Reaction example using lithium

The first example is a reaction which used lithium chemistry (Scheme 1). 

The treatment of ketoximes with lithium aluminum hydride is usually a facile method for the conversion of ketones into primary amines, although in certain cases secondary amine side products are also obtained. Application of this reaction to steroidal ketoximes, by using lithium aluminum deuteride and anhydrous ether as solvent, leads to epimeric mixtures of monodeuterated primary amines the ratio of the epimers depends on the position of the oxime function. An illustrative example is the preparation of the 3(x-dj- and 3j5-di-aminoandrostane epimers (113 and 114, R = H) in isotopic purities equal to that of the reagent. 

Solvent polarity is also important in directing the reaction bath and the composition and orientation of the products. For example, the polymerization of butadiene with lithium in tetrahydrofuran (a polar solvent) gives a high 1,2 addition polymer. Polymerization of either butadiene or isoprene using lithium compounds in nonpolar solvent such as n-pentane produces a high cis-1,4 addition product. However, a higher cis-l,4-poly-isoprene isomer was obtained than when butadiene was used. This occurs because butadiene exists mainly in a transoid conformation at room temperature (a higher cisoid conformation is anticipated for isoprene) ... 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

Carboxylic esters where R is methyl or ethyl can be cleaved by heating with lithium iodide in refluxing pyridine or a higher boiling amine. " The reaction is useful where a molecule is sensitive to acid and base (so that 10-10 cannot be used) or where it is desired to cleave selectively only one ester group in a molecule containing two or more. For example, refluxing O-acetyloleanolic acid methyl ester... 

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. 

As the final example in this section, a Li-mediated carboaddition/carbocycliza-tion process will be described. Thus, Cohen and coworkers observed a 5-e%o-trig-cy-clization by reaction of the lithium compound 2-349 and a-methyl styrene 2-350 to give 2-352 via 2-351 (Scheme 2.82). Quenching of 2-352 with methanol then led to the final product 2-353 [189]. In this process, 2-349 is obtained by a reductive lithia-tion of the corresponding phenyl thioether 2-348 with the radical anion lithium 1-(dimethylamino)naphthalenide (LDMAN) (2-354). Instead of the homoallylic substance 2-348, bishomoallylthioesters can also be used to provide substituted six-membered ring compounds. 

In contrast to these transformations, Michael additions of simple enolates to acceptor-substituted dienes often yield mixtures of 1,4- and 1,6-addition products27-30. For example, a 70 30 mixture of 1,4- and 1,6-adducts was isolated from the reaction of the lithium enolate of methyl propionate with methyl sorbate30. This problem can be solved by using the corresponding silyl ketene acetal in the presence of clay montmorillonite as acidic promoter under these conditions, almost exclusive formation of the 1,4-addition product (syn/anti mixture) was observed (equation ll)30. Highly regioselective 1,4-additions... 

The first example of a cuprate addition to an acceptor-substituted diene was reported by Naf et al. [9], who used lithium di-(Z)-l-heptenylcuprate in a Michael addition to dienoate 1 (Eq. 4.2). The reaction proceeded highly regioselectively, furnishing a 1 1 mixture of the two isomeric 1,6-adducts 2, which were converted into the Bartlett pear constituent ethyl (2 ,6Z)-2,6-dodecadienoate (3) by basic isomerization. 

The allylic alkylation products represent useful synthons, as exemplified by the reaction sequence outlined in Scheme 10.4. For example, reductive ozonolysis of the allylic alkylation product 15 afforded the y-lactone 16 as a single diastereoisomer. Sequential alkylation with methyl iodide, and reductive alkylation using lithium naphthalenide with allyl iodide furnished the ternary-quaternary substituted y-lactones 17a/17b in 72% overall yield, as a 10 1 mixture of diastereomers favoring 17a [18]. This method provides a versatile approach to the construction of a variety of a-quaternary-/9-ternary stereogenic centers. 

Another potentially useful amination procedure utilizes the reaction of organo-lithium compounds with mixtures of methoxyamine and methyllithium (Eqn. (85)) 343> for example ... 

Acyl silanes can display disparate behaviour when treated with carbon nucleophiles, even of related types5,61149. For example, when aroyl silanes were treated with a Wittig reagent, none of the expected alkenes was obtained, and the only reaction products isolated were silyl enol ether and triphenylphosphine (Scheme 73)182,183. When alkanoyl silanes were treated with Wittig reagents, however, only the normal olefinated vinyl silane products were isolated (Scheme 74)182-184 Under soluble lithium salt conditions, Z-vinyl silanes were produced with very high selectivities the reaction was used to prepare a pheromone component (50) of the sweet potato leaf folder moth (Scheme 75)183. 

Amines usually react with epoxides at the less substituted carbon atom (Scheme4.73) [329, 330], With sterically demanding reaction partners these reactions will often proceed slowly or, as with tetraalkyl epoxides, not at all [252, 331]. Higher reaction rates can be achieved by increasing the concentration of the reactants, by using lithium amides as nucleophiles [332], or by catalysis with Lewis acids [252, 333] or Bronsted acids [334]. Ammonia can also be alkylated by 2,3-dialkyl epoxides (80 °C, 15-60 h [335]). Hydroxymethyl epoxides (but not alkoxymethyl epoxides) can be activated toward nucleophilic attack by amines by use of stoichiometric amounts of Ti(OiPr)4 [336] (third example, Scheme4.73). 

For example, polymers having hydroxyl end groups can be prepared by reaction of polymer lithium with epoxides, aldehydes, and ketones III-113). Carboxylated polymers result when living polymers are treated with carbon dioxide (///) or anhydrides (114). When sulfur (115, 116), cyclic sulfides (117), or disulfides (118) are added to lithium macromolecules, thiol-substituted polymers are produced. Chlorine-terminus polymers have reportedly been prepared from polymer lithium and chlorine (1/9). Although lithium polymers react with primary and secondary amines to produce unsubstituted polymers (120), tertiary amines can be introduced by use of p-(dimethylamino)benzaldehyde (121). 

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