Highly Enantioselective One-Pot Synthesis of Chiral β-Heterosubstituted Alcohols via Ruthenium-Prolinamide-Catalyzed Asymmetric Transfer Hydrogenation.

The utility of a chiral Ru-prolinamide catalytic system has been demonstrated in one-pot synthesis of optically active β-triazolylethanol and β-hydroxy sulfone derivatives. The said methodology proceeds through asymmetric transfer hydrogenation of in situ formed ketones of the corresponding chiral products. Various chiral prolinamide ligands were screened, and ligand L6 with isopropyl groups substituted at the ortho position has shown excellent activity at 60 °C in aqueous medium producing up to 95% yield and 99.9% enantioselectivity.

Introduction

One-pot organic transformation is an excellent tool to construct complex molecules involving relatively cheap and easily accessible starting materials.[1] This methodology includes a one-pot sequential reaction, one-pot tandem reaction, which converts readily available raw materials into highly value-added products. From a green chemistry point of view, this type of transformation is essential because it avoids multistep reactions, thereby decreasing waste production. In addition, there is no need of isolation of the intermediate and the targeted product could be obtained with high yields. This type of transformation involving environmentally and economically friendly synthetic processes is highly advisable from an industrial point of view and hence resulted in the development of the one-pot synthetic method.

Chiral secondary alcohols have emerged as an important structural motif in pharmaceuticals, agrochemicals, and other fine chemical industries, resulting in greater demand of these fine chemicals.[2] Scientists across the world have accelerated the development of asymmetric catalytic methodologies to synthesize optically active compounds in a more efficient way. Transition-metal-catalyzed asymmetric transfer hydrogenation (ATH) involving metals like ruthenium, rhodium, and iridium is one of the highly utilized methods to prepare chiral secondary alcohols. For this purpose, the chiral N-sulfonylated ethylene diamine ligand[9] in the presence of a metal is widely used as a chiral source to induce chirality in the prochiral ketones.

Optically active chiral β-heterosubstituted alcohols, namely, β-triazolylethanol and β-hydroxy sulfone, have been found as a potent pharmacophore in medicinal chemistry.[3] In particular, these structures have been found to show significant antifungal and antimalarial activities. Due to this wide utility in the field of pharmaceutical and medicinal chemistry, various methods have been used to construct chiral β-triazolylethanol and β-hydroxy sulfone by researchers. For instance, Hua et al. reported a pathway via a reductase-catalyzed asymmetric reduction of azido alkanones, followed by copper(I)-catalyzed azide–alkyne [3 + 2] click cycloaddition to produce optically active triazolylethanol.[4]

Feringa et al. reported a one-pot cycloaddition to produce β-triazolylethanol with excellent enantioselectivity; however, the conversion to the desired product obtained is <50% in most cases (Scheme A,a).[5] Optically active β-hydroxy sulfone has been synthesized via one-pot transformation by Liu et al. (Scheme A,b).[6] Similarly, Zhang et al.[7] synthesized the β-hydroxy sulfone via dynamic kinetic resolution employing Noyori’s Ru–TsDPEN ligand. Recently, we have reported “catalytic asymmetric synthesis of β-triazolyl amino alcohols by asymmetric transfer hydrogenation of α-triazolyl amino alkanones” with excellent enantioselectivity (Scheme B).[8] In this work, we made use of the N-sulfonylated diamine ligand[9] as a chiral source in the presence of ruthenium as a metal source. However, the work involved the preparation of the substrate first, followed by its ATH.

Scheme 1

One-Pot Synthesis and Asymmetric Transfer Hydrogenation of β-Triazolyl Amino Ketones

The chiral prolinamide ligand emerged as an excellent chiral source to induce chirality in nonchiral compounds. These ligands are widely used in aldol and Michael reactions.[10] In addition to them, Ru–prolinamide complexes are equally effective in ATH of prochiral ketone and have shown chiral activity in ATH reactions.[11] One of the good features of this catalytic system is that the system can be fine-tuned by changing the substituent on the amide. Also, this complex system is inexpensive and easy to prepare compared with the TsDPEN ligand and shows excellent chiral activity in aqueous medium. To this end, we tried one-pot cyclization, followed by ATH in the presence of Ru–prolinamide as a chiral source. For this purpose, we prepared various amide-substituted chiral prolinamide ligands and tested them in ATH reactions. Herein, we report one-pot synthesis of optically active chiral β-heterosubstituted alcohols via ruthenium–prolinamide-catalyzed ATH with excellent enantioselectivity.

