TfOH-promoted transformation of TMS-ethers of diarylsubstituted CF₃-allyl alcohols with arenes into CF₃-indanes

Abstract

The reaction of TMS-ethers of 2,4-diaryl-1,1,1-trifluorobut-3-en-2-ols with arenes in TfOH at room temperature for 5 min results in the formation of trans-/cis-1,3-diaryl-1-trifluoromethyl indanes in good yields (up to 99%). The predominant or exclusive formation of indanes with a trans-configuration of 1,3-diaryl groups has been observed. The reaction proceeds through an intermediate formation of the corresponding mesomeric CF₃-allyl cations. A plausible reaction mechanism is discussed.

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Introduction

Allyl alcohols and their derivatives are widely used in organic synthesis. There are many various pathways for transformations of allyl alcohols leading to the formation of new carbon–carbon and carbon–heteroatom bonds. The most important reactions are C–H activation at the double bond,¹ addition to the double bond without breaking the C–O bond,^2–6 and transformations associated with the cleavage of the C–O bond,^7–15 including the classical Friedel–Crafts process.^16–19 Under the action of Brønsted superacids, some allyl alcohols gave rise to relatively stable intermediate allyl cations, which were studied by means of NMR.²⁰ The introduction of the trifluoromethyl group CF₃ into the allylic position of allyl alcohols significantly increases the electrophilicity of the corresponding intermediate allyl cations.

In general, including fluorinated moieties in organic molecules often changes important pharmacokinetic parameters such as lipophilicity, bioavailability and metabolic activity. Due to this, fluorinated organic compounds have a great theoretical and practical importance in chemistry, biology, medicine, and materials science.^21–26

We have previously shown that various CF₃-substituted allyl alcohols and their derivatives under the action of Brønsted and Lewis acids undergo the Friedel–Crafts intra- and inter-molecular reactions, yielding a number of important compounds, among them CF₃-substituted indanes and indenes.^27–31 Moreover, it was found that various 1-CF₃-indanes are effective ligands for cannabinoid receptors CB1 and CB2 types,³² and ligands for endocannabinoid degrading enzymes (FAAH and MAGL), and AEA uptake.³³

Taking into account the importance of fluorinated indanes and based on our recent study on acid-promoted intramolecular cyclization of diarylsubstituted CF₃-allyl alcohols into CF₃-indenes,²⁸ we have decided to develop a novel method for the synthesis of CF₃-indanes based on transformations of such CF₃-allyl alcohols under superelectrophilic activation conditions.

The main goal of this work was a study of reactions of TMS-ethers of 2,4-diaryl-1,1,1-trifluorobut-3-en-2-ols with arenes in Brønsted superacid, and trifluoromethanesulfonic acid CF₃SO₃H (TfOH).

Results and discussion

The initial TMS-ethers of 2,4-diaryl-1,1,1-trifluorobut-3-en-2-ols 2a–u were obtained by the reaction of the chalcones 1a–u with Rupert–Prakash reagent CF₃SiMe₃ in the presence of CsF in 1,2-dimethoxyethane (DME) at room temperature for 4 h (Scheme 1, see the ESI† for details).

Scheme 1 Synthesis of TMS-esters of 2,4-diaryl-1,1,1-trifluorobut-3-en-2-ols 2a–u, used in this study.

Then, reactions of TMS-ethers 2 with arenes under the action of various Brønsted and Lewis acids were conducted. It was found that reactions of compound 2a with benzene in H₂SO₄ or with strong Lewis acids AlX₃ (X = Cl, Br) afforded complex mixtures of oligomeric compounds. In contrast to that, the use of TfOH for electrophilic activation of 2a in this reaction led to the formation of trans-/cis-indanes 3a (entry 1, Table 1). Analogously, other TMS-ethers 2 in the reaction with benzene in TfOH at room temperature for just 5 min (!!!) gave mainly indanes 3 (see Table 1). With rare exceptions, the major or even sole reaction products were trans-indanes 3, bearing aryl groups in the trans-position in the indane core. The stereochemical trans-/cis-configuration of compounds 3 was determined by H–F NOESY correlations between the 1-CF₃ group and 3-H proton in the indane ring (Fig. 1). Exact structures of indanes 3b–h,k–n, and q–r were additionally confirmed by X-ray analysis (see the ESI†).

