Enantioselective addition of dialkylzinc to aldehydes catalyzed by (S)- 2-(N,N-disubstituted aminomethyl)indoline

Article abstract of DOI:10.1016/S0957-4166(98)00446-7

Chirai di- or triamines, (S)-2-(N,N-disubstituted aminomethyl)indoline 1a-d, derived from (S)-indoline-2-carboxylic acid were efficient chiral catalysts for the enantioselective addition of dialkylzincs to aldehydes. The best results were obtained by empl

Full text of DOI:10.1016/S0957-4166(98)00446-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4165–4173
Enantioselective addition of dialkylzinc to aldehydes catalyzed by
(S)-2-(N,N-disubstituted aminomethyl)indoline
Masatoshi Asami,∗ Hiroyasu Watanabe, Kiyoshi Honda and Seiichi Inoue
Department of Synthetic Chemistry, Faculty of Engineering, Yokohama National University, Tokiwadai, Hodogaya-ku,
Yokohama 240-8501, Japan
Received 7 October 1998; accepted 30 October 1998
Abstract
Chiral di- or triamines, (S)-2-(N,N-disubstituted aminomethyl)indoline 1a–d, derived from (S)-indoline-2-
carboxylic acid were efficient chiral catalysts for the enantioselective addition of dialkylzincs to aldehydes. The
best results were obtained by employing 15 mol% of (S)-2-(4-methylpiperazin-1-ylmethyl)indoline 1c, and chiral
secondary alcohols were obtained in up to 97% ee. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The catalytic enantioselective alkylation of aldehydes is a potentially important method for preparing
chiral secondary alcohols.1 To date, various types of catalyst such as chiral alcohols, amines, or amino
alcohols, have been developed as chiral auxiliaries for the enantioselective addition of dialkylzinc
to aldehydes.2 Most of the successful results were obtained by using sterically constrained β-amino
alcohols2 and several amino sulfur compounds3 and diols4 were recently reported to show high selecti-
vity. Although chiral amines have also been used as catalysts,5,6 the selectivity has not been high except
for a few cases.5b,c,e
We recently reported that chiral β-diamines derived from (S)-proline catalyze the enantioselective
addition of diethylzinc to aldehydes, but the selectivity of the reaction is not high.6 We anticipated that
higher selectivity would be achieved using a more acidic amine to ensure the bond formation between
the catalyst and dialkylzinc. Thus we synthesized chiral di- or triamines, (S)-2-(N,N-disubstituted
aminomethyl)indoline 1a–d, derived from (S)-indoline-2-carboxylic acid, and examined the reaction.
The amines 1a–d showed high selectivity in the reaction and various secondary alcohols were obtained
in good yields with 59–97% ee (Scheme 1).
∗
Corresponding author. E-mail: asami@syn.synchem.bsk.ynu.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00446-7

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Scheme 1.
2. Results and discussion
Chiral di- or triamines, (S)-2-(N,N-disubstituted aminomethyl)indoline 1a–d, were synthesized as
shown in Scheme 2. (S)-N-(Benzyloxycarbonyl)indoline-2-carboxylic acid 2 was coupled with amines
using dicyclohexylcarbodiimide (DCC) as the condensing reagent in dichloromethane to afford corres-
ponding amides 3a–d, respectively. Catalytic hydrogenation of 3a–d under a hydrogen atmosphere in
the presence of 5% Pd–C in methanol gave N,N-disubstituted (S)-indoline-2-carboxamides 4a–d, which
were then reduced with lithium aluminum hydride to give the chiral amines 1a–d. The reduction of 3a
with lithium alminum hydride afforded (S)-1-methyl-2-(pyrrolidin-1-ylmethyl)indoline 5 (Scheme 2).
Scheme 2.
In the first place, the reaction of diethylzinc and benzaldehyde was examined in the presence of (S)-
2-(pyrrolidin-1-ylmethyl)indoline 1a under a variety of reaction conditions. As shown in Table 1, the
selectivity of the reaction was highly dependent on the amount of catalyst, and (S)-1-phenyl-1-propanol
was obtained with 91% ee in 89% yield, when the reaction was carried out in cyclohexane–hexane at
rt for 15 h using 15 mol% of 1a (Table 1, entries 1–8). The selectivity was further improved by using
(S)-2-(morpholinomethyl)indoline 1b or (S)-2-(4-methylpiperazin-1-ylmethyl)indoline 1c in lieu of 1a
(Table 1, entries 9, 10), and the highest selectivity was achieved by conducting the reaction at 0°C using
1c (Table 1, entry 12).
