Reduction of Unsaturated Esters

The reduction of unsaturated esters encompasses the reduction of esters containing double and triple bonds, usually in positions, and/or aromatic rings. Such esters may be converted to less saturated or completely saturated esters, to unsaturated or less unsaturated alcohols or to saturated alcohols. Presence of aromatic rings in conjugation with the multiple bonds facilitates saturation of the bonds. Aromatic rings are hydrogenated only after the saturation of the double bonds. 

Hydrogenation over nickel catalyst at high temperatures and pressures affects aromatic rings. Over Urushibara nickel at 106-150° and 54atm, ethyl benzoate gave ethyl hexahydrobenzoate in 82% yield [48]. 

Methyl cinnamate was reduced quantitatively to methyl 3-phenylpropa-noate by hydrogen over colloidal palladium at room temperature and atmospheric pressure [7057] ethyl cinnamate was reduced to ethyl 3-phenyIpropa-noate over tris(triphenylphosphine)rhodium chloride in ethanol at 40-60° and 4-7 atm in 93% yield [55], and over copper chromite at 150° and 175 atm in 97% yield [420]. On the other hand, hydrogenation of ethyl cinnamate over 

Raney nickel at 250° and 100-200atm afforded 88% yield of ethyl 3-cyclo-hexylpropanoate [1068], and hydrogenation of the same compound over copper chromite at 250° and 220atm gave 83% yield of 3-phenylpropanol [7057] (p. 158). 

Conjugated double bonds were also reduced in methyl 3-methyl-2-buten-oate with tributylstamane on irradiation with ultraviolet light at 70° (yield of methyl isovalerate was 90%) [1071], and in diethyl maleate and diethyl fu-marate which afforded diethyl succinate in respective yields of 95% and 88% on treatment with chromous sulfate in dimethylformamide at room temperature [974,1072]. 

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Complete reduction of unsaturated esters to sativated alcohols takes place when the esters are hydrogenated over Raney nickel at 50° and 150-200 atm [44] or over copper chromite at temperatures of 250-300° and pressures of 300-3 50 atm [52,1056] (p. 153). In contrast to most examples in the literature the reduction of ethyl oleate was achieved at atmospheric pressure and 270-280° over copper chromite, giving 80-90% yield of octadecanol [1074]. a.,P-Unsaturated lactones are reduced to saturated ethers or alcohols, depending... 

The reduction of unsaturated esters has, until recently, proved rather more difficult to reduce in high yield and selectivity, possibly due in part to their inferior donor properties... 

A comparison of the Et3N/H20 method and HMPA/alcohol method in reduction of ketones indicates Et3N/H20 is approximately 100 times faster. This methodology has also been applied in the reduction of -unsaturated esters, imines and conjugated olefins with excellent... 

Enzyme-catalyzed hydrogenations have a long history as an alternative for stereoselective olefin reduction [12, 72). Selected illustrative examples of enzymatic olefin reductions are depicted below. In an elegant series of studies by scientists at Hoffmann-La Roche, it was found that baker s yeast effects the reduction of unsaturated ester 96 (Scheme 8.10) [73]. Unsaturated alcohol 99 was selectively transformed into lactone 100 by use of the fungus Geotrichum candidum. The optically pure substituted lactones, 98 and 100, were subsequently utilized in a synthesis of a-tocopherol (vitamin E 101) [74]. 

Reduction of iodates by ene-diols. . 100 Reduction of unsaturated acetates. 153 Replacement of a sulfonate ester... 

Conjugate reductions and conjugate alkylations of unsaturated esters are found in Section 74 (Alkyls from Alkenes). 

Semmelhack et al. chose CuBr, together with either Red-Al or LiAl(OMe)3H in a 1 2 ratio, to afford presumed hydrido cuprates, albeit of unknown composition [llj. In THF, both the former Na complex and the latter Li complex are heterogeneous (and of differing reactivities), yet each is capable of 1,4-reductions of unsaturated ketones and methyl esters (Eq. 5.4). Commins has used a modified version, prepared from lithium tri-t-butoxy-aluminium hydride and CuBr (in a 3 4.4 ratio), to reduce a 3-substituted-N-acylated pyridine regioselectively at the a-site [12]. 

