Room temperature and highly enantioselective additions of alkyltitanium reagents to aldehydes catalyzed by a titanium catalyst of (R)-h 8-binol

Article abstract of DOI:10.1002/chir.21018

Three alkyltitanium reagents of RTi(O-i-Pr)₃ (R = Cy (1a), i-Bu (1b), and n-Bu (1c)) were prepared in good yields. The high-resolution mass spectroscopy showed that 1b and 1c in the gas phase are monomeric species. However, the solid state of 1a revealed a dimeric structure. Asymmetric additions of 1a-1c to aldehydes catalyzed by a titanium catalyst of (R)-H ₈-BINOL were studied at room temperature. The reactions produced desired secondary alcohols in good yields with good to excellent enantioselectivities of up to 94% ee. Reactivity and enantioselectivity differences, in terms of steric bulkiness of the R nucleophiles, are herein described. The addition reactions of secondary c-hexyl to aldehydes were slower than the reactions of primary i-butyl or n-butyl nucleophiles. For the primary alkyls, lower enantioselectivities were obtained for products from addition reactions of the linear n-butyl as compared with the enantioselectivities of products from the addition reactions of the branched i-butyl group. The same stereochemistry of RTi(O-i-Pr)₃ addition reactions as the addition reactions of organozinc, organoaluminum, Grignard, or organolithium reagents directly supports the argument of that titanium-catalyzed addition reactions of aldehydes involve an addition of an organotitanium nucleophile.

Full text of DOI:10.1002/chir.21018

CHIRALITY 23:929–939 (2011)
Room Temperature and Highly Enantioselective Additions of
Alkyltitanium Reagents to Aldehydes Catalyzed by a Titanium Catalyst
of (R)-H8-BINOL
QINGHAN LI1,2 AND HAN-MOU GAU
1
*
1Department of Chemistry, National Chung Hsing University, Taichung, Taiwan, Republic of China
2College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu, People’s Republic of China
ABSTRACT
Three alkyltitanium reagents of RTi(O-i-Pr)3 (R 5 Cy (1a), i-Bu (1b), and n-
Bu (1c)) were prepared in good yields. The high-resolution mass spectroscopy showed that 1b
and 1c in the gas phase are monomeric species. However, the solid state of 1a revealed a di-
meric structure. Asymmetric additions of 1a–1c to aldehydes catalyzed by a titanium catalyst of
(R)-H8-BINOL were studied at room temperature. The reactions produced desired secondary
alcohols in good yields with good to excellent enantioselectivities of up to 94% ee. Reactivity and
enantioselectivity differences, in terms of steric bulkiness of the R nucleophiles, are herein
described. The addition reactions of secondary c-hexyl to aldehydes were slower than the reac-
tions of primary i-butyl or n-butyl nucleophiles. For the primary alkyls, lower enantioselectivities
were obtained for products from addition reactions of the linear n-butyl as compared with the
enantioselectivities of products from the addition reactions of the branched i-butyl group. The
same stereochemistry of RTi(O-i-Pr)3 addition reactions as the addition reactions of organozinc,
organoaluminum, Grignard, or organolithium reagents directly supports the argument of that ti-
tanium-catalyzed addition reactions of aldehydes involve an addition of an organotitanium nucle-
C
VV
ophile. Chirality 23:929–939, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: asymmetric catalysis; alkyltitanium triisopropoxide; alkyl addition; titanium
catalyst; H8-(R)-BINOL; BINOL derivative
INTRODUCTION
peratures at or below 2158C.42 Recently, we had successfully
synthesized [(3-furyl)Ti(O-i-Pr)3]2 for 3-furyl addition reac-
tions of aromatic ketones; the reactions could be conducted
at a mild temperature of 08C.43
The titanium-catalyzed asymmetric addition reaction of
alkylzinc compounds to aldehydes has been one of the most
important synthetic protocols for synthesis of bioactive chiral
secondary alcohols.1–4 Over the past two decades, a variety
of chiral ligands have been developed to deliver desired alco-
hols in high enantioselectivities.5–16 Recent studies have
shown that organoaluminum compounds are effective
reagents,17–29 and addition reactions can even be completed
in 10 min.24 Grignard30–33 and lithium34 reagents have also
been established recently as efficient nucleophiles for addi-
tion reactions despite their high reactivity. In these studies, a
presence of diamine additive and/or excessive amounts of
Ti(O-i-Pr)4 were used to deactivate the high reactivity of the
Grignard and lithium reagents. The presence of excess Ti(O-
i-Pr)4 is a general feature of titanium-catalyzed addition reac-
tions for products achieving high enantioselectivities. Mecha-
nistic studies have suggested that the reactions involve an
addition of organotitanium compounds, and one of the roles
of excess Ti(O-i-Pr)4 is an in situ generation of the organoti-
tanium reagent via transmetallation of organic nucleophile
from organozinc compounds to Ti(O-i-Pr)4.35–39 However,
only a few reports have demonstrated direct asymmetric
additions of organotitanium compounds. The first catalytic
asymmetric RTi(O-i-Pr)3 addition reaction was reported by
Seebach and coworkers using Ti-TADDOLate catalysts. The
use of salt-free RTi(O-i-Pr)3 and the reactions conducting at
an initial low temperature of 2788C were found to be essen-
tial for producing chiral secondary alochols in excellent enan-
tioselectivities.35,40,41 Later, titanium-acetylenide addition
reactions of aromatic ketones had been investigated at tem-
To further explore organoaluminum or organotitanium
compounds as efficient nucleophiles for catalytic reac-
tions,44–52 we report herein the synthesis of three alkyltita-
nium compounds of RTi(O-i-Pr)3 (R 5 Cy (1a), i-Bu (1b),
and n-Bu (1c)). Asymmetric additions of 1a–1c to aromatic,
heteroaromatic, or a,b-unsaturated aldehydes catalyzed by a
titanium catalyst of (R)-H8-BINOL have been studied at room
temperature, affording desired secondary alcohols in good to
excellent enantioselectivities of up to 94% ee.
MATERIALS AND METHODS
General Procedures for the Synthesis of RTi(O-i-Pr)3
To a two-necked round bottom flask containing magnesium turning
(2.40 g, 0.100 mol) in 100 mL of diethyl ether and equipped with an addi-
tion funnel and a condenser, alkyl bromide (0.102 mol) in 50 mL diethyl
ether was slowly added over a period of 1 h under a dry nitrogen atmos-
phere. The reaction mixture was stirred for another 2 h to give an alkyl
Grignard solution. The above solution was transferred via a cannula to a
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: National Science Council of Taiwan, ROC;
Contract grant numbers: NSC 99-2113-M-005-005-MY3.
