Method for Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents as Alkyl Sources

Article abstract of DOI:10.1021/acs.joc.8b00929

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 performed with good stoichiometry [1.5 equiv each of Grignard reagents and ClTi(OⁱPr)₃] at a 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.

Full text of DOI:10.1021/acs.joc.8b00929

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Article
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
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Method for Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents as
Alkyl Sources
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Kento Tanaka, Munehisa Tomihama, Koji Yamamoto, Naoki Matsubara, and Toshiro Harada*
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Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki,
Sakyo-ku, Kyoto, 606-8585, Japan
harada-t@kit.ac.jp
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 co-
produced 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
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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
2b
1-NaphCHO
1-NaphCHO
1-NaphCHO
1-NaphCHO
BuMgCl
BuMgCl
BuMgBr
EtMgCl
87
85
76
62
70
72
98
92
72
35
61
52
97
80
79
76
95
79
82
73
79
70
82
59
16
95
97
97
95
95
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96
95
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98
91
91
78
95
98
96
97
85
96
92
94
94
91
93
61
3a
3a
3a
3b
3b
3c
3d
3d
3e
3f
3
4
5c
6
1-NaphCHO
1-NaphCHO
1-NaphCHO
1-NaphCHO
1-NaphCHO
n-C5H11MgCl
n-C6H13MgCl
n-C6H13MgBr
PhCH2CH2MgCl
iBuMgCl
7
8
9
10d
11e,f
12f
13d
14
15
16
17
18
19c
20
21
22
23
24g
25
3f
1-NaphCHO
1-NaphCHO
PhCHO
CyMgCl
3g
3h
4a
4b
4c
4d
4e
5a
5a
5b
5b
6a
6b
7
PhMgBr
BuMgCl
PhCHO
PrMgCl
p-ClC6H4CHO
m-MeOC6H4CHO
o-ClC6H4CHO
2-ThieylCHO
2-ThieylCHO
2-ThieylCHO
2-ThieylCHO
PhCH=CHCHO
CH2=C(Me)CHO
PhCH2CH2CHO
n-C5H11MgCl
PrMgCl
BuMgCl
BuMgCl
BuMgBr
n-C6H11MgCl
n-C6H11MgBr
BuMgCl
BuMgCl
BuMgCl
a Unless otherwise noted, reactions were carried out at 1 mmol scale under the conditions shown
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c
in Scheme 2. b The reaction was carried out at 9.9 mmol scale. Titanium reagent was prepared
from EtMgCl (2 equiv) and ClTi(OiPr)4 (2 equiv) and Ti(OiPr)4 (0.4 equiv). Ti(OiPr)4 was not
d
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
9
g
after the addition of the titanium reagents in 5 min. See Experimental Section for detail. The
reaction was carried out at 2 mmol scale.
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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
iBuMgCl (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 1-
naphthaldehyde (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),
1
and PhMgBr (3 M in Et2O) were purchased from Sigma-Aldrich and used without titration. H
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
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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,
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131.8, 133.2, 136.5, 137.3, 148.0, 150.7; HRMS (FAB-double focusing) calcd for C20H21O2 Br
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,
1
CHCl3); H 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 2-
mL 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 1-
naphthaldehyde (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
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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.
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(R)-1-Naphthalen-1-ylpropan-1-ol (3b):40 (Table 1, entry 5, 130 mg, 70% yield) H 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
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(R)-1-Naphthalen-1-ylhexan-1-ol (3c):17 (Table 1, entry 6, 165 mg, 72% yield) H 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
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(R)-1-Naphthalen-1-ylheptan-1-ol (3d):42 (Table 1, entry 7, 236 mg, 98% yield) H 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)
1H 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)
1H 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
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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
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(R)-Naphthalen-1-ylphenylmethanol (3h):42 (Table 1, entry 13, 228 mg, 97% yield) H
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 R-
enantiomer). 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 S-
enantiomer) 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 R-
enantiomer) and 19.8 min (minor S-enantiomer). The retention times were concordant with
published values.39
1
(R)-1-Thiophen-2-ylpentan-1-ol (5a):48 (Table 1, entry 19, 140 mg, 82%) H 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
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(R)-1-Thiophen-2-ylheptan-1-ol (5b):42 (Table 1, entry 21, 157 mg, 79% yield) H NMR
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(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 R-
enantiomer). The retention times were concordant with published values.42
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(R)-1-Phenylhept-1-en-3-ol (6a):49 (Table 1, entry 23, 156 mg, 82% yield) H 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
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(R)-2-Methylhept-1-en-3-ol (6b):50 (Table 1, entry 24, 152 mg, 59% yield) H 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% i-
PrOH 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: harada-t@kit.ac.jp
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.
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