Synthesis of 1-Triﬂuorometylindanes and Close Structures: A Mini Review

: This review describes methods for the synthesis of 1-triﬂuomethylindanes and close structures, which are still quite rare and scarcely available compounds. There are two main approaches to obtain 1-CF 3 -indanes. The ﬁrst one is the construction of an indane system from CF 3 precursors; the main methods are acid-mediated Friedel–Crafts cyclization, transition metal-catalyzed [3+2] annulation, and free-radical transformations. The second approach is the triﬂuoromethylation of a ready-made indane core by various CF 3 sources, such as Ruppert–Prakash or Togni reagents. Many of these synthetic procedures possess high regio-and stereo-selectivity, allowing the preparation of unique 1-CF 3 -indane structures. In recent years, great attention has been paid to the synthesis of 1-CF 3 -indanes, due to the discovery of important biologically active properties for these compounds.

One of the most important types of organic compounds is indanes, which possess various valuable practical properties including biological activity. There are several reviews on the synthesis and use of indanes [14][15][16][17][18]. The introduction of a trifluorometyl group CF 3 in the indane core may bring new, important properties for these compounds. For instance, we have recently found that trans-1,3-diaryl-1-trifluoromethyl indanes are very good ligands for cannabinoid receptors of CB 1 and CB 2 types. The most potent compound showed sub-micromolar affinity for both receptor subtypes, with six-fold selectivity toward the CB 2 receptor and with no appreciable cytotoxicity toward SHSY5Y cells (Figure 1) [19]. Apart from this, various 1-CF 3 -substituted indanes have been tested for the inhibition of monoacylglycerol lipase (MAGL) and anandamide (AEA) uptake; the latter can be related to the low-micromolar inhibition of fatty acid amide hydrolase (FAAH) [20].
Thus, 1-trifluoromethyl indanes are extremely promising objects for medicinal chemistry. The development of novel methods of synthesis of CF 3 -indane derivatives and investigation of their biologically active properties is an important goal for chemistry, biology, and medicine. Moreover, these fluorinated derivatives must find broad application in material science and many other fields. However, to the best of our knowledge, CF 3 -indanes are still rare compounds. Their synthesis has not yet been developed. This Organics 2021, 2 349 mini review is focused on current methods of the synthesis of 1-CF 3 -indanes including trifluoromethylatedindanols and indanones to show the main approaches to the preparation of these compounds. Thus, 1-trifluoromethyl indanes are extremely promising objects for medicinal chemistry. The development of novel methods of synthesis of CF3-indane derivatives and investigation of their biologically active properties is an important goal for chemistry, biology, and medicine. Moreover, these fluorinated derivatives must find broad application in material science and many other fields. However, to the best of our knowledge, CF3indanes are still rare compounds. Their synthesis has not yet been developed. This mini review is focused on current methods of the synthesis of 1-CF3-indanes including trifluoromethylatedindanols and indanones to show the main approaches to the preparation of these compounds.

Discussion
One may classify the methods for thesynthesis of trifluoromethylindanes into two main approaches. The first one is the construction of anindane system from CF3precursors, including acid-mediated electrophilic Friedel-Crafts cyclization, transition metal-catalyzed [3+2] annulation, free-radical transformations, and some other procedures. The second approach is thetrifluoromethylation of suitable indane scaffolds or the reduction of trifluoromethylindene compounds. All these methods are considered in this mini review.

2.1.Construction of Trifluoromethylindane Core from CF3Precursors
In this typeof CF3-indane synthesis, one of the most effective methods is electrophilic Friedel-Crafts cyclization with the participation of various aromatic substrates having trifluoromethyl substituents.
One of the first reports in this field was published by Béguéet al.in 1989 [21]. The authors described the cycloalkylation of trifluoromethylated β-phenyl ketones, nonenolizable β-keto esters, and alcohols. In this work, the series of 1-trifluoromethylindanes has been prepared by intramolecular Friedel-Crafts alkylation. The best results have been demonstrated by electrophilic activation of the ketone carbonyl group of CF3-β-keto esters 1a-c under the action of TiCl4 (conditions a) or EtAlCl2 (conditions b), whichgives 1-trifluoromethylindan-1-ols 2a-c in excellent yield and perfect stereoselectivity; only one diastereomer was obtained (Scheme 1).   1 and CB 2 types) ligand properties of the CF 3 -indane (data from ref. [19]).

Discussion
One may classify the methods for the synthesis of trifluoromethyl indanes into two main approaches. The first one is the construction of an indane system from CF 3 precursors, including acid-mediated electrophilic Friedel-Crafts cyclization, transition metal-catalyzed [3+2] annulation, free-radical transformations, and some other procedures. The second approach is thetrifluoromethylation of suitable indane scaffolds or the reduction of trifluoromethylindene compounds. All these methods are considered in this mini review.

Construction of Trifluoromethylindane Core from CF 3 Precursors
In this type of CF 3 -indane synthesis, one of the most effective methods is electrophilic Friedel-Crafts cyclization with the participation of various aromatic substrates having trifluoromethyl substituents.
One of the first reports in this field was published by Béguéet al.in 1989 [21]. The authors described the cycloalkylation of trifluoromethylated β-phenyl ketones, non-enolizable β-keto esters, and alcohols. In this work, the series of 1-trifluoromethylindanes has been prepared by intramolecular Friedel-Crafts alkylation. The best results have been demonstrated by electrophilic activation of the ketone carbonyl group of CF 3 -β-keto esters 1a-c under the action of TiCl 4 (conditions a) or EtAlCl 2 (conditions b), which gives 1-trifluoromethylindan-1-ols 2a-c in excellent yield and perfect stereoselectivity; only one diastereomer was obtained (Scheme 1). Cannabinoid receptor (CB1 and CB2 types) ligand properties of the CF3-indane (data from ref. [19]).
Thus, 1-trifluoromethyl indanes are extremely promising objects for medicinal chemistry. The development of novel methods of synthesis of CF3-indane derivatives and investigation of their biologically active properties is an important goal for chemistry, biology, and medicine. Moreover, these fluorinated derivatives must find broad application in material science and many other fields. However, to the best of our knowledge, CF3indanes are still rare compounds. Their synthesis has not yet been developed. This mini review is focused on current methods of the synthesis of 1-CF3-indanes including trifluoromethylatedindanols and indanones to show the main approaches to the preparation of these compounds.

