Asymmetric transfer hydrogenation of unsymmetrical benzils

Abstract

In this paper, the asymmetric transfer hydrogenation of unsymmetrical benzils with m, p-substituents was conducted with a substrate/catalyst molar ratio of 100 at 40 °C for 24 h to produce (S,S)-hydrobenzoins in good yields (76.2% to 97.1%) with high diastereomeric (syn/anti = 10.8 to 29.7/1) and enantiomeric purities (86.1%ee syn to 98.9%ee syn). Unfortunately, the unsymmetrical benzils with the o-substituents such as electron-donating (R = CH₃, OCH₃) and electron-withdrawing groups (R = F, Cl, CF₃) resulted in poor yields (0% to 31.2%), even at 40 °C for 72 h. These products had inefficient diastereoselectivities (syn/anti = 1.5 to 5.0/1) caused by steric effects. Furthermore, the results of a dynamic–kinetic study were used to propose a plausible reaction pathway of unsymmetrical benzil using 3-methoxy-1,2-diphenyl ethanedione as an example.

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Introduction

Chiral 1,2-diols (especially, hydrobenzoins) are useful building materials for the syntheses of various biologically active compounds, as well as chiral ligands and auxiliaries in stereoselective organic syntheses.¹ These important chiral hydrobenzoins have been prepared through the resolution of racemic hydrobenzoins,² stereoselective pinacol coupling,³ Sharpless asymmetric dihydroxylation,⁴ and asymmetric transfer hydrogenation.⁵ As early as 1999, T. Ikariya et al. developed a practical stereoselective synthesis of chiral hydrobenzoins via asymmetric transfer hydrogenation of symmetrical benzils.^5d Until now, there was no report available on the asymmetric transfer hydrogenation of unsymmetrical benzils to optically active hydrobenzoins, with regard to unavailable raw materials, separation of four stereoisomers and absolute configuration assignment. In the current paper, we developed asymmetric synthesis of optically active hydrobenzoins via the asymmetric transfer hydrogenation of unsymmetrical benzils catalyzed by the well-defined RuCl(R,R)-Tsdpen(η⁶-arene) chiral catalysts (a–c) (Scheme 1).⁶ Furthermore, the dynamic–kinetic study on the reactant, intermediates and products, which was monitored through chiral high-performance liquid chromatography (HPLC), provided direct insight into asymmetric hydrogenation mechanism of unsymmetrical benzils to 1,2-diols.

Scheme 1 Asymmetric transfer hydrogenation of unsymmetrical benzils.

Results and discussion

Synthesis of unsymmetrical benzils

1,3-Diketones 2a–f in the enol form that were verified through ¹H NMR were prepared by the reaction of substituted acetophenone with ethyl benzoate from moderate to high yields (40% to 92%). The selective cleavage of the C–C bonds of 1,3-diketones 2a–f produced the useful unsymmetrical benzils 3a–f in 35% to 90% yields at 30 °C for 12 h using a combination of 20 mol% of FeCl₃ and 500 mol% tert-butyl nitrite.⁷ Fortunately, various 1,3-diketones 2a–f, with both the electron-donating (R = CH₃ and OCH₃) and electron-withdrawing (R = F, Cl, Br and CF₃) substituents in the o-, m- and p-position of aryl ring, tolerated the reaction conditions well to produce the corresponding unsymmetrical benzils 3a–f (Scheme 2).

Scheme 2 The synthetic route to various unsymmetrical benzils 3a–f.

Optimization of catalytic conditions

The catalytic conditions in the asymmetric transfer hydrogenation of unsymmetrical benzils 3a–f catalyzed by RuCl (R,R)-Tsdpen(η⁶-p-cymene) were screened out, and some representative examples are listed in Table 1. Chiral (R,R)-Ru(II) a with arene ligand η⁶-p-cymene [R_n = 1-CH₃ and 4-CH(CH₃)₂] showed the best catalytic performances (98.8%ee syn, Dr (syn/anti) = 28.3 : 1, and 94.9% yield, entry 1, Table 1); whereas the other benzene complexes b (R_n = H), c [R_n = 1,3,5-(CH₃)₃] were less reactive. The molar ratio of HCO₂H to NEt₃ had an important function in catalytic performance. The best catalytic results of 3e₂ in terms of yield and stereoselectivity were obtained at the 4 : 2 molar ratio of HCO₂H to NEt₃. Surprisingly, the 1,2-diol 6e₂ yields were apparently decreased to low to moderate yields (0–74.6%) in various organic solvents. However, some improved %ee syn (>99%) and Dr (syn/anti > 30/1) values were found in acetone, DMF, and acetonitrile (entries 4–9, Table 1). Therefore, it was concluded that organic solvent was not crucial for chiral (R,R)-Ru(II) catalyst a to be efficient and practical. At relatively higher temperatures (e.g., 60 °C and 80 °C), the enantioselectivity (98.8%ee syn → 97.2%ee syn) and diastereoselectivity (38.9/1 → 10.4/1) decreased slightly (entries 10–14, Table 1). The molar ratio of substrate to catalyst (S/C) critically affected the 1,2-diol yields. Unsymmetrical benzil 3e₂ with a S/C below 200 can produce more than 90% yields with an excellent enantioselectivity (98.6%ee syn to 99.4%ee syn) and diastereoselectivity (syn/anti = 21.8/1 to 28.3/1) (entries 15–18, Table 1). Fortunately, the excellent stereoselectivity (98.4%ee syn) and diastereoselectivity (syn/anti = 39.7) with the less reactivity (58.3%) can be obtained, even with a S/C = 500 at 40 °C for 24 h (Table 1, entry 19).

