Metal-Catalyzed Cascade Reactions between Alkynoic Acids and Dinucleophiles: A Review

Citation: Herrero, M.T.; Díaz de Sarralde, J.; Conde, N.; Herrán, A.; Urgoitia, G.; SanMartin, R. Metal-Catalyzed Cascade Reactions between Alkynoic Acids and Dinucleophiles: A Review. Catalysts 2023,13, 495. https://doi.org/ 10.3390/catal13030495 Academic Editors: Victorio Cadierno and Raffaella Mancuso Received: 30 January 2023 Revised: 25 February 2023 Accepted: 25 February 2023 Published: 28 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). catalysts Review Metal-Catalyzed Cascade Reactions between Alkynoic Acids and Dinucleophiles: A Review María Teresa Herrero, Jokin Díaz de Sarralde, Nerea Conde, Aitor Herrán, Garazi Urgoitia and Raul SanMartin * Department of Organic and Inorganic Chemistry, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Sarriena Auzoa, z/g, 48940 Leioa, Spain *Correspondence: [email protected] Abstract: Cascade reactions provide a straightforward access to many valuable compounds and reduce considerably the number of steps of a synthetic sequence. Among the domino and multicomponent processes that involve alkynes, the cascade reaction between alkynoic acids and C-, N-, Oand S-aminonucleophiles stands out as a particularly powerful tool for the one-pot construction of libraries of nitrogen-containing heterocyclic compounds with scaffold diversity and molecular complexity. This reaction, based on an initial metal-catalyzed cycloisomerization that generates an alkylidene lactone intermediate, was originally catalyzed by gold(I) catalysts, along with silver salts or Brönsted acid additives, but other alternative metal catalysts have emerged in the last decade as well as different reaction media. This review examines the existing literature on the topic of metalcatalyzed cascade reactions of acetylenic acids and dinucleophiles and discusses aspects concerning substrate/catalyst ratio for every catalyst system, nature of the aminonucleophile involved and substrate scope. In addition, alternative solvents are also considered, and an insight into the pathway of the reaction and possible intermediates is also provided. Keywords: cascade reactions; domino processes; metal catalysts; cycloisomerization 1. Introduction In contrast with classical stepwise synthesis of organic compounds, cascade-based strategies provide a much faster, and in many cases, more efficient approach to an increasingly larger number of complex structures [ 1 – 4 ]. In fact, terms such as atom-economy and green chemistry are often associated with metal-catalyzed cascade reactions [ 5 , 6 ]. The last decades have witnessed significant advances in the fields of metal-catalyzed hydrofunctionalization of alkynes [ 7 – 13 ], and, more specifically, of cascade reactions involving alkyne hydrofunctionalization steps [ 14 – 19 ]. The intramolecular version of such cascade reactions, often based on the presence of suitably located carboand heteronucleophiles in the starting materials, has been also described [ 16 , 18 , 19 ]. In this regard, π -coordination of the C-C triple bond to a carbophilic transition metal catalyst can promote an initial cycloisomerization process that becomes the key step for a cascade approach to relatively complex frameworks. Among a number of substrates bearing alkyne and nucleophilic moieties (o-, γ -, or δ -alkynyl N-arylnitrones, amines, carboxamides, alkenes, arenes and heteroarenes, inter alia) [ 20 – 25 ], alkynoic acids stand out for their synthetic potential, since cycloisomerization of these acetylenic derivatives generates alkylidene lactones, which are prone to undergo nucleophilic attack (Scheme 1) [26–30]. In many cases, as a result of the above cascade reactions starting from alkynoic acids, analogs and isosteres of a number of pharmacologically relevant compounds have been straightforwardly prepared. Among others, tetrahydroγ -carbolines (e.g., Gevotroline,Tubastatin A and Dimebon), identified as potent immunosuppressants and neuroprotective agents [ 31 – 38 ]; actinophenanthrolines [ 39 ] and quinazoline alkaloids such as Catalysts 2023,13, 495. https://doi.org/10.3390/catal13030495 https://www.mdpi.com/journal/catalysts Catalysts 2023,13, 495 2 of 20 Vasicine (peganine), Mackinazolinone,Batracyclin and Tryptanthrin that exhibit anticancer, antiinflammatory, antiprotozoal, antiallergic, antioxidant and antimicrobial activities [ 40 – 47 ] (Figure 1). Catalysts 2023, 13, x 2 of 22 OH O OONu Nu' O NuH Nu'H () n [M] () n R R () n Scheme 1. An overall picture of metal-catalyzed cascade reaction of acetylenic acids and dinucleophiles. In many cases, as a result of the above cascade reactions starting from alkynoic acids, analogs and isosteres of a number of pharmacologically relevant compounds have been straightforwardly prepared. Among others, tetrahydro-γ-carbolines (e.g., Gevotroline, Tubastatin A and Dimebon), identified as potent immunosuppressants and neuroprotective agents [31–38]; actinophenanthrolines [39] and quinazoline alkaloids such as Vasicine (peganine), Mackinazolinone, Batracyclin and Tryptanthrin that exhibit anticancer, anti-inflammatory, antiprotozoal, antiallergic, antioxidant and antimicrobial activities [40–47] (Figure 1). Figure 1. Structure of several tetrahydro-γ-carbolines, actinophenanthrolines and quinazoline alkaloids. The synthesis of the