Catalytic asymmetric borane reduction of prochiral ketones by the use of diazaborolidine catalysts prepared from chiral β-diamines

Article abstract of DOI:10.1016/S0957-4166(00)00414-6

The catalytic asymmetric borane reduction of prochiral ketones was examined in the presence of chiral diazaborolidine catalysts prepared in situ from chiral β-diamines and borane. Chiral secondary alcohols were obtained with modest to high enantiomeric excesses (up to 92% ee) using (S)-2-[(4-trifluoromethyl)anilinomethyl]indoline 2f. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00414-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4329–4340
Catalytic asymmetric borane reduction of prochiral ketones
by the use of diazaborolidine catalysts prepared from chiral
b-diamines
Shinsuke Sato, Hiroyasu Watanabe and Masatoshi Asami*
Department of Chemistry and Biotechnology, Faculty of Engineering, Yokohama National University, Tokiwadai,
Hodogaya-ku, Yokohama 240-8501, Japan
Received 12 September 2000; accepted 10 October 2000
Abstract
The catalytic asymmetric borane reduction of prochiral ketones was examined in the presence of chiral
diazaborolidine catalysts prepared in situ from chiral b-diamines and borane. Chiral secondary alcohols
were obtained with modest to high enantiomeric excesses (up to 92% ee) using (S)-2-[(4-tri-
fluoromethyl)anilinomethyl]indoline 2f. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
An asymmetric synthesis of enantiomerically enriched secondary alcohols has been extensively
studied as chiral secondary alcohols are important synthetic intermediates for various other
functionalities such as halide, amine, ester, and ether, and involved in many naturally occurring
compounds. A catalytic enantioselective borane reduction of prochiral ketones using oxazaborol-
idine catalysts prepared by the reaction of borane or boronic acid and chiral amino alcohols is
one of the most useful methods for the preparation of chiral secondary alcohols,1 and a
considerable number of studies have been reported over the decade after the original studies of
Itsuno et al.2 and Corey et al.3 Other chiral borane catalysts prepared from chiral sulfoximines,4
phosphinamides,5 or a mercapto alcohol6 were also reported to be effective for the reaction.
We have been working on asymmetric synthesis using chiral b-diamines prepared from
(S)-proline7 or (S)-indoline-2-carboxylic acid8 and reported highly stereoselective asymmetric
reactions using them. We then examined the effectiveness of chiral b-diamines for the modifica-
tion of borane and reported that (S)-2-[(4-trifluoromethyl)anilinomethyl]indoline 2f showed
relatively high selectivity in asymmetric reduction of prochiral ketones.9 Here we describe the
results in detail.
* Corresponding author. E-mail: m-asami@ynu.ac.jp
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00414-6

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2. Results and discussion
Chiral b-diamines, (S)-2-(N-substituted aminomethyl)indoline 2a–h, were prepared as shown
in Scheme 1 starting from commercially available homochiral amino acid, (S)-indoline-2-car-
boxylic acid. After protection of the amino group with the tert-butoxycarbonyl group, (S)-N-
(tert-butoxycarbonyl)indoline-2-carboxylic acid 3 was coupled with amines via mixed acid
anhydride to afford corresponding amides 4a–h. Homochiral b-diamines 2a–h were obtained by
removal of the tert-butoxycarbonyl group in 4a–h by trifluoroacetic acid in dichloromethane,
followed by reduction of N-substituted (S)-indoline-2-carboxamide 5a–h with lithium aluminum
hydride or borane–THF complex.
Scheme 1.
In the first place, an enantioselective reduction of acetophenone was carried out using
(S)-2-(anilinomethyl)pyrrolidine 1, which was effective for the modification of lithium aluminum
hydride in our previous work.7a A THF solution of acetophenone was added dropwise to the
mixture of 0.60 equiv. of borane–THF complex in THF in the presence of 0.10 equiv. of 1 over
1 h period at room temperature, and stirring was continued for 16 h at the temperature.
(R)-1-Phenylethanol was obtained in 93% yield with 14% ee (R) (Table 1, entry 1). The
enantioselectivity was dramatically increased to 83% (R) when (S)-2-(anilinomethyl)indoline 2a
was used (Table 1, entry 2). However, (S)-2-(cyclohexylaminomethyl)indoline 2b showed low
selectivity (9% ee (R)) (Table 1, entry 3). Therefore, it turned out that aromatic rings on both
nitrogen atoms of b-diamine 2 are necessary to achieve high selectivity. Next, the effect of the
substituent on the aromatic ring of the side chain of 2a upon the selectivity was examined using
b-diamines 2c–h derived from (S)-indoline-2-carboxylic acid and substituted anilines. In the first
place, a steric effect was examined using sterically hindered b-diamine 2c or 2d. The enantiose-
lectivity was decreased to 50 and 27% ee, respectively (Table 1, entries 4 and 5). Next,
b-diamines 2e–h were examined to evaluate electronic effects. The electron-withdrawing tri-
fluoromethyl group was effective in increasing the selectivity, while the electron-donating
methoxy group substantially decreased the selectivity (Table 1, entries 6–8). Another electron-
withdrawing group, nitro, did not improve the selectivity (Table 1, entry 9).

