Hydrogenation of β-Keto Sulfones to β-Hydroxy Sulfones with Alkyl Aluminum Compounds: Structure of Intermediate Hydroalumination Products

Abstract

β-Hydroxy sulfones are important in organic synthesis. The simplest method of β-hydroxy sulfones synthesis is the hydrogenation of β-keto sulfones. Herein, we report the reducing properties of alkyl aluminum compounds R₃Al (R = Et, i-Bu, n-Bu, t-Bu and n-Hex); i-Bu₂AlH; Et₂AlCl and EtAlCl₂ in the hydrogenation of β-keto sulfones. The compounds i-Bu₂AlH, i-Bu₃Al and Et₃Al are the at best reducing agents of β-keto sulfones to β-hydroxy sulfones. In reactions of β-keto sulfones with aluminum trialkyls, hydroalumination products with β-hydroxy sulfone ligands [R₂AlOC(C₆H₅)CH₂S(O)₂(p-R¹C₆H₄]_n [where n = 1,2; 2aa: R = i-Bu, R¹ = CH₃; 2ab: R = i-Bu, R¹ = Cl; 2ba: R = Et, R¹ = CH₃; 2bb: R = Et, R¹ = Cl] and {[Et₂AlOC(C₆H₅)CH₂S(O)₂(p-ClC₆H₄]∙Et₃Al}_n 3bb were obtained. These complexes in the solid state have a dimeric structure, while in solutions, they appear as equilibrium monomer–dimer mixtures. The hydrolysis of both the isolated 2aa, 2ab, 2ba, 2bb and 3bb and the postreaction mixtures quantitatively leads to pure racemic β-hydroxy sulfones. Hydroalumination reaction of β-keto sulfones with alkyl aluminum compounds and subsequent hydrolysis of the complexes is a simple and very efficient method of β-hydroxy sulfones synthesis.

1. Introduction

β-Hydroxy sulfones are motifs for the synthesis of a wide variety of organic products. The anions of these versatile β-hydroxy sulfones react, forming olefins by reductive elimination [1,2,3,4], vinyl sulfones by β-elimination reaction [5,6], lactones [7,8] and 2,5-disubstituted tetrahydrofurans [9,10]. It should be noted that chiral β-hydroxy sulfones are extremely useful building blocks for the synthesis of a variety of chiral organic compounds, e.g., γ-butenolides or allylic alcohols [11,12,13]. A number of methods for the β-hydroxy sulfones syntheses have been reported. They can be obtained, for instance, through a regioselective opening of β-epoxy sulfones [14] and oxiranes with various catalytic systems [15,16]. However, the reduction of carbonyl group of β-keto sulfones is considered as the most popular method of β-hydroxy sulfones synthesis. The reduction with NaBH₄ without the addition of chiral additives leads to a racemic mixture of β-hydroxy sulfones [17,18,19,20], while enzymatic reduction and chemical enantioselective reduction of the C=O group lead to the chiral β-hydroxy sulfones with high enantioselectivity [21,22,23,24,25].

In the solution of β-keto sulfones, a tautomeric equilibrium takes place that is, however, almost completely shifted towards the ketone form (Scheme 1).

Recently, we have found that the reaction between β-keto sulfones and t-Bu₂AlH leads to the formation of aluminum complexes with β-hydroxy sulfone ligands, which indicates the reduction of β-keto sulfone to β-hydroxy sulfone by the alkyl aluminum compound [26]. The results of these studies inspired the development of a method for the β-hydroxy sulfones synthesis that uses aluminum alkyls bearing hydrogen atoms in the β-position of the alkyl substituents as β-keto sulfone-reducing agents.

It should be noted that, for many decades, alkyl aluminum compounds have been widely used in carbonyls reduction [27,28,29,30,31,32,33,34] and alkenes and alkynes hydroalumination reactions [35,36,37]. i-Bu₂AlH is commonly used in selective reduction reactions, such as the reduction of trioxohexaaza[3.3.3]propelane to saturated hexaazapropelane derivatives, regioselective transformation of the CN group to the amine or the direct reduction of carboxylic acid esters to aldehydes [38,39,40].

In this paper, a β-keto sulfone reduction by various alkyl aluminum compounds, followed by the hydrolysis of the obtained aluminum complexes to β-hydroxy sulfones, is presented. Despite many methods that have been previously developed for the synthesis of chiral β-hydroxy sulfones, simple and efficient methods for the synthesis of racemic derivatives are still missing. We found that the efficiency of the reduction of β-keto sulfones to β-hydroxy sulfones depends mostly on the type of aluminum compounds, while the structure of β-keto sulfones affects the reduction process and the efficiency of β-hydroxy sulfone production to a lesser extent. Reactions of β-keto sulfones with i-Bu₃Al and Et₃Al, followed by the hydrolysis of postreaction mixtures, appear as a simple, efficient and cheap method of synthesizing β-hydroxy sulfones from starting β-keto sulfones. During the reaction of β-keto sulfones with aluminum alkyl compounds, complexes of aluminum alkyls with β-hydroxy sulfones as hydroalumination products are formed. The crystalline complexes were isolated and characterized by X-ray.

