Homoenolates, catalytic generation

One application of this catalytic generation of homoenolate type intermediates is in the stereoselective formation of y-butyrolactones 64 from a,/ -unsaturated aldehydes 62 and their reaction with aldehydes or ketones 63 [60]. (For experimental details see Chapter 14.19.2). Glorius [60a] and Bode [60b] almost simultaneously published their results utilizing a N-heterocyclic carbene generated from a bisar-ylimidazolium salt 65 (IMes). The corresponding disubstituted y-butyrolactones... 

Conjugate addition of catalytically generated zinc homoenolate (cf. Eq. 39) has been used for the stereoselective synth b of a key inl mediate to ( )-cortisone (38). Precedents of the cuprate addition onto a tronr-fused hydrindane such as 35 was expected to give 36 but attack of the nucleophilic copper reagent from the desirable, le hindered oc-side. Although treatm t of the enone 35 with the zinc homoenolate under standard condition (Eq. 39, MCjSiCI/HMPA/ cat. CuBr - MejS) afforded the adduct in quantitative yield, the product was a 1 1 mixture of 36 and 37. In contrast, use of BFj EtjO instead of M iO gave the desired isomer 36 with better than 9S% selectivity with some additional steps... 

The Bode group have documented an NHC-catalyzed enantioselective synthesis of ester enolate equivalents with a,p-unsaturated aldehydes as starting materials and their application in inverse electron demand Diels-Alder reactions with enones. Remarkably, the use of weak amine bases was crucial DMAP (conjugate acid = 9.2) andN-methyl morpholine (NMM, conjugate acid pAa = 7.4) gave the best results. A change in the co-catalytic amine base employed in these reactions could completely shift the reaction pathway to the hetero-Diels-Alder reaction, which proceeded via a catalytically generated enolate. An alternative pathway that occurred via a formal homoenolate equivalent was therefore excluded. It is demonstrated that electron-rich imidazolium-derived catalysts favor the homoenolate pathways, whereas tri-azolium-derived structures enhance protonation and lead to the enolate and activated carboxylates (Scheme 7.71). 

Since these initial reports, the NHC-catalyzed generation of activated carboxylates from a-functionalized aldehydes has been extended to a remarkably wide range of substrate classes. Bode first reported the generation of activated carboxylates from a,p-unsaturated aldehydes as part of his work on the catalytic generation of homoenolates vide infra) These studies were further explored to develop improved catalysts and render this a general process. This work, which identified the uniquely high reactivity of A-mesityl substituted triazolium pre-catalysts as superior to all other catalyst classes for NHC-catalyzed redox reactions of a,p-unsaturated aldehydes, was crucial to the development of the remarkable annulation reactions described below. Zeitler reported analogous... 

Scheme 14.13 NHC-promoted y-lactone forming annulations via catalytically generated homoenolate equivalents (TIPS = triisopropylsUyl).

To date, there have been no reports of C-alkylations of the homoenolates or enolates catalytically generated with NHCs. Fischer and Fu, however, reported an interesting example of an NHC-catalyzed cyclization that proceeds via the... 

In order to separate structural effects from the electronic differences of these two catalyst classes. Bode synthesized chiral imidazolium salt 57 (Scheme 14.28). This allowed direct comparison of imidazolium versus triazolium precatalysts across a number of different reaction manifolds including those involving the catalytic generation of homoenolate equivalents, ester enolate equivalents, and acyl anions. These studies conclusively demonstrated that imidazolium-derived catalysts are superior for homoenolate reactions with less reactive electrophiles, while the triazolium-derived pre-catalysts are preferred for all other reactions. Interestingly, from the currently published body of the work, it does not appear to be any effects from the counterion of the azolium pre-catalysts in the presence of bases. 

The power of NHC catalysts lies in the ability of these heterocycles to promote the transient generation of reactive species, such as acyl anion equivalents or activated carboxylates. Using the mechanistic postulates for these processes, it is possible to predict that the combination of an NHC catalyst and an a,p-unsatu rated aldehyde could lead to the generation of a wide variety of catalytically generated reactive intermediates (Scheme 14.12). The rapid developments of new catalysts and reaction conditions have made possible the selective generation of each of these classes of reactive species, including the synthetically powerful homoenolate and ester enolate equivalents. 

The choice of imidazolium vs. triazolium pre-catalyst is subtler. Triazolium-derived NHCs are nearly always preferred, with the exception of certain processes proceeding via catalytically generated homoenolate equivalents. For example, the y-lactone forming annulations of a,p-unsaturated aldehydes and aromatic aldehydes give extremely poor conversion with triazolium-derived pre-catalysts but proceed in excellent yield with IMes-HCl 19. When more reactive electrophiles, such as a-trifluoromethylketone or saccharine-derived imines, ° are employed, other catalyst classes including N-mesityl substituted triazoliums and thiazoliums again become viable pre-catalysts. This can be attributed to the increased electron donating... 