S. Sato et al. / Tetrahedron: Asymmetry 11 (2000) 4329–4340
4331
Table 1
Asymmetric reduction of acetophenone using chiral b-diamine
Next, the reaction was carried out under several reaction conditions to improve the selectivity
using 0.1 equiv. of 2f. The selectivity was improved when the reaction was conducted at a lower
temperature (0°C), but the yield was decreased slightly (Table 2, entry 2). High selectivity and
good yield were achieved by adding a THF solution of acetophenone during 2 h to a THF
solution of 2f and 1.0 equiv. of borane–THF complex (Table 2, entries 3 and 4). The selectivity
was further improved to 92% ee by using 0.15 equiv. of 2f at −15°C (Table 2, entry 6).
Then, the reaction was applied to other prochiral ketones to examine the generality of the new
catalyst 2f. The results, obtained under the optimized reaction conditions (Table 2, entry 6) are
summarized in Table 3. High enantioselectivities were achieved for aromatic ketones (Table 3,
entries 1–7) and modest selectivity was obtained in the cases of aliphatic ketones or a,b-unsatu-
rated ketones (Table 3, entries 8 and 9).

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Table 2
Examinations of reaction conditions
Entry
Temp. (°C)
2f (equiv.)
BH3–THF (equiv.)
Time (h)
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
Rt
0
0
0.10
0.10
0.10
0.10
0.10
0.15
0.10
0.60
0.60
0.60
1.0
1.0
1.0
1c
1c
2d
2d
2d
2d
2d
88
77
82
87
86
88
85
87
89
90
90
91
92
35
0
−15
−15
−30
1.0
a Isolated yield.
b Determined by HPLC.
c Acetophenone was added to a THF solution of borane and 2f during 1 h and then the reaction mixture was stirred
for 1 h.
d Acetophenone was added to a THF solution of borane and 2f during 2 h and then the reaction mixture was
stirred for 2 h.
It is known that an oxazaborolidine, derived from chiral amino alcohol and borane, plays a
crucial role as a chiral Lewis acid catalyst1b in the asymmetric borane reduction using a catalytic
amount of chiral amino alcohol. In the present reaction, we anticipated that diazaborolidine 6
would also be formed in situ by the reaction of a b-diamine and borane and acts as a chiral
Lewis acid catalyst. To confirm the formation of diazaborolidine 6, a 11B NMR study was
carried out using b-diamine 1, 2a, 2b and 2f. To a THF solution of the b-diamine was added a
THF solution of borane–THF complex (6 equiv.) and the solution was stirred for 30 min at 0°C.
Then the solvent and excess borane were removed under reduced pressure. In the case of
b-diamine 2a or 2f, a 11B NMR spectrum of the resulting residue in benzene-d6 showed the
broad peak at +26 or +24 ppm from BF3·OEt2 (external standard), respectively. The signal could
be assigned to 6 based on the 11B NMR spectrum of diazaborolidine in the literature.11 On the
other hand, the corresponding peak was not observed in the region in the case of 1 or 2b.
Therefore, the aromatic rings on both nitrogen atoms of b-diamine 2 were necessary to form the
effective diazaborolidine catalyst 6 by the reaction of 2 and BH3 at 0°C. The stereochemical
cause of the reduction by 6 was rationalized on the basis of the configurations of the resulting
alcohols as follows. Namely, after the coordination of BH3 to the nitrogen atom of the indoline
ring of catalyst 6, ketone approaches the catalyst 6–borane complex in a manner depicted in
Scheme 2. The catalytic activity of diazaborolidine 6 was increased and noncatalytic borane
reduction was diminished by introducing trifluoromethyl group (electron-withdrawing group) on
the aromatic ring to afford the alcohol in higher ee (Table 1, entries 7 and 8). The catalytic

S. Sato et al. / Tetrahedron: Asymmetry 11 (2000) 4329–4340
4333
Table 3
Asymmetric reduction of prochiral ketones using 2f
Entry
Ketone
Yield (%)a
Ee (%)b
[h]2D0
Config.b
1
2
3
4
5
6
7
8
9
Acetophenone
2%-Bromoacetophenone
Phenacyl chloride
1%-Acetonaphthone
Propiophenone
1-Tetralone
1-Indanone
2-Octanone
Benzalacetone
88
96
94
94
92
92
90
93c
80
92
91
91
88
82
81
80
61d
59
+52.5 (c 1.00, CHCl3)
+49.1 (c 0.99, CHCl3)
+48.1 (c 1.00, cyclohexane)
+67.8 (c 1.00, MeOH)
+39.4 (c 0.99, CHCl3)
−27.0 (c 1.00, CHCl3)
−23.4 (c 0.99, CHCl3)
−6.3 (c 1.01, EtOH)
R
R
S
R
R
R
R
R
R
+18.3 (c 1.07, CHCl3)
a Isolated yield.
b Ee was determined by HPLC analysis and the absolute configuration was determined by specific rotation7a,10
unless otherwise noted.
c Isolated as benzoate.
d Determined by HPLC of p-nitrobenzoate.
activity of 6 was decreased by introducing a methoxy group (electron-donating group) on the
aromatic ring (Table 1, entry 6) or by the steric hindrance around the boron atom of 6 (Table
1, entries 4 and 5) to give a substantial amount of racemic alcohol via noncatalytic reaction.
