Recent Strategies in the Synthesis of Spiroindole and Spirooxindole Scaffolds

Abstract

Spiroindole and spirooxindole scaffolds are very important spiro-heterocyclic compounds in drug design processes. Significant attention has been directed at obtaining molecules based on spiroindole and spirooxindole derivatives that have bioactivity against cancer cells, microbes, and different types of disease affecting the human body. Due to their inherent three-dimensional nature and ability to project functionalities in all three dimensions, they have become biological targets. Considering reports on spiroindole and spirooxindole-containing scaffolds in the past decades, introducing novel synthetic procedures has been an active research field of organic chemistry for well over a century and will be useful in creating new therapeutic agents. This review summarizes the pharmacological significance of spiroindole and spirooxindole scaffolds and highlights the latest strategies for their synthesis, focusing particularly on the past 2 years with typical examples. The spiroindole and spirooxindoles in this review are divided by the type and ring size of the spirocycle that is fused to indole or oxindole. Summarizing these procedures will be very beneficial for discovering novel therapeutic candidate molecules.

1 Introduction

Spiroindole and spirooxindoles, which containing a spirocycle fused at the C2 or C3 of the oxindole moiety, are a known subset of indole and also form the core building blocks of highly functionalized organic structures. These important scaffolds are known as the central skeletons of many alkaloids with potential pharmaceutical activity, such as Horsfiline 1, Mitraphylline 2, Marefortine 3, Welwitindolinone A 4, Elacomine 5, and Alstonisine 6 (Fig. 1) [1,2,3,4]. The inherent three-dimensional (3D) nature and rigidity of these spirocyclic systems leads to their good affinity to 3D proteins, thus converting these scaffolds into attractive synthetic targets in organic chemistry and drug discovery projects that have a broad spectrum of biological properties, including antimicrobial, antitumor, antidiabetic, anticonvulsant, potential antileukemic, local anesthetic, and antiviral activities. Spirocyclic systems can also be used as synthetic precursors for the production of various types of medicines. For instance, Spirotryprostatin A 7 and Spirotryprostatin B 8 show microtubule assembly inhibition, and Pteropodine 9 and Isopteropodine 10 dampen the operation of muscarinic serotonin receptors (Fig. 2) [5, 6].

Fig. 1

Biologically active spiroheterocyclic compounds

Fig. 2

Selected pharmaceutical structures containing a spirooxindole scaffolds

Therefore, the study of new and highly efficient procedures for the synthesis of compounds containing spirocarbocycles or spiroheterocycle scaffolds at the C-2 or C-3 position of the indole core has attracted growing attention from numerous researchers around the world. Obviously, among the various synthetic procedures, multicomponent reactions (MCRs) are preferable. For the synthesis of spirooxindole derivatives, the three-component reaction of isatin, amino acids, and 1,3-dipolarophils, Michael–Michael–aldol cascades, Heck reactions, and numerous other domino condensations have been introduced [7, 8].

Due to their considerable pharmaceutical importance and structurally uniqueness, these interesting scaffolds have been introduced as attractive synthetic targets and many review articles have been published on the formation of spiroindole and spirooxindoles. In 2014, Xia et al. [9] reviewed development of the synthesis of spirooxindole compounds produced from isatin. In 2012, Franz et al. [10] surveyed efficient procedures for the enantioselective formation of spirooxindoles, focusing on articles between 2010 and 2011. In 2018, Van der Eycken et al. reviewed recent progress towards achieving highly functionalized spiroindolines and spiroindoles to motivate additional research to discover novel and efficient procedures for achievement of new spiroindolines and spiroindoles, focusing on articles in 2016 and 2017 [11]. In 2016, Pavlovska et al. focused on the diverse methods available for the enantioselective synthesis of spirooxindoles, with an emphasis on articles published over the last decade [7]. In 2018, Shi and Mei [1] outlined recent developments in the catalytic asymmetric synthesis of spirooxindoles before 2018. In 2020, Youseftabar Miri et al. reviewed recent applications of isatin in the synthesis of spirooxindoles published by Iranian groups in the last 15 years [12].

Considering their biological importance, and the introduction of various synthetic methods for the synthesis of spiroindolines and spiroindoles, there is a need to collect the new methods introduced into this field. The procedures to obtain various spiroindolines and spiroindoles reported in the literature can be sorted into categories based on the type and size of the spirocycle that is fused to indole or oxindole such as 3-, 4-, 5-, or 6-membered rings, including different heteroatoms as illustrated in Fig. 3.

Fig. 3

Different spirocycles fused to oxindole

2 Synthetic Approaches Towards Spiroindole and Spirooxindole Scaffolds

This section lists numerous reactions, often using isatin as raw material, for the synthesis of spirooxaindole compounds, which often proceeds through MCRs as described in the following sections.

2.1 Fused with Carbocyclic Containing Spiro-cyclic Compounds

2.1.1 Five-Membered Ring

Larhed and coworkers have described a procedure for the formation of new spirooxindoles via high regio- and stereoselective intramolecular Mizoroki–Heck 5-exocyclization of aryl iodides [4]. Electron-rich and electron-deficient aryl iodide raw materials were selectively cyclized with high stereoselectivity and good efficiencies. The selection of reaction conditions results in the careful control of the double-bond location in the cyclopentene moiety. These new spiro products were subsequently functionalized to rigidified unnatural amino acid compounds by a consecutive gas-free Pd(0)-catalyzed alkoxycarbonylation, followed by selective O- and N-deprotection [4].

In this synthetic route, enantiomerically pure (+)-Vince lactam 11, was changed into the related methyl ester 12 as illustrated in Scheme 1 [13]. In the next step, the free amine in 12 was protected as 2,5-dimethylpyrrole, followed by double-bond isomerization to produce the more stable form 13. The protected ester 13 was coupled with numerous iodoanilines using trimethylaluminum to produce amide precursors 14 with high efficiency. Anilines containing electron-rich as well as electron-poor groups were formed with good efficiencies without any specified additional reactions, contrary to aryl iodide functionality (Scheme 1).

