Carbonyl compounds, condensation reactions amines

A variety of macrocyclic complexes which have adjacent nitrogen atoms (cyclic hydrazines, hydrazones or diazines) are formed by condensations of hydrazine, substituted hydrazines or hydrazones with carbonyl compounds. The reactions parallel in diversity those of amines, but are often more facile since the reacting NH2 groups is generally not coordinated and the electrophile is thus not in competition with the metal ion. The resulting macrocycles may be capable of coordination isomerism, since either of the adjacent nitrogen atoms can act as donor atom. 

In summary, the SMS reaction is a truly efficient process, possessing a broad scope and applicable to a number of carbonyls, allylsilanes, alcohols (silyl ethers) or amines. Its usefulness has been validated in several total syntheses and demonstrated by the preparation of chiral homoallylic alcohols. During the development of the SMS reaction, Melkafia and Marko [48] realized that the homoallylic alcohol (ether), if connected to an allylsilane, would form novel annelating agents that would lead to tetrahydropyran derivatives via condensation with carbonyl compounds. This reaction was called IMSC for intramolecular Sakurai cydization and will be discussed in the next section. 

Macrocycles with 2 nitrogen and 3 sulfur donors have been prepared (14) by a template synthesis in which the dialdehyde (XCI) is condensed with primary diamines, e.g., ethylenediamine gives XCII in boiling acetonitrile containing Fe(II) perchlorate. The reaction is typical of template condensation between carbonyl compounds and primary amines. An unusual monanionic macrocyclic ligand was produced (2) when formaldehyde was condensed with the hydrazine (XCIII) instead of a primary amine in the presence of Ni(II) salts, and complexes XCIV have been characterized. 

Condensation reactions between carbonyl compounds and primary amines have played a central role in the synthesis of new macrocyclic ligands [28-34]. Usually, though not in all cases, such reactions are conducted in the presence of metal ions which can serve to direct the condensation preferentially to cyclic rather than oligomeric/polymeric products and to stabilize the macrocycle once formed. The relative atomic radius of the templating ion has a considerable effect on the size of the macrocycle formed. For instance, in what is now classic work, cations such as Mg(Il) (r = 0.72 A) were found to stabilize the formation of macrocycles such as 60 from 1 1 condensations [35], while larger cations such as Sr(II)... 

Reductive alkylation of amines proceeds by the hydrogenation of the imine or enamine formed, in situ, by the condensation of the amine with a carbonyl compound. This reaction can give a mixture of products if the amine produced initially competes with the reactant amine in the carbonyl condensation step. The proper selection of reagent concentrations avoids this difficulty and leads to the formation of good yields of the desired product. 50 jhe use of a large excess of ammonia gives the primary amine as the predominant product (Eqn. 19.50). 51 An excess of a primary amine as the reactant leads to the preferential formation of the secondary amine product. An excess of the carbonyl compound gives the symmetrical secondary or tertiary amines (Eqn. 19.51). 50... 

The characteristic feature of the Ugi reaction s is the a-addition of an iminium ion (40) and the anion X of a suitable acid HX to an isocyanide, followed by a spontaneous rearrangement of the a-adduct (41) into a stable oi-aminocarboxamide derivative (42).2n 6. 6.37 Carbonyl compounds (4) and amines (43), or their condensation products, such as the imines, en-amines and aminals, in combination with the acid HX are generally the source of the iminium ion (40) and the anion. 

The Ugi reaction19 is a four-component condensation requiring a carbonyl compound 8, an amine 29, a carboxylic acid derivative 30, and an isocyanide 31. The product from this mixture is a-aminoacyl amide 32 that again could be hydrolyzed to an a-amino acid. Pharmaceutically valuable thiazoles 33 have been elaborated from intermediates formed by this reaction sequence.20... 

Reaction of disecondary amines and carbonyl compounds affords cyclic aminals if the amino groups are in suitable positions relative to one another (1,2-, 1,3-, or 1,4-). For example, 1,3-diamines condense readily with aldehydes or ketones to give hexahydropyrimidine derivatives,966 967 and disecpndary ethylenediamine derivatives give imidazolidines.968... 

Most of the elementary reactions in the classic MCRs are equilibrium processes. Therefore, thermodynamic factors can significantly impact the reaction pathways in addition to the reaction kinetics. A classic example is the Strecker synthesis of a-amino nitrile 9 from aldehydes, amines, and cyanide (Scheme 15.5). The key step in this reaction is the nucleophilic addition of cyanide to the in situ formed iminium. However, condensation of a carbonyl compound with an amine leading to iminium is an equilibrium process, especially under aqueous conditions. Therefore, the desired addition reaction is in competition with direct addition of cyanide to the aldehyde, leading to cyanohydrin 10. However, since the formation of both 9 and 10 were reversible, only the more stable adduct 9 was produced at the expense of cyanohydrin 10 under thermodynamically controlled conditions. 

