Lithium ynolate

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

A naphthalene-catalyzed (<10%) lithiation of a,a-dibromo esters 152 in THF at —78°C was used to generate ester dianions 153, which by warming at 0°C gave lithium ynolates 154. These intermediates were trapped by carbonyl compounds, for instance benzophenone, to give, after final hydrolysis with water, a,/3-unsaturated acids 155 (Scheme 55)" ... 

The cycloaddition of the /V-2-methoxvphenvI aldimines with lithium ynolates (for a review see [134]) has been reported to give (3-lactams enolates, that... 

In a new benzannulation procedure, the 4 + 2-cycloaddition of lithium ynolates (131) with (trialkylsilyl)vinylketenes (132) yields, via an intermediate 3-(oxido)dienyl-ketene (133), the highly substituted phenols (134), which can be converted to ben-zofurans and benzopyrans (Scheme 37).135 The reaction of buta-2,3-dienoate with vinylketenimine yields the expected Diels-Alder adduct together with an unexpected aniline formed by a competing 2 + 2-cycloaddition.136 The first example of a... 

Lithium ynolates from a-keto dianions derived from esters. 742... 

Potassium/lithium ynolates from a-chloro-a-sulfinyl ketones. 744... 

Lithium ynolates from lithium ester enolates. 746... 

A. Formal [2 + 2] Cycloaddition of Lithium Ynolates with Aldehydes and... 

B. Lithium Ynolate-initiated Cascade Reactions Leading to Multisubstimted... 

I. Reductive Conversion of Lithium Ynolates to Lithium Enolates... 774... 

Metal ynolates are not as easy to prepare in a similar fashion as metal enolates, because the intermediates may be labile monosubstituted ketenes. Several preparative methods for alkali metal ynolates have been reported, among which some have been used as intermediate steps in one-pot organic syntheses. Silyl ynolates have been prepared from lithium ynolates. There have been few reports on the other metal ynolates. Since there is no universal method to determine the yield of metal ynolates, the efficiency of preparation is estimated from the results of some of the following reactions. 

The first synthesis of lithium ynolates was reported by Schollkopf in 1975. The isoxazolyllithium 10, prepared by lithiation of 3,4-diphenylisoxazole (9), undergoes fragmentation to yield the lithium ynolate 11 (equation Tf. The dilithium ynolate dianion 14 is also synthesized by the same protocol from 3-phenylisoxazole (12) via the 3-phenyl-5-isoxazolyllithium (13) intermediate (equation 3). The maximum yields were around 80%, judged by the yields of the /3-lactones (Section IV.A). 

This homologation via lithium ynolates has been used to prepare silyl ynol ethers, as described in Section V. 

The a-chloro-a-sultinyl ketone 20 was prepared from methyl benzoate and chloromethyl phenyl sulfoxide 19 after in situ a-lithiation. Compound 20 is dimetallated by KH and f-BuLi to give the keto dianion 21, which is converted into a potassium/lithium ynolate 22 (equation 7). The resulting metal ynolates are converted into thioesters, carboxylic acids, amides and esters (Section V). 

Lithium acetylides 28 are oxygenated by lithium t-butylperoxide, prepared from anhydrous t-butylhydroperoxide and LHMDS, to give lithium ynolates 29 (equation 9) °. This method has been used as an efficient route for the preparation of the silyl ynolates 30" (Section V). Dioxygen, t-butyl perborate and bis(trimethylsilyl)peroxide have been unsuccessful as oxidation reagents " . ... 

Ynol tosylates are synthesized from terminal alkynes via a unique sequence (equation 10). The hypervalent organoiodine compound 32, prepared by treatment of iodosoben-zene diacetate with /i-toluenesulfonic acid, reacts with the terminal alkynes 31 to give the iodonium tosylates 33, which are then treated with 10 mol% of CuOTf or AgOTf to afford the ynol tosylates 34. Finally, the ynol tosylates 34 are converted into lithium ynolates 35 by treatment with MeLi. The ynolates are trapped with r-butyldimethylsilyl chloride, triethylgermyl chloride and tributylstannyl chloride to give the silyl ynol ethers 36, the germyl ketenes 37 and the stannyl ketene 38. ... 

