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

Corentin Pigot, Damien Brunel, Frédéric Dumur

► To cite this version:

Corentin Pigot, Damien Brunel, Frédéric Dumur. Indane-1,3-Dione: From Synthetic Strategies to Applications. Molecules, 2022, 27 (18), pp.5976. 10.3390/molecules27185976. hal-03779130

HAL Id: hal-03779130

https://hal.science/hal-03779130

Submitted on 16 Sep 2022

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Review

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

Corentin Pigot * and Damien Brunel * and Frédéric Dumur *

Aix Marseille Univ, CNRS, ICR, UMR 7273, F-13397 Marseille, France

* Correspondence: pigotcorentin2@gmail.com (C.P.); damienbru@laposte.net (D.B.); frederic.dumur@univ-amu.fr (F.D.)

**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.

**Keywords:** indanedione; chemical modification; domino reaction; MCR; spiro compounds

## 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 [1–3]. 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

<figure><img src="image_2.png" /></figure>

check for
updates

**Citation:** Pigot, C.; Brunel, D.; Dumur, F. Indane-1,3-Dione: From Synthetic Strategies to Applications.
*Molecules* **2022**, *27*, 5976.
https://doi.org/10.3390/molecules27185976

Academic Editor: José C. González-Gómez

Received: 10 August 2022
Accepted: 6 September 2022
Published: 14 September 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

<figure><img src="image_3.png" /></figure>

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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 [24–28] and 2,2'-(1H-indene-1,3(2H)-diylidene)dimalononitrile 29 [28–30] 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].
<figure><img src="image_4.png" /></figure>

1

2

3

4

<figure><img src="image_5.png" /></figure>

5

$$ \chemfig{*6(=-=-(-O_2)=-=)} \text{ (1 atm), NHPI (0.25mmol),} $$

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

4

<figure><img src="image_8.png" /></figure>

5

$$ \chemfig{*6(=-=-(-H_2O_2)=-=)} \text{, } \text{Mn}_3^+ \text{ catalyst} $$

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

4

<figure><img src="image_11.png" /></figure>

5

$$ \chemfig{*6(=-=-(-Na_2CO_3)=-=)} \text{, } 1.5 H_2O_2 $$

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

4

<figure><img src="image_14.png" /></figure>

6

$$ \chemfig{*6(=-=-(-Cul)=-=)} \text{, pyrrolidine} $$

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>

7

$$ \chemfig{*6(=-=-(-CrO_3)=-=)} \text{, } H_2SO_4 $$

<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

4

<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>

8

+

<figure><img src="image_21.png" /></figure>

<figure><img src="image_22.png" /></figure>

<figure><img src="image_23.png" /></figure>

10

+

<figure><img src="image_24.png" /></figure>

11

$$ \chemfig{*6(=-=-(-1)=-=)} \text{, } \text{Et}_3\text{N, Ac}_2\text{O} $$

<figure><img src="image_25.png" /></figure>

$$ \chemfig{*6(=-=-(-1)=-=)} \text{, } \text{H}_2\text{O} $$

$$ \chemfig{*6(=-=-(-2)=-=)} \text{, } \text{HCl / 70}^{\circ}\text{C} $$

87% yield for the two steps

<figure><img src="image_26.png" /></figure>

4

<caption>**Scheme 1.** Synthetic routes to indane-1,3-dione 4.</caption>
<figure><img src="image_27.png" /><figcaption>12</figcaption></figure>

<caption>15</caption>

<caption>16</caption>

<figure><img src="image_28.png" /><figcaption>13</figcaption></figure>

<caption>15</caption>

<caption>17</caption>

<figure><img src="image_29.png" /><figcaption>14</figcaption></figure>

<caption>15</caption>

<caption>18</caption>

<figure><img src="image_30.png" /><figcaption>21</figcaption></figure>

22 : R₁ = H, R₂ = Me

23 : R₁ = Me, R₂ = Me

<caption>24</caption>

1) AlCl₃, nitrobenzene, 80°C
overnight

2) aq. oxalic acid (10%)

3) Na₂CO₃

4) conc. HCl

25 : R₁ = H, R₂ = Me, 33% yield

26 : R₁ = Me, R₂ = Me, 15% yield

<figure><img src="image_31.png" /><figcaption>29</figcaption></figure>

<caption>4</caption>

<caption>27</caption>

<figure><img src="image_32.png" /><figcaption>30</figcaption></figure>

<caption>27</caption>

<caption>31</caption>

<figure><img src="image_33.png" /><figcaption>32</figcaption></figure>

<caption>27</caption>

<caption>33</caption>

<figure><img src="image_34.png" /><figcaption>34</figcaption></figure>

<caption>27</caption>

<caption>35</caption>

<caption>35'</caption>

<caption>**Scheme 3.** Synthetic routes to 28, 31, 31', 33, 33', 35, 35'.</caption>
<figure><img src="image_35.png" /></figure>

36a : R = Me

36b : R = Et

36c : R = Pr

36d : R = Bu

27

37a : R = Me, 63% yield

37b : R = Et, 56% yield

37c : R = Pr, 70% yield

37d : R = Bu, 78% yield

<figure><img src="image_36.png" /></figure>

38

27

39

<figure><img src="image_37.png" /></figure>

40

27

41

<figure><img src="image_38.png" /></figure>

42

27

43

<figure><img src="image_39.png" /></figure>

44

27

45

<figure><img src="image_40.png" /></figure>

46 : X = Cl

48 : X = F

27

47 : X = Cl, 72% yield

49 : X = F, 47-78% yield

<caption>**Scheme 4.** Synthetic routes to 37a–37d, 39, 41, 43, 45, 47 and 49.</caption>

### 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).
<figure><img src="image_41.png" /><figcaption>**Scheme 5.** Synthesis of bindone 50.</figcaption></figure>

### 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 [13,42–45]. Parallel to this, 1,3,4-thiadiazole groups also exhibit biological activities [46–54] 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 [12,56–60]. Introduction of lateral groups onto 67 is possible but involves a specific route to be developed. A Diels–Alder reaction between 1,3-diphenylbenzo[c]furan 69 and cyclopent-4-ene-1,3-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).
<figure><img src="image_42.png" /></figure>

56 : Ar = Ph, 78% yield

57 : Ar = 4-Me-Ph, 89% yield

58 : Ar = 4-Cl-Ph, 86% yield

<figure><img src="image_43.png" /></figure>

62 : Ar = Ph, 87% yield

63 : Ar = 4-Me-Ph, 79% yield

64 : Ar = 4-Cl-Ph, 90% yield

<figure><img src="image_44.png" /><figcaption>**Scheme 7.** Synthetic routes to 68, 72 and 75.</figcaption></figure>
### 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).

<figure><img src="image_45.png" /><figcaption>**Scheme 8.** Examples of halogenated indane-1,3-diones **76–82**, 84 reported in the literature.</figcaption></figure>

### 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].

<figure><img src="image_46.png" /><figcaption>**Scheme 9.** Synthesis of nitro-substituted indane-1,3-diones 19 and 21.</figcaption></figure>
### 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.

<figure><img src="image_47.png" /><figcaption>**Scheme 10.** Ethoxy-carbonyl compound **32**.</figcaption></figure>

## 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 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].

<table><caption>**Table 1.** Reaction yields obtained for the synthesis of **95–114**.</caption><thead><tr><th>compounds</th><th>95</th><th>96</th><th>97</th><th>98</th><th>99</th><th>100</th><th>101</th><th>102</th><th>103</th><th>104</th></tr></thead><tbody><tr><td>reaction yields</td><td>88</td><td>84</td><td>88</td><td>74</td><td>94</td><td>89</td><td>92</td><td>85</td><td>84</td><td>88</td></tr><tr><td>compounds</td><td><strong>105</strong></td><td><strong>106</strong></td><td><strong>107</strong></td><td><strong>108</strong></td><td><strong>109</strong></td><td><strong>110</strong></td><td><strong>111</strong></td><td><strong>112</strong></td><td><strong>113</strong></td><td><strong>114</strong></td></tr><tr><td>reaction yields</td><td>74</td><td>85</td><td>75</td><td>82</td><td>92</td><td>87</td><td>81</td><td>78</td><td>89</td><td>85</td></tr></tbody></table>

When 2-(3-oxo-2,3-dihydro-1*H*-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-9*H*-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-9*H*-indeno [2,1-*c*]pyridine-4-carbonitrile derivatives **115** instead of the expected push-pull dyes [62–64]. 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.
<figure><img src="image_48.png" /><figcaption>**Scheme 11.** Synthesis of push-pull dyes 95–114.</figcaption></figure>

<figure><img src="image_49.png" /><figcaption>**Scheme 12.** Mechanism resulting in the synthesis of 3-(dialkylamino)-1,2-dihydro-9-oxo-9H-indeno [2,1-c]pyridine-4-carbonitrile derivatives 115.</figcaption></figure>
<figure><img src="image_50.png" /><figcaption>**Scheme 13.** Mechanism supporting the formation of **117** starting from **116**.</figcaption></figure>

<figure><img src="image_51.png" /><figcaption>**Figure 1.** Crystal structure of **117**. Reproduced with permission from Ref. [57].</figcaption></figure>

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].

<figure><img src="image_52.png" /><figcaption>**Scheme 14.** Synthetic routes to **119** starting from **29**.</figcaption></figure>

Besides, several reports mention the use of the classical piperidine/ethanol conditions to condense **29** onto aromatic aldehydes, despite 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]).
<figure><img src="image_53.png" /></figure>

29

120

<figure><img src="image_54.png" /></figure>

121

<figure><img src="image_55.png" /></figure>

29

122

<figure><img src="image_56.png" /></figure>

123

<figure><img src="image_57.png" /></figure>

29

124

<figure><img src="image_58.png" /></figure>

125

<caption>**Scheme 15.** Knoevenagel reactions performed in classical ethanol/piperidine conditions.</caption>

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.

<figure><img src="image_59.png" /></figure>

29

126

127

<caption>**Scheme 16.** Synthetic route to push-pull dye **127**.</caption>

### 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].

<figure><img src="image_60.png" /></figure>

128: R₁ = H, R₂ = H

129: R₁ = H, R₂ = OMe

130: R₁ = H, R₂ = t-Bu

131: R₁ = H, R₂ = Me

132: R₁ = Me, R₂ = H

133: R₁ = H, R₂ = Br

134: R₁ = Br, R₂ = H

135: R₁ = H, R₂ = CF₃

136: R₁ = NO₂, R₂ = H

137: R₁ = H, R₂ = NO₂

138: R₁ = H, R₂ = H, 84% yield

139: R₁ = H, R₂ = OMe, 65% yield

140: R₁ = H, R₂ = t-Bu, 88% yield

141: R₁ = H, R₂ = Me, 74% yield

142: R₁ = Me, R₂ = H, 60% yield

143: R₁ = H, R₂ = Br, 73% yield

144: R₁ = Br, R₂ = H, 61% yield

145: R₁ = H, R₂ = CF₃, 7% yield

146: R₁ = NO₂, R₂ = H, 55% yield

147: R₁ = H, R₂ = NO₂, 51% yield

<figure><img src="image_61.png" /></figure>

<figure><img src="image_62.png" /></figure>

<figure><img src="image_63.png" /></figure>

<figure><img src="image_64.png" /></figure>

<figure><img src="image_65.png" /><figcaption>**Scheme 17.** Synthetic route to ninhydrin **138**.</figcaption></figure>
### 2.4.3. Halogenation

α,α-Dihalogenation reactions of carbonyl compounds have been extensively studied in the literature [78–88], 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].

