Multistep decarboxylation

The thermal decarboxylation of malonic acid derivatives is the last step m a multistep synthesis of carboxylic acids known as the malonic ester synthesis This synthetic method will be described m Section 21 7... 

Until recent years the only syntheses of 3-hydroxy quinoline involved multistep processes, the last step of which consisted of the conversion of 3-aminoquinoline to 3-hydroxyquinoline via the diazonium salt. " Small quantities of quinoline have been oxidized to 3-hydroxyquinoline in low yields by using oxygen in the presence of ascorbic acid, ethylenediaminetetraacetic acid, ferrous sulfate, and i)hosi)halc buffer. The decarboxylation of 3-hydroxycinchoninic, acid in boiling nitrobenzene has been re-... 

Step 4 of Figure 29.12 Oxidative Decarboxylation The transformation of cr-ketoglutarate to succinyl CoA in step 4 is a multistep process just like the transformation of pyruvate to acetyl CoA that we saw in Figure 29.11. In both cases, an -keto acid loses C02 and is oxidized to a thioester in a series of steps catalyzed by a multienzynie dehydrogenase complex. As in the conversion of pyruvate to acetyl CoA, the reaction involves an initial nucleophilic addition reaction to a-ketoglutarate by thiamin diphosphate vlide, followed by decarboxylation, reaction with lipoamide, elimination of TPP vlide, and finally a transesterification of the dihydrolipoamide thioester with coenzyme A. 

The amino acid leucine is biosynthesized from n-ketoisocaproate, which is itself prepared from -ketoisovalerate by a multistep route that involves (1) reaction with acetyl CoA, (2) hydrolysis, (3) dehydration, (4) hydration. (5) oxidation, and (6) decarboxylation. Show lhe steps in the transformation, and propose a mechanism for each. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

In addition to the two asymmetric syntheses above described, two racemic syntheses of tetraponerines based on the 5=6-5 tricyclic skeleton have been published. Thus, Plehiers et al. [199] have reported a short and practical synthesis of ( )-decahydro-5Tf-dipyrrolo[l,2-a r,2/-c]pyrimidine-5-carbonitrile (238), a pivotal intermediate in the synthesis of racemic tetraponerines-1, -2, -5 and -6, in three steps and 24% overall yield from simple and inexpensive starting materials. The key reaction of the synthesis was a one-pot stereoselective multistep process, whereupon two molecules of A pyrroline react with diethylmalonate to afford the tricyclic lactam ester 239, possessing the 5-6-5 skeleton (Scheme 10). Hydrolysis of the carboethoxy group of 239 followed by decarboxylation yielded lactam 240, that was converted into a-aminonitrile 238 identical in all respects with the pivotal intermediate described by Yue et al. [200] in their tetraponerine synthesis. 

We apply the concept of catalytic commitment, as proposed by Northrop, O Leary, and Cleland for multistep enzyme-catalyzed processes, to nonenzy-mic decarboxylation for comparison.52 The interpretation of CKIEs for decarboxylation reactions is dependent upon whether the process is viewed as a single-step or multi-step process. In a single-step mechanism, carbon-carbon bond-breaking is not affected by any other rate-limiting process. In this case, the CKIE for a particular compound will be constant under a standard set of conditions. Substantial changes in bond order must occur in the... 

Using a classical multistep route, 4- and 5-substituted-l,3-diseleno-2-selones (105) and (90) are obtained by cycloaddition of l,3-diselenolane-2-selone (104) and an ethyne (R = C02Me) hydrolysis in hydrochloric acid followed by decarboxylation in pyridine yield the parent l,3-diselenole-2-selone... 

Capecitabine (50)(Fig. 13.44) is a recently marketed site-selective multistep prodrug of the antitumor drug 5-fluorouracil (5-FU) (53) (221). The prodrug is well absorbed orally and is hydrolyzed by liver carboxylesterase. The resulting metabolite is a carbamic acid that spontaneously decarboxylates to 5 -deoxy-5-fluorocytidine (51). The enzyme cytidine deaminase, which is present in the liver and... 

TNT that resides in aerobic environments at the surface of the soil is often degraded by photocatalyzed oxidation of the methyl carbon. This oxidation is probably a multistep process by which the methyl group is initially oxidized to an alcohol, then to an aldehyde, and finally to a carboxylic acid. Decarboxylation of the resultant product yields trinitrobenzene. Evidence for this pathway was supplied by Spanggord et al. [29], who reported formation of trinitrobenzaldehyde and trinitrobenzoic acid during the degradation of TNT to trinitrobenzene. It has been reported that oxidation of the methyl group of TNT is mediated by surface catalysis on soil minerals [30], by ozonation [31], and by the action of sunlight [29], At sites where the TNT contamination is localized to the soil surface, the concentration of trinitrobenzene may often exceed that of TNT [32],... 

This review covers the catalytic literature on condensation reactions to form ketones, by various routes. The focus is on newer developments from the past 15 years, although some older references are included to put the new work in context. Decarboxylative condensations of carboxylic acids and aldehydes, multistep aldol transformations, and condensations based on other functional groups such as boronic acids are considered. The composition of successful catalysts and the important process considerations are discussed. The treatment excludes enantioselective aldehyde and ketone additions requiring stoichiometric amounts of enol silyl ethers (Mukaiyama reaction) or other silyl enolates, and aldol condensations catalyzed by enzymes (aldolases) or catalytic antibodies with aldolase activity. It also excludes condensations catalyzed at ambient conditions or below by aqueous base. Recent reviews on these topics are those of Machajewski and Wong, Shibasaki and Sasai, and Lawrence. " The enzymatic condensations produce mainly polyhydroxyketones. The Mukaiyama and similar reactions require a Lewis acid or Lewis base as catalyst, and the protecting silyl ether or other group must be subsequently removed. However, in some recent work the silane concentrations have been reduced to catalytic amounts (or even zero) this work is discussed. 

Alkyl and aryl nitriles readily hydrolyze when submitted to NCW conditions. The hydrolysis is a multistep sequence as shown in Fig. 9.26. For instance, Katritzky et al. have reported that benzonitrile is converted to benzamide and benzoic acid at 250°C over a period of 5 days, and they conclude that the amide and the acid were in equilibrium. Under these conditions some decarboxylation can also occur. An et al. have reported the product distribution for the hydrolysis of benzonitrile as a function of time and temperature. Specifically, the ratio of benzamide to benzoic acid varied as follows after 1 h at 250°C, the distribution was 5 4. However, at 280°C after 1 h, the ratio was 1 1, and became 1 25 when the reaction time was extended to 6 h. Alkylnitriles exhibit similar behaviors Siskin et ah reported that at 250°C for 2.5 days decanonitrile quantitatively yields two major products, decanoic acid and decanoamide. When octanenitrile was hydrolyzed to octanoic acid amide and octanoic acid, the reaction was slightly slower than that ofbenzonitrile. Only 29% conversion took place in 1 h at 290°C. The limited solubility of octanenitrile in water, even in NCW conditions, was suggested as a possible factor for the slow reaction. Again the product distribution was dependent on the residence time and the temperature. 

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