Decarboxylation facile

Alkynyl acids also underwent analogous decarboxylation facilely [75]. These decarboxylation processes have been extended to catalytic decarboxylative transformations (Chapter 4). 

The three isomers of thiazoleacetic acid can be decarboxylated, the order of facility being 2>5>4, though the relative stability depends on each particular compound and the reaction conditions (72-75). This reaction may be used to obtain certain alkylthiazoles (73). Malonic derivatives can also be decarboxylated to give aliphatic thiazole acids (49, 51)... 

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. 

Earlier sections have already provided several examples of radical fragmentation reactions, although this terminology was not explicitly used. The facile decarboxylation of acyloxy radicals is an example. 

Compound 2 is hydrolyzed in boiling water to form the hydrate of benzamidotrifluoroacetone (3) with loss of carbon dioxide. This behavior is readily understood in terms of a facile decarboxylation of the initially formed jS-keto acid. 

Aliphatic acyloxy radicals undergo facile fragmentation with loss of carbon dioxide (Scheme 3,69) and, with few exceptions,428 do not have sufficient lifetime to enable direct reaction with monomers or other substrates. The rate constants for decarboxylation of aliphatic acyloxy radicals are in the range l 10xl09 M 1 s at 20 °C.429 lister end groups in polymers produced with aliphatic diacyl peroxides as initiators most likely arise by transfer to initiator (see 3.3.2.1,4). The chemistry of the carbon-centered radicals formed by (3-scission of acyloxy radicals is discussed above (see 3.4.1). 

The alkoxycarbonyloxy radicals show little tendency to abstract hydrogen.188,431 For example, in the reaction of isopropoxycarbonyloxy radicals with MMA, hydrogen abstraction, while observed, is a minor pathway (<1%). When isopropoxycarbonyloxy radicals abstract hydrogen, isopropanol is the expected byproduct since the intermediate acid undergoes facile decarboxylation. Formation of isopropanol is not evidence for the involvement of isopropoxy radicals (Scheme 3.80). 

An improved route to fluorinated 4-hydroxycoumarins has been reported, based on a facile decarboxylation-deacetylation of their 3-(3-oxopropanoic acid) derivatives <96TL15S1>. The reaction of methyl salicylates with triphenylphosphoranylidene ketene, Ph3P=C=C=0, affords 4-methoxycoumarins <96JCS(P1)2799> and the formation of coumarin 3-phosphonates from salicylaldehydes and phosphonoacetates, Et02CCH2P(0)(0R)2, has been investigated <96T12597>. 

The reaction proceeds at room temperature and is rationalized invoking oxidative addition of a Pd(0) species upon the allylic C - O bond of 67, followed by decarboxylation to form an oxapalladacyclopentane intermediate 66 (Pd in place of Ni), which undergoes a facile b-C elimination to finally give an co-dienyl aldehyde 68 (Scheme 17). Recently, it has been revealed that a combination of Ni(cod)2 and a phosphine ligand also catalyzes the same... 

A specific case of the carbonium ion mechanism [Eq. (5)] with reasonable plausibility is decarboxylation of metal arenoates by classic electrophilic aromatic substitution [Eq. (12)]. This mechanism would be favored by electron-donating substituents and has been invoked to explain the relative ease of decarboxylation of p-methoxybenzoic acid in molten mercuric trifluoroacetate (77) as well as the very facile decarboxylation on reaction of polymethoxybenzoic acids with mercuric acetate (18) (see below). 

However, some binuclear -jr-allyl palladium complexes have been obtained by facile decarboxylations from palladium chloride and some... 

Further studies by Spenser demonstrated that l,2-13C-labeled acetate (13) was incorporated into lycopodine but gave a distribution of the labels that did not account for the pelletierine-route that was hypothesized (Scheme 6.2) [11]. An intact 3-carbon unit was desired for testing, but labeled acetoacetate (l,2,3,4-13C-acetoacetate (14), which could undergo decarboxylation to provide an intact 3-carbon unit) was found to give the same incorporation pattern as acetate (and therefore must have been cleaved to acetate prior to uptake). In addition, feeding studies using deuterated, 13C-labeled acetate provided a loss or washout of deuterium at the C16 methyl group. This could only occur if an intermediate had formed that would provide for facile enolization. Both the equal distribution of the 13C labels and loss of the deuteriums led the researchers to propose that the intermediate was symmetric, such as acetone dicarboxylic acid (15). 

A-Unsubstituted isoxazolidines such as 65 undergo facile decarboxylative peptide couplings with a-keto acids <06JA1452>. The use of water as solvent or cosolvent was particularly beneficial for the formation of amides in high yields. The methyl a-keto esters obtained could be saponified to the corresponding a-keto acids, and the (i-peptide chain could then be extended by reaction with another isoxazolidine. 

A facile synthesis of 5-substituted 3-aminopyrrole-2-carboxylates has been developed wherein condensation of diethyl aminomalonate with a-cyano ketones 46 was facilitated by prior formation of the p-toluenesulfonyl enol ether 47 <00JOC2603>. Addition of the amine component is followed by cyclization and decarboxylation to afford the pyrroles 48. 

