Homoenolates, formation

Scheldt and Chan have shown that NHC promoted homoenolate formation and addition to azomethine imines 37 generates pyridazinones 41 with high diastereoselectivity, via a proposed highly organised transition state 40 due to a key hydrogen bonding interaction (Scheme 12.6) [12]. 

Isomerization of siloxycydopropane 3 to the allylic silyl ether in the presence of Znl2 has close mechanistic similarity to the homoenolate formation, Eq. (11) [26]. The initial zwitterionic intermediate after ring cleavage undergoes a hydride shift rather than elimination of the silyl group. 

There are a few points to be addressed in order to understand the mechanism of homoenolate formation. Several lines of experimental evidence for the reaction of 1-alkoxy-l-siloxycyclopropanes have provided insights into the nature of the metal interacting with the siloxycyclopropane. 

Optimization of the titanium homoenolate formation consisted of selecting the most appropriate titaninm ligands (i.e., the ratio of chloride to aUcoxide, as well as aUcoxide structure). In our original commnnication, we described the nse of ClTi(OiPr)3 as the transmetallation reagent. This selection was made partly based upon prior precedent, but also upon an observation made when employing... 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

Nair and co-workers have extended the use of enals for homoenolate generation to allow ring annulation with enones [13], Cyclopentene formation is achieved via... 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

An alternative formation of titanated alkoxyallenes could be achieved by reaction of 3-alkoxy-2-propyn-l-yl carbonates 78 with (r/2-propene)titanium diisopropoxylate (79). Successive addition of 80 to benzaldehyde afforded the corresponding addition products 81 in high yield (Scheme 8.22) [70]. The results demonstrate that titanium species 75 and 80 can serve as easily available ester homoenolate equivalents. Notably, conversion of lithiated alkoxyallenes to the magnesium species by treatment with MgBr2 followed by addition to chiral carbonyl compounds resulted in a mixture of a- and y-products [71]. 

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). 

The formation of activated iminium intermediates derived from nitrogen heterocycles has been reported by Comins . The activation of pyridine derivative such as 214 with phenyl chloroformate provides the pyridinium salt 215, which smoothly reacts with the zinc homoenolate 216 leading to the addition product 217 in 66% yield . The reaction... 

The chemistry of cyclopropanol [7] has long been studied in the context of electrophilic reactions, and these investigations have resulted in the preparation of some 3-mercurio ketones. As such mercury compounds are quite unreactive, they have failed to attract great interest in homoenolate chemistry. Only recent studies to exploit siloxycyclopropanes as precursors to homoenolates have led to the use of 3-mercurio ketones for the transition metal-catalyzed formation of new carbon-carbon bonds [8] (vide infra). 

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

The chemical reactivities of such titanium homoenolates are similar to those of ordinary titanium alkyls (Scheme 2). Oxidation of the metal-carbon bond with bromine or oxygen occurs readily. Transmetalations with other metal halides such as SnCl4, SbClj, TeCl4, and NbCls proceed cleanly. Reaction with benzaldehyde gives a 4-chloroester as the result of carbon-carbon bond formation followed by chlorination [9]. Acetone forms an addition complex. No reaction takes place with acid chloride and tm-alkyl chlorides. 

Treatment of zinc homoenolates with Me3SiCl in a polar solvent also results in cyclopropane formation Eq. (23). This provides a very mild route to the siloxycyclopropanes [24]. 

Next to the cyclopropane formation, elimination represents the simplest type of a carbon-carbon bond formation in the homoenolates. Transition metal homoenolates readily eliminate a metal hydride unit to give a,p-unsaturated carbonyl compounds. Treatment of a mercurio ketone with palladium (II) chloride results in the formation of the enone presumably via a 3-palladio ketone (Eq. (24), Table 3) [8], The reaction can be carried out with catalytic amounts of palladium (II) by using CuCl2 as an oxidant. Isomerization of the initial exomethylene derivative to the more stable endo-olefin can efficiently be retarded by addition of triethylamine to the reaction mixture. 

