Enolates extended

Introduction The extended enolate problem Kinetic and thermodynamic control Wittig and Horner-Wadsworth-Emmons Reactions Extended Aza-Enolates Extended Lithium Enolates of Aldehydes Summary a-Alkylation of Extended Enolates Reaction in the y-Position Extended Enolates from Unsaturated Ketones Diels-Alder Reactions Extended Enolates from Birch Reductions The Baylis-Hillman Reaction The Synthesis of Mniopetal F 

A Synthesis of Vertinolide Using a -and y-Extended Enolates Conclusion Extended Enolate or Allyl Anion  

The extended enolate problem1 is easily stated but not so easily solved. If an unsaturated ester 1 is treated with base, a conjugated enolate 2 is formed. The conjugated ester 3 can form the same enolate 2 by loss of one of the marked protons. This intermediate 2 is an extended enolate, extended by conjugation into a double bond and interesting because a new dimension of versatility is added to its reactions. Enolates normally have to choose between reaction at oxygen or carbon, but the extended enolate may also choose at which carbon to react. This chapter is about the reasons for that choice. 

Organic Synthesis Strategy and Control, Written by Paul Wyatt and Stuart Warren Copyright 2007 John Wiley Sons, Ltd 

The kinetic site for reactivity is the a position, where the coefficient of the HOMO is larger,2 3 but reaction at the y position gives the more stable conjugated product. Ester 5 is the kinetic product and 7 and 10 are thermodynamic products. Early experiments4 soon revealed that reactive lithium enolates such as 12 were alkylated almost exclusively with kinetic control at the a position, making synthesis of rings 14 possible by double alkylation.5 

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The Y appendage of 2-cyclohexenone 191 cannot be directly disconnected by an alkylation transform. (y-Extended enolates derived from 2-cyclohexenones undergo alkylation a- rather than y- to the carbonyl group). However, 191 can be converted to 192 by application of the retro-Michael transform. The synthesis of 192 from methoxybenzene by way of the Birch reduction product 193 is straightforward. Another synthesis of 191 (free acid) is outlined in... 

Conversion of PGA2 to the highly sensitive PGC2 was accomplished by deconjugation of the enone system by formation of the y-extended enolate using rm-alkoxide as base and a-protonation by pH 4 buffer. 

As with any transformation, this methodology is not without limitations. For example, the y-hydroxy unsaturated ester 80 failed to undergo the desired cyclization [43]. Instead, elimination occurred, presumably leading to the extended enolate 82 which condenses onto the aldehyde unit to afford the [3.3.0] adduct 83 in a 45% yield. 

Organolithium 482 has been represented by the extended enolate structure 487 (Scheme 191), though the chirality of some analogues of 482 argues in favour of the localized structure 482 °". ... 

Treatment of the potentially electrophilic Z-xfi-unsaturated iron-acyl complexes, such as 1, with alkyllithium species or lithium amides generates extended enolate species such as 2 products arising from 1,2- or 1,4-addition to the enone functionality are rarely observed. Subsequent reaction of 2 with electrophiles results in regiocontrolled stereoselective alkylation at the a-position to provide j8,y-unsaturated products 3. The origin of this selective y-deproto-nation is suggested to be precoordination of the base to the acyl carbonyl oxygen (see structures A), followed by proton abstraction while the enone moiety exists in the s-cis conformation23536. 

Conditions employed for the generation of extended enolates by y-deprotonation of Z-oc,/ -un-saturated iron-acyl complexes are presented in Table 3. 

Reaction of Z-a./j-unsaturated iron-acyl complexes with bases under conditions similar to those above results in exclusive 1,4-addition, rather than deprotonation, to form the extended enolate species. However, it has been demonstrated that in the presence of the highly donating solvent hexamethylphosphoramide, y-deprotonation of the -complex 6 occurs. Subsequent reaction with electrophiles provides a-alkylated products such as 736 this procedure, demonstrated only in this case, in principle allows access to the a-alkylatcd products from both Z- and it-isomers of a,/j-unsaturated iron-acyl complexes. The hexamethylphosphoramide presumably coordinates to the base and thus prevents precoordination of the base to the acyl carbonyl oxygen, which has been suggested to direct the regioselective 1,4-addition of nucleophiles to -complexes as shown (see Section 1.1.1.3.4.1.2.). These results are also consistent with preference for the cisoid conformations depicted. 

The effect of variation of the counterion or phosphane ligand on the alkylation of these extended enolates remains unexplored. Electrophiles that have been successfully reacted with extended enolate species to generate new C —C bonds are limited to primary iodoalkanes and (bromomethyl)benzene (see Table 8)71. 

The absence of a hydroxyl group from C-2 makes elimination of the 4-hydroxyl group impossible, but two other reactions are possible for 57. The more important is, apparently, the formation, between C-l and C-4, of a 2,5-dihydrofuran ring that is readily dehydrated to the furan. A competitive reaction, namely, the elimination of the 5-hydroxyl group by an extended enolization, would lead to formation of carbocyclic compounds. 

