Pictet–Spengler-Based Multicomponent Domino Reactions to Construct Polyheterocycles

Abstract

The Pictet–Spengler reaction is one of the important methodological arsenals in synthetic and medicinal chemistry, acting as an amenable tool for preparing tetrahydroisoquinoline, tetrahydro-β-carbolines, polycyclic skeletons, and value-added products. More than 100 years after its initial discovery, the Pictet–Spengler reaction's response has not withdrawn from the stage, but it has once again become the focus of attention with new features. The review summarizes recent advances in Pictet–Spengler-based multicomponent reactions from 2007 to 2022, including three-component and four-component Pictet–Spengler cyclization reactions in the presence of metal catalysts, organocatalysts, biological enzyme catalysts, and so on. These Pictet–Spengler-based multicomponent protocols provide an atom-/step economic approach for the synthesis of a library of new chemical entities.

Keywords

Pictet–Spengler reaction - multicomponent reactions - domino reactions - cyclization - heterocycles

Introduction

The Pictet–Spengler reaction, discovered in 1911 by Amé Pickett and Theodore Spengler, is originally a cyclization of a phenethylamine 1 and a formaldehyde dimethyl acetal 2 to produce 1,2,3,4-tetrahydroisoquinoline 3 in the presence of hydrochloric acid ([Scheme 1]).[1] After that, a variety of modified reaction systems for the Pictet–Spengler reaction have been developed for the construction of valuable heterocyclic scaffolds,[2] such as Brønsted acids,[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] Lewis acids,[39] [40] [41] transition metal catalysts,[42] [43] [44] [45] [46] organocatalysts,[26] [27] [47] [48] and enzyme strictosidine synthases.[13] [49] Meanwhile, the use of suitably substituted amine derivatives such as β-arylethylamines, tryptamines, or functionalized aromatic amines with an aldehyde or ketone is essential for the progress of the Pictet–Spengler reaction.[50] Furthermore, the post-Pictet–Spengler cyclization strategy has been extensively employed in the preparation of stereochemically and structurally complex polycyclic heterocycles which have been found to exhibit significant biological activities.[51] [52] [53] [54]

Scheme 1 The Pictet–Spengler reaction.

In addition, the development of synthetic platforms to prepare compounds with minimum effort and exceptional synthetic efficiency is crucial for the discovery of new bioactive molecules. In this context, multicomponent reactions that significantly reduce the step of synthetic operations and diminish the generation of waste provide an alternative method to give complex and diverse products.[55] [56] [57] [58] Over the past decades, great effort has been devoted to the design and development of multicomponent reactions, in particular in the field of the synthesis of heterocycles.[59] [60] [61] [62] Although there are many literature reviews involving multicomponent reactions and Pictet–Spengler reactions,[63] the use of Pictet–Spengler cyclization-based multicomponent reactions in the generation of poly-heterocycles has rarely been touched in previous reviews.

In 2020, Calcaterra and coworkers published a review on the construction of polycyclic β-carboline-derived natural products and bioactive N-heterocycles using post-Pictet–Spengler cyclization strategies.[64] [65] [66] [67] Considering significant progress of Pictet–Spengler cyclization-based multicomponent reactions has been made and still no related review has been documented, this review is devoted to a discussion of this research area, covering mainly the literature from 2007 to 2022, and is divided into two categories: three-component and four-component Pictet–Spengler cyclization-based domino reactions including the Brønsted acid and Lewis acid-promoted, transition metal-catalyzed and organo-catalyzed methodologies.

Three-Component Pictet–Spengler Cyclization-Based Domino Reactions

As known, the classic Pictet–Spengler reaction involving two-component cyclization is not beneficial for the exploration of the chemical space of target products. The combination of the Pictet–Spengler reaction with the multicomponent reaction has been proven to be an economic and practical approach for the construction of highly complex and diverse scaffolds in a single operation. For example, in 2010, Znabet and coworkers demonstrated the domino Ugi-type multicomponent reaction/Pictet–Spengler cyclization strategy using a bridged imine 4, a phenylglyoxylic acid 5, and an isonitrile 6 for the construction of alkaloid-like polycyclic compound 7 ([Scheme 2]).[68] In the reaction, the Ugi-type adduct was first formed in dichloromethane at room temperature for 48 hours, then the mixture reacted at 10°C for 16 hours under trimethylsilyl fluorosulfonic acid conditions to obtain the desired product in good yield.

Scheme 2 Ugi-type/Pictet–Spengler-type cyclization sequence.

In 2011, Wang and coworkers developed an alternative approach to access polycyclic compounds through a concise two-step procedure including an Ugi-type reaction and subsequent Pictet–Spengler reaction ([Scheme 3]).[69] The first step was the Ugi-type reaction of phenylethylamine-derived isonitriles 8, aminoacetaldehyde dimethyl acetal 9, and a suitable bifunctional oxocarboxylic acid 10, followed by the Pictet–Spengler reaction in the presence of formic acid at room temperature or methanesulfonic acid at 70°C.

Scheme 3 Ugi-type/Pictet–Spengler sequence to polycyclic compounds.

Recently, Alonso et al also used formic acid as a catalyst to promote the three-component domino Ugi-type/Pictet–Spengler reaction.[70] As shown in [Scheme 4], the steroidal pyrazinoisoquinolines 15 were obtained from cholesterol-based oxalic acid 12, 2,2-diethoxyethylamine 13, and 3-(2-isocyanatoethyl)-1H-indole 14 by applying a synthetic sequence comprising the Ugi reaction followed by a Pictet–Spengler cyclization using formic acid at reflux conditions to generate the compound 15.

Scheme 4 Sequential Ugi-type/Pictet–Spengler reaction.

Furthermore, Kundu's group described a one-pot method for the synthesis of benzazepino-indoles from indoles 16, 2-aminobenzyl alcohols 17, and benzaldehydes 18 ([Scheme 5]).[71] In this reaction, alkylation and subsequent Pictet–Spengler reaction in trifluoroacetic acid (TFA; 30 % in DCE) at 80°C afforded the target products 19 in moderate to good yields. Interestingly, when 2-alkynylbenzaldehydes were introduced, the product benzazepino-indole then underwent a second consecutive ring closure through intramolecular hydroamination to access indole-based annulated polyheterocycles.

Scheme 5 Tandem alkylation/Pictet–Spengler reaction.

In 2018, Yan's group reported a trifluoromethanesulfonic acid-promoted one-pot domino reaction of tryptamines 20, alkyl propionates 21, and 2-aryl-3-nitro-2H-chromenes 22, which can conveniently yield the functionalized tetrahydrochromeno [4',3′:2,3]indolizino [8,7-b]indoles 23 in high yields ([Scheme 6]).[72] Using nitroolefins instead of 2-aryl-3-nitro-2H-chromenes, the corresponding tetrahydroindolizino[8,7-b]indoles were obtained under similar conditions. In this one-pot three-step reaction, the domino process of double Michael addition, Pictet–Spengler reaction, and annulation was performed, which has the advantages of high atomic economy.

Scheme 6 One-pot double Michael addition/Pictet–Spengler/annulation.

In 2019, Ali et al reported a one-pot two-step approach for the generation of pyrrolo[1,2-a][1,4]benzodiazepines under mild conditions ([Scheme 7]).[73] First step of the reaction was that the 3-(3-formyl cycloalkenyl)-acrylate derivatives 24 were reacted with amino benzylamines 25 in methanol for 5 minutes to give pyrrole intermediates (up to 95% yield). Then, aldehydes or ketones 26 were added to the reaction system, and the desired products were obtained in 70 to 92% yields by acetic acid or TFA-promoted Pictet–Spengler cyclization. This method has several advantages, such as a very short time, step and atom economic, and environmentally benign.

