Method for Catalytic Enantioselective Alkylation of Aldehydes Using

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Method for Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents as Alkyl Sources Kento Tanaka, Munehisa Tomihama, Koji Yamamoto, Naoki Matsubara, and Toshiro Harada J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00929 • Publication Date (Web): 10 May 2018 Downloaded from http://pubs.acs.org on May 11, 2018

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The Journal of Organic Chemistry

Method for Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents as Alkyl Sources Kento Tanaka, Munehisa Tomihama, Koji Yamamoto, Naoki Matsubara, and Toshiro Harada* Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan [email protected]

Abstract: Alkyltitanium reagents, generated in situ from Grignard reagents and ClTi(OiPr)3, can be employed without further manipulation in the enantioselective alkylation of aldehyde by the catalysis of a chiral titanium complex derived from DTBP-H8-BINOL. The reaction is carried out with good stoichiometry (1.5 equiv each of Grignard reagents and ClTi(OiPr)3) at low catalyst loading (2 mol%), affording a variety of chiral secondary alcohols in high enantioselectivity and yields and, hence, realizing an asymmetric version of the Grignard reaction in an indirect manner. Introduction The catalytic enantioselective addition of organometallic reagents to aldehydes and ketones is one of the most useful methods for the synthesis of chiral alcohols with simultaneous C–C bond formation.1–8 Although the recent development of efficient catalytic systems has extend the scope of organometallic reagents applicable to this reaction, the use of Grignard reagents is relatively less exploited.9-21 The preparation of Grignard reagents is well established. A variety of reagents are commercially available and commonly used both in the laboratory and in the industry. Accordingly, an asymmetric version of the Grignard reaction that enables the enantioselective preparation of chiral secondary and tertiary alcohols has been of considerable interest for a long time.22,23 However, the use of Grignard reagents in the catalytic enantioselective addition is a difficult task owing to their high activity that concurrently induces non-catalytic racemic reaction. Recently, Harutyunyan and Minnaard have shown for the first time that the enantioselective addition of alkyl Grignard reagents to ketones can be realized by chiral Cu(I) catalysts.24–28 Despite such advancement, the enantioselective addition to the significantly more reactive aldehydes remains a challenging problem. For aldehydes, indirect methods in which Grignard reagents are used after conversion to organotitanium and -zinc reagents have been developed. Seebach reported TADDOLate-Ti catalyzed enantioselective alkylation of aldehydes with alkyltitanium reagents RTi(OiPr)3, generated from RMgBr by transmetalation with ClTi(OiPr)3.10 The rigorous exclusion of coproduced magnesium salts is necessary to achieve high enantioselectivity, requiring complexation with 1,4-dioxane and centrifugation of the resulting precipitate. In the enantioselective addition to aldehydes catalyzed with a chiral amino-alcohol, diorganozinc reagents generated from Grignard reagents by transmetalation with Zn(OMe)2 was successfully employed by Charette after the removal of precipitated magnesium salts with centrifugation.11 We have recently reported a synthetically more simple method in which Grignard reagents are used as a mixed reagent with excess Ti(OiPr)4 without further manipulation.13–16 By virtue of the enhanced activity of chiral titanium catalysts derived from BINOL derivatives 1b and 2b bearing sterically demanding aryl group at the 3-position,29,30 the in-situ generated mixed reagents undergo highly enantioselective

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alkylation and arylation of aldehydes even at 2 mol %-catalyst loading. As a typical reaction protocol, 1.2 equiv of Grignard reagents and 3 equiv of Ti(OiPr)4 are used for the enantioselective arylation. On the other hand, for the alkylation, further excess of Grignard reagents (2.2 equiv) and the titanium alkoxide (5.8 equiv) are employed. Although Ti(OiPr)4 is a nontoxic, low-coast chemicals, reduction in the amount is desirable to improve practicality. Da et al. reported that the amount of Ti(OiPr)4 can be decreased to 0.9–1.4 equiv by the use of alkyl Grignard reagents (2 equiv) with bis[2-(N,Ń-dimethylamino)ethyl]ether as chelating additive albeit at the higher loading of the parent BINOL 1a (15 mol%).17–18

In the present study, we examined the use of alkyltitanium reagents, generated in-situ from Grignard reagents and ClTi(OiPr)3, in the alkylation of aldehydes with a titanium catalyst derived from DTBP-H8-BINOL ((R)-2c) (Scheme 1). We report herein the result of this study which demonstrates that (1) 1.5 equiv each of Grignard reagents and the titanium alkoxide is sufficient, (2) the resulting titanium reagents can be used directly without centrifugation, and (3) a variety of chiral secondary alcohols are obtained in high yields and enantioselectivities at 2 mol %catalyst loading. Scheme 1 Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents

Results and Discussion BuMgCl (1.5 equiv) (2 M in Et2O) was treated with ClTi(OiPr)3 (1.5 equiv) in the presence of Ti(OiPr)4 (0.3 equiv) at –78 °C in Et2O to give a mixture of BuTi(OiPr)3 and MgCl2 (Scheme 2). The titanium reagent was transferred to a syringe together with the suspended magnesium salts as a fine powder, added to a Et2O solution of 1-naphthaldehyde (1 mmol), (R)-2c (2 mol %), and 1,4-dioxane (1.5 equiv) at 0 °C for 1 h, and stirred for a further 0.5 h. Under these optimized conditions, (R)-alcohol 3a was obtained in 87% yield and 95% ee. Scheme 2 Catalytic Enantioselective Butylation of 1-Naphthaldehyde Using BuMgCl


