Ketone homoenolates

Siloxycylopropanes corresponding to ketone homoenolates (e.g. 3) also react smoothly with SnCl at 15 °C to give 3-stannyl ketones (e.g. 14) Eq. (17) [31]. In the same manner, the 3-stannyl aldehyde 15 has been prepared in good yield. Eq. (18). 

Warren and coworkers have described the alkylation of (diphenylphosphinoyl)alkyllithiums with epoxides as an effective means of synthesizing 3-(diphenylphosphinoyl) ketones, homoenolate anion equivalents. The treatment of the adducts of lithiated phosphine oxides and epoxides with base to form cyclopropanes was reported by Toscano et al ... 

The aryl- and heteroarylfluorosilanes 541 can be used for the preparation of the unsymmetrical ketones 542[400], Carbonylation of aryl triflate with the siloxycyclopropane 543 affords the 7-keto ester 545. In this reaction, transme-tallation of the siloxycyclopropane 543 with acylpalladium and ring opening generate Pd homoenolate as an intermediate 544 without undergoing elimination of/3-hydrogen[401],... 

The transmetallation of the siloxycyclopropane 751 with the aryl- or alke-nylpalladium 752 generates the Pd homoenolate 753. and subsequent reductive elimination gives the /3-aryl or alkenyl ketone 754[618]. It should be noted that the Pd homoenolate 753 generated in this reaction undergoes reductive elimination without d-elimination. 

The reaction of benzoyl chloride with (Me3Si)2 affords benzoyltrimethylsi-lane (878)[626,749,750]. Hexamethyldigermane behaves similarly. The siloxy-cyclopropane 879 forms the Pd homoenolate of a ketone and reacts with an acyl halide to form,880. The 1,4-diketone 881 is obtained by reductive elimination of 880 without undergoing elimination of /7-hydrogen[751]. 

Allyl anion synthons A and C, bearing one or two electronegative hetero-substituents in the y-position are widely used for the combination of the homoenolate (or / -enolate) moiety B or D with carbonyl compounds by means of allylmetal reagents 1 or 4, since hydrolysis of the addition products 2 or 5 leads to 4-hydroxy-substituted aldehydes or ketones 3, or carboxylic acids, respectively. At present, 1-hetero-substituted allylmetal reagents of type 1, rather than 4, offer the widest opportunity for the variation of the substitution pattern and for the control of the different levels of stereoselectivity. The resulting aldehydes of type 3 (R1 = H) are easily oxidized to form carboxylic acids 6 (or their derivatives). 

Only few allyltitanium reagents bearing a removable chiral auxiliary at the allylic residue are known. The outstanding example is a metalated 1-alkyl-2-imidazolinone14, derived from (—)-ephedrine, representing a valuable homoenolate reagent. After deprotonation by butyllithium, metal exchange with chlorotris(diethylamino)titanium, and aldehyde or ketone addition, the homoaldol adducts are formed with 94 to 98% diastereoselectivity. 

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]. 

DePuy, as early as 1966 [14], reported that cw-1-methyl-2-phenylcyclopropanol gave exclusively deuterated 4-phenyl-2-butenone in 0.1 M NaOD/D20/dioxane. However, homoenolates derived from simple cyclopropanols by base-induced proton abstraction fail to react with electrophiles such as aldehydes and ketones, which would afford directly 1,4-D systems. Lack of a reasonably general preparative method was another factor which impeded the studies of homoenolate chemistry. For this reason, in the past twenty years more elaborated cyclopropanols, which might be suitable precursors of "homoenolates", have been prepared and studied. 

The zinc homoenolates from cyclopropanes 15. react in the presence of MejSiCl/HMPA with a,[3-unsaturated ketones to give good yields of 1,6-D systems, by a copper-mediated (CuBr-Me2S) Michael-type addition (Table 5.4). 

Let us now consider a dissonant 1,6-dicarbonyl system, which provides a good example of a [3,3]-sigmatropic rearrangement. The "illogical disconnection" would lead to an a,p-unsaturated ketone and a "homoenolate" anion ... 

Concurrently, Glorius and co-workers reported the synthesis of y-butyrolactones under similar reaction conditions [122, 123], Glorius has extended this reactivity to include trifluoromethyl ketones (Scheme 36). In addition to intermolecular reactions, intramolecular homoenolate additions are possible in modest yield Eq. 21 [123],... 

The lithiation of y-chloro acetal 175 with lithium and a catalytic amount of naphthalene (4%) allowed the preparation of the intermediate 176, which can be considered as a masked lithium homoenolate, and was used for the preparation of the hydroxy ketone 179 through the hydroxy acetal 177 and dithiane 178 using known chemistry (Scheme 62)" . 

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). 

Among isolable metal homoenolates only zinc homoenolates cyclize to cyclo-propanes under suitable conditions. Whereas acylation of zinc alkyls makes a straightforward ketone synthesis [32], that of a zinc homoenolate is more complex. Treatment of a purified zinc homoenolate in CDC13 with acid chloride at room temperature gives O-acylation product, instead of the expected 4-keto ester, as the single product (Eq. (22) [33]). The reaction probably proceeds by initial electrophilic attack of acyl cation on the carbonyl oxygen. A C-acylation leading to a 4-keto ester can, however, be accomplished in a polar solvent Eq. (44)-... 

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. 

Trichlorotitanium homoenolate 2 smoothly adds to aldehydes at 0 °C [9, 10]. Due to the strongly acidic reaction conditions, however, addition products of aromatic aldehydes tend to undergo further transformations Eq. (29). The trichlorotitanium homoenolate does not react with ketones (Scheme 2). 

These alkoxytitanium homoenolates show high propensity for equatorial attack in their ir reactions with substituted cyclohexanones (Table 6). The basic trend of their chemical behavior is similar to that of simple titanium alkyls [35]. Chemo-selectivity of the reagent 19 is also noteworthy. The alkoxytitanium homoenolate reacts preferentially with an aldehyde even in the presence of a ketone Eq. (32). A notable difference of rate between the reaction with cyclohexanone and that with 2-methylcyclohexanone was also observed, the latter being far less reactive toward the homoenolate. 

Reaction between a siloxycyclopropane and Cu(BF3)2 in ether gives a product due to symmetrical coupling of two homoenolate moieties (Eq. 53, Table 12) [51]. This is particularly noteworthy as a simple route to 1,6-ketones superior to classical approaches such as the Kolbe electrolysis [52], Several lines of evidence suggest the intermediacy of Cu(II) homoenolates. AgBF3 and CuF2 effect the same reaction albeit with lower yields. The reactions with cupric halides give... 

Hoppe, D. Bronneke, A. Highly diastereose-lective synthesis of di- and trisubstituted 4-butanolides from aldehydes and ketones via three-carbon-extension by allylic homoenolate reagents. Tetrahedron Lett. 1983, 24, 1687-1690. 

We can continue both strategies by disconnections at the branchpoint, each needing simple aryl ketones 16 and 18, but 15b requires a homoenolate reagent for the d3 synthon 19 and we should rather avoid that, while 15c needs a simple enolate 17 and we prefer that. 

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... 

Allyl carbamates 19 are even more versatile, and the lithio derivatives 20 of allyl carbamates are the most important class of homoenolate equivalents.17 Lithiated allyl carbamates react reliably at the y-position with aldehydes and ketones but less regioselectively with alkylating and silylating agents. O-Benzyl carbamates 21 are readily deprotonated and can be quenched with electrophiles.17 20... 

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