Carbonyl compounds reactions under acid catalysis

The reaction can, however, be made preparative for (91) by a continuous distillation/siphoning process in a Soxhlet apparatus equilibrium is effected in hot propanone over solid Ba(OH)2 (as base catalyst), the equilibrium mixture [containing 2% (91)] is then siphoned off. This mixture is then distilled back on to the Ba(OH)2, but only propanone (b.p. 56°) will distil out, the 2% of 2-methyl-2-hydroxypentan-4-one ( diacetone alcohol , 91, b.p. 164°) being left behind. A second siphoning will add a further 2% equilibrium s worth of (91) to the first 2%, and more or less total conversion of (90) — (91) can thus ultimately be effected. These poor aldol reactions can, however, be accomplished very much more readily under acid catalysis. The acid promotes the formation of an ambient concentration of the enol form (93) of, for example, propanone (90), and this undergoes attack by the protonated form of a second molecule of carbonyl compound, a carbocation (94) ... 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

However, these reactions proceed under acid catalysis and assume an initial conversion of the carbonyl compound into cationoid electrophile which then reacts with a covalent nucleophile. The interaction of the carbonyl compounds with amides leads only seldom to the enamides9. Usually the a-hydroxyalkyl amides 8 or the bis-amides (amidals) 9 can be isolated under these conditions3,9. The Af-acylenamines can be then obtained by removal of water from 8, or by elimination of amide molecule from 919,20 (equation 5). 

Characterization of carbonyl compounds. Since it does not possess the evil odor of 1,2-ethanedithiol but condenses readily with aldehydes and ketones under acid catalysis, the reagent is useful for the preparation of characterizing derivatives. Aldehydes and ketones can be dilferentiated by their rate of reaction with the reagent. I. Shashak and B. D, Btrgmann,./. chrm. Stic. C, 100.5 (1966)... 

Under Lewis add catalysis, the reaction of allylsilanes takes place easily with a-enones but not with a,P-unsaturated esters [162]. Because disappointing results were obtained in reactions of allylmetals with a,P-unsaturated carbonyl compounds, reactions of allylsilanes with electrophiles bearing chiral auxiliaries have been examined. Schultz and Lee [1435] performed the T1CI4 catalyzed addition of trimethylallylsilane to compound 7.67 at -78°C. After treatment with methylhy-droxylamine in acidic media, the 1,4-adduct 7.80 was obtained with high ee (Figure 7.56). Under similar conditions, N-enoyloxazolidinone 7.68 (R = Ph) or sultam... 

Indoles react with aldehydes and ketones under acid catalysis - with simple carbonyl compounds, the initial products, indol-3-yl-carbinols are never isolated, for in the acidic conditions they dehydrate to 3-alkylidene-37f-indolium cations those from aromatic aldehydes have been isolated in some cases reaction of... 

Indoles react with aldehydes and ketones under acid catalysis - with simple carbonyl compounds, the initial products, indol-3-ylcarbinols are never isolated, for in the acidic conditions they dehydrate to 3-alkylidene-3//-indolium cations those from aromatic aldehydes have been isolated in some cases reaction of 2-methylindole with acetone under anhydrous conditions gives the simplest isolable salt of this class. Only where dehydration is not possible have hydroxyalkylindoles been isolated, for example from reaction with diethyl mesoxalate. Reaction with 4-dimethylaminobenzaldehyde (the Ehrlich reaction, see section 13.1.7) gives a mesomeric and highly-coloured cation. 

The Diels-Alder reaction of simple a,/3-unsaturated carbonyl compounds generally proceed only under vigorous thermal reaction conditions (150-250°C), " ° even when electron-rich dienophiles are employed. Under vigorous thermal conditions, dimerization and polymerization of the a,jS-unsaturated carbonyl compounds or thermally sensitive electron-rich dienophiles will compete effectively with the desired [4 + 2] cycloaddition. Two experimental methods have been employed to facilitate the 47t participation of simple a,/8-unsaturated carbonyl compounds in Diels-Alder reactions. Lewis acid catalysis has proved effective in accelerating the rate of [4 + 2] cycloadditions of simple a,/3-unsaturated carbonyl compounds with electron-rich olefins [Eqs. (3)-(5)], and it is surprising that this technique has not been... 

Oprean and Schaefer (72LA(765)1) have used protected 2-aminobenzenethiols 86 and 3-acetyl or 3-methoxy-carbonyl-2,5-dimethoxy-l,4-benzoquinones 87 to synthesize 2-hydroxy-3H-phenothiazin-3-ones 89 (Scheme 41). The reaction intermediate is 3-amino-1,4-benzoquinone 88A whose tautomer 88B undergoes dehydration under acid catalysis to provide the final compound 89. 

In the synthesis of pyridines it proved advantageous to make a dihydropyridine and oxidize it to a pyridine afterwards. The same idea works well in probably the most famous quinoline synthesis, the Skraup reaction. The diketone is replaced by an unsaturated carbonyl compound so that the quinoline is formed regiospecifically. The first step is conjugate addition of the amine. Under acid catalysis the ketone now cyclizes in the way we have just described to give a dihydroquinoline after dehydration. Oxidation to the aromatic quinoline is an easy step accomplished by many possible oxidants. 

Like most Lewis acids, SbFs promotes the rearrangement of epoxides to carbonyl compounds, and SbFs is an efficient catalyst for this reaction. However, the migratory aptitude of sub-stitutent groups in the reaction under SbFs catalysis is much less selective compared to that promoted by weak Lewis acids such as Methylaluminum Bis(4-bromo-2,6-di-t-butylphenoxide) Nevertheless, SbFs is well suited for the rearrangement of perfluoroepoxides. Excellent yields of ketones are obtained from the reaction. When diepoxides are used, diketones are obtained as the reaction products (eq 22). ... 