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In the first step of generating the butyltitanium reagent, Ti(OiPr)4 (0.3 equiv) is recommended as an additive to obtain reproducible yields. Otherwise, yields varied from 74% to 100%. An excess amount of BuMgCl with respect to ClTi(OiPr)3 induced considerable decomposition of the reagent. For example, the reaction using a reagent prepared from BuMgCl (2.1 equiv) and ClTi(OiPr)3 (1.5 equiv) gave 3a only in 10% yield. It is often difficult to adjust the mixing ratio exactly to 1:1. Ti(OiPr)4 as an additive assures the absence of the excess Grignard reagent. The enantioselectivity of 3a was not increased further when a filtered solution of the butyltitanium reagent was employed (95% ee, 67% yield). On the other hand, the selectivity was decreased to some extent when the reaction was carried out in the absence of 1,4-dioxane, that is known to form insoluble complex with MgCl2 (89% ee, 95% yield). We speculate that the precipitated magnesium salt does not deteriorate the enantioselectivity of the reaction whereas a small amount of the salt in the solution promotes the background racemic reaction pathway as a Lewis acid. The use of the parent ligand (R)-2a (2 mol %) resulted in the lower conversion and selectivity (40% yield, 47% ee). Even at a 10 mol % catalyst loading, the ligand exhibited inferior result (72% yield, 92% ee).31 The butyltitanium reagent is moderately reactive, affording racemic 3a in 27% yield in the absence of the chiral ligands. These results implies a high activity of the chiral titanium catalyst derived from (R)-2c that overrides the background racemic reaction of the titanium reagent. The results of the present enantioselective alkylation reaction with a variety of aldehydes and Grignard reagents are summarized in Table 1. Not only aromatic aldehydes but also a heteroaromatic aldehyde (entries 19–22) and an α,β-unsaturated aldehydes (entries 23 and 24) underwent enantioselective alkylation under the optimized conditions to give the product alcohols 3 in high yields and ee’s (85–98%). The reaction of an aliphatic aldehyde however resulted in poor conversion and selectivity (entry 25).



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Table 1 Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagentsa entry aldehydes RMgX product yield (%) ee (%) 1

1-NaphCHO

BuMgCl

3a

87

95

1-NaphCHO

BuMgCl

3a

85

97

3

1-NaphCHO

BuMgBr

3a

76

97

4 5c

1-NaphCHO

EtMgCl

3b 3b

62 70

95 95

6

1-NaphCHO

n-C5H11MgCl

3c

72

93

7

1-NaphCHO

n-C6H13MgCl

3d

98

96

8 9

1-NaphCHO 1-NaphCHO

n-C6H13MgBr PhCH2CH2MgCl

3d 3e

92 72

95 96

10d

1-NaphCHO

i

3f

35

98

3f

61

91

2

b

11

BuMgCl

e,f f

12 13d

1-NaphCHO 1-NaphCHO

CyMgCl PhMgBr

3g 3h

52 97

91 78

14

PhCHO

BuMgCl

4a

80

95

15

PhCHO

PrMgCl

4b

79

98

16 17

p-ClC6H4CHO m-MeOC6H4CHO

n-C5H11MgCl PrMgCl

4c 4d

76 95

96 97

o-ClC6H4CHO

BuMgCl

4e

79

85

2-ThieylCHO

BuMgCl

5a

82

96

20 21

2-ThieylCHO 2-ThieylCHO

BuMgBr n-C6H11MgCl

5a 5b

73 79

92 94

22

2-ThieylCHO

n-C6H11MgBr

5b

70

94

PhCH=CHCHO

BuMgCl

6a

82

91

18 19

c

23 g

24 CH2=C(Me)CHO BuMgCl 59 93 6b 25 PhCH2CH2CHO BuMgCl 16 61 7 a Unless otherwise noted, reactions were carried out at 1 mmol scale under the conditions shown


