Cyclization of 1-aryl-4,4,4-trichlorobut-2-en-1-ones into 3-trichloromethylindan-1-ones in triflic acid

Introduction

Superelectrophilic activation of organic compounds under the action of strong Brønsted and Lewis acids is an effective method for the synthesis of various carbocycles and heterocycles, and polyfunctional compounds (see books [1,2] and reviews [3-10]). Protonation (or coordination) of basic centers (carbons of unsaturated bonds and heteroatoms) of organic molecules in Brønsted (or Lewis) acids gives rise to not only monocations, but also to highly reactive dicationic (and even higher charged) species. Thus, different conjugated enones afford O,C-diprotonated forms under superelectrophilic activation conditions. These dications can participate in electrophilic aromatic substitution reactions with arenes ([11] and references therein).

Recently, we have shown that the reaction of (E)-5,5,5-trichloropent-3-en-2-one [Cl₃CCH=CHC(=O)Me] with arenes in Brønsted superacid TfOH (triflic acid, CF₃SO₃H) furnishes 3-methyl-1-trichloromethylindenes (Scheme 1a) [11]. Based on NMR analysis in TfOH and theoretical DFT calculations, it has been found that the reaction proceeds through an intermediate formation of the O-protonated form of the starting compound [Cl₃CCH=CHC(=OH⁺)Me]. The presence of two strong electron-withdrawing substituents, the trichloromethyl group (CCl₃) and a protonated carbonyl (C(OH⁺)Me), at the carbon–carbon double bond makes this O-protonated species electrophilic enough to react with arenes (Scheme 1a). The second protonation of the C=C bond is hampered due to a strong acceptor character of the substituents, contrary to other more donating enones.

As a continuation of the research on the electrophilic activation of electron-poor alkenes bearing two electron-withdrawing substituents at the C=C bond, we initiated this study on transformations of 1-aryl-4,4,4-trichlorobut-2-en-1-ones under superelectrophilic activation conditions (Scheme 1b). The main goals of this work were the investigation of the protonation of CCl₃-enones (1-aryl-4,4,4-trichlorobut-2-en-1-ones) by NMR spectroscopy and DFT calculations, and to study their intramolecular cyclization in triflic acid into the synthetically and medicinally relevant (see recent reviews [12-18]) indan-1-ones.

Results and Discussion

The synthesis of 1-aryl-4,4,4-trichloro-3-hydroxybutan-1-ones (CCl₃-hydroxy ketones) 1a–o was carried out by condensation of acetophenones with chloral under reflux in acetic acid using the known literature procedure [19] (Scheme 2). Based on another literature approach [20], compounds 1p–v were obtained by acylation of electron-donating arenes with Wynberg lactone [21] (Scheme 3). Additionally, exact structures of compounds 1g,h,s,t,v were confirmed by X-ray analysis (see Supporting Information File 1).

The hydroxy ketones 1 were used as precursors for the synthesis of 1-aryl-4,4,4-trichlorobut-2-en-1-ones (CCl₃-enones) 2 by dehydration of compounds 1 with p-toluenesulfonic acid monohydrate at reflux in toluene [19] (Scheme 4). By this route, mainly E-isomers of compounds 2 were formed except for compounds 2c,i,m which were obtained as mixtures of E,Z-isomers (see Experimental section). However, under the reaction conditions in the presence of TsOH, the hydroxy ketones 1k,p–s bearing strong electron-donating substituents in the aromatic ring gave oligomeric materials. Presumably, in these cases, after dehydration and formation of the corresponding enone 2, the latter underwent subsequent cationic oligomerization.

Next we studied the intramolecular cyclization of compounds 1 and 2 in TfOH. It was found that enones 2 were transformed into the corresponding 3-trichloromethylindan-1-ones 3 upon heating in neat TfOH at 80 °C for 2–10 h (Scheme 5). Under the same reaction conditions, hydroxy ketones 1 were cyclized into indanones 3 as well (Scheme 6). The structure of compound 3a was confirmed by X-ray analysis (see Supporting Information File 1). Both, hydroxy ketone 1 and the corresponding enone 2, can be converted into the same indanone 3 in comparable yields; see pairs of reactions for 1a and 2a (indanone 3a), 1d and 2d (indanone 3d), 1i and 3i (indanone 3i), and 1n and 3n (indanone 3n) in Scheme 5, Scheme 6 and the Experimental section).