2. Results and Discussion

2.1. Hydroalumination Reaction of β-Keto Sulfones

β-Keto sulfones 1a–1e were subjected to the reaction with alkyl aluminum compounds (i-Bu₃Al, i-Bu₂AlH, Et₃Al, n-Bu₃Al, n-Hex₃Al, Et₂AlCl and EtAlCl₂), providing postreaction mixtures of β-keto sulfone hydroalumination products and the appropriate alkyl aluminum complex supported by β-keto sulfones. The compositions of the mixtures depended on the type of alkyl aluminum compounds and their reducing ability, as well as the structure of β-keto sulfones or the reaction conditions. The five hydroalumination products 2aa, 2ab, 2ba, 2bb and 3bb were isolated as crystalline solids, and their structures were examined in the solid state (Scheme 2). Moreover, all postreaction mixtures were subjected to hydrolysis in order to determine the degree of conversion of β-keto sulfones to β-hydroxy sulfones.

The treatment of 2-((4-methylphenyl)sulfonyl)-1-phenylethanol (1a) or 2-((4-chlorophenyl)sulfonyl)-1-phenylethanol (1b) with the one equivalent of i-Bu₃Al or i-Bu₂AlH in CH₂Cl₂, followed by crystallization from n-C₆H₁₄/CH₂Cl₂ solutions, afforded the crystalline β-keto sulfone hydroalumination products 2aa and 2ab (Scheme 2). Reactions of 1a and 1b with Et₃Al in a molar ratio of 1:1 led to the hydroalumination products 2ba and 2bb. When the β-keto sulfones:Et₃Al molar ratio was changed to 1:2, in the obtained compounds, an additional Et₃Al molecule was coordinated to SO₂ oxygen atoms. Compound 3bb was crystallized and characterized (Scheme 2).

The molecular structures of compounds 2aa, 2ab, 2ba, 2bb and 3bb were determined by X-ray diffraction study and are shown in Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5. Data collection and structure analyses are listed in Tables S1 and S2 (see Supplementary Materials). In the solid state, all of the described compounds were presented as centrosymmetric dimers. They consisted of central four-membered Al₂O₂ rings formed by two monoanionic β-hydroxy sulfonic ligands and two alkylaluminium moieties with four-coordinate aluminum centrum. Additionally, in the 3bb molecule, there were two Et₃Al molecules coordinated to the oxygen atoms in the SO₂ groups. The sum of the angles around the O(3) atoms was 354.9° for compound 2aa and 354.7° for compound 2ab, which indicated slight stress in the central part of the molecule. Similarly, the sums of the angles around the oxygen atoms of the Al₂O₂ rings in compounds 2ba, 2bb and 3bb were 354.8, 354.7 and 355.6°, respectively.

The central Al₂O₂ rings are similar to that of typical alkoxides of group 13 metal alkyls obtained in reactions of R₃M (R = Me, Et, i-Bu; M = Al, Ga) with diverse monoalcohols [41,42,43]. The bond lengths C(1)-C(2) [1.533(2) Å in 2aa] C(7)-C(8) [1.533(2) Å in 2ab], C(1)-C(8) [1.534(2) Å in 2ba], C(5)-C(12) [1.538(2) Å in 2bb] and C(6)-C(13) [1.533(4) Å in 3bb] are typical for single C–C bonds, which proves the transformation of the C=C double bonds in the β-keto sulfones into single C–C bonds in the appropriate β-hydroxy sulfone residues.

Surprisingly, on the basis of NMR spectra of compounds 2aa, 2ab, 2ba, 2bb and 3bb, it was found that there are two types of structures in the solutions. Such was observed for both redissolved crystalline solids, as well as for postreaction mixtures. This was evidenced by the presence of four signals deriving from the alkyl groups of the alkyl aluminum moieties. For compound 2aa, four overlapping doublets at 0.81, 0.77, 0.76 and 0.71 ppm of AlCH₂C(H)(CH₃)₂) protons and four doublets at −0.28, −0.39, −0.41 and −0.51 ppm of AlCH₂C(H)(CH₃)₂) protons were observed (Figure S2). Similarly, in the ¹H NMR spectrum of compound 2ab, the following signals of i-Bu protons were present: four overlapping doublets at 0.82, 0.78, 0.77 and 0.72 ppm of AlCH₂C(H)(CH₃)₂) protons and four doublets at −0.26, −0.37, −0.39 and −0.50 ppm of AlCH₂C(H)(CH₃)₂) protons (Figure S5). For compound 2ba, one triplet at 0.80 ppm, two overlapping triplets at 0.72 ppm and one triplet at 0.64 ppm of AlCH₂CH₃ protons were observed, whereas the signals of AlCH₂CH₃ protons appeared as four quartets at −0.39, −0.53 (two overlapping signals) and −0.65 ppm. Signals of two structures of 2bb were also observed in the ¹H NMR spectrum: at 0.81, 0.73 (two overlapping triplets) and 0.65 ppm triplets of AlCH₂CH₃ protons and four quartets at −0.36, −0.50, −0.51 and −0.64 of AlCH₂CH₃ protons.

In compound 3bb, due to the presence of Et₃Al molecules coordinated to the oxygen atoms from the SO₂ groups, there was an additional triplet of (CH₃CH₂)₃Al protons and a quartet of (CH₃CH₂)₃Al protons (at 0.92 and −0.29 ppm, respectively) in the ¹H NMR spectrum (Figure S13). In addition, there were four triplets at 1.03, 0.84, 0.74 and 0.63 ppm of CH₃CH₂Al protons; three quartets at −0.03, −0.46, −0.64 ppm and one quartet at −0.29 ppm overlapping the signal of the (CH₃CH₂)₃Al protons.