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in Scheme 2. b The reaction was carried out at 9.9 mmol scale. c Titanium reagent was prepared from EtMgCl (2 equiv) and ClTi(OiPr)4 (2 equiv) and Ti(OiPr)4 (0.4 equiv). d Ti(OiPr)4 was not used. e The reaction was carried out at 0 °C for 18 h after the addition of the titanium reagents in five min. f The reaction was carried out at room temperature at higher concentration for 18 h after the addition of the titanium reagents in 5 min. See Experimental Section for detail. g The reaction was carried out at 2 mmol scale. The halogen atom of Grignard reagents could also be bromine as demonstrated in the reaction employing BuMgBr (entries 3 and 20) and n-C6H13MgBr (entries 8 and 22). In general, reactions using primary alkyl Grignard reagents proceeded efficiently (entries 1–3, 6–9, 14–25). Despite high selectivity, product yields were moderate for the reaction using EtMgCl (entry 4) and i BuMgCl (entry 10). In the former reaction, the pinacol coupling of 1-naphthaldehyde concurrently proceeded to give [1-NaphCH(OH)]2 as a byproduct (14%), suggesting the generation of Ti(III) species by the decomposition of the ethyltitanium reagents in the first step of the reaction.32 Improved yield was obtained when 2 equiv of the titanium reagent was employed (entry 5). In the later reaction, on the other hand, formation of the pinacol-coupling product was not observed, implying that the isobutyltitanium reagent is stable31 but less reactive probably for steric reasons. The longer reaction time resulted in decreased selectivity albeit with improvement in the product yield (entry 11). The reaction of secondary cyclohexyl Grignard reagents was very sluggish under the optimized conditions. However by carrying out the reaction at room temperature for 18 h at higher concentration, the corresponding alkylation product was obtained in 52% yield and 91% ee (entry 12).33 The reaction of PhMgBr was moderately selective although the product yield was high (entry 13). The preparative utility of the present reaction is demonstrated in a gram-scale synthesis of alcohol (R)-3a (entry 2). Even with 96 mg (2 mol %) of chiral ligand (R)-2c, the reaction of 1naphthaldehyde (9.9 mmol) and BuMgCl (15 mmol) provided 1.80 g (85% yield) of the alcohol in 97% ee after isolation by vacuum distillation. The ligand was recovered from the residue for reuse in 88% yield. Conclusion We have developed a practical method for the enantioselective alkylation of aldehydes using Grignard reagents as the alkyl-group sources. It has been demonstrated that the high activity of chiral titanium catalyst derived from DTBP-H8-BINOL (R)-2c enables the enantioselective addition of the in-situ generated alkyltitanium species from the Grignard reagents and ClTi(OiPr)3 without removal of co-produced magnesium salts. The reaction is carried out with good stoichiometry at low catalyst loading (2 mol %) affording a variety of chiral secondary alcohols in high enantioselectivity and yields. Experimental Section General. Et2O, 1,4-dioxane, and cyclopentyl methyl ether were distilled from sodium benzophenone ketyl prior to use. Ti(OiPr)4 and TiCl4 were purchased from Wako Pure Chemical Industries, LTD. and used as received. A stock solution of ClTi(OiPr)3 in Et2O (0.5 M) was prepared by mixing Ti(OiPr)4 and TiCl4 in a molar ratio of 3:1 in Et2O. BuMgCl (2 M in Et2O), PrMgCl (2 M in Et2O), EtMgCl (2 M in Et2O), iBuMgCl (2 M in Et2O), CyMgCl (2 M in Et2O), and PhMgBr (3 M in Et2O) were purchased from Sigma-Aldrich and used without titration. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance III spectrometer at 500 MHz and 125 MHz, respectively. HRMS analyses were performed with JEOL JMS-700 in FAB-double focusing mode. Flash chromatography was carried out with silica gel C-300 of Wako Pure Chemical Industries, Ltd. (R)-3-Bromo-2,2’-dihydroxy-5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-binaphthyl.34


To

a


solution of (R)-H8-BINOL (2.30 g, 7.81 mmol) in CH2Cl2 at –15 °C was added dropwise a solution of bromine (0.20 mL, 3.9 mmol) in CH2Cl2 for 1 h. Immediately after the addition, the reaction mixture is poured into water. An organic layer is separated and washed with aqueous Na2S2O3 (5%, 50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (5% ethyl acetate in toluene) to give 0.918 g (63% yield based on bromine) of the bromide as a light yellow powder: [α]D25 +74.1 (c 1.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1,62–1.77 (8H, m), 2.07–2.17 (2H, m), 2.23–2.36 (2H, m), 2.73–2.77 (4H, m), 4.39 (1H, s), 5.11 (1H, s), 6.81 (1H, d, J = 8.3 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.31 (1H, s); 13C NMR (125 MHz, CDCl3) δ 22.68, 22.74, 22.9, 23.0, 26.9, 27.1, 29.0, 29.2, 107.0, 112.9, 119.8, 120.9, 130.0, 130.9, 131.8, 133.2, 136.5, 137.3, 148.0, 150.7; HRMS (FAB-double focusing) calcd for C20H21O279Br M+ 372.0725, found 372.0727. (R)-3-(3,5-di-tert-Butylphenyl)-2,2’-dihydroxy-5,5’,6,6’,7,7’,8,8’-octahydro-1,1’binaphthyl ((R)-2c). A mixture of 3,5-di-tert-butylphenylboronic acid (0.351 g, 1.50 mmol),35 (R)-3-bromo-2,2’-dihydroxy-5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-binaphthyl (0.374 g, 1.00 mmol), and K2CO3 (0.218 g, 1.50 mmol), in DME (6 mL) was degassed through a freeze-pump-thaw cycle (three times). To this under argon atmosphere was added Pd(OAc)2 (11 mg, 0.050 mmol, 5 mol%) and di(1-adamantyl)butylphosphine (22 mg, 0.060 mmol, 6 mol%). The resulting gray suspension was heated under reflux for 21 h. Aqueous saturated NH4Cl (15 mL) is added. The mixture was extracted with ethyl acetate (2 x 50 mL), washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (10% ethyl acetate in hexane) to give 0.406 g (84% yield) of (R)-2c as a light yellow: [α]D23 = +63.3 (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.36 (18H, s), 1.64–1.82 (8H, m), 2.17–2.29 (2H, m), 2.31–2.45 (2H, m), 2.73–2.85 (4H, m), 4.65 (1H, br), 4.97 (1H, br), 6.85 (1H, d, J = 8.3 Hz), 7.07 (1H, d, J = 8.3 Hz), 7.14 (1H, s), 7.38 (2H, d, J = 1.8 Hz), 7.40 (1H, t, J = 1.8 Hz); 13C NMR (125 MHz, CDCl3) δ 22.98, 23.04, 23.06, 23.09, 27.1, 27.2, 29.26, 29.27, 31.5, 34.9, 112.8, 119.6, 120.1, 121.4, 123.5, 127.1, 129.9, 130.1, 130.7, 131.7, 136.5, 136.7, 136.9, 148.3, 150.9, 151.0; HRMS (FAB-double focusing) calcd for C34H42O2 M+ 482.3185, found 482.3177. n-C6H13MgCl Solution in Cyclopentyl Methyl Ether and Et2O. Magnesium turnings (2.40 g, 100 mmol) was placed in a reaction flask, heated under vacuum at 170 °C for 0.5 h, and suspended in cyclopentyl methyl ether (5 mL) under argon atmosphere. To this was added a 2mL portion of a solution of 1-chlorohexane (6.0 g, 50 mmol) in cyclopentyl methyl ether (13 mL) and the mixture was heated at 90 °C with stirring to start the reaction. After the initial exothermic reaction has ceased, the rest of the solution was added dropwise to the reaction mixture at 90 °C for 1.5 h. After being stirred for 1 h under gentle refluxing, the resulting suspension was diluted with Et2O (25 mL) and filtered through Celite to give a n-C6H13MgCl solution. The concentration of the Grignard reagent was determined to be 0.85 M by titration using salicylaldehyde phenylhydrazone as an indicator.36 n-C5H11MgCl (0.81 M) and PhCH2CH2Mg (0.96 M) were prepared by a procedure similar to that described above. Typical Procedure for Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents. (R)-1-Naphthalen-1-ylpentan-1-ol ((R)-3a)37 (Table 1, entry 1). Under argon atmosphere, ClTi(OiPr)3 (0.5 M in Et2O, 3.0 mL, 1.5 mmol) was diluted with dry Et2O (13 mL) and Ti(OiPr)4 (0.088 mL, 0.3 mmol) was added. To this solution at –78 °C was added BuMgCl (2 M in Et2O, 0.75 mL, 1.5 mmol). The mixture was stirred at –78 °C for 15 min and then at 0 °C for 10 min. The resulting suspension was added with a syringe pump for 1 h to a Et2O (4 mL) solution of ligand 2c (9.6 mg, 0.020 mmol), 1,4-dioxane (0.13 mL, 1.5 mmol), and 1naphthaldehyde (156 mg, 1.0 mmol) at 0 °C. After being stirred further at 0 °C for 0.5 h, the reaction mixture was quenched by the addition of aqueous 1 N HCl and extracted three times with ethyl acetate. The organic layers were washed successively with aqueous 5% NaHCO3 and with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (5–30% ethyl acetate in hexane) to give 186 mg (87% yield) of (R)-3a (95%


