Enolate condensations

Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Ghosh and co-workers have recently used the indanyl-derived auxiliary 69 (Table 1.9) in titanium enolate condensations with a range of aldehydes [34], Of the four possible diastereomers, only the anti 71 and syn TL were produced (the alternative anti and syn diastereomers were not detected by 1H or 13C NMR). The use of monodentate aliphatic aldehydes resulted in the formation of anti diastereomers... 

Table 10 shows examples of. vvn-sclcctive enolate condensations with imines using different types of enolates. All enolates used in these experiments were prepared based on the corresponding lithium enolate by treatment with different Lewis acids, where the lithium enolates themselves were generated with lithium diisopropylamide (LDA) at — 78 °C. 

One of the earliest studies to address the issue of aldehyde dia-stereoface selection in enolate condensation was performed by Matsumoto and coworkers (91). The Reformatsky reaction of methyl 2-bromopropionate and 2-phenylpropanal (98) afforded the four aldol adducts illustrated in eq. [70]. Although the aldol diastereo-... 

Conjugate addition to 1 proceeded across the open face of the bicyclic system to give an enolate, condensation of which with the enantiomerically-pure aldehyde 8 gave the enone 9. Conjugate reduction of the enone also removed the benzyl ether, to give the alcohol. Conversion of the alcohol to the azide gave 10. Ozonolysis followed by selective reduction then gave 2. 

The 12-step synthesis of imatinib mesylate (1) in the manufacturing process was accomplished by Novartis in an astonishingly short time. The synthesis began with a condensation reaction between 6 and ethyl formate. Deprotonation of the methyl group on 3-acetylpyndine (6) using freshly prepared sodium methoxide afforded an enolate. Condensation of the enolate with ethyl formate was followed by exchange with to produce 3-dimethylamino-l-(3-pyridyl)-2-propen-l-one (7). could be prepared from the condensation of 6 and N,N-... 

The direct condensation of pentan-3-one with ethyl formate failed to give 3,5-dimethyl-pyran-4-one. Instead, the diketone was produced, the enolate of which is apparently of insufficient reactivity to undergo condensation with a second molecule of ester. However, the isopropyl derivative (407) of the enol condensed with ethyl formate, and the potential triketone cyclized to the pyran-4-one (408) under acid conditions (Scheme 133) (64JOC2678). 

A more typical result from the days before specific enol condensation between butanone and butanal with... 

A relatively simple derivative of phenylalanine shows hypoglycemic activity. This compound, nateglinide, is usually prescribed for use as an adjunct to either metformin, or one of the thiazolidine hypoglycemic agents. Catalytic reduction of the benzoic acid (85) leads to the corresponding substituted cyclohexane as a mixture of isomers. This compound is then esterified with methanol to give the methyl esters (86). Treatment with sodium hydride leads 86 to equilibrate to the more stable trans isomer 87 via its enolate. Condensation of 87 with the ester of phenylalanine (88) yields nateglinide (89) after saponifications. ... 

Cyclopentenone annelation. Enolates condense with 1 in an alkylation-intramolecular Wittig reaction sequence to afford cyclopentenones (yields, 14-39%). 

The pinacolone lithium enolate condensation product with pivaldehyde (147) has been characterized as the tetrameric aggregate (148).However, an attempted condensation reaction of pinacolone with itself as shown in Scheme 8 led to crystallization of a product derived from subsequent dehydration and reenolization, i.e. (149). This dienolate (149) was characterized as the dimer (150) solvated by ditnethyl-propyleneurea (DMPU). ... 

A more typical result from the days before specific enol condensation between butanone and butanal with equivalents had been invented is this attempted crossed catalytic base. Two products were isolated in low yield. 

It should be noted that these chiral enolate condensations are stoichiometric and self-immolative that is, the chirality of the enolate is sacrificed in its conversion to the [3-hydroxy carboxylic acid. This problem can be circumvented by using a chiral auxiliary, such as an N-acyloxazolidinone. 

This mechanism looks strongly like the one given in Scheme 30 for aliphatic ketone enolate condensations. Paths (A) and (B) may intervene simultaneously. However, we think that (B) is the chief way68. ... 

Closing this section we have to point out that arynic condensations of ketone enolates may incidentally take a curious way78. Thus NaNH2-norcamphor lithium enolate condenses on bromobenzene to give directly the polycyclic alcohol 110 (Scheme 43). 

Of course ketone enolates condense very easily on 124 following a mechanism very similar to the one described with dehydrobenzenes. First nucleophilic attack must take place on two positions. In fact, as we said before, ketone enolates are very sensitive to steric hindrance and reactions on position two are strongly dominant. Thus numerous structures of the type exemplified in Scheme 47 may be prepared. 

IV.2.2.3. Ketone Enolates Condensations on Vinylic Halogeno Cyclohexenes and... 

We can conclude that nucleophilic complex base NaNH2-enolates are able to generate cyclohexynes. Ketone enolates condense on these to give chiefly alcohols 153 and/or ketones 151 and 152. 

Concerning the synthetic view-point of ketone enolate condensations on halogeno vinylic cyclohexenes, we shall give some examples of products which can be prepared. 

In connection with the synthesis of podophyllum lignans, ester (62) was deprotonated and the resulting enolate condensed with 3,4,5-trimethoxybenzaldehyde to give a 1 1 mixture of diastereomeric aldols (equation 68). The structure of (63) was established by X-ray analysis the other diastereomer was assigned the 2,3-anti relative stereochemistry (64) on circumstantial evidence. It was suggested that the 1 1 mixture of isomeric products results from a 1 1 mixture of the ( )- and (Z)-enolate, each of which shows complete simple and diastereofacial selectivity in its reactions with 3,4,5-trimethoxybenzaldehyde. For this to be true, it is also necessary that the ( )-enolate reacts through a non-Zimmerman , boat-like transition state, whereas the (Z)-enolate reacts through the normal chair-like transition state. 

Preformed cyclic /V,A-dialkyliminium salts i.e. where a ring Joins the a-caibon and positively charged nitrogen) have been used in enolate condensation reactions. The number of examples, however, is rather limited, probably because of complications arising through abstraction of enolizable protons. A -Dehy-droindolizidinium salt (69) represents one of the few examples of an enolizable, cyclic A, -dialkylimi-nium salt known to react with an enolate (equation 8). The use of a soft zinc enolate in this reaction may be crucial. The relative stereochemistry of the resulting 3-amino ester (70) is undefined. /V-Alkyl-3,4-dihydroisoquinolinium salts e.g. 71), a class of nonenolizable, cyclic iminium salts, have had extensive applications in the total synthesis of protoberberine and phthalide isoquinoline alkaloids. A review by Pai and coworkers has covered much of this work. In a more recent application by Yamazaki and co-... 

Conjugated amides can undergo both 1,2- and 1,4-addition with hydrides, but there is another competing side reaction. Reductive coupling is possible via generation of an intermediate amide enolate. Reduction of the relatively hindered MA -diethyl-3,3-dimethylacrylamide (44) gave a 47% yield of the expected conjugate reduction product 45, but also 12% of the enolate condensation product 46. Enolate condensations are discussed in Chapter 9. 

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