Discussion
One may classify the methods for thesynthesis of trifluoromethylindanes into two main approaches. The first one is the construction of anindane system from CF3precursors, including acid-mediated electrophilic Friedel-Crafts cyclization, transition metal-catalyzed [3+2] annulation, free-radical transformations, and some other procedures. The second approach is thetrifluoromethylation of suitable indane scaffolds or the reduction of trifluoromethylindene compounds. All these methods are considered in this mini review.

2.1.Construction of Trifluoromethylindane Core from CF3Precursors
In this typeof CF3-indane synthesis, one of the most effective methods is electrophilic Friedel-Crafts cyclization with the participation of various aromatic substrates having trifluoromethyl substituents.
One of the first reports in this field was published by Béguéet al.in 1989 [21]. The authors described the cycloalkylation of trifluoromethylated β-phenyl ketones, nonenolizable β-keto esters, and alcohols. In this work, the series of 1-trifluoromethylindanes has been prepared by intramolecular Friedel-Crafts alkylation. The best results have been demonstrated by electrophilic activation of the ketone carbonyl group of CF3-β-keto esters 1a-c under the action of TiCl4 (conditions a) or EtAlCl2 (conditions b), whichgives 1-trifluoromethylindan-1-ols 2a-c in excellent yield and perfect stereoselectivity; only one diastereomer was obtained (Scheme 1). Apart from this, in the presence of benzene, as a good trap for intermediate cationic species, the Lewis acid AlCl 3 -promoted cycloalkylation of β-phenyl CF 3 -ketone 1d furnishes 1-phenyl-1-trifluoromethylindane 2d in a good yield of 77% (Scheme 2) [21]. Meanwhile, Friedel-Crafts alkylation of tertiary alcohol 1e in Brønsted acids (CF 3 CO 2 H, H 2 SO 4 ) affords compound 2d in a lower yield of 53%.
Later on, the same scientific group developed Lewis acid (TiCl 4 or EtAlCl 2 )-induced ene-cyclization of ω-olefinic CF 3 -ketones into trifluoromethyl carbocycles [22]. However, in this reaction, phenyl substituted substrate 1b gives 1-CF 3 -indanol 2b (see in Scheme 1), rather than the expected cyclopentanes, as products of the cyclization of the carbonyl group onto the alkene bond.
Fruitful CF3precursors for the building of anindane core under electrophilic activation conditions are trifluoromethyl ketones. Thus, CF3-β-diketones bearing trifluoroalkyl or heterocyclic substituents 11a-d in reaction with benzene in neat TfOH give stereoselective 1-CF3-indanes 12a-d having phenyl groups in the cis-position relative to the indane plane [25] (Scheme 7). There is an electrophilic activation of carbonyl carbons in diketones 11a-d due to the protonation of carbonyl oxygens and heteroatoms (for 11c,d) in Brønsted-superacidTfOH. The generated cationic species react, in a cascadingmanner, with three molecules of benzene, leading finally to CF3-indanes 12a-d. The authors have explained the reaction's stereoselectivity by possible cation π-stacking stabilization between phenyl groups in intermediate cations [25]. A similar approach has been used in works [19,26] for the cyclization of CF3-enones, 1,1,1-trifluorobut-3-en-2-ones 13a,b, in their reaction with arenes in TfOH, affording 1,3diaryl-substituted 1-trifluoromethylindanes 14a-g with an exclusively trans-configuration of aryl groups (Scheme 8). Protonation of the enone system of 13a,b may give rise to either monocationic species B1 or dicationsB2, which further interact in two pathways with two molecules of arene, forming indanes14a-g through the intermediate formation of cations Similar cyclization of enantiomeric CF 3 -acid 9 into indanone 10 in TfOH has been described in work [24] (Scheme 6). The starting compound 9 was obtained by rhodium(I)catalyzed asymmetric hydrogenation of the corresponding β-CF 3 -substituted acrylic acid.
Fruitful CF3precursors for the building of anindane core under electrophilic activation conditions are trifluoromethyl ketones. Thus, CF3-β-diketones bearing trifluoroalkyl or heterocyclic substituents 11a-d in reaction with benzene in neat TfOH give stereoselective 1-CF3-indanes 12a-d having phenyl groups in the cis-position relative to the indane plane [25] (Scheme 7). There is an electrophilic activation of carbonyl carbons in diketones 11a-d due to the protonation of carbonyl oxygens and heteroatoms (for 11c,d) in Brønsted-superacidTfOH. The generated cationic species react, in a cascadingmanner, with three molecules of benzene, leading finally to CF3-indanes 12a-d. The authors have explained the reaction's stereoselectivity by possible cation π-stacking stabilization between phenyl groups in intermediate cations [25]. A similar approach has been used in works [19,26] for the cyclization of CF3-enones, 1,1,1-trifluorobut-3-en-2-ones 13a,b, in their reaction with arenes in TfOH, affording 1,3diaryl-substituted 1-trifluoromethylindanes 14a-g with an exclusively trans-configuration of aryl groups (Scheme 8). Protonation of the enone system of 13a,b may give rise to either monocationic species B1 or dicationsB2, which further interact in two pathways with two molecules of arene, forming indanes14a-g through the intermediate formation of cations Scheme 6. Cyclization of CF 3 -acid 9 into CF 3 -indanone 10 in TfOH.
Fruitful CF 3 precursors for the building of an indane core under electrophilic activation conditions are trifluoromethyl ketones. Thus, CF 3 -β-diketones bearing trifluoroalkyl or heterocyclic substituents 11a-d in reaction with benzene in neat TfOH give stereoselective 1-CF 3 -indanes 12a-d having phenyl groups in the cis-position relative to the indane plane [25] (Scheme 7). There is an electrophilic activation of carbonyl carbons in diketones 11a-d due to the protonation of carbonyl oxygens and heteroatoms (for 11c,d) in Brønsted superacid TfOH. The generated cationic species react, in a cascading manner, with three molecules of benzene, leading finally to CF 3 -indanes 12a-d. The authors have explained the reaction's stereoselectivity by possible cation π-stacking stabilization between phenyl groups in intermediate cations [25].
