Enolates formaldehyde

Two types of m-aminophenol modified adhesives have been reported. The first is a multicomponent system that is not too easy to handle. " " Part I is a slow reacting phenol-resorcinol-formaldehyde resin (A) mixed with paraformaldehyde (B) as hardener and Part II is a phenol-m-aminoph-enol-formaldehyde resin (C) at a high pH mixed with a very slow hardener (D). Each part is applied to one surface and, after mating, the reactive components are mixed by diffusion and a cure results within minutes. 

Keywords Dimethylsilyl enolates, formaldehyde, scandium(III) fluoride, THF-H2O (9 1), room temperature, hydroxymethylation, p-hydroxy ketones... 

Formaldehyde for example cannot form an enolate but can react with the enolate of an aldehyde or ketone that can... 

Indeed formaldehyde is so reactive toward nucleophilic addition that it suppresses the self condensation of the other component by reacting rapidly with any enolate present Aromatic aldehydes cannot form enolates and a large number of mixed aldol con densations have been carried out m which an aromatic aldehyde reacts with an enolate... 

Citral is prepared starting from isobutene and formaldehyde to yield the important C intermediate 3-methylbut-3-enol (29). Pd-cataly2ed isomeri2ation affords 3-methylbut-2-enol (30). The second C unit of citral is derived from oxidation of (30) to yield 3-methylbut-2-enal (31). Coupling of these two fragments produces the dienol ether (32) and this is followed by an elegant double Cope rearrangement (21) (Fig. 6). 

There have been extensive investigations on the reaction mechanism. In most cases the reaction proceeds via initial nucleophilic addition of ammonia 2 to formaldehyde 1 to give adduct 5, which is converted into an iminium ion species 6 (note that a resonance structure—an aminocarbenium ion can be formulated) through protonation and subsequent loss of water. The iminium ion species 6 then reacts with the enol 7 of the CH-acidic substrate by overall loss of a proton ... 

I If one of the carbonyl partners contains no or hydrogens, and thus can t form an enolate ion to become a donor, but does contain an unhindered carbonyl group and so is a good acceptor of nucleophiles, then a mixed aldol reaction is likely to be successful. This is the case, for instance, when either benz-aldehyde or formaldehyde is used as one of the carbonyl partners. 

Neither benzaldehyde nor formaldehyde can form an enolate ion to add to another partner, yet both compounds have an unhindered carbonyl group. 

Other compounds with reactive methylene and methyl groups are completely analogous to the nitroalkanes. Compounds with ketonic carbonyl groups are the most important. Their simplest representatives, formaldehyde and acetone, were considered for many decades to be unreactive with diazonium ions until Allan and Podstata (1960) demonstrated that acetone does react. Its reactivity is much lower, however, than that of 2-nitropropane, as seen from the extremely low enolization equilibrium constant of acetone ( E = 0.9 x 10-7, Guthrie and Cullimore, 1979 Guthrie, 1979) and its low CH acidity (pK = 19.1 0.5, Guthrie et al., 1982). ... 

The lanthanide salts are unique among Lewis acids in that they can be effective as catalysts in aqueous solution.61 Silyl enol ethers react with formaldehyde and benzaldehyde in water-THF mixtures using lanthanide triflates such as Yb(03SCF3)3. The catalysis reflects the strong affinity of lanthanides for carbonyl oxygen, even in aqueous solution. 

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

Fig. 2.6. Free-energy profile (B3LYP/6-31 + G with ZPE correction) for intermediates and transition structures for Wadsworth-Emmons reactions between the lithium enolate of trimethyl phosphonoacetate anion and formaldehyde in the gas phase and in tetrahydrofuran or ethanol. Adapted from J. Org. Chem., 63, 1280 (1998), by permission of the American Chemical Society.

Formal isomerization of the double bond of testosterone to the 1-position and methylation at the 2-position provides yet another anabolic/androgenic agent. Mannich condensation of the fully saturated androstane derivative 93 with formaldehyde and di-methylamine gives aminoketone 94. A/B-trans steroids normally enolize preferentially toward the 2-position, explaining the regiospecificity of this reaction. Catalytic reduction at elevated temperature affords the 2a-methyl isomer 95. It is not at all unlikely that the reaction proceeds via the 2-methylene intermediate. The observed stereochemistry is no doubt attributable to the fact that the product represents the more stable equatorial isomer. The initial product would be expected to be the p-isomer but this would experience a severe 1,3-diaxial non-bonded interaction and epimerize via the enol. Bromination of the ketone proceeds largely at the tertiary carbon adjacent to the carbonyl (96). Dehydrohalogenation... 

