Reduction of diethyl fumarate

Chromium (II) sulfate is capable of reducing a variety of functional groups under mild conditions 10). Of particular interest is its ability to reduce a,jS-unsaturated esters, acids, and nitriles to the corresponding saturated compounds. This capability is illustrated in the procedure by the reduction of diethyl fumarate. 

Chromium(II) sulfate is a versatile reagent for the mild reduction of a variety of bonds. Thus aqueous dimethylformamide solutions of this reagent at room temperature couple benzylic halides, reduce aliphatic monohalides to alkanes, convert vicinal dihalides to olefins, convert geminal halides to carben-oids, reduce acetylenes to /raw5-olefins, and reduce a,j3-unsatu-rated esters, acids, and nitriles to the corresponding saturated derivatives. These conditions also reduce aldehydes to alcohols. The reduction of diethyl fumarate described in this preparation illustrates the mildness of the reaction conditions for the reduction of acetylenes and o ,j8-unsaturated esters, acids, and nitriles. 

The reduction of diethyl fumarate to diethyl succinate has also been effected with diethyl l,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate and by catalytic hydrogenation. 

The present synthesis is an adaptation of a previously reported synthesis4 in a divided cell (i.e., separate anode and cathode compartments). The overriding consideration in making this modification has been to simplify the operations involved and render the synthesis more attractive to chemists not well acquainted with electrochemical procedures. The main simplification achieved is that the pH is controlled internally via the anodic generation of protons as noted above (in the reported procedure4 this is achieved by periodic addition of acetic acid to the cathode compartment). A further simplification has been to run the reaction with a constant current rather than at controlled cathode potential. After the electrolysis has been initiated, the reaction requires no special attention. A small price is paid for the simplicity of the present synthesis in that the yield is somewhat lower than that obtained previously.4 The major by-product formed is diethyl succinate, which results from a 2e reduction of diethyl fumarate or diethyl maleate ... 

Reduction of diethyl fumarate, 52a, and the simple enone 22a (1 10) in MeCN/water (Et4NOTs) at a potential between the two reduction potentials /S.E % 0.2 V) gave the MHC as the major product [104]. Reduction of dibutyl maleate, 53c, and 2-vinylpyridine, 6a (1 5), in DMF/water (Et4NOTs) at a potential where only the maleate is reduced /S.E % 0.15 V), leads to a mixture of the two LHDs and the MHC. Analogous results were found for coelectrolysis of 4-vinylpyridine, 6b, with an excess of the simple enone, 22a (AE 0.1 F) [33]. The distribution between the different hydrodimers was reported. 

Preparation (2. 77). The procedure cited for the preparation and the use for reduction of diethyl fumarate has now been published.1... 

A reaction in which the oxidized or reduced form of a compound isomerizes via a first-order process on the voltammetric time-scale is common for a wide range of organometallic and organic compounds (for example Bard etal., 1973 Bond et al., 1986,1988,1992). An example from the field of organic chemistry involves the reduction of diethyl maleate to its radical anion which then isomerizes to the diethyl fumarate anion, again an overall EC mechanism (Bard et al., 1973). There is a wide range of examples of other EC mechanisms such as the reduction of the antibiotic chloramphenicol in which a nitro unit (-NO2) is reduced to a hydroxylamine (-NHOH) (E step) which rapidly converts into a nitroso (-NO) species (C step) (Kissinger and Heineman, 1983). 

Diethyl succinate is the sole product of the reduction. I hc yield reflects the efficiency of the workup. The distilled )ro(luct gives a single sharp peak on gas chromatography employing a column packed with Carbowax 20M suspended on Chromo-sorl) P. On this column the checkers found the retention times of diethyl fumarate and diethyl succinate to be 38.8 minutes and 43.f) minutes, respectively. 

One of the few mechanistic studies of mixed coupling reactions involves the reduction of dimethyl fumarate, or diethyl maleate, in the presence of the less easily reduced compounds 7 or cinnamon trile, [151]. In anhydrous DMF (BU4NI), the individual rate constants for dimerization of 52b and of 9 are known (110 and 880 M s respectively, (Tables 11 and 3) that is, 9 dimerizes faster than 52b by a factor of 8, and A 1/, = 0.41 V. With a twofold excess of 9 RRDE experiments at potentials where only 52b is reduced indicated that the normal RR homocoupling of 52b took place with a second-order rate constant identical to that measured in the absence of 9. RRDE experiments at a potential where both substrates are reduced revealed that electron transfer from 9 to unreduced 52b was the major reaction of [151]. No product studies were reported for... 

