Indane-1,3-Dione: From Synthetic Strategies to Applications

Abstract

Indane-1,3-dione is a versatile building block used in numerous applications ranging from biosensing, bioactivity, bioimaging to electronics or photopolymerization. In this review, an overview of the different chemical reactions enabling access to this scaffold but also to the most common derivatives of indane-1,3-dione are presented. Parallel to this, the different applications in which indane-1,3-dione-based structures have been used are also presented, evidencing the versatility of this structure.

1. Introduction

Indane-1-3-dione is among one of the most privileged scaffolds in chemistry, as the derivatives of this structure can find applications in various research fields ranging from medicinal chemistry, organic electronics, photopolymerization, to optical sensing and non-linear optical (NLO) applications. One of its closest analogues, namely indanone, is commonly associated with the design of biologically active compounds [1,2,3]. The most relevant examples in this field are undoubtedly Donepezil, which is still under use for the treatment of Alzheimer’s disease [4], or Indinavir, which is used for the treatment of AIDs disease [5]. Interest for indanone derivatives is notably motivated by the fact that this structure can be found in numerous natural products (Caraphenol B isolated from Caragna sinica [6], Pterosin B isolated from marine cyanobacterium [7], another derivative extracted from filamentous marine cyanobacterium Lyngbya majuscula) [7], sustaining the interest for these compounds [8,9]. Due to the similarity of structure with indanone, indane-1,3-dione is also of high current interest, and this molecule has also been extensively studied as a synthetic intermediate for the design of many different biologically active molecules [10]. Beyond its common use in the design of biologically active molecules, indane-1,3-dione is also an electron acceptor widely used for the design of dyes for solar cells applications, photoinitiators of polymerization or chromophores for NLO applications [11]. As an interesting feature, indane-1,3-dione possesses an active methylene group, making this electron acceptor an excellent candidate for its association with electron donors by means of Knoevenagel reactions [12]. Ketone groups can also be easily functionalized with malononitrile, enabling to convert it as a stronger electron acceptor. In this review, an overview of the different chemical modifications performed on the indane-1,3-dione core is reported. Following the description of the synthetic access to the indane-1,3-dione derivatives, their uses in the design of biologically active molecules and organic dyes for various applications in organic electronics are reported. Finally, in the last part, an extensive scope of applications is detailed.

2. Chemical Modification of the Indane-1,3-Dione Core

2.1. Synthesis of Indane-1,3-Dione

Indane-1,3-dione can be synthesized following different synthetic procedures. Furthermore, the most straightforward one consists in the nucleophilic addition of alkyl acetate 2 on dialkyl phthalate 1 under basic conditions, enabling to produce the intermediate 2-(ethoxycarbonyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide anion 3. Then, by heating under acidic conditions, this intermediate can be hydrolyzed and decarboxylated in situ, producing indane-1,3-dione 4 in ca. 50% yield for the two steps [13,14]. However, several procedures were also reported to access 4 by oxidation of indane 5, using various oxidizing systems such as N-hydroxyphthalimide (NHPI) and tert-butyl nitrite (t-BuONO) [15], H₂O₂ with a Mn catalyst [16], pyridinium dichromate (PCC) in the presence of Adogen 464 and sodium percarbonate (Na₂CO₃·1.5 H₂O₂) [17]. Furthermore, in these different cases, reaction yields remained often limited (17 and 18% yields) while requiring expensive reagents so that the first procedure remains undoubtedly the most popular one to obtain indane-1,3-dione 4 in acceptable yield (see Scheme 1). Recently, a two-step procedure was developed, starting from 2-ethynylbenzaldehyde 6 [18]. By means of a Cu-catalyzed intramolecular annulation reaction, 3-hydroxy-2,3-dihydro-1H-inden-1-one 7 was prepared in 87% yield and a subsequent oxidation of 7 with Jones’ reagent enabled to obtain 4 in 95% yield. As alternative, o-iodoxybenzoic acid (IBX) can also be used as an oxidant, providing 4 in similar yield (92%) [19]. Several strategies were also developed to convert phthalic anhydride 8 into 4 using diethyl malonate 9 and montmorillonite KSF clay [20] or ethyl acetoacetate 11 in the presence of acetic anhydride and triethylamine [21]. In the case of substituted indane-1,3-diones, two distinct routes were developed depending on the substituents attached on the phthalic anhydrides. Thus, in the case of electron-withdrawing groups such as nitro and chlorine (12–14), the condensation of malonic acid in pyridine proved to be a straightforward route to access 19–21 [22]. Conversely, in the case of electron-donating groups such as alkyl substituents (22, 23), a specific procedure was developed, consisting [23] in a Friedel–Craft reaction of 4-methylbenzoyl chloride 22 or 3,4-dimethylbenzoyl chloride 23 with malonyl dichloride 24, followed by an acidic treatment with concentrated hydrochloric acid furnishing after purification of the two compounds 25 and 26 in 33 and 15% yield, respectively (see Scheme 2).

2.2. Chemical Engineering around the Ketone Groups

2.2.1. Functionalization with Cyano Groups

2-(3-Oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile 28 [24,25,26,27,28] and 2,2′-(1H-indene-1,3(2H)-diylidene)dimalononitrile 29 [28,29,30] can be synthesized by a Knoevenagel reaction of malononitrile 27 on 4 in ethanol using sodium acetate or piperidine as the bases. In the two cases, an excess of malononitrile was used, and the selection between the di- and the tetracyano-substituted derivative could be obtained by controlling the reaction temperature. Thus, the dicyano compound 28 can be obtained at room temperature contrarily to the tetracyano one 29 that is synthesized by heating the reaction media. In the case of 28, reaction yields ranging between 61 and 85% were determined, whereas 29 could be obtained with reaction yields ranging from 34 to 45% yield. Functionalization of substituted indane-1,3-diones (30, 32, 34) with only one dicyanomethylene group was also examined, and several situations were found. Thus, the Knoevenagel reaction furnished a mixture of inseparable isomers 31,31′, 33,33′ and 35,35′ when 5-methyl-1H-indene-1,3(2H)-dione 30 [23], ethyl 1,3-dioxo-2,3-dihydro-1H-indene-5-carboxylate 32 [31] or 5-fluoro-1H-indene-1,3(2H)-dione 34 [32] were used as the starting materials (see Scheme 3).

Conversely, 5-alkoxy-1H-indene-1,3(2H)-diones 36a furnished selectively 37a in 63% yield as a result of the specific activation of one of the two ketones by mesomeric effects [33]. A similar behavior was also observed during the synthesis of 39 [32], 41 [34] and 43 [35], their precursors 38, 40 and 42 being substituted with halogens. The steric hindrance generated by the substituents was another strategy to control the regioselectivity, and the synthesis of 45 is a relevant example of this (see Scheme 4) [36]. Concerning the symmetrically substituted indane-1,3-diones, those bearing halogens at the 5,6-positions were the most commonly studied, as exemplified with compounds 47 [37] or 49 [32,38].

2.2.2. Self-Condensation of Indane-1,3-Dione: The Bindone Adduct

Bindone 50 is an electron acceptor widely used due to its stronger electron-withdrawing ability compared to that of 29. It can be easily synthesized by self-condensation of indane-1,3-dione 4 in basic conditions (triethylamine [25], sodium acetate [39], sodium hydride [40]), or in acidic conditions (sulfuric acid [41]) (see Scheme 5).

2.2.3. Formation of bis-Thiazoles and bis-Thiazolidinone

Indane-1,3-dione 4 and corresponding derivatives have been extensively studied for their biological activities ranging from antitumor, antibacterian and anti-inflammatory activities [13,42,43,44,45]. Parallel to this, 1,3,4-thiadiazole groups also exhibit biological activities [46,47,48,49,50,51,52,53,54] so that their combinations were examined [55]. From a synthetic viewpoint, bis-thiazoles could be obtained in two steps starting from indane-1,3-dione 4. By first reacting 4 with hydrazinecarboxamide 51 in ethanol, in the presence of triethylamine, 2,2′-((1H-indene-1,3(2H)-diylidene)bis(hydrazine-1-carboxamide) 52 could be obtained. Then, upon reaction with a number of N-aryl-2-oxopropane-hydrazonoyl chloride derivatives 53–55, bis-thiazoles 56–58 could be isolated with reaction yields ranging from 78 to 89%. Using a similar procedure, reaction of 52 with ethyl (N-arylhydrazono)chloroacetate 59–61 could furnish the corresponding bis-thiazolidinone 62–64 in high yields (79–90%) (see Scheme 6).

2.3. Chemical Engineering around the Aromatic Groups

2.3.1. Polyaromatic Structures

To improve the electron-accepting ability of 4, an alternative to the substitution of indane-1,3-dione with malononitrile consists in developing polyaromatic structures. Notably, naphthalene derivatives were prepared, following the same synthetic route to that used for 4, consisting in the condensation of ethyl acetate 66 on diethyl naphthalene-2,3-dicarboxylate 65 in solvent-free and basic conditions. After decarboxylation, 67 could be prepared in 91% yield for the two steps [12,56,57,58,59,60]. Introduction of lateral groups onto 67 is possible but involves a specific route to be developed. A Diels–Alder reaction between l,3-diphenylbenzo[c]furan 69 and cyclopent-4-ene-l,3-dione 70 furnishes the 1,3-diphenylbenzo[c]furan-cyclopent-4 ene-1,3-dione adduct 71. By dehydration in acidic conditions (HCl/H₂SO₄), 71 could be converted to 72 in 25% yield. Recently, the design of a helical-shaped structure 75 was reported [36]. If the structure is innovative, the synthesis is identical to that used for 4, starting from dimethyl naphthalene-1,2-dicarboxylate 73 (see Scheme 7).

2.3.2. Halogenated Indane-1,3-Diones

Halogenation of indane-1,3-dione derivatives subsequent to their synthesis is not possible such that such derivatives can only be obtained by first introducing halogens onto their corresponding precursors. Notably, as a first synthetic approach, halogenated phthalic anhydrides were converted as indane-1,3-diones using ethyl acetoacetate, and a series of halogenated indane-1,3-diones 76–82 is presented in Scheme 8 [20,21,28,37,38,40,61]. Parallel to this, the strategy previously mentioned that AlCl₃-promoted acylation of a benzoyl chloride derivative (83) with malonyl chloride 24 proved to be another effective approach to design chlorinated indane-1,3-dione derivatives (84) (see Scheme 8).

2.3.3. Introduction of Various Electron-Withdrawing Groups on Aromatic Ring

Nitration

As previously mentioned for halogenation, electrophilic aromatic substitution cannot be carried out on indane-1,3-dione 4 such that a post-functionalization with nitro groups is required. To date, only few indane-1,3-diones bearing nitro groups have been reported in the literature (see Scheme 9) [21,22,62].

2.3.4. Cyanation

To the best of our knowledge, no cyano-substituted indane-1,3-dione derivatives have been reported to date. Furthermore, such acceptors are as crucial as the cyano groups, which are among the best electron-accepting groups.

2.3.5. Introduction of Alkoxy-Carbonyl Groups

Here again, only the post-functionalization of naphthalic anhydrides was used to introduce CO₂R groups. An example is provided below with 32 (see Scheme 10) [31]. By using ethyl acetoacetate 11, anhydride acetic as the solvent and triethylamine as the base, 32 could be obtained from 32a in 71% yield.

2.4. Chemical Engineering around the Methylene Group

2.4.1. Knoevenagel Reaction

Due to the presence of the two ketones groups on both sides of the methylene groups, indane-1,3-dione 4 possesses a privileged group for realizing Knoevenagel reactions. In the case of indane-1,3-dione 4 and its substituted derivatives, the condensation reaction can be carried out in the conditions initially used by Knoevenagel in 1894 to condense benzaldehyde with ethyl acetoacetate 11, namely in ethanol with a catalytic amount of piperidine [61]. Typically, Knoevenagel reactions performed with 4 or 68 can be realized with reaction yields higher than 70% (see

Table 1. Reaction yields obtained for the synthesis of 95–114.

compounds	95	96	97	98	99	100	101	102	103	104
reaction yields	88	84	88	74	94	89	92	85	84	88
compounds	105	106	107	108	109	110	111	112	113	114
reaction yields	74	85	75	82	92	87	81	78	89	85

and Scheme 11) [12]. As the main interest of this reaction, use of a highly polar solvent favors the precipitation of dyes 95–114 upon cooling, and the reaction can be carried out in green conditions since a non-dangerous solvent can be used. Additionally, the work-up can be limited to a simple filtration, avoiding the use of complicated purification processes [56,57].

When 2-(3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile 28 and its analogues are involved in Knoevenagel reactions, another amine should be used, and diisopropylethylamine (DIPEA), which is a none-nucleophilic base, is the most popular one. As reported in several recent works, an unexpected nucleophilic addition of secondary amines onto the cyano groups of the push–pull dyes can occur, giving rise to a cyclization reaction and producing 3-(dialkylamino)-1,2-dihydro-9-oxo-9H-indeno [2,1-c]pyridine-4-carbonitrile derivatives 115, according to the mechanism proposed in Scheme 12.

Numerous examples of undesired cyclization reactions have notably been reported with piperidine providing 3-(dialkylamino)-1,2-dihydro-9-oxo-9H-indeno [2,1-c]pyridine-4-carbonitrile derivatives 115 instead of the expected push–pull dyes [62,63,64]. In 2019, an unprecedented nucleophilic addition of piperidine on 101 was also reported, providing 102 after dehydration. The mechanism supporting the formation of this unexpected structure is depicted in Scheme 13, and the crystal structure of this molecule presented in Figure 1 undoubtedly proved its formation.

When 2,2′-(1H-indene-1,3(2H)-diylidene)dimalononitrile 29 and its derivatives are engaged in Knoevenagel reactions, the high stability of their anions in basic conditions impedes the Knoevenagel reactions to proceed. Therefore, acidic conditions should be used, and acetic anhydride is commonly used in this aim (see Scheme 14) [65,66].

Besides, several reports mention the use of the classical piperidine/ethanol conditions to condense 29 onto aromatic aldehydes, despites the strong deactivation of the 29 anion in basic conditions. A few examples of products obtained in these conditions are presented in Scheme 15 (121 [67], 123 [67] or 125 [68]).

To avoid the use of base, several authors replaced ethanol by solvents of higher boiling points such as methylethylketone (see Scheme 16) [69]. By refluxing 29 and 126 at elevated temperature, 127 could be obtained in 42% yield.

2.4.2. Oxidation Reaction

Among indane-1,3-dione derivatives, ninhydrin is well known, as it can be advantageously used as a revelator for thin layer chromatography (TLC). Over the years, several strategies have been developed to access to these structures [70]. For instance, oxidation of indane-1-one 128 with selenium oxide (SeO₂) can furnish ninhydrin 138 [71], but this reaction was not limited to 4, and the oxidation reaction tolerates various substituents such as OMe, tert-Bu, Me, Br, CF₃ or NO₂ (see compounds 139–147, Scheme 17) [72]. Direct oxidation of 4 was also investigated to convert it, as 138 and ninhydrin 138 could be prepared in 48% yield using the dual oxidizing system SeO₂/H₂O₂ [73] in 40% yield for the two steps using iodobenzene diacetate [74] and 94% yield using N-bromosuccinimide (NBS) in DMSO [75]. However, all attempts to oxidize 4 as 138 using sodium hypochlorite failed, and phthalic acid was isolated as the unique product of the reaction [76]. The authors also demonstrated 138 to be oxidized as phthalic acid, evidencing that sodium hypochlorite is a too strong oxidant. The oxidation reaction with N-bromosuccinimide (NBS) in DMSO was not limited to indane-1,3-dione 4, and indane-1-one 149 and indane-2-one 128 could also be oxidized using the same procedure, providing 138 in 82 and 85% yield, respectively. Photooxidation of 4 in the presence of tetrabutylammonium hexafluorophosphate and oxygen using Rose Bengal as the photosensitizer could convert 4 as 138 in 75% yield upon irradiation with a UV light [77].

2.4.3. Halogenation

α,α-Dihalogenation reactions of carbonyl compounds have been extensively studied in the literature [78,79,80,81,82,83,84,85,86,87,88], and different procedures were thus developed for the halogenation of indane-1,3-dione 4. Notably, traditional reagents of halogenation including N-chlorosuccinimide (NCS) or NBS in ethanol could provide 150 and 151 in 95% and 92% yields [89]. Several green syntheses were also developed, all based on mechanical ball milling. Using this approach, halogenating agents such as trichloroisocyanuric acid or tribromoisocyanuric acid could furnish 150 and 151 in 98 and 97% yields [90]. Similarly, mechanosynthesis of 150 could be efficiently achieved by employing sodium bromide and oxone (98% yield) [85] or ammonium bromide and oxone (see Scheme 18) [91].

The conversion of nucleophilic halogens to electrophilic ones could be realized by reacting Lewis acids such as ZnBr₂ or AlCl₃ with lead tetraacetate [92]. High reaction yields were also obtained during the synthesis of 150 while using KBr/KBrO₃ (86% yield) [93], 1,3-dibromo-5,5-dimethylhydantoin in acetic acid (88% yield) [94]. Similarly, 151 could be obtained while reacting 4 with 1,3-dichloro-5,5-dimethylhydantoin in acetic acid (89% yield) [94]. Finally, selectfluor^® (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate)) was the most widely studied fluorinated agent for fluorination of 4 in water while using a surfactant (Genapol LRO) (74% yield) [95], sodium dodecyl sulfate in water (93% yield) [96], or acetonitrile as solvent (60% yield) (see Scheme 19) [41,97]. Furthermore, numerous drawbacks concerning the electrophilic fluorination with selectfluor^® were reported in the literature. Notably, parallel to the formation of the expected F⁺ cation, formation of radical species (F^•) by single electron transfer has also been proposed, even if the mechanistic studies have not fully elucidated the mechanism. Nevertheless, formation of an intermediate monofluorination state could be demonstrated [98].

In the case of indane-1,3-dione 4, fluorination was proposed as occurring by means of an attack of the double bond of enol onto selectfluor^®, followed by a deprotonation with the resulting diazoniabicyclo [2.2.2]octane species. By iterating the reaction a second time, 152 could be obtained (see Scheme 20) [97]. Considering that there is still a lack of efficiency for the α,α-dibromination of 1,3-diketones, the photoredox catalysis was envisioned as a possible alternative to conventional chemistry to improve the selectivity during bromination [99,100,101,102]. Light is also a traceless reagent so that light-promoted chemistry perfectly fits with the concepts of green chemistry. For bromination, light-activated radical reactions are also extensively described in the literature, enabling to efficiently generate bromine radicals.

In 2019, an interesting reaction was developed to accelerate the formation of bromide radicals and, in this aim, N-bromosuccinimide (NBS) was irradiated in the presence of bromoacetic acid and under visible light [103]. By this unique combination, two concurrent bromination mechanisms could be evidenced, the first one consisting in an electrophilic bromination resulting from the photoassisted formation of bromine, and the second one consisting in a radical bromination process resulting from the formation of bromide radicals promoted by light (see Scheme 21).

By the presence of these double sources of brominating agents, the exceptional reaction yield of 99% could be obtained as well as accounts from the coexistence of both the electrophilic and the radical bromination reactions (see Scheme 22).

2.4.4. Cyanation

In 1977, an interesting procedure was developed to introduce a cyano group at the methylene position of indane-1,3-dione. Inspired by the synthesis of indane-1,3-dione 4 starting from dialkyl phthalate and ethyl acetate, an analogue procedure was proposed, where ethyl acetate 51 was replaced by acetonitrile (see Scheme 23) [104]. Using sodium methanoate as the base, 153 could be obtained in 78% yield.

2.4.5. Nitration

Nitration of the methylene group of indane-1,3-dione 4 can be performed in one step, by using nitric acid as the reagent [105]. Furthermore, 154 could be obtained in 78% yield (see Scheme 24).

