Cyclic Enamines Research Articles

Sulfonyl Radical-Induced Regioselective Cyclization of Enamide-Olefin To Form Sulfonylated 6-7-Membered Cyclic Enamines.

Remarkable progress has been made in the radical cascade cyclization of heteroaryl- or aryl-tethered alkenes to construct benzene-fused frameworks via the cracking of aryl C-H bonds. In contrast, the radical cascade cyclization of linear dienes through the cracking of vinyl C-H bonds to construct nonbenzene-fused ring frameworks with endocyclic double bonds has significantly lagged behind, and major advances have largely been restricted to the generation of 5-membered heterocycles, such as pyrrolinones. Herein, we report the silver-mediated regioselective sulfonylation-cyclization of linear dienes with sodium sulfinates to form sulfonylated 6- and 7-membered cyclic enamines.

Linear and Angular Heteroannulated Pyridines Tethered 6-Hydroxy-4,7-Dimethoxybenzofuran: Synthesis and Antimicrobial Activity.

2-Chloropyridine-3-carbonitrile derivative 1 was utilized as a key precursor to build a series of linear and angular annulated pyridines linked to a 6-hydroxy-4,7-dimethoxybenzofuran moiety. Reaction of substrate 1 with various hydrazines afforded pyrazolo[3,4-b]pyridines. Treatment of substrate 1 with 1,3-N,N-binucleophiles including 3-amino-1,2,4-triazole, 5-amino-1H-tetrazole, 3-amino-6-methyl-1,2,4-triazin-5(4H)-one and 2-aminobenzimidazole produced the novel angular pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine, pyrido[3,2-e][1,2,4]tetrazolo[1,5-a]pyrimidine, pyrido[3',2':5,6] pyrimido[2,1-c][1,2,4]triazine and benzo[4,5]imidazo[1,2-a]pyrido[3,2-e]pyrimidine, respectively. Reaction of substrate 1 with 1,3-C,N-binucleophiles including cyanoacetamides and 1H-benzimidazol-2-ylacetonitrile furnished 1,8-naphthyridines and benzoimidazonaphthyridine. Moreover, reacting substrate 1 with 5-aminopyrazoles gave pyrazolo[3,4-b][1,8]naphthyridines. Finally, reaction of compound 1 with 6-aminouracils as cyclic enamines yielded pyrimido[4,5-b][1,8]naphthyridines. Some of the synthesized products showed noteworthy antimicrobial efficiency against all types of microbial strains. Structures of the produced compounds were established using analytical and spectroscopic tools.

A Strongly Ambiphilic Ferrocene-Based Cyclic (Alkyl)(amino)carbene - Specific Decomposition to an Enamine by a 1,2-Phenyl Shift.

The recently described crystalline cyclic (alkyl)(amino)carbene with a 1,1'-ferrocenylene (fc) backbone fc(CPh2-C-NMes) (A, Mes = mesityl) is highly reactive due to its particularly pronounced ambiphilicity and is thermally not stable in solution due to an intramolecular insertion of the divalent carbon atom into a methyl C-H bond of the Mes substituent. The closely related congener fc(CPh2-C-N-p-C6H4-tBu) (1) cannot undergo such an insertion reaction. Nevertheless, 1 is too short-lived for isolation due to a rapid 1,2-shift of a phenyl group, furnishing the isomeric cyclic enamine fc[C(Ph)=C(Ph)-N-p-C6H4-tBu] (1') in a specific decomposition process unprecedented for CAACs. Trapping of 1 was possible with carbon monoxide, elemental selenium and with [CuBr(SMe2)], respectively affording the aminoketene 1=C=O, the selenoamide 1=Se and the homoleptic CuI complex [Cu(1)2][CuBr2]. 1 is an even stronger ambiphile than A according to NMR spectroscopic data. Similar to A, 1 does not react with H2, because the experimentally observed intramolecular process is kinetically more favourable according to DFT results.

Synthesis, Characterization and Antimicrobial and Anticancer Evaluations of Some Novel Heteroannulated Difuro[3,2-c:3',2'-g]Chromenes.

