Secondary enamines synthesis

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. 

Stork enamine synthesis takes advantage of the fact that an aldehyde or ketone reacts with a secondciry cimine to produce an enamine. Enamines cire resonance stabilized (see Figure 15-25) and have multiple applications. In the first resonance structure, the nitrogen is the nucleophile, while in the second resonance structure, the Ccirbanion is the nucleophile. Some commonly used secondary amines, pyrrolidine, piperidine, and morpholine, are shown in Figure 15-26. 

Some secondary amines commonly used in the Stork enamine synthesis. 

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

Synthesis and properties of secondary enamines of the 1,2,3,4-tetrahy-droisoquinolylidenecarboxylic acid series 90MI7. 

Show how you would accomplish each conversion using an enamine synthesis with pyrrolidine as the secondary amine. 

The alkylation of acyclic imines with electrophilic alkenes such as acrylonitrile, methyl acrylate or phenyl vinyl sulphone is also sensitive to steric effects and again, as a consequence, only mono-alkylation occurs398. The regioselectivity of the reaction in methanol varied from 100% attack at the more substituted a-position to 70% attack at the less substituted a -position depending upon the steric inhibition manifested and the stabilization of the competing secondary enamine tautomers (vide infra) (Scheme 204). In contrast, the reaction of butanone and other methyl ketone imines with phenyl vinyl ketone occurs twice at the more substituted a-position but this is then followed by a double cyclization process (Scheme 205). Four carbon-carbon bonds are formed sequentially in this one-pot synthesis of the bicyclo[2.2.2]octanone 205 from acyclic precursors399,400. 

A standard method for enamine synthesis from aldehydes or ketones is to heat the carbonyl compound and the secondary amine in benzene or toluene and remove the water formed by azeotropic distillation. This method cannot, however, be used the preparation of enamines from methyl ketones which undergo self-condensation under these conditions. A procedure which overcomes these difficulties has been given by White and Weingarten [31]. The method employs anhydrous titanium tetrachloride as water scavenger. In the original procedure by White and Weingarten, titanium tetrachloride is added dropwise to a cooled... 

A standard method for enamines synthesis from carbonyl compounds is to heat the parent aldehyde or ketone and a secondary amine in benzene or toluene and to remove the eliminated water by azeotropic distillation. However, this method fails with methyl ketone substrates which are prone to self-condensation imder these conditions. These difficulties could be overcome by a procedure using anhydrous titanium tetrachloride as water scavenger.[6] In the original procedure, titanium tetrachloride was added dropwise to a cold solution of the ketone and the amine, followed by prolonged stirring at room temperature. It was later found that the reaction time could be considerably shortened by a modified procedure, in which the... 

Enamines. The condensation of a secondary amine and a ketone to make an enamine is a well known reaction which has seen wide use in organic synthesis [176-178]. Imines of a primary amine and a ketone exist in a tautomeric equilibrium between the imine and secondary enamine forms, although in the absence of additional stabilization factors cf. Scheme 5.33), the imine is usually the only detectable tautomer. Nevertheless, the enamine tautomer is very reactive toward electrophiles and Michael additions occur readily [179]. The mechanism of the Michael additions of tertiary and secondary enamines are shown in Scheme 5.34. For tertiary enamines, the Michael addition is accompanied by proton transfer from the a -position to either the a-carbon or a heteroatom in the acceptor, affording the regioisomeric enamine as the initial adduct [180]. The proton transfer and the carbon-carbon bond forming operations may not be strictly concerted, but they are nearly so, since conducting the addition in deuterated methanol led to no deuterium incorporation [180]. 

Because the amines are removed in the subsequent hydrolytic workup, enamines are obviously amenable to an auxiliary-based asymmetric synthesis using a chiral amine. It is additionally significant from a preparative standpoint that unsym-metrical ketones alkylate at the less substituted position via tertiary enamines e.g., Ce of 2-methylcyclohexanone) whereas the more hindered position is alkylated preferentially with secondary enamines (e.g., C2 of 2-methylcyclohexanone). 

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) ... 

This strategy will not work, because it involves the use of an enolate, which is not an efficient Michael donor. Therefore, we consider a Stork enamine synthesis (in which we use an enamine, rather than an enolate, as a Michael donor). The enamine can be made from the starting ketone upon treatment with a secondary amine under acid-catalyzed conditions (with removal of water) ... 

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). 

The oxidation of amines by mercuric acetate is an old reaction (54) which up until recent years was employed primarily to modify alkaloid structures (55). A systemic study of the oxidizing action of mercuric acetate by Leonard and co-workers led to the development of a general method for the synthesis of enamines from cyclic tertiary amines. An observation made after a large number of compounds were oxidized, but which is worth noting at the onset, is that a tertiary hydrogen alpha to the nitrogen atom is removed preferentially to a secondary a-hydrogen. 

The addition of secondary amines to acetylenes is most applicable to the synthesis of conjugated acyclic enamines (50,171,172). Particularly the addition to acetylenic esters and sulfones has been investigated (173-177) and it appears that an initial trans addition is followed by isomerization to more stable products where the amine and functional group are in a trans orientation (178). Enamines have also been obtained by addition of secondary amines to allenes (179). 

A novel ring opening reaction of isoxazoles led to the formation of functionalized pyrroles <06S1021>. For example, treatment of isoxazole 52 with DBU led to the formation of pyrrole 53. A solid-phase synthesis of 3-amino-2,5-dicarboxylates was accomplished by transformation of pyrrol-3-one 54 <06JCC177>. The reaction between 54 and secondary amines led to the corresponding resin-bound aminopyrroles after enamine formation and loss... 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

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]. 

The synthesis of enamines by the reaction of some ketones or aldehydes with a secondary amine can lead to saturated by-products when the enamine is heated in a nitrogen atmosphere with a catalytic amount of p-toluenesulfonic acid [48-50] (Eq. 10). 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

Enamines are also potential ketones and accordingly have been used as the ketonic component in this type of pyrylium synthesis (63AG(E)394). The initial adducts, which form pyrylium salts on treatment with perchloric acid, are similar to those derived from secondary amines and pyrylium salts. The significant feature of this variant is that it gives access to pyrylium compounds which are unsubstituted at the 4- and 6-positions but which carry substituents at C-2 and C-5. More conventional enamines, such as 1-piperidinocyclohexene, afford bicyclic pyrylium salts (652), whilst polycyclic salts (653) result if cyclic chlorovinyl ketones are used. 

The same authors have also reported the synthesis of 2-amino quinolines46, Scheme 5.28. Secondary amines were reacted with aldehydes to form enamines subsequent addition of 2-azidobenzophenones initially forms triazoline intermediates, which undergo a thermal rearrangement and intermolecular base-catalysed cyclocondensation to produce 2-amino quinolines. The reactions were run at 180°C for 10 min (the time includes 3 min required for enamine formation) to give the products in 57-100% yields. 

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