Scheme 7 One-pot domino annulation/Pictet–Spengler reaction.

Subsequently in the year 2021, Peytam et al reported an efficient one-pot two-step reaction of tryptamine 28, arylglyoxal monohydrates 29, and acetylenic esters 30, which led to the formation of 18 dihydroindolizino[8,7-b]indole derivatives 31 with good to excellent yields ([Scheme 8]).[74] First, the TFA-promoted Pictet–Spengler cyclization of tryptamine and arylglyoxal monohydrates was conducted in chloroform for 1 hour to from an intermediate. Then, the 1,3-dipolar cycloaddition reaction of the intermediate with acetylenic esters afforded the target compounds, which were evaluated as new α-glucosidase inhibitors.

Scheme 8 One-pot two-step reaction to dihydroindolizino[8,7-b]indole derivatives.

Compared with a one-pot multi-step reaction, the multi-component one-step strategy has drawn widespread attention as it offers several advantages such as operational simplicity and convergent nature. In 2016, Cai and coworkers developed an acid-catalyzed, multi-component tandem reaction for the generation of polyfunctional dihydroindolizino [8,7-b]indoles from an arylglyoxal monohydrate 32, a tryptamine 32, and a trans-β-nitrostyrene 33 or a malonitrile 34 under mild, metal-free conditions ([Scheme 9]).[75] This reaction was based on utilizing the trifluoromethanesulfonic acid (CF₃SO₃H) and TFA as a catalyst and the domino Pictet–Spengler cyclization/Michael addition/intramolecular cyclization and oxidative aromatization to obtain the desired products 36 and 37 in 62 to 72% yields and 72 to 85% yields, respectively.

Scheme 9 Acid-catalyzed multi-component tandem cyclization.

In 2020, Hu and coworkers discovered that using toluene as a solvent in the presence of TFA, the multi-component of a 2-phenylethanamine, formaldehyde, and a propiolic acid gave the bicyclic N-propargyl tetrahydroisoquinoline in moderate to good yields ([Scheme 10]).[32] Metal-free decarboxylative A³-coupling provided the propargylamine intermediate, followed by the Pictet–Spengler cyclization to access target products. Meanwhile, a set of N-propargyl thienotetrahydropyridine and benzodiazepine skeletons could be obtained using the same protocol.

Scheme 10 A³-Coupling/Pictet–Spengler cascade.

In 2021, González-Pelayo and coworkers accomplished the construction of a set of metallocene analogs of the relevant tetrahydroisoquinoline motif 45 by TfOH-catalyzed three-component reactions of 2-aryl-N-sulfonyl aziridines 42 with ferrocene (or ruthenocene) 43 and formaldehyde 44 ([Scheme 11]).[76] Initially, the amino-functionalized metallocene derivatives were formed from a regioselective ring opening of the aziridine. Later, an intermolecular Pictet–Spengler cyclization of the formed intermediate and formaldehyde led to target products.

Scheme 11 Ring opening of 2-aryl-N-sulfonyl aziridines.

In the aforementioned methods, strong acids were employed, and, in some cases, trifluoromethanesulfonic anhydride was available for such a multi-component Pictet–Spengler reaction. For example, in 2019, Magyar and coworkers reported the three-component tandem reaction of amides 48, aldehydes 46, and amines 47 in the presence of trifluoromethanesulfonic anhydride, providing the corresponding 3,4-dihydroquinazolines 49 in moderate to good yields ([Scheme 12a]).[77] The reaction was first performed in CH₂Cl₂ for 18 hours with a 4 Å molecular sieve under room temperature conditions, then treated with Tf₂O and 2-ClPyr for 24 hours at room temperature to afford the desired compounds by Pictet–Spengler-type cyclization. This report showed great advantages including the wide scope of the substrate to afford extensive diversity about the heterocyclic scaffold. The following year, Campbell et al documented a similar tandem assembly procedure for the generation of diverse C4-quaternary 3,4-dihydroquinazolines 51 using ketones 50 instead of aldehydes ([Scheme 12b]).[78] This one-pot cascade reaction, involving the Tf₂O-mediated amide dehydration/ketimine addition/Pictet–Spengler cyclization, produced the corresponding products in moderate to excellent yields.

Scheme 12 Trifluoromethanesulfonic-mediated three-component tandem procedure.

In addition to the Brønsted acid-promoted three-component domino Pictet–Spengler reaction, great advances in organocatalytic and Brønsted acid-promoted Pictet–Spengler reaction have been achieved. For example, in 2009, the group of Gong reported the first asymmetric three-component [4 + 2] cycloaddition reaction of aryl ethylamine 52, cinnamaldehydes 53, and azlactones 54 in the presence of the phosphoric acid catalyst and trifluoroborane, providing the benzo[a]quinolizidines in 65 to 76% yields with 90 to 97% ee ([Scheme 13]).[79] They found that the 3-aminopiperidinone intermediates could be smoothly generated from 52, 53, and 54 under the catalysis of 20 mol% of A. Treatment of these intermediates with BF₃·Et₂O resulted in the generation of target products by Pictet–Spengler-type cyclization reactions.

Scheme 13 Formal [4 + 2] cycloaddition involving Pictet–Spengler reaction.

In 2010, Wu et al reported a chiral amine-catalyzed and benzoic acid-promoted three-component reaction of a β-keto ester 56, an α,β-unsaturated aldehyde 57, and a tryptamine 58, affording the indoloquinolizidines 59 in one pot ([Scheme 14a]).[63] The reaction was first conducted with benzoic acid as an additive and toluene as a solvent at 10°C, then substrate 56 was added with 57, followed by the addition of 58 and stoichiometric benzoic acid. The mixture was reacted at 50°C for 24 hours to give 88 to 95% yields of products.

Scheme 14 Domino Michael addition/Pictet–Spengler reaction.

In the following year, Wu and coworkers explored the domino Michael addition/Pictet–Spengler reaction employing the same reaction systems ([Scheme 14b]).[64] Using propionates 60 instead of β-keto esters 56, a similar process was performed to access the indoloquinolizidine derivatives in moderate to good yields. In addition, the Xu's group described the domino Michael addition/Pictet–Spengler reaction of α-oxo-γ-butyrolactams 61, α,β-unsaturated aldehydes, and tryptamines, delivering the butyrolactam-fused indoloquinolizidine compounds in the presence of the same Jørgensen–Hayashi catalyst and benzoic acid ([Scheme 14c]).[80] These methods provided an efficient and novel synthetic route for the construction of indole-based alkaloids.

Besides using benzoic acid as a promotor, other Brønsted acids such as acetic acid and TFA were also disclosed with the combination of the organocatalyst. For example, in 2011, Rueping et al developed an asymmetric Michael addition of 1,3-dicarbonyl compounds 62 and α,β-unsaturated aldehydes 63, and subsequent diastereoselective Pictet–Spengler cyclization ([Scheme 15]).[81] Michael addition was performed in the presence of the Jørgensen–Hayashi catalyst, followed by the acetic acid-promoted Pictet–Spengler cyclization of tryptamine at 50°C, giving the corresponding products 65 in 68 to 85% yields.