A highly intriguing isomerization of the homoenolate radical which probably proceeds via formation of a cyclopropyloxy radical, was noted in the reaction of a mercurio aldehyde [37]. The product ratio should reflect the ratio of internal/ external trapping, and in fact the ratio of unrearranged and rearranged product depends on the concentration of the trapping reagent, Eq. (37). 

The reaction of zinc homoenolate 9 with acid chlorides in ethereal solvents containing 2 equiv of HMPA rapidly produces 4-ketoesters in high yield Eq. (44) [33]. A palladium catalyst [40] (or less effectively a copper catalist) [28] accelerates the reaction. This is in contrast to the cyclopropane formation in a nonpolar solvent see (Eq. 22 above). 

Two groups independently reported the formation of titanium homoenolates by the transmetalation reaction of 3-stannyl-propionate esters with TiCl, Eq. (48) [45, 46]. Amide homoenolates become available along this route [47], The trichlorotitanium species thus obtained have been shown ( H NMR) to be similar to that generated along the siloxycyclopropane route and indeed exhibit very similar reactivities. This method does provide a conventient alternative to the siloxycyclopropane route. 

Polladium(II) chloride or its phosphine complex smoothly reacts with siloxy-cyclopropane 1 to produce acrylic ester and a palladium mirror. This reaction probably involves the formation of a chloropalladium homoenolate followed by elimination of palladium hydridochloride (Eq. (56) [56]. 

The observed stereoselectivity of this ring cleavage reaction [60] favors a mechanism, Eq. (65), in which formation of a Iead(IV) homoenolate by cleavage of the external bond with inversion of configuration is followed by rapid cleavage of the second bond. 

Signs X and/indicate no reaction and formation of no detectable homoenolate, respectively... 

The concept of homoenolization was recognized by Nickon in the 1960s but attempts at direct formation of homoenolates were frustrated by cyclopropanolate formation. This lack of success has prompted the development of homoenolate equivalents19 of which the first example, the 3-propionaldehyde anion equivalent (112), was previously discussed (Sections 1.2.2.1.2 and 1.2.2.1.3). Ghosez has shown that a-cyanoenamines (249 and 250) add preferentially in the 1,4(7)-mode to cycloalkenones. The versatility of (250) which serves as either a (3-carboxyvinyl anion equivalent [-CH=CHCChR] or 3-propionate anion equivalent ["Cl ClfcCChR] (Scheme 85) is notable.191... 

A further example of the effectiveness of these reagents is demonstrated in the synthesis of the complex spiroventivane phytoalexin-lubiminol 3 (Scheme 1.2).4 Generation in situ of a zinc homoenolate, Et02C(CH2)2ZnCl,3 allows formation of the functionalized cyclopentenone intermediate, essential for the synthesis. 

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... 

Employing a similar strategy, y-lactams could be synthesized by addition of the homoenolate equivalent to an appropriate imine (Scheme 9.20) [61]. A variety of functionalized a,/ -unsaturated aldehydes 62 and N-4-methoxybenzenesulfonyl imines 70 produced disubstituted y-lactams 71 in good yields and with a preference for the cis diastereomer. One crucial point is the reversibility of the addition of the catalyst to the imine to enable a reaction with the aldehyde. N-Aryl, N-alkyl, N-tosyl and N-phosphinoyl imines where either unreactive or inhibited any catalytic reaction due to the formation of a stable adduct with the catalyst. 

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. 

Werstiuk, 1983). Moreover, such a homoenolate anion could eventually undergo ring closure leading to the formation of a cyclopropoxide anion (Chandrasekhar et al., 1981). 

The formation of the observed products can be explained by the following catalytic cycle (Scheme 8). Addition of the nucleophilic carbene leads to adduct I, followed by proton transfer to give conjugate enamine Ha. Homoenolate equivalent Ha (see also resonance structure lib) can add to the aldehyde reaction partner providing zwitterion III and after... 

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