During the dehydration of pentoses in acidic solution, the cis and trans 2-enes (homologs of 44 and 46 see p. 177) react rapidly to form the 3-enes, 94a and 94b. Anet8 has presented evidence for the existence of cis and trans forms of the 6-carbon 2-enes. The relative proportion of the geometrical isomers 94a and 94b is controlled by the ratio of the cis and trans forms of the reacting 2-enes and by the rate of interconversion through the tautomer, 72. The trans form (94a) is unable to cyclize, whereas the cis isomer (94b) could readily cyclize to 28 and this could be dehydrated to 2-furaldehyde (27). Formed by extended enolization of 94, the diene 72 has the electronic arrangement needed for cyclization to afford 75a, a tautomer of re-... 

One interesting property of quinone methide 63 is that the terminal carbon of the extended conjugated system lies in both an extended quinone methide (carbons marked by +) and an extended enol (carbons marked by ). This carbon reacts as both a base in undergoing protonation to form a quinone (upper pathway, Scheme 30A) and a Lewis acid in undergoing addition of nucleophilic... 

The quinone methide carbon of 71 is also the terminal carbon of an extended enol, and therefore reacts as both a nucleophile and electrophile (Scheme 32). This carbon shows a higher relative reactivity with electrophiles compared with nucleophiles than is observed for the corresponding terminal quinone carbon of mitomycins (Scheme 30A).73 Furthermore, the addition of nucleophiles to 71 is readily reversible, but the nucleophile adduct can be trapped by reoxidation to... 

So the cyclopropane 36 isomerises at high temperature, no doubt via the [1,3] shift to 37, formation of the extended enol 38 and movement of the alkene into conjugation follows. The product 39 was used in a synthesis of the natural product zizaene.10... 

The asymmetric alkylation of other prochiral enolates has also been studied, and good results have been obtained provided that the intermediate enolate is stabilised by conjugation. For example, the extended enolate derived from 15 has been trapped with a range of alkylating agents to give a-alkylated esters such as 16 in 98% ee (Scheme 5) [12]. 

The extended enolate of the dihydropyran-3-one 23, formed using LDA, can be trapped as its silyl ether to afford the corresponding 2//-pyran (Equation 12) <20020L3059>. 

The acid-catalyzed reaction of salicylaldehydes with 2-tetralone 168 affords 12//-bcnzo[ ]xanthcncs 169. The reaction proceeds via an initial condensation of the aromatic aldehyde with the activated methylene group to form the intermediate 170. The extended enolate of the intermediate 170 undergoes electrocyclization, dehydration, and rearomatization to afford 12/7-benzo[ ]xanthenes (Scheme 54) <2004TL8999>. 

Styrylflavones can be accessed in modest yield by the reaction of l-(2-hydroxyphenyl)-3-phenylpropane-l,3-diones 759 with 2-phenylacetaldehydes. The reaction proceeds via an initial Knoevenagel condensation to form intermediate 760, which undergoes extended enolization and cyclization to afford 3-styrylflavones (Scheme 198) <1999TL6761>. 

The lithiation of allylic positions directed by remote carbonyl groups is observable even when enolates are formed - labelling shows that only the cis methyl group of 140 is deprotonated during the formation of the extended enolate 141.46... 

Phenol complexes of [Os] display pronounced reactivity toward Michael acceptors under very mild conditions. The reactivity is due, in part, to the acidity of the hydroxyl proton, which can be easily removed to generate an extended enolate. Reactions of [Os]-phenol complexes are therefore typically catalyzed using amine bases rather than Lewis acids. The regio-chemistry of addition to C4-substituted phenol complexes is dependent upon the reaction conditions. Reactions that proceed under kinetic control typically lead to addition of the electrophile at C4. In reactions that are under thermodynamic control, the electrophile is added at C2. These C2-selective reactions have, in some cases, allowed the isolation of o-quinone methide complexes. As with other [Os] systems, electrophilic additions to phenol complexes occur anti to the face involved in metal coordination. 

Protonation and hydrolysis of the extended enol ether to release the enone may occur during work-up and the stable enone is the first compound that can be isolated. The 50% yield of this compound represents a much better yield in four steps fragmentation, olefin cyclization, addition of formic acid, and enol ether hydrolysis. 

Removal of a proton from C4 forms an extended enol, which can be protonated at C2 or C4. Proto nation at C4 is thermodynamically favoured as it leads to the conjugated alkene. But protonation at C2 is kinetically favoured, and this leads to the nonconjugated alkene. The geometry of the new alkene depends on the conformation of the chain when the first (deprotonation) step occurs. It is thought that this is the best conformation for the previous reaction, the dehydration step, and that no rotation of the chain occurs before the isomerase gets to work. 

SCHEME 74. Kinetic protonation of extended enolate formed by intramolecular addition of lithium... 

The methodology was extended to show chemoselective hydioxylation (imide over ester) and a-hy-droxylation of extended enolates. It also provided support for a stepwise mechanism (see Section 2.3.2.1.2.iii) involving a counterion dependent equilibrium. 

Rehearsal of the mechanism of a conjugate addition with an extended enolate. 

The enone could form an enolate on the methyl group (kinetic) or a more stable extended enolate, removal of a proton from the far end (y) of the molecule. Evidently, this is what happens here and extended enolate attacks at the first carbon along the chain (a) to add one cyanoethyl group. Repetic-adds the second cyanoethyl group and blocks the a position against any further enolate formation... 

The aromatization can happen by an ionic mechanism. If the extended enol is protonated a remote end it can then lose a proton from the ring junction and form the phenol. 

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