Sc(OTf)3 is effective in aldol reactions in aqueous media (water-THF, Scheme 15).49 Direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enol ethers affords the corresponding aldol adducts in good yields. Water-sensitive silicon enolates can be used in aqueous solutions in the presence of a catalytic amount of Sc(OTf)3. 

Yohimbenone has also been prepared by Benson and Winterfeldt (213) from enol ether 377, obtained by Birch reduction of 376, via subsequent acid hydrolysis to 378 and formaldehyde cyclization to 370. 

On the other hand, Ln(OTf)3 compounds, which were found to be effective catalysts for the hydroxy-methylation in aqueous media, also activate aldehydes other than formaldehyde in aldol reactions with silyl enol ethers in aqueous solvents.1121 One feature of the present reactions is that water-soluble... 

S. Kobayashi, Lanthanide Trifluoromethanesulfonates as Stable Lewis Acids in Aqueous Media. Yb(OTf)3 Catalyzed Hydroxymethylation Reaction of Silyl Enol Ethers with Commercial Formaldehyde Solution Chem Lett. 1991, 2187-2190. 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

The excellent agreement with the experimental and calculated isotope effect (calculated for formaldehyde, 3.22, and for acetaldehyde, 3.3 experimental value 2.9) supports the computational approach. This suggests that the computed transition structure for hydride transfer in the reaction of the lithium enolate of acetone with acetaldehyde (Figure 30) is realistic. 

FIGURE 29. Optimized geometries for the reactants, transition structures and products in the sequence of reactions between the hthium enolate (LiEn) derived from acetaldehyde and formaldehyde. The total reaction sequence is LiEn- -CH20->complex-l- TSl->-Pl->-complex-2->-TS2->-P2 (Figure 28)->-TS3 (Figure 30)->-P3 (Figure 28). Theoretical calculations were carried out at the HF/6-31H—l-G level. Reprinted with permission from Reference 29. Copyright 1998 American Chemical Society... 

The other method is to choose a compound that doesn t have any a-hydrogen atoms, because a compound with no a-hydrogen cannot form an enolate. For example, if B has no a-hydrogen, then only two products are possible (A2 and A + B). Examples of aldehydes with no a-hydrogen atoms are formaldehyde and benzaldehyde. 

The ene reaction is strongly catalyzed by Lewis acids such as aluminum chloride and diethylaluminum chloride204 Coordination by the aluminum at the carbonyl group increases the electrophihcity of the conjugated system and allows reaction to occur below room temperature, as illustrated in Entry 6. Intramolecular ene reactions can be carried out under either thermal (Entry 3) or catalyzed (Entry 7) conditions 205 Formaldehyde in acidic solution can form allylic alcohols, as in entry 1. Other carbonyl ene reactions are carried out with Lewis acid catalysts. Aromatic aldehydes and acrolein undergo the ene reaction with activated alkenes such as enol ethers in the presence of Yb(fod)3 206 Sc(03SCF3)3 has also been used to catalyze ene reactions.207... 

Formaldehyde is one of the most important Cl electrophiles in organic synthesis. Whereas hydroxymethylation of enolate components with formaldehyde provides an efficient method to introduce a Cl functional group at the a-position of carbonyl groups, few successful examples of catalytic asymmetric hydroxymethylation have been reported (for other examples of asymmetric hydroxymethylation, see [30-33] for examples of catalytic asymmetric hydroxymethylation without using silicon enolates, see [32, 34, 35]). 

The ozonolyses of enol ethers has been reviewed <91MI 4l6-0l>. The relative dipolarophilicity of certain species to attack by carbonyl oxides has been investigated and, in general, the order of reactivity is aldehydes > enol ethers > esters ss ketones. It is apparent that enol ethers are very reactive towards carbonyl oxides, so much so that 1,2-dioxolane formation can be a major reaction pathway (especially for formaldehyde-O-oxide) <85JOC3365>. 

The route used to prepare the unsaturated 2 methyl androgen stenbolone provides yet a further illustration of the propensity for the formation of enolates at the 2 position. Thus reaction of dihydrotestosterone acetate (41-1) with formaldehyde and dimethylamine gives the Mannich product (41-2). Hydrogenolysis of that product gives the 2 methyl derivative (41-3) the relatively elevated temperature used for this last reaction suggests that the reaction may proceed via the methylene product... 

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