*Correspondence to: Han-Mou Gau, Department of Chemistry, National
Chung Hsing University, 250 Kuo-Kuang Road, Taichung 402, Taiwan,
Republic of China. E-mail: hmgau@dragon.nchu.edu.tw
Received for publication 5 May 2011; Accepted 6 July 2011
DOI: 10.1002/chir.21018
Published online 26 September 2011 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2011 Wiley-Liss, Inc.

930
LI AND GAU
solution of Ti(O-i-Pr)4 (22.1 mL, 0.0750 mol) and TiCl4 (2.74 mL, 0.0250
mol) in 50 mL THF cooling at 08C. The resulted solution was reacted for
3 h at 08C to give a brownish or black solution. The solvent was removed
under reduced pressures to give an oily solid. The residue was extracted
with hexane (33 100 mL), and the combined extract was concentrated
to furnish RTi(O-i-Pr)3. 1a was prepared in THF.
Hz, 2H), 6.88 (d, J 5 8.4 Hz, 2H), 4.30 (d, J 5 7.2 Hz, 1H), 3.81 (s, 3H),
2.08–1.52 (m, 6H), 1.42–0.82 (m, 6H) ppm; 13C{1H}NMR (100 MHz,
CDCl3): d 159.0, 135.8, 127.7, 113.6, 79.0, 55.2, 45.0, 29.3, 29.1, 26.4, 26.1,
26.0 ppm.56
Cyclohexyl-(naphthalen-1-yl)-methanol (5f). [a]2D5 5 152.4 (c
1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 8.18–8.10 (m, 1H), 7.90–
7.84 (m, 1H), 7.77 (d, J 5 8.4 Hz, 1H), 7.58 (d, J 5 7.8 Hz, 1H), 7.56–7.44
(m, 3H), 5.19 (d, J 5 6.4 Hz, 1H), 2.00–1.56 (m, 6H), 1.44–1.34 (m, 1H),
1.22–1.06 (m, 5H) ppm; 13C{1H} NMR (100 MHz, CDCl3): d 139.5, 133.8.
130.9, 128.8, 127.8, 125.7, 125.4, 125.2, 124.1, 123.6, 76.1, 44.3, 30.3, 28.2,
26.4, 26.3, 26.0 ppm.57
(Cy)Ti(O-i-Pr)3 (1a). Pale yellow crystals (25.0 g, 83.0%). 1H NMR
(400 MHz, CDCl3): d 4.52 (sept, J 5 6.0 Hz, 3H), 2.10–2.06 (m, 2H),
1.74–1.00 (m, 9H), 1.27 (d, J 5 6.4 Hz, 18H) ppm; 13C{1H} NMR (100
MHz, CDCl3): d 76.1, 34.6, 29.3, 27.2, 26.8, 25.6 ppm. Elemental analysis,
calcd. for C15H32O3Ti: C 58.44, H 10.46%, found: C 58.22, H 10.22%.
Cyclohexyl-(naphthalen-2-yl)-methanol (5g). [a]2D5 5 129.0 (c
1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.84–7.76 (m, 3H), 7.67 (s,
1H), 7.50–7.38 (m, 3H), 4.47 (d, J 5 6.4 Hz, 1H), 2.15 (d, J 5 1.6 Hz,
1H), 2.04–1.94 (m, 1H), 1.80–1.56 (m, 4H), 1.40–1.32 (m, 1H), 1.28–0.88
(m, 5H) ppm; 13C{1H}NMR (100 MHz, CDCl3): d 141.3, 133.4, 133.2,
128.2, 127.9, 126.3, 126.0, 125.7, 125.0, 79.7, 45.1, 29.6, 29.1, 26.7, 26.33,
26.27 ppm.58
(i-Bu)Ti(O-i-Pr)3 (1b). Brownish liquid (22.3 g, 78.0%). 1H NMR
(400 MHz, CDCl3): d 4.45 (sept, J 5 6.0 Hz, 3H), 2.10–1.75 (m, 1H),
1.25–1.18 (m, 2H), 1.19 (d, J 5 6.0 Hz, 18H), 0.84 (d, J 5 6.8 Hz, 6H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): d 76.2, 31.8, 30.7, 26.5, 19.0 ppm.
HR-MS m/z calcd. for C13H30O3Ti [M]1 282.1674, found: 282.1679.
(n-Bu)Ti(O-i-Pr)3 (1c). Gray liquid (21.5 g, 80.0%). 1H NMR (400
MHz, CDCl3): d 4.46 (sept, J 5 6.0 Hz, 3H), 1.63 (q, J 5 7.6 Hz, 2H),
1.25–1.06 (m, 4H), 1.20 (d, J 5 6.4 Hz, 18 H), 0.75 (t, J 5 7.2 Hz, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): d 76.2, 33.2, 27.3, 26.7, 26.0, 13.7
ppm. HR-MS m/z calcd. for C13H30O3Ti [M]1 282.1674, found: 282.1683.
Cyclohexyl-(2-fluorophenyl)-methanol (5h). [a]D25
5 116.0 (c
0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.32 (dt, J 5 1.6, 7.2 Hz,
1H), 7.20–7.12 (m, 1H), 7.10–7.02 (dt, J 5 1.6, 7.2 Hz, 1H), 6.97–6.90 (m,
1H), 4.63 (d, J 5 7.2, 1H), 1.94–1.84 (m, 2H), 1.74–1.65 (m, 1H), 1.64–
1.52 (m, 3H), 1.37–1.28 (m, 1H), 1.12–0.88 (m, 5H) ppm; 13C{1H}NMR
(100 MHz, CDCl3): d 160.0 (J 5 243 Hz), 130.6 (J 5 12.7 Hz), 128.6 (J 5
8.2 Hz), 128.2 (J 5 4.6 Hz), 124.0 (J 5 3.6 Hz), 115.1 (J 5 22.8 Hz), 72.9,
44.4, 29.0, 28.6, 26.3, 26.0, 25.9 ppm.59
General Procedures for Alkyl Additions to Aldehydes
Under
a dry nitrogen atmosphere, {(R)-H8-BINOLate}Ti(O-i-Pr)2
(0.023 g, 0.050 mmol), Ti(O-i-Pr)4 (0.30 mL, 1.0 mmol), and (Cy)Ti(O-i-
Pr)3 (0.247 g, 0.800 mmol) were mixed in hexane (2 mL) at room tem-
perature. After stirring the mixture for 1 h, an aldehyde (0.50 mmol) was
added. The resulted solution was allowed to react for 36 h at room tem-
perature and quenched with 2M NaOH (2 mL). The solution was
extracted with ethyl acetate (33 10 mL). The combined organic phase
was dried over MgSO4, filtered, and concentrated. The residue was puri-
fied by column chromatography to give the secondary alcohol. Enantio-
meric excesses of products were determined by HPLC using suitable
chiral columns from Daicel. The addition reactions of (i-Bu)Ti(O-i-Pr)3
or (n-Bu)Ti(O-i-Pr)3 (0.50 mmol) did not require the addition of Ti(O-i-
Pr)4 and were carried out in THF (4 mL).
