Nucleophilic substitution lithium enolates

Nucleophiles like lithium enolates and organocuprates can be added to the terminus of the allyl ligand of cationic cyclic allyl(carbene)iron complexes to give 4-substituted tricarbonyl[l,(3 )-diene]iron complexes. Subsequent to the nucleophilic addition, a ferra-Claisen rearrangement is supposed to be involved in the reaction mechanism. The free dienes can be released by treatment with ceric ammonium nitrate or alkaline hydrogen peroxide (Scheme 4-65). ... 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Imino-substituted pyridazine 68 reacted in the 5-position with the lithium enolate of ethyl 2-methylpropanoate 69 via an interesting cascade of nucleophilic addition, ring closure via addition-elimination and tautomerization (Scheme 13) <1996JHC1731>. 

Other kinds of propargylic-substituted products were prepared by this procedure. When Grignard reagents such as allylic and homoallylic magnesium bromides are used in place of lithium enolates as carbon-centered nucleophiles. 

Initial reports on the use of simple enolates as nucleophiles in TT-allylpalladium chemistry met with only limited success.77 106 The enolate of acetophenone reacted with allyl acetate in the presence of Pd(PPh3)4, but gave predominantly dialkylated product.106 The use of the enol silyl ether of acetophenone gave only monoalkylated product with allyl acetate and Pd° catalysis, but substituted allyl acetates did not function in this reaction.106 Enol stannanes, however, have been found to give monoalkylated products with a wide variety of allyl acetates (equation 19).106 In situ generation of enol stannanes from lithium enolates and trialkylstannyl trifluoroacetates followed by Pd°-catalyzed allylation has been demonstrated.107... 

Under conditions of kinetic control, the mixed Aldol Addition can be used to prepare adducts that are otherwise difficult to obtain selectively. This process begins with the irreversible generation of the kinetic enolate, e.g. by employing a sterically hindered lithium amide base such as LDA (lithium diisopropylamide). With an unsymmetrically substituted ketone, such a non-nucleophilic, sterically-demanding, strong base will abstract a proton from the least hindered side. Proton transfer is avoided with lithium enolates at low temperatures in ethereal solvents, so that addition of a second carbonyl partner (ketone or aldehyde) will produce the desired aldol... 

Enolate ions can be formed from aldehydes and ketones containing protons on an a-carbon (Following fig.). Enolate ions can also be formed from esters if they have protons on an a-carbon. Such protons are slightly acidic and can be removed on treatment with a powerful base like lithium diisopropylamide (LDA). LDA acts as a base rather than as a nucleophile since it is a bulky molecule and this prevents it attacking the carbonyl group in a nucleophilic substitution reaction. 

Occasionally, it can be useful to run this reaction in reverse, generating the lithium enolate from the silyl enol ether. This can be done with methyllithium, which takes part in nucleophilic substitution at silicon to generate the lithium enolate plus tetramethylsilane. The reason why you might want to carry out this seemingly rather pointless transformation will become clear in Chapters 26 and 27. 

The reactions in this section cover the conjugate (Michael) addition of various lithiated nucleophiles to activated olefins such as enones and enoates. Lithium enolates are formed as intermediates during the addition process. They can be treated as such and trapped, for instance, by an electrophile to provide ketones or esters substituted both in the a and positions. We will focus only on the most important information relevant to the intermediate enolates, and those are rarely discussed in the literature on the Michael addition. The reader can advantageously consult Chapter 14 of the first part of this volume133, which is entirely dedicated to the organolithium additions to double bonds, for a more extensive coverage of the topic. 

FIGURE 1. Stereoface differentiation during the electrophilic substitution and nucleophilic addition of preformed lithium enolate... 

Carbon-centered nucleophiles can also be used to advantage in the reaction with epoxides. For example, the lithium enolate of cyclohexanone 96 engages in nucleophilic attack of cyclohexene oxide 90 in the presence of boron trifluoride etherate to give the ketol 97 in 76% yield with predominant syn stereochemistry about the newly formed carbon-carbon bond <03JOC3049>. In addition, a novel trimethylaluminum / trialkylsilyl triflate system has been reported for the one-pot alkylation and silylation of epoxides, as exemplified by the conversion of alkenyl epoxide 98 to the homologous silyl ether 99. The methyl group is delivered via backside attack on the less substituted terminus of the epoxide <03OL3265>. 

In 1999 Trost and Schroder reported on the first asymmetric allylic alkylation of nonstabilized ketone enolates of 2-substituted cyclohexanone derivatives, e.g. 2-methyl-1-tetralone (45), by using a catalytic amount of a chiral palladium complex formed from TT-allylpaUadium chloride dimer and the chiral cyclohexyldiamine derivative 47 (equation 14). The addition of tin chloride helped to soften the lithium enolate by transmetala-tion and a slight increase in enantioselectivity and yield for the alkylated product 46 was observed. Besides allyl acetate also linearly substituted or 1,3-dialkyl substituted allylic carbonates functioned well as electrophiles. A variety of cyclohexanones or cyclopen-tanones could be employed as nucleophiles with comparable results . Hon, Dai and coworkers reported comparable results for 45, using ferrocene-modified chiral ligands similar to 47. Their results were comparable to those obtained by Trost. 

Similar information is available for other bases. Lithium phenoxide (LiOPh) is a tetramer in THF. Lithium 3,5-dimethylphenoxide is a tetramer in ether, but addition of HMPA leads to dissociation to a monomer. Enolate anions are nucleophiles in reactions with alkyl halides (reaction 10-68), with aldehydes and ketones (reactions 16-34, 16-36) and with acid derivatives (reaction 16-85). Enolate anions are also bases, reacting with water, alcohols and other protic solvents, and even the carbonyl precursor to the enolate anion. Enolate anions exist as aggregates, and the effect of solvent on aggregation and reactivity of lithium enolate anions has been studied. The influence of alkyl substitution on the energetics of enolate anions has been studied. ... 

A variety of C-nucleophiles can be added to 3-thiazolines to give the corresponding substituted thiazolidines <83TL4503>. Among those nucleophiles are organolithium compounds, Grignard reagents, nitronates, and silyl and lithium enol ethers. 

Some typical reactions of 1,1 -difluoroethene with nucleophiles are summarized in Scheme 2.18. Alkoxides [3], trialkylsilyl anion [4], ester enolates [5], and diphenylphosphinyl anion [6] attack the gem-difluorinated carbon of 5. However, it is noteworthy that nucleophilic substitution and proton abstraction are in some cases competitive, and thus s -butyl lithium abstracts the (3 -vinylic proton predominantly to generate vinyllithium. The lithium species can be trapped with an aldehyde, providing difluoroallyl alcohol, which is then hydrolyzed to a, (3-unsaturated carboxylic ester (11) [ 7 ] (Scheme 2.19). Some synthetically useful examples are shown in Schemes 2.20 and 2.21. Tetrathiafulvalene derivative (14) is prepared from difluorinated derivative (13) [8]. An elegant intramolecular version was demonstrated by Ichikawa, which provided a range of cyclized compounds (17), including dihydrofurans, thiophenes, pyrroles, and cyclopentenes, and also corresponding benzo derivatives (20) [2]. 

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