Fruitful CF3precursors for the building of anindane core under electrophilic activation conditions are trifluoromethyl ketones. Thus, CF3-β-diketones bearing trifluoroalkyl or heterocyclic substituents 11a-d in reaction with benzene in neat TfOH give stereoselective 1-CF3-indanes 12a-d having phenyl groups in the cis-position relative to the indane plane [25] (Scheme 7). There is an electrophilic activation of carbonyl carbons in diketones 11a-d due to the protonation of carbonyl oxygens and heteroatoms (for 11c,d) in Brønsted-superacidTfOH. The generated cationic species react, in a cascadingmanner, with three molecules of benzene, leading finally to CF3-indanes 12a-d. The authors have explained the reaction's stereoselectivity by possible cation π-stacking stabilization between phenyl groups in intermediate cations [25].
A similar approach has been used in works [19,26] for the cyclization of CF 3 -enones, 1,1,1-trifluorobut-3-en-2-ones 13a,b, in their reaction with arenes in TfOH, affording 1,3diaryl-substituted 1-trifluoromethylindanes 14a-g with an exclusively trans-configuration of aryl groups (Scheme 8). Protonation of the enone system of 13a,b may give rise to either monocationic species B1 or dications B2, which further interact in two pathways with two molecules of arene, forming indanes 14a-g through the intermediate formation of cations B3 or B4, and C. The excellent stereoselectivity of this reaction may be explained by the intermediate formation of cation C, which reacts with an arene molecule, which gives a more stable trans-orientation of bulky aromatic rings. It should be noted that the high sensitivity to steric effects of substituents in arenes in this transformation results also in the formation of an unexpected product of electrophilic attack to position 5 of m-xylene for compound 14c [19].
Organics2021, 2, FOR PEER REVIEW 5 B3 or B4, and C. The excellent stereoselectivity of this reaction may be explained by the intermediate formation of cation C, which reacts with an arene molecule, whichgives a more stable trans-orientation of bulky aromatic rings. It should be noted that the high sensitivity to steric effects of substituents in arenes in this transformation results also in the formation of an unexpected product of electrophilic attack to position 5 of m-xylene for compound 14c [19].  Running this reaction in another Brønstedsuperacid FSO3H at a low temperature of−60 °C for enone13c and benzene, the authors have been able to obtain intermediate ketone 15, as a product of the initial addition of benzene to the double carbon-carbon bond (Scheme 9) [19]. Then, compound 15 is cyclized into 1-CF3-indane 14h in reaction with benzene in TfOH at room temperature. The cyclization results in a more nucleophilic methoxy-substituted aromatic ring; the same regioselectivityis observed upon the formation of indane14i from enone13d.
It has been found that these diaryl-substituted trans-1-CF3-indanes 14 show high activity towards cannabinoid receptors of CB1 and CB2 types [19] (see Introduction). Under similar superelectrophilic activation conditions in TfOH, bromo-substituted CF3-enone 13e in reaction with benzene is stereoselectively transformed into 1-CF3-bromoindane 14j in moderate yield (Scheme 10) [27]. Running this reaction in another Brønsted superacid FSO 3 H at a low temperature of−60 • C for enone 13c and benzene, the authors have been able to obtain intermediate ketone 15, as a product of the initial addition of benzene to the double carbon-carbon bond (Scheme 9) [19]. Then, compound 15 is cyclized into 1-CF 3 -indane 14h in reaction with benzene in TfOH at room temperature. The cyclization results in a more nucleophilic methoxy-substituted aromatic ring; the same regioselectivityis observed upon the formation of indane 14i from enone 13d. B3 or B4, and C. The excellent stereoselectivity of this reaction may be explained by the intermediate formation of cation C, which reacts with an arene molecule, whichgives a more stable trans-orientation of bulky aromatic rings. It should be noted that the high sensitivity to steric effects of substituents in arenes in this transformation results also in the formation of an unexpected product of electrophilic attack to position 5 of m-xylene for compound 14c [19].  Running this reaction in another Brønstedsuperacid FSO3H at a low temperature of−60 °C for enone13c and benzene, the authors have been able to obtain intermediate ketone 15, as a product of the initial addition of benzene to the double carbon-carbon bond (Scheme 9) [19]. Then, compound 15 is cyclized into 1-CF3-indane 14h in reaction with benzene in TfOH at room temperature. The cyclization results in a more nucleophilic methoxy-substituted aromatic ring; the same regioselectivityis observed upon the formation of indane14i from enone13d.
In the series of papers [19,[28][29][30], it has been demonstrated that trifluoromethylatedallyl alcohols and their trimethylsilyl (TMS) ethers are good precursors for the preparation of 1-CF 3 -indanes. The protonation of oxygen of CF 3 -allyl alcohols with Brønsted acid or coordination of oxygen with Lewis acid gives rise to species D; dehydroxylation of the latter affords CF 3 -allyl cations E, having two resonance forms E and E , with electrophilic centers on the ends of the allylic system. Both species D and E (E ↔E ) may take part in interaction with aromatic nucleophiles, which depends on substituents in species D and E and the nucleophilicity of arenes (Scheme 11). In the series of papers [19,[28][29][30], it has been demonstrated that trifluoromethylatedallyl alcohols and their trimethylsilyl (TMS) ethers are good precursors for the preparation of 1-CF3-indanes. The protonation of oxygen of CF3-allyl alcohols with Brønsted acid or coordination of oxygen with Lewis acid gives rise to species D;dehydroxylation of the latter affords CF3-allyl cations E, having two resonance forms E′ and E″, with electrophilic centers on the ends of the allylic system. Both species D and E (E′↔E″) may take part in interaction with aromatic nucleophiles, whichdepends on substituents in species D and E and the nucleophilicity of arenes (Scheme 11). Thus, the reaction of CF3-allyl alcohols 17 with electron-donating arenes under the action of Lewis acid FeCl3 at room temperature or Brønstedsuperacid FSO3H at -75 o C can be used to obtain monoarylatedtrifluoromethylindanes18a-h (Scheme 12) [28]. Reactions with p-xylene and pseudocumene demonstrate high stereoselectivity, affording only cis-CF3-indanes 18a-h. More striking results are obtained for the reactions with pseudocumene, leading to 50-76% yields of target products. However, the interaction with p-xylene gives alkenes [Ar(2,5-Me2C6H3)CHCH=CHCF3] as major products.  