Aldehydes from amidines

Synthesis from amidines, isocyanates, aldehydes and ketones 512... 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

Simultaneously, Woodward and co-workers (21) confirmed structure X for the alkaloid by chemical methods. They first recorded the caly-canine synthesis already mentioned. The intermediate tetraaminodi-aldehyde, first postulated by Robinson and Teuber (10), was also the basis for their structural speculations. The mercuric acetate oxidation product (dehydrocalycanthine) of Marion and Manske (13), formed by loss of two hydrogens, was smoothly converted by the action of alcoholic alkali into methylamine, and the resulting amide alcohol was written as XI. It was concluded that dehydrocalycanthine is an ene-imine, the relevant portion of the molecule being shown as XII. Other structures derivable from the tetraaminodialdehyde would more probably generate on amidine, and this would be impossible with X because of steric strain at a bridgehead double bond. 

Enamines derived from 2,2-disubstituted aldehydes (e.g. 261) react with N-chloro-N -aryl- and N-chloro-N - aroylamidines (262) according to two different pathways affording either imidazoline rings (264) or open-chain amidines (265)139 depending on the substituent at the enamine double bond and at the N atom of the benzamidine (equation 56). 

The reaction between a suitable imidatc and an a-aminoaldehyde or a-aminoacetal to form an amidine, which cyclizes to an imidazole, rests largely on the availability of the aminoaldehydes from a-amino acids, which are readily reduced using the Akabori method [2], Dimethyl or diethyl acetals frequently replace the aldehydes in these reactions 13,4]. Table 2.2.1 lists some 2,5-disub.stituted imidazoles prepared (ultimately) from amino acids. It is not possible to introduce a range of substituents at both the 4- and 5-positions by this method unless the amino acid is converted into a ketone rather than an aldehyde (see Section 2.1.1) (Scheme 2.2.2). 

The aldehyde (5) can be made in high yield from the amidine (6) via the unisolated 2-dichloromethylimidazole (Scheme 2.2.3). Dichloroacetonitrile is converted into its imidate with methanolic sodium methoxide, and then into the amidine with aminoacetaldehyde dimcthylacetal. When (6) is heated in formic acid it is converted almost quantitatively into the 2-carbaldehyde the use of trifluoroacctic acid at reflux gives around 60% of (5). Using essentially the same method, imidazole-2-carboxylic acid and its ethyl ester can also be made veiy efficiently when trichloroacctonitrilc and the acetal arc used to prepare the amidine [16],... 

Appropriately functionalized alkenes (enamines, a-haloalkenes, silylenoi ethers, acylvinyl phosphonium salts) are frequently employed as the CC fragment in reaction with amidines, guanidines and ureas. An -chloro-A -alkylamidine will react with the enamine derived from an aldehyde to give in the first instance a 2-imidazoline (4). Such compounds deaminate readily to produce the fully aromatic imidazoles (5), especially when heated with pyridinium or triethylammonium chlorides or 50% sulfuric acid (Scheme 4.3.3). 

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