Synthesis and application of 3-substituted (S)-binol as chiral ligands for the asymmetric ethylation of aldehydes

Article abstract of DOI:10.1002/chir.20842

A series of (S)-BINOL ligands substituted at the 3 position with some five-membered nitrogen-containing aromatic heterocycles were effectively prepared and their catalytic abilities were evaluated in the asymmetric addition of diethylzinc to benzaldehyde in the presence of titanium tetraisopropoxide. Under the optimized reaction conditions, titanium complex of (S)-3-(1H-benzimidazol-1-yl)-1,1′-bi-2-naphthol was found to be the most efficient catalyst for asymmetric ethylation of various aldehydes to generate the corresponding secondary alcohols in up to 99% yield and 91% ee.

Full text of DOI:10.1002/chir.20842

CHIRALITY 22:820–826 (2010)
Synthesis and Application of 3-Substituted (S)-BINOL as Chiral
Ligands for the Asymmetric Ethylation of Aldehydes
1
ZHI-GUANG ZHANG,1 ZHI-BING DONG,1,2 AND JIN-SHAN LI
*
1State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
2School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, People’s Republic of China
ABSTRACT
A series of (S)-BINOL ligands substituted at the 3 position with some
five-membered nitrogen-containing aromatic heterocycles were effectively prepared and
their catalytic abilities were evaluated in the asymmetric addition of diethylzinc to benz-
aldehyde in the presence of titanium tetraisopropoxide. Under the optimized reaction
conditions, titanium complex of (S)-3-(1H-benzimidazol-1-yl)-1,10-bi-2-naphthol was found
to be the most efficient catalyst for asymmetric ethylation of various aldehydes to gener-
ate the corresponding secondary alcohols in up to 99% yield and 91% ee. Chirality
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22:820–826, 2010.
2010 Wiley-Liss, Inc.
KEY WORDS: BINOL; titanium; nitrogen-containing aromatic heterocycle; asymmetric
addition
INTRODUCTION
chlorobenzotriazole were also conveniently introduced at
the 3 position of (S)-BINOL and tested in the reaction of
diethylzinc with benzaldehyde.
Enantioselective construction of carbon–carbon bonds
is one of the most important and vigorously pursued areas
in organic chemistry.1–7 Since the pioneering work of
Oguni et al. in 1984,8,9 asymmetric ethylation of carbonyl
compounds in the presence of catalytic amounts of chiral
ligands has attracted great attention in recent years,10–19
not only because it is an effective and excellent method to
form chiral carbon–carbon bonds but also because the
products, optically active alcohols, are valuable building
blocks for many naturally occurring compounds, pharma-
cologically and biologically interesting molecules.20–23
Therefore, numerous kinds of chiral ligands, such as
amino alcohols (N,O-ligands), diamines (N,N-ligands), and
diols (O,O-ligands) have been designed and evaluated in
the catalytic asymmetric addition of diethylzinc to alde-
hydes.24–31 As an important O,O-ligand, BINOL and its
derivatives have been widely studied and earned a promi-
nent status because of their outstanding performance in a
good number of asymmetric reactions.32–39
EXPERIMENTAL
General Methods
The 1H and 13C NMR spectra were recorded on a
Bruker AC-400 instrument in CDCl3 or d6-DMSO solution
with TMS as internal standard. Optical rotations were
measured on a Perkin-Elmer 241 polarimeter. High-resolu-
tion mass spectra (HRMS) were obtained on a Varian
QFT-ESI mass spectrometer. Melting points were deter-
mined with XRC-1 and are uncorrected. All experiments
which are sensitive to moisture or air were carried out
under an argon atmosphere using standard Schlenk tech-
niques. Diethylzinc (1.5 M in toluene) was purchased
from Acors. All anhydrous solvents were purified and
dried by standard techniques just before use.
The preparation of 3-substituted (S)-BINOL ligands
and their intermediates (S)-2,20-bis(methoxyme-
thoxy)-1,10-binaphthyl (S)-1. This known compound
was prepared according to the literature method48 in 98%
yield as colorless crystals. M.p. 92–938C; 1H NMR (400
MHz, CDCl3) d (ppm) 3.14 (s, 6H), 4.97 (d, J 5 6.6 Hz,
2H), 5.08 (d, J 5 6.6 Hz, 2H), 7.15 (d, J 5 8.4 Hz, 2H),
7.20–7.24 (m, 2H), 7.32–7.36 (m, 2H), 7.57 (d, J 5 9.2 Hz,
2H), 7.87 (d, J 5 8.4 Hz, 2H), and 7.95 (d, J 5 9.2 Hz, 2H).