Scheme 15 Domino Michael addition/acetic acid-promoted Pictet–Spengler reaction.

In 2013, Hong et al performed a one-pot organocatalytic enantioselective double-Michael addition/Pictet–Spengler-lactamization domino reaction ([Scheme 16]).[82] This reaction represents an atom-economical pathway to delivering dodecahydrobenz[a]indolo[3,2-h]quinolizines with five contiguous stereogenic centers. The process of the reaction is that the double Michael reaction of (E)-ethyl 6-nitrohex-2-enoate 66 and α,β-unsaturated aldehydes 67 in CH₂Cl₂ under mild ambient temperature conditions, followed by TFA-promoted Pictet–Spengler and lactamization with 2-(1H-indol-3-yl)ethanamine provided the “inside yohimbine” 69 in good yields with high enantioselectivities.

Scheme 16 Domino double-Michael addition and Pictet–Spengler-lactamization reaction.

The three-component Pictet–Spengler reactions, only using the organocatalyst without any other acids, represent an alternative method. In this field, in 2014, Du et al reported the first organocatalytic multicomponent reaction for the synthesis of enantioenriched pyrrolopiperazines 73 through an enantioselective Michael addition/Pictet–Spengler cyclization sequence ([Scheme 17]).[83] In the reaction, various N-(2-aminoethyl)pyrroles 70, cinnamyl aldehydes 71, and β-keto esters 72 were evaluated in trifluorotoluene as a solvent at 0°C for 2 days, providing the desired products in 53 to 70% yields with excellent enantioselectivities.

Scheme 17 Organocatalytic Michael addition/Pictet–Spengler sequence.

In the same year, Dai et al discovered a three-component reaction of isatins 74, isatin-derived 3-indolylmethanols 75, and an amino ester 76 by chiral phosphoric acid-catalyzed cascade Michael addition/Pictet–Spengler cyclization, which was the first catalytic asymmetric multicomponent Pictet–Spengler reaction using chiral phosphoric acid A as a catalyst ([Scheme 18]).[84] Under the catalysis of A, the Michael addition of the in-situ-formed isatin-derived azomethine ylide from 75 and amino ester with 76 gave a transient intermediate. Subsequently, this intermediate underwent a Pictet–Spengler cyclization facilitated by the chiral phosphoric acid A to deliver the structurally complex and diverse bispirooxindoles 77 in excellent stereoselectivities.

Scheme 18 Chiral phosphoric acid-catalyzed asymmetric Michael addition/Pictet–Spengler sequence.

In 2018, Yu et al disclosed the total synthesis of strychnofoline from commercially available 6-methoxytryptamine 78. In the reaction, the first step was the generation of the quinolizidine derivative 81 ([Scheme 19]).[85] By sequential addition of 6-methoxytryptamine, diketene, acrolein derivative 80, and acyl chloride in the presence of the Jørgensen–Hayashi catalyst, 67% yield of product 81 was obtained by one-pot acylation/asymmetric Michael addition/Pictet–Spengler reaction.

Scheme 19 Application of domino Pictet–Spengler reaction to (−)-strychnofoline.

As known, the Pictet–Spengler reactions are generally realized by Brønsted acid or Lewis acid catalysis. In 2013, the group of Menéndez described a sequential multi-component reaction of tryptamines 82, α,β-unsaturated aldehydes 83, and β-dicarbonyl compounds 84 catalyzed by ammonium cerium nitrate (CAN), providing the indoloquinolizines 85 in good yields ([Scheme 20]).[86] The process of reaction involved the initial formation of an enamine from the tryptamines and β-dicarbonyl components, followed by Michael addition of α,β-unsaturated aldehyde and 6-exo-trig cyclization to form a vinylimide cation, then a Pictet–Spengler cyclization to access the target products.

Scheme 20 Michael addition/6-exo-trig cyclization/Pictet–Spengler reaction sequence.

In the same year, the group of Yan published a report on the construction of hexahydroindolo[2,3-a]quinolizine framework by utilizing a one-pot three-component reaction of tryptamines 86, propiolates 87, and α,β-unsaturated aldehydes 88 ([Scheme 21]).[87] The reaction involved the Michael addition of tryptamines and propiolates to generate β-enamino ester at room temperature, followed by the Pictet–Spengler reaction in the presence of anhydrous ZnCl₂, leading to the generation of desired products 89 in moderate to high yields and with high diastereoselectivity.

Scheme 21 Domino Michael addition and ZnCl₂-catalyzed Pictet–Spengler reaction.

In 2015, Xing et al reported a new Lewis acid-promoted three-component reaction of arenes 90, aziridines 91, and aldehydes 92, through a sequential ring opening of aziridine and Pictet–Spengler cyclization ([Scheme 22]).[88] This reaction provided a rapid and convergent approach for the synthesis of a library of cis-1,4-disubstituted tetrahydroisoquinolines 93 in 50 to 75% yields under mild conditions. Aziridines were treated with arenes in the presence of BF₃·OEt₂ to gain ring-opening adducts, followed by Pictet–Spengler cyclization with aldehydes to furnish desired tetrahydroisoquinoline derivatives.

Scheme 22 Lewis acid-promoted ring-opening/Pictet–Spengler sequence.

In 2020, Ghashghaei et al published an article in which the α-aminopyridines, indole 3-carbonaldehydes, and ethyl isocyanoacetate were reacted in the presence of Yb(OTf)₃ as a Lewis acid catalyst ([Scheme 23]).[89] This alternative method involved a cascade process of Groebke–Blackburn–Bienaymé reaction to form the fused adduct, acid-catalyzed Pictet–Spengler cyclization to obtain dihydropyridine, and oxidation by atmospheric O₂ to finally afford a series of polyheterocyclic compounds using acetonitrile as a solvent at 80°C in open air. Meanwhile, the processes can be performed in parallel and the products with fused, linked, and bridged scaffolds displayed remarkable bioactivity as potent ligands of the aryl hydrocarbon receptor.

Scheme 23 Extended Pictet–Spengler-based multi-component reaction.

On the other hand, following the Lewis acid-mediated Pictet–Spengler reactions, the combined Lewis acid and Brønsted acid catalysis systems were developed to explore the Pictet–Spengler-based multi-component reactions. In 2014, Zhu and coworkers applied ZnCl₂ and CF₃SO₃H in the three-component reaction of tryptamines 98, alkyl propiolates 99, and 3-phenacylideneoxindoles 100, providing a series of 6,11-dihydro-5H-indolizino[8,7-b]indoles 101 with high efficiency ([Scheme 24]).[90] First, the 2-pyrrolo-3′-yloxindole intermediate was obtained through a sequential formation of β-enamino ester and Michael addition in the presence of anhydrous ZnCl₂. Then, the 2-pyrrolo-3′-yloxindoles were converted to the corresponding products 101 by a CF₃SO₃H-catalyzed Pictet–Spengler cyclization process.

Scheme 24 One-pot sequential formation of β-enamino ester/Michael addition/Pictet–Spengler reaction.

In 2020, Wani and coworkers reported that the 1,4-disubstituted tetrahydro-β-carbolines and tetrahydropyrano[3,4-b]indoles 105 could be obtained in high yields and stereoselectivity by a simple and efficient method using indoles 102, aziridines or epoxides 103, and benzaldehydes 104 ([Scheme 25]).[91] In this report, LiClO₄-catalyzed ring opening of aziridines and epoxides with indoles was performed in acetonitrile at 85°C for 3 hours, followed by p-toluenesulfonic acid-catalyzed Pictet–Spengler cyclization with benzaldehydes. To improve the efficiency of the Pictet–Spengler cyclization, various reaction parameters were screened. The results showed that when using 20 mol% of p-toluenesulfonic acid as a catalyst in DCE at 50°C for 6 hours, 60 to 85% yields of the desired products were obtained.