Scheme 1

Synthesis of double-protected amino acid scaffolds 13 and Mizoroki–Heck cyclization precursors 14

Subsequently, excellent regio- and stereoselective intramolecular Mizoroki–Heck 5-exocyclization of aryl iodides 14 directs formation of the new spirooxindoles 15 and 16 (Scheme 2). The palladium(0)-catalyzed Mizoroki–Heck reaction is one of the most important ways of generating carbon–carbon bonds [14]. Intramolecular Mizoroki–Heck cyclization also provides good control over ring size, while requiring less reactive precursors [15].

Scheme 2

Regioselective Mizoroki–Heck cyclization for the synthesis of spirooxindoles 15 and 16

Due to the biological importance of spirooxindole compounds in designing new drugs, many attempts to introduce novel procedures to synthesize the spiro nucleus structures are still necessary.

Functionalization of spirooxindole 15 was attempted by considering previous methods based on palladium-catalyzed carbonylation conditions, as shown in Scheme 3. The procedure was designed based on utilization of the Herrmann–Beller palladacycle as the palladium source, with tri-tert-butyl phosphine tetrafluoride borate as pre-ligand. Molybdenum hexacarbonyl was used as a solid CO source, and benzyl alcohol was used as the nucleophile. The reaction was performed with microwave (MW) heating of a sealed reaction vial, and 17 was acquired completely.

Scheme 3

Carbonylation of 15 to produce protected unnatural amino acid 17

The free carboxylic acid 18 was synthesized with 74% yield from chemoselective deprotection of the benzyl ester 17 employing nickel hexahydrate and sodium borohydride (Scheme 4).

Scheme 4

Synthesis of free acid 18 using deprotection process of benzyl carboxylate 17

Benzyl ester 17 was also selectively N-deprotected to its free amine 19 in the presence of an excess of N-hydroxylamine hydrochloride and potassium hydroxide in a mixture of methanol/water (3:1) as reaction medium as illustrated in Scheme 5 [4].

Scheme 5

Synthesis of free amine 19 via selective N-deprotection of 17

2.1.2 Six-Membered Ring

Mori and Machida [16] described the diastereoselective formation of tetralin-fused spirooxindole products 21a and 21b using Lewis acid-catalyzed C(sp³)–H bond functionalization. A catalytic amount of Sc(OTf)₃ was used to activate the benzylidene oxindoles 20 in hexane and reflux conditions to create the target structures 21 in good efficiencies with excellent diastereoselectivity (up to 5 > 20:1) (Scheme 6). Two parameters were necessary to reach high diastereoselectivity: (1) the internal transformation of two diastereomers, and (2) a large difference in the solubility of the two isomers in the solvent. Based on the observations obtained, the high diastereoselectivity of the conversion was justified as shown in Scheme 6. The two diastereomers 21a and 21b transformed to each other easily using Sc(OTf)₃ catalyzed ring-opening and ring-closing procedures via B, and only a low thermodynamic bias exists between these diastereomers [16].

Scheme 6

Formation of tetralin-fused spirooxindoles via Lewis acid-catalyzed C(sp³)–H bond functionalization with excellent diastereoselectivity

2.2 Fusions with Nitrogen-Heterocycle Containing Spiro-cyclic Compounds

Spirooxindoles fused with N-heterocycles have been introduced as medicinal agents with various activities such as anti-breast cancer agents, antiviral agent, antimalarial agents, MDM2 inhibitiors, antimicrobial agents, Dengue virus inhibitor, and anti-tumor agents [17,18,19,20].

2.2.1 Five-Membered Ring

Cheng et al. have introduced a novel strategy for the formation of different 3,2′-pyrrolidinyl-spirooxindoles and its 6-/7-membered analogs using an intramolecular cyclization via an oxidative C–H/N–H bond coupling procedure in the presence of an iodide/H₂O₂ as a catalytic system. This method was carried out using conversion of [3-(benzylamino)propyl]-2-oxin 22 to the final compound 1′-benzylspiro[indoline-3,2-pyrrolidin]-2-one 23 in the presence of tetrabutylammonium iodide (TBAI) as an ideal iodide source and H₂O₂ as a final oxidant (Scheme 7) [21].

Scheme 7

Formation of diverse 3,2′-pyrrolidinyl-spirooxindoles 23 through an intramolecular cyclization procedure

In order to show the synthetic application of this method, the selective reduction of amide 23 using borane was subsequently carried out. The synthesized spiro[indoline-3,2′-pyrrolidine] 24, is an important scaffold found in many natural compounds and medicinal agents (Scheme 8).

Scheme 8

Selective reduction of amide 23 to produce spiro[indoline-3,2′-pyrrolidine] 24

Based on the experimental conclusions and recent studies, Li et al. [22] proposed a potential stepwise mechanism (Scheme 9). Firstly, two hypervalent iodine forms, i.e., IO⁻ and IO₂⁻ likely form by oxidation of iodide with H₂O₂. Those hypervalent iodines are then involved with aminoalkyl 2-oxindoles 22 to produce an iodoamino intermediate A, which is in equivalence with its enolate B. The second step readily undergoes an intramolecular cyclization to acquire the final product 23, and the removed iodide undergoes subsequent oxidation, reproducing the active hypervalent iodine forms [21].

Scheme 9

Proposed mechanism to produce 3,2′-pyrrolidinyl-spirooxindoles 23 through an intramolecular reaction

Yan and colleagues [23] reported the easy synthesis of a class of new functionalized spirooxindole-pyrrolidine derivatives 28 via 1,3-dipolar cycloaddition of azomethine ylide acquired from sarcosine 26 and paraformaldehyde 27 with several 2-(1-benzyl-5-chloro-2-oxoindolin-3-ylidene)malononitriles 25 (Scheme 10). This MCR yielded functionalized spirooxindoles in good efficiencies with excellent regio- and stereoselectivity. The skeleton of synthesized spiro[indoline-3,3′-pyrrolidines] 28 was well confirmed by obtaining single-crystal structures [23].