In connection with our interest in the design and prepa-
ration of a set of novel chiral ligands, for example, the
BINOL ligands bearing sulfur or nitrogen-containing het-
erocycles at 3 or 3,30 positions, and their applications in
the asymmetric ethylation of several kinds of aldehydes
and a,b-unsaturated ketones,40–46 herein, we report the
synthesis of 3-substituted BINOL bearing imidazole and
triazole groups and their utilization in the asymmetric
addition of diethylzinc to various aldehydes in the pres-
ence of titanium tetraisopropoxide. Although the (R) con-
figuration of Ligand-1, Ligand-3, and Ligand-6 have been
prepared and used as chiral ligands in the enantioselective
cyanation of aldehydes,47 their applications in the asym-
metric ethylation of aldehydes have not been reported so
*Correspondence to: J.-S. Li, State Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China.
E-mail: jinshanl@nankai.edu.cn
Received for publication 27 August 2009; Accepted 1 December 2009
DOI: 10.1002/chir.20842
Published online 21 April 2010 in Wiley Online Library
far. What is more, benzimidazole, benzotriazole, and 5- (wileyonlinelibrary.com).
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2010 Wiley-Liss, Inc.

SYNTHESIS AND APPLICATION OF 3-SUBSTITUTED (S)-BINOL
821
(S)-3-dihydroxyborane-2,20-bis(methoxymethoxy)- 133.71, 134.76, 143.38, 143.72, 148.66, 152.84; HR-MS
1,10-binaphthyl (S)-2.49 To a solution of (S)-1 (3.74 g, (ESI) calcd for C31H27N2O4 [M11H]: 491.1971, found:
10 mmol) in anhydrous THF (40 ml) was added n-BuLi 491.1965.
(4.2 ml, 11 mmol, 2.61 M in hexane) at 08C under Ar and
(S)-3-(1H-imidazol-1-yl)-1,10-bi-2-naphthol, Ligand-1.47
the reaction mixture was stirred for 5 h. B(OCH3)3 (3.4 (S)-3 (8.19 g, 18.6 mmol) was dissolved in the mixed sol-
ml, 30 mmol) was added slowly at 2788C. The solution vent of CH3OH/CH2Cl2 (30 ml/30 ml). Five milliliters of
was allowed to warm to r.t. and left stirring overnight. The HCl (12 M) was added dropwise at 08C. The reaction mix-
reaction mixture was cooled to 08C, and 30 ml saturated ture was stirred at room temperature for 3 h, neutralized
NH4Cl aqueous solution was added, and the reaction mix- with saturated NaHCO3, and extracted with CH2Cl2 (30 ml
ture was stirred for 2 h. Et2O (40 ml) was added and 3 3). The combined organic layers were dried over anhy-
stirred for 30 min. The phases were separated and the drous Na2SO4 and concentrated under reduced pressure.
aqueous phase was extracted with Et2O (20 ml 3 2). The The resulting residue was purified by flash column chro-
combined organic layers were dried over anhydrous matography on silica gel eluting with CH2Cl2/CH3OH
Na2SO4 and concentrated under reduced pressure. The (40:1) to give Ligand-1 (6.226 g, 95%) as a pale-yellow
1
resulting residue was purified by flash column chromatog- solid. [a]2D5 5 266.2 (c 2.0, CH3OH); M.p. 205–2068C; H
raphy on silica gel eluting with petroleum ether/ethyl ace- NMR (400 MHz, d6-DMSO) d (ppm) 6.80 (d, J 5 8.0 Hz,
tate (5:1) to give (S)-2 (3.722 g, 89%) as a white solid. 1H), 6.96 (d, J 5 8.0 Hz, 1H), 7.11 (s, 1H), 7.20–7.29 (m,
1
M.p. 204–2058C; H NMR (400 MHz, CDCl3) d (ppm) 3.09 3H), 7.34 (t, J 5 8.0 Hz, 2H), 7.61 (s, 1H), 7.88–7.94 (m,
(s, 3H), 3.17 (s, 3H), 4.47 (d, J 5 4.8 Hz, 1H), 4.63 (d, J 5 3H), and 8.07 (s, 2H).
4.8 Hz, 1H), 5.06 (d, J 5 6.8 Hz, 1H), 5.12 (d, J 5 6.8 Hz,
(S)-3-(1H-benzimidazol-1-yl)-1,10-bi-2-naphthol, Ligand-2.