The goal of this study was directed to synthesize a novel class of annulated compounds containing difuro[3,2-c:3',2'-g]chromene. Friedländer condensation of o-aminoacetyl derivative 3 was performed with some active methylene ketones, namely, 1,3-cyclohexanediones, pyrazolones, 1,3-thiazolidinones and barbituric acids, furnished furochromenofuroquinolines (4,5), furochromenofuropyrazolopyridines (6-8), furochromenofurothiazolopyridines (9,10) and furochromenofuropyridopyrimidines (11, 12), respectively. Also, condensation of substrate 3 with 5-amine-3-methyl-1H-pyrazole and 6-amino-1,3-dimethyluracil, as cyclic enamines, resulted in polyfused systems 13 and 14, respectively. In vitro antimicrobial efficiency of the prepared heterocycles against microbial strains exhibited variable inhibition action, where compound 3 was the most effective against all kinds of microorganisms. A significant cytotoxic activity was seen upon the annulation of the starting compound with thiazolopyridine (9 and 10) as well as pyridopyrimidine moieties (11, 12 and 14). The spectroscopic and analytical results were used to infer the structures of the novel synthesized compounds.

Development of a Safe and Scalable Method to Prepare 3-Bromo-N-alkyl-1,6-naphthyridones via Enamine Cyclization

Development of a Safe and Scalable Method to Prepare 3-Bromo-<i>N</i>-alkyl-1,6-naphthyridones via Enamine Cyclization

Streamlined Stereoselective Entry to (-)-Quinagolide and to 3-Substituted Octahydrobenzo[g]-Quinolines.

A very short stereoselective synthesis of enantiomerically pure (3S, 4aS, 10aR)-quinagolide has been developed. The key steps involved are a copper-catalyzed regioselective arylation of (S)-epichlorohydrin with 1,6-dimethoxynaphthalene and a diastereoselective trans-reduction of a cyclic enamine intermediate. The possibility to use both enantiomers of epichlorohydrin and the diastereodivergency found in the reduction process paves the way for a general preparation also in the nonracemic form of chiral trans-fused 3-substituted octahydrobenzo[g]quinolines that are privileged structures in medicinal chemistry.

Friedländer reactions for novel annulated pyridotriazolothiazolopyridines: Synthetic approaches and antimicrobial evaluation

o-Aminoaldehyde 1 was employed as starting precursor for construction of some linear heterocyclic compounds. o-Aminoaldehyde 1 was permitted to undergo Friedländer reaction with some acyclic and cyclic methylene ketones giving the novel annulated heterocyclic systems 2-10. Moreover, the reactivity of o-aminoaldehyde 1 was examined toward some cyclic enamines and enols producing the corresponding annulated heterocyclic systems. The prepared compounds were investigated for their antimicrobial efficiency displaying different inhibition action toward the tested microorganisms. Based on analytical spectral and results, structures of the produced compounds were established.

Iridium-Catalyzed Reductive (3+2) Annulation of Lactams Enabling the Rapid Total Synthesis of (±)-Eburnamonine.

A reductive (3+2) annulation of lactams through iridium-catalyzed hydrosilylation and photoredox coupling with α-bromoacetic acid was developed. The iridium-catalyzed hydrosilylation of the lactam carbonyl group and subsequent elimination provide a transient cyclic enamine, which undergoes iridium-catalyzed photoredox coupling with α-bromoacetic acid in a one-pot process. The developed conditions show high functional-group tolerance and provide cyclic N,O-acetals containing a quaternary carbon center. The resulting N,O-acetals undergo a variety of acid-mediated nucleophilic addition reactions via iminium ions to give substituted cyclic amines. The developed sequence including reductive (3+2) annulation and acid-mediated nucleophilic addition was successfully applied to the four-step total synthesis of (±)-eburnamonine.