(3-Chlorophenyl)-cyclohexylmethanol (5i). [a]2D5 5 118.0 (c 1.0,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.31–7.27 (m, 1H), 7.27–7.20 (m,
2H), 7.18–7.12 (m, 1H), 4.35–4.34 (d, J 5 6.8 Hz, 1H), 2.00–1.86 (m, 2H),
1.80–1.52 (m, 4H), 1.42–1.34 (m, 1H), 1.28–0.84 (m, 5H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): d 145.6, 134.1, 129.3, 127.4, 126.7, 124.7, 78.6,
44.9, 29.2, 28.4, 26.3, 26.0, 25.9 ppm.54
(3-Bromophenyl)-cyclohexylmethanol (5j). [a]D25
5 118.1 (c
1
0.55, CH2Cl2). H NMR (400 MHz, CDCl3): d 7.35 (s, 1H), 7.33–7.27 (m,
1H), 7.14–7.07 (m, 2H), 4.22 (d, J 5 6.8 Hz, 1H), 2.10 (br, 1H), 1.86–1.76
(m, 1H), 1.72–1.40 (m, 4H), 1.34–1.24 (m, 1H), 1.18–0.76 (m, 5H) ppm;
13C{1H}NMR (100 MHz, CDCl3): d 146.2, 130.6, 130.0, 129.9, 125.5,
122.6, 78.9, 45.2, 29.5, 28.8, 26.6, 26.3, 26.2 ppm. HR-MS: m/z calcd. for
(R)-Cyclohexylphenylmethanol ((R)-5a). [a]2D5 5 128.0 (c 1.0,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.38–7.24 (m, 5H), 4.37 (d, J 5
7.2 Hz, 1H), 2.04–1.96 (m, 1H), 1.84–1.72 (m, 1H), 1.70–1.52 (m, 5H),
1.42–1.32 (m, 1H), 1.30–0.86 (m, 4H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): d 143.6, 128.1, 127.4, 126.6, 79.3, 44.9, 29.3, 28.8, 26.4, 26.04,
25.96 ppm.31
C
13H17OBr: 268.0463 [M1], found: 268.0460.
(4-Bromophenyl)-cyclohexylmethanol (5k). [a]2D5 5 120.6 (c 1.0,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.40–7.35 (m, 2H), 7.12–7.06 (m,
2H), 4.25 (d, J 5 6.8 Hz, 1H), 1.93 (br, 1H), 1.88–1.80 (m, 1H), 1.74–1.65
(m, 1H), 1.64–1.52 (m, 2H), 1.52–1.42 (m, 1H), 1.34–1.26 (m, 1H), 1.20–
0.86 (m, 5H) ppm; 13C{1H}NMR (100 MHz, CDCl3): d 142.5, 131.2,
128.3, 121.0, 78.6, 44.9, 29.1, 28.5, 26.3, 26.0, 25.9 ppm.54
Cyclohexyl-o-tolylmethanol (5b). [a]2D5 5 129.6 (c 0.6, CH2Cl2).
1H NMR (400 MHz, CDCl3): d 7.44–7.38 (m, 1H), 7.25–7.10 (m, 3H),
4.65 (d, J 5 7.2 Hz, 1H), 2.34 (s, 3H), 2.06–1.98 (m, 1H), 1.82–1.74 (m,
1H), 1.72–1.58 (m, 4H), 1.42–1.36 (m, 1H), 1.28–0.98 (m, 5H) ppm;
13C{1H} NMR (100 MHz, CDCl3): d 142.2, 135.4, 130.6, 127.3, 126.5,
126.3, 75.4, 44.8, 29.8, 28.8, 26.7, 26.6, 26.3, 19.7 ppm.53
Cyclohexyl-(4-trifluoromethylphenyl)-methanol (5l). [a]D25
5
121.2 (c 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.59 (d, J 5 8.0 Hz,
2H), 7.41 (d, J 5 8.0 Hz, 2H), 4.46 (d, J 5 6.8 Hz, 1H), 1.98–1.84 (m,
1H), 1.82–1.72 (m, 1H), 1.72–1.52 (m, 4H), 1.44–1.34 (m, 1H), 1.28–0.90
(m, 5H) ppm; 13C{1H}NMR (100 MHz, CDCl3): d 147.5, 129.5 (J 5 32.8
Hz), 126.9, 125.1 (q, J 5 3.7), 124.2 (J 5 270 Hz), 78.6, 45.0, 29.2, 28.3,
26.3, 26.0, 25.9 ppm.55
Cyclohexyl-m-tolylmethanol (5c). [a]2D5 5 122.0 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): d 7.19–7.12 (m, 1H), 7.06–6.98 (m, 3H),
4.24 (dd, J 5 2.8, 7.2 Hz, 1H), 2.28 (s, 3H), 1.96–1.88 (m, 1H), 1.82–1.78
(m, 1H), 1.74–1.65 (m, 1H), 1.64–1.48 (m, 3H), 1.34–1.26 (m, 1H), 1.22–
0.78 (m, 5H) ppm; 13C{1H} NMR (100 MHz, CDCl3): d 143.6, 137.7,
128.1, 128.0, 127.2, 123.7, 79.4, 44.8, 29.3, 28.8, 26.4, 26.1, 26.0, 21.4
ppm.54
Cyclohexyl-(furan-2-yl)-methanol (5m). [a]2D5 5 115.5 (c 1.1,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.38–7.36 (m, 1H), 6.34–6.32 (m,
1H), 6.24–6.20 (m, 1H), 4.37 (d, J 5 7.6 Hz, 1H), 2.04–1.96 (m, 1H), 1.91
(br, 1H), 1.84–1.62 (m, 4H), 1.48–1.38 (m, 1H), 1.32–0.90 (m, 5H) ppm;
13C{1H} NMR (100 MHz, CDCl3): d 156.0, 141.7, 110.0, 106.5, 72.7, 42.9,
29.0, 28.8, 26.3, 25.9, 25.8 ppm.60
Cyclohexyl-p-tolylmethanol (5d). [a]2D5 5 128.0 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): d 7.20–7.11 (m, 4H), 4.31 (d, J 5 7.2 Hz,
1H), 2.34 (s, 3H), 2.04–1.94 (m, 1H), 1.82–1.70 (m, 2H), 1.69–1.54 (m,
3H), 1.40–1.32 (m, 1H), 1.28–0.82 (m, 5H) ppm; 13C{1H} NMR (100
