Secondary Enaminones Research Articles

One‐Step Synthesis of 3,4‐Diphenyl‐2‐pyrrolinones by Solvent‐Free and Bi2O3‐Catalyzed Approaches and Cytotoxicity Screening Against Glioma Cells

Multifunctionalized 2‐pyrrolinones were synthesized from the formal aza‐[3 + 2] cycloaddition reaction of acyclic enaminones and diphenylcyclopropenone. For primary enaminones, solventless reaction under microwave heating was developed. On the other hand, catalysis by Bi2O3 under conventional heating was the more suitable strategy when secondary enaminones were employed. These conditions allowed the synthesis of a set of 2‐pyrrolinones with two vicinal phenyl substituents, which were evaluated for cytotoxicity against U251 and C6 glioblastoma cells. In general, all tested 2‐pyrrolinones with two vicinal phenyl rings were more active than those without this structural moiety, and 1‐butyl‐5‐methyl‐5‐(2‐oxopropyl)‐3,4‐diphenyl‐1,5‐dihydro‐2H‐pyrrol‐2‐one was the most cytotoxic and appears to be a new possibility as an antitumor scaffold to this aggressive brain tumor.

Base-Promoted Synthesis of N-Substituted 1,2,3-Triazoles via Enaminone-Azide Cycloaddition Involving Regitz Diazo Transfer.

The domino reactions between NH-based secondary enaminones and tosyl azide have been developed for the synthesis of various N-substituted 1,2,3-triazoles by employing t-BuONa as the base promoter. Through a key Regitz diazo-transfer process with tosyl azide, the reactions proceed efficiently at room temperature with good substrate tolerance.

Lactic acid-catalyzed fusion of ninhydrin and enamines for the solvent-free synthesis of hexahydroindeno[1,2-b]indole-9,10-diones

Abstract The lactic acid-catalyzed reactions of ninhydrin and secondary enaminones were conducted by solvent-free grinding at room temperature to yield polycyclic 4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-diones.

ChemInform Abstract: Microwave‐Assisted Palladium‐Catalyzed Allylation of β‐Enaminones.

AbstractIn contrast to secondary enaminones, tertiary ones are unreactive.

Visible-light-mediated 1,2-acyl migration: the reaction of secondary enamino ketones with singlet oxygen.

Secondary enaminones were oxidized by photochemically generated singlet oxygen, followed by nucleophilic addition of alcohol and an unexpected 1,2-acyl migration to afford quaternary amino acid derivatives. An ene-type reaction pathway is proposed. It is distinctively different from the typical [2+2] addition of singlet oxygen to a C=C bond pathway.

Induction of intrinsic apoptosis pathway in colon cancer HCT-116 cells by novel 2-substituted-5,6,7,8-tetrahydronaphthalene derivatives

2-Acetyl tetralin (1) reacted with N,N-dimethylformamide dimethylacetal (DMF-DMA) to afford the enaminone 3. The reaction of 3 with piperidine and morpholine afforded the trans enaminone 5a,b, respectively. Compound 3 was treated with primary aromatic amines to give secondary enaminones 6a–e. The enaminone 3 reacted with acetylglycine and hippuric acid to yield pyranones 10a, b, respectively. The reaction of enaminone 3 with 1,4-benzoquinone and 1,4-naphthoquinone gave benzofuranyl tetralin derivatives 14a,b, respectively. Also, when 3 reacted with 5-amino-3-phenyl-1H-pyrazole 15a and 5-amino-1,2,3-triazole 15b, it afforded the new pyrazolo[1,5-a]pyrimidine 17a and 1,2,3-triazolo[1,5-a]pyrimidine 17b, respectively. While the reaction of 3 with pyrimidines 18a, b resulted in the formation of pyrido[2,3-d]pyrimidine derivatives 20a, b, respectively. Investigations of the cytotoxic effect of those compounds against different human cell lines indicated that some compounds showed high selective cytotoxicity against colon cancer HCT-116 cells. Some of these compounds led to DNA damaging and fragmentation that was associated with the induction of apoptosis via mitochondrial pathway. This pathway is initiated by the impairment of mitochondrial transmembrane potential (Δψm) and in response to that the mitochondria released cytochrome c increased, that in turn activated caspase-9 and caspase-3 and induced apoptosis. Compounds 17b and 20b were promising anti-cancer agents that induced intrinsic apoptosis pathway in colon cancer cells.