3. Indane-1,3-Diones as Reagents for Various Chemical Transformations

3.1. Synthesis of Cyclophanes

Cyclophanes play an important role in supramolecular chemistry [106,107,108,109,110,111,112,113,114,115,116,117,118,119], especially as hosts for host–guest strategies so that a continuous effort has been made to develop new, efficient and simple synthetic routes to access to these structures [120,121,122,123,124,125,126]. Among the main methods reported in the literature, Wurtz coupling [127] carbene insertion [128,129], Ni-catalyzed Grignard coupling [130], polymerization of p-xylene [131], pyrolysis of sulfones [132] or acyloin condensation [133] can be cited as popular reactions. Conversely, Suzuki-Miyaura cross-coupling reaction [134,135,136,137] or ring-closing metathesis [138,139,140,141,142,143,144,145,146,147] have been less studied. In 2012, a combination of these two key reactions (Suzuki-Miyaura cross-coupling reaction and ring-closing metathesis) has been conceived as a concise and efficient synthetic route to access to [4,4]-cyclophane derivatives [148]. In the first step, dialkylation of indane-1,3-dione 4 with meta or para-bromobenzyl bromide furnished 155a and 155b. The functionalization of the methylene group of indane-1,3-dione 4 was not an easy task since conventional alkylation conditions such as NaH in THF totally failed. After several attempts, use of freshly prepared KF-celite in dry acetonitrile enabled to produce 155a and 155b in moderate yields, 74 and 70%, respectively. These two intermediates were subsequently functionalized with allyl groups, by a Suzuki-Miyaura cross-coupling reaction using an excess of allylboronic acid pinacol ester. Finally, metathesis reactions of 156a and 156b using the first generation of Grubbs catalyst and titanium isopropoxide delivered the two macrocycles 157a and 157b in 54 and 45% yields. Finally, hydrogenation using a catalytic amount of Pd(C) yielded 158a and 158b in 80% for the two cyclophanes (see Scheme 25).

3.2. Synthesis of Crown Ether Derivatives of Indane-1,3-Dione

Compounds capable of changing the optical properties by complexation with metal cations are at the center of numerous researches, and in this field, crown ethers consisting in a ring containing ether groups capable to bind alkali cations have been extensively studied [149,150,151]. Considering that indane-1,3-dione 4 is a strong electron-acceptor, its combination with an electron donor connected to a crown ether could make the final assembly an interesting structure for ion sensing. Such a push–pull dye was reported in 2010 by Mitewa and coworkers [152]. Thus, 159 could be prepared by a Claisen–Schmidt condensation of 2-acetyl-1,3-indandione 160 with the appropriate aldehyde 161 in acetic acid. The different attempts to use piperidine as the base failed, and the starting materials 160 and 161 were entirely recovered after reaction. Unexpectedly, the Claisen–Schmidt reaction furnished a fully conjugated molecule, resulting from a deacetylation reaction, according to the mechanism depicted in Scheme 26.

To prepare 2-(1-hydroxyethylidene)-1H-indene-1,3(2H)-dione 162, several strategies can be developed, as shown in Scheme 27. Notably, a selective cyclo-oligomerization based on a self-condensation of acetyl chloride 163 in the presence of aluminum trichloride AlCl₃ followed by a cross-condensation reaction with benzoyl chloride 164 could provide 162 in 87% yield according to the mechanism depicted in Scheme 27 [153]. Parallel to this, 162 can also be synthesized using the Kilgore procedure [154], consisting in an addition–elimination process of a ketone (acetone 166) on diethyl phthalate 165 under basic conditions (sodium ethoxide) (see Scheme 27) [155].

Finally, examination of the complexation of 159 with various divalent cations revealed no drastic changes of its absorption spectrum upon complexation, except with Sr²⁺ and Ba²⁺. This unexpected result was assigned to the low involvement of the nitrogen lone pair of the crown ether in the coordination of the cations, thus weakly affecting the optical properties of the push–pull dye connected to the crown ether.

3.3. Synthesis of Tetracycline Heterocyclic Analogues

Tetracyclines are an extended family of compounds discovered and developed in the mid-1940s for their promising therapeutic properties [156]. Notably, tetracyclines are efficient as antibiotics and anti-malarial drugs, and these structures have also been identified as being beneficial of various pathologies such as cancers or Parkinson’s disease. Due to the increasing resistance of microbes to antimicrobials used from long ago, analogues to tetracyclines are actively researched, and a series of pentacyclines comprising the indane-1,3-dione motif have been synthesized [25]. The synthesis was relatively straightforward since the combination of malononitrile 27, salicylaldehyde 167 and indane-1,3-dione 4 in a one-pot procedure furnished 6-amino-7-imino-7H-indeno [2′,1′:5,6]pyrano [3,4-c]chromen-13(13bH)-one 168 in 80% yield. Imine group in 168 could be easily cleaved in acidic conditions, yielding 169 (see Scheme 28).

The one-pot synthesis of pentacyclines was not limited to 4 as the starting material, and another derivative 172 was also prepared starting from 28 following two different synthetic routes in order to confirm its chemical structure (see Scheme 29). Thus, following a first step consisting in the reaction of 28 with the diazonium salts 170 and 173, the two products 171 and 174 were subjected to an intramolecular cyclization reaction by reflux in ethanol in the presence of a catalytic amount of piperidine, providing 172 and 175 in 85 and 87% yields, respectively. Finally, hydrolysis of imine 175 under acidic conditions furnished 172 in 90% yield and confirmed the formation of this compound by the similitude of the ¹H NMR spectra.

On the basis of the two synthetic routes, other tetracycline derivatives comprising three fused cycles were also prepared, as exemplified with the indenopyrane derivatives 177 and 179 or the indeno-[2,1-c]-pyridazines 181 and 182 listed below (see Scheme 30).

3.4. Synthesis of Indane-1,3-Dione Derivatives via Tert-Butylisocyanide Insertion

Isocyanide insertion into palladium–carbon bonds has emerged as an effective strategy to form C-N, C-O or C-C bonds [157,158,159,160,161,162,163], and numerous derivatives such as quinazolinones [164], 6H-isoindolo [2,1-a]indol-6-ones or indenoindolones [165] have been prepared using this strategy. In this context, the chemoselective insertion of tert-butyl isocyanide 183 to form C-C has been examined to form indane-1,3-dione derivatives starting from 1-(2-bromophenyl)-2-phenylethanone 184 [166]. This reaction tolerated various substituents since good reaction yields were obtained with 1-(2-bromophenyl)-2-phenylethanone substituted with various electron rich and electron deficient groups (see Scheme 31). After hydrochloric acid hydrolysis, indane-1,3-diones substituted at the 2-position with various aromatic rings could be obtained with reaction yields ranging from 61% to 75% (185–192). Starting from 1-(2-bromophenyl)ethan-1-one derivatives, indane-1,3-dione with aliphatic substitutes at the 2-position could also be prepared (190, 191). Finally, tolerance of this reaction to the cyano group was also evidenced (192). In this last case, 192 was not hydrolyzed as in the other case.

3.5. Copper-Catalyzed Sulfonamidation of Benzylic C-H Bonds

The transformation of a C-H bond into a C-N bond is an important reaction in organic chemistry, and the amination of primary benzylic groups has not been excluded from this interest [167]. Especially, sulfonamidation of primary benzylic groups with primary and secondary sulfonamides could give access to molecules of biological interest. However, methodologies for sulfonamidation of primary benzylic groups remain scarce in the literature [168,169], and most of the reactions only afford dramatic low yields (9–30%) [168,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187]. Conscious of the paucity of methodologies available, Powell et al. proposed in 2010 after substantial efforts, optimized conditions for the sulfonamidation of toluene 193 with N,4-dimethylbenzenesulfonamide 194 at room temperature [188]. A reaction yield as high as 70% could be obtained for the synthesis of 196 while selecting the copper catalyst Cu(CH₃CN)₄.PF₆, the oxidant tert-butyl 3-(trifluoromethyl)benzoperoxoate 195 and the ligand, namely indane-1,3-dione 4 (see Scheme 32). Choice of the ligand was determined as being crucial, other ligands such as bathophenanthroline or 1,3-diphenylpropanedione only allowing a conversion of 33% and 52%, respectively. If indane-1,3-dione 4 was capable to enhance the overall yield, its exact role remained unclear, 4 being only capable to act as a monodentate ligand for copper. The substitution pattern of the oxidant was also determined as being of prime importance, and the presence of electron-withdrawing groups such as the trifluoromethyl group on tert-butyl 3-(trifluoromethyl)benzoperoxoate 195 could weaken the perester bond, thereby facilitating the formation of the tert-butoxy radical [189].

3.6. Michael Addition on β-Substituted meso-Tetraphenylporphyrins

meso-Tetraarylporphyrins are extensively studied due to their facile synthesis, high molar extinction coefficients, high photoluminescence quantum yields, excellent photochemical stability, but also for their ability to chelate a wide range of metal cations in their inner core [190,191].

An efficient strategy to finely tune their optical properties consists in the modification of the porphyrin core by means of changing the π-conjugation length [192,193,194], the introduction of peripheral groups [195,196,197,198,199,200,201] or breaking the planarity [202,203,204,205]. In this field, insertion of a nitro group at the β-position porphyrin macrocycle proved to be an effective approach to introduce various substituents on the porphyrin core. Notably, 2-nitro-5,10,15,20-tetraphenylporphyrin 197 and 198 could undergo a variety of nucleophilic aromatic substitution, the macrocycle behaving as a Michael acceptor. While using indane-1,3-dione 4 as the nucleophile, the nucleophilic substitution could undergo a variety of metalated and non-metalated porphyrins (175 and 176) according to the mechanism depicted in Scheme 33 [206].

As a result of the addition of indane-1,3-dione 4 onto porphyrins, meta-chlorins that differ from porphyrins by the reduction of one of the pyrrole ring could be obtained [207,208]. trans-chlorins are extensively studied due to their red-shifted absorption compared to their porphyrin analogues, enabling to design dyes with an infrared absorption [194,209,210,211,212,213]. The six chlorins could be prepared with reaction yields ranging from 67 to 87% yield. Lastly, the same authors reported an unprecedented ring-fusion of trans-chlorins bearing 1,3-indanedione functionalities. Upon addition of Ni cations inside the porphyrin core, trans-chlorins could undergo a skeletal rearrangement of the porphyrin macrocycle, and trans-chlorins could be converted to fused metalloporphyrins by elimination of one indane-1,3-dione unit (as shown in Scheme 34) [214]. By controlling the reaction time, the metalation of trans-chlorins (15–20 min) or the nickel insertion, followed by an indane-1,3-dione elimination and a ring-fusion (3–4 h) furnished in turn the fused metalloporphyrins. To clarify the role of the nickel cation in this mechanism, reflux in DMF of trans-chlorins 199-Zn, 199-Cu, 199-Ni, 200-Zn, 200-Cu, 200-Ni, 201-Zn, 201-Cu, 201-Ni with nickel acetate converted all trans-chlorins to the fused metalloporphyrins (202-Ni, 203-Ni and 204-Ni). Metalloporphyrins containing other divalent cations were also prepared, by first demetalating 202-Ni, 203-Ni and 204-Ni and then remetalating with the appropriate metal acetates (Co, Cu, Zn).

3.7. Synthesis of 1,4-Isochromandione

1,4-isochromandione is an important heterocyclic compound, as this molecule is the starting material for the synthesis of numerous biologically active compounds such as parvaquone, which is an antiprotozoal agent marketed as Clexon [215,216], or atovaquone, which is an anti-pneumocystic agent marketed as Mepron [217]. In this context, various strategies have been developed to access this elemental building block. The first report mentioning the synthesis of 1,4-isochromandione 208 was reported in 1966 by Holt et al. using indane-1,3-dione 4 as the starting materials, and 208 could be obtained in 86% yield [218]. Following this pioneering work, several improvements were performed in order to improve the reaction yield. Typically, by diazotation of 4 with tosyl azide [219], 2-diazo-1H-indene-1,3(2H)-dione 210 can be obtained with reaction yields ranging from 59% [220] in ethanol to 80% [221] in triethylamine, 88% [222] in THF and finally 93% for the best conditions in ethanol [223]. By treating first 210 in basic conditions, 211 could be obtained, and treatment in a second step with sulfuric acid could furnish 208 in 83% for the last step (see Scheme 35) [224,225].

3.8. Synthesis of Benzofurans by Electrooxidation of Hydroquinone Derivatives

Benzofurans are important compounds, as these structures are widely used for the treatment of cardiac arythmias, and amiodarone is a relevant example of benzofurans used for this purpose [226,227]. However, benzofurans are not restricted to these applications, and benzofurans are also reported as having numerous pharmaceutical applications so that the synthesis of these derivatives has been widely studied [228]. More generally, benzofurans can also be used as fluorescent probes [229], antioxidants or brightening agents [230,231]. In 2015, an electrochemical synthesis of 212 and 213 was reported by Ameri et al. consisting in oxidizing in situ hydroquinones 214 and 215 as benzoquinones in a phosphate buffer (pH = 7), thus acting as a Michael acceptor (see Scheme 36 and Scheme 37) [232]. Depending on the substitution of hydroquinone, one or two 1,4-michael additions could occur, according to the mechanism depicted in Scheme 37.

Compounds 212 and 213 could be isolated in high yields, 86 and 84%, respectively. By combining several electrochemical techniques, the presence of an ECECECEC and of an ECEC mechanism was proven for 212 and 213, respectively.

3.9. Combination of Knoevenagel Condensation and Michael Addition Reactions

In a purpose of synthetizing complex organic structures involving affordable building-blocks, multicomponent reactions (MCRs) have played an important role over the last twenty years. With the emergence of green chemistry purposes, the synthetic strategies developed to access to complex structures have to be shortened and the use of metal catalysts and organic solvents limited. To address these issues, MCRs constitute a powerful strategy but also an expeditious method enabling to rapidly generate a vast library of molecules by systematically changing one of the three reactants involved in this convergent approach [233]. Several examples of multicomponent reactions making use of indane-1,3-dione 4 as one of these substantial building blocks for MCRs have been reported during the last decades. Typically, MRCs consisted in the combination of Knoevenagel condensation followed by a cyclisation reaction resulting from a Michael addition. Considering the similarity of structures of all these cyclized compounds obtained during these different works in the presence of an identical moiety, i.e., indane-1,3-dione 4, these structures can be combined under the generic name of “indeno-fused structures” (see Scheme 38). From a structure viewpoint, interest for these heterocycles was notably motivated by their interesting properties in medicinal chemistry, these molecules possessing anti-bacterial, anticancer or cardiovascular activities [226,228,234,235]. Biological applications of these different indeno-fused structures are discussed in the section devoted to the different applications of indane-1,3-dione derivatives.

As first examples of MRCs are those that were devoted to the synthesis of quinolinone derivatives (see Scheme 38, structures 216, 217). In this work, Sandaroos and coworkers used iron triflate (Fe(OTf)₃) as the Lewis acid catalyst, and the reaction could be conducted in solvent free-conditions [234]. Choice of iron triflate as the catalyst was supported by the weak nucleophilic character of the triflate anion, making the metal cation a stronger Lewis acid. The reactions performed at 90 °C for 4 h could provide the products with reaction yields ranging from 80 to 92% after purification. Control experiments performed without Fe(OTf)₃ also revealed the MRCs not to proceed, highlighting the crucial role of the Lewis acid in the activation process. The authors could reuse the metal catalyst without any loss of catalytic activity, but no precision about the number of cycles examined is given. In an attempt to optimize the catalytic activity, several other metal triflates such as Zn(OTf)₂, Cu(OTf)₂ were examined, but iron triflate remained the most effective one. To obtain a deeper insight into the mechanism, the reaction could be successfully decomposed into two steps, either by mixing indane-1-3-dione 4 and the aldehyde (225) but also the aldehyde and the amine (226) in the first step (see Scheme 39). Although both synthetic pathways remain possible, the expected compound 217b could be obtained in the two cases.

Iron plays without contest an important role in catalysis, not only as a heterogenous catalyst but also for the design magnetic nanocomposites. Iron can also be used not only for its remarkable reactivity but also for the easy recovery of the metal catalyst. Such a strategy has been reported in an MCR synthesis of indenoquinoline-8-one derivatives. The Lewis acid developed in this work, namely sulfonic acid-functionalized cellulose-coated Fe₃O₄ (Fe₃O₄@cellulose-SO₃H) nanoparticles, could be easily removed from the reaction media by use of an external magnet (see Scheme 38, structures 218) [235]. The authors optimized this synthesis be rendering it applicable in solvent-free conditions but also in water media, with sulfonic groups covering the metal particles for water compatibility. Using these magnetic Fe₃O₄ nanoparticles, the desired products could be obtained within 5 min. at 40 °C. Additionally, after removal of the magnetic particles with a magnet, the final product could be purified by a simple recrystallization in EtOH. The metal catalyst proved to be reusable, but a reduction of the reaction yield was nevertheless noticed. Thus, by repeating the synthesis of 218d, the reaction yield decreased from 95 to 82% yield after five runs. Nevertheless, contrarily to what was observed for the 216/217 series, an aromatization of the structure was observed, leading to the formation of 4-azafluorenones (see Scheme 38, structures 218). Here again, the role of iron particles was essential, by activating the aromatization reaction (see Scheme 40).

Similarly to the strategy applied for the easy recovery of the Fe₃O₄@cellulose-SO₃H particles, Fe₃O₄@NCs/Cu(II) particles have also been developed for the synthesis of another family of indeno-fused structures, namely 219a–219o [236]. This bio-based catalyst showed remarkable efficiencies in EtOH at 60 °C since reaction yields ranging from 79 up to 97% could be obtained within only 5 min. of reaction. Here again, the recovery was easy since only a magnet and washing with EtOH was required to recover the catalyst in pure form. A good recyclability was found since the catalyst could be reused without significant loss of its catalytic activity, even after 4 runs. Thus, the reaction yield decreased from 95 to 79% yield after 4 runs for 219a.

Even though these metal catalysts were highly efficient, it is always desirable not to use catalysts or to use catalysts that can operate in homogeneous phase. In this field, several examples of ionic liquids (ILs) have been proposed as green and reusable catalysts (see Scheme 33, molecules 220 and 221) [237,238]. Ionic liquids have been proposed as an interesting alternative to the traditional catalysts in a variety of chemical reactions, as these molecules are often less pollutant than metals and can also act both as solvents and catalysts [239,240,241,242]. In the case of these reactions, ILs have thus a dual role of solvent and catalyst. A first example of IL is 1,2-dimethyl-N-butanesulfonic acid imidazolium hydrogen sulfate [DMBSI]HSO₄, which was not used as a solvent [237]. Reaction conditions were optimized in ethylene glycol, and the best temperature for the MCR was determined as being 120 °C. In these conditions, the reaction was relatively fast since it could be finished within 4 min. Feasibility of the reaction in solvent-free conditions was examined, but lower reaction yields and longer reaction times were found compared to the results obtained in ethylene glycol. Recyclability of the catalyst was also examined, and after three successive runs, no significant reduction of the reaction yield was found. A few years later, another interesting example was proposed with 1-hexyl-3-methyl-imidazolium iodide [HMIM]I as the ionic liquid. It may be mentioned that in this case, the reaction could be performed in water with high reaction yields (up to 95%) while using sonication as the activation mode [238]. Sonochemistry is not widely used in organic chemistry to activate a large variety of organic reactions due to its appealing features: shorter reaction times, higher reaction yields, less byproduct formed, milder reaction conditions. Even though the kinetic is a bit slower than with the previous IL [DMBSI]HSO₄ (reaction performed with reaction time ranging from 4 to 20 min.), the use of water as the solvent and the energy economy achieved while using sonochemistry as the activating mode turned out to be an attractive improvement. However, ILs exhibit a major drawback for large scale syntheses, namely, their relatively high costs. This is the reason why cheaper catalysts are continuously researched. Lastly, indeno-fused structures have been successfully synthesized by mechanosynthesis while simply using p-toluenesulfonic acid (PTSA) as the catalyst [243,244]. One of the most important principles of Green Chemistry consists in the development of environmentally benign synthetic methodologies enabling to avoid the use of solvents, to use environmentally friendly solvents or to reduce the quantity of solvent used. In this field, mechanochemistry is a promising alternative to conventional methods, notably for the synthesis of indeno-fused structures. While using PTSA as the catalyst, the reaction could be successfully performed in solvent-free conditions in a mortar by grinding at room temperature. Reaction yield ranging from 70 to 86% could be determined (see Scheme 33, molecules 224) [243]. PTSA was also used as the catalyst for MCR reactions performed in water at 90 °C for 2.5 h, providing the targeted compounds with higher reaction yields compared to that obtained by mechanosynthesis (see Scheme 33, molecules 224) [244]. Although the reaction yields and the reaction time may be a bit less interesting than that obtained for the different examples presented before, interest of PTSA is that this catalyst need not be prepared, contrarily to the different iron particles or ionic liquids previously mentioned.

