Carboxylic acid derivatives reaction with amine nucleophiles

Not only acylimino acids (VI. B.) but also 2-alkylidene- and 2-aryli-dene-A -oxazolin-5-ones (55) (pseudooxazolones) add nucleophiles. Simultaneous ring opening is usually observed 195, 237, 238, 239, 397) yielding the corresponding amino acid derivatives. Reaction with ammonia or amines resp. alcohols yields a,a-diamino carboxylic acid esters (56) or a-alkoxy-a-acylaminocarboxylic acid esters (58) respectively. Mercaptans add so rapidly that mercaptooxazolinones (57) can be isolated and then opened with other nucleophiles. 

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). 

The last of these special examples of SN reactions of heteroatom nucleophiles at the carboxyl carbon of a carboxylic acid derivative is given in Figure 6.21. There, the free carboxyl group of the aspartic acid derivative A is activated according to the in situ procedure of Figure 6.14 as a mixed carbonic acid/carboxylic acid anhydride B that is then treated with N,0-dimethylhydroxyl amine. This reagent is an N nucleophile, which is thus acylated to give the... 

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

The thiolates, though less sensitive to basicity, are more reactive than oxygen anions over the total accessible range of basicity, but intersect the amine line at ca. pA 12. Other reactive nucleophiles which do not fall in the amine, thiolate, or oxygen anion categories are fluoride, thiosulfate, nitrite, azide, and sulfite. Halides other than fluoride, and also thiocyanate, nitrate, sulfate, and thiourea have no reactivity towards p-nitrophenyl acetate (Jencks and Carriuolo, 1960a). The total lack of reactivity of thiocyanate, iodide, bromide, and thiourea, all very polarizable nucleophiles which are reactive to sp carbon, rules out any possibility that polarizability is at all important in nucleophilic reactions at the carbonyl carbon. In general, the order of nucleophilic reactivity to p-nitrophenyl acetate correlates well with nucleophilic reactivity to other carboxylic acid derivatives (see later). Nitrite, however, shows... 

A characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. In this reaction a negative or neutral nucleophile replaces a leaving group to form a substitution product. The leaving groups and nucleophiles are the groups that define the various acid derivatives as a result, the reaction usually involves the conversion of one acid derivative into another. The order of reactivity of acid derivatives is acid chloride > anhydride > acid or ester > amide. In general, reaction of any of these derivatives with water produces acids with alcohols, esters result and with amines, amides are formed. 

Hydroxide ion promotes only hydrolysis reactions, not transesterification reactions or aminolysis reactions. Hydroxide ion cannot promote reactions of carboxylic acid derivatives with alcohols or with amines because one function of hydroxide ion is to provide a strong nucleophile for the first step of the reaction. Thus, when the nucleophile is supposed to be an alcohol or an amine, nucleophilic attack by hydroxide ion would form a product different from the product that would be formed from nucleophilic attack by an alcohol or amine. Hydroxide can be used to promote a hydrolysis reaction because the same product is formed, regardless of whether the attacking nucleophile is H2O or HO . 

Four-Component Synthesis of Pyrrolopyridines If a primary amine were used as an input, the three-component reaction shown in Scheme 15.10 would produce an oxazole bearing a secondary amine. In other words, the so-produced adduct 24 would contain both a diene (oxazole) and a nucleophilic site (amine). Therefore, a dienophile bearing an electrophihc center would pair perfectly with the dual reactivity of 24. In practice, if an activated a,P-unsaturated carboxylic acid derivative were introduced after the three-component reaction, a sequence of N-acylation/intramolecular Diels-Alder reaction (IMDA) might occur to produce the four-component adducts. 

As an example, ferf-butyl (45)-l-methyl-2-oxoimidazolidine-4-carboxylate was used by Nunami and colleagues as a chiral auxiliary for DKR of a-bromo-carboxylic acids. In this case, the nucleophile was a malonic ester enolate and the role of the polarity of the solvent (hexamethylphosphoramide, HMPA) was demonstrated (Scheme 1.2). The alkylated products were further easily converted to chiral a-alkylsuccinic acid derivatives and chiral jS-amino acid derivatives. Moreover, these authors showed that this methodology could be extended to other nucleophiles such as amines." Therefore, the reaction of a diastereomeric mixture of tert-bvAy (45)-l-methyl-2-oxoimidazolidine-4-carb-oxylate with potassium phthalimide predominantly afforded fcrf-butyl (45)-1-methyl-3-((25)-2-(phthaloylamino)propionyl)-2-oxoimidazolidine-4-carboxylate in 90% yield and 94% diastereomeric excess (de). The successive removal of the chiral auxiliary afforded A-phthaloyl-L-alanine. 

When acid derivative 2 reacts with sulfuric acid, the oxygen atom is the base and the conjugate acid product of this acid-base reaction is oxocarbenium ion 3, which is resonance stabilized. When 2 is an acid chloride, anhydride, ester, or amide, a heteroatom is attached to the positive carbon in 3. As in Chapter 18 (Section 18.1), the acid-base reaction of the carbonyl unit in 2 to give 3 facilitates reactions with nucleophiles. The reaction of intermediate 3 with a nucleophile ( Y) gives tetrahedral intermediate 4 contrary to acyl addition, reaction 4 contains an X group that can function as a leaving group. Loss of X leads to the final product of this reaction 5. If the nucleophile ( Y) is hydroxide, compormd 5 is the carboxylic acid (X = OH). If the nucleophile Y is an alcohol, the product 5 is an ester, and if Y is an amine, the product 5 is an amide. This first reaction is therefore the acid-catalyzed acyl substitution reaction of acid derivatives. 

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