Enaminones alkylation

With a catalytic amount of the palladium complex PdCl2(CH3CN)2 the presence of benzoquinone, anilines 37 react with methyl vinyl ketone or methyl acrylate to afford the enaminones 38 in moderate to good yields, Scheme 11. The reaction is sensitive to the amine substitution for example, benzylamine and A-unsubstituted anilines except o-bromoaniline failed to give the desired enaminones. Alkyl-substituted enones (methyl crotonate, cyclopentenone, cyclohexenone) presumably were sterically inhibited from coordination with the palladium because they also failed to undergo the reaction (81JOC2561). 

Conventional conversion of amide, lactam, imide, and urea carbonyl groups into enaminones, enamino esters, or enamino nitriles requires prior activation of the carbonyl groups either by alkylation to imino ethers, followed by reaction with activated methylene groups, or by thiation, e.g. with P2S5, to thiocarbonyl groups followed by alkylation (and possibly also oxidation), and, again, subsequent reac-... 

The N-acylation product of the reaction of enaminones with either 2-chloronicotinoyl chloride or 2,6-dichloro-5-fluoronicotinoyl chloride readily undergoes cyclization (either directly or on treatment with sodium hydride) to give high yields of 8-acyl-7-alkyl[l,6]naphthyridin-5(6//)-ones, which themselves are attractive precursors for elaboration to naphtho[2,3-, ][l,6]naphthyridin-5-ones and pyrido[2,3-f][l,6]naphthyridin-6-ones <2002T58>. 

A large number of 5-deazaflavins (32 R1, R2 = H, alkyl, aryl R3, R4 = H, Cl, NO2, OH 48 examples in all), have been prepared in good yields via condensation of 6-substituted aminouracils with o-halo-benzaldehydes in DMF under reflux. The mechanism shown in Scheme 14 was proposed for this reaction.138 Several bis(5-deazaflavin-10-yl)alkanes (33 n = 6, 8, 10, 12) have also been prepared via the same route using bis(uracil-6-ylamino)alkanes.138 By an analogous reaction the substituted quinolines (34a) and (34b) were obtained in 87% and 50% yield, respectively, from enaminones (35a X = Y = NMe Z = O) and (35b X = Y = CH2 Z = Me2) and pentafluorobenzaldehyde in glacial acetic acid at reflux.139... 

During their work on 5-deaza-5-oxo analogues of AP, Broom s group also synthesized 5-deaza-5-oxo-10-thiaAP (339) via alkylation of the sodium salt of (40) with the bromomethyl enaminone (84) (see Scheme 3.17) [76]. As shown below, saponification of (339a) gave (339b) as expected Scheme 3.62a). 

An important advance was made when it was observed that photolysis of the (3-enamido ketone 165, which was readily available from the indoline 163 by Birch reduction followed by N-aryloylation, delivered the lactam 168 as the only photoproduct (Scheme 17) (125). Reduction of 168 with LiAlH4 gave ( )-a-anhydrodihydrocaranine (143), which was then converted to ( )--y-lycorane (93) on hydrogenation over Adams catalyst in acetic acid. In a similar fashion, irradiation of the bromo or iodo enaminones 166 (Z = Br, I), which were obtained by alkylation of the intermediate imino ether formed on Birch reduction of 163, afforded a mixture (approximately 3 2) of the lactam 168 together with the photoreduction product 167 (126). 

A stereospecific route to enantiopure all-cis-2,3,6-trisubstituted piperidines relies on a cyclization step that is dependent upon temperature, and choice and quantity of base (Scheme 42) <2003TL3963>. Further intramolecular alkylation reactions reported include that of the chiral enaminone to the bicylic structure 35, a key intermediate toward the synthesis of lepadin alkaloids (Equation 80) <2004AGE4222>. 

A facile preparation of F-alkyl enaminones F-MeCOCH=CHNRR1 in 90% yield involves refluxing MeCOCH2CH(OMe)2 with amines RRXNH (R = R1 = H, Me, Et R = Me, R1 = Ph, PhCH2 or RRXN = 1-pyrrolidino, piperidino, morpholino)593. 

Ring closure of enamines and acid chlorides39, esters601 or nitriles (equation 40) or intramolecular alkylation of enaminone602,603 (equation 41) are general methods for the preparation of cyclic enaminones. 

Enaminones were obtained from lactam acetals by reaction with active methylene compounds610. Heterocyclic / -enaminoesters are synthons in the preparation of condensed systems611. Acylated alkyl aminoisobutyrylmalonates (145) can be converted to 3-oxo-2-pyrrolines (146)612,613. 

Selective specific alkylations at the a-methylene group of enaminones are of interest because of their preparative value. The alkylation of cyclic enaminones involving deprotonation with w-butyllithium is called y-alkylation154 (equation 102). Similarly lithium diisopropylamide in THF ( — 78°C) can be also used155. 

Specific alkylation or acylation at the nitrogen has been observed in the case of secondary pyrrolidine enaminones in the presence of potassium terf-butoxide. The configuration of the double bond was changed from Z to E in this reaction157,158 (equation 105). 

The copper(I) iodide promoted cyclization of 7V-(2-haloaryl)-substituted enaminones is a good method to yield indoles and carbazoles. This type of intramolecular arylation is a reasonable alternative to the route via benzyne (see Section A.l.f) (equation 106). The method could be extended to 7V-(2-haloaryl)alkyl-substituted enaminones which give the expected dihydroisoquinolines whereas a nucleophilic attack of the nitrogen instead of the /1-carbon give the undesired indoles159 (equation 107). 

More interesting for the synthesis of carbazoles is the photochemical reaction of non-halogenated A-arylenaminones which stereospecifically leads to carbazoles in high yield208 (equation 147). The enaminone -position may be alkylated as well209. 

The use of a quinone monoimine resulted in the isolation of a spirocyclic compound (equation 160), thus providing evidence for the postulated course of the reaction with the quinone227,228. The reaction is initiated by alkylation of the -position of the enaminone. 

Two sets of enaminones, 36 and 37, were studied. Their hydrolysis reactions are shown as equations 35 and 36. For compounds 36, groups R1 and R2 were combinations of H and small alkyl groups (CH3, C2H5, [CH2]4), while R3 was H except for one compound for which R3 = CH3. Group R4 was usually CH3 with one instance each of R4 = Ph and OEt (an enaminoester). The R group in series 37 was varied from H to... 

Syntheses of heterocycles from alkyl 3-(dimethylamino)propenoates and related enaminones 04CRV2433. 

The 209D diastereomer (+ )-590 has also been made by Comins and Zhang (Scheme 78) 466,467). After 77-acylation of the 4-methoxypyridine 591 with (1 S,2R,4S)-4-isopropyl-2-( 1 -methyl-1 -phenylethyl)cyclohexyl chloroformate, the resulting pyridinium salt was intercepted with hexylmagnesium chloride to give the optically active enaminone 592. Removal of the chiral auxiliary and A -alkylation with (Z)-l,3-diiodopropene yielded 593, thereby setting the scene for a novel anionic... 

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