Molecular diversity of the reactions of MBH carbonates of isatins and various nucleophiles

• Zi-Ying Xiao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2025, 21, 286–295, doi:10.3762/bjoc.21.21

• biologically important 3-substituted and spirooxindole derivatives [5][6][7]. The unique molecular architecture and remarkable pharmacological activities have made spirooxindole one of the hottest synthetic targets with fruitful chemical and steric selectivity [8][9][10][11][12][13][14][15]. In recent years

• , the readily available Morita–Baylis–Hillman (MBH) carbonates of isatins have been recognized as one of the most powerful synthons for the construction of various spirooxindole skeletons [16][17][18][19][20][21][22][23][24][25]. MBH carbonates of isatins can be easily obtained via base-promoted MBH

• ]. In the presence of a Lewis base, MBH carbonates of isatins can be easily converted to activated allylic ylides, which in turn can undergo allylic substitution and annulation reactions to give diverse 3-substituted and spirooxindole derivatives [36][37][38][39][40][41]. Inspired by these elegant

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• leading to the synthesis of spirooxindole derivatives 6 bearing a thiourea moiety in high yields (91–97%), and with good to excellent diastereoselectivities (10:1–20:1 dr) and enantioselectivities (61–96%) (Scheme 2). Furthermore, the authors also investigated the reactivity of ketimines and dienimines

• with high diastereoselectivity (Scheme 5). In 2019, Shi and co-workers established a guanidine-catalyzed enantioselective (4 + 1) cyclization of benzofuran-derived azadienes 11 with 3-chlorooxindoles 18 [28]. This work provides a useful strategy for the synthesis of chiral spirooxindole derivatives 19

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• various tissues, with a prominent expression in the adult brain, where it contributes to metabolic processes, aging, and epigenetic regulation. In this context, the group of Hasaninejad et al. (2017) [49] described the synthesis of spirooxindole, spiroacenaphthylene, and bisbenzo[b]pyran derivatives using

• of the nitrogen in lactams 11 with an oxygen in 12 to influence hydrogen-bond donating properties and synthesis of the benzodioxepinone derivatives via Passerini reaction. MCR 3 + 2 reaction to develop spirooxindole, spiroacenaphthylene, and bisbenzo[b]pyran compounds. Synthesis of ML192 analogs

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

Construction of diazepine-containing spiroindolines via annulation reaction of α-halogenated N-acylhydrazones and isatin-derived MBH carbonates

• Xing Liu,
• Wenjing Shi,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1923–1932, doi:10.3762/bjoc.19.143

• features a broad substrate scope, simple reaction conditions, and high molecular convergence. Keywords: acylhydrazone; annulation; azepine; MBH carbonate; spirooxindole; Introduction Among the various N-containing heterocyclic compounds, 1,2-diazepine represents one of the important privileged structural

• [22][23][24][25][26][27]. In addition, spirooxindole is also a privileged structural scaffold, which has been recognized as key structural unit in many bioactive natural products and pharmaceuticals with broad biological activities [28][29][30]. The development of elegant synthetic methodologies for

• the synthesis of spirooxindole derivatives continues to be a highly active subject in organic synthesis [31][32][33][34][35]. In recent years, the readily available isatin-derived Morita–Baylis–Hillman (MBH) carbonates have become one of the most powerful reagents for the construction of diverse

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• AMYs B1 which then were reacted with nucleophiles to form C–H-functionalized pyrrolidines or subjected to the 1,3-dipolar cycloaddition with olefins to afford bicyclic compounds (Scheme 2A and B) [59][60]. We employed cyclic amines for the synthesis of spirooxindole-pyrrolidines 7a or 7b in good

• diastereoselectivity is caused by the different R2/R2’ and R3/R3’groups which no longer have the same stereochemistry as that shown in Scheme 8. Double cycloadditions for bis[spirooxindole-pyrrolizidine] compounds After completing the pseudo-five-component double cycloaddition reactions leading to polycyclic

• pyrrolizidines shown in Scheme 6 and Scheme 7, we then conducted similar reactions in order to synthesize spirooxindole-pyrrolidines. This unique ring skeleton exists in some natural products and biologically active compounds such as (−)-horsfiline, (+)-alstonisine, pteropodine and spirotryprostatin A (Figure 3

Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction

• Ziying Xiao,
• Fengshun Xu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1234–1242, doi:10.3762/bjoc.19.91

• substituent. A plausible reaction mechanism is proposed to explain the formation of the different spirooxindoles. Keywords: cascade reaction; dimedone; isatin; 3-methyleneoxindole; multicomponent reaction; spirooxindole; Introduction Spirooxindole is one important privileged structural skeleton and is found

• in many bioactive natural and synthetic compounds [1][2][3]. It is known that many spirooxindole derivatives show important biological activities [4][5][6]. On the other hand, a wide range of differently substituted spirooxindoles exist [7][8][9]. Therefore, the development of efficient synthetic

