Ketones reaction with formaldehyde

Alcohol synthesis via the reaction of Grignard reagents with carbonyl com pounds (Section 14 6) This is one of the most useful reactions in synthetic organ ic chemistry Grignard reagents react with formaldehyde to yield primary alco hols with aldehydes to give secondary alcohols and with ketones to form terti ary alcohols... 

Uses, cx-Aminonitriles may be hydrolyzed to aminoacids, such as is done in producing ethylenediaminetetracetate (EDTA) or nittilotriacetate (NTA). In these cases, formaldehyde is utilized in place of a ketone in the synthesis. The principal use of the ketone-based aminonitriles described above is in the production of azobisnittile radical initiators (see below). AN-64 is also used as an intermediate in the synthesis of the herbicide Bladex. Aminonitriles are also excellent intermediates for the synthesis of substituted hydantoins by reaction with carbon dioxide however, this is not currently commercially practiced. 

Formaldehyde condenses with itself in an aldol-type reaction to yield lower hydroxy aldehydes, hydroxy ketones, and other hydroxy compounds the reaction is autocatalytic and is favored by alkaline conditions. Condensation with various compounds gives methylol (—CH2OH) and methylene (=CH2) derivatives. The former are usually produced under alkaline or neutral conditions, the latter under acidic conditions or in the vapor phase. In the presence of alkahes, aldehydes and ketones containing a-hydrogen atoms undergo aldol reactions with formaldehyde to form mono- and polymethylol derivatives. Acetaldehyde and 4 moles of formaldehyde give pentaerythritol (PE) ... 

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

MEK is a colorless, stable, flammable Hquid possessing the characteristic acetone-type odor of low molecular weight aUphatic ketones. MEK undergoes typical reactions of carbonyl groups with activated hydrogen atoms on adjacent carbon atoms, and condenses with a variety of reagents. Condensation of MEK with formaldehyde produces methylisopropenyl ketone (3-methyl-3-buten-2-one) ... 

Reaction With Carbonyl Compounds. Primary and secondary nitroparaffins undergo aldol-type reactions with a variety of aldehydes and ketones to give nitro alcohols (11). Those derived from the lower nitroparaffins and formaldehyde are available commercially (see Nitro alcohols). Nitro alcohols can be reduced to the corresponding amino alcohols (see Alkanolamines). 

Reaction with Aldehydes and Ketones. Formaldehyde combines with primary and secondary alkanolamines in the presence of alkali to give methylol derivatives. For the reaction of monoethanolamine with formaldehyde (12), the reaction scheme shown in Figure 1 occurs. 

Reactions with Aldehydes and Ketones. An important use for alkylphenols is ia phenol—formaldehyde resias. These resias are classified as resoles or aovolaks (see Phenolic resins). Resoles are produced whea oae or more moles of formaldehyde react with oae mole of pheaol uader basic catalysis. These resias are thermosets. Novolaks are thermoplastic resias formed whea an excess of phenol reacts with formaldehyde under acidic conditions. The acid protonates formaldehyde to generate the alkylating electrophile (17). 

Several kinds of products can be obtained by reaction of thioglycolic acid and its esters with aldehydes to form mercaptals, RCH(SCH2COOH)2, or with ketones to form thiolketals, RR C(SCH2COOH)2. Reaction with formaldehyde (qv) yields di- -butyhnethylene-bisthioglycolate [1433882-0] (MET ester) ... 

Other modifications of the polyamines include limited addition of alkylene oxide to yield the corresponding hydroxyalkyl derivatives (225) and cyanoethylation of DETA or TETA, usuaHy by reaction with acrylonitrile [107-13-1/, to give derivatives providing longer pot Hfe and better wetting of glass (226). Also included are ketimines, made by the reaction of EDA with acetone for example. These derivatives can also be hydrogenated, as in the case of the equimolar adducts of DETA and methyl isobutyl ketone [108-10-1] or methyl isoamyl ketone [110-12-3] (221 or used as is to provide moisture cure performance. Mannich bases prepared from a phenol, formaldehyde and a polyamine are also used, such as the hardener prepared from cresol, DETA, and formaldehyde (228). Other modifications of polyamines for use as epoxy hardeners include reaction with aldehydes (229), epoxidized fatty nitriles (230), aromatic monoisocyanates (231), or propylene sulfide [1072-43-1] (232). 

In much the same vein, the Mannich product from acetophenone with formaldehyde and pyrrolidine (44b) affords procyclidine (49) Dn reaction with cyclohexylmagnesium bromide. In an interesting variation, the ketone is first reacted with phenylmagnesium bromide. Catalytic hydrogenation of the carbinol (50) thus obtained iTin be stopped after the reduction of only one aromatic ring. ... 

The presence of unsaturation in the side chain is also compatible with antihistaminic activity. Mannich condensation of p-chloroacetophenone with formaldehyde and pyrollidine affords the amino ketone, 109. Reaction with an organometallic reagent from 2-bromopyridine gives 110. Dehydration leads to triproli-dine (111). ... 

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

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. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

A propoxyphene-like analgesic which obeys the empirical morphine rule is pyrroliphene (101). A Mannich reaction involving pyrrolidine, formaldehyde and propiophenone gave amino ketone 99, which was converted to tertiary carbinol 100 by reaction with benzyl magnesium chloride reaction with acetyl... 

It should be noted that, on reaction with Grignard reagents, aldehydes will produce secondary alcohols, whereas ketones will form tertiary alcohols. Often forgotten is the possibility of synthesizing primary alcohols by using formaldehyde as the substrate. 

This is a fairly general reaction, and requires an amine plus an aldehyde (usually, but not necessarily, formaldehyde) together with an enolizable ketone, which together generate a P-aminoketone via an iminium system. The Mannich reaction is surprisingly... 

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. 

Treatment of the reduced intermediate (23-6) with butyl hthium leads to the anion from the removal of a proton on the methylene group reaction of that with methyl acetate affords the methyl ketone (24-1), which contains two of the three required side chain carbon atoms. The additional carbon atom and the basic function are incorporated by means of a Mannich condensation. Thus, reaction of (24-1) with A-methylpiperazine and formaldehyde leads to the aminoketone (24-2). The carbonyl group is then reduced with sodium borohydride and the resulting alcohol is dehydrated by reaction with phosphoms oxychloride in pyridine. In this case, too, the Z isomer is responsible for most of the activity. This is isolated from the resulting mixture of olefins to afford thiothixene (24-3) [25]. 

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