Synthesis of 1-indanones with a broad range of biological activity

This comprehensive review describes methods for the preparation of 1-indanones published in original and patent literature from 1926 to 2017. More than 100 synthetic methods utilizing carboxylic acids, esters, diesters, acid chlorides, ketones, alkynes, alcohols etc. as starting materials, have been performed. This review also covers the most important studies on the biological activity of 1-indanones and their derivatives which are potent antiviral, anti-inflammatory, analgesic, antimalarial, antibacterial and anticancer compounds. Moreover, they can be used in the treatment of neurodegenerative diseases and as effective insecticides, fungicides and herbicides.


Introduction
In the last few years, 1-indanone derivatives and their structural analogues have been widely used in medicine, agriculture and in natural products synthesis [1][2][3]. In addition, structurally related indanes also showed biological activity and have been reviewed by Ahmed in 2016 [4]. Extensive studies on bioactivity of 1-indanone derivatives open up more and more new possibilities of their applications as antiviral and antibacterial agents [5] (I and II), anticancer drugs [6] (VI), pharmaceuticals used in the Alzheimer's disease treatment [7] (III), cardiovascular drugs [7] (IV), insecticides, fungicides, herbicides [8] (V) and non-nucleoside, low molecular drugs for the hepatitis C treatment, which inhibit HCV replication [9,10] (Figure 1).  First publications concerning the preparation of 1-indanones appeared in the 1920s and since then this field has been intensively developed [11]. A huge interest in 1-indanones and their derivatives resulted in a considerable number of papers concerning their synthesis ( Figure 2). The commonly used reaction in this area is the Nazarov reaction which employs α,β-unsatu-Scheme 3: Synthesis of 1-indanones 5 from 3-arylpropionic acids 4. rated ketones as substrates and is carried out in the presence of Brønsted or Lewis acids. Despite extensive studies on 1-indanones and their biological activity, this group of compounds has never been reviewed in literature and therefore the present work is the first, comprehensive review of synthetic methods and applications of these compounds in medicine and agriculture published from 1926 to 2017.
We have divided the review into 4 sections, taking into account the formation of the 5-(section 1), 6-(section 2) and simultaneous formation of 5-and 6-membered rings of 1-indanones (section 3) as well as functionalization of 1-indanones or related compounds (section 4).
Another reaction leading to the formation of the unsubstituted 1-indanone (2) in higher 76% yield utilizes the cyclization of 3-(2-bromophenyl)propionic acid (3), conducted at −100 °C in the presence of n-BuLi (Scheme 2) [13]. A cyclization of 3-arylpropionic acids 4, catalyzed by Tb(OTf) 3 at 250 °C, led to the formation of at the aryl ring substituted 1-indanones 5 in yields of up to 74% and trace amounts of the auto-condensation products 6 (Scheme 3). Even in the deactivated derivatives containing halogen atoms at the aromatic system, the cyclopentanone ring closure took place quite easily [14]. If other Lewis acids, such as Bi(NTf 2 ) 3 or triflate derivatives of the transition metals (In, Sc, Ce, Pr, Nd, Eu, Dy, Yb, Lu, Hf, Gd) were used, the cyclization proceeded in unsatisfactory yields and with a large number of unidentified byproducts.
Cyclization of other 3-arylpropionic acids 7 led to the formation of 4,7-dimethoxy-1-indanones 8. They were used in the key step of the synthesis of kinamycin 9 derivatives, which exhibited a strong cytotoxic and anticancer activity (Scheme 4) [15].
Propionic acid derivatives are also useful substrates in syntheses of 1-indanones and isocoumarins [16]. These latter are essential reagents for the synthesis of bioactive compounds. Fluoroorganic compounds play a significant role as very effective therapeutics, and for this reason, Prakash, Olah et al. synthesized in 2010 trifluoromethyl-substituted arylpropanoic acids 12, 1-indanones 13 and dihydrocoumarins 14 (Scheme 5) [17]. These products have been obtained by utilizing arenes/phenols 11 (X = H/OH) and 2-(trifluoromethyl)acrylic acid (10) as a result of a Friedel-Crafts alkylation. An efficient and scalable one-pot process for the preparation of 1-indanones from benzoic acids has been described by Huang et al. [18]. In this synthesis, acyl chlorides formed in the reaction of benzoic acids 15 with thionyl chloride, reacted with ethylene and the resulting intermediates underwent an intramolecular Friedel-Crafts alkylation to form 1-indanones 16 (Scheme 6).