The reaction of diethylzinc and various aldehydes was then examined. In the presence of 15 mol%
of 1c, aromatic aldehydes were enantioselectively ethylated at 0°C for 15 h to afford the corresponding
alcohols in relatively high ees (Table 2, entries 1–4). Although in the cases of cinnamaldehyde and
sterically less hindered aliphatic aldehydes the selectivity was moderate (Table 2, entries 5–7), the best
results were obtained by the reaction of cyclohexanecarbaldehyde to yield (S)-1-cyclohexyl-1-propanol
in 97% ee (Table 2, entry 8). The reaction of dimethyl- and diisopropylzinc with benzaldehyde was also
examined. The reaction became slow and the yield of the corresponding alcohols was 34% (Me2Zn) or

M. Asami et al. / Tetrahedron: Asymmetry 9 (1998) 4165–4173
4167
Table 1
Enantioselective addition of diethylzinc to benzaldehydes in the presence of 1a
0% (i-Pr2Zn) at 0°C, even after 63 h, respectively. However, the corresponding S-alcohols were obtained
in good yields and high ees by conducting the reaction at rt for 15 h (Table 2, entries 9, 10).
In the enantioselective addition of dialkylzinc species to aldehydes catalyzed by chiral amino alcohols,
diols, and amino sulfur compounds, the zinc–oxygen or zinc–sulfur bond formed by the reaction of the
dialkylzinc and catalyst was considered to be important for realizing high selectivity.2a,3a,d,e,4b With
regard to amine catalysts, moderate selectivity was achieved by the coordination of an aprotic ligand,

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(S)-N,N,N0,N0-tetramethyl-2,2-diamino-1,1-binaphthyl.5a However, zinc–nitrogen bond formation was
essential to achieve high selectivity when 2-[(2S)-2-pyrrolidinyl]pyridine was employed as the catalyst.5c
We thus carried out a 1H NMR study of a 1:1 mixture of 1a and diethylzinc in toluene-d8. The 1H NMR
signal (δ=0.48 ppm, q, J=8.3 Hz) relating to the methylene group attached to zinc integrated to two
protons after 5 min at room temperature after solution preparation. This indicated that a zinc–nitrogen
bond was formed rapidly at room temperature by the protonolysis of a zinc–carbon bond by the
free secondary amine in 1a. We next carried out the reaction of benzaldehyde and diethylzinc in
the presence of an aprotic diamine, (S)-1-methyl-2-(1-pyrrolidin-1-ylmethyl)indoline 5, under similar
reaction conditions. (S)-1-Phenyl-1-propanol was obtained in high yield (94%), but the ee of the alcohol
was very low (7%). The lithium salt of 1c was also examined, since some amine catalysts were reported to
give better selectivity when they were used as the corresponding lithium salts.5b,e However, the selectivity
was not improved. Thus it appears that the Zn–N sigma bond played an important role in order to realize
high selectivity in the reaction using 1 as the catalyst (Scheme 3).
Scheme 3.
We postulate a similar stereochemical course of the reaction to the one proposed previously for (S)-2-
(N,N-disubstituted aminomethyl)pyrrolidine. Thus, a cis-fused 5-membered bicyclic complex is initially
formed by the reaction of 1 and the dialkylzinc.6 Another dialkylzinc molecule is chelated with the
nitrogen atom on the indoline ring to form the dinuclear zinc complex. The carbonyl oxygen of the
aldehyde approaches the more Lewis acidic diamine-chelated ZnA in such a manner as to prevent a non-
bonding repulsion between R1 in the aldehyde and a terminal alkyl group (R2) attached to ZnB. The
bridging alkyl group (R2) attached to ZnA then migrates to the aldehyde. The significant improvement of
the selectivity compared with (S)-2-(N,N-disubstituted aminomethyl)pyrrolidine would be attributed to a
more definite formation of the complex depicted in Fig. 1 as a result of the higher acidity of the aromatic
amine.
Figure 1.
In summary, new chiral di- and triamines 1 derived from (S)-indoline-2-carboxylic acid were found
to promote the enantioselective alkylation of aldehydes efficiently to afford the corresponding secondary
alcohols in up to 97% ee.