Scheme 25 Domino ring-opening/Pictet–Spengler reaction.

In addition, Feng and coworkers reported a CuI/TFA catalysis system to catalyze the domino Pictet–Spengler reaction/A³-type coupling/1,5-hydride transfer/alkynylation in 2022 ([Scheme 26]).[92] The mechanism studies showed that TFA promoted the Pictet–Spengler reaction of 2-arylethan-1-amines 106 and formaldehyde to form tetrahydroisoquinolines, followed by a reaction with another molecule of formaldehyde to give iminium ion, then Cu-catalyzed intermolecular hydride transfer and alkynylation with two molecules of terminal alkyne 108 to deliver nitrogen-tethered 1,6-enynes 109 with high selectivity.

Scheme 26 Synthesis of nitrogen-tethered 1,6-enynes through CuI/TFA catalysis.

To make the three-component Pictet–Spengler reaction greener, in recent years, enzyme catalysis, Brønsted acid, and Lewis acid-free strategies have received considerable attention. For example, α-amylase activation catalysis is an alternative protocol for the generation of highly substituted indoquinolines 113, which was uncovered by He and coworkers in 2019 ([Scheme 27]).[93] The reaction using tryptamines 110, β-keto esters 111, and α,β-unsaturated aldehydes 112 as starting materials afforded a variety of products in moderate to good yields.

Scheme 27 Biocatalytic one-pot three-component Pictet–Spengler reaction.

In addition, the field of acid-free Pictet–Spengler cyclization was also dominated. In 2010, Ruijter and Orru found that a domino N-acyliminium Pictet–Spengler/Diels–Alder reaction of β-arylethylamine 114, cinnamaldehyde derivatives 115, and alkynyl chloride 116 afforded the polycyclic alkaloid-type compounds 117 in high yield ([Scheme 28]).[94] The first procedure of the reaction used HC(OMe)₃ and dichloromethane as a solvent at 0°C for 3 hours to obtain the Pictet–Spengler adducts in 72 to 85% yields, then toluene was added as a solvent under microwave irradiation, providing the corresponding products in good yields by intramolecular Diels–Alder reaction.

Scheme 28 Pictet–Spengler/Diels–Alder sequence.

In 2021, Deng et al reported the selective synthesis of benzothiophene-fused polycyclic and eight-membered N-heterocycles 122 and 121 via the Pictet–Spengler reaction under catalyst-free conditions, where the selectivity depended on the R₃-substituted group ([Scheme 29]).[95] Using thioisatin 118, bromoacetophenone 119, and a tryptamine 120, the benzothiophene-fused polycycles 121 were obtained in 61 to 79% yields. When the D-tryptophan methyl ester hydrochloride was used instead of tryptamine, the corresponding products were switched to benzothiophene-fused eight-membered polycyclic compounds 122 (60–78% yields).

Scheme 29 Catalyst-free strategy for Pictet–Spengler reaction.

Four-Component Pictet–Spengler Cyclization-Based Domino Reactions

Brønsted acids, Lewis acids, organocatalysts, and catalyst-free reaction systems have been well developed in the domino Pictet–Spengler reactions. In addition to the above-mentioned three-component Pictet–Spengler reactions, some researchers have investigated the four-component Pictet–Spengler reactions in the past decade. In the case of this field, domino Ugi/Pictet–Spengler cyclization reactions have reached impressive levels. For example, in 2007, Gageat and coworkers described a one-pot two-step Ugi 4-CR/Pictet–Spengler reaction of a primary amine 123, an aldehyde 124, an α-keto acid 126, and an isocyanide 125 ([Scheme 30]).[96] When the α-keto acid was added to the aldehyde, primary amine, and isocyanide in methanol, the Uig adduct was produced at room temperature for 2 hours. The reaction mixtures just evaporated the solvent, then treated with TFA to generate a tricyclic 2,5-diketopiperazine 127 through a Pictet–Spengler-type cyclization.

Scheme 30 New Ugi4-CR/Pictet–Spengler domino reaction.

Similarly, Lesma and coworkers later reported a one-pot two-step reaction of isocyanide 128, N-protected 2-aminoacetaldehyde 129, functionalized amine 131, and acetic acid for the synthesis of tryptophan-derived peptidomimetics 132 by an Ugi 4-CR/Pictet–Spengler reaction sequence ([Scheme 31a])[97] The first step: Ugi 4-CR was performed in methanol as a solvent at room temperature for 24 hours. The second step: the Pictet–Spengler reaction was performed at 60°C for 30 minutes in the presence of HCOOH, giving the final products. It was important to note that N-protected 2-aminoacetaldehyde was for the first time used as the carbonyl component in the Ugi 4-CR.

Scheme 31 Ugi 4-CR/Pictet–Spengler reaction sequence.

In addition, Liu and coworkers described an Ugi 4-CR followed by the Pictet–Spengler reaction in a one-pot two-step procedure ([Scheme 31b]).[98] This reaction gave a series of tetrahydroisoquinoline drug praziquantel derivatives 137 in moderate to good yields from isocyanides with aromatic group 133, aldehydes 135, amines 136, and carboxylic acids 134 using DCE as a solvent at 80°C in the presence of MsOH.

Diversity-oriented syntheses of N-fused polycyclic heterocycles were reported by Tyagi and coworkers in 2012.[99] They developed a new protocol for the construction of two kinds of polycyclic skeletons by an Ugi-type reaction followed by a tandem Pictet–Spengler reaction or copper-catalyzed coupling reaction. Taking the domino Ugi-type/Pictet–Spengler reaction as an example, first, the Ugi-type reaction of aldehydes 138, isonitriles 139, and 2-amino aromatic heterocycles 140 was performed in methanol in the presence of PTSA. Then 50% TFA in DCE and another aromatic aldehyde were added and the desired products 142 were obtained in good yields by tandem Pictet–Spengler reaction [Scheme 32].

Scheme 32 Sequence of Ugi-type and Pictet–Spengler reaction.

In 2013, Sinha and coworkers developed the shortest scalable synthesis of the schistosomiasis drug praziquantel 147 through an Ugi 4-CR/Pictet–Spengler sequence ([Scheme 33]).[100] In this reaction, an α-amino acid 144, a ketone 146, an isocyanide 143, and an aminoacetaldehyde dimethyl acetal 145 were introduced for the first step to give the Ugi 4-CR adduct in MeOH/H₂O (4:1) at room temperature. Then concentrated formic acid was added and the mixture was stirred at room temperature for 16 hours, providing the corresponding Pictet–Spengler cyclization products in good to acceptable yields. In general, the reaction is compatible with many functional groups and different fragments.

Scheme 33 New Ugi variation and Pictet–Spengler reaction in one pot.

Very recently, Zhang et al found that the privileged scaffold dihydropyrrolo[1,2-a]pyrazine-dione 152 could be constructed by an Ugi 4-CR and Pictet–Spengler reaction sequence ([Scheme 34]).[101] Taking isonitriles 148, aldehydes 149, 2,2-dimethoxyethane-1-amines 150, and 3-bromopropanoic acid 151 as starting materials in the presence of methanol, the Ugi 4-CR adducts were produced at room temperature. Posttransformation of Ugi 4-CR adducts led to novel fused tricyclic systems under different acidic conditions. This approach also gave the alkaloid-type polycyclic scaffold with potential bioactivity.

