Synthesis of chiral exocyclic amines by asymmetric hydrogenation of aromatic quinolin-3-amines

Article abstract of DOI:10.1002/chem.201402592

Asymmetric hydrogenation of aromatic quinolin-3-amines was successfully developed with up to 94% enantiomeric excess (ee). Introduction of the phthaloyl moiety to the amino group is crucial to eliminate the inhibition effect caused by the substrate and pr

Full text of DOI:10.1002/chem.201402592

Supporting Information
ꢀ
Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2014
Synthesis of Chiral Exocyclic Amines by Asymmetric
Hydrogenation of Aromatic Quinolin-3-amines
[a, b]
[a]
[a]
[a]
[a]
Xian-Feng Cai,
Ran-Ning Guo, Mu-Wang Chen, Lei Shi, and Yong-Gui Zhou*
chem_201402592_sm_miscellaneous_information.pdf

Table of Contents
1
2
3
4
5
6
7
8
9
. General.....................................................................................................................................S2
. Synthesis of N-Substituted 2-Butylquinolin-3-amines.........................................................S2
. Asymmetric Hydrogenation of of Some Aromatic Amines (Scheme 3).............................S3
. Isotopic Labeling Experiment................................................................................................S5
. Synthesis of 3-Nitroquinolines 5............................................................................................S6
. Synthesis of Quinolin-3-amines 1...........................................................................................S8
. Asymmetric Hydrogenation of Quinolin-3-amines 1.........................................................S10
. Removal of Phth Group and Determination of the Absolute Configuration of 2a…….S13
. Copy of NMR and HPLC for Racemic and Chiral Compounds......................................S15
S1

1. General:
Commercially available reagents were used without further purification. Solvents were
1
13
19
treated prior to use according to the standard methods. H NMR, C NMR and F NMR spectra
were recorded at room temperature in CDCl on 400 MHz instrument with tetramethylsilane
3
(
TMS) as internal standard. Enantiomeric excess was determined by HPLC analysis, using chiral
column described below in detail. Optical rotations were measured by polarimeter. Flash column
chromatography was performed on silica gel (200-300 mesh).
2. Synthesis of N-Substituted 2-Butylquinolin-3-amines
The substrates 2-toluidine, 4-methyl-N-o-tolylbenzenesulfonamide, 2-butylquinolin-3-amine
are known compounds.
2.1. Synthesis of N-(2-butylquinolin-3-yl)-4-methylbenzenesulfonamide
Under an nitrogen atmosphere and at 0 ºC, a solution of 2-butylquinolin-3-amine (100 mg,
.5 mol) in THF (5 mL) was charged with 1.0 M lithium bis(trimethylsilyl)amide in THF/PhEt
0
(
1.1 mL, 1.1 mmol), followed by 4-methylbenzene-1-sulfonyl chloride (TsCl, 114 mg, 0.6 mmol)
in THF (4 mL). The cold bath was removed and the viscous mixture was allowed to stir for 5 h.
The solvent was evaporated, dissolved in dichloromethane (10 mL) and washed with 0.05 M HCl
(
10 mL) and brine. The organic layer was dried (Na SO ) and was taken to dryness under reduced
2 4
pressure, the residue was purified by flash chromatography on silica gel to yield the product.
N-(2-Butylquinolin-3-yl)-4-methylbenzenesulfonamide: 61% yield, light yellow solid, mp
o
1
1
f 2 2 3
26-127 C, R = 0.50 (pure CH Cl ). H NMR (400 MHz, CDCl ) δ = 8.21 (s, 1H), 7.95 (d, J =
8
1
3
.4, 1H), 7.75 (d, J = 8.1, 1H), 7.67 (d, J = 8.1, 2H), 7.62 (dd, J = 8.2, 7.1,
H), 7.48 (t, J = 7.5, 1H), 7.24-7.04 (m, 3H), 2.72-2.62 (m, 2H), 2.35 (s,
H), 1.58-1.45 (m, 2H), 1.31 (dq, J = 14.8, 7.4, 2H), 0.85 (t, J = 7.3, 3H);
NHTs
N
1
3
C NMR (100 MHz, CDCl
3
) δ = 156.7, 145.8, 144.5, 136.4, 130.1, 129.2, 128.9, 128.7, 128.7,
1
27.6, 127.3, 127.2, 126.6, 34.0, 30.6, 22.9, 21.7, 14.1; HRMS Calculated for C H N O S
20
23
2
2
+
[
M+H] 355.1480, found 355.1483.
2.2. Synthesis of N-(2-butylquinolin-3-yl)benzamide
Under an nitrogen atmosphere and at 0 ºC, to a solution of 2-butylquinolin-3-amine (150 mg,
.75 mmol) and triethylamine (92 mg, 0.13 mL) in CH Cl (5.0 mL) was slowly added the
0
2
2
solution of benzoyl chloride (PhCOCl, 116 mg, 0.10 mL) in CH Cl (3.0 mL). The ice bath was
2
2
allowed to warm to room temperature and the mixture was stirred for 4 h. H O (10 mL) was added,
2
the organic layer was separated and dried (Na SO ). Then it was taken to dryness under reduced
2
4
pressure and the residue was purified by flash chromatography on silica gel to yield product.
S2