latter structures has been limited to sequences involving two or more steps, although, recently, more efficient strategies often based on multiple condensations have been reported [45]. In this respect, the work of Sondhi and Rani on the solventless condensation of dicarboxylic acids with diamines under microwave irradiation [48], the one-pot oxidative condensation of anthranilamides with 3,3-dihydro-2H-pyrone followed by intramolecular Mitsunobu coupling, as reported by Kim and Cheon [49], the annulation/anodic oxidation of 2-aminobenzamides and aldehydes described by Cao et al. [50], the reductive condensation of o-nitrobenzaldehydes with amines using iron pentacarbonyl as reductant followed by oxidation, recently disclosed by the group of Chusov [51], and the reaction of tert-butyl 2-aminobenzylcarbamate and acid anhydrides to Scheme 1. An overall picture of metal-catalyzed cascade reaction of acetylenic acids and dinucleophiles. Catalysts 2023, 13, x 2 of 22 OH O OONu Nu' O NuH Nu'H () n [M] () n R R () n Scheme 1. An overall picture of metal-catalyzed cascade reaction of acetylenic acids and dinucleophiles. In many cases, as a result of the above cascade reactions starting from alkynoic acids, analogs and isosteres of a number of pharmacologically relevant compounds have been straightforwardly prepared. Among others, tetrahydro-γ-carbolines (e.g., Gevotroline, Tubastatin A and Dimebon), identified as potent immunosuppressants and neuroprotective agents [31–38]; actinophenanthrolines [39] and quinazoline alkaloids such as Vasicine (peganine), Mackinazolinone, Batracyclin and Tryptanthrin that exhibit anticancer, anti-inflammatory, antiprotozoal, antiallergic, antioxidant and antimicrobial activities [40–47] (Figure 1). Figure 1. Structure of several tetrahydro-γ-carbolines, actinophenanthrolines and quinazoline alkaloids. The synthesis of the latter structures has been limited to sequences involving two or more steps, although, recently, more efficient strategies often based on multiple condensations have been reported [45]. In this respect, the work of Sondhi and Rani on the solventless condensation of dicarboxylic acids with diamines under microwave irradiation [48], the one-pot oxidative condensation of anthranilamides with 3,3-dihydro-2H-pyrone followed by intramolecular Mitsunobu coupling, as reported by Kim and Cheon [49], the annulation/anodic oxidation of 2-aminobenzamides and aldehydes described by Cao et al. [50], the reductive condensation of o-nitrobenzaldehydes with amines using iron pentacarbonyl as reductant followed by oxidation, recently disclosed by the group of Chusov [51], and the reaction of tert-butyl 2-aminobenzylcarbamate and acid anhydrides to Figure 1. Structure of several tetrahydroγ -carbolines, actinophenanthrolines and quinazoline alkaloids. The synthesis of the latter structures has been limited to sequences involving two or more steps, although, recently, more efficient strategies often based on multiple condensations have been reported [ 45 ]. In this respect, the work of Sondhi and Rani on the solventless condensation of dicarboxylic acids with diamines under microwave irradiation [ 48 ], the one-pot oxidative condensation of anthranilamides with 3,3-dihydro-2H-pyrone followed by intramolecular Mitsunobu coupling, as reported by Kim and Cheon [ 49 ], the annulation/anodic oxidation of 2-aminobenzamides and aldehydes described by Cao et al. [ 50 ], the reductive condensation of o-nitrobenzaldehydes with amines using iron pentacarbonyl as reductant followed by oxidation, recently disclosed by the group of Chusov [ 51 ], and the reaction of tert-butyl 2-aminobenzylcarbamate and acid anhydrides to generate the corresponding imides, which are subsequently cyclized under acidic conditions [ 52 ] should be mentioned (Scheme 2). In order to cover the literature on cascade reactions between alkynoic acids and dinucleophiles, this review is organized according to the metal catalyst used to promote the aforementioned cycloisomerization and further reaction with the dinucleophile species. In addition to the reaction scope, special emphasis will be given to the substrate: catalyst ratio and reaction media, and in some cases, the mechanistic proposals for such transformations will be described, along with several experiments performed to shed light of the role of the metal catalyst and other additives employed. Catalysts 2023,13, 495 3 of 20 Catalysts 2023, 13, x 3 of 22 generate the corresponding imides, which are subsequently cyclized under acidic conditions [52] should be mentioned (Scheme 2). Scheme 2. Alternative strategies for the synthesis of triand tetracyclic quinazoline and quinazolinone derivatives. Sondhi, 2010: [48]; Afanasyev, 2020: [51]; Cao, 2018: [50]; Kshirsagar, 2009: [52]. In order to cover the literature on cascade reactions between alkynoic acids and dinucleophiles, this review is organized according to the metal catalyst used to promote the aforementioned cycloisomerization and further reaction with the dinucleophile species. In addition to the reaction scope, special emphasis will be given to the substrate:catalyst ratio and reaction media, and in some cases, the mechanistic proposals for such transformations will be described, along with several experiments performed to shed light of the role of the metal catalyst and other additives employed. 