The ¹³C NMR spectra of the compounds revealed two signals of (SCH₂CH) carbon atoms (at 71.86 and 71.81 ppm for 2aa, at 72.09 and 72.04 ppm for 2ab, at 71.42 and 71.40 ppm for 2bb, at 71.02 and 70.95 ppm for 3bb and at 71.40 ppm broadened for 2ba), which also confirmed the presence of two structures in solutions. Likewise, instead of single signals, the SCH₂CH carbon atoms showed two signals: at 61.92 and 61.85 ppm for 2aa, at 62.17 and 62.09 ppm for 2ab, at 61.66 and 61.64 ppm for 2ba, at 61.59 ppm broadened for 2bb and at 61.74 and 61.45 ppm for 3bb.

The complex nature of the NMR spectra of 2aa, 2ab, 2ba, 2bb and 3bb complexes could be explained by the monomer–dimer equilibria in the solutions (Scheme 3). To confirm this, the molecular weight of the dissolved compounds was determined by the cryometric method. In the solid state, the compounds had the structures of dimeric (R*,S*) diastereomers, as shown by X-ray measurements (Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5). After dissolving the compounds, Al₂O₂ rings in dimeric structures were easily dissociated to form monomeric structures stabilized by the formation of Al–O coordination bonds between the oxygen atoms of the SO₂ group and aluminum atoms. The association degrees calculated from the values of molecular weights ranged from 1.22 (for 3bb) to 1.50 (for 2ab), which means that, in solutions of compounds 3bb and 2ab, there were 22 and 49 mol% of the dimeric structure, respectively. Taking into account the results of NMR studies and molecular weight measurements, it can be concluded that hydroalumination products of β-keto sulfones exist as an equilibrium mixture of monomers–dimers in solutions (Scheme 3).

Since the tautomeric equilibrium in the β-keto sulfones solutions was almost completely shifted towards the ketone form, only this form was taken into account in the hydroalumination mechanism suggested. When i-Bu₂AlH was used, the mechanism was based on the assumption of a charge distribution between the carbonyl C=O and Al-H groups, allowing the formation of an intermediate state. The oxygen atom in the C=O group with a partially negative charge interacted with a partially positive aluminum, and the partially negative charged hydrogen atom Al–H was transferred to the C=O carbon atom simultaneously (Scheme 4). We have recently proposed a similar mechanism for the hydroalumination of β-keto sulfones with t-Bu₂AlH [26].

In the reactions of β-keto sulfones with i-Bu₃Al an Et₃Al, β-hydrogen from the i-Bu or Et group bonded to the partially positive C=O carbon, and the aluminum atom interacted with the negative oxygen atom C=O. An intermediate state involving six atoms, AlCCHCO, was formed. In the next step, the alkene molecule was removed, and the aluminum complex of β-hydroxy sulfone was formed (Scheme 4). The similar mechanism was previously published by Ashby for a ketone reduction reaction with i-Bu₃Al [27].

2.2. Hydrogenation of β-Keto Sulfones to β-Hydroxy Sulfones

Reaction mixtures of β-keto sulfones with aluminum compounds were hydrolyzed to decompose the complexes. The obtained products were characterized by NMR spectroscopy to determine the molar ratio of β-hydroxy sulfone to β-keto sulfone on the basis of an integration of SO₂CH proton signals in β-hydroxy sulfone and in β-keto sulfone. The yield of β-hydroxy sulfones (Table 1) illustrated an efficiency of the β-keto sulfone hydrogenation process. We determined the effect of the structure of β-keto sulfones, the type of aluminum compound and the reaction conditions on the efficiency of the hydrogenation of β-keto sulfones to β-hydroxy sulfones. We found that the hydrogenation reaction depended primarily on the nature of the aluminum alkyl compound. The most active reagent was i-Bu₃Al, which reduced quantitatively all β-keto sulfones regardless of their structure. Et₃Al was a good reducer for β-keto sulfones 1a,b and 1d,e, with electron-withdrawing substituents in the β-position, while the hydrogenation of β-keto sulfone 1c with an electron-donating methyl group was 75% efficient. Using an excess of Et₃Al slightly increased the yield of β-hydroxy sulfone 4c to 82% (Table 1, run 3). The activity of n-Bu₃Al, n-Hex₃Al and t-Bu₃Al in the hydrogenation of β-keto sulfones was weaker compared to the activity of i-Bu₃Al and Et₃Al. However, using an excess of n-Hex₃Al and t-Bu₃Al to reduce the β-keto sulfones 1a and 1b resulted in a significant increase in yield from 55 to 100% and from 8 to 92%, respectively (Table 1, runs 1 and 2). The presence of chloride substituents in alkyl aluminum compounds significantly reduced the activity of these compounds in the hydrogenation of β-hydroxy sulfones. In the presence of an equimolar amount of Et₂AlCl only 17% of the beta keto sulfone, 1b was reduced. For a 1:2 molar ratio of Et₂AlCl:1b, β-hydroxy sulfone 4b was obtained with a yield of 25% (Table 1, run 2). EtAlCl₂ was inactive in the hydrogenation of β-keto sulfones (Table 1, run 1).

