Halo esters, reduction

Stereoselective radical reduction or allylation.2 Radical reduction of (1-alkoxy-a-halo esters such as 1 shows marked onri-stereoselectivity with Bu3SnH (AIBN) at 50°, which is markedly improved when conducted under photochemical irradiation at —78°. Similar but even higher stereoselectivity obtains in reduction of the tetrahy-drofuran derivative 2. 

Allylation of these P-alkoxy-a-halo esters with allyltributyltin initiated with AIBN at 60° also shows good to impressive stereoselectivity, which can be improved by use of triethylborane as initiator at —78°. However, these reactions are generally slower than radical reductions. 

As esters are not typically reduced by Sml2, Molander proposed an alternative mechanism for the reduction of a-halo esters.29 He proposed that... 

In addition to the foregoing 1,4-difunctional compounds used for cyclizations, the following have been used to give pyridazines or theirreduced analogs , 4-hydroxy ketones, l,4-haloketones, l,4-dibromobutane, 2,5-dibromohexane, 1,4-halo-esters, or butadiene dioxide. Hexahydropyridazine results as one of the oxidation products of 1,4-diaminobutane and its 1-butyl analog is formed in the reduction of iV-nitroso-4-chloro-dibutylamine. ... 

A number of low-valent metal ions have been shown to reduce a-halocarbonyl compounds. The most commonly used species for this purpose have been chromium(II) and low-valent titanium " salts, although vanadium(II), samarium(II), iron(II) and tin(II) salts have also been used. 7 222 chloro, bromo and iodo ketones can all be reduced by chromium(II) and titanium(III) salts. Selective reductions are possible axial halides are reduced in preference to equatorial, and a,a-dihalo ketones can be selectively reduced to the corresponding monohalides (equation 10). 7 The use of samarium(II) iodide has recently been advocated for such a-cleavages.72 a-Halo esters and ketones are reduced instantaneously at -78 °C in excellent yields. a-Acetoxy esters are stable to this reagent. 

Another related method uses the anion of nitroalkanes in a reaction with halo-esters. Nitromethane reacted with lithium diisopropylamide to form the nitro enolate and then with methyl 3-chloropentanoatc to give 4.110. Reduction of the nitro group with ammonium formate gave methyl 2-phenyl-3-aminopropanoate, 4.111. 

In yeast, the reduction of P-ketoesters is carried out by dehydrogenase complexes that can individually afford either the (l)- or the (d)configuration (36e). Therefore inhibition of the (L)cnzyme will provide (D)-products and vice versa. Nakamura et al. [52] reported that addition of allyl alcohol or a,P-unsaturated carbonyls resulted in the formation of (D)-hydroxyesters 137, thereby inhibiting the (L)-enzyme. To shift the product formation toward the t-side 138 a-halo esters can be used. Thus, the best results were obtained with a-chloroacetates. In this way, the additive serves as a switch between the formation of the enantiomeric P-hydroxy esters 137 and 138. 

Metzer et al. reported an enantioselective radical reduction of a-halo carboxylic acid with chiral alkyl-substituted binaphthyltin compounds namely, optically active a,a-disubstituted esters were obtained from the corresponding a-halo esters by the treatments with stoichiometric amounts of chiral Sn(IV) hydride and chiral Sn(IV) bromide as an additive (Scheme 10.45) [70]. 

Guindon Y, LavaUee JP, Boisvert L, et al. Stereoselective radical-mediated reduction and alkylation of a-halo esters. Tetrahedron Lett. 1991 32 27-30. 

A large variety of methods is applicable to the formation of isolated double bonds. This permits selection of reagents compatible with other functionality present. Alcohol dehydration, ester elimination and other nonreductive p eliminations are the most common methods. Reductive elimination of halo-hydrins, vic-dihalides, etc., and of a variety of ketone derivatives has also been used. 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

Selective reduction of the ester function in products (37), step (2), affords nitro alcohols (38), which are either transformed into halo-containing compounds... 

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