Results and Discussion

Optimization study was started using 2-bromo-1-phenylethan-1-one as a model substrate. The model substrate was reacted at 50 °C with sodium azide, copper sulfate, sodium ascorbate, and phenyl acetylene in the presence of water/MeOH (1:3) as a solvent, followed by addition of [Ru(p-cymene)Cl2]2, HCOONa, and L1. Excellent enantioselectivity was obtained with poor conversion of the starting substrate (Table , entry 1). Similar conversion and enantioselectivity were observed when L2 was used as a chiral source (Table , entry 2). However, considerable drop in conversion and % ee was observed with L3 (Table , entry 3) and even poorer with L4 and L5 (Table , entries 4 and 5). This may be due to the functional group present on the amide part interfering with the stereodetermining transition state, resulting in lowering of % ee. Interestingly, amide substituted with the 2,6-diisopropyl substituent produced good % ee and conversion (Table , entry 6). Hence, ligand L6 was selected for further optimization studies. To optimize the solvent, first, ATH was tried only in water, with full conversion of reactant to intermediate ketone and only 33% of intermediate converted to the product with good enantiomeric excess (Table , entry 1). To increase the solubility of intermediate ketone, a cosolvent was introduced in the reaction mixture. The water–MeOH (1:2) system improved product formation up to 50% with full conversion of intermediate and 50% of the starting material remaining unreacted (Table , entry 2).

Table 1

Ligand Screeninga

entry	ligand	conv. (%)b	ee (%)b
1	L1	53	85
2	L2	56	86
3	L3	49	67
4	L4	10	48
5	L5	23	34
6	L6	61	90

Conditions: To 1a (0.5 mmol), phenyl acetylene (0.5 mmol), and sodium azide (1.5 mmol) in water/MeOH (1:3, 5 mL) were added copper sulfate (10 mmol %) and sodium ascorbate (0.05 mmol), followed by [RuCl2(p-cymene)]2 (2.5 mmol %), ligand (5 mmol %), and sodium formate (1.5 mmol) and stirred at 50 °C for 24 h.

The conversions and ee’s were for the chiral product determined by chiral high-performance liquid chromatography (HPLC).

Table 2

Reaction Optimization Studiesa

entry	solvent	temp.	time	conv. (%)b	ee (%)b
1	H2O	50	24	33	85
2	H2O/MeOH (1:2)	50	24	50	74
3	H2O/IPA (1:3)	50	24	59	89
4	H2O/t-BuOH (1:3)	50	24	49	81
5	IPA	50	24	8	24
6	H2O/IPA (1:2)	50	24	72	90
7	H2O/IPA (1:1)	50	24	91	92
8	H2O/IPA (1:1)	60	24	99	92
9	H2O/IPA (1:1)	27	24	10	39
10	H2O/IPA (1:1)	60	12	99	92
11	H2O/IPA (1:1)	60	6	99	93
12	H2O/IPA (1:1)	60	3	63	90
13	H2O/PA (1:1)	60	6	traces

Conditions: To 1a (0.5 mmol), phenyl acetylene (0.5 mmol), and sodium azide (1.5 mmol) in the given solvent were added copper sulfate (10 mmol %) and sodium ascorbate (0.05 mmol), followed by [RuCl2(p-cymene)]2 (2.5 mmol %), L6 (5 mmol %), and sodium formate (1.5 mmol) and stirred at a given time and temperature.

The conversions and ee’s were for the chiral product determined by chiral HPLC.

Other cosolvent systems like water–isopropyl alcohol (IPA) (1:3) and water–t-BuOH gave similar results in terms of conversion and ee (Table , entries 3 and 4). Of these, water–IPA (1:3) gave a slightly better result; thus, we tried a reaction in IPA only, and 8% of conversion was obtained with poor selectivity (Table , entry 5). The conversion of reactant and intermediate was increased in the water–IPA (1:2) solvent system, producing 72% of the product with 90% enantioselectivity (Table , entry 6). Even more conversion was obtained when equal amount of water and IPA was introduced in the reaction with an ee of 92% (Table , entry 7). Next, we turned our attention to the reaction temperature. By increasing the reaction temperature to 60 °C, full conversion was obtained with no loss in enantioselectivity (Table , entry 8). Traces of product were obtained at room temperature (rt) with full conversion into the intermediate (Table , entry 9). The product formation was not affected when the reaction time was reduced to 6 h, though poorer conversions were obtained when time was further reduced to 3 h (Table , entries 10 and 12). Traces of reactant were converted into product in the absence of sodium formate (Table , entry 13).

A kinetic study of this one-pot transformation was carried out to get more insight into the reaction. The reaction can proceed via two reaction pathways as shown in Figure . The first path follows a click cycloaddition to get the intermediate B followed by ATH to produce the desired product D. The other pathway proceeds first with ATH to produce intermediate C, followed by click cycloaddition to get chiral product D. As shown in Figure , starting material A get consumed rapidly within first 40 min. With the decrease of A, the intermediate B forms rapidly with a gradual formation of the desired product D. After first hour, there is a linear decrease of intermediate B with linear formation of product D. On the other hand, the intermediate C of other pathway remains constant throughout the reaction, which indicates that the reaction follows the path with first click cycloaddition followed by ATH. The intermediate B was isolated at the start of the reaction, and NMR is given in Supporting Information.

Figure 1

Kinetic study of one-pot transformation into β-triazolylethanol (A–D).

