Imine-formation

Probably one of the commonest reactions encountered in the template synthesis of macrocycles is the formation of imine C=N bonds from amines and carbonyl compounds. We have seen in the preceding chapters that co-ordination to a metal ion may be used to control the reactivity of the amine, the carbonyl or the imine. If we now consider that the metal ion may also play a conformational role in arranging the reactants in the correct orientation for cyclisation, it is clear that a limitless range of ligands can be prepared by metal-directed reactions of dicarbonyls with diamines. The Tt-acceptor imine functionality is also attractive to the co-ordination chemist as it gives rise to strong-field ligands which may have novel properties. All of the above renders imine formation a particularly useful tool in the arsenal of preparative co-ordination chemists. Some typical examples of the templated formation of imine macrocycles are presented in Fig. 6-12. 

The template method may be extended to derivatives of imines, and hence to the synthesis of cyclic hydrazones. An example of a templated cyclisation leading to a cyclic hydrazone is shown in Fig. 6-13. 

The co-ordination chemistry of macrocyclic ligands containing imine or hydrazone groups has been widely studied and, as expected, the presence of the imine functionality in the ring confers unusual redox properties to the complexes. 

The synthetic method may be seen to be complementary to direct nucleophilic displacement. Whereas amines often react relatively sluggishly in metal-mediated nucleophilic displacements, they usually undergo facile reaction with carbonyls to form imines. The reduction of the imines (free or co-ordinated) may then be achieved by reduction with Na[BH4] or (less conveniently) by direct hydrogenation. This provides a very convenient method for the preparation of cyclic amines (Fig. 6-14). 

The [Co(NH3)s(NH2CH2COCH3)] ion undergoes an intramolecular base-catalyzed cyclization reaction to give a coordinated carbinolamine, which undergoes a slower base-catalyzed dehydration to give a chelated imine. The synthesis, characterization and kinetics of formation of various reaction products are described. Several reactions of the imine product have been carried out, including BH4 reduction and condensation with methyl vinyl ketone. 

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FIGURE 17 10 The mechanism of imine formation from benzaldehyde and methylamine... 

FIGURE 17 11 Imine formation between the aldehyde function of 11 as retinal and an ammo group of a protein (opsin) is involved in the chemistry of vision The numbering scheme in retinal is specifically developed for carotenes and related compounds... 

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). 

Another type of bifunctional catalysis has been noted with a,cn-diamines in which one of the amino groups is primary and the other tertiary. These substituted diamines are from several times to as much as 100 times more reactive toward imine formation than similar monofunctional amines. This is attributed to a catalytic intramolecular proton transfer. 

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. ... 

Analogous to the selectivity observed for the conversion of 48 into 50, pyridyl 51 formed enamine 52 which underwent cyclization to give 4-pyridyl-substituted quinoline 53. Again, imine formation first occurs on the less hindered ketone and subsequent cyclization on the more reactive carbonyl occurred in high yield. ... 

Imine formation by reaction of aniline 58 and dione 49 under thermal conditions gave a mixture of imines. Cyclodehydration using PPA gave nearly a 1 1 mixture of isomers 59 and 60. These authors attempted thermal cyclization conditions (similar to Gould-Jacobs type conditions) to affect cyclization of this mixture and failed. Also, these authors reported difficulty in the clean formation of the imine. They observed large amounts of the A -acetyl compound presumably coming from fragmentation of the imine at the reported temperature... 

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... 

Skraup proposed a simple mechanism involving imine formation followed by an acid-mediated cyclization. Unfortunately the observed regioselectivity is not consistent with the proposed mechanism when, for example, electron-rich aniline 4 reacts with a, 3-unsaturated aldehyde 5 to give quinoline 6. ... 

Imine formation and enamine formation appear different because one leads to a product with a C=N bond and the other leads to a product with a C=C bond. Actually, though, the reactions are quite similar. Both are typical examples of nucleophilic addition reactions in which water is eliminated from the initially formed tetrahedral intermediate and a new C=Nu bond is formed. 