MHz, CDCl3): d 141.0, 137.3, 129.2, 126.9, 79.6, 45.2, 29.6, 29.2, 26.8,
26.4, 26.3, 21.4 ppm.55
(E)-1-Cyclohexyl-3-phenylprop-2-en-1-ol (5n). [a]2D5 5 222.8 (c
0.6, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.42–7.36 (m, 2H), 7.35–
7.28 (m, 2H), 7.26–7.20 (m, 1H), 6.56–6.54 (d, J 5 15.6 Hz, 1H), 6.23
(dd, J 5 7.2, 15.6 Hz, 1H), 4.01 (dd, J 5 6.8, 7.2 Hz, 1H), 1.96–1.86 (m,
1H), 1.82–1.70 (m, 3H), 1.70–1.62 (m, 2H), 1.56–1.44 (m, 1H), 1.32–0.98
(R)-Cyclohexyl-(4-methoxyphenyl)-methanol ((R)-5e). [a]D25
1
5 124.1 (c 1.1, CH2Cl2). H NMR (400 MHz, CDCl3): d 7.22 (d, J 5 8.4
Chirality DOI 10.1002/chir

ASYMMETRIC ALKYLTITANIUM ADDITION REACTION OF ALDEHYDE
931
(m, 5H) ppm; 13C{1H} NMR (100 MHz, CDCl3): d 136.8, 131.2, 131.0,
monochromated Mo-Ka radiation (k 5 0.71073 A); temperature 100(2)
K; / and x scan technique; multiscan absorptions were applied in the
data corrections. The structure was solved by direct methods, completed
by subsequent difference Fourier syntheses, and refined by full-matrix
least squares calculations based on F2 (SHELXTL-97).63 Crystallographic
data for [(c-hexyl)Ti(O-i-Pr)2(l2-O-i-Pr)]2 (1a): C30H64O6Ti2, MM 5
616.62, monoclinic, space group P2(1)/n, T 5 100(2) K, a 511.8924(2)
˚
128.5, 127.5, 126.4, 77.5, 43.9, 28.9, 28.6, 26.5, 26.1, 26.0 ppm.59,61
(R)-3-Methyl-1-phenylbutan-1-ol ((R)-6a). [a]2D5 5 145.0 (c 1.0,
CH2Cl2). 1H NMR (CDCl3, 400 MHz): d 7.36–7.31 (m, 4H), 7.30–7.23 (m,
1H), 4.76–4.70 (m, 1H), 1.84 (s, 1H), 1.78–1.64 (m, 2H), 1.56–1.44 (m,
1H), 0.97–0.94 (m, 3H), 0.94–0.91 (m, 3H) ppm. 13C{1H} NMR (CDCl3,
100 MHz): d 145.2, 128.4, 127.5, 125.8, 72.7, 48.3, 24.8, 23.1, 22.2 ppm.32
˚
˚
˚
A, b 5 9.4982(2) A, c 5 16.1349(3) A, b 5 94.382(2)8, V 5 1817.21(6)
3
A , Z 5 2, absorption coefficient 5 0.473 mm21, total reflections col-
˚
(R)-3-Methyl-1-p-tolylbutan-1-ol ((R)-6b). [a]2D5 5 144.1 (c 1.0,
CH2Cl2). 1H NMR (CDCl3, 400 MHz): d 7.25–7.20 (m, 2H), 7.18–7.12 (m,
2H), 4.72–4.66 (m, 1H), 2.34 (s, 3H), 1.79 (s, 1H), 1.76–1.60 (m, 2H),
1.54–1.44 (m, 1H), 0.98–0.94 (m, 3H), 0.94–0.90 (m, 3H) ppm.
13C{1H}NMR (CDCl3, 100 MHz): d 142.2, 137.1, 129.1, 125.8, 72.6, 48.2,
24.8, 23.0, 22.3, 21.0 ppm.32
lected 17,832, unique 3570 (Rint 5 0.0274), Goodness of fit indicator 5
1.309, R1 5 0.0540, wR2 5 0.1767. A cif file of 1a (CCDC 812103) has
been deposited to the Cambridge Crystallographic Data Centre and can
be obtained via www.ccdc.cam.ac.uk/data_request/cif.
RESULTS AND DISCUSSION
(R)-3-Methyl-1-(naphthalen-6-yl)-butan-1-ol ((R)-6c). [a]D25
5
171.6 (c 1.1, CH2Cl2). 1H NMR (CDCl3, 400 MHz): d 8.08 (d, J 5 8.0 Hz,
1H), 7.88–7.84 (m, 1H), 7.75 (d, J 5 8.0 Hz, 1H), 7.63 (d, J 5 6.8 Hz,
1H), 7.53–7.42 (m, 3H), 5.55–5.50 (m, 1H), 2.00–1.88 (m, 1H), 1.97 (s,
1H), 1.86–1.77 (m, 1H), 1.74–1.64 (m, 1H), 1.07 (d, J 5 6.4 Hz, 3H), 0.96
(d, J 5 6.8 Hz, 3H) ppm. 13C{1H}NMR (CDCl3, 100 MHz): d 140.7, 133.5,
129.9, 128.6, 127.4, 125.6, 125.13, 125.11, 122.7, 122.3, 69.0, 47.3, 24.9,
23.2, 21.5 ppm.32
RTi(O-i-Pr)3 (R 5 Me, C6H5, C6F5) had been synthesized
1
and characterized by H NMR spectroscopy in the 1970s.64
Other alkyltitanium compounds of RTi(O-i-Pr)3 (R 5 Et, Pr,
Bu, Hex, CH2CH2CH¼¼CH2, and CH2Ph) had been prepared
in situ for asymmetric addition reactions.35,40,41 In this study,
three alkyltitanium compounds of RTi(O-i-Pr)3 [R 5 Cy (c-
hexyl, 1a), i-Bu (i-butyl, 1b), and n-Bu (n-butyl, 1c)] were
prepared in good yields from a reaction of ClTi(O-i-Pr)3 with
corresponding alkyl Grignard reagents in THF or diethyl
ether (Eq. 1). Among them, 1a and 1b are novel com-
pounds. 1a was obtained as a crystalline material, and 1b
and 1c were liquids. 1b and 1c contained trace amounts of
impurities and were used directly for the addition reactions.
