Dimedone, enamines

The reaction of dimedone enamines with aldehydes is complex and the products depend on the structure of the aldehyde and the conditions. Acetaldehyde leads to benzoxazine as was independently reported by Greenhill27 and Akhrem and cow-orkers30. The same reaction proceeds according to Hammouda and coworkers with formaldehyde when the Af-phenylenaminone of dimedone31 or indanedione32 is used. 

Reaction of dimedone enamines with a-ketoacids has recently been shown to lead mainly to indole-2,4-dione derivatives64 (equation 47). Glyoxylic acid, however, reacts similarly to other aldehydes in a Hantzsch-type reaction yielding iV-phenylacridinedione in 30% yield64. 

According to the work of Greenhill and Mohamed dimedone enamine is attacked by methyl vinyl ketone in propionic acid at the / -position leading to quinoline ring closure. 

According to Stankevich and coworkers97 an enamino ester and an enamin nitrile lead similarly to condensed dihydropyridines when reacted with a benzylidenecyclo-pentanetrione derivative. Dimedone enamines react analogously to give an annelated tricyclic system (equation 67). 

When one of the components of such multicomponent reactions was a molecule of DMF, the formation of angular dihydropyrimidines was also observed. For example, amines 197,198 and 208 in boiling DMF reacted with dimedone 200, leading to azolopyrimidines 217-219 [184, 186, 187]. These treatments, in the opinion of Lipson et al. [184], resulted in the reaction passing through an enamine intermediate 216 formed at the endocyclic nitrogen atom (Scheme 3.60). 

The Mannich reaction of enaminones was examined intensively. Enamines derived from dimedone are aminoalkylated in the -position in good yield if the nitrogen is unsubstituted or monosubstituted31,34. Primary amines and formaldehyde react with enaminones to yield tetrahydropyrimidines34 (equation 21). A similar reaction is observed for acyclic enaminones. With primary amines and formaldehyde, tetrahydropyrimidines are formed35 (equation 22). 

Radical reactions of enamines are the subject of another chapter in the present book. Acyloxylation of anilinomethylene dimedone to a-hydroxy derivatives of / -diketones is achieved by treating enaminediones with a diacyl peroxide. The aminomethylene group is lost in this process302 (equation 226). 

Acyloxylation reactions have been performed on a secondary enamine of dimedone with a series of diacyl peroxides. The isolated monoadducts could undergo further acyloxylation to yield products of acyl rearrangement50 (Scheme 34). 

With the morpholino enaminone derived from dimedone the oxidized enamine adduct shown in Scheme 41 could be isolated. 

The CH-acid dimedone (pKa = 5.2) was chosen as the allyl transfer reagent in order to facilitate separation from the Liberated amine. When used in 7- to 8-fold excess, it also protonates the free amino group (pKa = 8) to such an extent that the Latter cannot function as an allyl acceptor. However, if the reaction times are long, an enamine may form with the dimedone in which case dimethylbarbituric acid (pKfl = 4.7) can be used instead.184185 It is also noteworthy that the thioether function of methionine is not detrimental to the activity of the Pd catalyst. A mechanism for the Pd 0)-cata lysed deprotection of Aloe derivatives using dimedone or NtN --dimethylbarbituric acid as scavengers is given in Scheme 8.75. 

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. 

Condensation of 5,5-dimethylhexan-l,3-dione (dimedone) with amino acid esters leads to Af -5,5-dimethyl-3-oxocyclohex-l-enyl derivatives 128 as particularly stable enamines that are converted into the free acids by saponification, for coupling by carbodiimides, carbonyldiimidazole, or Woodward s reagent K, or are transformed into the hydrazides for coupling via the azide method (Scheme... 

N-Protection of amino acWs. Dimedone reacts readily with an amino acid ester (but not with the free amino acid) to give an enamine derivative (1), characterized by remarkable stability of the enamine group to acid or base. Thus refluxing (1)... 

Dihydropyridines 46 (R = H, Me, Ph R1, R3 = Me and CH2C(Me)2CH2- R2 = Et) having unsymmetrical substitution patterns at C-2, C-6 and C-3, C-5 positions have been formed by reactions of equivalent amounts of ethyl-/ -aminocro-tonate and methyl acetoacetate or dimedone, with respective oxazinanes 31 in acetic acid/acetonitrile (1 10 v/v). Since methyl acetoacetate and dimedone fail to react with oxazinanes under these reaction conditions, it may be visualized that the preference of the reactivity of oxazinanes with enamines over the enols facilitates the generation of intermediate 45, the precursor of 46 (93JCR(S)120). 

Kaupp et al. described that the 1,3-dicarbonyl compounds such as 1,3-cyclohex-anedione, dimedone, and dehydracetic acid reacted in the solid state with aniline derivatives to obtain enamine ketones 250 and 252 in quantitative yields (Scheme 3.66) [18]. Advantages over the solvent synthesis were identified it is unnecessary to use acid catalysis, solvents, or liquid phases. A further benefit of avoiding iminiiim salt intermediates in such synthesis is the lack of workup requirements. 

The products could be easily isolated by filtration, and recrystallizafion from elhanol led to the pure desired compounds. The authors suggested an iminium ion-catalyzed Knoevenagel condensation mechanism, followed by enamine-Michael addition and intramolecular cyclization. One year later, the same group reported the diammonium hydrogenphosphate-catalyzed synthesis of various pyrano-pyrimidinones by exchanging dimedone by barbituric and thiobarbituric add in aqueous ethanol at ambient temperature [13]. The desired compounds could be afforded in good yields. 

Dihydropyridines and 3,4-Dihydropyridones In 2006, Wang et al. reacted the dimedone-derived enamine 101 with various benzaldehydes 100 and cyclic 1,3-dicarbonyl compounds 31 to afford the tricyclic 1,4-dihydropyridine products 102 in excellent yields (Scheme 13.30) [10]. The reactions... 

The reaction of dimedone-derived enamines 110, methyl (2-cyano)acetate 109, and formaldehyde 72 mediated by lithium perchlorate led to the formation of a Knoevenagel/ enamine-Michael addition product (Scheme 13.33) [52], This could be cyclized in a one-pot procedure with substoi-chiometric amounts of triphenyl phosphine to provide... 

Dimethylcyclohexane-l,3-dione (dimedone) (55) reacts with amines to form enamine derivatives which are stable toward adds and bases. Those derivatives are set apart from the enamines which are obtained by the reaction between amines and other /3-dicarbonyl compounds since deavage takes place only after bromination or... 

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