Selective reaction of camphor-derived exo-formyl [2.2.1]bicyclic carbinol with alkyl primary amines: Application to the preparation of new chiral catalysts for asymmetric reduction of aryl ketones

Article abstract of DOI:10.1016/j.tet.2010.09.008

Reaction of camphor-derived exo-formyl [2.2.1]bicyclic carbinol with various alkyl primary amines gave regio- and stereo-specific [3.2.1]bicyclic α-amino ketones. A detailed mechanism of the reaction was discussed. This reaction was further applied to the preparation of some camphor-derived oxazaborolidines, one of which proved to be an efficient chiral catalyst for the asymmetric borane reduction of prochiral aryl ketones at room temperature.

Full text of DOI:10.1016/j.tet.2010.09.008

Tetrahedron 66 (2010) 8734e8738
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective reaction of camphor-derived exo-formyl [2.2.1]bicyclic carbinol with
alkyl primary amines: application to the preparation of new chiral catalysts for
asymmetric reduction of aryl ketones
,
b
b
b
a
Te-Fang Yang a , Chien-Hung Shen , Chi-Tung Hsu , Li-Hsun Chen , Chih-Hsiang Chuang
*
a Department of Applied Chemistry, National Chi Nan University, Puli, 545, Nantou, Taiwan
b Department of Applied Chemistry, Chaoyang University of Technology, Wufong, 413, Taichung, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 May 2010
Received in revised form 2 September 2010
Accepted 3 September 2010
Available online 15 September 2010
Reaction of camphor-derived exo-formyl [2.2.1]bicyclic carbinol with various alkyl primary amines gave
regio- and stereo-specific [3.2.1]bicyclic -amino ketones. A detailed mechanism of the reaction was
discussed. This reaction was further applied to the preparation of some camphor-derived oxazabor-
olidines, one of which proved to be an efficient chiral catalyst for the asymmetric borane reduction of
prochiral aryl ketones at room temperature.
a
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ring expansion
Bicyclic amino ketone
Chiral catalyst
Asymmetric reduction of ketone
1. Introduction
Several decades ago, it had been reported that
could rearrange in the presence of heat, forming
a
a
-hydroxy imines
-amino ketones.1
Later on, Preiss and co-workers had applied the thermal reaction to
the conversion of 1-methylimino phenylmethyl cyclopentanols into
2-methylamino- 2-phenylcyclohexanone derivatives for medicinal
purposes.2 They concluded that ring expansion had occurred to the
cyclopentyl moiety of the reactant. Furthermore, the enantio-con-
trolled a-substituted a-amino cyclohexanones had been prepared
also by utilizing thermal rearrangement, and starting from their
corresponding imino cyclohexanols.3 However, it was believed that
the mechanism of this reaction involved a conventional 1,2-carbon
migration instead of ring expansion. Recently, we had found that
camphor-derived exo-formyl [2.2.1]bicyclic carbinol (1, Scheme 1)
underwent consecutive ring expansion-alkylation in the presence
of C-nucleophiles, and the regio- and stereo-specific alkyl [3.2.1]
bicyclic diol 2 was furnished.4 On the other hand, the solution of 1
in blank methanol afforded regio- and stereo-specific bicyclic hy-
droxy ketone 3.5
Scheme 1. Ring expansion and alkylation of 1.
the results of the reaction as well as the application of products to
the asymmetric reduction of prochiral aryl ketones.
All the interesting results mentioned above prompted us to
further investigate the reaction of carbinol 1 with alkyl primary
amines, which could be N-nucleophile donors. Herein, we report
2. Results and discussion
After being prepared from camphor in three steps using the
procedures previously reported, carbinol 14 was immediately
treated with various alkyl primary amines individually in toluene at
reflux for 3 h as shown in Table 1. Surprisingly, in each case, the
* Corresponding author. Tel.: þ886 49 2910960; fax: þ886 49 2917956; e-mail
address: tfyang@ncnu.edu.tw (T.-F. Yang).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.008

T.-F. Yang et al. / Tetrahedron 66 (2010) 8734e8738
8735
Table 1
new oxazaborolidines (Scheme 2), which were then employed as
chiral catalysts for the asymmetric reduction of prochiral ketones.7e9
Reduction of 4i with sodium borohydride in hot methanol smoothly
gave amino alcohol 7, in which the benzyl group was then removed
under hydrogenolysis conditions, providing bicyclic amino alcohol
8.10,11 Consequently, the new oxazaborolidines were prepared using
the procedures reported by Masui and Shioiri.9 Treatments of 8 with
borane in THF, and with trimethyl boroxine in toluene afforded
oxazaborolidines 9 and 10, respectively. Since 9 is unstable and may
not be isolated, it was prepared in situ for the following reduction
reaction of acetophenone (Table 2).9,12
Results of the reaction of exo-formyl [2.2.1]bicyclic carbinol 1 with alkyl primary
amines
RNH2
O
Toluene, , 3 h.