A one-step synthesis of 1-indanones 22 through the NbCl 5 -induced Friedel-Crafts reaction, has been described by Barbosa et al. in 2015 [20]. The reaction was carried out using 3,3-dimethylacrylic acid (19), aromatic substrate 20 and highly oxophilic NbCl 5 as a catalyst. By varying the type of substrate, a variety of 1-indanone derivatives 22 was obtained. Depending on the reaction conditions (A-C), 1-indanone derivatives 22 was obtained in 0-78% yields. The studies indicated that of two possible intermediates 21a and 21b, obtained as a result of acylation or alkylation reaction, the intermediate 21a with activated aromatic ring, always led to the 1-indanone formation, in contrast to the acylated intermediate 21b with deactivated aromatic ring (Scheme 8).
In the same year, Xu et al. have patented a synthesis of 5-chloro-1-indanone via the reaction of malonic acid with chlorobenzaldehyde [21]. In the first step, the substrates reacted in the presence of formic acid and diethylamine to form 3-chlorophenylpropionic acid followed by a intramolecular Friedel-Crafts acylation with malonyl chloride in the presence of zinc chloride to give 5-chloro-1-indanone.
New 1-indanone derivatives that may be used as multi-functional drugs for the treatment of Alzheimer's disease have been synthesized by Li et al. [8]. In this synthesis, ferulic acid (23) was hydrogenated in the presence of Pd/C catalyst to give the saturated derivative 24 and then cyclized to the 1-indanone 25. The latter was then converted to biologically active 1-indanone derivatives 26 in three steps (Scheme 9). The authors tested activities of the synthesized compounds 26 for inhibition of cholinesterases (AChE and BuChE) and inhibition of amyloid beta (Aβ) self-assembly. The studies have shown that most of the compounds 26 exhibited a good inhibitory activity against AChE. For instance, compounds 26d and 26i demonstrated IC 50 values of 14.8 and 18.6 nM, respectively and a remarkably inhibition of Aβ aggregation.
The environmentally benign synthesis of 1-indanones from 3-arylpropanoic and 4-arylbutanoic acids has been reported in 2015 by Le et al. [22]. The authors applied a microwaveassisted intramolecular Friedel-Crafts acylation catalyzed by metal triflate in triflate-anion containing ionic liquids. This synthesis proceeded with the goals of green chemistry and allowed to obtain 1-indanones in good yields. Moreover, the metal triflate could be recovered and reused without loss of catalytic activity.
Indatraline that blocks the action of cocaine contains moieties having antidepressant, antihistamine and blood pressurelowering properties. Yun et al. [23] have developed a new method for the synthesis of pure indatraline ((−)-29) in a sequence of reactions starting from carboxylic acid 27 (Scheme 10).

From acid chlorides:
The first synthesis of unsubstituted 1-indanone (2), obtained from the reaction of phenylpropionic acid chloride with aluminum chloride in benzene (90% yield), has been published in 1927 [24]. In the same year, Mayer and Müller have described a cyclization of unsaturated ketones with acid chlorides leading to the formation of 1-indanones [25].
The use of other acidic catalysts, like ZnBr 2 or Nafion ® -H also led to the formation of 1-indanones [26,27]. Thus, treatment of the acid chloride 30 with Nafion ® -H in refluxing benzene gave unsubstituted 1-indanone (2) in 90% yield (Scheme 11). In the reaction described above, acid chloride groups reacted with free sulfonic acid groups of Nafion ® -H to generate in situ highly Scheme 12: Synthesis of the mechanism-based inhibitors 33 of coelenterazine. reactive mixed anhydrides which cyclized to produce cyclic ketones. In order to complete the catalytic cycle, Nafion ® -H was regenerated in the acylation step. Investigation of luminescence is a source of valuable information in modern molecular biology, immunology and embryology. An example of a bioluminescent molecule is coelenterazine (luciferin) of which three inhibitors containing an 1-indanone core 33 have been synthesized to follow the bioluminescence reaction mechanism [28]. The intramolecular Friedel-Crafts acylation of 3-arylpropionic acid derivative 31 followed by conversion of the acid to the corresponding acyl chloride with thionyl chloride, led to the formation of 1-indanone 32 which was further transformed into the desired inhibitors 33 (Scheme 12).
