Enolizable substrates

Wadsworth-Emmons olefination with a variety of aldehydes to afford (E)-a,B-unsaturated and diene acyl tetramic and tetronic acids in good to excellent yields upon treatment with potassium tert-butoxide (2 equiv) in tetrahydrofuran. For readily enolizable substrates use of the N-protected systems is generally required. The following compounds have been prepared, in the indicated yields, in this manner ... 

It has recently been shown that when the tetrahedral intermediate of the reaction is cyclic, it is a better donor of nucleophilic CF3. These cyclic intermediates can be generated intramolecularly from trifluoroacetamides or trifluorosulfmamides derived from (9-silylated ephedrine. These reagents are able to trifluoromethylate aldehydes and ketones, even in the case of enolizable substrates, as a strong base is not required (Figure 2.34). However, while the source of CF3 is chiral, there is no chirality transfer to the addition product, and the replacement of ephedrine by other chiral amino alcohols did not show any improvement. " Similar to asymmetric trifluoromethylation with the Ruppert reagent, only the use of a fluoride salt of cinchonine can increase the enantioselectivity. " " ... 

Variants on this theme have provided many useful preparative procedures and a few representative examples are provided in Scheme 73.212-214 Acetic acid is a relatively unreactive substrate and is often used as a solvent. However, more enolizable substrates, especially those possessing two activating groups, are readily oxidized on a stoichiometric basis at 25-50 C in acetic acid. If the products contain enolizable hydrogens, over oxidation is a potential problem (see the first example). The reactions can often be monitored by the disappearance of the characteristic brown color of the oxidant. While it is clear... 

Ketones and aldehydes, including activated and enolizable substrates and those containing alcohol or carboxylic acid substituents, can be alkynylated using a rhodium(II) catalyst complexed with a bulky phosphine.194... 

Compounds with carbon-nitrogen multiple bonds were also successfully used in the Barbier procedure. Allylic groups add to imines in high yields (> 77% in the examples published), even enolizable substrates, possibly due to the low basicity of the medium.37 Additions to nitriles occur in THF in the presence of the zinc-silver couple.38 Terpenic ketones were prepared by this method. 

The direct enantioselective organocatalytic a-fluorination can also be performed with cinchona alkaloid derivatives as catalyst under phase-transfer reaction conditions [25]. The fluorination reaction by NFSI of / -ketoesters 21, readily enolizable substrates, generated a stereogenic quaternary C-F bond in high yields and with enantioselectivities up to 69% ee for the optically active products 26 (Eq. 6). 

Dithioesters can be reduced in anhydrous acetonitrileor in methanol,the best results being obtained with dimethyl sulfate as alkylating agent. The most convenient procedure involves a simple electrolysis cell with a lead cathode and methanol as solvent. Eight substrates (68 X = SMe) were tested, with R equal to phenyl, chloro- and methoxy-substituted phenyls, and f-butyl. Unlike the corresponding reductions of thioamides, the reactions were not entirely clean and gave substantial amounts of side products such as (70). The product dithioacetals (69 X = SMe, R = Me) were formed in yields of 40-60%. On two of the substrates, better yields (ca. 70%) could be obtained in anhydrous acetonitrile, but a more sophisticated apparatus was required. One enolizable substrate (71) was tested, but the yield was only 30%. ... 

The crystal structures of both Na Xr(CN)3 and K+C(CN)3 are known for comparison. In all examples of the nitrile-stabilized carbanions except the dianion (182), the metal coordination to the organic anion is through the nitrogen. No evidence of interaction between the metal and the nucleophilic carbon atom is seen. Lithiated imine (184) is somewhat analogous to dimer (150), although this species is not derived fiom an enolizable substrate. 