The HR-MS (high-resolution mass spectroscopy) revealed a
monomeric species for 1b and 1c in the gas phase. How-
(R)-1-(3-Chlorophenyl)-3-methylbutan-1-ol ((R)-6d). [a]D25
5
1
131.5 (c 1.1, CH2Cl2). H NMR (CDCl3, 400 MHz): d 7.36–7.34 (m, 1H),
7.30–7.20 (m, 3H), 4.75–4.70 (m, 1H), 1.81 (br, 1H), 1.78–1.66 (m, 2H),
1.52–1.42 (m, 1H), 0.95 (d, J 5 6.0 Hz, 6H) ppm. 13C{1H}NMR (CDCl3,
100 MHz): d 147.3, 134.3, 129.7, 127.5, 126.0, 123.9, 72.2, 48.4, 24.7, 23.1,
22.1 ppm.32
(R)-(E)-5-Methyl-1-phenylhex-1-en-3-ol ((R)-6e). [a]2D5 5 28.7
(c 1.1, CH2Cl2). 1H NMR (CDCl3, 400 MHz): d 7.42–7.36 (m, 2H), 7.36–
7.30 (m, 2H), 7.26–7.22 (m, 1H), 6.58 (d, J 5 16.0 Hz, 1H), 6.22 (dd, J 5
6.8, 16.0 Hz, 1H), 4.36 (m, 1H), 1.80–1.78 (sept, J 5 6.8 Hz, 1H), 1.63–
1.54 (m, 1H), 1.56 (s, 1H), 1.48–1.40 (m, 1H), 0.96 (d, J 5 6.4 Hz, 3H)
0.95 (d, J 5 6.4 Hz, 3H) ppm. 13C{1H}NMR (CDCl3, 100 MHz): d 136.7,
132.9, 130.1, 128.5, 127.6, 126.4, 71.3, 46.5, 24.6, 23.0, 22.5 ppm.32
43
ever, similar to the structures of [(3-furyl)Ti(O-i-Pr)3]2 and
[ArTi(O-i-Pr)3]2,50 1a has a dimeric structure in its solid
(R)-1-Phenylpentan-1-ol ((R)-7a). [a]2D5 5 128.3 (c 1.2, CH2Cl2).
1H NMR (CDCl3, 400 MHz): d 7.38–7.32 (m, 4H), 7.31–7.24 (m, 1H),
4.66 (t, J 5 6.8 Hz, 1H), 1.88–1.76 (m, 2H), 1.76–1.66 (m, 1H), 1.46–1.18
(m, 4H), 0.89 (t, J 5 6.8 Hz, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz):
d 144.9, 128.4, 127.4, 125.9, 74.7, 38.8, 27.9, 22.6, 14.0 ppm.30
(R)-1-(Naphthalen-1-yl)-pentan-1-ol ((R)-7b). [a]2D5 5 148.0 (c
1.0, CH2Cl2). 1H NMR (CDCl3, 400 MHz): d 8.14–8.08 (m, 1H), 7.90–
7.84 (m, 1H), 7.80–7.74 (d, J 5 8.0 Hz, 1H), 7.64 (d, J 5 6.8 Hz, 1H),
7.54–7.44 (m, 3H), 5.48–5.44 (m, 1H), 2.02–1.86 (m, 2H), 1.82 (br, 1H),
1.60–1.48 (m, 1H), 1.46–1.30 (m, 3H), 0.90 (t, J 5 7.2 Hz, 3H) ppm.
13C{1H} NMR (CDCl3, 100 MHz): d 140.6, 133.8, 130.4, 128.9, 127.8,
125.9, 125.44, 125.40, 123.2, 122.8, 71.3, 38.1, 28.4, 22.6, 14.0 ppm.32
1-(3-Chlorophenyl)pentan-1-ol (7c). [a]D25
5 120.0 (c 1.0,
CH2Cl2). 1H NMR (CDCl3, 400 MHz): d 7.36–7.34 (m, 1H), 7.30–7.24 (m,
2H), 7.24–7.19 (m, 1H), 4.66–4.65 (m, 1H), 1.82–1.64 (m, 3H), 1.44–1.20
(m, 3H), 0.88 (t, J 5 6.4 Hz, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz):
d 147.0, 134.3, 129.7, 127.5, 126.1, 124.0, 74.0, 38.8, 27.8, 22.5, 13.9
ppm.62
(E)-1-Phenylhept-1-en-3-ol (7d). [a]2D5 5 29.5 (c 1.0, CH2Cl2). 1H
NMR (CDCl3, 400 MHz), d 7.40–7.36 (m, 2H), 7.34–7.28 (m, 2H), 7.26–
7.20 (m, 1H), 6.56 (d, J 5 16.0 Hz, 1H), 6.22 (dd, J 5 6.8, 16.0 Hz, 1H),
4.28–4.26 (m, 1H), 1.69 (br, 1H), 1.68–1.54 (m, 2H), 1.46–1.30 (m, 4H),
0.91 (t, J 5 6.4 Hz, 3H) ppm. 13C{1H}NMR (CDCl3, 100 MHz): d 136.7,
132.6, 130.2, 128.5, 127.6, 126.4, 73.1, 37.0, 27.6, 22.6, 14.0 ppm.30
X-Ray Crystallography
Yellow crystals of 1a were grown in hexane. A suitable crystal was
covered with FOMBLIN1 Y and mounted on a cryoloop. Diffractions
were performed on an Oxford Gemini S diffractometer using graphite-
Fig. 1. The molecular structure of 1a. Hydrogen atoms are omitted for
clarity.
Chirality DOI 10.1002/chir

932
LI AND GAU
state (Fig. 1). 1a–1c are stable enough to be stored under a
dry nitrogen atmosphere for months.
conversion to 94% with the same enantioselectivity (entry
14). However, reducing the amount of (R)-2 to 5 mol % pro-
duced 5a in both a lower conversion of 88% and a lower
enantioselectivity of 87% ee (entry 15). The in situ-formed ti-
tanium catalyst from mixing of 10 mol % (R)-H8-BINOL
ligand and 2.2 equiv Ti(O-i-Pr)4 was also investigated, fur-
nishing 5a in an 83% conversion with an enantioselectivity of
91% ee (entry 16). The above results reveal that the pre-
formed titanium catalytic system of (R)-2 afforded the addi-
tion product in a somewhat better yield, but with similar
enantioselectivity as compared with the in situ-formed tita-
nium catalytic system of (R)-H8-BINOL. Titanium complexes
of (R)- and (S)-3 containing simple BINOLate ligand were
also examined, affording predominant (R)-5a and (S)-5a in
somewhat lower conversions of 89 and 86% and lower enan-
tioselectivities of 81% ee (entries 17 and 18).