<figure><img src="image_66.png" /><figcaption>**Scheme 18.** Different routes for halogenation of indane-1,3-dione 4 at the methylene position.</figcaption></figure>

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].
<figure><img src="image_67.png" /></figure>

4

150

<figure><img src="image_68.png" /></figure>

4

151

<figure><img src="image_69.png" /></figure>

4

150

<figure><img src="image_70.png" /></figure>

4

150

<figure><img src="image_71.png" /></figure>

4

151

<figure><img src="image_72.png" /></figure>

4

152

<caption>**Scheme 19.** Fluorination reactions of indane-1,3-dione 4.</caption>

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 [99–102]. 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.
<figure><img src="image_73.png" /><figcaption>**Scheme 20.** Mechanism involved in the fluorination of 4.</figcaption></figure>

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).

<figure><img src="image_74.png" /><figcaption>**Scheme 21.** Mechanism supporting the coexistence of a radical and an electrophilic bromination pathway for the bromination of 4.</figcaption></figure>

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).

<figure><img src="image_75.png" /><figcaption>**Scheme 22.** Synthesis of 150 using NBS as the bromination agent.</figcaption></figure>
#### 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.

<figure><img src="image_76.png" /><figcaption>**Scheme 23.** Synthetic route to **153**.</figcaption></figure>

#### 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).

<figure><img src="image_77.png" /><figcaption>**Scheme 24.** Synthetic route to **154**.</figcaption></figure>

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

#### 3.1. Synthesis of Cyclophanes

Cyclophanes play an important role in supramolecular chemistry [106–119], 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 [120–126]. 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 [134–137] or ring-closing metathesis [138–147] 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).
<figure><img src="image_78.png" /></figure>

<figure><img src="image_79.png" /></figure>

<figure><img src="image_80.png" /></figure>

<figure><img src="image_81.png" /></figure>

<figure><img src="image_82.png" /><figcaption>**Scheme 25.** Synthetic routes to cyclophanes **158a** and **158b**.</figcaption></figure>
### 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 [149–151]. 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.

<figure><img src="image_83.png" /><figcaption>**Scheme 26.** Synthetic routes to the crown ether derivative of 1,3-indandione **159**.</figcaption></figure>

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].
<figure><img src="image_84.png" /></figure>

<figure><img src="image_85.png" /></figure>

<figure><img src="image_86.png" /><figcaption>**Scheme 27.** Synthetic route to **162**.</figcaption></figure>

Finally, examination of the complexation of **159** with various divalent cations revealed no drastic changes of its absorption spectrum upon complexation, except with $Sr^{2+}$ and $Ba^{2+}$. 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).
<figure><img src="image_87.png" /><figcaption>**Scheme 28.** Synthetic routes to tetracycline heterocyclic analogues.</figcaption></figure>

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 [157–163], 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.
<figure><img src="image_88.png" /></figure>

27

4

<figure><img src="image_89.png" /></figure>

<figure><img src="image_90.png" /></figure>

28

<figure><img src="image_91.png" /></figure>

170

<figure><img src="image_92.png" /></figure>

171

<figure><img src="image_93.png" /></figure>

<figure><img src="image_94.png" /></figure>

<figure><img src="image_95.png" /></figure>

<figure><img src="image_96.png" /></figure>

<figure><img src="image_97.png" /></figure>

173

<figure><img src="image_98.png" /></figure>

86% yield

<figure><img src="image_99.png" /></figure>

<figure><img src="image_100.png" /></figure>

174

<figure><img src="image_101.png" /></figure>

<figure><img src="image_102.png" /></figure>

172

<figure><img src="image_103.png" /></figure>

AcOH/HCl
reflux, 1 hour
90% yield

175

<caption>Scheme 29. Synthetic routes to 172.</caption>
<figure><img src="image_104.png" /></figure>

<figure><img src="image_105.png" /></figure>

<figure><img src="image_106.png" /></figure>

182

<caption>**Scheme 30.** Synthetic Routes to 177, 179, 181 and 182.</caption>
<figure><img src="image_107.png" /></figure>

<figure><img src="image_108.png" /></figure>

185

66% yield

<figure><img src="image_109.png" /></figure>

186

75% yield

<figure><img src="image_110.png" /></figure>

187

73% yield

<figure><img src="image_111.png" /></figure>

188

62% yield

<figure><img src="image_112.png" /></figure>

189

61% yield

<figure><img src="image_113.png" /></figure>

190

76% yield

<figure><img src="image_114.png" /></figure>

191

63% yield

<figure><img src="image_115.png" /></figure>

192

61% yield

<caption>**Scheme 31.** Synthetic routes to 185–192.</caption>

### 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 inter-
est. 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%) [168,170–187]. 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(CH<sub>3</sub>CN)<sub>4</sub>.PF<sub>6</sub>, 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].

<figure><img src="image_116.png" /><figcaption>**Scheme 32.** Synthetic route to **196**.</figcaption></figure>

### 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 [192–194], the introduction of peripheral groups [195–201] or breaking the planarity [202–205]. 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 [194,209–213]. 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 ac-
etate 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).

<figure><img src="image_117.png" /><figcaption>**Scheme 33.** Synthetic routes to porphyrins **199** and **200**.</figcaption></figure>
<figure><img src="image_118.png" /><figcaption>**Scheme 34.** Synthetic routes to various (metallo)porphyrins.</figcaption></figure>
### 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].

<figure><img src="image_119.png" /><figcaption>**Scheme 35.** Synthetic route to **208**.</figcaption></figure>

### 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 arrhythmias, 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 Schemes 36 and 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.
<figure><img src="image_120.png" /><figcaption>**Scheme 36.** Mechanism involved in the synthesis of 212.</figcaption></figure>
<figure><img src="image_121.png" /><figcaption>**Scheme 37.** Synthetic routes to **212** and **213**.</figcaption></figure>

### 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.
<figure><img src="image_122.png" /></figure>

<figure><img src="image_123.png" /></figure>

<figure><img src="image_124.png" /></figure>

<figure><img src="image_125.png" /></figure>

<figure><img src="image_126.png" /></figure>

<figure><img src="image_127.png" /></figure>

<figure><img src="image_128.png" /></figure>

<figure><img src="image_129.png" /><figcaption>**Scheme 38.** Chemical structures of the indeno-fused structures **216–224** treated below.</figcaption></figure>
<figure><img src="image_130.png" /><figcaption>**Scheme 39.** Synthetic route to **217b**.</figcaption></figure>

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-azafluorenoones
(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 [239–242]. 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.
<figure><img src="image_131.png" /><figcaption>**Scheme 40.** Mechanism involved in the synthesis of indeno-fused structures 218.</figcaption></figure>

<figure><img src="image_132.png" /><figcaption>**Scheme 41.** General mechanism of indeno-fused structures synthesized by MCR.</figcaption></figure>

### 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 spiroin-
danediones, 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).

<figure><img src="image_133.png" /><figcaption>**Scheme 42.** The different synthetic routes to spiroindanediones discussed in this part.</figcaption></figure>

### 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 spiopyrrolidines 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 spiopyrrolidine 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).

<figure><img src="image_134.png" /><figcaption>**Scheme 43.** Synthesis of the ferrocenecarbocyaldehyde adduct **230**.</figcaption></figure>
<figure><img src="image_135.png" /><figcaption>**Scheme 44.** Synthetic route to 235.</figcaption></figure>

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, Scheme 51).
<figure><img src="image_136.png" /><figcaption>**Scheme 45.** Synthetic routes to 236, 238, 240 and 242.</figcaption></figure>

<figure><img src="image_137.png" /><figcaption>**Scheme 46.** Synthetic route to azomethine ylide 245.</figcaption></figure>

<figure><img src="image_138.png" /><figcaption>**Scheme 47.** Synthetic routes to dihydro-spiro[indene-2,3'-pyrrolidines] 247.</figcaption></figure>
<figure><img src="image_139.png" /><figcaption>**Scheme 48.** Mechanism supporting the formation of a unique diastereoisomer.</figcaption></figure>

<figure><img src="image_140.png" /><figcaption>**Scheme 49.** Synthetic route to 250.</figcaption></figure>

<figure><img src="image_141.png" /><figcaption>**Scheme 50.** Synthesis of azomethine imine.</figcaption></figure>

<table><caption>**Table 2.** Examples of cycloaddition reactions performed with various arylidene indane-1,3-diones 255 and azomethine imines 254.</caption><thead><tr><th>Ar<sub>1</sub></th><th>Ar<sub>2</sub></th><th>Yield <sup>a</sup></th><th>dr <sup>b</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>98</td><td>&gt;20:1</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>75</td><td>&gt;20:1</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>85</td><td>&gt;20:1</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>84</td><td>&gt;20:1</td></tr><tr><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>92</td><td>4:1</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>83</td><td>&gt;20:1</td></tr><tr><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>65</td><td>&gt;20:1</td></tr><tr><td>3-NO<sub>2</sub>C<sub>4</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>71</td><td>&gt;20:1</td></tr><tr><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>93</td><td>&gt;20:1</td></tr><tr><td>3-MeOC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>82</td><td>7:1</td></tr><tr><td>2-C<sub>4</sub>H<sub>3</sub>S</td><td>C<sub>6</sub>H<sub>5</sub></td><td>70</td><td>&gt;20:1</td></tr></tbody></table>

<footnote><sup>a</sup> Yield of isolated product; <sup>b</sup> Determined by ¹H NMR spectroscopy on the crude mixture.</footnote>
<figure><img src="image_142.png" /><figcaption>**Scheme 51.** Synthesis of 256.</figcaption></figure>

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).

<figure><img src="image_143.png" /><figcaption>**Scheme 52.** Mechanism supporting the synthesis of 256. Reproduced with permission from Ref. [254].</figcaption></figure>

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 and Scheme 55).

<figure><img src="image_144.png" /><figcaption>**Scheme 53.** Synthetic route to chromeno [3,4-*b*]pyrrolidine 259.</figcaption></figure>
<figure><img src="image_145.png" /><figcaption>**Scheme 54.** Synthesis of chromeno [3,4-c]pyrrolidine 262 while using TMG as the base.</figcaption></figure>

<table><caption>**Table 3.** Examples of chromeno [3,4-b]pyrrolidines 259 obtained using DMAP as the base.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>t (h)</th><th>Yield (%)<sup>a</sup></th></tr></thead><tbody><tr><td>5-Br</td><td>H</td><td>18</td><td>69</td></tr><tr><td>H</td><td>H</td><td>18</td><td>62</td></tr><tr><td>5-Cl</td><td>H</td><td>12</td><td>70</td></tr><tr><td>5-NO<sub>2</sub></td><td>H</td><td>30</td><td>58</td></tr><tr><td>5-OMe</td><td>H</td><td>18</td><td>59</td></tr><tr><td>4-OMe</td><td>H</td><td>24</td><td>71</td></tr><tr><td>3-OMe</td><td>H</td><td>18</td><td>79</td></tr><tr><td>5-F</td><td>H</td><td>11</td><td>46<sup>b</sup></td></tr><tr><td>5-Br</td><td>5-Cl</td><td>18</td><td>75</td></tr><tr><td>5-Br</td><td>5-Br</td><td>12</td><td>72</td></tr><tr><td>5-Br</td><td>5-NO<sub>2</sub></td><td>18</td><td>63</td></tr><tr><td>5-Br</td><td>5-OMe</td><td>24</td><td>72</td></tr><tr><td>5-Br</td><td>4-OMe</td><td>18</td><td>61</td></tr><tr><td>5-Br</td><td>3-OMe</td><td>48</td><td>48</td></tr></tbody></table>

<figure><img src="image_146.png" /><figcaption>**Scheme 55.** Synthesis of 259.</figcaption></figure>

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 and Scheme 56).

