Carbonyl compounds acetal formation

If alcohols can be used to protect carbonyl compounds by formation of an acetal (or ketal), then the same method can protect an alcohol using a carbonyl compound. For example, victual diols can be protected by forming a cyclic five-membered ketal with acetone. Similarly, 1,3-diols react with... 

A carbonyl group can be protected as a sulfur derivative—for example, a dithio acetal or ketal, 1,3-dithiane, or 1,3-dithiolane—by reaction of the carbonyl compound in the presence of an acid catalyst with a thiol or dithiol. The derivatives are in general cleaved by reaction with Hg(II) salts or oxidation acidic hydrolysis is unsatisfactory. The acyclic derivatives are formed and hydrolyzed much more readily than their cyclic counterparts. Representative examples of formation and cleavage are shown below. 

The equilibrium constants for addition of alcohols to carbonyl compounds to give hemiacetals or hemiketals show the same response to structural features as the hydration reaction. Equilibrium constants for addition of metiianoHb acetaldehyde in both water and chloroform solution are near 0.8 A/ . The comparable value for addition of water is about 0.02 The overall equilibrium constant for formation of the dimethyl acetal of... 

Three-dimensional potential energy diagrams of the type discussed in connection with the variable E2 transition state theory for elimination reactions can be used to consider structural effects on the reactivity of carbonyl compounds and the tetrahedral intermediates involved in carbonyl-group reactions. Many of these reactions involve the formation or breaking of two separate bonds. This is the case in the first stage of acetal hydrolysis, which involves both a proton transfer and breaking of a C—O bond. The overall reaction might take place in several ways. There are two mechanistic extremes ... 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

X0 to hydroxy compounds. Lower temperatures favor ketone formation and sterically hindered carbonyls, such as 2-thienyl t-butyl ketone, are not reduced. The sensitivity of desulfurization to steric factors is evident by the failure to desulfurize 2,5-di-i-butyl-3-acetylthiophene. The carbonyl groups of both aldehydes and ketones can be protected by acetal formation, as particularly cyclic acetals are stable during desulfurization in methanol at room temperature. " The free aldehydes give primary alcohols on desulfurization. Another method to obtain only keto compounds is to oxidize the mixtures of ketone and secondary alcohol with CrOs after the desulfurization. - Through the desulfurization of 5,5 -diacetyl-2,2, 5, 2"-terthienyl (228), 2,15-hexadecandione (229) has been obtained, which... 

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

Because all the steps in acetal formation are reversible, the reaction can be driven either forward (from carbonyl compound to acetal) or backward (from acetal to carbonyl compound), depending on the conditions. The forward reaction is favored by conditions that remove water from the medium and thus drive the equilibrium to the right. In practice, this is often done by distilling off water as it forms. The reverse reaction is favored by treating the acetal with a large excess of aqueous acid to drive the equilibrium to the left. 

Allylboronates are attractive reagents for the highly diastereoselective ally-lation of carbonyl compounds. A sequential cross-metathesis-allylation reaction has recently been developed by Grubbs et al. [88c] and by Miyaura et al. [103]. The sequence is illustrated in Scheme 23 for the formation of homoallylic alcohol 114 from allylboronate 112, acetal 113, and benzaldehyde [88c]. 

The use of the enolsilyl ether of 1-menthone [16, 19, 21-23] and of some free triflic acid favors the formation of the thermodynamically controlled products as with free 2,2 -dihydroxydiphenyl [22] and only subsequently added HMDS 2 [22]. On reacting silylated alcohols and carbonyl compounds with pure trimethylsilyl triflate 20 under strictly anhydrous conditions no conversion to acetals is observed [24]. Apparently, only addition of minor amounts of humidity to hydrolyze TMSOTf 20 to the much stronger free triflic acid and hexamethyldisiloxane 7 or addition of traces of free triflic acid [18-21, 24, 26] or HCIO4 [25] leads to formation of acetals. 