2. Au Catalysts 2.1. Introduction Although some rivalling candidates have appeared along the way, gold-based catalysts have dominated the field from the very beginning. In addition to a relatively low catalyst amount, gold catalysts allow for the use of most aminonucleophiles explored so Scheme 2. Alternative strategies for the synthesis of triand tetracyclic quinazoline and quinazolinone derivatives. Sondhi, 2010: [48]; Afanasyev, 2020: [51]; Cao, 2018: [50]; Kshirsagar, 2009: [52]. 2. Au Catalysts 2.1. Introduction Although some rivalling candidates have appeared along the way, gold-based catalysts have dominated the field from the very beginning. In addition to a relatively low catalyst amount, gold catalysts allow for the use of most aminonucleophiles explored so far. Indeed, this ample scope combined with a high efficiency have made gold the metal of choice for such transformations for a long time. In most cases, gold(I) catalysts were enough to promote the reactions, although occasionally combination with silver salts or Brönsted acids have led to optimized conditions. 2.2. Initial Reports In 2007, Dixon and col. presented a pioneering work on the Au(I)-catalyzed cascade reaction of alkynoic and 2-propargyloxyethanoic acids with 1-(2-aminoethyl)pyrrole and 3-(2-aminoethyl)indole (tryptamine) in toluene or xylene [ 53 ]. Good to excellent yields were achieved in this AuPPh 3 Cl/AgOTf-catalyzed reaction, and the authors proved not only the Catalysts 2023,13, 495 4 of 20 participation of the alkynyl group as a masked ketone moiety released after nucleophilic attack at the initially formed exocyclic alkylidene lactone but also that a Lewis acid-assisted Brønsted acid catalysis is responsible for the formation of the N-acyliminium intermediate, which is the third stage of the cyclization cascade (Scheme 3). Catalysts 2023, 13, x 4 of 22 far. Indeed, this ample scope combined with a high efficiency have made gold the metal of choice for such transformations for a long time. In most cases, gold(I) catalysts were enough to promote the reactions, although occasionally combination with silver salts or Brönsted acids have led to optimized conditions. 2.2. Initial Reports In 2007, Dixon and col. presented a pioneering work on the Au(I)-catalyzed cascade reaction of alkynoic and 2-propargyloxyethanoic acids with 1-(2-aminoethyl)pyrrole and 3-(2-aminoethyl)indole (tryptamine) in toluene or xylene [53]. Good to excellent yields were achieved in this AuPPh3Cl/AgOTf-catalyzed reaction, and the authors proved not only the participation of the alkynyl group as a masked ketone moiety released after nucleophilic attack at the initially formed exocyclic alkylidene lactone but also that a Lewis acid-assisted Brønsted acid catalysis is responsible for the formation of the N-acyliminium intermediate, which is the third stage of the cyclization cascade (Scheme 3). Scheme 3. Scope of the Au(I)-Catalyzed Cascade and mechanistic proposal. In this regard, N-(2-(1H-pyrrol-1-yl)ethyl)-4-oxopentanamide, proposed as the ketoamide intermediate after the ring-opening of the initial alkylidene lactone with 1-(2aminoethyl)pyrrole, was synthesized and subjected to several reaction conditions. Although boiling in toluene for 4 days resulted in no conversion, when a catalytic amount of triflic acid was added, the reaction provided target 10b-methyl-1,5,6,10b-tetrahydrodipyrrolo[1,2-a:2′,1′-c]pyrazin-3 (2H)-one. The results from these and other experiments with the same substrate in the presence of the 2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) base and the above gold catalyst led the authors to postulate that a Lewis acid-assisted Brønsted acid catalysis provides the activation required for the second stage of the cascade. 4-Hexynoic acid was also reacted with tryptamine and provided the corresponding heterocycle, although as a mixture of regioisomers. The same group published an enantioselective approach to the products derived from tryptamine by using preformed enol lactones and (R)-BINOL phosphoric acid derivatives as chiral Brönsted acid catalysts. A number of 5-monosubstituted and 4,5-disubstituted furan-2(3H)-ones Scheme 3. Scope of the Au(I)-Catalyzed Cascade and mechanistic proposal. In this regard, N-(2-(1H-pyrrol-1-yl)ethyl)-4-oxopentanamide, proposed as the ketoamide intermediateafter the ring-openingofthe initialalkylidene lactonewith1-(2-aminoethyl)pyrrole, was synthesized and subjected to several reaction conditions. Although boiling in toluene for 4 days resulted in no conversion, when a catalytic amount of triflic acid was added, the reaction provided target 10b-methyl-1,5,6,10b-tetrahydrodipyrrolo[1,2-a:2 0 ,1 0 -c]pyrazin-3 (2H)-one. The results from these and other experiments with the same substrate in the presence of the 2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) base and the above gold catalyst led the authors to postulate that a Lewis acid-assisted Brønsted acid catalysis provides the activation required for the second stage of the cascade. 4-Hexynoic acid was also reacted with tryptamine and provided the corresponding heterocycle, although as a mixture of regioisomers. The same group published an enantioselective approach to the products derived from tryptamine by using preformed enol lactones and (R)-BINOL phosphoric acid derivatives as chiral Brönsted acid catalysts. A number of 5-monosubstituted and 4,5-disubstituted furan-2(3H)-ones and 6-methyl-3,4-dihydro-2H-pyran-2-one were reacted with several tryptamine derivatives in the presence of 3,3 0 -bis(triphenylsilyl)-(R)- BINOL phosphoric acid to provide the corresponding indolizino[8,7-b]indol-3-ones [54]. 