o
N-(2-butylquinolin-3-yl)benzamide: 90% yield, white solid, mp 130-131 C, R
f
= 0.35
1
(
petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.90 (s, 1H), 8.11-7.96 (m, 2H),
7
7
3
.91 (d, J = 7.3, 2H), 7.78 (d, J = 6.6, 1H), 7.70-7.40 (m, 5H), 3.03 (t, J =
NHBz
.0, 2H), 1.96-1.78 (m, 2H), 1.50 (dd, J = 14.0, 6.8, 2H), 0.98 (t, J = 7.3,
N
13
H); C NMR (100 MHz, CDCl ) δ = 166.1, 154.8, 145.3, 134.7, 132.4,
3
1
29.8, 129.2, 128.7, 128.7, 127.7, 127.6, 127.2, 127.1, 126.5, 34.8, 30.6, 23.0, 14.1; HRMS
+
Calculated for C H N O [M+H] 305.1654, found 305.1657.
20
21
2
2.3. Synthesis of phenyl 2-butylquinolin-3-ylcarbamate
Under an nitrogen atmosphere and at 0 ºC, to a solution of 2-butylquinolin-3-amine (150 mg,
0
1
.75 mmol) in THF (5.0 mL) was slowly added the solution of phenyl chloroformate (ClCO
2
Ph,
29 mg, 0.10 mL) in THF (3.0 mL). The ice bath was allowed to warm to room temperature and
the mixture was stirred overnight. Saturated aqueous NaHCO (10 mL) was added, the organic
3
layer was separated. The aqueous phase was extracted with CH Cl (15 mL×3). The combined
2
2
organic layers were dried with Na SO . After filtration, the solvent was removed under reduced
2
4
pressure and the residue was purified by flash chromatography on silica gel to yield the
corresponding product.
o
Phenyl 2-butylquinolin-3-ylcarbamate: 57% yield, white solid, mp 118-120 C, R
f
= 0.50
1
(
petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.68 (s, 1H), 8.00 (d, J = 8.3, 1H),
7
3
2
.74 (d, J = 8.0, 1H), 7.61 (t, J = 7.4, 1H), 7.53-7.37 (m, 3H), 7.29-7.19 (m,
NHCO Ph
2
H), 7.05 (s, 1H), 3.01 (t, J = 7.6, 2H), 1.95-1.80 (m, 2H), 1.60-1.47 (m,
N
13
H), 1.02 (t, J = 7.2, 3H); C NMR (100 MHz, CDCl ) δ = 153.9, 152.0,
3
1
50.5, 144.8, 129.5, 129.3, 128.6, 128.4, 127.4, 127.4, 126.4, 126.0, 121.6, 34.3, 30.3, 22.8, 14.0;
+
HRMS Calculated for C H N O [M+H] 321.1603, found 321.1603.
20
21
2
2
3
. Asymmetric Hydrogenation of of Some Aromatic Amines (Scheme 3)
In a nitrogen-filled glove box, a mixture of [Ir(COD)Cl] (1.3 mg, 0.002 mmol) and
2
(S)-SegPhos (2.7 mg, 0.0044 mmol) in THF (1.0 mL) was stirred at room temperature for 10 min,
then aromatic amine (0.10 mmol) and I (2.5 mg, 0.010 mmol) together with THF (2.0 mL) were
2
added to the reaction mixture. The hydrogenation was performed under H
2
(600 psi) in a stainless
o
steel autoclave at 25 C for 18 h. After carefully releasing the hydrogen, the solvent was removed
S3

