Synthesis of Spirocyclopropane Scaffolds: A Review

Abstract

This review highlights different synthetic strategies for preparing a spirocyclopropane moiety, covering the literature from 1989 to 2024. The spirocyclopropane moiety is a structural scaffold that is used to access synthetic libraries of highly functionalized spirocarbo- and heterocyclic molecules. The review showcases different routes for the synthesis of spirocyclopropanes that utilize distinct precursors and methodologies, including cascade reactions, cyclopropanation, Michael-initiated ring closure (MIRC), and one-pot and multicomponent synthesis. These discussions are organized around the oxindole core, which include isatin, oxindole, 3-chlorooxindole, and 3-alkenyl oxindoles. Additionally, this review explores various ylides and other techniques. The goal of this review is to provide a background for synthetic chemistry researchers to develop new ideas and novel synthetic routes to spirocyclopropanes.

1 Introduction

2 Synthesis of Spirocyclopropanes from 3-Chlorooxindole Derivatives

3 Synthesis of Spirocyclopropanes from Isatin Derivatives

3.1 Synthesis of Spirocyclopropanes from Alkylidene Oxindole Derivatives

3.2 Synthesis of Spirocyclopropanes from Diazooxindole Compounds

4 Synthesis of Spirocyclopropanes from 1,3-Diones

5 Synthesis of Spirocyclopropanes from N-Ylides

6 Synthesis of Spirocyclopropanes from S-Ylides

7 Miscellaneous Syntheses of Spirocyclopropanes

8 Conclusion

9 List of Abbreviations

Biographical Sketches

Chirag D. Patel received a bachelor’s degree in chemistry from B. P. Baria Science Institute (Veer Narmad South Gujarat University), Gujarat, India, and a master of science in organic chemistry from the Department of Chemistry (Uka Tarsadia University), Gujarat, India. He is currently pursuing his doctorate at the P. G. Department of Chemistry (Sardar Patel University), working under the mentorship of Prof. H. M. Patel. His research interests primarily include organic synthesis, heterocyclic chemistry, green chemistry, multicomponent reactions (MCRs), and asymmetric reactions.

Fouad Damiri earned his Ph.D. in organic and polymer chemistry from Hassan II University of Casablanca, Morocco, in 2021, under the supervision of Prof. Mohammed Berrada. In 2024, he was accepted for a postdoctoral position at the Free University of Brussels. His research focuses on the development of smart nanobiomaterials based on polysaccharides for drug delivery systems and organic chemistry. He actively contributes as an editorial board member and reviewer for numerous international journals. He has authored over 39 papers and 14 book chapters, which have collectively garnered 1,258 citations.

Mehul P. Parmar obtained his bachelor's degree in chemistry from the Maharaja­ Sayajirao University of Baroda in 2018, and his master’s degree in organic chemistry in 2020 from B. N. Patel Institute of Paramedical & Science College, Sardar Patel University, Gujarat, India. He is currently a Ph.D. student at the P. G. Department of Chemistry, Sardar Patel University, under the supervision of Prof. H. M. Patel. His research interests focus on green chemistry, synthesis of biologically active heterocycles, organic synthesis, asymmetric synthesis, natural products, multicomponent reactions (MCRs), and Computational and medicinal chemistry.

Disha P. Vala obtained her B.Sc. in chemistry in 2019 from Bahauddin Science College, Bhakta Kavi Narsinh Mehta University, and her M.Sc. in organic chemistry in 2021 from the P. G. Department of Chemistry, Sardar Patel University, Gujarat, India. She is currently a Ph.D. student at the P. G. Department of Chemistry, Sardar Patel University, under the supervision of Prof. H. M. Patel. Her research interests mainly focus on organic synthesis, heterocyclic chemistry, green chemistry, multicomponent reactions (MCRs), and 1,3-dipolar cycloaddition reactions.

Mohammed Berrada is a pioneer within the realm of polymer science, with extensive involvement in a myriad of university–industry technology transfer initiatives. At present, he holds the position of Head of the Innovation and Technology Platform at Hassan II University in Casablanca, Morocco, simultaneously fulfilling the role of a distinguished professor specializing in organic chemistry and polymer science. His unwavering devotion to pushing the boundaries of polymer science is underscored by his track record in both academic and industrial spheres. His contributions throughout the field have consistently reshaped and redefined the landscape of polymer research and innovation.

Hitendra M. Patel received his M.Sc. degree in chemistry from Veer Narmad South Gujarat University in 1996 and obtained his Ph.D. from Sardar Patel University in 2008. Between 1997 and 1998, he was a lecturer in chemistry at St. Xavier’s College, Ahmadabad, Gujarat, India. From 1998 to 2015, he was a lecturer at the V. P. & R. P. T. P. Science College, Vallabh Vidyanagar, Gujarat, India. In 2015, he became an associate professor (organic chemistry) at the Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, Gujarat, India. Since 2016 he has been working as a professor at the Department of Chemistry, Sardar Patel University, India. He is a co-author of more than 66 publications in organic synthesis, green synthesis, computational and medicinal chemistry, and antimicrobial and anticancer studies. His research interests include the development of bioactive heterocyclic scaffolds via multicomponent reactions, with a focus on green chemistry approaches and medicinal chemistry, including the synthesis of small molecules, and virtual and biomolecular screening.

Introduction

Cyclopropane, a structural motif found in various pharmaceutical drugs and biomolecules, plays a significant role in the synthesis of numerous heterocyclic organic compounds.[1] [2] It was first identified by Freund in 1882, who also correctly elucidated its molecular structure.[3] The cyclopropane ring consists of three methylene groups (CH₂) that are covalently bonded to form a three-membered ring. This structure induces considerable ring strain due to the small size of the ring. In 1929, Henderson and Lucas demonstrated its potential as an anesthetic, although it has since been replaced by more modern anesthetic agents.[4] The spirocyclopropane unit is commonly found in many pharmaceutical compounds and is an indispensable intermediate in the synthesis of bioactive molecules in drug discovery.[5] [6] [7] As a structurally unique scaffold, the spirocyclopropane moiety enables the generation of synthetic libraries containing highly functionalized spirocarb- and heterocyclic derivatives.[8] [9] [10] Due to the widespread occurrence of spirocyclic motifs as key pharmacophores in both medicinal chemistry and natural products, substantial progress has been made in recent years on the development of synthetic methodologies that exploit the selective cleavage of carbon–carbon bonds in spirocyclopropanes.[11]

The Simmons–Smith synthesis is one of the most versatile and widely utilized methods for the preparation of spirocyclopropanes. The Corey–Chaykovsky cyclopropanation is another prominent approach for constructing cyclopropane structures. In this reaction, an in situ generated sulfur ylide nucleophile reacts with a variety of electrophilic alkenes, including α,β-unsaturated carbonyl compounds.[12a] Aggarwal and colleagues extended this reaction by using sulfur- and nitrogen-based ylides for cyclopropanation. Later­, Connon and collaborators introduced the Michael-initiated ring closure (MIRC) method for the preparation of spirocyclopropanes, employing cinchona-based thiourea non-covalent catalysts to improve reaction efficiency. These methods provide highly diastereoselective products with modest enantiomeric excesses. Subsequently, Yan and co-workers further enhanced the diastereoselectivity of these reactions.[12b]

In the last twenty years, significant contributions from scientists, including Nobel laureates, have revitalized organocatalysis, solidifying its role as a fundamental component of asymmetric catalysis alongside organometallic and enzymatic systems. Research has demonstrated that organocatalytic methods are highly effective for efficient syntheses, with these techniques standing out for their precise stereochemical predictability, compatibility with various functional groups, and their metal-free nature.[14] Spirocyclopropanes have generated significant interest in lead innovation programs due to their biological and pharmaceutical applications,[15] with spirocyclopropane structural motifs­ being prevalent in anticancer drugs and pharmaceuticals.[6] Spirocyclopropyl oxindoles[16] [17] [18] [19] can be used to synthesize oxindole-containing natural products, including (±)-strychnofoline, (–)-horsfiline, and (–)-spirotryprostatin B.[20] In addition, they have a wide range of biological and pharmaceutical applications, such as in HIV-1 NNRTI (non-nucleoside reverse transcriptase inhibitors) and arginine vasopressin inhibition.[21] Furthermore, acylfulvene and irofulven were found to possess antitumor activity (Figure [1]).[22]

Several reviews have been published on the preparation of spirocyclopropanes. For example, Noroozi Pesyan and Rashidnejad[23] have discussed spirocyclopropanes annelated to both six- and five-membered rings. Meanwhile, Wu et al.[24] reported on synthetic routes to cyclopropanes based on catalytic systems in a review covering the years 2012–2017. Sakla and co-workers[12c] have reviewed methods for the preparation of spirocyclopropyl oxindoles based on synthetic precursors covering the literature from 2010 to 2020. They describe ring-opening strategies and the synthesis of three-, five- and six-membered spirocyclopropyl rings. Sibi and co-workers[14] have covered synthetic strategies towards cyclopropanes via Michael-initiated ring closure (MIRC) reactions, whilst Beutner and George[12a] mainly focused on the Corey–Chaykovsky cyclopropanation. We noticed that there was a gap in literature with respect to methods for the preparation of three-membered rings. Hence, in this review, we have focused on the diverse synthetic methodologies and wide range of precursors available for the construction of spirocyclopropanes.