1H), 6.04 (s, 2H), 7.17 (t, J 5 8.0 Hz, 2H), 7.28–7.34 (m, Ligand-2 was prepared from (S)-4 by the same method as
3H), 7.60 (d, J 5 8.8 Hz, 1H), 7.88 (d, J 5 8.0 Hz, 1H), 7.97 Ligand-1. Colorless crystals, Yield 95%; [a]2D5 5 285 (c 2.0,
1
(t, J 5 8.8 Hz, 2H), and 8.55 (s, 1H).
CH2Cl2); M.p. 203–2058C; H NMR (400 MHz, d6-DMSO)
d (ppm) 6.96 (d, J 5 7.6 Hz, 1H), 7.06 (d, J 5 8.4 Hz, 1H),
(S)-3-(1H-imidazol-1-yl)-2,20-bis(methoxymethoxy)- 7.27–7.30 (m, 5H), 7.37 (t, J 5 8.4 Hz, 2H), 7.44 (t, J 5 4.4
1,10-binaphthyl (S)-3. (S)-2 (8.36 g, 20 mmol) was Hz, 1H), 7.78 (t, J 5 4.8 Hz, 1H), 7.89–7.95 (m, 2H), 7.99
added in one portion to a vigorously stirred mixture of im- (d, J 5 8.0 Hz, 1H), 8.17 (s, 1H), 8.50 (s, 1H), 8.84 (s, 1H),
idazole (2.72 g, 40 mmol) and a catalytic amount of CuCl 9.51 (s, 1H); 13C NMR (100 MHz, d6-DMSO) d (ppm)
(198.0 mg, 2 mmol) in absolute methanol (100 ml). The 111.47, 113.23, 118.41, 118.77, 119.53, 121.93, 122.46,
mixture was then refluxed for 3 h under dry Oxygen. The 122.88, 123.67, 123.94, 124.50, 125.61, 126.09, 126.31,
reaction was filtered and the filtrate was concentrated 126.80, 127.84, 128.07, 128.13, 128.27, 129.66, 133.45,
under reduced pressure, and the residue was purified by 134.13, 134.66, 143.16, 144.39, 147.99, 153.83; HR-MS
flash column chromatography on silica gel eluting with Pe- (ESI) calcd for C27H19N2O2 [M11H]: 403.1447, found:
troleum Ether/Acetone (2:1) to give (S)-3 (8.193 g, 95%) 403.1441.
as a white powder. [a]2D5 5 292 (c 0.45, CH2Cl2); M.p.
1
117–1188C; H NMR (400 MHz, CDCl3) d (ppm) 2.51 (s,
3H), 3.24 (s, 3H), 4.31 (d, J 5 6.0 Hz, 1H), 4.37 (d, J 5 6.0
Hz, 1H), 5.10 (d, J 5 6.8 Hz, 1H), 5.16 (d, J 5 6.8 Hz, 1H),
(S)-3-Iodo-2,20-bis(methoxymethoxy)-1,10-binaphthyl,
7.19–7.40 (m, 5H), 7.43–7.52 (m, 3H), 7.61 (d, J 5 9.2 Hz, (S)-5. To a solution of (S)-1 (3.74 g, 10 mmol) in anhy-
1H), 7.90 (t, J 5 8.4 Hz, 3H), 7.98 (s, 1H), 8.01 (s, 1H); 13C drous THF (40 ml) was added n-BuLi (4.2 ml, 11 mmol,
NMR (100 MHz, CDCl3) d (ppm) 56.02, 56.31, 94.81, 2.61 M in hexane) at 08C under Ar and the reaction mix-
98.99, 116.24, 119.34, 120.84, 124.29, 124.56, 125.23, ture was stirred for 5 h. A solution of I2 (0.508 g, 20 mmol)
126.06, 126.16, 126.94, 127.06, 127.89, 128.04, 129.49, in 20 ml THF was added slowly at 2788C. The solution
129.63, 130.34, 130.53, 130.88, 133.12, 133.72, 138.00, was allowed to warm to r.t. and left stirring overnight. The
147.25, 152.86; HR-MS (ESI) calcd for C27H25N2O4 reaction mixture was cooled to 08C, and 30 ml saturated
[M11H]: 441.1814, found: 441.1809.