The reaction scope was then studied on aromatic alde-
hydes, 2-furaldehyde, and (E)-cinnamaldehyde (Eq. 3) under
optimized reaction conditions (Table 1, entry 14); the results
are summarized in Table 2. The c-hexyl addition to benzalde-
hyde proceeded over 24 h to afford addition product 5a in a
90% yield and a 92% ee (entry 1). For aromatic aldehydes bear-
ing an electron-donating group and for naphthylaldehydes,
the addition reactions required a reaction time of 36 h to
Asymmetric reactions were first optimized on the addi-
tions of (Cy)Ti(O-i-Pr)3 (1a) to benzaldehyde (4a) using a
10 mol % catalyst of [{(R)-H8-BINOLate}Ti(O-i-Pr)2]x ((R)-
2),65 [{(R)-BINOLate}Ti(O-i-Pr)2]x ((R)-3), or [{(S)-BINOLa-
te}Ti(O-i-Pr)2]x ((S)-3)38 (Eq. 2); the results are listed in Ta-
ble 1. When the reaction was conducted at 08C in THF using
the catalytic system of (R)-2, but without an addition of Ti(O-
i-Pr)4, the addition of the cyclohexyl group to benzaldehyde
proceeded slowly and produced addition product 5a in a low
conversion of 12%, but with a good enantioselectivity of 87%
ee (entry 1). Though additions of Ti(O-i-Pr)4 to the catalytic
solution improved the enantioselectivities of up to 92% ee,
conversions of 5a were still low (11–25%, entries 2–5). The
solvent effect was then investigated (entries 6–9) while keep-
ing the amount of Ti(O-i-Pr)4 at 2.0 equiv. Hexane was found
to be the best solvent to afford 5a in a 42% conversion.
Increasing the amount of (c-hexyl)titanium reagent 1a from
1.2 to 1.8 equiv resulted in increasing conversions of 5a to
65% (entries 9–12). When the reaction was carried out at
room temperature using 1.6 equiv of 1a, a good 86% conver-
sion of 5a was obtained with a 92% ee (entry 13). Reducing
the solvent amount of hexane to 2 mL further improved the
TABLE 1. Optimizations of asymmetric (Cy)Ti(O-i-Pr)3 additions to benzaldehyde catalyzed by a titanium catalyst of (R)-H8-BINOL,
(R)-BINOL, or (S)-BINOLa
Entry
1a (equiv)
Ti(O-i-Pr)4 (equiv)
Solvent
Temp (8C)
Conv.b(%)
Eec(%)
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.4
1.6
1.8
1.6
1.6
1.6
1.6
1.6
1.6
0
0.2
1.0
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.2
2.0
2.0
THF
THF
THF
THF
THF
0
0
0
0
0
0
0
0
0
0
0
0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
12
11
25
22
14
23
4
20
42
45
54
65
86
94
88
83
89
86
87 (R)
84 (R)
86 (R)
92 (R)
92 (R)
89 (R)
87 (R)
87 (R)
92 (R)
92 (R)
92 (R)
90 (R)
92 (R)
92 (R)
87 (R)
91 (R)
81 (R)
81 (S)
Et2O
CH2Cl2
Toluene
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
9
10
11
12
13
14d
15d,e
16d,f
17d,g
18d,h
aBenzaldehyde/(R)-2 5 0.50/0.050 mmol; solvent, 4 mL.
bConversions of 5a were determined by 1H NMR.
cEe values were determined by HPLC.
d2 mL of hexane.
e0.025 mmol of (R)-2 (5 mol %).
f(R)-H8-BINOL, 0.050 mmol; Ti(O-i-Pr)4, 1.1 mmol.
g[{(R)-BINOLate}Ti(O-i-Pr)2]x ((R)-3), 0.050 mmol.
h[{(S)-BINOLate}Ti(O-i-Pr)2]x ((S)-3), 0.050 mmol.
Chirality DOI 10.1002/chir

ASYMMETRIC ALKYLTITANIUM ADDITION REACTION OF ALDEHYDE
933
TABLE 2. Asymmetric (Cy)Ti(O-i-Pr)3 additions to aldehydes catalyzed by the titanium catalyst of (R)-H8-BINOLa
Entry
1d
Substrate 4
Product 5
Yieldb(%)
Eec(%)
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
90
92 (R)
2
3
4
5
67
80
83
80
90
90
90
90 (R)
6
4f
4g
4h
4i
5f
5g
5h
5i
68
73
66
81
80
81
90
91
7
8
93 (R)
9
91
10
11
4j
5j
91
4k
5k
85
Chirality DOI 10.1002/chir

934
LI AND GAU
TABLE 2. (Continued)
Entry
12
Substrate 4
Product 5
Yieldb(%)
77
Eec(%)
94
4l
5l
13
14
4m
4n
5m
5n
85
77
90
76 (R)
a4/1a/Ti(O-i-Pr)4 5 0.50/0.80/0.050/1.0 mmol; hexane, 2 mL.
bIsolated yields of 5.
c1Ee values were determined by HPLC.
d24 h.
produce corresponding secondary alcohols 5b–5g in good
yields and excellent enantioselectivities ranged from 90 to 91%
ee (entries 2–7). In this study, a steric effect of the substrates
was observed. The addition reactions of aromatic aldehydes
with an ortho-substituent, such as 2-methylbenzaldehyde and 1-
naphthylaldehyde, produced products 5b (entry 2) and 5f
(entry 6) in moderate yields of 67 and 68%, respectively. The
addition reactions of aromatic aldehydes containing an elec-
tron-withdrawing substituent afforded 5h–5l in good yields
and excellent enantioselectivities (entries 8–12) except a 66%
yield for the addition reaction of 2-fluorobenzaldehyde (4h;
entry 8). The addition reaction of heteroaromatic 2-furaldehyde
furnished product 5m in good yield with an excellent enantio-
selectivity of 90% ee (entry 13). However, the addition reaction
of a,b-unsaturated (E)-cinnamaldehyde afforded 5n in a mod-
erate enantioselectivity of 76% ee (entry 14).
