Carbonyl nucleophilic allylation

Double-bond isomerization can also take place in other ways. Nucleophilic allylic rearrangements were discussed in Chapter 10 (p. 421). Electrocyclic and sigmatropic rearrangements are treated at 18-27-18-35. Double-bond migrations have also been accomplished photochemically, and by means of metallic ion (most often complex ions containing Pt, Rh, or Ru) or metal carbonyl catalysts. In the latter case there are at least two possible mechanisms. One of these, which requires external hydrogen, is called the nwtal hydride addition-elimination mechanism ... 

Among all the nucleophilic addition reactions of carbonyl compounds, allylation reaction has been the most successful, partly due to the relatively high reactivity of allyl halides. Various metals have been found to be effective in mediating such a reaction (Scheme 8.4). Among them, indium has emerged as the most popular metal for such a reaction. 

Various allylhalostannanes can transfer allyl groups to carbonyl compounds. In this case, the reagent acts both as a Lewis acid and as the source of the nucleophilic allyl group. Reactions with halostannanes are believed to proceed through cyclic transition states. 

The mechanism for the carbonylation of allylic substrates is considered to be composed of the following processes (a) oxidative addition involving allylic C-0 bond cleavage to form r 3-allyltransition metal complexes (b) CO insertion into the metal-allylic bond and (c) nucleophilic attack to liberate carboxylic acid derivatives (Scheme 6). 

The influence of the amount of amine can be elucidated by mechanistic considerations of the double carbonylation. An allyl halide readily forms an allypalladium halide by oxidative addition to Pd(0) species and the amine can attack the allyl ligand to generate allylamine. However, the nucleophilic attack is a reversible process and CO insertion into the allylpalladium species can take place in the presence of a small amount of amine to allow the formation of the acylpalladium species. Attack of the amine on the coordinated CO giving the carbamoylpalladium species followed by reductive elimination by coupling with another alkenoyl ligand produces the a-keto amide [132],... 

Less reactive allylic alcohols are carbonylated under harsh conditions. However, carbonylation of allylic alcohols proceeds smoothly in the presence of phenol as a nucleophile. Phenyl 4-phenyl-3-butenoate (374) was obtained in 80 % yield from cinnamyl alcohol under 5 atm of CO at 100 °C. The carbonylation may proceed by the formation of allyl phenyl ether, which is a reactive compound [145]. Allyl alcohol was carbonylated under high pressure of CO2 (50 atm) and CO (50 atm) in dioxane to provide 2-butenoic acid as the main product and 3-butenoic acid as the minor product at 110°C. Presumably monoallyl carbonate 375 is generated from... 

Kanai and colleagues developed an enantioselective synthesis of various 2-(2-hydroxyethyl)indole scaffolds via the amido-cupration of allenes followed by the asymmetric addition of carbonyl compounds. Treatment of allene 88 with a copper catalyst forms a stable and highly nucleophilic allyl-copper species, which then adds into benzaldehyde (89) to furnish indole 90. A range of carbonyl compounds are competent in the sequence, including aryl- and heteroaryl aldehydes, alkyl aldehydes, and aryl ketones. This is reported to be the first example of a combined catalytic indole generation and subsequent enantioselective addition of carbonyl compormds (14CS1585). 

Cyanide addition to the lactamic carbonyl group has been described in a reaction in which the cyanide ion acts as a catalyst (Fig. 14).The intermediate acyl cyanide can be attacked by an added nucleophile (allylic, propargylic, benzylic alcohols, aniline, benzylmercaptan). Comparative experiments were carried out using more classical procedures, such as under catalysis by potassium cyanide with stirring at room temperature, and with sodium alkoxides at -78 C. This last method provides the highest yields, up to 95% in most of the cases tested, but the sonochemical method proceeds under less basic conditions. Both methods preserve the integrity of the asymmetric center. 

The titanium-catalyzed diastereoselective nucleophilic allylation of carbonyl compounds has been well studied. In this respect, the titanium Lewis acid catalyzed... 

Secondary alkyl halides Sjvj2 substitution occurs if a weakly basic nucleophile is used in a polar aprotic solvent, E2 elimination predominates if a strong base is used, and ElcB elimination takes place if the leaving group is two carbons away from a carbonyl group. Secondary allylic and benzyiic alkyl halides can also undergo S l and El reactions if a weakly basic nucleophile is used in a pro tic solvent. 

Allylic bromides can also serve as progenitors for nucleophilic organochromium reagents. An elegant example is found in Still and Mobilio s synthesis of the 14-membered cembranoid asperdiol (4) (see Scheme 2).7 In the key step, reduction of the carbon-bromine bond in 2 with chromium(n) chloride in THF is attended by intramolecular carbonyl addition, affording a 4 1 mixture of cembranoid diastereoisomers in favor of the desired isomer 3. Reductive cleav-... 

Lewis acids, particularly the boron trifluroride diethyl ether complex, are used to promote the reaction between allyl(trialkyl)- and allyl(triaryl)stannanes and aldehydes and ketones52-54. The mechanism of these Lewis acid promoted reactions may involve coordination of the Lewis acid to the carbonyl compound so increasing its reactivity towards nucleophilic attack, or in situ transmetalation of the allyl(trialkyl)stannane by the Lewis acid to generate a more reactive allylmetal reagent. Which pathway operates in any particular case depends on the order of mixing of the reagents, the Lewis acid, temperature, solvent etc.55- 58. 

Finally, intermediate cationic allyl complexes of palladium15,16 and ruthenium17, produced from allylic esters by the action of substoichiometric amounts of the metal catalyst, have been electronically inverted by reduction to become nucleophilic anion equivalents, which are capable of carbonyl addition. 

So far, only reactions in which the internal nucleophile is tethered to the nitrogen atom of the A -acyliminium ion have been discussed, however, cyclizations with nucleophiles attached to other positions are also possible. If the nucleophile is connected to the carbon atom adjacent to the carbonyl group, bridged azabicycloalkane derivatives are obtained in high yield by using the more reactive allyl- or propargylsilanes. 

Allylic derivatives are particularly important in the case of boranes, silanes, and stannanes. Allylic boranes effect nucleophilic addition to carbonyl groups via a cyclic TS that involves the Lewis acid character of the borane. 1,3-Allylic transposition occurs through the cyclic TS. 

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