under reduced pressure. Purification was performed by a silica gel column eluted with
1
hexane/EtOAc to give desire product. Reaction conversion and d.r. were determined by H NMR
spectroscopy.
N-((cis)-2-Butyl-1,2,3,4-tetrahydroquinolin-3-yl)-4-methylbenzenesulfonamide
:
78%
= 0.60 (petroleum ether/EtOAc 5:1). H NMR (400
MHz, CDCl ) δ = 7.72 (d, J = 7.5, 2H), 7.27 (d, J = 8.3, 2H), 6.98 (t, J = 7.4,
o
1
yield, 62% ee, white solid, mp 164-166 C, R
f
NHTs
3
1
H), 6.77 (d, J = 7.3, 1H), 6.63 (t, J = 7.1, 1H), 6.47 (d, J = 7.8, 1H), 4.92 (d,
N
H
J = 9.0, 1H), 3.72 (d, J = 7.6, 1H), 3.62 (s, 1H), 3.18 (d, J = 6.2, 1H), 2.86
13
(
d, J = 16.5, 1H), 2.57 (d, J = 16.5, 1H), 2.42 (s, 3H), 1.06-1.45 (m, 6H), 0.83 (t, J = 5.5, 3H); C
NMR (100 MHz, CDCl ) δ = 143.7, 143.4, 138.9, 130.6, 129.8, 127.4, 127.2, 118.6, 118.0, 114.4,
3
+
5
3
5.0, 48.5, 34.5, 31.8, 27.8, 22.8, 21.7, 14.1; HRMS Calculated for C H N O S [M+H]
20 27 2 2
o
59.1793, found 359.1790; Chirapak AD-H column, 254 nm, 30 C, n-hexane/i-propanol = 80/20,
flow = 0.9 mL/min, retention time 11.6 min and 13.3 min (major).
N-((trans)-2-Butyl-1,2,3,4-tetrahydroquinolin-3-yl)-4-methylbenzenesulfonamide : 11%
1
yield, colorless oil, R
f
= 0.55 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 7.72
(
d, J = 8.2, 2H), 7.28 (d, J = 8.1, 2H), 6.98 (t, J = 7.6, 1H), 6.78 (d, J = 7.4,
H), 6.61 (td, J = 7.4, 0.8, 1H), 6.47 (d, J = 7.9, 1H), 4.90 (d, J = 9.1, 1H),
3.95 (s, 1H), 3.63 (td, J = 8.0, 3.6, 1H), 3.05–2.94 (m, 1H), 2.82 (dd, J =
NHTs
1
N
H
13
1
6.7, 4.5, 1H), 2.52–2.44 (m, 1H), 2.43 (s, 3H), 1.38–1.13 (m, 6H), 0.84 (t, J = 7.0, 3H); C NMR
(
100 MHz, CDCl ) δ = 143.3, 142.0, 138.6, 130.3, 129.7, 127.5, 126.9, 117.7, 116.5, 114.3, 55.1,
3
+
4
9.0, 33.8, 29.7, 27.7, 22.4, 21.5, 13.9; HRMS Calculated for C H N O S [M+H] 359.1793,
20
27
2
2
found 359.1793.
