Alkenes substituted carboxylic acids

The addition of Grignard reagents to 1,1-doubly activated alkenes, e.g. alkylidenemalonates (105),68 84a d alkylidenecyanoacetates (106),84e-f alkylideneisocyanatoacetates (107),alkylidenephos-phonoacetates (108),848 isopropylidenemethylenemalonates (109)84iaddition mode exclusively (Schemes 34 and 35). Similarly, as shown in Scheme 36, Mukaiyama reports that the addition of Grignard reagents to chiral oxazepines (110) and (111) affords an enantiose-lective synthesis of -substituted carboxylic acids.85... 

Oxidative carbonylation of alkenes is a unique reaction of Pd(II). Three types of oxidative carbonylation to give -substituted acid derivatives 130, a, -unsaturated esters 132 and succinate derivatives 134 are known, which can be understood by the following mechanism. Palladation of alkenes with PdX2, followed by CO insertion, generates the acylpalladium intermediate 129 whose reductive elimination affords -substituted carboxylic acid derivatives 130 (path a). Reaction in alcohol in the presence of a base starts by the formation of the alkoxycarbonylpalladium 128. Carbopalladation of alkene with 128 generates 131. Then y3-H elimination of the intermediate 131 yields the a-unsaturated ester 132 (path b). Further CO insertion to 131 gives the acylpalladium intermediate 133 and its alcoholysis yields the succinate derivative 134 (path c). Formation of the jS-alkoxy ester 130 (X-OR) is regarded as nucleophilic substitution of Pd-X in 131 with alcohols. 

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

The ruthenium carbene catalysts 1 developed by Grubbs are distinguished by an exceptional tolerance towards polar functional groups [3]. Although generalizations are difficult and further experimental data are necessary in order to obtain a fully comprehensive picture, some trends may be deduced from the literature reports. Thus, many examples indicate that ethers, silyl ethers, acetals, esters, amides, carbamates, sulfonamides, silanes and various heterocyclic entities do not disturb. Moreover, ketones and even aldehyde functions are compatible, in contrast to reactions catalyzed by the molybdenum alkylidene complex 24 which is known to react with these groups under certain conditions [26]. Even unprotected alcohols and free carboxylic acids seem to be tolerated by 1. It should also be emphasized that the sensitivity of 1 toward the substitution pattern of alkenes outlined above usually leaves pre-existing di-, tri- and tetrasubstituted double bonds in the substrates unaffected. A nice example that illustrates many of these features is the clean dimerization of FK-506 45 to compound 46 reported by Schreiber et al. (Scheme 12) [27]. 

Table 11.5. Substituted cyclopropanols 31 from carboxylic acid esters and alkenes via ligand-exchanged titanium intermediates generated from Grignard reagents and XTi(OiPr)3 (X = OiPr, Cl, Me).

The supported Co2+-substituted Wells-Dawson POM, Cs6H2[P2W17061Co(OH2)], on silica was stable up to 773 K and catalyzed the heterogeneous oxidation of various aldehydes to the corresponding carboxylic acids with 02 as a sole oxidant [116], The H5PV2Mo10O40 POM, impregnated onto meso-porous MCM-41, catalyzed the aerobic oxidation of alkanes and alkenes using isobutyraldehyde as a... 

Oxidation is the first step for producing molecules with a very wide range of functional groups because oxygenated compounds are precursors to many other products. For example, alcohols may be converted to ethers, esters, alkenes, and, via nucleophilic substitution, to halogenated or amine products. Ketones and aldehydes may be used in condensation reactions to form new C-C double bonds, epoxides may be ring opened to form diols and polymers, and, finally, carboxylic acids are routinely converted to esters, amides, acid chlorides and acid anhydrides. Oxidation reactions are some of the largest scale industrial processes in synthetic chemistry, and the production of alcohols, ketones, aldehydes, epoxides and carboxylic acids is performed on a mammoth scale. For example, world production of ethylene oxide is estimated at 58 million tonnes, 2 million tonnes of adipic acid are made, mainly as a precursor in the synthesis of nylons, and 8 million tonnes of terephthalic acid are produced each year, mainly for the production of polyethylene terephthalate) [1]. 

Alcohols can react in several ways, depending on the reactants and on the conditions of the reaction. For example, alcohols can undergo substitution with halogen acids, elimination to form alkenes, and oxidation to form aldehydes, ketones, or carboxylic acids. 

D (and by implication E and F) is para substituted. In addition, both branches must be identical, which means each has one degree of unsaturation (two alkenes and not one alkyne). The branches are -CH=CH2. Hydrogenation converts the branches to -CH2-CH3. Heating with chromic acid eliminates the carbon atom furthest from the ring and converts the remaining carbon atoms to carboxylic acid groups (-CO2H). 

Oxidation of a number of substituted ethenylcyclopropanes to propanecarboxy-lic acids was achieved with RuCyaq. Na(10 )/CCl -CH3CN (Eig. 3.19) [342], while perfluoro alkenes were cleaved by RnO /aq. IO(OH)3, Na(ClO) or CH3COOOH/Ereon 113 to carboxylic acids [343] anthocyanidins, flavones, chal-... 

Problem 16.7 Account for the fact that on oxidative cleavage all substituted alkynes give carboxylic acids, whereas some alkenes give ketones. ... 

Oxidation of Other Arenes. Aromatic compounds with longer alkyl side chains can be converted to ketones or carboxylic acids. All the previously discussed reagents except Cr02Cl2 usually afford the selective formation of ketones from alkyl-substituted arenes. Oxidation with Cr02Cl2 usually gives a mixture of products. These include compounds oxidized in the P position presumably formed via an alkene intermediate or as a result of the rearrangement of an intermediate epoxide.110,705... 

The dibromobutene 149 could be monosubstituted using 2-lithio-l,3-dithiane as a carboxylic acid precursor, followed by substitution of the remaining bromide with sodium azide as the amine precursor (Scheme 32). The azide was reduce under Staudinger conditions and acy-lated. After separation of the EIZ isomers, further functional group transformations gave the dimethyl-substituted Gly-Gly alkene isostere 152J123 ... 

---