Synthesis of carboxylic acid derivatives

Carboxylic acid derivatives can be created via FGIs, beginning with either a carboxylic acid or from another carboxylic acid derivative. Since it is possible to make enolates from esters, tertiary amides, and nitriles, these compounds can also be prepared by alkylation at the alpha carbon. 

RELATIVE REACTIVITIES OF CARBOXYLIC ACID DERIVATIVES (RCOLG) 

The interconversion of carboxylic acid derivatives relies on the ability to replace one leaving group with another (addition-elimination mechanism involving collapse of a CTl). 

Synthesis of Carboxylic Acid Derivatives via Acyl Substitution 

Introduction to Strategies for Organic Synthesis, First Edition. Laurie S. Starkey. 2012 John Wiley Sons, Inc. Published 2012 by John Wiley Sons, Inc. 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups are the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

Acyl azides may loose N2 on heating and rearrange to isocyanates (Curtius rearrangement), which may be solvolyzed. Some of the possibilities of classical carboxyl conversions are exemplified in the schemes below, which are taken from a triquinacene synthesis (R. Russo, 1971 C. Merrier, 1973) and the ergotamine synthesis of A. Hofmann (1963). 

In these cases the acyl azides formed have been used to prepare amines via Curtius rearrangement. The acyl chloride or azide intermediates can. however, also be reacted with amines or alcohols to form amides or esters. 

As a catalyst for ester and amide formation from acyl chlorides or anhydrides, 4-(di-meihylamino)pyridine has been recommended (DMAP G. HOfle, 1978). In the presence of this agent highly hindered hydroxyl groups, e.g. of steroids and carbohydrates, are acylated under mild conditions, which is difficult to achieve with other catalysts. 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1 -hydroxy-1 ff-benzotriazole ( HBT ) and DCC has been very successful in increasing yields and decreasing racemization (W. Konig, 1970, G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(AcyIoxy)-lff-benzotriazoles or 1-acyl-1 H-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l-yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with rert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

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A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

It has long been known that autoxidation of aldehydes leads to carboxylic acids via a radical mechanism which involves the formation and oxidation of acyl radicals, leading to acyl cations via one-electron oxidation processes [68]. However, the recent topic in this field relates to the fact that many new synthetic methods for the synthesis of carboxylic acids derivatives have been developed which rely on the power of one-carbon homologative radical reactions. 

Section 17.20 Synthesis of Carboxylic Acid Derivatives 711 A cyclic ether can also be prepared by an intramolecular electrophilic addition reaction. 

Several groups have studied the synthesis of carboxylic acid derivatives of polypyrrole however, the electrochemistry of very few carboxylic acid substituted polypyrroles has been reported. Smith et al. [64] reported... 

Acid halides and acid anhydrides allow convenient synthesis of carboxylic acid derivatives... 

A known method [221] for the preparation of C-glycosyl cyanides from tri-chloroacetimidates has been applied to the reaction of the 0-acetyl-protected O-glucosyl trichloroacetimidate [222, 223], Reaction with trimethylsilyl cyanide gave the a-glycoside, a valuable intermediate in the synthesis of carboxylic acid derivatives or other C-glycosides, in quantitative yield. 

Hydrolysis and Synthesis of Carboxylic Acid Derivatives such as Esters and Amides... 

Hydrolysis and synthesis of carboxylic acid derivatives such as esters and amides. 

The oxidation of aldehydes (alkanals) and ketones (alkanones) has been reviewed extensively [1-3], and there are compilations based on reagent types [4-8] and oxidation methods for most functionalized compounds including those having carbonyl groups. Books [9, 10] and comprehensive review articles [11-16] on carboxylic acids and their derivatives also provide important background information on the oxidation of carbonyl compounds. This account will focus exclusively on the synthesis of carboxylic acid derivatives. After a brief summary of the well-estabHshed methods, new directions in oxidative transformations of carbonyl compounds will be described. Among these, in particular, catalytic [17, 18] and asymmetric versions will be emphasized. 

Electrochemical [143, 144] and biochemical processes [145] are also effective for the synthesis of carboxylic acid derivatives from aldehydes. 

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