Adrenergic receptors are metabotropic receptors located on cell membranes and stimulated by catecholamines, especially adrenaline and noradrenaline. A new method for the synthesis of the indane 2-imidazole derivative 37 acting as a strong adrenergic receptor agonist has been proposed by Roberts et al. [30]. In this synthesis, the diacid 34 was converted to 1-indanone 36 via the AlCl 3 promoted Friedel-Crafts acylation of the acid dichloride 35. Then, in a sequence of reactions, the 1-indanone 36 was transformed to 37 (Scheme 13).
Kabdulov, Amsharov and Jansen have proposed a methodology for the synthesis of fluorinated polyaromatic hydrocarbons (PAH's) via the 1-indanone intermediates 40 [31]. In this synthesis, acids 38 have been transformed to the corresponding acid chlorides 39, followed by an intramolecular Friedel-Crafts acylation in the presence of AlCl 3 in dichloromethane to give the corresponding 1-indanones 40. The latter were cyclized using TiCl 4 in o-dichlorobenzene to fluorinated PAHs 41 (Scheme 14).

From esters and diesters:
In 1951, Gilmore has demonstrated that use of esters, rather than free arylpropionic acids in phosphoric acid, in the presence of phosphorus pentoxide also led to 1-indanones in equally good or even better yields [32].
Transition metal complexes have been used by Negishi et al. as catalysts in the carbonylative cyclization reaction of carboxylic acid methyl and ethyl esters 42 which led to the formation of 1-indanones 43 [33]. This reaction was carried out in acetonitrile, in the presence of triethylamine, under carbon monoxide atmosphere, achieving efficiency in the range of 88-92%, when using lithium, nickel and palladium catalysts (Scheme 15). A general mechanism illustrating the role of transition metal complexes and CO in this reaction is shown in Scheme 15.
Cyclic esters were also used in the syntheses of 1-indanones. Thus, by adding β-propiolactone to aluminum chloride in benzene, 1-indanone has been obtained in 80% yield. Interestingly, when aluminum chloride was added to the lactone in benzene, the yield of this reaction decreased (30%) [34].
A new route for the synthesis of an anticancer agent, benzopyronaphthoquinone 51 from the spiroindanone 50 has been proposed by Estévez et al. [38]. Thus, starting from 2,2-disubstituted-1-indanone 49, the spiro-1-indanone 50 was formed via cyclization using HBr/AcOH and next converted in a sequence of reactions to the biologically active benzopyronaphthoquinone 51 (Scheme 18).
Endothelins are 21-amino acid peptides with vasoconstrictor properties, produced primarily in the endothelium. They play a key role in vascular homeostasis and are responsible for proper vascular tone and vascular perfusion maintaining. In 2006, Miyaura et al. have synthesized selective endothelin A receptor antagonists 55 via a formal 1,4-addition of arylboronic acids to β-aryl-α,β-unsaturated ketones and esters [39]. Thus, the α,βunsaturated diester 52 was coupled with arylboronic acid in the presence of rhodium(I)/Chiraphos ® complex as a catalyst to obtain derivative 53, which next underwent a Claisen condensation to form 1-indanone 54. The latter was further used as a substrate for the synthesis of selective endothelin A receptor antagonist 55 (Scheme 19).
A simple and efficient synthesis of 1-indanones 60 from methyl vinyl ketone (57) has been proposed by Felpin et al. [40]. In this synthesis, the authors have applied a Heck-reduction-cyclization-alkylation (HRCA) methodology under mild and simple reaction conditions. First, diazonium salts 56 underwent the Heck reaction with methyl vinyl ketone (57) to give the crosscoupling products 58 followed by hydrogenation of the latter to give aromatic ketoesters 59. The base-mediated cyclization of the latter in the presence of sodium ethoxide led to the formation of the corresponding 1-indanone anions α to carbonyl, which next were alkylated to give 2-substituted 1-indanones 60 (Scheme 20). This one-pot process utilizing a multi-task palladium catalyst allowed the synthesis of 60 in yields ranged from 31 to 56%.