The nature of the starting β-keto sulfones had a less significant effect on their ability to be hydrogenated with alkyl aluminum compounds. The presence of electron-withdrawing groups on the C=O carbon atom, such as the phenyl substituent in compounds 1a,b and 1d,e, caused an increase in the partial positive charge on the C=O carbon atom, which favored the reduction of β-keto sulfones, as shown in the Scheme 4.

Earlier studies on ketone hydrogenation showed that the presence of a Lewis base (e.g., diethyl ether, THF) inactivates the reducing properties of aluminum alkyls [31]. That was why we used methylene dichloride, n-pentane and n-hexane as solvents; however, methylene dichloride proved to be the best due to the good solubility of the compounds.

The reaction of aluminum alkyls with β-keto sulfones and subsequent hydrolysis of postreaction mixtures was a simple method of β-keto sulfones hydrogenation. However, this method was suitable when the β-keto sulfone was completely hydroaluminated by an alkyl aluminum compound. On the other hand, in the presence of less active aluminum alkyls, only a part of the β-keto sulfone could be hydroaluminated. Then, in the postreaction mixture, there were alkyl aluminum complexes with β-hydroxy sulfone and β-keto sulfone ligands, which, after hydrolysis, yielded a mixture of β-hydroxy sulfone and β-keto sulfone. In order to avoid a difficult separation of β-hydroxy sulfone from this mixture, the alkyl aluminum complex with β-hydroxy sulfone ligands should be crystallized from the reaction mixture and then hydrolyzed to pure β-hydroxy sulfone. Complexes with β-keto sulfone ligands were thick liquids, which facilitated the separation of solid complexes with β-hydroxy sulfone ligands.

3. Materials and Methods

3.1. General Remarks

All manipulations were carried out using standard Schlenk techniques under an inert gas atmosphere. Methylene dichloride was deacidified with basic Al₂O₃ and distilled over P₂O₅ under argon. ¹H and ¹³C NMR spectra were obtained on a Varian Mercury-400 MHz spectrometer (Varian International AG, Switzerland). Chemical shifts were referenced to the residual proton signals of CDCl₃ (7.26 ppm). ¹³C NMR spectra were acquired at 100.60 MHz (standard: chloroform ¹³CDCl₃, 77.20 ppm). NMR spectra can be found in the Supporting Information (Figures S1–S15). Tri-iso-butyl aluminum and di-iso-butyl aluminum hydride were from Sigma-Aldrich Company (Poznań, Poland). β-Keto sulfones 1a–e were synthesized according to the literature data [44]. Hydrolysable alkyl groups bonded to Al atoms for products 2aa, 2ab, 2ba, 2bb and 3bb were determined by hydrolysis of the compound (0.2 to 0.3 g) using HNO₃ solution (10% concentrated, 5 cm³) and measurement of the volume of gaseous alkane (C₄H₁₀ or C₂H₆). Subsequently, the sample was transformed into Al₂O₃ by mineralization, and the obtained white solid was dissolved in a diluted water solution of HNO₃. The content of aluminum was determined by the complexation of Al³⁺ cations with versenate anions using an excess of the titrated solution of calcium disodium versenate. Then, the excess of calcium disodium versenate was titrated by FeCl₃.

3.2. X-ray Crystallography

The X-ray measurements of compounds 2aa, 2ab, 2ba, 2bb and 3bb were performed at 100(2) K on a Bruker D8 Venture Photon100 diffractometer equipped with a TRIUMPH monochromator and a MoKα fine focus-sealed tube (λ = 0.71073 Å). The total frames were collected with the Bruker APEX2 program [45]. The temperature of the samples was 100 K. The frames were integrated with the Bruker SAINT software package [46] using a narrow frame algorithm. Data were corrected for absorption effects using the multi-scan method (SADABS) [47]. The structures were solved and refined using the SHELXTL software package [48,49]. The atomic scattering factors were taken from the International Tables [50]. All hydrogen atoms were placed in calculated positions and refined within the riding model. Detailed crystallographic data are listed in Tables S1 and S2.

3.3. Reactions of β-Keto Sulfones with Alkyl Aluminum Compounds—General Procedure

A solution of a suitable amount of alkyl aluminum compound in methylene dichloride was added to a solution of 2 mmol of β-keto sulfone in 10 cm³ of methylene dichloride at 0–5 °C with stirring. After warming up to room temperature, the postreaction mixture was subjected to hydrolysis.