Na2S2O3 aqueous solution was added, and the reaction
mixture was stirred for 2 h. Et2O (40 ml) was added and
(S)-3-(1H-benzimidazol-1-yl)-2,20-bis(methoxyme- stirred for 30 min. The phases were separated and the
thoxy)-1,10-binaphthyl (S)-4. This compound was pre- aqueous phase was extracted with Et2O (20 ml 3 2). The
pared by the same method as (S)-3. Colorless crystals, combined organic layers were dried over anhydrous
Yield 95%; [a]2D5 5 2110.5 (c 2.0, CH2Cl2); M.p. 132–1348C; Na2SO4 and concentrated under reduced pressure. The
1H NMR (400 MHz, CDCl3) d (ppm) 2.25 (s, 3H), 3.27 (s, resulting residue was purified by flash column chromatog-
3H), 4.21 (d, J 5 8.0 Hz, 1H), 4.29 (d, J 5 2.4 Hz, 1H), 5.15 raphy on silica gel eluting with petroleum ether/ethyl ace-
(d, J 5 6.8 Hz, 1H), 5.21 (d, J 5 2.4 Hz, 1H), 7.28–7.42 (m, tate (10:1) to give (S)-5 (4.5 g, 90%). Yellow powder; M.p.
1
7H), 7.49–7.55 (m, 2H), 7.63 (d, J 5 9.2 Hz, 1H), 7.69–7.96 124–1258C; H NMR (400 MHz, CDCl3) d (ppm) 2.72 (s,
(m, 3H), 8.00 (d, J 5 8.8 Hz, 1H), 8.07 (s, 1H), 8.30 (s, 3H), 3.21 (s, 3H), 4.71 (d, J 5 7.2 Hz, 1H), 4.75 (d, J 5 7.2
1H); 13C NMR (100 MHz, CDCl3) d (ppm) 56.05, 94.83, Hz, 1H), 5.06 (d, J 5 9.2 Hz, 1H), 5.16 (d, J 5 9.2 Hz, 1H),
99.13, 111.14, 116.23, 119.22, 120.31, 122.61, 123.60, 7.15–7.44 (m, 6H), 7.60 (d, J 5 12 Hz, 1H), 7.80 (d, J 5
124.28, 125.18, 126.17, 126.22, 126.98, 127.25, 127.99, 10.8 Hz, 1H), 7.87 (d, J 5 10.8 Hz, 1H), and 7.98 (d, J 5 12
128.09, 128.30, 129.36, 129.63, 130.36, 130.65, 133.53, Hz, 1H).
Chirality DOI 10.1002/chir

822
ZHANG ET AL.
Ligand-3–Ligand-6 and their precursors were synthe- (s, 1H), 8.33 (s, 1H), 9.10 (s, 1H), 9.24 (s, 1H), 9.51
sized according to the similar procedure described by Gau (s, 1H).
and co-workers.47
(S)-3-(1H-benzotriazol-1-yl)-1,10-bi-2-naphthol, Ligand-4.
White powder, Yield 94%; [a]2D5 5 282 (c 2.0, CH2Cl2);
1
(S)-3-(1H-1,2,4-triazol-1-yl)-20-methoxymethoxy-1,10- M.p. 216–2188C; H NMR (400 MHz, d6-DMSO) d (ppm)
binaphthyl-2-ol, (S)-6. White solid, Yield 60%; M.p. 194– 7.24 (d, J 5 8.0 Hz, 1H), 7.30 (s, 1H), 7.33–7.47 (m, 5H),
1
1958C; H NMR (400 MHz, CDCl3) d (ppm) 3.19 (s, 3H), 7.48–7.52 (m, 2H), 7.59 (t, J 5 7.2 Hz, 1H), 7.74 (d, J 5 8.4
5.08 (d, J 5 6.8 Hz, 1H), 5.13 (d, J 5 6.8 Hz, 1H), 7.16 (q, J Hz, 1H), 7.92 (d, J 5 8.8 Hz, 1H), 8.00 (d, J 5 8.8 Hz, 2H),
5 8.4 and 8.8 Hz, 2H), 7.28–7.31 (m, 4H), 7.40 (t, J 5 6.8 8.18 (d, J 5 8.8 Hz, 1H), 8.31 (s, 1H); 13C NMR (100 MHz,
Hz, 1H), 7.62 (d, J 5 9.2 Hz, 1H), 7.92 (d, J 5 8.4 Hz, 2H), d6-DMSO) d (ppm) 111.67, 111.94, 116.82, 118.49, 119.72,
8.05 (t, J 5 7.2 and 9.2 Hz, 2H), 8.20 (s, 1H), and 8.26 123.75, 124.20, 124.68, 124.96, 125.03, 125.22, 126.85,
(s, 1H).
