Substituted acetic acid derivatives

Reactions. Heating an aqueous solution of malonic acid above 70°C results in its decomposition to acetic acid and carbon dioxide. Malonic acid is a useful tool for synthesizing a-unsaturated carboxyUc acids because of its abiUty to undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic acids are formed from the reaction of malonic acid and benzaldehyde derivatives (1). If aUphatic aldehydes are used acryhc acids result (2). Similarly this facile decarboxylation combined with the condensation with an activated double bond yields a-substituted acetic acid derivatives. For example, 4-thiazohdine acetic acids (2) are readily prepared from 2,5-dihydro-l,3-thiazoles (3). A further feature of malonic acid is that it does not form an anhydride when heated with phosphorous pentoxide [1314-56-3] but rather carbon suboxide [504-64-3] [0=C=C=0], a toxic gas that reacts with water to reform malonic acid. 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

The Taft analysis has the working disadvantage that it requires two measurements to define a a value, and it also suffers from the problem that the parameters of some substituents cannot be obtained either because the ester decomposes too quickly for measurements to be made or because it would not decompose by ester hydrolysis. Such restrictions apply to the halogen substituents, nitrile or the nitro group, which would require study of such compounds as Hal-CO-OR, NC-CO-OR and O2N-CO-OR. This problem can be solved by use of Taft analysis of esters of the type X-CH2-CO-OR instead of X-CO-OR. In this analysis the similarity coefficient, p, for the substituted acetic acid derivatives is attenuated by 0.41 from the set value of p = 2.48 for the formic acid derivatives (Equations 8 and 9). The a constants based on formic acid derivatives are recorded in Table 1 in Appendix 3. ... 

Two specific j8-dicarbonyl compounds have had broad use in organic synthesis. These are acetoacetic ester (ethyl acetoacetate, ethyl 3-oxobutanoate), which can be used to make substituted acetone derivatives, and diethyl malonate (diethyl 1,3-propanedicarboxylic acid), which can be used to make substituted acetic acid derivatives. We shall consider syntheses involving ethyl acetoacetate and diethyl malonate in the upcoming sections of this chapter. 

A. Chiriac, V. Chiriac, D. Ciubotariu, S. Holban, and Z. Simon, Eur. J. Med. Chem., 18,507 (1983). Minimal Steric Difference (MTD) Study for Flexible Molecules Substituted Acetic Acid Derivatives with Auxinic Activity. 

Alkylation of the sodio derivative affords the C-substituted cyanoacetic ester, which when heated with dilute acid gives the mono-substitut acetic acid. 

Note 2. To maintain integrity of carbohydrate names, it is sometimes helpful to overstep the strict order of principal group preference specified in general organic nomenclature [13,14]. For example, a carboxymethyl-substituted sugar can be named as such, rather than as an acetic acid derivative (see 2-Carb-31.2). 

Besides the large number of a-amino acids found in nature, )3-amino acids are gaining an ever increasing attention [100]. Amino acids are e.g. found in the side chain of the cancerostatic taxol [101] as well as the new antibiotics sperabillin and TAN 1057 A/B [102]. The simple deprotection of 2 -substituted cyclopropylacetic acid derivatives 196-R by hydrogenolysis (and hydrolysis for the methyl esters 196b,i,j,m-Me) yielded enantiomerically pure 2-(r-amino-cyclopropyl)acetic acids (Scheme 59) [10]. 

Scheme 59. Preparation of enantiomerically pure 2-(r-aminocyclopropyl)acetic acids 200 by deprotection of 2 -substituted cyclopropylacetic acid derivatives 196 [10]...

In addition, the following o-substituted arylacetic acid derivatives are suitable starting materials for the syntheses of 3(2//)-isoquinolinones o-formylphenyl-acetamides [71T4653 80JCS(P1)2013], o-cyanophenyl-acetic esters (68BSF3403), and o-cyanophenylacetic acid chlorides [68AG(E)484]. 

What is needed in the synthesis of C is a two-carbon nucleophile (or its equivalent) which is less basic titan an enolate so elimination is not competitive. If product C is recognized as an acetic acid derivative, then the following analysis can be made. A malonate ion used as the carbon nucleophile is much less basic than a simple ester enolate and hence undergoes substitution readily but does not promote elimination effectively, particularly in secondary systems. 

The same author has reported chiral recognition of a-amino acids by native, anionic, and cationic a- and (3-cyclodextrins [17]. Both carboxylates and amines (monosubstituted as well as hexa- and heptasubstituted) were included in this study. The best results obtained were those from a combination of (S)- and (P)-AcTrp complexed by per-NH -[3-cyclodextrin with K=2,310 and 1,420 (1/mol). In the detailed study of chiral recognition of substituted phenyl-acetic acid derivatives by aminated cyclodextrins, these were found to be again only modest with respect to the enantioselection attained [18]. 

Esterification of salicylaldehydes with acetic acid derivatives forms 2-formylphenyl acetate intermediates, which cyclize in high yield to afford 3-substituted coumarins (Scheme 168) <2004SC3129>. 

Substituted pipecolic acid derivatives can be accessed from a suitably protected allylglycine derivative by first use of a palladium-catalyzed N, O-acetal formation followed by RCM.43 Treatment of 19 with boron trifluoride etherate followed by a variety of nucleophiles formed the corresponding substituted products 20 and 21 (Scheme 28.12). 

Another S l reaction that leads to a substitution product that cyclized in a subsequent step is the reaction of (o-iodoaryl)acetic acid derivatives with ketone enolate ions. Thus, substrate 298 reacts under irradiation with ketone enolate ions to give 299 [R = Me (75-80%), R = z-Pr (75-80%), R = t-Bu (85-90%)] (equation 183)332. The substitution products 299 are the key intermediates for the synthesis of 3-benzazepines and 3-benzoxepines332. 

Substituted derivatives of type (105) have been reported to undergo cleavage in the presence of acid to yield the acetic acid derivative (106 Scheme 48) (65AHC(5)119). The nitrile functions of the isomeric compounds (107) and (108) have been converted into the corresponding amides, carboxylic acids and methyl esters in the usual fashion (81JOC771). 

Any carboxylic acid with a carbonyl group in the jS position is prone to decarboxylate. At the temperature of the hydrolysis, the alkylmalonic acid loses CO2 to give a substituted derivative of acetic acid. Decarboxylation takes place through a cyclic transition state, initially giving an enol that quickly tautomerizes to the product, a substituted acetic acid. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

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