3.4. Preparation of Hydroalumination Products

Reactions of i-Bu₃Al, i-Bu₂AlH and Et₃Al with β-Keto Sulfones

A solution of i-Bu₂AlH (0.284 g, 2 mmol) or i-Bu₃Al (0.396 g, 2 mmol) in 10 cm³ of methylene dichloride was added to a solution of β-keto sulfone (0.548 g, 2 mmol of 1a or 0.589 g, 2 mmol of 1b) in 10 cm³ at 0–5 °C with stirring. A solution of Et₃Al (0.228 g, 2 mmol) in 10 cm³ of methylene dichloride was added to a solution of β-keto sulfone (0.548 g, 2 mmol of 1a or 0.589 g or 2 mmol of 1b) in 10 cm³ at −76 °C with stirring. A solution of Et₃Al (0.456 g, 2 mmol) in 20 cm³ of methylene dichloride was added to a solution of β-keto sulfone 1b (0.589 g, 2 mmol) in 10 cm³ at −76 °C with stirring. The mixtures were stirred for 1 h at this temperature and then allowed to warm to ambient temperature. The solvent was removed from the postreaction mixtures by distillation under vacuum. A thick liquid was obtained when the reagent was i-Bu₂AlH, while white solids were obtained when the reagents were i-Bu₃Al and Et₃Al. White crystals of the complexes 2aa, 2ab, 2ba, 2bb and 3bb suitable for X-ray measurements were precipitated from n-C₆H₁₄/CH₂Cl₂ solutions. Before measuring the molecular weight by the cryoscopic method in benzene and analysis, samples of compounds were placed under vacuum (10⁻² Torr) for 5 h to remove the solvent. Yield: i-Bu₃Al reacted with β-keto sulfones 1a and 1b, yielding compounds 2aa and 2ab quantitatively (based on NMR spectra), while postreaction mixtures of i-Bu₂AlH with β-keto sulfones 1a and 1b, besides 2aa and 2ab, consisted of side products.

Di-iso-butyl aluminum complex with 2-((4-methylphenyl)sulfonyl)-1-phenylethanol (2aa): ¹H NMR (Figures S1 and S2) δ: 7.40–7.15 (9H, m, H_aromat), 5.20 (1H, m, CH), 3.93–3.75 (2H, m, CH₂), 2.37 (3H, s, CH₃), 1.49, 1.40 and 1.31 (2 H, 3 multiplets, AlCH₂C(H)(CH₃)₂), 0.81, 0.77, 0.76 and 0.71 (6H, 4 overlapping doublets, ³J_H—4 Hz, AlCH₂C(H)(CH₃)₂), −0.28, −0.39, −0.41 and −0.51 (4H, 4 doublets, ³J_H—4 Hz, AlCH₂C(H)(CH₃)₂). ¹³C NMR (Figure S3) δ 144.69, 144.65, 136.53, 136.45, 135.90, 135.86 129.80, 129.66, 129.65, 128.98, 128.38, 127.75, 127.72 (C_aromat), 71.86, 71.81 (SCH₂CH), 61.92, 61.85 (SCH₂CH), 28.13, 28,10, 28.03 (AlCH₂C(H)(CH₃)₂), 25.37, 25.27, 25.18 (AlCH₂C(H)(CH₃)₂), 23.03, 22.99, 22.82 (AlCH₂C(H)(CH₃)₂), 21.52 (PhCH₃) ppm. Mp.: 153–156 °C. Molecular weight: 590 g/mol (cal. for 2aa monomer 416.5 g/mol; for 2aa dimer 833 g/mol). Anal. Al, 6.15; hydrolysable i-Bu groups, 26.55; calcd for 2aa (C₄₆H₆₆Al₂O₆S₂): Al, 6.49; i-Bu groups, 27.40 wt%.

Di-iso-butyl aluminum complex with 2-((4-chlorophenyl)sulfonyl)-1-phenylethanol (2ab): ¹H NMR (Figures S4 and S5) δ: 7.38–7.13 (9H, m, H_aromat), 5.24 (1H, m, CH), 3.93–3.77 (2H, m, CH₂), 1.50, 1.40 and 1.32 (2 H, 3 multiplets, AlCH₂C(H)(CH₃)₂), 0.82, 0.78, 0.77 and 0.72 (6H, 4 overlapping doublets, ³J_H—4 Hz, AlCH₂C(H)(CH₃)₂), −0.26, −0.37, −0.39 and −0.50 (4H, 4 doublets, ³J_H—4 Hz, AlCH₂C(H)(CH₃)₂). ¹³C NMR (Figure S6) δ: 140.63, 140.60, 137.43, 137.38, 136.31, 136.23, 130.35, 129.52, 129.38, 129.35, 128.65 (C_aromat), 72.09, 72.04 (CH₂CH), 62.17, 62.09 (S-CH₂), 28.40, 28,37, 28.31 (AlCH₂C(H)(CH₃)₂), 25.67, 25.57, 25.49 (AlCH₂C(H)(CH₃)₂), 23.33, 23.26, 23.04 (broad, AlCH₂C(H)(CH₃)₂) ppm. Mp.: 113–118 °C. Molecular weight: 651 g/mol (calc. for 2ab monomer 436.5 g/mol; for 2ab dimer 873 g/mol). Anal. Al, 5.87; hydrolysable i-Bu groups, 25.30; calcd for 2ab (C₄₄H₆₀Al₂Cl₂O₆S₂): Al, 6.18; i-Bu groups, 26.09 wt%.

