Condensation imine formation

In Ugi s four-component condensation, imine formation from an aldehyde 1 and an amine 2 is likewise the initiating step [5, 6] a carboxylic acid 9 and an isonitrile 10 are the other reaction components, which finally yield the bisamide 11. Both for this reaction and the Strecker synthesis, the galactosylamine 12 is particularly suitable for carrying out a stereoselective reaction (synthesis of 13) [4d-e, 5f. With an aminoglucopyranose as a chiral auxiliary, the stereoselectivity of the reaction can be further increased [5b]. Amino acids as condensation components yield particularly impressive results. For instance, the imino-... 

Amin omethyl-3,5,5-trimethyl cyclohexyl amine (21), commonly called isophoronediamine (IPD) (51), is made by hydrocyanation of (17) (52), (53) followed by transformation of the ketone (19) to an imine (20) by dehydrative condensation of ammonia (54), then concomitant hydrogenation of the imine and nitrile functions at 15—16 MPa (- 2200 psi) system pressure and 120 °C using methanol diluent in addition to YL NH. Integrated imine formation and nitrile reduction by reductive amination of the ketone leads to alcohol by-product. There are two geometric isomers of IPD the major product is ds-(22) [71954-30-5] and the minor, tram-(25) [71954-29-5] (55). 

We have previously discussed that keto-aldehydes react with anilines first at the aldehyde carbon to form the aldimine. Subsequent condensation with another aniline formed a bis-imine or enamino-imine. The aniline of the ketimine normally cyclizes on the aldimine (24 —> 26). Conversely, cyclization of the aldimine could be forced with minimal aniline migration to the ketimine using PPA (30 —> 31). The use of unsymmetrical ketones has not been thoroughly explored a few examples are cited below. One-pot enamine formation and cyclization occurred when aniline 48 was reacted with dione 49 in the presence of catalytic p-TsOH and heat. Imine formation occurred at the less-hindered ketone, and cyclization with attack on the reactive carbonyl was preferred. ... 

Two possible mechanisms exist for the Friedlander reaction. The first involves initial imine formation followed by intramolecular Claisen condensation, while the second reverses the order of the steps. Evidence for both mechanisms has been found, both... 

Imine formation via condensation of aminotriazole 260 with l-methyl-4,5-dioxopyrrolidine-3-carboxylic acid methyl ester 259 leads to formation of the linear tricyclic system 261 under base-mediated conditions (Equation 71) <1997PHA276>. 

Finally, indole ring formation is via condensation of the amino and keto functions. This is analogous to imine formation, as seen in part (a), but dehydration produces the aromatic pyrrole ring rather than an imine. Alternatively, one could write imine formation followed by tautomerism to the aromatic enamine. 

Polyquinolines (PQ) are obtained by the Friedlander reaction of a bis-o-aminoaromatic aldehyde (or ketone) with an aromatic hisketomethylene reactant [Concilio et al., 2001 Stille, 1981]. The quinoline ring is formed hy a combination of an aldol condensation and imine formation (Eq. 2-221). Polymerization is carried out at 135°C in m-cresol with poly (phosphoric acid) as the catalyst. The reaction also proceeds under base catalysis, but there... 

Shu and co-workers (35) identified 2-isobutyl-3,5-diisopropylpyridine, 2-pentyl-3,5-dimethylpyridine, and its dihydro derivative obtained under similar conditions. Sultan (29) confirmed the presence of 3,5-diethyl-2-propylpyridine in a model system consisting of butyraldehyde and ammonium sulfide. Our proposed mechanism of their formation (20) consists of three steps 1) aldol condensation of the starting aldehydes to 2,4-alkadienals, 2) imine formation with ammonia, and 3) subsequent cyclization and oxidation to corresponding pyridines. An alternate mechanism, suggested by Shu and co-workers (33), takes into consideration the isolated dihydro derivatives. Hwang and co-workers described another dihydro derivative (19, R = Bu, R = R" = Pr, R= H) (37). 

One of the two classic schemes for constructing the thiazole ring involves the condensation of a thioamide or its equivalent with an a-haloketone. The reaction can be visualized as involving, as the first step, the displacement of halogen by sulfur from the enol form of the amide imine formation will then close the ring. Thus, reaction of bromoketone (99-2) obtained from the bromination of the corresponding keto-acid with thioamide (99-1) affords thiazole (99-3) in a single step. There is thus obtained the NSAID fentiazac [109]. 

