Electrophilic centers ketones

Replacement of the carbonitrile by the ethoxycarbonyl group leads to compounds with two electrophilic centers (ketone and ester carbonyl) of similar order. With these compounds, base catalyzed ring enlargement was not observed. The main products were explained by attack of the nucleophile at the ethoxycarbonyl group [79]. 

When an ionic organic reaction (the kind catalyzed by most enzymes) occurs a nucleophilic center joins with an electrophilic center. We use arrows to show the movement of pairs of electrons. Tire movement is always away from the nucleophile which can be thought of as "attacking" an electrophilic center. Notice the first step in the second example at right. The unsaturated ketone is polarized initially. However, this is not shown as a separate step. Rather, the flow of electrons from the double bond, between the a- and (1-carbons into the electron-accepting C=0 groups, is coordinated with the attack by the nucleophile. Dotted lines are often used to indicate bonds that will be formed in a reaction step, e.g., in an aldol condensation (right). Dashed or dotted lines are often used to indicate partially formed and partially broken bonds in a transition state, e.g., for the aldol condensation (with prior protonation of the aldehyde). However, do not put arrows on transition state structures. 

Glutathione S-transferases. Addition of glutathione (Box 11-B) to a large variety of different substrates containing electrophilic centers, such as that at the (3 position in an a,P-unsaturated ketone (Eq. 13-9), is catalyzed by the ubiquitous group of enzymes called glutathione S-transferases. There are six classes of... 

By bond polarity and resonance, the carbonyl carbon and a carbon (i to the carbonyl carbon can be utilized as electrophilic centers—die carbonyl group by direct nucleophilic addition and die /3 carbon by Michael addition to an a,/3-unsaturated ketone. By resonance interaction, the a position in carbonyl compounds and y positions in o, /3-unsaturated carbonyl compounds can be converted to nucleophilic centers by proton removal. These normal polarities are used frequently in retrosynthetic planning as points of disconnection to establish potential bond-forming steps using carbonyl groups. 

In this monofunctional compound, the ketone could serve as an electrophilic center in a cyclization step. Disconnection at the indicated bond leads to the polarity shown however, it is immediately obvious that the carbon nucleophile occurs at an unactivated position, and there is no good way to produce it there without a control element at that position. 

One of the features of a,/3-unsaturated ketones is the presence of two electrophilic centers. Because of this feature, reactions with binucleophiles can proceed as a 1,2-addition or as a 1,4-addition. Regarding three-membered nitrogen-containing heterocycles formed from a,/3-unsaturated ketones and their derivatives, the unsaturated ketone acts either as a 1,2-bielectrophile (substituted ethylene), which leads to the formation of ethyleneimines, or as a 1,4-bielectrophile, giving rise to either bi- or tricyclic aziridines. Hence, the present chapter is divided into two parts, one which is entirely dedicated to aziridinyl ketones and the other to bi- and tricyclic aziridines. 

Gordon and Danishefsky [112] used the reaction of a chromium Fischer car-bene complex 164 with a cycloalkine 163 to build the naphthoquinone core 165 (Dotz reaction, review [113]), a procedure often used for synthesis of the linearly condensed anthracyclinones (e.g., [114]). The quinone ketone 165 has nucleophilic and electrophilic centers correctly positioned to furnish a ben-zo[fl]anthraquinone. However, treatment with NaH or Triton B gave the spiro-compounds 166 as a mixture of two stereoisomers. These products evidently arose from Michael addition of the ketone enolate to the naphthoquinone double bond. But the weaker base DBU induced cyclization at ambient temperature to the benzo[a]anthraquinone 167 in 65% yield (Scheme 42). The primary aldol adduct apparently eliminated water and the resulting dihydrobenzo[a]anthraquinone aromatized under basic conditions in the presence of air. This is an instructive example of the influence of the base on the cyclization mode. 

P unsaturated acids, ketones, or acyl-CoA derivatives. Highly polarized groups such as carbonyl and enamine generate electrophilic centers as indicated by the positive charges. They also affect more distant positions in conjugated systems, e.g., in a, P-unsaturated acyl-CoA derivatives, and in intermediates formed from thiamin diphosphate and pyri-doxal phosphate. 

The metallation of acidic hydrocarbons (pK 15-30), such as ketones and esters, and their nitrogen-containing analogues are complicated because the substrates contain a reactive electrophilic center. Sterically hindered RjNM, (CgH5)3CM or nonnucleophilic... 