Iridium‐Catalyzed Reductive (3+2) Annulation of Lactams Enabling the Rapid Total Synthesis of (±)‐Eburnamonine

AbstractA reductive (3+2) annulation of lactams through iridium‐catalyzed hydrosilylation and photoredox coupling with α‐bromoacetic acid was developed. The iridium‐catalyzed hydrosilylation of the lactam carbonyl group and subsequent elimination provide a transient cyclic enamine, which undergoes iridium‐catalyzed photoredox coupling with α‐bromoacetic acid in a one‐pot process. The developed conditions show high functional‐group tolerance and provide cyclic N,O‐acetals containing a quaternary carbon center. The resulting N,O‐acetals undergo a variety of acid‐mediated nucleophilic addition reactions via iminium ions to give substituted cyclic amines. The developed sequence including reductive (3+2) annulation and acid‐mediated nucleophilic addition was successfully applied to the four‐step total synthesis of (±)‐eburnamonine.

The Synthetic Progress of Fused Bicyclic N,O-acetals

Abstract: Owing to the prevalent occurring in natural products and abundant bioactivities, the effective synthetic methods of fused bicyclic N,O-acetals skeletons are of great interest to chemists. This mini-review summarized the thus far synthetic progress of fused bicyclic N,O-acetals. These works were elaborated according to the different reaction types, including a) hetero-Diels-Alder cycloaddition of cyclic enamines with oxadienes; b) step-by-step reactions between cyclic enamines and electrophiles with pendant hydroxyl groups; c) [3+2] cycloaddition of indole with quinone or its equivalent and d) other novel strategies. The catalytic systems and reaction mechanisms are mainly described.

Design, synthesis and antimicrobial activity of heteroannulated chromeno[3′,2′:5,6]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidines

The current research is directed to construct a novel category of linear annulated chromeno[3`,2`:5,6]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidines. The chemical reactivity of the recently synthesized aldehyde 1 was examined toward a diversity cyclic methylene ketones, cyclic enamines and cyclic enols. Friedländer condensation of aldehyde 1 with 1,3-cyclohexanediones gave the multi-linear chromenopyrido- pyrimidothiazoloquinolines 2 and 3. Also, treating aldehyde 1 with some pyrazolones furnished annulated chromenopyridopyrazolopyridothiazolopyrimidines 4-6. Further, 1,3-thiazolidine-2,4-dione and barbituric acid condensed with aldehyde 1 giving chromenopyridothiazolopyridothiazolopyrimidine 7 and chromenopyridopyrimido-thiazolopyridopyrimidine 8, respectively. Moreover, reacting aldehyde 1 with cyclic enamines (6-amino-2-thiouracil and 6-amino-1,3-dimethyluracil) and cyclic enols (4-hydroxycoumarin and 1-ethyl-4-hydroxyquinolin-2(1H)-one) furnished polyfused heterocycles 9-12, respectively. During in vitro investigation of the antimicrobial efficiency, the synthesized compounds showed considerable activity against yeast and fungal strains, as well as moderate to high activity against Gram-positive and Gram-negative bacteria. Polyfused compounds 4-6 showed significant efficiency against all types of tested microorganisms.

First Approaches for the Novel Pyrido[1'',2'':2',3'][1,2,4]Triazolo [5',1',2,3][1,3]Thiazolo[4,5-b] Pyridines: Synthesis, Characterization and Antimicrobial Efficiency

Vilsmeier–Haack formylation of 3-aminothiazolotriazolopyridine-7,9-dicarbonitrile 3 afforded the corresponding aldehyde derivative 4 in a 65% yield. Some Schiff bases 5-7 were efficiently synthesized by reacting substrate 4 with some primary amines. Reaction of substrate 4 with some active methylene nitriles produced 2-amino-3-substituted-pyridotriazolothiazolopyridines 8–12. Substrate 4 was utilized as a key intermediate for a diversity of pyridotriazolothiazolopyrazolopyridines 13–15, through the Friedlander reaction with pyrazolidine-3,5-dione, 5-amino-2,4-dihydro-3H-pyrazol-3-one, and 5-phenyl-2,4-dihydro-3H-pyrazol-3-one. Further, the reaction of substrate 4 with 5-amino-3-methyl-1H-pyrazole and 6-aminouracil, as cyclic enamines, produced pyridotriazolothiazolopyrazolopyridine 16 and pyridotriazolothiazolopyridopyrimidine 17, respectively. The antimicrobial efficiency was assessed for the synthesized products, and some of them showed notable activity. The structures of the synthesized products were confirmed using analytical and spectroscopic data.