Scheme 10

Three-component reaction for the formation spiro[indoline-3,3′-pyrrolidines] 28

To prove the synthetic importance of this method, they also used another series of 3-methyleneoxindoles named 3-(2-oxo-2-phenylethylidene)indolin-2-ones 29 instead of 25. If the three-component reaction was performed in toluene under reflux condition, reactions proceeded in a smooth way to obtain spiro[indoline-3,3′-pyrrolidines] 30 (Scheme 11).

Scheme 11

Three-component reaction for the synthesis of spiro[indoline-3,3′-pyrrolidines 30

Yan's group proposed that the reaction proceeds via a rational mechanism as illustrated in Scheme 12 for the formation of spiro[indoline-3,3′-pyrrolidines] 32a and 32b (Z/E isomers) using 2-cyano-2-(2-oxoindolin-3-ylidene)acetate 31a and 31b (Z/E isomers) as raw materials. Initially, the thermal depolymerization of paraformaldehyde obtained formaldehyde, which subsequently became involved with sarcosine to form the expected azomethine A by removing H₂O and CO₂. The precursor 2-cyano-2-(2-oxoindolin-3-ylidene)acetate 31 has two Z/E isomers in distinct proportions. Afterwards, the [3 + 2] cycloaddition of azomethine with 2-cyano-2-(2-oxoindolin-3-ylidene)acetate 31 led to the spiro[indoline-3,3′-pyrrolidines] 32 with two major E-isomers 32a and minor Z-isomers 32b [23].

Scheme 12

A rational mechanism to produce spiro[indoline-3,3′-pyrrolidines] with Z/E isomers

Deepthi and colleagues have developed the synthesis of a library of spiro(oxindole-3,2′-pyrrolidine) attached to heteroaromatics in the pyrrolidine unit 36 applying the 1,3-dipolar cycloaddition reaction of azomethine ylide with heterocyclic ylidenes using isatin 33, sarcosine 34, and thiophene-3-ylidene 35 as starting materials (Scheme 13). The method shows a two-phase functionalization of thiophene/furan with spiropyrrolidine oxindoles in the second/third positions. The reactions of the heterocyclic ylidenes were also carried out applying other α-amino acids 37, named l-proline, thioproline, and phenylalanine. Under the same reaction conditions, azomethine ylide was produced by reaction of isatin with α-amino acid with removal of carboxyl from the intermediate, which, under [3 + 2] cycloaddition with ylidene ,formed the related spirooxindoles [24].

Scheme 13

Synthesis of spiro(oxindole-3,2′-pyrrolidine) attached to heteroaromatics in pyrrolidine unit 36

Muthusubramanian and colleagues [27] introduced the formation of novel benzosuberone-tethered spirooxindoles 38, which proceeded via a 1,3-dipolar cycloaddition reaction of azomethine ylide (produced in situ using isatin 33 and sarcosine 34) with arylidene benzosuberone 37 in refluxing methanol (Scheme 14). The 1,3-dipolar cycloaddition reaction creates an important means of forming compounds with complex structures with high regio- and stereoselectivities [25, 26].

Scheme 14

Synthesis approach towards novel benzosuberone-tethered spirooxindoles 38

A rational mechanism for the synthesis of benzosuberone-tethered spirooxindoles 38 is displayed in Scheme 15. In the first step, the azomethine ylide is produced by the reaction between isatin 33 and sarcosine 34 via the removal of carboxyl. Subsequently, dipole A and dipolarophile 37 form a single diastereomer via cycloaddition. To justify the diastereoselectivity despite the presence of three stereocenters, the most plausible reason is illustrated in Scheme 15. Probably, the cycloaddition prefers track 1 to track 2. In track 1, the pyrrolidine moiety and carbonyl of the benzosuberone structure are trans to each other to prevent steric strain. In a similar way, to escape electrostatic repulsion, two carbonyls of the compounds are placed in a trans position relative to each other [27].

Scheme 15

Proposed mechanism for the formation of 38

Barakat et al. [28] have designed an easy and smooth procedure for the formation of spirooxindoles derivatives named spiro[indoline-3,5′-pyrrolo[1,2-c]thiazol]-2-one 41 having four stereogeneric centers as potent MDM2 inhibitors with an asymmetric 1,3-dipolar cycloaddition as the main stage. This method contains the one-pot multi-component condensation of α,β-unsaturated dienone derivatives 39, with the dicarbonyl compound (isatin derivatives 33), and amino acid derivatives 40 (L-4-thiazolidinecarboxylic acid), which was heated in methanol to produce the final spirooxindole series 41 (Scheme 16). The structural complexity and the certain stereochemistry of final compounds were certified by X-ray crystallographic analysis [28].

Scheme 16

Synthesis of substituted spirooxindoles named spiro[indoline-3,5′-pyrrolo[1,2-c]thiazol]-2-one 41 with four stereogeneric centers

Yan's group have described a novel procedure for the formation of a pharmaceutical important hybrid molecule named CF₃-containing spirooxindole-pyrrolidine-pyrazolone compounds 44 via the organocatalytic [3 + 2] cycloaddition reaction. This reaction involves the cycloaddition of α,β-unsaturated pyrazolones 42 with N-2,2,2-trifluoroethylisatin ketimines 43 in dichloromethane at ambient temperature in the presence of a cinchonine-derived squaramide catalyst to produce a spiro-pyrrolidine-attached oxindole and pyrazolone product 44 with four adjacent stereocenters and two adjacent spiroquaternary chiral centers, in high efficiencies and stereoselectivities (Scheme 17) [29].

Scheme 17

Formation of spiro-pyrrolidine–pyrazoline oxindoles 44

Yan and colleagues described a three-component reaction between pyrrolidine 45, aromatic aldehydes 46, and 3-arylideneoxindolin-2-ones 47 catalyzed by acetic acid in refluxing toluene for the synthesis of functionalized 7′-arylidenespiro[indoline-3,1′-pyrrolizines] 48 in good efficiency with excellent diastereoselectivity (Scheme 18), although the reaction with 3-phenacylideneoxindoles 49 led to a mixture of spiro[indoline-3,1′-pyrrolizines] 50 and 7′-arylidene-substituted spirooxindoles 51 in moderate efficiencies (Scheme 19). The synthesis of spiroheterocyclic products proceeds by [3 + 2] cycloaddition of the in situ formed azomethine ylides with three cyclic 1,3-dipolarophiles [30].