A-heterocyclic carbenes (NHC) are also efficient organocatalytic tools for generating homoenolate equivalents from a,P-unsaturated aldehydes. These reactive intermediates display a versatile reactivity in a number of catalytic transformations attesting to an important synthetic potential [38]. Recently, Scheldt et al. [39a] accomplished the first enantioselective protonation of a homoenolate species generated by a chiral NHC precursor 93 in the presence of DIE A and an excess of ethanol as the achiral proton source (Scheme 3.46). The suggested mechanism involves an initial addition of NHC 93 to the enal 89 followed by a formal 1,2-proton shift resulting in the formation of the chiral homoenolate equivalent 91. A diastereose-lective P-protonation/tautomerization sequence leads to the acyl triazolinium inter-... 

Homoenolates generated catalytically with NHCs can also be employed for C-C and C-N bond formation. Bode and Glorias have independently accomplished the diastereoselective synthesis of y-butyrolactones by annulation of enals and aldehydes [121, 122]. Bode and co-workers envisioned that increasing the steric bulk of the acyl anion equivalent would allow reactivity at the homoenolate position. While trying to suppress the competing benzoin and enal dimerization the authors comment on the steric importance of the catalyst. Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation. A-mesityl substituted imidazolium salt 200 was found to provide up to 87% yield and moderate diastereoselectivities (Scheme 34). 

Lithium homoenolates derived from carboxylic acids were generated from the corresponding /3-chloro acids by means of an arene-catalyzed lithiation. Chloro acids 186 were deprotonated with n-butyllithium and lithiated in situ with lithium and a catalytic amount of DTBB (5%) in the presence of different carbonyl compounds to yield, after hydrolysis, the expected hydroxy acids (187). Since the purification of these products is difficult, they were cyclized without isolation upon treatment with p-toluenesulfonic acid (PTSA) under benzene reflux, into substituted y-lactones 188 (Scheme 64) . 

Lithinm homoenolates 560 were generated by lithiation of enones 559 with lithium and a catalytic amonnt of naphthalene (4%) in the presence of different carbonyl com-ponnds as electrophiles and a Lewis acid (LiCl, TiCLj, SnBu4, SnCLj, BF3) in THF at... 

Zinc homoenolate reacts with allylic halides and diene monoepoxides under copper catalysis [29]. Treatment of the zinc nomoenolate with a catalytic amount of Cu(II) in a polar solvent (e.g. hexamethylphosphoramide, HMPA, N,N-dimethylacetamide, DMA) generates a copper species which undergoes clean Sn2 allylation reactions Eq. (40). Polar solvents not only accelerate the reaction but greatly improve the SN2 selectivity. A variety of allylating reagents can be employed in this reaction (Table 9). The SN2 /SN2 ratio is particularly high (close to 100%) when the alkylated carbon bears no substituents. The reaction of... 

Recently, Bode et al. were able to demonstrate that the products formed after generation of the homoenolate equivalents 67 are determined by the catalytic base [64]. Strong bases such as KOt-Bu led to carbon-carbon bond-formation (y-butyrolactones), while weaker bases such as diisopropylethylamine (DIPEA) allowed for protonation of the homoenolate and the subsequent generation of activated carboxylates. The combination of triazolium catalyst 72 and DIPEA in THF as solvent required no additional additives and enabled milder reaction conditions (60 °C), accompanied by still high conversions in the formation of saturated esters out of unsaturated aldehydes (Scheme 9.21). Aliphatic and aromatic enals 62, as well as primary alcohols, secondary alcohols and phenols, are suitable substrates. a-Substituted unsaturated aldehydes did not yield the desired products 73. 

Palladium homoenolates readily undergo p-elimination to give a,P-unsaturated carbonyl compounds. Treatment of a mercurio ketone with a catalytic amount of palladium(II) in the presence of CuCh results in the formation of an enone via a 3-palladio ketone (Scheme 3). Treatment of a silyloxycyclopropane (8) with PdCh also generates in situ a palladium homoenolate which then undergoes -elimination (Scheme 3). Heating a mixture of a 3-trichlorostannyl ketone or aldehyde with DMSO results in the formation of an enone or an enal in excellent yield (Scheme 4). ... 

Abstract The discovery and development of new A-heterocyclic carbene-catalyzed reaction is described. Based on inspiration from nature, we have taken thiazolium-based approaches to umpolung reactivity and invented a suite of related reactions involving acyl anions, homoenolate, and enolate nucleophiles all generated under catalytic conditions. 

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