Scope and Mechanistic Studies on the Ruthenium-Catalyzed Multicomponent Deaminative C–H Coupling Reaction of Phenols with Aldehydes and Enamines for the Formation of Xanthene and Dioxacyclic Derivatives

The in situ generated catalytic system from the tetranuclear Ru–H complex [(PCy3)(CO)RuH]4(O)(OH)2 (1) with 3,4,5,6-tetrachloro-1,2-benzoquinone (L1) has been found to mediate a multicomponent deaminative coupling reaction of phenols with aldehydes and enamines to form xanthene products. The multicomponent C–H coupling reaction of phenols with 2-hydroxybenzaldehydes and cyclic enamines efficiently installed the tricyclic 1,3-dioxacin derivatives, while the analogous coupling reaction of phenols with 2-hydroxybenzaldehydes and triethylamine selectively formed bicyclic 1,5-dioxacyclic derivatives. The density functional theory (DFT) calculations established two energetically viable mechanistic pathways for the formation of xanthene products, in which both pathways identified the C–O bond cleavage step as the turnover limiting step. A Hammett plot from the coupling reaction of 3,5-dimethoxyphenol with an enamine and para-substituted benzaldehydes p-X-C6H4CHO (X = OMe, Me, H, Cl, CF3) showed a negative slope (ρ = −0.98). The calculated energy analysis showed a similar trend (ρ = −0.59) for the mechanism via the C–O cleavage rate-limiting step. The combined experimental and DFT computational results support a mechanistic path that involves the dehydrative C–H coupling of phenol with aldehyde, followed by the deaminative coupling reaction with an enamine in forming the xanthene product.

Design and Facile Synthesis of Spiro-s-tetrazine Derivatives of 2,4- diphenyl-3-azabicyclo[3.3.1]nonane-9-one.

Literature survey suggested various methods of synthesis of the 3- azabicyclo [3.3.1] nonanes which include, Mannich reaction, α, α'-Annelation of Cyclic Ketones or through Enamines, Michael addition, Intramolecular Cyclizations, etc. However, a mechanism following a Michael addition path through the formation of the dibenzylidene cyclohexanone intermediate can not be ignored. Thus to ensure the mechanistic pathway for the formation of 2,4-diphenyl- 3-azabicyclo[3.3.1]nonan-9-one and to understand the reactivity of a conformationally and biologically important molecule for the synthesis of spiro-s-tetrazine derivatives and its further functionalization with thiazole and thiazolidinone derivatives the present work has been undertaken. Direct reaction of dibenzylidene cyclohexanone and ammonium acetate has been tried to get the confirmation of Mannich/ Michael reaction pathway for the formation of 2,4-diphenyl-3- azabicyclo[3.3.1]nonan-9-one. Synthesis of the spiro-s-tetrazine derivative has been accomplished by the simple condensation reaction of azabicyclic system and thiocarbohydrazide (TCH). Simple methods have been adopted for the installation of heterocyclic moieties like thiazolidinone, thiazole. Failure of the attempts to prepare 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-onedirectly from dibenzylidene cyclohexanone ruins the possibility of Michael addition reaction and supports the formation of the product through Mannich reaction. Synthesis of the spiro derivatives containing tetrazine, thiazole, thiazolidinone moieties were achieved by using simple techniques and products were obtained in good yield. FTIR, NMR spectroscopy are used for the characterization of all the molecules. Formation of 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-onewas confirmed by using some additional data like mass and single crystal XRD. Confirmation of the mechanistic route for the 2 2,4-diphenyl-3- azabicyclo[3.3.1]nonan-9-one was achieved and simple methods for the formation of spiro derivatives containing tetrazine, thiazole, thiazolidinone were established.