N-(2-Butyl-1,2,3,4-tetrahydroquinolin-3-yl)benzamide: 90% yield, 84% ee, d.r. 8:1,
1
colorless oil. H NMR (400 MHz, CDCl
3
) δ = 7.69 (d, J = 7.8, 2H), 7.41 (dt, J = 15.1, 7.3, 3H),
7
1
.01 (dd, J = 18.1, 7.6, 2H), 6.76-6.51 (m, 3H), 4.67-4.44 (m, 1H), 3.77 (s,
H), 3.44-3.24 (m, 1H), 3.20-3.03 (m, 1H), 2.94 (d, J = 16.9, 0.89H), 2.82
(
d, J = 16.8, 0.11H), 1.73-1.56 (m, 1H), 1.53-1.28 (m, 5H), 0.92 (t, J = 6.9,
1
3
3
1
3
H); C NMR (100 MHz, CDCl ) δ = 167.3, 143.9, 140.8, 139.5, 134.8, 131.3, 131.3, 130.6,
3
30.5, 128.5, 128.4, 127.3, 127.0, 127.0, 126.9, 119.3, 118.7, 117.8, 117.7, 114.5, 54.3, 45.3, 44.8,
9.1, 34.0, 33.8, 32.3, 28.9, 28.1, 27.9, 22.7, 22.6, 14.0, 13.9; HRMS Calculated for C H N O
2
0
25
2
+
o
[
M+H] 309.1967, found 309.1965; Chirapak AD-H column, 254 nm, 30 C, n-hexane/i-propanol
=
70/30, flow = 0.7 mL/min, retention time 7.3 min (major) and 8.5 min.
Phenyl 2-butyl-1,2,3,4-tetrahydroquinolin-3-ylcarbamate: 97% yield, 63% ee, d.r. 8:1,
1
colorless oil. H NMR (400 MHz, CDCl
3
) δ = 7.40-7.28 (m, 2H), 7.22-7.07 (m, 3H), 7.06-6.97 (m,
H), 6.77-6.65 (m, 1H), 6.53 (t, J = 9.0, 1H), 5.45 (d, J = 9.0, 0.89H), 5.20
d, J = 8.9, 0.11H), 4.30-4.17 (m, 1H), 3.70 (s, 1H), 3.34 (t, J = 6.0, 0.89H),
.25 (d, J = 2.9, 0.11H), 3.18-2.99 (m, 1H), 2.97-2.75 (m, 1H), 1.76-1.57
2
(
3
1
3
(
m, 1H), 1.55-1.29 (m, 5H), 0.99-0.87 (m, 3H); C NMR (100 MHz, CDCl ) δ = 154.6, 151.1,
3
1
1
2
51.1, 143.8, 130.6, 130.5, 129.4, 129.2, 127.4, 127.2, 126.3, 125.5, 125.1, 121.7, 121.6, 121.5,
18.7, 118.5, 117.7, 114.4, 114.3, 54.2, 46.8, 46.4, 34.8, 34.2, 33.9, 32.1, 29.2, 28.0, 27.8, 22.7,
+
2.6, 14.0, 14.0; HRMS Calculated for C H N O [M+H] 325.1916, found 325.1920; HPLC:
2
0
25
2
2
o
Chiracel OD-H column, 254 nm, 30 C, n-hexane/i-propanol = 95/5, flow = 0.8 mL/min, retention
time 25.4 min (major) and 28.0 min.
S4

