Tertiary Enaminones Research Articles

An In‐Depth Review on Recent Progress in Synthetic Approaches and Biological Activities of Thiazol‐2(3H)‐Imine Derivatives

AbstractThis review presents the in‐dept analysis of the synthetic approaches towards thiazol‐2(3H)‐imine and embarks at its various biological properties published during 2000 to 2023. The most important method of synthesis involves the reaction of substituted thioureas and α‐halo carbonyl compounds, and condensation and nucleophilic addition of 2‐amino‐1,3‐thiazoline with aldehydes. Additionally, isothiocyanate‐based multicomponent synthesis, and α‐nitroepoxides have been proved as benign precursors for this motif. Several eco‐friendly and solvent‐free synthesis from diazonium salts, acetylenes, tertiary enaminones and thiosemicarbazides have also been reported. This epitome is a unique combination of synthetic methods as well as biological activities like anti‐inflammatory, anti‐bacterial, anti‐cancer, anti‐leishmanial, anti‐microbial, herbicidal, anti‐HIV, and may be a valuable tool for researchers to tailor the synthetic procedures according to specific target structures and applications. Moreover, this review enlightens the applications of thiazol‐2(3H)‐imine as platelet GPIIB/IIIA receptor antagonists, alkaline phosphatase inhibitors, neurodegenerative drug Pifithrin‐α analogues, and skin whitening agents.

Metal-free assembly of diverse polysubstituted pyridines via an efficient cascade approach using tertiary enaminones and α,β-unsaturated sulfonylketimines

A metal-free, scalable, and cascade protocol for assembling diverse polysubstituted pyridines from tertiary enaminones and α,β-unsaturated sulfonylketimines by cleaving C–N/N–S bonds is reported.

Thiazole-5-carbaldehyde Synthesis by Cascade Annulation of Enaminones and KSCN with Dess-Martin Periodinane Reagent.

The Dess-Martin periodinane (DMP) reagent-mediated reactions of tertiary enaminones with potassium thiocyanate for the synthesis of thiazole-5-carbaldehydes are developed. The product formation involves cascade hydroxyl thiocyanation of the C═C double bond, intramolecular hydroamination of the C≡N bond, and thiazole annulation by condensation on the ketone carbonyl site, representing novel reaction pathways in the reactions between enaminones and thiocyanate salt. DMP plays dual roles in mediating the free radical thiocyanation and inducing the unconventional selective thiazole-5-carbaldehyde formation by masking the in situ generated formyl group during the reaction process.

Cascade Reaction of Tertiary Enaminones, KSCN, and Anilines: Temperature-Controlled Synthesis of 2-Aminothiazoles and 2-Iminothiazoline.

A one-pot cascade strategy for the synthesis of 2-aminothiazole derivatives by tertiary enaminones, KSCN, and anilines was developed. By changing the reaction temperature, the three-component reaction could be transformed in different ways to obtain moderate to good yields of polysubstituted 2-aminothiazoles and 2-iminothiazolines. This protocol provides an efficient and concise approach to accessing 2-aminothiazole derivatives with potential bioactivity from readily accessible building blocks and reagents.

Tunable Trifunctionalization of Tertiary Enaminones for the Regioselective and Metal-Free Synthesis of Discrete and Proximal Phosphoryl Nitriles.

This paper reports an unprecedented trifunctionalization of tertiary enaminones for the synthesis phosphoryl nitriles by the reactions of enaminones with diarylphosphine oxides and trimethylsilyl cyanide (TMSCN) without the use of any metal reagent. Employing tetrabutyl ammonium hydroxide (TBAH) as the catalyst (0.2 equiv) enables discrete cyanophosphonation. On the other hand, selective proximal cyanophosphonation has been realized in the presence of acetic acid only (AcOH).

Scissoring Enaminone C═C Double Bond by Free Radical Process for the Synthesis of α-Trifluoromethyl Ketones with CF3SO2Na.

The C═C double bond cleavage on tertiary enaminones, enabling the formation of a new C-CF3 bond, has been realized as a practical method for the synthesis of α-trifluoromethyl ketones with only the promotion of TBHP and ambient heating. Control experiments support that the reactions proceed via a featured free radical process. The deuterium labeling experiment employing D2O indicates that water participated in the product formation by donating the hydrogen atom for the newly generated α-C-H bond in the product.