O
HO
NH
R
1
4
Entry
Primary amine
Product 4
Yieldc (%)
1
2
3
4
5
6
7
MeNH2
EtNH2
4a (R¼Me)a
4b (R¼Et)b
4c (R¼n-Pr)
4d (R¼i-Pr)
64
66
75
74
86
77
82
n-PrNH2
i-PrNH2
CH2CHCH2NH2
n-BuNH2
t-BuNH2
4e (R¼CH2CHCH2)
4f (R¼n-Bu)
4g (R¼t-Bu)b
8
9
a
4h (R¼Cyclohexyl)
4i (R¼Bn)
66
85
NH2
BnNH2
The structure of this compound was found to be unstable in the air at room
temperature.
b
c
Single crystal was obtained for the X-ray crystallography.
Yield of isolated product.
reaction exclusively provided [3.2.1]bicyclic a
-amino ketone 4,6 in
which C-2 possesses the new amino group with endo orientation.
The orientation of amino groups on 4b and 4g was determined with
X-ray diffraction.6b,c Among all possible regio- and stereoisomers of
product, structure 4 was the only one observed. The yield of 4 is
approximately proportional to the number of carbon atoms con-
tained in the alkyl moiety of amine (entries 1e5). It is deduced that
the primary amine with larger alkyl group possesses higher elec-
tron density, which is necessary for the ring expansion to occur.
Nevertheless, the reaction with cyclohexyl amine (entry 8), for
some unknown reasons, did not give the product with high yield.
A plausible mechanism for the reaction shown in Table 1 is il-
lustrated in Fig. 1. Presumably, an imino [2.2.1]bicyclic carbinol 5
was formed at the beginning of the reaction. Then the nitrogen
atom on 5 abstracted the proton from hydroxyl group on C2, such
that C1eC2 bond was forced to break, similar to the situation
occurred in the solution of 1 in blank methanol (Scheme 1).5 Thus,
Scheme 2. Preparation of oxazaborolidines 9 and 10.
Table 2
Effects of chiral catalysts 9 and 10 on the asymmetric reduction of acetophenone
O
OH
9
catalyst or
10
BH3 S(CH3)2, solvent
Entry Catalyst (equiv) Solvent
T (ꢀC) Time (h) Yielda (%) eeb (%)
the C1 immediately attacked C3 from re-face, providing bicyclic a-
1
2
3
4
5
6
7
8
9 (0.1)
THF
THF
THF
THF
THF
THF
CH2Cl2
Toluene rt
rtc
rt
1
1
1
1
1
1
3
8
83
93
88
87
93
91
92
84
87
91
72
70
86
91
89
61
amino ketone 4. In order to confirm the mechanism of the reaction,
carbinol 1 was particularly treated with benzyl amine in dichloro-
methane at room temperature for 30 min. Then, intermediate 6 was
expected to be detected upon work up. Indeed, the existence of
structure 6 was verified with NMR experiments. On the 1H NMR
spectrum of crude 6, a singlet signal appeared at 7.97 ppm, corre-
sponding to the proton atom of imino moiety. Furthermore, on the
13C NMR of 6, a signal appeared at 170 ppm, corresponding to the
carbon atom of the imino group.
10 (0.1)
10 (0.1)
10 (0.1)
10 (0.05)
10 (0.2)
10 (0.1)
10 (0.1)
ꢁ20
0
rt
rt
rt
a
Yield of isolated product.
A chiralcel OD-RH column was employed for HPLC analysis for the assignment of
configuration of the product, and for the determination of enantiomeric excess (ee)
b
For one of the applications of the title reaction, bicyclic amino
ketone 4i (entry 9 in Table 1) was adopted as the precursor of some
value.
c
Room temperature.
Fig. 1. Plausible mechanism for the reaction of formyl carbinol 1 with primary amines.