Scheme 2.

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3. Conclusion
In summary, we have studied catalytic asymmetric borane reductions of prochiral ketones
using chiral b-diamines. It was found that diazaborolidines were generated in situ from chiral
b-diamine and borane, which catalyzed the reaction effectively, and chiral secondary alcohols
were obtained with good to high ee’s. Furthermore, this study has shown that the reactivity and
the selectivity of the reaction were affected significantly by steric and electronic effects of the
substituent of the catalyst.
4. Experimental
4.1. General
Most manipulations were carried out under an atmosphere of argon. Solvents were dried and
purified in the usual manner.
Melting points were obtained on a Bu¨chi 535 apparatus and are uncorrected. Infrared spectra
1
were recorded on a Perkin–Elmer Paragon 1000. H and 11B NMR spectra were measured with
1
a Jeol JNM-EX-270 spectrometer, using tetramethylsilane as the internal standard for H and
trifluoroborane-etherate as the external standard for 11B. Mass spectra (MS) were obtained on
a Jeol JMS SX102QQ mass spectrometer. Specific rotations were measured on a Horiba
SEPA-200 polarimeter in the indicated solvent. HPLC analyses were carried out with Tosoh
instruments (pump, CCPS; detector, UV-8020). TLC analyses were carried out on silica-gel 60
F
254-coated plates (E. Merck). Column chromatography was carried out with Wakogel C-200 gel
unless otherwise described. Preparative TLC was performed on silica-gel-coated plates (Wakogel
B-5F, 20×20 cm).
4.2. Preparation of (S)-N-(tert-butoxycarbonyl)indoline-2-carboxylic acid 3
To (S)-indoline-2-carboxylic acid (3.26 g, 20 mmol) in dioxane (20 ml) and 0.5 M NaOH (40
ml) was added slowly di-tert-butyl dicarbonate (4.80 g, 22 mmol) in dioxane (20 ml) at 0°C and
stirring was continued for 16 h at room temperature. Hexane (20 ml) was added to the reaction
mixture and the aqueous layer was separated. Then, the aqueous layer was acidified with
saturated citric acid and extracted three times with ethyl acetate. The organic layer was washed
with brine, and dried over anhyd. sodium sulfate. The solvent was removed under reduced
pressure and the crude product was purified by recrystallization from ethyl acetate and hexane
to give (S)-N-(tert-butoxycarbonyl)indoline-2-carboxylic acid 3 (4.59 g, 87%) (mp 124.1–
124.8°C). [h]2D0 −77.3 (c 1.00, CHCl3); IR (KBr) w: 1708 cm−1; H NMR (DMSO-d6) l: 1.43 (s,
1
9H, OC(CH3)3), 3.01 (d, J=16.5 Hz, 1H, 1×H-3), 3.52 (dd, J=11.9, 16.5 Hz, 1H, 1×H-3), 4.76
(dd, J=4.0, 11.6 Hz, 1H, H-2), 6.93 (dd, J=7.4, 7.4 Hz, 1H, Ar-H), 7.14–7.74 (m, 3H, Ar-H),
12.89 (s, 1H, COOH). Found: m/z 263.1153. Calcd for C14H17NO4: M, 263.1157.
4.3. Preparation of N-phenyl-(S)-Na-(tert-butoxycarbonyl)indoline-2-carboxamide 4a
To a THF solution (2 ml) of (S)-N-(tert-butoxycarbonyl)indoline-2-carboxylic acid 3 (263
mg, 1.0 mmol) was added a THF solution (1.5 ml) of N-methylmorpholine (101 mg, 1.0 mmol)

S. Sato et al. / Tetrahedron: Asymmetry 11 (2000) 4329–4340
4335
at −15°C. After stirring for 15 min, a THF solution (1.5 ml) of isobutyl chloroformate (155 mg,
1.1 mmol) was added slowly to the reaction mixture at −15°C and the reaction mixture was
stirred for 15 min. Then a THF solution (1.5 ml) of aniline (93 mg, 1.0 mmol) was added at
−15°C and the reaction temperature was then gradually warmed to room temperature. Stirring
was continued for 14 h at this temperature. After addition of water and ethyl acetate to the
reaction mixture, the separated organic layer was washed successively with 1 M HCl, saturated
sodium hydrogencarbonate, and brine. The organic layer was dried over anhyd. sodium sulfate
and the solvent was removed under reduced pressure. The crude product was purified by column
chromatography (dichloromethane:hexane:ether=16:16:1) to give N-phenyl-(S)-Nh-(tert-
butoxycarbonyl)indoline-2-carboxamide 4a (212 mg, 63%) (mp 178.3–178.8°C). [h]2D0 −67.6 (c
1
1.00, CHCl3); IR (KBr) w: 1701, 1673 cm−1; H NMR (CDCl3) l: 1.56 (s, 9H, OC(CH3)3), 3.49
(brs, 2H, 2×H-3), 4.98–5.03 (m, 1H, H-2), 6.98–7.11 (m, 2H, Ar-H), 7.17–7.32 (m, 4H, Ar-H),
7.49 (d, J=7.9 Hz, 2H, Ar-H), 7.63 (brs, 1H, Ar-H). Found: C, 70.97; H, 6.61; N, 8.28%. Calcd
for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28%. N-Substituted (S)-Nh-(tert-butoxycar-
bonyl)indoline-2-carboxamide 4b–f,h were prepared in a similar manner.
