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

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.


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 πand σ-complexes can help in the choice of catalysts for the desired transformations when bi-or polyfunctional substrates are involved [6]. The reaction of γand δ-aminoalkynes with sulfonyl azides in the presence of Ru 3 (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

Sequential Reactions of α-Aminoalkynes (Propargylamines) with Carbonyls
Propargylic amine derivatives represent useful α-aminoalkynes building blo the construction of nitrogen-containing heterocyclic scaffolds through their seque actions with carbonyls. The gold-catalyzed reaction of propargylamine 1 with dial clic/cyclic ketones, methyl, aryl/heteroaryl ketones and aldehydes bearing α-hydr allowed a simple approach to pyridines 3 through a sequential amination-cycli aromatization cascade (Scheme 1) [18]. 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% CuCl 2 in air. Decreased yields among cyclic ketones were observed in the following order: six-membered >> eight-membered > five-membered ∼ sevenmembered. 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]. 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].
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 4ene-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]. 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 17βhydroxyandrost-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]. 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 NaAuCl 4 ·2H 2 O instead of CuCl and the addition of activated molecular sieves (MS) to the reaction mixture led to significant improvement (Scheme 8) [25]. 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].
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 pyridine 17 as the ligand for the synthesis of an olefin polymerization catalyst (Scheme 17) [35]. The sequential gold-catalyzed condensation/annulation reaction of the 1,3-dihyrdo-2H-inden-2-one with the propargylamine provided the corresponding 9H-indeno [2,1b]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 NaAuCl 4 in MeOH as solvent. The dichloro(2-pyridinecarboxilato)gold (pic)AuCl 2 ) resulted in a less effective catalyst, and the reaction failed to occur in the presence of (Ph 3 P)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 NaAuCl 4 ruled out the formation of the product by Brønsted acid catalysis. Propargylamines unsubstituted at the triple bond (R 4 =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].
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 (R 4 =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 Ag 2 CO 3 /HNTf 2 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 electronwithdrawing group at the acetylenic position, which underwent unusual inversion of the reactivity usually observed in Michael-type reactions. CH 3 CN was the solvent of choice in this one-pot transformation (Scheme 19) [37]. 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]. 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 (CsCO 3 , NaHCO 3 , NaOAc, K 2 HPO 4 , 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 NaHCO 3 at 80 • C [40]. The application to the synthesis of a variety of natural products was reported (Scheme 22) [41]. 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 process also achieved the total syntheses of suaveoline alkaloids (Scheme 24) [42]. 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 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].
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). . Synthesis of naphthyridines 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 H 2 O under otherwise identical conditions was advantageous for the reaction outcome. The [(Ph 3 P)AuNTf 2 ] 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 [(Ph 3 P)AuNTf 2 ] with [P(tBu) 2 (o-biphenyl)AuNTf 2 ]. AuCl 3 resulted in a less effective catalyst, while different Lewis acid catalysts, such as PtCl 2 , InCl 3 , Bi(OTf) 3 , ZnCl 2 , and AgNTf 2 , 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]. 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-1,4dihydropyrazine 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.
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.  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].

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 InBr 3 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].

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 NaAuCl 4 ·2H 2 O as the catalyst in a sealed tube (Scheme 41) [59]. 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]. The procedure also accomplished the preparation of quinoline dimers 43 with alkyl or aryl linkers at C-4 (Scheme 43). . p-TsOH promoted synthesis of 4-alkyl-2,3-disubstituted quinolines 42.
The procedure also accomplished the preparation of quinoline dimers 43 with alkyl or aryl linkers at C-4 (Scheme 43).
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)(H 2 O) 2 (OTf) 2 (Scheme 56) [75]. 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].

Scheme 56. Palladium-catalyzed synthesis of N-tosyl-3-hyroxymethyl indoles.
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). 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 oneelectron 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]. 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]. 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].

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).  . Alternative mechanism for the synthesis of quinolines 73.
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]. 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-∆ 4 -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]. 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-Δ 4 -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·H 2 O 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·H 2 O 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]. . Product-selectivity control in the synthesis of polycyclic steroidal quinolines 76.
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 threecomponent 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]. 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- . Sequential aminopalladation of β-amino alkynes 79.

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-1yl)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 electronwithdrawing 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[1,2a]quinolines 98. [Cp*RhCl2]2 (Cp* = η 5 -1,2,3,4,5-pentamethylcyclopentadienyl) resulted in a more effective catalyst under the presence of Cu(OAc) 2 ·H 2 O 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]. The sequential rhodium(III)-catalyzed intramolecular annulation/aromatization of oalkynyl amino aromatic ketones 97 achieved a one-pot building up of the pyrrolo[1,2a]quinolines 98. [Cp*RhCl2]2 (Cp* = η 5 -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 K 2 PtCl 4 (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].
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].

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.