2.3. Au-Catalyzed Reaction between Alkynoic Acids and C-, Oand N-Aminonucleophiles; Further Advances in the Field A large variety of pyrroloand pyrido[2,1-b]benzo[d][1,3]oxazin-1-ones 1 were synthesized by Liu and col. from o-aminobenzyl alcohols and 4-pentynoicand 5-hexynoic acids in the presence of a 2 mol% of [Au{P(t-Bu) 2 (o-biphenyl)}{CH 3 CN}]SbF 6 . Tetrahydrofuran Catalysts 2023,13, 495 5 of 20 (THF) was the solvent of choice when dealing with most of the 4-pentynoic acid derivatives, while toluene was employed for reactions with 5-hexynoic acid. Regarding the reaction mechanism, the authors proposed that, after the initial cycloisomerization step, nucleophilic attack by the amino group generates a ketoamide intermediate A that, upon intramolecular condensation and the formation of the corresponding N-acyliminium ion B , undergoes nucleophilic attack by the carbinol moiety, thus providing triand tetracycles 1 with good yields [55] (Scheme 4). Catalysts 2023, 13, x 5 of 22 and 6-methyl-3,4-dihydro-2H-pyran-2-one were reacted with several tryptamine derivatives in the presence of 3,3′-bis(triphenylsilyl)-(R)-BINOL phosphoric acid to provide the corresponding indolizino[8,7-b]indol-3-ones [54]. 2.3. Au-Catalyzed Reaction between Alkynoic Acids and C-, Oand N-Aminonucleophiles; Further Advances in the Field A large variety of pyrroloand pyrido[2,1-b]benzo[d][1,3]oxazin-1-ones 1 were synthesized by Liu and col. from o-aminobenzyl alcohols and 4-pentynoicand 5-hexynoic acids in the presence of a 2 mol% of [Au{P(t-Bu)2(o-biphenyl)}{CH3CN}]SbF6. Tetrahydrofuran (THF) was the solvent of choice when dealing with most of the 4-pentynoic acid derivatives, while toluene was employed for reactions with 5-hexynoic acid. Regarding the reaction mechanism, the authors proposed that, after the initial cycloisomerization step, nucleophilic attack by the amino group generates a ketoamide intermediate A that, upon intramolecular condensation and the formation of the corresponding N-acyliminium ion B, undergoes nucleophilic attack by the carbinol moiety, thus providing triand tetracycles 1 with good yields [55] (Scheme 4). OH R5 NH2 R2 R3 () n R1 COOH O R5 N R2 R3 O R1 () n (2 mol%) THF or PhMe, 120 ºC, 12_24h, Ar O N O R1 () n O N O O O n= 0, 1; R1=H,Hex R3= H, Cl; R4=H,Me R2=H,Me,F,Cl,Br,I,Ph 23 examples (53_98%) R4 R4R5=H,Me n= 0, 1; R1=H,Hex 3examples(78 _96%) 69% O O R1 Au(I) NH2 OH R NH OH R O R1 O OH N () n () n O ( ) n Au(I) A B 1 Ph P(tBu)2 Au NSbF6 Scheme 4. Direct approach to benzo[e]indolo[1,2-a]pyrrolo[2,1-c][1,4]diazepine-3,9-diones and benzo[e]indolo[1,2-a]pyrido[2,1-c][1,4]diazepine-3,9-diones. Almost simultaneously, this group reported the use of o-aminobenzoic acids and oaminobenzamides as dinucleophiles to generate pyrrolo/pyrido[2,1-a][1,3]benzoxazinones and pyrrolo/pyrido [2,1-a]quinazolinones 2. After a screening of different Au(III) and Au(I) sources, the same catalyst system was employed, although, this time, in 1,2dichloroethane (DCE) was the solvent. It was confirmed not only that the reaction system was not sensitive to air and moisture at low catalyst loadings (1.5 mol%) but also that no silver salt or Brönsted acid (AgSbF6 or CF3COOH, respectively) was required to obtain optimal results or shorter reaction times. A similar mechanism was proposed for this transformation that took place at the same temperature (120 °C, Scheme 5) [56]. Scheme 4. Direct approach to benzo[e]indolo[1,2-a]pyrrolo[2,1-c][1,4]diazepine-3,9-diones and benzo[e]indolo[1,2-a]pyrido[2,1-c][1,4]diazepine-3,9-diones. Almost simultaneously, this group reported the use of o-aminobenzoic acids and o-aminobenzamides as dinucleophiles to generate pyrrolo/pyrido[2,1-a][1,3]benzoxazinones and pyrrolo/pyrido [2,1-a]quinazolinones 2 . After a screening of different Au(III) and Au(I) sources, the same catalyst system was employed, although, this time, in 1,2-dichloroethane (DCE) was the solvent. It was confirmed not only that the reaction system was not sensitive to air and moisture at low catalyst loadings (1.5 mol%) but also that no silver salt or Brönsted acid (AgSbF 6 or CF 3 COOH, respectively) was required to obtain optimal results or shorter reaction times. A similar mechanism was proposed for this transformation that took place at the same temperature (120 ◦C, Scheme 5) [56]. In 2011, another type of dinucleophiles, (2-aminophenyl)(1H-indol-1-yl)methanone derivatives 3 , was reacted with pentynoic, hexynoic and 2-propargyloxyethanoic acids. In this case, [Au{P(t-Bu) 2 (o-biphenyl)}{CH 3 CN}]SbF 6 was combined with AgSbF 6 for optimal results in toluene as a solvent, thus obtaining benzo[e]indolo[1,2-a]pyrrolo[2,1c][1,4]diazepine-3,9-diones and benzo[e]indolo[1,2-a]pyrido[2,1-c][1,4]diazepine-3,9-diones 4 with good yields. In order to prove the proposed mechanism, the authors reacted alfaangelica lactone 5 (5-methyl-2(3H)-furanone) with dinucleophile 3 under the optimized reaction conditions, and the corresponding benzo[e]indolo[1,2-a]pyrrolo[2,1-c][1,4]diazepine3,9-dione 4a was obtained in 90% yield [57] (Scheme 