M. Asami et al. / Tetrahedron: Asymmetry 9 (1998) 4165–4173
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Table 2
Enantioselective addition of diethylzinc to aldehydes catalyzed by 1ca7,8
3. Experimental section
3.1. General
Melting points were obtained on a Büchi 535 apparatus and are uncorrected. Infrared spectra were
1
recorded on a Hitachi 260-10 spectrometer or Perkin–Elmer Paragon 1000. H and 13C NMR spectra

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M. Asami et al. / Tetrahedron: Asymmetry 9 (1998) 4165–4173
were measured with a JEOL JNM-EX-270 spectrometer, using tetramethylsilane as the internal standard.
CDCl3 was used as the solvent. Mass spectra (MS) were determined on a JEOL JMS SX102QQ mass
spectrometer. Specific rotations were measured on a Horiba SEPA-200 polarimeter in the indicated
solvent. GC analyses were carried out with Shimadzu GC-14A. HPLC analyses were carried out with
Tosoh instruments (pump, CCPS; detector, UV-8020).
3.2. (S)-N-(Benzyloxycarbonyl)indoline-2-carboxylic acid 2
To (S)-indoline-2-carboxylic acid (32.64 g, 0.2 mol) in water (280 ml) was slowly added benzyloxy-
carbonyl chloride (18.77 g, 0.11 mol) in toluene (60 ml) at 0°C. After addition of sodium hydrogen
carbonate (40.0 g, 0.4 mol) the mixture was stirred at room temperature for 2 h and benzyloxycarbonyl
chloride (18.77 g, 0.11 mol) in toluene (60 ml) was again added to the mixture at 0°C and the mixture was
stirred overnight at room temperature. The aqueous layer was washed several times with ether, acidified
with 6 N HCl, and extracted with ethyl acetate. The organic layer was washed with water and brine, and
dried over anhydous sodium sulfate. The solvent was removed under reduced pressure and the residue
was recrystallized from toluene to give (S)-N-benzyloxycarbonylindoline-2-carboxylic acid (57.25 g,
96%) (mp 116.2–117.0°C). [α]D −67.4 (c 1.00, CHCl3); IR (KBr) ν: 1714 cm−1; 1H NMR (CDCl3)
25
δ: 3.19 (dd, J=3.8, 16.5 Hz, 1H, 1×H-3), 3.54 (dd, J=11.7, 16.5 Hz, 1H, 1×H-3), 4.85–5.45 (m, 3H,
H-2, CH2Ph), 6.98 (dd, J=7.3, 7.6 Hz, 1H, H-5), 7.12 (d, J=7.3 Hz, 1H, H-4), 6.90–8.05 (m, 7H, H-6,
H-7, C6H5), 10.39 (s, 1H, COOH). Found: C, 68.74; H, 5.09; N, 4.71%. Calcd for C17H15NO4: C, 68.68;
H, 5.09; N, 4.71%.
3.3. Preparation of N,N-disubstituted (S)-Nα-(benzyloxycarbonyl)indoline-2-carboxamide 3a–d
To a dichloromethane solution (100 ml) of (S)-N-benzyloxycarbonylindoline-2-carboxylic acid 2
(14.87 g, 50 mmol) was added a dichloromethane solution (50 ml) of N,N0-dicyclohexylcarbodiimide
(10.32 g, 50 mmol) at 0°C under an argon atmosphere. After stirring for 30 min, a dichloromethane
solution (30 ml) of amine (50 mmol) was slowly added to the reaction mixture at 0°C. The reaction
temperature was then gradually warmed to room temperature and stirring was continued overnight. After
removal of the precipitate, the filtrate was washed successively with 2% HCl, 4% sodium hydrogencar-
bonate, water, and brine. The organic layer was dried over anhydous sodium sulfate and the solvent was
removed under reduced pressure. The crude product was recrystallized from ethyl acetate to give the
N,N-disubstituted Nα-(benzyloxycarbonyl)indoline-2-carboxamide 3.
3.3.1. (S)-1-[N-(Benzyloxycarbonyl)indoline-2-carbonyl]pyrrolidine 3a
Yield: 66%; mp 131.3–131.9°C; [α]D −32.4 (c 1.00, CHCl3); IR (KBr) ν: 1711, 1649 cm−1; H
NMR (CDCl3) δ: 1.50–2.14 (m, 4H, 2×H-30, 2×H-40), 3.07 (dd, J=4.8, 16.0 Hz, 1H, 1×H-3), 3.15–3.90
(m, 4H, 2×H-20, 2×H-50), 3.48 (dd, J=11.0, 16.0 Hz, 1H, 1×H-3), 4.90–5.45 (m, 3H, H-2, CH2Ph), 6.95
(dd, J=6.6, 7.3 Hz, 1H, H-5), 7.10 (d, J=7.3 Hz, 1H, H-4), 7.00–8.05 (m, 7H, H-6, H-7, C6H5). Found:
C, 71.99; H, 6.30; N, 7.96%. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99%.