Table 1 Asymmetric hydrogenation of benzil 3e₂ under various conditions^a

Entry	Cat.	Solv.	Temp. (°C)	S/C	Conv.^d (%)	Yield^b (%)	%ee syn^c	Dr (syn/anti)^d
a Molar ratio of HCOOH : N(C2H5)3 = 2 : 1, 24 h.b Isolated yield.c Determined by HPLC analysis using an OJ-H column.d Determined by ^1H NMR.e Not obtained.
1	a	—	40	100	>99	94.9	98.8	28.3
2	b	—	40	100	78.5	74.6	98.3	21.8
3	c	—	40	100	79.4	76.3	99.0	27.6
4	a	DMF	40	100	38.4	32.3	98.9	35.8
5	a	DMSO	40	100	40.4	—^e	—	—
6	a	CH3CN	40	100	77.8	74.6	99.1	37.7
7	a	CH2Cl2	40	100	69.4	65.7	98.2	27.6
8	a	CH3OH	40	100	58.3	54.2	98.7	27.0
9	a	Acetone	40	100	59.6	53.9	>99	26.9
10	a	—	0	100	37.6	35.4	98.8	38.9
11	a	—	20	100	81.8	74.8	98.6	34.1
12	a	—	40	100	97.8	94.2	98.8	28.1
13	a	—	60	100	98.2	95.7	98.3	17.7
14	a	—	80	100	>99	97.2	97.2	10.4
15	a	—	40	25	>99	96.8	99.4	21.8
16	a	—	40	50	>99	96.1	98.7	21.4
17	a	—	40	100	96.1	94.8	98.8	28.3
18	a	—	40	200	93.8	89.3	98.6	28.3
19	a	—	40	500	61.2	58.3	98.4	39.7

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Asymmetric transfer hydrogenation of various unsymmetrical benzils

The optimized protocol was expanded to a wide variety of various unsymmetrical benzils 3a–f with o-, m- and p-substituents on aromatic rings to investigate catalytic performance of (R,R)-Ru(II) catalyst a. Based on the results in Table 2, the transfer hydrogenation of unsymmetrical benzils was closely related to the presence of o-, m- and p-substituting position on phenyl group. When the substituents, including electron-donating (R = CH₃ and OCH₃) and electron-withdrawing groups (R = F and Cl) groups, were in the ortho-position on phenyl group, unsymmetrical benzils 3a₁–e₁ were reduced with the low reactivities (0% to 31.2% yields) and reduced diastereoselectivities (syn/anti = 1.3 to 5.0) at 40 °C for 72 h; these results were caused by sterically hindered interaction between the o-position substituent and carbonyl group. However, the excellent enantioselectivities (92.0%ee syn to 97.4%ee syn) of starting materials 3a₁–e₁ were observed (entries 1, 4, 10 and 13, Table 2). Our attempted reduction of unsymmetrical benzil 3f₁ with a bulky and strong electron-withdrawing o-CF₃ group under the same conditions only produced the intermediates 4f₁ and 5f₁ with low % ees and yields. Moreover, hydrobenzoin 6f₁ was not obtained. Especially, benzil 3c₁ with the o-Br substituent gave the excellent stereoselectivity (98.7%ee syn, syn/anti = 21.6) owing to the suitable volume of bromine atom. Therefore, it could be concluded that the bulkier o-position substituent resulted in the slower reactivity, even hydrogenation reaction could not proceeded smoothly.

Table 2 Asymmetric transfer hydrogenation of various unsymmetrical benzils^a

Entry	Benzil	R	Time (h)	Conv.^b (%)	Yield^c (%)	%ee syn^d	Dr (syn/anti)^b
a Molar ratio of HCOOH/N(C2H5)3 = 2 : 1, 40 °C, no solvent, S/C = 100, (R,R)-Ru Cat. (a).b Determined by ^1H NMR.c Isolated yield.d Determined by HPLC analysis.e Not be isolated by chiral HPLC.f Not proceeded smoothly.
1	3a1	o-F	72	24.7	20.4	93.1	1.8
2	3a2	m-F	24	73.5	76.2	96.4	12.3
3	3a3	p-F	24	97.4	91.8	87.3	10.8
4	3b1	o-Cl	72	25.6	22.6	93.2	1.3
5	3b2	m-Cl	24	>99	95.9	—^e	13.3
6	3b3	p-Cl	24	>99	97.1	98.0	11.0
7	3c1	o-Br	72	59.9	55.4	98.7	21.6
8	3c2	m-Br	24	>99	97.6	—^e	10.5
9	3c3	p-Br	24	>99	93.2	98.4	14.6
10	3d1	o-CH3	72	25.3	22.7	97.4	5.0
11	3d2	m-CH3	24	82.5	78.7	86.1	11.1
12	3d3	p-CH3	24	89.6	84.6	93.0	24.5
13	3e1	o-OCH3	72	34.8	31.2	92.0	1.5
14	3e2	m-OCH3	24	97.8	93.5	98.9	29.7
15	3e3	p-OCH3	24	77.8	78.5	—^e	13.6
16	3f1	o-CF3	72	—^f	—^f
17	3f2	m-CF3	24	95.7	92.2	98.8	14.0
18	3f3	p-CF3	24	98.8	94.9	97.6	12.9