1-Indanones exhibit a broad spectrum of biological activity including anti-inflammatory [41], analgesic [42], antimicrobial [43], antiviral [5], anticancer [44] and antimalarial [45] activity. A combination of two or more biologically active moieties may increase or decrease the biological activity. A series of isoxa- zole fused 1-indanones 64 with increased anti-inflammatory and antimicrobial activity has been synthesized by Giles et al. [46]. In this synthesis, diethyl phthalate (61) was reacted with ethyl acetate to obtain indane-1,3-dione (62), followed by a Knoevenagel condensation with a variety aromatic aldehydes to give chalcone derivatives 63 (Scheme 21). The reaction of the latter with hydroxylamine hydrochloride, followed by intramolecular 1,4-addition gave 1-indanone derivatives 64a-l which were further tested for in vitro antibacterial activity against Escherichia coli and Bacillus subtilis, and antifungal activity against Aspergillus niger and Penicillium notatum. Among the synthesized series of 1-indanone derivatives 64, the highest antibacterial activity was exhibited by derivatives 64k and 64l, whereas the most potent antifungal activity was revealed for derivatives 64h and 64j. The authors have also studied anti-inflammatory properties of these derivatives using the carrageenan induced paw edema method in rats. The anti-inflammatory activity of the synthesized compounds was com- pared with standard indomethacin (a non-steroidal anti-inflammatory drug used in rheumatoid arthritis treatment). 1-Indanone derivatives 64k, 64j, 64f, 64g and 64i exhibited a stronger inhibition of the paw edema than indomethacin.
Another example of the 1-indanone synthesis using N-heterocyclic carbenes (NHC) has been described by Gravel et al. [50,51]. The benefit of the described reaction was a rapid construction of three new carbon-carbon bonds and a carbon quaternary center with high diastereoselectivity as a consequence of the Stetter-Aldol-Aldol (SAA) reaction sequence. gave the β-hydroxy ketone 82, which was deprotonated to enolate 83. The latter underwent a Michael cyclization reaction to afford 84. Finally, dehydratation of 84 gave the spiro bisindane product 85 (Scheme 27).
A new method to synthesize 2-benzylidene-1-indanone derivatives 88a-d has been proposed in 2014 by Álvarez-Toledano et al. [52]. These derivatives were obtained from the reaction of o-phthalaldehyde (86) with acetophenone 87 (Scheme 28). Iron(III) complexes of 88a-d turned out to be promising candidates for potential photovoltaic or luminescence applications.
An intramolecular hydroacylation, catalyzed by nickel(0)/Nheterocyclic carbenes leading to the formation of a variety of 1-indanones and 1-tetralones has been proposed by Ogoshi et al. [53]. Thus, hydroacylation of o-allylbenzaldehyde derivatives 89 in the presence of [Ni(cod) 2 ] and the N-heterocyclic carbene with an It-Bu substituent gave 1-indanones 90a-i in high yields (Scheme 29). In the case of 90, it has been proved that this reaction proceeds with participation of Ni-complex 91 isolated in 83% yield which next was converted to 1-indanone 90a via the monomeric complex 92 or its dimer.
o-Bromobenzaldehyde 93, in the presence of a palladium catalyst, underwent intermolecular carbopalladation with alkynes 94, followed by intramolecular nucleophilic vinylpalladation to give indenol derivatives 95 [54]. Further heating of 95 led to isomerization of the double bond to give the corresponding 1-indanones 96 (Scheme 30).

From 1,3-dienones:
The major role in the synthesis of 1-indanones plays the Nazarov reaction of 1,3-dienones in which one of two double bonds is derived from the aromatic system. Nakiterpiosin (117) is a marine sponge metabolite which demonstrates a potent cytotoxicity against the P388 leukemic cell line. The photo-variant of the Nazarov cyclization has been applied as one of the steps in the total synthesis of nakiterpiosin (117, Scheme 37) [63]. Starting from substrate 115, 1-indanone 116 was isolated in 60% yield and further used in the synthesis of the natural product.
Hexamethylenetetramine (HMTA) is a commonly used promoter of aryl alkyl ketones in the Mannich reaction which has been applied in the synthesis of α,β-unsaturated ketones 119 [64]. The HMTA/acetic anhydride-promoted α-methylenation of compounds 118 followed by cyclization of the resulting enones 119 allowed to obtain a series of 2-alkyl-1-indanones 120 in very good yields (Scheme 38).