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ee):38 1H NMR (500 MHz, CDCl3) δ 0.91 (3H, t, J = 7.2 Hz), 1.32–1.60 (4H, m), 1.78 (1H, br), 1.96–2.01 (2H, m), 5.48 (1H, dd, J = 4.8 and 7.9 Hz), 7.46–7.54 (3H, m), 7.64 (1H, d, J = 7.1 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.87 (1H, d, J = 9.5 Hz), 8.13 (1H, d, J = 8.4 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1.0 mL/min, 4% i-PrOH in hexane; retention times: 13.8 min (minor S-enantiomer) and 29.4 min (major R-enantiomer). The retention times were concordant with published values.39 The above reaction was carried out in a 9.92 mmol-scale by following the same procedure except that a dropping funnel was used for the addition of the titanium reagent (Table 1, entry 2). Kugelrohr distillation (130–140 °C/5 mmHg) of the crude products gave 1.803 g (85% yield) of (R)-3a (97% ee). Flash chromatography (silica gel, 5% ethyl acetate in hexane) of the residue gave 84.8 mg (88% recovery) of ligand 2c. (R)-1-Naphthalen-1-ylpropan-1-ol (3b):40 (Table 1, entry 5, 130 mg, 70% yield) 1H NMR (500 MHz, CDCl3) δ 1.04 (3H, t, J = 7.4 Hz), 1.82 (1H, br), 1.88–2.18 (2H, m), 5.41 (1H, dd, J = 5.0 and 7.6 Hz), 7.46–7.54 (3H, m), 7.64 (1H, d, J = 7.1 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.88 (1H, d, J = 9.5 Hz), 8.12 (1H, d, J = 8.3 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1.0 mL/min, 10% i-PrOH in hexane; retention times: 8.7 min (minor S-enantiomer) and 15.6 min (major R-enantiomer). The retention times were concordant with published values.41 (R)-1-Naphthalen-1-ylhexan-1-ol (3c):17 (Table 1, entry 6, 165 mg, 72% yield) 1H NMR (500 MHz, CDCl3) δ 0.88 (3H, t, J = 6.9 Hz), 1.28–1.63 (6H, m), 1.9 (1H, br), 1.87–2.01(2H, m), 5.48 (1H, dd, J = 4.8 and 8.0 Hz), 7.46–7.54 (3H, m), 7.65 (1H, d, J = 7.1 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.88 (1H, d, J = 9.5 Hz), 8.13 (1H, d, J = 8.4 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1.0 mL/min, 10% i-PrOH in hexane; retention times: 7.1 min (minor S-enantiomer) and 13.6min (major R-enantiomer). The retention times were concordant with published values.17 (R)-1-Naphthalen-1-ylheptan-1-ol (3d):42 (Table 1, entry 7, 236 mg, 98% yield) 1H NMR (500 MHz, CDCl3) δ 0.87 (3H, t, J = 6.8 Hz), 1.24–1.60 (8H, m), 1.76 (1H, br), 1.88–2.00 (2H, m), 5.48 (1H, dd, J = 4.8 and 7.9 Hz), 7.47–7.54 (3H, m), 7.65 (1H, d, J = 7.1 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.88 (1H, d, J = 7.7 Hz), 8.13 (1H, d, J = 8.4 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1 mL/min, 4% i-PrOH in hexane; retention times: 12.6 min (minor S-enantiomer) and 26.0 min (major R-enantiomer). The retention times were concordant with published values.42 (R)-1-Naphthalen-1-yl-3-phenylpropan-1-ol (3e):18 (Table 1, entry 9, 189 mg, 72% yield) 1 H NMR (500 MHz, CDCl3) δ 1.57 (1H, br), 2.20–2.28 (2H, m), 2.81–2.93 (2H, m), 5.48 (1H, dd, J = 4.8 and 7.9 Hz), 7.18–7.26 (3H, m), 7.28–7.32 (2H, m), 7.46–7.51 (3H, m), 7.68 (1H, d, J = 7.2 Hz), 7.78 (1H, d, J = 8.3 Hz), 7.87 (1H, n), 7.93 (1H, m). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1 mL/min, 10% i-PrOH in hexane; retention times: 14.7 min (minor S-enantiomer) and 26.3 min (major R-enantiomer). The retention times were concordant with published values.18 (R)-3-Methyl-1-(naphthalen-1-yl)butan-1-ol (3f):17 (Table 1, entry 10, 75 mg, 35% yield) 1 H NMR (500 MHz, CDCl3) δ 1.01 (3H, d, J = 7.8 Hz), 1.12 (3H, d, J = 7.8 Hz), 1.73 (1H, m), 1.83 (1H, m), 1.97 (1H, m), 2.07 (1H, br), 5.54 (1H, dd, J = 3.8 and 9.4 Hz), 7.46–7.56 (3H, m), 7.66 (1H, d, J = 7.1 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.89 (1H, d, J = 8.7 Hz), 8.11 (1H, d, J = 8.2 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1 mL/min, 9% i-PrOH in hexane; retention times: 7.62 min (minor S-enantiomer) and 13.4 min (major R-enantiomer). The retention times were concordant with published values.17 (R)-Cyclohexyl(naphthalen-1-yl)methanol (3g):31 (Table 1, entry 12) To a solution of ligand 2c (9.6 mg, 0.020 mmol) dry Et2O (0.25 mL) under argon atmosphere at room temperature was added ClTi(OiPr)3 (0.5 M in Et2O, 3.0 mL, 1.5 mmol). To the resulting solution at –78 °C was added CyMgCl (2 M in Et2O, 0.75 mL, 1.5 mmol). The mixture was stirred at –78 °C for 15 min and then at room temperature for 10 min. To the resulting suspension was added 1.4-dioxane (0.13