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Fortunately, the various unsymmetrical benzils 3a_2,3–f_2,3 with the m-, p-substituents attached to the phenyl group, both electron-donating (R = CH₃ and OCH₃) and electron-withdrawing (R = F, Cl, Br and CF₃) substituents, can be stereoselectively reduced to optically active (S,S)-hydrobenzoins 6a_2,3–f_2,3. These products exhibited good to excellent enantioselectivities (86.1%ee syn to 98.9%ee syn) and diastereoselectivities (syn/anti = 10.8 to 29.7) in 76.2% to 97.1% yields in HCOOH/N(C₂H₅)₃ = 2 : 1 with a S/C molar ratio of 100 at 40 °C for 24 h. Notably, a pair of (S,S) and (R,R)-hydrobenzoins 6b₂, 6c₂, 6e₃ enantiomers were difficult to be isolated through chiral HPLC equipped with current commercial chromatographic columns (entries 5, 8, and 15, Table 2).

Dynamic kinetic study

First, to identify the intermediates, two racemic α-hydroxy ketones 4e₂ and 5e₂ were synthesized according to the reference materials (Scheme 3).⁸ To elucidate the hydrogenation mechanism of unsymmetrical benzil, e.g., 3e₂ with m-OCH₃ substituent, the stereoselectivities and reactivities during the course of catalytic reaction were monitored using HPLC. Based on the peak areas in chiral HPLC, the reactivity and enantioselectivity profiles of benzil 3e₂, intermediates 4e₂ and 5e₂, and hydrobenzoin 6e₂ were plotted versus time during the whole process; the plots are shown in Fig. 1 and 2, respectively.

Scheme 3 Synthesis of racemic α-hydroxy ketones 4e₂ and 5e₂.

Fig. 1 The reactivity profiles of benzil, intermediates and 1,2-diol plotted versus time during the experiment.

Fig. 2 The enantioselectivity profiles of benzil, intermediates and 1,2-diol plotted versus time during the experiment.

From Fig. 1, the conversion of benzil 3e₂ to α-hydroxy ketones 4e₂ and 5e₂ was completed in 2 h at 40 °C; and most of α-hydroxy ketones (>90%) were converted to (S,S)-hydrobenzoin 6e₂ within 12 h. A few points were noted that need further investigation. First, the regioselective reduction of unsymmetrical benzil 3e₂ to α-hydroxy ketones 4e₂ and 5e₂ was not observed as expected. In addition, the intermediate 4e₂ was less abundant than 5e₂, although two carbonyl functional groups possessed the different cloud densities caused by the electron effect of electron-donating m-OCH₃ group. Second, the excellent enantioselectivities of (S,S)-6e₂ (>98%ee) had been maintained at a high level from beginning to end during the entire catalytic process and were not influenced by the enantioselectivities of 4e₂ and 5e₂; although, the low to moderate %ee values of 4e₂ (10%ee to 70%ee) and 5e₂ (−25%ee to 70%ee) changed in the action of oscillation process (Fig. 2). In particular, the enantioselectivity of intermediate 5e₂ changed from negative to positive values at about 2 h. Therefore, (R)-enantiomers 4e₂ and 5e₂ gradually predominated over their (S)-enantiomers, and proceeded more slowly than their enantiomers (S)-4e₂ and 5e₂ (Fig. 3). Theoretically, (R)-4e₂ and 5e₂ can be hydrogenated sequentially to two possible stereoisomers, (R,R)-6e₂ and (R,S)-7e₂. Unfortunately, small amounts of (R,R)-6e₂ and (R,S)-7e₂ were observed in the resulting products monitored through HPLC. In fact, whether 4e₂ and 5e₂ were (R) or (S)-configuration, these enantiomers produced (S,S)-hydrobenzoin 6e₂ with an excellent stereoselectivity of 98.9%ee syn and syn/anti = 29.7. The events that occurred with regard to intermediates (R)-4e₂ and 5e₂ need to be discussed.

Fig. 3 The relative contents of (S)-4e₂, 5e₂ and (R)-4e₂, 5e₂ in asymmetric hydrogenation of benzil 3e₂ over 6 h.