Scheme 18

Synthesis of 7′-benzylidene-spiro[indoline-3,1′-pyrrolizines] 48

Scheme 19

Synthesis of spiro[indoline-3,2′-pyrrolizines] 50 and 51

The reaction mechanism proceeds via the formation of azomethine ylides, β-C − H functionalization of pyrrolidine, and subsequent [3 + 2] cycloaddition (Scheme 20). Benzaldehyde 46 is involved with pyrrolidine 45 to obtain iminium ion A. The related iminium ion B would be acquired by a [1,3]-H shift step. In the following, deprotonation of B would produce normal azomethine ylide C, which, after a 1,3-dipolar cycloaddition with 3-phenacylideneoxindole 49, synthesized the spiro compound 50. In another route, enamine intermediate D would be produced via deprotonation of B. After an aldol-type reaction of D with a second molecular benzaldehyde 46, and following dehydration, the iminium ion E was acquired, which would be deprotonated to obtain a conjugated azomethine ylide F. In the following, [3 + 2] reaction of F with 3-phenacylidneoxindole 49 produced the spiro product 51. As a result, both normal azomethine ylide and conjugated azomethine ylide could be produced in situ and involved 1,3-dipolarophiles. The reaction with 2-arylidene-1,3-indanedione or 3-arylideneindolin-2-one was carried out mainly with the [3 + 2] cycloaddition of the conjugated azomethine ylide, while the reaction with 3-phenacylideneoxindole contains both [3 + 2] cycloaddition reactions of normal azomethine and conjugated azomethine ylide [30].

Scheme 20

Proposed mechanism of [3 + 2] cycloaddition reaction for the formation of spiro[indoline-3,2′-pyrrolizines] 50 and 51

Dai and coworkers have developed a Rh(III)-catalyzed domino annulation of N-(pivaloyloxy)acrylamide 52 as a simple olefin with diazooxindole 53 to give spirooxindole pyrrolone products 54 with excellent regioselectivities (Scheme 21). The potential application of this protocol in the next step of diversification for drug finding was illustrated in the directed presentation of spirooxindole pyrrolone skeleton into medicinal molecules pentoxifylline, endofolliculina, and pregnenolone [31].

Scheme 21

C(sp²)–H activation/annulation to synthesis spirooxindole pyrrolone scaffold 54

The reaction proceeds via a tentative mechanism involving cleavage of the C–H bond with Rh(III), followed by carbene migratory insertion with the diazo substrate to obtain a novel alkyl rhodium intermediate C. In the following, a formal Lossen rearrangement offers isocyanate D, which, via further nucleophilic addition at the isocyanate, intramolecularly generates the final compound 54 (Scheme 22).

Scheme 22

Rational mechanism for the synthesis of spirooxindole pyrrolone 54

Tripathi et al. have described the synthesis of a new class of five-membered heterocyclic scaffolds named hexahydrospiro[indoline-3,3′-pyrrolizine]-2-one 57 in good-to-excellent efficiencies through [3 + 2] cycloaddition reaction in the regioselective procedure. The synthesized products were obtained via MCR of substituted 3-cinnamoyl-4-hydroxy-6-methyl-2H-pyran-2-one 55, isatin 33, L-proline 56 at ambient temperature conditions (Scheme 22). The final products are key cores of numerous natural compounds and may become potential biological drug scaffolds in the near future. The chalcone analogues 55 used in this reaction were produced via aldol condensation of substituted benzaldehyde 46 and dehydro acetic acid in dry chloroform using a catalytic amount of piperidine (Scheme 23) [32].

Scheme 23

Formation of new hexahydrospiro[indoline-3,3′-pyrrolizine]-2-one 57

Shao and colleagues introduced various catalytic asymmetric synthetic protocols for the formation of tricyclic and tetracyclic 3,3′-pyrrolidonyl spirooxindoles. This method proceeds through a one-pot asymmetric propargylation catalyzed by a chiral Brønsted base for the formation of oxindole 1,6-enynes A from the common and available precursors, 3-allyl oxindole 58 and C-alkynyl N-Boc-acetal 59, and a subsequent interchangeable site-selective and excellent diastereoselective electrophilic iodocyclization of 1,6-enynes via alkenyl-activation and alkenyl/alkynyl dual activation to form tricyclic 3,3′-pyrrolidonyl spirooxindoles 60 and tetracyclic 3,3′-pyrrolidonyl spirooxindoles 61 (Scheme 24) [33].

Scheme 24

Asymmetric synthesis of tri- and tetracyclic spirooxindoles

Although halogen-atom-promoted electrophilic cyclization (electrophilic halocyclization) of alkenes or alkynes has been widely discussed, electrophilic halocyclization of unconjugated enynes has been less studied due to the difference in the reactivity of alkenes relative to alkynes [34]. The heterocyclic products obtained from this type of reaction are very important due to having easily modifiable halogen handles [35].

The oxidation process of indoles is a basic organic conversion for the formation of a diversity of synthetically and medicinally valuable nitrogen-containing compounds. The electron-rich property of indoles leads to easy oxidation using many oxidation reagents. Since catalysis methods in the presence of secure oxidants (H₂O₂, oxone, O₂) is highly favorable, Tong and coworkers have introduced three unique, efficient halide catalyzed oxidation processes of tetrahydro-β-carbolines (THCs) indoles 62 applying oxone as the terminal oxidant, which leads to the formation of oxindoles 63, 65 and 67 (Scheme 25) [36].

Scheme 25

Oxidative rearrangement of tetrahydro-β-carbolines 62 for the formation of spirooxindole natural compounds

Compared to previous procedures, this method was relatively more useful due to the in situ formed halenium ion (X⁺) catalyst, which has suitable reactivity towards the C2–C3 double bond of indoles, therefore largely preventing other competitive oxidations/rearrangements. Furthermore, there is no requirement for protection of indole nitrogen, while most past protocols needed to protect the indole nitrogen with electron-withdrawing groups (e.g., N-Ts, N-Boc, N-Ac, etc.) to improve the chemo-selectivity and regio-selectivity of the final compounds [36].