With the optimized condition in hand, substrate scope for one-pot synthesis was investigated using a range of α-bromo ketones and substituted phenyl acetylenes, and the results are summarized in Scheme .

Scheme 2

Substrate Study

Conditions: To 1a–j (0.5 mmol), substituted phenyl acetylene (0.5 mmol) and sodium azide (1.5 mmol) in water/IPA (1:1) were added copper sulfate (10 mmol %) and sodium ascorbate (0.05 mmol), followed by [RuCl2(p-cymene)]2 (2.5 mmol %) and L6 (5 mmol %) at 60 °C and stirred for 6 h. The yields are isolated yields, and ee’s were for the chiral product determined by chiral HPLC.

The compounds with electron-donating substituents (1a, 1b, and 1c) converted into products 2a, 2b, and 2c, respectively, with excellent % ee. We did not find the effect of the electron-withdrawing substituent at the para or meta position as substrates 1d and 1e with fluoro and chloro substituents at para and meta positions, respectively, furnished products 2d and 2e with slightly better ee’s than 2a and 2b. Similarly, substrates 1f and 1g with the naphthyl system converted to corresponding products 2f and 2g with 95.3 and 93.3% ee’s, respectively. The different substitution pattern on the phenyl acetylene part did not show any substantial effect on % ee because the chiral products 2h (93.6%), 2i (93.8%), and 2j (90.6%) were obtained with great enantioselectivity. We have also screened other α-halogenated ketones such as 2-chloro-1-phenylethan-1-one (1i), and only 4% of product was formed.

Furthermore, one-pot synthesis of chiral β-hydroxy sulfone was carried by employing this methodology. A variety of α-bromoacetophenones were reacted with substituted aryl sulfonic acid, and results are summarized in Scheme . The electron-donating substituent at the para position produced the chiral product with excellent enantiomeric excess, and 3a, 3b, and 3c were obtained with >96% ee in all cases. The methoxy substituent at the meta position (3d) produced even higher enantioselectivity compared with the para substituent. Similarly, electron-withdrawing fluoro and bromo groups showed similar enantioselectivities, and products 3e and 3f formed with 97.5 and 93.6% ee’s, respectively, with a slightly higher yield compared to that in the earlier class of compounds. The naphthyl substrate produced the corresponding chiral products 3g and 3h with 97.6 and 96.6% ee’s, respectively. Similarly, the heteroaromatic substrate converted into chiral products with high enantiomeric excess, with 3i and 3j forming with 93.9 and 94.9% ee, respectively. Similar to the earlier case, α-chloro ketone was unable to convert into the product and only 6% of compound was observed.

Scheme 3

One-Pot Synthesis of β-Hydroxy Sulfone

Conditions: To substituted 2-bromo ketone (0.5 mmol) and sodium benzenesulfinate (0.5 mmol) in water/IPA (1:1) were added [RuCl2(p-cymene)]2 (2.5 mmol %) and L6 (5 mmol %) at 60 °C and stirred for 6 h. The yields are isolated yields and ee was for the chiral product determined by chiral HPLC.

Conclusions

In summary, we have developed a one-pot route to synthesize optically active β-triazolylethanol and β-hydroxy sulfone derivatives via ruthenium-catalyzed ATH of corresponding intermediate ketones. A variety of Ru–prolinamide ligands were screened, and one with the isopropyl group situated at the ortho position produced desired results. The optically active compounds were synthesized in aqueous medium with enantiomeric excess comparable to that of the earlier reported Noyori’s catalyst.

Experimental Section

General Materials and Methods

[Ru(p-cymene)Cl2]2 was commercially purchased from Sigma-Aldrich and used as received. All reactions were carried out under a nitrogen atmosphere, unless otherwise stated, and at the temperature specified in experimental procedures. Yields refer to isolated yields. All other chemicals and solvents were purchased from different sources and used as received without further purification. Melting points were recorded using an Analab melting point apparatus by the open capillary method. 1H NMR and 13C NMR (distortionless enhancement by polarization transfer) spectra were recorded at 24 °C in CDCl3 and dimethyl sulfoxide on 400, 500, 101, and 126 MHz instrument, respectively, with tetramethylsilane as the internal standard in the case of CDCl3. Enantiomeric excess was determined by HPLC analysis using a chiral column described below in detail. Column chromatography was performed on silica gel (100–200 mesh). The progress of reaction was monitored by thin-layer chromatography analysis.

