Stabilized anions, allylations

For the deprotonation of less acidic precursors, which do not lead to mesomerically stabilized anions, butyllithium/TMEDA in THF or diethyl ether, or the more reactive, but more expensive,. seobutyllithium under these conditions usually are the most promising bases. Het-eroatomic substitution on the allylic substrate, which docs not contribute to the mesomeric or inductive stabilization often facilitates lithiation dramatically 58. In lithiations, in contrast to most other metalations, the kinetic acidity, caused by complexing heteroatom substituents, may override the thermodynamic acidity, which is estimated from the stabilization of the competing anions. These directed lithiations59 should be performed in the least polar solvent possible, e.g.. diethyl ether, toluene, or even hexane. 

While the chemistry of alkyl and allylic sulfoxide anions is similar to that of phosphine oxides, phosphinates and sulfone stabilized anions (Sections 1.5.2.2.1 -2), the situation is further complicated by the additional stereogenic center at sulfur. Therefore in all cases, asymmetric induction may arise from the stereocenter at sulfur. 

It has been contended that here too, as with the benzene ring (Ref 6), the geometry is forced upon allylic systems by the a framework, and not the 7t system Shaik, S.S. Hiberty, P.C. Ohanessian, G. Lefour, J. Nouv. J. Chim., 1985, 9, 385. It has also been suggested, on the basis of ab initio calculations, that while the allyl cation has significant resonance stabilization, the allyl anion has little stabilization Wiberg, K.B. Breneman, C.M. LePage, T.J. J. Am. Chem. Soc., 1990, 112, 61. 

Extensive theoretical studies have been carried out to probe the nature of the allyl anion. These studies supplement and extend the experimental results. Allyl anion is of special interest because it is the simplest 7r-delocalized carbanion with 4 electrons and 3 Pjr-centers. Much recent theoretical discussion has concerned the role of resonance in the stabilization of such conjugated systems, a stabilization defined as the enthalpy difference between the localized double-bonded system and its conjugated state. The stabilization of allyl anion has generally been attributed to the delocalization of charge associated... 

The reaction of methylenesulphones with allyl halides in the presence of quaternary ammonium salts produces the 1-allyl derivatives [52], unlike the corresponding reaction in the absence of the catalyst in which the SN- product is formed (Scheme 6.5). In contrast, alkylation of resonance stabilized anions derived from allyl sulphones produces complex mixtures [51] (Scheme 6.6). Encumbered allyl sulphones (e.g. 2-methylprop-2-enyl sulphones) tend to give the normal monoalkyl-ated products. Methylene groups, which are activated by two benzenesulphonyl substituents, are readily monoalkylated hydride reduction leads to the dithioacetal and subsequent hydrolysis affords the aldehyde [61]. 

The transition state can be modeled by an acrolein interacting with an allylic anion. A thioalkoxy substituent at position 4 or 6 stabilizes the allylic anion and favors the reaction. In fact, the 3-4 bond rupture becomes so easy that the reaction then occurs by a stepwise mechanism. MeO, being a donor, destabilizes the anion and impedes the reaction. 

The use of a metal catalyst, such as palladium, also provides for some asymmetric induction when an allylic system is treated with a stabilized anion (Scheme 22.13)82-103 or with other nucleophiles.82,87,104-111 This approach also allows for the kinetic resolution of allyl acetates.104,112... 

The alkylation of sulfur-stabilized anions has been the subject of an excellent recent review633. Anions adjacent to a wide range of sulfur functionalities may be alkylated readily, the most common being sulfoxide and sulfone a-anions. In the synthesis of retinoic acid derivatives and vitamin A634-636, a-sulfonyl anions have been alkylated with an co-acetoxy-containing allyl halide in good yield (equation 96). 