127.32, 128.29, 128.33, 128.61, 129.04, 131.04, 133.87,
133.92, 134.13, 145.44, 146.97, 153.21; HR-MS (ESI) calcd
(S)-3-(1H-benzotriazol-1-yl)-20-methoxymethoxy-1,10- for C26H18N3O2 [M11H]: 404.1399, found: 404.1394.
binaphthyl-2-ol, (S)-7. White powder, Yield 70%; [a]2D5 5
(S)-3-(5-chloro-1H-benzotriazol-1-yl)-1,10-bi-2-naphthol,
280 (c 2.0, CH2Cl2); M.p. 159–1608C; H NMR (400 MHz, Ligand-5. White powder, Yield 94%; [a]2D5 5 2110.3 (c
d6-DMSO) d (ppm) 3.14(s, 3H), 5.17 (d, J 5 6.8 Hz, 1H), 2.0, CH3OH); M.p. 163–1648C; 1H NMR (400 MHz, d6-
5.21 (d, J 5 6.8 Hz, 1H), 6.96 (d, J 5 8.0 Hz, 1H), 7.17 (d, J DMSO) d (ppm) 6.99–7.07 (m, 2H), 7.27–7.41 (m, 5H),
5 8.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.43–7.39 (m, 2H), 7.51– 7.64 (s, 1H), 7.71 (d, J 5 1.6 Hz, 1H), 7.91–7.95 (m, 2H),
7.46 (m, 1H), 7.63–7.56 (m, 2H), 7.67 (d, J 5 8.8 Hz, 1H), 8.03–8.06 (m, 1H), 8.32 (t, J 5 6.0 Hz, 2H), 9.05–9.07 (m,
8.00 (d, J 5 7.6 Hz, 1H), 8.01 (d, J 5 9.2 Hz, 1H), 8.05 (d, J 1H), 9.52 (t, J 5 6.0 Hz, 1H); 13C NMR (100 MHz, d6-
5 7.6 Hz, 1H), 8.19 (d, J 5 8.4 Hz, 1H), 8.32 (s, 1H), 9.12 DMSO) d (ppm) 111.57, 112.97, 113.36, 118.62, 118.77,
(s, 1H); 13C NMR (100 MHz, d6-DMSO) d (ppm) 55.85, 120.97, 122.54, 123.99, 124.59, 124.94, 125.45, 126.42,
94.58, 111.94, 117.33, 118.55, 119.00, 119.83, 124.41, 127.06, 127.51, 127.66, 128.09, 128.29, 128.45, 128.57,
124.51, 124.65, 124.85, 124.96, 126.26, 127.23, 127.61, 129.79, 132.92, 134.08, 134.24, 134.63, 143.87, 145.78,
128.01, 128.45, 128.61, 129.03, 129.95, 130.46, 134.04, 147.34, 153.83; HR-MS (ESI) calcd for C26H16ClN3NaO2
134.461, 145.62, 147.76, 153.56; HR-MS (ESI) calcd for [M11Na]: 460.0829, found: 460.0823.
1
C28H22N3O3 [M11H]: 448.1661, found: 448.1656.
(S)-3-(1H-pyrazol-1-yl)-1,10-bi-2-naphthol, Ligand-6.
White solid. Yield 92%; [a]2D5 5 271.9 (c 2.0, CH2Cl2);
1
(S)-3-(5-chloro-1H-benzotriazol-1-yl)-20-methoxyme- M.p. 185–1878C; H NMR (400 MHz, CDCl3) d (ppm) 6.63
thoxy-1,10-binaphthyl-2-ol, (S)-8. Colorless crystals, (s, 1H), 7.17 (q, J 5 4.4 and 8.4 Hz, 2H), 7.32 (t, J 5 6.8
Yield 76%; [a]2D5 5 290 (c 2.0, CH2Cl2); M.p. 120–1228C; Hz, 2H), 7.41 (t, J 5 6.8 and 8.8 Hz, 3H), 7.80 (s, 1H), 7.91
1H NMR (400 MHz, d6-DMSO) d (ppm) 3.15 (d, J 5 8.4 (m, 4H), 8.06 (s, 1H), 8.30 (d, J 5 2 Hz, 1H), 11.76 (s, 1H).