Synthesis of Spirocyclopropanes from 3-Chlorooxindole Derivatives

Serving as a key precursor for spirocyclopropane formation, 3-chlorooxindole benefits from the dual functionality of the C3 atom. This reactivity has made it a preferred reagent for many researchers in recent times. The chloro substituent is an effective leaving group in nucleophilic substitution reactions, facilitating cyclopropanation.[25]

In a plausible mechanism (Scheme [1]),[26] 3-chlorooxindole is deprotonated by a base and forms an enolate. Next, this enolate and an arylidene form an intermediate via a Michael addition. This is followed by nucleophilic substitution of chloride to furnish the final spirocyclopropane.

Noole and co-workers[27] reported the synthesis of spirocyclopropane derivative 3 through the reaction of 3-chlorooxindole (1) with α,β-unsaturated aldehydes 2, catalyzed by amine catalyst A (20 mol%) in the presence of NaHCO₃ in toluene at room temperature. The reaction resulted in product yields of 44–76%, with diastereoselectivity of up to >20:1 and enantiomeric excesses of up to 99% (Scheme [2]). In addition, another method for synthesizing bis-spirooxindole 5 was developed by treating 3-chlorooxindole (1) with alkylidene oxindoles 4, using squaramide B (20 mol%) as the catalyst. This process gave products 5 in yields of 71–99%, with diastereoselectivity of up to >20:1 and enantiomeric excesses of 83–99%.

Ošeka and co-workers[25] reported that N-Boc-protected 3-chlorooxindole 1a and aryl-substituted unsaturated 1,4-diketones 6 reacted via a cascade reaction to give spirocyclopropane oxindoles 7 (Scheme [3]). They also used 3-chlorooxindole (1) without amine protection, but the low acidity of the hydrogen atom at C3 prevented the reaction from moving forward. When they used N-protected 3-chlorooxindole 1a, the reactions proceeded easily and gave good enantioselectivities and yields. In these reactions, thiourea-based catalysts E and F (10 mol%) gave products with similar ee values, whereas the squaramide catalyst D was not suitable for the reaction. Cinchona alkaloid F gave the best enantio- (75–87%) and diastereoselectivity (9:1 to 20:1) but the yields (42–70%) were low.

Li and co-workers[26] reported that treatment of arylidene pyrazolone 8 and 3-chlorooxindole (1) in the presence of a base at room temperature in different solvents gave the desired spirocyclopropane product 9 (Scheme [4]). They noticed that the reaction occurred very smoothly with many different bases, including K₂CO₃ (potassium carbonate), Et₃N (triethylamine), and DIPEA (N,N-diisopropylethylamine), delivering the desired products 9 with good yields and diastereoselectivities. The yield of product 9 was very low when NaHCO₃ was used as the base. When compared to other bases like K₂CO₃, Et₃N, and NaHCO₃, DIPEA provided an outstanding yield (up to 99%) and diastereoselectivity (up to >25:1). Furthermore, they explored different solvents for this reaction and observed that the best was dichloromethane, as it delivered a reasonable diastereoselectivity. The authors also explored various substituted 3-chlorooxindoles 1 and their effect on the yield and diastereoselectivity. From this evaluation, they suggested that the diastereoselectivity of product 9 was enhanced by the steric effect of 4-Cl and 3-Br substituents.

Kuang and co-workers[28] reported a cascade reaction of 3-chlorooxindole (1) with β,γ-unsaturated-α-ketoester 10 in the presence of the chiral N,N′-dioxide L-PrPr₂ and Na₂CO₃­ as a base at 0 °C, catalyzed by Sc(OTf)₃ (scandium(III) triflate) or Mg(OTf)₃ (magnesium(III) triflate) to afford the spirocyclopropane 11 (Scheme [5]). Different diastereomers were formed with Sc(OTf)₃ and Mg(OTf)₃. Employing La-RaPr₂/Sc(OTf)₃ increased the yield to 92% and achieved an enantiomeric excess of 78%. When the reaction temperature was lowered to 0 °C, the base stoichiometry was increased to 1.3 equivalents and the reaction time was increased to 72 hours, a 97% yield and a 92% ee were achieved.

Avula and co-workers[29] reported that treatment of CAC (chloroacetyl chloride) (13) and aniline (12) in the presence of K₂CO₃ and AlCl₃ (aluminum trichloride) in CH₂Cl₂ as a solvent gave intermediate 14, which on further treatment with CMOBSC ((chloromethoxy)benzenesulfonic acid) in acetonitrile gave 3-chlorooxindole (1). Furthermore, treatment of 2-benzylidene malononitrile 17 and chlorooxindole 1 in the presence of Et₃N in DCM at room temperature overnight gave spirocyclopropane 18 (Scheme [6]). Another strategy, which employs a one-pot method, utilizes substituted benzaldehydes 15, malononitrile (16), and 3-chlorooxindole (1) in the presence of Et₃N and ammonium acetate in CH₂Cl₂ and acetic acid under reflux conditions to also yield product 18.

Wen and co-workers[30] have reported that 2,3-dioxopyrrolidines 19 and 3-chlorooxindoles 1 reacted in the presence of squaramide catalyst B (5 mol%) and NH₄HCO₃ (ammonium bicarbonate) (0.1 mmol) in AcOEt (1.0 mL) at 0 °C to afford spirocyclopropane 20 (Scheme [7]). They employed an extensive range of inorganic and organic bases, and observed that organic bases did not produce the desired compound 20 with good yields and enantioselectivity. Utilizing organic bases in place of inorganic bases resulted in a decrease in diastereoselectivity. NH₄HCO₃ gave excellent yields (up to 94%) with ee values of >99% and diastereomeric excesses of >25:1. The reactivity of the substrate is largely dependent on the electronic characteristics of the substituents on the phenyl ring. Excellent yields and enantioselectivities were achieved when the aryl group was located on the N-atom of the 2,3-dioxopyrrolidines. On the other hand, the yield and enantioselectivity decreased when a methyl group was present on the N atom of the 3-chlorooxindole.

Chen and co-workers[31] have reported the reaction of 3-bromooxindoles 21 and α,β-unsaturated acyl phosphonates 22 using DABCO (1,4-diazabicyclo[2.2.2]octane) and NaHCO₃ under a nitrogen atmosphere at room temperature. Subsequently, the mixture was heated in an oil bath at 90–120 °C and then cooled to 0 °C on an ice bath and quenched with an alcohol and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) for 20 minutes. The reaction slurry was diluted with CH₂Cl₂ and filtered through a thin pad of silica gel. The filtrate was then concentrated under reduced pressure and the residue purified to give the desired product 23 (Scheme [8]). In addition, the authors utilized pyridine, Et₃N, DBU, imidazole, DIPEA, DMAP (4-dimethylaminopyridine), and other catalysts; however, each of these catalysts caused a decrease in the product yield and diastereoselectivity compared to DABCO. They also screened several solvents and concluded that the polarity of the solvent influenced the reaction. Hydrocarbon and ester solvents gave decreased yields, whilst toluene was found to be the best candidate for the reaction 3-bromooxindoles having electron-withdrawing groups. 3-Bromooxindoles with electron-donating groups gave lower yields, even on raising the reaction temperature. In terms of the C6 position, the presence of weaker electron-donating halogen groups gave good diastereoselectivities (up to 99:1) and yields (10–72%) of the target compounds.

Zhang and co-workers[32] reported that p-QMs (para-quinone methides) 24 and 3-chlorooxindoles 1, in the presence of DBN (1,5-diazabicyclo[4.3.0]non-5-ene) in THF and stirring the reaction mixture at room temperature for 5 minutes, gave bis-spiro cyclopropanes 25 (Scheme [9]). After examining a range of solvents, including ether, organic solvents, and aprotic solvents, it transpired that ether was the most suitable in the presence of the base in THF. The authors also investigated several types of base, including organic, inorganic, acyclic, and fused bicyclic amidine bases. Of these, the fused bicyclic amidine base DBN was among the most efficient and appealing since it led to a respectable 93% yield and 95:5 dr in only five minutes. In practice, DBU and DBN performed identically when utilized as bases. Both electron-donating and electron-withdrawing groups on the substituted p-QMs were appropriate for the reaction. Furthermore, the authors observed that the presence of substrates with electron-withdrawing groups slightly lowered the reaction efficiency. When the p-QMs contained a weak or strong electron-donating group on the phenyl ring, the reactions proceeded smoothly to afford a good yield and diastereoselectivity (>95:5 dr). By fixing the p-QMs and then examining different substituents, such as halo and methoxy groups, on the 3-chlorooxindole, they obtained excellent yields and diastereoselectivities. When substrate 1 contained a substituent like methyl or benzyl on the N atom, the yield decreased and some unidentified by-products were obtained; however the products exhibited good diastereoselectivity. The authors also found that the target compounds were obtained in high yields when both substrates had substituents on the phenyl ring.

