Nucleophilic addition reactions lithium salts

Substituted derivatives of 3,4-didehydropyridine have also been prepared, and these have been utilized in a variety of cycloaddition and nucleophilic addition reactions (82T427 89ACR275). A recent example involves the synthesis of azaanthraquinones by reaction of the pyridyne with the lithium salt of 3-cyanophthalide (Scheme 156), in a sequence that also involves the intermediacy of a 3-pyridyl carbanion (88H2643). 

The other major synthetic use of alkyne anions is their reaction with ketones and aldehydes to give an alkynyl alcohol via nucleophilic acyl addition. The lithium salt of 1-propyne, for example, reacted with aldehyde 40 to give alcohol 41 as part of Smith s synthesis of (+)-acutiphycin.50 The reaction is selective for ketones and aldehydes in the presence of acid derivatives, if the acetylide is not present in large excess. l... 

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. 

In the reduction of acids there is a tendency for the lithium salt, RCO20Li to separate from the ethereal solution, and thus bring reduction to a halt this can be avoided by first converting the acid to a simple, e.g. Me or Et, ester. In the reduction of the latter, the initial nucleophilic attack by AIH4 results in an addition/elimination reaction—OR is a good leaving group in (40)—followed by normal attack, as above, on the resultant carbonyl compound (41) to yield the primary alcohol (42) ... 

Reactions of allylic electrophiles with stabilized carbon nucleophiles were shown by Helmchen and coworkers to occur in the presence of iridium-phosphoramidite catalysts containing LI (Scheme 10) [66,69], but alkylations of linear allylic acetates with salts of dimethylmalonate occurred with variable yield, branched-to-linear selectivity, and enantioselectivity. Although selectivities were improved by the addition of lithium chloride, enantioselectivities still ranged from 82-94%, and branched selectivities from 55-91%. Reactions catalyzed by complexes of phosphoramidite ligands derived from primary amines resulted in the formation of alkylation products with higher branched-to-linear ratios but lower enantioselectivities. These selectivities were improved by the development of metalacyclic iridium catalysts discussed in the next section and salt-free reaction conditions described later in this chapter. 

Nucleophilic addition takes place at C-1, and this is considerably enhanced if the reaction is carried out upon an isoquinolinium salt. Reduction with lithium aluminium hydride [tetrahydroaluminate(III)] in THF (tetrahydrofuran), for example, gives a 1,2-dihydroisoquinoline (Scheme 3.15). These products behave as cyclic enamines and if isoquinolinium salts are reacted with sodium borohydride [tetrahy-droboronate(III)] in aqueous ethanol, further reduction to 1,2,3,4-tetrahydroisoquinolines is effected through protonation at C-4 and then hydride transfer from the reagent to C-3. 

The reacuons of electrophihc tnflyl sources with nucleophiles were investi gated The reaction of tnfhc anhydride with an organolithium reagent is not synthetically promising because of ditnflylation and other side reactions [20] When phenyllithium reacts with tnfhc anhydnde, dimerization products and acetylenic Michael diadducts are observed [20] (equation 17), but using the sodium salt of the alkynes instead of the lithium salt provides the alkynyl tnfluoromethyl sulfones [21] (equation 18) (Table 7) Alkynyl tnfluoromethyl sulfones are of synthetic interest, because they show a pronounced reactivity toward nucleophiles in addition reactions and cyclopentadiene in Diels-Alder reactions [21] (Table 7)... 

The lithium salt of indole can be alkylated or vinylated by ethylene complexed with PdCl2. These reactions follow patterns established for Pd-catalyzed addition of many other nucleophiles and presumably involve an organopalladium intermediate which can either undergo elimination to form the N-vinylindole or reduction to give the N-ethylindole as shown in Scheme 21 (81JOC2215). Although at the present time this procedure would seldom be competitive with the use of SN2 conditions for alkylation, the development of vinylation conditions which were catalytic in Pd might be useful. 

The chlorine atom of 5-chlorodibenzoborole 41 has previously been displaced by a variety of nucleophiles including hydride ion from sodium triethylborohydride <1996CHEC-II(2)919>. However, the reaction of 41 with excess lithium hydride in THF goes a step further to give lithium dihydrodibenzoborole 20. It is postulated that the reaction occurs by addition of hydride ion to 41, loss of lithium chloride from lithium salt 45, and addition of hydride ion to unsubstituted dibenzoborole (Scheme 4) <2000JOM168>. 

Additions of the Michael type of nucleophiles to the carbon-carbon double bond of thiete 1,1-dioxides to give 3-substituted thietane 1,1-dioxides occur readily. The addition of hydrogen has been discussed in Section A. Nucleophiles include cyanide, the anion of nitroethane, the lithium salt of r-butyl o-tolyl sulfone, dimethylamine, cyclohexylamine, ethoxide, and hydrogen sulfide. The reaction is exemplified by the synthesis of 278. Additions to 3-chloro-2H-thiete 1,1-dioxide most likely proceed by an addition-elimination mechanism an example is shown for the addition of the anion of dimethylmalonate to give 279. The replacement of a 3-morpholinyl group by a 3-A methyl-A-phenylamino group in thiete 1,1-dioxide is another example of addition-elimination. An addition of ethoxide with elimination of p-nitrophenyl anion may occur with 268 (Ar = / -N02C6H4). " Addition of bromine via N-bromo-succinimide to the double bond of 4-phenyl-2H-thiete 1,1-dioxide occurs only in 1.5% yield. ... 

This seemingly simple result may have far reaching consequences. For example, it may help to explain the effect of added lithium salts in nucleophilic additions to cyclohexanones as discussed earlier in this chapter. Thus, model (63) shown in Figure 472.135-137 explain the enhancement of rate and may also be relevant to the origins of stereoselectivity in this reaction. Of course, the exact location of the lithium atom and the aggregation state of the adding nucleophile are subject to speculation, since for lithium these parameters seem to be highly variable. 

The lithium salt of diethyl 2-propenylphosphonate behaves as an ambident nucleophile in reactions with a variety of electrophilic reagents. In reaction with methyl methacrylate, the intermediate formed in the lirsl step (conjugate addition at the y-carbon of the phosphonate) has a carbanionic center developed at C-5. The second step involves intermolecular conjugate addition to a second molecule of methyl methacrylate, yielding an intermediate capable of the final 1,6-cyclization to produce a phosphonylated polyfunctionalized derivative of cyclohexane in good overall yield (60%, Scheme 8.63). ... 

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