Acyl compounds, nucleophilic addition-elimination

Carbonyl Compounds II Nucleophilic Acyl Addition, Nucleophilic Acyl Substitution, and Nucleophilic Addition-Elimination Reactions of a, 6-Unsaturated Carbonyl Compounds... 

As we begin now to explore the syntheses of carboxylic acid derivatives, we shall find that in many instances one acid derivative can be synthesized through a nucleophilic addition—elimination reaction of another. The order of reactivities that we have presented gives us a clue as to which syntheses are practical and which are not. In general, less reactive acyl compounds can be synthesissed from more reactive ones, but the reverse is usually difficult and, when possible, requires special reagents. 

CHAPTER 17 CARBOXYLIC ACIDS AND THEIR DERIVATIVES Nucleophilic Addition-Elimination at the Acyl Carbon 17.53 An alternative synthesis of ibuprofen is given below. Supply the structural formulas for compounds A-D ... 

Acyl transfer reactions (Section 17.4) A reaction in which a new acyl compound is formed by a nucleophilic addition-elimination reaction at a carbonyl carbon bearing a leaving group. 

The relative reactivities toward nucleophilic addition-elimination are acyl chlorides > acid anhydrides > esters carboxylic acids > amides > carboxylate ions. Hydrolysis, alcoholysis, and aminolysis are reactions in which water, alcohols, and amines, respectively, convert one compound into two compounds. 

Acyl halides undergo addition-elimination reactions in which nucleophiles displace the halide leaving group. These compounds are so reactive that catalysts are usually not necessary for their conversion. 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

Ethynyl carbinols (propargylic alcohols) such as 134 (Scheme 2.58) represent another important group of oxidation level 3 compounds. Their preparation involves nucleophilic addition of acetylides to the carbonyl group, a reaction that is nearly universal in its scope. Elimination of water from 134 followed by hydration of the triple bond is used as a convenient protocol for the preparation of various conjugated enones 135. Easily prepared O-acylated derivatives are extremely useful electrophiles in reactions with organocuprates, which proceed with propargyl-allenyl rearrangements to furnish allene derivatives 136. 

In unsaturated aliphatic systems the most important reactions are those of czirbonyl compounds of the type —COX, in which X is a good leaving group such as halogen. In general, most displacement reactions of anionic nucleophiles on the carbonyl carbon atom of acyl halides involve an addition-elimination mechanism " (e.g. equation 16). In such reactions bond-formation is in advance of bond-rupture... 

As outlined above, isolated acyl Meldrum s adducts react with amines to afford the corresponding [3-ketoamides. More interestingly, nonbasic amine derivatives, such as carbamates, amides, and hydroxylamines, as well as alcohols, can also react with these adducts to effectively provide the corresponding 1,3-dicarbonyl compounds. To investigate the effect of the nature of the nucleophile, we initiated these studies with BocNHOBoc, because it is nonbasic and is a much weaker bulky nucleophile than the triazole 4. Comparison of the k s with other weak or strong nucleophiles would reveal whether nucleophilic addition or the following elimination is involved in the rate-determining step. 

The second reaction is free of metal catalysis. It takes place in the presence of acetyl chloride, proceeds faster, and results in compounds which have the same core structure of indolyl imidazoles, but with the loss of the A-oxide group The imidazole ring is activated for a nucleophilic attack by acylation of the Al-oxide function, and the reaction proceeds according to addition-elimination protocol (Scheme 71) [212]. 

As mentioned before, all acyl compounds participate in the addition-elimination process. Acid chlorides are especially reactive toward nucleophiles. Their carbonyl groups, being the least stabilized by resonance, have the highest energy and are the most reactive. So, an initial addition reaction with a nucleophile is relatively easy. The chloride atom of acid chlorides is an excellent leaving group, and sits poised, ready to depart once the tetrahedral intermediate has been formed... 

Many nucleophiles are effective in the addition—elimination reaction of acid chlorides, and a great many acyl compounds can he made using acid chlorides as starting materials. 

Cyclopentadienes can be prepared by double Michael addition of zirconacyclopentadienes with propynoates <1997CC2069> or nucleophilic attack of zirconacyclopentadienes on acyl halides mediated by copper(l) chloride and accompanied by elimination <1995CC1503, 1996TL7521>. Tetraethylzirconacyclopentadiene with benzal chloride in THF in the presence of copper(l) chloride and DMPU yield l,2,3,4-tetraethyl-5-phenylcyclopenta-l,3-diene <2000TL7471>. A series of other similar compounds were prepared from tetra- -propylzirconacyclopenta-diene and 0 ,Q -dichlorotoluene, tetra- -butylzirconacyclopentadiene and 0 ,Q -dichlorotoluene or 0 ,Q -dibromotoluene, as well as some other combinations. Tetraethylzirconacyclopentadiene reacts with l,l-dibromo-l-alkene-3-ynes under the same conditions (copper(l) chloride and DMPU) to yield alkynylfulvenes. 

The procedure shown here describes the preparation of a-silyl ketones from aldehydes and acyl chlorides. The a-silyl ketones undergo Cram addition of various nucleophiles to produce diastereoselectively p-hydroxysilanes. These compounds are then subjected directly to elimination in situ under basic or acidic conditions to produce the corresponding alkenes. 

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