Synthesis of substituted 5-N-(R)amino-4-cyclohexyl-1-ols by the reaction of secondary enaminones of β-dicarbonyl compounds with chalcones

Reaction of secondary enaminones of acetylacetone or acetoacetic ester with chalcones at room temperature, is shown to lead to 5-N-(R)amino-4-cyclohexen-1-ols, distinctly to the reaction of the related primary derivatives leading to 1,4-dihydropyridines. Tertiary enaminones of identical structure are found not reacting with chalcones under the similar conditions. The reasons for the difference in the behavior of primary, secondary and tertiary enaminones in the reaction with chalcones are discussed.

A novel application of DDQ as electrophile in the Nenitzescu reaction

Reaction of 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) with secondary enaminones yields surprisingly 2-aza-spiro[4,5]decatrienes. The reaction occurs via cyclisation of the primary Michael-adduct with the nitrile group. Reaction of DDQ with tertiary and also certain secondary enamines leads to 3-amino-benzo[ b]furan derivatives. This is formed not by Michael-addition, but via geminate radical ion pair formation with subsequent generation of an oxygen–carbon bond to yield benzofurans. The new products are investigated with regards to inhibition of purified human proteinkinase CK2 and their general cytostatic activity. It turned out, that the most active compound is the 3-amino-5-hydroxy-benzofuran derivative 11s with an IC 50 value of 0,2 μM for CK2.

Silver-catalysed hydroamination: synthesis of functionalised pyrroles

It has been shown that functionalised pyrroles can be efficiently prepared using a two-step sequence. This sequence involves the propargylation of secondary enaminones using n-BuLi and propargyl bromide, followed by intramolecular hydroamination catalysed by silver nitrate. The hydroamination can be carried out at room temperature (overnight) or in a domestic microwave oven (60 s).

A study of aryl radical cyclization in enaminone esters.

Aryl radical cyclization in N-phenyl, N-benzyl, and N-phenethyl enaminone esters 1a-f was studied. N-Benzyl and N-phenethyl enaminones afforded 5-exo and 6-exo cyclization products, respectively, but radical cyclization did not occur in N-phenyl enaminones. The rate constants for the 5-exo and 6-exo cyclization processes in secondary enaminones were estimated as being on the order of 10(7) s(-1) at 353 K; since DNMR experiments showed the rate constant for rotation around the enaminone C3-N bond to be on the order of 10(4) s(-1) at this temperature, the initial enaminone configuration is maintained throughout the cyclization process. PM3 calculations suggested that the nonoccurrence of endo and 4-exo cyclizations is due to the corresponding transition structures involving significant distortion of the conjugated enaminone system.

Ultraviolet spectroscopy of anticonvulsant enaminones

The ultraviolet (UV) spectra of selected enaminones were determined in acidic, alkaline and neutral media and compared to their anticonvulsant activities. The wavelength of maximum absorption and molar absorptivity were compared with the anticonvulsant activity of the selected secondary and tertiary enaminones, and general inferences were made. The UV spectra of the enaminones had hypsochromic shifts in acidic media in comparison with neutral media. Generally, a small hypsochromic shift occurred in alkaline media when compared to the neutral solutions of the enaminones. The tertiary enaminones absorbed UV light at longer wavelength than the secondary enaminones in acidic, neutral and alkaline media. In particular, the tertiary enaminones displayed absorption at the higher end and secondary enaminones towards the lower end of the UV wavelength range 292–315 nm in aqueous media. Tertiary enaminones ( 30– 33) which were devoid of the NH proton were found to be uniformly inactive in a mouse model of electroshock seizures, while some secondary enaminones ( 1, 5– 8, 12, 16, 18, 20, 23– 25, 28 and 29) had anticonvulsant activity. Thus the NH group of secondary enaminones is very important for anticonvulsant activity, and this agrees with an already established trend in proton NMR spectroscopy. In addition, the para-substitution on the phenyl group in some enaminones result in higher molar absorptivity (ε) values that enhance anticonvulsant activity. These results indicate that the anticonvulsant activity of enaminones is not due to electronic effect alone, but is probably due to a combination of factors including electronic and steric effects, lipophilicity, and hydrogen bonding.