In the series of papers [19,[28][29][30], it has been demonstrated that trifluoromethylatedallyl alcohols and their trimethylsilyl (TMS) ethers are good precursors for the preparation of 1-CF3-indanes. The protonation of oxygen of CF3-allyl alcohols with Brønsted acid or coordination of oxygen with Lewis acid gives rise to species D;dehydroxylation of the latter affords CF3-allyl cations E, having two resonance forms E′ and E″, with electrophilic centers on the ends of the allylic system. Both species D and E (E′↔E″) may take part in interaction with aromatic nucleophiles, whichdepends on substituents in species D and E and the nucleophilicity of arenes (Scheme 11). Thus, the reaction of CF3-allyl alcohols 17 with electron-donating arenes under the action of Lewis acid FeCl3 at room temperature or Brønstedsuperacid FSO3H at -75 o C can be used to obtain monoarylatedtrifluoromethylindanes18a-h (Scheme 12) [28]. Reactions with p-xylene and pseudocumene demonstrate high stereoselectivity, affording only cis-CF3-indanes 18a-h. More striking results are obtained for the reactions with pseudocumene, leading to 50-76% yields of target products. However, the interaction with p-xylene gives alkenes [Ar(2,5-Me2C6H3)CHCH=CHCF3] as major products. Thus, the reaction of CF 3 -allyl alcohols 17 with electron-donating arenes under the action of Lewis acid FeCl 3 at room temperature or Brønsted superacid FSO 3 H at −75 • C can be used to obtain monoarylatedtrifluoromethylindanes 18a-h (Scheme 12) [28]. Reactions with p-xylene and pseudocumene demonstrate high stereoselectivity, affording only cis-CF 3 -indanes 18a-h. More striking results are obtained for the reactions with pseudocumene, leading to 50-76% yields of target products. However, the interaction with p-xylene gives alkenes [Ar(2,5-Me 2 C 6 H 3 )CHCH=CHCF 3 ] as major products. In the series of papers [19,[28][29][30], it has been demonstrated that trifluoromethylatedallyl alcohols and their trimethylsilyl (TMS) ethers are good precursors for the preparation of 1-CF3-indanes. The protonation of oxygen of CF3-allyl alcohols with Brønsted acid or coordination of oxygen with Lewis acid gives rise to species D;dehydroxylation of the latter affords CF3-allyl cations E, having two resonance forms E′ and E″, with electrophilic centers on the ends of the allylic system. Both species D and E (E′↔E″) may take part in interaction with aromatic nucleophiles, whichdepends on substituents in species D and E and the nucleophilicity of arenes (Scheme 11). Thus, the reaction of CF3-allyl alcohols 17 with electron-donating arenes under the action of Lewis acid FeCl3 at room temperature or Brønstedsuperacid FSO3H at -75 o C can be used to obtain monoarylatedtrifluoromethylindanes18a-h (Scheme 12) [28]. Reactions with p-xylene and pseudocumene demonstrate high stereoselectivity, affording only cis-CF3-indanes 18a-h. More striking results are obtained for the reactions with pseudocumene, leading to 50-76% yields of target products. However, the interaction with p-xylene gives alkenes [Ar(2,5-Me2C6H3)CHCH=CHCF3] as major products. The use of mesitylene results in the formation of the same indanes 18a-d (Scheme 13), as in the case of pseudocumene (Scheme 12), due to the methyl group shift during the electrophilic aromatic substitution step. However, both the yields of the target reaction products and stereoselectivity are lower compared to the reaction with pseudocumene (compare Schemes 12 and 13). The formation of a cis-/trans-isomeric mixture for indane 18i is also observed in reaction with m-xylene (Scheme 13) [28].
Organics2021, 2, FOR PEER REVIEW 7 ucts and stereoselectivity are lower compared to the reaction with pseudocumene (compare Schemes 12 and 13). The formation of a cis-/trans-isomeric mixture for indane18i is also observed in reaction with m-xylene (Scheme 13) [28]. A plausible mechanism of Brønsted or Lewis acid-promoted formation of 1-CF3-indanes 18 from CF3-allyl alcohols 17 and arenes includes theinitial generation of species D (Scheme 14). The latter possesses a sufficientlyelectrophilic reactive center on allylic carbon to interact with polymethylatedπ-donating arenes, giving alkenes F, which are protonated to form cations G. Cyclization of the latter furnishes finally indanes18 [28]. The same approach of superelectrophilic activation of TMS-ethers of diaryl-substituted CF3-allyl alcohols 19 in TfOH has been applied in the synthesis of 1-CF3-indanes 20 (Scheme 15) [29]. This reaction has been studied for a broad series of starting alcohols 19. The reaction proceeds very rapidly, within just 5 min, at room temperature, and leads mainly to indanes20 with trans-configuration of aryl groups in high yields. At the first stage of this transformation, there is an intermediate generation of allylcationH↔H′, which is cyclized into indene I. Protonation of the latter gives rise to cation J, which reacts with the arene, forming 1-CF3-indane 20. The predominant formation of trans-indanes 20 is probably explained by sterical hindrance between aryl moieties Ar′ and Ar″at the last stage of the reaction (Scheme 15) [29].
Apart from this, the TfOH-promoted reaction of TMS-ethers 19 and their corresponding alcohols with arenes havebeen used for the stereoselective synthesis of several trans-1-CF3-indanes 20 to study their biologically active properties [20] (see Introduction). A plausible mechanism of Brønsted or Lewis acid-promoted formation of 1-CF 3indanes 18 from CF 3 -allyl alcohols 17 and arenes includes the initial generation of species D (Scheme 14). The latter possesses a sufficiently electrophilic reactive center on allylic carbon to interact with polymethylatedπ-donating arenes, giving alkenes F, which are protonated to form cations G. Cyclization of the latter furnishes finally indanes 18 [28].