mL, 1.5 mmol) and 1-naphthaldehyde (156 mg, 1.0 mmol). After being stirred at room temperature for 17 h, the reaction mixture was quenched by the addition of aqueous 1 N HCl and extracted three times with ethyl acetate. The organic layers were washed successively with aqueous 5% NaHCO3 and with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (5–30% ethyl acetate in hexane) to 125 mg (52% yield) of (R)-3g (91% ee): 1H NMR (500 MHz, CDCl3) δ 1.1–1.24 (5H, m), 1.41 (1H, m), 1.60– 2.00 (6H, m), 5.20 (1H, d, J = 6.5 Hz), 7.46–7.53 (3H, m), 7.58 (1H, d, J = 7.1 Hz), 7.78 (1H, d, J = 8.2 Hz), 7.87 (1H, d, J = 8.7 Hz), 8.15 (1H, d, J = 8.1 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OJ-H column, 1 mL/min, 5% i-PrOH in hexane; retention times: 8.5 min (minor S-enantiomer) and 12.0 min (major R-enantiomer). The retention times were concordant with published values.31 (R)-Naphthalen-1-ylphenylmethanol (3h):42 (Table 1, entry 13, 228 mg, 97% yield) 1H NMR (500 MHz, CDCl3) δ 1.75 (1H, br), 6.55 (1H, s), 7.28 (1H, m), 7.34 (2H, m), 7.41–7.51 (5H, m), 7.64 (1H, d, J = 7.1 Hz), 7.82 (1H, d, J = 8.3 Hz), 7.87 (1H, m), 8.05 (1H, d, J = 9.2 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1 mL/min, 10% i-PrOH in hexane; retention times: 15.5 min (minor S-enantiomer) and 33.1 min (major Renantiomer). The retention times were concordant with published values.42 (R)-1-Phenylpentan-1-ol (4a):40 (Table 1, entry 14, 132 mg, 80% yield) 1H NMR (500 MHz, CDCl3) δ 0.88 (3H, t, J = 7.2 Hz), 1.20–1.45 (4H, m), 1.68–1.77 (2H, m), 1.78–1.87 (1H, m), 4.67 (1H, dd, J = 5.6 and 7.5 Hz), 7.26–7.30 (2H, m), 7.34–7.36 (3H, m). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 0.8 mL/min, 2% i-PrOH in hexane; retention times: 17.0 min (major R-enantiomer) and 18.3 min (minor S-enantiomer). The retention times were concordant with published values.43 (R)-1-Phenylbutan-1-ol (4b):44 (Table 1, entry 15, 119 mg, 79% yield) 1H NMR (500 MHz, CDCl3) δ 0.93 (3H, t, J = 7.4 Hz), 1.32 (1H, m), 1.43 (1H, m), 1.62–1.83 (3H, m), 4.68 (1H, dd, J = 5.9 and 7.6 Hz), 7.28 (2H, m), 7.34–7.36 (3H, m). Enantioselectivity was determined by HPLC analysis using a Chiralcel OB-H column, 0.5 mL/min, 3% i-PrOH in hexane; retention times: 16.6 min (minor S-enantiomer) and 19.8 min (major R-enantiomer). The retention times were concordant with published values.45 (R)-1-(4-Chlorophenyl)hexan-1-ol (4c):46 (Table 1, entry 16, 161 mg, 76% yield) 1H NMR (500 MHz, CDCl3) δ 0.87 (3H, t, J = 7.1 Hz), 1.21–1.44 (6H, m), 1.55–1.80 (3H, m), 4.65 (1H, dd, J = 5.9 and 7.4Hz), 7.27–7.33 (4H, m). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1 mL/min, 0.5% i-PrOH in hexane; retention times: 30.5 min (minor S-enantiomer) and 34.0 min (major R-enantiomer). The absolute stereochemistry was assumed by analogy. (R)-1-(3-Methoxyphenyl)butan-1-ol (4d):47 (Table 1, entry 17, 171 mg, 95% yield) 1H NMR (500 MHz, CDCl3) δ 0.94 (3H, t, J = 7.4 Hz), 1.34 (1H, m), 1.44 (1H, m), 1.65–1.83 (3H, m), 3.82 (3H, s), 4.66 (1H, dd, J = 5.8 and 7.6 Hz), 6.91 (1H, ddd, J = 1.2, 2.4. 8.3 Hz), 6.91– 6.93 (2H, m), 7.26 (1H, t, J = 8.1 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 0.5 mL/min, 7% i-PrOH in hexane; retention times: 23.8 min (minor Senantiomer) and 26.6 min (major R-enantiomer). The retention times were concordant with published values. 47 (R)-1-(2-Chlorophenyl)pentan-1-ol (4e):15 (Table 1, entry 18, 156 mg, 79% yield) 1H NMR (500 MHz, CDCl3) δ 0.91 (3H, t, J = 7.1 Hz), 1.31–1.52 (4H, m), 1.66–1.82 (2H, m), 1.88 (1H, br), 5.13 (1H, dd, J = 4.5 and 8.1 Hz), 7.20 (1H, dt, J = 1.7 and 7.6 Hz), 7.27–7.34 (2H, m), 7.54 (1H, dd, J = 1.6 and 7.7 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralpak OB-H column, 1 mL/min, 0.3% i-PrOH in hexane; retention times: 16.1 min (major Renantiomer) and 19.8 min (minor S-enantiomer). The retention times were concordant with published values.39 (R)-1-Thiophen-2-ylpentan-1-ol (5a):48 (Table 1, entry 19, 140 mg, 82%) 1H NMR (500 MHz, CDCl3) δ 0.90 (3H, t, J = 7.2 Hz), 1.26–1.50 (4H, m), 1.78–2.00 (3H, m), 4.92 (1H, t, J =