Synthesis of Chiral Ligands

Step I

A solution of Boc-protected proline (14 mmol) in tetrahydrofuran (THF) (25 mL) and Et3N (14 mmol) was cooled to 0 °C. Ethyl chloroformate (14 mmol) was added dropwise over 15 min, and the resulting white mixture was stirred at 0 °C for 30 min. A solution of substituted amines (14 mmol) in THF (10 mL) was added over 10 min at 0 °C. The reaction was stirred at rt overnight, and then the mixture was washed with ethyl acetate. The combined organic layers were dried with anhydrous Na2SO4, and the solvent was removed in vacuo. To the crude product dissolved in dichloromethane (DCM) (10 mL) at rt was added trifluoroacetic acid (100 mmol). The solution was stirred at rt for 1 h, and upon completion, the solvent was removed by rotary evaporation. The residue was dissolved in DCM (10 mL), and water (6 mL) was added. The mixture was neutralized with solid Na2CO3 until pH ∼ 9, and then it was extracted with DCM (3 × 15 mL). The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation to afford amino amide (65–73% yield) as a solid, which was directly used in DKR–ATH.[11d]

(S)-N-Phenylpyrrolidine-2-carboxamide[11d]

White solid, mp = 78–80 °C, 1.89 g, 70.7% yield. [α]D25 = −37.3 (c = 0.1 in CHCl3).

1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.31 (s, 2H), 7.14–7.04 (m, 1H), 4.21 (q, J = 7.1 Hz, 1H), 3.84 (dd, J = 9.3, 5.2 Hz, 1H), 3.12–2.92 (m, 2H), 2.26–2.14 (m, 1H), 1.81–1.67 (m, 2H), 1.30 (t, J = 7.1 Hz, 1H).

13C NMR (101 MHz, CDCl3) δ 173.49, 138.08, 129.00, 123.90, 119.27, 61.05, 47.37, 30.77, 26.33.

(S)-N-Mesitylpyrrolidine-2-carboxamide[11d]

Colorless oil, 2.18 g, 67.1% yield. [α]D25 = −55.0 (c = 0.1 in CHCl3).

1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 6.87 (s, 2H), 3.91 (dd, J = 9.2, 5.0 Hz, 1H), 3.13–2.98 (m, 2H), 2.19 (d, J = 21.2 Hz, 11H), 1.88–1.73 (m, 2H).

13C NMR (101 MHz, CDCl3) δ 173.54, 136.36, 134.63, 131.34, 128.83, 60.84, 47.50, 31.05, 26.33, 20.91, 18.34.

(S)-N-Benzylpyrrolidine-2-carboxamide[11d]

White solid, mp = 101–103 °C, 2.08 g, 72.8% yield. [α]D25 = −42.0 (c = 0.1 in CHCl3).

1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.39–7.15 (m, 5H), 4.42 (d, J = 6.1 Hz, 2H), 3.84 (dd, J = 9.1, 5.4 Hz, 1H), 3.07–2.96 (m, 1H), 2.94–2.82 (m, 2H), 2.25–2.09 (m, 1H), 2.01–1.90 (m, 1H), 1.79–1.65 (m, 2H).

13C NMR (101 MHz, CDCl3) δ 174.68, 138.61, 128.61, 127.56, 127.28, 60.56, 47.22, 42.96, 30.81, 26.11.

(S)-N-(2-Bromophenyl)pyrrolidine-2-carboxamide[12]

Colorless oil, 2.67 g, 71.4% yield. [α]D25 = −17.3 (c = 0.1 in CHCl3).

1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.44 (dd, J = 8.3, 1.5 Hz, 1H), 7.52 (dd, J = 8.1, 1.3 Hz, 1H), 7.36–7.23 (m, 1H), 7.04–6.85 (m, 1H), 3.89 (dd, J = 9.3, 4.9 Hz, 1H), 3.15–2.99 (m, 2H), 2.27–2.14 (m, 2H), 2.10–2.01 (m, 1H), 1.85–1.68 (m, 2H).

13C NMR (101 MHz, CDCl3) δ 173.89, 135.95, 132.27, 128.23, 124.76, 121.08, 113.57, 61.36, 47.40, 30.95, 26.29.

(S)-N-(2-Methoxyphenyl)pyrrolidine-2-carboxamide[13]

White solid, mp = 68–70 °C, 2.18 g, 70.7% yield. [α]D25 = −34.3 (c = 0.1 in CHCl3).

1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.42 (dd, J = 7.9, 1.7 Hz, 1H), 7.05–6.82 (m, 3H), 3.87 (s, 4H), 3.09–2.95 (m, 2H), 2.24–2.14 (m, 2H), 2.07–1.99 (m, 1H), 1.83–1.65 (m, 2H).

13C NMR (101 MHz, CDCl3) δ 173.47, 148.55, 127.57, 123.55, 120.95, 119.47, 110.07, 61.50, 55.76, 47.36, 30.90, 26.27.

(S)-N-(2,6-Diisopropylphenyl)pyrrolidine-2-carboxamide[11d]

White solid, mp = 133–135 °C, 2.68 g, 70.0% yield. [α]D25 = −28.0 (c = 0.1 in CHCl3).

1H NMR (500 MHz, CDCl3) δ 9.20–9.11 (m, 1H), 7.28 (d, J = 7.0 Hz, 1H), 7.17 (d, J = 7.7 Hz, 2H), 3.96 (dd, J = 9.3, 4.9 Hz, 1H), 3.19–3.09 (m, 1H), 3.08–2.98 (m, 3H), 2.31–2.19 (m, 1H), 2.15–2.07 (m, 1H), 1.89–1.79 (m, 2H), 1.21 (t, J = 6.9 Hz, 13H).