An efficient microwave-assisted synthesis of 1-indanones 132a-s related to combretastatin A-4 has been proposed by Lawrence et al. [68]. Two of the indanones were obtained via a Nazarov cyclization of chalcones 131 without using microwaves, in the presence of trifluoroacetic acid (TFA) at 120 °C (4 hours). The authors have proved that the microwave heating would significantly shorten the reaction time up to 20 minutes under the same reaction conditions (TFA, 120 °C, Scheme 42). The cell growth inhibitory properties of the synthesized 1-indanones 132a-s were also investigated on the K562 human chronic myelogenous leukaemia cell line. The strongest cytotoxicity against the K562 cell line showed the following com- pounds: 132a, 132b, 132d, 132f, 132g, 132i, 132k, 132m [69]. They synthesized a series of the Nazarov substrates 133 with electron-donating substituents at C-2 and electron-withdrawing substituents at C-4. By using catalytic amounts of Cu(OTf) 2 or Cu(ClO 4 ) 2 as Lewis acids, cyclic products 134-137 have been obtained as single diastereoisomers in high yields (Figure 3). It has been proven that the reactivity and the selectivity of this cyclization can be controlled by positioning of the dienone 133 substituents. In the previous studies of the reductive Nazarov cyclization, similar results were obtained -two E and Z dienone isomers were converted into one diastereoisomeric product [70,71].
A dicationic iridium(III)-catalyzed Nazarov cyclization has been applied for the synthesis of functionalized 1-indanones and their heteroatom analogues 138-142 which may be further converted into biologically active compounds (Figure 4) [72]. Products 138-142 were obtained by electrocyclization of the sub-   strates substituted by electron-withdrawing groups, such as CO 2 Me, P(O)(OEt) 2 , CN or NO 2 . This reaction was carried out in the presence of an iridium catalyst and antimony hexafluoride (AgSbF 6 ) under mild conditions. The starting chalcones were almost completely converted into 1-indanones 138-142 and isolated in very good yields.
Photochemical reactions play an important role in the synthesis of 1-indanone derivatives. Thus, photolysis of the ketone 149 gave the 1-indanone 150 in 94% yield. It is worth mentioning that photolysis of the ketone 151a did not lead to the formation of 1-indanone 152 corresponding to 150 but led to the derivative 153a (Scheme 44) [74].
The Nazarov-type cyclization has been proposed for the synthesis of polysubstituted-1-indanones 155a-m, and 157a-l [75]. They were obtained from 1,4-enediones 154 and aryl vinyl β-ketoesters 156 in the presence of AlCl 3 as a promoter, in high yields (up to 99%) (Scheme 45). It was further proved that the pattern of substituents at C-2, C-4 and C-5 positions was essential for the reaction efficiency.

From alcohols
An interesting synthesis of optically active 1-indanones 159a-g by a rhodium-catalyzed isomerization of racemic α-arylpropargyl alcohols 158 has been developed by Shintani, Okamoto and Hayashi (Scheme 46) [76]. By the mechanistic investigations using deuterium-labeled substrates, the authors have disclosed that the methine proton of the alcohol goes to the β-position of the 1-indanone, while the ortho-proton of the phenyl group is shifted to the α-position. The same research group has proposed another asymmetric isomerization of racemic alcohols 161 leading to the formation of 1-indanones 162 [77]. In this reaction, β-chiral 1-indanones 162 were obtained by isomerization of racemic α-arylpropargyl alcohols 161 in the presence of a rhodium catalyst. A high enan-tioselectivity has been achieved by the use of the chiral bisphosphine ligand (R,R)-160 (Scheme 47). A catalytic cycle of this isomerization is shown in Scheme 48. First, alkoxorhodium 163, next alkenylrhodium 165 were formed as intermediates as a result of dehydration and β-H elimination followed by  hydrorhodation, respectively. Then, rhodium 1,4-migration, alkylrhodation and finally rhodium elimination led to 1-indanones 162 via intermediates 166 and 167.