Di-ethyl aluminum complex with 2-((4-methylphenyl)sulfonyl)-1-phenylethanol (2ba): ¹H NMR (Figures S7 and S8) δ: 7.42 (2H, m, H_aromat), 7.28–7.11 (7H, m, H_aromat), 5.17 (1H, m, CH), 3.88–3.80 (1H, m, CH₂), 3.73–3.67 (1H, m, CH₂), 2.35 (3H, s, CH₃Ph), 0.80 (1.5H, t, AlCH₂CH₃), 0.72 (3H, two overlapping triplets, AlCH₂CH₃), 0.64 (1.5H, t, AlCH₂CH₃), −0.39 (1H, q, AlCH₂CH₃), −0.53, −0.53 (2H, two quartets, AlCH₂CH₃), −0.65 (1H, q, AlCH₂CH₃). ¹³C NMR (Figure S9) δ: 144.80, 144.77, 136.90, 135.87, 135.60, 129.73, 129.69, 129.67, 128.93, 127.86, 127.75, 127.74 (Caromat), 71.40 (CH₂CH, broadened), 61.66, 61.64 (S-CH₂), 21.53 (CH₃Ph), 8.63, 8.57, 8.49 (AlCH₂CH3), 0.42 (AlCH₂CH₃, broadened) ppm. Mp.: = 132–136 °C. Molecular weight: 450 g/mol (calc. for 2ba monomer 360 g/mol; for 2ba dimer 720 g/mol). Anal. Al, 7.28; hydrolysable Et groups, 15.82; calcd for 2ba (C₃₈H₅₀Al₂O₆S₂): Al, 7.50; Et groups, 16.11 wt%.

Di-ethyl aluminum complex with 2-((4-chlorophenyl)sulfonyl)-1-phenylethanol (2bb): ¹H NMR (Figures S10 and S11) δ: 7.40–7.12 (9H, m, H_aromat), 5.19 (1H, m, CH), 3.90–3.69 (2H, m, CH₂), 0.81 (1.5H, t, AlCH₂CH₃), 0.73 (3H, two triplets, AlCH₂CH₃), 0.65 (1.5H, t, AlCH₂CH₃), −0.36 (1H, q, AlCH₂CH₃), −0.50, −0.51 (2H, two quartets, AlCH₂CH₃), −0.64 (1H, q, AlCH₂CH₃). ¹³C NMR (Figure S12) δ: 140.43, 140.40, 136.92, 136.34, 130.02, 129.28, 129.26, 129.16, 129.14, 129.09, 127.86 (C_aromat), 71.42, 71.40 (CH₂CH), 61.59 (S-CH₂), 8.62, 8.56, 8.48 (AlCH₂CH₃), 0.35 (AlCH₂CH₃, broadened) ppm. Mp.: 130–133 °C. Molecular weight: 505 g/mol (calc. for 2bb monomer 380.5 g/mol; for 2bb dimer 761 g/mol). Anal. Al, 7.01; hydrolysable Et groups, 15.79; calcd for 2bb (C₃₆H₄₄Al₂Cl₂O₆S₂): Al, 7.10; Et groups, 16.11 wt%.

Di-ethyl aluminum complex with 2-((4-chlorophenyl)sulfonyl)-1-phenylethanol and triethyl aluminum (3bb): ¹H NMR (Figures S13 and S14) δ: 7.31–7.08 (9H, m, H_aromat), 5.20 (1H, m, CH), 4.26–3.94 (2H, m, CH₂), 1.03, 0.84, 0.74, 0.63 (6H, four triplets, AlCH₂CH₃), 0.92 (9H, t, Al(CH₂CH₃)₃), −0.03, −0.46, −0.64 (3H, 3q, AlCH₂CH₃), −0.29 (6H of Al(CH₂CH₃)₃ and 1H of AlCH₂CH₃, q, AlCH₂CH₃). ¹³C NMR (Figure S15) δ: 142.50, 142.47, 134.90, 134.83, 133.28, 130.79, 129.99, 129.91, 129.56, 129.08, 129.05, 128.72, 128.49, 128.35, 127.77, 125.39 (C_aromat), 71.02, 70.95 (CH₂CH), 61.74, 61.45 (S-CH₂), 9.38, 8.50, 8.40, 8.27 (AlCH₂CH₃), 1.05, 0.67, 0.16, 0.08 (AlCH₂CH₃) ppm. Mp.: 148–150 °C. Molecular weight: 604 g/mol (calc. for 3bb monomer 494.5 g/mol; for 3bb dimer 989 g/mol). Anal. Al, 10.65; hydrolysable Et groups, 28.97; calcd for 3bb (C₄₈H₇₄Al₄Cl₂O₆S₂₎: Al, 10.92; Et groups, 29.32 wt%.

3.5. Preparation of β-Hydroxy Sulfones

Method 1: Hydrolysis of isolated compounds 2aa, 2ab, 2ba, 2bb and 3bb. A solution of 0.5 mmol of compounds 2 (or 3bb) in 10 cm³ of CH₂Cl₂ and 10 cm³ of a 10% solution of hydrochloric acid was added to the separating funnel. After shaking, the organic layer was separated, and the aqueous layer was washed twice with 10 cm³ of CH₂Cl₂. The organic layers were combined, and the solvent was distilled under vacuum. White solids of a pure β-hydroxy sulfones 4a (or 4b) were obtained.

Method 2: Hydrolysis of postreaction mixtures of the reactions of β-keto sulfones 1a–1e with aluminum compounds. The postreaction mixtures of the reaction of 0.5 mmol of β-keto sulfone (10 cm³ of the CH₂Cl₂ solution) reacted with water, according to the procedure described in Method 1.