To indicate the synthetic value of this procedure, Tong and colleagues carried out the total synthesis of two well-known spirooxindoles as target natural compounds named (±)-coerulescine 65 and (±)-horsfiline 67 from THC 62 (Scheme 25). Reduction of THC 62 using LiAlH₄ and oxidative rearrangement of the obtained THC 64 in the presence of oxone-KBr in acidic medium (THF/AcOH/H₂O = 1:1:1) produced (±)-coerulescine 65 with 39% yield in two steps. Whereas the oxidative rearrangement of THC 64 proceeds with stoichiometric KBr and 2.4 equivalent of oxone, consecutive one-pot oxidative rearrangement and bromination synthesizes C5-bromo spirooxindole 66 in 41% yield, which could be applied for CuI-catalyzed Ullmann ether synthesis to furnish (±)-horsfiline 67 in 60% yield [36].

Finally, they used this procedure for the biomimetic oxidative rearrangement of a natural alkaloid named Yohimbine hydrochloride 68, and synthesized the related Yohimbine oxindole 69 (Scheme 26) with 56% efficiency [36], which seemed better than the previous three-step procedure [37] with only 38% overall efficiency.

Scheme 26

Biomimetic oxidative rearrangement to produce Yohimbine oxindole 69

2.2.2 Six-Membered Ring

Choudhury and coworkers have described a medium-dependent and metal-free three-component condensation of isatin 33, 4-hydroxycoumarin 70 and aminopyrazole 71 in MW-assisted conditions for the formation of two diverse kinds of fused spirooxindoles 72 and 73. Isatin 33, 4-hydroxycoumarins 70 and aminopyrazole 71 reacted together under MW-assisted conditions in acetonitrile solvent and produced spirooxindoles fused with pyrazolo-tetrahydropyridinones 72 via opening the ring of the hydroxycoumarin core. Additionally, when acidic conditions are used as the reaction medium, related fused spirooxindoles containing a tetracyclic coumarin-dihydropyridine-pyrazole scaffold 73 were obtained. This medium-dependent three-component condensation led to the production of a class of pharmaceutically important spiroxindoles under metal-free conditions (Scheme 27) [38].

Scheme 27

Synthesis of fused spirooxindoles 72 and 73 via the reaction of 4-hydroxy coumarin and amino pyrazole

The proposed reaction mechanism for the synthesis of 72 or 73 is illustrated in Scheme 28. It is expected that 4-hydroxycoumarin 70 first becomes involved with isatin 33 to form intermediate I and then amino pyrazole 71 undergoes 1,4-addition to obtain tri-substituted methane II. In non-acidic conditions, II remains at the step of enol formation, so the masked carbonyl’s reactivity is less than that of the ester part. Therefore, intramolecular cyclization happens in the ester group of the coumarin species and produces intermediate III, and eventually stable compound 72 synthesizes via ring-opening of the coumarin. Besides, by using acid, tri-substituted methane intermediate II remains as protonated form IIA, containing the active protonated carbonyl group (ketone) IV, so ring closure happens intramolecularly by involving the ketone group of the coumarin instead of the ester group, and product 73 is formed.

Scheme 28

A rational mechanism for the formation of products 72 and 73

In order to expand the substrate scope, they have prepared new spirooxindole fused with coumarin-dihydropyridine-isooxazole tetracycle 75 by applying 3-amino-5-methylisoxazole 74 instead of aminopyrazoles (Scheme 29) [38].

Scheme 29

Formation of spirooxindole scaffolds containing coumarin-dihydropyridine-isoxazole tetracycles 75

Wu et al. [39] have developed an easy, efficient and environmentally benign method to produce the structurally diverse spirooxindole scaffolds named spiro[indole-[4H]pyrazolo[3,4-b]quinoline] 79 and spiro[indoline pyrazolo[3,4-b]pyridine]carbonitrile 80 through a three-component condensation of isatin 33, 5-aminopyrazole 76, and 1,3-dicarbonyl compounds 77 (or b-oxo-benzenepropanenitrile 78) catalyzed by copper triflate [Cu(OTf)₂] in ethanol (Scheme 30).

Scheme 30

Synthesis of spiro[indole-[4H]pyrazolo[3,4-b]quinoline] 79 and spiro[indoline pyrazolo[3,4-b]pyridine]carbonitrile 80

A rational mechanism for this three-component condensation is demonstrated in Scheme 31. It is expected that, in the first step, the 1,3-diketone 77 involves with isatin 33 to form the condensation adduct 81, which, under a Michael-type addition of 5-aminopyrazole 76 continues by the cyclocondensation of the intermediate 82 to obtain the related compounds 79. But when b-oxo-benzenepropanenitrile 78 was used instead of 1,3-diketone, product 80 was produced by a similar mechanism [39].

Scheme 31

Rational mechanism for the Cu(OTf)₂-catalyzed synthesis of spirooxindoles 79

Khojasteh-Khosro and Shahbazi-Alavi [40] developed an efficient and rapid procedure for the formation of new spirooxindoles named 10-methyl-8H-spiro[benzo[5,6]chromeno[2,3-c]pyrazole-11,3′-indol]-2′(1′H)-one 87 and 8-methyl-10-phenyl-10,11-dihydrospiro[pyrazolo[3,4-b]benzo[h]quinolin-7,3′-indol]-2′(1′H)-one 88 through a four-component reaction of phenylhydrazine or hydrazine hydrate 83, isatins 33, ketoesters 84, and 2-naphthol 85 or naphthylamine 86 in presence of nano-Co₃S₄ in MW-assisted reaction conditions (Scheme 32) [40].

