Amines azomethines, synthesis

Johnston JN, Plotkin MA, Viswanathan R, Prabhakaran EN (2001) Nonconventional carbon additions to azomethines. Aryl amination/indoline synthesis by direct aryl radical addition to azomethine nitrogtar. Org Lett 3 1009—1011... 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

A -Silylmethyl-amidines and -thioamides (42) (X=NR or S) undergo alkylation at X with, for example methyl triflate, and then fluorodesilylation to give the azomethine ylides 43 (identical with 38 for the thioamides) (25,26). Cycloaddition followed by elimination of an amine or thiol, respectively, again leads to formal nitrile ylide adducts. These species again showed the opposite regioselectivity in reaction with aldehydes to that of true nitrile ylides. The thioamides were generally thought to be better for use in synthesis than the amidines and this route leads to better yields and less substituent dependence than the water-induced desilylation discussed above. 

The azomethine ylides applied in synthesis can be divided into two groups. The traditional azomethine ylide 2 is one that consists of a central nitrogen atom with three carbon substituents (Scheme 12.5). This type of azomethine ylide is most frequently formed by the condensation of an aldehyde with a secondary amine 1. The second type are the so-called stabilized azomethine ylides 4. They consist of a central nitrogen atom with two carbon substituents and the nitrogen atom also... 

Soloshonok and co-workers have developed a method for the synthesis of a-(perfluoro-alkyl)amines from perfluoroalkyl carbonyl compounds by a transamination involving an azomethine a/omethine (Schiffbase) isomerization. They call this method a biomimetic, base-catalyzed 1,3-proton shift reaction, and have applied it to perfluoroaldehydes,12-15 perfluoroalkyl ketones,12 18 / -(perfluoroalkyl)-/l-oxo esters,15 16 19 24 and - -( perfluoroalkyl)-a-oxo es-ters2 " -26 to synthesize the corresponding a-(perfluoroalkyl)amincs, / -(perfluoroalkyl )-/i-amino acids, and 3 -(perfluoroalkyl)- x-amino acids. 

The three-component reaction of amines 220-222 with pyruvic acid 239 and aromatic aldehydes has as the first step the formation of the appropriate azomethine intermediate D (Scheme 3.72). This hypothesis was proved by Chebanov et al. [202] through the synthesis of compounds 249-251 by the reaction of azomethine D with pyruvic acid. 

Similarly, the reaction of alkenyl boronic acids with azomethines can be found. Indeed, the corresponding 3-CR was used by Petasis [33] for the enantioselective synthesis of a-amino acids starting from amines, a-keto acids and alkenyl boronic acids. 

During the reaction silver(0) deposits on the sides of the reaction vessel. The sequence of events leading to the azomethine ylide is unclear. However, evidently single-electron transfer (SET) from the amine to silver takes place either prior or subsequent to fluoride-enabled silyl cleavage. This process is repeated with a second equivalent of silver fluoride resulting in the formation of 38 either in free form or more likely as its silver complex. The scope of the method was expanded to the synthesis of bicylic systems exemplified here by tropinone 42 (Scheme 2.11).19 Pandey has also extended the protocol to the synthesis of tricycloalkanes20 and applied it to a total synthesis of the poisonous frog alkaloid epibatidine.21... 

Friestad GK (2009) Addition of carbanions to azomethines. In Enders D, Shaumann E (eds) Science of synthesis vol 40a compounds with one saturated carbon-heteroatom bond amines and ammonium salts. Thieme, Stuttgart... 

Johnston and coworkers reported a base-free aryl amination method based on radical additions to azomethines through nonconventional addition pathways (equation 6)42,43. By this route, the aryl radical adds to nitrogen, rather than to the carbon of the ketimines. For example, the ketimine prepared from o-bromophenethylamine and acetophenone was subjected to tributylstannane and the radical initiator AIBN to give the corresponding indoline in 87% yield. The only side product observed was the directly reduced compound. The fact that only the intramolecular radical addition can afford the high yield limited its application in synthesis of other arylamines. 

The reactions of phosphorous acid are paralleled still further by the additions of hypophosphorus acid to azomethines in practice, mixtures of amines and carbonyl reactants may be employed ", but the drawbacks to the procedure found for the synthesis of aminoalkylphosphonic acids may well apply here also. In a valuable publication, Dingwall and coworkers described the syntheses of (aminoalkyl)phosphinic acid analogues of many of the naturally occurring aminocarboxylic acids by the simple treatment of the benzyhydrylimine derivatives of the necessary amines with hypophosphorous acid, formed in situ when diphenylmethylammonium hypophosphite is treated with an appropriate aldehyde this step is followed by removal of the A -protection with 48% aqueous HBr, with 18% aqueous HCl or with trifluoroacetic acid in boiling methoxybenzene any second amino group was protected as the phthalimido derivative. 

Intramolecular 1,3-dipolar cycloaddition reactions normally proceed efficiently to give bicyclic products and these reactions do not require the presence of an electron-withdrawing group on the dipolarophile. Thus, in an approach to the alkaloid sarain A, the aziridine 221 was heated to generate the intermediate azomethine ylide 222, and hence, after intramolecular cycloaddition, the pyrrolidine 223 (3.143). " An alternative method for the formation of the required azomethine ylide, and which avoids the need for the prior synthesis of an aziridine ring, uses the simple condensation of an aldehyde and a primary or secondary amine. Thus, in another approach to sarain A, addition of formaldehyde to the amine 224 resulted in the formation of the cycloadduct 226 (3.144). Notice that in both cases the... 

A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyelization (N-alkylation ), followed by intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. 

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