The addition reactions of primaryl alkyltitanium reagent of
(i-Bu)Ti(O-i-Pr)3 (1b) were subsequently investigated at 08C
(Eq. 4); the results are presented in Table 3. The solvent
effect was first screened in the absence of Ti(O-i-Pr)4 (entries
1–4), affording addition product 6a in conversions ranging
from 53 to 76%. Interestingly, it was found that THF is the
best solvent for i-butyl addition reactions. Though conver-
sions of 6a vary in different solvents, the enantioselectivities
TABLE 3. Optimizations of asymmetric (i-Bu)Ti(O-i-Pr)3 additions to benzaldehyde catalyzed by a titanium catalyst of (R)-H8-
BINOL, (R)-BINOL, or (S)-BINOLa
Entry
1b (equiv)
Ti(O-i-Pr)4 (equiv)
Solvent
Temp. (8C)
Conv.b (%)
Eec (%)
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.1
1.2
1.0
1.0
1.0
1.0
1.0
0
0
0
0
0
THF
toluene
hexane
CH2Cl2
THF
THF
THF
THF
THF
0
0
0
0
0
0
0
0
76
63
66
53
60
72
55
24
81
49
48
93 (R)
91 (R)
93 (R)
91 (R)
92 (R)
92 (R)
93 (R)
93 (R)
94 (R)
94 (R)
94 (S)
0
0.2
0.5
0
0
0
9
r.t.
r.t.
r.t.
10d
11e
THF
THF
aBenzaldehyde/(R)-2, (R)-3, or (S)-3 5 0.50/0.050 mmol; solvent, 4 mL.
bConversions of 6a were determined by 1H NMR.
cEe values were determined by HPLC.
d(R)-3, 0.050 mmol.
e(S)-3, 0.050 mmol.
Chirality DOI 10.1002/chir

ASYMMETRIC ALKYLTITANIUM ADDITION REACTION OF ALDEHYDE
935
TABLE 4. Asymmetric (i-Bu)Ti(O-i-Pr)3 or (n-Bu)Ti(O-i-Pr)3 additions to aldehydes catalyzed by the titanium catalyst
of (R)-H8-BINOLa
Entry
1
1
Substrate 4
Time (h)
16
Product 6 or 7
Yieldb (%)
78
Eec(%)
1b
6a
6b
6c
6d
6e
7a
7b
7c
7d
94 (R)
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1c
1c
1c
1c
16
24
20
20
16
24
16
20
78
80
80
76
78
72
80
74
92 (R)
86 (R)
91 (R)
83 (R)
84 (R)
76 (R)
86 (R)
75 (R)
a4/1b or 1c/(R)-25 0.50/0.50/0.050; THF, 4 mL.
bIsolated yields.
cEe values were determined by HPLC.
Chirality DOI 10.1002/chir

936
LI AND GAU
remain excellent from 91 to 93% ee in (R)-configuration.
Increasing the amount of 1b to 1.1 or 1.2 equiv did not
improve the conversions of 6a (entries 5 and 6). Additions of
0.2 or 0.5 equiv of Ti(O-i-Pr)4 to the catalytic reaction mixture
suppressed the reactions with lower conversions of 55 and
24%, although the enantioselectivities remained an excellent
93% ee (entries 7 and 8). When the reaction was conducted
at room temperature, the best enantioselectivity of 94% ee
was obtained for 6a with a good 81% conversion (entry 9).
The i-butyl addition reactions using the simple BINOLate
catalytic system of (R)- or (S)-3 produced corresponding sec-
ondary alcohols of (R)- and (S)-6a in excellent enantioselec-
tivities of 94% ee. However, conversions were low at 49 and
48% over a reaction time of 16 h (entries 10 and 11).
equiv of 1b or 1c, without the addition of Ti(O-i-Pr)4, and in
THF at room temperature (Eq. 5). The results are summar-
ized in Table 4. Additions of i-butyl to aromatic aldehydes
afforded (R)-6a to (R)-6d in good yields and excellent enan-
tioselectivities of 91–94% ee (entries 1–4) except an 86% ee
for the addition reaction of 1-naphthylaldehyde (entry 3).
Similar to the c-hexyl addition reaction, the addition reaction
of i-butyl to (E)-cinnamaldehyde furnished product (R)-6e in
a lower 83% ee (entry 5). For addition reactions of the linear
n-butyl nucleophile, it was found that lower enantioselectiv-
ities of 75–84% ee were obtained for products 7a–7d (entries
6–9).
This study demonstrates features of differences on reac-
tion conditions, reactivities, and enanatioselectivities in terms
of nucleophiles’ steric nature. First, for sterically hindered
secondary alkyl of c-hexyl, addition reactions are slower with
a longer reaction time of 36 h required (Table 2) as com-
Asymmetric i-butyl or n-butyl addition reactions of some
aldehydes were then carried out under optimized conditions
of 10 mol % of the titanium catalytic system of (R)-2, 1.0
TABLE 5. The stereochemistry of organometallic additions to aldehydes catalyzed by titanium catalysts of BINOLs
or BINOL derivatives
Entry
RꢀꢀM
L*
Ee (%)
Re- or Si-addition
Ref.
1
2.
3
PhCHO
PhCHO
PhCHO
ZnEt2
ZnEt2
ZnEt2
ZnEt2
(S)-BINOL
(R)-H4-BINOL
(S)-H8-BINOL
(R)-3-R-BINOL
92 (S)
91 (R)
98 (S)
94 (R)
Si
Re
Si
66
69
71
11
4
Re
5
ZnEt2
(R)-3,30-R2-BINOL
53 (R)
Re
67
6
7
8
9
10
11
12
13
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
n-BuMgBr
n-BuMgCl
Phenylacetylene/ZnMe2
Phenylacetylene/ZnEt2
AlEt3
(S)-BINOL
(R)-3-R-BINOL
(R)-H8-BINOL
(S)-BINOL
92 (S)
93 (R)
92 (S)
90 (R)
81 (R)
96 (S)
92 (S)
96 (R)
Si
Re
Re
Si
Re
Si
32
30
72
73
17
17
34
24
(R)-BINOL
AlEt3
p-tolylLi
AlPh3(THF)
(S)-H8-BINOL
(R)-3-R-H8-BINOL
(R)-H8-BINOL
Re
Re
14
AlPhEt2(THF)
(R)-H8-BINOL
96 (R)
Re
28
15
16
17
PhCHO
PhCHO
PhCHO
(Cy)Ti(O-i-Pr)3
(i-Bu)Ti(O-i-Pr)3
(n-Bu)Ti(O-i-Pr)3
(R)-H8-BINOL
(R)-H8-BINOL
(R)-H8-BINOL
90 (R)
94 (R)
84 (R)
Re
Re
Re
This work
This work
This work
Chirality DOI 10.1002/chir

ASYMMETRIC ALKYLTITANIUM ADDITION REACTION OF ALDEHYDE
937
pared with reaction times of 16–24 h for addition reactions of
the primary alkyl of i-butyl or n-butyl nucleophile (Table 4).
