From enolate dianions

Enolate dianions from 3-benzoyl-2-fc-rt-butylT-methyl-5-oxo-4-imidazolidineacetic and -propanoic acids 4, obtained from aspartic and glutamic acid, have also been used in diastcreose-lective alkylation reactions (see Table 4)7. 

On the other hand, an electron-withdrawing substituent, particularly a carbonyl group 63, will attract the anion 64 and again we get a non-conjugated product. If the acid 63 R=H is used, the less stable, non-conjugated anion in the intermediate 64 R=H captures the proton from the acid giving the enolate dianion 66 as the immediate product. This can be combined with electrophiles such as alkyl halides as we shall see. 

Three examples of nitrile-stabilized enolates have been described by Boche et al. Two of these structures incorporate the anion of phenylacetonitrile. Hie TMEDA-solvated dimer (178) crystallizes out of benzene solution however, the mixed nitrile anion LDA-(TMEDA)2 complex (179) is obtained when excess LDA is present. This latter complex has often been mistaken as a geminal d anion since it frequently gives products that appear to arise from a dianion. The crystal structure of the anion l-cyano-2,2-dimethylcyclopropyllithium (180) consists of an infinite polymer (181) that is solvated by THF. Interestingly, there are C— Li contacts in this structure and the carbanionic carbon remains tetrahedral. 

Unsaturated Esters.—A full report has been published on non-stereoselective approaches to a,/3-unsaturated esters using condensations between aldehydes or ketones and the dithiocarbonate anion (116) or dianion (117) derived from ethyl mercaptoacetate (c/. 1, 193 2, 198). The reactions involve the intermediacy of a,j8-episulphide esters, and give overall yields of between 60 and 80%. The related carbanion (118) displays similar properties. A more stereoselective approach to a,/3-unsaturated esters is the displacement of phosphate groups from enol phosphates by dialkylcuprates (Scheme 42). The dianion derived from... 

P-Ketophosphonates are valuable intermediates in the realm of Homer-Emmons alkenation methodology. Acyclic variants are difficult to obtain from enol phosphates due to competing alkyne and allene formation. One solution utilized the dianion derived from a-bromo ketones and trapping with diethyl phosphorochloridate however, only moderate yields of P-keto phosphonates were reported. The most efficient procedure utilizes the anion derived from dialkyl methylphosphonate, addition to an aldehyde, followed by oxidation (eq 8). ... 

Addition of hydride ion from the catalyst gives the adsorbed dianion (15). The reaction is completed and product stereochemistry determined by protonation of these species from the solution prior to or concurrent with desorption. With the heteroannular enolate, (13a), both cis and trans adsorption can occur with nearly equal facility. When an angular methyl group is present trans adsorption (14b) predominates. Protonation of the latter species from the solution gives the cis product. Since the heteroannular enolate is formed by the reaction of A" -3-keto steroids with strong base " this mechanism satisfactorily accounts for the almost exclusive formation of the isomer on hydrogenation of these steroids in basic media. The optimum concentration of hydroxide ion in this reaction is about two to three times that of the substrate. 

Thus, the dianion derived from a-amino acid substitutes the /1-chloride to give the ester of 2-(phenylsulfonyl)ethenyl amino acid and subsequent desulfonylation provides N-(benzoyl)vinylalanine methyl ester (62) (equation 61). The conjugate addition of enolates to methyl styryl sulfone (63) and subsequent intramolecular addition to the carbonyl moiety provide a synthetically valuable method for the construction of bicyclic and tricyclic skeletons52. Desulfonylation of the cyclization product 64 with sodium in ethanol-THF gives the diene 65 in good yield (equation 62). 

A careful study of the alkylation of several enolates of dialkyl malate esters has been reported.74 These esters form dianions resulting from deprotonation of the hydroxy... 

The stereochemistry is controlled by a stereoelectronic preference for protonation perpendicular to the enolate system and, given that this requirement is met, the stereochemistry normally corresponds to protonation of the most stable conformation of the dianion intermediate from its least hindered side. 

When monomeric metaphosphate anion POf (102) is generated form the phos-phonate dianion 170 in the presence of the hindered base 2,2,6,6-tetramethylpiper-idine, it undergoes reaction with added carbonyl compounds147), Thus, it phosphoryl-ates acetophenone to yield the enol phosphate, whereas in the presence of acetophenone and aniline the Schiff base is formed from both compounds, probably by way of the intermediate C6H5—C(CH3) (OPO e) ( NH2C6HS). This reactivity pattern closely resembles that of monomeric methyl metaphosphate 151 (see Sect. 4.4.2). 