<footnote><sup>a</sup> Isolated yield; <sup>b</sup> 17% of the other product was obtained.</footnote>
<figure><img src="image_147.png" /><figcaption>**Scheme 56.** Synthesis of **262**.</figcaption></figure>

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.

<table><caption>**Table 4.** Examples of chromeno [3,4-*c*]pyrrolidines **262** obtained using TMG as the base.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>t (h)</th><th>Yield (%)<sup>a</sup></th></tr></thead><tbody><tr><td>5-Br</td><td>H</td><td>4</td><td>79</td></tr><tr><td>H</td><td>H</td><td>5</td><td>65</td></tr><tr><td>5-Cl</td><td>H</td><td>4</td><td>71</td></tr><tr><td>5-NO<sub>2</sub></td><td>H</td><td>4</td><td>50</td></tr><tr><td>5-OMe</td><td>H</td><td>24</td><td>26</td></tr><tr><td>4-OMe</td><td>H</td><td>15</td><td>10</td></tr><tr><td>3-OMe</td><td>H</td><td>15</td><td>47</td></tr><tr><td>5-F</td><td>H</td><td>5</td><td>53</td></tr><tr><td>5-Br</td><td>5-Cl</td><td>6</td><td>75</td></tr><tr><td>5-Br</td><td>5-Br</td><td>4</td><td>79</td></tr><tr><td>5-Br</td><td>5-NO<sub>2</sub></td><td>48</td><td>56</td></tr><tr><td>5-Br</td><td>5-OMe</td><td>5</td><td>70</td></tr><tr><td>5-Br</td><td>4-OMe</td><td>8</td><td>76</td></tr><tr><td>5-Br</td><td>3-OMe</td><td>4</td><td>69</td></tr></tbody></table>

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).

<footnote><sup>a</sup> Isolated yield.</footnote>
<figure><img src="image_148.png" /><figcaption>**Scheme 57.** Synthetic route to a fluorinated dipolarophile 264 further used for cycloaddition reactions.</figcaption></figure>

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).

<figure><img src="image_149.png" /><figcaption>**Scheme 58.** Cycloaddition reaction using TEBAB 266 as the catalyst.</figcaption></figure>

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 and Scheme 59).
<table><caption>**Table 5.** Reaction yields obtained during the cycloaddition reactions using TEBAB **266** as the catalyst.</caption><thead><tr><th>R<sub>1</sub></th><th>Ar<sub>1</sub></th><th>Ar<sub>2</sub></th><th>Yield (%) <sup>a</sup></th><th>dr <sup>b</sup></th></tr></thead><tbody><tr><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>98</td><td>100:0:0:0</td></tr><tr><td>H</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>70</td><td>100:0:0:0</td></tr><tr><td>H</td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>32</td><td>96:4:0:0</td></tr><tr><td>H</td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>73</td><td>100:0:0:0</td></tr><tr><td>H</td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>68</td><td>100:0:0:0</td></tr><tr><td>H</td><td>4-PhC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>84</td><td>100:0:0:0</td></tr><tr><td>H</td><td>C<sub>10</sub>H<sub>7</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>72</td><td>100:0:0:0</td></tr><tr><td>H</td><td>C<sub>4</sub>H<sub>3</sub>O</td><td>C<sub>6</sub>H<sub>5</sub></td><td>61</td><td>100:0:0:0</td></tr><tr><td>H</td><td>C<sub>4</sub>H<sub>3</sub>S</td><td>C<sub>6</sub>H<sub>5</sub></td><td>56</td><td>100:0:0:0</td></tr><tr><td>F</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>40</td><td>50:50:0:0</td></tr><tr><td>NO<sub>2</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>46</td><td>60:40:0:0</td></tr><tr><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>69</td><td>100:0:0:0</td></tr><tr><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>74</td><td>100:0:0:0</td></tr><tr><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>3,5-(CF<sub>3</sub>)<sub>2</sub>C<sub>6</sub>H<sub>3</sub></td><td>31</td><td>100:0:0:0</td></tr></tbody></table>

<figure><img src="image_150.png" /><figcaption>**Scheme 59.** Synthesis of **269**.</figcaption></figure>

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 and Scheme 60).

<footnote><sup>a</sup> Isolated yield; <sup>b</sup> determined by ¹H and ¹⁹F NMR.</footnote>
<table><caption>**Table 6.** Reaction yields obtained during the formation of spiro-indanedione derivatives **271**.</caption><thead><tr><th>R</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>94</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>93</td></tr><tr><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>88</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>89</td></tr><tr><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>91</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>92</td></tr><tr><td>4-CNC<sub>6</sub>H<sub>4</sub></td><td>90</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>91</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>95</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>96</td></tr><tr><td>3,4,5-Me<sub>3</sub>C<sub>6</sub>H<sub>2</sub></td><td>91</td></tr><tr><td>2-C<sub>10</sub>H<sub>7</sub></td><td>92</td></tr><tr><td>2-C<sub>4</sub>H<sub>3</sub>O</td><td>88</td></tr><tr><td>2-C<sub>4</sub>H<sub>3</sub>S</td><td>91</td></tr><tr><td>C<sub>6</sub>H<sub>13</sub></td><td>65</td></tr></tbody></table>

<figure><img src="image_151.png" /><figcaption>**Scheme 60.** Synthesis of **271**.</figcaption></figure>

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 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 and Scheme 63). The mechanism proposed by the authors was the following: the intermediates, once activated by the organocatalyst, can release CO<sub>2</sub>, 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).

<footnote><sup>a</sup> Reaction yield determined after purification and column chromatography.</footnote>
<table><caption>**Table 7.** Reaction yields obtained during the synthesis of coumarin-indanedione derivatives **274**.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>R<sub>3</sub></th><th>t (d)</th><th>Yield (%)</th><th>ee<sup>a</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>1</td><td>89</td><td>96</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>1</td><td>84</td><td>92</td></tr><tr><td>4-CNC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>2</td><td>90</td><td>94</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>2</td><td>88</td><td>94</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>1</td><td>85</td><td>93</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>3</td><td>92</td><td>93</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>4</td><td>84</td><td>91</td></tr><tr><td>4-HOC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>7</td><td>70</td><td>69</td></tr><tr><td>2-MeOC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>7</td><td>93</td><td>88</td></tr><tr><td>2-HOC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>5</td><td>42</td><td>25</td></tr><tr><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>2</td><td>88</td><td>91</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>4</td><td>73</td><td>89</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>5</td><td>76</td><td>88</td></tr><tr><td>C<sub>5</sub>H<sub>4</sub>N</td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>1</td><td>82</td><td>77</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>2</td><td>90</td><td>95</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>CH<sub>3</sub></td><td>3</td><td>85</td><td>93</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-Cl</td><td>C<sub>6</sub>H<sub>5</sub></td><td>1</td><td>92</td><td>91</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-Br</td><td>C<sub>6</sub>H<sub>5</sub></td><td>2</td><td>82</td><td>95</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-MeO</td><td>C<sub>6</sub>H<sub>5</sub></td><td>1</td><td>86</td><td>92</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2,4-Cl<sub>2</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>2</td><td>87</td><td>90</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-MeO</td><td>C<sub>6</sub>H<sub>5</sub></td><td>2</td><td>95</td><td>93</td></tr></tbody></table>

<figure><img src="image_152.png" /><figcaption>**Scheme 61.** Synthesis of **274**.</figcaption></figure>

<footnote><sup>a</sup> Enantiomeric excess determined by HPLC analyses on a chiral stationary phase.</footnote>
<figure><img src="image_153.png" /><figcaption>**Scheme 62.** Mechanism of formation of the coumarin-indanedione cycloadducts. Reproduced with permission from Ref. [258].</figcaption></figure>

<figure><img src="image_154.png" /><figcaption>**Scheme 63.** Synthesis of 277.</figcaption></figure>
<table><caption>**Table 8.** Reaction yields obtained during asymmetric cycloadditions between 2-arylidene-indane-1,3-diones **255** and Morita-Baylis-Hillman carbonates **275**.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield (%) <sup>a</sup></th><th>ee (%) <sup>b</sup></th></tr></thead><tbody><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-Cl</td><td>52</td><td>88</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-Br</td><td>51</td><td>92</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-CN</td><td>65</td><td>91</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-CF<sub>3</sub></td><td>50</td><td>91</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>2-Cl</td><td>68</td><td>97</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>2-Br</td><td>50</td><td>97</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>3-NO<sub>2</sub></td><td>75</td><td>87</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>3-Cl</td><td>60</td><td>91</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>3-Br</td><td>51</td><td>90</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>2,4-Cl<sub>2</sub></td><td>62</td><td>96</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>2,3-Cl<sub>2</sub></td><td>67</td><td>98</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>3,4-Cl<sub>2</sub></td><td>54</td><td>92</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>2,6-Cl<sub>2</sub></td><td>30</td><td>92</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-F, 3-Br</td><td>50</td><td>90</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-CH<sub>3</sub></td><td>Trace</td><td>-</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-NO<sub>2</sub></td><td>75 <sup>c</sup></td><td>66</td></tr><tr><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub></td><td>64 <sup>c</sup></td><td>67</td></tr><tr><td>4-C<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub></td><td>75 <sup>c</sup></td><td>65</td></tr><tr><td>C<sub>6</sub>H<sub>11</sub></td><td>4-NO<sub>2</sub></td><td>68 <sup>c</sup></td><td>67</td></tr></tbody></table>

[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 $Pd_2bda_3$ (*tris*(dibenzyldieneacetone)dipalladium(0)), 6.7 mol% of ligand **279**, in THF and at room temperature for two days (see Table 9 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).