Scheme 34 Highly stereoselective Ugi 4-CR/Pictet–Spengler sequence.

A combined Brønsted acid and Lewis acid catalysis system has been proven to be an effective tool for domino Ugi 4-CR/Pictet–Spengler reactions. In 2011 Cano-Herrera and coworker applied a sequential Ugi 4-CR/Pictet–Spengler/reductive methylation reaction protocol for the synthesis of a piperazinohydroisoquinoline ring system ([Scheme 35]).[102] They employed N-Boc amino acids 156 for the InCl₃-promoted Ugi reaction of aldehydes 153, 2,2-dimethoxyethane-1-amines 154, and isonitriles 155, followed by an N-Boc-deprotection process and iminium formation. The iminium intermediate then afforded the desired products 157 via the Pictet–Spengler reaction and reductive N-methylation in the presence of formic acid. All these processes were performed in the same reaction flask.

Scheme 35 Sequential Ugi/Pictet–Spengler/reductive methylation reaction.

In addition, an organocatalytic TsOH-promoted cascade reaction of aliphatic aldehydes 159 and 158, nitroethylenes 161, and tryptamine 160 was reported by Tan et al in 2014 ([Scheme 36]).[103] This one-pot two-step reaction involved Michael addition, aza-Henry reaction, hemiaminalization, and dehydration sequence in the presence of the Jørgensen–Hayashi catalyst at 0°C or room temperature for 12 hours, followed by TsOH-promoted Pictet–Spengler cyclization to afford the indoloquinolizidine derivatives 162 in 30 to 55% overall yields with excellent d.r. (>20:1 in all cases) and ee (91–98%) at room temperature for 4 hours.

Scheme 36 Organocatalytic TsOH-promoted cascade reaction.

In 2019, the group of Kumbhare reported a novel one-pot four-component cyclization reaction for constructing dihydroindolizino[8,7-b]indoles 167 from ninhydrin 163, tryptamine 164, dimetylene acetylene dicarboxylates 165, and aliphatic alcohols 166 in the presence of TFA ([Scheme 37]).[104] In this reaction, the tandem Pictet–Spengler cyclization reaction and construction of C–C and C–N bonds could be produced under transition metal-free conditions at 120°C for 14 hours, finally providing the desired fused-indole derivatives in good yields.

Scheme 37 Acid-catalyzed four-component tandem double cyclizations.

Conclusion and Prospects

In the nearly two decades since the centenary of the Pictet–Spengler cyclization, a pile of chaotic papers has proved that the reaction has not withdrawn from the historical stage, but has once again attracted attention with new characteristics. In this review, we have highlighted the recent developments in multi-component Pictet–Spengler-based reactions including the three-component and four-component reactions. These reactions represent the most useful tool for the efficient and straightforward construction of polyheterocycles from readily available starting materials, such as tetrahydroisoquinolines, quinoline-indole derivatives, tetrahydro-β-carbolines, and so on. In addition to the importance of Brønsted acid in this field, researchers have widely explored several other catalysis systems such as Lewis acid, organocatalysts, combined Lewis acid and Brønsted acid, and synergistic organocatalyst and Brønsted acid. The major advantage of these reactions is that the complex and diverse molecular structures can be easy to obtain with a wide scope, modularity, high atom economy, good scalability, and high yields. Although multi-component Pictet–Spengler-based reactions have become a useful tool for obtaining complex scaffolds and new chemical entities in one pot, the extension of the Pictet–Spengler cyclization to more diverse domino reactions and the application of other types of organocatalysts are expected to be developed.

Conflict of Interest

None declared.

Acknowledgments

We gratefully acknowledge the National Natural Science Foundation of China (Grant No: 22078192) and the Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Noncoding RNA for financial support.