Superbase‐Promoted N‐α‐sp3C‐H Functionalization of Tertiary Enaminones: Synthesis of Polysubstituted Pyrroles

AbstractAn efficient superbase‐promoted N‐α‐sp3C−H functionalization of tertiary enaminones for the regiospecific synthesis of structurally diversified pyrroles under mild conditions has been exploited. The developed methodology led to a wide panel of pyrroles with broad substrate scope in an atom‐economy manner. Various substituted pyrroles are provided in up to 94% yield for 36 examples.

C3‐Functionalized Chromones Synthesis by Tandem C−H Elaboration and Chromone Annulation of Enaminones

AbstractChromone is a heterocyclic entity presents in a number of natural products, clinical pharmaceuticals, as well as molecules with enriched biological functions. As cutting‐edge area, the synthesis of chromones has seen spectacular progress over the past decade. Among the available synthetic modes toward chromone scaffolds, the annulation of ortho‐hydroxyphenyl functionalized N,N‐disubstituted enaminones has turned out to be one of the most reliable and practical ones. By combining this annulation with the featured transformation of the vinyl α‐C−H bond in the enaminone structure, a large number of tandem reactions providing structurally diverse chromones with C3‐functionalization have been recently realized. As a practical strategy in the synthesis of valuable heterocyclic molecules and an important branch in the enaminone‐based organic synthesis, such synthetic reactions are highly instructive for organic chemistry and many other disciplines related to this heterocyclic moiety. Herein, we present for the first time the research advances on the synthesis of C3‐functionalized chromones via tandem vinyl C−H bond elaboration and chromone annulation of ortho‐hydroxyphenyl functionalized tertiary enaminones.

Visible Light-Induced Thiocyanation of Enaminone C-H Bond to Access Polyfunctionalized Alkenes and Thiocyano Chromones.

The visible light induced C-H bond thiocyanation on the α-site of tertiary enaminones has been realized under metal-free, photocatalytic conditions in the presence of Rose Bengal, which enables the synthesis of thiocyanated alkene derivatives and chromones using NH4SCN as the thiocyano source under an aerobic atmosphere. In addition, employing Ru(bpy)3Cl2·6H2O as the photocatalyst switches the reaction pathway to provide NH2-functionalized thiocyanated enamines via the difunctionalization process consisting of C-H bond thiocyanation and vinyl C-N bond transamination.

Thermoinduced Free-Radical C-H Acyloxylation of Tertiary Enaminones: Catalyst-Free Synthesis of Acyloxyl Chromones and Enaminones.

In this paper, the direct acyloxylation of the α-C(sp2)-H bond in tertiary β-enaminones is accomplished under catalyst-free conditions and ambient temperature by using aroyl peroxides as coupling partners. By means of a thermoinduced free-radical pathway, the present method enables facile and efficient synthesis of both acyloxylated chromones and enaminones.

Redox neutral [4+2] benzannulation of dienals and tertiary enaminones for benzaldehyde synthesis

By employing the featured amine elimination of tertiary enaminones as a key transformation, cascade reactions of dienals and tertiary enaminones involving [4+2] annulation, Hofmann-like amine elimination and aromatization are devised for benzaldehyde synthesis. This method is of particular interest in providing benzaldehydes containing an electron withdrawing group at the C3 position which are hard to access by previous methods for benzaldehyde synthesis.

Reactions of Enaminones with Diazocarbonyl Compounds

AbstractThe [Cu(acac)2]‐catalyzed reactions of several tertiary enaminones with three diazocarbonyl compounds, i.e., dimethyl diazomalonate, ethyl diazoacetoacetate, and ethyl diazoacetate, yielded amino‐ and additionally carbonyl‐substituted dihydrofurans, together with further furan derivatives. Due to the conjugation of α‐carbonyl/α‐Ph groups, reactions proceeded only via 1,5‐electrocyclization of corresponding keto‐ylides. On the other hand, in the absence of any α‐substituent, tertiary enaminone and ethyl diazoacetate, reacted via an accompanying mechanism by a push‐pull cyclopropane intermediate, to yield a 2,4‐dicarbonyl‐substituted furan in one step with moderate yield.

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.