Organics2021, 2, FOR PEER REVIEW 7 ucts and stereoselectivity are lower compared to the reaction with pseudocumene (compare Schemes 12 and 13). The formation of a cis-/trans-isomeric mixture for indane18i is also observed in reaction with m-xylene (Scheme 13) [28]. A plausible mechanism of Brønsted or Lewis acid-promoted formation of 1-CF3-indanes 18 from CF3-allyl alcohols 17 and arenes includes theinitial generation of species D (Scheme 14). The latter possesses a sufficientlyelectrophilic reactive center on allylic carbon to interact with polymethylatedπ-donating arenes, giving alkenes F, which are protonated to form cations G. Cyclization of the latter furnishes finally indanes18 [28]. The same approach of superelectrophilic activation of TMS-ethers of diaryl-substituted CF3-allyl alcohols 19 in TfOH has been applied in the synthesis of 1-CF3-indanes 20 (Scheme 15) [29]. This reaction has been studied for a broad series of starting alcohols 19. The reaction proceeds very rapidly, within just 5 min, at room temperature, and leads mainly to indanes20 with trans-configuration of aryl groups in high yields. At the first stage of this transformation, there is an intermediate generation of allylcationH↔H′, which is cyclized into indene I. Protonation of the latter gives rise to cation J, which reacts with the arene, forming 1-CF3-indane 20. The predominant formation of trans-indanes 20 is probably explained by sterical hindrance between aryl moieties Ar′ and Ar″at the last stage of the reaction (Scheme 15) [29].
Apart from this, the TfOH-promoted reaction of TMS-ethers 19 and their corresponding alcohols with arenes havebeen used for the stereoselective synthesis of several trans-1-CF3-indanes 20 to study their biologically active properties [20] (see Introduction).
The same approach of superelectrophilic activation of TMS-ethers of diaryl-substituted CF 3 -allyl alcohols 19 in TfOH has been applied in the synthesis of 1-CF 3 -indanes 20 (Scheme 15) [29]. This reaction has been studied for a broad series of starting alcohols 19. The reaction proceeds very rapidly, within just 5 min, at room temperature, and leads mainly to indanes 20 with trans-configuration of aryl groups in high yields. At the first stage of this transformation, there is an intermediate generation of allyl cation H↔H , which is cyclized into indene I. Protonation of the latter gives rise to cation J, which reacts with the arene, forming 1-CF 3 -indane 20. The predominant formation of trans-indanes 20 is probably explained by sterical hindrance between aryl moieties Ar and Ar" at the last stage of the reaction (Scheme 15) [29].  Cyclization of dibromo-CF3-allyl alcohols 21a-e into CF3-indanones 20a-e in TfOH-CH2Cl2 has been described in work [30] (Scheme 16). This reaction is in concurrence with the formation of 2,3-dibromo-1-CF3-indenes. It has been found that prolongation of the reaction to1 h leads to the exclusive or predominant formation of indanones 22. Apart from this, the TfOH-promoted reaction of TMS-ethers 19 and their corresponding alcohols with arenes have been used for the stereoselective synthesis of several trans-1-CF 3 -indanes 20 to study their biologically active properties [20] (see Introduction).
Cyclization of dibromo-CF 3 -allyl alcohols 21a-e into CF 3 -indanones 20a-e in TfOH-CH 2 Cl 2 has been described in work [30] (Scheme 16). This reaction is in concurrence with the formation of 2,3-dibromo-1-CF 3 -indenes. It has been found that prolongation of the reaction to1 h leads to the exclusive or predominant formation of indanones 22. Cyclization of dibromo-CF3-allyl alcohols 21a-e into CF3-indanones 20a-e in TfOH-CH2Cl2 has been described in work [30] (Scheme 16). This reaction is in concurrence with the formation of 2,3-dibromo-1-CF3-indenes. It has been found that prolongation of the reaction to1 h leads to the exclusive or predominant formation of indanones 22. A plausible mechanism of the cyclization includes the formation of O-protonated cation K, which is cyclized into indene L (Scheme 17). Subsequent protonation of the formed indene gives rise to cation M, which has been studied by NMR in TfOH. The quenching of the reaction mixture with water leads to CF3-indanone 22 along with 2,3-dibromo-1-CF3-indenes; the latter are formed at the deprotonation of species M [30]. A plausible mechanism of the cyclization includes the formation of O-protonated cation K, which is cyclized into indene L (Scheme 17). Subsequent protonation of the formed indene gives rise to cation M, which has been studied by NMR in TfOH. The quenching of the reaction mixture with water leads to CF 3 -indanone 22 along with 2,3dibromo-1-CF 3 -indenes; the latter are formed at the deprotonation of species M [30]. Cyclization of dibromo-CF3-allyl alcohols 21a-e into CF3-indanones 20a-e in TfOH-CH2Cl2 has been described in work [30] (Scheme 16). This reaction is in concurrence with the formation of 2,3-dibromo-1-CF3-indenes. It has been found that prolongation of the reaction to1 h leads to the exclusive or predominant formation of indanones 22. A plausible mechanism of the cyclization includes the formation of O-protonated cation K, which is cyclized into indene L (Scheme 17). Subsequent protonation of the formed indene gives rise to cation M, which has been studied by NMR in TfOH. The quenching of the reaction mixture with water leads to CF3-indanone 22 along with 2,3-dibromo-1-CF3-indenes; the latter are formed at the deprotonation of species M [30]. Karpov et al., in their study on the synthesis and reactions of perfluorinated aromatics, have found an interesting transformation of perfluoro-1-phenyltetralin 23 into 1-CF 3perfluoroindane 24, along with other perfluoroorganics, under the action of SbF 5 or the system HF-SbF 5 underharshconditions at 130-200 • C in a nickel autoclave (Scheme 18) [31]. The authors explain the formation of indane 24 by multi-step cationic transformations of starting tetralin 23, in which one of the CF 2 groups is transformed into a CF 3 -substituent of 24 under a ring contraction process. Later on, the same group developed the synthesis of perfluorofluorenes, containing a 1-CF 3 -indane structural fragment, by the reaction of perfluoro-1,1-diphenylalkanes with SbF 5 [32].   [33]. This coupling furnishes a set of diverse spirocycles 27 and 27 with three stereogenic centers, stereochemistry of which can be regulated by silver additives. For N-sulfonyl ketimines, it has been found that the use of AgOAc increases the yield of diastereomer 27 with thecis-orientation of CF 3 and NH groups. Meanwhile, the application of AgOTf shifts thediastereomer ratio in favor of another isomer 27 with trans-orientation of these moieties. In contrast to this, for the annulation of N-acyl ketimines, the use of a AgTFA additive increases the yields of diastereomers, and diastereomer 27 is formed in a predominant amount. The authors have extensively studied the scope and limitations of this reaction. The yields of target products 27 and 27 are increased by electron-donating groups in the para-position of N-sulfonyl and N-acyl ketimines, such as the methoxy group, and decreased by electron-withdrawing groups, such as fluorine. It is worth mentioning that the use of the N-sulfonyl ketimine with the o-methoxyphenyl substituent resulted in the formation of only one diastereomer 27 due to steric hindrance affected by the transition state during the insertion of the imine group. The reaction results in a broad range of CF 3 -enones 25. In this way, substrates bearing both electron acceptors (4-NO 2 , 2-CF 3 , halogens) and donors (4-OMe, 2-Me, 3-Me-, 2,4-Me 2 or 3,4-OMe 2 ) in the aryl ring of 25 demonstrate moderate to excellent yields of the target products and high stereoselectivity [33].  [33]. This coupling furnishes a set of diverse spirocycles 27 and 27′with three stereogenic centers, stereochemistry of whichcan be regulated by silver additives. For N-sulfonylketimines, it has been found that the use of AgOAc increases the yield of diastereomer 27 with thecis-orientation of CF3 and NH groups. Meanwhile,the application of AgOTf shifts thediastereomer ratio in favor of another isomer 27′with trans-orientation of these moieties.In contrast to this, for the annulation of N-acyl ketimines, the use of a AgTFA additive increases the yields of diastereomers, and diastereomer 27′is formed in a predominant amount. The authors have extensively studied the scope and limitations of this reaction. The yields of target products 27 and 27′ are increased by electron-donating groups in the para-position of N-sulfonyl and N-acyl ketimines, such as the methoxy group, and decreased by electron-withdrawing groups, such as fluorine. It is worth mentioning that the useof the N-sulfonylketimine with theo-methoxyphenyl substituent resulted in the formation of only one diastereomer 27′due to steric hindrance affected bythe transition state during the insertion of the imine group. The reaction results in a broad range of CF3-enones 25. In this way, substrates bearing both electron acceptors (4-NO2, 2-CF3, halogens) and donors (4-OMe, 2-Me, 3-Me-, 2,4-Me2or 3,4-OMe2) in the aryl ring of 25 demonstrate moderate to excellent yields of the target products and high stereoselectivity [33]. This reaction affords an inseparable diastereomeric mixture of CF3-aminoindanes 29. Contrary to cyclic ketimines26 (Scheme 19), such high diastereoselectivity in reactions of aldimines 28 has not been observed, presumably due to the lowersteric hindrance for noncyclic compounds 28. Various tosylaldimines and N-(p-methoxyphenyl)aldimine, in contrast to tosylhydrazone, have been successfully involved in this coupling. At the same  [34]. This reaction affords an inseparable diastereomeric mixture of CF 3 -aminoindanes 29. Contrary to cyclic ketimines 26 (Scheme 19), such high diastereoselectivity in reactions of aldimines 28 has not been observed, presumably due to the lower steric hindrance for non-cyclic compounds 28. Various tosylaldimines and N-(p-methoxyphenyl)aldimine, in contrast to tosylhydrazone, have been successfully involved in this coupling. At the same time, the reaction with β-CF 3 -enones 25, containing electron-rich aryl rings, gives CF 3 -aminoindanes 29 in moderate to high yields, whereas the use of compounds 25 with electron-withdrawing substituents in the aryl moiety leads to the target products 29 in lower yields.
Organics2021, 2, FOR PEER REVIEW 10 time, the reaction with β-CF3-enones 25, containing electron-rich aryl rings, gives CF3-aminoindanes 29 in moderate to high yields, whereas the use of compounds 25 with electronwithdrawing substituents in the aryl moiety leads to the target products 29 in lower yields. Another type of fluorinated substrate for transition metal-catalyzed [3+2] annulationvia C−H activation is CF 3 -ketimines 30 (Scheme 21). Xiong, Zhang et al. [35] have found that the Re-catalyzed reaction of CF 3 -ketimines 30 with alkyl acrylates 31 results in the formation of compounds 32, having geminal trifluoromethyl and amino substituents along with a vicinal ester group in the indane core. CF 3 -aminoindanes 32 are important precursors for the synthesis of fluorinated β-amino acids. CF 3 -ketimines 30 bearing both electron-rich and -poor aromatic substituents as well as an alkyl group in the amine part can be successfully involved in this coupling. The reaction is also tolerated by various paraand meta-substituents in the aryl group in the ketone part of 30. Remarkably, due to steric factors, only one regioisomer 32 with cis-configuration is formed. It is worth mentioning that meta-substituted ketimines 30 give two regioisomers of desirable products in excellent general yields. Moreover, the interaction of diketimine with acrylate affords two regioisomers of the tricyclic skeleton, bearing two CF 3 -amino-esterindane moieties in high yield. One more example of the transition metal-catalyzed construction of a 1-CF3-indane core is the stereoselective Rh(I)-catalyzed intramolecular hydroacylation of 2-(1-CF3-ethenyl)benzaldehyde 33,furnishing CF3-indanone 34 in high yield and with high ee value (Scheme 22) [36]. One more example of the transition metal-catalyzed construction of a 1-CF 3 -indane core is the stereoselective Rh(I)-catalyzed intramolecular hydroacylation of 2-(1-CF 3 -ethenyl)benzaldehyde 33, furnishing CF 3 -indanone 34 in high yield and with high ee value (Scheme 22) [36].
There are some methods forbuilding CF 3 -indane systems on the basis of free-radical transformations.
Kimoto et al. have studied di-t-butylperoxide-induced reactions of alkylbenzenes35a-c with hexafluoropropene36 under harsh conditions (130-160 °C, 6 h) (Scheme 23) [37]. One of the reaction products isfluorinated 1-CF3-indanes 37a-c, along with fluoroalkyl arenes 38a-c and other unidentified substances. However, the yields of the obtained compounds are rather low. The initial step in the reaction is the generation of aphenylmetyl radical, One of the reaction products is fluorinated 1-CF 3 -indanes 37a-c, along with fluoroalkyl arenes 38a-c and other unidentified substances. However, the yields of the obtained compounds are rather low. The initial step in the reaction is the generation of a phenylmetyl radical, which is added to the double bond of 36, and then transformations of secondary radical species lead to 1-CF 3 -indanes 37a-c. Later on, this scientific group, using the same radical reaction between hexafluoropropene 36 and benzaldehyde, prepared 2,2,3-trifluoro-3-trifluoromethylindan-one, which was transformed to other 1-CF 3 -indanes by reactions onto carbonyl group [38].
ics2021, 2, FOR PEER REVIEW 12 which is added to the double bond of 36, and then transformations of secondary radical species lead to 1-CF3-indanes 37a-c. Later on, this scientific group, using the same radical reaction between hexafluoropropene 36 and benzaldehyde, prepared 2,2,3-trifluoro-3-trifluoromethylindan-one, which was transformed to other 1-CF3-indanes by reactions onto carbonyl group [38]. The reaction between substrates 35 and 36 has been also investigated by Haszeldineet al. under thermal conditions at 250 °C without the addition of any peroxide for the initiation; however, target 1-CF3-indanes 37 have been obtained in very low yields [39].  The reaction between substrates 35 and 36 has been also investigated by Haszeldine et al. under thermal conditions at 250 • C without the addition of any peroxide for the initiation; however, target 1-CF 3 -indanes 37 have been obtained in very low yields [39].
