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Article

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

by
Michał Kotecki
1,
Zbigniew Ochal
1,
Paweł Socha
2,
Vadim Szejko
1,
Łukasz Dobrzycki
2,
Mariola Stypik
1 and
Wanda Ziemkowska
1,*
1
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
2
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(7), 2357; https://doi.org/10.3390/molecules27072357
Submission received: 27 February 2022 / Revised: 30 March 2022 / Accepted: 4 April 2022 / Published: 6 April 2022
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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.

Graphical Abstract

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, Haromat), 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, 3JH—4 Hz, AlCH2C(H)(CH3)2), −0.28, −0.39, −0.41 and −0.51 (4H, 4 doublets, 3JH—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 (Caromat), 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, Haromat), 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, 3JH—4 Hz, AlCH2C(H)(CH3)2), −0.26, −0.37, −0.39 and −0.50 (4H, 4 doublets, 3JH—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 (Caromat), 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, Haromat), 7.28–7.11 (7H, m, Haromat), 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, Haromat), 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 (Caromat), 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, Haromat), 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 (Caromat), 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.

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: (+44)-1223-336-033 or e-mail: [email protected].

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.

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Molecules 27 02357 sch001 550
Scheme 1. An equilibrium of β-keto sulfone tautomers.
Scheme 1. An equilibrium of β-keto sulfone tautomers.
Molecules 27 02357 sch001
Molecules 27 02357 sch002 550
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).
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).
Molecules 27 02357 sch002
Molecules 27 02357 g001 550
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 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.
Molecules 27 02357 g001
Molecules 27 02357 g002 550
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 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.
Molecules 27 02357 g002
Molecules 27 02357 g003 550
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 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).
Molecules 27 02357 g003
Molecules 27 02357 g004 550
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 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).
Molecules 27 02357 g004
Molecules 27 02357 g005 550
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).
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).
Molecules 27 02357 g005
Molecules 27 02357 sch003 550
Scheme 3. Equilibrium monomer-dimer mixtures of the hydroalumination products.
Scheme 3. Equilibrium monomer-dimer mixtures of the hydroalumination products.
Molecules 27 02357 sch003
Molecules 27 02357 sch004 550
Scheme 4. The proposed mechanism for β-keto sulfone hydroalumination with i-Bu2AlH, i-Bu3Al and Et3Al.
Scheme 4. The proposed mechanism for β-keto sulfone hydroalumination with i-Bu2AlH, i-Bu3Al and Et3Al.
Molecules 27 02357 sch004
Table
Table 1. Hydrogenation of β-keto sulfones to β-hydroxy sulfones.
Table 1. Hydrogenation of β-keto sulfones to β-hydroxy sulfones.
Runβ-Keto SulfoneAlkyl
Aluminum Reagents		Molar
Ratio a		SolventYield
Molar Ratio b		β-Hydroxy
Sulfone
1. Molecules 27 02357 i001
1a		i-Bu3Al c
i-Bu2AlH c
Et3Al c
i-Bu3Al
i-Bu2AlH
Et3Al
Et3Al
n-Bu3Al
n-Bu3Al
n-Hex3Al
n-Hex3Al
EtAlCl2
EtAlCl2		1:1
1:1
1:1
1:1
1:1
1:1
1:2
1:1
1:1
1:1
1:3
1:1
1:2		CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C6H5CH3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2		100:0 c
100:0 c
100:0 c
100:0
100:0
100:0
100:0
76:24
52:48
55:45
100:0
0:100
0:100		 Molecules 27 02357 i002
4a
2. Molecules 27 02357 i003
1b		i-Bu3Al c
i-Bu2AlH c
Et3Al c
Et3Al c
i-Bu3Al
i-Bu2AlH
Et3Al
Et3Al
t-Bu3Al
t-Bu3Al
Et2AlCl
Et2AlCl		1:1
1:1
1:2
1:1
1:1
1:1
1:2
1:1
1:1
1:2
1:1
1:2		CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
n-C5H12
n-C5H12
CH2Cl2
CH2Cl2		100:0 c
100:0 c
100:0 c
100:0 c
100:0
100:0
100:0
100:0
8:92
92:8
17:83
25:75		 Molecules 27 02357 i004
4b
3. Molecules 27 02357 i005
1c		Et3Al
Et3Al
i-Bu3Al		1:1
1:2
1:1		CH2Cl2
CH2Cl2
CH2Cl2		75:25
82:18
100:0		 Molecules 27 02357 i006
4c
4. Molecules 27 02357 i007
1d		Et3Al
Et3Al
i-Bu3Al		1:1
1:2
1:1		CH2Cl2
CH2Cl2
CH2Cl2		100:0
100:0
100:0		 Molecules 27 02357 i008
4d
5. Molecules 27 02357 i009
1e		Et3Al
Et3Al
i-Bu3Al		1:1
1:2
1:1		CH2Cl2
CH2Cl2
CH2Cl2		100:0
100:0
100:0		 Molecules 27 02357 i010
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.
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Kotecki, M.; Ochal, Z.; Socha, P.; Szejko, V.; Dobrzycki, Ł.; Stypik, M.; Ziemkowska, W. Hydrogenation of β-Keto Sulfones to β-Hydroxy Sulfones with Alkyl Aluminum Compounds: Structure of Intermediate Hydroalumination Products. Molecules 2022, 27, 2357. https://doi.org/10.3390/molecules27072357

AMA Style

Kotecki M, Ochal Z, Socha P, Szejko V, Dobrzycki Ł, Stypik M, Ziemkowska W. Hydrogenation of β-Keto Sulfones to β-Hydroxy Sulfones with Alkyl Aluminum Compounds: Structure of Intermediate Hydroalumination Products. Molecules. 2022; 27(7):2357. https://doi.org/10.3390/molecules27072357

Chicago/Turabian Style

Kotecki, Michał, Zbigniew Ochal, Paweł Socha, Vadim Szejko, Łukasz Dobrzycki, Mariola Stypik, and Wanda Ziemkowska. 2022. "Hydrogenation of β-Keto Sulfones to β-Hydroxy Sulfones with Alkyl Aluminum Compounds: Structure of Intermediate Hydroalumination Products" Molecules 27, no. 7: 2357. https://doi.org/10.3390/molecules27072357

APA Style

Kotecki, M., Ochal, Z., Socha, P., Szejko, V., Dobrzycki, Ł., Stypik, M., & Ziemkowska, W. (2022). Hydrogenation of β-Keto Sulfones to β-Hydroxy Sulfones with Alkyl Aluminum Compounds: Structure of Intermediate Hydroalumination Products. Molecules, 27(7), 2357. https://doi.org/10.3390/molecules27072357

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