<footnote><sup>a</sup> Isolated yield; <sup>b</sup> determined by Chiral HPLC; <sup>c</sup> the reaction was carried out within 48 h.</footnote>
<figure><img src="image_155.png" /><figcaption>**Scheme 64.** Mechanism involved in the cycloaddition reaction with Morita–Baylis–Hillman carbonates 275. Reproduced with permission from Ref. [259].</figcaption></figure>

<table><caption>**Table 9.** Reaction yields obtained during the [3+2] cycloaddition of vinylaziridine 280 and indane -1,3-dione derivatives 255.</caption><thead><tr><th>R</th><th>Yield (%)</th><th>er</th><th>dr</th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>97</td><td>92:8</td><td>3:1</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>98</td><td>75:25</td><td>3:1</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>90</td><td>77:23</td><td>3:1</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>98</td><td>80:20</td><td>3:1</td></tr><tr><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>93</td><td>87:13</td><td>3:1</td></tr><tr><td>C<sub>10</sub>H<sub>7</sub></td><td>99</td><td>84:16</td><td>10:1</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>90</td><td>72:28</td><td>3:1</td></tr><tr><td>3-MeOC<sub>6</sub>H<sub>4</sub></td><td>90</td><td>83:17</td><td>3:1</td></tr><tr><td>C<sub>5</sub>H<sub>4</sub>N</td><td>81</td><td>75:25</td><td>3:1</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>59</td><td>97:3</td><td>4:1</td></tr><tr><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>91</td><td>74:26</td><td>3:1</td></tr></tbody></table>
<figure><img src="image_156.png" /><figcaption>**Scheme 65.** Synthesis of 281.</figcaption></figure>

<figure><img src="image_157.png" /><figcaption>**Scheme 66.** Mechanism supporting the formation of only one diastereoisomer during the Pd-catalyzed reaction.</figcaption></figure>

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 and Scheme 67).
<table><caption>**Table 10.** Reaction yields obtained during the cyclization reaction with vinylethylene carbonate **282** and arylidene-indane-1,3-diones **255**.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield (%)<sup>a</sup></th><th>dr<sup>b</sup></th><th>ee<sup>c</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>99</td><td>53:47</td><td>99.98</td></tr><tr><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>99</td><td>52:48</td><td>99.95</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>97</td><td>51:49</td><td>96.95</td></tr><tr><td>2-MeOC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>82</td><td>54:46</td><td>99.95</td></tr><tr><td>3-MeOC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>84</td><td>53:47</td><td>99.98</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>93</td><td>54:46</td><td>96.89</td></tr><tr><td>2-FC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>96</td><td>53:47</td><td>93.92</td></tr><tr><td>3-FC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>86</td><td>56:44</td><td>97.94</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>96</td><td>52:48</td><td>94.92</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>94</td><td>52:48</td><td>93.95</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>76</td><td>51:49</td><td>96.95</td></tr><tr><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>77</td><td>52:48</td><td>93.89</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>68</td><td>50:50</td><td>95.95</td></tr><tr><td>4-PhC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>71</td><td>53:47</td><td>93.95</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>94</td><td>56:44</td><td>96.97</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-MeOC<sub>6</sub>H<sub>4</sub></td><td>73</td><td>64:36</td><td>84.88</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-MeOC<sub>6</sub>H<sub>4</sub></td><td>99</td><td>62:38</td><td>96.96</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>93</td><td>59:41</td><td>98.97</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3,4-(MeO)<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>79</td><td>81:19</td><td>99.95</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-FC<sub>6</sub>H<sub>4</sub></td><td>89</td><td>68:32</td><td>91.90</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-FC<sub>6</sub>H<sub>4</sub></td><td>91</td><td>68:32</td><td>96.90</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>89</td><td>53:47</td><td>94.92</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>90</td><td>73:27</td><td>93.91</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>99</td><td>59:41</td><td>97.81</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-C<sub>4</sub>H<sub>3</sub>O</td><td>97</td><td>63:37</td><td>99.99</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-Br-2-C<sub>4</sub>H<sub>2</sub>S</td><td>99</td><td>76:24</td><td>99.96</td></tr></tbody></table>

<figure><img src="image_158.png" /></figure>

282

<figure><img src="image_159.png" /></figure>

255

<figure><img src="image_160.png" /></figure>

CHCl<sub>3</sub>, 0 °C, 48 h

<figure><img src="image_161.png" /></figure>

284

<figure><img src="image_162.png" /></figure>

285

<figure><img src="image_163.png" /></figure>

283

<caption>**Scheme 67.** Synthesis of **285**.</caption>

<footnote>a Isolated yield; b dr was determined by ¹H NMR analysis of the product; c determined by chiral HPLC analysis.</footnote>
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].

<figure><img src="image_164.png" /><figcaption>**Scheme 68.** Synthetic route to spirovinylcyclopropaneindanedione (VCP) **287**.</figcaption></figure>

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.

<figure><img src="image_165.png" /><figcaption>**Scheme 69.** Synthetic route to a five-membered spiroindanedione **289**.</figcaption></figure>

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].

<figure><img src="image_166.png" /><figcaption>**Scheme 70.** Cycloaddition reaction with VCP **287** and cinnamaldehyde **292**.</figcaption></figure>

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).

<figure><img src="image_167.png" /><figcaption>**Scheme 71.** Cycloaddition reactions with aryl and naphthyl derivatives 295 and 296.</figcaption></figure>

<figure><img src="image_168.png" /><figcaption>**Scheme 72.** Mechanism of cyclization determined for cycloaddition reactions occurring with nitroalkenes. Reproduced with permission from Ref. [262].</figcaption></figure>

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 and Scheme 73).

<table><caption>**Table 11.** Reaction yields obtained with various nitroalkene derivatives.</caption><thead><tr><th>R.</th><th>Yield (%) <sup>a</sup></th><th>dr <sup>b</sup></th><th>ee <sup>c</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>80</td><td>5:1</td><td>97:95</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>87</td><td>5:1</td><td>96:95</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>84</td><td>4:4:1</td><td>92:80</td></tr><tr><td>2-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>75</td><td>14:1</td><td>99:55</td></tr><tr><td>2-FC<sub>6</sub>H<sub>4</sub></td><td>82</td><td>6:4:1</td><td>96:89</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>92</td><td>5:5:1</td><td>98:90</td></tr><tr><td>2-F-6-ClC<sub>6</sub>H<sub>3</sub></td><td>85</td><td>5:3:1</td><td>97:90</td></tr><tr><td>2-MeOC<sub>6</sub>H<sub>4</sub></td><td>90</td><td>2:6:1</td><td>97:97</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>81</td><td>5:1</td><td>96:88</td></tr><tr><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>79</td><td>4:1:1</td><td>92:84</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>90</td><td>5:3:1</td><td>92:68</td></tr><tr><td>1-C<sub>10</sub>H<sub>7</sub></td><td>83</td><td>2:3:1</td><td>97:97</td></tr><tr><td>2-C<sub>10</sub>H<sub>7</sub></td><td>81</td><td>5:7:1</td><td>98:80</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>80</td><td>6:1</td><td>97:87</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>89</td><td>5:7:1</td><td>96:78</td></tr><tr><td>C<sub>3</sub>H<sub>4</sub></td><td>86</td><td>1:7:1</td><td>99:99</td></tr><tr><td>C<sub>6</sub>H<sub>11</sub></td><td>88</td><td>1:2:1</td><td>99:99</td></tr></tbody></table>

<figure><img src="image_169.png" /></figure>

<figure><img src="image_170.png" /><figcaption>**Scheme 73.** Synthesis of 299.</figcaption></figure>

[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 Pd<sub>2</sub>dba<sub>3</sub> 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 and Scheme 74).

<footnote><sup>a</sup> Isolated yield of diastereoisomer; <sup>b</sup> the diastereoisomeric ratios were determined by ¹H NMR spectroscopy;</footnote>

<footnote><sup>c</sup> the enantiomeric excess values were determined by chiral HPLC analyses.</footnote>
<table><caption>**Table 12.** Reaction yields obtained during the synthesis of oxindole-fused spiropyrazolidine compounds.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield % <sup>a</sup></th><th>ee % <sup>b</sup></th></tr></thead><tbody><tr><td>H</td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>95</td><td>78</td></tr><tr><td>5-F</td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>99</td><td>64</td></tr><tr><td>5-Cl</td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>92</td><td>78</td></tr><tr><td>5-I</td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>98</td><td>69</td></tr><tr><td>5-Me</td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>99</td><td>82</td></tr><tr><td>6-Me</td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>78</td><td>59</td></tr><tr><td>6-MeO</td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>96</td><td>77</td></tr><tr><td>6-Cl</td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>96</td><td>65</td></tr><tr><td>7-CF<sub>3</sub></td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>52</td><td>68</td></tr><tr><td>5,7-Me<sub>2</sub></td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>80</td><td>48</td></tr><tr><td>5,7-Cl<sub>2</sub></td><td>CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>39</td><td>75</td></tr><tr><td>H</td><td>CH<sub>2</sub>OMe</td><td>65</td><td>77</td></tr><tr><td>H</td><td>Me</td><td>81</td><td>84</td></tr></tbody></table>

<figure><img src="image_171.png" /><figcaption>**Scheme 74.** Synthesis of **302**.</figcaption></figure>

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 $Pd_2(dba)_3$ 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** and Scheme **77**). The different imines used in these reactions were prepared in situ.

<footnote><sup>a</sup> Isolated yield; <sup>b</sup> the enantiomeric excess was determined by chiral HPLC analysis on chiral cel IB-3.</footnote>
<figure><img src="image_172.png" /><figcaption>**Scheme 75.** Mechanism involved in the synthesis of the oxindole-fused spiropyrazolidine. Reproduced with permission from Ref. [265].</figcaption></figure>

<figure><img src="image_173.png" /><figcaption>**Scheme 76.** Annulation reaction between *para*-quinone methide **307** and 2-vinylspiro[cyclopropane-1,2'-indene]-1',3'-dione **289**.</figcaption></figure>

<figure><img src="image_174.png" /><figcaption>**Scheme 77.** Synthesis of **308**.</figcaption></figure>
<table><caption>**Table 13.** Reaction yields obtained during cycloaddition reactions using diphenylphosphoric acid **306** and a Pd (0) catalyst.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield (%) <sup>a</sup></th><th>dr <sup>b</sup></th></tr></thead><tbody><tr><td>C<sub>10</sub>H<sub>7</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>75</td><td>3:1</td></tr><tr><td>3,4-(OMe)<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>93</td><td>1:4.2</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>80</td><td>3.5:1</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>86</td><td>10.0:1</td></tr><tr><td>C<sub>4</sub>H<sub>9</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>84</td><td>9.5:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>81</td><td>4.8:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>77</td><td>1:1.2</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>79</td><td>1.6:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub>CH<sub>2</sub></td><td>50</td><td>1:9.2</td></tr></tbody></table>

<sup>a</sup> Yields determined after purification by chromatography on silica gel; <sup>b</sup> diastereomeric ratio determined after purification by chromatography.

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 NaHSO<sub>3</sub> 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** and Scheme **78**.