Intermolecular N-H...O Hydrogen Bonding Assisted by Resonance. II. Self Assembly of Hydrogen-Bonded Secondary Enaminones in Supramolecular Catemers

The crystal structures of 15 compounds containing the 2-en-3-amino-1-one heterodienic system and forming intermolecular N—H...O hydrogen bonds assisted by resonance (RAHB) are reported: (1) 3-phenylamino-2-cyclohexen-1-one; (2) 3-(4-methoxyphenylamino)-2-cyclohexen-1-one; (3) 3-(4-chlorophenylamino)-2-cyclohexen-1-one; (4) 3-(4-methoxyphenylamino)-2-methyl-2-cyclohexen-1-one; (5) 3-(4-methoxyphenylamino)-5-methyl-2-cyclohexen-1-one; (6) 3-isopropylamino-5,5-dimethyl-2-cyclohexen-1-one; (7) 3-phenylamino-5,5-dimethyl-2-cyclohexen-1-one; (8) 3-(3-methoxyphenylamino)-5,5-dimethyl-2-cyclohexen-1-one; (9) N,N-3-aza-pentane-1,5-bis[1-(3-oxo-5,5-dimethyl-1-cyclohexenyl)]; (10) 3-phenylamino-6,6-dimethyl-2-cyclohexen-1-one; (11) 3-(2-methoxyphenylamino)-6,6-dimethyl-2-cyclohexen-1-one; (12) 3-(3-chlorophenylamino)-6,6-dimethyl-2-cyclohexen-1-one; (13) 3-(4-chlorophenylamino)-6,6-dimethyl-2-cyclohexen-1-one; (14) 1-(4-chlorophenyl)-4-(4-chlorophenylamino)-6-methyl-2-pyridone; (15) 3-(4-chlorophenylamino)-5-phenyl-2-cyclopenten-1,4-dione. All compounds form intermolecular N—H...O=C hydrogen bonds assisted by resonance connecting the heteroconjugated enaminonic groups in infinite chains. Chain morphologies are analyzed to find out crystal engineering rules able to predict and interpret the crystal packing. Simple secondary enaminones [i.e. (1)–(13) together with a number of structures retrieved from the Cambridge Structural Database] are found to form hydrogen bonds having π-delocalizations, as characterized by a C=O bond-length average of 1.239 ± 0.004 Å, and hydrogen-bond strengths, represented by the N...O average distance of 2.86 ± 0.05 Å, very similar to those previously found for amides. Enaminones, however, can be easily substituted by chemical groups able to influence both π-conjugations and N...O hydrogen-bond distances. Some substituted enaminones, retrieved from the literature, display, in fact, N...O hydrogen-bond distances as short as 2.627 Å and large π-delocalizations with C=O double-bond distances as long as 1.285 Å. These effects appear to be associated with (a) the presence of further π-conjugated systems involving the C=O and NH groups of the enaminone moiety or (b) the transformation of the enaminone carbonyl group in an amidic function.

Nuclear Magnetic Resonance Studies of Anticonvulsant Enaminones

1H nuclear magnetic resonance (NMR) spectra of enaminones were determined and compared to the anticonvulsant activity of the compounds. Although the precise employment of the NMR data to predict anticonvulsant activity of the enaminones could not be established, general inferences were made. The NMR data confirmed that the enaminones existed predominantly in the amino tautomer, and no evidence was found for the imino tautomer. The ketamine form of the enaminones was supported by the observed spin-spin splittings of the NH with the α-protons on certain enaminones. The NH of secondary enaminones was very important in conferring anticonvulsant activity to the enaminones. The peak for the NH proton which could be seen between δ (ppm) 4.50 and 9.70 was present in all of the active enaminones. The tertiary enaminones, which were devoid of the NH proton, were uniformly inactive. It appeared that a combination of steric and electronic effects, lipophilicity, and hydrogen bonding were necessary for the anticonvulsant activity of the enaminones. The cyclic enaminones existed in thetrans-S-transfixed conformation, and the NMR data supported our hypothesis that enantioselectivity is retained in synthesizing enaminones from cyclic, diasteriomeric 1,3-diketones. In addition, the AB system and many unique features were observed in some enaminones. The para, meta, and ortho substituted patterns were observed for monosubstituted phenyl protons, and the NMR patterns for di- and trisubstituted phenyl groups were elucidated.

Halogenierung und Acyloxylierung von N-Cyclohex-2-en-1-on-3-yl-aminosäuren / Halogenation and Acyloxylation of N-Cyclohex-2-en-1-on-3-yl-amino Acids

Secondary enaminones 2 are easily halogenated to yield the so far unknown halogenides 3,4 and 5. Acyloxylation of enaminones 2 by dibenzoylperoxide leads to benzoyloxylated substances 13, which also have not been described jet. Bisacylated products could not be traced. Only the rearranged compounds 14 could be isolated. 14b showed cytotoxic activity.

