A. M. Maj et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Table 2
low catalyst loadings (1 mol %), although the enantiomeric
excesses remained low (632%). In addition, in numerous cases,
we faced the problem of selectivity towards the synthesis of amine
2. The intermediate cyclic primary ketimine appears unstable and
was easily hydrolysed into the parent ketone, indanone, providing,
after reaction with the already produced amine 2, a more stable
secondary ketimine 3. The discovery of a highly selective and enan-
tioselective catalyst for the hydrogenation of indanone oxime
remains a challenge and research will continue in this direction.
Variation of the chiral ligand for the hydrogenation of 1a
OH
N
NH2
[Rh(cod)(OH)]2
ligand
*
+
H2
Cs2CO3
i-PrOH
17h
1
2
Entry
Ligand
Conv.b (%) Yield 2b (%)
Ee 2c (%)
1
2
L1
L2
(S)-MeO-Biphep
(R)-P-Phos
100
98
95
98
2
0
4. Experimental
4.1. General
3
4
5
6
L3
L4
L5
L6
(R)-Segphos
(R)-Difluorphos
(R)-Ph-Garphos
(R)-BTFM-Garphos
(R)-Binap
100
77
64
45
26
100
19
44
31
26
3
0
25
19
7
All reactions were carried out under an inert nitrogen atmo-
sphere using standard Schlenk techniques. Toluene, iso-propanol
and THF were obtained from a solvent purification system MBraun
SPS-800. Dioxane was distilled over CaH2. All the solvents were
degassed prior to use. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded using a Bruker AC 300 spectrometer
(300 MHz). Chemical shifts are reported in delta (d) units, part
per million (ppm) downfield from tetramethylsilane (TMS) relative
to the singlet at 7.26 ppm for deuterated chloroform. Coupling con-
stants are reported in Hertz (Hz). Carbon-13 nuclear magnetic res-
onance (13C NMR) spectra were recorded using a Bruker 300
(75 MHz). Chemical shifts are reported in delta (d) units, part per
million (ppm) relative to the centre line of the triplet at
77.16 ppm for deuterated chloroform. 13C NMR analyses were
run with broadband decoupling. The conversions of substrates
and hydrogenation yields were determined by CG on an EC-5
Econo-CAP Alltech column. The ee’s were determined with a Chir-
acel AD-H (25 cm  4.6 mm) column (hexane/iPrOH/DEA = 97/3,
flow = 0.2 mL/min, at 254 nm, tR1 = 49 min, tR2 = 52 min). The
retention times were checked by GC and HPLC chromatography
by the injection of the commercial racemic amine 2. (E)-2,3-Dihy-
dro-1H-inden-1-one oxime 1 was purchased from Aldrich.
7
L7
8d
9d
10
11
12
13
14
15
16
17d
L8
L9
Ureaphos-1
Ureaphos-2
Catasium T1
W006-1
W008-1
J-404-1
82
21
65
53
70
28
100
66
100
48
97
32
10
1
100
100
70
28
100
69
100
55
100
L10
L11
L12
L13
L14
L15
L16
L17
8
28
17
8
0
14
6
M009-2
(R)-MeBophoz
(S)-Phanephos
(R)-Siphos
a
T = 55 °C;
(OH)]2 = 6.2
Cs2CO3 = 0.613 mmol.
P(H2) = 130 bar;
t = 17 h;
substrate = 1.24 mmol,
[Rh(cod)
lmol, diphosphine
ligand = 12.4
l
mol,
iPrOH = 15 mL;
b
Determined by GC analysis.
Determined by HPLC analysis.
Ligand = 24.8 lmol.
c
d
Table 3
Hydrogenation of oxime acetate 4 and ether 5a
[Rh(cod)(OH)]2
Ligand
NH2
*
N
OCH2Ph
H2
N
OAc
or
+
Cs2CO3
iPrOH
2
4
5
4.2. Preparation of (E)-2,3-dihydro-1H-inden-1-one O-acetyl
oxime 417
Entry
Substrate
Ligand
t (h)
Conv.b (%) Yield 2b (%)
Ee 2c (%)
1
2
3
4
5
6
4
L1
L5
17
17
17
17
17
17
100
20d
100
90d,e
100
100
96
0
65
15
84
43
13
—
4
<2
12
<2
In a 100 mL flask equipped with a magnetic stirrer, (E)-2,3-dihy-
dro-1H-inden-1-one
(4.2 mL, 44.4 mmol), DMAP (6.8 mg, 40.9
1
(3.273 g, 22 mmol), acetic anhydride
mol) and pyridine
L8f
L9f
L11
L13
l
(10 mL, 0.124 mmol) were introduced and the reaction mixture
was stirred at ambient temperature. The progress of the reaction
was followed by TLC (CH2Cl2/MeOH: 20/1). At the end of the acyla-
tion, the solvent was evaporated under reduced pressure. The
crude orange solid was dissolved in ethyl acetate (30 mL). The
organic phase was first washed with water (30 mL), then the aque-
ous phase was extracted three times with ethyl acetate. The com-
bined organic phases were washed with HCl (25 mL, HCl 1 M), and
then brine (25 mL). After drying over magnesium sulfate, filtration
and evaporation, 4 was obtained as a white powder (3.67 g). Yield:
88%; 1H NMR (300 MHz, CDCl3): 2.19 (3H, s, CH3), 2.98 (2H, m,
CH2), 3.03 (2H, m, CH2), 7.27 (2H, m, CHar), 7.37 (1H, m, CHar),
7.86 (1H, m, CHar); 13C NMR (75 MHz, CDCl3) 19.11, 27.70, 28.44,
123.14, 125.69, 127.25, 131.94, 134.31, 149.78, 169.00, 170.24.
7
8
9
10
11
12
5
L1
L5
L8
L9
L11
L13
39
62
17
17
17
17
3
18
90
3
7
42
2
18
80
2
5
40
nd
<2
0
nd
nd
13
a T = 55 °C; P(H2) = 130 bar; substrate = 1.24 mmol, [Rh(OH)cod]2 = 6.2
Ligand = 12.4 mol, iPrOH = 15 mL; Cs2CO3 = 0.613 mmol.
lmol,
l
b
Determined by GC analysis.
Determined by HPLC analysis.
During hydrogenation process, acetyl oxime 4 decomposed into the free oxime
c
d
1.
e
f
6% of indanone was also observed.
Ligand = 24.8 lmol.
4.3. Preparation of (E)-2,3-dihydro-1H-inden-1-one O-benzyl
3. Conclusion
oxime 518
In conclusion, we have performed the asymmetric hydrogena-
tion of indanone oxime and two of its derivatives in the presence
of rhodium based catalysts modified by chiral phosphine ligands.
The yields into the desired amine 2 can be quantitative under
In a 100 mL flask equipped with a magnetic stirrer, (E)-2,3-dihy-
dro-1H-inden-1-one oxime 1 (1 g, 6.8 mmol), benzyl bromide
(1.6 mL, 13.6 mmol) and dichloromethane (34 mL) were stirred at
0 °C for 10 min. Next, Ag2O (1.5 g, 7.5 mmol) was added and the