4.3.1. N-Cyclohexyl-(S)-Na-(tert-butoxycarbonyl)indoline-2-carboxamide 4b
1
Yield: 66%; mp 164.9–165.4°C; [h]D20 −87.8 (c 1.00, CHCl3); IR (KBr) w: 1710, 1658 cm−1; H
NMR (CDCl3) l: 0.90–1.92 (m, 10H, 2×H-2%, 2×H-3%, 2×H-4%, 2×H-5%, 2×H-6%), 1.54 (s, 9H,
OC(CH3)3), 3.23–3.28 (m, 1H, 1×H-3), 3.42–3.52 (m, 1H, 1×H-3), 3.68–3.82 (m, 1H, H-1%),
4.77–4.83 (m, 1H, H-2), 5.99 (brs, 1H, CONH), 6.98 (t, J=7.4 Hz, 1H, Ar-H), 7.13–7.21 (m, 2H,
Ar-H), 7.70 (brs, 1H, Ar-H). Found: C, 69.58; H, 8.04; N, 8.17%. Calcd for C20H28N2O3: C,
69.74; H, 8.19; N, 8.13%.
4.3.2. N-(o-Tolyl)-(S)-Na-(tert-butoxycarbonyl)indoline-2-carboxamide 4c
1
Yield: 56%; mp 154.4–155.1°C; [h]D20 −76.5 (c 1.00, CHCl3); IR (KBr) w: 1712, 1668 cm−1; H
NMR (CDCl3) l: 1.59 (s, 9H, OC(CH3)3), 2.17 (s, 3H, Ar-CH3), 3.53 (brs, 2H, 2×H-3),
5.04–5.09 (m, 1H, H-2), 6.99–7.06 (m, 2H, Ar-H), 7.13–7.25 (m, 4H, Ar-H), 7.64 (brs, 1H,
Ar-H), 7.94 (d, J=7.9 Hz, 1H, Ar-H). Found: m/z 352.1783. Calcd for C21H24N2O3: M,
352.1787.
4.3.3. N-(2,6-Xylyl)-(S)-Na-(tert-butoxycarbonyl)indoline-2-carboxamide 4d
1
Yield: 49%; mp 186.0–186.4°C; [h]D20 −106.7 (c 0.99, CHCl3); IR (KBr) w: 1708, 1664 cm−1; H
NMR (CDCl3) l: 1.61 (s, 9H, OC(CH3)3), 2.10 (s, 6H, Ar-CH3), 3.39–3.62 (m, 2H, 2×H-3),
5.05–5.10 (m, 1H, H-2), 7.00–7.10 (m, 4H, Ar-H), 7.20–7.25 (m, 2H, Ar-H), 7.68 (brs, 1H,
Ar-H). Found: m/z 366.1956. Calcd for C22H26N2O3: M, 366.1943.
4.3.4. N-(4-Methoxyphenyl)-(S)-Na-(tert-butoxycarbonyl)indoline-2-carboxamide 4e
Yield: 57%; mp 200.7–201.3°C; [h]D20 −71.9 (c 1.01, CHCl3); IR (KBr) w: 1714, 1664 cm−1; H
1
NMR (CDCl3) l: 1.57 (s, 9H, OC(CH3)3), 3.51 (brs, 2H, 2×H-3), 3.78 (s, 3H, Ar-OCH3),
4.96–5.02 (m, 1H, H-2), 6.84 (dd, J=2.0, 6.9 Hz, 2H, Ar-H), 7.01 (dd, J=7.4, 7.4 Hz, 1H,
Ar-H), 7.18–7.24 (m, 2H, Ar-H), 7.40 (d, J=8.9 Hz, 2H, Ar-H), 7.67 (brs, 1H, Ar-H). Found:
C, 68.21; H, 6.54; N, 7.60%. Calcd for C21H24N2O4: C, 68.46; H, 6.57; N, 7.60%.

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S. Sato et al. / Tetrahedron: Asymmetry 11 (2000) 4329–4340
4.3.5. N-[(4-Trifluoromethyl)phenyl]-(S)-Na-(tert-butoxycarbonyl)indoline-2-carboxamide 4f
Yield: 60%; mp 143.0–143.5°C; [h]D20 −37.3 (c 1.00, CHCl3); IR (KBr) w: 1710, 1688 cm−1; H
NMR (CDCl3) l: 1.58 (s, 9H, OC(CH3)3), 3.46–3.55 (m, 2H, 2×H-3), 5.03–5.08 (m, 1H, H-2),
7.03 (dd, J=7.4, 7.4 Hz, 1H, Ar-H), 7.19–7.24 (m, 2H, Ar-H), 7.54 (d, J=8.6 Hz, 2H, Ar-H),
7.63 (d, J=8.9 Hz, 2H, Ar-H), 7.53–7.65 (brs, 1H, Ar-H). Found: C, 62.11; H, 5.29; N, 6.90%.
