Primary enamines synthesis

The catalytic cycles are, however, different in the reaction sequence for formation of the enamines which are key intermediates in these aldol reactions. With the type I aldolase a primary amino function of the enzyme is used for direct formation of a neutral imine (Ha) whereas starting from L-proline enamine synthesis proceeds via a positive iminium system (lib) (Scheme 6.23). In this respect, investigations by List et al. on the dependence of the catalytic potential on the type of amino acid are of particular interest. In these studies it has been shown that for catalytic activity the presence of a pyrrolidine ring (in L-proline (S)-37) and the carboxylic acid group is required [69]. 

The synthesis of primary alkenylphosphines has been accomplished utilizing the same rDA method that was used to synthesize primary enamines. The synthesis of primary alkenylphosphines had been an unsolved problem owing to the high reactivity of the phosphine group under acidic, basic and neutral conditions. The preparation of vinylphosphine (38a) and isopropenylphosphine (38b) by FVP of the apprc riate anthracene (37) or 1,3-diphenylbenzofuran (39) adduct has been accomplished as shown in equation (26). ( )-Prop-l-enylphosphine was synthesized by a similar rDA route. These phosphines were found to be surprisingly stable, with a half-life of approximately 8 d for (38a). 

An interesting recent development is the synthesis of protected primary enamines N-Mono(trimethylsilyl)enamines have been prepared by trimethylsilylation of metalloenamines . The stereoselective synthesis of ( )-N,iV-bis(trimethylsilyl)enamines PhCH2CH=CHN(SiMe3)2 has been described. ... 

A variety of secondary cyclic and acyclic amines may also couple with vinyl bromides catalyzed by Pd/BINAP or L13.117 This serves as a useful alternative for enamine synthesis. The vinylation of primary amines gives enamines which immediately tataumerize to the corresponding imine. Competition experiments reveal that vinyl bromides react in preference to aryl bromides. Vinyl chlorides are also aminated to give enamines or amino dienes118 as well. These may then serve as useful nucleophiles or dienes for Diels-Alder reactions. 

Imine or enamine synthesis It has been shown by Varma et al. [97] that reaction of primary and secondary amines with aldehydes and ketones is substantially accelerated by microwaves under solvent-free conditions in the presence of montmorUlon-ite KIO day, affording high yields of imines and enamines (Eq. 13) ... 

An improved method (Scheme 40) for the synthesis of stabilized primary enamines (69) from j8-dicarbonyl compounds utilizes the easily prepared N-trimethylsilyliminotriphenylphosphorane (68). The observation that no reac-... 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

By adhering to these conditions, Kaupp and coworkers performed a remarkable one-pot synthesis of highly substituted pyrroles [21]. When primary or secondary enamine esters 10-58 were ground with trans- 1,2-dibenzoylethene 10-59 in a ball-mill, the pyrroles 10-60 were obtained in quantitative yield (Scheme 10.15). In contrast, when in solution the yields were much lower and the reaction also required higher reaction temperatures. 

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]. 

An important pyrrole synthesis, known as the Knorr synthesis, is of the cyclizative condensation type. An a -amino ketone furnishes a nucleophilic nitrogen and an electrophilic carbonyl, while the second component, a /3-keto ester or similar /3-dicarbonyl compound, furnishes an electrophilic carbonyl and a nucleophilic carbon. The initial combination involves enamine formation between the primary amine and the dicarbonyl compound. Subsequent cyclization occurs as a result of the nucleophilic jg-carbon of the enamine adding to the electrophilic carbonyl group of the a-amino ketone (equation 76). Since a-amino... 

Support-bound triacylmethanes (e.g. 2-acetyldimedone) readily react with primary aliphatic amines to yield enamines. These are stable towards weak acids and bases, and can be used as linkers for solid-phase peptide synthesis using either the Boc or Fmoc methodologies, as well as for the solid-phase synthesis of oligosaccharides [456]. Cleavage of these enamines can be achieved by treatment with primary amines or hydrazine (Entries 2 and 3, Table 3.23 see also Section 10.1.10.4). 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

If the amino group forms part of the ketone, as it does with y-87, 88 and 8-amino-ketones,89,90 heterocyclic enamines are obtained. 1,2-Dialkyl-J2-pyrrolines and 1,2-dialkyl-J2-piperideines (15) are formed from secondary amino groups, whereas primary amino groups 91 lead to 2-alkyl-J pyrrolines and 2-alkyl-J -piperideines. Gabriel90 used the suitably substituted phthalimidoketone for the synthesis of the alkaloid y-coniceine (15 R = H, R = n-Pr, n = 2). 

Synthesis of lactams by reactions of primary and secondary enamines with electrophilic olefins 90MI6. 

Heterocyclic azadienes like di- and triazines have been used in the synthesis of pyridine rings. In general terms the reaction involves a regiospecific inverse electron demand Diels-Alder cycloaddition between the heterocycle and the enamine 280 followed by elimination of HCN (diazines) or N2 (triazines) and an amine from the primary cycloadduct 281 or 283, respectively, to give pyridines 282 and 284 (equation 61). At least in one case the latter type of intermediate has been isolated and fully characterized148. 

This classification is illustrated in Scheme 291. By definition, imidazole synthesis under this classification requires an amine or its derivatives as one of the starting materials. Enamines, imines, and isonitriles have been used as the other reactants. Thus, reaction of primary amines with methyl 3-bromo-2-isocyanoacrylates 1189 leads to methyl 1,5-disubstituted imidazole-4-carboxylates 1190, which can undergo decarboxylation to give 1,5-disubstituted imidazoles 1191 (Scheme 292) <1996JME596>. 

Addition of HaS to nitriles (73) represents an important method for the synthesis of primary thioamides (74 equation 33). The reaction is carried out under base or acid catalysis. The base-catalyzed process is particularly useful in the preparation of aromatic thioamides, i.e. for R = aryl, hetaryl in (73) triethylamine in molar proportion or pyridine, which at the same time also serves as solvent, are employed most commonly. The approach tolerates the presence of various other functionalities such as an amide, hydrazone, enamine, a-oxo, a-acetoxy ° or a-amino group. Moreover, the reaction has been applied to the synthesis of thioasparagine as such or incorporated into a dipeptide, as shown... 

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