Mechanism of imine formation by reaction of an aldehyde or ketone with a primary amine. 

We can explain the observed pH dependence of imine formation by looking at the individual steps in the mechanism. As indicated in Figure 19.8, an acid catalyst is required in step 3 to protonate the intermediate carbinolamine, thereby converting the —OH into a better leaving group. Thus, reaction will be slow if not enough acid is present (that is, at high pH). On the other hand, if too much acid is present (low pH), the basic amine nucleophile is completely protonated, so the initial nucleophilic addition step can t occur. 

Imine formation from such reagents as hydroxylamine and 2,4-dinitro-phenylhydrazine is sometimes useful because the products of these reactions— oximes and 2,4-dinitrophenylhydrazones (2,4-DNPs), respectively—are often crystalline and easy to handle. Such crystalline derivatives are occasionally prepared as a means of purifying and characterizing liquid ketones or aldehydes. 

Reaction of an aldehyde or ketone with a secondary amine, R2NH, rather than a primary amine yields an enamine. The process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the a carbon), yielding an enamine (Figure 19.10). 

Imine formation is reversible. Show all the steps involved in the acid-catalyzed reaction of an imine with water (hydrolysis) to yield an aldehyde or ketone plus primary amine. 

Reductive animations also occur in various biological pathways, fn the biosynthesis of the amino acid proline, for instance, glutamate 5-semjaldehyde undergoes internal imine formation to give 1-pyrrolinium 5-carboxylate, which is then reduced by nucleophilic addition of hydride ion to the C=N bond. 

Initial imine formation between PMP and cr-keioglutatate is followed by double-bond rearrangement to an isomeric imine and hydrolysis. 

L-idose 293, 311 ff. imine formation 57 imine-enamine tautomerization 467 iminium-RhH jt complex 351 f. imipenem 348 indoline ligands 681, 684 indolizomycin 47 Iff. -.retrosynthetic analysis 472ff. 

After reduction of the nitro function of the porphyrin, the porphyrinamine intermediate can be reacted with z./l-unsaturated carbonyl compounds to yield porphyrins with a fused pyridine ring, which is formed by Michael addition, imine formation and dehydrogenation. 

Scheme 2.54 Imine formation through hydrogen shifts.

The mechanistic possibilities for the imine formation by a base-promoted 1,2-elimination reaction are shown in Scheme 3. 

An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

Aromatic aldehydes can be reductively aminated with the combination Zn(BH4)2-ZnCl2,97 and the ZnCl2 assists in imine formation. 

SCHEME 7.9 Ene-imine formation by reductive activation and by metabolic activation. The 13C labels are designated with asterisks ( ). 

Compared to the cyclic ketones, the coupling of aliphatic aldehydes to prepare 3-substituted indoles was less successful, except for phenyl acetaldehyde, which afforded 3-phenyl indole 83 in 76% yield (Scheme 4.22). The lack of imine formation or the instability of the aliphatic aldehyde towards the reaction conditions may be responsible for the inefficiency of these reactions. Therefore, a suitable aldehyde equivalent was considered. With the facile removal of a 2-trialkylsilyl group from an indole, an acyl silane was tested as a means of preparing 3-substituted indoles. Indeed, coupling of acetyl trimethylsilane with the iodoaniline 24 gave a 2 1 mixture of 2-TMS-indole 84 and indole (85) in a combined 64% yield. Evidently, the reaction conditions did lead to some desilylation. Regardless, the silyl group of 84 was quantitatively removed upon treatment with HC1 to afford indole (85). 

An interesting reaction ensues when the intermediate synthetic precursor (65) to synthon 60 is heated with phenylenediamine. The reaction can be rationalized as involving initial enamine-imine formation (66), followed by intramolecular attack on the ester carbonyl groups resulting in carbamate formation (67), which carbamate undergoes intramolecular trans-amidation to give urea 66. Other scenarios can be proposed and defended, but the net result is formation... 

Scheme 2.160. Imin-formation/radical-cyclization for the synthesis of pyrrolidines.

Scheme 2.192. Three-component imine formation/Diels-Alder reaction.

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