8736
T.-F. Yang et al. / Tetrahedron 66 (2010) 8734e8738
Masui and Shioiri had further reported the results of asym-
metric reduction of ketones,9 using
-pinene-derived oxazabor-
A plausible structure of the transition state for the reduction of
a
the prochiral ketones in the presence of catalytic amount of oxa-
zaborolidine 10 is shown in Fig. 2.11 Once the stable double-chair
conformation was formed,13,14 the hydride might be released from
borane, and primarily attack the ketone from re-face. Thus, a sec-
ondary alcohol with S-configuration was predominantly afforded.
olidines as the catalysts. They concluded that the reaction could be
carried out at 25e30 ꢀC, and provide good results. Interestingly, we
also found that room temperature was the most convenient and
efficient condition for the reaction in the presence of oxazabor-
olidines 9 and 10. Furthermore, as shown in Table 2, 10 turned out
to be a better chiral catalyst than 9 for the asymmetric reduction of
acetophenone in THF (entries 1 and 2). Both yield and stereo-
selectivity were decreased at low temperatures (entries 3 and 4).
Increasing the amount of 10 could not raise the yield and ee (%)
value of the secondary alcohol (entry 6). Non-polar solvent, such as
CH2Cl2 and toluene, could not help increase the stereoselectivity
(entries 7 and 8).
Finally, catalytic amount (0.1 equiv) of oxazaborolidine 10 was
adopted for the reduction of various prochiral aryl ketones in THF at
room temperature. As shown in Table 3, among the starting ma-
terials, hydroxy acetophenone (entry 4) was reduced in lowest
enantioselectivity although the phenyl diol was obtained in high
yield. Excitingly, on the other hand, (S)-1-indanol (entry 7) was
furnished in almost excellent enantiomeric purity. In addition, the
reduction of 1-tetralone (entry 8) also provided the corresponding
product in both high chemical and high optical yields.
Fig. 2. Plausible structure of the transition state for the reduction of prochiral ketones.
3. Conclusion
Table 3
In conclusion, the reaction of camphor-derived exo-formyl
[2.2.1]bicyclic carbinol with alkyl primary amines proved to be
Results of asymmetric reduction of aryl prochiral ketones in the presence of
0.1 equiv of 10 at room temperature
regio- and stereoselective, providing [3.2.1]bicyclic
a-amino ke-
Entry
Ketone
Time (h)
Producta
Config.b Yield (%)c eed (%)
tones as the products. The reaction was composed of consecutive
coupling and ring expansion. This reaction could be applied to the
preparation of some oxazaborolidines, which demonstrated to be
good chiral catalysts for the asymmetric borane reduction of aryl
prochiral ketones at room temperature. Other applications of the
title reaction to the synthesis of some more useful compounds are
under investigation.
O
OH
1
1
S
S
S
S
S
S
S
S
93
93
90
98
87
92
97
96
91
80
86
78
82
80
99
98
O
O
OH
2
3
4
5
6
7
1
2
2
4
2
3
3
4. Experimental
OH
4.1. General information
Round bottom flasks were employed for carrying out all the
reactions. Moisture-sensitive solvents were dried with standard
methods and transferred via a syringe when necessary. Crude
product solutions were dried on Na2SO4, filtered, and then con-
centrated with a rotary evaporator below 40 ꢀC at w30 Torr. Flash
column chromatography was performed employing 230e400 mesh
silica gel. TLC was performed on silica gel sheets with organic binder
and detected by 0.5% phosphor-molybdic acid solution in 95% eth-
anol. Melting points were measured on a Fargo MP-1D apparatus
and were uncorrected. An FT/IR spectrophotometer (PerkineElmer-
paragon 500) was used for obtaining the infrared spectra. Data were
expressed as wave number of absorption (cmꢁ1). 1H NMR and 13C
NMR spectra were obtained using a 200 MHz (Varian) spectrometer.
O
OH
OH
OH
O
OH
Ph
O
Ph
OH
Chemical shifts (
downfield from tetramethylsilane (
d scale) were expressed in parts per million
OH
O
d
¼0.00). 1H NMR data were
presented as follows: chemical shift, multiplicity (s¼singlet, br
s¼broad singlet, d¼doublet, dd¼doublet of doublet, t¼triplet,
m¼multiplet and/or multiple resonances), coupling constant in Hz
O
OH
(Hertz), integration. Optical rotation ([a]) values were recorded at
8
room temperature on JASCO (P-1010), digital polarimeter.
a
4.2. General procedure for the reaction of carbinol 1 with
alkyl primary amines
A chiralcel OD-RH column was used for HPLC analysis for the assignment of
configuration of each product.
b
Configuration.