Synthesis of the Naphthalenone, Dihydroquinoline, and Dihydrofuran Derivatives

AbstractThe reactions of enaminones with dimethyl diazomalonate were investigated in the presence of copper(II) acetylacetonate. From the reaction of (E)‐3‐[methyl(phenyl)amino]‐1‐phenylprop‐2‐en‐1‐one (6c), dimethyl 2‐[methyl(phenyl)amino]‐4‐oxonaphthalene‐1,1‐(4H)‐dicarboxylate, was unexpectedly obtained as the major product. Quinoline derivatives were formed as the major products in the case of N‐methyl‐p‐anisidino and N‐methyl‐p‐toluidino enaminones. The reactions of acetyl enaminones were also realized, and quinoline derivatives were isolated as the major products. 3H‐ and 5H‐dihydrofurans were also formed as side products in these reactions. These results differ from those reported earlier on the reactions of tertiary enaminones with carbenes/metal carbenes.

N- and C-Acylation in β-Enamino Ketones: Structural Effects on Regiocontrol

The acylation reaction of secondary (R 1 = H) β-enamino ketones [RCOCH=CHNR 1 R 2 , where R = CF 3 , CCl 3 , Ph, 4-FC 6 H 4 , 4-NO 2 C 6 H 4 , thien-2-yl; R 1 = H, Me; R 2 = Me, Bn, Ph, 4-NO 2 C 6 H 4 ] with trifluoroacetic anhydride or ethyl oxalyl chloride in pyridine led regiospecifically to a series of 14 N-acylated enaminones in good yields (72-88%). On the other hand, when tertiary enaminones (R 1 , R 2 = Me) were used, the acylation reaction led to a series of 12 C-acylated enaminones in good to excellent yields (75-92%).

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.

Organic Syntheses via Transition Metal Complexes. Part 103: Pyrylium Carbonylmetalates and Related Compounds Derived from (1-Alkynyl)carbene Complexes (M=Cr, W)

Cyclic tertiary enaminones 2a-e and (2-phenylalkynyl)carbene tungsten complex (OC)5W=C(OEt)CCPh (1a) gave cross-conjugated carbiminium carbonylmetalates 3, which isomerized to pyrilium carbonylmetalates 4 in 62–90% yields. The isomerization involves a skeletal rearrangement of a cross-conjugated carbiminium carbonyltungstate to a (conjugated) 1-tungsta-1,3,5-hexatriene by formation of (4-aminocyclobutenyl)carbene complexes as intermediates. Dinuclear carbene derivatives of dihydrobarrelene 5 were derived from pyrilium carbonylmetalates 4 by [4+2] cycloaddition to (1-alkynyl)carbene complexes 1 in 63–73% yields. Reactions of cyclic 1,3-diketones 7 with (1-alkynyl)carbene complexes 1 gave pyrilium carbonylmetalates 10 and 11 in 35–91%.

Alkoxycarbonylcarbene Transfer to Acyclic Tertiary Enaminones

Copper-catalyzed alkoxycarbonylcarbene transfer from methyl or tert-butyl diazoacetate to acyclic enaminoesters 6a,b and enaminocarboxanilide 13 yields vicinal push-pullsubstituted cyclopropanes 7a,b,8, and 14. In contact with dry silica gel, the latter compounds undergo facile ring-opening leading to enaminoesters 9, 10, and 15. Treatment with aqueous acid transforms 9 and 10 into 2-acylsuccinates 11 and 12, and 15 into pyrrolinone 16. Methoxycarbonylcarbene transfer to enaminoketones 1a–c does not yield isolable cyclopropanes, but after hydrolytic work-up α-acyl-γ-ketoesters 2a–c are obtained.

α-Iodination of enaminones with bis(pyridine)iodonium(I) tetrafluoroborate

Primary, secondary and tertiary enaminones react with bis(pyridine)iodonium(I) tetrafluoroborate in methylene chloride at room temperature to give α-iodo enaminones in almost quantitative yields. The reported reaction is the first known example of direct iodination of tertiary enaminones.

Unexpected α-Chlorination of Tertiary Enaminones using Benzyltrimethylammonium Dichloroiodate

Unexpected α-Chlorination of Tertiary Enaminones using Benzyltrimethylammonium Dichloroiodate