Abicoviromycin (168) is an antiviral and antifungal molecule produced by bacteria. Because of its interesting biological activity, Mitchell and Liebeskind have decided to synthesize abicoviromycin (168) derivatives [78]. In spite of the potent biological activity, abicoviromycin (168) is extremely heat-and acid-sensitive. Moreover, this compound polymerizes rapidly even at low temperatures, such as −50 °C. Therefore, until 1989 abicoviromycin (168) has not been successfully synthesized. The unit which probably determines the reactivity and unstability of abicoviromycin (168) is the diene-imine fragment. Due this fact, the authors have decided to replace the double bond at the 6,7 position by the benzene ring in the new abicoviromycin derivative 169 to increase the stability while still retaining the biological activity ( Figure 5). Thus, the palladium-catalyzed ring expansion of 2-alkynyl-2-hydroxybenzocyclobutenone 170 allowed to obtain alkylidenoindanedione intermediate 171, which was further converted into racemic benzoabicoviromycin 172 (Scheme 49). The racemic benzoabicoviromycin 172 as well as its (Z)-ethylidene stereoisomer have been screened for in vitro biological activity (antiviral, anticancer and antifungal). The significant in vitro cytotoxicity was observed against the following cell lines: A549 (IC 50 : 5.48-5.01 mg/mL), A549/VP (IC 50 : 4.76-4.18 mg/mL), B16-PRIM (IC 50 : 0.16 mg/ mL), HCT116 (IC 50 : 1.47-141 mg/mL), HCT/VP35 (IC 50 : 1.26-1.16 mg/mL). Unfortunately, these levels of activity turned out to be useless in vivo. However, considering the enormous potential of abicoviromycin, syntheses of its additional analogs are reasonable. The same reaction sequence involving the Friedel-Crafts acylation of disubstituted benzene derivatives 177 with 3-chloropropionyl chloride 174 followed by a intramolecular Friedel-Crafts alkylation afforded 1-indanones 178 (Scheme 51) [80]. A direct reaction of the latter with n-butylnitrite led to the formation of keto-oximes 179 which underwent a Pd/C catalytic reduction to give 2-amino substituted 1-indanones 180. Both keto-oximes 179 and 2-amino derivatives 180 are β 2 -adrenergic agonists tested for bronchodilating activity. The pterosin family are sesquiterpenoids naturally occurring in bracken fern (Pteridium aquilinum), some of them exhibit antibacterial and cytotoxic activity. A practical synthesis of pterosin A (186), being a 1-indanone derivative, has been proposed by Uang et al. [81]. In this synthesis, 3-chloropropionyl chloride (174) reacted with 2-bromo-1,3-dimethylbenzene (181) in the presence of AlCl 3 to give two isomeric products 182 and 183. The mixture of 182 and 183 was heated with concentrated H 2 SO 4 at 90 °C to form the corresponding 1-indanones 184 and 185 (in 39% and 40% yield, respectively). The 1-indanone 184 was converted to pterosin A (186) in a sequence of reactions (Scheme 52).

From nitriles
Nitrile derivatives are also useful substrates for the synthesis of 1-indanones. An efficient synthesis of 1-indanones 194 via palladium-catalyzed cyclization of 3-(2-iodoaryl)propanenitriles 193 has been described by Pletnev and Larock [84]. This reaction was compatible with a wide variety of electron-donor Atipamezole is a synthetic α 2 -adrenergic receptor antagonist used in veterinary for reversal of the sedative and analgesic effects induced by α 2 -adrenergic receptor agonists. Vacher et al. synthesized α 2 -adrenergic receptor antagonists, potentially more selective than known compounds [87]. Transformation of diazo compounds 209 into 1-indanone derivatives 210, catalyzed by rhodium acetate, has been one of the steps in the total synthesis of atipamezole analogues 211 (Scheme 58).
The most common symptom of the menopause is hot flash, which is characterized by sweating, sudden feeling of heat, palpitation or anxiety. Hormone replacement therapy (HRT) alleviates above mentioned symptoms but its use has been limited because of many side effects, such as increased hormone-dependent cancers risk. Watanabe et al. have synthesized a selective estrogen receptor modulator, 3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (216) which may be used for a new treatment of hot flush [88]. In this synthesis, the reaction of 5-methoxyindan-1one (212) with the Grignard reagent 217 followed by acid-catalyzed dehydration and hydrogenolysis of the resulting double bond with Pd(OH) 2 /C, gave benzoic acid 213. Next, the latter was converted to α-diazo-β-keto ester 214 which then was

From epoxides and cyclopropanes
The chalcone epoxides 221 ring opening catalyzed by indium(III) chloride, followed by a intramolecular Friedel-Crafts alkylation has been used by Ahmed  best yields (up to 84%) were achieved by using substrates 226 with electron-acceptor substituents at the para position of the aryl group.
A new method for the synthesis of optically active α-hydroxy ketones by asymmetric oxidation of the enol phosphates catalyzed by Sharpless reagents or chiral dioxirane has been pro-posed by Krawczyk et al. [93]. For example, optically active 1-indanone 230 was obtained from the cyclic enol phosphate 228 which next was reacted with a fructose-derived dioxirane 232 generated in situ from the ketone 231, to provide the epoxide 229 (Scheme 64). Then, the latter was hydrolyzed with CF 3 C(O)OH in Et 2 O/H 2 O at 0 °C to obtain optically active 1-indanone 230.