Yield of isolated product.
In the HPLC analyses, the retention time of each product was compared with
c
To a solution of carbinol 1 (0.5 g, 3.23 mmol) in toluene (30 ml)
was added alkyl primary amine (1.30 equiv, 4.20 mmol) at room
temperature. The reaction mixture was heated at reflux for 3 h
d
that of the corresponding commercially available chiral compound for the de-
termination of ee value.

T.-F. Yang et al. / Tetrahedron 66 (2010) 8734e8738
8737
under argon, then cooled to room temperature, and washed with
water (30 mlꢂ3). The organic layers were combined, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified with flash column chromatography (n-hex-
32.46, 30.95, 26.94, 24.50, 20.21, 18.37, 17.43, 13.87. HRMS calcd for
15H27NO: 237.2093; found: 237.2100.
C
4.3.7. Compound 4g. White solid: Rf¼0.78 (3:1, hexanes/EtOAc);
28
anes/EtOAc¼3:1) to give the corresponding [3.2.1]bicyclic
a
-amino
mp 45e47 ꢀC; 82%yield; [
a]
ꢁ5.5 (0.2, CH2Cl2); IR (film): 3352
D
ketone (4).
(br), 2960, 2882, 1703, 1514 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d
3.24
(s, 1H, CHNH), 2.74 (m, 1H), 2.24 (dd, J¼1.4, 14.4 Hz, 1H), 1.99e1.80
4.3. Data of [3.2.1]bicyclic a-amino ketones
(m, 3H),1.42e1.13 (m, 3H), 1.26 (s, 3H), 0.99 (s, 3H), 0.98 (s, 12H, CH3
and t-BuNH); 13C NMR (50 MHz, CDCl3):
d 213.00, 65.04, 52.32,
28
4.3.1. Compound 4a. Syrup: Rf¼0.70 (3:1, hexanes/EtOAc); [
a
]
50.61, 46.82, 45.93, 44.90, 30.82, 29.56, 27.16, 24.87, 18.53, 18.41.
HRMS calcd for C15H27NO: 237.2093; found: 237.2096.
D
ꢁ55.9 (0.2, CH2Cl2); IR (film): 3333 (br), 2956, 2881, 2975, 1708,
1479, 1448 cmꢁ1 1H NMR (200 MHz, CDCl3): 2.91 (s, 1H, CHNH),
;
2.72 (m, 1H), 2.41 (s, 3H, CH3NH), 2.24 (dd, J¼3.0, 15.4 Hz, 1H), 2.09
(br s, 1H, NH), 1.96e1.88 (m, 2H), 1.61 (m, 1H), 1.43e1.24 (m, 2H),
1.20 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H); 13C NMR (50 MHz, CDCl3):
4.3.8. Compound 4h. Syrup: Rf¼0.78 (3:1, hexanes/EtOAc); 66%
28
yield; [
a
]
ꢁ24.0 (0.2, CH2Cl2); IR (film): 3312, 2956, 2883, 1709,
1476 cmꢁD1; 1H NMR (200 MHz, CDCl3):
d 3.10 (s, 1H, CHNH), 2.70 (m,
d
211.33, 73.97, 52.31, 46.23, 45.66, 44.50, 38.81, 30.14, 27.09, 24.62,
1H), 2.14e2.03 (m, 2H), 2.20 (dd, J¼3.0, 15.2 Hz, 1H), 1.97e1.64 (m,
18.54, 17.60. HRMS calcd for C12H21NO: 195.1623; found: 195.1630.
7H),1.57e1.10 (m, 6H),1.18 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.92e0.80
(m, 2H); 13C NMR (50 MHz, CDCl3):
d 212.42, 68.94, 57.94, 52.03, 46.19,
4.3.2. Compound 4b. White solid: Rf¼0.70 (3:1, hexanes/EtOAc);
45.74, 44.52, 34.27, 33.72, 30.33, 27.04, 26.09, 25.23, 25.16, 24.65,
18.48, 17.64. HRMS calcd for C17H29NO: 263.2249; found: 263.2248.
