Carbonyl, addition lithium enolate

The reaction is believed to proceed via a six-membered cyclic transition state, analogously to the carbonyl addition of enolates, but the energy differences between boat- and chair-like arrangements are lower for x-sulfinyl carbanions69. Tor tert-butyl sulfoxides only anti- and, vn-products are obtained, arising from the approach onto the same diastereotopic face of the anion, but with different relative topicity. The exchange of lithium by zinc causes an increase of the anft-produci, but attempts to titanate the anion failed (see Table 3)69. 

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

Murai and coworkers reported on operationally simple aldol reactions with lithium enolates generated from carbonylation of silylmethyl lithium species [57]. Upon 1,2-silicon shift, a-silyl acyllithium species can be stereo-selectively converted to (E) lithium enolates that undergo addition to aldehydes to give /3-hydroxy acylsilanes (Scheme 14). 

Diastereoface selection has been investigated in the addition of enolates to a-alkoxy aldehydes (93). In the absence of chelation phenomena, transition states A and B (Scheme 19), with the OR substituent aligned perpendicular to the carbonyl a plane (Rl = OR), are considered (Oc-or c-r transition state R2 Nu steric parameters dictate that predoniinant diastereoface selection from A will occur. In the presence of strongly chelating metals, the cyclic transition states C and D can be invoked (85), and the same R2 Nu control element predicts the opposite diastereoface selection via transition state D (98). The aldol diastereoface selection that has been observed for aldehydes 111 and 112 with lithium enolates 99, 100, and 101 (eqs. [81-84]) (93) can generally be rationalized by a consideration of the Felkin transition states A and B (88) illustrated in Scheme 19, where A is preferred on steric grounds. 

Diastereoselectivity in the aldol and the conjugate additions of 2 -hydroxy-1,T-binaphthyl ester enolates with a variety of carbonyl electrophiles has also been explored the tendency of the ester enolates, generated by BuLi, to react with aldehydes to give threo products preferentially with high diastereoselectivity has been interpreted in terms of an acyclic transition state of chelated lithium enolate involving the aldehyde carbonyl and the 2 -hydroxy group. 

In this study, benzaldehyde and benzaldehyde-methyllithium adduct were fully optimized at HF/6-31G and their vibrational frequencies were calculated. The authors used MeLi instead of lithium pinacolone enolate, since it was assumed that the equilibrium IBs are not much different for the MeLi addition and lithium enolate addition. Dehalogena-tion and enone-isomerization probe experiments detected no evidence of a single electron transfer to occur during the course of the reaction. The primary carbonyl carbon kinetic isotope effects and chemical probe experiments led them to conclude that the reaction of lithium pinacolone enolate with benzaldehyde proceeds via a polar mechanism. 

This strategy was very recently used for the total synthesis of 5-Araneosene. In the first step of the synthesis, methyl rert-butyldimethylsilyl ketone 47 was treated with 2-propenyllithium 48 in ether and then with 2-isopropylallyl bromide 49 in THF to give the (Z)-enol silyl ether 50 in 82% yield. The sequence of reactions that leads to 50 includes (1) carbonyl addition of 48, (2) Brook isomerization and (3) allylation of the resulting ally lie lithium reagent (equation 18) ". ... 

Finally, the addition of the carbanion of 1-chloroalkyl p-tolyl sulfoxides 154 to carbonyl compounds gave the adducts 155, which were treated with alkyllithium such as f-C4H9Li to afford the one-carbon homologated carbonyls compounds 158, from their lithium enolate forms 157, having an alkyl group at the a-position, via the carbenoid /S-alkoxides 156 (equation 53) °. 

Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired... 

This type of addition reaction shown in Eq. 2 and 3 [8,9] is expected to be accelerated either through activation of the carbonyl group of a, 0 -acetylenic ester (ynoates) by acid, or through enhancement of nucleophilicity of ester enolate with a strong base, for example, by use of a lithium enolate. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

The stereoelectronic requirements for carbonyl addition are that electron donation occurs by interaction of die donor with the it orbital of the carbonyl group. To meet the stereoelectronic requirements and explain the diastereoselectivity, the Zimmerman-Traxler model is used. Interaction of the lithium cation with the oxygen of die enolate and of die carbonyl electrophile leads to a six-membered... 

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... 

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... 

One difference between this method and the malonate method is that lithium enolates add direct to the carbonyl group of enals 76 while malonates do conjugate addition. Further, malonate adducts such as 62 normally dehydrate under the reaction conditions while lithium enolates normally give the aldol product 77 without dehydration. 

The aldol reaction is an addition of metal enolates to aldehydes or ketones to form P-hydroxy carbonyl compounds.1 The simplest aldol reaction would be the reaction of acetaldehyde lithium enolate with formaldehyde (Scheme 2.1). As the transition state of this reaction involves six atoms, the aldol reaction is another example where a six-membered transition state is presumed to be operating. The transition state of the aldol reaction is very similar to those of Claisen and Cope rearrangements, and therefore the remarkable facility of the lithium enolate reaction is attributed to the stability of an aromatic transition state.2... 

Aldehydes are so electrophilic that, even with LDA at -78°C, the rate at which the deprotonation takes place is not fast enough to outpace reactions between the forming lithium enolate and still-to-be-deproton ated aldehyde remaining in the mixture. Direct addition of the base to the carbonyl group of electrophilic aldehydes can also pose a problem, reactions which compete with aldehyde eno at formation... 

If the conditions are right, good yields are sometimes observed from k/net/ca//y control led conjugate addition even with lithium enolates. This unlikely outcome is favoured by hindered nucleophiles and conjugated or hindered carbonyls. In these cases the lack of reversibility is not an issue as the aldol product is never formed. In this example the enolate of the t-butyl ketone the hindered nucleophile and the conjugated ketone is rather... 

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