Acetophenone nucleophilic addition reactions

Reductions by NaBKt are characterized by low enthalpies of activation (8-13kcal/mol) and large negative entropies of activation (—28 to —40eu). Aldehydes are substantially more reactive than ketones, as can be seen by comparison of the rate data for benzaldehyde and acetophenone. This relative reactivity is characteristic of nearly all carbonyl addition reactions. The reduced reactivity of ketones is attributed primarily to steric effects. Not only does the additional substituent increase the steric restrictions to approach of the nucleophile, but it also causes larger steric interaction in the tetrahedral product as the hybridization changes from trigonal to tetrahedral. 

There is no doubt that aldehydes are more reactive than ketones toward nucleophiles. However, both carbonyl substrates are functionalized by activated nucleophiles e.g. RLi or RMgX (X=halogen), with poor chemoselectivity. For example, benzaldehyde is not a dominant species to be alkylated in the coexistence of acetophenone. Reetz and co-workers addressed these difficulties by systematic studies on ligand effects in carbonyl addition reactions of RMgL (L=relatively bulky ligand) [31]. Upon reacting a 1 1 mixture of PhCHO and PhCOMe with 1 equiv of RMgL in a competition experiment, the aldehyde reacted essentially exclusively to form adduct 2-H (Table 2-2, entries 2-A). 

Pyrimidine reacts with trimethylsilyl cyanide and benzoyl chloride with aluminum chloride as catalyst, to give the Reissert-type compound (366) <81JHC443>. The intermediate acylpyrimidinium cation (367) adds a soft nucleophile such as the silyl ether of acetophenone, and the adduct rapidly undergoes a second A-quaternization to (368) with a subsequent nucleophilic attack to form (369) (Scheme 61). The reactive intermediate can also be trapped by reactions with heteronucleophiles <88JCS(P1)725>. Intramolecular nucleophilic addition is shown in the formation of the spiran derivative (370) <92JOC2526>. 

The foregoing reaction is probably initiated by nucleophilic addition of the iY-imines to the 2H-azirines to form 36 which may undergo homo-1,5-dipolar cyclization or ring opening followed by cyclization of 1,6-dipoles 37. This novel heterocyclic system was first prepared by the reaction of pyridine N-imines with a-chlorocinnamates, in which azirine intermediates were postulated.164 As a variation, use of azirine intermediates generated in situ from acetophenone oxime O-tosylate or dimethylhydrazone methiodide under the Neber reaction conditions also produces the pyrido[l,2-/>]triazines... 

The established mechanism for pinacolate formation has also been challenged by an analysis of the reaction between acetophenone and TiCl3(DME)-Zn(Cu). Aliquots quenched at various stages of the reaction revealed products from which a nucleophilic addition mechanism could be inferred. DFT calculations indicated that this reaction pathway is more energetically favorable than the corresponding ketyl pathway. 

Potassium or lithium derivatives of ethyl acetate, dimethyl acetamide, acetonitrile, acetophenone, pinacolone and (trimethylsilyl)acetylene are known to undergo conjugate addition to 3-(t-butyldimethylsiloxy)-1 -cyclohexenyl t-butyl sulfone 328. The resulting a-sulfonyl carbanions 329 can be trapped stereospecifically by electrophiles such as water and methyl iodide417. When the nucleophile was an sp3-hybridized primary anion (Nu = CH2Y), the resulting product was mainly 330, while in the reaction with (trimethylsilyl)acetylide anion the main product was 331. 

In contrast to the thermal solvolysis, a rearranged enol ether 45 (and also the hydrolysis product, acetophenone) is formed in addition to the unrearranged product 44. The rearrangement is more apparent in less nucleophilic TFE. The results are best accounted for by heterolysis to give the open primary styryl cation 46 (Scheme 8). This cation gives products of substitution 44 and elimination 30 by reaction with the solvent. Alternatively, 46 can rearrange to the a-phenyl vinyl cation 47 via 1,2-hydride shift, which gives rise to 45 and 30. 

The reaction proceeds via an enamine, since the same product results when the preformed enamine is allowed to react with the acetophenone. An initial addition product (598) can be pictured which may eliminate pyrrolidine to give the enone (599) and hence the chromanone or which may undergo nucleophilic displacement of pyrrolidine by the phenolic moiety (Scheme 226). 

The Michael reaction involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic partners are typically a,fi-unsaturated ketones, esters or nitriles, but other electron-withdrawing substituents can be used to activate the carbon—carbon double bond to nucleophilic attack. A tandem aldol-Michael reaction has been recently described. Wachter-Jurcsak and coworkers66 reported that the reactions involving 2-pyridinecarboxaldehyde, 71, and 2-quinolinecarboxaldehyde with the enolates of acetophenone, 70, afforded the unexpected symmetric l,5-diphenyl-3-(2-heteroaryl)-1,5-pentanediones (Scheme 24). 

The range of substrates in the aldol reaction (and in allylation, see Section 21.2) employing trichlorosilyl reagents is generally restricted to aldehydes, while less-reactive ketones remain essentially inert. However, the exceptionally high nucleophilicity of silyl ketene acetals provides an opportunity to employ ketones as substrates (Scheme 21.14). In the absence of an activator, addition of trichlorosilyl ketene acetal 21.109 to acetophenone (21.108, = Ph, = Me, Scheme 21.14) slowly takes place at 0 °C, paving... 

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