Carbonyl reactions are extremely important in chemistry and biochemistry, yet they are often given short shrift in textbooks on physical organic chemistry, partly because the subject was historically developed by the study of nucleophilic substitution at saturated carbon, and partly because carbonyl reactions are often more difhcult to study. They are generally reversible under usual conditions and involve complicated multistep mechanisms and general acid/base catalysis. In thinking about carbonyl reactions, 1 find it helpful to consider the carbonyl group as a (very) stabilized carbenium ion, with an O substituent. Then one can immediately draw on everything one has learned about carbenium ion reactivity and see that the reactivity order for carbonyl compounds ... 

In 1991, Li and Chan reported the use of indium to mediate Barbier-Grignard-type reactions in water (Eq. 8.49).108 When the allylation was mediated by indium in water, the reaction went smoothly at room temperature without any promoter, whereas the use of zinc and tin usually requires acid catalysis, heat, or sonication. The mildness of the reaction conditions makes it possible to use the indium method to allylate a methyl ketone in the presence of an acid-sensitive acetal functional group (Eq. 8.50). Furthermore, the coupling of ethyl 2-(bromomethyl)acrylate with carbonyl compounds proceeds equally well under the same reaction conditions, giving ready access to various hydroxyl acids including, for example, sialic acids. 

Alcohols can also be prepared from support-bound carbon nucleophiles and carbonyl compounds (Table 7.4). Few examples have been reported of the a-alkylation of resin-bound esters with aldehydes or ketones. This reaction is complicated by the thermal instability of some ester enolates, which can undergo elimination of alkoxide to yield ketenes. Traces of water or alcohols can, furthermore, lead to saponification or transesterification and release of the substrate into solution. Less prone to base-induced cleavage are support-bound imides (Entry 2, Table 7.4 see also Entry 3, Table 13.8 [42]). Alternatively, support-bound thiol esters can be converted into stable silyl ketene acetals, which react with aldehydes under Lewis-acid catalysis (Entries 3 and 4, Table 7.4). 

Reactions were studied under the pseudo first-order condition of [substrate] much greater than [initial dihydroflavin]. Under these conditions, the reactions are characterized by a burst in the production of Flox followed by a much slower rate of Flox formation until completion of reaction. The initial burst is provided by the competition between parallel pseudo first-order Reactions a and b of Scheme 3. These convert dihydroflavin and carbonyl compound to an equilibrium mixture of carbinolamine and imine (Reaction a), and to Flox and alcohol (Reaction b), respectively. The slower production of Flox, following the initial burst, occurs by the conversion of carbinolamine back to reduced flavin and substrate and, more importantly, by the disproportionation of product Flox with carbinolamine (Reaction c followed by d). Reactions c and d constitute an autocatalysis by oxidized flavin of the conversion of carbinolamine back to starting dihydroflavin and substrate. In the course of these studies, the contribution of acid-base catalysis to the reactions of Scheme 3 were determined. The significant feature to be pointed out here is that carbinolamine does not undergo an elimination reaction to yield Flox and lactic acid (Equation 25). The carbinolamine (N(5)-covalent adduct) is formed in a... 

A major problem in the reaction of a,/3-unsaturated carbonyl compounds and alkenes proves to be the competition between hetero Diels-Alder and ene reactions. Intramolecular cycloadditions of 1,6- and 1,7-dienes with ester and cyano groups at the double bond yield the ene product nearly exclusively, but with alkylidene- and benzylidene-ketoesters and 1,3-diketones the Diels-Alder reaction is preferred under thermal conditions, however under Lewis acid catalysis also ene reactions occur [12]. 

Base catalysis is not required for conjugate addition. If the nucleophile is sufficiently enolized under the reaction conditions then the enol form is perfectly able to attack the unsaturated carbonyl compound. Enols are neutral and thus soft nucleophiles favouring conjugate attack, and p-dicarbonyl compounds are enolized to a significant extent (Chapter 21). Under acidic conditions there can be absolutely no base present but conjugate addition proceeds very efficiently. In this way methyl vinyl ketone (butenone) reacts with the cyclic P-diketone promoted by acetic acid to form a quaternary centre. The yield is excellent and the triketone product is an important intermediate in steroid synthesis as you will see later in this chapter. 

Preparation of imines and enamines from carbonyl compounds and amines can be achieved with a dehydrating agent under acid/base catalysis [563]. Basically, primary amines afford imines unless isomerization to an enamine is favored as a result of conjugation, etc (see Eq. 252), and secondary amines afford iminium salts or enamines. These transformations can be conducted efficiently with a catalytic or stoichiometric amount of a titanium salt such as TiCU or Ti(0-/-Pr)4. Equation (247) illustrates an advantageous feature of this method in the imination of a hindered ketone. f-Butyl propyl ketone resisted the formation of the imine even by some methods reported useful for sterically hindered ketones [564,565]. The TiCU-based method works well, however, for this compound, giving the desired imine in high yield within a relatively short reaction period [566]. Imine derivatives such as iV-sulfonylimines could be... 

Although C—C connecting reactions are discussed elsewhere in Comprehensive Organic Synthesis , it may be mentioned that epoxides react regioselectively with carbon monoxide under rhodium catalysis (equation 51) and benzyl bromides undergo carbonylation and subsequent lactonization under the influence of a Pd" catalyst (equation 52). The [2 -( 2] cycioaddition of ketenes to carbonyl compounds, catalyzed by Lewis acids, is a familiar route to 3-lactones (equation 53). 

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