<figure><img src="image_175.png" /><figcaption>**Scheme 78.** Synthesis of **310**.</figcaption></figure>

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**).
<table><caption>**Table 14.** [3+2] Cycloadditions of 2-arylideneindane-1,3-diones **255** with ketoxime acetates **309** using a copper catalyst.</caption><thead><tr><th>Ar<sub>1</sub></th><th>Ar<sub>2</sub></th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>95</td></tr><tr><td>2-BrC<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>92</td></tr><tr><td>2-NO<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>78</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>85</td></tr><tr><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>88</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>81</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>61</td></tr><tr><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>95</td></tr><tr><td>C<sub>10</sub>H<sub>7</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>51</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>C<sub>6</sub>H<sub>5</sub></td><td>56</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>C<sub>6</sub>H<sub>5</sub></td><td>54</td></tr><tr><td>C<sub>3</sub>H<sub>7</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>21</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>82</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>85</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>86</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>86</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>93</td></tr><tr><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>84</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>87</td></tr><tr><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>84</td></tr><tr><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>92</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>3</sub>S</td><td>77</td></tr></tbody></table>

<figure><img src="image_176.png" /><figcaption>**Scheme 79.** Mechanism proposed to support the formation of 2-arylideneindane-1,3-diones. Reproduced with permission from Ref. [268].</figcaption></figure>

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

<footnote><sup>a</sup> Isolated yield.</footnote>
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 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**.

<table><caption>**Table 15.** Reaction yields obtained during the cycloaddition of azomethine ylides and arylidene-indane-1,3-diones.</caption><thead><tr><th>Ar<sub>1</sub></th><th>R</th><th>Ar<sub>2</sub></th><th>Yield (%) <sup>a</sup></th><th>ee (%) <sup>b</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>56</td><td>−87</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Et</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>60</td><td>−74</td></tr><tr><td>2,4-Cl<sub>2</sub>C<sub>6</sub>H<sub>3</sub></td><td>Et</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>85</td><td>−70</td></tr><tr><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>79</td><td>−73</td></tr><tr><td>1-Br-2-C<sub>10</sub>H<sub>6</sub></td><td>Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>89</td><td>−81</td></tr><tr><td>1-Br-2-C<sub>10</sub>H<sub>6</sub></td><td>Et</td><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>73</td><td>−81</td></tr><tr><td>2,4-F<sub>2</sub>C<sub>6</sub>H<sub>3</sub></td><td>Et</td><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>89</td><td>−76</td></tr><tr><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>Me</td><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>75</td><td>−76</td></tr><tr><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>Et</td><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>76</td><td>−72</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>5</sub></td><td>Et</td><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>55</td><td>64</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>Et</td><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>76</td><td>−77</td></tr><tr><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>Et</td><td>2-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>59</td><td>−79</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>Me</td><td>C<sub>6</sub>H<sub>5</sub></td><td>90</td><td>−74</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>Me</td><td>2-C<sub>4</sub>H<sub>3</sub>O</td><td>65</td><td>−78</td></tr></tbody></table>

<figure><img src="image_177.png" /><figcaption>**Scheme 80.** Synthesis of **315**.</figcaption></figure>

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 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

<footnote><sup>a</sup> yield of the isolated product; <sup>b</sup> determined by Chiral HPLC.</footnote>
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.

<figure><img src="image_178.png" /><figcaption>**Scheme 81.** Mechanism supporting the formation of a unique diastereoisomer during the cycloaddition of azomethine ylides **314** and arylidene-indane-1,3-diones **255**. Reproduced with permission from Ref. [269].</figcaption></figure>

<figure><img src="image_179.png" /><figcaption>**Scheme 82.** Synthesis of **317**.</figcaption></figure>

<table><caption>**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**.</caption><thead><tr><th>Ar.</th><th>R</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Me</td><td>81</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Me</td><td>88</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>CO<sub>2</sub>Me</td><td>92</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Me</td><td>92</td></tr><tr><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Me</td><td>70</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Me</td><td>73</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Et</td><td>56</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Et</td><td>72</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>CO<sub>2</sub>Et</td><td>90</td></tr></tbody></table>
<table><caption>**Table 16.** *Cont.*</caption><thead><tr><th>Ar.</th><th>R</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>3-FC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Et</td><td>68</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Et</td><td>70</td></tr><tr><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Et</td><td>65</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Et</td><td>78</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Et</td><td>90</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub>Et</td><td>75</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>CO<sub>2</sub><sup>t</sup>Bu</td><td>86</td></tr><tr><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub><sup>t</sup>Bu</td><td>55</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub><sup>t</sup>Bu</td><td>60</td></tr><tr><td>3-FC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub><sup>t</sup>Bu</td><td>63</td></tr><tr><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub><sup>t</sup>Bu</td><td>54</td></tr><tr><td>4-BtC<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub><sup>t</sup>Bu</td><td>62</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>CO<sub>2</sub><sup>t</sup>Bu</td><td>63</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>CN</td><td>73</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>CN</td><td>48</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>CN</td><td>37</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>CN</td><td>55</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>CN</td><td>57</td></tr></tbody></table>

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 and Scheme 84).

<table><caption>**Table 17.** Reaction yields obtained during the synthesis of various 3'-arylspiro[indene-2,2'-oxirane]-1,3-diones 318.</caption><thead><tr><th>Ar.</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>70</td></tr><tr><td>3-OMeC<sub>6</sub>H<sub>4</sub></td><td>68</td></tr><tr><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>92</td></tr><tr><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>81</td></tr><tr><td>3-FC<sub>6</sub>H<sub>4</sub></td><td>73</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>89</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>56</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>72</td></tr></tbody></table>

<footnote><sup>a</sup> yield of the isolated product.</footnote>

<footnote><sup>a</sup> yield of the isolated product.</footnote>
<figure><img src="image_180.png" /><figcaption>**Scheme 83.** The two plausible mechanisms supporting the cycloaddition reaction or the epoxidation reaction. Reproduced with permission from Ref. [270].</figcaption></figure>

<figure><img src="image_181.png" /><figcaption>**Scheme 84.** Synthesis of 318.</figcaption></figure>

[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.

<figure><img src="image_182.png" /><figcaption>**Scheme 85.** Synthetic route to 320.</figcaption></figure>

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).
<figure><img src="image_183.png" /><figcaption>**Scheme 86.** Cyclotrimerization reaction of **319** and **320**.</figcaption></figure>

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 and Scheme 87).

<table><caption>**Table 18.** Reaction yields obtained during the synthesis of spiroindanediones **325**.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>CH<sub>2</sub>Br</td><td>CH<sub>2</sub>Br</td><td>72</td></tr><tr><td>CH<sub>2</sub>Cl</td><td>H</td><td>80</td></tr><tr><td>CH<sub>2</sub>Cl</td><td>CH<sub>2</sub>Cl</td><td>79</td></tr></tbody></table>

<figure><img src="image_184.png" /><figcaption>**Scheme 87.** Synthesis of **325**.</figcaption></figure>

The team of Ratovelomanana-Vidal and coworkers used another metal, namely ruthenium, to catalyze [2+2+2]cycloadditions, enabling to form pyridines [273–277]. 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].

<figure><img src="image_185.png" /><figcaption>**Scheme 88.** Synthetic route to **327**.</figcaption></figure>

<footnote><sup>a</sup> yield after purification by column chromatography.</footnote>
<figure><img src="image_186.png" /><figcaption>**Scheme 89.** Synthetic route to 329 and 331.</figcaption></figure>

<figure><img src="image_187.png" /><figcaption>**Scheme 90.** Synthetic route to 329 and 334.</figcaption></figure>

The procedure described before used Cp*Ru(CH<sub>3</sub>CN)<sub>3</sub>PF<sub>6</sub> as the catalyst. However, another procedure was also proposed using RuCl<sub>3</sub> as a more accessible catalyst and allowing the formation of the spiro compound 335 using a cheaper synthetic approach (see Scheme 91) [275].

<figure><img src="image_188.png" /><figcaption>**Scheme 91.** Synthesis of 335.</figcaption></figure>

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).
<figure><img src="image_189.png" /><figcaption>**Scheme 92.** Synthesis of compounds 338 and 339.</figcaption></figure>

<figure><img src="image_190.png" /><figcaption>**Scheme 93.** Cobalt-catalyzed cycloaddition reactions.</figcaption></figure>

<figure><img src="image_191.png" /><figcaption>**Scheme 94.** Rhodium-catalyzed cycloaddition reactions.</figcaption></figure>
<figure><img src="image_192.png" /><figcaption>**Scheme 95.** Mechanism involved in the Co and Rh-catalyzed cyclization reaction.</figcaption></figure>

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].

<figure><img src="image_193.png" /><figcaption>**Scheme 96.** Synthetic route to **346**.</figcaption></figure>

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** and Scheme **97**).
<table><caption>**Table 19.** Reaction yields obtained during cycloaddition reactions of 2-arylidene-indane-1,3-dione **255** and cyclic carbonate **347**.</caption><thead><tr><th>R</th><th>t (h)</th><th>Yield (%) <sup>a</sup></th><th>ee (%) <sup>b</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>12</td><td>87</td><td>97</td></tr><tr><td>2-FC<sub>6</sub>H<sub>4</sub></td><td>14</td><td>99</td><td>98</td></tr><tr><td>3-FC<sub>6</sub>H<sub>4</sub></td><td>48</td><td>62</td><td>97</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>94</td><td>97</td></tr><tr><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>5</td><td>62</td><td>98</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>36</td><td>94</td><td>98</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>24</td><td>99</td><td>98</td></tr><tr><td>2,4-Cl<sub>2</sub>C<sub>6</sub>H<sub>3</sub></td><td>4</td><td>90</td><td>98</td></tr><tr><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>5</td><td>99</td><td>98</td></tr><tr><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>12</td><td>99</td><td>96</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>12</td><td>83</td><td>95</td></tr><tr><td>4-EtC<sub>6</sub>H<sub>4</sub></td><td>12</td><td>64</td><td>97</td></tr><tr><td>2-MeOC<sub>6</sub>H<sub>4</sub></td><td>11</td><td>99</td><td>97</td></tr><tr><td>3-MeOC<sub>6</sub>H<sub>4</sub></td><td>14</td><td>99</td><td>99</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>14</td><td>99</td><td>94</td></tr><tr><td>1-C<sub>10</sub>H<sub>6</sub></td><td>20</td><td>99</td><td>99</td></tr><tr><td>2-C<sub>4</sub>H<sub>3</sub>S</td><td>24</td><td>n.r.</td><td>-</td></tr></tbody></table>

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

<figure><img src="image_194.png" /><figcaption>**Scheme 97.** Synthesis of **349**.</figcaption></figure>

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 dibenzocyclooctadiene 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.

<figure><img src="image_195.png" /><figcaption>**Scheme 98.** Ni-catalyzed cycloaddition reaction furnishing **352**.</figcaption></figure>

<figure><img src="image_196.png" /><figcaption>**Scheme 99.** Base-catalyzed [4+1] cycloaddition.</figcaption></figure>

<figure><img src="image_197.png" /><figcaption>**Scheme 100.** Rh-catalyzed cycloaddition reactions.</figcaption></figure>
<figure><img src="image_198.png" /></figure>

<figure><img src="image_199.png" /><figcaption>**Scheme 101.** [4+4] Cycloaddition of indanone containing benzo[c]oxepines providing dibenzocyclooctadiene derivatives 359, 360, 363 and 364.</figcaption></figure>

<figure><img src="image_200.png" /><figcaption>**Scheme 102.** Examples of asymmetric cross [10+2] cycloadditions producing 367 starting from 365 and 249.</figcaption></figure>
### 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 becomes 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 and Scheme 103).