20
1
3.3.2. (S)-4-[N-(Benzyloxycarbonyl)indoline-2-carbonyl]morpholine 3b
Yield: 62%; mp 183.0–183.6°C; [α]D −61.7 (c 1.02, CHCl3); IR (KBr) ν: 1712, 1666 cm−1; H
NMR (CDCl3) δ: 3.00 (dd, J=4.1, 16.2 Hz, 1H, 1×H-3), 3.49 (dd, J=11.2, 16.2 Hz, 1H, 1×H-3),
3.25–3.90 (m, 8H, 2×H-20, 2×H-30, 2×H-50, 2×H-60), 5.05–5.50 (m, 3H, H-2, CH2Ph), 6.96 (dd, J=6.6,
20
1

M. Asami et al. / Tetrahedron: Asymmetry 9 (1998) 4165–4173
4171
7.3 Hz, 1H, H-5), 7.10 (d, J=7.3 Hz, 1H, H-4), 7.00–8.05 (m, 7H, H-6, H-7, C6H5). Found: C, 68.87; H,
5.99; N, 7.62%. Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65%.
3.3.3. (S)-4-Methyl-1-[N-(benzyloxycarbonyl)indoline-2-carbonyl]piperazine 3c
Yield: 61%; mp 163.6–164.4°C; [α]D −66.5 (c 1.00, CHCl3); IR (KBr) ν: 1702, 1656 cm−1; H
NMR (CDCl3) δ: 2.24 (s, 3H, NCH3), 1.95–2.65 (m, 4H, 2×H-30, 2×H-50), 2.98 (dd, J=4.0, 16.2 Hz,
1H, 1×H-3), 3.49 (dd, J=11.4, 16.2 Hz, 1H, 1×H-3), 3.30–3.80 (m, 4H, 2×H-20, 2×H-60), 5.05–5.50 (m,
3H, H-2, CH2Ph), 6.80–8.10 (m, 9H, H-4, H-5, H-6, H-7, C6H5). Found: C, 69.73; H, 6.70; N, 11.04%.
Calcd for C22H25N3O3: C, 69.64; H, 6.64; N, 11.07%.
20
1
3.3.4. (S)-4-Benzyl-1-[N-(benzyloxycarbonyl)indoline-2-carbonyl]piperazine 3d
Yield: 82%; mp 172.6–173.6°C; [α]D −63.2 (c 1.02, CHCl3); IR (KBr) ν: 1708, 1660 cm−1; H
NMR (CDCl3) δ: 2.10–2.70 (m, 4H, 2×H-30, 2×H-50), 2.98 (dd, J=4.1, 16.0 Hz, 1H, 1×H-3), 3.45 (s,
2H, NCH2Ph), 3.20–3.80 (m, 5H, 1×H-3, 2×H-20, 2×H-60), 5.05–5.50 (m, 3H, H-2, OCH2Ph), 6.94 (dd,
J=6.9, 7.3 Hz, 1H, H-5), 7.09 (d, J=7.3 Hz, 1H, H-4), 7.00–8.05 (m, 12H, H-6, H-7, 2×C6H5). Found:
C, 73.95; H, 6.44; N, 9.20%. Calcd for C28H29N3O3: C, 73.82; H, 6.42; N, 9.22%.
20
1
3.4. Preparation of (S)-2-(N,N-disubstituted aminomethyl)indoline 1a–d
N,N-Disubstituted Nα-(benzyloxycarbonyl)indoline-2-carboxamide 3 (30 mmol) and 5% Pd–C
catalyst (0.75 g) were stirred vigorously in methanol (60 ml) under a hydrogen atmosphere overnight.
The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give crude
N,N-disubstituted (S)-indoline-2-carboxamide 4. Crude 4 in THF (75 ml) was slowly added to a THF
(60 ml) suspension of lithium aluminum hydride (3.42 g, 90 mmol) at 0°C, under an argon atmosphere,
and the reaction mixture was refluxed for 15 h. Saturated sodium sulfate solution was added to the
reaction mixture. After removal of the inorganic material, the organic layer was concentrated in vacuo.