Yuan and co-workers[33] reported that the reactions of 3-benzoylcoumarins 26, 3-bromo- 21 or 3-chlorooxindoles 1, Na₂CO₃ and DABCO or 1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)thiourea (20 mol%) performed with catalyst B in CH₂Cl₂ at room temperature gave racemic products 27 (Scheme [10]). They used quinidine as the catalyst and CH₂Cl₂ as the solvent to afford the desired products. Next, they used bifunctional squaramide catalysts G and H, however, catalyst B gave the best result in terms of yield, diastereoselectivity and ee. After screening various solvents, the authors found that CH₂Cl₂ was the most suitable. When the catalyst concentration was decreased from 10 mol% to 5 mol%, the enantioselectivity of the reaction decreased. 3-Benzylcoumarins with substituents at C5, C6, C7, or C8 can affect the reactivity and stereoselectivity, with ee values of 90–97% being obtained. Coumarin substrates with electron-donating groups like methyl, methoxy, ethoxy and t-Bu gave the target compounds with satisfactory yields. 3-Bromooxindoles with electron-donating groups gave high yields and excellent diastereoselectivity (98:2 to 99:1 and 91–94% ee), whilst examples with electron-withdrawing groups also gave high yields and diastereoselectivities, albeit with moderate enantioselectivities. When the authors used 3-chlorooxindoles instead of 3-bromooxindoles 21, the resulting products were obtained in good yields, although the ee values were lower. Thus, the nature of the 3-halooxindole 21/1 affects the enantioselectivity of the product 27.

In 2022, Wang and co-workers[34] reported an effective asymmetric cascade Michael addition/alkylation reaction between 3-chlorooxindoles 1 and α-cyanochalcones 28 utilizing chiral catalysts I, J and K. The use of catalyst H and KHCO₃ (potassium bicarbonate) as the base in chloroform gave the desired product 29 in 68% yield but with low diastereoselectivity (Scheme [11]). The yield increased slightly when catalyst B was used, however, catalysts J and K proved to be best, increasing the diastereoselectivity and enantioselectivity. When the authors added 4 Å MS (molecular sieves) to the reaction, the enantioselectivity of the product increased. α-Cyanochalcones with electron-donating, electron-withdrawing or heteroaryl substituents all reacted to give the desired products in high yields and moderate to high diastereoselectivities (7.5:1 to 12:1) and ee values (83% to 93%). 3-Chlorooxindoles 1 with electron-donating substituents gave products with increased diastereoselectivity (12:1 and 13:1) and enantioselectivity (90%), whilst those with electron-withdrawing groups gave diastereoselectivities of 6.5:1 and 8:1 and decreased enantioselectivities of 64–70%.

Synthesis of Spirocyclopropanes from Isatin Derivatives

In 1840, Erdmann and Laurent succeeded in isolating 1H-indole-2,3-dione (isatin). Isatin derivatives undergo a wide range of chemical reactions, including aldol condensation, the Friedel–Crafts reaction, ring expansion, and oxidation.[35] Isatin is a key compound in the synthesis of many spirocyclopropanes, and the available routes can be systematically categorized into three distinct paths: (1) From isatin to diazo, (2) directly away from isatin, and (3) from isatin to alkylidene. These are based on whether isatin is utilized directly or after transforming one of its carbonyl groups (Figure [2]).

Kayukova and co-workers[36] reported that isatin (30) and 1,5-disubstituted isatins 30a reacted with bromomalononitrile (31) in IPA (isopropyl alcohol). Subsequent treatment with an aqueous solution of sodium iodide led to formation of the corresponding spirocyclopropane derivatives 35 (Scheme [12]).

Peng and co-workers[37] reported the reaction of [(Me₃Si­)₂N]₃Yb(μ-Cl)Li(THF)₃ (0.20 mmol), N-allyl isatin 30a (0.5 mmol) and diethyl phosphite (0.6 mmol) in MeCN (0.5 mL) with a solution of alkene 36 (1.5 mmol) in MeCN for the preparation of spirocyclopropanes 37. When the methyl acrylate and isatin ratio was 3:1, the obtained yield was high. Also, when the amount of the [(Me₃Si)₂N]₃Yb(μ-Cl)Li(THF)₃ catalyst was increased from 30 mol% to 40 mol%, the yield rose from 84% to 92%. However, further increases beyond 40 mol% did not impact the yield. The authors also investigated different lanthanide amides and discovered that [(Me₃Si)₂N]₃Yb(μ-Cl)Li(THF)₃ was the best candidate as a catalyst. An isatin containing an electron-donating group on the phenyl ring resulted in decreased reactivity, an increased reaction time and also had impact on the yield of 37 (Scheme [13]). Benzyl, N-ethyl, and n-propyl isatins reacted smoothly and gave products 37.

Hajra and co-workers[38] reported the reaction of a solution of TMSOI (trimethylsulfoxonium iodide) (39) in DMSO (dimethyl sulfoxide) and NaH (sodium hydride) with stirring at 25 °C for 5 minutes to produce a sulfur ylide, which reacted with substituted isatin 30b, spiro epoxides 38 or spiro aziridines 38a via a domino Corey–Chaykovsky reaction in one pot to afford spirocyclopropyloxindoles 40 (Scheme [14]). In this study, the authors tested substrates possessing different electron-donating and electron-withdrawing substituents, but these groups did not affect the results. They also experimented with unprotected oxindoles, which yielded spirocyclopropyl oxindoles 40. In addition, they utilized several substituted spiro epoxy oxindole, which gave good product yields (up to 73%).

In 2022, Ma and co-workers[39] reported that the reaction of isatin 30b and α-bromo(chloro)acetophenone 41 in MeCN in the presence of triethylamine 20 mol% and α-picoline as an additive gave the desired spiro product 42 after stirring at reflux for 12 hours (Scheme [15]). In the absence of an additive, the spiro product was only formed in trace quantities. Different additives such as pyridine, 3-methylpyridine, 4-methylpyridine, 2,6-lutidine, 2-methylpyrazine, and 2-methylquinoline were used but α-picoline proved to be the best. As a base catalyst they utilized DABCO, DBU, NaOH and Et₃N, of which Et₃N emerged as the best. DMF, THF, water and MeCN were tested as solvents, with MeCN emerging as the best choice. The yield was reduced to 62% when a methyl group (an electron-donating group) was present on the benzene ring, while the presence of a methoxy group on the bromoacetophenone phenyl ring did not yield the final product. When chloro and bromo groups were present, the reactions proceeded very well and good yields (74–85%) were obtained.

Jiang and co-workers[40] have reported that isatin 30a and Wittig reagents reacted to form two stereoisomers, 43a and 43b, with a ratio of 5:1. In the next step, the olefins were treated with diazomethane (44) under reflux conditions in toluene, yielding spirocyclopropane derivatives 45 (Scheme [16]). The nitro-substituted analog was then hydrogenated for 7 hours to give aniline analogue 46.

In 2006, Jiang and co-workers[41] reported the synthesis of tetrazole analogues 51a and 51b. A Wittig reaction of isatin 30a was initially performed to yield olefin 47. The olefin was then treated with diazomethane (44) at room temperature, followed by reflux in toluene, which produced spirocyclopropane oxindole 48 (Scheme [17]). Compound 48 was reacted with azidotrimethyltin (49) to yield tetrazole 50. Finally, methylation of compound 50 using diazomethane 44 led to a 2:1 regioisomeric ratio of tetrazoles 51a and 51b.

Jiang and co-workers[41] have also reported the reaction of substituted isatin 30a with different aldehydes 15 in the presence of piperidine as the catalyst and ethanol as the solvent to form olefins 52. The olefins were then treated with diazomethane (44) in the presence of a rhodium(II) acetate catalyst, resulting in various heteroaryl analogues 53 (Scheme [18]).

Reddy and co-workers[42] reported the reactions of isatins 30/30b with acetophenones 54 to give 3-methyleneindolin-2-one derivatives 55, which were then refluxed with ethylenediamine (56) in THF for 24 hours to yield diastereomerically pure spiro[cyclopropan-1,3-indolin]-2-ones 57. Reduction of the carbonyl group in 57 with sodium borohydride in ethanol gave the corresponding alcohol 58. In addition, isatins 30/30b and (ethoxycarbonylmethylene)-triphenylphosphorane (59) were refluxed in THF for 6 hours, giving (E)-ethyl 2-(2-oxoindolin-3-ylidene) acetates 60. These were subsequently treated with ethylenediamine (56) to afford diastereomerically pure spiro[cyclopropan-1,3-indolin]-2-ones 61 (Scheme [19]).

