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Review

Synthesis of Nitrogen-Containing Heterocyclic Scaffolds through Sequential Reactions of Aminoalkynes with Carbonyls

Dipartimento di Scienze Fisiche e Chimiche, Università degli Studi dell’Aquila, Via Vetoio, 67100 Coppito, L’Aquila, Italy
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(12), 4725; https://doi.org/10.3390/molecules28124725
Submission received: 10 May 2023 / Revised: 8 June 2023 / Accepted: 9 June 2023 / Published: 12 June 2023
(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)

Abstract

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Sequential reactions of aminoalkynes represent a powerful tool to easily assembly biologically important polyfunctionalized nitrogen heterocyclic scaffolds. Metal catalysis often plays a key role in terms of selectivity, efficiency, atom economy, and green chemistry of these sequential approaches. This review examines the existing literature on the applications of reactions of aminoalkynes with carbonyls, which are emerging for their synthetic potential. Aspects concerning the features of the starting reagents, the catalytic systems, alternative reaction conditions, pathways and possible intermediates are provided.

1. Introduction

Aminoalkynes are bifunctional derivatives that can undergo a diverse array of transformations. They offer sequential reactions with an electrophile and a nucleophile, and are ideal for cascade reactions. Sequential reactions represent a powerful tool to build up simple or more complex polyfunctionalized organic scaffolds from readily available reagents with high efficiency, selectivity, and atom economy [1,2,3]. Recently, applications of sequential reactions of aminoalkynes have been a very active research field in organic synthesis and medicinal chemistry. In particular, sequential reactions of β-, γ-, and δ-aminoalkynes to afford a variety of heterocyclic scaffolds were explored. Inactivated alkynes moieties are not very reactive toward nucleophiles. Their behavior changes by activation of the C-C triple bond by a metal catalyst. Various biologically important nitrogen heterocycles were directly synthesized in an easy way by means of intramolecular hydroamination of aminoalkynes in the presence of several transition metal as well as lanthanide catalysts [4,5]. The aptitude to form π- and σ-complexes can help in the choice of catalysts for the desired transformations when bi- or polyfunctional substrates are involved [6]. The reaction of γ- and δ-aminoalkynes with sulfonyl azides in the presence of Ru3(CO)12 catalyst efficiently afforded cyclic amidines of relevance in medicinal and coordination chemistry as well as in materials science [7]. The gold(I)-catalyzed tandem cyclization of γ-aminoalkynes with alkynes in water led to diversely substituted pyrrolo[1,2-a]quinolines [8]. Zhou et al. extended this reaction using less active terminal amidoalkynes in similar conditions [9]. The CuCl-catalyzed cascade transformation of internal β-aminoalkynes with alkynes under microwave irradiation gave diversely substituted tetrahydropyrrolo[1,2-a]quinolones [10]. An intramolecular gold-catalyzed hydroamination/aza-Diels–Alder tandem process of β-/γ-aminoalkynes with high regio- and diastereoselectivity and up to almost complete chemoselectivity showed great efficiency in a one-pot approach to the complex nitrogen heterocyclic derivatives of medicinal importance, such as the one-step synthesis of incargranine B aglycone and (±)-seneciobipyrrolidine (I) [11]. Faňanás, Rodríguez, and co-workers [12] described the preparation of complex pyrrolidines from readily available N-Boc-derived β-aminoalkynes and alkenes or alkynes through relay actions of PtII or Brønsted acids [13]. The reaction of α-aminoalkynes with carbon monoxide and selenium yielded 5-alkylideneselenazolin-2-ones stereoselectively via cycloaddition of in situ generated carbamoselenoates to a carbon–carbon triple bond. β-Aminoalkyne also afforded the corresponding six-membered selenium-containing heterocycle with the aid of CuI [14]. An operationally simple palladium-catalyzed intramolecular hydroaminocarbonylation of a variety of aminoalkynes directly provided a viable approach to a variety of valuable seven- and eight-membered lactams with high chemoselectivity and regioselectivity [15]. A sequential heterogeneous PtI2-catalyzed hydration of δ-aminoalkynes followed by intramolecular cyclization and intermolecular addition as well as ring-expansion cascade reaction with another electron-deficient alkynes was developed for the synthesis of various eight-membered nitrogen heterocycles with excellent yields under mild reaction conditions. The simple PtI2 could be easily recycled [16]. Moreover, a PtI2-catalyzed formal three-component cascade cycloaddition reactions between γ-aminoalkynes and electron-deficient alkynes gave highly functionalized cyclohexadiene-b-pyrrolidines with good yields [17]. Finally, among the domino and multicomponent processes that involve aminoalkynes, their cascade reactions with carbonyl derivatives stand out as a highly versatile tool to build up libraries of nitrogen-containing heterocyclic scaffolds with diversity and molecular complexity. This review will examine the literature on this last topic and is organized according to the structure of the aminoalkyne substrate. Aspects concerning the features of the catalytic systems, the substrate scope, insight into the reaction pathways, possible intermediates, and alternative conditions are discussed.