Hz, 3H), 5.15–5.23 (m, 2H), 6.96 (d, J 5 8.4 Hz, 1H), 7.18
General Procedure for Enantioselective Addition of
(t, J 5 8.0 Hz, 1H), 7.35 (t, J 5 6.8 and 8.0 Hz, 2H), 7.39–
Diethylzinc to Aldehydes
7.44 (m, 2H), 7.53 (m, 1H), 7.59 (m, 1H), 7.66 (m, 2H),
Ligand-2 (20 mg, 0.05 mmol) and Ti(O-iPr)4 (341 mg,
1.2 mmol) were dissolved in CH2Cl2 (5 ml) or other sol-
vents under argon. The resulting mixture was stirred for
30 min at room temperature (258C). Diethylzinc solution
(1 ml, 1.5 M in toluene) was added to the above flask and
the color of the solution became orange–green. After 30
min, 1 mmol of the corresponding aldehyde was added at
08C. The mixture was stirred at 08C for 5 h and the reac-
tion was quenched with saturated NH4Cl aqueous solu-
tion. The resulting mixture was filtered, extracted with
ethyl acetate (10 ml 3 3) and the combined organic layers
were dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue was
purified by flash chromatography column to afford the
expected sec-alcohol. The enantiomeric excess was deter-
mined by chiral GC.
8.00 (d, J 5 8.4 Hz, 1H), 8.06 (m, 1H), 8.11 (d, J 5 8.8 Hz,
1H), 8.24 (d, J 5 8.8 Hz, 1H), 8.36 (t, J 5 8.4 and 9.6 Hz,
1H), 9.20 (d, J 5 8.0 Hz, 1H); 13C NMR (100 MHz, d6-
DMSO) d (ppm) 55.88, 94.51, 111.81, 112.87, 115.46,
117.22, 117.31, 118.38, 119.18, 120.20, 121.53, 124.43,
124.60, 124.88, 124.96, 125.04, 125.47, 127.61, 128.03,
128.14, 128.60, 129.03, 129.08, 129.11, 129.23, 129.93,
130.49, 134.02, 134.05, 134.56; HR-MS (ESI) calcd for
C28H20ClN3NaO3 [M11Na]: 504.1091, found: 504.1085.
(S)-3-(1H-pyrazol-1-yl)-20-methoxymethoxy-1,10-
binaphthyl-2-ol, (S)-9. White solid, Yield 58%; M.p.
1
188–1898C; H NMR (400 MHz, CDCl3) d (ppm) 3.20 (s,
3H), 5.03 (d, J 5 7.6 Hz, 1H), 5.16 (d, J 5 7.6 Hz, 1H), 6.60
(t, J 5 2.0Hz, 1H), 7.15 (d, J 5 8.4 Hz, 1H), 7.21–7.25 (m,
2H), 7.32–7.38 (m, 3H), 7.61 (d, J 5 8.8 Hz, 1H), 7.76 (d, J
5 2.0 Hz, 1H), 7.85–7.91 (m, 2H), 7.98 (d, J 5 8.4 Hz, 2H),
8.28 (d, J 5 2.8 Hz, 1H), 11.34 (s, 1H).
RESULTS AND DISCUSSION
(S)-3-(1H-1,2,4-triazol-1-yl)-1,10-bi-2-naphthol, Ligand-3.
White crystals, Yield 98%; [a]2D5 5 299.9 (c 2.0, THF);
The synthetic routes for ligands Ligand-1–Ligand-6 are
M.p. > 2248C (dec.); H NMR (400 MHz, CDCl3) d (ppm) depicted in Scheme 1.
1
6.91 (d, J 5 8.4 Hz, 1H), 6.96 (d, J 5 8.0 Hz, 1H), 7.20–
Protection of two hydroxyl groups of (S)-BINOL with
7.29 (m, 3H), 7.37 (t, J 5 8.8 Hz, 2H), 7.89 (d, J 5 7.6 Hz, methoxymethyl (MOM) group using chloromethyl methyl
1H), 7.93 (d, J 5 9.2 Hz, 1H), 8.00 (d, J 5 8.0 Hz, 1H), 8.31 ether gave (S)-2,20-bis(methoxymethoxy)-1,10-binaphthyl
Chirality DOI 10.1002/chir

SYNTHESIS AND APPLICATION OF 3-SUBSTITUTED (S)-BINOL
823
Scheme 1. Reagents and conditions: (a) THF, MOMCl, 08C; (b) (i) THF, 1.1 equiv n-BuLi, 08C, (ii) B(OMe)3, 2788C, (iii) NH4Cl; (c) CH3OH, CuCl,
imidazole, Reflux; (d) CH2Cl2, CH3OH, 12 M HCl, rt; (e) CH3OH, CuCl, benzimidazole, Reflux; (f) THF, 1.1 equiv n-BuLi, 08C, (ii) I2, 2788C, (iii)
Na2S2O3; (g) CuI, K2CO3, DMSO, N,N-dimethylglycine, 1,2,4-triazole; (h) CuI, K2CO3, DMSO, N,N-dimethylglycine, benzotriazole; (i) CuI, K2CO3,
DMSO, N,N-dimethylglycine, 5-chlorobenzotriazole; (j) CuI, K2CO3, DMSO, N,N-dimethylglycine, pyrazole.
