Condensation enamine-imine

Hydroaminomethylation is a promising reaction to functionalize unsaturated compounds with an amino group [13, 48, 49], The tandem reaction was discovered by Reppe in 1949 and has been further developed in recent years by Eilbracht and Beller. Hydroaminomethylation consists of three consecutive reactions which are carried out in the same reaction vessel [48], The first reaction is hydroformylation which is followed by the condensation with an amine. Hydrogenation of the generated enamine/imine to the amine is the last step. The conditions for hydroaminomethylation are related to the hydroformylation reaction but are not similar due to the two other reactions. The reaction is called an auto-tandem reaction because two of the three reactions need the same catalyst [9] (Scheme 16). 

Very little is known about the chemistry of later steps of in vitro phaeomelanogenesis beyond the benzothiazine stage. Radiotracer studies (160) and model experiments (161) suggest that the alanyl side chain of the postulated intermediates does not take part in the polymerization process, which probably proceeds via an enamine-imine type condensation of the 1,4-thiazine ring system rather than by oxidative coupling at positions 2 and 8 and subsequent ring closure of the alanyl side chain as previously suggested by Minale et al. (162,163). 

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. ... 

Tile existence of two annular tautomers in solution has been concluded from NMR spectroscopy for the cyclic A -acylbenzazoles 83 [82JPR(324)569]. Enamine and methylene imine tautomers have been described for condensed azolo-quinoxalines [93JHC782, 93JHC1463 95H2057] this type of tautomerism is discussed in detail for the [6.6]bicyclic compounds (see Section III,E,2). 

A mechanism has been formulated, starting with a condensation to give the imine 4, that can tautomerize to the corresponding enamine 5. The latter can be isolated in some cases, thus supporting the formulated mechanism. A cyclization and subsequent dehydration leads to the imine 6, which tautomerizes to yield the aromatic pyrrole 3 ... 

The self-condensation is largely suppressed in reactions with those ketones 2, that are activated by an electron-withdrawing substituent or R". The carbonyl activity is then increased, and the enamine-intermediate 5 is favored over the imine 4, by conjugation with the electron-withdrawing group. ... 

Chlorophyll, heme, vitamin B,2, and a host of other substances are bio-synthesized from porphobilinogen (PEG), which is itself formed from condensation of two molecules of 5-aminolevulinate. The two 5-aminolevulinates are bound to lysine (Lys) amino acids in the enzyme, one in the enamine form and one in the imine form, and their condensation is thought to occur by the following steps. Using curved arrows, show the mechanism of each step. 

Secondary and tertiary amines can be obtained if the hydroformylation of olefins is conducted in the presence of primary and secondary amines under elevated hydrogen partial pressures. Here the rhodium catalyst is involved in both steps, the hydroformylation of an olefin as well as the hydrogenation of the imine or enamine resulting from a condensation of the oxo-aldehyde with the amine (Scheme 14). This combination of hydroformylation and reductive amination is also known as hydroaminomethylation and has been applied to the synthesis of various substrates of pharmaceutical interest [55-57] as well as to the synthesis of macrocycles [60-63] and dendrimers [64,65]. 

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. 

Most enamines, unfortunately, are sensitive to hydrolysis. The parent enamine, iV,iV-dimethylvinylamine, has in fact been prepared [3], but appears to be unstable. Enamines of cyclic ketones and many aldehydes can readily be isolated, however [4-7]. The instability of enamines might at first appear to diminish the utility of enamines as nucleophiles, but actually this property can be viewed as an added benefit enamines can be readily and rapidly generated catalytically by using a suitable amine and a carbonyl compound. The condensation of aldehydes or ketones with amines initially affords an imine or iminium ion, which then rapidly loses a proton to afford the corresponding enamine (Scheme 1). 

Quinolines are reduced in alkaline solution at a lead cathode or by sodium and alcohol to another cla.s.s of dimeric product [85,86]. The meso-4,4 -hydrodimer is again an intermediate in the process. It undergoes slower conversion to the imine tautomer under alkaline conditions and the intramolecular aldol condensation between one imine function and the remaining enamine function leads to the product 23 [86]. 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

Rhodium oxide,200 cobalt carbonyl,201 rhodium and ruthenium carbonyls,202 and rhodium compounds203,204 were later found to be effective catalysts. A three-step mechanism with hydroformylation of the alkene to yield an aldehyde in the first step can be written [Eq. (7.24)]. Condensation to form an imine [Eq. (7.25)] (or enamine) and hydrogenation of this intermediate leads to the product amine ... 

The aldol condensation and the reverse cleavage reaction catalyzed by these enzymes both involve a Schiff base. The cleavage reaction is similar to the acetoac-etate decarboxylase mechanism, with the protonated imine being expelled. The condensation reaction illustrates the other function of a Schiff base, the activation of carbon via an enamine (equation 2.40). 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

The preferred tautomer of the products derived from the condensation reaction of phenylenediamine with cyclic /3-keto esters (Scheme 5) is highly dependent on the structure of the /3-ketoester <2005JHC1001>. H and 13C NMR analysis of the l,5-benzodiazepin-2-one 34, formed from methyl 2-oxocyclohexanecarboxylate under micro-wave conditions, indicated the presence of the C(4)-N(5) imine <2005JHC1001>. In contrast, the products arising from condensation with methyl 2-oxocyclopentanecarboxylate and methyl l-alkyl-4-oxopiperidine-3-carboxylates were found to be in the enamine form 35. 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

Figure 6-17. The formation of a C-C bond using a Claisen-type condensation. A nucleophilic enol, enolate or enamine reacts with the electrophilic carbon of a carbonyl compound or an imine.

A range of imines and enamines, formed from tir/Zw-haloaminopyridines and ketones, may be converted to a variety of substituted 4-, 5-, 6-, and 7-azaindoles by microwave-assisted intramolecular Heck reaction <2005S2571>. As an example, 4-amino-3-iodopyridine is converted to azaindole 85 in 46% yield by condensation with ketone 86 followed by Heck reaction of the resulting enamine (Equation 59). 

Now consider condensation of ammonia with ketoester 1.18. The isolated product is not imine 1.19 but the thermodynamically more stable enamine tautomer 1.20 which has a conjugated double bond system and a strong intramolecular hydrogen-bond. Although not a heterocyclic example, 1.20 illustrates that an enamine-like linkage, as in generalised heterocycle 1.21, is also accessible by a condensation reaction. 

Imines are formed by condensation of aldehydes or ketones with primary amines, but they form with more difficulty than enamines.84,85 A special case of enamine preparation was described with 20-oxo-steroids.86 Treatment of these ketones with a primary amine gives a 20-ketimine, which is acetylated with acetic anhydride, with migration of the double bond and formation of 20-(A-acetylalkylamino)-J17(20)-pregnene (14) reduction of 14 with lithium aluminum hydride affords the enamine. 

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).

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