2. Sequential Reactions of α-Aminoalkynes (Propargylamines) with Carbonyls

Propargylic amine derivatives represent useful α-aminoalkynes building blocks for the construction of nitrogen-containing heterocyclic scaffolds through their sequential reactions with carbonyls. The gold-catalyzed reaction of propargylamine 1 with dialkyl acyclic/cyclic ketones, methyl, aryl/heteroaryl ketones and aldehydes bearing α-hydrogens 2 allowed a simple approach to pyridines 3 through a sequential amination–cyclization–aromatization cascade (Scheme 1) [18].
The catalyst was envisaged to promote both the amination of carbonyl compounds 2 and the regioselective 6-endo-dig cyclization of the N-propargylenamine (N-propargyldienamine) intermediate 5 (Scheme 2).
A variety of catalysts were tested in the reaction of 1 with 2. In particular, NaAuCl4·2H2O resulted in a highly efficient catalyst. Moreover, Au 8 was synthesized and applied as bifunctional catalyst. It was found that imidazolyl group acted as a Lewis base to catalyze the condensation of carbonyl compounds with propargylamine to form the imino intermediate, and the involved Au+-complex species activated the alkynyl moiety to give the dehydropyridine derivative, which underwent auto-oxidation reaction to afford the target pyridines (Scheme 3) [19].
Copper salts were also effective catalysts in the reaction of cyclic ketones with propargylamine, and the highest product yields were observed in isopropanol (i-PrOH) in the presence of 5.0 mol% CuCl2 in air. Decreased yields among cyclic ketones were observed in the following order: six-membered >> eight-membered > five-membered ∼ seven-membered. However, the inexpensiveness of the catalyst and the tolerance to a wide number of functional groups (FG) in the ketone make the procedure very suitable for large-scale preparation of fused pyridines (Scheme 4) [20].
Selective aspects of the reaction of steroidal carbonyls with propargylamine were investigated. According to the results, the regioselective pyridine fusion to the cyclic skeleton was addressed by suitable choice between the substrate bearing a saturated or conjugated carbonyl group (Scheme 5) [18].
Analogously, new A-ring pyridine fused androstanes in 17a-homo-17-oxa (D-homo lactone), 17α-picolyl or 17(E)-picolinylidene series were obtained by reacting 4-en-3-one or 4-ene-3,6-dione D-modified androstane derivatives with propargylamine under the presence of a Cu(II) catalyst, and evaluated for potential anticancer activity in vitro (Scheme 6) [21].
Similarly, the efficient synthesis of pyridine rings fused to the 3,4-positions of the steroid nucleus was described via the Cu(II)-catalyzed reaction of propargylamine with 17β-hydroxyandrost-4-en-3-one, 17α-methyl-17β-hydroxyandrost-4-en-3-one, or 17β-hydroxyestr-4-en-3-one [22]. The procedure was also applied to the synthesis of heterocyclic betulin derivatives (Scheme 7) [23,24].
Optimization of the synthesis of steroidal pyridines was tried by prolonging the reaction time and varying the catalyst loading. In some cases, the use of NaAuCl4·2H2O instead of CuCl and the addition of activated molecular sieves (MS) to the reaction mixture led to significant improvement (Scheme 8) [25].
Several other applications of the methodology accomplished the preparation of significant scaffolds. Indeed, the chemical synthesis of highly potent and acid-stable inhibitors of hedgehog signaling carbacyclopamine analogue 11 was reported. The gold-catalyzed amination–annulation–aromatization sequence applied to the inseparable mixture of the isomers 9 and 10 regioselectively furnished, after removal of the tert-butyldimethylsilyl ether (tetrabutylammonium fluoride, THF, 25 °C), carbacyclopamine analogue 11 with 36% overall yield for the two steps (Scheme 9) [26].
Furthermore, the gold-catalyzed reaction of 1-benzylpiperidin-4-one with propargylamine efficiently afforded the potassium channel modulator 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthirine 12 (Scheme 10) [27].
The methodology was extended to the synthesis of Wnt signal path inhibitors (Scheme 11) [28,29].
The gold-catalyzed synthesis of BAY-298, a nanomolar small molecule (SMOL) hLH-R antagonist, reducing sex hormone levels in vivo has been described (Scheme 12) [30].
Moreover, the gold-catalyzed sequential condensation–cyclization–aromatization procedure was extended as the key step for the preparation of BMS-846372, a potent and orally active human CGRP receptor antagonist employed for migraine therapy (Scheme 13) [31].
The methodology also resulted in a viable tool for the preparation of aryl and heteroaryl derivatives of benzomorphanes 13, pharmacologically active as inhibitors of 11ß-hydroxysteroid dehydrogenase (HSD1) (Scheme 14) [32].
The synthetic approach has yielded a number of scaffolds suitable for the design of performance-diverse screening libraries (Scheme 15) [33].
The reaction of 2-tetralones and propargylamine in the presence of complexes of gold or copper, preferably NaAuCl4 and CuC1, was employed to synthesize octahydrobenzoquinoline derivatives 16 as inhibitors of 11β-hydroxysteroid dehydrogenase for the treatment of metabolic disorders, such as metabolic syndrome, diabetes, obesity, and dyslipidemia. The reaction is usually run in alcohols at temperatures ranging from 20 to 120 °C through conventional heating or microwave irradiation. The resulting pyridine was reduced to the corresponding piperidine (Scheme 16) [34].
The sequential gold-catalyzed condensation/annulation reaction of the 1,3-dihyrdo-2H-inden-2-one with the propargylamine provided the corresponding 9H-indeno [2,1-b]pyridine 17 as the ligand for the synthesis of an olefin polymerization catalyst (Scheme 17) [35].
The gold(III)-catalyzed reaction of simple β-ketoesters with propargylamines achieved the synthesis of potentially bioactive 2,5-dihydropyridines 18 with satisfactory yields. The best results were observed using 5 mol% of the cheaper NaAuCl4 in MeOH as solvent. The dichloro(2-pyridinecarboxilato)gold (pic)AuCl2) resulted in a less effective catalyst, and the reaction failed to occur in the presence of (Ph3P)AuCl/AgOTf catalytic system or by using platinum(II) and platinum(IV) catalysts. Recovery of the starting materials when triflic acid (TfOH) was used instead of NaAuCl4 ruled out the formation of the product by Brønsted acid catalysis. Propargylamines unsubstituted at the triple bond (R4=H) or with an aromatic ring at this position gave higher yields than propargylamines bearing an aliphatic chain at the same position (Scheme 18) [36].
Substituted pyridinium salts 19 were obtained under mild conditions by a condensation reaction between carbonyls and propargylamine under the presence of an Ag2CO3/HNTf2 synergistically acting catalyst system. The one-pot transformation should proceed via sequential 6-endo-dig cyclization of the in situ generated propargylenamine/protonolysis of the resulting vinyl–silver intermediate. The silver(I)-catalyzed cyclization reaction was exclusively selective for the formation of six-membered rings. Only 6-endo-dig cyclized pyridinium products were obtained, even with substrates bearing an electron-withdrawing group at the acetylenic position, which underwent unusual inversion of the reactivity usually observed in Michael-type reactions. CH3CN was the solvent of choice in this one-pot transformation (Scheme 19) [37].
Interestingly, hetero-anthracene derivatives such as 20, used in the preparation of organic light-emitting devices, were practically obtained under metal-free conditions (Scheme 20) [38].
Moreover, substituted dihydrophenanthrolines 21 were easily obtained from 2-substituted 6,7-dihydroquinoline-8(5H)-ketones and propargylamine in alcohol at 70–130 °C. This metal-free method has the advantages of safety, cleanness and wide substrate applicability. The product can be efficiently isolated by adjusting the temperature or prolonging the reaction time (Scheme 21) [39].
The reaction of readily available α,ß-unsaturated carbonyl compounds with propargylamine provided a high atom- and pot-economy strategy for the synthesis of polyfunctionalized pyridines under metal-free conditions with relevant functional group tolerance. The exploration of bases (CsCO3, NaHCO3, NaOAc, K2HPO4, DBU) and solvents (toluene, DCE, THF, DMSO, DMF) achieved the optimization of the reaction conditions by reacting the propargylamines with the unsaturated aldehydes in DMF in the presence of NaHCO3 at 80 °C [40]. The application to the synthesis of a variety of natural products was reported (Scheme 22) [41].
The method was applied to the synthesis of pyridines from the cosmetic, flavor and fragrance agent (S)-(−)-perillaldehyde and the flavoring agent found in cardamom, (1R)-myrtenal (Scheme 23).
The process also achieved the total syntheses of suaveoline alkaloids (Scheme 24) [42].
The practicality of the protocol for the sustainable synthesis of these kinds of molecules through a tandem condensation–alkyne isomerization–6π-3-azatriene electrocyclization sequence was highlighted (Scheme 25) [43].
The reaction of propargylamines with (hetero)aromatic aldehydes efficiently afforded β-carbolines, γ-carbolines and other fused azaheteroaromatics under metal-free conditions (Scheme 26) [44].
A one-pot, three-component method allowed the preparation of 3-substituted pyridines and carbolines 22 via copper-free, palladium-catalyzed Sonogashira cross-coupling with aryl iodides, followed by 6π-aza cyclization. This method selectively provided the fused pyridines with good yields (67–92%) (Scheme 27) [45].
Alternatively, a further preparation method for the polysubstituted pyridine derivatives comprised the employment of an α,β-unsaturated carbonyl compound and propargylamine hydrochloride as raw materials in chlorobenzene (PhCl) with the sequential addition of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) and magnesium sulfate (MgSO4) (Scheme 28). The advantage of this alternative procedure is a relatively strong industrial application prospect [46].
Accordingly, an easy synthesis of onychine 23, an azafluorenone alkaloid isolated from a plant of the Annonaceae family, was reported to occur through aza-Claisen rearrangement, tautomerization, 1,5-sigmatropic hydrogen shift, 6π-electron cyclization, and oxidation of the N-propargyl enamine, obtained in a yield of 61% by dehydration condensation of but-2-yn-1-amine with 1,3-indanedione (Scheme 29) [47].
The sequential O-propargylation of aromatic hydroxyaldehydes/condensation reaction with propargylamine allowed a simple approach to the synthesis of chromenopyridine and chromenopyridinone derivatives. The intramolecular cycloaddition reaction between the alkyne and azadiene of 24, which is formed as an intermediate, furnished the desired skeleton of chromenopyridine 25 (Scheme 30) [48].
Moreover, the N-propargylation of aromatic aminobenzaldehydes, followed by reaction with propargylamine in the presence of DBU, gave the corresponding benzo[h][1,6]-naphthyridines 30 (Scheme 31) [49]. The lack of reactivity of the 2-(prop-2-yn-1-ylamino)benzaldehyde was surmounted by double propargylation of the aniline derivative leading to the intermediate 27, which cyclized in refluxing ethanol to afford the N-propargyl derivative 28 with 80% yield. The 3-methylbenzo[h][1,6]-naphthyridine 30 was isolated by increasing the reaction time to 48 h. Oxidation of 28 with CrO3 in pyridine in dichloromethane at room temperature gave the desired product 29 with 95% yield.
Moreover, a variety of starting materials 31 synthesized by Sonogashira coupling reactions afforded the corresponding naphthyridine derivatives 32 by reacting with propargylamine in refluxing EtOH in the presence of DBU (Scheme 32).
The approach was extended to the synthesis of the chromenopyrazinone 33 (Scheme 33).
Pyrazines 34 were also synthesized through the gold-catalyzed coupling reaction of aldehydes with propargylamine by means of a different sequential process; 1,2-dichloroethane (DCE) was the best choice as solvent. The addition of five equivalents of H2O under otherwise identical conditions was advantageous for the reaction outcome. The [(Ph3P)AuNTf2] catalyst (5 mol%) was identified as the most effective. The feature of the phosphine showed little effect. Any significant difference was observed by the substitution of [(Ph3P)AuNTf2] with [P(tBu)2(o-biphenyl)AuNTf2]. AuCl3 resulted in a less effective catalyst, while different Lewis acid catalysts, such as PtCl2, InCl3, Bi(OTf)3, ZnCl2, and AgNTf2, failed to afford the product. The reaction of aromatic and α,β-unsaturated aldehydes with two equivalents of propargylamine gave the corresponding pyrazine derivatives with high yields. The catalyst loading could be reduced from 5 mol% to 1 mol% without significant loss of yield of the product when the reaction was carried on a 1 gram scale (Scheme 34) [50].
The following reaction mechanism was suggested on the base of labeling experiments and density functional theory (DFT) (Scheme 35). In situ generated gold(I)-imine complex A undergoes a chemo- and regioselective hydroamination reaction with propargylamine to produce the intermediate B. The following protonolysis of the Au-C bond generates the intermediate C, which cyclizes to afford the intermediate D. This new cationic species readily releases benzaldehyde by hydrolysis, regenerating the gold catalyst and producing the 2,5-dimethylenepiperazine E, which readily isomerizes to its more stable 2,5-dimethyl-1,4-dihydropyrazine isomer F. Then, an intermolecular enamine addition from F towards the gold-activated benzaldehyde occurs to produce the intermediate G. Finally, the subsequent isomerization–aromatization sequence gives the reaction product 34.
The heterogeneous gold(I)-catalyzed version of the cascade reaction of aldehydes with propargylamine occurred in 1,2-dichloroethane (DCE) at 40 °C under the presence of the readily available mesoporous MCM-41-immobilized phosphine gold(I) complex (MCM-41-PPh3-AuNTf2). The easy-to-prepare heterogeneous gold(I) catalyst could be recovered by filtration and recycled (Scheme 36) [51].
A variant of a sequential multicomponent assembly process (MCAPs)–cyclization approach in accord with the plan outlined in Scheme 37 was explored for preparing a variety of 1,2,3-triazolo-1,4-benzodiazepines 35 of possible medical relevance by a sequential reductive amination of 2-azidobenzaldeyde derivatives with propargylamine/intramolecular Huisgen cycloaddition [52].
A wide library was obtained through N-functionalizations, palladium-catalyzed cross-coupling reactions, and applications of α-aminonitrile chemistry (Scheme 38). [53]
An atom-economical multicomponent sequential InCl3-catalyzed cyclocondensation/azide-alkyne 1,3-dipolar cycloaddition of 2-azidobenzaldehydes with propargylamines under the presence of α-diketone and ammonium acetate efficiently afforded the corresponding 9H-benzo[f]imidazo [1,2-d][1,2,3]triazolo [1,5-a][1,4]diazepines 37 (Scheme 39) [54].