Rodriguez and co-workers[43] reported the reaction of a mixture of isatin 30b and alkylidene oxindoles 62 in CH₂Cl₂ with cooling at –78 °C. Following the dropwise addition of P(NMe₂)₃ (tris(dimethylamino)phosphine), the reaction mixture was allowed to warm to room temperature for 2 to 2.5 hours to yield the spirocyclopropane products 63 in yields of 46–96% and diastereoselectivities of 6:1 to 10:1 (Scheme [20]).

Synthesis of Spirocyclopropanes from Alkyl­idene Oxindole Derivatives

Trisubstituted alkenes serve as very favorable precursors for building three- to seven-membered 3-spiro(hetero)- or 3-spiro(carbo)-cyclic indoles.[35] Alkylidene oxindoles are electron-rich compounds that favor cyclopropanation reactions, and this results in the formation of spirocyclopropane products via a wide range of precursors and methodologies.

In 2015, Sampson and co-workers[44] reported a modified Corey–Chaykovsky synthesis by adding a solution of trimethylsulfoxonium iodide (39) in anhydrous DMF (40 mL) to NaH at 0 °C. The reaction mixture was stirred for 15 minutes, after which methylene-indolin-2-one 64 (1 equiv) was added and the resulting mixture was stirred overnight. The authors obtained spirocyclopropanes 65a/65b from substrates 64, which existed as racemic mixtures of trans and cis diastereomers (Scheme [21]).

Kapure and co-workers[21] reported that 3-methyleneindolin-2-ones 66 and tosyl-hydrazone salts 67, in the presence of a THF/acetonitrile mixture (4:1, v/v), afforded spirocyclopropanes 68 (Scheme [22]). They also tested other solvents, and to achieve a better yield, they used 10 mol% of BTEAC (benzyltriethylammonium chloride) as an additive, which enhanced the reaction by increasing the solubility of the salt. Using an excess amount of the salt improved the yield. Increasing the temperature also accelerated the reaction, with 50 °C being the optimal temperature; however, further increasing the temperature led to a decrease in the yield. Substituted aromatic aldehydes with electron-donating groups underwent cyclopropanation more quickly compared to those with electron-withdrawing groups. The use of substituted oxindoles had a slight effect on the yield (75–88%).

In 2017, Han and co-workers[45] reported the reaction of compound 71 with in situ generated CF₂HCHN₂ (70) in CH₂Cl₂ at room temperature for 48 hours, followed by refluxing the reaction mixture in toluene for 2 hours, which led to the formation of CF₂H-containing spirocyclopropyl oxindole (±)-72 (Scheme [23]) in 88% overall yield and a 94:6 (trans/cis) ratio. 3-Ylideneoxindoles 71 with various electron-donating and electron-withdrawing substituents at the C5 position gave product yields ranging from 71–91%, with trans/cis ratios of 93:7 to 99:1. Ester-substituted 3-ylideneoxindoles resulted in increased yields, from moderate to high, and diastereoselectivities, from high to excellent.

Noole and co-workers[46] reported a [2+1] cycloaddition method for synthesizing spirocyclopropane oxindoles 75, which contain two quaternary centers, using chiral catalysts C, D, F and L. In this method, they treated the oxindole with ethyl α-chloroacetoacetate and catalyst D as a base in CH₂Cl₂ at room temperature, yielding a 3:1 diastereomeric ratio with a minor amount of a third diastereomer. The major product had 96% ee. Next, they used bifunctional thiourea catalysts C and F. When they tested different solvents such as CH₂Cl₂, THF, CHCl₃, toluene and MeCN, CHCl₃ gave the best results in terms of both diastereoselectivity (90:10) and yield. NaHCO₃ was preferred as the base compared to other bases such as CsF and K₂CO₃. Catalyst F gave identical results to catalyst C, while catalyst L, with bulky ⁱ Pr groups at the ortho positions, resulted in increased diastereoselectivity and provided good yields. Substitution on the aromatic ring of substrates 73 did not affect the results (Scheme [24]).

Xiao and co-workers[47] reported that N-benzyl-3-alkenyl-oxindoles 76 and diazo compounds 77 in the presence of B(C₆F₅)₃ as the catalyst gave substituted 3-spirocyclopropane-oxindoles 78. These reactions were performed in different solvents like dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate, and n-hexane, among which n-hexane was the best candidate. The authors also utilized different catalysts such as Fe(OTf)₃ and Sc(OTf)₃ as Lewis acid catalysts but the reaction did not proceed, hence B(C₆F₅)₃ is the best catalyst for this reaction. They also stated that 10 mol% of the catalyst was optimum (98% yield and 14:1 dr); decreasing the amount of catalyst to 5 mol% maintained the diastereoselectivity but the yield was decreased. Reaction optimization showed that ArN₂CCO₂Me substrates having electron-withdrawing groups (e.g., Ar = 4-BrC₆H₄, Ph, 4-FC₆H₄, 4-ClC₆H₄, 4-CF₃C₆H₄, 3-BrC₆H₄) reacted smoothly and gave excellent yields (93–99%), with diastereoselectivities ranging from 12:1 to 20:1. With respect to the C5 position of the oxindole, electron-donating groups resulted in excellent yields and dr values of up to 14:1, whilst electron-withdrawing groups also gave excellent yields (79–99%) and high diastereoselectivities (20:1). When the oxindole had an electron-donating or an electron-withdrawing at the C6 position, the yield and diastereoselectivity decreased (Scheme [25]).

In 2023, Manna and co-workers[48] reported a Michael-initiated ring-closure reaction (MIRC) using an organocatalyst. In this reaction, 3-alkylidene oxindole 79, 5-(chloromethyl)-3-methyl-4-nitroisoxazole 80, and sodium bicarbonate in the presence of various organocatalysts in PhCF₃ as the solvent at room temperature gave the desired product 81. The authors screened various cinchona-alkaloid-based bifunctional organocatalysts G, M, N and O, which yielded moderate to good results with excellent stereoselectivity (up to 55% ee and >20:1 dr) under the same reaction conditions. Among these organocatalysts, M was found to be the best candidate. When substituted oxindoles with electron-donating groups were used, good yields were obtained along with excellent diastereoselectivities and enantioselectivities. Oxindoles containing halogens at the C5 and C6 positions afforded the corresponding products with high levels of stereoselectivity. A phenyl-substituted 4-nitroisoxazole also gave a good yield along with excellent diastereoselectivity and enantioselectivity (Scheme [26]).

Synthesis of Spirocyclopropanes from Diazooxindole Compounds

Diazooxindoles are excellent entry points for constructing spirocyclopropanes. Isatin is primarily utilized in synthesizing diazooxindoles. Because of their electrophilic nature diazooxindoles react with species that are rich in electrons during cyclopropanation, eliminating N₂ to form spirocyclopropanes. A plausible mechanism for the synthesis of spirocyclopropanes via diazooxindoles is shown in Scheme [27].[20]

In 2006, Jiang and co-workers[40] reported that isatin 30a and tosyl hydrazine (82) react via the tosyl hydrazone to give diazo lactam 83. Diazo lactam 83 further reacts with olefins 84 in the presence of a rhodium catalyst to form the cyclopropane analogues 85 (Scheme [28]).

Cao and co-workers[49] reported substrate scope studies using diazo oxindoles 83a and a variety of cis-alkenes 86. The reactions were performed at 0 °C for 0.3 hours in PhF as the solvent in the presence of L1 (4.4 mol%), (Me₂S)AuCl (8.8 mol%) and AgBF₄ (4.0 mol%) as the catalyst to give excellent yields of products 87 (Scheme [29]).

Muthusamy and Ramkumar[50] reported the synthesis of spiro[cyclopropan-1,3-oxindoles] 89 and 91. The reaction of diazo amides 83 (1 equiv) with monosubstituted alkenes 88 was carried out at 90 °C or 110 °C under metal-free and solvent-free thermal conditions, yielding spirocyclopropanes 89. The authors conducted reactions at different temperatures and found that no reaction occurred in the range of 30–40 °C. As the temperature increased, the yields also increased. When the reaction was carried out at 90 °C or 110 °C, a 95% yield was achieved with a diastereomeric ratio of (70:30 to 90:10). The reaction of diazo amides 83 (1 equiv) and disubstituted alkenes 90 in the presence of two drops of toluene carried out at 90 °C gave spiro[cyclopropan-1,3-oxindoles] 91 (Scheme [30]).

In 2014, Karthik and co-workers[20] reported the cyclopropanation of substituted diazo oxindole 83a with ylidene oxindole 92. The reaction took place in benzene at reflux to give strained bis-spirocyclopropyloxindole 93 in 86% yield as an inseparable mixture of diastereomers (Scheme [31]).