28
mp 39e40 ꢀC; [
a]
ꢁ50.9 (0.2, CH2Cl2); IR (KBr): 3313 (br), 2962,
D
2881, 1708, 1479 cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 3.03 (s, 1H,
CHNH), 2.77e2.52 (m, 3H), 2.25 (dd, J¼3.0, 15.4 Hz, 1H), 2.04 (br s,
1H), 1.98e1.89 (m, 2H), 1.95 (m, 1H), 1.41e1.14 (m, 2H), 1.21 (s, 3H),
1.07 (t, J¼7.2 Hz, 3H, CH2CH3), 1.00 (s, 3H), 0.98 (s, 3H); 13C NMR
4.3.9. Compound 4i. Syrup: Rf¼0.78 (3:1, hexanes/EtOAc); 82%
yield; [
a
]
28 ꢁ8.8 (0.2, CH2Cl2); IR (film): 3510 (br), 3077, 2957, 2881,
D
1710, 1607, 1450 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d 7.35e7.18 (m,
(50 MHz, CDCl3):
d
211.69, 71.69, 52.19, 46.24, 46.13, 45.70, 44.47,
5H, CH2C6H5), 3.81 (d, J¼13.2 Hz, 1H, CHACHBPh), 3.73 (d, J¼13.2 Hz,
1H, CHACHBPh), 3.14 (s, 1H, CHNH), 2.70 (d, J¼15.4 Hz, 1H), 2.46 (br
s, 1H, CHNH), 2.23 (dd, J¼2.8, J¼15.4 Hz,1H), 1.98e1.82 (m, 2H), 1.66
(m, 1H), 1.44e1.20 (m, 2H), 1.15 (s, 3H), 1.03 (s, 3H), 0.96 (s, 3H); 13C
NMR (50 MHz, CDCl3): d 211.42,140.61,128.16,128.06,126.74, 70.29,
55.15, 52.41, 46.22, 45.66, 44.45, 30.21, 26.99, 24.55, 18.40, 17.16.
HRMS calcd for C18H25NO: 271.1936; found: 271.1939.
30.29, 27.11, 24.66, 18.51, 17.58, 15.52. HRMS calcd for C13H23NO:
209.1780; found: 209.1788.
28
4.3.3. Compound 4c. Syrup: Rf¼0.72 (3:1, hexanes/EtOAc); [
a
]
D
ꢁ48.7 (0.2, CH2Cl2); IR (film): 3315 (br), 2958, 2883, 1706, 1477,
1390 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d
2.99 (s, 1H, CHNH), 2.70
(m, 1H), 2.49 (m, 2H), 2.21 (dd, J¼3.0, 15.2 Hz, 1H), 1.93e1.79 (m,
2H), 1.66e1.00 (m, 6H), 1.17 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.88 (t,
4.4. Preparation of 7
J¼7.4 Hz, 3H, CH2CH2CH3); 13C NMR (50 MHz, CDCl3):
d 211.64,
71.72, 53.95, 52.26, 46.19, 45.65, 44.44, 30.32, 27.05, 24.61, 23.45,
18.48, 17.55, 11.67. HRMS calcd for C14H25NO: 223.1936; found:
223.1942.
To a solution of 4i (0.5 g, 1.85 mmol) in methanol (20 ml) was
added sodium borohydride (0.21 g, 5.55 mmol). The reaction
mixture was heated at reflux for 3 h, then quenched with water
(5 ml), and extracted with ethyl acetate (20 mlꢂ3). The organic
layers were combined, dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified with flash column
4.3.4. Compound 4d. Syrup: Rf¼0.78 (3:1, hexanes/EtOAc); 80%
28
yield; [
a]
ꢁ4.3 (0.2, CH2Cl2); IR (film): 3312 (br), 2925, 2852,
D
1706, 1449 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d
3.08 (s, 1H, CHNH),
chromatography (n-hexanes/EtOAc¼3:1) to give [3.2.1]bicyclic
a-
2.74 (m, 1H), 2.57 (hept. J¼6.4 Hz, 1H, MeCHMe), 2.24 (dd, J¼3.2,
11.4 Hz, 1H), 1.96e1.82 (m, 3H), 1.53e1.46 (m, 1H), 1.39e1.13 (m,
2H), 1.21 (s, 3H), 1.02 (d, J¼4.4 Hz, 3H, CH3CHCH3), 1.00 (s, 3H), 0.99
(d, J¼4.4 Hz, 3H, CH3CHCH3), 0.98 (s, 3H); 13C NMR (50 MHz,
amino alcohol 7 (0.48 g, 96%) as a syrup: Rf¼0.80 (3:1, hexanes/
28
EtOAc); [
a
]
ꢁ60.9 (0.2, CH2Cl2); IR (film): 3377 (br), 3065, 2928,
D
1452 cmꢁ1
;
1H NMR (200 MHz, CDCl3):
d 7.35e7.23 (m, 5H,
CH2C6H5), 3.83 (d, J¼12.6 Hz, 1H, CHACHBPh), 3.84 (s, 1H, CHOH),
3.66 (d, J¼12.6 Hz, 1H, CHACHBPh), 2.63 (dd, J¼1.2, 5.4 Hz, 1H,
CHNH), 2.03e1.66 (m, 5H), 1.59 (m, 1H), 1.37e1.10 (m, 2H), 0.86 (s,
CDCl3):
d 215.46, 67.18, 49.95, 49.13, 46.68, 44.29, 35.54, 26.87,
25.14, 24.96, 23.43, 22.71, 20.93. HRMS calcd for C14H25NO:
223.1936; found: 223.1931.