Several total syntheses of antirhine (11) and 18,19-dihydroantirhine (14) have been developed during the last decade. Wenkert et al. (136) employed a facile route to ( )-18,19-dihydroantirhine, using lactone 196 as a key building block. Base-catalyzed condensation of methyl 4-methylnicotinate (193) with methyl oxalate, followed by hydrolysis, oxidative decarboxylation with alkaline hydrogen peroxide, and final esterification, resulted in methyl 4-(methoxycar-bonylmethyl)nicotinate (194). Condensation of 194 with acetaldehyde and subsequent reduction afforded nicotinic ester derivative 195, which was reduced with lithium aluminum hydride, and the diol product obtained was oxidized with manganese dioxide to yield the desired lactone 196. Alkylation of 196 with tryptophyl bromide (197) resulted in a pyridinium salt whose catalytic reduction... 

The tert-butyl esters of 2-pyrrolylaminomethylenemalonates (1438, R2 = COO/Bu) were selectively hydrolyzed with methanesulfonic acid or concentrated sulfuric acid at 0°C or at ambient temperature to afford the corresponding carboxylic acids (1438, R2 = COOH) in 26-98% yields. The carboxylic acid (1438, R = Me, R1 = H, R2 = COOH) underwent facile decarboxylation upon heating at 190-200°C to give 2-pyrrolylamino-methylenemalonate (1438, R = Me, R1 = R2 = H) in 73% yield (85JHC1429). 

Relatively acidic carbon acids such as malonic esters and jS-keto esters were the first class of carbanions for which reliable conditions for alkylation were developed. The reason being that these carbanions are formed using easily accessible alkoxide ions. The preparation of 2-substiuted /i-kcto esters (entries 1, 4, and 8) and 2-substituted derivatives of malonic ester (entries 2 and 7) by the methods illustrated in Scheme 1.5 are useful for the synthesis of ketones and carboxylic acids, since both /1-ketoacids and malonic acids undergo facile decarboxylation ... 

Simple considerations such as these account adequately for many of the familiar reactions of substituted 7r-deficient heterocycles, such as nucleophilic displacement, tautomerism in hydroxy, mercapto and amino heterocycles, facile deprotonation of alkyl substituents, decarboxylation of carboxymethyl groups and electrophilic substitution of benzo-fused and aryl-substituted heterocycles. These individual effects are discussed separately in the following subsections. 

Side-chain carboxylic acids containing a carboxymethyl group a or y to the ring nitrogen are susceptible to facile decarboxylation (Scheme 75). The process is analogous to that with /3-keto acids and it is often very difficult to isolate the compounds (64CPB588). In consequence, it is usual to isolate them as esters or other suitable derivatives (see example in Scheme 55) (550SC(3)413). 

Although metal ions do not catalyze the decarboxylation of monocarboxylic acids in solution, a variety of metal ions catalyze the decarboxylation of oxaloacetic acid anion, leading to the formation of pyruvic acid (27). The metal ions involved were cupric, zinc, magnesium, aluminum, ferric, ferrous, manganous, and cadmium, approximately 10-2 to 10-3 M (27). Of these, the aluminum, ferric, ferrous, and cupric ions were the most efficient sodium, potassium, and silver ions were inactive. This process involves the decarboxylation of a / -keto acid, which undergoes a relatively facile uncatalyzed decarboxylation. However, not every decarboxylation of a / -keto acid is catalyzed by metal ions—only those... 

Pyridines with an a- or y-carboxymethyl group (e.g. 685) undergo facile decarboxylation by a zwitterion mechanism (685 — 688) somewhat similar to that for the decarboxylation of 3-keto acids (cf. Section 3.2.3.1.1). Carboxymethylpyridines often decarboxylate spontaneously on formation thus, hydrolysis of (689) gives (690). The corresponding 2- and 4-pyridone and 2- and 4-pyrone acids are somewhat more stable, e.g. (691) decarboxylates at 170°C. 3-Pyridineacetic acid shows no pronounced tendency to decarboxylate. 

IJC4). It has been suggested that protonation at C-3 with formation of (388) may be responsible for such facile decarboxylation (Scheme 125). The acid (389) also undergoes base-catalyzed decarboxylation the imine tautomer (390) may be an intermediate in this process (Scheme 125). 

The properties of the carboxylic acids are quite predictable. Esterification is a facile process, and the compounds are decarboxylated on heating. The 1,3,5-triazine ring is readily ruptured on treatment with warm water (equation 11) (59HC(l3)i, p.169). The corresponding esters are hydrolyzed to the acid by cold alkali solution, but the ring is cleaved if the ester is heated with base. 

The electron sink allows facile decarboxylation (equation 2.48). The decar-boxylated adduct will add a proton to the amino acid carbonyl carbon and... 

The cadmium secocorrinoid carboxylic acid (102 M = Cd) also undergoes photocyclization to the acid (103 M = Cd), which on transmetallation to the nickel(II) complex (103 M = Ni) and treatment with triethylamine and acetic acid yields the parent corrin complex (100 M = Ni).268 The decarboxylation process is extremely facile. A related base-catalyzed cyclization of the secocorrinoid aldehyde (104) gives the corrin complex (105), which can be decarbonylated to the parent complex (100 M = Ni) by treatment with potassium hydroxide (Scheme 66).268... 

Indirect methods, which are primarily essentially of academic interest, nevertheless may find use under special circumstances. One of these, involving the brominative decarboxylation (Borodin-Huns-diecker reaction) of silver a-fluorocyclopropanecarboxylate, provides a convenient and stereospecific route to the synthesis of fluorobromocyclopropyl compounds (equation 26).96 Another approach makes use of the Diels-Alder reaction between tetrachlorocyclopropene and dienes (equation 27).97,98 The adducts can undergo facile dehydrohalogenation or ring opening. 

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