• References

• 1 Pictet A, Spengler T. Über die bildung von isochinolin-derivaten durch einwirkung von methylal auf phenyl-äthylamin, phenyl-alanin und tyrosin. Ber Dtsch Chem Ges 1911; 44: 2030-2036
• 2 Maity P, Adhikari D, Jana AK. An overview on synthetic entries to tetrahydro-β-carbolines. Tetrahedron 2019; 75 (08) 965-1028
• 3 Hanyu M, Takada Y, Hashimoto H, Kawamura K, Zhang MR, Fukumura T. Carbon-11 radiolabeling of an oligopeptide containing tryptophan hydrochloride via a Pictet-Spengler reaction using carbon-11 formaldehyde. J Pept Sci 2013; 19 (10) 663-668
• 4 Mazzeo G, Longhi G, Abbate S. et al. Solvent-free, uncatalyzed asymmetric “ene” reactions of N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines: a general approach to enantiomerically pure α-(trifluoromethyl)tryptamines. Org Biomol Chem 2017; 15 (18) 3930-3937
• 5 Du H, Tian S, Chen J, Gu H, Li N, Wang J. Synthesis and biological evaluation of N(9)-substituted harmine derivatives as potential anticancer agents. Bioorg Med Chem Lett 2016; 26 (16) 4015-4019
• 6 Megyesi R, Mándi A, Kurtán T. et al. Dynamic kinetic resolution of ethyl 1,2,3,4-tetrahydro-β-carboline-1-carboxylate: use of different hydrolases for stereocomplementary processes. Eur J Org Chem 2017; 2017 (32) 4713-4718
• 7 Kumar D, Vaya D, Chundawat TS. Total synthesis of 6-hydroxymetatacarboline-d discovered from mycena metata via the Pictet-Spengler reaction followed by the Horner-Wadsworth-Emmons reaction. ACS Omega 2021; 6 (13) 8933-8941
• 8 Liu J, Jiang X, Zhao M. et al. A class of 3S-2-aminoacyltetrahydro-β-carboline-3-carboxylic acids: their facile synthesis, inhibition for platelet activation, and high in vivo anti-thrombotic potency. J Med Chem 2010; 53 (08) 3106-3116
• 9 Liu Y, Song H, Huang Y. et al. Design, synthesis, and antiviral, fungicidal, and insecticidal activities of tetrahydro-β-carboline-3-carbohydrazide derivatives. J Agric Food Chem 2014; 62 (41) 9987-9999
• 10 Bi W, Bi Y, Gao X. et al. Indole-TEMPO conjugates alleviate ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function. Bioorg Med Chem 2017; 25 (09) 2545-2568
• 11 Sasaki T, Li W, Ohmoto T, Koike K. Evaluation of canthinone alkaloids as cerebral protective agents. Bioorg Med Chem Lett 2016; 26 (20) 4992-4995
• 12 Murai K, Kobayashi T, Miyoshi M, Fujioka H. Oxidative rearrangement of secondary amines using hypervalent iodine (III) reagent. Org Lett 2018; 20 (08) 2333-2337
• 13 Dalpozzo R. The chiral pool in the Pictet-Spengler reaction for the synthesis of β-Carbolines. Molecules 2016; 21 (06) 699-717
• 14 Klausen RS, Jacobsen EN. Weak Brønsted acid-thiourea co-catalysis: enantioselective, catalytic protio-Pictet-Spengler reactions. Org Lett 2009; 11 (04) 887-890
• 15 Li L, Aibibula P, Jia Q, Jia Y. Total syntheses of naucleamides A-C and E, geissoschizine, geissoschizol, (E)-isositsirikine, and 16-epi-(E)-isositsirikine. Org Lett 2017; 19 (10) 2642-2645
• 16 Rao RS, Ramanathan CR. Brønsted acid-mediated cyclization-dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines. Beilstein J Org Chem 2017; 13 (01) 428-440
• 17 Yin Q, Wang SG, You SL. Asymmetric synthesis of tetrahydro-β-carbolines via chiral phosphoric acid catalyzed transfer hydrogenation reaction. Org Lett 2013; 15 (11) 2688-2691
• 18 Lu X, Pan X, Yang Y. et al. Synthesis and cytotoxicity of a novel series of saframycin-ecteinascidin analogs containing tetrahydro-β-carboline moieties. Eur J Med Chem 2017; 135: 260-269
• 19 Singh D, Kumar V, Devi N. et al. Metal-free decarboxylative amination: an alternative approach towards regioselective synthesis of β-Carboline N-fused imidazoles. Adv Synth Catal 2017; 359 (07) 1213-1226
• 20 Ashok P, Chander S, Chow LMC. et al. Synthesis and in-vitro anti-leishmanial activity of (4-arylpiperazin-1-yl)(1-(thiophen-2-yl)-9H-pyrido[3,4-b]indol-3-yl)methanone derivatives. Bioorg Chem 2017; 70: 100-106
• 21 Wang Q, Chai H, Yu Z. Acceptorless dehydrogenation of N-heterocycles and secondary alcohols by Ru (II)-NNC complexes bearing a pyrazoyl-indolyl-pyridine ligand. Organometallics 2018; 37 (04) 584-591
• 22 Bathula C, Roma-Rodrigues C, Chauhan J. et al. Synthesis of tetrahydro-1 H-indolo [2,3-b] pyrrolo [3,2-c] quinolones via intramolecular oxidative ring rearrangement of tetrahydro-β-carbolines and their biological evaluation. New J Chem 2018; 42 (08) 6538-6547
• 23 Pingaew R, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V. Synthesis, cytotoxicity and QSAR study of N-tosyl-1,2,3,4-tetrahydroisoquinoline derivatives. Arch Pharm Res 2013; 36 (09) 1066-1077
• 24 Gholamzadeh P. Chapter Three - The Pictet-Spengler reaction: a powerful strategy for the synthesis of heterocycles. Adv Heterocycl Chem 2019; 127: 153-226
• 25 Voznesenskaia NG, Shmatova OI, Nenajdenko VG. Pictet-Spengler synthesis of perfluoroalkylated tetrahydro-γ-carbolines and tetrahydropyrrolopyrazines. Synthesis 2020; 52 (02) 263-272
• 26 Dou Y, Kouklovsky C, Vincent G. Bioinspired divergent oxidative cyclization from strictosidine and vincoside derivatives: second-generation total synthesis of (-)-cymoside and access to an original hexacyclic-fused furo [3,2-b] indoline. Chemistry 2020; 26 (71) 17190-17194
• 27 Anthony SM, Tona V, Zou Y. et al. Total synthesis of (-)-strictosidine and interception of aryne natural product derivatives “strictosidyne” and “strictosamidyne”. J Am Chem Soc 2021; 143 (19) 7471-7479
• 28 Kondo M, Matsuyama N, Aye TZ. et al. Practical stereoselective synthesis of C3-Spirooxindole and C2-Spiropseudoindoxyl-Pyrrolidines via organocatalyzed Pictet-Spengler reaction/oxidative rearrangement sequence. Adv Synth Catal 2021; 363 (10) 2648-2663
• 29 Andres R, Wang Q, Zhu J. Asymmetric total synthesis of (-)-arborisidine and (-)-19-epi-arborisidine enabled by a aatalytic enantioselective Pictet-Spengler reaction. J Am Chem Soc 2020; 142 (33) 14276-14285
• 30 Pu LY, Yang F, Chen JQ. et al. Enantioselective total synthesis of pentacyclic proaporphine alkaloid (-)-misramine. Adv Synth Catal 2021; 363 (03) 785-790
• 31 Sakamoto J, Umeda Y, Rakumitsu K, Sumimoto M, Ishikawa H. Total syntheses of (-)-strictosidine and related indole alkaloid glycosides. Angew Chem Int Ed Engl 2020; 59 (32) 13414-13422
• 32 Hu Y, Shen Y, Huang L. et al. Metal-free decarboxylative A³-coupling/Pictet-Spengler cascade accessing polycyclic scaffolds: propiolic acids exceed alkynes. Eur J Org Chem 2020; 2020 (11) 1695-1699
• 33 Ling Y, Jiang J, Wu B, Gao X. Serum triglyceride, high-density lipoprotein cholesterol, apolipoprotein B, and coronary heart disease in a Chinese population undergoing coronary angiography. J Clin Lipidol 2017; 11 (03) 646-656
• 34 Reddy KR, Brand D, Wijewardana C, Gao W. Temperature effects on cotton seedling emergence, growth, and development. Agron J 2017; 109 (04) 1379-1387