Purely aromatic ketones generally do not give satisfactory results pinacols and resinous products often predominate. The reduction of ketonic compounds of high molecular weight and very slight solubility is facilitated by the addition of a solvent, such as ethanol, acetic acid or dioxan, which is miscible with aqueous hydrochloric acid. With some carbonyl compounds, notably keto acids, poor yields are obtained even in the presence of ethanol, etc., and the difficulty has been ascribed to the formation of insoluble polymolecular reduction products, which coat the surface of the zinc. The adffition of a hydrocarbon solvent, such as toluene, is beneficial because it keeps most of the material out of contact with the zinc and the reduction occurs in the aqueous layer at such high dilution that polymolecular reactions are largdy inhibited (see Section IV,143). 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

Various other examples in this chapter have already highlighted how N,N-dimeth-ylformamide dimethyl acetal can be efficiently utilized as a synthon for the construction of heterocydic rings (see Schemes 6.189, 6.194, 6.195, 6.229, and 6.230). West-man and coworkers have described a two-step method for the generation of a wide variety of heterocydic scaffolds, based on the initial formation of alkylaminoprope-nones and alkylaminopropenoates from N,N-dimethylformamide diethyl acetal (DMFDEA) and the corresponding CH-acidic carbonyl compounds (Scheme 6.256)... 

Durandetti et al. have described iron-catalyzed electrochemical allylation of carbonyl compounds with allylic acetates (Equation (27)).333 In the case of aldehydes, slow addition of the corresponding aldehyde is required in order to avoid pinacol formation. With crotyl acetate (R3 = Me), the reaction proved to be highly regioselective, providing almost exclusively branched homoallylic alcohols 150. 

Studies on the electrochemical oxidation of silyl-substituted ethers have uncovered a rich variety of synthetic application in recent years. Since acetals, the products of the anodic oxidation in the presence of alcohols, are readily hydrolyzed to carbonyl compounds, silyl-substituted ethers can be utilized as efficient precursors of carbonyl compounds. If we consider the synthetic application of the electrooxidation of silyl-substituted ethers, the first question which must be solved is how we synthesize ethers having a silyl group at the carbon adjacent to the oxygen. We can consider either the formation of the C-C bond (Scheme 15a) or the formation of the C-O bond (Scheme 15b). The formation of the C Si bond is also effective, but this method does not seem to be useful from a view point of organic synthesis because the required starting materials are carbonyl compounds. 

Silylation using the silylacetate (3.1.14) [49] involves the initial formation of the acetate carbanion, which abstracts a proton from the carbonyl compound or alcohol (Scheme 3.2, Table 3.5). When the reaction with a ketone is conducted in the presence of an aldehyde, crossed aldol products are obtained (see Chapter 6). 

Treatment of Fischer-type carbene complexes with different oxidants can lead to the formation of carbonyl compounds [150,253]. Treatment with sulfur leads to the formation of complexed thiocarbonyl compounds [141]. Conversion of the carbene carbon atom into a methylene or acetal group can be achieved by treatment with reducing agents. Treatment of vinylcarbene complexes with diborane can also lead to demetallation and formation of diols [278]. The conversion of heteroatom-substituted carbene complexes to non-heteroatom-substituted carbene complexes... 

Acetal formation is reversible (K for MeCHO/EtOH is 0-0125) but the position of equilibrium will be influenced by the relative proportions of R OH and H2O present. Preparative acetal formation is thus normally carried out in excess R OH with an anhydrous acid catalyst. The equilibrium may be shifted over to the right either by azeotropic distillation to remove H2O as it is formed, or by using excess acid catalyst (e.g. passing HCl gas continuously) to convert H2O into the non-nucleophilic H3O . Hydrolysis of an acetal back to the parent carbonyl compound may be effected readily with dilute acid. Acetals are, however, resistant to hydrolysis induced by bases—there is no proton that can be removed from an oxygen atom, cf. the base-induced hydrolysis of hydrates this results in acetals being very useful protecting groups for the C=0 function, which is itself very susceptible to the attack of bases (cf. p. 224). Such protection thus allows base-catalysed elimination of HBr from the acetal (27), followed by ready hydrolysis of the resultant unsatu-... 

Rate constants and Arrhenius parameters for the reaction of Et3Si radicals with various carbonyl compounds are available. Some data are collected in Table 5.2 [49]. The ease of addition of EtsSi radicals was found to decrease in the order 1,4-benzoquinone > cyclic diaryl ketones, benzaldehyde, benzil, perfluoro propionic anhydride > benzophenone alkyl aryl ketone, alkyl aldehyde > oxalate > benzoate, trifluoroacetate, anhydride > cyclic dialkyl ketone > acyclic dialkyl ketone > formate > acetate [49,50]. This order of reactivity was rationalized in terms of bond energy differences, stabilization of the radical formed, polar effects, and steric factors. Thus, a phenyl or acyl group adjacent to the carbonyl will stabilize the radical adduct whereas a perfluoroalkyl or acyloxy group next to the carbonyl moiety will enhance the contribution given by the canonical structure with a charge separation to the transition state (Equation 5.24). 

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