Electrophiles carbonyls

These examples and those in Scheme 2.6 illustrate the key variables that determine the stereochemical outcome of aldol addition reactions using chiral auxiliaries. The first element that has to be taken into account is the configuration of the ring system that is used to establish steric differentiation. Then the nature of the TS, whether it is acyclic, cyclic, or chelated must be considered. Generally for boron enolates, reaction proceeds through a cyclic but nonchelated TS. With boron enolates, excess Lewis acid can favor an acyclic TS by coordination with the carbonyl electrophile. Titanium enolates appear to be somewhat variable but can be shifted to chelated TSs by use of excess reagent and by auxiliaries such as oxazolidine-2-thiones that enhance the tendency to chelation. Ultimately, all of the factors play a role in determining which TS is favored. 

Symmetrically substituted BODIPY dyes are relatively easy to be synthesized via the condensation of pyrroles with carbonyl electrophiles, such as acyl chlorides,... 

Several other examples of zz/z/z -diastereoselectivc aldol reactions with titanium enolates and carbonyl electrophiles have been reported in the literature.58-65... 

Various other examples of, sy -diastereoselective 60-67 or non-selective aldol reactions of titanium enolates with carbonyl electrophiles have been described.68... 

Finally, several diastereoselective aldol reactions using titanium enolates and carbonyl electrophiles have also been applied to the total synthesis of natural products.69-72... 

As mentioned already, new methylidene-group IV metal complexes have been prepared and were subsequently used in nucleophilic additions to carbonyl electrophiles (Scheme 43).53 In contrast to titanium and zirconium, the reaction of methylidene hafnium dichloride 97 benzophenone stopped at the first stage (i.e., addition). The tertiary alcohol was obtained in 73% yield, while the corresponding alkene was formed only as minor product. 

Additionally, various intra- and intermolecular iron-catalyzed Barbier-type reactions of organosamarium com-pounds and carbonyl electrophiles have been reported by Molander and co-workers. 

Diastereoselectivity in the aldol and the conjugate additions of 2 -hydroxy-1,T-binaphthyl ester enolates with a variety of carbonyl electrophiles has also been explored the tendency of the ester enolates, generated by BuLi, to react with aldehydes to give threo products preferentially with high diastereoselectivity has been interpreted in terms of an acyclic transition state of chelated lithium enolate involving the aldehyde carbonyl and the 2 -hydroxy group. 

An aza-Wittig reaction with carbonyl electrophiles, accessible from im-inophosphorane (177) and aldehydes, gives 5-alkyl- or 5-aryl-lf/-l,2,4-triazoles (Scheme 69) (85S304). The reaction of 177 with isocyanate generates two different products, both of which occur from primary adduct... 

This is a further example of a carbonyl-electrophile complex, and equivalent to the conjugate acid, so that the subsequent nucleophilic addition reaction parallels that in hemiacetal formation. Loss of the leaving group occurs first in an SNl-like process with the cation stabilized by the neighbouring oxygen an SN2-like process would be inhibited sterically. It is also possible to rationalize why base catalysis does not work. Base would simply remove a proton from the hydroxyl to initiate hemiacetal decomposition back to the aldehyde - what is needed is to transform the hydroxyl into a leaving group (see Section 6.1.4), hence the requirement for protonation. 

Both the aldol and reverse aldol reactions are encountered in carbohydrate metabolic pathways in biochemistry (see Chapter 15). In fact, one reversible transformation can be utilized in either carbohydrate biosynthesis or carbohydrate degradation, according to a cell s particular requirement. o-Fructose 1,6-diphosphate is produced during carbohydrate biosynthesis by an aldol reaction between dihydroxyacetone phosphate, which acts as the enolate anion nucleophile, and o-glyceraldehyde 3-phosphate, which acts as the carbonyl electrophile these two starting materials are also interconvertible through keto-enol tautomerism, as seen earlier (see Section 10.1). The biosynthetic reaction may be simplihed mechanistically as a standard mixed aldol reaction, where the nature of the substrates and their mode of coupling are dictated by the enzyme. The enzyme is actually called aldolase. 

Accordingly, it is possible to generate analognes of enolate anions containing cyano and nitro groups, and to use these as nucleophiles towards carbonyl electrophiles in aldol-like processes. Simple examples are shown. 

A second, even more worrying problem is the side reaction, the formation of condensation products. This process is essentially irreversible in most cases. The condensation products can arise either from the aldol product or directly through a Knoevenagel-Mannich type reaction where the enamine reacts with an imininm ion [26, 81, 82]. The condensation process requires only an external Brpnsted acid, whereas the aldol process appears to require simultaneous activation of the carbonyl electrophile by an internal Brpnsted acid/hydrogen bond donor (Scheme 15). 

SCHEME 2. The a- and y-selectivity in the addition reaction of carbonyl electrophiles to. gem-dichloroaUyl anion... 