Calcd for C21H21F3N2O3: C, 62.06; H, 5.21; N, 6.89%.
1
4.3.6. N-(4-Nitrophenyl)-(S)-Na-(tert-butoxycarbonyl)indoline-2-carboxamide 4h
The reaction was carried out at 50°C for 20 h. Yield: 30% (yellow viscous oil); [h]2D0 −7.27 (c
1
1.00, CHCl3); IR (KBr) w: 1716, 1693 cm−1; H NMR (CDCl3) l: 1.61 (s, 9H, OC(CH3)3),
3.44–3.60 (m, 2H, 2×H-3), 5.08–5.11 (m, 1H, H-2), 7.04 (dd, J=7.4, 7.4 Hz, 1H, Ar-H),
7.18–7.25 (m, 2H, Ar-H), 7.54 (brs, 1H, Ar-H), 7.68 (d, J=8.6 Hz, 2H, Ar-H), 8.17 (d, J=8.5
Hz, 2H, Ar-H). Found: m/z 383.1472. Calcd for C20H21N3O5: M, 383.1481.
4.4. Preparation of N-[(3,5-bistrifluoromethyl)phenyl]-(S)-Na-(tert-butoxycarbonyl)indoline-
2-carboxamide 4g
To a THF solution (4 ml) of (S)-N-(tert-butoxycarbonyl)indoline-2-carboxylic acid 3 (500
mg, 1.9 mmol) and triethylamine (192 mg, 1.9 mmol) was slowly added a THF solution (2 ml)
of pivaloyl chloride (229 mg, 1.9 mmol) at −15°C. After stirring for 5 min at 0°C, a THF
solution (2 ml) of 3,5-bis(trifluoromethyl)aniline (435 mg, 1.9 mmol) was added at −15°C. The
reaction mixture was stirred at 0°C for 1 h. Then the reaction mixture was warmed to room
temperature and stirring was continued for 27 h. After removal of the solvent under reduced
pressure, water and ethyl acetate was added. The separated organic layer was washed succes-
sively with saturated sodium hydrogen carbonate, water, and brine. The organic layer was dried
over anhyd. sodium sulfate and the solvent was removed under reduced pressure. The crude
product was purified by column chromatography (hexane:ethylacetate=5:1) to give N-[(3,5-
bistrifluoromethyl)phenyl]-(S)-Nh-(tert-butoxycarbonyl)indoline-2-carboxamide 4g (392 mg,
1
44%) (mp 91.3–92.3°C). [h]2D0 −28.4 (c 0.99, CHCl3); IR (KBr) w: 1718, 1662 cm−1; H NMR
(CDCl3) l: 1.63 (s, 9H, OC(CH3)3), 3.39–3.60 (m, 2H, 2×H-3), 5.10–5.15 (m, 1H, H-2), 7.03 (dd,
J=7.4, 7.4 Hz, 1H, Ar-H), 7.19–7.24 (m, 2H, Ar-H), 7.52 (s, 2H, Ar-H), 7.98 (s, 2H, Ar-H).
Found: C, 55.70; H, 4.34; N, 5.89%. Calcd for C22H20F6N2O3: C, 55.70; H, 4.25; N, 5.91%.
4.5. Preparation of (S)-2-(anilinomethyl)indoline 2a
To a dichloromethane (10 ml) solution of N-phenyl-(S)-Nh-(tert-butoxycarbonyl)indoline-2-
carboxamide 4a (167 mg, 0.50 mmol) was added trifluoroacetic acid (0.76 ml) at room
temperature and stirring was continued for 3 h. After addition of trifluoroacetic acid (0.20 ml),
the reaction mixture was stirred for 1 h at this temperature. The solvent and excess tri-
fluoroacetic acid were removed under reduced pressure and dichloromethane was added to the
residue. The organic layer was washed successively with saturated sodium hydrogencarbonate,
water, and brine and dried over anhyd. sodium sulfate. The solvent was removed under reduced
pressure and the crude product was purified by column chromatography (dichloro-
methane:hexane:ether=4:4:1) to give N-phenyl-(S)-indoline-2-carboxamide 5a (112 mg, 94%)
(mp 125.3–126.8°C). [h]2D0 −236.6 (c 1.00, CHCl3); IR (KBr) w: 1662 cm−1; H NMR (CDCl3) l:
1
3.21 (dd, J=8.6, 16.5 Hz, 1H, 1×H-3), 3.67 (dd, J=10.9, 16.5 Hz, 1H, 1×H-3), 4.32

S. Sato et al. / Tetrahedron: Asymmetry 11 (2000) 4329–4340
4337
(brs, 1H, NH), 4.52 (dd, J=8.6, 10.9 Hz, 1H, H-2), 6.79–6.88 (m, 2H, Ar-H), 7.08–7.13 (m, 3H,
Ar-H), 7.23–7.34 (m, 2H, Ar-H), 7.58 (d, J=7.6 Hz, 2H, Ar-H), 9.01 (s, 1H, CONH). Found:
m/z 238.1089. Calcd for C15H14N2O: M, 238.1106. Amide 5a (1.90 g, 7.98 mmol) in THF (45 ml)
was added slowly to lithium aluminum hydride (907 mg, 23.9 mmol) in THF (45 ml) at 0°C and
the reaction mixture was stirred for 50 h at room temperature. Then saturated sodium sulfate
was added to the reaction mixture at 0°C and the resulting inorganic material was removed by
suction filtration. The organic layer was dried with anhyd. sodium sulfate and concentrated
under reduced pressure. The crude product was purified by column chromatography (hex-
ane:ether=2:1) to afford (S)-2-(anilinomethyl)indoline 2a (1.63 g, 91%) (mp 61.2–61.6°C). [h]D20
1
+79.4 (c 0.99, CHCl3); IR (KBr) w: 3347, 3320 cm−1; H NMR (CDCl3) l: 2.82 (dd, J=7.6, 15.8
Hz, 1H, 1×H-3), 3.11 (dd, J=8.9, 15.8 Hz, 1H, 1×H-3), 3.18 (d, J=5.6 Hz, 2H, C2-CH2N), 3.74
(brs, 2H, 2×NH), 4.01–4.11 (m, 1H, H-2), 6.57–6.61 (m, 3H, Ar-H), 6.70 (dt, J=1.0, 7.3 Hz, 2H,
Ar-H), 7.01 (t, J=7.6 Hz, 1H, Ar-H), 7.07 (d, J=7.3 Hz, 1H, Ar-H), 7.13–7.18 (m, 2H, Ar-H).