4
. Isotopic Labeling Experiment
In a nitrogen-filled glove box, a mixture of [Ir(COD)Cl] (1.3 mg, 0.002 mmol) and
2
(
S)-SegPhos (2.7 mg, 0.0044 mmol) in THF/CD OD (3:1, 1.0 mL) was stirred at room
3
temperature for 10 min, then aromatic amine (0.10 mmol) and I (2.5 mg, 0.010 mmol) together
2
with THF/CD OD (3:1, 2.0 mL) were added to the reaction mixture. The hydrogenation was
3
o
performed under H (600 psi) in a stainless steel autoclave at 25 C for 18 h. After carefully
2
releasing the hydrogen, the solvent was removed under reduced pressure. Purification was
performed by a silica gel column eluted with hexane/EtOAc to give desire product.
D (75%)
NHTs
nBu
D (24%)
H
N
cis
S5

D (67%)
NHTs
nBu
D (14%)
N
H
trans
5
. Synthesis of 3-Nitroquinolines 5
3
-Nitroquinoline derivatives can be conveniently synthesized according to the known
[1,2]
literature procedure.
The compounds 2-butyl-3-nitroquinoline (5a), 2-methyl-3-nitroquinoline
(
5b), 2-ethyl-3-nitroquinoline (5c), (E)-2-styryl-3-nitroquinoline (5i), 2-phenyl-3-nitroquinoline
5j) are known compounds.
(
5
.1. Synthesis of 3-Nitroquinolines 5d-h via Suzuki Coupling
[2]
Following a known literature report: A mixture of 2-chloro-3-nitroquinoline (150 mg, 0.72
mmol), boronic acid (0.86 mmol), Pd(PPh ) (83 mg, 0.07 mmol) and K CO (297 mg, 2.15 mmol)
3
4
2
3
in 1,4-dioxane (6 mL) was stirred at reflux for 18 h, then cooled to rt, diluted with water (15mL),
then extracted with CH Cl (15 mL×3). The combined organic layers were dried with Na SO .
2
2
2
4
After filtration, the solvent was removed under reduced pressure and the residue was purified by
flash chromatography on silica gel to yield the corresponding product.
[
[
1] M.-C. Yan, Z. Tu, C. Lin, S. Ko, J. Hsu, C.-F. Yao, J. Org. Chem.2004, 69, 1565.
2] G. A. Molander, C.-S. Yun, Tetrahedron 2002, 58, 1465.
S6