Chirality DOI 10.1002/chir

824
ZHANG ET AL.
TABLE 1. Screening of reaction conditions for the asymmet-
ric ethylation of benzaldehyde catalyzed by ligand in the
TABLE 2. Asymmetric addition of diethylzinc to various
aldehydes catalyzed by Ligand-2a
a
presence of Ti(O-iPr)4
Entry
R
Yield (%) b
e.e. (%) c
Entry
Ligand (mol %)
Solvent
Yield (%)b
e.e. (%) c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4-fluorophenyl
4-chlorophenyl
4-bromophenyl
>99
93
98
97
92
78
90
98
93
83
>99
93
>99
94
86
>99
>99
98
82
82
84
80
83
85
82
84
88
78
76
70
74
64
76
91
80
48 d
82
1
2
3
4
5
6
7
8
9
Ligand-1 (10)
Ligand-2 (10)
Ligand-3 (10)
Ligand-4 (10)
Ligand-5 (10)
Ligand-6 (10)
Ligand-2 (10)
Ligand-2 (10)
Ligand-2 (15)
Ligand-2 (5)
Ligand-2(2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Hexane
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
>99
>99
90
91
90
90
92
85
77
81
74
79
75
41
79
81
81
83
72
4-methoxylphenyl
4-methylphenyl
4-trifluoromethylphenyl
4-dimethylaminophenyl
4-diethoxymethylphenyl
3-methoxylphenyl
3-methylphenyl
2-methoxylphenyl
2-chlorophenyl
2,4-dichlorophenyl
2,4-dimethoxyphenyl
3,4-dichlorophenyl
1-naphthyl
>99
>99
>99
10
11
aTi(O-iPr)4/Et2Zn/benzaldehyde 5 1.2:1.5:1.
bIsolated yield.
cData were determined by GC analysis using a chiral column (Chiral beta-
DEX 120 capillary column).
trans-PhCH¼CH
2-Furyl
5-piperonyl
>99
(S)-1 in 98% yield. Lithiation of (S)-1 with 1.1 equiv. of n-
BuLi at 08C for 4 h, followed by the addition of B(OCH3)3
at 2788C, and subsequently quenching with saturated
NH4Cl aqueous solution generated (S)-3-dihydroxyborane-
2,20-bis(methoxymethoxy)-1,10-binaphthyl (S)-2 in 89%
yield, and the unreacted (S)-1 could be recovered and
reused. According to the procedure reported by Gau and
co-workers,47 N-arylation reaction of (S)-2 with imidazole
aLigand-2/Ti(O-iPr)4/Et2Zn/aldehyde 5 0.05:1.2:1.5:1.
bIsolated yield.
cData were determined by GC analysis using a chiral column (Chiral beta-
DEX 120 capillary column).
dDatum was determined by HPLC analysis using a chiral OD-H column.
and benzimidazole successfully produced the cross-cou- Increasing steric hindrance of the substituents improved
pling products (S)-3 and (S)-4 nearly quantitatively. After the enantioselectivity slightly (entries 1 and 2, 3, and 4).
deprotection, ligands Ligand-1 and Ligand-2 were Reducing the electronic nature of Ligand-4 by introducing
obtained in 80% and 82% overall yields, respectively, start- a chlorine atom at the 5 position of benzotriazole had a
ing from (S)-BINOL.
weak effect on the result, which implied that the electronic
Iodination of (S)-1 also proceeded smoothly to give (S)- property of ligand could be neglected (entries 4 and 5). As
5 in 90% yield. CuI catalyzed cross-coupling reactions of a result, Ligand-2 was the choice of ligand in terms of
(S)-5 with 1,2,4-triazole, benzotriazole, 5-chlorobenzotria- yield and enantiomeric excess (entry 2). Further screen-
zole, or pyrazole efficiently delivered the corresponding ing of solvents revealed that inferior results were achieved
products with good yields, and deprotection of the MOM when reactions were conducted in hexane and toluene
group subsequently afforded the desired ligands Ligand-3, (entries 7 and 8). An increase of the ligand loading from
Ligand-4, Ligand-5, and Ligand-6.