13C NMR (126 MHz, CDCl3) δ 174.41, 145.67, 131.49, 127.83, 123.31, 60.81, 47.59, 30.91, 28.81, 26.43, 23.58, 23.47.

Experimental Procedure for the One-Pot Synthesis of β-Triazolyl Amino Alcohols (2a–j)

To a slurry of substituted α-bromoalkanones (0.5 mmol), substituted alkynes (0.5 mmol), and sodium azide (0.75 mmol) in water/IPA (1:1, 10 mL), copper sulfate (10 mmol %) and sodium ascorbate (0.05 mmol) were added, followed by [RuCl2(p-cymene)]2 (2.5 mmol %), chiral prolinamide ligand (5 mmol %), and sodium formate (1.5 mmol). The reaction mixture was stirred for 6 h at 60 °C. After completion of reaction, water (5 mL) was added to the mixture and was then extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, and solvent removed under vacuum till dryness. The crude compound was purified by column chromatography (EtOAc/hexanes: 25:75) (88–99% yield).

(S)-1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-ol (2a)[8]

White solid, mp = 150–152 °C, 118 mg, 90% yield, 93.9% ee, 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.75–7.72 (m, 2H), 7.45–7.32 (m, 8H), 5.25 (dt, J = 9.1, 2.6 Hz, 1H), 4.66 (dd, J = 14.0, 3.2 Hz, 1H), 4.46 (dd, J = 14.1, 9.0 Hz, 1H), 3.64 (d, J = 19.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 147.38, 140.17, 130.34, 128.83, 128.80, 128.50, 128.11, 125.89, 125.63, 121.19, 72.92, 57.52. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 210 nm, flow rate: 0.7 mL/min), tmajor = 30.3 min, tminor = 33.4 min.

(S)-2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(p-tolyl)ethan-1-ol (2b)[8]

White solid, mp = 160–162 °C, 127 mg, 92% yield, 92.5% ee, 1H NMR (500 MHz, CDCl3) δ 7.87–7.70 (m, 3H), 7.45–7.17 (m, 7H), 5.20 (dd, J = 8.9, 3.2 Hz, 1H), 4.64 (dd, J = 14.0, 3.3 Hz, 1H), 4.46 (dd, J = 14.0, 8.8 Hz, 1H), 3.33 (s, 1H), 2.37 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 147.42, 138.35, 137.17, 130.44, 129.50, 128.79, 128.09, 125.81, 125.66, 121.15, 72.86, 57.46, 21.16. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 210 nm, flow rate: 0.7 mL/min), tmajor = 26.8 min, tminor = 31.6 min.

(S)-1-(3-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-ol (2c)[8]

White solid, mp = 140–142 °C, 129 mg, 88% yield, 95.6% ee, 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 1.0 Hz, 1H), 7.68–7.63 (m, 2H), 7.38–7.26 (m, 4H), 7.02–6.96 (m, 2H), 6.91–6.84 (m, 1H), 5.21 (dd, J = 9.1, 3.0 Hz, 1H), 4.66–4.58 (m, 1H), 4.47–4.31 (m, 2H), 3.80 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 159.91, 147.20, 141.98, 141.97, 129.82, 128.79, 128.09, 125.55, 121.35, 118.15, 114.01, 111.25, 72.62, 57.64, 55.30. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 210 nm, flow rate: 0.7 mL/min), tmajor = 49.9 min, tminor = 55.2 min.

(S)-1-(4-Fluorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-ol (2d)[8]

White solid, mp = 180–182 °C, 111 mg, 84% yield, 92.0% ee, 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.79–7.76 (m, 2H), 7.44–7.39 (m, 4H), 7.36–7.32 (m, 1H), 7.13–7.05 (m, 2H), 5.25 (dd, J = 8.5, 3.1 Hz, 1H), 4.64 (dd, J = 14.0, 3.2 Hz, 1H), 4.46 (dd, J = 14.0, 8.7 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 162.69 (d, J = 247.0 Hz), 147.54, 135.83, 130.27, 128.86, 128.23, 127.63 (d, J = 8.4 Hz), 125.66, 121.14, 115.80 (d, J = 21.8 Hz), 72.38, 57.42. HPLC (OJ-H elute: hexanes/i-PrOH = 90:10, detector: 210 nm, flow rate: 0.7 mL/min), tmajor = 41.2 min, tminor = 45.2 min.

1-(3-Chlorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-ol (2e)[8]

White solid, mp = 176–178 °C, 132 mg, 89% yield, 94.3% ee, 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.77–7.72 (m, 2H), 7.52–7.47 (m, 1H), 7.43–7.39 (m, 2H), 7.36–7.31 (m, 3H), 7.28–7.26 (m, 1H), 5.26 (dd, J = 8.9, 3.0 Hz, 1H), 4.66 (dd, J = 14.0, 3.0 Hz, 1H), 4.43 (dd, J = 14.0, 9.0 Hz, 1H), 3.70 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 147.51, 142.10, 134.84, 130.17, 130.12, 128.85, 128.66, 128.25, 126.13, 125.64, 124.08, 121.22, 72.31, 57.37. HPLC (OD-H elute: hexanes/i-PrOH = 80:20, detector: 250 nm, flow rate: 0.7 mL/min), tmajor = 36.4 min, tminor = 45.9 min.