<table><caption>**Table 20.** Examples of a domino Knoevenagel/Diels-Alder/Epimerization sequence.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield (%)</th><th>dr cis:trans</th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>97</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>71</td><td>6:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-HOC<sub>6</sub>H<sub>4</sub></td><td>≥99</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>≥99</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>80</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-CNC<sub>6</sub>H<sub>4</sub></td><td>≥99</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-CO<sub>2</sub>MeC<sub>6</sub>H<sub>4</sub></td><td>≥99</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>10</sub>H<sub>7</sub></td><td>≥99</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>3</sub>O</td><td>≥99</td><td>10:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>3</sub>S</td><td>57</td><td>13:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>4</sub>N</td><td>30</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>2</sub>H<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>74</td><td>≥99:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>93</td><td>≥99:1</td></tr><tr><td>C<sub>10</sub>H<sub>7</sub></td><td>C<sub>10</sub>H<sub>7</sub></td><td>95</td><td>≥99:1</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>C<sub>4</sub>H<sub>3</sub>S</td><td>93</td><td>≥99:1</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>C<sub>4</sub>H<sub>3</sub>O</td><td>60</td><td>≥99:1</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>95</td><td>≥99:1</td></tr><tr><td>C<sub>7</sub>H<sub>5</sub>O<sub>2</sub></td><td>C<sub>7</sub>H<sub>5</sub>O<sub>2</sub></td><td>98</td><td>≥99:1</td></tr><tr><td>4-Me<sub>2</sub>NC<sub>6</sub>H<sub>4</sub></td><td>4-Me<sub>2</sub>NC<sub>6</sub>H<sub>4</sub></td><td>90</td><td>≥99:1</td></tr><tr><td>4-HOC<sub>6</sub>H<sub>4</sub></td><td>4-HOC<sub>6</sub>H<sub>4</sub></td><td>95</td><td>≥99:1</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>98</td><td>≥99:1</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>98</td><td>≥99:1</td></tr><tr><td>4-CNC<sub>6</sub>H<sub>4</sub></td><td>4-CNC<sub>6</sub>H<sub>4</sub></td><td>85</td><td>≥99:1</td></tr><tr><td>4-CO<sub>2</sub>MeC<sub>6</sub>H<sub>4</sub></td><td>4-CO<sub>2</sub>MeC<sub>6</sub>H<sub>4</sub></td><td>83</td><td>≥99:1</td></tr></tbody></table>

<figure><img src="image_201.png" /><figcaption>**Scheme 103.** Synthesis of **370**.</figcaption></figure>

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.

<figure><img src="image_202.png" /><figcaption>**Scheme 104.** Mechanism of domino Knoevenagel/Diels-Alder/Epimerization sequence providing **370**.</figcaption></figure>

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** and Scheme **105**).
<table><caption>**Table 21.** Domino reaction involving a sulfa Michael/Michael sequence.</caption><thead><tr><th>Ar</th><th>Yield (%) <sup>b</sup></th><th>ee (%) <sup>c</sup></th><th>dr cis:trans</th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>86</td><td>99</td><td>94.8:5.2</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>81</td><td>99</td><td>95.3:4.7</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>80</td><td>98</td><td>95.6:4.4</td></tr><tr><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>78</td><td>97</td><td>91.6:8.4</td></tr><tr><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub> <sup>a</sup></td><td>85</td><td>91</td><td>84.4:15.6</td></tr><tr><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>83</td><td>98</td><td>95.0:5.0</td></tr><tr><td>2-C<sub>4</sub>H<sub>3</sub>O</td><td>78</td><td>97</td><td>92.1:7.9</td></tr></tbody></table>

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

<figure><img src="image_203.png" /><figcaption>**Scheme 105.** Synthesis of 373.</figcaption></figure>

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).

<figure><img src="image_204.png" /><figcaption>**Figure 2.** Crystal structure of a product used to determine the reaction mechanism. Reproduced with permission of Duan et al. [287].</figcaption></figure>

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** and Scheme **106**.
<table><caption>**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**.</caption><thead><tr><th>R</th><th>Time (h)</th><th>Yield (%) <sup>a</sup></th><th>dr cis:trans <sup>b</sup></th><th>ee <sup>c</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3</td><td>96</td><td>9:1</td><td>68</td></tr><tr><td>C<sub>10</sub>H<sub>7</sub></td><td>3</td><td>93</td><td>8:1</td><td>65</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>2</td><td>99</td><td>7.5:1</td><td>56</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>1</td><td>96</td><td>9:1</td><td>66</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>5</td><td>97</td><td>1.3:1</td><td>68</td></tr><tr><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>2</td><td>93</td><td>1.5:1</td><td>72</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>2.5</td><td>98</td><td>9:1</td><td>71</td></tr><tr><td>3-MeOC<sub>6</sub>H<sub>4</sub></td><td>3</td><td>88</td><td>9:1</td><td>60</td></tr><tr><td>3,4-(OCH<sub>2</sub>O)C<sub>6</sub>H<sub>3</sub></td><td>4.5</td><td>96</td><td>9:1</td><td>74</td></tr><tr><td>3-C<sub>4</sub>H<sub>3</sub>S</td><td>24</td><td>98</td><td>9:1</td><td>72</td></tr></tbody></table>

<figure><img src="image_205.png" /><figcaption>**Scheme 106.** Synthesis of **376**.</figcaption></figure>

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 and Scheme 107) [289].

<table><caption>**Table 23.** Domino reactions involving a Knoevenagel condensation/1,3 dipolar cycloaddition sequence.</caption><thead><tr><th>Ar</th><th>Yield (%) <sup>a</sup></th><th>rr <sup>b</sup></th></tr></thead><tbody><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>78</td><td>≥95:5</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>83</td><td>≥95:5</td></tr><tr><td>2-C<sub>10</sub>H<sub>7</sub></td><td>74</td><td>≥95:5</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>79</td><td>≥95:5</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>80</td><td>≥95:5</td></tr></tbody></table>

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

<footnote><sup>a</sup> Isolated yield; <sup>b</sup> determined by ¹H NMR analysis of the crude reaction mixture.</footnote>
<figure><img src="image_206.png" /><figcaption>**Scheme 107.** Synthesis of 378.</figcaption></figure>

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 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.

<table><caption>**Table 24.** Domino reactions carried out with benzoimidazoles **379**.</caption><thead><tr><th>Ar</th><th>X</th><th>Yield (%)</th></tr></thead><tbody><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>NH</td><td>78</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>NH</td><td>80</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>S</td><td>76</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>S</td><td>85</td></tr></tbody></table>

<figure><img src="image_207.png" /><figcaption>**Scheme 108.** Synthesis of 380.</figcaption></figure>

<figure><img src="image_208.png" /><figcaption>**Scheme 109.** Domino reactions carried out with (benzo)thiazoles **382** and **383**.</figcaption></figure>

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).
<figure><img src="image_209.png" /><figcaption>**Scheme 110.** Domino reactions involving 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.</figcaption></figure>

<figure><img src="image_210.png" /><figcaption>**Scheme 111.** Mechanism supporting the formation of the previous compound 395. Reproduced with permission from Ref. [290].</figcaption></figure>

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 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).

<table><caption>**Table 25.** Reaction yields obtained during domino reaction of ynones **391** and 2-arylidene-indane-1,3-diones **255**.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>R<sub>3</sub></th><th>t (h)</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>15</td><td>90</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>93</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>96</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>90</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>91</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>95</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>94</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>12</td><td>88</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>12</td><td>87</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>3</td><td>90 <sup>b</sup></td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>24</td><td>73</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2,4-Cl<sub>2</sub>C<sub>6</sub>H<sub>3</sub></td><td>12</td><td>62</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2-C<sub>4</sub>H<sub>3</sub>O</td><td>48</td><td>87</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2-C<sub>4</sub>H<sub>3</sub>S</td><td>53</td><td>84</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>1-C<sub>10</sub>H<sub>7</sub></td><td>20</td><td>96</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>C<sub>2</sub>H<sub>4</sub>C<sub>6</sub>H<sub>4</sub></td><td>35</td><td>89</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>18</td><td>95</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Di-Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>18</td><td>97</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>21</td><td>83</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>21</td><td>84</td></tr><tr><td>n-Bu</td><td>H</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>22</td><td>NR</td></tr></tbody></table>

<figure><img src="image_211.png" /><figcaption>**Scheme 112.** Synthesis of **392**.</figcaption></figure>

<figure><img src="image_212.png" /><figcaption>**Scheme 113.** Synthetic route to **395**.</figcaption></figure>

<footnote><sup>a</sup> Isolated yields; <sup>b</sup> the reaction was carried out at 70 °C with a 2:1 ratio for ynone:indane-1,3-dione.</footnote>
<figure><img src="image_213.png" /><figcaption>**Scheme 114.** Mechanism of the domino reaction between ynones 397 and 2-arylidene-indane-1,3-diones 255. Reproduced with permission from Ref. [291].</figcaption></figure>

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).

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 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).

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).

<figure><img src="image_214.png" /><figcaption>**Scheme 115.** Synthesis of spiro-compounds **403** by domino reaction involving a silver-based catalyst.</figcaption></figure>
<figure><img src="image_215.png" /><figcaption>**Scheme 116.** Mechanism of the domino reaction involving a silver-based catalyst. Reproduced with permission from Ref. [292].</figcaption></figure>

<figure><img src="image_216.png" /><figcaption>**Scheme 117.** Synthetic access to **404**.</figcaption></figure>

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).

<figure><img src="image_217.png" /><figcaption>**Scheme 118.** Synthesis of 5'-hydroxy-6'-methyl-1',3'-dihydro-2,2'-spirobi[indene]-1,3-dione **406**.</figcaption></figure>
<table><caption>**Table 26.** Spiro compounds **408** obtained by cascade Michael addition/cycloaddition reactions between 2-arylidene-indane-1,3-diones **255** and allenoates **407**.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>R<sub>3</sub></th><th>t (h)</th><th>Yield (%)</th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>C<sub>6</sub>H<sub>5</sub></td><td>15</td><td>90</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>93</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>96</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>90</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>91</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>95</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>94</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>12</td><td>88</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>12</td><td>87</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>3</td><td>90</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>24</td><td>73</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2,4-Cl<sub>2</sub>C<sub>6</sub>H<sub>3</sub></td><td>12</td><td>62</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2-C<sub>4</sub>H<sub>3</sub>O</td><td>48</td><td>87</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>2-C<sub>4</sub>H<sub>3</sub>S</td><td>53</td><td>84</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>1-C<sub>10</sub>H<sub>7</sub></td><td>20</td><td>96</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>C<sub>2</sub>H<sub>4</sub>C<sub>6</sub>H<sub>4</sub></td><td>35</td><td>89</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>18</td><td>95</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Di-Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>18</td><td>97</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>21</td><td>83</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>Me</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>21</td><td>84</td></tr><tr><td>n-Bu</td><td>H</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>22</td><td>NR</td></tr></tbody></table>

<figure><img src="image_218.png" /><figcaption>**Scheme 119.** Synthesis of **408**.</figcaption></figure>
<figure><img src="image_219.png" /><figcaption>**Scheme 120.** Mechanism of the cascade Michael addition/cycloaddition reaction between 2-arylidene-indane-1,3-diones 255 and allenoates 407. Reproduced with permission from Ref. [293].</figcaption></figure>
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** and Scheme **121**).