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6.7 Hz), 6.96–6.98 (2H, m), 7.25 (1H, dd, J = 1.6 and 4.6 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OB-H column, 2 mL/min, 2% i-PrOH in hexane; retention times: 12.6 min (minor S-enantiomer) and 13.7 min (major R-enantiomer). The retention times were concordant with published values.39 (R)-1-Thiophen-2-ylheptan-1-ol (5b):42 (Table 1, entry 21, 157 mg, 79% yield) 1H NMR (500 MHz, CDCl3) δ 0.88 (3H, t, J = 6.9 Hz), 1.23–1.37 (7H, m), 1.45 (1H, m), 1.79–1.95 (3H, m), 4.92 (1H, t, J = 6.7 Hz), 6.96–6.98 (2H, m), 7.24 (1H, dd, J = 1.7 and 4.6 Hz). Enantioselectivity was determined by HPLC analysis using a Chiralcel OB-H column, 1 mL/min, 3% i-PrOH in hexane; retention times: 8.9 min (minor S-enantiomer) and 10.1 min (major Renantiomer). The retention times were concordant with published values.42 (R)-1-Phenylhept-1-en-3-ol (6a):49 (Table 1, entry 23, 156 mg, 82% yield) 1H NMR (500 MHz, CDCl3) δ 0.92 (3H, t, J = 7.3 Hz), 1.32–1.46 (5H, m), 1.56–1.70 (2H, m), 4.28 (1H, q, J = 6.5 Hz), 6.23 (1H, dd, J = 6.8 and 15.9 Hz), 6.57 (1H, d, J = 15.9 Hz), 7.24 (1H, m), 7.33 (2H, m), 7.49 (2H, m). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1 mL/min, 9% i-PrOH in hexane; retention times: 8.2 min (major R-enantiomer) and 13.0 min (minor S-enantiomer). The retention times were concordant with published values.49 (R)-2-Methylhept-1-en-3-ol (6b):50 (Table 1, entry 24, 152 mg, 59% yield) 1H NMR (500 MHz, CDCl3) δ 0.91 (3H, d, J = 7.2 Hz), 1.22–1.38 (4H, m), 1.50–1.62 (3H, m), 1.72 (3H, t, J = 1.0 Hz), 4.06 (1H, t, J = 6.5 Hz), 4.83 (1H, m), 4.93 (1H, m). Enantioselectivity was determined by HPLC analysis of the benzoate derivative using a Chiralcel OB-H column, 1 mL/min, 0.1% iPrOH in hexane; retention times: 5.6 min (minor S-enantiomer) and 7.9 min (major R-enantiomer). The retention times were concordant with published values.15 Benzoate derivative of 6b: 1H NMR (500 MHz, CDCl3) δ 0.91 (3H, d, J = 7.2 Hz), 1.28–1.42 (4H, m), 1.70–1.85 (5H, m, including t (J = 1.0 Hz, 3H) at 1.80), 4.92 (1H, t, J = 1.5 Hz), 5.03 (1H, m), 5.42 (1H, t, J = 6.8 Hz), 7.44 (2H, m), 7.56 (1H, tt, J = 1.3 and 7.5 Hz), 8.07 (2H, m). (R)-1-Phenylheptane-3-ol (7):51 (Table 1, entry 25, 31 mg, 16% yield) 1H NMR (500 MHz, CDCl3) δ 0.91 (3H, t, J = 7.0 Hz), 1.25–1.55 (7H, m), 1.70–1.85 (2H, m), 2.67 (1H, m), 2.79 (1H, m), 3.63 (1H, tt, J = 4.4 and 7.8 Hz), 7.18–7.24 (2H, m), 7.27–7.32 (3H, m). Enantioselectivity was determined by HPLC analysis using a Chiralcel OD-H column, 1 mL/min, 2% i-PrOH in hexane; retention times: 17.2 min (major R-enantiomer) and 27.4 min (minor S-enantiomer). The retention times were concordant with published values.51 Supporting Information. NMR Spectra and LC charts of products. Corresponding Author *E-mail: [email protected] ORCID Toshiro Harada: 0000-0002-9818-5386 Notes The authors declare no competing financial interest. Acknowledgments This work was supported by KAKENHI (No. 15K05500) from Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan. References and Notes (1) Soai, K.; Niwa, S. Enantioselective Addition of Organozinc Reagents to Aldehydes. Chem. Rev. 1992, 92, 833–856.