A slightly different type of indeno-fused structures deserves to be mentioned in this section, namely the indenopyrimidine derivatives (see Scheme 33, molecules 224) [245]. Even if the central core of pyrimidine contains two nitrogen atoms instead of one for the previous structures, the strategy used to prepare these structures remains the same versus those previously described, consisting in a Knoevenagel reaction activated by the presence of the catalyst, followed by a Michael addition, a cyclization reaction and finally, an aromatization as classically observed for azafluorenones. In 2018, a heterogeneous catalyst, Ag₂O–ZrO₂, was proposed to catalyze the MCR, where zirconia was used as the support to immobilize Ag₂O, which was the key part of this catalyst. Notably, Ag₂O was capable to coordinate the aldehyde and favor the condensation of indane-1,3-dione 4 (see Scheme 41). Recyclability of the catalyst was also quite interesting since a reaction yield of 90% could still be obtained after six cycles (starting from 96% yield for the first run). Although the reaction was performed in ethanol for 30 min, at room temperature, the catalyst only needed to be washed with acetone and dried at 100 °C for 3 h before being reused. Parallel to this, all compounds could be purified by recrystallization in ethanol, evidencing once again the compatibility of the green protocols for the synthesis of complex structures, as exemplified with these indenopyrimidine derivatives.

3.10. Indane-1,3-Dione: Versatile Building Block for Spirocyclic Compounds Synthesis

Spirocyclic compounds are chemical structures where two cyclic rings are linked by at least one atom. Such a configuration is strongly present in natural compounds [246]. Spiroindanediones moieties are also present in numerous bioactive compounds [247], and these molecules are efficient as antitumor and antibiotic compounds [248] and antiproliferative molecules [249]. Synthesis of these spiroindanediones can be relatively complex, since the formation of these spiro compounds can led to a wide range of isomers depending on the regioselectivity, the diastereoselectivity and even the enantioselectivity of the reaction. Even if complex mixtures can be obtained during their syntheses, this approach remains however the only one to form elaborated structures. Cycloaddition, domino reaction, and multi-component reactions (MCRs) are the main synthetic pathways leading to spiroindanediones, and these different reactions are described successively. Finally, the other synthetic routes giving access to spiroindanediones are briefly described in the final part (see Scheme 42).

3.10.1. Synthesis of Spiroindanediones by Cycloaddition

Spiroindanediones can be synthesized by various types of cycloadditions. Azomethine ylide is a versatile reactant capable to easily reacting with arylidene-1,3-indanedione in 1,3-dipolar cycloadditions or in [3+2] cycloadditions. Azomethine ylide can also be generated by various procedures, such that this reactant was involved in numerous reactions [250].

It was notably used to synthesize spiropyrrolidines starting from 2-ferrocenylidene-2(H)-indane-1,3-dione 230 [251]. 2-Ferrocenylidene-2(H)-indane-1,3-dione 230 could be synthesized by a Knoevenagel reaction between ferrocene-carboxyaldehyde 229 and indane-1,3-dione 4 (see Scheme 43). Then, by mixing sarcosine 232 and indoline-2,3-dione (isatin) 231, sarcosine 232 could condense with 231 and after decarboxylation, give rise to the azomethine ylide 234. This ylide can thus react with 230 in a [3+2] cycloaddition furnishing the ferrocenyl spiropyrrolidine adduct 235 (see Scheme 44). Using the same strategy, various compounds (236, 238, 240 and 242) could be synthesized in good yields (higher than 75% yields) by refluxing the methanol solutions for 12 h (see Scheme 45).

Single crystal X-ray diffraction analyses performed on different reaction products revealed how this reaction could give the product as a unique regio and stereo isomer. Notably, isatin 231 can react with different amines and give rise to more complex molecules, for example, by reaction with the azomethine ylide resulting from the reaction between ethyl glucinate hydrochloride 243 and dimethyl but-2-ynedioate 244 (see Scheme 46). The azomethine ylide 245 thus obtained is capable to react with an arylidene indanedione 246, as shown in Scheme 46. Such a reactivity was notably used to form various dihydro-spiro[indene-2,3′-pyrrolidines] 247 by a one-pot reaction at room temperature and in polar solvent, using triethylamine as the base. The different products could be obtained with reaction yields ranging between 56% and 69% (see Scheme 47) [252]. Examination of the single-crystal X-ray diffraction patterns and the 2D NMR spectra revealed that one diastereoisomer was mostly formed. Such a diastereoselectivity was assigned to a steric effect induced by the ester group and occurred during the reaction of the azomethine ylide with the indane-1,3-dione adduct during the concerted cycloaddition (see Scheme 48).

Azomethine ylide can also be formed by a decarboxylative condensation of isatin 231 with 1,3-thiazolane-4-carboxylic acid 248 [252]. Such ylides, when formed in situ, can react with various derivatives of 2-arylidene-1,3-indanediones 249 to give bispiro compounds 250 (see Scheme 49) that were tested as inhibitors for M. tuberculosis H37Rv. The reaction yields ranged between 60 and 92% depending on the aryl group. This reaction was also regioselective, furnishing only one diastereoisomer.

Azomethine imine can also be synthesized by condensation of the commercially available 3-pyrazolidinone 251 and benzaldehyde 252, as exemplified with 253 (see Scheme 50) [253]. The resulting azomethine imines 254 could react with different arylidene indane-1,3-diones 255 at room temperature using triethylamine as the organocatalyst. Reaction yields ranging between 65 and 98% could be determined, depending on the substituents [254]. The reaction can operate with a good diastereoselectivity (in most cases (>20/1)), (see

Table 2. Examples of cycloaddition reactions performed with various arylidene indane-1,3-diones 255 and azomethine imines 254.

Ar1	Ar2	Yield a	dr b
C6H5	C6H5	98	>20:1
4-FC6H4	C6H5	75	>20:1
4-ClC6H4	C6H5	85	>20:1
4-BrC6H4	C6H5	84	>20:1
4-CF3C6H4	C6H5	92	4:1
4-MeC6H4	C6H5	83	>20:1
3-BrC6H4	C6H5	65	>20:1
3-NO2C4H4	C6H5	71	>20:1
3-MeC6H4	C6H5	93	>20:1
3-MeOC6H4	C6H5	82	7:1
2-C4H3S	C6H5	70	>20:1

^a Yield of isolated product; ^b Determined by ¹H NMR spectroscopy on the crude mixture.

, Scheme 51).

The reaction is also tolerant to a wide range of substituents, and the electronic effects induced by the substituents were determined as having no influence on the cyclization reaction, the mechanism involving a π-π stacking interaction between the two reactants (see Scheme 52).

Iminodiesters can also be used as precursors for the synthesis of azomethine ylides, and an example is given in Scheme 53. This synthesis can be base-directed, giving after a [3+2] cycloaddition of 258 with the arylideneindane-1,3-dione 260 and a lactonization reaction, the chromenopyrrolidine 259 [255]. When DMAP was used as the base, the reaction was driven by electronics factors so that chromeno [3,4-b]pyrrolidines were obtained in these conditions irrespective of the aryl derivatives (see Scheme 54). The substrate was determined as only slightly influencing the reaction yields. Furthermore, when 257 was substituted with fluorine atoms, lower reactions yields were obtained compared to the other substituents (Br, Cl, OMe, Me, NO₂, …) (see

Table 3. Examples of chromeno [3,4-b]pyrrolidines 259 obtained using DMAP as the base.

R1	R2	t (h)	Yield (%) a
5-Br	H	18	69
H	H	18	62
5-Cl	H	12	70
5-NO2	H	30	58
5-OMe	H	18	59
4-OMe	H	24	71
3-OMe	H	18	79
5-F	H	11	46 b
5-Br	5-Cl	18	75
5-Br	5-Br	12	72
5-Br	5-NO2	18	63
5-Br	5-OMe	24	72
5-Br	4-OMe	18	61
5-Br	3-OMe	48	48

^a Isolated yield; ^b 17% of the other product was obtained.

and Scheme 55).

Conversely, when 1,1,3,3-tetramethylguanidine (TMG) was used as the base, chromeno [3,4-c]pyrrolidine 262 was obtained instead of 259, as the steric factors became predominant during the cyclization reaction (see Scheme 54). The reaction products 259 and 262 differ by the intermediate anions 258 and 261 formed by reaction of 257 with DMAP and TMG. During this reaction driven by steric factors, the reaction yield was lower when 257 was substituted with methoxy groups (see

Table 4. Examples of chromeno [3,4-c]pyrrolidines 262 obtained using TMG as the base.

R1	R2	t (h)	Yield (%) a
5-Br	H	4	79
H	H	5	65
5-Cl	H	4	71
5-NO2	H	4	50
5-OMe	H	24	26
4-OMe	H	15	10
3-OMe	H	15	47
5-F	H	5	53
5-Br	5-Cl	6	75
5-Br	5-Br	4	79
5-Br	5-NO2	48	56
5-Br	5-OMe	5	70
5-Br	4-OMe	8	76
5-Br	3-OMe	4	69

^a Isolated yield.

and Scheme 56).

Influence of the catalysts on the regioselectivity of the reaction was not clearly demonstrated. Furthermore, the formation of H-bonds between reactants was suggested as the key element supporting the formation of a unique isomer. When TMG was used as the catalyst, H-bonding interactions were more pronounced than with the other bases. Various chromeno [3,4-b]pyrrolidines 259 (see Table 3) and chromeno [3,4-c]pyrrolidines 262 (see Table 4) were synthesized using these procedures.

Other 1,3-dipolar cycloadditions were also performed with trifluoropyruvate imines in order to introduce fluorine groups [256]. Starting from ethyl 3,3,3-trifluoropyruvate 263, formation of the imine 264 led to a dipolarophile, which could be used for cycloaddition reactions (see Scheme 57).

After optimization of the reaction conditions, addition of a phase transfer catalyst (benzyltriethylammonium bromide (TEBAB)) 266 and at least one equivalent of LiOH as the base could lead to a complete conversion of the reactants 255 and 265 with an excellent diastereoselectivity as 267 (see Scheme 58).

This procedure was notably tested on various substrates, and the reaction proved to tolerate a wide range of functional groups such as chloride, nitro, methoxy and fluoride groups, even if in this case, the reaction yield was lower. The reaction tolerates other aromatic groups such as thiophene, furane and naphthalene (see

Table 5. Reaction yields obtained during the cycloaddition reactions using TEBAB 266 as the catalyst.

R1	Ar1	Ar2	Yield (%) a	dr b
H	C6H5	C6H5	98	100:0:0:0
H	4-BrC6H4	C6H5	70	100:0:0:0
H	4-OMeC6H4	C6H5	32	96:4:0:0
H	4-NO2C6H4	C6H5	73	100:0:0:0
H	4-ClC6H4	C6H5	68	100:0:0:0
H	4-PhC6H4	C6H5	84	100:0:0:0
H	C10H7	C6H5	72	100:0:0:0
H	C4H3O	C6H5	61	100:0:0:0
H	C4H3S	C6H5	56	100:0:0:0
F	C6H5	C6H5	40	50:50:0:0
NO2	C6H5	C6H5	46	60:40:0:0
H	C6H5	4-ClC6H4	69	100:0:0:0
H	C6H5	4-NO2C6H4	74	100:0:0:0
H	C6H5	3,5-(CF3)2C6H3	31	100:0:0:0

^a Isolated yield; ^b determined by ¹H and ¹⁹F NMR.

and Scheme 59).

Tamura cycloaddition is a common cycloaddition reaction occurring with an enolisable anhydride is used. A version where an anhydride 270 can react with an arylidene-indane-1,3-dione 255 was developed that allowed for the development of many spiro-indanedione derivatives 271 [247]. In this procedure, a base was used to promote the cycloaddition between 270 and 255, and various arylidene-indane-1,3-dione 255 could be converted as spiro-indanedione derivatives 271 (see

Table 6. Reaction yields obtained during the formation of spiro-indanedione derivatives 271.

R	Yield (%) a
C6H5	94
4-FC6H4	93
2-ClC6H4	88
4-ClC6H4	89
2-BrC6H4	91
4-BrC6H4	92
4-CNC6H4	90
4-NO2C6H4	91
4-MeC6H4	95
4-OMeC6H4	96
3,4,5-Me3C6H2	91
2-C10H7	92
2-C4H3O	88
2-C4H3S	91
C6H13	65

^a Reaction yield determined after purification and column chromatography.

and Scheme 60).

Coumarin is a common functional group present in various natural products [257]. In order to obtain new coumarin-based molecules with biological activities, a [3+2] cycloaddition procedure between arylidene-indane-1,3-diones 255 and a coumarin-based 1,3-dipole precursor 272 was developed [258]. Such a cycloaddition could be catalyzed by an organic catalyst, and the best conditions were found while using 10 mol% of 1-phenyl-3-((1R)-(6-methoxyquinolin-4-yl)((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea QN-T 273 in dichloromethane at 30 °C. Using these conditions, various substrates could be screened as reactants. Thus, 21 coumarin-indanedione derivatives 274 could be synthesized in moderate to high yields, as shown in

Table 7. Reaction yields obtained during the synthesis of coumarin-indanedione derivatives 274.

R1	R2	R3	t (d)	Yield (%)	ee a
C6H5	H	C6H5	1	89	96
4-NO2C6H4	H	C6H5	1	84	92
4-CNC6H4	H	C6H5	2	90	94
4-ClC6H4	H	C6H5	2	88	94
4-BrC6H4	H	C6H5	1	85	93
4-MeC6H4	H	C6H5	3	92	93
4-MeOC6H4	H	C6H5	4	84	91
4-HOC6H4	H	C6H5	7	70	69
2-MeOC6H4	H	C6H5	7	93	88
2-HOC6H4	H	C6H5	5	42	25
2-BrC6H4	H	C6H5	2	88	91
C4H3O	H	C6H5	4	73	89
C4H3S	H	C6H5	5	76	88
C5H4N	H	C6H5	1	82	77
C6H5	H	4-ClC6H4	2	90	95
C6H5	H	CH3	3	85	93
C6H5	4-Cl	C6H5	1	92	91
C6H5	4-Br	C6H5	2	82	95
C6H5	4-MeO	C6H5	1	86	92
C6H5	2,4-Cl2	C6H5	2	87	90
C6H5	2-MeO	C6H5	2	95	93

^a Enantiomeric excess determined by HPLC analyses on a chiral stationary phase.

and Scheme 61.

The mechanism of cycloadditions could be determined due to several control reactions. In the mechanism, the coumarin first interacts with the catalyst due to H-bonding. After this initial step, the adduct and the arylidene-indane-1,3-dione can react via a [3+2] cycloaddition concerted step furnishing the spiro compounds (see Scheme 62).

Organocatalysis was also used to achieve asymmetric cycloadditions between 2-arylidene-indane-1,3-diones 255 and Morita–Baylis–Hillman carbonates 275 [259]. In this procedure, a thiourea-phosphine organocatalyst (276) was used to achieve the synthesis of various cyclopentene spiro-indanedione derivatives 277 (see

Table 8. Reaction yields obtained during asymmetric cycloadditions between 2-arylidene-indane-1,3-diones 255 and Morita–Baylis–Hillman carbonates 275.

R1	R2	Yield (%) a	ee (%) b
4-NO2C6H4	4-Cl	52	88
4-NO2C6H4	4-Br	51	92
4-NO2C6H4	4-CN	65	91
4-NO2C6H4	4-CF3	50	91
4-NO2C6H4	2-Cl	68	97
4-NO2C6H4	2-Br	50	97
4-NO2C6H4	3-NO2	75	87
4-NO2C6H4	3-Cl	60	91
4-NO2C6H4	3-Br	51	90
4-NO2C6H4	2,4-Cl2	62	96
4-NO2C6H4	2,3-Cl2	67	98
4-NO2C6H4	3,4-Cl2	54	92
4-NO2C6H4	2,6-Cl2	30	92
4-NO2C6H4	4-F, 3-Br	50	90
4-NO2C6H4	4-CH3	Trace	-
C6H5	4-NO2	75 c	66
3-BrC6H4	4-NO2	64 c	67
4-C6H4	4-NO2	75 c	65
C6H11	4-NO2	68 c	67

^a Isolated yield; ^b determined by Chiral HPLC; ^c the reaction was carried out within 48 h.

and Scheme 63). The mechanism proposed by the authors was the following: the intermediates, once activated by the organocatalyst, can release CO₂, and ^tBuOH can react in a cycloaddition reaction with arylidene-indane-1,3-dione 255. After releasing the organocatalyst 276, the spiro-compounds 277 can be obtained (see Scheme 64).

[3+2] Cycloadditions enabling to prepare spiro-indane-1,3-diones can also be achieved with metal catalysts. Palladium is a common metal capable of catalyzing various cycloaddition reactions. Palladium was notably used as a catalyst in the [3+2] cycloaddition of vinylaziridine 278 and indane-1,3-dione derivatives 255 [260]. Such a procedure used a palladium (0) catalyst and a ligand (279) whose structures were carefully selected among a series of eleven ligands investigated. The optimal conditions were found to be 2.5 mol% of the palladium catalyst Pd₂bda₃ (tris(dibenzylideneacetone)dipalladium(0)), 6.7 mol% of ligand 279, in THF and at room temperature for two days (see

Table 9. Reaction yields obtained during the [3+2] cycloaddition of vinylaziridine 280 and indane-1,3-dione derivatives 255.

R	Yield (%)	er	dr
C6H5	97	92:8	3:1
4-MeC6H4	98	75:25	3:1
4-BrC6H4	90	77:23	3:1
4-NO2C6H4	98	80:20	3:1
4-CF3C6H4	93	87:13	3:1
C10H7	99	84:16	10:1
3-ClC6H4	90	72:28	3:1
3-MeOC6H4	90	83:17	3:1
C5H4N	81	75:25	3:1
C4H3O	59	97:3	4:1
CH2C6H5	91	74:26	3:1

and Scheme 65). The scope of applicability of this reaction was examined with a wide range of substrates. Even if the reaction tolerated a wide range of substituents attached to the arylidene-indane-1,3-diones 255, the enantiomeric ratio greatly changed with the substrates, as shown in Table 9 and Scheme 65.

When a cyclohexyl group was used instead of an aromatic group to prepare the indane-1,3-dione adducts, no reaction could take place, demonstrating the importance of starting from arylidene-indane-1,3-diones. The proposed mechanism involves the formation of a pi-allyl-palladium complex, obtained by the oxidative addition of Pd (0) to vinylaziridine 278. Then, after an aza Michael addition, the resulting adducts can form H-bonds with the amide ligand, giving rise to two reversible transition states. Then, an enolate ring closure can occur, and on the basis of steric factors, only one diastereoisomer forms (see Scheme 66).

Vinylethylene carbonate 282 can also react with arylidene-indane-1,3-diones 255 in [3+2] cycloadditions using a palladium catalyst to give tetrahydrofuran-fused spirocyclic 1,3-indandiones 284 and 285 [261]. Such cycloaddition involves the formation of carbon dioxide and proceeds in the optimized conditions, with a phosphoramidite ligand L 283, in chloroform at 0 °C for two days. This reaction could be tested at gram scale. Here again, tolerance of the reaction to the substitution pattern of carbonates 282 and arylidene-indane-1,3-diones 255 was remarkable. A unique product could be obtained in high yield in all cases and with a high enantioselectivity (see

Table 10. Reaction yields obtained during the cyclization reaction with vinylethylene carbonate 282 and arylidene-indane-1,3-diones 255.

R1	R2	Yield (%) a	dr b	ee c
C6H5	C6H5	99	53:47	99.98
3-MeC6H4	C6H5	99	52:48	99.95
4-MeC6H4	C6H5	97	51:49	96.95
2-MeOC6H4	C6H5	82	54:46	99.95
3-MeOC6H4	C6H5	84	53:47	99.98
4-MeOC6H4	C6H5	93	54:46	96.89
2-FC6H4	C6H5	96	53:47	93.92
3-FC6H4	C6H5	86	56:44	97.94
4-FC6H4	C6H5	96	52:48	94.92
3-ClC6H4	C6H5	94	52:48	93.95
4-ClC6H4	C6H5	76	51:49	96.95
3-BrC6H4	C6H5	77	52:48	93.89
4-BrC6H4	C6H5	68	50:50	95.95
4-PhC6H4	C6H5	71	53:47	93.95
C6H5	3-MeC6H4	94	56:44	96.97
C6H5	2-MeOC6H4	73	64:36	84.88
C6H5	3-MeOC6H4	99	62:38	96.96
C6H5	4-MeOC6H4	93	59:41	98.97
C6H5	3,4-(MeO)2C6H4	79	81:19	99.95
C6H5	2-FC6H4	89	68:32	91.90
C6H5	3-FC6H4	91	68:32	96.90
C6H5	4-FC6H4	89	53:47	94.92
C6H5	3-CF3C6H4	90	73:27	93.91
C6H5	4-CF3C6H4	99	59:41	97.81
C6H5	2-C4H3O	97	63:37	99.99
C6H5	4-Br-2-C4H2S	99	76:24	99.96

^a Isolated yield; ^b dr was determined by ¹H NMR analysis of the product; ^c determined by chiral HPLC analysis.

and Scheme 67).