Fractional distillation, bulb-to-bulb distillation, or column chromatography of the resulting material
afforded (S)-2-(N,N-disubstituted aminomethyl)indoline 1.
3.4.1. (S)-2-(Pyrrolidin-1-ylmethyl)indoline 1a
20
Yield: 83%; bp 103–106°C/0.18 mmHg; [α]D +133.2 (c 1.00, CHCl3); IR (neat) ν: 3350 cm−1; 1H
NMR (CDCl3) δ: 1.65–1.90 (m, 4H, 2×H-30, 2×H-40), 2.25 (dd, J=4.0, 11.9 Hz, 1H, 1×C2-CH2N),
2.35–2.80 (m, 6H, 2×H-20, 2×H-50, 1×H-3, 1×C2–CH2N), 3.15 (dd, J=9.1, 15.7 Hz, 1H, 1×H-3),
3.85–4.05 (m, 1H, H-2), 4.45 (s, 1H, NH), 6.63 (d, J=7.6 Hz, 1H, H-7), 6.69 (dd, J=7.3, 7.6 Hz, 1H, H-
5), 7.01 (t, J=7.6 Hz, 1H, H-6), 7.07(d, J=7.3 Hz, 1H, H-4). Found: m/z 202.1449. Calcd for C13H18N2:
M, 202.1470.
3.4.2. (S)-2-(Morpholinomethyl)indoline 1b
Yield: 87%; bp 165°C (bath temperature)/0.3 mmHg (bulb-to-bulb distillation); [α]D20 +138.8 (c 1.10,
1
CHCl3); IR (neat) ν: 3352 cm−1; H NMR (CDCl3) δ: 2.26 (dd, J=3.8, 12.0 Hz, 1H, 1×C2–CH2N),
2.30–2.70 (m, 4H, 2×H-30, 2×H-50), 2.47 (dd, J=10.4, 12.0 Hz, 1H, 1×C2–CH2N), 2.66 (dd, J=5.0, 15.8
Hz, 1H, 1×H-3), 3.15 (dd, J=9.1, 15.8 Hz, 1H, 1×H-3), 3.53–3.80 (m, 4H, 2×H-20, 2×H-60), 3.90–4.05
(m, 1H, H-2), 4.44 (s, 1H, NH), 6.66 (d, J=7.6 Hz, 1H, H-7), 6.70 (dd, J=7.3, 7.6 Hz, 1H, H-5), 7.02 (t,
J=7.6 Hz, 1H, H-6), 7.08 (d, J=7.3 Hz, 1H, H-4). Found: m/z 219.1515. Calcd for C13H19N2O: M+H,
219.1498.

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3.4.3. (S)-2-(4-Methylpiperazin-1-ylmethyl)indoline 1c
Yield: 95%; bp 122–123°C/0.2 mmHg; [α]D20+138.6 (c 1.00, CHCl3); IR (neat) ν: 3353 cm−1; H
NMR (CDCl3) δ: 2.15–2.80 (m, 9H, 2×H-20, 2×H-30, 2×H-50, 2×H-60, 1×C2–CH2N,), 2.29 (s, 3H,
NCH3), 2.49 (dd, J=10.2, 12.2 Hz, 1H, 1×C2–CH2N), 2.64 (dd, J=4.8, 15.7 Hz, 1H, 1×H-3), 3.14 (dd,
J=9.1, 15.7 Hz, 1H, 1×H-3), 3.90–4.05 (m, 1H, H-2), 4.46 (s, 1H, NH), 6.64 (d, J=7.6 Hz, 1H, H-7),
6.69 (dd, J=7.3, 7.6 Hz, 1H, H-5), 7.01 (t, J=7.6 Hz, 1H, H-6), 7.07 (d, J=7.3 Hz, 1H, H-4). Found: m/z