• 35 Kamal A, Sathish M, Prasanthi AVG. et al. An efficient one-pot decarboxylative aromatization of tetrahydro-β-carbolines by using N-chlorosuccinimide: total synthesis of norharmane, harmane and eudistomins. RSC Advances 2015; 5 (109) 90121-90126
• 36 Sattely ES, Meek SJ, Malcolmson SJ, Schrock RR, Hoveyda AH. Design and stereoselective preparation of a new class of chiral olefin metathesis catalysts and application to enantioselective synthesis of quebrachamine: catalyst development inspired by natural product synthesis. J Am Chem Soc 2009; 131 (03) 943-953
• 37 Huang YQ, Song HJ, Liu YX, Wang QM. Dehydrogenation of N-heterocycles by superoxide ion generated through single-electron transfer. Chemistry 2018; 24 (09) 2065-2069
• 38 Zheng C, You SL. Exploring the chemistry of spiroindolenines by mechanistically-driven reaction development: asymmetric Pictet-Spengler-type reactions and beyond. Acc Chem Res 2020; 53 (04) 974-987
• 39 Ahmad S, Shukla L, Szawkało J. et al. Synthesis of novel chiral guanidine catalyst and its application in the asymmetric Pictet-Spengler reaction. Catal Commun 2017; 89: 44-47
• 40 Amat M, Santos MMM, Bassas O. et al. Straightforward methodology for the enantioselective synthesis of benzo[a]- and indolo[2,3-a]quinolizidines. J Org Chem 2007; 72 (14) 5193-5201
• 41 Milcendeau P, Zhang Z, Glinsky-Olivier N, van Elslande E, Guinchard X. Au (I)-catalyzed Pictet-Spengler reactions all around the indole ring. J Org Chem 2021; 86 (09) 6406-6422
• 42 Wagen CC, McMinn SE, Kwan EE, Jacobsen EN. Screening for generality in asymmetric catalysis. Nature 2022; 610 (7933) 680-686
• 43 Reid JP, Sigman MS. Holistic prediction of enantioselectivity in asymmetric catalysis. Nature 2019; 571 (7765) 343-348
• 44 Mohr JT, Krout MR, Stoltz BM. Natural products as inspiration for the development of asymmetric catalysis. Nature 2008; 455 (7211) 323-332
• 45 Burai Patrascu M, Pottel J, Pinus S. et al. From desktop to benchtop with automated computational workflows for computer-aided design in asymmetric catalysis. Nat Catal 2020; 3 (07) 574-584
• 46 Taran F, Gauchet C, Mohar B. et al. High-throughput screening of enantioselective catalysts by immunoassay. Angew Chem Int Ed 2002; 41 (01) 124-127
• 47 Jarret M, Tap A, Turpin V. et al. Bioinspired divergent oxidative cyclizations of geissoschizine: total synthesis of (-)-17-nor-excelsinidine,(+)-16-epi-pleiocarpamine, (+)-16-hydroxymethyl-pleiocarpamine and (+)-taberdivarine. Eur J Org Chem 2020; 2020 (40) 6340-6351
• 48 Liu XY, Qin Y. Recent advances in the total synthesis of monoterpenoid indole alkaloids enabled by asymmetric catalysis. Green Synth Catal 2022; 3 (01) 25-39
• 49 Kim A, Kim A, Park S. et al. Catalytic and enantioselective control of the C-N stereogenic axis via the Pictet-Spengler reaction. Angew Chem Int Ed Engl 2021; 60 (22) 12279-12283
• 50 Singh R, Kumar S, Patil MT. et al. Post-Pictet-Spengler cyclization (PPSC): a strategy to synthesize polycyclic β-carboline-derived natural products and biologically active N-heterocycles. Adv Synth Catal 2020; 362 (19) 4027-4077
• 51 Boltjes A, Dömling A. The Groebke-Blackburn-Bienaymé reaction. Eur J Chem 2019; 2019 (42) 7007-7049
• 52 Kar S, Sanderson H, Roy K, Benfenati E, Leszczynski J. Green chemistry in the synthesis of pharmaceuticals. Chem Rev 2022; 122 (03) 3637-3710
• 53 Il'in MV, Novikov AS, Bolotin DS. Sulfonium and selenonium salts as noncovalent organocatalysts for the multicomponent Groebke-Blackburn-Bienaymé reaction. J Org Chem 2022; 87 (15) 10199-10207
• 54 Liu J, Yang T, Wang ZP. et al. Pyrimidazole-based covalent organic frameworks: integrating functionality and ultrastability via isocyanide chemistry. J Am Chem Soc 2020; 142 (50) 20956-20961
• 55 Ishwar Bhat S. One-Pot construction of Bis-heterocycles through isocyanide based multicomponent reactions. ChemistrySelect 2020; 5 (27) 8040-8061
• 56 Al-Jumaili MHA, Hamad AA, Hashem HE. et al. Comprehensive review on the Bis-heterocyclic compounds and their anticancer efficacy. J Mol Struct 2023; 1271: 133970
• 57 Chen D, Li J, Wang X. et al. Catalytic metal-enabled story of isocyanides for use as “C1N1” synthons in cyclization: beyond radical chemistry. Org Chem Front 2022; 9 (15) 4209-4220
• 58 Wang C, Yu B, Li W, Zou W, Cong H, Shen Y. Effective strategy for polymer synthesis: multicomponent reactions and click polymerization. Mater Today Chem 2022; 25: 100948
• 59 Pashev AS, Burdzhiev NT, Stanoeva ER. Synthetic approaches toward the benzo [a] quinolizidine system: a review. Org Prep Proced Int 2016; 48 (06) 425-467
• 60 Chen H, Xiao T, Li L. et al. Synthesis of fluorinated benzo [a] quinolizidines via visible light-induced tandem substitution of two fluorine atoms in a CF₃ group. Adv Synth Catal 2017; 359 (20) 3642-3647
• 61 Balci M. Acyl Azides: Versatile compounds in the synthesis of various heterocycles. Synthesis 2018; 50 (07) 1373-1401
• 62 Liu S, Wang H, Wang B. Catalyst-free construction of spiro [benzoquinolizidine-chromanones] via a tandem condensation/1,5-hydride transfer/cyclization process. Org Biomol Chem 2020; 18 (43) 8839-8843
• 63 Wu X, Dai X, Nie L. et al. Organocatalyzed enantioselective one-pot three-component access to indoloquinolizidines by a Michael addition-Pictet-Spengler sequence. Chem Commun (Camb) 2010; 46 (16) 2733-2735
• 64 Wu X, Dai X, Fang H. et al. One-pot three-component syntheses of indoloquinolizidine derivatives using an organocatalytic Michael addition and subsequent Pictet–Spengler cyclization. Chemistry 2011; 17 (38) 10510-10514
• 65 Shiri M. Indoles in multicomponent processes (MCPs). Chem Rev 2012; 112 (06) 3508-3549
• 66 Zeng X. Recent advances in catalytic sequential reactions involving hydroelement addition to carbon-carbon multiple bonds. Chem Rev 2013; 113 (08) 6864-6900
• 67 Calcaterra A, Mangiardi L, Delle Monache G. et al. The Pictet-Spengler reaction updates its habits. Molecules 2020; 25 (02) 414
• 68 Znabet A, Zonneveld J, Janssen E. et al. Asymmetric synthesis of synthetic alkaloids by a tandem biocatalysis/Ugi/Pictet-Spengler-type cyclization sequence. Chem Commun (Camb) 2010; 46 (41) 7706-7708
• 69 Wang W, Ollio S, Herdtweck E, Dömling A. Polycyclic compounds by Ugi-Pictet-Spengler sequence. J Org Chem 2011; 76 (02) 637-644
• 70 Alonso F, Galilea A, Mañez PA. et al. Beyond pseudo-natural products: sequential Ugi/Pictet-Spengler reactions leading to steroidal pyrazinoisoquinolines that trigger caspase-independent death in hepG2 cells. ChemMedChem 2021; 16 (12) 1945-1955
• 71 Samala S, Saifuddin M, Mandadapu AK, Kundu B. Three-component tandem-intramolecular hydroamination reactions in one pot involving indoles, 2-aminobenzyl alcohols, and 2-alkynylbenzaldehydes: consecutive 7-endo-trig and electrophilic 6-endo-dig cyclizations. Eur J Org Chem 2013; 2013 (18) 3797-3806
• 72 Sun J, Jiang W, Yan CG. Convenient construction of tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles and tetrahydroindolizino[8,7-b]indoles via one-pot domino reaction. RSC Advances 2018; 8 (50) 28736-28744