• methodologies for diverse spirooxindoles have become one of the hottest research fields in organic and pharmaceutical chemistry [10][11]. In order to synthesize diverse spirooxindole derivatives, commercially available isatins and easily obtainable 3-methyleneoxindolines were the most employed building blocks

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

• Juan Lu,
• Bin Yao,
• Desheng Zhan,
• Zhuo Sun,
• Yun Ji and
• Xiaofeng Zhang

Beilstein J. Org. Chem. 2022, 18, 1607–1616, doi:10.3762/bjoc.18.171

• ; pyrrolothiazoles; spirooxindole; Introduction Nitrogen-containing heterocycles play a dominant role as a structural fragment of therapeutic agents in medicinal chemistry and drug discovery [1][2][3][4][5][6][7][8][9]. The nitrogen-containing heterocyclic moieties are currently discovered in more than 75% of the

• ]. Pyrrolothiazole and spirooxindole moieties occupy exclusive positions as valuable source of natural products and therapeutic agents in organic synthesis and drug discovery [60][61][62][63][64][65][66][67][68]. We have developed a number of asymmetric reactions to construct spirooxindole-based scaffolds through

• ][71]. With the promising applications of spirooxindolepyrrolothiazoles in drug discovery (Figure 1) [72][73][74], the structural integration of spirooxindole and pyrrolothiazole with diverse substituted groups via an efficient synthesis is a challengeable research in green chemistry. The corresponding

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles

• Pavel A. Topanov,
• Anna A. Maslivets,
• Maksim V. Dmitriev,
• Irina V. Mashevskaya,
• Yurii V. Shklyaev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2022, 18, 1532–1538, doi:10.3762/bjoc.18.162

• -2,3-diones; spirooxindole; Introduction Compounds with a spirooxindole scaffold have attracted the attention of researchers, which is demonstrated by the publication of several reviews of both the biological activities of compounds with the spirooxindole moiety [1][2][3][4][5], and methods for

• constructing spirooxindole systems by employing different approaches [6][7][8][9][10][11][12]. Cyclopiazonic acid derivatives such as aspergillins A–E [13] (Figure 1) and speradines C and F [14][15] are secondary metabolites of fungi, and include a furan fragment spiro-fused with 2-oxindole. Cyclopiamides I

• be unknown. To evaluate the possibility of synthesizing the target spirooxindole compounds, we initially investigated a reaction of benzoxazine-containing FPD 1a with diazooxindole 2a in anhydrous acetonitrile at room temperature (Scheme 3). The reaction came to an end in 24 hours, with the color of

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• [carbazole-2,3'-indolines], spiro[carbazole-3,5'-pyrimidines] and spiro[carbazole-3,1'-cycloalkanes] in satisfactory yields and with high diastereoselectivity. Keywords: Diels–Alder reaction; indole; indolo-2,3-quinodimethane; Levy reaction; tetrahydrocarbazole; spirooxindole; Introduction

Tri(n-butyl)phosphine-promoted domino reaction for the efficient construction of spiro[cyclohexane-1,3'-indolines] and spiro[indoline-3,2'-furan-3',3''-indolines]

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 669–679, doi:10.3762/bjoc.18.68

• . Additionally, the tri(n-butyl)phosphine-promoted domino annulation reaction of isatins and ethyl isatylidene cyanoacetates produced spiro[indoline-3,2'-furan-3',3''-indolines] in satisfactory yields. Keywords: isatin; spiro[cyclohexane-1,3'-indoline]; spiro[indoline-3,2'-furan-3',3''-indoline]; spirooxindole

• ; tri(n-butyl)phosphine; Introduction Spirooxindole is a privileged heterocyclic core existing in many natural products and medicinally relevant compounds. A variety of spirooxindole derivatives has been identified with a broad range of biological activities [1][2][3][4][5]. On the other hand

• , spirooxindoles can be constructed by introduction of various carbocyclic and heterocyclic units, which made them suitable for chemistry and many potential applications [6][7][8][9]. The development of unique spirooxindole systems and efficient synthetic methods for these compounds have attracted continual

Tosylhydrazine-promoted self-conjugate reduction–Michael/aldol reaction of 3-phenacylideneoxindoles towards dispirocyclopentanebisoxindole derivatives

• Sayan Pramanik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 469–478, doi:10.3762/bjoc.18.49

• and operational simplicity through one pot reaction. Keywords: chemoselective conjugate reduction; dispirocyclopentanebisoxindole scaffolds; metal-free; one-pot operation; reductive cyclization; Introduction There is a vast demand of the structurally complex spirooxindole scaffold which is an

• important structural motif that is embodied in a number of bioactive natural products and medicinally relevant compounds [1][2]. Among various spirooxindole motifs, bispirooxindoles fusing two spirooxindole cores exhibit a wide range of important biological activities, for example, anticancer