6H, 2CH3), 0.84 (s, 3H, CH3); 13C NMR (50 MHz, CDCl3):
d 139.91,
128.39, 128.17, 127.14, 63.26, 63.07, 52.76, 45.67, 44.18, 43.83, 33.76,
29.35, 26.10, 24.99, 18.78, 17.11. HRMS calcd for C18H27NO:
273.2093; found: 273.2089.
28
4.3.5. Compound 4e. Syrup: Rf¼0.74 (3:1, hexanes/EtOAc); [
a]
D
ꢁ15.2 (0.2, CH2Cl2); IR (film): 3320 (br), 3075, 2956, 2390, 1700,
1472, 1396 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d
5.86 (m, 1H, CH2]
CHCH2), 5.29e5.13 (m, 2H, CH2]CHCH2), 3.36 (m, 2H, CH2]
CHCH2), 3.22 (s,1H, CHNH), 2.76 (m,1H), 2.34 (m,1H),1.99e1.03 (m,
6H), 1.20 (s, 3H), 1.08 (s, 3H), 0.99 (s, 3H); 13C NMR (50 MHz, CDCl3):
4.5. Preparation of 8
To a solution of 7 (0.35 g, 1.28 mmol) in methanol at room
temperature was added PdeC (10%, 0.05 g) and applied hydrogen.
The system was stirred at room temperature for 3 h. The reaction
mixture was then filtered through Celite, and the filtrate was col-
lected, and concentrated under reduced pressure to give 8 (0.22 g,
d
211.33, 137.16, 115.59, 70.06, 53.71, 52.19, 46.16, 45.58, 44.43, 30.17,
26.97, 24.55, 18.37, 17.51. HRMS calcd for C14H23NO: 221.1780;
found: 221.1782.
4.3.6. Compound 4f. Syrup: Rf¼0.78 (3:1, hexanes/EtOAc); 77%
92%) as
124e126 ꢀC; [
1620, 1430 cmꢁ1; 1H NMR (200 MHz, CDCl3):
CHOH), 2.90 (dd, J¼1.4, 5.5 Hz, 1H, CHNH2), 2.10e1.11 (m, 10H), 0.88
(s, 6H, 2CH3), 0.85 (s, 3H, CH3); 13C NMR (50 MHz, CDCl3):
67.24,
a
white solid: Rf¼0.20 (3:1, hexanes/EtOAc); mp
28
28
yield; [
a]
ꢁ44.3 (0.2, CH2Cl2); IR (film): 3314, 2957, 2876, 1707,
a]
ꢁ77.0 (0.2, CH2Cl2); IR (KBr): 3358 (br), 2927,
D
D
1477 cmꢁ1
;
1H NMR (200 MHz, CDCl3):
d
3.05 (s, 1H, CHNH), 2.74
d
3.80 (t, J¼5.5 Hz, 1H,
(m, 1H), 2.58 (t, J¼7.2 Hz, 2H, NHCH2CH2CH2CH3), 2.26 (dd, J¼3.0,
15.4 Hz, 1H), 1.96e1.89(m, 1H), 1.64e1.16 (m, 9H), 1.21 (s, 3H), 01.02
(s, 3H), 0.98 (s, 3H), 0.90 (t, J¼7.2 Hz, 3H, CH2CH2CH2CH3); 13C NMR
d
55.45, 46.29, 44.14, 43.88, 34.68, 28.30, 26.24, 25.18, 18.65, 17.10.
HRMS calcd for C11H21NO: 183.1623; found: 183.1621.