Muthusamy and Ramkumar[51] reported the reaction of diazo compounds 83 and chalcones 94 by using various catalysts in water (2 mL) at room temperature to afford spirocyclopropanes 95 (Scheme [32]). They also used rhodium(II), copper(I) and copper(II) as catalysts but did not obtain the desired products. On using Sc(OTf)₃, Yb(OTf)₃ (ytterbium(III) trifluoromethanesulfonate) or ZnCl₂ (zinc chloride), they obtained spirocyclopropanes, but when InCl₃ (indium chloride) was used, the corresponding spirocyclopropane was obtained in a good yield. The yield was affected when substituted chalcones were used. If the chalcone had an electron-donating group the yield of 95 increased, but if an electron-withdrawing group was present the yield of 95 decreased. The reaction of diazo amide 83 with diethyl fumarate gave spirocyclopropane 95 but the product was a single isomer, and with methyl acrylate the expected spirocyclopropane was obtained with good diastereoselectivity. In this process, 20 mol% of InCl₃ was recovered and reused as the catalyst.

In 2019, Suleman and co-workers[52] reported the reactions of 3-diazoindolin-2-imines 96 and sulfoxonium ylides 97 in the presence of Cu(CH₃CN)₄PF₆ as the catalyst in DCE at room temperature to give spiro[cyclopropan-1,3′-indolin]-2′-imines 98 (Scheme [33]). They also utilized other catalysts for this reaction. For example, CuI gave a 24% yield of 98 along with recovered starting compound 96. The reaction did not occur with Cu(OTf)₂ (Cu(II)), Rh(III), Rh(II) and Ru(II). When the N atom of the 3-diazoindolin-2-imine 96 was substituted with Me, Et, isopropyl, benzyl or allyl, yields of 60–94% and diastereoselectivities from 74:26 to 90:10 (trans/cis) were obtained. Without protection of the N atom the reaction did not occur. Substrates 96 with electron-donating groups at the C5 position gave yields of 98 of 68–80% and diastereoselectivities of 91:9 to 90:10, whilst electron-withdrawing groups at the same position gave yields of 98 of 64–67% and diastereoselectivities of 87:13. Substituents at C7, C6 and C4 of 96 gave good yields and diastereoselectivities. Sulfoxonium ylides with electron-donating groups gave product yields of 64–87% and diastereoselectivities of 90:10 to 95:5, whilst those with electron-withdrawing groups gave yields of 68–91% and diastereoselectivities of 84:16 to 90:10. When a methyl group was present at the para position, trans (major) and cis (minor) diastereomers were isolated. When the keto-sulfoxonium ylide had an electron-withdrawing group at the meta position the product yield was 61% with 84:16 dr, and with an electron-donating group the yield was 73% and the diastereoselectivity was 94:6. No reaction took place when the ortho position had an electron-withdrawing group. In addition, a 2-methyl-substituted sulfoxonium ylide gave only the cis product.

Zhao and co-workers[53] reported the reaction of isatins and TsNHNH₂ in THF at 60 °C, stirring for 2 hours and then adding to a solution of NaOH (0.2 N) and stirring at 60 °C for 1 hour to yield 3-diazooxindoles 83. The 3-diazooxindoles 83 were dissolved in benzene (99%) and stirred at room temperature while being irradiated with blue LEDs (470 nm, 6 W) for 72 hours, resulting in the final products 100 (Scheme [34]). The authors also investigated different concentrations of the 3-diazooxindoles and obtained varying yields of products 100, concluding that lower concentrations were more suitable for cyclopropanation. Using a concentration of 0.01 M and a reaction time of 24 hours, they obtained an 82% yield of product 100 with highly diastereoselectivity.

In 2022, Pan and co-workers[54] reported that styrenes 102 and diazo thio-oxindoles 101 in DCE at 0 °C in the presence of dirhodium chiral complexes P, Q and R gave the target compounds 103 with enantiomeric excesses of up to 51% (Scheme [35]). The ee increased to 81% when they used complex S, where X is Rh₂(S-PTTL), and further increased to 86% and 93% when X is Rh₂(S-TFPTTL)₄ and Rh₂(S-TCPTTL)₄ (fluorinated and chlorinated catalysts), whilst also lowering the diastereomeric ratio. Rh₂(S-TCPTTL)₄ in diethyl ether gave a 9:1 dr and 93% ee; other ether solvents were used but no improvements in the results were observed. When they decreased the concentration of the diazo thio-oxindole from 0.1 to 0.05 M, 10:1 dr, 97% ee and a 92% yield of the desired product 103 were obtained. Styrenes with electron-donating or electron-withdrawing groups at the para position gave the desired products 103 in yields of 85–94%, diastereomeric ratios of 6:1 to 13:1 and ee values of 90–97%. m-Bromostyrene gave similar results: 14:1 dr, 98% ee and 83% yield, however, o-bromostyrene gave a low yield and diastereomeric ratio of the expected product, albeit with 97% ee. Thio-oxindoles substituted with Me, OMe or Cl groups gave the desired products with diastereomeric ratios of 12:1 to 16:1, enantioselectivities of 82–96% and yields of 93–99%.

Synthesis of Spirocyclopropanes from 1,3-Diones

One active CH₂ group and two carbonyl groups are present in 1,3-diones, which thus have three contiguous reactive electrophilic and nucleophilic sites.[55] The active CH₂ group in 1,3-diones interacts with electron-rich species and forms spirocyclopropanes with this carbon atom by cyclopropanation. In this section we discuss routes towards spirocyclopropane formation from 1,3-diones. Plausible reaction mechanisms are followed for the synthesis of spirocyclopropanes via 3-chlorooxindoles and S-ylides depending on the reaction precursors.

In 2010, Elinson and co-workers[56] reported the direct transformation of benzylidene malononitriles 17 and N,N′-dialkylbarbituric acids 104 in the presence of bromine and EtONa in ethanol as the solvent, yielding 2-aryl-4,6,8-trioxo-5,7-diazaspiro[2,5]octane-1,1-dicarbonitriles 105 in yields of up to 95% yield (Scheme [36]). However, increasing the amount of EtONa resulted in a decreased yield of 105 and also led to the oligomerization of the starting compound.

Russo and co-workers[13] reported that the reactions of compounds 106 with dimethyl bromomalonate 107 and tertiary and secondary amines in the presence of CHCl₃ at room temperature gave cyclopropanes 108 (Scheme [37]). Among various amines, triethylamine proved to be the best base, producing a 99% yield and 60–85% ee of the desired cyclopropane. A variety of α-bromomethylene-active compounds were treated with substrate 106. The corresponding cyclopropanes were obtained in quantitative yields in short reaction times, but in the case of bromonitromethane, the product 108 was not formed.

Li and co-workers[57] synthesized cyclopropanes 110 via reactions of aldehydes 15 with Meldrum’s acid (109) and benzoyl sulfoxonium ylides 97 in the presence of DIPEA as a catalyst in ethyl acetate at room temperature for 5 hours (Scheme [38]). They tested various solvents: in CCl₄ the yield of 110 decreased to 32%, while in ethyl acetate the yield was 76%. Therefore, ethyl acetate was found to be the best solvent for the reaction. The authors also studied the effect of the amount of starting materials on the formation of products 110. Decreasing the amount of aldehyde resulted in a decreased yield of the product. When 15 and 109 were used in a 1.5:2 equivalent ratio, an 86% yield of 110 was obtained. The presence of electron-withdrawing groups (EWGs) and electron-donating groups (EDGs) on the benzoyl sulfoxonium ylides resulted in moderate to good yields of products 110 at 50 °C for some substrates, which helped reduce the reaction times. Steric hindrance did not affect the yields of 110.

In 2008, Ren and co-workers[58] synthesized cyclopropanes 112 by treatment of 2-(4-chlorobenzylidene)-2H-indan-1,3-diones 106 with phenacyl bromide (111) using NaHCO₃ in different solvents under reflux in the presence of Ph₃As (10 mol%) as the catalyst. In this reaction, polar solvents such as CCl₄, THF and MeCN gave higher yields, while the reaction carried out in dioxane at a higher temperature did not produce spirocyclopropanes 113 and 113a (Scheme [39]). This shows that a higher temperature was not favorable for the reaction and that MeCN was the best candidate as solvent. The use of a surfactant increased the solubility of the substrates and the reactions proceeded smoothly in water to give products 113/113a. However, in the absence of a surfactant, the reaction did not proceed. The authors also attempted to carry out the reaction using CTMAB (cetyltrimethylammonium bromide) as the surfactant in water at 40 °C, which resulted in an 86% yield of 113/113a, being higher than that obtained in MeCN as the solvent.

Banothu and co-workers[59] have synthesized trans-2-(4-chlorobenzoyl)-3-aryl-spiro[cyclopropane-1,2′-inden]-1′,3′-diones 115 by initial treatment of pyridine with 4-chlorophenacyl bromide (114) in acetonitrile with stirring for 30 minutes at room temperature. Next, the intermediate N-4-chlorophenacylpyridinium bromide (pyridinium ylide), aryl aldehyde 15 and 1,3-indandione 106a were refluxed for 8–10 hours with the crude product 115 separating out, which was then filtered and purified (Scheme [40]).

