Ketones nucleophile acceptance

Propadienyl phenyl sulfone can accept enamines of cyclic ketones as nucleophiles to afford fi,y-or a,/8-unsaturated ketones 193 and 194 as the major products [102],... 

It is interesting that the reaction of triphenylphosphine with a 1,2-allenyl ketone leads to the formation of a vinyl phosphonium salt 449, which upon protection of the carbonyl group would accept nucleophilic attack followed by elimination in the presence of Et3N to afford y-nudeophile substituted- ,/j-unsaturated enones 451 [197]. 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

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. 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

Examples of the preparation of cyclopropanes by intramolecular nucleophilic substitution are illustrated in Scheme9.17. The first example is a synthesis of [l.l.ljpro-pellane, which yields the product in acceptable yields, despite the high strain and poor stability of this compound [66]. The second and third examples illustrate the remarkable ease with which 3-halopropyl ketones cyclize to yield cyclopropanes instead of cyclic, five-membered enol ethers or ketones. Similarly, carbamates of 2-haloethylglycine esters do not undergo intramolecular N- or O-alkylation on treatment with bases, but yield cyclopropanes instead [67, 68]. Some nucleophiles can undergo Michael addition to 3-halomethyl acrylates faster than direct Sn2 reaction, to yield cyclopropanes by cyclization of the intermediate enolates (fourth example, Scheme9.17) [69]. 

The reaction of isatins with ketones leading to 4-quinolinecarboxylic acids is carried out in the presence of strong nucleophiles (sodium hydroxide or potassium hydroxide). For this reason the generally accepted mechanism of the process is the following. The isatins 1 are converted by the action of alkalis into the salts of... 

The next example is particularly impressive. The enol partner is a symmetrical ketone that is very hindered—there is only one a hydrogen on either side. The electrophilic partner is a conjugated enal that is not enolizable but that might accept the nucleophile in a conjugate manner. In spite of these potential problems, the reaction goes in excellent yield. 

Finally, it should be pointed out that the configuration of a newly formed stereocenter at the /1-position of the accepting C —C double bond may be controlled by temporarily tethering the incoming 0-nucleophile to an adjacent stereocenter. For example, acid-catalyzed addition of aldehydes or ketones to the hydroxy enone rac-16 resulted in exclusive cw-fusion of the newly formed 1,3-dioxolane ring53. This method could potentially be applied to more complex problems. In any case, exploring its scope should prove worthwhile. 

Simple alicyclic enamines are readily hydrolysed by basic or weakly, acidic media, although strong acids merely protonate the nitrogen atom, leading to a stable ammonium ion (6a). Recent studies [222] on enamine hydrolysis show it to be a general-acid-catalysed process involving the unprotonated form (6). This can accept a proton from an acidic species HA at the a -carbon atom to give the iminium ion (7). Nucleophilic attack by solvent or a base then affords the carbinol-amine (8) which breaks down into ketone and amine. 

Another important coupling reaction uses esters as the electron-accepting species and leads to a-hydroxy ketones (acyloin coupling). Sodium, potassium (less frequently) or sodium-potassium alloys are commonly used as electron donors in nonpolar solvents such as toluene or xylene. The first detectable reaction intermediate after the primary reductive step is the enediolate which can be trapped with tri-alkylsilyl chloride. This method is widely used to synthesize highly nucleophilic alkenes and/or protected acyloins (Scheme 12) [50, 51]. 

It is widely accepted that the carbonyl reactivity toward nucleophiles increases in the order aldehyde>ketone>ester>amide [6]. This reactivity order is simply based on the extent to which each carbonyl carbon is sterically and electronically activated. However, reactivities might change when these carbonyl substrates are subjected to a Lewis acid. It is generally assumed that the coordination capability of the carbonyl oxygen to Lewis acids is the means by which Lewis acids activate carbonyl substrates. Thus, in some re.spects, the reaction rate parallels the Lewis basicity of the carbonyls. Furthermore, the reactivity of a carbonyl substrate depends on the reaction type as well as the Lewis acid employed. Special care must be taken in assessing the relationship between the relative reaction rate, the relative Lewis basicity, and the inherent carbonyl reactivity of each substrate. It is instructive to take a look at the following example (Schemes 2-2 and 2-3 Fig. 2-1). 

Carbohydrates are either polyhydroxyaldehydes (aldoses, oses) or polyhydroxyke-tones (ketoses, uloses) there is an electron gap at their carbonyl carbon atom. Typically, aldehydes and ketones accept nucleophiles such as water to form hydrates or alcohols to form hemiketals (5.1 and 5.3) and hemiacetals (5.4 and 5.6), respectively. In pentoses, pentuloses, hexoses, hexuloses, and higher carbohydrates, one of the hydroxyl groups can play the role of internal nucleophile. Thus, open-chain structure (5.2 and 5.5) cyclizes into internal hemiacetals and ketals, all with either five- (5.1 and 5.3) or six- (5.4 and 5.6) membered cycles. 

This iron anion is a good soft nucleophile for alkyl halides and can be used twice over to produce first a monoanion with one alkyl group and then a neutral complex with two alkyl groups and four CO ligands. Each of these complexes has 18 electrons. If extra CO is added by increasing the pressure, CO inserts into one Fe—C bond to form an iron acyl complex. Finally, reductive elimination couples the acyl group to the other alkyl group in a conceptually simple ketone synthesis. It does not matter which Fe—C bond accepts the CO molecule the same unsymmetrical ketone is produced at the end. 

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