There are some features of this cyclization. The electron-poor enones 2l,m are unreactive and do not give rise to the corresponding indanones due to the low nucleophilicity of the nitro-substituted aromatic ring. On the other hand, the electron-rich enones 2o,t,u, bearing electron-donating substituents in the aromatic rings, afford complex mixtures of oligomeric materials. The cyclization of hydroxy ketone 1k into indanone 3k is accompanied by demethylation of one of the methoxy groups (Scheme 6). The positions of hydroxy and methoxy groups in the aryl ring of compound 3k were determined by NOESY correlations between protons in this structure (see Supporting Information File 1). Surprisingly, enone 2j transformed into the phenoxy-substituted indanone 3j in a low yield of 13% (Scheme 5). The formation of the latter represents an interesting rearrangement with the intermolecular transfer of a phenyl group in the starting methoxy-substituted enone 2j under the rather harsh reaction conditions (TfOH at 80 °C).

To study the cyclization further, reactions of some hydroxy ketones 1 were run for shorter time (1–4.5 h) in TfOH at 80 °C, i.e., under conditions of incomplete conversion of the starting compounds. It was found that, apart from the target indanones 3, substantial amounts of the corresponding enones 2 were detected (Table 1). This means that, in the superacid TfOH, hydroxy ketones 1 may initially undergo dehydration to enones 2, which are subsequently cyclized into indanones 3. From a synthetic point of view, the use of hydroxy ketones 1 as starting compounds for the cyclization without additional preparation and isolation of the corresponding enones 2 is more economical as it reduces the number of steps in the synthesis.

Other Brønsted and Lewis acids were also tested for this cyclization. Thus, enones 2a and 2e were not transformed into the corresponding indanones 3 in neat sulfuric acid (H₂SO₄) at room temperature for 3 days. That is in accord with literature data [19], where H₂SO₄ was used for dehydration of hydroxy ketones 1 into enones 2, and no cyclization into indanones was detected in this acid. However, in the current study, we carried out the reaction of electron-donating naphthyl-substituted enone 2n in H₂SO₄ at room temperature, which resulted in the quantitative formation of indanone 3n after 3 days. The reactions of enones 2a,e,n with an excess (5 equiv) of AlBr₃ or AlCl₃ in CH₂Cl₂ solution at room temperature for 3 days afforded complex mixtures of compounds.

Then, the protonation of compounds 1 and 2 in TfOH was investigated by means of NMR spectroscopy. According to the ¹H, ¹³C, and ¹⁹F NMR data, hydroxy ketones 1 and enones 2 afford stable O-protonated forms A and B, respectively, in TfOH at room temperature (Table 2 and spectra in Supporting Information File 1).

In species A both oxygens should be protonated by the superacid. The differences in chemical shifts (∆δ = δ_acid − δ_CDCl3) for the corresponding atoms H² and H³ in cations Aa,c,d and their neutral precursors 1a,c,d were 0.59–0.86 and 0.28–0.31 ppm (Table 2). These downfield shifts of the signals point to an inductively induced positive charge on these hydrogens due to the protonation of the oxygens of the carbonyl and hydroxy groups. According to the ¹³C NMR spectra, the largest downfield shift was observed for the carbonyl carbon С¹, with ∆δ = 17.7–21.1 ppm, showing a substantial degree of protonation of the carbonyl group in TfOH.

The tendencies are the same for the protonation of enones 2a,c,d,m leading to cations Ba,c,d,m (Table 2). Thus, in the ¹H NMR spectra, downfield shifts of vinyl protons H² and H³ upon protonation were 0.50–0.61 and 0.41–0.54 ppm, respectively. In the ¹³C NMR spectra, ∆δ values for carbons С¹ and С³ were 12.7–21.3 and 6.0–13.4 ppm, respectively. The NMR data revealed that the positive charge in the O-protonated forms B is substantially delocalized from the carbonyl group to vinyl carbon C³.

For fluorophenyl-substituted compounds and cations 1d and Ad, 2d and Bd, also a large downfield shift of the corresponding fluorine signals is observed in the ¹⁹F NMR spectra (∆δ = 25.3–25.7 ppm), which shows a delocalization of the positive charge from the carbonyl group to the aromatic ring.