3. Sequential Reactions of β-Aminoalkynes with Carbonyls

Versatile β-aminoalkyne building blocks for the synthesis of nitrogen-containing heterocyclic compounds are represented by 2-alkynylanilines 38 [55,56,57]. Their sequential reaction with carbonyl derivatives was directed towards the formation of different scaffolds by changing the reaction conditions. The reaction of 38 with simple ketones or β-ketoesters selectively afforded the corresponding N-(Z)-alkenyl indoles 40 under the presence of InBr3 catalyst. The sequential reaction was considered to proceed through the activation of the β-ketoesters/formation of β-enamino esters 39/intramolecular 5-endo-dig cyclization promoted by activation of the acetylene (Scheme 40) [58].
Conversely, the divergent cyclization–alkenylation sequence to give the indole derivative 41 occurred by reacting the 2-alkynylanilines 38a with 1,3-dicarbonyls in the presence of NaAuCl4·2H2O as the catalyst in a sealed tube (Scheme 41) [59].
Moreover, reactions between readily available 2-alkynylanilines and activated ketones promoted by p-toluenesulfonic acid (p-TsOH) afforded 4-alkyl-2,3-disubstituted quinolines 42. The features of substituents at the other end of the triple bond of 2-alkynylanilines achieved access to the 4-alkylquinolines, difficult to obtain by classical Friedländer reaction (Scheme 42) [60].
The procedure also accomplished the preparation of quinoline dimers 43 with alkyl or aryl linkers at C-4 (Scheme 43).
Alternatively, the one-pot synthesis of 4-methyl-2,3-disubstituted quinolines 44 was allowed by means of the inexpensive iron(III)catalyzed sequential condensation, cyclization and aromatization of 1,3-diketones with 2-ethynylaniline derivatives (Scheme 44) [61].
Furthermore, a cost-effective p-TsOH promoted synthetic strategy for the synthesis of substituted quinolines was explored by the reaction between levulinic acid with different 2-alkynylanilines under mild metal-free solventless conditions (Scheme 45) [62].
The combination of CuBr and trifluoroacetic acid (TFA) directly afforded the corresponding quinolines by reacting the 2-ethynylaniline with ethyl glyoxylate (Scheme 46) [63].
N,O-acetals also functioned as a C1 part leading to the preparation of quinoline derivatives 45 according to the following path (Scheme 47) [64].
A three-component, one-pot sulfuric acid-mediated reaction of 2-(2-(trimethylsilyl) ethynyl)anilines with arylaldehydes in alcohol efficiently provided 4-alkoxy-2-arylquinolines 46 (Scheme 48) [65].
This strategy was extended to afford the unusual formation of 8-aryl-8,9-dihydro-3H-pyrano [3,2-f]quinoline-3,10(7H)-dione derivatives 48 with good yields by condensative cyclization of 6-amino-5-[(trimethylsilyl)ethynyl]-2H-chromen-2-one 47 with aromatic aldehydes (Scheme 49) [66].
It was envisioned that the in situ generated N-(2-alkynylphenyl)imine might be cyclized to give ring-fused quinoline derivatives. Indeed, a tandem reaction of 2-alkynylanilines 49 with aldehydes catalyzed by the combination of Pd(OAc)2 and p-TsOH allowed the regioselective synthesis of ring-fused quinolines 50 (Scheme 50) [67].
Moreover, a Sc(OTf)3-catalyzed tandem aza-Prins cyclization reaction of 2-alkynylaniline derivatives 51 with aldehydes afforded under mild reaction conditions fused tricyclic derivatives 52. Interestingly, when the enantiopure optically active 2-alkynylaniline (R)-51b, having a central chirality (99% ee), was subjected to the optimized reaction conditions followed by subsequent treatment with NaOH, the quinoline derivative (R)-52b was obtained directly (86% yield, 98% ee) (Scheme 51). Six- and seven-membered oxacyclo-fused products were also easily synthesized [68].
It is worth noting that the N-(2-alkynylphenyl) imines 53 readily available by means of condensation of 2-iodoanilines with ketones or aldehydes followed by Sonogashira coupling with acetylenes were prone to undergo different sequential processes. Ring-fused indoles 54 were obtained from N-(2-alkynylphenyl) imines 53a with high yields under mild conditions and in the presence of a gold (III) as a catalyst (Scheme 52) [69].
Furthermore, the N-(2-alkynylphenyl) imines intermediates 53 treated with N-iodosuccinimide (NIS) in DCM induced novel iodonium mediated domino reaction cascades, which provided ring-fused indole compounds 55 or simply by changing the reaction conditions ring-fused quinoline compounds 56 (Scheme 53) [70].
The application of the methodology to the synthesis of iodoquinolones from suitable N-(2-alkynylphenyl)imine [71] as well as to the construction of polycyclic indole derivatives through the [3 + 2] cycloaddition of metal-containing azomethine ylides generated from N-(o-alkynylphenyl)imine derivatives and W(CO)5(L) was also reported [72]. A different sequential cycloisomerization/C3-functionalization of the in situ generated 2-alkynylanilines via Sonogashira coupling of 2-iodoanilines determined a one-pot synthesis of 2,2′-disubstituted diindolylmethanes 57 (Scheme 54) [73].
A one-pot strategy for the synthesis of 1-substituted 2-tosyl-2,3,4,5-tetrahydropyrido [4,3-b]indole scaffolds 62 through a sequential gold-catalyzed hydroamination/Pictet–Spengler cyclization of 2-(4-aminobut-1-yn-1-yl)aniline with aldehydes was demonstrated (Scheme 55) [74]. The initial π-coordination of cationic Au(I) species with the alkyne moiety of 2-(4-aminobut-1-yn-1-yl)aniline 58 forms a π-complex that gives the cyclic intermediate 59. The following protodemetalation affords the isotryptamine 60. Subsequently, activation of aldehyde by Au(I) species followed by an intramolecular nucleophilic addition of indole moiety of 60 to a highly reactive N-sulfonyliminium intermediate 61 provides the tetrahydropyridoindole 62 with regeneration of the catalyst. Ag(I) also promotes the Pictet–Spengler reaction.
The sequential aminopalladation of N-tosyl-2-arylethynylanilines followed by the addition to the carbonyl group of an aldehyde as the quenching step of the carbon–palladium bond gave corresponding 3-hyroxymethyl indole derivatives with good yields. Cationic palladium complexes bearing bipyridine or dppp as ligands resulted in suitable catalysts, and the best conditions were observed by carrying out the reaction in dioxane at 60 °C in the presence of the catalyst Pd(bpy)(H2O)2(OTf)2 (Scheme 56) [75].
A Cu(OTf)2-catalyzed intramolecular radical cascade reaction efficiently enabled the synthesis of quinoline-annulated compounds 64 [76]. The method represents an effective route to natural products and a variety of drug-like libraries (Scheme 57).
The proposed mechanism for the synthesis of the polyheterocyclic scaffolds is shown in the following Scheme 58. The intermediate 65 undergoes a copper salt-promoted one-electron oxidation to generate the intermediate 66. Subsequent radical addition into the C-C bond of 67 affords the radical 68, which cyclizes to give the radical 69. Finally, trapping of the nitrogen radical by the iodine radical generated from the oxidation of iodide affords the complex 70, which after iodide elimination furnishes the product 64.
A regio- and stereoselective three-component, one-pot cascade reaction involving an imination–annulation–cyanation sequence was achieved by combining palladium(II) trifluoroacetate and copper(II) acetate with the readily available 2-alkynylanilines, cyclic ketones and trimethylsilyl cyanide in dimethyl sulfoxide to efficiently afford the corresponding 1-benzoazepine carbonitrile derivatives 71 (Scheme 59) [77].
The construction of spirocyclic quinolones 72, which are difficult to synthesize through traditional methodologies, was explored by selectively directing the reaction of 2-alkynylanilines with ketones under suitable reaction conditions. Interestingly, the same starting reagents selectively produced the quinolines 73 or the N-alkenyl indoles 74 under different reaction conditions (Scheme 60) [78].
Very likely, the condensation reaction under the Brønsted acid-mediated conditions in EtOH led to the iminium ion intermediate [I] which undergoes aza-Prins to afford an intermediate, which—after quenching by ethanol, hydrolysis and tautomerization reactions—generated the quinolinone 72 (Scheme 61).
Conversely, isomerization of the iminium ion intermediate [I] to the intermediate [J] should lead selectively to the indoles 74 via a 5-endo-dig cyclization or to the quinoline 73 via a regiodivergent 6-exo-dig cyclization (Scheme 62).
Alternatively, the quinolines 73 could be generated from the 2-aminoaryl ketone obtained by the fast hydration reaction of the 2-alkynylaniline, both in the presence of a stoichiometric amount of p-TsOH·H2O or 0.2 equiv. of FeCl3 in toluene at 110 °C (Scheme 63).
Interestingly, the features of the substituent bonded at the terminal position of the triple bond of the 2-alkynylaniline and of the reaction medium determined the reaction path. Internal alkynes allowed the p-TsOH·H2O-mediated preparation of quinolones 72 in EtOH at reflux or the formation of the quinolines 73 in toluene at 110 °C both in the presence of a stoichiometric amount of p-TsOH·H2O or FeCl3 as the catalyst. Conversely, the ZnBr2-catalyzed reaction in toluene at 110 °C of the same internal alkyne derivatives gave only the N-alkenylindoles 75. The presence of a trimethylsilyl group or the absence of substituents at the terminal position of the starting aminoalkyne resulted in the formation of the corresponding quinolines. The Lewis acid-promoted reaction of 2-arylethynylanilines with α-tetralones under the presence of the strong oxidant (diacetoxyiodo)benzene (PIDA) triggered a decarbonylative cascade approach to the synthesis of acridines (Scheme 64) [79].
A general procedure was described for the direct preparation of 2-methyl-3,4-diacylquinolines in short periods under mild reaction conditions by means of the Mn(OAc)3 mediated reaction in acetic acid of 2-alkynylanilines with β-ketoesters (Scheme 65). The presence of molecular oxygen and Na2SO4 as desiccant displayed a key role. It was suggested that the formation of the radical intermediate [L] generated by Mn(OAc)3 oxidation of the enaminoate [K] underwent a fast 6-exo-dig cyclization, resulting in the formation of the vinyl intermediate [M]. The subsequent addition of molecular oxygen to the vinyl radical should provide a peroxy radical species [N], which—after protonation and loss of water—produced the 2-methyl-3,4-diacylquinolines [80].
Moreover, the sequential Brønsted acid mediated reaction with enolizable ketones of the starting aminoalkynes β-(2-aminophenyl)-α,β-ynones 75 in EtOH resulted in an efficient approach to only polycyclic quinolines 76 (Scheme 66) [81].
Steroids bearing a simple ketone group at position 3, such as 5α-cholestan-3-one, formed only the corresponding linear cholestanoquinoline derivative in moderate yield. On the contrary, the optimized methodology allowed the divergent generation of the angular quinoline derivative, whose synthesis is generally considered more challenging and demanding, from 3-keto-Δ4-polycyclic steroidal derivatives. Interestingly, with steroidal dicarbonyl derivatives, the condensation reaction took place selectively only on the conjugated carbonyl group at position 3, leaving the ketone group at position 17 unreacted (Scheme 67). A- and D-ring fused steroidal quinoline analogues represent potential as antibacterial agents [82].
The Brønsted acid-promoted reaction of β-(2-aminophenyl)-α,β-ynones with ketones was expanded to activated carbonyl compounds, such as β-ketoesters and β-diketones. The carbonyl group at position 3 of the quinoline nucleus could further react with the other keto functionality in the alkyl substituent at position 4, generating an additional [3,4]-fused six-membered ring whose structure depends on the type of β-dicarbonyl compound used. Indeed, for β-ketoesters, a thorough screening of reaction conditions revealed that catalytic amounts of p-TsOH·H2O were sufficient to efficiently promote a cascade double cyclization leading to 4H-pyrano [3,4-c]quinoline-4-one derivatives 77. On the contrary, with β-diketones, a stoichiometric amount of p-TsOH·H2O triggered a three-component reaction, involving a molecule of the alcoholic solvent to afford 78. Both procedures appear to be simple and versatile, and are expected to be of great impact because of the multiple potential applications of the obtained organic compounds (Scheme 68) [83].
A sequential aminopalladation of β-amino alkyne derivatives 79, followed by intramolecular nucleophilic addition of the generated carbon–palladium bond to a tethered aldehyde group, accomplished the synthesis of a variety of benzo[a]carbazoles 80 with remarkable diversification (Scheme 69) [84].
The ongoing research activity devoted to the synthesis of indole derivatives encouraged the exploration of a highly flexible approach to 11H-indolo [3,2-c]quinolines 82 according to the retrosynthetic Scheme 70.
Subsequently, the selective build-up of the 11H-indolo [3,2-c]quinoline 82 was carried out through a two-step, one-pot, gold-catalyzed reaction in CH3CN at room temperature of aldehydes with the 2,2′-(ethyne-1,2-diyl)dianiline derivative 81a as the starting β-aminoalkynes, which was cyclized under the presence of Au catalyst (5 mol%). Then, the aldehyde (2 equiv.) was added and the reaction mixture was stirred till completion. This alternative highly regioselective protocol is of wide applicability in mild neutral reaction conditions (Scheme 71) [85].
Surprisingly, the reaction of inexpensive aryl(heteroaryl)aldehydes with the same starting 2,2′-(ethyne-1,2-diyl)dianiline derivatives 81 in the presence of a catalytic amount of HCl achieved the synthesis of 2,2′-disubstituted-1H,1H-3,3′-biindoles 83 (Scheme 72) [86].
Accordingly, a class of double D-π-A branched organic dyes based on 2,2′-disubstituted-1H,10H-3,3′-biindole moiety has been synthesized as photosensitizers for dye-sensitized solar cells [87]. Alternatively, the 2,2′-disubstituted 3,3′-biindoles were obtained by using an acidic deep eutectic solvent (DES) able to exploit double activity, i.e., solvent and Brønsted acid (BA) catalyst under microwave heating at 70 °C [88]. Very likely, the BA promotes the formation of the iminium ion [O] by reaction of 83 with two equiv. of the aldehyde. The iminium ion [O] undergoes an aza-Prins type 5-exo-dig cyclization to the intermediate [P] quenched by the nucleophilic addition of water to give intermediate [Q]. The subsequent cyclization generates the stabilized benzylic carbocation intermediate [R] which provides the desired biindoles 83 by the loss of a molecule of water and proton regeneration (Scheme 73).
Conversely, the tandem gold-catalyzed 5-endo-dig/spirocyclization of 2-[(2-aminophenyl)ethynyl]phenylamines 81 with isatins regioselectively afforded the corresponding 5′,11′-dihydrospiro-[indoline-3,6′-indolo [3,2-c]quinolin]-2-one derivatives 84 with good yields at room temperature. The reaction with ketones gave the 6,6-disubstituted-6,11-dihydro-5H-indolo [3,2-c]-quinolones 85 (Scheme 74) [89].
A sequential intramolecular nucleophilic attack–intermolecular cycloaddition–dehydration reaction addressed the synthesis of ring-condensed heteroaromatic compounds 86 starting from 2-alkynylbenzaldehydes and 2-alkynylanilines in the presence In(OTf)3 catalyst (Scheme 75) [90].
An intriguing three-component reaction of 2-alkynylanilines, aldehydes and α-(4-nitrophenyl)-α-isocyanoacetates in methanol at room temperature, followed by addition of toluene and heating to reflux, provided the polysubstituted furo[2,3-c]quinolines 87 with satisfactory yields (Scheme 76) [91].
The reaction of the in situ formed imine intermediate 88 with α-isocyanoacetates produces the 5-alkoxyoxazoles 89, which—through an intramolecular Diels–Alder cycloaddition between the oxazole and the tethered triple bond—generate oxa-bridged heterocycles 90. Their subsequent fragmentation by a retro Diels–Alder process furnishes derivatives 91 and benzonitrile. Finally, oxidation mediated by atmospheric oxygen leads to the target aromatic 2-alkoxyfuro [2,3-c]-quinolones 87 (Scheme 77).
Similarly, the three-component reaction of an aminopentanoate, an aldehyde, and an α-isocianoacetamide produced in a one-pot process the 4,5,6,7-tetrahydrofuro [2,3-c]pyridines by simply heating the solution in toluene in the presence of ammonium chloride. [92] A base-promoted post-Ugi 5-exo-dig “Conia-ene”-type cyclization efficiently afforded a variety of 2,2-disubstituted 3-methyleneindoline derivatives 93 (Scheme 78) [93].