Since most of the synthetically useful enolate anions described in the previous section are prepared by the reactions of enolizable substrates with alkali metal amide bases, it is appropriate to note a few structures of these amide bases. The common bases in synthetic organic chemistry include LDA and LHMDS. The structures of both of these bases are known as the THF solvates.Both of these compounds form bis-solvated dimers corresponding to structure (201). The diethyl ether solvate of LHMDS also forms a bis-solvated dimer (202).Sodium hexamethyldisilazide crystallizes as an unaggregated monomer from benzene solution.Two different cryst line forms of KHMDS are known as the polymeric dioxane solvate (203), ° and the unsolvated dimer (204). ... 

In direct analogy to the Peterson methylenation, the triaryl- and trialkyl-stannylmethyllithiurn reagent (91) can be added to aldehydes and ketones (90), followed by elimination of the hydroxystannane (92) to obtain the methylene derivative (93 Scheme 20). This reaction, like the titanium and cerium modifications of the Peterson methylenation of Kaufmann and Johnson, may prove advantageous, in comparison to the Wittig reaction, for enolizible substrates. 

The Peterson reaction can be used to synthesize a number of heterosubstituted alkenes. Methoxydi-methylsilyl(trimethylsilyl)methyllithium (316) can be added to aldehydes and ketones, including enoliz-able substrates, to form Ae vinylsilane (317 equation 71). Modest ( ) (Z)-selectivity was observed in unsymmetrical cases. This reagent may represent an improvement over the bis(trimethylsilyl)methyl anion, which is ineffective for enolizable substrates. 

In the original study by Peterson, the alkenation procedure was found to be compatible with sulfur and phosphorus substitution. The alkenation reaction has been tqrplied successfully to a variety of substituted alkenes. Because of the aiuon-stabilizing nature of the thiophenyl, the p-hydroxysiliuie is not isolated and the elimination to the alkene takes place directly to form a 1 1 mixture of ( )- and (Z)-isomers. Ager studied the reaction of the lithio anions of phenyl (trimethylsilyl)methyl sulfides (318) with a variety of carbonyl compounds (equation 72). Yields of this process were good, and addition occurred even with enolizable substrates. This reaction was extended to vinyl sulfones. In contrast to the sulfide case, the substituted sulfone silyl anion behaves as a base, leading to undesired enolization. The best yields were observed for the case where R is a hydrogen or phenyl. 

Radical generation through oxidation of enolizable substrates using Mn(III) salts is by far the most common and the field is rapidly expanding. Mn(OAc)3 xH2Q... 

Although non-enolizable substrates are not arylated by arylbismuth(V) compounds under neutral conditions, their derived enolate anions react easily with Ph3BiCl2, Ph3BiC03 and tetraphenylbismuth(V) compounds to produce... 

A complementary process, which succeeds with a wide range of enolizable substrates, makes use of transition metals for the generation of enol radicals (Scheme 24) [52], Although Mn(lll) acetate is commonly used, the combination of Mn(II) and Mn(III) acetates is usually more effective [52fj. 

Formation of Esters, Amides, and Anhydrides. Tosyl chloride and JV-methylimidazole in acetonitrile can be used to promote esterifications, thioesterifications, and amide bond formations in excellent yields (eq 46). Various functionalities are tolerated in this reaction and enolizable substrates, including V-Cbz amino acids, can be esterified without racemization. 

Haloform reactions are generally performed with halogens in the presence of hydroxide [251] or directly with hypohalites [252]. Alternative methods affording carboxylic acids from methyl ketones (or other enolizable substrates) include the aerobic oxidation in the presence of a catalytic amount of dinitrobenzene [253] with a base in a dipolar aprotic solvent such as DMF [254] or HMPT (hexamethylphospho-ric triamide) [255, 256] and the use of stoichiometric quantities of hypervalent iodide derivatives [95, 257] or nitrosylpentacyanoferrate [258]. Furthermore, metal catalysts can be used, and systems such as tert-butyl hydroperoxide in the presence of rhenium oxide [259], oxygen in combination with a copper complex [260], heteropolyacids [261] and Mn"/Co" systems [262] were found to be applicable. Finally, aryl ketones are selectively oxidized to aliphatic carboxylic acids by treatment with periodate [81] in the presence of ruthenium trichloride [263]. 

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