Pyridines bearing secondary amides may be lithiated with n-BuLi at —78°C with tertiary amides the optimum conditions are LiTMP, DME, 5-15 min (Scheme 23) . Lithiated tertiary amidopyridines react well with carbonyl electrophiles but poorly with alkylating agents. Lithiation of the bromopyridine 49 with LDA is a key step in the synthesis of eupoluramine . ... 

Comparison of the configuration of the stannane with the prodncts of reaction reveals that primary alkyl halides that are not benzyhc or a to a carbonyl react with inversion at the lithium-bearing carbon atom. In the piperidine series, the best data are for the 3-phenylpropyl compound, which was shown to be >99 1 er. In the pyrrolidine series, the er of the analogous compound indicates 21-22% retention and 78-79% inversion of configuration. Activated alkyl halides such as benzyl bromide and teri-butyl bromoacetate afford racemic adducts. In both the pyrrolidine and piperidine series, most carbonyl electrophiles (i.e. carbon dioxide, dimethyl carbonate, methyl chloroformate, pivaloyl chloride, cyclohexanone, acetone and benzaldehyde) react with virtually complete retention of configuration at the lithium-bearing carbon atom. The only exceptions are benzophenone, which affords racemic adduct, and pivaloyl chloride, which shows some inversion. The inversion observed with pivaloyl chloride may be due to partial racemization of the ketone product during work-up. 

In summary (Scheme 15), 2-lithiopiperidines and 2-lithiopyrrolidines appear to be very versatile nucleophiles for the elaboration of these heterocyclic systems, affording a variety of 2-substituted heterocycles in excellent yields. The stereoselectivity of the reaction is near 100% in the piperidine series with most carbonyl electrophiles (retention of configuration) and alkyl halides (inversion of configuration). In the pyrrolidine series, the selectivity is also near 100% with carbonyl electrophiles (retention), but less selective (inversion predominates) with alkyl halides (less problematic with Af-aUylpyrrolidines). 

The metalation chemistry of the imidazoline system has received attention only recently, with the lithiation of l-benzyl-2-imidazoline being found to occur at the 2-position (90TL1767). Although the reactivity of the lithi-ated species with alkyl halides was poor, better results were achieved with disulfide and carbonyl electrophiles (90TL1767,90TL1771). The products formed by reaction with ketones were found to be unstable with respect to fragmentation, and this result was utilized to provide a new route for the synthesis of unsymmetric ketones (Scheme 138). 

The pronounced electron-withdrawing nature of the 1,2,5-thiadiazole system is also evidenced by strong carbonyl electrophilic activation and by enhancement of carboxy acidity. The acid dissociation constants of thiadiazole acids, discussed in Section 4.09.4.1, fall in the range 1.5-2.5. The 1,2,3-thiadiazole carboxylic acids are easily decarboxylated at 160-200 °C. This reaction has been used for the synthesis of monosubstituted derivatives as well as the parent ring and deuterated derivatives <68AHC(9)107>. An efficient bromo-decarboxylation of 3-amino-1,2,5-thiadiazole-carboxylic acid has also been reported <70BRP1190359>. 

Application of the equilibrium-shift procedure (addition of LDA to a mixture of a halo derivative and a carbonyl electrophile) to 5-bromopyrimidine (30) and benzaldehyde leads to formation of the 4-substituted product 33 (Scheme 32) (79JOC2081). Similarly, the reaction... 

Enolates are important nucleophiles which react nicely with a variety of carbonyl compounds. In this case, the nucleophilic reactivity of the enolate and the electrophilic reactivity of the carbonyl group are well matched and a wide variety of products can be made. The type of enolate (ketone, ester, etc.) and the type of carbonyl electrophile (aldehyde, ketone, ester, etc.) determine the structure of the final product. Furthermore these reactions are often named according to the two partners that are reacted and the type of product produced from them. 

The aldol condensation is the reaction of an aldehyde or ketone enolate with an aldehyde or ketone to give a /3-hydroxy aldehyde or ketone. A simple aldol reaction is one in which the enolate nucleophile is derived from the carbonyl electrophile. Very often the /3-hydroxy carbonyl product dehydrates to give an... 

If die enolate nucleophile is derived from an aldehyde or ketone different than die carbonyl electrophile, a crossed-aldol condensation results. Normally best success is achieved if the carbonyl electrophile employed for the crossed-aldol condensation is more reactive than the carbonyl electrophile from which the enolate is derived. For example, ketone etiolates react with aldehydes effectively, but aldehyde enolates do not give the crossed aldol with most ketones but self-condense instead. 

As long as nucleophilic addition of the preformed enolate to the second carbonyl component is rapid and the carbonyl electrophile is added after the enolate is formed, the product is predictable and is not a mixture. The rule of thumb to ensure success is that the carbonyl electrophile should be more reactive than the carbonyl compound from which the enolate is derived. If this condition is met, the carbonyl electrophile can have a protons and the structural possibilities are increased tremendously. Typical enolate-carbonyl pairs that have been condensed by this methodology include the following ... 

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