• operation without chiral catalyst is still an atom-economical and operationally simple procedure to demonstrate the construction of dispirooxindoles. In the recent years, the diastereoselective construction of dispirocyclopentanebisoxindoles consisting of two spirooxindole motifs has acquired attention from

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• , 3-monohalooxindoles have emerged as a class of versatile building blocks for the construction of various 3,3-disubstituted oxindole and spirooxindole derivatives, such as spirocyclopropaneoxindoles [3][4][5][6][7][8][9][10][11], 3-β-amino-substituted 3-halooxindoles [12][13][14], five-membered-ring

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• '-disubstituted-2-oxindoles are particularly widespread and can also be found in a diverse array of pharmaceutical agents (Figure 1A) [1][2][3][4]. In addition, their facile transformation into pyrroloindoline and spirooxindole derivatives as well as more structurally complex molecules renders them potentially

• -alkylated with bromo ester 13. The formed product (i.e., 14) was first amidated and then cyclised using benzylamine 11 to generate spirooxindole 15 in 54% yield and 94% ee. Chlorination with NCS, followed by tert-butyl ester cleavage in TFA/CH2Cl2 provided the final bioactive compound 6 in 93% ee

• of biological interest, as evidenced by the facile preparation of the (S)-enantiomer of a potent CRTH2 receptor antagonist. The importance of the 3,3-spirooxindole core and its access through enantioselective enolate alkylation. Substrate scope. aIsolated yield. bDetermined by CSP-HPLC. cValue in

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• marketed drugs structured around indole implying its pharmacological significance such as oxypertine (27), ateviridine (28) [47] and spirooxindole-based potent cytotoxic agents 29, 30 and 31 [48]. In 2017, Lin and co-workers [49] designed a TFA-catalyzed three-component reaction for the regioselective

• -component reaction whereas a further reaction with phenacyl bromide 41 results the product of the four-component reaction 42. Recently, our group [52] efficiently employed the synergistic approach of MWA-MCR to deliver pyrrolidinyl spirooxindole 44. The isatin 35, primary amino acids 37 and 3

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• toceranib [38] are also found in the market for the treatment of several tumours (Figure 5) and some others are under development or have been entered clinical trials [39]. There are also natural spirooxindole-containing complex molecules that have shown potential medicinal applications, such as NITD609

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• considered as the analogues of both 3,3’-spirooxindole and 2-aminoimidazole marine sponge alkaloids. Keywords: 2-amino-4-arylimidazole; (2-amino-4-arylimidazolyl)propanoic acid; isatin; Meldrum’s acid; multicomponent reactions; pyrrolo[1,2-c]imidazole; 3,3’-spirooxindoles; Introduction Heterocyclic

• )propanoic acid 11b according to X-ray diffraction data. Thermal ellipsoids of atoms are shown at 50% probability level. Molecular structure of aminoimidazo[1,2-c]pyrrole 16a according to X-ray diffraction data. Thermal ellipsoids of atoms are shown at 50% probability level. 3,3’-Spirooxindole alkaloids

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

• Yonglei Du,
• Jian Li,
• Kerong Chen,
• Chenglin Wu,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2017, 13, 1342–1349, doi:10.3762/bjoc.13.131

• ] have been used to construct successfully spirooxindole privileged scaffolds. However, most of them were devoted to exploring new catalyst systems to improve the reaction efficiency and selectivity [51][52][53][54][55][56][57][58][59][60][61][62][63][64], and studies extending the reaction scope using

• [35] (Scheme 1, reaction 1A) and Michael–Henry cascade reactions [25] (Scheme 1, reaction 1B) reported by Barbas III's group involve the cyclization between α,β-unsaturated aldehydes and nitrostyrenes with 3-substituted oxindoles to generate the corresponding CHO- or NO2-substituted spirooxindole

• mL CH2Cl2, the catalyst d (0.01 mmol) was added at −10 °C for 24 h. After nitrovinylacetamide (2a) was consumed completely, the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel to afford the desired products 3k–o. Representative spirooxindole

Multicomponent synthesis of spiropyrrolidine analogues derived from vinylindole/indazole by a 1,3-dipolar cycloaddition reaction

• Manjunatha Narayanarao,
• Lokesh Koodlur,
• Vijayakumar G. Revanasiddappa,
• Subramanya Gopal and
• Susmita Kamila

Beilstein J. Org. Chem. 2016, 12, 2893–2897, doi:10.3762/bjoc.12.288

• synthesis of multifunctionalized spiranes. The earlier works reveal the use of different reaction conditions to prepare functionalized spiroindane, spiropyrolidine, spiropyrrolizidine and spirooxindole derivatives. Among them, the 1,3-dipolar cycloaddition based route is preferred due to multiple advantages