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Luderer, M. R.; Bailey, W. F.; Luderer, M. R.; Fair, J. D.; Dancer, R. J.; Sommer, M. B. Asymmetric Addition of Achiral Organomagnesium Reagents or Organolithiums to Achiral Aldehydes or Ktones: a Review. Tetrahedron: Asymmetry 2009, 20, 981−998. (23) For recent advancements, see; (a) Osakama, K.; Nakajima, M. Asymmetric Direct 1,2Addition of Aryl Grignard Reagents to Aryl Alkyl Ketones. Org. Lett. 2015, 18, 236–239. (b) Bieszczad, B.; Gilheany D. G. Asymmetric Grignard Synthesis of Tertiary Alcohols through Rational Ligand Design. Angew. Chem. Int. Ed. 2017, 56, 4272–4276. (24) Madduri, A. V. R.; Harutyunyan, S. R.; Minnaard, A. J. Asymmetric Copper-Catalyzed Addition of Grignard Reagents to Aryl Alkyl Ketones. Angew. Chem. Int. Ed. 2012, 51, 3164– 3167. (25) Madduri, A. V. R.; Minnaard, A. J.; Harutyunyan, S. R. Access to Chiral α-Bromo and α-HSubstituted Tertiary Allylic Alcohols via Copper(I) Catalyzed 1,2-Addition of Grignard Reagents to Enones. Org. Biomol. Chem. 2012, 10, 2878–2884. (26) Caprioli, F.; Madduri, A. V. R.; Minnaard, A. J.; Harutyunyan, S. R. Asymmetric Amplification in the Catalytic Enantioselective 1,2-Addition of Grignard Reagents to Enones. Chem. Commun. 2013, 49, 5450–5452. (27) Rong, J.; Oost, R.; Desmarchelier, A.; Minnaard, A. J.; Harutyunyan, S. R. Catalytic Asymmetric Alkylation of Acylsilanes. Angew. Chem. Int. Ed. 2015, 54, 3038–3042. (28) Rong, J.; Pellegrini, T.; Harutyunyan, S. R. Synthesis of Chiral Tertiary Alcohols by CuICatalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones. Chem. Eur. J. 2016, 22, 3558–3570. (29) Harada, T. Development of Highly Active Chiral Titanium Catalysts for the Enantioselective Addition of Various Organometallic Reagents to Aldehydes. Chem. Record 2016, 16, 1256–1273. (30) Hayashi, Y.; Yamamura, N.; Kusukawa, T.; Harada, T. Enhancement of Catalytic Activity of Chiral H8-BINOL Titanium Complexes by Introduction of Sterically Demanding Group at the 3 Position. Chem. Eur. J. 2016, 22, 12095–12105. (31) An enantioselective alkylation of aldehydes catalyzed by H8-BINOLate-Ti complex (10 mol %) has been reported using purified alkyltitanium triisopropoxides; Li, Q.; Gau, H.-M. Room Temperature and Highly Enantioselective Additions of Alkyltitanium Reagents to Aldehydes Catalyzed by a Titanium Catalyst of (R)-H8-BINOL. Chirality 2011, 23, 929–939. (32) The pinacol coupling reaction with a putative Ti(III) alkoxides generated by the reaction of Ti(OiPr)4 with EtMgBr has been reported; Matiushenkov, E. A.; Sokolov, N. A.; Kulinkovich, O. G. Alkylative Reduction of Titanium(IV) Isopropoxide with EtMgBr: Convenient Method for the Generation of Subvalent Titanium Alkoxide Reagents and their Reactivity in Pinacol Coupling Reactions. Synlett 2004, 77–80. (33) An attempted reaction of 1-naphthaldehyde with iPrMgCl resulted in a poor yield of the product, probably owing to the decomposition of the organotitanium intermediate. (34) The procedure is based on a previous report. Jiang, A. J.; Zhao, Y.; Schrock, R. R.; Hoveyda, A. H. Highly Z-Selective Metathesis Homocoupling of Terminal Olefins. J. Am. Chem. Soc. 2009, 131, 16630–16631. (35) Nomura, N.; Ishii, R.; Yamamoto, Y.; Kondo, T. Stereoselective Ring-Opening Polymerization of a Racemic Lactide by Using Achiral Salen- and Homosalen-Aluminum Complexes. Chem. Eur. J. 2007, 13, 4433–4451. (36) Love, B. E. Jones E. G. The Use of Salicylaldehyde Phenylhydrazone as an Indicator for the Titration of Organometallic Reagents. J. Org. Chem. 1999, 64, 3755–3756. (37) Ansell, M. F.; Berman, A. M. Intramolecular Acylation. Part II. The Ring Closure of Some β-substituted β-1-naphthylpropionic acids. J. Chem. Soc. 1954, 1792–1795. (38) Bouffard, J.; Itami, K. A Nickel Catalyst for the Addition of Organoboronate Esters to Ketones and Aldehydes. Org. Lett. 2009, 11, 4410–4413. (39) Kinoshita, Y.; Kanehira, S.; Hayashi, Y.; Harada, T. Catalytic Enantioselective Alkylation of Aldehydes by Using Organozinc Halide Reagents. Chem. Eur. J. 2013, 19, 3311–3314.