(S)-1-(Naphthalen-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-ol (2f)[8]

White solid, mp = 170–172 °C, 147 mg, 93% yield, 95.3% ee, 1H NMR (500 MHz, CDCl3) δ 7.90–7.69 (m, 6H), 7.57–7.28 (m, 7H), 5.40 (dd, J = 9.0, 3.1 Hz, 1H), 4.74 (dd, J = 14.1, 3.2 Hz, 1H), 4.54 (dd, J = 14.0, 8.8 Hz, 1H), 3.61 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 147.52, 137.44, 133.30, 133.23, 130.37, 128.81, 128.75, 128.15, 128.05, 127.75, 126.52, 126.39, 125.68, 125.10, 123.44, 121.20, 73.14, 57.41. HPLC (OJ-H elute: hexanes/i-PrOH = 75:25, detector: 250 nm, flow rate: 1.0 mL/min), tmajor = 47.6 min, tminor = 55.4 min.

(S)-1-(Naphthalen-1-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-ol (2g)[8]

White solid, mp = 195–197 °C, 148 mg, 95% yield, 93.3% ee, 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 8.3 Hz, 1H), 7.92 (dd, J = 7.9, 1.5 Hz, 1H), 7.87–7.77 (m, 3H), 7.68–7.61 (m, 2H), 7.59–7.48 (m, 3H), 7.37–7.25 (m, 3H), 6.07 (dd, J = 9.1, 2.4 Hz, 1H), 4.84 (dd, J = 14.2, 2.4 Hz, 1H), 4.63 (s, 1H), 4.41 (dd, J = 14.1, 9.1 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 147.19, 135.91, 133.72, 130.89, 130.16, 129.96, 129.11, 128.76, 128.05, 126.83, 125.85, 125.53, 125.51, 123.54, 122.49, 121.36, 69.94, 57.26. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 250 nm, flow rate: 0.7 mL/min), tmajor = 48.7 min, tminor = 55.6 min.

(S)-1-Phenyl-2-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)ethan-1-ol (2h)[8]

White solid, mp = 156–158 °C, 114 mg, 82% yield, 93.6% ee, 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 1H), 7.66–7.59 (m, 2H), 7.46–7.33 (m, 5H), 7.23–7.16 (m, 2H), 5.23 (dd, J = 8.8, 3.2 Hz, 1H), 4.64 (dd, J = 14.0, 3.2 Hz, 1H), 4.44 (dd, J = 14.0, 8.8 Hz, 1H), 3.66 (s, 1H), 2.38 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 147.47, 140.20, 137.96, 129.46, 128.80, 128.46, 127.53, 125.90, 125.56, 120.86, 72.91, 57.50, 21.28. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 250 nm, flow rate: 0.7 mL/min), tmajor = 31.1 min, tminor = 38.8 min.

(S)-2-(4-(4-Ethylphenyl)-1H-1,2,3-triazol-1-yl)-1-phenylethan-1-ol (2i)

White solid, mp = 126–128 °C, 105 mg, 86% yield, 93.8% ee, 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (dd, J = 8.1, 1.5 Hz, 2H), 7.45–7.33 (m, 5H), 7.21 (d, J = 7.9 Hz, 2H), 5.25 (dd, J = 8.9, 3.2 Hz, 1H), 4.68–4.59 (m, 1H), 4.47–4.37 (m, 1H), 3.96 (s, 1H), 2.67 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 147.41, 144.33, 140.25, 128.79, 128.41, 128.28, 127.67, 125.92, 125.60, 120.96, 72.81, 57.58, 28.67, 15.55. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 250 nm, flow rate: 0.7 mL/min), tmajor = 26.2 min, tminor = 30.1 min.

(S)-2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-phenylethan-1-ol (2j)

White solid, mp = 122–124 °C, 117 mg, 84% yield, 90.6% ee, 1H NMR (500 MHz, CDCl3) δ 7.37–7.17 (m, 11H), 5.13 (dd, J = 8.5, 3.4 Hz, 1H), 4.51 (dd, J = 14.0, 3.5 Hz, 1H), 4.38 (dd, J = 14.0, 8.5 Hz, 1H), 4.02 (d, J = 3.2 Hz, 2H), 3.61 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 147.22, 140.23, 138.92, 128.75, 128.67, 128.60, 128.40, 126.49, 125.84, 123.09, 72.84, 57.29, 32.08. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 250 nm, flow rate: 0.7 mL/min), tminor = 18.2 min, tmajor = 20.8 min.