ChemInform Abstract: Some Reactions of Enaminones with Isothiocyanates.

Two primary and two secondary enaminones derived from cyclohexane-1,3-dione have been shown to react with methyl isothiocyanate and phenyl isothiocyanate. The dimedone derivatives (1) and (2) only reacted at high temperature to give products of C-2 substitution, (4)–(6). The primary enaminones (1) and (10) were deprotonated with strong bases to give products of N-substitution, (8), (9), (11), and (12). 3-Aminocyclohex-2-enone (10) reacted with methyl isothiocyanate in the presence of sodium hydride to give an unexpected new spirodihydrotriazine (15) the structure of which was established by an X-ray crystal structure determination of its diethyl acetal (16). The reaction of 5,5-dimethyl-3-methylaminocyclohex-2-enone (2) with sodium hydride and phenyl isothiocyanate in tetrahydrofuran gave the same mixture of four products as the reaction of 3-anilino-5,5-dimethylcyclohex-2-enone (3) with methyl isothiocyanate under the same conditions.

Experimental and theoretical study of the reactivity of primary and secondary enaminones toward diphenylketene. A comparison of AM1 and HAM/3 semiempirical methods

Diazodiphenylethanone reacts with acyclic enamino ketones and enamino esters to form products of electrophilic attack of diphenylketene at C α and nitrogen. The relative reactivity of the different enaminones was shown to be consistent with HOMO energies determined by the HAM/3 semiempirical method. However, this approach could not completely explain the reactivity of the cyclic enamino ketones, which, by HAM/3, show a high-energy second HOMO corresponding to the nonbonded pair of electrons on oxygen

The use of AM1 in structural analyses of primary and secondary enaminones

The AM1 semiempirical method was employed to study the structural features of some primary and secondary acyclic and cyclic enaminones. This method was shown to be very suitable for these compounds, enabling the correct prediction of the more stable tautomer and geometric forms and other features such as strength of intramolecular hydrogen bonds and rotational barriers. In comparison, its predecessor, the MNDO method, very often gave incorrect or inconsistent results.

Some reactions of enaminones with isothiocyanates

Two primary and two secondary enaminones derived from cyclohexane-1,3-dione have been shown to react with methyl isothiocyanate and phenyl isothiocyanate. The dimedone derivatives (1) and (2) only reacted at high temperature to give products of C-2 substitution, (4)–(6). The primary enaminones (1) and (10) were deprotonated with strong bases to give products of N-substitution, (8), (9), (11), and (12). 3-Aminocyclohex-2-enone (10) reacted with methyl isothiocyanate in the presence of sodium hydride to give an unexpected new spirodihydrotriazine (15) the structure of which was established by an X-ray crystal structure determination of its diethyl acetal (16). The reaction of 5,5-dimethyl-3-methylaminocyclohex-2-enone (2) with sodium hydride and phenyl isothiocyanate in tetrahydrofuran gave the same mixture of four products as the reaction of 3-anilino-5,5-dimethylcyclohex-2-enone (3) with methyl isothiocyanate under the same conditions.

Photocyclization of aryl enaminones. An efficient route to indole alkaloid synthons

The photocyclization of enaminones was extended to aryl enaminones bearing a substituent on the aromatic moiety. This reaction was studied in order to achieve the synthesis of indole alkaloid synthons. Trials of regioselectivity control were made by using groups with enhanced steric hindrance. The reactivity of secondary enaminones was tested, and the ratio of C-alkylation to N-alkylation was shown to be dependent on the nature of the aromatic substituent. During this work, new hexahydrocarbazolones were synthesized, with substituents on the A ring or the modified C ring. Keywords: photocyclization, aryl enaminones, indole alkaloids, hexahydrocarbazolones-4, cyclopenta[b]indoles.

Carbonsäure‐iminovinylester – O‐Acylierungsprodukte der Enaminone mit Carbonsäurechloriden

Iminovinyl Carboxylates – O‐Acyl Products of Enaminones with Acyl ChloridesOn reaction of cyclic, secondary enaminones 6 with pivaloyl or benzoyl chloride the hitherto unknown iminovinyl carboxylates 7 are obtained; with acetyl chloride the O,N‐diacetyl compounds 8 are formed. The esters 7 are present as E,Z isomers.