The a-bromo esters 39 are treated with LDA to form the bromo ester enoiates 40, which are subjected to lithium-halogen exchange with t-BuLi (3 equiv) at —78 °C. The resulting dilithium ester dianions 41 are thermally cleaved at 0 °C into the ynoiates 42 in good yields (equation 12). This procedure finally regenerates LDA from diisoprpylamine and t-BuLi along with the lithium ynolate (equation 12 ). 

Since metal ynolates are metallated ketene equivalents, metallation of ketenes is expected to afford metal ynolates. Direct metallation of monoalkylketenes is, however, fairly difficult due to the high lability of these ketenes (e.g. dimerization) and the strong elec-trophilicity of the carbonyl carbon . In contrast, silylketenes are so stable that lithiation of trimethylsilylketene (45) with BuLi at —100 °C provides the lithium ynolate 46 in good yield (equation 18). The f-butyldimethylsilylketene (47) is also lithiated to afford the lithium ynolate 48 (equation 19). ... 

Lithium ynolates are stable and keep their reactivity at 0 °C under inert gas for several days, but they decompose in 1 day at 20 Silyl ynolates (sUyl ynol ethers) are stable for a long period and they can be purified by distillation, but they are labile to acids (Section V). The stability of ynolates of metals other than hthium is unknown. 

Compared with metal enolates, there have been very few reports on the direct structural analysis and theoretical studies of ynolates. An X-ray crystal structure of a vanadium complex of lithium ynolate with a porphyrinogen ligand (56) is reported. This metal complex was incidentally formed from VCl3(THF)3 with tetralithium salt of the octaethyl-porphyrinogen ligand. In this complex, the lithium cation seems to interact with the 7T-electrons of the ynolate. The four atoms of the ynolate group in 56 are not collinear due to a partial sp character of the group in this complex. 

Multisubstituted five-membered aromatic heterocycles are synthesized via this cascade protocol (equation 34). The cycloadditions of a-acyloxyketones 78a with lithium ynolates afford /3-lactone lithium enolates 79a, which spontaneously cyclize to give bicyclic compounds 80a. These intermediates, which are stable enough to be isolated, are treated with TsOH under heating to provide substituted furans 81a via decarboxylation and dehydration. Thiophenes (e.g. 81b) are also synthesized by the analogous scheme via intermediate 80b using a-acylthioketones (78b) as a substrate. In the synthesis of pyrroles using a-acylaminoketones as a substrate, the cyclization proceeded at —20 °C, and the -lactone was subsequently ring-opened via /3-elimination to furnish pyrroles in one-pot (equation 35). ... 

The anionic inverse electron-demand 1,3-dipolar cycloaddition of nitrones 95 with lithium ynolates (equation 41) proceeds at 0°C to afford the substituted isoxazolidinones 97. The relative configuration is determined during the protonation step of the initial isoxazolidinone enolate adduct 96. With a thermodynamically controlled protonation, the trans products are mainly produced. The in situ alkylation of the resulting enolate adduct 96 furnishes the trisubstituted isoxazolidinone 98 with high diastereoselectivity. The isoxazolidinones are easily converted into /3-amino acids (99, 100) in good yield . 

Asymmetric cycloadditions of the chiral non-racemic nitrones 101 and 103 afford the isoxazolidinones 102 and 104 respectively, with high diastereoselectivity. This process can lead to an efficient asymmetric synthesis of /3-amino acids (equations 42 and 43) . This is the first example of asymmetric reactions with ynolates. It is noteworthy that the ynolates show higher reactivity and stereoselectivity than the corresponding lithium ester enolates and demonstrate the high potential of lithium ynolates in asymmetric reactions. 

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