The condensation reactions of carbonyl compounds with primary amines are influenced by the presence of metal ions. Metal ions bring together reactants in a structure suitable for complex formation so that products are obtained in their presence that are obtained sparingly or not at all in their absence. 

In several cases, it has been established that the amines do not function as simple bases but instead are involved in prior reaction with the carbonyl compounds as well. Kinetic evidence in support of such a mechanism in the condensation of aromatic aldehydes with nitromethane has been reported. The fact that such condensations are often most effectively catalyzed when a weak acid is present in addition to the amine suggests that amines do not function as simple base catalysts. The reactive electrophile is probably the protonated form of the imine formed by condensation of the carbonyl compound and the amine. This iminium ion will be considerably more electrophilic than a carbonyl group because of the positive charge. 

The most widely employed methods for the synthesis of nitrones are the condensation of carbonyl compounds with A-hydroxylamines5 and the oxidation of A+V-di substituted hydroxylamines.5 9 Practical and reliable methods for the oxidation of more easily available secondary amines have become available only recently.10 11 12 13. These include reactions with stoichiometric oxidants not readily available, such as dimethyldioxirane10 or A-phenylsulfonyl-C-phenyloxaziridine,11 and oxidations with hydrogen peroxide catalyzed by Na2W044 12 or Se02.13 All these methods suffer from limitations in scope and substrate tolerance. For example, oxidations with dimethyldioxirane seem to be limited to arylmethanamines and the above mentioned catalytic oxidations have been reported (and we have experienced as well) to give... 

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. 

Iminium ions are intermediates in a group of reactions that form ,( -unsaturated compounds having structures corresponding to those formed by mixed aldol addition followed by dehydration. These reactions are catalyzed by amines or buffer systems containing an amine and an acid and are referred to as Knoevenagel condensations,2U The reactive electrophile is probably the protonated form of the imine, since it is a more reactive electrophile than the corresponding carbonyl compound.212... 

Amines can react with various carbonyl compounds and their derivatives in aqueous media to give the corresponding imine derivatives. These reactions have been discussed in related chapters. The synthetically most useful reaction of this type is the formation of imines and imine derivatives from the condensation of amines with aldehydes and ketones. Water is an excellent solvent for such condensation reactions. For example, water was found to be an ideal solvent for a high-yield, fast preparation of easily hydrolyzable 2-pyrrolecarbaldimines.23 In the presence of Cu2+, the reaction afforded the corresponding Cu(II) chelates (Eq. 11.19). 

The condensation of activated thiols onto adjacent nitriles is a common method for the preparation of amine-substituted thiophenes. A three component condensation was utilized to prepare a-aminothiophene 11 <00TL1597>. An alternate method for preparing amino-substituted thiophenes involved the treatment of ketene S,JV-acetal 12 with an activated carbonyl compound 13 which gave thiophene 14 <00JOC3690>. This type of reaction has also been utilized to prepare building blocks for the synthesis of fused thiophenes <00JHC363>. 

T. Akiyama, J. Takaya, H. Kagoshima, One-Pot Mannich-Type Reaction in Water HBF4 Catalyzed Condensation of Aldehydes, Amines, and Silyl Enolates for the Synthesis of (5-Amino Carbonyl Compounds Synlett. 1999,1426-1428. 

The successful synthesis of 2-thienyl and substituted 2- and 3-thienyl-acetylenes in yields as high as 60-80% opened a wide variety of synthetic applications. Various addition reactions with carbonyl compounds or epoxides could be carried out with ease. Aliphatic as well as aromatic amine addition reactions, or condensation reactions with hydrazine or hydroxylamine could be easily performed. 

This reaction is reversible, since the condensation of a carbonyl compound and a primary amine yields the imine under dehydrating conditions. In fact, acidic conditions usually tend to favor hydrolysis, whereas neutral or slightly alkaline conditions lead to deprotonation of the amine, which then behaves as a nucleophile toward the carbonyl. 

A one pot formation and purification of a 5-arylidine 4-thiazolidinone library has also been reported using polymer scavenging as the principle method of purification. An automated synthesizer was employed to make a parallel array of 4080 4-thiazolidinones, prepared simultaneously from a 3-component condensation of mercaptoacetic acid with an amine and a carbonyl compound. Further structural decoration was then introduced using the libraries from libraries principle where the core template was derivatized via an aldol reaction with a second carbonyl unit at the 5-methylene position (Scheme 2.57) [84]. After both synthetic steps. 

Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction. 

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