Formaldehyde, reaction with nitriles

Other acid-catalysed addition reactions include reaction with nitriles (Ritter reaction), formaldehyde (Prins reaction) and carbon monoxide and water (Koch reaction). These reactions are normally catalysed by concentrated sulphuric acid. Extensive isomerization occurs and may even lead to quaternary compounds of the type RC(CH3)XR where X is the new functional group introduced into the molecule. Homogeneous catalysts have been developed which give simpler products without extensive isomerization. 

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). 

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). 

Reaction with formaldehyde yields glycolic nitrile (a cyanohydrin), but in... 

A compound that includes an aminopyrimidine ring as well as the quaternary salt present in thiamine shows preferential inhibition of absorption of that co-factor by coccidia parasites over uptake by vertebrates. The compound is thus used in poultry where coccidiosis is an economically important disease. Condensation of ethoxymethylenemalononitrile (42-1) with the amidine (42-2) leads to the aminopyrimidine (42-4), probably via the intermediate addition-elimination intermediate (42-3). The nitrile group is then reduced to the methylamino derivative (42-5) by means of hthium aluminum hydride. Exhaustive methylation, for example by reaction with formaldehyde and formic acid, followed by methyl iodide leads to the quaternary methiodide (42-6). The quaternary salt is then displaced by bromine, and the resulting benzyhc-like cylic halide (42-7) is displaced by 2-picoline (42-8). There is thus obtained amprolium (42-9) [43]. 

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

Monoalkylation of primary amines. A two-step sequence for this reaction involves conversion of the amine to the N-(cyanomethyl)amine (2) by reaction with chloroaceto-nitrile or with formaldehyde and KCN. Reaction of 2 with an organolithium or a Grignard reagent generates an unstable formaldehyde imint (a) that reacts with a second equivalent of the organometallic reagent to form a secondary amine (3). 

Once again, ( )-carvone was chosen as starting material (Scheme 48) (727). Aldol reaction with formaldehyde led to 6-hydroxymethylcarvone. The primary alcohol was protected as silylether 415 to permit addition of (cyanomethyl)lithium. The 5 1 mixture of epimeric tertiary alcohols was separated and the main product, 416, the alcohol generated by axial attack, was protected stereoselectively as bromoether 417 utilizing pyridinium hydrobromide perbromide. To introduce the necessary alkyne, the nitrile was reduced to the aldehyde with diisobutylaluminum hydride and subsequent hydrolysis. Addition of the alkyne led to a 2 1 mixture of... 

The cyanomethylamine, formed from the amine and bromoacetonitrile (DMF, TEA, 86-96% yield), is cleaved by reduction of the nitrile followed by hydrolysis (Pt02, H2, EtOH, 96-98% yield) or with AgNOs/EtOH (92% yield). A/-protected amides and O-protected phenols are also cleaved using similar hydrogenation conditions. These are also the products of the Strecker reaction with an amine and formaldehyde. 

The amidation of a-hydroxyallylic phosphonates (2IS) with nitriles in the presence of trifluoromethanesulfonic acid proceeds with high ( )-stereoselectivity and with moderate to good yields of (216) [R = H, R = Me or Ph R = Me, = Ph R R = (CH2)n, n = 2-4 R = Me or Ph]. Mannich reactions between diethoxyphosphinoylacetic acid, a primary amine, and formaldehyde, have been used for the preparation of (217). ... 

CHEMICAL PROPERTIES noncombustible solid reacts vigorously with acids and hot water hydrolyzes in hot acid solution elevated temperatures cause a highly exothermic reaction with water dehydrates liquid or solid amides to nitriles liberates ammonia at elevated temperatures and forms imidodisulfonates forms addition products with formaldehyde and aldehydes readily oxidized by bromine and chlorine has flame retardant properties because heat decomposition produces non-inflammable gases decomposes at 200°C (392°F) at 760 mmHg FP (N/A) LFL/UFL(N/A) AT (N/A). 

Formaldehyde dimethylhydrazone readily added to nitro-alkene 21 under neutral conditions and gave branched-derivative 22 as the major diastereomer. The hydrazone group in 22 was further transformed to an aldehyde or nitrile functional group by treatment with ozone or magnesium monoperoxyphthalate, respectively. The same reaction with other sugar nitro-alkenes has been previously described in preliminary form. (See J.-M. Lassaletta and R. Fernandez, Tetrahedron Lett., 1992,32, 3691). ... 

Condensation of two moles of formaldehyde produces the a-hydroxymethylserinebis-(l,2-diaminoethane)cobalt(m) ion (4), and a further six moles of formaldehyde condense with the two co-ordinated 1,2-diaminoethane ligands of (4) to produce the co-ordinated dioxacyclam (3) in the [Co(dioxacyclam) (a-HOCHa-serine)] ion. The considerable enhancement of the rate of attack of bases at co-ordinated nitriles is well documented, and recently this has been used to preparative advantage in reactions of co-ordinated acrylonitrile with carbanions (Michael addition) ... 

Indole (I) condenses with formaldehyde and dimethylamine in the presence of acetie acid (Mannich reaction see Section VI,20) largely in the 3-position to give 3 dimethylaminomethylindole or gramine (II). The latter reaets in hot aqueous ethanol with sodium cyanide to give the nitrile (III) upon boiling the reaction mixture, the nitrile undergoes hydrolysis to yield 3-indoleaeet-amide (IV), part of which is further hydrolysed to 3-indoleacetic acid (V, as sodium salt). The product is a readily separable mixture of 20 per cent, of (IV) and 80 per cent, of (V). 

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

Nitrile oxides react in situ with formaldehyde dimethylhydrazone (129) to give oxime-hydrazones RC( NOH)CH NNMe2 (R = 4-O2NC6H4, MeCO, MeC ( NOH)). The reaction is performed on treatment of oximes with CH2 NNMe2 in the presence of Et3N without isolation of the intermediate nitrile oxides. 

In the synthesis developed by von Baeyer the starting material is also aniline, which is treated with a buffered solution of sodium bisulphite, cyanide and formaldehyde, to give a nitrile, in a reaction which, at least formally, resembles a Mannich condensation ... 

---