Fumaric monoester

Toward this goal, a furane ring was included in the carbonyl or amine component, since this moiety will furnish a highly reactive diene for the following IMDA. In most cases 2-furaldehyde (or the corresponding 5-methyl derivative) was employed. The acid component was chosen in order to introduce an activated dienophile suited for the IMDA and was in turn a fumaric acid monocarboxyamide [82, 84], a maleic or fumaric acid monoester [84] or a 3-substituted propynoic acid [83]. Benzylamine (or a para-substituted derivative) [81-83] or t-butylamine [83] have been chosen as amine component for the Ugi reactions. 

The first example of a tandem Ugi-4CR/intramolecular Diels-Alder reaction was reported by Paulvannan at Affimax [95], who obtained precursors for intramolecular Diels-Alder cycloadditions by an Ugi-4CR between furan-2-carboxaldehydes, monoamides or monoesters of fumaric or maleic acids, benzylamine, and benzyl isocyanide. The Ugi-4CR adducts 172 were never isolated since they underwent... 

Furans in general can be attacked by nucleophiles, if they are substituted with electron-withdrawing groups (exceptions are the metalation reactions with butyl lithium, etc.). It is possible to cleave 2-nitrofuran with sodium methoxide in methanol, and the reaction yields fumaric acid monoester and methyl-imws-3-formylacrylate304 ... 

Ethoxy-4-methyloxaole has been used to form pyridoxine (MI-286, R = H). With maleic anhydride it gives an adduct that, on treatment with ethanolic hydrogen chloride, forms the products W-287 and XII-288 (R = R - Et) and a monoester (XII-288 R = Et, R = H or R = H, R = Et). The diethyl ester MI-288 is also formed from ethyl maleate or ethyl fumarate and 5-ethoxy-4-methyloxazole. Fumaronitrile and ethoxy-4inethyloxazol ve 4,5-dicyano-2-methyl-3-pyridinol, ° also a known precursor to pyridoxine. 5-Ethoxy 4-irethyloxaolesand 2-butene-1,4-diol give pyridoxine (XII-286, R = H), which is difficult to purify when prepared in this way (assay, 23%). 

The acid (pKi =4.19 pK2 = 5.63) is appfied as a plasticizer in dough making. Succinic acid monoesters with glycerol are used as emulsifiers in the baking industry. The acid is synthesized by catalytic hydrogenation of fumaric or maleic acids. 

The diol 4 had never been described in the literature before we used it in the synthesis of 1. Initially, we tried to synthesize it using an enantioselective Diels-Alder reaction between a chiral fumarate equivalent 5 (Scheme 10.1) and butadiene 6, followed by double-bond dihydroxylation [41]. However, a more effective protocol for large-scale synthesis could finally be based on the procedure shown in Scheme 10.2, leading to enantiomericaUy pure (lS,2S)-cyclohex-4-ene-1,2-dicarboxylic acid 7 [42]. Here, a Bolm desymmetrization of tetrahydrophthahc anhydride 8 using quinine leads to monoester 9 in 89% ee. The monoester 9, in turn, can be epimerized to the trans isomer 10 which is hydrolyzed to obtain 7, after crystallization. This intermediate is the starting material for the synthesis of 4 and of other conformationally constrained DCCHD to be used as monosaccharide mimics [43, 44]. Our current best protocol for the large-scale synthesis of 7 is reported at the end of this chapter. 

A similar behavior is observed from competitive dissociations of protonated monoamides of maleic and fumaric acids which lead to the formation of [MH H2O] and [MH NH3] +, respectively. They are accompanied by the presence of NH, although the loss of water corresponds to the base peak from the Z stereochemistry but is of lower abundance from the E isomer. From fumarate monomethyl ester or monoamide, the major pathway for protonated molecule dissociation corresponds to the loss of XH as methanol or ammonia, respectively, which suggests that the modified carboxylic group is the preferred protonation site (Scheme 17.8). Consequently, the favorable loss of water from the Z isomers (not only for maleic acid, but also for the monoester and monoamide derivatives) indicates that the water loss rate constant, via 1,6-H" transfer, is much larger than that occurring from the E isomer which involves either 1,3-H" transfer (a symmetry forbidden process) or a multistep proton migration which is characterized by higher transition state level(s) (Scheme 17.8). 

The most common examples of this class are diesters of 2-ethylhexanol. However, there are commercial products which are monoesters, diesters, or mixtures of the two. The alcohol portion of the ester may be fatty alcohol, fatty acid alkanolamide, or ethoxylated fatty amine. They are typically synthesized by forming the ester or amide with maleic anhydride, followed by reaction of the alkyl fumarate with sodium bisulfite. The monoesters are often used in cosmetics and shampoos. 

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