Spirovinylcyclopropaneindanedione (VCP) 287 is a reactive spiro compound, usually obtained by reaction of indanedione 4 with 1,4-dibromobut-2-ene 286 in basic media (see Scheme 68) [262].

This spirovinylcyclopropaneindanedione 287 was notably used in a cycloaddition with palladium (0) as the catalyst with a sulfonyl-activated imine 288 [263]. Such a procedure can be advantageously used to increase the size of cycles of spiroindanedione compounds. An example of procedure giving access to the five-membered spiroindanedione 289 in 96% yield and with a diastereomeric ratio of 22:1 is presented in Scheme 69.

Spirovinylcyclopropaneindanedione (VCP) 287 is also capable of reacting with enals, as exemplified with cinnamaldehyde 290, enabling to increase by a [3+2] cycloaddition the size of the cycle of the spiro derivatives 292 from three to five carbons (see Scheme 70) [264].

The scope of application of this cycloaddition was rapidly studied, showing that aryl derivatives (293) or naphthyl-based enals (294) were compatible with this reaction, giving the cycloadducts 295 and 296 in 98% and 92% yields, respectively (see Scheme 71).

Spirovinylcyclopropaneindanedione (VCP) 287 can also react with nitroalkenes 297 in cycloaddition reactions, producing spiro-cyclopentane-indane-1,3-diones 298. Such a reaction typically operates according to a two-step procedure [262]. In a first step, the palladium will oxidatively add to VCP 287, opening the cyclopropane ring and giving an anion and a π-allylpalladium complex. The anion formed by ring opening is thus sufficiently nucleophile to add on the alkene 297. The nitro substituent present on nitroalkenes 297 is capable of stabilizing the carbanion, and this anion can give rise to an intramolecular cyclization, regenerating the catalyst (see Scheme 72, 298).

Such a procedure was tested with various nitroalkene derivatives, and the substitution pattern of the aryl substituents (presence of electron-donating or -withdrawing groups) did not impact the reaction process. The different products could be obtained in good yields (>80%). Only when the substituent was o-CF₃C₆H₄, the product was obtained with the lowest reaction yield of the series (75%) and with the worse diastereoselectivity (14:1). Even with other aromatic, heterocycle rings and alkane groups, the reaction yields remained good as well as the diastereoselectivity ratio and the enantiomeric excess (see

Table 11. Reaction yields obtained with various nitroalkene derivatives.

R.	Yield (%) a	dr b	ee c
C6H5	80	5:1	97:95
4-FC6H4	87	5:1	96:95
4-BrC6H4	84	4.4:1	92:80
2-CF3C6H4	75	14:1	99:55
2-FC6H4	82	6.4:1	96:89
4-MeOC6H4	92	5.5:1	98:90
2-F-6-ClC6H3	85	5.3:1	97:90
2-MeOC6H4	90	2.6:1	97:97
4-MeC6H4	81	5:1	96:88
2-BrC6H4	79	4.1:1	92:84
4-ClC6H4	90	5.3:1	92:68
1-C10H7	83	2.3:1	97:97
2-C10H7	81	5.7:1	98:80
C4H3S	80	6:1	97:87
C4H3O	89	5.7:1	96:78
C3H4	86	1.7:1	99:99
C6H11	88	1.2:1	99:99

^a Isolated yield of diastereoisomer; ^b the diastereoisomeric ratios were determined by ¹H NMR spectroscopy; ^c the enantiomeric excess values were determined by chiral HPLC analyses.

and Scheme 73).

[3+2] Cycloaddition can also be used to construct oxindole-fused spiropyrazolidine compounds 302 starting from spirovinylcyclopropaneindanedione 287 (VCP) catalyzed by palladium (0) [265]. 1-Benzyl-3-diazoindolin-2-one 300 could react with 289 in the presence of Pd₂dba₃ using a chiral (P,N) ligand 301 in toluene at 0 °C, affording various spiropyrazolidines 302 with reaction yields ranging from 39% to 99% (see

Table 12. Reaction yields obtained during the synthesis of oxindole-fused spiropyrazolidine compounds.

R1	R2	Yield % a	ee % b
H	CH2C6H5	95	78
5-F	CH2C6H5	99	64
5-Cl	CH2C6H5	92	78
5-I	CH2C6H5	98	69
5-Me	CH2C6H5	99	82
6-Me	CH2C6H5	78	59
6-MeO	CH2C6H5	96	77
6-Cl	CH2C6H5	96	65
7-CF3	CH2C6H5	52	68
5,7-Me2	CH2C6H5	80	48
5,7-Cl2	CH2C6H5	39	75
H	CH2OMe	65	77
H	Me	81	84

^a Isolated yield; ^b the enantiomeric excess was determined by chiral HPLC analysis on chiral cel IB-3.

and Scheme 74).

The mechanism of cyclization was similar to the mechanism previously depicted for the cycloaddition of VCP 289 with nitroalkenes 297. Thus, the palladium catalyst opens the cyclopropane ring, giving a zwitterionic species with an anion and a π-allylpalladium complex. Then, a [3+2] cycloaddition can occur between the anion and the diazo group, generating the cyclopentane ring after cyclization (see Scheme 75).

Palladium was also used in cooperation with an organic base to promote the annulation of vinylcyclopropanes indane-1,3-dione 287 with para-quinone methides 303 via a [3+2] cycloaddition [266]. Association of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), a thiourea-based ligand 304, and Pd₂(dba)₃ could catalyze the intramolecular annulation reaction between para-quinone methides 303 and 2-vinylspiro[cyclopropane-1,2′-indene]-1′,3′-dione 287 giving the product 305 in 61% yield with a diastereoisomeric ratio of 93:7 (see Scheme 76).

Palladium catalysis was also used in synergy with diphenylphosphoric acid 306 [267]. Such a mixture could catalyze the reaction between VCP 287 and various imines 307, producing 308 (see

Table 13. Reaction yields obtained during cycloaddition reactions using diphenylphosphoric acid 306 and a Pd (0) catalyst.

R1	R2	Yield (%) a	dr b
C10H7	C6H5	75	3:1
3,4-(OMe)2C6H4	C6H5	93	1:4.2
4-BrC6H4	C6H5	80	3.5:1
3-ClC6H4	C6H5	86	10.0:1
C4H9	C6H5	84	9.5:1
C6H5	4-NO2C6H4	81	4.8:1
C6H5	4-OMeC6H4	77	1:1.2
C6H5	3-MeC6H4	79	1.6:1
C6H5	4-ClC6H4CH2	50	1:9.2

^a Yields determined after purification by chromatography on silica gel; ^b diastereomeric ratio determined after purification by chromatography.

and Scheme 77). The different imines used in these reactions were prepared in situ.

Other metals can also be used for the cycloaddition reactions. Thus, copper was notably used to catalyze the [3+2] cycloaddition of 2-arylideneindane-1,3-diones 255 with ketoxime acetates 309 [268]. In a first study, the authors optimized the reaction conditions by screening various copper catalysts such as CuI, CuCN, CuOAc and even solid copper with various additives, at various temperatures and in various solvents. The best conditions to produce 310 were determined as being CuCN as the catalyst while using NaHSO₃ as the base and dichloroethane as the solvent at 100 °C. Then, a screening of different arylidene-indane-1,3-diones 255 was realized, as shown in

Table 14. [3+2] Cycloadditions of 2-arylideneindane-1,3-diones 255 with ketoxime acetates 309 using a copper catalyst.

Ar1	Ar2	Yield (%) a
C6H5	C6H5	95
2-BrC6H5	C6H5	92
2-NO2C6H5	C6H5	78
4-FC6H4	C6H5	85
4-CF3C6H4	C6H5	88
4-MeC6H4	C6H5	81
4-MeOC6H4	C6H5	61
3-BrC6H4	C6H5	95
C10H7	C6H5	51
C4H3O	C6H5	56
C4H3S	C6H5	54
C3H7	C6H5	21
C6H5	2-BrC6H4	82
C6H5	4-MeC6H4	85
C6H5	4-MeOC6H4	86
C6H5	4-NO2C6H4	86
4-FC6H4	3-BrC6H4	93
3-BrC6H4	4-ClC6H4	84
4-BrC6H4	4-MeC6H4	87
3-NO2C6H4	4-MeOC6H4	84
2-ClC6H4	4-MeOC6H4	92
C6H5	C4H3S	77

^a Isolated yield.

and Scheme 78.

The screening showed that the reaction could work with various aryl derivatives, giving the different products with reaction yields higher than 80%. When the methoxy group was attached in para-position of the aromatic ring, the reaction yield was lower than with the other groups. However, when the substituent was another aromatic group such as naphthyl, furyl or thienyl groups, the reaction yield decreased slightly, giving the products in around 50% yield. When the substituent was an alkyl group, such as an isopropyl group, the yield was relatively low (21% yield), demonstrating the importance of an aryl ring on the ketoxime acetates to obtain high reaction yields. The reaction mechanism was investigated by the authors, and the following one was proposed. Thus, after an oxidative addition of the copper catalyst 311 on the oxime 309, a copper enamide 312 formed. Then, this enamide 312 could undergo an intramolecular annulation with 255, releasing acetic acid as a by-product and producing 313. Then, the metallocycle could undergo a reductive elimination, giving the final product 310 and regenerating the catalyst 311 (see Scheme 79).

Cobalt (II) was also used as a metal catalyst to initiate 1,3-dipolar cycloadditions between azomethine ylides 314 and 2-arylidene-indane-1,3-diones 255 [269]. This metal cation can be chelated with two phenylalanine units, forming a planar complex of cobalt (II). After a careful screening of the reaction conditions, cesium carbonate was determined as being the best base to produce 315, and the optimal reaction conditions were determined as being 10 mol% cobalt(L-phenylalanine)₂, 10 mol% cesium carbonate in dichloromethane at −5 °C for two days. Using these conditions, a wide range of azomethine ylides 314 and arylidene-indane-1,3-diones 255 could be tested in these conditions (see

Table 15. Reaction yields obtained during the cycloaddition of azomethine ylides and arylidene-indane-1,3-diones.

Ar1	R	Ar2	Yield (%) a	ee (%) b
C6H5	Me	4-BrC6H4	56	−87
C6H5	Et	4-BrC6H4	60	−74
2,4-Cl2C6H3	Et	4-BrC6H4	85	−70
2-MeC6H4	Me	4-BrC6H4	79	−73
1-Br-2-C10H6	Me	4-BrC6H4	89	−81
1-Br-2-C10H6	Et	3-NO2C6H4	73	−81
2,4-F2C6H3	Et	3-NO2C6H4	89	−76
3-MeC6H4	Me	3-NO2C6H4	75	−76
2-MeC6H4	Et	3-NO2C6H4	76	−72
4-ClC6H5	Et	3-NO2C6H4	55	64
4-BrC6H4	Et	3-NO2C6H4	76	−77
2-ClC6H4	Et	2-NO2C6H4	59	−79
4-NO2C6H4	Me	C6H5	90	−74
4-ClC6H4	Me	2-C4H3O	65	−78

^a yield of the isolated product; ^b determined by Chiral HPLC.

and Scheme 80). The reaction tolerates all substituents examined, except that higher reaction yields were obtained while introducing electron withdrawing groups on the azomethine ylides 314.

A reaction mechanism was also proposed to explain the stereoselectivity of the reactions. In this mechanism, the azomethine ylides 314 chelate to the cobalt metal, leading to an octahedral complex. This complex will hide the Re face of the azomethine ylides, allowing arylidene-indane-1,3-diones 255 to attack the deprotonated azomethine ylides by the Si face exclusively. This stereoselectivity is directly related to the fact that the two aromatic rings (one of L-phenylalanine and the other on the azomethine ylides) will shield the Re face of the azomethine ylides 255 (see Scheme 81).

Ruthenium complexes were also used in combination with visible light to catalyze the [3+2] cycloaddition of 2-arylidene-indane-1,3-diones 255 with methyl 2-(3,4-dihydroisoquinolin-2-yl)acetate 316 [270]. The visible-light catalyzed reaction was tested with various methyl 2-(3,4-dihydroisoquinolin-2-yl)acetate 316, the substituent varying from ester to nitrile groups on the dihydroisoquinoline core and by testing various groups attached to the aromatic ring of 2-arylidene-indane-1,3-diones 255 (see

Table 16. Reaction yields obtained during the [3+2] cycloadditions of 2-arylidene-indane-1,3-diones 255 with methyl-2-(3,4-dihydroisoquinolin-2-yl) acetate 316.

Ar.	R	Yield (%) a
4-OMeC6H4	CO2Me	81
4-MeC6H4	CO2Me	88
C6H5	CO2Me	92
3-ClC6H4	CO2Me	92
3-NO2C6H4	CO2Me	70
4-ClC6H4	CO2Me	73
4-OMeC6H4	CO2Et	56
4-MeC6H4	CO2Et	72
C6H5	CO2Et	90
3-FC6H4	CO2Et	68
3-ClC6H4	CO2Et	70
3-NO2C6H4	CO2Et	65
4-ClC6H4	CO2Et	78
4-BrC6H4	CO2Et	90
4-NO2C6H4	CO2Et	75
C6H5	CO2tBu	86
2-ClC6H4	CO2tBu	55
3-ClC6H4	CO2tBu	60
3-FC6H4	CO2tBu	63
3-NO2C6H4	CO2tBu	54
4-BtC6H4	CO2tBu	62
4-NO2C6H4	CO2tBu	63
C6H5	CN	73
4-MeC6H4	CN	48
3-ClC6H4	CN	37
4-ClC6H4	CN	55
4-BrC6H4	CN	57

^a yield of the isolated product.

and Scheme 82). The nature of the aromatic group on the 2-arylidene-indane-1,3-diones 255 strongly influenced the structure of the final product 317. Thus, when the aromatic ring was substituted with electron-withdrawing groups, the reaction gave spiro[indene-2,1′-pyrrolo [2,1-a]isoquinoline]s 317, whereas when the substituent on the aromatic ring was an electron-releasing group, 3′-arylspiro[indene-2,2′-oxirane]-1,3-diones 318 were obtained.

Such a difference of products (317 or 318) can be explained due to the two plausible mechanisms proposed by the authors and that are depicted in Scheme 83 where an azomethine ylide is produced due to the photoredox catalyst. If the double bond of 2-arylideneindane-1,3-dione 255 is electronically depleted due to the electron withdrawing group and the ester group is not too big in terms of size, the azomethine can react with 2-arylideneindane-1,3-dione 255 via a cycloaddition reaction. Conversely, if the double bond is electronically enriched by electron-donating groups and the ester group is bulky (for instance with tert-butyl groups), then only the epoxidation reaction will occur.

This difference of reactivity can be advantageously used to produce various 3′-arylspiro[indene-2,2′-oxirane]-1,3-diones 318 (see

Table 17. Reaction yields obtained during the synthesis of various 3′-arylspiro[indene-2,2′-oxirane]-1,3-diones 318.

Ar.	Yield (%) a
4-MeC6H4	70
3-OMeC6H4	68
2-ClC6H4	92
2-BrC6H4	81
3-FC6H4	73
3-ClC6H4	89
4-ClC6H4	56
4-BrC6H4	72

^a yield of the isolated product.

and Scheme 84).

[3+2] Cycloaddition is not the only possible cycloaddition capable of produce spiroindanediones. The [2+2+2] cycloaddition is a smart and inventive procedure to construct aromatic rings, or heterocycles. These reactions are often metal-catalyzed [271]. 2,2-Di-2-propynyl-1,3-indandione 320 can be synthesized from indane-1,3-dione 4 and propargyl bromine 319 (see Scheme 85), and the resulting adduct 320 is a common substrate used in numerous cycloaddition reactions.

Using Molybdenum hexacarbonyl, it is also possible to realize cyclotrimerization. By reaction of 2,2-di-2-propynyl-1,3-indanedione 320 with propargyl bromide 319 upon catalysis with Mo(CO)₆, a complex mixture of products was obtained, showing the strong reactivity of the alkyne [272]. If the desired product 321 was obtained in 34% yield, the self-dimerized product 323 was also produced as well as another side-product 322 whose origin was determined due to the elucidation of the mechanism (see Scheme 86).

After further investigations, conventional heating was replaced by microwaves heating, giving a better selectivity for the product, and at the same time, use of acetonitrile as the solvent could increase the reaction yield. The scope of application of the reaction was also studied, and various spiroindanediones 325 were obtained by [2+2+2] cycloadditions of 320 and 324 (see

Table 18. Reaction yields obtained during the synthesis of spiroindanediones 325.

R1	R2	Yield (%) a
CH2Br	CH2Br	72
CH2Cl	H	80
CH2Cl	CH2Cl	79

^a yield after purification by column chromatography.

and Scheme 87).

The team of Ratovelomanana-Vidal and coworkers used another metal, namely ruthenium, to catalyze [2+2+2]cycloadditions, enabling to form pyridines [273,274,275,276,277]. Notably, ruthenium complexes were used to undergo a cycloaddition reaction of 2,2-di-2-propynyl-1,3-indanedione 320 with cyanamide 326 (see Scheme 88). This reaction could give the expected spiro-compound 327 in 97% yield within 5 min [277]. A similar procedure could be used for another cyanamide, i.e., pyrrolidine-1-carbonitrile 328 (see Scheme 89), and the reaction conditions could be greatly improved while using microwave irradiation (see Scheme 90). Using these improved conditions, all compounds (333 and 334) could be obtained in high to almost quantitative yields [274,276].

The procedure described before used Cp*Ru(CH₃CN)₃PF₆ as the catalyst. However, another procedure was also proposed using RuCl₃ as a more accessible catalyst and allowing the formation of the spiro compound 335 using a cheaper synthetic approach (see Scheme 91) [275]

Selenocyanates such as 336 and 337 could also be used as reactants with 2,2-di-2-propynyl-1,3-indandione 320 to form the spiro compounds 338 and 339 according to the procedure shown in Scheme 92 [273].

Other metals were also employed as exemplified with cobalt, which can be used to catalyze the [2+2+2] cycloaddition of 2,2-di-2-propynyl-1,3-indanedione 340 with a methyl indole derivative, namely 341 (see Scheme 93) [278]. Rhodium catalysis is also interesting, and in this case, an amide group can act as a directing group to ensure the cycloaddition and allow for the synthesis of polycyclic molecules bearing indanedione moieties such as 344 (see Scheme 94) [279].

The mechanisms involved in these two types of catalyzed cycloaddition reactions are similar. The C-H activation allows for the formation of a carbon-metal bond with the indole compound, and after coordination of the diyne, a migratory insertion of the two alkynes gave a metallocycle, which furnished the product after reductive elimination (see Scheme 95).

Phosphabenzenes are heterocycles containing one phosphorous atom in the cycle, and such heterocycles are only poorly described in the literature. The synthesis of these molecules involve multi-step reactions, cycloadditions and reversible cycloadditions sequences [280], with dangerous sylilated compounds, constituting a major impediment for their developments [281]. To address this issue, iron was notably used to perform the synthesis of phosphabenzene 346 in safe conditions, involving in one reaction, a diyne 320, a phosphaalkyne 345 and iron diiodide in xylene (see Scheme 96) [282].

However, spiro-indanedione can also be obtained by other cycloaddition reactions that are also metal-catalyzed. For example, by starting from a cyclic carbonate 347 and by using the same procedure of that reported by Guo, various derivatives of 349 could be prepared [261]. Cyclic carbonate 347 can react with various 2-arylidene-indane-1,3-dione 255 in palladium-catalyzed cycloadditions and give six-membered spiro compounds 349 (see

Table 19. Reaction yields obtained during cycloaddition reactions of 2-arylidene-indane-1,3-dione 255 and cyclic carbonate 347.

R	t (h)	Yield (%) a	ee (%) b
C6H5	12	87	97
2-FC6H4	14	99	98
3-FC6H4	48	62	97
4-FC6H4	10	94	97
2-ClC6H4	5	62	98
3-ClC6H4	36	94	98
4-ClC6H4	24	99	98
2,4-Cl2C6H3	4	90	98
2-MeC6H4	5	99	98
3-MeC6H4	12	99	96
4- MeC6H4	12	83	95
4-EtC6H4	12	64	97
2-MeOC6H4	11	99	97
3-MeOC6H4	14	99	99
4- MeOC6H4	14	99	94
1-C10H6	20	99	99
2-C4H3S	24	n.r.	-

n.r., no reaction; ^a yield of isolated product; ^b determined by HPLC analysis using a chiral stationary phase.

and Scheme 97).