• 73 Ali SA, Mondal SK, Das T. et al. One-pot tandem cyclisation to pyrrolo[1,2-a][1,4]benzodiazepines: a modified approach to the Pictet-Spengler reaction. Org Biomol Chem 2019; 17 (18) 4652-4662
• 74 Peytam F, Adib M, Shourgeshty R. et al. Synthesis and biological evaluation of new dihydroindolizino [8,7-b] indole derivatives as novel α-glucosidase inhibitors. J Mol Struct 2021; 2021 (1224) 129290-129300
• 75 Cai Q, Li DK, Zhou RR, Shu WM, Wu YD, Wu AX. Acid-catalyzed multicomponent tandem cyclizations: Access to polyfunctional dihydroindolizino [8,7-b] indoles. Org Lett 2016; 18 (06) 1342-1345
• 76 González-Pelayo S, Bernardo O, Borge J, López LA. Synthesis of metallocene analogues of the phenethylamine and tetrahydroisoquinoline scaffolds via regioselective ring opening of 2-aryl-N-sulfonyl aziridines. Adv Synth Catal 2021; 363 (03) 819-825
• 77 Magyar CL, Wall TJ, Davies SB. et al. Triflic anhydride mediated synthesis of 3,4-dihydroquinazolines: a three-component one-pot tandem procedure. Org Biomol Chem 2019; 17 (34) 7995-8000
• 78 Campbell MV, Iretskii AV, Mosey RA. One-pot tandem assembly of amides, amines, and ketones: synthesis of C4-quaternary 3, 4-and 1,4-dihydroquinazolines. J Org Chem 2020; 85 (17) 11211-11225
• 79 Jiang J, Qing J, Gong LZ. Asymmetric synthesis of 3-amino-δ-lactams and benzo[a]quinolizidines by catalytic cyclization reactions involving azlactones. Chemistry 2009; 15 (29) 7031-7034
• 80 Zhu HL, Ling JB, Xu PF. α-Oxo-γ-butyrolactam, N-containing pronucleophile in organocatalytic one-pot assembly of butyrolactam-fused indoloquinolizidines. J Org Chem 2012; 77 (17) 7737-7743
• 81 Rueping M, Volla CMR, Bolte M, Raabe G. General and efficient organocatalytic synthesis of indoloquinolizidines, pyridoquinazolines and quinazolinones through a one-pot domino Michael addition-cyclization-Pictet-Spengler or 1,2-amine addition reaction. Adv Synth Catal 2011; 353 (14–15): 2853-2859
• 82 Hong BC, Liao WK, Dange NS, Liao JH. One-pot organocatalytic enantioselective domino double-Michael reaction and Pictet-Spengler-lactamization reaction. A facile entry to the “inside yohimbane” system with five contiguous stereogenic centers. Org Lett 2013; 15 (03) 468-471
• 83 Du H, Rodriguez J, Bugaut X, Constantieux T. Organocatalytic enantioselective multicomponent synthesis of pyrrolopiperazines. Adv Synth Catal 2014; 356 (04) 851-856
• 84 Dai W, Lu H, Li X, Shi F, Tu SJ. Diastereo- and enantioselective construction of a bispirooxindole scaffold containing a tetrahydro-β-carboline moiety through an organocatalytic asymmetric cascade reaction. Chemistry 2014; 20 (36) 11382-11389
• 85 Yu Q, Guo P, Jian J, Chen Y, Xu J. Nine-step total synthesis of (-)-strychnofoline. Chem Commun (Camb) 2018; 54 (09) 1125-1128
• 86 Suryavanshi PA, Sridharan V, Menéndez JC. A β-enaminone-initiated multicomponent domino reaction for the synthesis of indoloquinolizines and benzoquinolizines from acyclic precursors. Chemistry 2013; 19 (39) 13207-13215
• 87 Sun J, Zhang LL, Yan CG. Facile construction of 1,2,6,7,12,12b-hexahydroindolo [2,3-a] quinolizines via one-pot three-component reactions of tryptamines, propiolate, and α,β-unsaturated aromatic aldehydes or ketones. Tetrahedron 2013; 69 (26) 5451-5459
• 88 Xing S, Ren J, Wang K. et al. Lewis acid promoted three-component reactions of aziridines, arenes and aldehydes: an efficient and diastereoselective synthesis of cis-1, 4-disubstituted tetrahydroisoquinolines. Tetrahedron 2015; 71 (36) 6290-6299
• 89 Ghashghaei O, Pedrola M, Seghetti F. et al. Extended multicomponent reactions with indole aldehydes: access to unprecedented polyheterocyclic scaffolds, ligands of the aryl hydrocarbon receptor. Angew Chem Int Ed Engl 2021; 60 (05) 2603-2608
• 90 Zhu D, Sun J, Yan CG. One-pot synthesis of 6, 11-dihydro-5 H-indolizino [8,7-b] indoles via sequential formation of β-enamino ester, Michael addition and Pictet-Spengler reactions. RSC Advances 2014; 4 (108) 62817-62826
• 91 Wani IA, Goswami G, Sk S, Mal A, Sayyad M, Ghorai MK. A synthetic route to 1,4-disubstituted tetrahydro-β-carbolines and tetrahydropyranoindoles via ring-opening/Pictet-Spengler reaction of aziridines and epoxides with indoles/aldehydes. Org Biomol Chem 2020; 18 (02) 272-287
• 92 Cao L, Huang L, Xu X, Van der Eycken EV, Feng HD. Synthesis of nitrogen-tethered 1,6-enynes through CuI/TFA catalysis. Org Chem Front 2022; 9 (02) 394-399
• 93 He WX, Xing X, Yang ZJ, Yu Y, Wang N, Yu XQ. Biocatalytic one-pot three-component synthesis of indoloquinolizines with high diastereoselectivity. Catal Lett 2019; 149 (02) 638-643
• 94 Ruijter E, Garcia-Hartjes J, Hoffmann F. et al. Synthesis of polycyclic alkaloid-type compounds by an N-acyliminium Pictet-Spengler/diels-alder sequence. Synlett 2010; 2010 (16) 2485-2489
• 95 Deng QS, Yu AM, Zhang L, Meng XT. Selective synthesis of benzothiophene-fused polycyclic, eight-membered N-heterocycles via amine-mediated three-component domino strategy. Adv Synth Catal 2021; 363 (04) 1081-1087
• 96 Gageat M, Gaultier L, El Kaim L. et al. New Ugi/Pictet-Spengler multicomponent formation of polycyclic diketopiperazines from isocyanides and a-keto acids. Synlett 2007; 38 (25) 500-502
• 97 Lesma G, Cecchi R, Crippa S. et al. Ugi 4-CR/Pictet-Spengler reaction as a short route to tryptophan-derived peptidomimetics. Org Biomol Chem 2012; 10 (45) 9004-9012
• 98 Liu H, William S, Herdtweck E, Botros S, Dömling A. MCR synthesis of praziquantel derivatives. Chem Biol Drug Des 2012; 79 (04) 470-477
• 99 Tyagi V, Khan S, Bajpai V, Gauniyal HM, Kumar B, Chauhan PM. Skeletal diverse synthesis of N-fused polycyclic heterocycles via the sequence of Ugi-type MCR and CuI-catalyzed coupling/tandem Pictet-Spengler reaction. J Org Chem 2012; 77 (03) 1414-1421
• 100 Sinha MK, Khoury K, Herdtweck E, Dömling A. Tricycles by a new Ugi variation and Pictet-Spengler reaction in one pot. Chemistry 2013; 19 (25) 8048-8052
• 101 Zhang B, Kurpiewska K, Dömling A. Highly stereoselective Ugi/Pictet-Spengler sequence. J Org Chem 2022; 87 (11) 7085-7096
• 102 Cano-Herrera MA, Miranda LD. Expedient entry to the piperazinohydroisoquinoline ring system using a sequential Ugi/Pictet-Spengler/reductive methylation reaction protocol. Chem Commun (Camb) 2011; 47 (38) 10770-10772
• 103 Tan Y, Luan HL, Lin H. et al. One-pot enantioselective construction of indoloquinolizidine derivatives bearing five contiguous stereocenters using aliphatic aldehydes, nitroethylenes, and tryptamine. Chem Commun (Camb) 2014; 50 (70) 10027-10030
• 104 Shirsat PK, Narasimhulu V, Kumbhare RM. Acid-catalyzed four-component tandem double cyclization: access to dihydroindolizino [8,7-b] indoles. ChemistrySelect 2019; 4 (29) 8550-8553

Publication History

Received: 24 July 2023

Accepted: 04 November 2023

Article published online:
08 December 2023