Ghorbani-Vaghei and co-workers[60] reacted aldehydes 15 (1 mmol), indane-1,3-dione (106a), NaOAc, TBBDA (tetrabromobenzene-1,3-disulfonamide) or PBBS (polybrominated biphenyl) or TCBDA (N′-tetrachlorobenzene-1,3-disulfonamide) or PCBS (polychlorinated biphenyl) in ethanol at room temperature to prepare cyclopropanes 116 (Scheme [41]). After completion of the reaction, the solid product was filtered and washed with ethanol. When pyridine/Et₃N was used as a base, product 116 was obtained in only a trace amount. Other bases such as K₂CO₃, DBU, NaHCO₃, DABCO, and NaOEt were also used but none of these gave better results than sodium acetate. The use of N-bromosuccinimide and N-chlorosuccinimide as halogen sources resulted in decreased yields of 116 and longer reaction times. The reaction was also carried out in various solvents and ethanol was found to be the best. Increasing the temperature of the reaction did not affect the isolated yield of product 116. Various arylaldehydes bearing EWGs and EDGs reacted with the diones to give the corresponding spirocyclopropanes 116 in good to high yields.

In 2016, Qian and co-workers[61] utilized a white-light-promoted methodology for the preparation of spiro[2.4]heptane-4,7-diones 117 at room temperature via treatment of substrates 102a with dione 106a in the presence of an additive and a base in ethyl acetate under an argon atmosphere (Scheme [42]). Among various inorganic and organic bases, TDB (triazabicyclodecane) was found to be best for this reaction. Olefins with methyl or phenyl substituents gave products 117 in yields of 70% and 71%, respectively. The presence of electronegative substituents decreased the yields of spirocyclopropanes 117.

Nie and co-workers[62] treated acetophenone 54 with pyridine and then added I₂ to the mixture. After stirring the reaction mixture at room temperature and then for 30 minutes under reflux conditions, 1,3-indandione (106a), Et₃N and aromatic aldehyde 15 were added, and the resulting mixture was heated at reflux under an argon atmosphere to afford products 118 (Scheme [43]). Several solvents, such as THF, CH₂Cl₂, dioxane, MeCN, MeOH, and water, along with different bases, including Et₃N, piperidine, p-dimethylaminopyridine and K₂CO₃, were evaluated, and it was determined that Et₃N and MeCN were optimal for this reaction.

Penjarla and co-workers[63] have developed a MIRC (Michael­-initiated ring closure) assisted and Cu(OAc)₂ (copper(II) acetate) catalyzed oxidative dehydrogenation coupling in the presence of oxygen. The copper acetate was used to form a C–C bond in the presence of oxygen. Some reports also claim that it can be used for the synthesis of spiro systems. Treatment of 2-benzylidine-1,3-indandione 106 with 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (8a) in the presence of Cu(OAc)₂ and Et₃N as the base in ethyl acetate at room temperature for 10 hours resulted in the formation of cyclopropanes 119 (Scheme [44]) in up to 90% yield and with 16:1 diastereoselectivity. When they used different reagents such as I₂ and DAIB ((diacetoxyiodo)benzene) instead of copper acetate, the yield decreased and the diastereomeric ratios showed nominal/minor changes. They also utilized various solvents like CH₂Cl₂, THF, ethanol and toluene, which all resulted in lower yields of products 119. When the reaction was carried out under a nitrogen atmosphere, the yield as well as the diastereomeric ratio of 119 decreased. Halogen-substituted arylidenes 106 gave the desired products in yields of 78–91%. 2,5-Difluoro- and 2-chloro-4-fluoro- substitution patterns had a negative impact on the reaction yield.

In 2023, Wang and Yang[64] reported that the grinding of phenylidene malononitrile 17 and 1,3-indandione (106a) in the presence of iodine and KF·2H₂O produced the desired spirocyclopropane 120 with a yield of 57% (Scheme [45]). The authors used various bases like Na₂CO₃, NaHCO₃, Cs₂CO₃, NaOMe, DMAP, Et₃N and KF·2H₂O (potassium fluoride dihydrate). Among these, KF·2H₂O was the most suitable base. It enabled a shorter reaction time and increased the yield to 61%. They also tried different amounts of KF·2H₂O and found that 3 equivalents, along with 1.1 equivalents of I₂, was best, resulting in an increase in the yield of 120 to 84%. Alkenes 17 having EWGs and EDGs at the para position reacted smoothly, giving rise to higher product yields of 89% and 83%. Additionally, ortho- and meta-substituted alkenes 17 reacted smoothly and gave 77–94% yields of cyclopropanes 120; the steric hindrance of the substituents did not affect the yields of products 120.

Zhang and co-workers[65] reported that the reaction of 1,3-indandione (106a), styrene 102, Pd(OAc)₂ (5 mol%), Cu(OAc)₂, and TFA in toluene as the solvent gave spirocyclopropane 121 (Scheme [46]). Different substituted styrenes 102 gave similar results. When electron-donating and electron-withdrawing groups were present on the styrene, the reactions proceeded smoothly and gave good yields (65–84%) of the corresponding products.

Noroozi Pesyan and co-workers[66] have reported the reaction of Meldrum’s acid (109) (2.0 mmol) with aldehydes 15 using Et₃N (0.63mmol) in methanol. Cyanogen bromide (BrCN) (0.96 mmol) was dissolved in methanol at 0 °C and the resulting solution was added dropwise at 0 °C. The stirred mixture was then allowed to warm to room temperature. Following work-up, spirocyclopropanes 122 were obtained in yields of 45–85% (Scheme [47]). The experimental findings showed that aromatic aldehydes were more reactive than aliphatic examples. Aromatic aldehydes with electron-withdrawing substituents were more reactive than those with electron-donating groups. Furthermore, aromatic aldehydes bearing strong electron-donating groups produced only Knoevenagel adducts.

Synthesis of Spirocyclopropanes from N-Ylides

N-Ylides are inner-salts that promote the generation of spirocyclopropanes via cyclopropanation reactions. They possesses a positively charged nitrogen and a negatively charged halogen or carbanion, and cyclopropanation takes place by elimination of nitrogen-containing compounds.

In this mechanism,[67] a pyridinium salt is deprotonated by the base and forms a pyridinium ylide/N-ylide. Subsequent Michael addition of the N-ylide on the arylidene bond of an oxindole forms an intermediate. This intermediate undergoes intramolecular substitution of the carbanion with elimination of pyridine to form the spirocyclopropane product (Scheme [48]).

In 2013, Fu and Yan[67] developed a new method for the formation of cyclopropanes 125 by the reaction of pyridinium bromides 124 with 3-phenacylideneoxindoles 123 in the presence of triethylamine as a catalyst in ethanol at 50 °C for 6 hours. After work-up, they obtained the desired spiro[cyclopropan-1,3′-indolines] 125 (Scheme [49]).

Yavari and co-workers[68] have reported the reaction of 2-methylquinoline (126) with pyridine in the presence of iodine (100 mol%) as a Lewis acid catalyst and MeCN as the solvent. DIPEA was added as a base and the resulting mixture was stirred at 60 °C for 2 hours after which arylidene pyrazolone 8 was added. The reaction mixture was then stirred at room temperature for 2 hours to yield the desired spirocyclopropane-linked pyrazolones rac-anti 127 and rac-syn 127a (Scheme [50]). In this work, they used catalysts such as CuI (copper(I) iodide), CuBr (copper(I) bromide) and Cu(OAc)₂, which proved to be very poor, whilst AlCl₃ and BF₃·Et₂O gave the target compounds 127 and 127a. When they used iodine as the catalyst, the desired rac-anti and rac-syn spirocyclopropanes were obtained in yields of 25% and 45%, respectively. In addition, various bases including sodium carbonate, sodium bicarbonate, potassium carbonate, Et₃N, DBU, and DIPEA were examined. Of these, DIPEA was the most effective. Substrates with EDGs (methoxy and amino) failed to give products 127 and 127a.

Roiser and Waser[69] have reported a highly enantioselective synthesis of chiral spiro[2.5]octa-4,7-dien-6-ones 129 via treatment of para-quinone methides 24 with Cinchona-alkaloid-based chiral ammonium ylides 128. They carried out the synthesis of compounds 129 using different reaction conditions, but the highest er (trans/cis, i.e., 99.8:0.2) was attained when they used 5 equivalents of the base Cs₂CO₃ as the catalyst (Scheme [51]). The strong-base-mediated isomerization of the cis-cyclopropane into the trans-cyclopropane at elevated temperature was the main reason behind the trans-selectivity. Also, the chiral amine could be reused after completion of the reaction by recovery using Al₂O₃ column chromatography. Furthermore, in all cases, more or less stereocontrol was achieved. Different types of acceptors and nucleophiles were well tolerated and gave moderate to good yields of products 129.