Nickel can catalyze the formation of spiro compounds containing an eight-membered ring cycle [283]. Due to the association of nickel with a NHC ligand 351, such spiro cyclization of 2,2-di-2-butyn-1-yl-1H-indene-1,3(2H)-dione 332 and 1-benzhydrylazetidin-3-one 350 could be achieved in toluene after 8 h at 0 °C, furnishing 352 in 88% yield (see Scheme 98).

A base-catalyzed [4+1] cycloaddition was also described in the literature, enabling the synthesis of spiroindanes 354 bearing a para-phenol moiety (see Scheme 99) [260]. Rhodium was also used in metal-catalyzed intramolecular [4+3] cycloadditions of dienyltriazoles 355 to give the spiro-indanedione compound 356 (see Scheme 100).

o-Quinodimethanes (o-QDM) can be used to generate various compounds containing spiroindanediones moieties. Such molecules were obtained through a [4+4] cycloaddition, producing dibenzocycloooctadiene structures (see Scheme 101) [284]. Starting from indanone containing benzo[c]oxepines such as compounds 357 and 361, and by heating in a polar solvent, it was possible to create in situ o-QDM 358 and 362, producing after [4+4] cycloaddition the different spiroindanediones 359, 360, 363 and 364.

Asymmetric cross [10+2] cycloadditions were also successfully achieved by opposing electron-deficient alkenes such as 365 and 2-arylidene-indane-1,3-dione 249 by phase transfer catalysis [285]. Such reactions can furnish spirofused polycyclic structures such as 367 as shown in Scheme 102.

To conclude, cycloaddition reactions can lead to a large variety of spiro-indanediones, even if [3+2] and [2+2+2] cycloadditions are the two privileged routes to synthesize spiro-indanedione moieties. Other cycloaddition reactions can give promising results as shown in this paragraph.

3.10.2. Synthesis of Spiro-Indane-1,3-Diones by Domino Reaction

Domino reactions are defined as chemical processes where the final product comes from a sequence of reactions. The product of a first reaction become the reactant of another one. In contrast to a one-pot procedure or a multi-component procedure, the reaction conditions cannot be changed after the beginning of the reaction, and no additional compounds can be introduced in the reaction mixture.

One of the first examples of domino reaction described in the literature concerned the synthesis of spiro-compounds 378 by means of a domino Knoevenagel/Diels–Alder /Epimerization sequence [286]. This domino reaction was performed at room temperature in methanol for four days (see

Table 20. Examples of a domino Knoevenagel/Diels–Alder/Epimerization sequence.

R1	R2	Yield (%)	dr cis:trans
C6H5	4-NO2C6H4	97	≥99:1
C6H5	4-MeOC6H4	71	6:1
C6H5	4-HOC6H4	≥99	≥99:1
C6H5	4-ClC6H4	≥99	≥99:1
C6H5	2-NO2C6H4	80	≥99:1
C6H5	4-CNC6H4	≥99	≥99:1
C6H5	4-CO2MeC6H4	≥99	≥99:1
C6H5	C10H7	≥99	≥99:1
C6H5	C4H3O	≥99	10:1
C6H5	C4H3S	57	13:1
C6H5	C4H4N	30	≥99:1
C6H5	C2H2C6H5	74	≥99:1
C6H5	C6H5	93	≥99:1
C10H7	C10H7	95	≥99:1
C4H3S	C4H3S	93	≥99:1
C4H3O	C4H3O	60	≥99:1
4-MeOC6H4	4-MeOC6H4	95	≥99:1
C7H5O2	C7H5O2	98	≥99:1
4-Me2NC6H4	4-Me2NC6H4	90	≥99:1
4-HOC6H4	4-HOC6H4	95	≥99:1
4-ClC6H4	4-ClC6H4	98	≥99:1
4-NO2C6H4	4-NO2C6H4	98	≥99:1
4-CNC6H4	4-CNC6H4	85	≥99:1
4-CO2MeC6H4	4-CO2MeC6H4	83	≥99:1

and Scheme 103).

The mechanism supporting the chemical structure of the final products was suggesting as proceeding according to the following steps (see Scheme 104): First, the amine, i.e., L-proline, catalyzes the classical Knoevenagel condensation between 4 and 368, providing 255. In a second step, L-proline reacts with the Michael acceptor 369, generating the diene 370. Then, the diene 370 can react with the dienophile 255, regenerating the amine. Finally, by epimerization still in the presence of L-proline, the final product 370 can be obtained.

This strategy was notably applied to the construction of chiral spiro[indane-1,3-dione-tetrahydrothiophenes] 373. For this reaction, a tertiary amine-thiourea organocatalyst 372 was used, enabling a sulfa Michael/Michael sequence to occur [287]. By mixing indane-1,3-dione 4, an aldehyde 368 and a thiol, the aforementioned organocatalyst 372 and molecular sieves in toluene at −20 °C, spiro-compounds could be obtained. The scope of application of this reaction was examined with various aromatic groups (see

Table 21. Domino reaction involving a sulfa Michael/Michael sequence.

Ar	Yield (%) b	ee (%) c	dr cis:trans
C6H5	86	99	94.8:5.2
4-FC6H4	81	99	95.3:4.7
4-MeOC6H4	80	98	95.6:4.4
3-BrC6H4	78	97	91.6:8.4
3-NO2C6H4 a	85	91	84.4:15.6
3-MeC6H4	83	98	95.0:5.0
2-C4H3O	78	97	92.1:7.9

^a The reaction time was 48 h; ^b yield of a mixture of two isolated isomers; ^c determined by HPLC analysis on a chiral stationary phase; ee of the major diastereoisomer.

and Scheme 105).

X-ray structure of one of the substrates could be obtained and enabled to determine how the organocatalyst was interacting with the substrate and could promote the reaction at the Si face of the substrate (see Figure 2).

More recently, the scope of application has been expanded to the synthesis of spiro tetrahydrothiophene-indan-1,3-diones 376 starting from 1,4-dithiane-2,5-diol 374. The reaction was performed at room temperature in dichloromethane [288]. The scope of application of this reaction was studied, as shown in

Table 22. Reaction yields determined during the synthesis of spiro tetrahydrothiophene-indan-1,3-diones 376 starting from 1,4-dithiane-2,5-diol 374.

R	Time (h)	Yield (%) a	dr cis:trans b	ee c
C6H5	3	96	9:1	68
C10H7	3	93	8:1	65
4-NO2C6H4	2	99	7.5:1	56
4-FC6H4	1	96	9:1	66
4-BrC6H4	5	97	1.3:1	68
2-ClC6H4	2	93	1.5:1	72
4-MeC6H4	2.5	98	9:1	71
3-MeOC6H4	3	88	9:1	60
3,4-(OCH2O)C6H3	4.5	96	9:1	74
3-C4H3S	24	98	9:1	72

^a Yield of isolated product after column chromatography; ^b diastereoisomeric ratio (cis to trans) was determined by HPLC of the acylated product; ^c enantiomeric excess of the major diastereoisomer was determined by chiral HPLC analysis of the acylated product.

and Scheme 106.

Lewis acids were also used to synthesize spiro compounds by domino reactions, and the combination of a Knoevenagel condensation and a 1,3-dipolar cycloaddition was notably examined. ZnCl₂ was used as the Lewis acid-based catalyst and bromonitrile oxide 377 as the main reactant. Starting from indane-1,3-dione 4, aromatic aldehydes 368 and dibromonitrile oxide 377 in basic conditions in THF at 45 °C, spiro-compounds comprising an isoxazole moiety 378 could be obtained (see

Table 23. Domino reactions involving a Knoevenagel condensation/1,3 dipolar cycloaddition sequence.

Ar	Yield (%) a	rr b
4-MeC6H4	78	≥95:5
4-MeOC6H4	83	≥95:5
2-C10H7	74	≥95:5
4-ClC6H4	79	≥95:5
4-BrC6H4	80	≥95:5

^a Isolated yield; ^b determined by ¹H NMR analysis of the crude reaction mixture.

and Scheme 107) [289].

The same procedure was also applied to the synthesis of spiro-compounds 380 by replacing the former aromatic aldehyde 368 with benzoimidazoles 379 (see

Table 24. Domino reactions carried out with benzoimidazoles 379.

Ar	X	Yield (%)
4-BrC6H4	NH	78
4-MeOC6H4	NH	80
4-ClC6H4	S	76
4-MeOC6H4	S	85

and Scheme 108), thiazole 382 or benzothiazole 383 (see Scheme 109). These two reactions can lead to interesting compounds since the two families of products (380, 384 and 385) were tested as ligands for coupling reactions.

Other domino reactions involved a Michael addition followed by a 1,3-dipolar cycloaddition of 2-arylidene-1,3-indanediones 255 and 5-aryl-1,3,4-oxathiazol-2-ones 388 in toluene (see Scheme 110) [290]. A mechanism involving the formation of a benzonitrile sulfide intermediate was proposed by the authors (see Scheme 111).

Phosphine can also act as an initiator for the synthesis of spiro compounds containing cyclopentanones [291]. In this aim, 2-arylidene-indane-1,3-diones 255 and ynones 391 were mixed in EtOH. The reaction was studied for different ynones 391 and 2-arylidene-indane-1,3-diones 255 (see

Table 25. Reaction yields obtained during domino reaction of ynones 391 and 2-arylidene-indane-1,3-diones 255.

R1	R2	R3	t (h)	Yield (%) a
C6H5	H	C6H5	15	90
C6H5	H	2-BrC6H4	10	93
C6H5	H	3-BrC6H4	10	96
C6H5	H	4-BrC6H4	10	90
C6H5	H	2-MeC6H4	10	91
C6H5	H	3-MeC6H4	10	95
C6H5	H	4-MeC6H4	10	94
C6H5	H	4-ClC6H4	12	88
C6H5	H	4-FC6H4	12	87
C6H5	H	4-MeOC6H4	3	90 b
C6H5	H	4-NO2C6H4	24	73
C6H5	H	2,4-Cl2C6H3	12	62
C6H5	H	2-C4H3O	48	87
C6H5	H	2-C4H3S	53	84
C6H5	H	1-C10H7	20	96
C6H5	H	C2H4C6H4	35	89
C6H5	Me	4-BrC6H4	18	95
C6H5	Di-Me	4-BrC6H4	18	97
4-FC6H4	H	4-BrC6H4	21	83
4-MeC6H4	Me	4-BrC6H4	21	84
n-Bu	H	4-BrC6H4	22	NR

^a Isolated yields; ^b the reaction was carried out at 70 °C with a 2:1 ratio for ynone:indane-1,3-dione.

and Scheme 112). Since 2-arylidene-indane-1,3-diones 255 can be synthesized by a Knoevenagel reaction, a tentative of one-pot procedure involving indane-1,3-dione 4, an aromatic aldehyde 393 and an ynone 394 revealed than the one-pot procedure was possible and that the separated synthesis of 2-arylidene-indane-1,3-diones 255 was not necessary (see Scheme 113). Moreover, a mechanism was proposed, where the phosphine binds to the alkyne 394 in first step, creating a α,β-unsaturated ketone 396. Then, the phosphorous will stabilize the oxygen, allowing for the formation of a carbanion in the methyl in α-position of the ketone (397), and the resulting conjugated system 397 can react with 2-arylidene-indane-1,3-diones 255. The carbanion 398 formed during the addition is stabilized by the two ketones of indane-1,3-dione and can undergo an addition at the C3-position of the α,β unsaturated ketone, generating a cyclopentanedione 399. The phosphine is then regenerated, providing the product 395 (see Scheme 114).

Silver can be used as a catalyst in association with diphenylphosphine oxide 402 and a magnesium salt as an additive to synthesize spiro-compounds 403 [292]. The mechanism of reaction involves the formation of a radical that can undergo a cyclisation process (see Scheme 115). Such a reaction was used to synthesize spiro-compounds with indane-1,3-dione (see Scheme 116).

Gold was also used as a catalyst for domino reactions. Starting from indane-1,3-dione 4, a double propargylation of indane-1,3-dione produced 320, which was converted as 404 by the mono functionalization of one of the two propargyl groups by a Sonogashira reaction. Compound 404 was later used for the gold-catalyzed enediyne cyclization (see Scheme 117).

Then, a domino intramolecular cyclization could be carried out with 404 leading to 5′-hydroxy-6′-methyl-1′,3′-dihydro-2,2′-spirobi[indene]-1,3-dione 406 using 405 as the catalyst (see Scheme 118).

In 2020, a cascade Michael addition/cycloaddition reaction between 2-arylidene-indane-1,3-dione 255 and allenoates 407 was reported [293]. Various spiro-derivatives 408 could be obtained by this domino reaction, the overall reaction being catalyzed by a phosphine (see

Table 26. Spiro compounds 408 obtained by cascade Michael addition/cycloaddition reactions between 2-arylidene-indane-1,3-diones 255 and allenoates 407.

R1	R2	R3	t (h)	Yield (%)
C6H5	H	C6H5	15	90
C6H5	H	2-BrC6H4	10	93
C6H5	H	3-BrC6H4	10	96
C6H5	H	4-BrC6H4	10	90
C6H5	H	2-MeC6H4	10	91
C6H5	H	3-MeC6H4	10	95
C6H5	H	4-MeC6H4	10	94
C6H5	H	4-ClC6H4	12	88
C6H5	H	4-FC6H4	12	87
C6H5	H	4-MeOC6H4	3	90
C6H5	H	4-NO2C6H4	24	73
C6H5	H	2,4-Cl2C6H3	12	62
C6H5	H	2-C4H3O	48	87
C6H5	H	2-C4H3S	53	84
C6H5	H	1-C10H7	20	96
C6H5	H	C2H4C6H4	35	89
C6H5	Me	4-BrC6H4	18	95
C6H5	Di-Me	4-BrC6H4	18	97
4-FC6H4	H	4-BrC6H4	21	83
4-MeC6H4	Me	4-BrC6H4	21	84
n-Bu	H	4-BrC6H4	22	NR

and Scheme 119). The mechanism is the combination of a Michael addition of activated allenoates (A) on 2-arylidene- indane-1,3-diones 255. After a proton migration, a second 2-arylidene-indane-1,3-dione is attacked, forming (D). Then, by an intramolecular cycloaddition, (E) is formed, and by regeneration of the phosphine catalyst, the final product (408) can be obtained. This reaction also led to the by-product 409 coming from the [4+2] cycloaddition of the activated allenoates to the arylidene indanedione, furnishing 4aa (see Scheme 120).

A domino process was also reported with 2-arylidene-indane-1,3-diones 255 and N-alkoxyacrylamides 410 in the presence of a base and allowing for the formation of spiro-compounds 411 bearing an indane-1,3-dione moiety and a lactam group [294]. In this process, twenty different derivatives were obtained (see

Table 27. Domino reaction between 2-arylidene-indane-1,3-diones 255 and N-alkoxyacrylamides 410 in the presence of a base.

Ar	R1	R2	Yield %	dr
C6H5	C6H5	H	85	4:1
C6H5	4-FC6H4	H	81	4:1
C6H5	4-OMeC6H4	H	69	4:1
C6H5	4-NO2C6H4	H	51	4:1
4-OMeC6H4	C6H5	H	60	4:1
4-OMeC6H4	4-FC6H4	H	48	4:1
4-OMeC6H4	4-OMeC6H4	H	51	4:1
4-OMeC6H4	4-NO2C6H4	H	40	4:1
C6H5	Me	H	72	3:2
4-OMeC6H4	Me	H	60	3:2
C6H5	H	Me	60 a	- b
C6H5	Me	Me	69	-

^a The reaction was carried at 60 °C; ^b only one diastereoisomer was observed by ¹H NMR.

and Scheme 121).

A mechanism was tentatively proposed by the authors, where the base activates first N-alkoxyacrylamide 410, and the resulting anion 412 can thus react with 2-arylidene-indane-1,3-dione 255 in an aza-Michael reaction followed by an intramolecular Michael addition, forming a spiro compound 414 containing an enol. By reaction of this enol 414 with another N-alkoxyacrylamide 410, the final product 411 can be obtained (see Scheme 122).

In order to achieve the synthesis of more complex molecules that can exhibit biological properties, a cascade double Michael addition/acetalization proved to be an interesting approach to synthesize complex spiro indane-1,3-dione derivatives 416 and 417. The reaction between a 2-hydroxyarylidene-indane-1,3-dione 260 and hexenedione derivatives 415 could lead to various spiro compounds 416 and 417, when the reaction was catalyzed by DABCO (see

Table 28. Reaction yields obtained during the cascade double Michael addition/acetalization reactions.

R1 a	R2	R3	Time (h)	Yield % b
-	C6H5	C6H5	24	82
5-OH	C6H5	C6H5	24	82
5-OMe	C6H5	C6H5	36	77
4-OMe	C6H5	C6H5	27	83
5-Br	C6H5	C6H5	24	82
-	4-OMeC6H4	C6H5	75.5	72
-	4-BrC6H4	C6H5	96	72
-	4-ClC6H4	C6H5	24.5	67
-	3-ClC6H4	C6H5	24	72
-	2-ClC6H4	C6H5	24	72
-	C6H5	4-BrC6H4	24.5	76c
-	C6H5	3-BrC6H4	24.5	76
-	C6H5	4-ClC6H4	27	82
-	C6H5	3-ClC6H4	24.5	73
-	C6H5	2-ClC6H4	24.5	77 c
-	C6H5	4-OMeC6H4	48	84
-	C6H5	C4H3S	24	71
-	C6H5	C3H7	24	58 c

^a If nothing, there is 2-OHC₆H₄; ^b isolated yield; ^c in this case, only the intermediate was obtained in this yield.

and Scheme 123) [295]. A mechanism was notably proposed: firstly, the enolate of the dione 415 is formed by deprotonation of the amine (see Scheme 124). Then, the enolate can proceed to the nucleophilic attack onto the Michael acceptor, i.e., 2-arylideneindane-1,3-dione 260 (see Scheme 124). Then, the enone part of the hexenedione 261 can act as a second Michael acceptor. The indane-1,3-dione anion can also attack the Michael acceptor. An acetalization reaction can occur when the deprotonated hydroxyl group of indane-1,3-dione attacks the enolisable ketone, and after protonation, DABCO is regenerated, and the product 416 is formed (see Scheme 124).

A quadruple cascade reaction was also reported to create complex molecules starting from 2-arylidene-indane-1,3-diones 260 and conjugated enals 421. An iminium–enamine–iminium–enamine sequential activation followed by an oxo-Michael addition showed that it was possible to synthesize complex molecules bearing indanedione moieties (see Scheme 125) [296]. The mechanism proposed by the authors was the following one: after condensation of proline on the α,β-unsaturated aldehyde, the resulting iminium 424 could be attacked on its Re face by the alcohol of 2-arylidene-indane-1,3-dione. This oxo-Michael reaction forms an enamine 425 that can react via an intramolecular Michael addition, giving a nucleophilic iminium 426 capable of reacting with another equivalent of α,β-unsaturated aldehyde. The enamine 427 thus obtained can react in an intramolecular condensation, giving the final product 423 and releasing the catalyst (see Scheme 126).

3.10.3. Synthesis of Spiro-Indane-1,3-Diones by MCR

Multicomponent reaction (MCR) is a process where more than two chemical reagents react together to form one product. Such processes are interesting, since they reduce the number of steps to form the final product, facilitate in the purification of the product by avoiding the presence of side-products and, enable the perfect control of the stereoisomeric parameters at the same time.

With regard to the interest of MRC, numerous spiro-indane-1,3-diones 428 were prepared with this procedure. By use of pyridine as the base, spiro-indane-1,3-diones 428 could be easily synthesized starting from indane-1,3-dione 4, an aromatic aldehyde 429 and a pyridinium ylide 431 [297]. The pyridinium ylide 431 could be synthesized from an aromatic ketone 432 and pyridine, furnishing in a first way the pyridinium salt 433. Then, this pyridinium salt 433 can be converted as a pyridinium ylide 431 due to a base. Parallel to this, indane-1,3-dione 4 can react with the aromatic aldehyde 429 in a Knoevenagel condensation, furnishing 2-arylidene-indane-1,3-dione 430. Then, the pyridinium ylide 431 can add on the 2-arylidene-indane-1,3-dione adduct 430, furnishing in turn 428 (see Scheme 127). Due to this procedure, various aldehydes were tested, and moderate to good yields were obtained during the screening of the different aldehydes (see

Table 29. Reaction yields obtained during the synthesis of spiro-indane-1,3-diones 428.

