Reductions methyl acetoacetate

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The batch containing 1% starting material was resubjected to the dehydrogenation reaction using a reduced charge of DDQ and the batch was saved. This story has been told many times and has become legend in Merck Process Research. There are clearly some important lessons here that every process chemist should learn-and best not the hard way. We later showed that methyl acetoacetate could be used as a quench, eliminating the potential for reduction. 

Fig (22) 2-isopropylphenol (183) is converted to allylic alcohol (185). Its bromide derivative reacts with methyl acetoacetate. The resulting compound undergoes radical cyclization yields ketoester (186) whose vinyl triflate on reduction and carbonylation furnishes lactone (187). Diol (188) obtained from (187), is converted to monoepoxide (189) which on further epoxidation produces triptonide (148). Its conversion to triptolide (149) is accomplished by reduction. 

If chelation to a neigbouring group is possible, the use of HMPA is often not required for reduction of the carbonyl and reactions can be carried out under mild conditions. To examine the impact of chelation, Flowers studied the rate of reduction of 2-butanone, methyl acetoacetate and /V,/V-dimethylacetoace-tamide by Sml2.20 Reduction of the (1-keto ester or amide was several orders of magnitude faster than that of the unsubstituted ketone, which is consistent with chelation playing a major role. Further rate and mechanistic studies on the reduction of acetophenone and a series of 2 - and 4 -substituted acetophenone derivatives showed that both chelation and coordination provide highly... 

Keto esters, such as methyl acetoacetate and methyl benzoylacetate, have been converted to carbethoxyketenes by nitrosation, reduction, diazotization, and finally decomposition of the intermediate diazoketo... 

Reductive cyclization has been used in a novel, recent synthesis of the alkaloids ( )-isoretronecanol (22) and ( )-trachelanthamidine (23) by Borch and Ho. Condensation of the dianion derived from methyl acetoacetate with Z-l,4-dichlorobut-2-ene, followed by cyclization with sodium meth-oxide yielded the cycloheptenone ester intermediate (32) (Scheme 2). Reductive amination of this ketoester with sodium cyanoborohydride and ammonium nitrate gave a mixture of the diastereoisomeric aminoesters 33 and 34. Oxidation with osmium tetroxide and periodate, followed by reductive cyclization, again using sodium cyanoborohydride, gave the two pyrrolizidine esters 35 and 36 in a ratio of 1 2 [gas-liquid chromatography (GLC) analysis]. The esters were separated by preparative layer chromatography, and lithium aluminum hydride reduction of the individual esters gave the two pyrrolizidine alkaloids 22 and 23. 

We referred above to a synthesis of bryostatin that contained a reduction controlled by a 1,3-relationship. Evans synthesis34 contains a 1,3-selective aldol as well as a 1,3-controlled reduction The aldehyde 202, made by an asymmetric aldol reaction, was combined with the double silyl enol ether of methyl acetoacetate to give, as expected, the anti-aldol 203. However, the only Lewis acid that gave this good result was (<-PrO)2TiCl2 and not BF3 thus emphasising the rather empirical aspect of this type of control. Evans s own 1,3-controlled reduction gave the anti,anti-triol 204 that was incorporated into bryostatin. 

Figure 7.3. (a) Conformation of P-BINAP in two crystal structures [74,81]. (b) Ik Topicity transition structure for asymmetric reduction of methyl acetoacetate. (c) ul Topicity transition structure. (After ref. [76]). Inset definition of Re and Si faces of ketone. 

Table 4.9. The influence of the catalysts preparation method, the nature of the support, the reduction temperature (Td and the added palladium on enantioselectivity in the hydrogenation of methyl acetoacetate (MAA) to (i )-(-)methyl hydroxybutyrate (according to Nitta et al. ).

A cathode containing a Raney-Ni-Tartaric acid catalyst coated with CdS particles proved to be rather effective. Irradiation of this electrode by a xenon-lamp during reduction of methyl acetoacetate in EtOH solution leads to methyl 3-hydroxybutyrate with an ee of 67%... 

According to Kambe et al., the mechanism of reaction consists not in the reduction of methyl acetoacetate by photochemically produced hydrogen, but in the electrochemical reduction of the C=0 bond and proton by photogenerated electrons. Thus, the hydrogen production sites on the surface of Raney Ni are different from methyl 3-hydroxybutyrate production sites. 

Fujihira, M., Yokozawa, A., Kinoshita, N. and Osa, T. (1982) Asymmetric synthesis by modified Raney Ni powder electrode, Chem. Lett. 1089-1092. (see also Osa T., and Matsue T. (1985) Asymmetric reduction of methyl acetoacetate on powder electrode modified Ni, Denld Kagaku. Kaguo Butsuri Kagaku. 53, 104-108, CAe/w. Abstr. 1985,103, 13491L Izumi, Y. and Tai, A. (1977) Stereo-differentiating reactions, Kodansha, Academic Press, N.Y. 

Reduction Remove the stopper in the Erlenmeyer flask, and add 2.5 ml of methyl acetoacetate. Replace the stopper and continue to stir the contents of the flask vigorously, under anaerobic conditions, and in a warm place, ideally at 30-35 °C, for at least 48 h, although one week is better." ... 

The keto group of methyl acetoacetate may also be reduced selectively with sodium borohydride. Describe how the product of this reaction would differ from the product of the enzymatic reduction of methyl acetoacetate with baker s yeast. 

What is the purpose of using sucrose in the baker s yeast reduction of methyl acetoacetate ... 

What gas is evolved dming the reduction of methyl acetoacetate with baker s yeast ... 

Discuss the differences observed in the IR and NMR spectra of methyl acetoacetate and methyl (S)-(+)-3-hydroxybutanoate that are consistent with the reduction of the carbonyl group in this experiment. 

In this experiment, you will use the chiral europium shift reagent 17 to determine the enantiomeric excess of the product that you obtained upon enantioselec-tive reduction of methyl acetoacetate with baker s yeast. 

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