Our results and related literature data (7) clearly show that the P=E double bond in two-coordinate phosphines undergoes facile addition of polar reagents to give three-coordinate P derivatives. It is also well known that the three-coordinate pin center is relatively nucleophilic and that, in molecules containing an electrophilic site, further chemical transformations are usually observed. Thus, in certain reactions of the two-coordinate phosphines, it is possible to find both types of reactions electrophilic addition to the P=E bond, followed by nucleophilic attack by the three-coordinate P atom on an internal electrophilic center. For example, in the enol form of a ketone, the O-H moiety is capable of undergoing addition to the P=E double bond of the two-coordinate phosphines. Acetylacetone and related reagents react rapidly with the phosphinimine at low temperature (ca. -50 C) and with the (methylene)phosphine at 0 °C to give the new 2,3-dihydro-... 

This mechanism is, however, difficult to apply to the fast cycloaddition of diazoacetates (Alder et al., 1931) and 3-diazobutane-2-one (Diels and Konig, 1938) with alkenes of the bicyclo[2.2.1]heptene type, because alkene C-atoms without electron-withdrawing substituents show no electrophilic character. The reverse sequence of steps in (6-4), i. e., first an additon of N at the central C-atom of the acrylate, would also be unusual, as the N ()ff)-atom of diazoalkanes is only a weak electrophilic center. Fleischmann (in Huisgen s group, 1958) showed that, in such cyclization reactions, the rate of reaction of diazomethane with bicyclic alkenes relative to that of )ff-diazo ketones and 2-diazo-l,3-diketones is higer by a factor of 10" -10. ... 

If the carbon atom in 3 is electrophilic, then the carbon in 2 must be nucleophilic. This assumption is based on simple bond polarization and it makes it possible to correlate the imaginary 3 with a carbonyl compound that has an electrophilic carbon with a polarized C-0 bond. Nucleophilic acyl addition to a ketone is a known reaction, so 3 correlates with a real molecule—acetone. If 3 correlates with an electrophilic center, then 2 must be a nucleophilic center and an alkyne anion is a reasonable choice. It is known that an alkyne anion will react with a ketone via acyl addition (see Chapter 18, Section 18.3.2). The correlation of 2 with an alkyne simply requires adding a hydrogen atom to the red carbon to give terminal alkyne, 7. Conversion of alkyne 7 to the anion, followed by acyl addition to acetone, should lead to 1. Disconnection of 1 generates acetone and 7, and the reaction of 7 and acetone leads to 1. Recognizing the forward and reverse relationships is essential for correlating the disconnection (retrosynthesis) with the reactions that make the bond (synthesis). 

The polarity of the carbon-magnesium bond is opposite that of the carbon—halogen bond of haloalkanes. Because the carbon atom in a Grignard reagent has a partial negative charge, it resembles a carb-anion, and it reacts with electrophilic centers such as the carbonyl carbon atom of aldehydes, ketones, and esters. We will discuss this chemistry extensively in later chapters. 

Acylsilanes cross-couple with allyicl trifluoroacetates in the presence of a palladium catalyst to give y0,) unsaturated ketones. Use of the trifluoroacetates is crucial Other carboxylates such as allyl acetate are completely futile. Carbamoylsilanes serve as an efficient donor of a carbamoyl group to a wide range of electrophiles in the presence or absence of palladium catalysts (Scheme 3-186). Thus, the carbamoylsilanes work as versatile reagents for carbamoylation at electrophilic centers. 

Catalysis of Intramolecular Sakurai Reactions. Et AICI2 has been extensively used as a catalyst for intramolecular Sakurai additions. Enones (eqs 12 and 13) have been most extensively explored. Different products are often obtained with fluoride or Lewis acid catalysis. EtAlCl2 is the Lewis acid used most often although TiCLi and BF3 have also been used. EtAlCl2 also catalyzes intramolecular Sakurai reactions with ketones and other electrophiles. The cyclization of electrophilic centers onto alkylstannanes and Prins-type additions to vinylsilanes are also catalyzed by EtAlCl2. 

Iminothiobutyramide (30), containing four nucleophilic centers (only two of which might react with two electrophilic sites in phenacylbromide), undergoes the Hantzsch reaction preferentially, yielding the enamine (31) in dry dioxane or (4-phenylthiazol-2-yl)acetone (32) in isopropanol. Other enamines are obtainable from the ketone (32) by standard methods (626) (Scheme 15). 

The reaction starts with the nucleophilic addition of a tertiary amine 4 to the alkene 2 bearing an electron-withdrawing group. The zwitterionic intermediate 5 thus formed, has an activated carbon center a to the carbonyl group, as represented by the resonance structure 5a. The activated a-carbon acts as a nucleophilic center in a reaction with the electrophilic carbonyl carbon of the aldehyde or ketone 1 ... 

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