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

Abstract

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 Pt^II 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,1′H-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.