Experimental Procedure for the One-Pot Synthesis of β-Hydroxy Sulfones (3a–j)

α-Bromoketone (0.5 mmol), 0.55 mmol of sodium benzene sulfinate, 2.5 mmol % [RuCl2(p-cymene)]2, 5 mmol % L6, 1.5 mmol of HCOONa, and 10 mL of H2O/IPA (1:1, v/v) at 60 °C for 6 h. After completion of the reaction, 5 mL of water was added to the mixture, which was extracted by ethyl acetate (3 × 5.0 mL). The combined organic layer was washed with brine twice and dehydrated with anhydrous Na2SO4. After the evaporation of ethyl acetate, the residue was purified by silica gel column chromatography.

1-Phenyl-2-(phenylsulfonyl)ethan-1-ol (3a)[6a]

White solid, mp = 112–114 °C, 109 mg, 83% yield, 96.7% ee, 1H NMR (400 MHz, CDCl3) δ 7.97–7.89 (m, 2H), 7.67 (dd, J = 8.5, 6.3 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.32–7.20 (m, 5H), 5.26 (d, J = 10.0 Hz, 1H), 3.74 (d, J = 2.4 Hz, 1H), 3.50 (dd, J = 14.4, 10.0 Hz, 1H), 3.32 (dd, J = 14.4, 2.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 140.66, 139.13, 134.11, 129.45, 128.75, 128.34, 127.97, 125.65, 68.43, 63.89. HPLC (AD-H elute: hexanes/i-PrOH = 90:10, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 36.4 min, tminor = 32.0 min.

2-(Phenylsulfonyl)-1-(p-tolyl)ethan-1-ol (3b)[6a]

White solid, mp = 102–104 °C, 121 mg, 88% yield, 98.8% ee, 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.4 Hz, 2H), 7.71–7.51 (m, 2H), 7.20–7.04 (m, 4H), 5.22 (d, J = 9.9 Hz, 1H), 3.66 (s, 1H), 3.48 (d, J = 9.9 Hz, 1H), 3.31 (d, J = 14.4 Hz, 1H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 139.19, 138.14, 137.74, 134.05, 129.42, 129.39, 127.97, 125.59, 68.30, 63.89, 21.11. HPLC (AD-H elute: hexanes/i-PrOH = 90:10, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 39.7 min, tminor = 37.1 min.

1-(4-Methoxyphenyl)-2-(phenylsulfonyl)ethan-1-ol (3c)[6a]

White solid, mp = 123–125 °C, 122 mg, 84% yield, 96.1% ee, 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 7.7, 2.1 Hz, 2H), 7.68–7.62 (m, 1H), 7.59–7.51 (m, 2H), 7.20–7.13 (m, 2H), 6.83–6.75 (m, 2H), 5.19 (dd, J = 10.0, 1.9 Hz, 1H), 3.74 (s, 3H), 3.62 (s, 1H), 3.48 (dd, J = 14.3, 10.0 Hz, 1H), 3.28 (dd, J = 14.3, 2.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 159.51, 139.18, 134.04, 132.80, 129.41, 127.94, 126.96, 114.08, 68.05, 63.85, 55.28. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 64.9 min, tminor = 44.5 min.

1-(3-Methoxyphenyl)-2-(phenylsulfonyl)ethan-1-ol (3d)

White solid, mp = 97–99 °C, 127 mg, 87% yield, 99.9% ee, 1H NMR (400 MHz, CDCl3) δ 7.97–7.89 (m, 2H), 7.69–7.52 (m, 3H), 7.20 (t, J = 7.9 Hz, 1H), 6.86–6.74 (m, 3H), 5.23 (d, J = 10.0 Hz, 1H), 3.75 (s, 4H), 3.48 (dd, J = 14.4, 10.0 Hz, 1H), 3.32 (dd, J = 14.4, 1.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 159.86, 142.30, 134.10, 129.44, 127.96, 117.82, 113.87, 111.08, 68.35, 63.90, 55.25. HPLC (AD-H elute: hexanes/i-PrOH = 90:10, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 43.7 min, tminor = 45.6 min.

1-(4-Fluorophenyl)-2-(phenylsulfonyl)ethan-1-ol (3e)[6a]

White solid, mp = 94–96 °C, 126 mg, 90% yield, 97.5% ee, 1H NMR (400 MHz, CDCl3) δ 7.96–7.86 (m, 2H), 7.70–7.63 (m, 1H), 7.56 (dd, J = 8.4, 7.0 Hz, 2H), 7.28–7.18 (m, 2H), 7.02–6.92 (m, 2H), 5.24 (d, J = 9.6 Hz, 1H), 3.78 (d, J = 2.3 Hz, 1H), 3.45 (dd, J = 14.3, 10.0 Hz, 1H), 3.28 (dd, J = 14.3, 2.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 163.68, 161.23, 139.00, 136.46, 136.43, 134.18, 129.48, 127.93, 127.47, 127.39, 115.73, 115.52, 67.79, 63.85. HPLC (AD-H elute: Hexanes/i-PrOH = 90:10, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 42.6 min, tminor = 38.4 min.