R	t (h)	Yield (%) a
C6H5	10	67
2-ClC6H4	10	69
4-ClC6H4	8	72
4-FC6H4	9	64
3-NO2C6H4	10	62
4-MeC6H4	10	52
4-MeOC6H4	9	62
3,5-(MeO)2C6H3	9	58
2-HOC6H4	10	63
4-HOC6H4	9	55
2-HO-3-MeOC6H4	8	57
3-MeO-4-HOC6H4	8	60
4-NMe2C6H4	10	52

^a Isolated yield.

and Scheme 128).

Benzothiazole can also be used to achieve the synthesis of spiro compounds starting from indane-1,3-dione 4 [298]. By using indane-1,3-dione, dimethyl but-2-ynedioate 434 and substituted benzothiazoles (435 or 436), spiro compounds 437 and 438 could be respectively obtained with 2-methylbenzo[d]thiazole 435 and 2,5-dimethylbenzo[d]thiazole 436 (see Scheme 129). The mechanism of the reaction was not clearly established, but it seems to proceed via the formation first of a nitrogen-carbon bond between benzothiazole and the alkyne, and in a second step of the formation of a carbon-carbon bond between the alkyne and indane-1,3-dione 4 (see Scheme 130).

Synthesis of spiro compounds can also be obtained through a microwave and catalyst-free procedure. By mixing proline 439, an aromatic aldehyde 368 and 2-arylidene-indane-1,3-diones 255 and by using a microwave-assisted synthesis, spiro-N-fused indanedione compounds 441 and 442 could be successfully prepared [299]. In this procedure, the combination of a condensation, a decarboxylation and a 3+2 cycloaddition, could produce two isomers 441 and 442, as shown in Scheme 131. The scope of application of this reaction was studied with various aromatic substrates (see

Table 30. Scope of application of the microwave-assisted reaction.

R1	R2	Yield Product 1 (%)	Yield Product 2 (%)
C6H5	C6H5	30	31
4-NMe2C6H4	4-NMe2C6H4	28	32
4-OMeC6H4	4-OMeC6H4	32	36
4-NO2C6H4	4-NO2C6H4	20	22
4-C6H5C6H4	4-C6H5C6H4	32	28
C4H3S	C4H3S	42	41
C4H3O	C4H3O	36	36
3-NO2C4H2O	3-NO2C4H2O	39	31
3-MeC4H2O	3-MeC4H2O	30	33

and Scheme 132).

A one-pot five-component reaction was also developed, associated with a CuAAC (Copper catalyzed alkyne azide cycloaddition), a [3+2] cycloaddition and a condensation, furnishing triazole-containing spiro-indane-1,3-diones 435 [300]. In this procedure, five components were used, namely indane-1,3-dione 4, an aromatic azide 444, an aromatic aldehyde 368, 1-(prop-2-yn-1-yl)indoline-2,3-dione 443 and sarcosine 232 that could react with copper sulfate, sodium ascorbate as the catalyst in PEG 400 as the solvent. This reaction proved to be versatile since various aromatic azides 444 or aromatic aldehydes 368 could be used (see

Table 31. Reaction yields obtained during the synthesis of triazole-containing spiro-indane-1,3-diones 445.

R1	R2	Time (min)	Yield (%)
4-ClC6H4	4-FC6H4	45	85
4-ClC6H4	4-MeC6H4	50	80
4-BrC6H4	4-FC6H4	50	83
4-FC6H4	4-MeC6H4	40	82
4-BrC6H4	4-MeC6H4	50	81
4-FC6H4	4-FC6H4	45	84
4-ClC6H4	4-NO2C6H4	50	82
4-BrC6H4	4-NO2C6H4	45	86
4-MeC6H4	4-NO2C6H4	40	79
4-NO2C6H4	4-OMeC6H4	45	84
4-FC6H4	4-NO2C6H4	40	82
4-(CF3)C6H4	4-NO2C6H4	40	87
4-(CF3)C6H4	7-ClC9H5N	50	80
4-(CF3)C6H4	4-FC6H4	45	85
4-MeC6H4	7-ClC9H5N	50	74
C4H3O	C4H9	50	80
(CH2O2)C6H3	4-FC6H4	50	86
C4H9	7-ClC9H5N	60	78
C4H9	4-(Ome)C6H4	65	74

and Scheme 133). The mechanism proposed by the authors demonstrated that two products can be obtained. However, for unexpected reasons, the reaction proved to be regioselective, and 445 was obtained as the unique product of the reaction.

MCR conditions were also used for the design of spiro-indandiones exhibiting medicinal properties [249]. Indane-1,3-dione 4, aromatic aldehydes 368 and methyl enones 446 were mixed together with an organocatalyst 447, allowing for the formation of spiro compounds 448 containing a halogenated aromatic ring capable of reacting subsequently in a Suzuki cross-coupling reaction, and allowing for the formation of various derivatives 450, which were tested for biological applications (see

Table 32. MRC used for the design of spiro-compounds 450 with biological properties.

Ar	Yield (%) a
4-CH2OHC6H4	81
4-CHOC6H4	80
4-OMeC6H4	93
3,5-(OMe)2C6H4	40
4-CF3C6H4	81
4-OHC6H4	70
4-COOHC6H4	54

^a Yield of the purified product after chromatography column.

and Scheme 134).

Nanoparticles were also used as catalysts in one-pot three-component reactions [301]. By using proline-functionalized Fe₃O₄ particles (LPSF) and DABCO as the base, spiro-cyclopropanes 452 could be synthesized starting from indane-1,3-dione 4, aromatic aldehydes 368 and aromatic ketones 451, bearing a bromine in β-position. Various derivatives were prepared due to this strategy (see

Table 33. MRC reactions involving Fe-based nanoparticles.

R1	R2	Yield (%) a
-	-	84
4-Me	-	80
4-OMe	-	73
2-OMe	-	70
3-OMe	-	78
4-Cl	-	92
4-Br	-	90
3-OMe	4-OMe	83
4-Br	4-OMe	86
4-Br	4-Br	91

^a Isolated yield.

and Scheme 135). Another advantage of this strategy is that iron-based nanoparticles were magnetic, allowing for an easy recovery of the catalyst. The mechanism was supposed to work as depicted below: the nanoparticles due to the amine groups present on the external core of the nanoparticles can interact with substituted benzaldehyde 368 and indane-1,3-dione 4, promoting the Knoevenagel condensation and providing 2-arylidene-indane-1,3-dione 255. Parallel to this, the ketone 451 can interact with nanoparticles (interaction between the amine and the ketone), and then DABCO can easily react with the bromine atom, forming a zwitterion, composed of the quaternary amine and a carbanion in beta position of the ketone. The zwitterion thus prepared can undergo an addition onto 2-arylidene-indane-1,3-dione 255. Then, an intramolecular cycloaddition reaction can give the desired product 452 (see Scheme 136).

If cycloadditions, Domino processes and multicomponent reactions can lead to numerous spiro compounds; several other procedures were also developed to access to spiro compounds.

3.10.4. Synthesis of Spiro-Indane-1,3-Diones by Miscellaneous Way

In this part, all the other synthetic procedures leading to spiro-compounds are discussed. pH-switchable compounds belong to a recent concept that is born with molecular machines [302]. Using 5-(2-bromoethyl)phenanthridin-5-ium bromide 453 and indane-1,3-dione 4, a simple reaction in basic media could lead to the formation of a spiro compound, where the spiro compound can be in a closed/opened position 454a/454b depending on the pH (see Scheme 137). Such pH switchable compounds have the advantage to be easily tunable in terms of absorption and emission maxima [303].

Indane-1,3-dione 4 is an interesting scaffold that was extensively used in organic photovoltaics cells. In this way, it is interesting to synthesize new molecules for optoelectronic applications. Synthesis of spirobisindanedione was successfully obtained through a multi-step synthesis. The same team succeeded in synthesizing bindone 50 as well as spiroindanedione 455-457 (see Scheme 138) [40]. Indane-1,3-dione 4 by reacting with phthaloyl dichloride 458 and sodium hydride, and depending on the reaction conditions used, can give 50 or 456 (see Scheme 139). The reaction of oxidative cleavage of 456 with sodium periodate and ruthenium trichloride can give the spirobisindanedione 455 (see Scheme 140). A similar version of these molecules was also performed with a bromine atom attached to indane-1,3-dione (see Scheme 141).

Iron can be used as a catalyst in an alkene hydrofunctionnalization with 2-arylidene-indane-1,3-diones 255 [304]. In this process, an iron (III) catalyst, the selected 2-arylidene-indane-1,3-dione 255 could react with a terminal bromo-alkene 462. Various substrates were tested (see

Table 34. Reaction yields obtained during alkene hydrofunctionnalizations of 2-arylidene-indane-1,3-diones 255.

R	Methyle	n	Yield (%) a
C6H5	Yes	1	82
4-BrC6H4	Yes	1	55
4-CF3C6H4	Yes	1	59
4-MeC6H4	Yes	1	53
4-NMe2C6H4	Yes	1	45
4-ClC6H4	Yes	1	42
4-CO2MeC6H4	Yes	1	69
4-OMeC6H4	Yes	1	54
2-OMeC6H4	Yes	1	72
3-OMeC6H4	Yes	1	54
3-CNC6H4	Yes	1	48
2,4,5-C6H2	Yes	1	50
C4H3O	Yes	1	58
C4H3S	Yes	1	48
C10H7	Yes	1	74
3-CNC6H4	No	1	63 b
C4H3S	No	1	46 b
4-OMeC6H4	No	2	58
C6H5	Yes	2	50

^a Yield refers to isolated product; ^b dr was determined by ¹H NMR.

and Scheme 142), and a mechanism was proposed by the authors to support the synthesis of 463 (see Scheme 143).

Copper was also used as a catalyst for the synthesis of spiro compounds. In a [3+2] radical cycloaddition catalyzed by copper, 2-arylidene-indane-1,3-dione 255 could react in the presence of N-acetyl enamides 464 at high temperature [305]. Many N-acetyl enamides 464 and 2-arylidene-indane-1,3-diones 255 were mixed, providing a wide range of spiro structures 465 (see

Table 35. Copper-catalyzed synthesis of spiro-compounds.

R1	R2	Yield (%) a
4-FC6H4	C6H5	90
4-BrC6H4	C6H5	61
4-CF3C6H4	C6H5	84
4-MeC6H4	C6H5	73
4-OMeC6H4	C6H5	82
3-MeC6H4	C6H5	81
3-OMeC6H4	C6H5	66
3-ClC6H4	C6H5	69
2-BrC6H4	C6H5	85
C10H7	C6H5	71
C4H3O	C6H5	64
C4H3S	C6H5	66
C6H5	4-FC6H4	74
C6H5	4-ClC6H4	87
C6H5	4-BrC6H4	91
C6H5	4-NO2C6H4	75
C6H5	4-MeC6H4	76
C6H5	4-OMeC6H4	60
C6H5	3-ClC6H4	89
C6H5	3-MeC6H4	78
C6H5	3-OMeC6H4	74
C6H5	2-BrC6H4	68
C6H5	2-MeC6H4	70
4-BrC6H4	4-MeC6H4	58
4-FC6H4	3-BrC6H4	62
3-BrC6H4	4-ClC6H4	71
C4H3O	4-NO2C6H4	71
C6H5	CO2Me	Nr
C6H5	C6H11	Nr

^a Isolated yield; Nr, no reaction.

and Scheme 144). The plausible mechanism involves an air oxidation of the copper (I) complex to a copper (II) complex, producing in the meantime a radical (see Scheme 145).

Copper was also used in combination with oximes to produce spiro indanedione derivatives 467 (see

Table 36. Copper-catalyzed cycloaddition reaction of 2-arylene-indane-1,3-dione 255 with various oximes 466.

R1	R2	R3	R4	Yield (%) a
C6H5	C6H5	H	H	74
C6H5	4-MeC6H4	H	H	82
C6H5	4-OMeC6H4	H	H	80
C6H5	4-IC6H4	H	H	64
C6H5	4-ClC6H4	H	H	83
C6H5	4-CF3C6H4	H	H	81
C6H5	4-NO2C6H4	H	H	66
C6H5	4-CNC6H4	H	H	78
C6H5	4-MeSC6H4	H	H	81
C6H5	3-BrC6H4	H	H	85
C6H5	3-MeC6H4	H	H	89
C6H5	2-MeC6H4	H	H	78
C6H5	C10H7	H	H	74
C6H5	C4H9	H	H	79
C6H5	C6H5	CH3	CH3	50
C6H5	C6H5	C2H5	H	65 a
C6H5	C3H5	H	H	78
C6H5	CO2Et	H	H	30
C6H5	C10H20		H	32 a
C6H5	C8H8		H	40 a
4-OMeC6H4	C2H5	CH3	H	51 a
C6H5	C5H4N	H	H	51
C6H5	C4H3O	H	H	86
C6H5	C4H3S	H	H	56
C6H5	C9H8N	H	H	40
C6H5	C5H6N	H	H	96
C6H5	C4H5N2	H	H	77
C6H5	C6H4C3H2SN	H	H	70
4-BrC6H4	C6H3(O2CH2)	H	H	72
2-MeC6H4	C8H5S	H	H	52

^a > 19:1 dr value was determined by ¹H NMR spectroscopy.

and Scheme 146) [306]. A copper (I) salt was used as the catalyst, and the mechanism was similar to the previous mechanism, in which the copper catalyst is first oxidized, allowing for the formation of a radical. Then, the copper complex forms a metallocycle, where the oxidation state of copper is Cu(III). Being unstable and by reductive elimination, the product 467 can be formed and the copper catalyst regenerated (see Scheme 147).

Seyferth–Gilbert reagent 468 is a reagent classically used to transform carbonyl groups into alkynes. Such a reactant was notably used in association with indanedione derivatives 255 to form spiropyrazolineindane-1,3-diones 458 using CsF as the base [307]. When the 2-arylidene-indane-1,3-diones 255 and the Seyferth–Gilbert reagent 468 were mixed with sodium hydroxide, 3-pyrazolylphthalide 470 could be obtained. Therefore, the possibility to design various structures by modifying the quantities and the nature of the base was demonstrated, as shown in Scheme 148. By using CsF in 0.1 equivalent, the authors could synthesize a wide range of spiropyrazolineindane-1,3-diones 469 (see

Table 37. Reaction yields obtained during the reaction of of 2-arylidene-indane-1,3-diones 255 and the Seyferth–Gilbert reagent 457 in the presence of CsF.

R	Yield (%) a
C6H5	87
4-OMeC6H4	75
4-iPrC6H4	92
4-EtC6H4	88
4-MeC6H4	88
4-PhC6H4	90
4-BrC6H4	85
4-ClC6H4	77
3-ClC6H4	93
4-OMeC6H4	86
2-MeC6H4	88
3,4-(OMe)2C6H3	65
3,4,5-(OMe)3C6H2	80
C4H4N	80
C4H3S	87
C10H7	89
Fc	87

^a Isolated yield after chromatography by silica gel.

and Scheme 149).

To sum up, spiroindane-1,3-dione are interesting structures that can be obtained using various synthetic procedures. Due to their similitudes with natural compounds, these compounds are promising structures for the design of biologically active compounds, active pharmaceutical ingredients or biomimetic compounds. If cycloaddition remains one of the privileged ways to produce spiroindane-1,3-diones, highly complex structures could also be prepared and imply the development of appropriate synthetic procedures such as domino or multicomponent reactions. The list of the synthetic strategies developed to access to spiro compounds has been exhaustively detailed. Furthermore, other reviews were written on these topics, specially devoted to the synthesis of spiro compounds [308]. The importance of such moieties shows that this field is clearly not unveiled, and future discovery will allow for the design of highly biologically active spiroindane-1,3-diones.

4. Applications of Indane-1,3-Dione-Based Structures

4.1. Photopolymerization

During the past decades, substantial efforts have been devoted to develop photopolymerization processes under visible light and low light intensity [309,310,311,312,313,314,315]. Visible light is a safe spectral range of irradiation for the manipulators, and light is also a traceless reagent, making photopolymerization a green approach for the design of polymeric materials. Several parameters govern the photoinitiating ability of the photosensitizers such as their molar extinction coefficients, their redox properties and notably their easiness to be oxidized or reduced, depending of the additives used in the photoinitiating system [316,317,318,319,320,321,322,323,324,325]. Additionally, efficiency of the polymerization process is also highly dependent on the rate constant of interaction with the additives [326]. With the aim at developing dyes with high molar extinction coefficients, push–pull dyes are the most favorable structures, as the careful selection of the electron-donating and electron-accepting moieties connected at both ends of the π-conjugated spacer can efficiently tune the broadness but also the position of the intramolecular charge transfer band [327,328,329,330]. In this field, indane-1,3-dione and its derivatives have been extensively studied as photoinitiators, and a selection of structures (470 [331], 471–475 [332], 476 [333], 477 [334], 478–497 [335]) is presented in Scheme 150. Among the most interesting findings, photoinitiating ability was demonstrated as being directly related to the solvatochromic properties of the push–pull dyes. Only dyes for which linear correlations using empirical solvent polarity scales (Bakhshiev’s [336], Kawski−Chamma−Viallet’s [337], Lippert−Mataga [338], McRae’s [339], and Suppan’s [340] solvatochromic scales) could be established to initiate a polymerization process. If the direct relation existing between solvatochromic properties and photoinitiating abilities could be demonstrated, no clear explanations could be provided to support this unexpected behavior. Intrigued by these results and considering that little exploration as to the scope of push–pull dyes as photoinitiators has been disclosed, in 2020, Lalevée and coworkers examined this point with a new series of 21 dyes 478–497 in which the optical properties were finely tuned by modification of the electron-accepting core through an extended π-conjugation or by converting 4 and 68 into stronger electron acceptors.

All dyes showed an excellent ability to initiate the free radical polymerization of acrylate (Ebecryl 40) upon irradiation with a light-emitting diode (LED) at 405 nm, which is the wavelength currently under use for 3D printers [341,342,343]. As an appealing feature, beyond simply initiating a polymerization process, dyes 486 could also exhibit excellent photobleaching properties, what is rarely observed and what is actively researched for visible light photoinitiators, considering that these dyes are highly colored compounds often imposing their own colors to the final coating [344,345,346].

4.2. Non-Linear Optical Properties

Push–pull dyes exhibiting a large ground state dipole moment usually have high molecular non-linear optical (NLO) efficiencies [347,348]. Considering this, indanedione-1,3-dione 4, by its electron-withdrawing ability, is an excellent candidate for the design of dyes exhibiting such a property [349,350]. To present large optical nonlinearities, molecules should be organized in a none-centrosymmetric arrangement, and different strategies have been developed to stabilizing the dipole orientation. Thus, introduction of indane-1,3-dione derivatives into polymer composites (498–500) [351] or formation of Langmuir-Blodgett films with amphiphilic derivatives (501–504) [352,353] proved to be effective strategies to address this issue (see Scheme 115). In this last case, introduction of an additional double bond did not significantly modify the structure of the Langmuir–Blodgett films. Highest hyperpolarizability was obtained with 501, indicating the high order of the LB film obtained with this molecule. Parallel to this, an increase in the number of layers enhanced the NLO signal. Covalent linkages to polymers proved as being another strategy to retain the molecular orientation obtained by electrical poling [354]. By heating the polymer 505 at a temperature higher than its T_g and upon application of an intense electric field, an orientation of the push–pull dyes connected to the polymer backbone could be obtained. While maintaining the polymer film at a temperature lower than the polymer T_g, relaxation of the chromophore alignment could be efficiently slowed down, maintaining the molecular orientation of the dyes over time. Improvement of the molecular hyperpolarizability could also be obtained by improving the electron withdrawing of the acceptor, as exemplified with the dye 506 based on 2-methylidene-3-(dicyano-methylidene)-1-indanone [24]. Comparison with a reference compound, i.e., disperse red 1, revealed 243 to exhibit an hyperpolarizability as high as 1558 × 10⁻³⁰ esu·D, greatly higher than that of the reference compound (814 × 10⁻³⁰ esu·D). Most of the dyes prepared for NLO applications are synthesized by means of a Knoevenagel reaction, as exemplified by the selection of molecules 498–506 presented in Scheme 151.