In 2021, Zhang and co-workers[70] reacted (E)-3-benzylideneindolin-2-one 52 and N-ethoxycarbonyl methylpyridinium bromide 130 in the presence of Cs₂CO₃ in DMF as the solvent, producing spirocyclopropane oxindole 131 (Scheme [52]). When they used DBU as the base with DMAc (dimethylacetamide) as the solvent at 110 °C for 12 hours, they obtained the desired products 131 in yields of 63–69%. They also used other bases, including DABCO, DIPEA, Et₃N and K₂CO₃, however, Cs₂CO₃ was the best suited for the reaction, giving a 77% yield. Shortening the reaction time led to a yield of 82%. 3-Ylidene oxindoles 52 containing EDGs or EWGs at the β-position reacted well and yields increased from 41 to 93%. An ortho-substituted derivative of 130 gave a higher yield of product 131. The authors also used a chiral pyridinium salt and obtained a 1:1 diastereomeric product mixture in 70% yield.

Yavari and co-workers[71] have developed a method for the synthesis of cyclopropanes 134 via the reaction of acetophenone 54, pyridine and I₂ in MeCN under ultrasonic irradiation (USI) (frequency = 20 kHz, amplitude = 40% of the maximum power output). Subsequently, DIPEA and a solution of intermediate 132 in MeCN were added and the resulting mixture was irradiated for the appropriate amount of time (15–30 min) to give the desired products 134 (Scheme [53]).

Synthesis of Spirocyclopropanes from S-Ylides

Similar to nitrogen ylides, S-ylides are inner-salts that can be used to prepare spirocyclopropanes through cyclopropanation reactions. They possesses a positively charged sulfur and a negatively charged halogen/carbanion, with cyclopropanation taking place with elimination of sulfur. In this mechanism,[72] the reaction is initiated by nucleophilic attack of the sulfur ylide on the arylidene bond of the oxindole via conjugate addition to give an intermediate. Next, intramolecular dearomatization cyclization provides the cycloadduct and releases SMe₂ (Scheme [54]).

Luo and co-workers[73] have utilized sulfonium salt 136, 2-methyl-substituted arene sulfonyl indole 135 and K₂CO₃ as the base in CH₂Cl₂ to form the corresponding spirocyclopropanes 137 and 137a (Scheme [55]). Screening various solvents led to the finding that ethanol gave an 87% yield of 137 and 137a and that iPrOH gave an excellent diastereoselectivity of 19:1. They also used mixtures of solvents and found that iPrOH/ethanol increased the diastereoselectivity up to 10:1. The electronic nature of the indole influenced reaction. When fluorine or methyl groups were present at the C5 position of the indole ring, excellent product yields were obtained along with higher diastereoselectivities. However, the diastereoselectivity was reversed when a phenyl group was present at C2 of the indole. Indoles with no substituent at the C2 position were preferable for this reaction. When a chiral sulfonium salt was used, a moderate enantioselectivity of 64% was obtained along with a much lower yield of 137/137a.

In 2015, Nambu and co-workers[74] reported that the treatment of (1-aryl-2-bromoethyl)dimethylsulfonium bromides 139 and 1,3-cyclohexanediones 138 in the presence of K₂CO₃ gave spirocyclopropanes 140 (Scheme [56]). On screening various solvents, they found that CH₂Cl₂ gave a tetrahydrobenzofuran-4(5H)-one instead of the desired product 140, while other solvents like MeCN, iPrOH and THF gave lower yields. In DMF and DMSO, the product yields were 26% and 35%, respectively. The reaction was complete in 90 minutes with a yield of 81% of 140 in ethyl acetate. The authors also used 1,3-cyclopentanedione and acyclic 1,3-diones and obtained the desired products in good yields.

Li and co-workers[22] developed a new protocol for the synthesis spirocyclopropane 142 with a diastereoselectivity 93:7 by reacting a cyclic enone 19 and sulfur ylide 141 in CH₂Cl₂ at room temperature (Scheme [57]). The authors utilized different solvents such as DCE, methanol, ethanol, THF and 1,4-dioxane. Among these, 1,4-dioxane was the best, resulting in higher yields and diastereoselectivities of up to 98:2.

You and co-workers[72] reported a protocol for the synthesis of novel spirocyclopropane derivatives 143 via treatment of isatin-derived p-QMs 24b and sulfur ylides 141 in ethyl acetate for 8 hours (Scheme [58]). When various solvents were screened, the reaction in CH₂Cl₂ gave the desired compound 143 in 89% yield with a dr of 14:1. Reactions in hexane and toluene took more time and gave low yields due to poor solubility. The reaction did not take place in water. However, the reaction proceeded smoothly in ethyl acetate and gave a 92% yield of 143 with a dr of 15:1. Thus, ethyl acetate proved to be the most suitable solvent for this reaction. Substitution on the phenyl ring of 141 had a more significant effect on the reactivity. EDGs such as methyl and methoxy on the aryl ring gave higher yields of 143 with excellent diastereoselectivities in short reaction times. In contrast, EWG-containing sulfur ylides took more time for reaction completion. Also, 2-naphthyl-substituted and heteroaromatic sulfur ylides gave the desired products 143. p-QMs substituted with electron-donating and electron-withdrawing groups also gave the desired spirocyclopropanes 143 with good to excellent yields and high diastereoselectivities, but the reactions took longer to complete.

In 2019, Liu and co-workers[75] utilized a cascade reaction approach for the synthesis of spirocyclopropyl-fused pyrazolin-5-ones 144. Treatment of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-ones 8a and sulfur ylides 141 (2 equiv) under an acidic environment in the presence of toluene gave the desired products 144 (Scheme [59]). In the absence of an additive, the yield of 144 was only 27%, while in the presence of an additive, the yield increased significantly. Other acids like benzoic acid and p-methylbenzoic acid as additives were less effective, and p-nitrobenzoic acid was preferred as it gave a 79% yield of the desired product. The use of 3 equivalents of p-nitrobenzoic acid increased the efficiency as well as the yield. EDGs and EWGs at the para position of the benzene ring of substrate 8a resulted in good yields of products 144. Meanwhile, substitution at the meta position of the substrate led to smooth reactions. In contrast, an ortho-substituted substrate did not give the desired product 144 because of the steric effect. The presence of a phenyl or ethyl group at C3 of the pyrazalone produced the desired spirocyclopropanes 144 in yields of 57% and 59%, respectively. However, a CF₃ substituent at C3 led to reduced reactivity. Substrates 141 bearing EWGs and EDGs at the para-position gave moderate to good yields of products 144. Substitution at the meta position also gave a smooth reaction, leading to the desired product in a moderate yield. A heterocyclic ylide also reacted smoothly and gave the corresponding product in 66% yield.

Gong and co-workers[76] reported that the reaction of o-alkenyl arylisocyanide 145, sulfur ylide141, Pd(OAc)₂ (0.02 mmol), Cu(OAc)₂ (0.06 mmol) and dppp (1,3-bis(diphenylphosphino)propane) (0.02 mmol) in CF₃CH₂OH/THF 6:1 at 55 °C for 12 hours gave spirocyclopropane 147 (Scheme [60]). The authors used various palladium and copper salts, and ligands such as Pd(CN)₂Cl₂, Pd(PPh)₃Cl₂, PdCl₂, CuCl₂, CuBr₂, CuOAc, dppe, dppf and PPh₃, but all gave moderate results. In screening solvents, they found that CF₃CH₂OH/THF was the best combination among solvents like CF₃CH₂OH/CH₂Cl₂, CF₃CH₂OH/DMSO and CF₃CH₂OH/ MeCN. Benzoyl-substituted sulfur ylides containing an electron-withdrawing or electron-donating group on the phenyl ring at ortho or para positions reacted smoothly and gave the corresponding spirocyclopropanes with good to high diastereoselectivities. Various aryl isocyanides containing electron-withdrawing or electron-donating groups reacted smoothly and gave moderate to high yields and good to high diastereoselectivities.

Miscellaneous Syntheses of Spirocyclopropanes

In 2013, Roy and Chen[77] reported that indolin-2-ones 14a reacted with (Z)-2-bromo-2-nitro-1-phenylethenes 148 in the presence of Et₃N and CH₂Cl₂ as the solvent to give the corresponding spirocyclic oxindoles 149 (Scheme [61]). When the reaction was carried out in different solvents, toluene gave a lower yield with moderate diastereoselectivity, while the reaction in diethyl ether gave a lower yield and a decreased stereoselectivity. Performing the reaction in methanol at ambient temperature afforded 149 in 68% yield and the diastereomeric ratio increased from 92:8 to 98:2. Decreasing the reaction temperature to –20 °C led to an increase in the product yield.

Prakash and Samanta[78] have synthesized cyclopropane derivatives 152 via reactions of cyclopropanes 150 with 2-hydroxyacetophenones 151 in the presence of Cs₂CO₃ in DMF at 80 °C in an oil bath under an argon atmosphere (Scheme [62]). They examined different organic solvents like toluene, 1,4-dioxane, DCE, DMF, acrylonitrile and ethanol, and the results showed that DMF was the most suitable, giving an 84% yield of 152. Next, they investigated various bases like K₂CO₃, Cs₂CO₃, DBU, DABCO and DBN and found that Cs₂CO₃ was the best suited candidate. Increasing the amount of Cs₂CO₃ did not considerably affect the yield of 152.

