Formaldehyde imines synthesis

Of the various imines known to condense with active methylene compounds, a-arylimines have been the most widely used, especially in earlier work, because of their stability, ease of preparation and the absence of enolizable protons. Aliphatic imines containing enolizable protons have broader synthetic applications but their use is more restricted because they are prone to deprotonation and self aldol type condensations. As will be discussed, new methods utilizing Lewis acids and the less basic boron enolates have been devised to overcome the problem of deprotonation. Other innovations that have extended the scope of imine condensations include in situ methods for the preparation of elusive formaldehyde imines (CH2=NR2> and the utilization of A/-heterosubstituted imines (N = Si, O and S) for the synthesis of primary Mannich bases and A(-unsubstituted 3-lactams, available via hydrolysis or reduction of the N—X bond. 

Reaction of 2-aminopyridines with formaldehyde and electron rich styrenes 383 permitted the synthesis of 3,4-dihydro-2//-pyrido[l,2-n]pyr-imidines 384 (96TL2615). First imines 382 formed they are involved in a formal aza-Diels-Alder reaction to give compounds 384. 

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). 

The most dramatic formation of cages has been provided by kinetic template reactions of ligands attached to cobait(III). The deprotonated amine ligands undergo reaction with formaldehyde to produce bound imines which can be trapped by a variety of nucleophiles (Schemes 66 and 67).205-208 The synthesis of cages of this type will be considered further in Section 61.1.2. 

Ab initio calculations indicate that in the gas phase the reaction of ketene inline and formaldehyde is concerted but asynchronous whereas in dichloromethane it is a two-step zwitterionic reaction.38 The 2 + 2-cycloadditions of keteniminium triflates with imines yields 2-azetidiniminium salts with cis stereoselectivity.39 The intramolecular 2 + 2-cycloaddition of ketenimines with imines (24) provides a novel synthesis of azeto[2,l-Z>]quinazolines (25) (Scheme 9).40... 

In the second step of the synthesis, amine plus formaldehyde gives an imine, present as its protonated iminium form, which gets reduced. Formaldehyde is so reactive that it reacts again with the secondary amine to give an iminium ion again, this is reduced to the amine. 

In the forward synthesis, it turned out that the nitrile reduction was best done using hydrogen and a metal (Rh) catalyst, The final methylation of the primary amine had to be done via the imine and iminium ion (see Chapter 24) to prevent further unwanted alkylations. The reagent was an excess of formaldehyde (methanal CH2=0) in the presence of formic acid (HCO2H),... 

The gas phase acid-catalyzed synthesis of pyridines from formaldehyde, ammonia and an alkanal is a complex reaction sequence, comprising at least two aldol condensations, an imine formation, a cyclization and a dehydrogenation (9). With acetaldehyde as the alkanal, a mixture of pyridine and picolines (methylpyridines) is formed. In comparison with amorphous catalysts, zeolites display superior performance, particularly those with MFI or BEA topology. Because formation of higher alkylpyridines is impeded in the shape-selective environment, the lifetime of zeolites is much improved in comparison with that of amorphous materials. Moreover, the catalytic performance can be enhanced by doping the structure with metals such as Pb, Co or Tl, which assist in the dehydrogenation. 

In addition to four component condensation, several other applications of chiral primary ferrocenylalkyl amines have been published. Thus, an asymmetric synthesis of alanine was developed (Fig. 4-3la), which forms an imine from 1-ferrocenylethyl amine and pyruvic acid, followed by catalytic reduction (Pd/C) to the amine. Cleavage of the auxiliary occurs readily by 2-mercaptoacetic acid, giving alanine in 61% ee and allowing for recycling of the chiral auxiliary from the sulfur derivative by the HgClj technique [165]. Enantioselective reduction of imines is not limited to pyruvic acid, but has recently also been applied to the imine with acetophenone, although the diastereoisomeric ferrocenylalkyl derivatives of phenylethylamine were obtained only in a ratio of about 2 1 (Fig. 4-31 b). The enantioselective addition of methyl lithium to the imine with benzaldehyde was of the same low selectivity [57]. Recycling of the chiral auxiliary was possible by treatment of the secondary amines with acetic acid/formaldehyde mixture that cleaved the phenylethylamine from the cation and substituted it for acetate. 

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