Homoenolate acylation

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]. 

A formal [3h-2] cycloaddition reaction with homoenolates has also been realised with nitrogen-based electrophiles such as A-acyl-A -aryldiazenes 180. Pyrazolidi-nones 178 can be prepared from enals 27 and acyldiazenes 180, as demonstrated by Scheldt and Chan [75]. An example of the asymmetric variant demonstrates excellent levels of enantioselectivity in this reaction (90% ee) (Scheme 12.39). 

A few further general examples of zinc catalytic activity or reactivity include the following. Other zinc-containing systems include a zinc phenoxide/nickel(0) catalytic system that can be used to carry out the chemo- and regioselective cyclotrimerization of monoynes.934 Zinc homoenolates have been used as novel nucleophiles in acylation and addition reactions and shown to have general utility.935,936 Iron/zinc species have been used in the oxidation of hydrocarbons, and the selectivity and conditions examined.362 There are implications for the mechanism of metal-catalyzed iodosylbenzene reactions with olefins from the observation that zinc triflate and a dizinc complex catalyze these reactions.937... 

Addition of A-mesityl benzimidazolyl carbene 720 to an a,/3-unsaturated aldehyde generates a homoenolate intermediate that undergoes an addition/acylation sequence with azomethine imine 719 to afford (3R, 5S, 6S )-177-pyrazolo[l,2- ]pyridazine-l,8(5//)-diones 721 with excellent diastereoselectivity. Compound 721 (Ar = R = Ph) treated with sodium hydoxide in methanol or benzylamine provided nearly quantitatively, ring-opened products 722a and 722b, respectively (Scheme 116) <2007JA5334>. 

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 proposed catalytic cycle is shown in Scheme 35 and begins with the imida-zolylidene carbene adding to the enal. Proton transfer provides acyl anion equivalent XLVII, which may be drawn as its homoenolate resonance form XLVIII. Addition of the homoenolate to aldehyde followed by tautomerization affords L the precursor for lactonization and regeneration of the carbene. 

In 2007, Scheldt and co-workers reported the intramolecular desynunetrization of 1,3-diketones utilizing triazolinm pre-catalyst 249 (Scheme 39) [129], Generation of a homoenolate is followed by P-protonation and aldol reaction. In accordance with the proposed mechanism by Nair (Scheme 37), acylation occurs followed by loss of carbon dioxide. Cyclopentenes are formed in enantioselectivities up to 94% ee. The scope of this reaction is limited to aryl substitution of the diketone and alkyl substitution of R. 

In a related paper, Scheldt and co-workers described a stereoselective formal [3 + 3] cycloaddition catalyzed by imidazolinylidine catalyst 256 Eq. 25 [130]. Ultimately this is an intermolecular addition of the homoenolate intermediate to an azomethine ylide followed by intramolecular acylation and presumably follows the same mechanistic path as described previously. Pyridazinones are obtained as single diastereomers in good to high yield from a number of aldehydes. Unfortunately no reaction occurs with the presence of electron-withdrawing groups on the aryl ring of the enal. 

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)-... 

A very practical route to zinc homoenolate involves reduction of 3-iodoesters with zinc/copper couple in the presence of a polar solvent, e.g. DMF, DMA [49] Eq. (51). The nature of the species obtained in this approach is not well-defined, but appears to be essentially the same as the one obtained along the siloxycyclo-propane route. Acylation, arylation, and vinylation reactions have been reported. 

The zinc homoenolate a reacts with acid chlorides in CH2C12 to form l-(acyl-oxy)cyclopropanes. 

You might think you could escape this problem by choosing the alternative disconnection 8, but this is not so. We have more choice here we can use the a3 synthon 7 with natural polarity, in real life an enone, but then we shall have to use the acyl anion equivalents 6 that we met in chapter 23. Reversing the polarity gives us the naturally polarised electrophile, an a1 synthon 9 represented by an acylating agent and the homoenolate, or d3 synthon, 10 with unnatural polarity. 

The same disconnection but of the opposite polarity requires some acylating agent for synthon 9 this is no problem as we have various acid derivatives at our disposal. But the nucleophilic synthon 10, a d3 synthon or homoenolate, is another matter. There is no stabilisation of the anion as drawn but if it were to cyclise to the oxyanion 56, it would be rather more stable and there is evidence-trapping with silicon to give 57 for example-that this can occur. 

This homoenolate anion also acylates acid chlorides readily to give y-keto esters (equation I), but does not react with aldehydes or epoxides. 

The mechanism of the benzoin condensation, as depicted in Scheme 1, suggested that anions derived from a protected aldehyde cyanohydrin should function as nucleophilic acylating reagents. The use of protected cyanohydrins as carbanion equivalents has been studied by Stork and by Hunig and has found wide applicability in chemical synthesis. Such species may serve as either acyl anion equivalents or homoenolate anions. ... 

Trimethylsiloxy cyanohydrins (9) derived from an a,3-unsaturatied aldehyde form ambident anions (9a) on deprotonation. The latter can react with electrophiles at the a-position as an acyl anion equivalent (at -78 C) or at the -y-position as a homoenolate equivalent (at 0 C). The lithium salt of (9) reacts exclusively at the a-position with aldehydes and ketones. The initial kinetic product (10) formed at -78 C undergoes an intramolecular 1,4-silyl rearrangement at higher temperature to give (11). Thus the initial kinetic product is trapped and only products resulting from a-attack are observed (see Scheme 11). The a-hydroxyenones (12), -y-lactones (13) and a-trimethylsiloxyenones (11) formed are useful precursors to cyclopentenones and the overall reaction sequence constitutes a three-carbon annelation procedure. 

Otherwise a-methoxy allyl sulfides have played the role of an a-methylenated acyl anion (Scheme 76, entry a) or a homoenolate dianion (Scheme 76, entry b) equivalent. 

The unsaturated version of the homoenolate synthon, the 3-acyl vinyl anion80 133, can be generated simply in the carboxylic acid series from the halide 134, and has been used in butenolide 135 synthesis81. ... 

Treatment with zinc/copper couple activated by ultrasound in dimethylacetamide gave the zinc homoenolate 57 stabilised by chelation to either the ester or the carbamate. Acylation with acid chlorides and Pd(0) catalysis gave the enantiomerically pure y-oxo-amino acids 58 in good yield. 

The acyl cation 2a or acylium ion 2b is a familiar intermediate in the Friedel-Crafts reaction. It is easy to make (acid chloride + Lewis acid 1) and it can be observed by NMR as it expresses the natural reactivity pattern of the acyl group. The acyl anion by contrast has umpolung or reverse polarity.1 One might imagine making it from an aldehyde by deprotonation 3 and that it would be trigonal 4a or possibly an oxy-carbene 4b. Such species are (probably) unknown and their rarity as well as their potential in synthesis has led to many synthetic equivalents for this elusive synthon. The acyl anion, the d1 synthon, is the parent of all synthons with umpolung2 and should perhaps have been treated before the homoenolates dealt with in the previous chapter. 

Just as anions of allyl derivatives can be homoenolate equivalents (chapter 13) so anions of vinyl derivatives can be acyl anion equivalents. Vinyl (or enol) ethers can be lithiated reasonably easily, especially when there is no possibility of forming an allyl derivative, as with the simplest compound 81. The most acidic proton is the one marked and the vinyl-lithium derivative 82 reacts with electrophiles to give the enol ether of the product17 84. However, tertiary butyl lithium is needed and compounds with y-CHs usually end up as the chelated allyl-lithium 85. These vinyl-lithium compounds add directly to conjugated systems but the cuprates will do conjugate addition.18... 

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