To investigate how (R) and (S)-4e₂ and 5e₂ were converted to 1,2-diols, the racemic α-hydroxy ketones 4e₂ and 5e₂ were hydrogenated independently with a S/C molar ratio of 100 in HCOOH/N(C₂H₅)₃ = 2 : 1 at 40 °C, and were monitored via HPLC. As shown in Fig.4, in the hydrogenation of racemic 4e₂, the conversion of (S)-4e₂ was three to five times faster than that of (R)-4e₂ within 3 h. In particular, the (R) and (S)-5e₂ intermediates were unexpectedly found, and the (S)-5e₂ content was also lower than (R)-5e₂. Likewise, (R) and (S)-4e₂ intermediates were also observed in the hydrogenation of racemic 5e₂ (also see ESI†). Therefore, based on these findings and final (S,S)-6e₂ product, the slow-reacting (R)-isomers were subjected to rapid racemization among (R)-5e₂, (S)-5e₂, (S)-4e₂, and (R)-4e₂ intermediates through keto–enol tautomerism equilibrium; and the intermediates (S)-5e₂ and (S)-4e₂ were hydrogenated asymmetrically to (S,S)-6e₂ in 94% yield with syn/anti = 29.7/1 and 98.9%ee syn. Otherwise, (R,R)-6e₂ and (R,S)-7e₂ can be formed by the direct hydrogenation of intermediates (R)-4e₂ and (R)-5e₂. Therefore, a plausible reaction pathway for the catalytic asymmetric transfer hydrogenation of unsymmetrical benzil 3e₂ was proposed in Scheme 4.

Fig. 4 The reactivity profiles of racemic α-hydroxy ketones 4e₂ plotted versus time within 9 h.

Scheme 4 A plausible asymmetric transfer catalytic pathway of unsymmetrical benzil 3e₂.

Conclusions

This work presented the successful reductive transformation of unsymmetrical benzils to optically active syn-(S,S)-1,2-diols in terms of good activity and occasionally excellent diastereoselectivity and enantioselectivity. Through dynamic kinetic study on the entire catalytic process monitored using chiral HPLC, a plausible catalytic hydrogenation pathway of unsymmetrical benzil to hydrobenzoin was proposed.

Experimental section

General remarks

All chemicals were purchased and used without any further purification. Unsymmetrical benzils 3a–f and (R,R)-Ru catalysts a, b, and c were synthesized according to the reference, and were ascertained by ¹H and ¹³C NMR.⁸

Instrumentation and methods

TLC, where applicable, was performed on pre-coated aluminium-backed plates and spots were made visible by quenching ultraviolet (UV) fluorescence (λ = 254 nm). Mass spectra (MS) performed on mass spectrometer (Brucker Daltonics, USA, Brucker Co.) with HCT ultra ion trap. ¹H NMR were performed on a Bruker AV-300 NMR instrument at 300.1 MHz. All chemical shifts were reported downfield in ppm relative to hydrogen resonance of TMS. The anti/syn ratios of 1,2-diols 6a–f were determined by ¹H NMR of crude products in CDCl₃. For example, the chemical shifts of CHOH in 6e₂ and 7e₂ were 4.65 and 4.78 ppm, respectively. The enantiomeric excesses (%ee) of products with two pairs of enantiomers were determined on Agilent LC-1200 HPLC with a Lux 5u Amylose-2 or Daicel Chiralcel OJ-H chiral column: eluents, (n-hexane–2-propanol = 80/20); 20 °C; UV detector, 254 nm; flow rate, 0.5 mL min⁻¹. Process monitoring containing a mixture of 3e₂ (t_R = 39.945 min), 4e₂ [t_R = 54.111 min (S) and 68.884 min (R)], 5e₂ [t_R = 65.063 min (S) and 76.590 min (R)], 6e₂ [t_R = 47.257 min (R,R) and 57.126 min (S,S)] and 7e₂ [t_R = 61.603 min (R,S) and 62.851 min (S,R)] was completely isolated and identified using HPLC on an OJ-H column: eluents, n-hexane–i-PrOH (90 : 10); flow rate, 1.0 mL min⁻¹; UV detector, λ = 220 (see Fig. S1 in ESI†).

General procedure for 1,3-diketones 2a–f

Sodium hydride (60% in mineral oil, 1.0 g, 25 mmol) was added to a 100 mL three-necked, round-bottom flask. This solution was flushed thrice with Ar atmosphere and cooled to 0 °C to 5 °C. Subsequently, the charged anhydrous THF (35 mL) and a mixture of 4-methoxyacetophenone (1.5 g, 10 mmol) and ethyl benzoate (0.15 g, 1.0 mmol) were added. After stirring for 20 min, another aliquot of ethyl benzoate (1.5 g, 10 mmol) was added to the reaction mixture. The mixture was refluxed for 16 h and cooled to room temperature. Subsequently, ethyl acetate and 10% diluted HCl were added to dissolve all kinds of solids. The organic phase was separated and washed thrice with brine (50 mL × 3) and dried on anhydrous magnesium sulfate. After removal of organic solvent, the residue was purified via chromatography eluting with petroleum ether–ethyl acetate (v/v = 80/1) to produce the corresponding 1,3-diketones 2a–f.

