Ketones regiochemistry

Minuti L., Taticchi A., Costantini L. High Pressnre Diels-Alder Reactions of Cycloalkenones in Organic Synthesis Recent Res. Dev. Org. Chem. 1999 3 105-116 Keywords ketones, regiochemistry, stereoselectivity, reactivity... 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

The chemistry of alkynes is dominated by electrophilic addition reactions, similar to those of alkenes. Alkynes react with HBr and HC1 to yield vinylic halides and with Br2 and Cl2 to yield 1,2-dihalides (vicinal dihalides). Alkynes can be hydrated by reaction with aqueous sulfuric acid in the presence of mercury(ll) catalyst. The reaction leads to an intermediate enol that immediately isomerizes to yield a ketone tautomer. Since the addition reaction occurs with Markovnikov regiochemistry, a methyl ketone is produced from a terminal alkyne. Alternatively, hydroboration/oxidation of a terminal alkyne yields an aldehyde. 

Non-symmetrical ketones suffer from the fact that the regiochemistry cannot be predicted. Since both adjacent C-C bonds migrate, the yield is decreased. 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

The most synthetically valuable method for converting alkynes to ketones is by mercuric ion-catalyzed hydration. Terminal alkynes give methyl ketones, in accordance with the Markovnikov rule. Internal alkynes give mixtures of ketones unless some structural feature promotes regioselectivity. Reactions with Hg(OAc)2 in other nucleophilic solvents such as acetic acid or methanol proceed to (3-acetoxy- or (3-methoxyalkenylmercury intermediates,152 which can be reduced or solvolyzed to ketones. The regiochemistry is indicative of a mercurinium ion intermediate that is opened by nucleophilic attack at the more positive carbon, that is, the additions follow the Markovnikov rule. Scheme 4.8 gives some examples of alkyne hydration reactions. 

Organomercury reagents do not react with ketones or aldehydes but Lewis acids cause reaction with acyl chlorides.187 With alkenyl mercury compounds, the reaction probably proceeds by electrophilic attack on the double bond with the regiochemistry being directed by the stabilization of the (3-carbocation by the mercury.188... 

Both the regiochemistry and stereochemistry of Wacker oxidation can be influenced by substituents that engage in chelation with Pd. Whereas a single y-alkoxy function leads to a mixture of aldehyde and ketone, more highly oxygenated systems such as the acetonide or carbonate of the diol 1 lead to dominant aldehyde formation.107 The diol itself gives only ketone, which perhaps indicates that steric factors are also important. 

In one case, the intermolecular Heck reaction of 3-pyridyltriflate with ethyl acrylate was accelerated by LiCl to give 159 [127,128], Here, both electronic and steric effects all favored p-substitution. In another case, however, electronic effects prevailed and complete a-substitution was observed. In the presence of an electron-donating substituent (i.e., a protected amine), 3-bromopyridine 160 was coupled with f-butoxyethylene to give 3-pyridyl methyl ketone 162 [126]. The regiochemistry of the Heck reaction was governed by inductive effects, leading to intermediate 161. 

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. 

Control of Regiochemistry and Stereochemistry of Mixed Aldol Reactions of Aliphatic Aldehydes and Ketones... 

The Shapiro reaction has been particularly useful for cyclic ketones, but the scope of the reaction also includes acyclic systems. In the case of unsymmetrical acyclic ketones, questions of both regiochemistry and stereochemistry arise. 1-Octene is the exclusive product from 2-octanone.207... 

A mechanistically significant feature of this reaction is the kinetic preference for formation of jS,y-unsaturated ketones. It has been suggested that this regiochemistry results from an intramolecular deprotonation, as shown in the mechanism above.5 A related reaction occurs between alkenes and acylium ions, as in the reaction between 2-methylpropene and... 

Whereas 260 does not react with electron-rich dipolarophiles, the more delocalized isomiinchnone 261 does react with both electron-rich and -deficient dipolarophiles (154). A detailed FMO analysis is consistent with these observations and with the regiochemistry exhibited by diethyl ketene acetal and methyl vinyl ketone as shown in Scheme 10.36. The reaction of 261 with the ketene acetal to give 262 is LUMO-dipole HOMO-dipolarophile controlled (so-called lype III process). In contrast, the reaction of 261 with methyl vinyl ketone to give 263 is HOMO-dipole LUMO-dipolarophile controlled (so-called lype I process). In competition experiments using a mixture of A-phenylmaleimide and ketene acetal only a cycloadduct from the former was isolated. This result is consistent with a smaller energy gap for... 

Cycloaddition of CO2 with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiochemistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /J-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

The classical method for preparing isoxazole involves the condensation of 1,3-dicarbonyl compounds with hydroxylamine, a reagent that contains the preformed N—O bond. The regiochemistry of the reactions can usually be rationalized by assuming that the first step involves imine bond formation at the more reactive carbonyl group. Thus, reaction of formyl ketone (44-1) with hydroxylamine gives... 

A further example stressing the effect on regiochemistry exerted by the presence of a methyl group on the dienolate moiety is given by ketone 199 in the reaction with pure... 

---