4. Sequential Reactions of γ- and δ-Aminoalkynes with Carbonyls

Sequential reactions of of γ- and δ-aminoalkynes with carbonyls have been less investigated. A library of 1-tosyl-2,3,4,5-tetrahydro-1H-indeno [1,2-b]-pyridines 95 has been established by cascade cyclization/Friedel–Crafts reaction of 4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamides 94 and aldehydes with good yields. The reaction was performed by using 2 equiv. of BF3·OEt2 in 1,2-dichloroethane (DCE). Worse results were obtained under the presence of different Lewis and Brønsted acids or metal triflates. Both electron-withdrawing and electron-donating groups in the aromatic ring of the aldehyde were tolerated. The methodology was applied to the total synthesis of the antidepressant agent (±)-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-indeno [1,2-b]pyridine 96 (Scheme 79) [94].
The sequential rhodium(III)-catalyzed intramolecular annulation/aromatization of o-alkynyl amino aromatic ketones 97 achieved a one-pot building up of the pyrrolo[1,2-a]quinolines 98. [Cp*RhCl2]2 (Cp* = η5-1,2,3,4,5-pentamethylcyclopentadienyl) resulted in a more effective catalyst under the presence of Cu(OAc)2·H2O as the oxidant. The reaction did not occur under an air atmosphere. DCE was the solvent of choice, and inferior yields of the product were isolated when the reaction was conducted in 1,4-dioxane, acetonitrile, p-xylene, methanol, or acetic acid. The strategy provides a complementary synthetic method for the construction of 4-aryl-5-alkylpyrrolo[1,2-a]quinolines or those containing different aryl substituents at 4,5-positions, which are difficult to prepare by the conventional methods. The protocol could be scaled up and allowed the synthesis of challenging products suitable for further elaboration (Scheme 80) [95].
Although the metal-catalyzed reaction of γ-aminoalkynes 99 with 1,3-diketones is expected to afford a wide variety of products, unexpectedly the reaction accomplished the isolation of only indolines 100 with up to 99% yield. Different solvents and a variety of catalysts based on Cu, Co, Ni, Ag, Au, Pd, or Pt were screened. The results revealed that the optimized reaction conditions were observed in methanol as the solvent at 40 °C in the presence of K2PtCl4 (1 mol%) and 4Å molecular sieves. The reaction times could be shortened by subjecting the reaction to microwave irradiation. Very likely, the procedure involves a platinum-catalyzed intramolecular hydroamination of aminoalkynes to generate the corresponding enamine, which—after sequential nucleophilic attack of the enol form of the 1,3-dicarbonyl/cyclization and elimination of two water molecules—gives the indoline derivatives (Scheme 81) [96].
The extension of the reaction to δ-aminoalkynes 101 gave with high yields the 1,2,3,4-tetrahydroquinolines 102 of importance in medicinal chemistry (Scheme 82).

5. Conclusions and Outlook

A variety of aminoalkynes can trigger sequential reactions with carbonyls to generate valuable heterocyclic scaffolds. The increasing number of aminoalkynes as building blocks has greatly widened the scope of sequential approaches to large libraries of valuable nitrogen-containing heterocyclic compounds that can be obtained from easily available reagents. Coinage metals dominated the field, and in particular, gold complexes demonstrated superior performance as catalysts for these transformations. Inexpensive and less toxic iron and zinc salts are growing in importance as efficient catalysts. As for reaction media, greener alternatives such as water, ionic liquids and solventless reactions have been reported. Advantages of microwave irradiation over conventional heating have also been highlighted. Extensive mechanistic studies allowed the identification of several intermediates and helped to explain the key role of the catalyst and the additives employed. Often, the activation of the alkyne moiety by metal catalysis is essential to boost the sequential process. We foresee that further advancements will achieve straightforward alternative easy access to a wide array of polyheterocyclic scaffolds with potentially remarkable biological activity.

Author Contributions

V.M. contributed to searching and collating the relevant literature. Coauthor L.P. and corresponding author A.A. wrote the body of the article. All authors have read and agreed to the published version of the manuscript.

Funding

This research received financial support from the University of L’Aquila.

Data Availability Statement

Not applicable.

Acknowledgments

We gratefully acknowledge the University of L’Aquila for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

