding a base[8] [9] such as NaH, NaNH2, imidazole sodium (ImNa), NaOR, triethylamine, diazabicyclononene (DBN), diazabicycloimdecene (DBU), or /7-dimethylaminopyridine to the reaction mixture (see Tables 3—1 and 3—2). This causes the alcohol to become more nucleophilic. Sodium alcoholate applied in catalytic amounts accelerates the ester synthesis to such an extent that even at room temperature esterification is complete after a short time, usually within a few minutes.[7H9] This catalysis is a result of the fact that alcoholate reacts with the imidazolide very rapidly, forming the ester and imidazole sodium. 

The desired polymer-bound tryptophan was rapidly generated under microwave irradiation, employing a classical esterification protocol using N,N -dicydohexylcar-bodiimide (DCC) and a catalytic amount of N,N-dimethylaminopyridine (DMAP), followed by subsequent Fmoc deprotection (Scheme 7.68). Cyclocondensations with various carbonyl compounds were performed with catalytic amounts of p-toluene-... 

FIGURE 3.21 Esterification by decomposition of a mixed anhydride by triethylamine in the presence of 4-dimethylaminopyridine.55 The active intermediate is probably the acylpyridium ion. 

During the first decade when solid-phase synthesis was executed using Fmoc/tBu chemistry, the first Fmoc-amino acid was anchored to the support by reaction of the symmetrical anhydride with the hydroxymethylphenyl group of the linker or support. Because this is an esterification reaction that does not occur readily, 4-dimethylaminopyridine was employed as catalyst. The basic catalyst caused up to 6% enantiomerization of the activated residue (see Section 4.19). Diminution of the amount of catalyst to one-tenth of an equivalent (Figure 5.21, A) reduced the isomerization substantially but did not suppress it completely. As a consequence, the products synthesized during that decade were usually contaminated with a small amount of the epimer. In addition, the basic catalyst was responsible for a second side reaction namely, the premature removal of Fmoc protector, which led to loading of some dimer of the first residue. Nothing could be done about the situation,... 

Neises, B. and W. Steglich, Esterification ofcarboxyic acids with dicyclohexylcarbodiimide/4-dimethylaminopyridine tert-butyl ethyl fumarate. Organic Syntheses, 1990.7 p. 93-94. 

Protection of an alcohol function by esterification sometimes offers advantages over use of acetal or ether groups. Generally, ester groups are stable under acidic conditions. Esters are especially useful in protection during oxidations. Acetates and benzoates are the most commonly used ester derivatives. They can be conveniently prepared by reaction of unhindered alcohols with acetic anhydride or benzoyl chloride, respectively, in the presence of pyridine or other tertiary amines. 4-Dimethylaminopyridine (DMAP) is often used as a catalyst. The use of A-acylimidazolides (see Section 3.4.1) allows the... 

Scheme 44 summarizes an addition reaction by the Barton method. Thiohydroxamate esters (32) are readily prepared and isolated, but, more typically, they are generated in situ. Experimental procedures have been described in detail148151 and often entail the slow addition of an acid chloride to a refluxing chlorobenzene solution of the readily available sodium salt (31), dimethylaminopyridine (DMAP, to catalyze the esterification), and excess alkene. The products are usually isolated by standard aqueous work-up and chromatographic purification. 

A typical procedure is a follows An esterification solution was prepared by dissolving 3.5 g(+)-menthol,0.12 g DCC, 3 mg 4-dimethylaminopyridine (4-DMAP), and 3 mg 4-DMAP-HCI in one mL dry CH2CI2. For the analysis of a product sample, about 0.05mg of the compound in about 10 microliter dichloromethane is mixed well with 10(0.1 esterification solution at ambient temperature for 30 minutes. The final solution was analyzed on a Varian 370 GC with a 25-meter Chirasil-L-Val column at 195°C isothermally. Excellent baseline separations of the diasteromers are usually obtained. A calibration with naproxen of known optical purity is carried out before using this method for analysis. 

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. 

Esterification of succinic anhydride in dimethylformamide with 4-dimethylaminopyridine gives O-succinoylated inulin (Vermeersch and Schacht, 1985), which can be used as a drug carrier. Esterification of alkenyl succinic anhydrides having chain lengths of C8 to C20 in dimethylformamide, with or without a catalyst, produces potential deflocculating agents for use in detergents... 

Esterification. DCC has been satisfactory only for esterification of phenols and thiophenols because of variable yields. However, if 4-dimethylaminopyridine (3, 118-119 5, 26) or 4-pyrrolidinopyridine (this volume) is added as catalyst, alcohols and thiols are csterified readily at rm temperature in satisfactory yields. Sterically... 

Two strategies have been developed for the preparation of esters of diazoacetic acid. If the alcohol is inexpensive, it is first converted (diketene) into the corresponding acetoacetate (120 equation 49). Diazo transfer with subsequent deacylation then yields the diazoacetate (121). If the alcohol is particularly valuable or sensitive, it may alternatively be esterified with a more direct precursor to diazoacetate. One reagent that has been used for this purpose is glyoxalic acid 2,4,6-triisopropylbenzenesulfonylhydrazone (TIPPS) (123 equation 50). Esterification of the alcohol (122) with (123), using dicyclohexylcarbo-diimide followed by addition of 4-dimethylaminopyridine, gives the diazoacetate (124). ... 

Polymeric counterparts of 4-dimethylaminopyridine have been prepared by several groups. Reilly Industries sells one as Reillex PolyDMAP (5.32a).141 When used in esterifications, the polymeric catalyst offers easy separation, reduced toxicity and the ability to use it in excess. It can be reused. The monomeric reagent is highly toxic. The two other polymeric analogues of 4-dimethylaminopyridine (5.33) are based on other chemistry.142 The first is a polyamide, the second, a polyurethane. In the second case, glycerol was also sometimes added to produce an insoluble product. 

ESTERIFICATION OF CARBOXYLIC ACIDS WITH DICYCLOHEXYLCARBODIIMIDE/4-DIMETHYLAMINOPYRIDINE tert-BUTYL ETHYL FUMARATE... 

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