A very interesting approach for the synthesis of 1-indanones 234 based on the rearrangement of cyclopropanol derivatives 233, has been reported in 2012 by Rosa and Orellana [94]. This reaction was carried out in the presence of palladium catalyst and gaseous oxygen as the terminal oxidant (Scheme 65).

Construction of the 6-membered ring
The titles of subsections in this chapter contain names of the 1-indanone precursors which provide the biggest number of carbon atoms during the synthesis of the 1-indanone benzene ring.
For instance, 1,3-dienes in the Diels-Alder reaction provide 4 carbon atoms of the six ones needed to construct the benzene ring of 1-indanone compared to dienophiles which deliver only two of them. as starting compounds [96]. 7-Methyl substituted 1-indanone 241 has been obtained in the Diels-Alder reaction between 1,3pentadiene (238) and 2-cyclopentenone (239) followed by the oxidative aromatization with Pd/C (Scheme 67). The latter was further used as a substrate for the synthesis of bisoxazolidine ligand 242. The same Diels-Alder reaction to obtain 241 has been used by Katsumura et al. [97]. In this case, 241 was further converted to cis-1-amino-7-methyl-2-indanol (243, Scheme 67).
The Diels-Alder reaction of 262 and phenylselenyl-substituted cyclopentenone 269 was less effective and gave 1-indanone 265 in 28% yield only (Scheme 75) [102]. Another example of this reaction catalyzed by a Lewis acid has also been reported [104]. The flash vacuum pyrolysis has been applied for aromatization of 271 to afford 1-indanone 272 in 76% yield. The former 271 was obtained from the trienone 270/270' which underwent ring closure to give the 6-membered ring [105] (Scheme 76).

From alkynes
DBU and CpRu(PPh 3 ) 2 Cl dual catalysts enabled a one-pot annulation of aldehyde 273 and cyclopentanone (274) to give the 1-indanone derivative 276 [106]. The new catalytic reaction which replaced a previously described four-step synthesis [107], involved a tandem aldol condensation/dehydration and cyclization of the intermediate 275 to 276 (Scheme 77). In 1999, Ikeda and Mori have presented a cyclotrimerization of enones (e.g., cyclopentenone 239) with alkynes in the presence of nickel and aluminum complexes [108]. This [2 + 2 + 2] cycloaddition run with a high regioselectivity and led mostly to meta isomers. The authors used, as catalytic systems, the following complexes: Ni(acac) 2 , Ni(cod) 2 , Me 3 Al, Me 2 Al(OPh), MeAl(OPh) 2 and Al(OPh) 3 . In 2000, Ikeda and Kondo have continued their studies on regioselectivity of the cyclotrimerization [109] and investigated the effects of various ligands (L) on regioselectivity and yields of this reaction (Scheme 78). In case of application of triarylphosphines (Ph 3 P and (o-MeC 6 H 4 ) 3 P) as ligands, only para isomers 279 were formed in moderate 33% and 49% yields, respectively. On the contrary, when oxazolines 280 or 281 were used as ligands, mainly meta isomers 278 were formed with high yields.

From other compounds
Albrecht, Defoin and Siret have synthesized benz[f]indan-1-one (295) from the anthracene epidioxide 292, which underwent thermal isomerization to give the reactive intermediate 293 [114]. As a result of the Diels-Alder reaction of the latter with cyclopentenone 239, the adduct 294 was formed, which was further subjected to the TEA-induced cleavage at 100 °C to give the desired 1-indanone 295 (Scheme 82). (298) and cyclopentynone 297 generated from the phosphorane 296 by the intramolecular Wittig reaction (Scheme 83) [115].

.1 From alkynes
The intramolecular, dehydro-Diels-Alder reaction of ketene dithioacetals 302 leading to formation of various benzo[f]-1indanones 303-305, has been described in 2015 by Bi et al. [117]. Modulation on the reaction parameters such as addition of DBU and the type of atmospheric gas used (O 2 , N 2 ), regulated the regioselective formation of the 1-indanones 303-305 (Scheme 85).
A new, simple approach for the synthesis of natural and unnatural 1-indanones 309-316 has been proposed by Deiters et al. [118]. The key step of this synthesis was associated with [2 + 2 + 2] cyclotrimerization of the dialkyne 306 with variously disubstituted alkynes 307 performed on a solid phase Tenta-Gel ® resin (0.25 mmol/g) in the presence of Ru catalyst (Scheme 86). In case of 309-316, this reaction led to the formation of mixtures of two regioisomers. The examined regioisomeric ratios (a/b) were ranged from 1:2 to 2:3 with a preference to 310a-315a regioisomers.