References

  1. Hwang, E.T.; Lee, S. Multienzymatic cascade reactions via enzyme complex by immobilization. ACS Catal. 2019, 9, 4402–4425. [Google Scholar] [CrossRef]
  2. Nicolaou, K.C.; Edmonds, D.J.; Bulger, P.G. Cascade reactions in total synthesis. Angew. Chem. Int. Ed. 2006, 45, 7134–7186. [Google Scholar] [CrossRef] [PubMed]
  3. Nicolaou, K.C.; Chen, J.S. The art of total synthesis through cascade reactions. Chem. Soc. Rev. 2009, 38, 2993–3009. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Oishi, M.; Nakanishi, Y.; Suzuki, H. Selective incorporation of primary amines into a trizirconium imido system and catalytic cyclization of aminoalkynes. Inorg. Chem. 2017, 56, 9802–9813. [Google Scholar] [CrossRef]
  5. Arcadi, A. Gold-catalyzed synthesis of nitrogen heterocyclic compounds via hydroamination reactions. In Au-Catalyzed Synthesis and Functionalization of Heterocycles; Topics in Heterocyclic Chemistry Book Series; Bandini, M., Ed.; Springer: Cham, Switzerland, 2016; Volume 46, pp. 53–86. [Google Scholar] [CrossRef]
  6. Arcadi, A.; Abbiati, G.; Rossi, E. Tandem imination/annulation of γ- and δ-ketoalkynes in the presence of ammonia/amines. J. Organomet. Chem. 2011, 696, 87–98. [Google Scholar] [CrossRef]
  7. Chang, S.; Lee, M.; Jung, D.Y.; Yoo, E.J.; Cho, S.H.; Han, S.K. Catalytic one-pot synthesis of cyclic amidines by virtue of tandem reactions involving intramolecular hydroamination under mild conditions. J. Am. Chem. Soc. 2006, 128, 12366–12367. [Google Scholar] [CrossRef]
  8. Liu, X.-Y.; Che, C.-M. A highly efficient and selective AuI-catalyzed tandem synthesis of diversely substituted pyrrolo[1,2-a]quinolines in aqueous media. Angew. Chem. Int. Ed. 2008, 47, 3805–3810. [Google Scholar] [CrossRef]
  9. Zhou, Y.; Feng, E.; Liu, G.; Ye, D.; Li, J.; Jiang, H.; Liu, H. Gold-catalyzed one-pot cascade construction of highly functionalized pyrrolo[1,2-a]quinolin-1(2H)-ones. J. Org. Chem. 2009, 74, 7344–7348. [Google Scholar] [CrossRef]
  10. Ma, C.-L.; Zhao, J.-H.; Yang, Y.; Zhang, M.-K.; Shen, C.; Sheng, R.; Dong, X.-W.; Hu, Y.-Z. A copper-catalyzed tandem cyclization reaction of aminoalkynes with alkynes for the construction of tetrahydropyrrolo[1,2-a]quinolines scaffold. Sci. Rep. 2017, 7, 16640. [Google Scholar] [CrossRef] [Green Version]
  11. Ma, C.-L.; Li, X.-H.; Yu, X.-L.; Zhu, X.-L.; Hu, Y.-Z.; Dong, X.-W.; Tan, B.; Liu, X.-Y. Gold-catalyzed tandem synthesis of bioactive spiro-dipyrroloquinolines and its application in the one-step synthesis of incargranine B aglycone and seneciobipyrrolidine (I). Org. Chem. Front. 2016, 3, 324–329. [Google Scholar] [CrossRef]
  12. Galvàn, A.; Calleja, J.; Faňanás, F.J.; Rodríguez, F. Synthesis of pyrrolidine derivatives by a platinum/Brønsted acid relay catalytic cascade reaction. Chem. Eur. J. 2015, 21, 3409–3414. [Google Scholar] [CrossRef]
  13. Huple, D.B.; Liu, R.-S. One-pot stereocontrolled synthesis of bicyclic pyrrolidine derivatives by a platinum-Brønsted acid relay cascade reaction. ChemCatChem 2015, 7, 2824–2825. [Google Scholar] [CrossRef]
  14. Fujiwara, S.-I.; Shikano, Y.; Shin-ike, T.; Kambe, N.; Sonoda, N. Stereoselective synthesis of new selenium-containing heterocycles by cyclocarbonylation of aminoalkynes with carbon monoxide and selenium. J. Org. Chem. 2002, 67, 6275–6278. [Google Scholar] [CrossRef] [PubMed]
  15. Hu, Y.; Huang, H. Highly selective construction of medium-sized lactams by palladium-catalyzed intramolecular hydroaminocarbonylation of aminoalkynes. Org. Lett. 2017, 19, 5070–5073. [Google Scholar] [CrossRef]
  16. Li, X.; Wang, S.; Wang, H.; Wang, W.; Liu, L.; Chang, W.; Li, J. Synthesis of eight-membered nitrogen heterocycles via a heterogeneous PtI2-catalyzed cascade cycloaddition reaction of δ-aminoalkynes with electron-deficient alkynes. Adv. Synth. Catal. 2020, 362, 1525–1531. [Google Scholar] [CrossRef]
  17. Li, X.; Jiang, C.; Wang, X.; Ren, J.; Zeng, T.; Xu, X.; Li, J.; Liu, L. Platinum iodide-catalyzed formal three-component cascade cycloaddition reactions between γ-aminoalkynes and electron-deficient alkynes. J. Org. Chem. 2021, 86, 16614–16624. [Google Scholar] [CrossRef]
  18. Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Sequential amination/annulation/aromatization reaction of carbonyl compounds and propargylamine: A new one-pot approach to functionalized pyridines. J. Org. Chem. 2003, 68, 6959–6966. [Google Scholar] [CrossRef]
  19. Yang, D.; Liu, H.; Wang, D.-L.; Lu, Y.; Zhao, X.-L.; Liu, Y. Au complex containing phosphino and imidazolyl moieties as a bifunctional catalyst for one-pot synthesis of pyridine derivatives. J. Mol. Catal. A Chem. 2016, 424, 323–330. [Google Scholar] [CrossRef]
  20. Sotnik, S.O.; Subota, A.I.; Kliuchynskyi, A.Y.; Yehorov, D.V.; Lytvynenko, A.S.; Rozhenko, A.B.; Kolotilov, S.V.; Ryabukhin, S.V.; Volochnyuk, D.M. Cu-catalyzed pyridine synthesis via oxidative annulation of cyclic ketones with propargylamine. J. Org. Chem. 2021, 86, 7315–7325. [Google Scholar] [CrossRef]
  21. Savić, M.P.; Ajduković, J.J.; Plavša, J.J.; Bekić, S.S.; Ćelić, A.S.; Klisurić, O.R.; Jakimov, D.S.; Petri, E.T.; Djurendić, E.A. Evaluation of A-ring fused pyridine D-modified androstane derivatives for antiproliferative and aldo-keto reductase 1C3 inhibitory activity. Med. Chem. Commun. 2018, 9, 969–981. [Google Scholar] [CrossRef]
  22. Yan, J.-Z.; Li, J.; Rao, G.-W. One-pot synthesis of new A-ring fused steroidal pyridines. Steroids 2007, 7, 736–739. [Google Scholar] [CrossRef]
  23. Laavola, M.; Haavikko, R.; Hämäläinen, M.; Leppänen, T.; Nieminen, R.; Alakurtti, S.; Moreira, V.M.; Yli-Kauhaluoma, J.; Moilanen, E. Betulin derivatives effectively suppress inflammation in vitro and in vivo. J. Nat. Prod. 2016, 79, 274–280. [Google Scholar] [CrossRef]
  24. Haavikko, R.; Nasereddin, A.; Sacerdoti-Sierra, N.; Kopelyanskiy, D.; Alakurtti, S.; Tikka, M.; Jaffe, C.L.; Yli-Kauhaluoma, J. Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes. Med. Chem. Commun. 2014, 5, 445–451. [Google Scholar] [CrossRef] [Green Version]
  25. Hodoň, J.; Frydrych, I.; Trhlíková, Z.; Pokorný, J.; Borková, L.; Benická, S.; Vlk, M.; Lišková, B.; Kubíčková, A.; Medvedíková, M.; et al. Triterpenoid pyrazines and pyridines—Synthesis, cytotoxicity, mechanism of action, preparation of prodrugs. Eur. J. Med. Chem. 2022, 243, 114777. [Google Scholar] [CrossRef]
  26. Rabe, S.; Moschner, J.; Bantzi, M.; Heretsch, P.; Giannis, A. C-H-Functionalization logic guides the synthesis of a carbacyclopamine analog. Beilstein J. Org. Chem. 2014, 10, 1564–1569. [Google Scholar] [CrossRef] [Green Version]
  27. Simcere Pharmaceutical Group. Compound as Potassium Channel Modulating Agents. CN108250128 A, 6 July 2018. [Google Scholar]
  28. Suzhou Yunxuan Pharmaceutical Co Ltd. Heterocyclic Compound with Wnt Signal Path Inhibitory Activity and Application Thereof. CN105254613 A, 20 January 2016. [Google Scholar]
  29. Zhang, X.; Zheng, J.; Ma, H. Heteroaryl Compounds as cxcr4 Inhibitors, Composition and Method Using the Same. Patent WO2019/60860 A1, 28 March 2019. [Google Scholar]
  30. Wortmann, L.; Lindenthal, B.; Muhn, P.; Walter, A.; Nubbemeyer, R.; Heldmann, D.; Sobek, L.; Morandi, F.; Schrey, A.K.; Moosmayer, D.; et al. Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-based, potent, and selective antagonists of the luteinizing hormone receptor which reduce sex hormone levels in vivo. J. Med. Chem. 2019, 62, 10321–10341. [Google Scholar] [CrossRef] [PubMed]
  31. Luo, G.; Chen, L.; Conway, C.M.; Denton, R.; Keavy, D.; Gulianello, M.; Huang, Y.; Kostich, W.; Lentz, K.A.; Mercer, S.E.; et al. Discovery of BMS-846372, a potent and orally active human CGRP receptor antagonist for the treatment of migraine. ACS Med. Chem. Lett. 2012, 3, 337–341. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. C.H. Boehringer Sohn AG & Co. KG. Aryl- and Heroarylcarbonyl Derivatives of Benzomorphanes and Related Scaffolds, Medicaments Containing Such Compounds and Their Use. EP2220048 B1, 25 January 2017. [Google Scholar]
  33. Lowe, R.A.; Taylor, D.; Chibale, K.; Nelson, A.; Marsden, S.P. Synthesis and evaluation of the performance of a small molecule library based on diverse tropane-related scaffolds. Biorg. Med. Chem. 2020, 28, 115442. [Google Scholar] [CrossRef]
  34. Eckhardt, M.; Peters, S.; Nar, H.; Himmelsbach, F.; Zhuang, L. Boehringer Ingheleim Int, Aryl-and Heteroarylcarbonyl Derivatives of Hexahydroindenopyridine and Octahydrobenzoquinoline. U.S. Patent 2011/0136800 A1, 9 June 2011. [Google Scholar]
  35. Park, N.Y.; Lee, H.S.; Piao, L.H.; Park, S.Y.; Jeong, W. Transition Metal Compound for Olefin Polymerization Catalyst, and Olefin Polymerization Catalyst Including Same. U.S. Patent 11254759 B2, 22 February 2022. [Google Scholar]
  36. Faňanás, F.J.; Arto, T.; Mendoza, A.; Rodríguez, F. Synthesis of 2,5-dihydropyridine derivatives by gold-catalyzed reactions of β-ketoesters and propargylamines. Org. Lett. 2011, 13, 4184–4187. [Google Scholar] [CrossRef] [PubMed]
  37. Lee, S.; Yoo, H.; Park, S.; Yoon, R.; Kim, S. Facile one-pot synthesis of polysubstituted pyridinium salts by annulation of enamines with alkynes. Chem. Eur. J. 2023, e202300059. [Google Scholar] [CrossRef] [PubMed]
  38. Changchun Haipurunsi Tech Co Ltd. A Kind of Miscellaneous Anthracene Derivant and Preparation Method Thereof and Organic Luminescent Device. CN108218860 A, 29 June 2018. [Google Scholar]
  39. University Zhejlang Technology. Method for Synthesizing Substituted Dihydrophenanthroline Compound. CN112480112 A, 15 October 2021. [Google Scholar]
  40. Watkins, E.B.; Uredi, D.; Motati, D.R. Novel Methods for Preparation of Substituted Pyridines and Related Novel Compounds. U.S. Patent 2020/0095245 A1, 10 August 2020. [Google Scholar]
  41. Uredi, D.; Motati, D.R.; Watkins, E.B. A simple, tandem approach to the construction of pyridine derivatives under metal-free conditions: A one-step synthesis of the monoterpene natural product, (-)-actinidine. Chem. Commun. 2019, 55, 3270–3273. [Google Scholar] [CrossRef] [PubMed]
  42. Zhao, Z.; Wei, H.; Xiao, K.; Cheng, B.; Zhai, H.; Li, Y. Facile synthesis of pyridines from propargyl amines: Concise total synthesis of suaveoline alkaloids. Angew. Chem. Int. Ed. 2019, 58, 1148–1152. [Google Scholar] [CrossRef] [PubMed]