Typical procedure for unsymmetric benzils 3a–f

tert-Butyl nitrite (4.5 mL, 2.5 mmol) was added to a mixture of FeCl₃ (16 mg, 20 mol%) and 1,3-diketone (0.5 mmol). The reaction mixture was stirred at 30 °C under air for 12 h. After the reaction was completed, ethyl acetate (2 mL) was added, and the solids were filtered through a Celite pad. After the solvent was evaporated under reduced pressure, the residue was subjected to flash column chromatography by eluting with petroleum ether–ethyl acetate (v/v = 80/1) to obtain the unsymmetric benzils 3a–f.

General procedure for transfer hydrogenation of benzils

A 30 mL tube was filled with benzil (0.5 mmol), (R,R)-Ru catalyst a (3.3 mg, 5.0 × 10⁻³ mmol), formic acid (1.1 mL, 27.2 mmol), and triethylamine (1.9 mL, 13.6 mmol), successively. The mixture was stirred at 40 °C for 24 h, and 2 mL of ethyl acetate was added. The mixture was evaporated under reduced pressure. The residue was purified via flash column chromatography by eluting with petroleum ether–ethyl acetate (v/v = 3/1) to obtain enantiomerically pure (S,S)-hydrobenzoins 6a–f.

6a₁ + 7a₁. 20.4%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.36–7.27 (m, 1H, Ar-H), 7.25–7.10 (m, 5H, Ar-H), 7.03 (d, J = 6.7 Hz, 1H, Ar-H), 6.93–6.79 (m, 2H, Ar-H), [5.14 (d, J = 5.6 Hz), 4.96 (d, J = 5.6 Hz), 4.92 (d, J = 6.5 Hz), 4.86 (d, J = 6.5 Hz)] (2H, CHOH). Anal. calcd for C₁₄H₁₃FO₂: C, 72.40; H, 5.64; O, 13.78. Found: C, 72.36; H, 5.53; O, 13.72%. Mass (MS): m/z 233.1 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6a₁, t_R = 52.35 min; (R,R)-6a₁, t_R = 32.69 min; (R,S or S,R)-7a₁, t_R = 41.15, 45.17 min.

6a₂. 70.2%, white solid. [α]²⁵_D = −56.2 (c 0.86, CDCl₃). δ_H (300 MHz, CDCl₃, Me₄Si) 7.25–7.21 (m, 3H, Ar-H), 7.19–7.06 (m, 3H, Ar-H), 6.99–6.87 (m, 2H, Ar-H), 6.81 (d, J = 7.7 Hz, 1H, Ar-H), [4.85–4.82 (m) and 4.80–4.62 (m)] (2H, CHOH), 2.67 (s, 2H, OH). δ_C (Me₄Si) 160.2, 138.4, 134.0, 128.8, 127.6, 127.1, 126.4, 115.3 (Ph), 79.8, 78.2 (CH). Anal. calcd for C₁₄H₁₃FO₂: C, 72.40; H, 5.64; O, 13.78. Found: C, 72.34; H, 5.57; O, 13.79%. Mass (MS): m/z 233.1 [M + H]⁺. Daicel Chiralcel OJ-H column: (S,S)-6a₂, t_R = 25.36 min (major); (R,R)-6a₂, t_R = 37.85 min; (R,S or S,R)-7a₂, t_R = 31.70, 33.55 min.

6a₃. 91.8%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.26–7.22 (m, 3H, Ar-H), 7.12–7.02 (m, 4H, Ar-H), 6.89 (t, J = 8.7 Hz, 2H, Ar-H), [4.83–4.79 (m), 4.69–4.59 (m)] (2H, CHOH), 2.70 (s, 2H, OH). δ_C (Me₄Si) 162.6, 143.1, 138.3, 130.6, 129.0, 127.6, 127.0, 122.8, 114.4, 114.0 (Ph), 79.6, 77.8 (CH). Anal. calcd for C₁₄H₁₃FO₂: C, 72.40; H, 5.64; O, 13.78. Found: C, 72.39; H, 5.63; O, 13.76%. Mass (MS): m/z 233.1 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6a₃, t_R = 34.04 min (major); (R,R)-6a₃, t_R = 31.65 min; (R,S or S,R)-7a₃, t_R = 20.96, 26.94 min.

6b₁ + 7b₁. 22.6%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.62 (d, J = 6.5 Hz, 1H, Ar-H), 7.33–7.27 (m, 4H, Ar-H), 7.25–7.18 (m, 2H, Ar-H), 7.15–7.11 (m, 2H, Ar-H), [5.48 (d, J = 4.7 Hz), 5.26 (d, J = 4.5 Hz), 5.05 (d, J = 4.7 Hz), 4.95 (d, J = 4.5 Hz)] (2H, CHOH), 2.66 (s, 2H, OH). Anal. calcd for C₁₄H₁₃ClO₂: C, 67.61; H, 5.27; O, 12.87. Found: C, 67.59; H, 5.23; O, 12.79%. Mass (MS): m/z 249.1 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6b₁, t_R = 34.62 min (major); (R,R)-6b₁, t_R = 27.05 min; (R,S or S,R)-7b₁, t_R = 23.39, 24.99 min.