231.1750. Calcd for C14H21N3: M, 231.1735.
1
3.4.4. (S)-2-(4-Benzylpiperazin-1-ylmethyl)indoline 1d
Yield: 68%; mp 59.3–59.8°C (column chromatography); [α]D20 +138.8 (c 1.00, CHCl3); IR (KBr) ν:
3348 cm−1; 1H NMR (CDCl3) δ: 2.22 (dd, J=4.0, 12.2 Hz, 1H, 1×C2–CH2N), 2.28–2.75 (m, 8H, 2×H-
20, 2×H-30, 2×H-50, 2×H-60), 2.47 (dd, J=10.4, 12.2 Hz, 1H, 1×C2–CH2N), 2.63 (dd, J=4.8, 15.7 Hz,
1H, 1×H-3), 3.13 (dd, J=9.1, 15.7 Hz, 1H, 1×H-3), 3.51 (s, 2H, CH2Ph), 3.87–4.02 (m, 1H, H-2), 4.45
(s, 1H, NH), 6.63 (d, J=7.6 Hz, 1H, H-7), 6.69 (dd, J=7.3, 7.6 Hz, 1H, H-5), 7.01 (t, J=7.6 Hz, 1H, H-6),
7.06 (d, J=7.3 Hz, 1H, H-4), 7.20–7.38 (m, 5H, C6H5). Found: m/z 307.2048. Calcd for C20H25N3: M,
307.2048.
3.5. (S)-1-Methyl-2-(pyrrolidin-1-ylmethyl)indoline 5
(S)-1-[N-(Benzyloxycarbonyl)indoline-2-carbonyl]pyrrolidine 3a (1.00 g, 2.8 mmol) in THF (10 ml)
was slowly added to a THF (5 ml) suspension of lithium aluminum hydride (0.26 g, 6.8 mmol) at 0°C
under an argon atmosphere. The reaction mixture was refluxed for 15 h, and saturated sodium sulfate
solution was added to the reaction mixture. After removal of the inorganic material, the organic layer
was concentrated in vacuo. The crude product was purified by column chromatography followed by
bulb-to-bulb distillation to afford (S)-1-methyl-2-(pyrrolidin-1-ylmethyl)indoline 5 (0.45 g, 78%); bp
20
140°C (bath temperature)/0.3 mmHg (bulb-to-bulb distillation); [α]D −80.0 (c 1.18, CHCl3); IR (neat)
ν: 2795, cm−1; 1H NMR (CDCl3) δ: 1.70–1.90 (m, 4H, 2×H-30, 2×H-40), 2.48–2.66 (m, 6H, 2×H-20,
2×H-50, 1×C2–CH2N, 1×H-3), 2.80 (s, 3H, NCH3), 2.89 (dd, J=4.5, 12.1 Hz, 1H, 1×C2–CH2N), 3.24
(dd, J=8.8, 15.7 Hz, 1H, 1×H-3), 3.42–3.55 (m, 1H, H-2), 6.46 (d, J=7.9 Hz, 1H, H-7), 6.65 (dt, J=1.0,
7.4 Hz, 1H, H-5), 6.99–7.11 (m, 2H, H-6, H-4). Found: m/z 217.1722. Calcd for C14H21N2: M, 217.1705.
3.6. The enantioselective addition of diethylzinc to aldehydes catalyzed by 1: typical procedure (Table 1,
entry 3)
To a cyclohexane (6.0 ml) solution of benzaldehyde (159.2 mg, 1.5 mmol) and 1a (45.5 mg, 0.225
mmol) was added a hexane (2.7 ml) solution of diethylzinc (2.7 mmol) at 0°C, and the reaction mixture
was stirred at rt for 15 h. Saturated ammonium chloride solution (3 ml) and 2 N HCl (3 ml) were added to
the reaction mixture, and the mixture was extracted with ether. The combined organic layers were washed
with water and brine, and dried over anhydous sodium sulfate. The solvent was removed under reduced
pressure and the resulting oily substance was purified by preparative TLC (silica gel, hexane:ether=2:1) to
give 1-phenyl-1-propanol (181.2 mg, 89%). The alcohol was further purified by bulb-to-bulb distillation
20
for the measurement of the specific rotation ([α]D −44.1 (c 1.00, CHCl3)). The ee was determined
by HPLC analysis using a chiral column (Daicel Chiralcel OD-H (25 cm×0.46 cm i.d.); eluent, 5%
2-propanol in hexane; flow rate, 0.5 ml/min; tR, 14.9 min for minor peak, 16.5 min for major peak).