An interesting approach to the synthesis of 1-indanones and 1-indenones is based on the hexadehydro-Diels-Alder (HDDA) reaction in which an alkyne reacts in the [4 + 2] cycloaddition with diyne and forms a reactive benzyne species as a precursor of the benzene ring (Scheme 87).
This methodology has been applied in the synthesis of 1-indanones (Scheme 88 and Scheme 89).
In 2012, Hoye et al. have presented the synthesis of 1-indenone 318 via a hexadehydro-Diels-Alder (HDDA) reaction with simultaneous formation of five and six-membered rings from the tetrayne 317 (Scheme 88) [119]. In the reaction participates only three triple bonds marked by red lines. This, catalyzed by MnO 2 reaction, is fully regioselective. During the cycloaddition after the formation of the five and six-membered rings, one of the tert-butyldimethylsilyl (TBS) group migrates from an oxygen to the triple bond of benzyne to give 318. In 2014, the authors have shown that the HDDA cyclization of the unsymmetrical substituted ketotetrayne 319 gives a mixture of isomeric 1-indanones 320 and 321 (Scheme 88) [120]. It is the effect of competition between two modes of the cycloaddition reaction. In the "normal" mode of this reaction, cyclization takes place between the triple bond in α,β-position and the diyne in γ',ε'-position to give 320. In the "abnormal" mode, the cyclization takes places between the triple bond in γ'-position and the diyne in α,γ-position to give 321. hydro-Diels-Alder (HDDA) conditions gave the corresponding 1-indanone 323 in 80% yield (Scheme 89).

From furans
Van der Eycken et al. have synthesized 1-indanone 328 by utilizing 2-methylfuran (324) as a starting compound which was converted to the Mannich adduct 325, followed by the anion exchange reaction to give ammonium hydroxide 326 [121]. The latter underwent dimerization to afford the furanocyclophane 327, which was next oxidized with meta-chloroperoxybenzoic acid (m-CPBA), followed by a Diels-Alder reaction and dehydration to obtain 1-indanone 328 in 88% yield (Scheme 90).
In 2003, Hashmi et al. have demonstrated an intramolecular gold catalyzed [4 + 2] cycloaddition of furans 329 with a tethered alkyne moiety [122]. The reaction was regioselective and gave 1-indanones 330 at room temperature, in good yields up to 75%. The second regioisomer was formed only in 3-7% yield (Scheme 91). 7-Hydroxy-6-methylindan-1-one 330 has later been used in the synthesis of natural sesquiterpene, jungianol isolated from Jungia malvaefolia.  4 Functionalization of the 5-or 6-membered ring of 1-indanones or related compounds Another approach to obtain bioactive 1-indanones is their functionalization. In this way, scientists have synthesized C5-and C6-alkoxy and benzyloxy-substituted 1-indanones by the alkylation reaction of 5-hydroxy-1-indanone or 6-hydroxy-1indanone with various alkyl or benzyl bromides. These 1-indanone derivatives are potential inhibitors of two separate isoforms of monoamine oxidases: MAO-A and MAO-B [124]. Monoamine oxidases (MAO) are mitochondrial enzymes that catalyze two-electron oxidation of amine substrates. MAO terminates physiological actions of amine neurotransmitters in brain; therefore, MAO inhibitors have been applied in the treatment of neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. The studies have shown that synthesized C6-substituted 1-indanones are effective and selective MAO-B inhibitors, while C5-substituted 1-indanones are less effective MAO-B inhibitors.

Conclusion
This article is the first comprehensive work reviewing original and patent literature of synthetic methods and biological applications of 1-indanones. It has been shown that these bioactive molecules may be obtained from a variety of starting materials. The commonly used reactions leading to the formation of the title compounds are Nazarov, Knoevenagel, Diels-Alder, and Friedel-Crafts alkylation and acylation reactions. The structural diversity of 1-indanones implies various biological responses and these compounds may be applied in agriculture and medicine. Some of the 1-indanone derivatives may constitute a new hope, as future drugs, for the patients suffering from Alzheimer's and Parkinson's diseases, and those infected with hepatitis C virus. Single applications for organic optoelectronics have also been reported. Due to the wide application potential, 1-indanones are interesting objects for further investigations and it is desirable to design new methods for their synthesis.