6). Catalysts 2023,13, 495 6 of 20 Catalysts 2023, 13, x 6 of 22 Scheme 5. Anthranilic acids and o-aminobenzamides as dinucleophiles for the gold-catalyzed cascade reaction with alkynoic acids. In 2011, another type of dinucleophiles, (2-aminophenyl)(1H-indol-1-yl)methanone derivatives 3, was reacted with pentynoic, hexynoic and 2-propargyloxyethanoic acids. In this case, [Au{P(t-Bu)2(o-biphenyl)}{CH3CN}]SbF6 was combined with AgSbF6 for optimal results in toluene as a solvent, thus obtaining benzo[e]indolo[1,2-a]pyrrolo[2,1-c][1,4]diazepine-3,9-diones and benzo[e]indolo[1,2-a]pyrido[2,1-c][1,4]diazepine-3,9-diones 4 with good yields. In order to prove the proposed mechanism, the authors reacted alfa-angelica lactone 5 (5-methyl-2(3H)-furanone) with dinucleophile 3 under the optimized reaction conditions, and the corresponding benzo[e]indolo[1,2-a]pyrrolo[2,1-c][1,4]diazepine-3,9dione 4a was obtained in 90% yield [57] (Scheme 6). Contemporaneously, Patil and col. reported the cascade reaction of alkynoic acids with phenylenediamines or o-aminobenzylamines in the presence of 1 mol% of Ph3PAuOTf catalyst. Considering the substitution at the aromatic ring of these nucleophiles, the excellent regioselectivity observed for the 37 triand tetracycles obtained was attributed to the difference in nucleophilicity between amino groups. When αor α,α′- substituted pentynoic acids were employed, the corresponding dihydrobenzimidazoles 6 and tetrahydroquinazolines 7 were obtained with good to excellent diastereomeric ratios (Figure 2), which was confirmed by NOE studies. In addition, the authors provided an alternative procedure based on microwave irradiation in the same solvent (1,2-dichloroethane), thus enhancing the reaction rate in comparison with conventional heating (30 min vs. 24 h). Finally, several mechanistic studies were conducted in order to shed light not only on the role of the Au(I) catalyst and the possible participation of Brönsted acid TfOH but also on the reason for the diastereoselectivity observed [58]. Scheme 5. Anthranilic acids and o-aminobenzamides as dinucleophiles for the gold-catalyzed cascade reaction with alkynoic acids. Catalysts 2023, 13, x 7 of 22 Scheme 6. Cascade reaction with aminophenyl)(1H-indol-1-yl)methanone derivatives. Figure 2. Diastereoselectivity observed in the cascade reactions with phenylenediamines or o-aminobenzylamines reported by Patil and col. Scheme 6. Cascade reaction with aminophenyl)(1H-indol-1-yl)methanone derivatives. Contemporaneously, Patil and col. reported the cascade reaction of alkynoic acids with phenylenediamines or o-aminobenzylamines in the presence of 1 mol% of Ph 3 PAuOTf catalyst. Considering the substitution at the aromatic ring of these nucleophiles, the excellent regioselectivity observed for the 37 triand tetracycles obtained was attributed to the difference in nucleophilicity between amino groups. When α - or α , α0 -substituted pentynoic acids were employed, the corresponding dihydrobenzimidazoles 6 and tetrahy- Catalysts 2023,13, 495 7 of 20 droquinazolines 7 were obtained with good to excellent diastereomeric ratios (Figure 2), which was confirmed by NOE studies. In addition, the authors provided an alternative procedure based on microwave irradiation in the same solvent (1,2-dichloroethane), thus enhancing the reaction rate in comparison with conventional heating (30 min vs. 24 h). Finally, several mechanistic studies were conducted in order to shed light not only on the role of the Au(I) catalyst and the possible participation of Brönsted acid TfOH but also on the reason for the diastereoselectivity observed [58]. Catalysts 2023, 13, x 7 of 22 Scheme 6. Cascade reaction with aminophenyl)(1H-indol-1-yl)methanone derivatives. Figure 2. Diastereoselectivity observed in the cascade reactions with phenylenediamines or o-aminobenzylamines reported by Patil and col. Figure 2. Diastereoselectivity observed in the cascade reactions with phenylenediamines or o-aminobenzylamines reported by Patil and col. In 2013, the same group expanded dramatically the scope and synthetic potential of this cascade reaction by reacting equimolecular amounts of 30 different dinucleophiles (scaffold-building agents) and 8 alkynoic acids in dichloroethane at 100 ◦ C for 24–36 h in the presence of the same Au(I) catalyst (Ph 3 PAuOTf, 5 mol%). As a result of this combination, a library of 61 polycyclic structures (Figure 3) were readily prepared. Indeed, this reaction was used as a basis for a catalytic branching cascade that generates a large scaffold diversity, and therefore implemented as a powerful strategy for diversity-oriented synthesis. It should be also pointed out that most reactions took place with good yields and complete chemoand regioselectivity [59]. In 2012, Liu’s group reported a more sustainable reaction media for the cascade between 4-pentynoic acid and 2-(1H-indol-1-yl)ethan-1-amine derivatives. The reaction was carried out in water using 10 mol% of chloro[(1,1 0 -bi-phenyl-2-yl)ditert-butylphosphine]gold(I) catalyst at 150 ◦ C under microwave irradiation, providing several tetrahydropyrrolopyrazino[1,2a]indolones with good yields (88–97%). However, when α -substituted pentynoic acids or 5-hexynoic acid or 3-(1H-indol-1-yl)propan-1-amine were employed as substrates or when electron-withdrawing groups were present in the 