4.3. Fluorescent Chemosensors and Chemodosimeters

The detection of metal cations, halide ions, cyanides and even of neutral species has been an active research field so that two types of detectors were developed [355]. The first category of fluorescent sensors are those comprising a binding site giving rise to an irreversible chemical reaction with ions, and these first types of compounds are named chemodosimeters. The second type of optical sensors are those capable of initiate a communication mechanism between the binding site and the ions, but in a reversible way. In this last case, these compounds are thus named fluorescent chemosensors. Indane-1,3-dione 4 has been at the origin of the elaboration of an efficient chemodosimeter for cyanide detection. Cyanides are extremely toxic anions so that a concentration as low as 2.7 µM is tolerated in drinking water [356,357]. In 2009, a chemodosimeter based on calix[4]pyrrole with an indane-1,3-dione unit at the β-pyrrolic position was reported by Lee and coworkers [213]. A dependence of the dye discoloration with the cyanide concentration was clearly evidenced, and a disappearance of the yellow color of 507 upon addition of cyanides could be easily detected with the naked eye. Chemodosimeter proved also to be highly selective since only cyanide ions were detected even when hidden within other ions. The remarkable selectivity and affinity for cyanide anions was explained by the fast equilibrium process involved in the complexation followed by the reaction induced by this extremely nucleophilic anion. After complexation of cyanide anions in the binding site of the calix[4]pyrrole, a nucleophilic addition at the β-position of the indane-1-3-dione group could occur, as shown in Scheme 152.

Based on the same nucleophilic addition of cyanides onto the double bond of push–pull dyes developed with indane-1,3-dione, 508 could be used as a dosimeter enabling to combine two detection modes [358]. Thus, upon addition of cyanide anions on 508, a clear discoloration of the dye could be detected with the naked eye. Parallel to this, a complete quenching of luminescence could be evidenced by photoluminescence measurements. If the detection of cyanides anions in THF was extremely fast, in water, kinetic of addition was considerably reduced, assigned to a solvatation effect of water molecules around the cyanide anions (see Scheme 153). Here again, 508 proved to be selective for the detection of cyanide anion, and this is again related to the small size of cyanides but also to their averred nucleophilic character. A similar strategy was developed with diketopyrrolopyrrole 509 [359]. A dual mode of detection was also observed with this compound. In this last case, a mechanism of exciplex formation was proposed to support the fluorescence quenching observed experimentally (see Scheme 153 and Figure 3).

4.4. Solar Cells

Organic solar cells have received significant attention for the possibility to convert photons to electrons. Among the most widely studied electron-acceptors, [6,6]-phenyl C₆₁ butyric acid methyl ester (PC₆₁BM) is the most popular one [99,360,361,362]. Due to a severe phase segregation upon aging of the device, the low solubility of PC₆₁BM in most of the common organic solvents and non-fullerene acceptors has been identified as promising alternatives to address the segregation issue and the solubility issue. Furthermore, the photon-to-electron conversions remain low, lingering around 3–6% for non-fullerene acceptors [363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378], justifying the constant efforts to develop new structures. To create strong electron acceptors that could replace PC₆₁BM, indane-1,3-dione 4 was notably combined with dibenzosilole [379]. A photon-to-current conversion efficiency (PCE) of 2.76% could be obtained for the solution-processed devices comprising a poly(3-hexylthiophene) (P3HT)/510 blend as the active layer. By replacing dibenzosilole by a naphthalimide unit, encouraging results were obtained with 511, with a PCE reaching 3.52% in the same conditions [380]. However, other authors also tested the opposite situation, using the dibenzosilole-based compounds as electron donors [381]. End-groups on 512 and 513 were determined as drastically affecting the morphology of the active layer, more than the photophysical properties of the dyes. Even after solvent vapor annealing, the power conversion efficiency of solar cells fabricated with the 512/PC₆₁BM blend remained low, peaking around 0.5% contrarily to 6.6% for devices fabricated with the 513/PC₆₁BM blend. The excellent electron-donating ability of 513 can also be assigned to the presence of the thiophene moiety, reported as improving both the optical and photovoltaic properties of the dyes comprising this group [382]. This trend was confirmed with 514 [11] and 515a [383] or 515b [384], with which a PCE of 2.4%, 6.46% and 8.22% were determined with solar cells of similar structures than that used for 513. In the case of 515b, improvement of the photovoltaic properties was assigned to the more balanced charge transportation in the devices and the use of copper isothiocyanate acting as a hole transport/injection layer. However, counterexamples exist, as exemplified with the asymmetric structure 516 [385]. Photovoltaic properties of 516 in bulk heterojunction solar cells remained poor, and a PCE of 1.7% was obtained for an active layer composed of a 1:1 515/PC₆₁BM blend. This low efficiency was notably assigned to the low hole mobility of 516 and adverse charge transport within the active layer (see Scheme 154). Finally, a similar low power conversion efficiency was obtained with 517 and 518, still based on an asymmetric structure [386]. Here again, the low efficiency (0.24–0.33%) obtained with 517 and 518 was assigned to an unfavorable morphology of the active layer as well as its high roughness.

5. Biological Applications

Indane-1,3-dione 4 has been the focus of intense research efforts in medicinal chemistry since the demonstration in the early 1930s of the bacteriostatic activity of indane-1,3-dione and related derivatives, but also of many 1,3-diketo compounds showing interesting physiological activities [387,388]. This section provides an explicit overview of the importance of indane-1,3-dione 4 as a building block for the design of molecules with potential biological applications.

5.1. Indane-1,3-Dione as Antimicrobial Agent

Any agent that kills or slows down the growth of a micro-organism may be defined as an antimicrobial agent. The increasing demand of antimicrobial drugs resulting from a faster microbial resistance to drugs requires the development of new compounds of innovative structures. Thus, antiseptics have been designed with indane-1,3-dione 4 as soon as 1931 by Walker et al. and their biological activities improved one year later by Robinson et al., who developed 1,3-diketo systems exhibiting remarkable physiological properties In Robinson’s work, the indane-1,3-dione core was formed by a Friedel–Craft reaction, enabling to introduce various n-alkyl groups or hydroxyl groups onto the aromatic core (compounds 521) (see Scheme 155). Notably, the presence of phenol groups was identified as improving the bacteriostatic effect of the resulting compounds [388,389].

All of these compounds were tested in vitro on Gram-positive bacteria: Staphylococcus albus Rosenbach (S. epidermidis), Staphylococcus aureus (S. aureus), (Bacillus megatherium (B. megatherium), Bacillus subtilis (B. subtilis), Bacillus mycoides (B. mycoides), Gram-negative bacteria: Bacterium pyocyaneum (P. aeruginosa), Bacterium prodigiosum (B. Prodigiosum) and Escherichia coli (E coli) but also on acid-fast bacteria such as Mycobacterium phlei (M. phlei) according to the Rideal–Walker method. Even though this method is not used anymore due to its lack of reliability on phenols, it was replaced by the McFarland protocol to furnish more reproducible data and to determine the minimum inhibitory concentration (MIC) [390]. This difference of protocols does not facilitate the comparison with recent research, but the activity of other phenol compounds still allows us to obtain a general picture of the antiseptic properties of this set of compounds. Notably, Robinson’s team noticed that all the molecules they developed were particularly effective against Gram-positive bacteria but had small efficiency against Gram-negative bacteria. Concerning the acid-fast bacteria (M. phlei), some molecules could also kill these organisms but only at high concentrations. Finally, the authors demonstrated an improvement of the bactericidal activity by increasing the number of carbons in the side-chains toward Gram-positive bacteria but also on Bacterium typhosum, responsible for typhoid fever [391]. This effect reaches its maxima for three molecules (see Scheme 156: 522, 523 and 524), with an activity more than ten times higher than that of the methyl or p-n-octylphenol (expressed in equimolecular phenol coefficient of bactericidal power). Even if these molecules have not been used as antibiotics later, modern researchers may inspire for sure from these former studies to design modern drugs due to the rise in antibiotic resistance.

The place of indane-1,3-dione in this field has clearly evolved. A structure related to indane-1,3-dione, namely indan-1-one, also showed interesting antimicrobial properties so that these two structures were often studied concomitantly for the design of antimicrobial compounds [1,2,3]. Considering that the biological activity of indane-1,3-dione 4 can be greatly improved by chemical engineering, indane-1,3-dione 4 has thus been extensively used as a building block in multicomponent reactions (MCRs) to combine the properties of indanones or indane-1,3-dione with that of other structures also displaying physiological properties.

A relevant example of this strategy has been reported in 2011 with a study devoted to the antimicrobial activity of 1,3-disubstituted indeno [1,2-c]pyrazoles [392]. Pyrazoles are an important class of pharmaceutical compounds. Considering that heterocyclic systems have been the focus of intense synthetic efforts during the last decades, indenopyrazoles have thus been extensively screened. In this study, the authors have notably synthetized 16 compounds possessing a 4-substituted thiazole moiety, all prepared with indane-1,3-dione as the starting material, and two different series were developed (see Scheme 157) in order to compare the impact of the fused indenopyrazole on the antimicrobial properties.

Several micro-organisms were tested such as Gram-positive bacteria (S. aureus, B. subtilis), Gram-negative-bacteria (E. Coli) and fungus (Aspergillus niger, Candida albicans). In this series of molecules, three molecules showed noticeable activities against C. albicans, A. niger, S. aureus and E. Coli (528h, 529d, and 529h). More precisely, antimicrobial activity of these molecules proved to be on par with that of the reference compound, i.e., Norfloxacin. Nevertheless, 528h was less effective against B. subtilis, whereas the two others only showed moderate minimum inhibitory concentration (MIC) with this micro-organism. Noticeably, an improved antimicrobial activity was found for all compounds once cyclized as indenopyrazoles, and a higher activity was also determined for all molecules substituted with 4-chlorophenyl groups.

After highlighting the importance of this structure, the same team published a second work in which the synthetic strategy was modified compared to the previous work and seventeen 3-aryl-1-heteroarylindeno [1,2-c]pyrazol-4(1H)-ones 532 could be prepared with this new synthetic method [393]. Indane-1,3-dione 4 was used to perform Knoevenagel condensations with various aldehydes 368, and the formation of the pyrazole cycle could be obtained by reaction of 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl6-substituted benzo[d]thiazoles 530 and the Knoevenagel adduct 255 in stoichiometric amount, according to the reaction presented in Scheme 158. Despite mild reaction conditions, the reaction yields remained low, ranging between 25 and 41%, even after optimization. Nonetheless, almost all of these new synthetized molecules showed an activity against four bacteria, Gram-positive and Gram-negative, but also against fungi.

In 2018, another multicomponent reaction involving indane-1,3-dione 4 was reported by Alsharif et al. for the design of an antimicrobial agent comprising nitrogen-based heterocyclic compounds [394]. The four-component reaction involving indane-1,3-dione 4, 9-ethyl-9H-carbazole-3-carbaldehyde 533, ethyl acetoacetate 534 and ammonium acetate 535 in the presence of a catalytic amount of piperidine could furnish ethyl 4-(9-ethyl-9H-carbazol-3-yl)-2-methyl-5-oxo-4,5-dihydro-1H-indeno [1,2-b]pyridine-3-carboxylate (ECPC, 536), following a procedure previously reported in the literature (see Scheme 159) [395]. This molecule was notably tested for its antibacterial activity, and for this study, S. aureus Streptococcus pyogenes (S. pyogenes) was selected as the Gram-positive bacteria and E. Coli as Salmonella typhimurium (S. typhimurium) as the Gram-negative bacteria. Biological activity of ECPC was also compared with that of tetracycine used as a standard for these tests. ECPC 536 showed an interesting antibacterial activity, since minimum inhibitory concentrations as low as 32 µg/mL were determined with the four bacteria, comparable to that required with the reference tetracycline.

In 2012, another series of heterocyclic molecules was synthetized using indane-1,3-dione 4 as the building block in an ionic liquid-catalyzed three-component condensation involving thiourea 537 and the appropriate aromatic aldehyde 368, and the resulting molecules 538 were tested as antimicrobial agents (see Scheme 160 and

Table 38. Antibacterial and antifungal activities of 538 derivatives.

Entry	Zone of Inhibition/mm
	Gram-Positive		Gram-Negative		Fungi
	B. subtilis	S. aureus	P. aeruginosa	E. coli	A. niger	C. albicans	A. fumigatus
538a	9	10	6	8	8	10	11
538b	15	14	10	11	12	14	17
538c	21	24	12	14	19	17	19

) [396]. In this work, the authors focused their attention on the pyrimidine scaffold, which is present in numerous natural physiologically active substances. The authors improved the biological activity of indane-1,3-dione derivatives by attaching a thione moiety to the pyrimidine group, this group being also known for its antifungal, antibiotic and antibacterial activities. Among the fourteen 4,6-diaryl- and 4,5-fused pyrimidine-2-thiones synthesized in this work, only three of them were prepared with indane-1,3-dione, the other compounds being variously substituted tetrahydrobenzo[h]quinazoline-2-thiones and pyrimidine-2-thiones. Among the three indane-1,3-dione derivatives, only 538c showed a better antibacterial activity toward B. subtilis, S. aureus, Pseudomonas aeruginosa (P. aeruginosa) and E. coli and a better antifungal activity toward A. niger, C. albicans, A. fumigatus than the variously substituted tetrahydrobenzo[h]quinazoline-2-thiones and pyrimidine-2-thiones. In addition, among the eleven other 4,6-diaryl- and 4,5-fused pyrimidine-2-thiones, only two of them showed similar antimicrobial properties than 538c, even if all of them have a less important zone of inhibition than the reference compound, namely Ampicillin trihydrate.

Finally, in 2016, another research group designed a series of spiro[indolo-3,10′-indeno [1,2-b]quinolin]-2,4,11′-triones 540 by means of a three-component condensation of enaminones 539, isatin 231 and indane-1,3-dione 4 using a mixture of ethanol/water as the solvent and cerium ammonium nitrate (CAN) as the catalyst (see Scheme 161) [397]. As the main advantage of this approach, spiro[indolo-3,10′-indeno [1,2-b]quinolin]-2,4,11′-triones 540 could be obtained with short reaction times, in high yields and by using a simple synthetic protocol. From this viewpoint, spiro[indolo-3,10′-indeno [1,2-b]quinolin]-2,4,11′-triones 540 reported in this work could be obtained by a greener approach than that previously reported in the literature [300,398,399,400,401]. Antimicrobial activities of these compounds have been tested on Gram-positive bacteria (S. aureus and B. subtilis) and Gram-negative bacteria (E. coli and P. aeruginosa) as well as their antifungal activity in two yeasts: Candida albicans and Saccharomyces cerevisiae. Among the twenty-two molecules synthetized in this work, all of them showed good antibacterial and antifungal activities, but none of them were effective against P. aeruginosa. Nevertheless, the best results were obtained for 540-IVc. Notably, 540-IVc exhibited the lowest MIC of 16 mg/mL against S. aureus, a MIC of 8 µg/mL against B. subtilis and a MIC of 64 µg/mL against E. coli. In the case of yeast, 540-IVc, 540-IVk and 540-IVn showed the best inhibition ability against C. albicans and S. cerevisiae with inhibition zones of 15 and 16 mm, respectively. Furthermroe, 540-IVc and 540-IVn were also determined as being more efficient against B. subtilis and S. aureus, the inhibition zone reaching 22 and 24 mm, respectively. However, despite these promising results, none of the new compounds could surpass the inhibition diameters obtained with the reference compound, i.e., ciprofloxacin (26, 24 and 25 nm against S. aureus, B. subtilis and E. Coli, respectively).

5.2. Indane-1,3-Diones as Anticancer Agents

Cancer is a generic name that regroups all diseases where the proliferation of abnormal cells is observed. Since only half of the cancer patients do not recover with systemic chemotherapy or obtain only a partial recovery, the development of anticancer agents is thus the focus of intense research efforts [402]. This research was also supported by the current incapacity to cure cancers combined with longer life expectancy but also by the fact that cancer is the second leading cause of death.

The combination of N-heterocycles and indenones has been widely studied during the last 40 years for the design of various compounds exhibiting anti-cancer properties [403,404,405]. Inspired by Onychine, which is a natural biologically active azafluorenone, numerous synthetic azafluorenones have been prepared and identified as exhibiting promising cytotoxic, phosphodiesterase inhibitory, adenosine A2a receptor antagonistic, anti-inflammatory/antiallergic, coronary-dilating and calcium-modulating properties [406,407]. Following the course of these investigations, a series of indeno-heterocycles has been designed by an MCR involving indane-1,3-dione 4 as the building block, and a library of 33 indeno-heterocycles 541 could be obtained (see Scheme 162). All these molecules were evaluated for their potential cytotoxic and apoptosis-inducing properties [407]. As specificities, all molecules reported in this work exhibited the same indenopyridine moiety in order to maintain the planarity of the structure. Planar structures are required in order for these molecules to act as DNA intercalators and topoisomerase inhibitors. Even if a similar synthetic protocol was used for the synthesis of the 33 molecules, different structures were nevertheless obtained. These compounds were notably tested for their cytotoxicity on Jurkat cells, a model for human T-cell leukemia, with Annexin-V/propidium iodide assay [408]. However, cytotoxicity of molecules 541 remained low since viability of the Jurkat cells was around 85–98% relative to the control experiments, and apoptosis induction was even lower, ranging between 1–6%. Aniline, pyrazole and triazole-based indeno-heterocycles 541 proved to be totally inactive for apoptosis induction. Only the pyrimidinedione-containing indeno-heterocycle showed a somewhat enhanced cytotoxicity, the cell viability being reduced to 80%. All attempts to mix the pyrimidinedione-containing indeno-heterocycle with the other compounds did not improve the cytotoxicity, evidencing that the pyrimidinedione moiety was the key-element to obtain an acceptable cytotoxicity. To obtain a deeper insight into the biological activity of this pyrimidinedione-containing indeno-heterocycle, this compound was compared to etoposide, which is an anti-cancer clinical drug agent known for its remarkable cytotoxic effect through topoisomerase II-dependent DNA cleavage. The two molecules could manifest good apoptosis-induction activities against Jurkat cells. Furthermore, the indeno-pyrimidine compound could demonstrate better cell-killing and apoptosis-induction activities than etoposide at low concentration (cytotoxic IC₅₀ = 3 μM). Nevertheless, clinical tests still need to be performed with this pyrimidinedione-containing indeno-heterocycle, and the authors also highlight the important drawback of poor water solubility of this compound, which may affect its future use as anti-cancer agent.

Three years later, in the continuation of the pioneering work initiated by Manpadi et al., another series of 35 pentacycle-based indeno-heterocycles 544 and 545 was prepared in order to investigate the cell-killing and the apoptosis mechanism toward a panel of human cancer cell lines [409]. All these structures were inspired by camptothecin, which is extensively used in traditional Chinese medicine. As the main motivation of this study, the authors suggested the drug action of these molecules to operate via an intracellular oxidation of the dihydropyridine cycle of 544, leading to the formation of the pyridine moiety 545 in situ (see Scheme 163). To demonstrate this, all compounds were synthetized with a hydrogenated (“h”) and an aromatized (“a”) version of the indenopyridine core using the same three-component synthesis of that used by Manpadi. When no spontaneous oxidation was observed, an additional oxidation step with chloranil in DMF was required to obtain the aromatized structure. These molecules were further tested for their antiproliferative properties on a panel of human cancer cell lines (HeLa, Jurkat, MCF-7, A-549, Lovo, U373, SKMEL, PC3, MG-MID), representing many species of cancer such as T-cell leukemia, cervical, breast, or lung cancers. The authors demonstrated that the modification of the R group on the aromatic ring did not significantly modify the biological activity of the molecules, except that the molecule bearing R=H showed no cytotoxic activity. The biological tests also revealed that the dihydropyridines 544 do not have cytotoxic activities contrarily to the pyridine analogues 545, supporting an intracellular oxidation process of the dihydropyridines 544 to the corresponding pyridines 545.

Sulfonamides are well known to act as inhibitors of numerous human α-carbonic anhydrases [410]. Carbonic anhydrases are essential in humans, as these anhydrases are capable of catalyzing the reversible hydration of CO₂ and allow for the respiration and the transportation of carbon dioxide within the human body. In 2012, the idea of Ghorab et al. was to combine the remarkable properties of sulfonamides to that of indenopyridines, which also possess anti-cancer properties [411]. To obtain these structures (549), a two-step synthesis involving indane-1,3-dione 4, 4-aminobenzenesulfonamide 546 and an aromatic aldehyde 368 as the starting materials was performed, the two steps being both realized in EtOH as the solvent. Anti-cancer activity of the resulting 18 compounds 549a-549q was tested in vivo against breast cancer cell-line (MCF 7) and their biological activities compared to that of doxorubicin, a reference drug. Among all compounds, 549d exhibited an IC₅₀ of 4.34 μM, lower than that of the reference doxorubicin (5.40 μM), evidencing the pertinence of the approach. Furthermore, 549d, which is specifically substituted with a hydroxyphenyl group at the 4-position and a cyano group at the 3-position exhibited an increased cytotoxic activity compared to the other compounds, and this specific substitution is certainly at the origin of the higher potency of this molecule (see Scheme 164).