Selective 1,4-reduction of unsaturated aldehydes and ketones by 6 occurs smoothly in THF between —25 °C and room temperature within a few hours (Eq. 5.7). Particularly noteworthy is the realization that phosphines are noticeably absent from the reaction medium. The analogous combination of CuCl/BusSnH in N-methyl-2-pyrrolidinone (NMP) or DMF does not behave identically [22], failing to react with the hindered substrate isophorone, whereas a 72% yield of the corresponding reduced ketone is formed with reagents XCu(H)Li/Bu3SnH. Nonetheless, a form of CuH is being generated in this more polar medium, effectively utilized by Tanaka to arrive at 3-norcephalosporin 8 upon reaction with allenic ester 7 (Scheme 5.3). 

Catalysts suitable specifically for reduction of carbon-oxygen bonds are based on oxides of copper, zinc and chromium Adkins catalysts). The so-called copper chromite (which is not necessarily a stoichiometric compound) is prepared by thermal decomposition of ammonium chromate and copper nitrate [50]. Its activity and stability is improved if barium nitrate is added before the thermal decomposition [57]. Similarly prepared zinc chromite is suitable for reductions of unsaturated acids and esters to unsaturated alcohols [52]. These catalysts are used specifically for reduction of carbonyl- and carboxyl-containing compounds to alcohols. Aldehydes and ketones are reduced at 150-200° and 100-150 atm, whereas esters and acids require temperatures up to 300° and pressures up to 350 atm. Because such conditions require special equipment and because all reductions achievable with copper chromite catalysts can be accomplished by hydrides and complex hydrides the use of Adkins catalyst in the laboratory is very limited. 

Reduction of y-amino-a, -unsaturated esters These substrates when com-plexed with BF3 etherate can be reduced selectively to y-amino esters with only slight reduction of the ester group (equation I). 

Different solid-phase techniques for the synthesis of C-terminal peptide aldehydes have gained much attention and allowed greater accessibility to such compounds. Solid-phase techniques have been used to synthesize peptide aldehydes from semicarbazones, Weinreb amides, phenyl esters, acetals, and a, 3-unsaturated y-amino acids)47-50,60 63 The examples presented below use unique linkers to enhance the automated efficiency of C-terminal peptide aldehyde synthesis)47 For instance, the reduction of phenyl esters led to the aldehyde as the major product, but also a small amount of alcohol)50 The cleavage of u,p-unsaturated y-amino acids via ozonolysis yielded enantiomeric pure C-terminal peptides)49,61 The semicarbazone from reduction of peptide esters technique laid the initial foundation for solid-phase synthesis. Overall, Weinreb reduction is an ideal choice due to its high yields, optical purity, and its adaptability to a solid-phase platform)47 ... 

The mildness of the procedure provides the selective reduction of unsaturated carbonyl groups in the presence of almost any other functional groups such as ester, amide, carboxylic acid, nitro, halogen, nitrile, etc. It is evident that this reagent is far superior in purity and yield of products as compared to the conventional reagents, without any observable 1,4-reduction. 

In contrast, reduction of enamino esters of cyclohexanone resulted in the formation of a series of fragmentation products, among which the a,/ -unsaturated aldehyde is of interest160. The ratio of the products depended on the amount of the reducing agent (Scheme 112). 

Mulzer (Scheme 8 upper left) obtained the a,/(-unsaturated ester 33 with Z configuration from aldehyde 26a via a Still-Gennari olefination with phosphonate ester 34. Reduction of the ester with DIBAH and application of L-imidazole-PPhj gives allylic iodide 35. This acts as electrophile on the -anion of sulfone 36. After reductive removal of the phenylsulfone, group 28b is obtained [23]. 

Substituted malonic acids are obtained by alkaline hydrolysis of alkyl-cyano esters prepared either by direct alkylation or by reduction of unsaturated cyano esters from the Knoevenagel reaction. ... 

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