M. Asami et al. / Tetrahedron: Asymmetry 9 (1998) 4165–4173
4173
3.7. The enantioselective addition of diethylzinc to benzaldehyde catalyzed by the lithium salt of 1c
To a cyclohexane (1.5 ml) solution of 1c (52.1 mg, 0.225 mmol) was added a hexane solution (0.14
ml) of butyllithium (0.225 mmol) at 0°C and the reaction mixture was stirred at 0°C for 30 min. A
cyclohexane (4.5 ml) solution of benzaldehyde (159.2 mg, 1.5 mmol) and a hexane (2.7 ml) solution of
diethylzinc (2.7 mmol) were added to the reaction mixture successively at 0°C. The reaction mixture was
stirred at 0°C for 15 h and worked up in the same manner as described above to give 1-phenyl-1-propanol
(143.5 mg, 70%). The ee was determined by HPLC analysis using a Daicel Chiralcel OD-H column to
be 88% ee.
3.8. The enantioselective addition of diethylzinc to benzaldehydes catalyzed by 5
To a cyclohexane (6.0 ml) solution of benzaldehyde (159.2 mg, 1.5 mmol) and 5 (48.6 mg, 0.225
mmol) was added a hexane (2.7 ml) solution of diethylzinc (2.7 mmol) at 0°C. The reaction mixture was
stirred at rt for 15 h and worked up in the same manner as described earlier, to give 1-phenyl-1-propanol
(192.7 mg, 94%). The ee was determined by HPLC analysis using a Daicel Chiralcel OD-H column to
be 7% ee.
Acknowledgements
One of the authors (M. A.) gratefully acknowledges General Sekiyu Research and Development
Encouragement and Assistance Foundation for financial support. We thank Dr Hiroko Suezawa for NMR
measurements and Mr Takeo Kaneko for mass spectra measurements.
References
1. Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley: New York; 1994, Chapter 5.
2. For reviews: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49–69. (b) Soai, K; Niwa, S. Chem.
Rev. 1992, 92, 833–856. For recent examples: (c) Prasad, K. R. K.; Joshi, N. N.; J. Org. Chem. 1997, 62, 3770–3771.
(d) Nakano, H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.; Hongo, H. Tetrahedron: Asymmetry 1997, 8, 1391–1401. (e)
Beliczey, J.; Giffels, G.; Kragl, U.; Wandrey, C. Tetrahedron: Asymmetry 1997, 8, 1529–1530. (f) Solà, L.; Vidal-Ferran,
A.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron: Asymmetry 1997, 8, 1559–1568. (g) Wilken, J.; Kossenjans, M.;
Gröger, H.; Martens, J. Tetrahedron: Asymmetry 1997, 8, 2007–2015. (h) Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry
1998, 9, 1489–1492.
3. (a) Hof, R. P.; Poelert, M. A.; Peper, N. C. M. W.; Kellogg, R. M. Tetrahedron: Asymmetry 1994, 5, 31–34. (b) Kang, J.;
Lee, J. W.; Kim, J. I. J. Chem. Soc., Chem. Commun. 1994, 2009–2010. (c) Kang, J.; Kim, D. S.; Kim, J. I. Synlett. 1994,
842–844. (d) Fitzpatrick, K.; Hulst, R.; Kellogg, R. M.; Tetrahedron: Asymmetry 1995, 6, 1861–1864. (e) Gibson, C. L.
Chem. Commun. 1996, 645–646. (f) Aurich, H. G.; Soeberdt, M. Tetrahedron Lett. 1998, 39, 2553–2554.
4. (a) Prasad, K. R. K.; Joshi, N. N. Tetrahedron: Asymmetry 1996, 7, 1957–1960. (b) Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki,
T. Bull. Chem. Soc. Jpn 1997, 70, 207–217.
5. (a) Rosini, C.; Franzini, A.; Iuliano, A.; Pini, D.; Salvadori, P. Tetrahedron: Asymmetry 1991, 2, 363–366. (b) Niwa,
S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1991, 2717–2720. (c) Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli,
G.; Tetrahedron 1991, 47, 8251–8258. (d) Pini, D.; Mastantuono, A.; Uccello-Barretta, G.; Iuliano, A.; Salvadori, P.
Tetrahedron 1993, 49, 9613–9624. (d) Dai, W.-H.; Zhu, H. J.; Hao, X.-J. Tetrahedron: Asymmetry 1996, 7, 1245–1248. (e)
Eilers, J.; Wilken, J.; Martens, J. Tetrahedron: Asymmetry 1996, 7, 2343–2350.
6. Asami, M.; Inoue, S. Bull. Chem. Soc. Jpn. 1997, 70, 1687–1690.
7. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071–6072.
8. Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber. 1992, 125, 1191–1203.