Formaldehyde aldol products

An enantioselective reaction of a-hydroxymethyl acrylates, using a bis-oxazoline chiral catalyst, gives the equivalent of formaldehyde aldol products in good yield and ee.m... 

In the pentaerythritol case, the dianion reducing agent is formed from formaldehyde first hydroxide attacks it as a nucleophile, then as a base. The dianion transfers hydride to a different aldehyde, the third aldol product, to... 

By using this reaction, you can add one molecule of formaldehyde—one only—to carbonyl compounds. You might, of course, reasonably object that the product is not actually an aldol product at all—indeed, if you wanted the aldol product, the Mannich reaction would be of little use to you. It nevertheless remains a very important reaction. First of all, it is a simple way to make amino-ketones and many drug molecules belong to this class, Secondly, the Mannich products can be converted to enones. We will discuss this reaction next. 

The aldol products from the base-catalysed reaction between aliphatic aldehydes and formaldehyde react with 2-tetralone under acidic conditions to give 2,2-dialkyl-2,3-dihydro-3Ef-naphtho[2,l-b]pyrans 22 <07SL3127>. 

The aldol reaction is synthetically useful because it forms new carbon-carbon bonds, generating products with two functional groups. Moreover, the P-hydroxy carbonyl compounds formed in aldol reactions are readily transformed into a variety of other compounds. Figure 24.3 illustrates how the crossed aldol product obtained from cyclohexanone and formaldehyde (CH2=0) can be converted to other compounds by reactions learned in earlier chapters. 

Neither benzaldehyde nor formaldehyde can form an enolate ion to condense with itself or with another partner, yet both compounds have an unhindered and reactive carbonj l group. The ketone 2-methylcyclohexanone, for instance, reacts preferentially with benzaldehyde to give the mixed aldol product. 

Tollens reaction The reaction of an aldehyde or ketone that has an a-hydrogen with formaldehyde, in the presence of Ca(OH)2 to give initially a mixed aldol product this is then usually reduced by... 

Control of the pH is also of importance for the Mannich-based bispidine synthesis. Formation of an aldol product competes with the Mannich condensation in the basic pH region. It is for this reason that, in some cases, the reaction is sensitive to the order in which the reactants are added to the reaction mixture. It is possible to add the aldehyde and amine components one after another to a solution of the CH-acidic compound, but sometimes the aldol reaction can be disfavored by changing the order. This allows the imminium ion to be formed in advance. The precursors of 45 and 46 have been prepared by this method. In some cases, it has been useful to use a protonated amine component as the acetate salt (e.g., 49 or precursors for 44, 47, and 48), as the chloride salt (e.g., 11) or to carry out the reaction in acetic acid. Aromatic amines (e.g., aniline) give rise to para-substituted aromatic amines if the solution is not approximately neutral. In a very elegant procedure, a condensate of formaldehyde and aniline, which is the trimeric methyleneaniline, was prepared separately, and treated in the Mannich reaction with dimethyl acetonedicarboxylate and formaldehyde to yield the 3,7-diphenylbispidone... 

Since formaldehyde is known to be a catalyst poison it was removed from the reagent mixture prior to hydrogenation by distillation. In order to prevent oligomerization of formaldehyde [14], water was gradually added to the mixture during distillation. The water feeding was adjusted in order to maintain a constant liquid volume in the distillation flask. Distillation was performed imder atmospheric pressure and at 100 °C using a total batch volume of 400 ml (200 ml of aldolization product mixed with 200 ml of distilled water). As the first distilled droplets from the condenser were observed, the addition of extra water was commenced. In this way, the formaldehyde content of the solution was easily suppressed below 0.5 wt.%. 

In this case, only one major aldol product is produced. Why Formaldehyde has no a protons and therefore cannot form an enolate. As a result, only the enolate formed from propionaldehyde is present in solution. Under these conditions, there are only two possible products. The enolate can attack a molecule of propionaldehyde to produce a symmetrical aldol reaction, or the enolate can attack a molecule of formaldehyde to produce a crossed aldol reaction. The latter occurs more rapidly because the carbonyl group of formaldehyde is less hindered than the carbonyl group of propionaldehyde. As a result, one product predominates. 

The synthetic design based on the molybdic acid catalyzed carbon-skeleton rearrangement of the branched chain aldose as applied above to prepare sedo-heptulose has also been exploited for the synthesis of D-glycero-D-ido-octu ose [63]. The necessary branched-chain aldose 45,2-C-(hydroxymethyl)-D-g/ycero-D-gw/o-heptose,was obtained by the potassium carbonate catalyzed aldolization of the D-glycero-D-gulo-heiptose derivative 43 [64], which has an anchored configuration at C-2,by 2,3-0-isopropylidenation with formaldehyde and by subsequent deprotection of the aldolization product 44. 

Recently, Maruoka and coworkers presented an asymmetric aldol reaction of a-substituted nitroacetates with aqueous formaldehyde under base-free neutral phase-transfer conditions [127]. In the presence of 0.1mol% (S)-43a, the aldol products were obtained in 62-86% yield with 74-91% ee (Scheme 12.21). Two of the aldol products were treated with zinc and acetic acid in isopropanol to give the corresponding a-methylserinates 96, which are core structure of biologically active natural products such as conagenin and piperazimycins. 

The base-catalyzed reaction of acetaldehyde with excess formaldehyde [50-00-0] is the commercial route to pentaerythritol [115-77-5]. The aldol condensation of three moles of formaldehyde with one mole of acetaldehyde is foUowed by a crossed Cannizzaro reaction between pentaerythrose, the intermediate product, and formaldehyde to give pentaerythritol (57). The process proceeds to completion without isolation of the intermediate. Pentaerythrose [3818-32-4] has also been made by condensing acetaldehyde and formaldehyde at 45°C using magnesium oxide as a catalyst (58). The vapor-phase reaction of acetaldehyde and formaldehyde at 475°C over a catalyst composed of lanthanum oxide on siHca gel gives acrolein [107-02-8] (59). 

Pentaerythritol is produced by reaction of formaldehyde [50-00-0] and acetaldehyde [75-07-0] in the presence of a basic catalyst, generally an alkah or alkaline-earth hydroxide. Reaction proceeds by aldol addition to the carbon adjacent to the hydroxyl on the acetaldehyde. The pentaerythrose [3818-32-4] so produced is converted to pentaerythritol by a crossed Cannizzaro reaction using formaldehyde. All reaction steps are reversible except the last, which allows completion of the reaction and high yield industrial production. 

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