1-(4-Bromophenyl)-2-(phenylsulfonyl)ethan-1-ol (3f)[6a]

White solid, mp = 101–103 °C, 156 mg, 92% yield, 93.6% ee, 1H NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 8.4, 1.4 Hz, 2H), 7.71–7.65 (m, 1H), 7.61–7.54 (m, 2H), 7.45–7.38 (m, 2H), 7.19–7.12 (m, 2H), 5.23 (dd, J = 9.9, 1.9 Hz, 1H), 3.82 (s, 1H), 3.44 (dd, J = 14.4, 10.0 Hz, 1H), 3.28 (dd, J = 14.3, 1.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 139.62, 138.92, 134.25, 131.84, 129.53, 127.94, 127.38, 122.20, 67.84, 63.68. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 46.1 min, tminor = 35.2 min.

1-(Naphthalen-1-yl)-2-(phenylsulfonyl)ethan-1-ol (3g)

White solid, mp = 119–121 °C, 143 mg, 93% yield, 97.6% ee, 1H NMR (400 MHz, CDCl3) δ 8.02–7.91 (m, 2H), 7.86–7.79 (m, 1H), 7.76–7.63 (m, 3H), 7.60–7.34 (m, 6H), 6.02 (dd, J = 8.0, 3.1 Hz, 1H), 3.95 (s, 1H), 3.51–3.39 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 141.39, 138.97, 135.99, 134.16, 133.64, 129.50, 129.17, 128.69, 128.09, 126.65, 125.99, 125.73, 125.53, 123.23, 122.00, 121.71, 65.10, 63.36. HPLC (AD-H elute: hexanes/i-PrOH = 90:10, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 46.4 min, tminor = 29.2 min.

1-(Naphthalen-2-yl)-2-(phenylsulfonyl)ethan-1-ol (3h)[6a]

White solid, mp = 132–134 °C, 142 mg, 92% yield, 96.6% ee, 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.3 Hz, 1H), 7.83–7.74 (m, 4H), 7.70–7.62 (m, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.48–7.40 (m, 2H), 7.37–7.29 (m, 1H), 5.43 (dt, J = 9.9, 2.0 Hz, 1H), 3.79 (d, J = 2.2 Hz, 1H), 3.57 (dd, J = 14.4, 10.0 Hz, 2H), 3.47–3.37 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 139.08, 137.82, 134.13, 133.13, 129.46, 128.70, 127.97, 127.89, 127.66, 126.44, 126.31, 126.12, 125.76, 124.75, 123.77, 123.19, 68.56, 63.84. HPLC (OJ-H elute: hexanes/i-PrOH = 70:30, detector: 250 nm, flow rate: 1.0 mL/min), tmajor = 75.3 min, tminor = 46.2 min.

(S)-1-(Furan-2-yl)-2-(phenylsulfonyl)ethan-1-ol (3i)

White solid, mp = 71–73 °C, 98 mg, 78% yield, 93.9% ee, 1H NMR (400 MHz, CDCl3) δ 7.92–7.85 (m, 2H), 7.66–7.58 (m, 1H), 7.56–7.50 (m, 2H), 7.23 (d, J = 1.3 Hz, 1H), 6.24 (d, J = 1.5 Hz, 2H), 5.23 (dd, J = 9.2, 3.0 Hz, 1H), 3.66 (dd, J = 14.5, 9.1 Hz, 2H), 3.51 (dd, J = 14.5, 2.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 152.59, 142.60, 139.05, 134.04, 129.38, 127.94, 110.44, 107.40, 62.63, 62.61, 60.54. HPLC (OJ-H elute: hexanes/i-PrOH = 80:20, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 28.7 min, tminor = 27.0 min.

2-(Phenylsulfonyl)-1-(thiophen-2-yl)ethan-1-ol (3j)

White solid, mp = 80–82 °C, 107 mg, 80% yield, 94.9% ee, 1H NMR (400 MHz, CDCl3) δ 7.98–7.86 (m, 2H), 7.71–7.51 (m, 3H), 7.25–7.16 (m, 1H), 6.90 (d, J = 3.2 Hz, 2H), 5.53 (dt, J = 9.9, 2.2 Hz, 1H), 3.84 (d, J = 2.6 Hz, 1H), 3.60 (dd, J = 14.3, 9.8 Hz, 1H), 3.45 (dd, J = 14.4, 2.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 144.16, 139.02, 134.20, 129.48, 128.01, 126.82, 125.58, 124.24, 64.90, 63.73. HPLC (AD-H elute: hexanes/i-PrOH = 90:10, detector: 210 nm, flow rate: 1.0 mL/min), tmajor = 52.9 min, tminor = 42.2 min.

NMR Data of Isolated Intermediate Ketone B

1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-one (B)

1H NMR (400 MHz, CDCl3) δ 8.19–7.73 (m, 5H), 7.56–7.21 (m, 6H), 5.86 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 190.26, 134.59, 133.90, 130.47, 129.15, 128.80, 128.16, 128.14, 125.78, 121.49, 55.45.