It should be mentioned that cation Bm was generated by two ways in TfOH: either directly by protonation of enone 2m or from hydroxy ketone 1m. The latter was found to undergo fast dehydration into enone 2m in TfOH at room temperature.

Then, we carried out DFT calculations of cations Aa–Da derived from protonation of compounds 1a and 2a. Thermodynamics of their formation, as Gibbs energies ΔG₂₉₈ of the corresponding reactions, energies of HOMO/LUMO, electrophilicity indices ω [22,23], charge distribution, and contribution of atomic orbital into LUMO in species Aa–Da were estimated (Table 3).

The formation of O-monoprotonated species Ba and Ca from enone 2a and hydroxy ketone 1a is favorable, with negative ΔG₂₉₈ values for protonation of −52 and −39 kJ/mol, respectively (see overview scheme of Table 3). The second protonation of the C=C bond of species Ba is very unfavorable. Moreover, the corresponding O,C-diprotonated form Da was found to be extremely unstable and spontaneously rearranges into species Ea via a shift of a chlorine atom. Therefore, the DFT calculations and NMR data for enones 2 in TfOH (Table 2) indicate that the formation of dications D does not take place. Species B should be the key reactive intermediates that undergo cyclization into indanones 3 with a negative Gibbs energy of −7 kJ/mol for the reaction Ba→3a.

According to the calculations, the subsequent complete protonation of the hydroxy group in species Ca leading to dication Aa is thermodynamically unfavorable (ΔG₂₉₈ = 68 kJ/mol) as well (see overview scheme of Table 3). NMR experiments allowed us to observe the formation of O,O-diprotonated species in the superacid TfOH (Table 2). The dication Aa should not be transformed to species Da analogously to cation Ba. The cyclization of dication Aa into indanone 3a is very favorable (ΔG₂₉₈ = −101.3 kJ/mol). However, the formation of both enones 2 and indanones 3 from hydroxy ketones 1 is observed in TfOH (Table 1). We assume that, at first, hydroxy ketones 1 undergo dehydration into enones 2, which then cyclize into the target indanones 3. Despite thermodynamic gain in energy, the cyclization of dications Aa in compounds 3 may have a high activation barrier.

The calculations showed that the largest part of the positive charge in the key reactive species Ba is localized on the carbonyl carbon C¹ (0.60 e). This carbon atom gives 14.9% contribution to the LUMO. Contrary to that, the carbon C³ bears no positive charge (−0.13 e) and contributes 12.1% to the LUMO. The intramolecular cyclization of cation Ba takes place between the atom C³ and the ortho-carbons of the phenyl ring. Thus, electrophilic properties of atom C³ should be mainly explained by orbital factors, rather than charge ones.

Summarizing the data obtained during the synthesis of indanones 3 (Scheme 5, Scheme 6 and Table 1), NMR, and DFT studies on intermediate cations (Table 2 and Table 3), one may propose plausible reaction mechanisms for the cyclization of compounds 1 and 2 into indanones 3 in TfOH (Scheme 7). Protonation of the carbonyl oxygen of enone 2 gives rise to cation B which is followed by cyclization into indanone 3 through mesomeric form B'. The hydroxy ketone 1 is protonated at the oxygen atoms leading to cation A, followed by dehydration resulting in cation B, which is cyclized into indanone 3. The transformation of species B into indanone 3 can be also considered as a variant of Nazarov cyclization. It should be noted that such 3-trichloromethylindanones 3 have been obtained for the first time in this study, which structurally resemble the known 3-dichloromethylindanones [24] and 3-trifluoromethylindanones [25-27].

Conclusion

A method for the synthesis of CCl₃-indanones (3-trichloromethylindan-1-ones), as a novel class of indanones, has been developed and involves an intramolecular cyclization of both, CCl₃-enones (1-aryl-4,4,4-trichlorobut-2-en-1-ones) and CCl₃-hydroxy ketones (1-aryl-4,4,4-trichloro-3-hydroxybutan-1-ones) in Brønsted superacid TfOH at an elevated temperature of 80 °C within 2–18 h. In both cases, the reaction proceeds through an intermediate formation of the O-protonated carbonyl form of the CCl₃-enones, that are finally cyclized into the target CCl₃-indanones.