Figure 7.4 depicts the simulated voltammetric response for the reduction of diethyl maleate (DEM) at three different scan rates. It should be highlighted that in order to allow direct comparison of the voltammograms, the current has been normalised with respect to the square root of the scan rate. DEM consists of a double bond where the ester groups are situated cis to each other. The stereoisomer of DEM is diethyl fumarate (DEF) where the ester groups are situated trans to each other, as shown in Fig. 7.5. The reduction potential for DEF is known to be less negative than that of DEM.

The cathodic coupling of prenyl chloride with diethyl fumarate and methyl crotonate proceeds with different regios-electivities as shown in Fig. 17 [94]. Also in this case, the change in the regioselectivity appears to be due to the reduction of the diethyl fumarate to a radical anion that undergoes a nucleophilic substitution at the prenyl chloride, and in the other case there is a 2e reduction of the prenyl... 

It is likely that many reductive eliminations also proceed by radical pathways, but few studies have been reported. The reaction of [PtR Ls] (R = Me, CD3, or Et, and La = bipy or R = Me and L2 = phen or 1,5-cyclooctadienc) with diethyl fumarate or maleatc in the dark at room temperature in the presence of Bu NO led to the detection (ESR) of complex XX, which was interpreted in terms of the following sequence (91) ... 

As a model study of methyl cobalamine (methyl transfer) in living bodies, a methyl radical, generated by the reduction of the /s(dimethylglyoximato)(pyridine)Co3+ complex to its Co1+ complex, reacts on the sulfur atom of thiolester via SH2 to generate an acyl radical and methyl sulfide. The formed methyl radical can be trapped by TEMPO or activated olefins [8-13]. As a radical character of real vitamin B12, the addition of zinc to a mixture of alkyl bromide (5) and dimethyl fumarate in the presence of real vitamin B12 at room temperature provides a C-C bonded product (6), through the initial reduction of Co3+ to Co1+ by zinc, reaction of Co1+ with alkyl bromide to form R-Co bond, its homolytic bond cleavage to form an alkyl radical, and finally the addition of the alkyl radical to diethyl fumarate, as shown in eq. 11.4 [14]. 

The C—X reduction potentials of allylic halides and unsaturated a-haloesters are similar, and vary depending on their substitution pattern. The regioselectivity of the addition, therefore, is also influenced by the relative reduction potentials. l-Chloro-3-methyl-2-butene (41) reacts with diethyl fumarate (42) through attack from the primary carbon (equation 31), whereas with methyl crotonate (44) allylation takes place at the more highly substituted tertiary carbon (equation 32). 

Reaction of 0s02(NBu )2 with alkenes followed by reductive cleavage gives vicinal diamines (IV Scheme 9), and the intermediate ester (I) (see p. 557) was isolated using dimethyl or diethyl fumarate as the reacting alkene. Again, the preference for Os—N rather than Os—0 bond formation is noteworthy.290... 

Carbon tetrachloride undergoes stepwise reduction at mercury in DMF containing TEABr [45]. Several groups of workers [46-52] have electrogenerated the shortlived trichloromethyl anion, which can react with acrylonitrile, ethyl acrylate, diethyl fumarate, alkyl monohalides, and a variety of aldehydes and ketones. De Angelis and coworkers [53] have used dichlorocarbene, generated via reduction of carbon tetra-... 

Geissman and Waiss (i<3 )have effected the first stereospecific synthesis of retronecine (CXLIV in 1) by a series of reactions which is shown in Chart I. Ethyl A-carbethoxy-3-aminopropionate (LI) was added to diethyl fumarate and the product ring-closed to the pyrrolidone, LII, which on hydrolysis and reduction yielded the required 3-hydroxy-pyrrolidine-2-acetic acid lactone (LIII). Reaction of this lactone with ethyl bromoacetate gave the A-acetic ester, LIV which by ring closure... 

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