2-(1H-indol-1-yl)ethan-1-amine dinucleophile, a one-pot two-step procedure was required to prepare target tetracycles in Catalysts 2023,13, 495 8 of 20 good yields. Thus, after reacting in the presence of the above Au(I) catalyst, trifluoroacetic acid (1 equiv.) was added and microwave heating continued for a further 30 min [60]. Catalysts 2023, 13, x 9 of 22 N H N R R O R= H, _(CH2)4_ N H NO N H N OR R R= H, _(CH2)5N H N O R3 R2 R1 R1=H,Me R2=R 3=H,_(_CH=CH_)2 N N O () n n= 1, 2 N H RNO () n n= 1, 2 R= H, Br N N R2 R3R3 R1 O R1=H,CF 3 R2=H; R3=H,_(CH2)4_ R2=R 3=( _CH=CH_)2 N R1 NO R2R3 R1=H,Me R2=R 3=H, (_CH=CH_)2 N R O O O R= H, Me NN H R O R= H, Me N H N R O R= H, Me NNO NNO R1 R2 R1=R 2=H,_(_CH=CH_)2 NNO O O N R O R= H, OMe N NH R O S N RR O R= H, Me R= H, _(CH2)4_ O N R O R= H, Me O N O N N O N N R O N R= H, Me N R () n O O n= 0, 1 R= H, n-Hept N NH O R1 R2 R1 R2 R1=R 2=H,_(_CH=CH_)2 S N R O R= H, n-Hept S N O R1R1 R2 R1=H,_(CH2)4_ NNO R1R2R3 R4 R1=R 2=H,Me R3=R 4=H, _(_CH=CH_)2 N N R1 R2 O R1=R 2=H,_(_CH=CH_)2 NNO R1 R2 R1=R 2=H,_(_CH=CH_)2 N N N O R R= H, Me N N N O R R= H, Me N N NN N OR R R= H, _(CH2)4_ Figure 3. Library of compounds prepared by a relay catalytic branching cascade from alkynoic acids and dinucleophiles. Note: The moieties derived from alkynoic acids and dinucleophiles are depicted respectively in red and blue in the final products. Figure 3. Library of compounds prepared by a relay catalytic branching cascade from alkynoic acids and dinucleophiles. Note: The moieties derived from alkynoic acids and dinucleophiles are depicted respectively in red and blue in the final products. Catalysts 2023,13, 495 9 of 20 The same group reported the preparation of 31 benzo[4,5]imidazo[1,2-c]pyrrolo[1,2a]quinazolinones 8 by reacting 2-(1H-benzo[d]imidazol-2-yl)anilines with 4-pentynoic acids in the presence of 10 mol% of [Au{P(t-Bu) 2 (o-biphenyl)}{CH 3 CN}]SbF 6 and 20 mol% of AgBF 4 in toluene at 120–130 ◦ C. These optimized conditions were determined by testing a number of Au(I) and Ag catalysts, including AuCl(PPh 3 ), AgSbF 6 , and AgBF 4 , among others. Possible additive effects from the combination of cocatalysts (AgSbF 6 , AgBF 4 , AgO 2 CCF 3 , AgOTf, and trifluoroacetic acid) were also examined. The authors studied the influence of the substituents at both the benzoimidazole and aniline moieties in the reaction outcome. In this regard, they observed that the presence of electron-donating substituents such as methyl or methoxy at the aniline moiety, and specially at the ortho-position (R 4 substituent, Scheme 7) caused a substantial decrease in the reaction yield. A similar effect related to the presence of methyl or chloro groups at the benzimidazole moiety of the 2-(1H-benzo[d]imidazol-2-yl)aniline reagent was also observed (R 2 and R 3 substituents). A decreased yield could be attributed to a possible steric hindrance when using α -substituted 3-ethynylnonanoic acid was also accounted for. When the optimized protocol was applied to 5-hexynoic acid, the corresponding benzo[4,5]imidazo[1,2-c]pyrido[1,2-a]quinazolin6-ones 9 were obtained, albeit in lower yields than those from 4-pentynoic acid, even at slightly higher temperatures (130 ◦ C). The same decreasing effects related to the presence of R 2 -R 3 substituents at the benzimidazole moiety, and R 4 -R 6 at the aniline fragment of the 2-(1H-benzo[d]imidazol-2-yl)aniline N-aminonucleophile were noticed, with 5-hexynoic acid as the counterpart [61] (Scheme 7). Catalysts 2023, 13, x 10 of 22 Scheme 7. Cascade reaction with 2-(1H-benzo[d]imidazol-2-yl)aniline derivatives. Some years later, in 2019, this group described the first use of 1,3-unsubstituted 2- (1H-indol-2-yl)ethanamines as aminonucleophiles. Taking Au(PPh3)Cl as catalyst and an extensive number of dinucleophiles, they carried out the construction of a library of indole/pyrrole/thiophene/benzene/naphthalene/pyridine-based nitrogen-containing heterocyclic compounds with scaffold diversity (more than 78 examples were prepared). However, in many cases, it was necessary to perform a one-or two-step procedure which involved the addition of trifluroacetic acid and heating in the second step (1. Au(PPh3)Cl (5 mol%), DCE, 120–140 °C, 20–24 h; 2. CF3COOH (1 equiv.), 120–140 °C, 20–24 h). Several additional experiments (Scheme 8) showed not only the participation enol lactone intermediates but also that the gold catalyst is responsible for the formation of enol lactone intermediate and for the iminium ion formation. In addition, a 90% yield was obtained from the reaction between 2-(1H-indol-2-yl)ethanamine and 4-pentynoic acid on a gram scale. A simple carbonyl group reduction with LiAlH4-AlCl3 of some the compounds of the above library provided several α1A-adrenoceptor antagonists. In addition, after a pharmacological screening of the compounds directly accessed through the cascade reaction, the authors reported the antiproliferative activities against human cancer cell lines of two compounds, a tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione and a tetrahydroindolo[3′,2′:3,4]pyrido[2,1-a]isoquinolin-6(5H)-one [62]. Following their research on such cascade reactions in water [60], Liu and Zhao’s group also disclosed a more efficient method based on the same Au(I) catalyst (1 mol%) and Bronsted acid for reactions performed in water as the only solvent. More than 