This effect is attributed to the steric hindrance of secondary
c-hexyl nucleophile on active metallic species that retards an
access of the aldehyde substrate. Second, a larger amount of
1.6 equiv (Cy)Ti(O-i-Pr)3 (1a) is required to ensure higher
yields and enantioselectivities for the addition products
(Tables 1 and 2) as compared with 1.0 equiv of 1b or 1b
used for primary alkyl addition reactions (Tables 3 and 4).
Third, additional Ti(O-i-Pr)4 of up to 2.0 equiv is required to
improve both conversion and enantioselectivity of the prod-
uct derived from the addition of the secondary c-hexyl nucle-
ophile. The above phenomenon is a general feature for tita-
nium-catalyzed addition reactions of organozinc, organoalu-
minum, Grignard, or organolithium reagents to organic
carbonyls.5–34 In contrast, addition reactions of primary
alkyls of i-butyl and n-butyl do not require the addition of
Ti(O-i-Pr)4 to the reaction mixture which is a feature
observed for the asymmetric addition reactions of alkyltita-
nium reagents.35,40,41 Fourth, hexane is the best solvent for
c-hexyl addition reactions as compared with THF solvent for
i-butyl or n-butyl addition reactions. THF’s coordinating abil-
ity is unfavorable for the addition of bulkier c-hexyl toward
aldehydes. Fifth, for addition reactions of primaryl alkyls, the
addition reactions of linear n-butyl nucleophile to aldehydes
furnish the addition products in enantioselectivities of ꢁ10%
ee lower than those of corresponding branched i-butyl addi-
tion products.
compounds suggests that the catalytic reactions involve
acitve species with similar structures which are proposed to
be dititanium species I containing one BINOLate ligand and
the nucleophile.11,24,33,36,38
CONCLUSIONS
Three alkyltitanium reagents of RTi(O-i-Pr)3 (R 5 Cy, i-
Bu, and n-Bu) were synthesized in high yields. Asymmetric
RTi(O-i-Pr)3 additions to aldehydes catalyzed by the titanium
complexes of (R)-H8-BINOL were investigated. The titanium
catalyst of H8-BINOL showed better reactivity and enantiose-
lectivity than BINOL’s catalysts. This study demonstrates
that alkyltitanium addition reactions could be conducted
under a mild condition at room temperature, affording sec-
ondary alcohols in good yields and good to excellent enantio-
selectivities of up to 94% ee. For the catalyst of (R)-H8-BINOL
or (R)-BINOL, alkyl nucleophiles added to the aldehydes
from a Re-face to produce the (R)-products, and the catalyst
of (S)-BINOL provided the (S)-product from a Si-face addi-
tion. Substrates’ steric effect was observed, and lower yields
of addition products were obtained for aromatic aldehydes
bearing an ortho-substitutent. For RTi(O-i-Pr)3 reagents, pro-
found steric effects in terms of the bulkiness of R nucleo-
philes were observed. Addition reactions of the secondary c-
hexyl nucleophile required the addition of 2.0 equiv of Ti(O-
i-Pr)4, the higher amount of 1.6 equiv (Cy)Ti(O-i-Pr)3, the
longer reaction time of 36 h, and the reaction conducting in
noncoordinating hexane solvent. On the other hand, addition
reactions of primary alkyl of i-butyl or n-butyl did not require
the addition of Ti(O-i-Pr)4 and were carried out in coordinat-
ing solvent of THF using 1.0 equiv (i-Bu)Ti(O-i-Pr)3 or (n-
Bu)Ti(O-i-Pr)3 over shorter reaction times of 16–24 h. This
study directly supports the argument of that titanium-cata-
lyzed asymmetric additions of organozinc, organoaluminum,
Grignard, or organolithium reagents to organic carbonyls
involve the addition of organotitanium reagents.
This study shows that the stereochemical nature of the
addition products is governed by the steric configuration of
the BINOLate ligands. To illustrate the generality of the ster-
eochemical nature for addition products using different orga-
nometallic reagents, catalytic reactions of titanium complexes
of BINOLs,32,36,66 3-substituted BINOLs,11,30,67,68 3,30-disub-
stituted BINOLs,67,68 H4-BINOLs,69,70 or H8-BINOLs71 were
examined (Eq. 6). The stereochemical nature of products are
summarized in Table 5. For addition reactions of
11,66,67,69,71
ZnEt2
or RMgX,30–33 it is found that regardless of
that the ligands are the simple BINOLs, 3-substituted
BINOLs, 3,30-disubstituted BINOLs, H4-BINOLs, or H8-
BINOLs, the absolute structures of the predominant prod-
ucts are determined by the absolute configurations of the
BINOLate ligands (entries 1–7). For catalysts of (S)-BINOL
and its derivatives, the nucleophile adds to aromatic alde-
hydes predominantly from the Si-face to give the (S)-alcohols
as major products, and the catalysts of (R)-BINOL and its
derivatives produce major R-products from the Re-face addi-
tion of the nucleophile. Similarly, products from the Re-face
17
or the Si-face addition of Zn-phenylacetylide72,73 or AlEt3
reagents have been obtained using the catalysts of (R)- or
(S)-BINOL derivatives (entries 8–11), respectively. The same
phenomena have also been observed for the aryl addition of
p-tolylLi,34 AlPh3(THF),24,27 or AlPhEt2(THF)28 to benzalde-
hyde or 2-methylbenzaldehyde (entries 13–15). This study
shows that addition reactions of RTi(O-i-Pr)3 produced
desired products having the same stereochemistry (entries
15–17). The above observations illustrate that substituents at
3-position or 3,30-positions of the BINOLate ligands do not
affect the stereochemistry of the major products. The same
phenamenon also applies to catalysts of H4-BINOL or H8-
BINOL ligands. In addition, the same stereochemistry for
products derived from addition reactions of organozinc, Gri-
gnard, organolithium, organoaluminum, or organotitanium
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