  43. Wei, H.; Li, Y. Quick access to pyridines through 6π-3-azatriene electrocyclization: Concise total synthesis of suaveoline alkaloids. Synlett 2019, 30, 1615–1620. [Google Scholar] [CrossRef]
  44. Uredi, D.; Motati, D.R.; Watkins, E.B. A unified strategy for the synthesis of β-carbolines, γ-carbolines, and other fused azaheteroaromatics under mild, metal-free conditions. Org. Lett. 2018, 20, 6336–6339. [Google Scholar] [CrossRef]
  45. Uredi, D.; Burra, A.G.; Watkins, E.B. Rapid access to 3-substituted pyridines and carbolines via a domino, copper-free, palladium-catalyzed Sonogashira cross-coupling/6π-aza cyclization sequence. J. Org. Chem. 2021, 86, 17748–17761. [Google Scholar] [CrossRef]
  46. Lanzhou University. A Kind of Polysubstituted Pyridine Derivative and Preparation Method Thereof. CN108358834 A, 3 August 2018. [Google Scholar]
  47. Chikayuki, Y.; Miyashige, T.; Yonekawa, S.; Kirita, A.; Matsuo, N.; Teramoto, H.; Sasaki, S.; Higashiyama, K.; Yamauchi, T. Transition-metal-free synthesis of pyridine derivatives by thermal cyclization of N-propargyl enamines. Synthesis 2020, 52, 1113–1121. [Google Scholar] [CrossRef]
  48. Keskin, S.; Balci, M. Intramolecular heterocyclization of O-propargylated aromatic hydroxyaldehydes as an expedient route to substituted chromenopyridines under metal-free conditions. Org. Lett. 2015, 17, 964–967. [Google Scholar] [CrossRef]
  49. Hoplamaz, E.; Keskin, S.; Balci, M. Regioselective synthesis of benzo[h][1,6]-naphthyridines and chromenopyrazinones through alkyne cyclization. Eur. J. Org. Chem. 2017, 1489–1497. [Google Scholar] [CrossRef]
  50. Alcaide, B.; Almendros, P.; Alonso, J.M.; Fernández, I.; Gómez-Campillosa, G.; Torres, M.R. A gold-catalysed imine-propargylamine cascade sequence: Synthesis of 3-substituted-2,5-dimethylpyrazines and the reaction mechanism. Chem. Commun. 2014, 50, 4567–4570. [Google Scholar] [CrossRef] [Green Version]
  51. Nie, Q.; Yao, F.; Yi, F.; Cai, M. A heterogeneous gold(I)-catalyzed cascade annulation of aldehydes with propargylamine leading to 3-substituted 2,5-dimethylpyrazines. J. Organomet. Chem. 2017, 846, 343–350. [Google Scholar] [CrossRef]
  52. Donald, J.R.; Martin, S.F. Synthesis and diversification of 1,2,3-triazole-fused 1,4-benzodiazepine scaffolds. Org. Lett. 2011, 13, 852–855. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Donald, J.R.; Wood, R.R.; Martin, S.F. Application of a sequential multicomponent assembly process/Huisgen cycloaddition strategy to the preparation of libraries of 1,2,3-triazole-fused 1,4-benzodiazepines. ACS Comb. Sci. 2012, 14, 135–143. [Google Scholar] [CrossRef] [Green Version]
  54. Nguyen, H.H.; Palazzo, T.A.; Kurth, M.-J. Facile one-pot assembly of imidazotriazolobenzodiazepines via indium(III)-catalyzed multicomponent reactions. Org. Lett. 2013, 15, 4492–4495. [Google Scholar] [CrossRef] [Green Version]
  55. Festa, A.A.; Raspertov, P.V.; Voskressensky, L.G. 2-(Alkynyl)anilines and derivatives-versatile reagents for heterocyclic synthesis. Adv. Synth. Catal. 2022, 364, 466–486. [Google Scholar] [CrossRef]
  56. Vavsari, V.F.; Nikbakht, A.; Balalaie, S. Annulation of 2-alkynylanilines: The versatile chemical compounds. Asian J. Org. Chem. 2022, 11, e202100772. [Google Scholar] [CrossRef]
  57. Kamble, O.S.; Khatravath, M.; Dandela, R. Applications of ethynylanilines as substrates for construction of indoles and indole-substituted derivatives. ChemistrySelect 2021, 6, 7408–7427. [Google Scholar] [CrossRef]
  58. Murai, K.; Hayashi, S.; Takaichi, N.; Kita, Y.; Fujioka, H. Tandem β-enamino ester formation and cyclization with o-alkynyl anilines catalyzed by InBr3: Efficient synthesis of-β-(N-indolyl)-α,β-unsaturated esters. J. Org. Chem. 2009, 74, 1418–1421. [Google Scholar] [CrossRef]
  59. Arcadi, A.; Alfonsi, M.; Bianchi, G.; D’Anniballe, G.; Marinelli, F. Gold-catalysed direct couplings of indoles and pyrroles with 1,3-dicarbonyl compounds. Adv. Synth. Catal. 2006, 348, 331–338. [Google Scholar] [CrossRef]
  60. Peng, C.; Wang, Y.; Liu, L.; Wang, H.; Zhao, J.; Zhu, Q. p-Toluenesulfonic acid promoted annulation of 2-alkynylanilines with activated ketones: Efficient synthesis of 4-alkyl-2,3-disubstituted quinolines. Eur. J. Org. Chem. 2010, 818–822. [Google Scholar] [CrossRef]
  61. Sivaraman, M.; Perumal, P.T. Synthesis of 4-methyl-2,3-disubstituted quinoline scaffolds via environmentally benign Fe(III) catalysed sequential condensation, cyclization and aromatization of 1,3-diketone and 2-ethynylaniline. RSC Adv. 2014, 4, 52060–52066. [Google Scholar] [CrossRef]
  62. Ortiz-Cervantes, C.; Flores-Alamo, M.; García, J.J. Synthesis of pyrrolidones and quinolines from the known biomass feedstock levulinic acid and amines. Tetrahedron Lett. 2016, 57, 766–771. [Google Scholar] [CrossRef]
  63. Wang, G.; Jia, J.; Liu, G.; Yu, M.; Chu, X.; Liu, X.; Zhao, X. Copper(I)-catalyzed tandem synthesis of 2-acylquinolines from 2-ethynylanilines and glyoxals. Chem. Commun. 2021, 57, 11811–11814. [Google Scholar] [CrossRef] [PubMed]
  64. Sakai, N.; Tamura, K.; Shimamura, K.; Ikeda, R.; Konakahara, T. Copper-catalyzed [5+1] annulation of 2-ethynylanilines with an N,O-acetal leading to construction of quinoline derivatives. Org. Lett. 2012, 14, 836–839. [Google Scholar] [CrossRef]
  65. Wang, Y.; Peng, C.; Liu, L.; Zhao, J.; Su, L.; Zhu, Q. Sulfuric acid promoted condensation cyclization of 2-(2-(trimethylsilyl)ethynyl)anilines with arylaldehydes in alcoholic solvents: An efficient one-pot synthesis of 4-alkoxy-2-arylquinolines. Tetrahedron Lett. 2009, 50, 2261–2265. [Google Scholar] [CrossRef]
  66. Majumdar, K.C.; Taher, A.; Ponra, S. Unusual product from condensative cyclization: Pyrano[3,2-f]quinolin-3,10-diones from 6-amino-5-[(trimethylsilyl)ethynyl]-2H-chromen-2-one and aryl aldehydes. Synlett 2010, 735–740. [Google Scholar] [CrossRef]
  67. Ock, S.K.; Youn, S.W. Synergistic effect of Pd(II) and acid catalysts on tandem annulation reaction for the regioselective synthesis of ring-fused quinolines. Bull. Korean Chem. Soc. 2010, 31, 704–707. [Google Scholar] [CrossRef] [Green Version]
  68. Zhu, C.; Ma, S. Sc(OTf)3-catalyzed bicyclization of o-alkynylanilines with aldehydes: Ring-fused 1,2-dihydroquinolines. Angew. Chem. Int. Ed. 2014, 53, 13532–13535. [Google Scholar] [CrossRef] [PubMed]
  69. Fu, W.; Xu, C.; Zou, G.; Hong, D.; Deng, D.; Wang, Z.; Ji, B. AuCl3-catalyzed tandem reaction of N-(o-alkynylphenyl)imines: A modular entry to polycyclic frameworks containing an indole unit. Synlett 2009, 5, 763–766. [Google Scholar] [CrossRef]
  70. Halim, R.; Scammells, P.J.; Flynn, B.L. Alternating iodonium-mediated reaction cascades giving indole- and quinoline-containing polycycles. Org. Lett. 2008, 10, 1967–1970. [Google Scholar] [CrossRef]
  71. Halim, R.; Aurelio, L.; Scammells, P.J.; Flynn, B.L. Scaffold-divergent synthesis of ring-fused indoles, quinolines, and quinolones via iodonium-induced reaction cascades. J. Org. Chem. 2013, 78, 4708–4718. [Google Scholar] [CrossRef]
  72. Kusama, H.; Takaya, J.; Iwasawa, N. A facile method for the synthesis of polycyclic indole derivatives: The generation and reaction of tungsten-containing azomethine ylides. J. Am. Chem Soc. 2002, 124, 11592–11593. [Google Scholar] [CrossRef] [PubMed]
  73. Kayeta, A.; Singh, V.K. A one-pot synthesis of 2,2’-disubstituted diindolylmethanes (DIMs) via a sequential Sonogashira coupling and cycloisomerization/C3-functionalization of 2-iodoanilines. Org. Biomol. Chem. 2017, 15, 6997–7007. [Google Scholar] [CrossRef] [PubMed]
  74. Subba Reddy, B.V.; Swain, M.; Madhusudana Reddy, S.; Yadav, J.S.; Sridhar, B. Gold-catalyzed domino cycloisomerization/Pictet-Spengler reaction of 2-(4-aminobut-1-yn-1-yl)anilines with aldehydes: Synthesis of tetrahydropyrido[4,3-b]indole scaffolds. J. Org. Chem. 2012, 77, 11355–11361. [Google Scholar] [CrossRef] [PubMed]
  75. Han, X.; Lu, X. Cationic Pd(II)-catalyzed tandem reaction of 2-arylethynylanilines and aldehydes: An efficient synthesis of substituted 3-hydroxymethyl Indoles. Org. Lett. 2010, 12, 3336–3339. [Google Scholar] [CrossRef] [PubMed]
  76. Yuan, S.; Zhang, J.; Zhang, D.; Wei, D.; Zuo, J.; Song, J.; Yu, B.; Liu, H.-M. Cu(OTf)2-catalyzed intramolecular radical cascade reactions for the diversity-oriented synthesis of quinoline-annulated polyheterocyclic frameworks. Org. Lett. 2021, 23, 1445–1450. [Google Scholar] [CrossRef]
  77. Dhandabani, G.K.; Mutra, M.R.; Wang, J.-J. Palladium-catalyzed regioselective synthesis of 1-benzoazepine carbonitriles from o-alkynylanilines via 7-endo-dig annulation and cyanation. Adv. Synth. Catal. 2018, 360, 4754–4763. [Google Scholar] [CrossRef]
  78. Marsicano, V.; Arcadi, A.; Chiarini, M.; Fabrizi, G.; Goggiamani, A.; Iazzetti, A. Synthesis of 2,2,3-substituted-2,3-dihydroquinolin-4(1H)-ones vs. quinoline or N-alkenylindole derivatives through sequential reactions of 2-alkynylanilines with ketones. Org. Biomol. Chem. 2021, 19, 421–438. [Google Scholar] [CrossRef]
  79. Dhandabani, G.K.; Shih, C.-L.; Wang, J.-J. Acid-promoted intramolecular decarbonylative coupling reactions of unstrained ketones: A modular approach to synthesis of acridines and diaryl ketones. Org. Lett. 2020, 22, 1955–1960. [Google Scholar] [CrossRef]
  80. Punjajom, K.; Ruengsangtongkul, S.; Tummatorn, J.; Paiboonsombat, P.; Ruchirawat, S.; Thongsornkleeb, C. Mn(OAc)3-mediated one-pot condensation-oxidative annulation of 2-alkynylanilines and 1,3-ketoesters: Synthesis of 2-substituted quinolines. J. Org. Chem. 2023, 88, 6736–6749. [Google Scholar] [CrossRef]
  81. Marsicano, V.; Chiarini, M.; Marinelli, F.; Arcadi, A. Synthesis of polycyclic quinolines by means of Brønsted acid mediated reaction of β-(2-aminophenyl)-α,β-ynones with ketones. Adv. Synth. Catal. 2019, 361, 2365–2370. [Google Scholar] [CrossRef]
  82. Gogoi, S.; Shekarrao, K.; Duarah, A.; Bora, T.C.; Gogoi, S.; Boruah, R.C. A microwave promoted solvent-free approach to steroidal quinolines and their in vitro evaluation for antimicrobial activities. Steroids 2012, 77, 1438–1445. [Google Scholar] [CrossRef] [PubMed]