(40) Hatano, M.; Miyamoto, T.; Ishihara, K. 3,3’-Diphosphoryl-1,1’-bi-2-naphthol-Zn(II) Complexes as Conjugate Acid-Base Catalysts for Enantioselective Dialkylzinc Addition to Aldehydes. J. Org. Chem. 2006, 71, 6474–6484. (41) Harada, T.; Kanda, K. Enantioselective Alkylation of Aldehydes Catalyzed by a Highly Active Titanium Complex of 3-Substituted Unsymmetric BINOL. Org. Lett. 2006, 8, 3817–3819. (42) Kumar, R.; Kawasaki, H.; Harada, T. Enantioselective Alkylation of Aldehydes Using Functionalized Alkylboron Reagents Catalyzed by a Chiral Titanium Complex. Org. Lett. 2013, 15, 4198–4201. (42) Glynn, D.; Shannon, J.; Woodward, S. On the Scope of Trimethylaluminium-Promoted 1,2Additions of ArZnX Reagents to Aldehydes. Chem. Eur. J. 2010, 16, 1053–1060. (43) Ying-Chuan, Q.; Liu, L.; Sabat, M.; Pu, L. Synthesis of the Bifunctional BINOL Ligands and Their Applications in the Asymmetric Additions to Carbonyl Compounds. Tetrahedron 2006, 62, 9335–9348. (44) Du, D.-M.; Fang, T.; Xu, J.; Zhang, S. Structurally Well-Defined, Recoverable C3-Symmetric Tris(β-hydroxy phosphoramide)-Catalyzed Enantioselective Borane Reduction of Ketones. Org. Lett. 2006, 8, 1327–1330. (45) Matsumura, Y.; Ogura, K.; Kouchi, Y.; Iwasaki, F.; Onomura, New Efficient Organic Activators for Highly Enantioselective Reduction of Aromatic Ketones by Trichlorosilane. Org. Lett. 2006, 8, 3789–3792. (46) Carlos, A. M. M.; Contreira, M. E.; Martins, B. S.; Immich, M. F.; Moro, A. V.; Ludtke, D. S. Catalytic Asymmetric Arylation of Aliphatic Aldehydes Using a B/Zn Exchange Reaction. Tetrahedron 2015, 71, 1202–1206. (47) Chen, R.-Y.; Dhondge, A. P.; Lee, G.-H.; Chen, C. A Chiral Bipyridyl Alcohol for Catalytic Enantioselective Nozaki–Hiyama–Kishi Allylation of Aldehydes and Ketones. Adv. Synth. Catal. 2015, 357, 961–966. (48) Tanaka, T.; Sano, Y.; Hayashi, M. Chiral Schiff Bases as Highly Active and Enantioselective Catalysts in Catalytic Addition of Dialkylzinc to Aldehydes. Chem. Asian J. 2008, 3, 1465–1471. (49) Node, M.; Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K. A Novel Tandem Michael Addition/Meerwein−Ponndorf−Verley Reduction: Asymmetric Reduction of Acyclic α,βUnsaturated Ketones Using A Chiral Mercapto Alcohol. J. Am. Chem. Soc. 2000, 122, 1927–1936. (50) Bassetti, M.; D'Annibale, A.; Fanfoni, A.; Minissi, F. Synthesis of α,β-Unsaturated 4,5Disubstituted γ-Lactones via Ring-Closing Metathesis Catalyzed by the First-Generation Grubbs' Catalyst. Org. Lett. 2005, 7, 1805–1808. (51) Buszek, K. R.; Brown, N. Improved Method for the Diimide Reduction of Multiple Bonds on Solid-Supported Substrates. J. Org. Chem. 2007, 72, 3125–3128.


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Method for Catalytic Enantioselective Alkylation of Aldehydes Using

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