Enamines by condensation

The synthetic utility of enamines presupposes their general accessibility. In most cases, ketones are readily converted to enamines by condensation of the carbonyl compound with a secondary amine such as pyrrolidine, morpholine, or piperidine and azeotropic removal of water with a solvent such as benzene (3-19). 

A. Preparation op Enamines by Condensation of Aldehydes and Ketones with Amines... 

A procedure for the formation of enamines by condensation of the parent ketone and secondary amines in the presence of molecular sieves was studied. The role of the molecular sieve is to trap the water formed. The enamine-forming reaction is acid catalyzed and both Bronsted acids and Lewis acids can be used. 

Due to the relative rapidity of the reactions and to the protonation of the free amine by the excess scavenger during the deprotection of allyl carbamates, the risk of formation of allylamine seems very limited and has not been reported. In the reactions with dimedone, a possible complication is the formation of substantial amounts of hydrolytically stable oxo-enamine by condensation with the liberated amine. For this reason, the use of N,N-di-methylbarbituric acid is probably a safer solution. 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

Synthesis at 4-chromanones by condensation of saiicylaldehydes or o-hydroxyaryi ketones with enamines or ketones. 

The secondary amines used in the preparation of enamines have been primarily simple dialkylamines or cyclic amines of five- or higher-membered rings. Azetidine (4) yields a stable enamine with cyclopentanone (28). No simple enamines formed by condensation of ethylenimine (5) or a substituted ethylenimine with an aldehyde or ketone have been reported. 

Preparation of Heterocyclic Enamines by Means of Claisen Condensation of Lactams... 

Heteroaromatic substituents can be incorporated onto the quinoxaline 1,4-dioxide ring system by condensing BFO with the appropriately substituted enamine, cyanomethyl, or 1,3-dicarbonylcompound. 2-Cyanomethyl-l,3-benzothiazole 27 reacted readily with BFO 1 in the presence of potassium carbonate to give the quinoxaline 1,4-dioxide 28 in good yield. 

The ring synthesis then proceeds in subsequent steps by condensation of the unsaturated ketoester 6 and enamine 7 to yield a 1,4-dihydropyridine 3 ... 

The enamines 199 and 191, prepared by condensation of tropinone (124) with piperidine and morpholine, respectively, have proved to be useful synthetic intermediates 98,108). Addition of acrylonitrile to enamine 199, followed by hydrolysis, produced cyanoethyltropinone (200) in 43% yield 108) (Scheme 21). The reaction of the enamine 191 with diketene permitted the preparation of isobellendine (114) vide supra) in 53% yield 98). 

In classical Hantzsch procedure, an enaminocarbonyl is formed in sim by condensation of ammonia source onto the 1,3-dicarbonyl substrate. But many groups have used a three-component modified-Hantzsch protocol in which the preformed enamine is introduced as a partner. Thus, utilization of cyclic or acyclic 1,3-dicarbonyl compounds, aldehydes, and acyclic or cyclic enamines has been reported, leading regioselectively to diversely substituted 1,4-DHP derivatives (Scheme 7). The sequence involving such starting materials was performed in numerous efficient systems, and more particularly in the following (1) microwave-assisted reaction in acetic acid [50], DMF [51], or an acetic acid/DMF system [52] (2) sonification in ethylene glycol [53] and (3) use of ionic liquids such as [bmim]BF4 [54]. 

Trimethoprim has also been synthesized by condensing 3,4,5-trimethoxybenzaldehyde with malonic acid dinitrile in a Knoevenagel reaction, which forms the derivative (33.1.53), which is partially reduced to the enamine (33.1.54) by hydrogen using a palladium on carbon catalyst, which upon being reacted with guanidine is transformed into trimethoprim [52,53]. 

The synthesis of zaleplon (Scheme 15.3) starts by condensing acetophenone derivative 13 with dimethylformamide dimethylacetal (DMF-DMA) to provide enamine 14 (Mealy et ah, 1996 Dusza et al., 1987). A subsequent alkylation with ethyl iodide in the presence of sodium hydride gave 15. Zaleplon (2) is assembled by condensing amino-pyrazole 16 with enamine 15 in refluxing acetic acid. 

The acetic anhydride-induced cyclodehydration of the symmetrical diamide 411, derived from the tetrahydro-benzothiophene / -amino ester 410 and diethyl malonate, afforded the thieno[2,3-r7 [h3]oxazine derivative 413 rather than the expected bis-oxazine 412 (Scheme 78). The reaction probably takes place through sequential cyclizations, in which the pyridine ring of 413 is produced by condensation of the exocyclic double bond of the enamine tautomeric form of the 1,3-oxazine moiety and the mixed anhydride formed by the carboxylic group and acetic anhydride <2003PS245>. 

The formation of azine derivatives by condensation of enamines and enamides with 1,3-dielectrophiles has been known for almost a century, and there are a number of reactions (e.g. the Hantzsch pyridine synthesis) which proceed by intermediate formation of such compounds. Examples are shown in equations (117)—(119). The transformations outlined in equations (120) and (121) are mechanistically related processes. 

Solid-phase synthesis of pyrido[2,3 pytirtiidines 514 was achieved by Hantzsch condensation of Wang resin-supported Knoevenagel derivative 513 with 6-aminouracil derivatives 512 as an a-oxo enamine component in the presence of ceric ammonium nitrate (CAN) in DMA followed by hydrolysis with TFA in CH2GI2. Compound 513 was prepared by treatment of a hydroxylated polymer, such as Wang or Sasrin resin, with diketene, followed by condensation with benzaldehyde (Equation 41) <1996TL4643>. 

Preparation of heterocyclic enamines by the intramolecular condensation of A-(5-oxohexyl) nitrogen heterocycles [201]. 

Certain polyaryl-substituted pyrroles can be prepared by condensation of a benzoin and a benzyl aryl ketone with ammonium acetate (equation 128) (38JOC361, 71ZOR1264). The details of the mechanism are not known but one assumes enamines are involved and that the carbonyl and hydroxymethylene oxidation level of the benzoin are probably interconvertible via an enediol or related substance. A possible formulation is given in Scheme 15. 

Benzo[6]furans and 2,3-dihydrobenzo[6]furans have been obtained by condensation of quinones with compounds having an active methylene group (B-74MI31201) and 2-aminobenzo[6 ]furan derivatives are obtained with malononitrile (68M2359). The reaction of p-benzoquinone with enamines also affords benzo[6]furans. 

The pathway also operates in some bacteria and apparently is the sole source of isoprenoid compounds for the unicellular alga Scenedesmus.28 The pathway is outlined in Fig. 22-2. Pyruvate is decarboxylated by a thiamin diphosphate-dependent enzyme,29 and the resulting enamine is condensed with D-glyceraldehyde 3-phosphate to form 1-deoxyxylulose 5-phosphate.28, i0 31a The latter undergoes an isomeroreductase rearrange-... 

Dimethylaminomethylene derivatives, usually obtained by condensation of the dimethyl acetal or diethyl acetal of dimethylformamide with an active methylene group, can react with carbanions. This results in various heterocyclization reactions including formation of the pyridine ring (91TL1999 95S557). Thus, enamine 176 and the 2-acetylpyridone anion give 2,2 6, 2"-terpyridine (177) (91TL1999). 

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