6b₂. 95.9%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.33–7.27 (m, 1H, Ar-H), 7.26–7.22 (m, 3H, Ar-H), 7.19 (s, 1H, Ar-H), 7.14–7.10 (m, 3H, Ar-H), 6.90 (d, J = 7.5 Hz, 1H, Ar-H), [4.84–4.79 (m), 4.74–4.60 (m)] (2H, CHOH), 2.87 (s, 2H, OH). δ_C (Me₄Si) 142.8, 138.8, 134.1, 132.3, 128.6, 127.9, 127.4, 127.1, 125.7, 124.8 (Ph), 80.0, 79.4 (CH). Anal. calcd for C₁₄H₁₃ClO₂: C, 67.61; H, 5.27; O, 12.87. Found: C, 67.55; H, 5.20; O, 12.72%. Mass (MS): m/z 249.1 [M + H]⁺.

6b₃. 97.1%, white solid. [α]²⁵_D = −63.0 (c 0.92, CDCl₃). δ_H (300 MHz, CDCl₃, Me₄Si) 7.26–7.24 (m, 3H, Ar-H), 7.21 (s, 1H, Ar-H), 7.18 (s, 1H, Ar-H), 7.17–7.09 (m, 2H, Ar-H), 7.03 (d, J = 8.4 Hz, 2H, Ar-H), [4.83 (s), 4.66 (dd, J = 18.9, 7.5 Hz)] (2H, CHOH), 2.34 (s, 2H, OH). δ_C (Me₄Si) 138.9, 137.1, 133.5, 129.7, 129.0, 128.4, 127.1, 126.4 (Ph), 80.0, 79.7 (CH). Anal. calcd for C₁₄H₁₃ClO₂: C, 67.61; H, 5.27; O, 12.87. Found: C, 67.55; H, 5.20; O, 12.72%. Mass (MS): m/z 249.1 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6b₃, t_R = 40.39 min (major); (R,R)-6b₃, t_R = 22.30 min; (R,S or S,R)-7b₁, t_R = 35.31, 38.89 min.

6c₁. 55.4%, white solid. [α]²⁵_D = −69.3 (c 0.84, CDCl₃). δ_H (300 MHz, CDCl₃, Me₄Si) 7.58–7.47 (m, 6H, Ar-H), 7.12–7.06 (m, 3H, Ar-H), [4.82 (s), 4.69 (s)] (2H, CHOH), 3.04 (s, 2H, OH). δ_C (Me₄Si) 144.6, 138.4, 133.4, 130.2, 128.9, 127.9, 127.7, 127.1, 126.5, 120.3 (Ph), 79.8, 76.0 (CH). Anal. calcd for C₁₄H₁₃BrO₂: C, 57.36; H, 4.47; O, 10.92. Found: C, 57.35; H, 4.40; O, 10.87%. Mass (MS): m/z 293.0 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6c₁, t_R = 27.80 min (major); (R,R)-6c₁, t_R = 31.90 min; (R,S and S,R)-7c₁, t_R = 39.18 min.

6c₂. 97.6%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.36 (d, J = 6.4 Hz, 2H, Ar-H), 7.30–7.27 (m, 1H, Ar-H), 7.25–7.22 (m, 2H, Ar-H), 7.13–7.04 (m, 3H, Ar-H), 6.94 (d, J = 7.7 Hz, 1H, Ar-H), [4.81 (m), 4.71–4.62 (m)] (2H, CHOH), 2.37 (s, 2H, OH). δ_C (Me₄Si) 143.2, 138.6, 132.2, 130.8, 129.8, 129.0, 127.9, 127.3, 126.4, 123.8 (Ph), 80.1, 79.2 (CH). Anal. calcd for C₁₄H₁₃BrO₂: C, 57.36; H, 4.47; O, 10.92. Found: C, 57.31; H, 4.42; O, 10.82%. Mass (MS): m/z 293.0 [M + H]⁺.

6c₃. 93.2%, white solid. [α]²⁵_D = −65.8 (c 1.02, CDCl₃). δ_H (300 MHz, CDCl₃, Me₄Si) 7.34 (d, J = 8.4 Hz, 2H, Ar-H), 7.25 (d, J = 3.2 Hz, 2H, Ar-H), 7.12–7.07 (m, 2H, Ar-H), 6.97 (d, J = 8.4 Hz, 2H, Ar-H), [4.82 (s), 4.65 (q, J = 7.5 Hz)] (2H, CHOH), 2.91 (s, 2H, OH). δ_C (Me₄Si) 138.9, 137.8, 132.2, 129.0, 127.6, 127.1, 126.5, 122.0 (Ph), 80.1, 80.0 (CH₃). Anal. calcd for C₁₄H₁₃BrO₂: C, 57.36; H, 4.47; O, 10.92. Found: C, 57.31; H, 4.43; O, 10.86%. Mass (MS): m/z 293.0 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6c₃, t_R = 43.17 min (major); (R,R)-6c₃, t_R = 23.23 min; (R,S and S,R)-7c₃, t_R = 35.72, 40.22 min.