  83. Marsicano, V.; Arcadi, A.; Chiarini, M.; Fabrizi, G.; Goggiamani, A.; Iazzetti, A. Sequential condensation/biannulation reactions of β-(2-aminophenyl)-α,β-ynones with1,3-dicarbonyls. Org. Biomol. Chem. 2021, 19, 5177–5190. [Google Scholar] [CrossRef] [PubMed]
  84. Jash, M.; Das, B.; Chowdhury, C. One-pot access to benzo[a]carbazoles via palladium(II)-catalyzed hetero- and carboannulations. J. Org. Chem. 2016, 81, 10987–10999. [Google Scholar] [CrossRef]
  85. Abbiati, G.; Arcadi, A.; Chiarini, M.; Marinelli, F.; Pietropaolo, E.; Rossi, E. An alternative one-pot gold-catalyzed approach to the assembly of 11H-indolo-[3,2-c]quinolines. Org. Biomol. Chem. 2012, 10, 7801–7808. [Google Scholar] [CrossRef]
  86. Arcadi, A.; Chiarini, M.; D’Anniballe, G.; Marinelli, F.; Pietropaolo, E. Brønsted acid catalyzed cascade reactions of 2-[(2-aminophenyl)ethynyl]phenylamine derivatives with aldehydes: A new approach to the synthesis of 2,2′-disubstituted 1H,1′H-3,3′-biindoles. Org. Lett. 2014, 16, 1736–1739. [Google Scholar] [CrossRef]
  87. Qian, X.; Gao, H.-H.; Zhu, Y.-Z.; Lu, L.; Zheng, J.-Y. Biindole-based double D-π-A branched organic dyes for efficient dye-sensitized solar cells. RSC Adv. 2015, 5, 4368–4375. [Google Scholar] [CrossRef]
  88. Brambilla, E.; Gritti, A.; Pirovano, V.; Arcadi, A.; Germani, R.; Tiecco, M.; Abbiati, G. Acidic deep eutectics solvents as active media for a sustainable synthesis of biindoles starting from 2,2’-diaminotolanes and aldehydes. Eur. J. Org. Chem. 2023, e202300204. [Google Scholar] [CrossRef]
  89. Subba Reddy, B.V.; Swain, M.; Madhusudana Reddy, S.; Yadav, J.S.; Sridhar, B. Gold-catalyzed 5-endo-dig cyclization of 2-[(2-aminophenyl)-ethynyl]phenylamine with ketones for the synthesis of spiroindolone and indolo[3,2-c]quinolone scaffolds. Eur. J. Org. Chem. 2014, 3313–3318. [Google Scholar] [CrossRef]
  90. Yanada, R.; Hashimoto, K.; Tokizane, R.; Miwa, Y.; Minami, H.; Yanada, K.; Ishikura, M.; Takemoto, Y. Indium(III)-catalyzed tandem reaction with alkynylbenzaldehydes and alkynylanilines to heteroaromatic compounds. J. Org. Chem. 2008, 73, 5135–5138. [Google Scholar] [CrossRef]
  91. Bouma, M.J.; Masson, G.; Zhu, J. Exploiting the divergent reactivity of isocyanoacetates: One-pot three-component synthesis of functionalized angular furoquinolines. Eur. J. Org. Chem. 2012, 475–479. [Google Scholar] [CrossRef]
  92. Fayol, A.; Zhu, J. Synthesis of polysubstituted 4,5,6,7-tetrahydrofuro[2,3-c]pyridines by a novel multicomponent reaction. Org. Lett. 2004, 6, 115–118. [Google Scholar] [CrossRef] [PubMed]
  93. Zhao, S.; He, Y.; Gao, F.; Wei, Y.; Zhang, J.; Chen, M.; Gao, Y.; Zhang, Y.; Liu, J.-Y.; Guo, Z.; et al. Rapid access to C2-quaternary 3-methyleneindolines via base-mediated post-Ugi Conia-ene cyclization. Chem. Commun. 2023, 59, 3099–3102. [Google Scholar] [CrossRef] [PubMed]
  94. Borthakur, U.; Borah, M.; Deka, M.J.; Saikia, A.K. Synthesis of tetrahydro-1H-indeno[1,2-b]pyridine via cascade cyclization and Friedel-Crafts reaction. J. Org. Chem. 2016, 81, 8736–8743. [Google Scholar] [CrossRef]
  95. Hu, Y.; Jia, Y.; Tuo, Z.; Zhou, W. Rhodium(III)-catalyzed intramolecular annulation and aromatization for the synthesis of pyrrolo[1,2-a]quinolines. Org. Lett. 2023, 25, 1845–1849. [Google Scholar] [CrossRef] [PubMed]
  96. Liu, X.-Y.; Che, C.-M. Highly efficient and regioselective platinum(II)-catalyzed tandem synthesis of multiply substituted indolines and tetrahydroquinolines. Angew. Chem. Int. Ed. 2009, 48, 2367–2371. [Google Scholar] [CrossRef]
Scheme 1. Gold-catalyzed synthesis of pyridines from propargylamine and carbonyls.
Scheme 1. Gold-catalyzed synthesis of pyridines from propargylamine and carbonyls.
Molecules 28 04725 sch001
Scheme 2. Transition metal-catalyzed sequential amination–cyclization–aromatization reaction.
Scheme 2. Transition metal-catalyzed sequential amination–cyclization–aromatization reaction.
Molecules 28 04725 sch002
Scheme 3. Sequential reactions of carbonyl compounds and propargylamine catalyzed by Au-complex 8.
Scheme 3. Sequential reactions of carbonyl compounds and propargylamine catalyzed by Au-complex 8.
Molecules 28 04725 sch003
Scheme 4. Cu-catalyzed pyridine synthesis from cyclic ketones and propargylamine.
Scheme 4. Cu-catalyzed pyridine synthesis from cyclic ketones and propargylamine.
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Scheme 5. Linear vs. angular steroidal pyridines.
Scheme 5. Linear vs. angular steroidal pyridines.
Molecules 28 04725 sch005
Scheme 6. Copper-catalyzed synthesis of A-ring fused pyridine D-modified androstane derivatives.
Scheme 6. Copper-catalyzed synthesis of A-ring fused pyridine D-modified androstane derivatives.
Molecules 28 04725 sch006
Scheme 7. Copper-catalyzed synthesis of betulin derivatives.
Scheme 7. Copper-catalyzed synthesis of betulin derivatives.
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Scheme 8. Optimization of the synthesis of relevant steroidal pyridines.
Scheme 8. Optimization of the synthesis of relevant steroidal pyridines.
Molecules 28 04725 sch008
Scheme 9. Gold-catalyzed synthesis of the carbacycloamine analogue 11.
Scheme 9. Gold-catalyzed synthesis of the carbacycloamine analogue 11.
Molecules 28 04725 sch009
Scheme 10. Gold-catalyzed synthesis of the potassium channel modulator 12.
Scheme 10. Gold-catalyzed synthesis of the potassium channel modulator 12.
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Scheme 11. Synthesis of Wnt signal path inhibitors.
Scheme 11. Synthesis of Wnt signal path inhibitors.
Molecules 28 04725 sch011
Scheme 12. Gold-catalyzed synthesis of BAY-298.
Scheme 12. Gold-catalyzed synthesis of BAY-298.
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Scheme 13. Synthesis of BMS-846372.
Scheme 13. Synthesis of BMS-846372.
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Scheme 14. Gold-catalyzed synthesis of the benzomorphane derivative 13.
Scheme 14. Gold-catalyzed synthesis of the benzomorphane derivative 13.
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Scheme 15. Gold-catalyzed synthesis of the tropane-related scaffold 14.
Scheme 15. Gold-catalyzed synthesis of the tropane-related scaffold 14.
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Scheme 16. Synthesis of 11β-hydroxysteroid dehydrogenase inhibitors.
Scheme 16. Synthesis of 11β-hydroxysteroid dehydrogenase inhibitors.
Molecules 28 04725 sch016
Scheme 17. Gold-catalyzed synthesis of the ligand 17.
Scheme 17. Gold-catalyzed synthesis of the ligand 17.
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Scheme 18. Gold-catalyzed synthesis of 2,5-dihydropyridines 18.
Scheme 18. Gold-catalyzed synthesis of 2,5-dihydropyridines 18.
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Scheme 19. Synthesis of pyridinium salts.
Scheme 19. Synthesis of pyridinium salts.
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Scheme 20. Metal-free synthesis of the hetero-anthracene derivative 20.
Scheme 20. Metal-free synthesis of the hetero-anthracene derivative 20.
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Scheme 21. Synthesis of the dihydrophenanthroline 21.
Scheme 21. Synthesis of the dihydrophenanthroline 21.
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Scheme 22. Synthesis of natural products.
Scheme 22. Synthesis of natural products.
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Scheme 23. Construction of pyridines starting from (S)-(−)-perillaldehyde and (1R)-myrtenal.
Scheme 23. Construction of pyridines starting from (S)-(−)-perillaldehyde and (1R)-myrtenal.
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Scheme 24. Retrosynthetic pathway of suaveoline alkaloids.
Scheme 24. Retrosynthetic pathway of suaveoline alkaloids.
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Scheme 25. Pyridine synthesis by a 6π-3-azatriene electrocyclization.
Scheme 25. Pyridine synthesis by a 6π-3-azatriene electrocyclization.
Molecules 28 04725 sch025
Scheme 26. Synthesis of β- and γ-carbolines from indole aldehydes and substituted propargylic amines.
Scheme 26. Synthesis of β- and γ-carbolines from indole aldehydes and substituted propargylic amines.
Molecules 28 04725 sch026
Scheme 27. Synthesis of 4-benzylated carbolines 22.
Scheme 27. Synthesis of 4-benzylated carbolines 22.
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Scheme 28. Alternative synthesis of polysubstituted pyridine derivatives from α,β-unsaturated carbonyl compounds and propargylamine hydrochloride.
Scheme 28. Alternative synthesis of polysubstituted pyridine derivatives from α,β-unsaturated carbonyl compounds and propargylamine hydrochloride.
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Scheme 29. Total synthesis of onychine 23.
Scheme 29. Total synthesis of onychine 23.
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Scheme 30. Mechanism for the formation of chromenopyridines 25.
Scheme 30. Mechanism for the formation of chromenopyridines 25.
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Scheme 31. Sequential reaction of 2-(bis(prop-2-yn-1-ylamino)methyl benzaldehyde 26 with propargylamine.
Scheme 31. Sequential reaction of 2-(bis(prop-2-yn-1-ylamino)methyl benzaldehyde 26 with propargylamine.
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Scheme 32. Synthesis of naphthyridines 32.
Scheme 32. Synthesis of naphthyridines 32.
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Scheme 33. Synthesis of the chromenopyrazinone 33.
Scheme 33. Synthesis of the chromenopyrazinone 33.
Molecules 28 04725 sch033
Scheme 34. Gold-catalyzed synthesis of pyrazines 34 from the reaction of propargylamine with aldehydes.
Scheme 34. Gold-catalyzed synthesis of pyrazines 34 from the reaction of propargylamine with aldehydes.
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Scheme 35. Proposed mechanism for the Au-catalyzed formation of pyrazines 34.
Scheme 35. Proposed mechanism for the Au-catalyzed formation of pyrazines 34.
Molecules 28 04725 sch035
Scheme 36. Sequential reaction of propargylamine with aldehydes catalyzed by MCM-41-immobilized phosphine gold(I) complex [MCM-41-PPh3-AuNTf2].