Fig. 1 H–F NOESY correlations in indanes 3, clarifying their trans-/cis-stereochemical configuration.

Table 1 Reactions of TMS-ethers 2 with benzene in TfOH at room temperature for 5 min

Entry	Initial TMS-ethers 2	Reaction products, yields (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

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However, in some cases the formation of indanes 3 was accompanied by aryl group exchange under the superacidic conditions. Thus, TMS-ethers 2e and 2k bearing electron donating aryl rings gave indene 3a (entries 5 and 11) as a result of exchange of these aryl groups into phenyl one (see the below discussion on the reaction mechanism). Apart from indanes 3, in some reactions, other compounds were obtained, such as indenes 4a–d1 (entries 14, 16, 19) as products of intramolecular cyclization of initial TMS-ethers without any interaction with benzene. Also, E-/Z-alkene 5 was obtained from compound 2s (entry 19). All initial TMS-ethers 2 were successfully involved in the transformation with benzene (Table 1), except compound 2t having two electron poor 3,4-dichlorophenyl rings; the reaction of it with benzene finally led to a complex mixture of products.

Having the data obtained (Table 1) and based on our previous work,²⁸ one may propose a plausible mechanism of the reaction of TMS-ethers 2 with benzene in TfOH (Scheme 2). In the beginning, protonation of oxygen in ether 2 followed by elimination of TMSOH gives rise to mesomeric CF₃-allyl cation A ↔ A′, which is cyclized into indene C through resonance form A′. Under superacidic reaction conditions, indene C is further protonated leading to CF₃-benzyl cation D. The latter reacts with benzene forming finally trans-/cis-indenes 3. The predominant formation of trans-indenes 3 (see Table 1) may be explained by less sterical hindrance in the corresponding intermediates of electrophilic substitution between species D and benzene. An exchange of donating aryl moiety Ar′ into the phenyl group at the benzylic position in indanes 3 may occur in the superacid TfOH, as it was previously observed for various substrates.^34,35 This is why the formation of indene 3a from ethers 2e and k took place (entries 5 and 11, Table 1). Compounds 4 were obtained after chromatographic isolation as a result of isomerization of indene C. This isomerization has been already described by us.²⁸ The formation of alkene 5 is caused by alternative alkylation of benzene by species A ↔ A′, rather than its cyclization into an electron poor 3,4-dichlorophenyl ring leading to the corresponding indene C that seems to be less favorable.

Scheme 2 Plausible mechanism of the reaction of TMS-ethers 2 with benzene in TfOH.

We also ran reactions of TMS-ethers 2a,b, ande with selected arenes (Table 2). Thus, reactions with bromobenzene, meta-xylene, and veratrol gave stereoselectively only trans-indanes 3q–s (entries 1–3). However, transformations with mesitylene resulted in the formation of indenes 4e,f (entries 4 and 5). Probably, in this case, an interaction of the corresponding CF₃-benzyl cations D with bulky mesitylene molecules does not take place.

Table 2 Reactions of TMS-ethers 2 with selected arenes in TfOH at room temperature for 5 min

Entry	Initial TMS-ether 2	Arene	Reaction products, yields (%)
1
2	2a
3
4	2a
5

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Conclusions

We have developed a novel synthesis of 1,3-diaryl-1-trifluoromethylindanes on the basis of the reaction of TMS-ethers of 2,4-diaryl-1,1,1-trifluorobut-3-en-2-ols with arenes under superelectrophilic activation in TfOH. The reaction proceeds rather highly stereoselectively leading mainly or solely to such 1-CF₃-indanes having a trans-configuration of 1,3-diaryl substituents. These CF₃-indanes have great importance for medicinal chemistry.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by Russian Scientific Foundation (grant no. 18-13-00008). Spectral studies were performed at the Center for Magnetic Resonance, Center for Chemical Analysis and Materials Research, and Research Center for X-ray Diffraction Studies of Saint Petersburg State University, Saint Petersburg, Russia.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1875102, 1875106–1875119. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9qo00822e

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