The results of the conversion of β-keto sulfones to β-hydroxy sulfones are presented in Table 1. Mp of 2-hydroxy-2-phenyethyl-4-mehylphenylsulfone 4a: 74–75 °C, (literature data 69–71 °C [17], 69.4–70.8 °C [51], 78–79 °C [52] and 74–75 °C [53]; Mp of 2-hydroxy-2-phenyethyl-4-chlorophenylsulfone 4b: 105–107 °C (literature data 106–108 °C [53], 105–106 °C [54] and 103.5–105 °C [55]); Mp of 1-(4-methylphenylsulfonyl)propan-2-ol 4c: 75–76 °C (literature data 78 °C [56]); Mp of 2-[(4’-methylphenyl)sulfonyl]-1,2-diphenylethanol 4d: 159–160 °C (literature data 156–157 °C [57]) and Mp of 1-phenyl-2-(4-methylphenylsulfonyl)propan-1-ol 4e: 100–103 °C (literature data 99–100.5 °C [58]).

4. Conclusions

Although aluminum trialkyls R₃Al with substituents that have β-hydrogens are active reducing agents of β-keto sulfones to β-hydroxy sulfones, the reducing properties of aluminum iso-butyl compounds (i-Bu₃Al and i-Bu₂AlH) and Et₃Al are the greatest. In reactions of β-keto sulfones with R₃Al, the hydroalumination of β-keto sulfones takes place, resulting in the formation of aluminum complexes with β-hydroxy sulfones considered as intermediates in the production of β-hydroxy sulfones. In the solid state, these complexes exhibit as dimers, while, in solutions, they undergo an equilibrium between monomeric and dimeric forms. The hydrolysis of both the isolated aluminum complexes with β-hydroxy sulfones and the postreaction mixtures quantitatively lead to pure racemic β-hydroxy sulfones. Summarizing, the hydroalumination reaction of β-keto sulfones with i-Bu₃Al, i-Bu₂AlH and Et₃Al, followed by the hydrolysis of the resulting complexes in the postreaction mixtures, is a simple and efficient method for racemic β-hydroxy sulfones.

Author Contributions

Conceptualization and writing—original draft preparation, W.Z.; methodology and investigation, M.K., Z.O., M.S. and P.S.; supervision, Ł.D. and software and formal analysis, V.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research work was carried out as part of the project entitled “MatFizChemPW—raising mathematical and natural science and ICT competences in school youth” (POWR.03.01.00-00-T163/18), implemented by the Warsaw University of Technology and co-financed by the National Center for Research and Development (NCBR) from the European Social Fund under Knowledge, Education and Development Program 2014-2020.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The date presented in this study are available in the Supplementary Materials.

Acknowledgments

The authors would like to thank the Advanced Crystal Engineering Laboratory (aceLAB) at the Chemistry Department of the University of Warsaw, Poland for the X-ray structure determinations.

Conflicts of Interest

The authors declare no conflict of interest.

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

Figures, Schemes and Table

Scheme 1. An equilibrium of β-keto sulfone tautomers.

Scheme 2. Synthesis of β-hydroxy sulfones 4a–4e by hydroalumination of β-keto sulfones and hydrolysis of the compounds 2aa, 2ab, 2ba, 2bb and 3bb or hydrolysis of postreaction mixtures of the reactions of β-keto sulfones 1a–1e with R3Al (where R = i-Bu, Et) or R2AlH (where R = i-Bu).

Figure 1. Thermal ellipsoid plot (50% probability) of compound 2aa. Hydrogen atoms have been omitted for the sake of clarity. Selected bonds and distances (Å) and angles (°): Al(1)-O(3#) 1.859(1), Al(1#)-O(3#) 1.879(2), O(3)-C(2) 1.448(2), C(1)-C(2) 1.533(3), S(1)-C(1) 1.791(2), O(3)-Al(1)-O(3#) 80.00(6), Al(1)-O(3)-Al(1#) 100.00(6), C(2)-O(3)-Al(1) 124.2(1), C(2)-O(3)-Al(1) 130.7(1) and C(2)-C(1)-S(1) 113.0(1). The crystal structure contains two CH2Cl2 molecules per one C46H66Al2O6S2 molecule.

Figure 2. Thermal ellipsoid plot (50% probability) of compound 2ab. Hydrogen atoms have been omitted for the sake of clarity. Selected bonds and distances (Å) and angles (°): Al(1#)-O(3#) 1.852(1), Al(1#)-O(3) 1.8723(1), O(3#) C(8)-1.444(2), C(7)-C(8) 1.533(2), S(1)-C(7) 1.784(1), C(8)-O(3)-Al(1) 130.69(9), C(8)-O(3)-Al(1) 124.11(8), Al(1)-O(3)-Al(1) 99.89(5), O(3)-Al(1)-O(3#) 80.12(5) and O(3)-C(8)-C(7) 107.2(1). The crystal structure contains 1.91 CH2Cl2 molecules per one C44H60Al2Cl2O6S2 molecule.

Figure 3. Thermal ellipsoid plot (50% probability) of compound 2bb. Hydrogen atoms have been omitted for the sake of clarity. Selected bonds and distances (Å) and angles (°): Al(1)–O(1#) 1.851(1), Al(1)–O(1) 1.872(1), S(1)–O(2) 1.439(1), S(1)–O(3), 1.441(1), S(1)–C(8) 1.792(1), C(1)–C(8) 1.534(2), C(1)–O(1)–Al(1) 128.72(8), C(1)–O(1)–Al(1#)–126.46(8), Al(1)–O(1)–Al(1#) 99.63(5), C(1)–C(8)–S(1) 115.3(1) and C(2)–C(1)–C(8) 114.9(1).