Scheme 32

Synthesis of new spirooxindoles 87 and 88 under microwave (MW) irradiation

Tripathi has introduced an efficient multicomponent synthetic method for the formation of new spiroindole quinazolines named spiro[indoline-3,2′-quinazoline]-2,4′ (3′H)-dione 91 from isatoic anhydride 89, isatin 33, and primary amine 90, which is catalyzed by β-cyclodextrin in an aqueous medium (Scheme 33). Due to the use of environmentally friendly catalysts and green solvents, the method presented in this work is a green method to produce valuable spiroheterocycles [41].

Scheme 33

Synthesis of various spiroindole quinazolines derivatives via an environmentally benign procedure

Cyclodextrins are glyco macromolecules containing cyclic glucose oligomers with cylindrical shapes in such a way that the primary hydroxyl groups are located at the more restricted rim of the cylinder. Cyclodextrins are used as water-soluble catalysts for reactions in supramolecular catalysis including the reversible generation of host–guest complexes by non-covalent bonding as observed in enzymes. Cyclodextrins activate raw material by molecular distinction and catalyze reactions in a selective way.

Tripathi tried to justify the possible mechanism of the reaction based on observations. The mechanistic protocol (Scheme 34) illustrated the role of cyclodextrin in activating the carbonyl carbon in isatoic anhydride 89 resulting in anhydride ring-opening and generation of intermediate 92. Intermediate 92 then reacts with the ketonic functional group of isatin 33 to produce intermediate 93 and the final product 91 [41].

Scheme 34

Plausible mechanistic pathway for synthesis of spiroindole quinazolines 91 using cyclodextrin as glyco macromolecules

2.3 Fused with Oxygen-Heterocycle Containing Spiro-cyclic Compounds

2.3.1 Four-Membered Ring

In recent years, the existence of four-membered rings in compounds containing a spirocenter has gathered much consideration. For example, oxetanes have attracted wonderful interest from synthetic and medicinal researchers. Oxetanes not only exist in natural compounds and bioactive molecules but are also used as effective precursors in the synthesis of novel heterocyclic products due to the ring strain that leads to ring-opening or ring expansion processes [42, 43].

Marini and colleagues described an unprecedented Michael/intramolecular etherification cascade reaction of 3-hydroxyoxindoles 94 with phenyl vinyl selenone 95 for the formation of novel spirooxindole 2,2-disubstituted oxetanes 96 in water and in the presence of a base at ambient temperature without the addition of surfactants (Scheme 35). The spirooxindole oxetanes could be produced based on the bis-nucleophilic character of 3-hydroxyoxindoles and proceeded via the domino Michael addition-cyclization subsequence illustrated in Scheme 36. Methods for the synthesis of oxetanes, especially 2,2-disubstituted oxetanes, are still in demand, and the discovery of novel methods for enhancing structural diversity is highly favorable [44].

Scheme 35

Synthesis of novel spirooxindole 2,2-disubstituted oxetanes 96

Scheme 36

Synthetic routes to spirooxindole oxetanes 96

2.3.2 Five-Membered Ring

Kanger and coworkers have revealed an enantio- and regioselective organocatalytic cascade reaction for the formation of tetrahydrofuranyl spirooxindoles 99 and 100 starting from isatin 33 and enolizable unsaturated 1,4-diketones 97 and 98 as multifunctional synthons catalyzed by cinchonine-based thiourea (Scheme 37). In this method, excellent amounts of diastereoselectivity and enantioselectivity (ee up to 99%) were acquired [45].

Scheme 37

Synthetic routes for the formation of tetrahydrofuranyl spirooxindoles 99 and 100

The proposed mechanism involves the aldol reaction between enol nucleophile generated by the reaction of isatin 33 and multifunctional enolizable unsaturated 1,4-diketones 98 subsequent by the intramolecular Michael reaction at C3 of intermediate A result in straight cyclization and the synthesis of spiro products 100 containing with quaternary and tertiary stereogenic centers (Scheme 38).

Scheme 38

Schematic design for the synthesis of tetrahydrofuranyl spirooxindoles 100

Kanger and coworkers also afforded a triple cascade reaction for the formation of pentacyclic spirooxindole compound 101 containing two quaternary and tertiary stereocenters in excellent enantioselectivities. This triple cascade reaction involves the aldol reaction, oxa-Michael reaction giving enolate B, which is in equilibrium with the deprotonated pyrrole, which, in the final nucleophilic attack of pyrrole to the carbonyl functional group of the tetrahydrofuranyl, leads to product 101 (Scheme 39) [45].

Scheme 39

Synthesis of the pentacycle spirooxindole 101 through a triple cascade reaction

Liu’s group described an asymmetric cascade double Michael addition between terminal alkynones 102 and 3-alkyl substituted oxindoles embellishing a OH end group 103 to produce 2′-substituted 3,3′-spirooxindoles comprising dihydrofuran 104 in the presence of a chiral guanidine organocatalyst with high diastereo- and enantioselectivities, which may be converted to potential medicinal targets (Scheme 40). This protocol provides an asymmetric synthetic method for the formation of (−)-salacin for the first time [46].

Scheme 40

An asymmetric cascade double Michael addition for the formation of spirooxindoles containing dihydrofuran 104

Ye and colleagues reported the reaction of dioxindoles 105 and β,β-disubstituted enals 106 based on oxidative [3 + 2] annulation catalyzed by N-heterocyclic carbene (NHC) for the synthesis of spirocyclic oxindole-γ-lactones 107 containing two adjacent quaternary stereocenters in good efficiencies with high diastereo- and acceptable enantioselectivities (Scheme 41) [47].

Scheme 41

N-heterocyclic carbene (NHC)-catalyzed oxidative [3 + 2] annulation reaction for the synthesis of spirocyclic oxindole-γ-lactones 107

The proposed catalytic cycle is illustrated in Scheme 42. Initially, NHC reacts with aldehyde 106 to generate homoenol I, followed by single electron transfer by nitrobenzene leading to oxidation to obtain homoenol radical II. On the other, the enol radical III is produced from dioxindole 105. In the following, via cross-coupling, two radicals afford intermediate IV, and, under basic conditions, lactonization occurs to synthesis compound 107 and recycle the NHC catalyst [47].