Metal‐Free Synthesis of Pyrimidine and Naphthoquinone‐Fused Pyrroles from Arylglyoxal‐Based Domino Reactions

AbstractHerein we report acid mediated two and three‐component domino reactions of cyclic enamines such as 2‐amino‐1,4‐naphthoquinone, and 6‐amino‐1,3‐dimethyluracil with arylglyoxals for the synthesis of diverse fused pyrroles. The two‐component reaction of arylglyoxal and 2‐amino‐1,4‐naphthoquinone in the acetic acid medium provided substituted naphthoquinone‐fused pyrroles tethered with hydroxyl and aryl substituents. On the other hand, under similar reaction conditions, the reaction of phenylglyoxal with 6‐amino‐1,3‐dimethyluracil provided an unusual bipyrrolopyrimidine with a quaternary carbon center following a domino reaction involving the formation of five new sigma bonds in one‐pot. Interestingly, the reaction of arylglyoxals with 6‐amino‐1,3‐dimethyluracil in ethanol medium in the presence of 10‐mol% PTSA provided a three‐component product having pyrimidine fused pyrrole linked with 6‐aminouracil moiety. We have also developed a three‐component reaction of 2‐amino‐1,4‐naphthoquinone, arylglyoxals, and 4‐hydroxy‐1‐methylquinolin‐2(1H)‐one for the synthesis of naphthoquinone‐fused pyrroles linked with hydroxyquinoline derivatives.

Merging Alkene Isomerization Enables Difunctionalization of Cyclic Enamines toward Ring-Fused Aminal Synthesis.

Here we report a Pd-catalyzed isomerization of alicyclic allyl amine to achieve the unprecedented α,β-difunctionalization of synthetically inaccessible trisubstituted cyclic enamine. The dual role of in situ formed enamine intermediate allows for the intermolecular formal [4 + 2] reaction with acrylamide or isatoic anhydride to simultaneously construct the C-C bond and C-N bond, thus realizing the expedient construction of [4.3.0]-aminal with excellent diastereoselectivity and high atom economy.

Concise synthesis of 2,3-disubstituted quinoline derivatives via ruthenium-catalyzed three-component deaminative coupling reaction of anilines, aldehydes and amines.

The Ru-H complex (PCy3)2(CO)RuHCl (1) was found to be a highly effective catalyst for the three-component deaminative coupling reaction of anilines with aldehydes and allylamines to form 2,3-disubstituted quinoline products. The analogous coupling reaction of anilines with aldehydes and cyclic enamines led to the selective formation of the tricyclic quinoline derivatives. The reaction profile study showed that the imine is initially formed from the dehydrative coupling of aniline and aldehyde, and it undergoes the deaminative coupling and annulation reaction with amine substrate to form the quinoline product. The catalytic coupling method provides a step-efficient synthesis of 2,3-disubstituted quinoline derivatives without employing any reactive reagents or forming wasteful byproducts.

Synthesis of 1,2-Dicarbonyls from Five-Membered Cyclic Enamines and Arylglyoxal Hydrates under Metal-Free Conditions

Synthesis of 1,2-Dicarbonyls from Five-Membered Cyclic Enamines and Arylglyoxal Hydrates under Metal-Free Conditions

Metal-free transfer hydrogenation/cycloaddition cascade of activated quinolines and isoquinolines with tosyl azides.

The difficulty in isolating cyclic enamines emanating from their intrinsic instability has impeded their exploration in cycloaddition reactions. Here, we achieved a metal-free domino reaction providing quinoline and isoquinoline-derived cyclic amidines by the cycloaddition of azides with in situ generated enamines via dearomatization.

KI-Catalyzed Oxidative Cyclization of Enamines and tBuONO to Access Functional Imidazole-4-Carboxylic Derivatives.

A simple protocol for the noble-metal-free oxidative cyclization of enamines and tBuONO has been developed. This KI-mediated formal [4 + 1] cycloamination reaction provides a practical strategy for the synthesis of imidazole-4-carboxylic derivatives using tBuONO both as an aminating reagent and oxidant. The reaction features wide substrate scope and good functional tolerance for enamine compounds, even the unactivated ones.