(50 MHz, CDCl3):
d 211.47, 71.66, 52.14, 51.64, 46.07, 45.53, 44.29,

8738
T.-F. Yang et al. / Tetrahedron 66 (2010) 8734e8738
4.6. Preparation of 9
References and notes
1. (a) Stevens, C. L.; Elliott, R. D.; Winch, B. L. J. Am. Chem. Soc. 1963, 85,
1464e1470; (b) Stevens, C. L.; Thuillier, A.; Daniher, F. A. J. Org. Chem. 1965, 30,
2962e2966; (c) Stevens, C. L.; Ash, A. B.; Thuillier, A.; Amin, J. H.; Balys, A.;
Dennis, W. E.; Dickerson, J. P.; Glinski, R. P.; Hanson, H. T.; Pillai, M. D.; Stoddard,
J. W. J. Org. Chem. 1966, 31, 2593e2601; (d) Stevens, C. L.; Hanson, H. T.; Taylor,
K. G. J. Am. Chem. Soc. 1966, 88, 2769e2774; (e) Stevens, C. L.; Pillai, P. M.; Munk,
M. E.; Taylor, K. G. Mech. Mol. Migr. 1971, 271e296.
To a solution of 8 (0.18 g, 1.00 mmol) in THF (5 ml) was added
boraneedimethyl sulfide complex (2.0 M, 5 ml). The reaction
mixture was stirred at room temperature for 1 h, then used directly
for the reduction of acetophenone as shown in Table 2.
2. (a) Brunner, H.; Kagan, H. B.; Kreutzer, G. Tetrahedron: Asymmetry 2003, 14,
2177e2187; (b) Preiss, D. Patent DE 44 09 671 C1, 1995. (c) Menzer, M.; Kaz-
mirowski, H.-G.; Moller, G.; Laban, G. Patent DD 217 511 A1, 1985. (d) Klose, R.;
Hoppe, U. (S)-Ketamin; Springer: Berlin, Heidelberg, New York, NY, 2002; (e)
Steiner, K. Patent WO 97/43244, 1997. (f) Russo, T.; Freire, V. Patent WO 01/
98265 A2, 2001.
3. (a) Vatele, J.-M.; Dumas, D.; Gore, J. Tetrahedron Lett. 1990, 31, 2277e2280; (b)
Compain, P.; Gore, J.; Vatele, J.-M. Tetrahedron Lett. 1995, 36, 4059e4062; (c)
Compain, P.; Gore, J.; Vatele, J.-M. Tetrahedron Lett. 1995, 36, 4063e4064; (d)
Compain, P.; Gore, J.; Vatele, J.-M. Tetrahedron 1996, 52, 6647e6664.
4. (a) Yang, T.-F.; Tseng, C.-H. T.; Wu, K.-I.; Chang, C.-N. J. Org. Chem. 2007, 72,
7034e7037; (b) Yang, T.-F.; Zhang, Z.-N.; Tseng, C.-H.; Chen, L.-H. Tetrahedron
Lett. 2005, 46, 1917e1920; (c) Yang, T.-F.; Chao, H.-H.; Lu, Y.-H.; Tsai, C.-J.
Tetrahedron 2003, 59, 8827e8831.
4.7. Preparation of 10
To a solution of 8 (0.18 g, 1.00 mmol) in toluene (20 ml) was
added trimethyl boroxine (0.10 g, 0.80 mmol). The reaction mixture
was stirred at room temperature under argon for 5 h, then con-
centrated under reduced pressure to a volume of 5 ml. Toluene
(20 ml) was added to the reaction mixture, which was then con-
centrated to 5 ml again. This process was repeated for two times.
Finally, the solvent in the reaction mixture was removed under
reduced pressure to give 10 (0.15 g, 90%) as a white solid: Rf¼0.80
(3:1, hexanes/EtOAc); mp 130e131 ꢀC; [
(KBr): 3380 (br), 2925 cmꢁ1
a]
28 ꢁ26.9 (0.2, CH2Cl2); IR
D
5. Yang, T.-F.; Tseng, C.-H.; Shen, C.-H.; Chen, L.-H.; Kao, L.-T. Tetrahedron 2009, 65,
9854e9861.