Scheme 42

Plausible catalytic cycle for the synthesis of spirocyclic oxindole-γ-lactones 107

2.3.3 Six-Membered Ring

Jiang et al. [48] introduced a general method for the production of a wide range of enantioenriched chiral pentacyclic spirooxindoles comprising a tetrahydropyrano[2,3-b]indole skeleton 109 via a catalytic one-pot sequential aldol/chloroetherification/aromatization from 3-(3-indolomethyl) oxindole 108, paraformaldehyde, and NCS (Scheme 43). In addition, the pentacyclic spirooxindoles could be converted to other compounds with structural diversity such bispirooxindole and spirocyclic oxindoles.

Scheme 43

Catalytic one-pot sequential aldol/chloroetherification/aromatization procedure for the formation of pentacyclic spirooxindoles

Based on previous studies, Jiang et al. [48] proposed a rational reaction mechanism (Scheme 44). Formaldehyde was generated gently in monomeric form from its polymeric form. Afterwards, the chiral bifunctional thiourea catalyst C has the ability to convert the intermolecular reaction of 3-(3-indolomethyl) oxindole 108 and formaldehyde into an intramolecular-type reaction because of the simultaneous motivation and activation of 3-substituted oxindoles as nucleophile and formaldehyde as electrophile for high enantioselectivity. In the following, nucleophilic attack of the aldol compound I to NCS produced a chloronium ion II; then 1,4-diazabicyclo[2.2.2]octane (DABCO) can act as a possible Lewis base, stimulating ring-closure to produce a pyran core in III. In the final stage, aromatization with the release of HCl occurs, yielding a tetrahydropyrano[2,3-b]indole structure 109 [48].

Scheme 44

Rational mechanism for the formation of tetrahydropyrano[2,3-b]indole 109

In order to further expand the capabilities of this method, Jiang et al. [48] carried out different conversions of the products obtained in the previous step to increase molecular diversity of spirocyclic oxindoles (Scheme 45). After the aldol procedure in a one-pot process, substrate 110 could be readily involved with three equivalents of NCS and converted to dearomatizated product 111 in 76% efficiency and 94% ee. Furthermore, high diastereoselectivity was acquired due to the steric strain of the chlorine atom exist in the precursors. In particular, compound 109a could undergo oxidative rearrangement in the presence of NBS-HOAc-H₂O-THF, providing the structure bispirooxindole 112 in a moderate yield, high enantioselectivity, and 1:1 dr. In addition, compound 109b reacts with bulky p-nitrobenzene sulfonyl chloride using trimethylamine and 4-(dimethylamino)pyridine (DMAP), producing compound 113. The only chiral quaternary carbon of the pentacyclic spirooxindoles 109 was generated in the first aldol reaction and was not transformed in the next step [48].

Scheme 45

Direct conversion of products 109 to various spirocyclic oxindoles

Zhang et al. described a three-component condensation promoted by iodine for the production of heterocyclic compounds named spiro[chromeno[4,3-b]chromene-7,3′-indoline]trione 114 via the green reaction system using molecular iodine as a suitable catalyst instead of Lewis acids. Several substituted isatins 33 used in this reaction strategy that react with 4-hydroxyl coumarins 70 and various cyclic 1,3-dicarbonyls 77 and offers good functional group diversity and yield (Scheme 46).

Scheme 46

Synthesis of spiro[chromeno[4,3-b]chromene-7,3′-indoline]trione 114

Two mechanism pathways for this reaction seem rational (Scheme 47), with the difference between them being the time of bond generation. In path a, N-methylisatin 33 reacts with 1,3-cyclohexanedione 77 to produce oxoindolylidene I followed by the reaction with 4-hydroxy-2H-chromen-2-one 70 to obtain intermediate II. In the following, intramolecular acetal generation III and removal of water leads to the synthesis of the final product 114. In path b, initially, N-methylisatin 33 involves with 4-hydroxy-2H-chromen-2-one 70, followed by the reaction with 1,3-cyclohexanedione 77 to produce compound 114 with the same path as path a. At all steps of the mechanism, it is suggested that iodine, as a suitable catalyst instead of Lewis acids, activates carbonyl groups [3].

Scheme 47

Plausible mechanistic pathways for the condensation of cyclohexane-1,3-dione with various isatins and 4-hydroxyl coumarins

Mirza and colleagues have described an effective and appropriate procedure for the electrocatalytic formation of nano-sized spirooxindole containing 4H-pyran scaffolds 116 via a one-pot, three-component and sustainable condensation of cyclic-1,3-diketones 77 [such as pyrimidine-2,4,6(1H,3H,5H)-trione, cyclohexane-1,3-dione, 1H-indene-1,3(2H)-dione, cyclopentane-1,3-dione], malononitrile or ethyl cyanoacetate 115, and isatins 33 in an undivided electrochemical cell in the presence of potassium bromide as the supporting electrolyte in ethanol solvent (Scheme 48). In Mirza’s work, electrosynthesis was used as a dependable, cost-effective and highly efficient (76–92%) method for the synthesis of the expected products. The obtained spirooxindole containing 4H-pyran and chromene nanoparticles could introduce a valuable way to produce drugs in nano size that are very attractive in the fields of pharmacy and medicine [49].

Scheme 48

Formation of nano-sized spirooxindole containing 4H-pyran derivatives 116 through a green electrosynthesis method

Bayat and coworkers have developed a sustainable, easy, catalyst-free, and one-pot multi-component condensation of N-alkyl-1-(methylthio)-2-nitroethenamine 117 (gain from the reaction between different amines 90 and nitroketene dithioacetal 118) with isatin 33 and barbituric acids 119 for the formation of novel library of spiro[indolinepyranopyrimidine] products 120 (Scheme 49). This procedure proceeds through Knoevenagel condensation, Michael addition, and O-cyclization arrangement in water media and reflux conditions without using any catalyst [50].

