Carbonyl groups, activation

A white solid, m.p. 178 C. Primarily of interest as a brominaling agent which will replace activated hydrogen atoms in benzylic or allylic positions, and also those on a carbon atom a to a carbonyl group. Activating influences can produce nuclear substitution in a benzene ring and certain heterocyclic compounds also used in the oxidation of secondary alcohols to ketones. 

In a sophisticated variation of the Knoevenagel condensation ("Panizzi ) methyl 3,3-dimethoxypropanoate (from ketene and dimethoxymethenium tetrafluoroborate D.J. Crosby, 1962) is used as a d -reagent. Because only one carbonyl group activates the methylene group, a strong base with no nucleophilic properties (p. 10) has to be used. A sodium-sand mixture, which presumably reacts to form silicate anions in the heat, was chosen... 

The benzanthrone system is susceptible to both electrophilic and nucleophilic attack. The most reactive sites towards electrophiles are the 3- and 9-positions, which can be compared with the 4,4 -positions in biphenyl. The 9-position is somewhat deactivated by the carbonyl group, however. Thus, for example, monobromination takes place at the 3-position and further substitution gives 3,9-dibromobenzanthrone. Nitration and benzoylation similarly give rise to the 3-substituted product. The 3-position is in fact peri-hindered (compare naphthalene) so that sulphonation yields the 9-sulphonic acid. Electron withdrawal by the carbonyl group activates the 4- and 6-positions towards nucleophilic attack for example, hydroxylation occurs at these sites. 

In the case of the synthesis of cortisone, Oppenhauer oxidation of hydroxyl group at C(14) -after the necessary acetalisation of the unsaturated carbonyl group-leads to intermediate 16a. which, under the basic conditions of Oppenhauer oxidation, spontaneously isomerises to 17a. with the more stable trans-BIC junction. An additional advantage of this sequence is that the carbonyl group activates the C(13) vicinal position, and allows not only the introduction of the methyl group, but facilitates the construction of ring D of the cortisone molecule. 

The mechanism by which the group III hydrides effect reduction involves nucleophilic transfer of hydride to the carbonyl group. Activation of the carbonyl group by coordination with a metal cation is probably involved under most conditions. As reduction proceeds and hydride is transferred, the Lewis acid character of boron and aluminum can also be involved. 

The results of infrared investigations and 0-labeling experiments support the mechanism depicted in Scheme 165, which includes carbonyl group activation by the catalyst and oxygen transfer via Criegee adduct. Two years later Pillai and Sahle-Demessie could... 

Under acidic conditions, the mechanism of amide hydrolysis resembles the acid-catalyzed hydrolysis of an ester. Protonation of the carbonyl group activates it toward nucleophilic attack by water to give a tetrahedral intermediate. Protonation of the amino group enables it to leave as the amine. A fast exothermic proton transfer gives the acid and die protonated amine. 

FIGURE 10.17 a-Carbonyl group activation of (3-ether cleavage in a nonphenolic lignin unit. 

A TMSOTf-initiated cyclization of the dicarbonyl substrate was invoked to explain the reactivity pattern [79]. Selective complexation of the less hindered carbonyl group activates it toward intramolecular nucleophilic attack by the more hindered carbonyl which leads to an oxocarbenium species. Subsequent attack by the enol ether results in addition to the more hindered carbonyl group. The formation of this cyclic intermediate also explains the high stereochemical induction by existing asymmetric centers in the substrates, as demonstrated by Eq. 52, where the stereochemistry at four centers is controlled. A similar reactivity pattern was observed for the bis-silyl enol ethers of / -diketones. The method is also efficient for the synthesis of oxabicyclo[3.3.1] substrates via 1.5-dicarbonyl compounds, as shown in Eq. 53. Rapid entry into more complex polycyclic annulation products is possible starting from cyclic dicarbonyl electrophiles [80]. 

In an unusual reaction, a furan derivative has been cyclized with hydrazine to give, after aerial oxidation in alkali, 6,9-dihydroxybenzo[ ]phthalazine-5,10-dione in excellent yield (Equation (40)). Normally furans need to be converted into unsaturated 1,4-dicarbonyl derivatives (bromine/ methanol, followed by hydrolysis) prior to reaction with hydrazine to give pyridazines, but in this case the carbonyl groups activate the furan to attack by hydrazine <93JHC1597>. 

Woodward has now reported reliable procedures for the preparation of trimethylene and ethylene dithiotoluene-jp-sulphonates, reagents used in the formation of dithians and dithiolans from active methylene compounds, including those adjacent to a carbonyl group activated by prior hydroxy-methylene or enamine formation. Applications include carbon-carbon bond cleavage and ketone transposition (Scheme 148). 

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