6d₁ + 7d₁. 22.7%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 8.12–8.04 (m, 1H, Ar-H), 7.64–7.55 (m, 1H, Ar-H), 7.50–7.45 (m, 1H, Ar-H), 7.36–7.28 (m, 1H, Ar-H), 7.26–7.19 (m, 2H, Ar-H), 7.15–7.09 (m, 2H, Ar-H), 6.95 (d, J = 7.5 Hz, 1H, Ar-H), [5.13 (d, J = 5.9 Hz), 4.93 (d, J = 7.4 Hz), 4.86 (d, J = 5.9 Hz), 4.76 (d, J = 7.4 Hz)] (2H, CHOH), 3.57 (s, 2H, OH), [2.65 (s), 1.75 (s)] (3H, CH₃). Anal. calcd for C₁₅H₁₆O₂: C, 78.92; H, 7.06; O, 14.02. Found: C, 78.84; H, 6.95; O, 13.96%. Mass (MS): m/z 229.1 [M + H]⁺. Daicel Chiralcel OJ-H column: (S,S)-6d₁, t_R = 20.94 min (major); (R,R)-6d₁, t_R = 25.56 min; (R,S and S,R)-7d₁, t_R = 33.03 min.

6d₂. 78.7%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.24 (d, J = 2.2 Hz, 3H, Ar-H), 7.16–7.09 (m, 3H, Ar-H), 7.04 (d, J = 7.6 Hz, 1H, Ar-H), 6.99 (s, 1H, Ar-H), 6.90 (d, J = 7.3 Hz, 1H, Ar-H), [4.78 (q, J = 6.4 Hz), 4.70 (q, J = 7.0 Hz)] (2H, CHOH), [2.32 (s), 2.28 (s)] (3H, CH₃). δ_C (Me₄Si) 140.8, 139.6, 138.0, 129.5, 129.0, 128.8, 127.7, 127.2, 126.8, 124.0 (Ph), 80.3, 79.8 (CH), 21.6 (CH₃). Anal. calcd for C₁₅H₁₆O₂: C, 78.92; H, 7.06; O, 14.02. Found: C, 78.84; H, 6.97; O, 13.92%. Mass (MS): m/z 229.1 [M + H]⁺. Daicel Chiralcel OJ-H column: (S,S)-6d₂, t_R = 28.07 min (major); (R,R)-6d₂, t_R = 25.56 min; (R,S and S,R)-7d₂, t_R = 30.93, 33.20 min.

6d₃. 80.6%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.22–7.20 (m, 3H, Ar-H), 7.12–7.10 (m, 2H, Ar-H), 7.04–6.98 (m, 4H, Ar-H), [4.68 (q, J = 6.2 Hz), 4.65 (q, J = 7.4 Hz)] (2H, CHOH), 3.31 (s, 2H, OH), [2.40 (s), 2.29 (s)] (3H, CH₃). δ_C (Me₄Si) 138.0, 137.1, 134.8, 129.8, 128.6, 128.0, 127.2, 125.5 (Ph), 80.2, 80.0 (CH), 21.3 (CH₃). Anal. calcd for C₁₅H₁₆O₂: C, 78.92; H, 7.06; O, 14.02. Found: C, 78.80; H, 7.93; O, 13.94%. Mass (MS): m/z 229.1 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6d₃, t_R = 54.11 min (major); (R,R)-6d₃, t_R = 51.10 min; (R,S and S,R)-7d₃, t_R = 28.84, 44.54 min.

6e₁ + 7e₁. 31.2%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.27 (s, 1H, Ar-H), 7.25–7.24 (m, 1H, Ar-H), 7.22–7.16 (m, 3H, Ar-H), 7.15–7.12 (m, 1H, Ar-H), 6.92–6.82 (m, 3H, Ar-H), [5.17 (d, J = 5.5 Hz), 4.94 (d, J = 5.5 Hz), 4.86 (q, J = 6.6 Hz)] (2H, CHOH), [3.76 (s), 3.71 (s)] (3H, OCH₃), 2.69 (s, 2H, OH). Anal. calcd for C₁₅H₁₆O₃: C, 73.75; H, 6.60; O, 19.65. Found: C, 73.69; H, 6.53; O, 19.34%. Mass (MS): m/z 245.1 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6e₁, t_R = 68.05 min; (R,R)-6e₁, t_R = 46.31 min; (R,S and S,R)-7e₁, t_R = 52.27, 60.47 min.