70 compounds were prepared under these conditions, with yields ranging 18–96%. As in previous cases, depending on the substrates involved, an Au(I)-catalyzed genuine cascade or a one-pot two-step tandem reaction was required to access target compounds. The authors also conducted deuteration and 18O labeling experiments for mechanistic purposes, and some of the obtained tetraand pentacycles were derivatized by reducing the amide carbonyl group with LiAlH4/AlCl3 [63]. Scheme 7. Cascade reaction with 2-(1H-benzo[d]imidazol-2-yl)aniline derivatives. Some years later, in 2019, this group described the first use of 1,3-unsubstituted 2- (1H-indol-2-yl)ethanamines as aminonucleophiles. Taking Au(PPh 3 )Cl as catalyst and an extensive number of dinucleophiles, they carried out the construction of a library of indole/pyrrole/thiophene/benzene/naphthalene/pyridine-based nitrogen-containing heterocyclic compounds with scaffold diversity (more than 78 examples were prepared). However, in many cases, it was necessary to perform a one-or two-step procedure which involved the addition of trifluroacetic acid and heating in the second step (1. Au(PPh 3 )Cl (5 mol%), DCE, 120–140 ◦ C, 20–24 h; 2. CF 3 COOH (1 equiv.), 120–140 ◦ C, 20–24 h). Several additional experiments (Scheme 8) showed not only the participation enol lactone intermediates but also that the gold catalyst is responsible for the formation of enol lactone intermediate and for the iminium ion formation. In addition, a 90% yield was obtained from the reaction between 2-(1H-indol-2-yl)ethanamine and 4-pentynoic acid on a gram scale. A simple carbonyl group reduction with LiAlH 4 -AlCl 3 of some the compounds of the above library provided several α1A -adrenoceptor antagonists. In addition, after a pharmacological screening of the compounds directly accessed through the cascade reaction, the authors reported the antiproliferative activities against human cancer cell lines of two compounds, Catalysts 2023,13, 495 16 of 20 In order to determine the role of the catalysts in this cascade reaction, the authors carried out a series of experiments. 5-Methylenedihydrofuran-2(3H)-one was easily prepared by reacting 4-pentynoic acid with the above NNC complex (10 −2 mol%) and triethylamine (2 mol%) in dichloromethane at room temperature and then treated with anthranilic acid under the optimized reaction conditions to provide target benzo[d]pyrrolo[2,1-b][1,3]oxazine1,5(2H)-dione 18 in 90% yield. The kinetic plot of the conversion of anthranilic acid vs. time showed neither sigmoidal shape nor induction time, and when the reaction was performed in the presence of several poisoning agents (mercury drop test, carbon disulfide and polyvinylpyridine, among others), no inhibition was observed, thus suggesting the participation of truly homogeneous catalytic species in the reaction. The absence of palladium nanoparticles, as determined by TEM-EDX analysis of the reaction mixture, provided additional proof to confirm the hypothesis of homogeneous catalysis. Moreover, some key intermediates were detected by UPLC-MS of the reaction mixture. Accordingly, a more nuanced mechanism describing the role of the metal species and transient intermediates detected by UPLC-ESI was also proposed [ 79 ] (Figure 4). These results are in accordance with several examples of bimetallic co-catalysis, including the aforementioned reports on the gold-silver co-catalyzed cascade reactions (Sections 2.2 and 2.3, Schemes 3,6and 7) [53,57,61] and other accounts on metal-metal synergistic effects and metal–ligand cooperation [80–82]. Catalysts 2023, 13, x 17 of 22 anthranilic acid vs. time showed neither sigmoidal shape nor induction time, and when the reaction was performed in the presence of several poisoning agents (mercury drop test, carbon disulfide and polyvinylpyridine, among others), no inhibition was observed, thus suggesting the participation of truly homogeneous catalytic species in the reaction. The absence of palladium nanoparticles, as determined by TEM-EDX analysis of the reaction mixture, provided additional proof to confirm the hypothesis of homogeneous catalysis. Moreover, some key intermediates were detected by UPLC-MS of the reaction mixture. Accordingly, a more nuanced mechanism describing the role of the metal species and transient intermediates detected by UPLC-ESI was also proposed [79] (Figure 4). These results are in accordance with several examples of bimetallic co-catalysis, including the aforementioned reports on the gold-silver co-catalyzed cascade reactions (Sections 2.2 and 2.3, Schemes 3, 6 and 7) [53,57,61] and other accounts on metal-metal synergistic effects and metal–ligand cooperation [80–82]. Figure 4. Proposed catalytic pathway for the cascade reaction performed in the presence of a palladium pincer complex and iron(II) bromide. 