Condensation of a 2-aminopyridine with an a-haloketone provides an alternative method for budding the imidazopyiridine. For example, reaction of 2-aminopicoline (9-1) with para-methylphenacyl bromide (9-2) leads directly to the imidazopyridine (9-4). The overall transformation can be rationalized by assuming an initial alkylation on ring nitrogen (9-3) imine formation followed by bond reorganization then forms... 

One of the most spectacular and useful template reactions is the Curtis reaction , in which a new chelate ring is formed as the result of an aldol condensation between a methylene ketone or inline and an imine salt. The initial example of this reaction was the formation of a macrocyclic nickel(II) complex from tris(l,2-diaminoethane)nickel(II) perchlorate and acetone (equation 53).182 The reaction has been developed by Curtis and numerous other workers and has been reviewed.183 In mechanistic terms there is some circumstantial evidence to suggest that the nucleophile is an uncoordinated aoetonyl carbanion which adds to a coordinated imine to yield a coordinated amino ketone (equation 54). If such a mechanism operates then the template effect is largely, if not wholly, thermodynamic in nature, as described for imine formation. Such a view is supported by the fact that the free macrocycle salts can be produced by acid catalysis alone. However, this fact does not... 

Aminoacetonitrile (83) can be condensed with a-ketoximes such as 82 using a stoichiometric amount of FeCl3 (Scheme 8.35). The reaction presumably proceeds with initial imine formation (intermediate 85) followed by tautomerization to give ketenimine 86 and ring closure to 2-aminopyrazine N-oxide 87, which can be isolated. In a one-pot protocol this product 87 can be further reduced with Pd/C/H2 to give aminopyrazine 84 (80% over two steps) [105]. 

Fig. 9.27. Condensation of diamines with dicarbonyl compounds (and/or their hydrates) to give N heterocycles. Double imine formation yields quinoxalines (B), double enamine formation leads to dimethylpyrrole (D).

Reactions proceeding more than once in the transformation of a substrate can be more effective than a single process If the reaction in question is a condensation of an N nucleophile with a carbonyl compound, the combination of the of two such reactions—allows for the synthesis of heterocycles like, the two depicted in Figure 9.27. The synthesis of quinoxaline (B) from glyoxal dihydrate (A) and orfho-phenylene diamine consists of two imine formations. Somewhat more complicated is the synthesis of dimethylpyrrole D from acetonyl acetone (C) and ammonia. After the formation of the first imine, an imine enamine isomerization occurs. A condensation followed by another imine — enamine isomerization leads to the product. 

Like amines, imines are basic a substituted imine is also called a Schiff base. Imine formation is an example of a large class of reactions called condensations, reactions that join two or more molecules, often with the loss of a small molecule such as water or an alcohol. 

Ketones and aldehydes also condense with other ammonia derivatives, such as hydroxyl amine and substituted hydrazines, to give imine derivatives. The equilibrium constants for these reactions are usually more favorable than for reactions with simple amines. Hydroxylamine reacts with ketones and aldehydes to form oximes hydrazine and its derivatives react to form hydrazones and semicarbazide reacts to form semicarbazones. The mechanisms of these reactions are similar to the mechanism of imine formation. 

The key to the success of the aza-enolates is that the imine is first formed from the aldehyde with the primary amine, a relatively weak base, and under these conditions imine formation is faster than self-condensation. Only after the imine is formed is LDA added when self-condensation cannot occur simply because no aldehyde is left. 

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 the early 1960s, seminal work by Jencks and coworkers demonstrated that formation and hydrolysis of C=N bonds were proceeding via a carbinolamine intermediate, thus leading to a more general mechanism of addition reactions on carbonyl groups [17-19]. The dynamic nature of the reaction of imine formation can be exploited to drive the equilibrium either forward or backwards. Since the reaction involves the loss of a molecule of water, adding or removing water from the reaction mixture proved an efficient way to shift the equilibrium in either direction. The responsive behavior of imines to external stimuli makes the reversible reaction of imine formation perfectly suited for DCC experiments [20], Thermodynamically controlled reactions based on imine chemistry include (1) imine condensation/hydrolysis, (2) transiminations, and (3) imine-metathesis reactions... 

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