6e₂. 93.5%, white solid. [α]²⁵_D = −113.6 (c 1.10, CDCl₃). δ_H (300 MHz, CDCl₃, Me₄Si) 7.25–7.21 (m, 3H, Ar-H), 7.12 (t, J = 7.6 Hz, 3H, Ar-H), 6.75 (dd, J = 8.2, 1.9 Hz, 1H, Ar-H), 6.67 (d, J = 9.2 Hz, 2H, Ar-H), [4.78 (s), 4.65 (s)] (2H, CHOH), 3.68 (s, 3H, OCH₃), 2.88 (s, 2H, OH). δ_C (Me₄Si) 160.8, 141.8, 138.4, 129.9, 128.9, 127.6, 127.1, 119.4, 113.2, 111.2 (Ph), 80.3, 80.0 (CH), 55.8 (OCH₃). Anal. calcd for C₁₅H₁₆O₃: C, 73.75; H, 6.60; O, 19.65. Found: C, 73.71; H, 6.55; O, 19.49%. Mass (MS): m/z 245.1 [M + H]⁺. Daicel Chiralcel OJ-H column: (S,S)-6e₁, t_R = 53.65 min (major); (R,R)-6e₁, t_R = 46.31 min; (R,S and S,R)-7e₁, t_R = 59.21, 61.10 min.

6e₃. 68.5%, white solid. δ_H (300 MHz, CDCl₃, Me₄Si) 7.26–7.21 (m, 3H, Ar-H), 7.58–7.47 (m, 2H, Ar-H), 7.03 (d, J = 8.6 Hz, 2H, Ar-H), 6.75 (d, J = 8.6 Hz, 2H, Ar-H), [4.78 (q, J = 6.1 Hz), 4.65 (q, J = 7.7 Hz)] (2H, CHOH), 3.76 (s) (3H, OCH₃), 2.98 (s, 2H, OH). δ_C (Me₄Si) 159.8, 138.0, 131.1, 128.3, 128.1, 127.8, 127.3, 127.0 (Ph), 80.5, 80.0 (CH), 55.5 (OCH₃). Anal. calcd for C₁₅H₁₆O₃: C, 73.75; H, 6.60; O, 19.65. Found: C, 73.65; H, 6.49; O, 19.52%. Mass (MS): m/z 245.1 [M + H]⁺.

6f₂. 92.2%, white solid. [α]²⁵_D = −89.8 (c 0.96, CDCl₃). δ_H (300 MHz, CDCl₃, Me₄Si) 7.46 (d, J = 7.7 Hz, 1H, Ar-H), 7.30 (d, J = 7.9 Hz, 2H, Ar-H), 7.25–7.17 (m, 4H, Ar-H), 7.05–7.03 (m, 2H, Ar-H), [4.88 (d, J = 5.1 Hz), 4.82 (d, J = 5.3 Hz), 4.71 (d, J = 7.4 Hz), 4.57 (d, J = 7.4 Hz)] (2H, CHOH), 3.20 (s, 2H, OH). δ_C (Me₄Si) 141.2, 138.8, 131.3, 129.8, 128.9, 127.9, 127.3, 125.1, 124.2 (Ph), 123.4 (CF₃, q, ²J_C–F = 15.6 Hz), 80.3, 80.0 (CH). Anal. calcd for C₁₅H₁₃F₃O₂: C, 63.83; H, 4.64; O, 11.34. Found: C, 63.74; H, 4.56; O, 11.29%. Mass (MS): m/z 283.1 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6f₂, t_R = 20.79 min (major); (R,R)-6f₂, t_R = 14.15 min; (R,S and S,R)-7f₂, t_R = 16.64, 19.67 min.

6f₃. 94.9%, white solid. [α]²⁵_D = −87.1 (c 1.02, CDCl₃). δ_H (300 MHz, CDCl₃, Me₄Si) 7.45 (d, J = 8.1 Hz, 2H, Ar-H), 7.24 (d, J = 3.4 Hz, 2H, Ar-H), 7.16 (d, J = 8.0 Hz, 2H, Ar-H), 7.07 (dd, J = 6.4, 2.8 Hz, 2H, Ar-H), [4.88 (d, J = 5.4 Hz), 4.82 (d, J = 5.3 Hz), 4.72 (d, J = 7.4 Hz), 4.60 (d, J = 7.4 Hz)] (2H, CHOH), 3.03 (s, 2H, OH). δ_C (Me₄Si) 141.9, 138.8, 130.2, 128.5, 127.6, 127.0, 126.1, 125.4 (Ph), 123.8 (CF₃, q, ²J_C–F = 18,3 Hz), 80.2, 80.0 (CH). Anal. calcd for C₁₅H₁₃F₃O₂: C, 63.83; H, 4.64; O, 11.34. Found: C, 63.74; H, 4.56; O, 11.29%. Mass (MS): m/z 283.1 [M + H]⁺. Phenomenex Lux 5u Amylose-2 chiral column: (S,S)-6f₃, t_R = 21.61 min (major); (R,R)-6f₃, t_R = 15.35 min; (R,S and S,R)-7f₃, t_R = 17.85, 19.81 min.

Acknowledgements

The work was financially supported by the National Science Foundation of China (grants 21071116) and Chongqing Scientific Foundation (CSTC, 2010BB4126).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR of 2a–f, 3a–f, 4e₂, 5e₂, 6a–f; HPLC diagram of 6a–f; kinetic data of 3e₂, 4e₂ and 5e₂ in catalytic process. See DOI: 10.1039/c3ra47129b

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