7. Conclusions and Outlook In the presence of several dinucleophiles, a carbophilic metal-catalyzed intramolecular hydrocarboxylation of alkynoic acids triggers a cascade reaction that generates relatively complex polycyclic structures. The increasing number of acetylenic acids and dinucleophiles (C-, N-, Oand S-aminonucleophiles) that can serve as substrates have greatly extended the scope of this multi-step process so that a large library of valuable nitrogencontaining heterocyclic compounds can be easily prepared from commercially or readily available substrates or reagents. Regarding the catalyst required for these transformations, although gold(I) complexes either alone or along with Ag(I) salts or Brönsted acid (trifluroacetic acid) have dominated the field and demonstrated a superior performance and substrate scope, other competitors based on copper(II) salts in ionic liquids, ruthenium carbenes, palladium(II) complexes and iron salts have appeared in recent years. These alternative candidates show an excellent catalyst profile, but, with the exception of ruthenium carbenes, they appear to be unable to promote the reaction with C-aminonucleophiles, thus limiting the reaction scope to N-, Oor S-aminonucleophiles. It is certainly difficult to compare all these catalytic profiles if, in addition to the substrate scope, efficiency and economic value are also considered. Indeed, typical catalyst loading ranges from 1 to 20 mol% for Au, Figure 4. Proposed catalytic pathway for the cascade reaction performed in the presence of a palladium pincer complex and iron(II) bromide. 7. Conclusions and Outlook In the presence of several dinucleophiles, a carbophilic metal-catalyzed intramolecular hydrocarboxylation of alkynoic acids triggers a cascade reaction that generates relatively complex polycyclic structures. The increasing number of acetylenic acids and dinucleophiles (C-, N-, Oand S-aminonucleophiles) that can serve as substrates have greatly extended the scope of this multi-step process so that a large library of valuable nitrogencontaining heterocyclic compounds can be easily prepared from commercially or readily available substrates or reagents. Regarding the catalyst required for these transformations, although gold(I) complexes either alone or along with Ag(I) salts or Brönsted acid (trifluroacetic acid) have dominated the field and demonstrated a superior performance and substrate scope, other competitors based on copper(II) salts in ionic liquids, ruthenium carbenes, palladium(II) complexes and iron salts have appeared in recent years. These alter- Catalysts 2023,13, 495 17 of 20 native candidates show an excellent catalyst profile, but, with the exception of ruthenium carbenes, they appear to be unable to promote the reaction with C-aminonucleophiles, thus limiting the reaction scope to N-, Oor S-aminonucleophiles. It is certainly difficult to compare all these catalytic profiles if, in addition to the substrate scope, efficiency and economic value are also considered. Indeed, typical catalyst loading ranges from 1 to 20 mol% for Au, Ag, Cu, Ru and Fe catalysts, although the use of a PCN palladium complex along with FeBr 2 allowed a much higher substrate/catalyst ratio (10,000:1). Iron, an abundant and less toxic first row transition metal, can also catalyze the reaction although with the substrate limitations noted above. The high economic value of Au, Ag, Ru and Pd precious metal catalysts cannot be underestimated, although this issue should be examined in view of the amount of catalyst required (e.g., the economic cost of 20 mol% of a silver catalyst is much higher than that of a 10 −2 mol% of a palladium complex). As for reaction media, toluene is by far the solvent of choice in many of the transformations described, even if greener alternatives such as water, ionic liquids and solventless reactions have been described. Conventional heating is almost ubiquitous in all the reports, although microwave irradiation has been also reported. Exhaustive mechanistic studies carried out for many of the catalyst systems reported have led to the identification of several intermediates of the reaction (the alkylidene lactone generated from the initial cycloisomerization step, the ketoamide produced as a result of the subsequent aminolysis and the N-acyliminium ion prior to the attack by the second nucleophilic group of the aminonucleophile). In addition, such experiments have aided to define the role of the catalyst and the additives employed. In most cases, metal catalyst is essential for the initial intramolecular alkyne hydrocarboxylation (sometimes helped by substoichiometric amounts of a base-like triethylamine or pyridine) and provides, alone or with the help of certain silver or Brönsted acid additives, the activation required for the second stage of the cascade. We foresee the development of new catalyst systems for this synthetically powerful reaction in the coming years. Such future catalysts will probably overcome the described limitations and will provide more sustainable protocols for a cascade reaction that offers straightforward access to a whole array of polyheterocyclic compounds, some of them showing remarkable biological activity. Author Contributions: Co-authors G.U., J.D.d.S., N.C. and A.H. contributed to searching and collating of the relevant literature and the proofreading of the document. Co-author M.T.H. and corresponding author R.S. wrote the body of the article. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Basque Government (IT1583-22) and the Spanish Ministry of Economy and Competitiveness (CTQ2017-86630-P). Acknowledgments: Technical and human support provided by SGIker of UPV/EHU are gratefully acknowledged. Conflicts of Interest: The authors declare no conflict of interest. References 1. Nicolaou, K.C.; Chen, J.S. 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