Found: C, 80.11; H, 7.01; N, 12.52%. Calcd for C15H16N2: C, 80.32; H, 7.19; N, 12.49%.
(S)-2-(N-substituted aminomethyl)indoline 2b–d were prepared in a similar manner.
4.5.1. (S)-2-(Cyclohexylaminomethyl)indoline 2b
The reduction of amide 5b was carried out under refluxing THF for 12 h and the crude
product was purified by column chromatography (hexane:ether=1:2) using Chromatorex
DM1020 (Fuji Silysia Chemical). Yield: 42% (two steps from 4b); mp 70.6–72.6°C; [h]2D0 +72.2
1
(c 0.99, CHCl3); IR (KBr) w: 3298 cm−1; H NMR (CDCl3) l: 1.01–1.90 (m, 11H, NH, 2×H-2%,
2×H-3%, 2×H-4%, 2×H-5%, 2×H-6%), 2.41 (tt, J=3.6, 10.2 Hz, 1H, H-1%), 2.63–2.81 (m, 3H,
1×H-3, C2-CH2N), 3.15 (dd, J=8.9, 15.8 Hz, 1H, 1×H-3), 3.83–3.94 (m, 1H, H-2), 4.29 (brs, 1H,
NH), 6.63 (d, J=7.6 Hz, 1H, Ar-H), 6.68 (dd, J=7.4, 7.4 Hz, 1H, Ar-H), 7.01 (t, J=7.6 Hz,
1H, Ar-H), 7.07 (d, J=7.3 Hz, 1H, Ar-H). Found: m/z 230.1758. Calcd for C15H22N2: M,
230.1783.
4.5.2. (S)-2-(o-Toluidinomethyl)indoline 2c
The reduction of amide 5c was carried out under refluxing THF for 10 h. Yield: 59% (two
steps from 4c) (colorless viscous oil); bp 220°C (bath temperature)/0.2 mmHg (bulb-to-bulb
1
distillation); [h]2D0 +80.0 (c 1.01, CHCl3); IR (neat) w: 3364 cm−1; H NMR (CDCl3) l: 2.09 (s,
3H, Ar-CH3), 2.87 (dd, J=7.1, 15.7 Hz, 1H, 1×H-3), 3.17 (dd, J=8.9, 15.9 Hz, 1H, 1×H-3), 3.27
(d, J=5.6 Hz, 2H, C2-CH2N), 3.89 (brs, 2H, 2×NH), 4.08–4.18 (m, 1H, H-2), 6.60–6.74 (m, 4H,
Ar-H), 6.99–7.16 (m, 4H, Ar-H). Found: m/z 238.1443. Calcd for C16H18N2: M, 238.1470.
4.5.3. (S)-2-(2,6-Xylidinomethyl)indoline 2d
The reduction of amide 5d was carried out under refluxing THF for 18 h. Yield: 22% (two
steps from 4d) (colorless viscous oil); bp 220°C (bath temperature)/0.2 mmHg (bulb-to-bulb
distillation); [h]2D0 −27.2 (c 1.00, CHCl3); IR (neat) w: 3360 cm−1; H NMR (CDCl3) l: 2.29 (s,
1
6H, Ar-CH3), 2.88 (dd, J=7.8, 15.7 Hz, 1H, 1×H-3), 3.09 (d, J=5.9 Hz, 2H, C2-CH2N), 3.17
(dd, J=7.8, 15.7 Hz, 1H, 1×H-3), 3.66 (brs, 2H, 2×NH), 4.03–4.14 (m, 1H, H-2), 6.66 (d, J=7.9
Hz, 1H, Ar-H), 6.71 (dd, J=7.4, 7.4 Hz, 1H, Ar-H), 6.83 (dd, J=7.4, 7.4 Hz, 1H, Ar-H), 6.99
(d, J=7.3 Hz, 2H, Ar-H), 7.00–7.10 (m, 2H, Ar-H). Found: m/z 252.1646. Calcd for C17H20N2:
M, 252.1627.