Although free-radical halogenation is a poor synthetic method in most cases, free-radical bromination of alkenes can be carried out in a highly selective manner. An allylic position is a carbon atom next to a carbon-carbon double bond. Allylic intermediates (cations, radicals, and anions) are stabilized by resonance with the double bond, allowing the charge or radical to be delocalized. The following bond dissociation enthalpies show that less energy is required to form a resonance-stabilized primary allylic radical than a typical secondary radical. 

Just as delocalization stabilizes the allyl cation, anion, and radical, so too is the amide group stabilized by the conjugation of the nitrogen s lone pair with the carbonyl group. 

The first step is conjugate addition of the highly stabilized anion. The intermediate enolate then closes the three-membered ring by favourable nucleophilic attack on the allylic carbon. The leaving group is the sulfinate anion and the stereochemistry comes from the most favourable arrangement in the transition state for this ring closure. The product is the methyl ester of the important chrysan-themic acid found in the natural pyrethrum insecticides. 

Dipoles without a double bond but with internal octet stabilization, the allyl anion type, are shown in Table 4. 1,3-Dipoles without octet stabilization, such as vinylcarbenes and iminonitrenes, are all highly reactive intermediates with only transient existence. 

Stereoselective, conjngate allylation of more remote positions nsing aUyl trimethylsilane and TiCU is possible. Further transformation by nucleophilic addition and ringclosing metathesis affords fused polycychc ring systems (Scheme 88). Stabilized anions and organocopper see Copper OrganometaUic Chemistry) reagents also participate in Michael-type additions to complexed Q, /3-unsaturated aromatic enones. 

There are many examples of BF3-OEt2 promoted openings of (1) by carbanions, including sulfone-stabilized anions, vinylic anions, allylic anions, and phosphonate-stabilized anions. For example, the lithium anion of trans-1,2-Bis(tributylstannyl)ethylene opens (5)-(l) in the presence of BF3-OEt2 in THF at —78°C, affording fra/w-l-(tributylstannyl)-5-tosyl-4-hydroxypent-l-ene in 50% yield the latter is converted into oxirane (3) in 76% yield on treatment with powdered Sodium Hydroxide in monoglyme. ... 

A high degree of asymmetric induction has been realized in the carbanion-accelerated Claisen rearrangement of phosphorus-stabilized anions. Treatment of 1,3,2-oxazaphosphorinane (166) with freshly prepared lithium dimsylate led to a 95 5 ratio of a-methyl ketones (167) and (168) (Scheme 33). Li coordination combined with steric interactions provide the necessary control elements for stabilization of the highly organized allyl anion conformation (169). 

With anionic allylic sources, highly polar aprotic solvents increase the amount of lone pair alkylation because poor solvent stabilization of the anion leaves the heteroatom end less hindered by solvent. Conversely, groups bound to the heteroatom increase the steric hindrance about it, and therefore decrease the tendency toward heteroatom alkylation. For example, enamines (R2N-C=C) tend to alkylate on carbon rather than nitrogen (as shown in Section 8.4.5). 

Reaction (7.7) involves the reversible removal of a proton from an allylic position by a base to give the stabilized anion 10, which then reacts suprafacially with tra w-l,2-diphenylethene to give the cyclopentane product in which the relative stereochemistry of the two phenyl groups has been preserved. 

More exotic electrophiles include cobalt-stabilised cations derived the alcohol (S)-138 made by a sequence of reactions that shows the stability of allyl silanes to bases. The cuprate from Z-135 adds to a single enantiomer of the epoxide (5)-136 and the tosylate in the product (S) -137 is displaced by a Co(I) anion to give the intermediate (S)-138 as a stable orange solid.38... 

Since 1988 the chemistry of 2-aryl-2,l-benzothiazine 2-oxides has been studied in some detail. The benzothiazine oxide (112) can be smoothly deprotonated by n-BuLi, and the resulting sulfoximine-stabilized anion can be trapped by an assortment of electrophiles (Scheme 20). However, none of the alkylation reactions showed any diastereoselectivity (e.g., (113) was obtained as a 2.5/1 isomeric mixture <88TL5229> no allylic deprotonation was observed). 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

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