;
1H NMR (200 MHz, CDCl3):
d
4.35 (t,
6. (a) The structure of compound 4a was found to be unstable in the air at room
temperature; (b) Since compounds 4a, 4cef, 4h, and 4i are syrup at room
temperature (see Experimental), the stereo structures of these compounds
were inferred from the stereo structures of 4b and 4g, and from the principle of
mechanism discussed for the formation of compound 3, as shown in Scheme 1
and Ref. 5; (c) Crystallographic data for structures 4b and 4g in this paper have
been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 778512 and CCDC 778513, respectively.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or e-mail: de-
posit@ccdc.cam.ac.uk).
J¼7.2 Hz, 1H, CHOH), 3.28 (d, J¼7.6 Hz, 1H, CHNH), 2.63 (br s, 1H),
2.17e2.03 (m, 1H), 1.90e1.22 (m, 6H), 0.87 (s, 3H), 0.85 (s, 3H), 0.73
(s, 3H), 0.24 (s, 3H); 13C NMR (50 MHz, CDCl3):
d
69.20, 62.10, 45.96,
43.42, 34.74, 28.65, 26.64, 24.65, 18.72, 18.61, 17.13, 0.13; 11B NMR
(CDCl3) 31.1. HRMS calcd for C12H22BNO: 207.1794; found:
207.1788.
d
4.8. General procedure for the reduction of ketones
7. Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 497e526.
8. Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475e1504.
9. (a) Masui, M.; Shioiri, T. Tetrahedron 1995, 51, 8363e8370; (b) Masui, M.;
Shioiri, T. Synlett 1996, 49e50.
10. The orientation of benzyl amino group on compound 7 was originated from
compound 4i. Furthermore, the NOESY NMR spectra of both 7 and 8 demon-
strated that the proton on the carbon atom, which possesses hydroxyl group
(CHOH) and the proton on the carbon atom, which possesses amino group
(CHNH2) are syn to each other. Thus, the stereo structure of compound 8 was
confirmed.
To a solution of the oxazaborolidine (9 or 10) in anhydrous THF
(5 ml) was added BH3eS(CH3)2 (0.70 ml, 10 M in THF, 1.70 mmol)
under argon. The solution of prochiral aryl ketone (2.45 mmol) in
anhydrous THF (5 ml) was then added dropwise to the mixture by
using an automatic syringe pump over 2 h at room temperature.
The reaction mixture was kept stirring at room temperature until
the ketone was completely consumed. Hydrochloric acid (2 N) was
then added dropwise to quench the reaction, and the system was
extracted with diethyl ether (10 mlꢂ3). The organic layers were
combined, washed, dried (Na2SO4), and concentrated under re-
duced pressure. The residue was purified with silica gel column
chromatography (n-hexanes/EtOAc¼5:1) to give the chiral sec-
ondary alcohol.
11. As shown in Experimental Section, the 1H NMR COSY spectrum of amino al-
cohol 8 revealed that the triplet signal at 3.80 ppm is corresponding to the
proton on carbon atom, which possesses OH group. It is deduced that the triplet
signal should be a doublet of doublet signal (dd), and the two coupling con-
stants are identical (J1¼J2¼5.5 Hz). This proton is believed to couple to the
proton on carbon atom, which possesses amino group, and also to couple to
only one (HA) of the two protons (HA and HB) in the adjacent ring-methylene
group. The other proton (HB) did not couple to the proton, which is corre-
sponding to the signal at 3.80 ppm, according to vicinal Karplus correlation. On
the other hand, the quartet signal at 2.90 ppm is corresponding to the proton on
the carbon atom, which possesses amino group. This proton is believed to have
long range coupling to one of the two protons (HA and HB) in the ring-meth-
ylene group, which was just mentioned above. Indeed, the possibility of the
existence of boat form for amino alcohol 8 could not be excluded. However,
based on our molecular model study, the possibility of the existence of chair
form should be larger than that of boat form for amino alcohol 8.
12. Li, X.; Yeung, C.-H.; Chan, A. S. C.; Yang, T.-K. Tetrahedron: Asymmetry 1999, 10,
759e763.
Acknowledgements
This work was supported by National Science Council of Taiwan
(Grant NSC 96-2113-M-324-001), which is gratefully acknowl-
edged. The authors thank the Instrumental Center at National Tai-
wan University and the Regional Instruments Center at National
Chung-Hsing University for elemental analysis, high resolution
mass spectra, and X-ray crystallography.
13. Jones, D. K.; Liotta, D. C.; Shinkai, I,; Mathre, D. J. Org. Chem. 1993, 58, 799e801.
14. Quallich, G. J.; Blake, J. F.; Woodall, T. M. J. Am. Chem. Soc. 1994, 116, 8516e8525.