The synthesis of diastereomeric 1-CF 3 -indanes 41 and 42 has been described in work [40] (Scheme 24). Starting 1-CF 3 -perfluoroindene 39 is subjected to cyclopropanation by difluorocarbene generated from hexafluoropropylene oxide that gives compound 40. The latter is brominated under thermal conditions (intermediate free-radical species generation) with the formation of 1-CF 3 -indanes 41 and 42 in a ratio of 2.5 : 1 in a good general yield.
Organics2021, 2, FOR PEER REVIEW 12 which is added to the double bond of 36, and then transformations of secondary radical species lead to 1-CF3-indanes 37a-c. Later on, this scientific group, using the same radical reaction between hexafluoropropene 36 and benzaldehyde, prepared 2,2,3-trifluoro-3-trifluoromethylindan-one, which was transformed to other 1-CF3-indanes by reactions onto carbonyl group [38]. The reaction between substrates 35 and 36 has been also investigated by Haszeldineet al. under thermal conditions at 250 °C without the addition of any peroxide for the initiation; however, target 1-CF3-indanes 37 have been obtained in very low yields [39].    Intramolecular radical cyclization has been used in the stereoselective synthesis of 1-CF 3indane 44 from compound 43 in the presence of (n-Bu) 3 SnH and AIBN (Scheme 25) [41]. Intramolecular radical cyclization has been used in the stereoselective synthesis of 1-CF3-indane 44 from compound 43 in the presence of (n-Bu)3SnH and AIBN (Scheme 25) [41].  Among all approaches to the synthesis of trifluoromethylindanes, there is an example of a complex nucleophilic process to create a 1-CF3-indane structure [43]. The reaction of perfluoro-4-methyl-pent-2-ene 48 with trimethylsilylpentafluorobenzene under the action of CsF in MeCN results in the formation of two compounds 49 and50 in a general yield of ~50% (Scheme 27). The authors provide a multi-step mechanism of this nucleophilic transformation, according to whichtrifluoromethyl groups form the structure of tri-CF3-indane 49 from starting alkene 48 [43].

2.2.Trifluoromethylation of Indane Scaffolds
The next group of synthesis methods of trifluoromethylindanes is based on the introduction of a CF3 group into a suitable indane carcass.
One of the simplest approachesin these methods is the trifluoromethylation of the carbonyl group by Ruppert-Prakash reagent CF3SiMe3 (CF3TMS). Thus, Gassmanet al. carried out the synthesis of 1-CF3-indan-1-ole 51 from indan-1-one using CF3TMS and tetra-n-butylammonium fluoride as a catalyst (Scheme 28) [44]. Among all approaches to the synthesis of trifluoromethylindanes, there is an example of a complex nucleophilic process to create a 1-CF 3 -indane structure [43]. The reaction of perfluoro-4-methyl-pent-2-ene 48 with trimethylsilylpentafluorobenzene under the action of CsF in MeCN results in the formation of two compounds 49 and 50 in a general yield of~50% (Scheme 27). The authors provide a multi-step mechanism of this nucleophilic transformation, according to which trifluoromethyl groups form the structure of tri-CF 3indane 49 from starting alkene 48 [43]. Among all approaches to the synthesis of trifluoromethylindanes, there is an example of a complex nucleophilic process to create a 1-CF3-indane structure [43]. The reaction of perfluoro-4-methyl-pent-2-ene 48 with trimethylsilylpentafluorobenzene under the action of CsF in MeCN results in the formation of two compounds 49 and50 in a general yield of ~50% (Scheme 27). The authors provide a multi-step mechanism of this nucleophilic transformation, according to whichtrifluoromethyl groups form the structure of tri-CF3-indane 49 from starting alkene 48 [43].

2.2.Trifluoromethylation of Indane Scaffolds
The next group of synthesis methods of trifluoromethylindanes is based on the introduction of a CF3 group into a suitable indane carcass.

Trifluoromethylation of Indane Scaffolds
The next group of synthesis methods of trifluoromethylindanes is based on the introduction of a CF 3 group into a suitable indane carcass.
One of the simplest approaches in these methods is the trifluoromethylation of the carbonyl group by Ruppert-Prakash reagent CF 3 SiMe 3 (CF 3 TMS). Thus, Gassman et al. carried out the synthesis of 1-CF 3 -indan-1-ole 51 from indan-1-one using CF 3 TMS and tetra-n-butylammonium fluoride as a catalyst (Scheme 28) [44].

2.2.Trifluoromethylation of Indane Scaffolds
The next group of synthesis methods of trifluoromethylindanes is based on the introduction of a CF3 group into a suitable indane carcass.