Figure 4. Thermal ellipsoid plot (50% probability) of compound 2ba. Hydrogen atoms have been omitted for the sake of clarity. Selected bonds and distances (Å) and angles (°): S(1)–O(2) 1.443(1), S(1)–O(3) 1.444(1), Al(1#)–O(1) 1.853(1), O(1)–Al(1) 1.874(1), C(5)–C(12) 1.538(2), C(5)–C(12)–S(1) 114.3(1), C(5)–O(1)–Al(1#) 128.31(9), C(5)–O(1)–Al(1) 126.70(9) and Al(1)–O(1)–Al(1#) 99.72(6).

Figure 5. Thermal ellipsoid plot (50% probability) of compound 3bb. Hydrogen atoms have been omitted for the sake of clarity. Selected bonds and distances (Å) and angles (°): Al(1)–O(1#) 1.858(2), Al(1)–O(1) 1.874(2), C(6)–C(13) 1.533(4), S(1)–O(2) 1.432(2), S(1)–O(3) 1.465(2), Al(2)–O(3) 1.971(2), O(1)–Al(1)–O(1) 79.59(8), Al(1)–O(1)–Al(1#) 100.41(8), C(6)–O(1)–Al(1#) 129.2(2), C(6)–O(1)–Al(1) 127.0(2) and C(6)–C(13)–S(1) 115.0(2).

Scheme 3. Equilibrium monomer-dimer mixtures of the hydroalumination products.

Scheme 4. The proposed mechanism for β-keto sulfone hydroalumination with i-Bu2AlH, i-Bu3Al and Et3Al.

Table 1

Hydrogenation of β-keto sulfones to β-hydroxy sulfones.

Run	β-Keto Sulfone	AlkylAluminum Reagents	MolarRatio a	Solvent	YieldMolar Ratio b	β-HydroxySulfone
1.	[Image omitted. Please see PDF.] 1a	i-Bu3Al ci-Bu2AlH cEt3Al ci-Bu3Ali-Bu2AlHEt3AlEt3Aln-Bu3Aln-Bu3Aln-Hex3Aln-Hex3AlEtAlCl2EtAlCl2	1:11:11:11:11:11:11:21:11:11:11:31:11:2	CH2Cl2CH2Cl2CH2Cl2CH2Cl2CH2Cl2CH2Cl2CH2Cl2CH2Cl2C6H5CH3CH2Cl2CH2Cl2CH2Cl2CH2Cl2	100:0 c100:0 c100:0 c100:0100:0100:0100:076:2452:4855:45100:00:1000:100	[Image omitted. Please see PDF.] 4a
2.	[Image omitted. Please see PDF.] 1b	i-Bu3Al ci-Bu2AlH cEt3Al cEt3Al ci-Bu3Ali-Bu2AlHEt3AlEt3Alt-Bu3Alt-Bu3AlEt2AlClEt2AlCl	1:11:11:21:11:11:11:21:11:11:21:11:2	CH2Cl2CH2Cl2CH2Cl2CH2Cl2CH2Cl2CH2Cl2CH2Cl2CH2Cl2n-C5H12n-C5H12CH2Cl2CH2Cl2	100:0 c100:0 c100:0 c100:0 c100:0100:0100:0100:08:9292:817:8325:75	[Image omitted. Please see PDF.] 4b
3.	[Image omitted. Please see PDF.] 1c	Et3AlEt3Ali-Bu3Al	1:11:21:1	CH2Cl2CH2Cl2CH2Cl2	75:2582:18100:0	[Image omitted. Please see PDF.] 4c
4.	[Image omitted. Please see PDF.] 1d	Et3AlEt3Ali-Bu3Al	1:11:21:1	CH2Cl2CH2Cl2CH2Cl2	100:0100:0100:0	[Image omitted. Please see PDF.] 4d
5.	[Image omitted. Please see PDF.] 1e	Et3AlEt3Ali-Bu3Al	1:11:21:1	CH2Cl2CH2Cl2CH2Cl2	100:0100:0100:0	[Image omitted. Please see PDF.] 4e

^a Molar ratio of β-keto sulfone:alkyl aluminum reagent. ^b Molar ratio of β-hydroxy sulfone:β-keto sulfone in the reaction products based on ¹H NMR spectra. ^c The isolated hydroalumination reaction product of β-keto sulfone with aluminum compounds 2aa, 2ab, 2ba, 2bb and 3bb were subjected to hydrolysis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27072357/s1: characterization of β-keto sulfones 1a–e and β-hydroxy sulfones 4a–e; NMR spectra of the compounds 2aa, 2ab, 2ba, 2bb and 3bb and crystal data and data collection parameters for the compounds 2aa, 2ab, 2ba, 2bb and 3bb. CCDC reference numbers 2104787, 2104788, 2154603, 2154605 and 2154606 contain the supplementary crystallographic data of compounds 2aa, 2ab, 2ba, 2bb and 3bb for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone] or e-mail: [email protected].

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