Related to indenopyridines, indenopyrazoles are another family of structures showing important inhibiting tyrosine kinase activities, but also anti-cancer or anti-proliferative properties [412]. Nevertheless, for this purpose, indane-1,3-dione 4 was not directly used for their synthesis but a derivative containing a close scaffold: 2-(4-methoxybenzoyl)indan-1,3-dione 552. Its synthesis is similar to that of compounds 4 and 67 described in Section 1 except that no heating was required for the last step to obtain the triketone molecule and, in a second step, the intramolecular cyclization of 552 with hydrazine hydrate could furnish the targeted indenopyrazoles 553, as shown in Scheme 165 [413]. In 2002, another library of indenopyrazoles mainly substituted at the 5-position of aniline and at the 3-position with various groups was examined as Cyclin-dependent kinase (CDK) inhibitors [414]. Cclin-dependent kinases play a key role in the cell cycle regulatory machinery and the replication process. Considering that the different indenopyrazoles can regulate the development of proliferative tumors such as cancers, these molecules have notably been tested against various cancer cell lines (HCT116, NCI-H460, PC-3, MiaPaCa-2, HT-29, HT-1080 and B16-F0). After selecting 553-k for its good activity and selectivity against kinase targets (CDK2/E: IC₅₀ = 13 nM, CDK1/B: IC₅₀ = 44 nM), this molecule exhibited good cytotoxicity, particularly for HCT116 cells, which died not only by CDK inhibition but also by activation of the apoptotic machinery and by inhibition of Rb phosphorylation. This strong activity combined with a remarkable selectivity of cells offers very promising therapeutic applications, explaining why several patents have been established for structures close to that of 553-k [412,415,416].

5.3. Indane-1,3-Dione as Building Block for Bioimaging Agents

Fluorescent imaging techniques play an important role in medicinal chemistry by enabling to localize tumors at the cellular level and in this aim; extensive works are performed to develop fluorescent dyes capable of target specific cells or ions [417]. With the aim at gaining a better understanding of all these complex diseases, multiple recent techniques have been developed to visualize tumors, and numerous fluorescent agents have been proposed with indane-1,3-dione, which remains a cheap and versatile building-block in chemistry.

One of the most popular imaging techniques is named aggregation-induced emission (AIE). As specificity, dyes exhibiting AIE properties are often weakly emissive in solution but highly emissive in the solid state due to a restriction of the intramolecular rotations that constitute non-radiative deactivation processes. In addition to enhancing the fluorescence intensity of dyes, AIE is also extensively used for bioimaging due to its biocompatibility, its high-fidelity imaging, high brightness and long-living excited state favorable for an efficient in-situ imaging [418]. In 2020, an interesting study demonstrated that beyond imaging, AIE dyes could also be used for the generation of reactive oxygen species (ROS), enabling to combine bioimaging and photodynamic therapy (PDT) [419]. However, the key point of this strategy relies in a perfect targeting of the infected lysosomes by AIE dyes. To achieve this goal, three molecules based on triphenylamines were designed, bearing morpholines as pendant groups. In these structures, triphenylamine was used as the electron donor for the design of the different push–pull dyes and indane-1,3-dione, malononitrile or the formyl group were used as the electron acceptors (see MPAA 554, MPAN 555 and MPAT 556 in Scheme 166).

Among the three dyes, MPAT 556 exhibited the most red-shifted absorption and emission of the series so that this dye was the focus of extensive works. The three dyes showed a remarkable fluorescence stability since upon irradiation with a laser for 20 min., a decrease of less than 10% of the initial fluorescence intensity was determined, far from the loss of 50% determined with the benchmark LysoTracker Green DND-26 [420]. Examination of the fluorescence properties of MPAA 554, MPAN 555 and MPAT 556 in water revealed these dyes to exhibit high stoke shifts ranging between 187, 160 and 188 nm for MPAA 554, MPAN 555 and MPAT 556, respectively. For MPAT 556 displaying the most red-shifted emission, fluorescence maxima at 673 nm in water and 675 nm in the solid state could be determined. Conversely, for the other dyes, emissions located at 530 and 614 nm could be respectively determined in water for MPAA 554 and MPAN 555. For these reasons, the indane-1,3-dione adduct MPAT 556 was selected for the biological tests in A549, HeLa and HepG2 cells. No significant decrease for the cells’ viability was detected after 24 h of incubation, even at high concentration (100 μM), demonstrating that MPAT 556 can be used for long-term monitoring of cells without inducing cells apoptosis. In vivo experiments in zebrafish also furnished nice lysosome images with a good dot distribution during imaging of vertebrates. Finally, the ability of MPAT 556 to promote ROS production was evidenced while using H2DCF-DA as the probe. In PBS buffer solutions, a 36-fold enhancement of the photoluminescence of H2DCF-CA was evidenced, demonstrating the production of ROS by MPAT 556 upon green light irradiation. In HeLa cells, cell viability showed a remarkable decline, the cell viability reducing to 19% at 40 μM MPAT and after 10 min. of irradiation with a green light (see Figure 4).

In 2017, Gao et al. used AIE dyes for a completely different application, namely the lipid droplet-specific (LD) imaging and the dynamic movement tracking [421]. Lipid droplets (LDs) are involved in many metabolic processes. However, conventional dyes used to stain LDs suffer from numerous drawbacks such that new fluorophores are actively researched. Several families of molecules have been tested over the years, but the different fluorophores exhibited numerous limitations such as aggregation-caused quenching (ACQ), low stoke shift (40 nm), high background noise or even difficulty of preparation [422,423,424,425,426,427,428,429,430]. Consequently, the molecule selected in this study was a classical push–pull dye made of triphenylamine, as the electron-donating group was connected to indane-1,3-dione acting as the electron-withdrawing group and prepared by means of a Knoevenagel reaction. In addition of its AIE properties, 557 also exhibits what is named a twisted intramolecular charge transfer (TICT), resulting from restricted intramolecular rotations in the solid state. Based on both AIE and TICT properties, 557 was thus identified as a promising candidate for LD-specific imaging and movement tracking due to its high two-photon absorption cross-sections in the near infrared (NIR) range (see Scheme 167). For this reason, 557 was notably used as fluorescent dye for near infrared (NIR) two-photon excited fluorescence (TPEF).

To evidence the AIE effect in 557, UV–visible absorption and emission spectra were recorded in a THF/water mixture. A raise in the water fraction in THF from 0 to 70% led to a decrease in the fluorescence but also to a significant redshift not only of the emission spectrum (from 594 to 609 nm) but also of the absorption spectrum (from 478 to 489 nm), which can be attributed to TICT effects. A further increase in the water fraction in THF up to 99% induced a further redshift of the emission maximum up to 612 nm, resulting from the formation of nanoaggregates of average diameter of 119.6 nm, measured by light scattering analyses. Finally, 557 was tested on HCC827 and A549 cells. As shown in Figure 5, 557 could efficiently stain the cells with high signal-to-noise ratios. From the different tests, several advantages were determined for 557 such as:

A fast permeability;

An excellent selectivity for LD;

A high photostability;

A low cytotoxicity.

Finally, photostability of 557 was examined upon irradiation at 514 nm with a laser (7% power) for 10 min. As shown in Figure 6, the fluorescence intensity loss was less than 20%, evidencing the good photostability of this dye.

As we saw previously, the selectivity of dyes to target the right cells is a primordial need, especially when photodynamic therapy (PDT) is envisioned in complement to cell visualization. In 2019, Mondal et al. performed an MCR using indane-1,3-dione 4 as a component to elaborate a series of spiro-heterocyclic compounds 561–564 (see Scheme 168) that was subsequently tested as chromophores for the selective detection of Zn²⁺ ion and cell imaging [431]. Regarding specificity, this synthesis was realized by means of a microwave-assisted multi-component reaction (MWAMCRs); the reaction was carried out in EtOH, and the products could be obtained in pure form without chromatography, making this approach highly biocompatible.

Nine of the compounds were selected for further tests aiming at evaluating the possibility to coordinate Zn²⁺ ion, determining the selectivity toward other ions other than Zn²⁺ or the fluorescence emission at physiological pH. Among the nine dyes, one of them (i.e., 564f) was even selected for further in vivo tests on human hepatocellular liver carcinoma cells (HepG2 cells). This chemosensor could be successfully used as an intracellular Zn²⁺ imaging agent due to its remarkable cell permeability properties, where this molecule exhibited a fluorescence comportment only when coordinated with Zn²⁺ even in vivo. Cytotoxicity tests also revealed 564f to be weakly toxic since the cell viability was higher than 90% at 10 µM. Thus, 564f can be effectively used in vivo as chemosensors for the detection of Zn²⁺ cations. A mechanism supporting the enhancement of fluorescence upon coordination to Zn²⁺ cations was also proposed by the authors and is depicted in Scheme 169.

5.4. Indane-1,3-Dione in Neurology Drugs

The brain is the most complex organ in humans, and its working principle is still not fully understood yet, which explains the lack of medicines specific to this organ, despite all the research performed in this field. Moreover, the eldering of the populating on Earth will cause a significant increase in the neurodegenerative diseases that usually occur after 65 years, so that the demand on treatments for these illnesses will increase in the coming decades [432,433]. Parkinson’s disease (PD) is one of the most important neurodegenerative diseases and causes an important loss of dopamine in the brain, altering motor function cognition and the mood of the patient. Common treatments to PD are antagonists of two brain receptors, namely A_2a and A₁. However, it is still unknown yet if either one of the two brains receptors plays a more important role than the other in the disease [434].

In this context, Shook’s team published a series of arylindenopyrimidines 565 that were developed as potential dual A_2A/A₁ antagonists and that could be potentially used for the treatment of AD [435]. These arylindenopyrimidines 565 were synthetized through a two-step synthesis using indane-1,3-dione 4 as the starting material (see chemical structures in Scheme 170). In vitro and in vivo tests performed with eight molecules revealed unequal results depending on the substitution pattern. Notably, the different tests revealed the necessity to let the NH₂ group be unsubstituted, whereas the substitution of the pendant aromatic group had almost no incidence on the in vivo and in vitro activity. Furthermore, molecules substituted with morpholine or pyrrolidine groups showed the highest in vivo activity in mouse catalepsy.

To improve the biological activity, two different syntheses were developed to obtain substitutions on the heterocycle next to the indane group. The 12-step synthesis developed by the authors could give access to twelve compounds 577 substituted at the 9-position, and the seven-step synthesis developed in parallel could furnish 12 other compounds 584 substituted at the 8-position (see Scheme 171).

Comparison between the two series of analogs 577 and 584 revealed an improved biological activity for all molecules substituted at the 8-positions compared to those bearing a substitution at the 9-positions. Notably, a difference in the mouse catalepsy as high as 0.2 and 10.7 mg/kg for the ED₅₀ for the regioisomers 577-(1) and 584-(1) bearing a piperidine substituent could be determined. Furthermore, several adducts, particularly those containing cyclic amines and heterocyclic functions attached with an alkyl secondary amine showed ED₅₀ in the micro-scale for the mouse catalepsy. These adducts also showed decent in vitro activity so that these structures can be cited as promising candidates for AD treatments (see Scheme 172). Nevertheless, the lack of the commercially available substituted indane-1,3-diones allowing access to these structures is relatively complex and costly.

Furthermore, these structures remain promising, as exemplified with JNJ-40255293 (585) for which preclinical tests have been carried out (see Scheme 173) [436]. These additional tests revealed a better selectivity of the JNJ-40255293 antagonist toward the A2a receptors than the A1 ones. Unfortunately, preclinical tests were rapidly abandoned due to genotoxicity, neuronal necrosis and edema observed in several animals [437].

In 2002, more promising results were obtained with another series of indeno-fused structures, namely arylindenopyridines 588 and 593 that were patented for AD treatments (see Scheme 174) [438]. To support the biological efficiency, the authors suggested a binding of arylindenopyridines onto the A2a receptors. Anti-inflammatory activity was also identified, with phosphodiesterase (PDE)-inhibiting activity. The starting materials for these syntheses were various 1,3-indanedione adducts (586 or 590), such as 5-nitroindane-1,3-dione (see Scheme 138). The MCR used to access to these structures involved in the first step a Knoevenagel reaction between the indane-1,3-dione derivative 586 or 590 with the appropriate aldehyde 368, followed by a condensation of guanidine carbonate 588 to the push–pull compound 587 to form the indenopyrimidine 589. In the case of 491, an aromatization with DDQ was required, providing 593. The selectivity toward the A_2a receptor and A₁ were tested in vitro, and it turned out that some of these molecules could exhibit K_i lower than 50 nM, particularly with the A_2a binding. Despite these interesting preliminary results, no in vivo tests were performed with these molecules.

In 2011, a series of tricyclic 3,4-dihydropyrimidine-2-thiones 595 was proposed as a potential A₁ receptor and TRPA1 antagonists. The TRPA1 channel is implicated in numerous inflammatory or neuropathic pains [439]. These molecules were notably prepared via a Biginelli reaction with indane-1,3-dione 4 due to which the effects of the substitution of the phenyl groups along with the replacement of urea by thiourea in the cyclization reaction were studied. According to the in vitro tests performed on human and rats cells, experimental results revealed that all compounds prepared with thiourea were more biologically active than those prepared with urea. Influence of the stereochemistry is also clearly evidenced, as shown for compounds 595-(3) and 595-(4). Thus, for 595-(2), a half maximal inhibitory concentration hTRPA1 IC₅₀ of 0.075µM was determined for the S,R-stereoisomer, whereas for the S,S-stereoisomer 595-(3), an hTRPA1 IC₅₀ higher than 10 µM was determined (see Scheme 139). The meta-substitution on the phenyl ring could induce a significant increase in the activity (see Scheme 175).

Nevertheless, only in vitro tests were performed with these molecules, and the authors highlighted some drawbacks such as a low solubility, a poor metabolic stability and the potential toxicity of thiourea used to prepare these molecules [440].

In 2015, Ahmed et al. described a solvent-free three-component synthesis based on 1,3-indanedione as the starting material and developed a series of 14 potential anticonvulsants compounds with this strategy [243]. Seizure is a transient occurrence of signs and/or symptoms due to an abnormal excessive or synchronous neuronal activity in the brain [441]. This condition is often affiliated with epilepsy, which concerns about 0.5–1% of the population. Moreover, serious improvement needs to be performed concerning their efficiency but also to address the important issue of side effects [442]. The authors principally acted on one factor, namely the substitution on the pendant phenyl group. After synthesis, each molecule was tested via an anticonvulsant evaluation with the maximal electroshock (MES) method and compared with the results obtained with a standard drug, i.e., phenytoin, along with their toxicity with the Rotorod test. Most of the compounds designed in this study seemed to have positive effects on seizures ranging from moderate to good activity, particularly 222d, 222e, and 222j (see Scheme 176), which proved to be significantly active at a dose of 40 mg/kg. Moreover, the Rotarod tests showed no toxicity for all the compounds tested. However, none of them were as efficient as the reference compound phenytoin.

Among the neurodegenerative diseases, Alzheimer’s disease (AD) is the most common one, but this disease is also badly treated. During the last 25 years, only five medicines were approved for AD treatment with two different strategies of action. Thus, cholinesterase inhibitors (ChEIs) such as tacrine (1), donepezil (2), rivastigmine (3) and galantamine (4) were proposed in parallel to N-methyl-D-aspartate (NMDA) antagonists such as memantine (5) [443]. Nonetheless, none of them can repair the damage or delay the disease progression, which could constitute a major improvement in this field. The aggregation of a small peptide named amyloid β (Aβ) is associated with AD, and the inhibition of both cholinesterase sites (acetylcholinesterase, AChE, and butyrylcholinesterase, BChE) may prevent this aggregation [444].

In 2018, Tanoli et al. developed a series of tricyclic fused ring systems exhibiting activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Precisely, this study was supported by previous works reported in the literature, demonstrating that other tricyclic structures based on pyrimidine or quinazoline could act as AChE and BChE inhibitors [445]. In order to access the pyrimidine-fused rings, indane-1,3-dione 4 was used in a Biginelli reaction along with thiourea 597 and benzaldehyde 368 (Scheme 177).

The dihydropyrimidine (DHPM) scaffold is a potential inhibitor of cholinesterases so that in vitro tests were carried out. Interesting results were obtained with these molecules since the introduction of the indanone-pyrimidine fused ring could lead to an improved inhibition activity compared to tacrine and donepezil for both electric eel AChE (IC₅₀ = 0.09 µM) and equine serum BChE (IC₅₀ = 1.04 µM) assays. These results are close to that obtained with the commercially available Donepezil with IC₅₀ eeAChE = 0.05 µM and IC₅₀ eqBChE = 5.4 µM. Docking studies on this molecule have also exposed the well accommodation of this molecule into the bottom of the gorge and the importance of the hydrogen bonding with its environment, such as Ser200, or even the phenyl ring at the 4-position, which forms π-π stacking interactions with trp84 (see Figure 7).

In 2010, the good activity of 2-[(2-(4-chlorophenyl)hydrazinyl) methylene]-1H-indene-1,3(2H)-dione 605f as a novel inhibitor capable of prevent amyloid aggregation (IC₅₀ = 23µM) [446] motivated the group of Campana to obtain a deeper insight into the biological activity of this molecule and in this aim a series of indane-2-arylhydrazinylmethylene-1,3-diones 605a–f and indol-2-aryldiazenylmethylene-3-ones 608a–m (see Scheme 178) [447].

In this work, the authors clearly highlight a significant increase in the biological activity with the molecules prepared with indane-1,3-dione compared to those prepared with 1,3-cyclopentanedione. Nonetheless, even if all the compounds exhibited decent to good AB aggregation processes, none of them could overcome the reference quercetin (IC₅₀ = 0.8 µM).

5.5. Indane-1,3-Dione as Anticoagulant Drugs

One of the oldest utilizations of indanedione derivatives in medicine concerns the anticoagulant properties. Since the 1940s, several authors reported the insecticidal properties of acylated indane-1,3-diones (see Scheme 179), especially for houseflies [154]. Later on, this toxicity has been attributed to an anticoagulant property, especially marked for acylated indane-1,3-diones (see Scheme 179) [448]. However, this activity can also be used as treatment for vitamin K antagonists (VKAs), as observed for phenindione derivatives (see Scheme 179) [449]. However, pheindione is not so much used anymore and was replaced by its homologue, fluindione, or other coumarins VKA due to side effects such as hypersensitivity identified for pheindione [450]. However, despite a proven efficiency as vitamin K epoxide reductase, fluindione 609b is used almost only in France because of a lack of study data on old people [451].

The synthesis of these indane-1,3-dione derivatives is actually not performed anymore starting from the unsubstituted indane-1,3-dione, but a recent study uses a similar structure with indane-1,3-dione as the starting material [452]. Nonetheless, this molecule is only an intermediary of reaction for the synthesis of 2,3-disubstituted indoles.

Concerning the synthesis of acylindanediones 613, the standard synthetic strategy is quite similar to that used for indane-1,3-dione 4 since it consists in a Claisen condensation using an alcoolate as the base (see Scheme 180) [453]. However, an alternative was proposed in 2018 by Larsen et al. involving indane-1,3-dione 4 as the starting material with the possibility to afford 25 different C2 acylated 1,3-indandiones 616 (see Scheme 181) [454]. This strategy, which is quite efficient, makes use of an easy set up and producing the molecules in high yields using 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP) as the coupling agents. Furthermore, all tests made with this new strategy have only been performed at a small scale compared to the initial synthesis.

These type of indanes are more commonly used as rodenticides than as for pharmaceutical purposes. All commercially available rodenticides are either 4-hydroxycoumarins or indane-1,3-diones and even if coumarins are more widely used, a resistance has recently been evidenced toward derivatives such as Warfarin. At present, less resistances have been identified toward indane derivatives. Chlorophacinone, which belongs to the first generation of rodenticides, is still commonly used in many countries. Even if the second generation is more effective against rodents, their impact on the environment is quite significant with multiple poisoning detected in cats, dogs or even otters [455,456].

6. Conclusions-Perspectives

Indane-1,3-dione is a versatile molecule that has found applications in numerous research fields. Directly related to the broadness of applications, numerous synthetic routes have been examined first to prepare indane-1,3-dione, the corresponding derivatives bearing various substituents. If indane-1,3-dione is an excellent electron acceptor for the design of various push–pull dyes, the most popular use of indane-1,3-dione is undoubtedly in multicomponent or domino reactions to prepare polycyclic structures for biological activities. Considering the remarkable biological activity of indane-1,3-dione derivatives, future work will certainly be more focused on these biological applications than on the optoelectronics applications. Numerous electron acceptors have already been prepared with this scaffold, limiting the possibility of new developments.