Copper-catalyzed radical trifluoromethylation may be also used to access CF3-indanes. Very recently, in 2021, Fang, Zhu, Li et al. have successfully developed ring-opening 1,3-aminotrifluoromethylation of the wide series of arylcyclopropanes including indane derivatives [47]. The radical reaction of tetrahydrocyclopropa[a]indene with trifluoromethylating agent (bpy)Zn(CF3)2 under the action of Cu(OTf)2 as a catalyst leads to 1-CF3-indane 52 in a good yield of 62% and high stereo-and chemoselectivity (Scheme 31). Earlier, the same scientific group described the copper-catalyzed ring-opening radical trifluoromethylation of cycloalkanone oxime derivatives [48]. In this reaction, copper(II) triflate and bipyridyl act as catalysts, and Zn(CF3)2 complex is a reagent. Oxime derivative 53 affords 1-CF3-indane 54 in a high yield of 84% and with good stereoselectivity with atrans-/cis-isomeric ratio of 94:6 (Scheme 32). Earlier, the same scientific group described the copper-catalyzed ring-opening radical trifluoromethylation of cycloalkanone oxime derivatives [48]. In this reaction, copper(II) triflate and bipyridyl act as catalysts, and Zn(CF 3 ) 2 complex is a reagent. Oxime derivative 53 affords 1-CF 3 -indane 54 in a high yield of 84% and with good stereoselectivity with a trans-/cisisomeric ratio of 94:6 (Scheme 32). Several recent works have been devoted to metal-catalyzed trifluoromethylation with hypervalent iodine-based reagents. Thus, MacMillan et al. [49] reported ametallaphotoredox methodology including sodium decatungstate(NaDT)-photocatalyzed hydrogen atom transfer and copper catalysis, which allows the conversion of C-H bonds into the corresponding C(sp 3 )-CF3 one using Togni reagent II. This provides the transformation of unprotected amine 55 into a single regioisomer of 1-CF3-indane 56 with good stereoselectivity (Scheme 33). Togni reagent II and TMSCN have been also applied for the copper-catalyzed spiroannulation-cyanotrifluoromethylation of 1,5-enynes 57 for the synthesis of spiro-1-CF3indanes 58 (Scheme 34) [50]. The set of substituents R 1 in the acetylene moiety of compounds 57 includes a wide rangeof electron-rich and electron-poor aryl groups. However, starting enynes57 bearing alkyl or cycloalkyl groups R 1 do not converge into target compounds 58. Remarkably, 1,5-enynes containing anortho-substituted aryl group give inseparable diastereomeric mixtures; otherwise, only Z-products are obtained in good yields. Several recent works have been devoted to metal-catalyzed trifluoromethylation with hypervalent iodine-based reagents. Thus, MacMillan et al. [49] reported ametallaphotoredox methodology including sodium decatungstate(NaDT)-photocatalyzed hydrogen atom transfer and copper catalysis, which allows the conversion of C-H bonds into the corresponding C(sp 3 )-CF 3 one using Togni reagent II. This provides the transformation of unprotected amine 55 into a single regioisomer of 1-CF 3 -indane 56 with good stereoselectivity (Scheme 33).
Organics2021, 2, FOR PEER REVIEW 15 Cu(OTf) 2 , bpy (DMPU) 2 Zn(CF 3  Several recent works have been devoted to metal-catalyzed trifluoromethylation with hypervalent iodine-based reagents. Thus, MacMillan et al. [49] reported ametallaphotoredox methodology including sodium decatungstate(NaDT)-photocatalyzed hydrogen atom transfer and copper catalysis, which allows the conversion of C-H bonds into the corresponding C(sp 3 )-CF3 one using Togni reagent II. This provides the transformation of unprotected amine 55 into a single regioisomer of 1-CF3-indane 56 with good stereoselectivity (Scheme 33). Togni reagent II and TMSCN have been also applied for the copper-catalyzed spiroannulation-cyanotrifluoromethylation of 1,5-enynes 57 for the synthesis of spiro-1-CF3indanes 58 (Scheme 34) [50]. The set of substituents R 1 in the acetylene moiety of compounds 57 includes a wide rangeof electron-rich and electron-poor aryl groups. However, starting enynes57 bearing alkyl or cycloalkyl groups R 1 do not converge into target compounds 58. Remarkably, 1,5-enynes containing anortho-substituted aryl group give inseparable diastereomeric mixtures; otherwise, only Z-products are obtained in good yields. Togni reagent II and TMSCN have been also applied for the copper-catalyzed spiroannulation-cyanotrifluoromethylation of 1,5-enynes 57 for the synthesis of spiro-1-CF 3 -indanes 58 (Scheme 34) [50]. The set of substituents R 1 in the acetylene moiety of compounds 57 includes a wide range of electron-rich and electron-poor aryl groups. However, starting enynes57 bearing alkyl or cycloalkyl groups R 1 do not converge into target compounds 58. Remarkably, 1,5-enynes containing an ortho-substituted aryl group give inseparable diastereomeric mixtures; otherwise, only Z-products are obtained in good yields.
One more synthetic approach to 1-CF 3 -indanes is the reduction of 1-CF 3 -indenes. In this area, it is worth mentioning the recent work by Chirik et al. [51], which focused on the diastereoselective cobalt-catalyzed hydroboration of substituted indenes, including trifluoromethylated ones. Thus, the reduction of 1-CF 3 -indene by HBP in the presence ofcobalt catalyst 59 results in the stereoselective formation of trans-1,3-disubstituted CF 3indanyl boronate ester 60 (Scheme 35).
Togni reagent II and TMSCN have been also applied for the copper-catalyzed spiroannulation-cyanotrifluoromethylation of 1,5-enynes 57 for the synthesis of spiro-1-CF3indanes 58 (Scheme 34) [50]. The set of substituents R 1 in the acetylene moiety of compounds 57 includes a wide rangeof electron-rich and electron-poor aryl groups. However, starting enynes57 bearing alkyl or cycloalkyl groups R 1 do not converge into target compounds 58. Remarkably, 1,5-enynes containing anortho-substituted aryl group give inseparable diastereomeric mixtures; otherwise, only Z-products are obtained in good yields. One more synthetic approach to 1-CF3-indanes is the reduction of 1-CF3-indenes. In this area, it is worth mentioning the recent work by Chiriket al. [51], which focused on the

Conclusions
Thissurvey of methods for thesynthesis of 1-trifluoromethylindanes and close substances reveals that existing approaches allow these compounds to be obtained in regioand stereoselective ways by two main procedures: the construction of a 1-CF3-indane core from CF3precursors and thetrifluoromethylation of indane structures. The latter method needs further deep investigation, since the regio-and stereoselective introduction of a CF3 group into anindane core allows novel structures of this series to be obtained.
The combination of an indane scaffold, which is suitable for the creation of asymmetric carbons, along with a lipophilic CF3 group, in various 1-CF3-indane containing structures, makes these compounds extremely important for medicinal chemistry, as the basisfor the search fornovel biologically active substances. In the near future, one should expect further intensive research on the development of the synthesis of 1-CF3-indanes and the discovery of new methods in this area.