<table><caption>**Table 27.** Domino reaction between 2-arylidene-indane-1,3-diones **255** and *N*-alkoxyacrylamides **410** in the presence of a base.</caption><thead><tr><th>Ar</th><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield %</th><th>dr</th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>85</td><td>4:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>81</td><td>4:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>69</td><td>4:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>H</td><td>51</td><td>4:1</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>60</td><td>4:1</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>48</td><td>4:1</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>51</td><td>4:1</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>H</td><td>40</td><td>4:1</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Me</td><td>H</td><td>72</td><td>3:2</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>Me</td><td>H</td><td>60</td><td>3:2</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>Me</td><td>60<sup>a</sup></td><td>-<sup>b</sup></td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Me</td><td>Me</td><td>69</td><td>-</td></tr></tbody></table>

<figure><img src="image_220.png" /><figcaption>**Scheme 121.** Synthesis of **411**.</figcaption></figure>

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** 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**).

<footnote><sup>a</sup> The reaction was carried at 60 °C; <sup>b</sup> only one diastereoisomer was observed by ¹H NMR.</footnote>
<figure><img src="image_221.png" /><figcaption>**Scheme 122.** Mechanism of the domino reaction between 2-arylidene-indane-1,3-diones 255 and N-alkoxyacrylamides 410 in the presence of a base. Reproduced with permission from Ref. [294].</figcaption></figure>

<figure><img src="image_222.png" /><figcaption>**Scheme 123.** Synthesis of 417.</figcaption></figure>
<figure><img src="image_223.png" /><figcaption>**Scheme 124.** Mechanism involved in the cascade double Michael addition/acetalization reactions. Reproduced with permission from Ref. [295].</figcaption></figure>

<table><caption>**Table 28.** Reaction yields obtained during the cascade double Michael addition/acetalization reactions.</caption><thead><tr><th>R<sub>1</sub><sup>a</sup></th><th>R<sub>2</sub></th><th>R<sub>3</sub></th><th>Time (h)</th><th>Yield %<sup>b</sup></th></tr></thead><tbody><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>24</td><td>82</td></tr><tr><td>5-OH</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>24</td><td>82</td></tr><tr><td>5-OMe</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>36</td><td>77</td></tr><tr><td>4-OMe</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>27</td><td>83</td></tr><tr><td>5-Br</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>24</td><td>82</td></tr><tr><td>-</td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>75.5</td><td>72</td></tr><tr><td>-</td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>96</td><td>72</td></tr><tr><td>-</td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>24.5</td><td>67</td></tr><tr><td>-</td><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>24</td><td>72</td></tr><tr><td>-</td><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>24</td><td>72</td></tr><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>24.5</td><td>76c</td></tr><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>24.5</td><td>76</td></tr><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>27</td><td>82</td></tr><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>24.5</td><td>73</td></tr><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>24.5</td><td>77 c</td></tr><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>48</td><td>84</td></tr><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>3</sub>S</td><td>24</td><td>71</td></tr><tr><td>-</td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>3</sub>H<sub>7</sub></td><td>24</td><td>58 c</td></tr></tbody></table>

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

<footnote><sup>a</sup> If nothing, there is 2-OHC<sub>6</sub>H<sub>4</sub>; <sup>b</sup> isolated yield; <sup>c</sup> in this case, only the intermediate was obtained in this yield.</footnote>
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).

<figure><img src="image_224.png" /><figcaption>**Scheme 125.** Product 423 obtained in a quadruple cascade reaction.</figcaption></figure>

<figure><img src="image_225.png" /><figcaption>**Scheme 126.** Mechanism involved in the quadruple cascade reaction.</figcaption></figure>
### 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 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 and Scheme 132).

<table><caption>**Table 29.** Reaction yields obtained during the synthesis of spiro-indane-1,3-diones **428**.</caption><thead><tr><th>R</th><th>t (h)</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>10</td><td>67</td></tr><tr><td>2-ClC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>69</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>8</td><td>72</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>9</td><td>64</td></tr><tr><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>10</td><td>62</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>52</td></tr><tr><td>4-MeOC<sub>6</sub>H<sub>4</sub></td><td>9</td><td>62</td></tr><tr><td>3,5-(MeO)<sub>2</sub>C<sub>6</sub>H<sub>3</sub></td><td>9</td><td>58</td></tr><tr><td>2-HOC<sub>6</sub>H<sub>4</sub></td><td>10</td><td>63</td></tr><tr><td>4-HOC<sub>6</sub>H<sub>4</sub></td><td>9</td><td>55</td></tr><tr><td>2-HO-3-MeOC<sub>6</sub>H<sub>4</sub></td><td>8</td><td>57</td></tr><tr><td>3-MeO-4-HOC<sub>6</sub>H<sub>4</sub></td><td>8</td><td>60</td></tr><tr><td>4-NMe<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>10</td><td>52</td></tr></tbody></table>

<footnote><sup>a</sup> Isolated yield.</footnote>
<figure><img src="image_226.png" /><figcaption>**Scheme 127.** Mechanism involved in the synthesis of spiro-indane-1,3-diones **428**.</figcaption></figure>

<figure><img src="image_227.png" /><figcaption>**Scheme 128.** Synthesis of **428**.</figcaption></figure>

<figure><img src="image_228.png" /><figcaption>**Scheme 129.** Examples of compounds **437** and **438** obtained during the MRC of indane-1,3-dione 4, dimethyl but-2-ynedioate **434** and various substituted benzothiazoles **435** or **436**.</figcaption></figure>
<figure><img src="image_229.png" /><figcaption>**Scheme 130.** Mechanism of MRC between the MRC between indane-1,3-dione 4, dimethyl but-2-ynedioate 434 and benzothiazoles 437 or 438.</figcaption></figure>

<figure><img src="image_230.png" /><figcaption>**Scheme 131.** Synthesis of spiro-N-fused indane-1,3-diones 441 and 442.</figcaption></figure>
<table><caption>**Table 30.** Scope of application of the microwave-assisted reaction.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield Product 1 (%)</th><th>Yield Product 2 (%)</th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>30</td><td>31</td></tr><tr><td>4-NMe<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-NMe<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>28</td><td>32</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>32</td><td>36</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>20</td><td>22</td></tr><tr><td>4-C<sub>6</sub>H<sub>5</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-C<sub>6</sub>H<sub>5</sub>C<sub>6</sub>H<sub>4</sub></td><td>32</td><td>28</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>C<sub>4</sub>H<sub>3</sub>S</td><td>42</td><td>41</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>C<sub>4</sub>H<sub>3</sub>O</td><td>36</td><td>36</td></tr><tr><td>3-NO<sub>2</sub>C<sub>4</sub>H<sub>2</sub>O</td><td>3-NO<sub>2</sub>C<sub>4</sub>H<sub>2</sub>O</td><td>39</td><td>31</td></tr><tr><td>3-MeC<sub>4</sub>H<sub>2</sub>O</td><td>3-MeC<sub>4</sub>H<sub>2</sub>O</td><td>30</td><td>33</td></tr></tbody></table>

<figure><img src="image_231.png" /><figcaption>**Scheme 132.** Synthesis of **441** and **442**.</figcaption></figure>

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 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 and Scheme 134).

Nanoparticles were also used as catalysts in one-pot three-component reactions [301]. By using proline-functionalized $Fe_3O_4$ 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 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 carbocation 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).
<table><caption>**Table 31.** Reaction yields obtained during the synthesis of triazole-containing spiro-indane-1,3-diones **445**.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Time (min)</th><th>Yield (%)</th></tr></thead><tbody><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>45</td><td>85</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>50</td><td>80</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>50</td><td>83</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>40</td><td>82</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>50</td><td>81</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>45</td><td>84</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>50</td><td>82</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>45</td><td>86</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>40</td><td>79</td></tr><tr><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>45</td><td>84</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>40</td><td>82</td></tr><tr><td>4-(CF<sub>3</sub>)C<sub>6</sub>H<sub>4</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>40</td><td>87</td></tr><tr><td>4-(CF<sub>3</sub>)C<sub>6</sub>H<sub>4</sub></td><td>7-ClC<sub>9</sub>H<sub>5</sub>N</td><td>50</td><td>80</td></tr><tr><td>4-(CF<sub>3</sub>)C<sub>6</sub>H<sub>4</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>45</td><td>85</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>7-ClC<sub>9</sub>H<sub>5</sub>N</td><td>50</td><td>74</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>C<sub>4</sub>H<sub>9</sub></td><td>50</td><td>80</td></tr><tr><td>(CH<sub>2</sub>O<sub>2</sub>)C<sub>6</sub>H<sub>3</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>50</td><td>86</td></tr><tr><td>C<sub>4</sub>H<sub>9</sub></td><td>7-ClC<sub>9</sub>H<sub>5</sub>N</td><td>60</td><td>78</td></tr><tr><td>C<sub>4</sub>H<sub>9</sub></td><td>4-(Ome)C<sub>6</sub>H<sub>4</sub></td><td>65</td><td>74</td></tr></tbody></table>

<figure><img src="image_232.png" /><figcaption>**Scheme 133.** Synthesis of **445**.</figcaption></figure>

<table><caption>**Table 32.** MRC used for the design of spiro-compounds **450** with biological properties.</caption><thead><tr><th>Ar</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>4-CH<sub>2</sub>OHC<sub>6</sub>H<sub>4</sub></td><td>81</td></tr><tr><td>4-CHOC<sub>6</sub>H<sub>4</sub></td><td>80</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>93</td></tr><tr><td>3,5-(OMe)<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>40</td></tr><tr><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>81</td></tr><tr><td>4-OHC<sub>6</sub>H<sub>4</sub></td><td>70</td></tr><tr><td>4-COOHC<sub>6</sub>H<sub>4</sub></td><td>54</td></tr></tbody></table>

<footnote><sup>a</sup> Yield of the purified product after chromatography column.</footnote>
<figure><img src="image_233.png" /></figure>

<figure><img src="image_234.png" /><figcaption>**Scheme 134.** Synthesis of 448 and 450.</figcaption></figure>

<table><caption>**Table 33.** MRC reactions involving Fe-based nanoparticles.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>Yield (%)<sup>a</sup></th></tr></thead><tbody><tr><td>-</td><td>-</td><td>84</td></tr><tr><td>4-Me</td><td>-</td><td>80</td></tr><tr><td>4-OMe</td><td>-</td><td>73</td></tr><tr><td>2-OMe</td><td>-</td><td>70</td></tr><tr><td>3-OMe</td><td>-</td><td>78</td></tr><tr><td>4-Cl</td><td>-</td><td>92</td></tr><tr><td>4-Br</td><td>-</td><td>90</td></tr><tr><td>3-OMe</td><td>4-OMe</td><td>83</td></tr><tr><td>4-Br</td><td>4-OMe</td><td>86</td></tr><tr><td>4-Br</td><td>4-Br</td><td>91</td></tr></tbody></table>

<figure><img src="image_235.png" /><figcaption>**Scheme 135.** Synthesis of 452.</figcaption></figure>

<footnote><sup>a</sup> Isolated yield.</footnote>
<figure><img src="image_236.png" /><figcaption>**Scheme 136.** Mechanism involved in the MRC reaction using Fe-particles as catalysts. Reproduced with permission from Ref. [301].</figcaption></figure>

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].