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S. Sato et al. / Tetrahedron: Asymmetry 11 (2000) 4329–4340
4.6. Preparation of (S)-2-(p-anisidinomethyl)indoline 2e
Amide 5e was prepared in a similar manner as described for the preparation of 5a from
N-(4-methoxyphenyl)-(S)-Nh-(tert-butoxycarbonyl)indoline-2-carboxamide 4e. To the THF (10
ml) solution of amide 5e (279 mg, 1.04 mmol) was added slowly borane–THF complex (0.9 M
THF solution, 3.5 ml, 3.1 mmol) at 0°C and the reaction mixture was stirred for 15 h at room
temperature. Then 6 M HCl (2 ml) was added to the reaction mixture and stirring was continued
for 30 min. After the solution was made basic with saturated sodium hydrogen carbonate, the
aqueous layer was separated and extracted twice with ether. The combined organic layer was
washed successively with water and brine, and dried over anhyd. sodium sulfate. The solvent
was removed under reduced pressure and the crude product was purified by preparative TLC
(hexane:ether=1:1) to afforded (S)-2-(p-anisidinomethyl)indoline 2e as colorless viscous oil (187
mg, 62% (two steps from 4e)). Bp 220°C (bath temperature)/0.1 mmHg (bulb-to-bulb distilla-
tion); [h]2D0 +75.2 (c 1.00, CHCl3); IR (neat) w: 3363 cm−1; H NMR (CDCl3) l: 2.82 (dd, J=7.4,
1
15.7 Hz, 1H, 1×H-3), 3.07–3.16 (m, 1H, 1×H-3), 3.14 (d, J=5.6 Hz, 2H, C2-CH2N), 3.71 (s, 5H,
2×NH, Ar-OCH3), 3.99–4.09 (m, 1H, H-2), 6.54–6.59 (m, 3H, Ar-H), 6.70 (dd, J=7.8, 7.8 Hz,
1H, Ar-H), 6.76 (dd, J=1.7, 8.9 Hz, 2H, Ar-H), 7.01 (dd, J=7.6, 7.6 Hz, 1H, Ar-H), 7.07 (d,
J=7.3 Hz, 1H, Ar-H). Found: m/z 254.1403. Calcd for C16H18N2O: M, 254.1419. (S)-2-(N-Sub-
stituted aminomethyl)indoline 2f–h were prepared in a similar manner.
4.6.1. (S)-2-[(4-Trifluoromethyl)anilinomethyl]indoline 2f
Yield: 86% (two steps from 4f); mp 85.4–86.3°C; [h]2D0 +46.7 (c 1.00, CHCl3); IR (KBr) w:
1
3434, 3351 cm−1; H NMR (CDCl3) l: 2.88 (dd, J=7.9, 15.8 Hz, 1H, 1×H-3), 3.18 (dd, J=8.9,
15.8 Hz, 1H, 1×H-3), 3.30 (brs, 2H, C2-CH2N), 3.96 (brs, 1H, NH), 4.12–4.23 (m, 1H, H-2), 4.34
(brs, 1H, NH), 6.62 (d, J=8.2 Hz, 2H, Ar-H), 6.64 (d, J=7.3 Hz, 1H, Ar-H), 6.74 (dd, J=7.4,
7.4 Hz, 1H, Ar-H), 7.04 (t, J=7.6 Hz, 1H, Ar-H), 7.10 (d, J=7.3 Hz, 1H, Ar-H), 7.40 (d, J=8.2
Hz, 2H, Ar-H). Found: C, 65.94; H, 5.31; N, 9.70%. Calcd for C16H15F3N2: C, 65.75; H, 5.17;
N, 9.58%.
4.6.2. (S)-2-[(3,5-Bistrifluoromethyl)anilinomethyl]indoline 2g
Yield: 83% (two steps from 4g) (colorless viscous oil); bp 200°C (bath temperature)/0.5 mmHg
(bulb-to-bulb distillation); [h]D20 +23.7 (c 1.00, CHCl3); IR (neat) w: 3401 cm−1; 1H NMR (CDCl3)
l: 2.90 (dd, J=7.9, 15.8 Hz, 1H, 1×H-3), 3.19 (dd, J=8.9, 15.8 Hz, 1H, 1×H-3), 3.30 (t, J=5.3
Hz, 2H, C2-CH2N), 3.90 (brs, 1H, NH), 4.14–4.24 (m, 1H, H-2), 4.48 (brs, 1H, NH), 6.65 (d,
J=7.9 Hz, 1H, Ar-H), 6.75 (dd, J=7.4, 7.4 Hz, 1H, Ar-H), 6.95 (s, 2H, Ar-H), 7.03–7.09 (m,
2H, Ar-H), 7.15 (s, 1H, Ar-H). Found: m/z 360.1039. Calcd for C17H14F6N2: M, 360.1061.
