Ketones heteroatomic nucleophiles

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

Nucleophiles. Trapping of acylpaUadium species formed via cycUc acylpaUadation with external heteroatom nucleophiles has been achieved almost exclusively by using alcohols, such as MeOH, EtOH, i-PrOH, and t-BuOH. Their nucleophUicity is such that the above-mentioned requirement for the relative rates among three competing processes, that is, intramolecular Ac-Pd > nucleophilic trapping > intermolecular Ac-Pd, can often be satisfied at least in cases where five- and six-membered ketones are desired. 

The acyl palladium intermediate may also be trapped by heteroatom nucleophiles (Schemes 4.17 and 4.18), such as alcohols and amines as part of the catalytic process, to give esters (Scheme 4.19) and amides (Scheme 4.20), respectively. Less commonly used nucleophiles include water, to give carboxylic acids, carboxylate salts, to give anhydrides, and ketones, via their enol form, to give enol esters. Metal carbonyl complexes may be used as both the source of CO and as the catalyst for the reaction (Scheme 4.21). ... 

The thiolate bridged diruthenium complex [(r] -C5Me5)RuCl(jLz-SR)2Ru(/] -C5Me5)Cl] 211, or its derivative with various anions, proved to be a very efficient catalyst for substitution of propargylic alcohols with a number of nucleophiles. The substitution of propargylic alcohols proceeds with heteroatom nucleophiles such as alcohols, thiols, amines, amides, and phosphineoxides to give the corresponding ethers 212, thioethers 213, amines 214, amides 215, and phosphineoxides 216 (Scheme 97) [135]. Carbon nucleophiles such ketones and... 

In a manner largely complementary to secondary amine-catalyzed asymmetric conjugate addition to enals with heteroatom nucleophiles, chiral primary amines were recently found to be the catalysts of choice for similar Michael addition to a,p-unsaturated ketones. With their previously developed cinchona-type catalyst 91, Melchiorre and coworkers achieved the asymmetric sulfa-Michael addition to a,p-unsaturated ketones with either benzyl or tert-butyl mercaptane (Scheme 5.30) [58a]. The same catalyst could be further extended to oxa-Michael addition to enones by optimizing the ratio of acidic additive and solvents (Scheme 5.30) [58b]. 

Aryl and alkyl hydroxylations, epoxide formation, oxidative dealkylation of heteroatoms, reduction, dehalogenation, desulfuration, deamination, aryl N-oxygenation, oxidation of sulfur Oxidation of nucleophilic nitrogen and sulfur, oxidative desulfurization Oxidation of aromatic hydrocarbons, phenols, amines, and sulfides oxidative dealkylation, reduction of N-oxides Alcohol oxidation reduction of ketones Oxidative deamination... 

Bis(trimethylsilyl)monoperoxysulfate 6 is also an excellent agent for oxygen transfer to nucleophilic substrates such as alkenes and heteroatoms. Compound 6 could oxidize alkenes such as 1-methylcyclohexene and fraw5-/3-methylstyrene, producing 2-methyl-cyclohexanone and benzyl methyl ketone, respectively, in high yield, most likely via the... 

There are many important [5 + 1] two-bond formation heterocyclic syntheses and in certain instances this approach constitutes the method of choice for the preparation of particular classes of heterocycle. Where a carbon atom constitutes the one-atom fragment it is almost invariably present in the form of an electrophilic species such as an aldehyde, carboxylic acid, ketone, ester, acid chloride, urea, etc., and fundamentally condensation consists of reaction of this electrophilic species with a 1,5-dinucleophilic reagent. Where the one-atom fragment is either nitrogen, oxygen or sulfur then the heteroatom may function either as a nucleophile or, in the case of nitrogen and sulfur, also as an electrophile. Almost... 

Carbonyl groups not adjacent to a heteroatom are less stabilized by resonance and react with the relatively weakly nucleophilic ketonic reagents. If carbonyl groups of both types are present, as in... 

The conjugate addition of heteronucleophiles to activated alkenes has been used very often in organic synthesis to prepare compounds with heteroatoms [3 to various activating functional groups, e.g. ketones, esters, nitriles, sulfones, sulfoxides and nitro groups. As in the Michael reaction, a catalytic amount of a weak base is usually used in these reactions (with amines as nucleophiles, no additional base is added). 

The installation of heteroatom groups based on elements other than oxygen can be readily achieved by a two-step (usually one-pot) sequence in which ketones are first converted to tosyloxy ketones with HTIB, and nucleophilic reagents are then introduced [6,8]. The nosylate analog 18 of HTIB can also be used for this purpose. Recent examples of C-S, C-Se, C-N, and C-I bond formation by this approach are shown in Scheme 28 [86 - 89]. 

In chapter 10 we compared C-C disconnections with related two-group C-X disconnections, mainly at the alcohol oxidation level. In this chapter we deal more fully with carbonyl compounds, chiefly aldehydes and ketones, by two related disconnections. We start by comparing the acylation of heteroatoms by acid derivatives such as esters (a 1,1-diX disconnection 1 that can also be described as a one-group C-X disconnection) with the acylation of carbon nucleophiles and move on to compare the 1,2-diX disconnection 3 with the alkylation of enolates 6. Here we have reversed the polarity. We mention regioselectivity—a theme we shall develop in chapter 14. 

For instance, the preparation of isoxazole 4.17 is virtually regiospecific because the reaction commences with the more nucleophilic heteroatom (i.e. nitrogen) attacking the more electrophilic ketone (activated by the electron-withdrawing inductive effect of the adjacent ester group). The reader is encouraged to consider the regiochemical bias in the preparation of isoxazole 4.15 and pyrazole 4.16. 

When a nucleophile containing a heteroatom reacts at a carboxyl carbon SN, reactions occur that convert carboxylic acid derivatives into other carboxylic acid derivatives, or they convert carbonic acid derivatives into other carbonic acid derivatives. When an organometallic compound is used as the nucleophile, SN reactions at the carboxyl carbon make it possible to synthesize aldehydes (from derivatives of formic acid), ketones (from derivatives of higher carboxylic acids), or—starting from carbonic acid derivatives—carboxylic acid derivatives. Similarly, when using a hydride transfer agent as the nucleophile, SN reactions at a carboxyl carbon allow the conversion of carboxylic acid derivatives into aldehydes. 

Most SN reactions of hydride donors, organometallic compounds, and heteroatom-stabi-lized carbanions at the carboxyl carbon follow the mechanism shown in Figure 6.2. Thus, the substitution products, i.e., the aldehydes and ketones C, form in the presence of the nucleophiles. Thus, when the nucleophile and the acylating agent are used in a 2 1 ratio, alcohols F are always produced. 

Hydroxy aldehydes or ketones normally exist in equilibrium with the corresponding 2-hydroxytetrahydrofurans, which afford 2,3-dihydrofurans on dehydration. Similarly, 7-aminoketones spontaneously yield pyrrolines. From a mechanistic viewpoint the-initial cyclizations may be regarded as being initiated by nucleophilic attack of the heteroatom upon the carbonyl group. While such reactions occur with facility, their synthetic applicability is largely determined by the accessibility of appropriate precursors. A selection of examples of this type of ring closure is provided in Scheme 12. 

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