Scheme 49

Synthesis of novel spiro[indolinepyranopyrimidine]derivatives 120 based on N,S-ketene acetals

A proposed mechanistic route for the synthesis of 120 is illustrated in Scheme 49. In the first step, isatin 33 interacts with barbituric acid 119 derivatives via Knoevenagel condensation to produce 121, which, under Michael addition with N-alkyl-1-(methylthio)-2-nitroethenamine 117 (formed from the addition of different amines 90 to nitroketene dithioacetal 118) yields 122. Subsequently, intermediate 122 undergoes imine-enamine tautomerization to produce 123 followed by O-cyclization to synthesize 120 through the removal of methanethiol (Scheme 50) [50].

Scheme 50

Synthetic mechanism for the formation of spiro[indolinepyranopyrimidine] derivatives 120 based on N,S-ketene acetals

2.4 Fusion with More Than One Heteroatom Containing Spiro-Cyclic Compounds

2.4.1 Five-Membered Ring

Due to the broad application of organofluorines containing a group of fluorinated substances in pharmaceuticals, agrochemicals, and polymers, Budovská et al. [52] have developed and produced a class of novel biologically active trifluoromethyl including indole scaffolds such as (4-trifluoromethylphenylamino) or 3,5-bis(trifluoromethyl)phenylamino strictures through a spirocyclization procedure. This method simply employs thioureas as precursors, bromine as cyclization agent, and methanol, 4-(trifluoromethyl)aniline, or 3,5-bis(trifluoromethyl)aniline as nucleophiles.

Initially, the thioureas 126 and 127 prepared via the reduction of 1-methoxyindole-3-carboxaldehyde oxime 124 with sodium cyanoborohydride catalyzed by titanium (III) chloride is converted to 1-methoxyindole-3-ylmethylamine 125 based on previously published methodology [51]. The unstable raw amine 125 was immediately engaged in reaction in the next step. The amine 125 reacts with commercially accessible 4-(trifluoromethyl)phenyl isothiocyanate or 3,5-bis(trifluoromethyl)phenyl isothiocyanate in methanol using triethylamine as a base catalyst, leading to the synthesis of N-(1-methoxyindol-3-yl)methyl-N′-(4-trifluoromethylphenyl) thiourea 126 and N-(1-methoxyindol-3-yl)methyl-N′-[3,5-bis(trifluoromethyl)phenyl]thiourea 127 (Scheme 51).

Scheme 51

Synthesis of spirooxindoles 128 and 129 via cyclization reactions of thioureas 126 and 127

Subsequently, Budovská et al. [52] used this procedure to extend the diversity of products, considering the key bromospirocyclizations of thioureas 126 and 127 with methanol, which led to the synthesis of 2′-(4-trifluoromethylphenylamino) and 2′-[3,5-bis(trifluoromethyl)phenylamino] analogues of 1-methoxyspirobrassinol methyl ether 128 and 129 (Scheme 51) [52].

In order to achieve a higher antiproliferative effect, they surveyed the formation of 2,2′-diamino analogs of 1-methoxyspirobrassinol methyl ether containing (4-trifluoromethylphenylamino) or 3,5-bis(trifluoromethyl)phenylamino group 130 and 131. Target compounds (±)cis and (±)trans 130 and 131 were produced via bromospirocyclization procedure of thioureas 126 and 127 using 4-(trifluoromethyl)aniline or 3,5-bis(trifluoromethyl)aniline (Scheme 52) [52].

Scheme 52

Cyclization reactions of thioureas 126 and 127 to produce target compounds (±)cis and trans 130 and 131

Aksenov et al. [53] have discovered an uncommon reactivity of nitrostyrenes 132 in phosphorous acid that allows these accessible precursors to react as 1,4-dipoles of CCNO-type in excellent diastereoselective [4 + 1] cycloaddition with indoles 133 to produce 4′H-spiro[indole-3,5′-isoxazoles] 134 with excellent levels of diastereoselectivity.

During this work, they encountered a class of P₂O₅ with low quality and involving considerable some red phosphorus. Polyphosphoric acid generated from this substance had a distinct pink color. Under this condition, the reaction of nitrostyrene 132 and 2-phenylindole 133 proceeded at room temperature and resulted in the production of significant amounts of unexpected spirocyclic compound 134 (Scheme 53). Indeed, they found that the reaction catalyzed by H₃PO₃ in formic acid produces 134 as the single product with quite high efficiency.

Scheme 53

Synthesis of 4′H-spiro[indole-3,5′-isoxazoles] 134 through a highly diastereoselective (4 + 1)-cycloaddition of indoles

Based on analysis of experimental data acquired, Aksenov et al. [53] proposed a rational mechanism route (Scheme 54). Nitrostyrene 132 reacts with phosphorous acid to make intermediate 135, which can undergo Michael addition of indole 133. The electron-deficient substituents at C2 of indoles reduce nucleophilicity and lead to unsuccessful reactions of some substrates at this stage. In the following, deprotonation at C3 of the indole in 136 is followed by the intramolecular abstraction of a proton from the benzylic position by the phosphite ester of the aci-nitro center in 137, leading to N-phosphoryloxyenamine oxide intermediate 138. In a second step, deprotonation again led to hydroxylamine 139 as a tautomer product. Subsequently, acid-promoted 5-endo-trigcyclization of 139 happens to produce spiro-2,5-dihydroisoxazole compounds 140, which, under reaction conditions may produce two tautomer products 134 or 4,5-dihydroisoxazole 141 [53, 54].

Scheme 54

Mechanistic rationale for transformation of indoles to 4′H-spiro[indole-3,5′-isoxazoles] 134 through [4 + 1] cycloaddition

3 Conclusion

Spiroindole and spirooxindoles are important therapeutic agents with unique structurally skeletons, which have attracted tremendous interest from academic and industrial researchers because of their rigidity and particular 3D stereochemistry. In the past 2 years, we witnessed significant progress in presenting synthetic procedures of these important classes of N-heterocycles utilizing diverse precursors, and this review has outlined recent advances in the synthesis of spiroindole and spirooxindole scaffolds, focusing on the past 2 years. This review will surely assist chemists in the discovery and introduction of new heterocyclic compounds. Consequently, the design and development of new synthetic methods for the synthesis of heterocyclic frameworks involving spirooxindole are expected to have considerable benefits, producing complex natural compounds and aiding the discovery of novel drug candidates in the future.