Zhu and co-workers[79] synthesized mixtures of diastereomeric spirocyclopropanes 155 by treating (E)-3-arylmethylenebenzofuran-2(3H)-ones 153 with CF₃CHN₂ (154) solution in acetonitrile (0.44 mmol). Brine (0.55 equiv) was used as an additive at 82 °C (Scheme [63]).

In 1998, Pfeiffer and co-workers[80] reported that the reaction of 9-diazo-9H-fluorene (156), electron-rich olefins 157 (1:1 molar ratio), and pentacarbonyl(η ²-cis-cyclooctene)chromium (T) (2 mol%) in dichloromethane for 8 hours followed by stirring for a further 8 hours gave the desired spirocyclopropanes 158 in yields of 15–93% after work-up (Scheme [64]A). When the electron-deficient olefin ethyl acrylate (157a) was used, spirocyclopropane 158a was obtained in the absence of the catalyst (Scheme [64]B). In all reactions involving the catalyst, the outcome was determined by varying the amounts of 9,9′-bifluorenylidene and bis(9,9′-9H-fluorenylidene)azine. In this case (B), the reaction of compound 156 with allyl vinyl ether 157a catalyzed by the chromium complex gave the cyclopropane 158a in 79% yield as a single regioisomer. In the reaction of compound 156 with 2-vinyloxyethyl acrylate (157b), cyclopropane 158b was obtained both in the absence and presence of a catalyst (Scheme [64]C).

Guarna and co-workers[81] reported the reactions of nitroethane, triethylamine, phenyl isocyanates 160 and methylene cyclopropanes 159 in cooled (–50 °C) ether solutions followed by stirring for 6 hours at 0 °C and then for 10 hours at room temperature. Next, the crude reaction mixture was passed over a silica gel pad and the clear solution was concentrated (Vigreux column) and distilled (80 °C at 12 torr) to give products 161 and 161a in yields of 35–72% (Scheme [65]).

In 1989, de Meijere and co-workers[82] reported the reactions of 1,2- and 1,3-bidentate nucleophiles 163 and cyclopropanes 162 to form intermediate compounds 164. Subsequent ring closing through nucleophilic substitution of the C1 atom formed products 165. Alternatively, intermediate 164 could undergo cyclization by nucleophilic attack on the methoxycarbonyl group to form compounds 165a (Scheme [66]).

In the presence of methanol and triethylamine, the reaction of 2-aminothiophenol (166) and chloroacrylate 163 did not lead to a product. However, when the reaction was carried out under heterogeneous conditions using dichloromethane, potassium hydroxide, and dibenzo[18]crown-6 as a phase-transfer catalyst (PTC), the reaction gave product 167. In these reactions, the product type is dependent on the nature of the base used during the reaction. Thus, 1,2-dihydroxybenzene (168) gave the six-membered heterocyclic compound 169. When 2-aminophenol (170) and 2-aminoethane-1-thiol (171) were used, the corresponding compounds, dihydro-4H-1,4-oxazine 172 and tetrahydro-4H-1,4-thiazine derivative 173, were obtained. On using potassium hydroxide rather than potassium carbonate as the base, the reaction with 2-aminoethane-1-thiol (as ammonium salt) (171) gave the seven-membered heterocyclic compound 174 (Scheme [67]).

Shen and co-workers[83] reported that treatment of (cyclopropylidenemethyl)benzenes 175 with 4,4-dimethyl-1-phenylpyrazolidin-3-ones 176 and CF₃CH₂OH (177) using [Cp*RhCl₂]₂ as the catalyst, AgSbF₆ and K₂CO₃ in TFE at 50 °C under air for 12 hours gave cyclopropane products 178 in yields of 19–72% (Scheme [68]).

In 2014, Noroozi Pesyan and Rezaee[84] reported a one-pot solvent-free synthesis of spirocyclopropanes. Aldehyde 15, sodium ethoxide, malononitrile (16) and cyanogen bromide were milled at 0 °C to room temperature until the mixture homogenized. After 30 minutes, spirocyclopropanes 179 were obtained in yields of 80–100% (Scheme [69]). During studies on the substrate scope, they found that the use of bulky 9-anthracene carbaldehyde and hydroxy-containing aldehydes afforded Knoevenagel adducts rather than the desired spirocyclopropanes.

Noroozi Pesyan and co-workers[85] reported the reactions of aldehydes 15, triethylamine, malononitrile (16) (2.0 mmol), and cyanogen bromide (1.2 mmol) at room temperature. The reactions occurred within 5 seconds, resulting in the formation of spirocyclopropanes 180 (Scheme [70]).

Conclusion

Based on our literature review, we conclude that there are various routes available for the synthesis of spirocyclopropanes, with most of them proceeding through cascade reactions. These spirocyclopropane-ring-containing compounds are found in natural products as well as synthetic drug intermediates. In fact, some of the compounds are important drugs in the medical field. Chiral catalysts and organocatalysts are also useful for the synthesis of spirocyclopropanes. 3-Chlorooxindoles are important precursors for the preparation of the title compounds due to their bifunctional nucleophilic/electrophilic character that allows for the easy incorporation of diverse functionalities on the cyclopropane ring. Isatin-derived arylidene oxindoles and diazooxindoles are the most preferable precursors for the synthesis of spirocyclopropanes due to their di-electrophilic and di-nucleophilic natures, respectively. However, the explosive and unstable characteristics of diazo compounds restrict their direct utilization in many reactions. Numerous researchers have chosen to prepare such diazo compounds in situ and subsequently utilize them in cyclopropanation reactions. Also, N-ylides and S-ylides are good di-nucleophilic synthons. Furthermore, 1,3-diones possessing an active methylene group are favorable starting compounds for the one-pot and multicomponent syntheses of spirocyclopropanes. It is anticipated that this review will be helpful to the synthetic community due to the constant developments on the synthesis of spirocyclopropane derivatives. However, regio- and stereospecific/selective syntheses still need to be considered, along with new methodologies for the synthesis of spirocyclopropanes.

List of Abbreviations

AcOEt: ethyl acetate

AgBF₄: silver tetrafluoroborate

AlCl₃: aluminum trichloride

BTEAC: benzyltriethylammonium chloride

CAC: chloroacetyl chloride

CCl₄: carbon tetrachloride

CH₂Cl₂: dichloromethane

CMOBSC: (chloromethoxy)benzenesulfonic acid

Cs₂CO₃: cesium carbonate

CTMAB: cetyltrimethylammonium bromide

CuBr: copper(I) bromide

CuI: copper(I) iodide

Cu(OAc)₂: copper(II) acetate

DABCO: 1,4-diazabicyclo[2.2.2]octane

DAIB: (diacetoxyiodo)benzene

DBN: 1,5-diazabicyclo[4.3.0]non-5-ene

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE: 1,2-dichloroethane

DIPEA: N,N-diisopropylethylamine

DMAc: dimethylacetamide

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

dr: diastereomeric ratio

EDA: ethylenediamine

EDG: electron-donating group

ee: enantiomeric excess

Et₃N: triethylamine

EtONa: sodium ethoxide

EWG: electron-withdrawing group

InCl₃: indium chloride

K₂CO₃: potassium carbonate

KF·2H₂O: potassium fluoride dihydrate

KHCO₃: potassium bicarbonate

KOH: potassium hydroxide

LED: light-emitting diode

MeCN: acetonitrile

MIRC: Michael-initiated ring closure

MS: molecular sieves

NaBH₄: sodium borohydride

Na₂CO₃: sodium carbonate

NaH: sodium hydride

NaHCO₃: sodium bicarbonate

NH₄HCO₃: ammonium bicarbonate NH₄Cl: ammonium chloride

NaOH: sodium hydroxide

PBBS: polybrominated biphenyl

PCBS: polychlorinated biphenyl

Ph₃As: triphenylarsine

PhF: fluorobenzene

P(NMe₂)₃: tris(dimethylamino)phosphine

p-QMs: para-quinone methides

PTC: phase-transfer catalyst

Sc(OTf)₃: scandium(III) triflate

TBBDA: tetrabromobenzene-1,3-disulfonamide

TBD: triazabicyclodecene

TCBDA: N′-tetrachlorobenzene-1,3-disulfonamide

THF: tetrahydrofuran

TLC: thin-layer chromatography

TMSOI: trimethylsulfoxonium iodide

Yb(OTf)₃: ytterbium(III) trifluoromethanesulfonate

ZnCl₂: zinc chloride

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgement

We are grateful to the Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar for providing research necessary facilities.

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Corresponding Author

Publication History

Received: 12 December 2024

Accepted after revision: 19 March 2025

Article published online:
04 June 2025

© 2025. Thieme. All rights reserved

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