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• azomethine ylides generated in situ from the corresponding amines and aldehydes, affording the piperidine-fused spirooxindole frameworks in high yields (up to 93% yield) and with excellent enantioselectivities (>99% ee), albeit with moderate diastereoselectivities (Scheme 54) [71]. Similarly, the same group

• enantioselectivities (90–98% ee, Scheme 57) [74]. Following above success, Shi et al. developed other CPA-catalyzed cascade reactions of 3-indolylmethanols with 7-vinylindoles, affording C7-functionalized indoles and constructing the cyclopenta[b]indole and spirooxindole frameworks with excellent

• -promoted Prins cyclization reactions of 3-allyl-3-hydroxyoxindoles with aldehydes, accessing functionalized spirooxindole pyrans as single diastereoisomers in good yields (71–91%) under mild conditions [76]. Interestingly, when BF3·Et2O was used, they obtained the biologically important fluorinated

One-pot four-component reaction for convenient synthesis of functionalized 1-benzamidospiro[indoline-3,4'-pyridines]

• Chao Wang,
• Yan-Hong Jiang and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2014, 10, 2671–2676, doi:10.3762/bjoc.10.281

• ; multicomponent reaction; one-pot reaction; spiro[indoline-3,4'-pyridine]; Introduction The spirooxindole system is the core structure of many natural products and pharmaceutically important structures with notable structural complexity and biological activities of great interest [1][2][3][4]. Accordingly, many

• efficient and practical synthetic procedures have emerged for the synthesis of versatile spirooxindole-fused heterocycles [5][6][7][8][9]. In recent years, because of the emphasis on the development of green and sustainable chemistry, multicomponent reactions have been developed as efficient and potent

Primary-tertiary diamine-catalyzed Michael addition of ketones to isatylidenemalononitrile derivatives

• Akshay Kumar and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2014, 10, 929–935, doi:10.3762/bjoc.10.91

• -component version of the reaction by a domino Knoevenagel–Michael sequence. The Michael adduct 4a was transformed into spirooxindole 6 by a reduction with sodium borohydride in a highly enantioselective manner. Keywords: 3,3'-disubstituted oxindoles; Michael reaction; organocatalysis; primary-tertiary

• enantioselectivity – albeit with a slight loss in yield. We further demonstrated that Michael adducts could be transformed into spirooxindoles by following a simple strategy. The reduction of Michael adduct 4a with sodium borohydride in ethanol followed by spontaneous cyclization gave spirooxindole product 6 in 90

• isatylidenemalononitrile. Substrate scope of the addition of 2 with 3 catalyzed by 1a D-CSA. One-pot, three-component Knoevenagel condensation–Michael addition. Cascade reduction–cyclization for the synthesis of spirooxindole. Solvent screening the Michael addition of acetone (2a) to isatylidenemalononitrile (3a

Additive-assisted regioselective 1,3-dipolar cycloaddition of azomethine ylides with benzylideneacetone

• Chuqin Peng,
• Jiwei Ren,
• Jun-An Xiao,
• Honggang Zhang,
• Hua Yang and
• Yiming Luo

Beilstein J. Org. Chem. 2014, 10, 352–360, doi:10.3762/bjoc.10.33

• 4-nitrobenzoic acid, respectively. The substituent effects on the regioselectivity were also investigated. Keywords: 1,3-dipolar cycloaddition; azomethine ylide; regioselectivity; spirooxindole; Introduction Spirooxindoles are important synthetic targets due to their significant biological

• employed as starting materials to conduct 1,3-dipolar cycloadditions to yield spirooxindole core structures [16][17][18][19][20]. Owing to the ease of preparation, the azomethine ylides generated from isatin with α-amino acids or amines were frequently chosen as important 1,3-dipolar intermediates to react

• spirooxindoles in good to excellent chemical yields with good regioselectivities. Furthermore, the regioselectivity can be conveniently tuned and reversed by simply adding water or 4-nitrobenzoic acid, which provides a facile approach to access a wide range of spirooxindole ring systems with novel substitution

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• and CCDC 972494 for 6a). The NOE correlations of the signals in 1H NMR spectra of compounds 4b–4d. Molecular structure of spirooxindole 4a according to X-ray diffraction data. The NOE correlations of the signals in 1H NMR spectrum of compound 6c. Molecular structure of spirooxindole 6a observed in

Facile synthesis of functionalized spiro[indoline-3,2'-oxiran]-2-ones by Darzens reaction

• Qin Fu and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 918–924, doi:10.3762/bjoc.9.105

• ; oxindole; oxirane; spiro-epoxyoxindole; spirooxindole; Introduction The spirooxindole unit is a privileged heterocyclic motif that forms the core structure of a large family of natural alkaloids and many pharmacological agents with important bioactivity and interesting structural properties [1][2][3][4][5