10 to 15 mol % did not lead to a positive result (entry 9).
With this sterically and electronically varied set of 3-sub- Much to our delight, the best enantioselectivity was real-
stituted (S)-BINOL derivatives, first we chose the asym- ized when 5 mol % of Ligand-2 was employed (entry 10).
metric addition of Et2Zn to benzaldehyde as a model reac- However, a further decrease to 2 mol % deteriorated the
tion to examine their efficiencies as chiral ligands. The asymmetric induction remarkably (entry 11). Conse-
active catalyst was formed in situ by mixing the ligand quently, 5 mol % was regarded as the optimal amount.
with 1.2 equiv. Ti(O-iPr)4 in CH2Cl2. The results are sum- Based on the above observations, the condition used in
marized in Table 1.
entry 10 was selected in the following reactions.
It could be concluded that all ligands provided excellent
Encouraged by the excellent performance of Ligand-2
to almost quantitative yield, along with the significant in the enantioselective ethylation of benzaldehyde, we
changes in the enantioselectivity. Compared with Ligand- next examined the generality of this procedure using a
1, a sharp decrease in enantioselectivity was observed broad spectrum of aromatic, a,b-unsaturated, and hetero-
when Ligand-6 was used as ligand (entries 1 and 6), sug- aromatic aldehydes with diverse electronic and steric prop-
gesting that the position of sp2-hybridized nitrogen atom erties under the optimized reaction conditions, and the
in heterocycles plays a crucial role in the catalytic process. results are depicted in Table 2.
Chirality DOI 10.1002/chir

SYNTHESIS AND APPLICATION OF 3-SUBSTITUTED (S)-BINOL
825
6. Corey EJ, Guzman-Perez A. The catalytic enantioselective construc-
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As can be seen from Table 2, both the position and elec-
tronic nature of substituents on the phenyl ring could
affect enantioselectivities dramatically. To our surprise,
very good yields were gained in all cases. Various benzal-
dehyde derivatives, bearing no matter electron-withdraw-
ing or electron-donating groups substituted at the para
position, were smoothly converted to the corresponding
alcohols with the similar ee value to benzaldehyde (entries
1–8). Optically active hydroxyaldehyde could be obtained
when 4-(diethoxymethyl) benzaldehyde was used as sub-
strate (entry 8), since the corresponding intermediate was
not stable during the acid hydrolysis.50 Replacing the
methoxyl group with a methyl, one caused an apparent
decline in enantiomeric excess, indicating that the elec-
tronic character of the substituent at meta-position of benz-
aldehyde plays an important role (entries 9 and 10). The
presence of ortho-substituents, regardless of electronic-
rich or electronic-poor groups, diminished enantioselectiv-
ities obviously (entries 11–14), although in good yields,
probably because the substituents could weaken the coor-
dination of the aldehyde to the chiral catalyst and thus
reduce the effect of the chiral environment of the cata-
lyst.51,30 For instance, 2-methoxybenzaldehyde provided a
lower ee compared with 4-methoxybenzaldehyde, and the
similar phenomenon was observed in entries 2 and 12.
Gratifyingly, 1-naphthaldehyde was ethylated successfully
with the highest ee (entry 16). The reaction with trans-cin-
namaldehyde gave exclusively the 1,2-addition product in
good yield and 80% ee value (entry 17). To our disappoint-
ment, only an acceptable enantiomeric excess was gained
in the case of 2-furaldehyde (entry 18). Asymmetric ethyla-
tion of piperonal proceeded effectively to generate (S)-1-
(benzodioxol-5-yl)-1-propanol with 82% ee (entry 19),
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molecules and fine chemicals.52,53
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In summary, five-membered nitrogen-containing aromatic
heterocycles were successfully introduced to the 3 position
of (S)-BINOL to give a series of chiral ligands. Among them
surveyed, Ligand-2, easily obtained in 82% overall yield
starting from the commercially available (S)-BINOL
through a six-step sequence, exhibited the best catalytic ac-
tivity in the enantioselective addition of diethylzinc to a
wide range of aromatic aldehydes and trans-cinnamalde-
hyde. Further studies will be focused on the detailed mech-
anism and application of this ligand to other asymmetric
transformations, such as allylation, methylation, and phenyl-
ation of carbonyl compounds are currently underway in our
laboratory and the results will be reported in due course.
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