Scheme 36. Sequential reaction of propargylamine with aldehydes catalyzed by MCM-41-immobilized phosphine gold(I) complex [MCM-41-PPh3-AuNTf2].
Molecules 28 04725 sch036
Scheme 37. Synthesis of 1,2,3-triazolo-1,4-benzodiazepines 35.
Scheme 37. Synthesis of 1,2,3-triazolo-1,4-benzodiazepines 35.
Molecules 28 04725 sch037
Scheme 38. Diversely substituted 1,2,3-triazolo-1,4-benzodiazepine 36.
Scheme 38. Diversely substituted 1,2,3-triazolo-1,4-benzodiazepine 36.
Molecules 28 04725 sch038
Scheme 39. Indium-catalyzed multicomponent synthesis of 9H-benzo[f]imidazo [1,2-d][1,2,3]triazolo [1,5-a][1,4]diazepines 37.
Scheme 39. Indium-catalyzed multicomponent synthesis of 9H-benzo[f]imidazo [1,2-d][1,2,3]triazolo [1,5-a][1,4]diazepines 37.
Molecules 28 04725 sch039
Scheme 40. Indium-catalyzed synthesis of β-(N-indolyl)-α,β-unsaturated esters 40.
Scheme 40. Indium-catalyzed synthesis of β-(N-indolyl)-α,β-unsaturated esters 40.
Molecules 28 04725 sch040
Scheme 41. Divergent sequential gold-catalyzed cyclization/alkenylation reaction of 2-alkynylanilines with 1,3-dicarbonyl compounds.
Scheme 41. Divergent sequential gold-catalyzed cyclization/alkenylation reaction of 2-alkynylanilines with 1,3-dicarbonyl compounds.
Molecules 28 04725 sch041
Scheme 42. p-TsOH promoted synthesis of 4-alkyl-2,3-disubstituted quinolines 42.
Scheme 42. p-TsOH promoted synthesis of 4-alkyl-2,3-disubstituted quinolines 42.
Molecules 28 04725 sch042
Scheme 43. Synthesis of dimeric quinolines 43.
Scheme 43. Synthesis of dimeric quinolines 43.
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Scheme 44. Iron(III)-catalyzed sequential condensation, cyclization and aromatization of 1,3-diketones with 2-ethynylaniline to afford 4-methyl-2,3-disubstituted quinolines 44.
Scheme 44. Iron(III)-catalyzed sequential condensation, cyclization and aromatization of 1,3-diketones with 2-ethynylaniline to afford 4-methyl-2,3-disubstituted quinolines 44.
Molecules 28 04725 sch044
Scheme 45. Sequential reaction of levulinic acid with 2-ethynylaniline under solventless conditions.
Scheme 45. Sequential reaction of levulinic acid with 2-ethynylaniline under solventless conditions.
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Scheme 46. Copper(I)-catalyzed synthesis of 2-acylquinolines.
Scheme 46. Copper(I)-catalyzed synthesis of 2-acylquinolines.
Molecules 28 04725 sch046
Scheme 47. Copper-catalyzed synthesis of quinolines 45 from ethynylaniline and N, O-acetals.
Scheme 47. Copper-catalyzed synthesis of quinolines 45 from ethynylaniline and N, O-acetals.
Molecules 28 04725 sch047
Scheme 48. Synthesis of 4-alkoxy-2-arylquinolines 46.
Scheme 48. Synthesis of 4-alkoxy-2-arylquinolines 46.
Molecules 28 04725 sch048
Scheme 49. Condensative cyclization of 6-amino-5-[(trimethylsilyl)ethynyl]-2H-chromen-2-one 47.
Scheme 49. Condensative cyclization of 6-amino-5-[(trimethylsilyl)ethynyl]-2H-chromen-2-one 47.
Molecules 28 04725 sch049
Scheme 50. Synergistic effect of Pd(II) and acid catalysts on the synthesis of ring-fused quinolines.
Scheme 50. Synergistic effect of Pd(II) and acid catalysts on the synthesis of ring-fused quinolines.
Molecules 28 04725 sch050
Scheme 51. Sc(OTf)3-catalyzed bicyclization of 2-alkynylanilines with aldehydes.
Scheme 51. Sc(OTf)3-catalyzed bicyclization of 2-alkynylanilines with aldehydes.
Molecules 28 04725 sch051
Scheme 52. Gold-catalyzed synthesis of polycyclic frameworks 54.
Scheme 52. Gold-catalyzed synthesis of polycyclic frameworks 54.
Molecules 28 04725 sch052
Scheme 53. Iodonium-induced tandem cyclization of N-(2-alkynylphenyl) imines 53.
Scheme 53. Iodonium-induced tandem cyclization of N-(2-alkynylphenyl) imines 53.
Molecules 28 04725 sch053
Scheme 54. One-pot synthesis of 2,2′-disubstituted diindolylmethanes 57.
Scheme 54. One-pot synthesis of 2,2′-disubstituted diindolylmethanes 57.
Molecules 28 04725 sch054
Scheme 55. Gold-catalyzed synthesis of 1-substituted 2-tosyl-2,3,4,5-tetrahydropyrido [4,3-b]indoles 62.
Scheme 55. Gold-catalyzed synthesis of 1-substituted 2-tosyl-2,3,4,5-tetrahydropyrido [4,3-b]indoles 62.
Molecules 28 04725 sch055
Scheme 56. Palladium-catalyzed synthesis of N-tosyl-3-hyroxymethyl indoles.
Scheme 56. Palladium-catalyzed synthesis of N-tosyl-3-hyroxymethyl indoles.
Molecules 28 04725 sch056
Scheme 57. Cu(OTf)2-catalyzed synthesis of quinoline-annulated polyheterocyclic frameworks 64.
Scheme 57. Cu(OTf)2-catalyzed synthesis of quinoline-annulated polyheterocyclic frameworks 64.
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Scheme 58. Plausible reaction mechanism.
Scheme 58. Plausible reaction mechanism.
Molecules 28 04725 sch058
Scheme 59. Palladium-catalyzed synthesis of 1-benzoazepine carbonitriles 71.
Scheme 59. Palladium-catalyzed synthesis of 1-benzoazepine carbonitriles 71.
Molecules 28 04725 sch059
Scheme 60. Product-selectivity control of the sequential reaction of 2-alkynylaniline with ketones.
Scheme 60. Product-selectivity control of the sequential reaction of 2-alkynylaniline with ketones.
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Scheme 61. Proposed mechanism for the synthesis of quinolinones 72.
Scheme 61. Proposed mechanism for the synthesis of quinolinones 72.
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Scheme 62. Proposed mechanism for the synthesis of quinolines 73 and N-alkenylindoles 74.
Scheme 62. Proposed mechanism for the synthesis of quinolines 73 and N-alkenylindoles 74.
Molecules 28 04725 sch062
Scheme 63. Alternative mechanism for the synthesis of quinolines 73.
Scheme 63. Alternative mechanism for the synthesis of quinolines 73.
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Scheme 64. Synthesis of acridine derivatives.
Scheme 64. Synthesis of acridine derivatives.
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Scheme 65. Mn(OAc)3-mediated synthesis of 2-substituted quinolines from 2-alkynylanilines and β-ketoesters.
Scheme 65. Mn(OAc)3-mediated synthesis of 2-substituted quinolines from 2-alkynylanilines and β-ketoesters.
Molecules 28 04725 sch065
Scheme 66. Sequential amination–annulation–aromatization reactions of β-(2-aminophenyl)-α,β-ynones 75 with enolizable ketones.
Scheme 66. Sequential amination–annulation–aromatization reactions of β-(2-aminophenyl)-α,β-ynones 75 with enolizable ketones.
Molecules 28 04725 sch066
Scheme 67. Product-selectivity control in the synthesis of polycyclic steroidal quinolines 76.
Scheme 67. Product-selectivity control in the synthesis of polycyclic steroidal quinolines 76.
Molecules 28 04725 sch067
Scheme 68. Domino reactions of β-(2-aminophenyl)-α,β-ynones with 1,3-dicarbonyls.
Scheme 68. Domino reactions of β-(2-aminophenyl)-α,β-ynones with 1,3-dicarbonyls.
Molecules 28 04725 sch068
Scheme 69. Sequential aminopalladation of β-amino alkynes 79.
Scheme 69. Sequential aminopalladation of β-amino alkynes 79.
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Scheme 70. Retrosynthetic assembly of 11H-indolo [3,2-c]quinolines.
Scheme 70. Retrosynthetic assembly of 11H-indolo [3,2-c]quinolines.
Molecules 28 04725 sch070
Scheme 71. Gold-catalyzed synthesis of 11H-indolo [3,2-c]quinoline 82.
Scheme 71. Gold-catalyzed synthesis of 11H-indolo [3,2-c]quinoline 82.
Molecules 28 04725 sch071
Scheme 72. Brønsted acid-catalyzed synthesis of 2,2′-disubstituted 1H,1′H-3,3′-biindoles 83.
Scheme 72. Brønsted acid-catalyzed synthesis of 2,2′-disubstituted 1H,1′H-3,3′-biindoles 83.
Molecules 28 04725 sch072
Scheme 73. Proposed mechanism.
Scheme 73. Proposed mechanism.
Molecules 28 04725 sch073
Scheme 74. Gold-catalyzed reaction of 2-[(2-aminophenyl)ethynyl]phenylamines 81 with isatins and ketones.
Scheme 74. Gold-catalyzed reaction of 2-[(2-aminophenyl)ethynyl]phenylamines 81 with isatins and ketones.
Molecules 28 04725 sch074
Scheme 75. Indium(III)-catalyzed sequential reaction of 2-alkynylanilines with 2-alkynylbenzaldehydes.
Scheme 75. Indium(III)-catalyzed sequential reaction of 2-alkynylanilines with 2-alkynylbenzaldehydes.
Molecules 28 04725 sch075
Scheme 76. Synthesis of 2-alkoxyfuro [2,3-c]quinolones 87.
Scheme 76. Synthesis of 2-alkoxyfuro [2,3-c]quinolones 87.
Molecules 28 04725 sch076
Scheme 77. Proposed mechanism.
Scheme 77. Proposed mechanism.
Molecules 28 04725 sch077
Scheme 78. Sequential multicomponent approach to 2,2-disubstituted 3-methyleneindolines 93.
Scheme 78. Sequential multicomponent approach to 2,2-disubstituted 3-methyleneindolines 93.
Molecules 28 04725 sch078
Scheme 79. Synthesis of 1-tosyl-2,3,4,5-tetrahydro-1H-indeno [1,2-b]-pyridines 95.
Scheme 79. Synthesis of 1-tosyl-2,3,4,5-tetrahydro-1H-indeno [1,2-b]-pyridines 95.
Molecules 28 04725 sch079
Scheme 80. Synthesis of pyrrolo[1,2-a]quinolines 98.
Scheme 80. Synthesis of pyrrolo[1,2-a]quinolines 98.
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Scheme 81. Platinum(II)-catalyzed synthesis of indolines 100.
Scheme 81. Platinum(II)-catalyzed synthesis of indolines 100.
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Scheme 82. Platinum(II)-catalyzed synthesis of tetrahydroquinolines 102.
Scheme 82. Platinum(II)-catalyzed synthesis of tetrahydroquinolines 102.
Molecules 28 04725 sch082
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Arcadi, A.; Morlacci, V.; Palombi, L. Synthesis of Nitrogen-Containing Heterocyclic Scaffolds through Sequential Reactions of Aminoalkynes with Carbonyls. Molecules 2023, 28, 4725. https://doi.org/10.3390/molecules28124725

AMA Style

Arcadi A, Morlacci V, Palombi L. Synthesis of Nitrogen-Containing Heterocyclic Scaffolds through Sequential Reactions of Aminoalkynes with Carbonyls. Molecules. 2023; 28(12):4725. https://doi.org/10.3390/molecules28124725

Chicago/Turabian Style

Arcadi, Antonio, Valerio Morlacci, and Laura Palombi. 2023. "Synthesis of Nitrogen-Containing Heterocyclic Scaffolds through Sequential Reactions of Aminoalkynes with Carbonyls" Molecules 28, no. 12: 4725. https://doi.org/10.3390/molecules28124725

APA Style

Arcadi, A., Morlacci, V., & Palombi, L. (2023). Synthesis of Nitrogen-Containing Heterocyclic Scaffolds through Sequential Reactions of Aminoalkynes with Carbonyls. Molecules, 28(12), 4725. https://doi.org/10.3390/molecules28124725

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