<figure><img src="image_237.png" /><figcaption>**Scheme 137.** Example of pH-switchable compound **454**.</figcaption></figure>

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).

<figure><img src="image_238.png" /><figcaption>**Scheme 138.** Various products obtained by reacting indane-1,3-dione 4 in the presence of base.</figcaption></figure>

<figure><img src="image_239.png" /><figcaption>**Scheme 139.** Synthetic routes to 50 and 458.</figcaption></figure>

<figure><img src="image_240.png" /><figcaption>**Scheme 140.** Synthetic route to 455.</figcaption></figure>
<figure><img src="image_241.png" /><figcaption>**Scheme 141.** Synthetic route to 457.</figcaption></figure>

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

<table><caption>**Table 34.** Reaction yields obtained during alkene hydrofunctionnalizations of 2-arylidene-indane-1,3-diones **255**.</caption><thead><tr><th>R</th><th>Methyle</th><th>n</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Yes</td><td>1</td><td>82</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>55</td></tr><tr><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>59</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>53</td></tr><tr><td>4-NMe<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>45</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>42</td></tr><tr><td>4-CO<sub>2</sub>MeC<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>69</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>54</td></tr><tr><td>2-OMeC<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>72</td></tr><tr><td>3-OMeC<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>54</td></tr><tr><td>3-CNC<sub>6</sub>H<sub>4</sub></td><td>Yes</td><td>1</td><td>48</td></tr><tr><td>2,4,5-C<sub>6</sub>H<sub>2</sub></td><td>Yes</td><td>1</td><td>50</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>Yes</td><td>1</td><td>58</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>Yes</td><td>1</td><td>48</td></tr><tr><td>C<sub>10</sub>H<sub>7</sub></td><td>Yes</td><td>1</td><td>74</td></tr><tr><td>3-CNC<sub>6</sub>H<sub>4</sub></td><td>No</td><td>1</td><td>63 <sup>b</sup></td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>No</td><td>1</td><td>46 <sup>b</sup></td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>No</td><td>2</td><td>58</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>Yes</td><td>2</td><td>50</td></tr></tbody></table>

<footnote><sup>a</sup> Yield refers to isolated product; <sup>b</sup> dr was determined by ¹H NMR.</footnote>
<figure><img src="image_242.png" /><figcaption>**Scheme 142.** Synthesis of 463.</figcaption></figure>

<figure><img src="image_243.png" /><figcaption>**Scheme 143.** Mechanism occurring during alkene hydrofunctionnalizations of 2-arylidene-indane-1,3-diones 255 providing 463. Reproduced with permission from Ref. [304].</figcaption></figure>

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 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 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 and Scheme 149).

<table><caption>**Table 35.** Copper-catalyzed synthesis of spiro-compounds.</caption><thead><tr><th>R1</th><th>R2</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>90</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>61</td></tr><tr><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>84</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>73</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>82</td></tr><tr><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>81</td></tr><tr><td>3-OMeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>66</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>69</td></tr><tr><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>85</td></tr><tr><td>C<sub>10</sub>H<sub>7</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>71</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>C<sub>6</sub>H<sub>5</sub></td><td>64</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>C<sub>6</sub>H<sub>5</sub></td><td>66</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>74</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>87</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>91</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>75</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>76</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>60</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>89</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>78</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-OMeC<sub>6</sub>H<sub>4</sub></td><td>74</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-BrC<sub>6</sub>H<sub>4</sub></td><td>68</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>70</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>58</td></tr><tr><td>4-FC<sub>6</sub>H<sub>4</sub></td><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>62</td></tr><tr><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>71</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>O</td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>71</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>CO<sub>2</sub>Me</td><td>Nr</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>11</sub></td><td>Nr</td></tr></tbody></table>

<figure><img src="image_244.png" /><figcaption>**Scheme 144.** Synthesis of **465**.</figcaption></figure>

<footnote><sup>a</sup> Isolated yield; Nr, no reaction.</footnote>
<figure><img src="image_245.png" /><figcaption>**Scheme 145.** Mechanism involved in the copper-catalyzed synthesis of spiro compounds. Reproduced with permission from Ref. [305].</figcaption></figure>

<figure><img src="image_246.png" /><figcaption>**Scheme 146.** Synthesis of 467.</figcaption></figure>

<figure><img src="image_247.png" /><figcaption>**Scheme 147.** Mechanism occurring in the copper catalyzed cycloaddition reaction of 2-arylene-indane-1,3-dione 255 with various oximes 466. Reproduced with permission from Ref. [306].</figcaption></figure>
<table><caption>**Table 36.** Copper-catalyzed cycloaddition reaction of 2-arylene-indane-1,3-dione 255 with various oximes 466.</caption><thead><tr><th>R<sub>1</sub></th><th>R<sub>2</sub></th><th>R<sub>3</sub></th><th>R<sub>4</sub></th><th>Yield (%)<sup>a</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>H</td><td>H</td><td>74</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>82</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>80</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-IC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>64</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>83</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>81</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>66</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-CNC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>78</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>4-MeSC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>81</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-BrC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>85</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>3-MeC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>89</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>H</td><td>H</td><td>78</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>10</sub>H<sub>7</sub></td><td>H</td><td>H</td><td>74</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>9</sub></td><td>H</td><td>H</td><td>79</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>CH<sub>3</sub></td><td>CH<sub>3</sub></td><td>50</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>2</sub>H<sub>5</sub></td><td>H</td><td>65<sup>a</sup></td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>3</sub>H<sub>5</sub></td><td>H</td><td>H</td><td>78</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>CO<sub>2</sub>Et</td><td>H</td><td>H</td><td>30</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>10</sub>H<sub>20</sub></td><td></td><td>H</td><td>32<sup>a</sup></td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>8</sub>H<sub>8</sub></td><td></td><td>H</td><td>40<sup>a</sup></td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>2</sub>H<sub>5</sub></td><td>CH<sub>3</sub></td><td>H</td><td>51<sup>a</sup></td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>5</sub>H<sub>4</sub>N</td><td>H</td><td>H</td><td>51</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>3</sub>O</td><td>H</td><td>H</td><td>86</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>3</sub>S</td><td>H</td><td>H</td><td>56</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>9</sub>H<sub>8</sub>N</td><td>H</td><td>H</td><td>40</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>5</sub>H<sub>6</sub>N</td><td>H</td><td>H</td><td>96</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>4</sub>H<sub>5</sub>N<sub>2</sub></td><td>H</td><td>H</td><td>77</td></tr><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>C<sub>6</sub>H<sub>4</sub>C<sub>3</sub>H<sub>2</sub>SN</td><td>H</td><td>H</td><td>70</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>C<sub>6</sub>H<sub>3</sub>(O<sub>2</sub>CH<sub>2</sub>)</td><td>H</td><td>H</td><td>72</td></tr><tr><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>C<sub>8</sub>H<sub>5</sub>S</td><td>H</td><td>H</td><td>52</td></tr></tbody></table>

<footnote><sup>a</sup> > 19:1 dr value was determined by ¹H NMR spectroscopy.</footnote>
<figure><img src="image_248.png" /><figcaption>**Scheme 148.** The different products obtained during the reaction of 2-arylidene-indane-1,3-diones 255 and the Seyferth–Gilbert reagent 468.</figcaption></figure>

<table><caption>**Table 37.** Reaction yields obtained during the reaction of 2-arylidene-indane-1,3-diones 255 and the Seyferth–Gilbert reagent 457 in the presence of CsF.</caption><thead><tr><th>R</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>C<sub>6</sub>H<sub>5</sub></td><td>87</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>75</td></tr><tr><td>4-iPrC<sub>6</sub>H<sub>4</sub></td><td>92</td></tr><tr><td>4-EtC<sub>6</sub>H<sub>4</sub></td><td>88</td></tr><tr><td>4-MeC<sub>6</sub>H<sub>4</sub></td><td>88</td></tr><tr><td>4-PhC<sub>6</sub>H<sub>4</sub></td><td>90</td></tr><tr><td>4-BrC<sub>6</sub>H<sub>4</sub></td><td>85</td></tr><tr><td>4-ClC<sub>6</sub>H<sub>4</sub></td><td>77</td></tr><tr><td>3-ClC<sub>6</sub>H<sub>4</sub></td><td>93</td></tr><tr><td>4-OMeC<sub>6</sub>H<sub>4</sub></td><td>86</td></tr><tr><td>2-MeC<sub>6</sub>H<sub>4</sub></td><td>88</td></tr><tr><td>3,4-(OMe)<sub>2</sub>C<sub>6</sub>H<sub>3</sub></td><td>65</td></tr><tr><td>3,4,5-(OMe)<sub>3</sub>C<sub>6</sub>H<sub>2</sub></td><td>80</td></tr><tr><td>C<sub>4</sub>H<sub>4</sub>N</td><td>80</td></tr><tr><td>C<sub>4</sub>H<sub>3</sub>S</td><td>87</td></tr><tr><td>C<sub>10</sub>H<sub>7</sub></td><td>89</td></tr><tr><td>Fc</td><td>87</td></tr></tbody></table>

<figure><img src="image_249.png" /><figcaption>**Scheme 149.** Synthesis of 469.</figcaption></figure>

To sum up, spiroindane-1,3-dione are interesting structures that can be obtained using various synthetic procedures. Due to their similarities 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

<footnote><sup>a</sup> Isolated yield after chromatography by silica gel.</footnote>
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 [309–315]. 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 [316–325]. 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 [327–330]. 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 [341–343]. 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 [344–346].
<figure><img src="image_250.png" /></figure>

470

<figure><img src="image_251.png" /></figure>

471

<figure><img src="image_252.png" /></figure>

472

<figure><img src="image_253.png" /></figure>

473

<figure><img src="image_254.png" /></figure>

474

<figure><img src="image_255.png" /></figure>

475

<figure><img src="image_256.png" /></figure>

476

<figure><img src="image_257.png" /></figure>

477

<figure><img src="image_258.png" /></figure>

478

<figure><img src="image_259.png" /></figure>

479

<figure><img src="image_260.png" /></figure>

480

<figure><img src="image_261.png" /></figure>

481

<figure><img src="image_262.png" /></figure>

482

<figure><img src="image_263.png" /></figure>

483

<figure><img src="image_264.png" /></figure>

484

<figure><img src="image_265.png" /></figure>

485

<figure><img src="image_266.png" /></figure>

486

<figure><img src="image_267.png" /></figure>

487

<figure><img src="image_268.png" /></figure>

488

<figure><img src="image_269.png" /></figure>

489

<figure><img src="image_270.png" /></figure>

490

<figure><img src="image_271.png" /></figure>

491

<figure><img src="image_272.png" /></figure>

492

<figure><img src="image_273.png" /></figure>

493

<figure><img src="image_274.png" /></figure>

494

<figure><img src="image_275.png" /></figure>

495

<figure><img src="image_276.png" /></figure>

496

<figure><img src="image_277.png" /></figure>

497

<caption>**Scheme 150.** Chemical structures of indane-1,3-dione-based push-pull dyes **470–497**.</caption>