4.6.3. (S)-2-(4-Nitroanilinomethyl)indoline 2h
Yield: 77% (two steps from 4h); mp 111.5–112.1°C; [h]2D0 +49.3 (c 0.99, CHCl3); IR (KBr) w:
1
3364 cm−1; H NMR (CDCl3) l: 2.90 (dd, J=8.4, 15.7 Hz, 1H, 1×H-3), 3.21 (dd, J=9.2, 15.8
Hz, 1H, 1×H-3), 3.40 (t, J=5.3 Hz, 2H, C2-CH2N), 3.97 (brs, 1H, NH), 4.20–4.30 (m, 1H, H-2),
4.92 (brs, 1H, NH), 6.57 (d, 2H, J=9.2 Hz, Ar-H), 6.67 (d, J=7.6 Hz, 1H, Ar-H), 6.77 (dd,
J=7.4, 7.4 Hz, 1H, Ar-H), 7.03–7.12 (m, 2H, Ar-H), 8.09 (d, 2H, J=9.2 Hz, Ar-H). Found: C,
66.79; H, 5.65; N, 15.51%. Calcd for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60%.

S. Sato et al. / Tetrahedron: Asymmetry 11 (2000) 4329–4340
4339
4.7. The asymmetric reduction of acetophenone catalyzed by 2f: typical procedure (Table 2,
entry 6)
To a THF (0.5 ml) solution of 2f (44 mg, 0.15 mmol) was added borane–THF complex (1.0
M THF solution, 1.0 ml, 1.0 mmol) at 0°C and stirring was continued for 30 min at the
temperature. Then the reaction mixture was cooled to −15°C and a THF (1.5 ml) solution of
acetophenone (120 mg, 1.0 mmol) was added dropwise via syringe during 2 h and the reaction
mixture was stirred at the temperature for a further 2 h. After addition of 1 M HCl at the
temperature, the reaction mixture was stirred at room temperature for 10 min. The aqueous
layer was separated and extracted twice with ether, and the combined organic layer was washed
with 1 M HCl, water, and brine successively. The organic layer was dried over anhyd.
magnesium sulfate and the solvent was removed under reduced pressure. The resulting crude
product was purified by column chromatography (hexane:ether=3:1), followed by bulb-to-bulb
distillation (170°C/15 mmHg) to give (R)-1-phenylethanol (108 mg, 88%) ([h]2D0 +52.5 (c 1.00,
CHCl3)). The ee was determined to be 92% by HPLC analysis using a chiral column (Daicel
Chiralcel OD-H (25×0.46 cm i.d.)); eluent, 5% 2-propanol in hexane; flow rate, 0.5 ml/min; tR,
16.7 min for major peak, 19.6 min for minor peak). The asymmetric reduction of the other
ketones was performed by a similar manner. The ee’s were determined by HPLC using Daicel
Chiralcel OD-H (25×0.46 cm i.d.), Daicel Chiralcel OB (25×0.46 cm i.d.) or Waters Opti-pak TA
(30×0.39 cm i.d.). 1-(2-Bromophenyl)ethanol: OB; eluent, 2% 2-propanol in hexane; tR, 20.3 min
for minor peak, 28.0 min for major peak. 1-Phenyl-2-chloroethanol: OD-H; eluent, 3% 2-
propanol in hexane; tR, 32.6 min for major peak, 40.4 min for minor peak. 1-(a-Naph-
thyl)ethanol: OD-H; eluent, 5% 2-propanol in hexane; tR, 31.6 min for minor peak, 53.5 min for
major peak. 1-Phenylpropanol: OD-H; eluent, 5% 2-propanol in hexane; tR, 15.5 min for major
peak, 17.0 min for minor peak. 1,2,3,4-Tetrahydro-1-naphthol: OD-H; eluent, 2% 2-propanol in
hexane; tR, 28.4 min for minor peak, 30.7 min for major peak. 1-Indanol: OD-H; eluent, 5%
2-propanol in hexane; tR, 18.9 min for minor peak, 21.0 min for major peak. 2-Octanol (as
p-nitrobenzoate): TA; eluent, 0.1% 2-propanol in hexane; tR, 21.5 min for minor peak, 29.9 min
for major peak. 1-Phenyl-1-buten-3-ol: OD-H; eluent, 10% 2-propanol in hexane; tR, 16.5 min
for major peak, 25.2 min for minor peak.
4.8. 11B NMR measurement of diazaborolidine catalyst
Borane–THF complex (0.9 M THF solution, 1.33 ml, 1.2 mmol) was added to a THF (1 ml)
solution of 2f (58 mg, 0.2 mmol) at 0°C and stirring was continued for 30 min at the
temperature. The solvent and excess borane were removed under reduced pressure. 11B NMR of
the resulting residue was measured in benzene-d6. 11B NMR peaks corresponding to diazaborol-
idine 6 (R=4-CF3Ph) were observed at +24 ppm using trifluoroborane-etherate as external
standard. 11B NMR experiments using 1, 2a and 2b were carried out in a similar manner.
Acknowledgements
We appreciate Dr. Hiroko Suezawa for NMR measurements and Mr. Takeo Kaneko for mass
spectra measurements. We thank Professors Seiichi Inoue and Kiyoshi Honda for helpful
discussions.

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