Anhydrides Nucleophilic catalyst, pyridine

This is how the N-Boc pyrrole was made for use in the synthesis of epibatidine. The base used was the pyridine derivative DMAP, which you met earlier in the chapter. It has a p Tan of 9.7 and so produces small, equilibrating amounts of the anion as well as acting as a nucleophilic catalyst. Boc anhydride is used as the acylating agent. 

In 1993, Vedejs et al. [5,6] showed that tributylphosphine is a potent catalyst for the acylation of alcohols by acetic and benzoic anhydrides as efficient as 4-(di-methylamino)pyridine DMAP [7,8]. However, the DMAP catalyst is more versatile since it presents catalytic activity in the reaction of alcohols with a larger variety of electrophiles. Due to these properties, Fu [9] realized the design and synthesis of a new family of chiral nucleophilic catalysts illustrated by the planar-chiral DMAP derivative I which is a very efficient catalyst in different enantioselective reactions such as addition of alcohols to ketenes [10], rearrangement of O-acylated azalactones [11], and kinetic resolution of secondary alcohols [12-14]. 

A nucleophilic catalyst speeds up a reaction by acting as both a good nucleophile and a good leaving group. You saw pyridine performing a similar function in substitution reactions at the C=0 group of acid anhydrides in Chapter 10. 

This reaction was initially reported by Einhorn and Hollandt in 1898. It is the acylation of alcohols using anhydride or acyl haUde in a tertiary amine such as pyridine. Therefore, this reaction is known as the Einhorn acylation, Einhorn reaction, and Deninger-Einhorn method." The function of tertiary amines in this reaction have been identified as both nucleophilic acylation catalyst and acid scavenger. The solid evidence of nucleophilic catalyst is to record the UV spectrum of the intermediate acetylpyridinium salt in water. Subsequently, a number of highly nucleophilic tertiary amines have been employed for the acylation of alcohols. These tertiary amines include triethylamine, 4-(dimethylamino)pyridine (DMAP), l,4-diazabicyclo[2.2.2]octane and... 

Acylation catalysts, typically nucleophilic amines and imines that activate caiboxylates by forming highly nucleophile-susceptible acyliminium intermediates, promote a wide variety of synthetically useful caiboxylate transformations. Many are sufiSciently water-soluble to evaluate as anhydride hydrolysis catalysts. Scheme 1 depicts a representative example of this class of reaction, the hydrolysis of a P(NB/MA) polymer matrix in aqueous base (TMAH) catalyzed by 4-(dimethylamino)pyridine (DMAP). 

Nucleophilic catalysis may be defined as the catalysis of a chemical reaction by a (rate-determining) nucleophilic substitution. Thus, if a particular nucleophilic reaction is slow, then the reactant may undergo attack by a nucleophilic catalyst to give rise to an intermediate that is more susceptible to the desired nucleophilic displacement than the reactant. A classical example of nucleophilic catalysis is the acetylation of alcohols with acetic anhydride in pyridine ... 

In 2010, Fossey et al. developed a new class of planar chiral ferrocene nucleophilic catalysts combining both central and planar chirality [59]. Inspired by Fu s planar chiral DMAP and by Birman s 2-phenyl-2,3-dihydroimidazo[l,2-a]pyridine, Rp-57 proved to be a remarkably effective catalyst for the KR of various racemic secondary aryl alkyl alcohols, particularly bulky aryl alkyl alcohols, which are usually difficult to resolve. Typically, by performing the reaction in the presence of Rp-57 (2mol%), propionic anhydride (0.75 equiv.) and i-Pr2NEt (0.75 equiv.) in toluene at 0°C, selectivity factors ranging from s = 31 for substrates such as a-methyl benzyl alcohol to s = 534 in the case of the more bulky a-tert-butyl benzyl alcohol could be obtained (Scheme 41.13). Remarkably, the selectivity could be further increased by running the reaction at lower temperatures (s = 801 at -20 °C and up to s = 1892 at -40 °C), albeit with a concomitant loss in activity. 

Chiral n complexes of heterocycles with transition metals can serve as effective catalysts for an array of useful organic reactions.The most efficient nucleophilic catalysts previously used had planar structures, e.g., 4-(dimethylamino)pyridine, and therefore required an asymmetric environment in the vicinity of an sp -hybridized nucleophilic atom. In a recent paper, G. C. Fu et al describe a procedure, which they call a second-generation system for kinetic resolution, that employs an iron complex at a mole fraction of 2% as the chiral catalyst, and acetic anhydride as the acylating agent (Figure 9.7.1). The authors attached the 4-(dimethylamino)pyridine moiety to a chiral ferrocene analog. The lower portion of the ferrocene, coordinated to the iron atom is pentaphenylcyclopentadiene, as shown in Figure 9.7.1. 

The scope of this reaction is similar to that of 10-21. Though anhydrides are somewhat less reactive than acyl halides, they are often used to prepare carboxylic esters. Acids, Lewis acids, and bases are often used as catalysts—most often, pyridine. Catalysis by pyridine is of the nucleophilic type (see 10-9). 4-(A,A-Dimethylamino)pyridine is a better catalyst than pyridine and can be used in cases where pyridine fails. " Nonbasic catalysts are cobalt(II) chloride " and TaCls—Si02. " Formic anhydride is not a stable compound but esters of formic acid can be prepared by treating alcohols " or phenols " with acetic-formic anhydride. Cyclic anhydrides give monoesterified dicarboxylic acids, for example,... 

The above types of catalysis function by stabilizing the transition state of the reaction without changing the mechanism. Catalysts may also involve a different reaction, pathway. A typical example is nucleophilic catalysis in an acyl transfer or hydrolytic reaction. The hydrolysis of acetic anhydride is greatly enhanced by pyridine because of the rapid formation of the highly reactive acetylpyridinium ion (equation 2.12). For nucleophilic catalysis to be efficient, the nucleophile... 

In Chapter 12 pyridine was often used as a catalyst in carbonyl substitution reactions. It can act in two ways. In making esters from acid chlorides or anhydrides pyridine can act as a nucleophile as well as a convenient solvent. It is a better nucleophile than the alcohol and this nucleophilic catalysis is discussed in Chapter 12 (p. 282). But nonnucleophilic bases also catalyse these reactions. For example, acetate ion catalyses ester formation from acetic anhydride and alcohols. 

In the preceding examples, the asymmetric catalyst is a Lewis acid and hence the catalytic processes reported so far involve electrophilic activation by a metal-centred chiral Lewis acid. There is another strategy, although less explored, which consists of designing chiral Lewis bases for nucleophilic catalysis. It is well known that Lewis bases such as nitrogen heterocycles and tertiary phosphines and amines catalyse a variety of important chemical processes. For instance 4-(dimethylamino)pyridine (DMAP) catalyses the acylation of alcohols by anhydrides the mechanism by which DMAP accelerates this process provides an instmctive illustration of how nucleophiles can... 

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