Nitroalkenes react with lithium dianions of carboxylic acids or with hthium enolates at -100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives y-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives a,P-unsaturated ketones (Eq. 4.53).67... 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

When the lithium dianion was prepared in a completely different manner, viz from an a,j -epoxy ester 8 by treatment of the latter with lithium in liquid ammonia and tetrahydrofuran at - 78 C, alkylation experiments (CH3I, — 40 °C) gave the expected a-alkyl- -hydroxy ester 10, but in a ratio of only 4 1 in favor of the anti-isomer and not in the usual 19 1 ratio15. This result could be interpreted as a direct consequence of the participation of an intermolecularly chelated dianionic enolate such as 7 which gains importance because of the use of ammonia as a cosolvent. 

The stability of the enolates 13, derived from 1,3-dioxan-4-ones 12, is unexpectedly high enough for them to be alkylated93. At — 40°C after 2 hours more than 60% of the enolate 13 (R1 = CH3) is still present. Methylation of this enolate shows an even higher diastereoselectivity than methylation of the dianion of ethyl /i-hydroxybutanoate (Section 1.1.1.3.2.1.1.1.2.). 

Treatment of the pyrrolidone mixture 5 with 2.1 equivalents of lithium diisopropylamide at — 78 °C for 1 hour, and then — 25 °C for 1 hour, yields the dianionic enolate. Alkylation at -117 °C or - 78 °C then provides a 50-80% yield of the (3S)-alkylated 3,4-tran.v-product as a 85 15 mixture of the 5-epimers19,20. No trace of the 3,4-a.s-product could be detected by NMR. The electrophile attacks from the side opposite to the alkoxide group. Evidently, in this case, the stereogenic center in the 5-position has no influence on the stereoselectivity. 

The opportunity for chelation in the various enolate intermediates offers a possible explanation for the observed diastereoselectivities. In the dianions derived from l-acyl-2-pyrrolidinemethanols strong chelation of both of the lithium cations should lead to a rigid enolate structure 9. It is reasonable to assume that the pyrrolidine ring is locked in one conformation. Since, according to models, it is difficult to attribute the observed high diastereoselectivity to steric hindrance, it is probable that the lone pair on the nitrogen directs the facial selectivity of electrophilic attack (see Section 1.1.1.3.3.1.) to one side of the enolate a-carbon. 

The alkylation of enolates from 1-acyl-2-pyrrolidinemethanols is not limited to compounds carrying two a-hydrogens. An example of an interesting type of dianion is that derived from the a-oxoamide 17, which is then alkylated with iodomethane to give a 87 13 ratio of diastereomers, as determined by NMR7. 

Aromatic esters may be used to aroylate the dianions derived from 1,3-diketones by reaction with potassium amide (60JOC538). Not only are acetyl and benzoyl acetones suitable for reaction, but alicyclic diketones and 2-hydroxyacetophenone are also acceptable. Cycliz-ation of the triketones occurs in cold sulfuric acid, presumably via the enolic form and the hemiacetal (Scheme 132). 

In contrast to the ester enolates, the a.O-carboxylic dianions are intrinsically more reactive and their use in conjugate reactions is thus limited. Typically, a-substituted-a.O-carboxylic dianions add exclusively to a,(3-unsaturated esters155a and nitroalkenes,155b while additions to ot,(3-enones are sensitive to the substitution pattern of the enones.155c>d Notable is the conjugate addition of dihydrobenzoic acid dianions (207), from Birch reduction of benzoic acids, to oi,3-unsaturated esters (Scheme 77).155e... 

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

The mechanism of the chemical reduction of enones with metal (Li, Na, etc.) in liquid ammonia can be described by the following equation in which the substrate 212 receives two electrons from the metal to give the dianion intermediate 213. This intermediate is then successively transformed into the enolate salt 214 and the ketone 2T5 with an appropriate proton donor source. It can readily be seen that the stereochemical outcome of this reaction depends on the stereochemistry of the protonation step 213 - 214. An excellent review on this topic has been recently written by Caine (60). This subject will be only briefly discussed here. 

Ivanov Reagents are carboxylate enolates (enediolates, or carboxyl 0 acid dianions) derived from phenyl acetic acid or... 

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