2
-Propyl-3-nitroquinoline (5d): 68% yield, light brown oil, R
f
= 0.70 (petroleum
1
ether/EtOAc 10:1). H NMR (400 MHz, CDCl
3
) δ = 8.72 (s, 1H), 8.12 (d, J = 8.5, 1H), 7.92 (d, J
=
8.2, 1H), 7.84-8.90 (m, 1H), 7.67-7.60 (m, 1H), 3.29-3.18 (m, 2H),
13
1
1
.94-1.84 (m, 2H), 1.06 (t, J = 7.4, 3H); C NMR (100 MHz, CDCl ) δ =
3
55.6, 148.8, 144.0, 133.2, 132.9, 129.3, 128.9, 128.0, 125.5, 38.4, 22.5,
+
1
4.3; HRMS Calculated for C H N O [M+H] 217.0977, found 217.0970.
12
13
2
2
2
-Isobutyl-3-nitroquinoline (5e): 33% yield, light brown oil, R
f
= 0.65 (petroleum
1
ether/EtOAc 10:1). H NMR (400 MHz, CDCl ) δ = 8.69 (s, 1H), 8.12 (d, J = 8.5, 1H), 7.92 (d, J
3
=
8.2, 1H), 7.89-7.83 (m, 1H), 7.63 (t, J = 7.6, 1H), 3.18 (d, J = 7.2, 2H), 2.26
13
(
dp, J = 13.6, 6.8, 1H), 0.98 (d, J = 6.7, 6H); C NMR (100 MHz, CDCl ) δ =
3
1
54.8, 148.7, 144.4, 133.0, 132.8, 129.3, 128.9, 128.0, 125.5, 44.6, 28.8, 22.7;
+
HRMS Calculated for C H N O [M+H] 231.1134, found 231.1130.
13
15
2
2
2
-Isopentyl-3-nitroquinoline (5f): 67% yield, brown oil, R
f
= 0.60 (petroleum ether/EtOAc
1
1
0:1). H NMR (400 MHz, CDCl
3
) δ = 8.71 (s, 1H), 8.11 (d, J = 8.4, 1H), 7.99-7.80 (m, 2H), 7.62
(
1
t, J = 7.5, 1H), 3.35-3.19 (m, 2H), 1.85-1.65 (m, 3H), 0.99 (d, J = 6.0, 6H);
3
3
C NMR (100 MHz, CDCl ) δ = 156.1, 148.8, 143.9, 133.3, 132.9, 129.2,
1
28.9, 127.9, 125.5, 38.1, 34.7, 28.6, 22.6; HRMS Calculated for
+
C H N O [M+H] 245.1290, found 245.1285.
14
17
2
2
2
-Hexyl-3-nitroquinoline (5g): 60% yield, brown oil, R
f
= 0.60 (petroleum ether/EtOAc
1
1
0:1). H NMR (400 MHz, CDCl
3
) δ = 8.68 (s, 1H), 8.09 (d, J = 8.5, 1H), 7.92-7.81 (m, 2H),
7
2
.64-7.56 (m, 1H), 3.30-3.17 (m, 2H), 1.89-1.75 (m, 2H), 1.40-1.53 (m,
1
3
H), 1.39-1.26 (m, 4H), 0.89 (dd, J = 9.4, 4.7, 3H); C NMR (100
MHz, CDCl ) δ = 155.7, 148.8, 143.9, 133.2, 132.8, 129.2, 128.9,
3
+
1
2
27.9, 125.4, 36.5, 31.7, 29.5, 29.1, 22.7, 14.2; HRMS Calculated for C H N O [M+H]
15
19
2
2
59.1447, found 259.1443.
o
2
-Phenethyl-3-nitroquinoline (5h): 49% yield, white solid, mp 118-120 C, R
f
= 0.45
1
(
petroleum ether/EtOAc 10:1). H NMR (400 MHz, CDCl
3
) δ = 8.75 (s, 1H), 8.16 (d, J = 8.5, 1H),
7
3
1
.96-7.85 (m, 2H), 7.69-7.62 (m, 1H), 7.38-7.28 (m, 4H), 7.26-7.19 (m, 1H),
1
3
.63-3.54 (m, 2H), 3.26-3.18 (m, 2H); C NMR (100 MHz, CDCl ) δ =
3
54.5, 148.9, 143.8, 141.4, 133.5, 133.1, 129.3, 129.0, 128.8, 128.7, 128.1,
+
1
26.3, 125.6, 38.5, 35.0; HRMS Calculated for C H N O [M+H] 279.1134, found 279.1135.
17
15
2
2
5.2. Synthesis of 3-Nitroquinolines 5k
[
1]
Following a known literature report: To a solution of 2-amino-5-methoxybenzaldehyde (5.6
mmol) in toluene (25 mL) was added (E)-1-nitrohex-1-ene (6.7 mmol). The resulting mixture was
o
placed in an oil bath and heated at 45 C for 9 h, then 1,4-diaza-bicyclo[2.2.2]octane (DABCO,
2
2
.8 mmol) was added, the mixture was stirred for another 5 h. After cooled to room temperature,
,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 8.4 mmol) was added and the solution was
vigorously stirred for 1.5 h. After evaporation of the solvent, the residue was purified by flash
S7

chromatography on silica gel to yield the product 5k.
-Butyl-6-methoxy-3-nitroquinoline (5k): 39% yield, light brown solid, mp 66-68 C, R =
o
2
f
1
0
.50 (petroleum ether/EtOAc 10:1). H NMR (400 MHz, CDCl ) δ = 8.59 (s, 1H), 7.98 (d, J = 9.3,
3
1
3
0
H), 7.49 (dd, J = 9.3, 2.8, 1H), 7.12 (d, J = 2.8, 1H), 3.94 (s, 3H),
.24-3.16 (m, 2H), 1.74-1.84 (m, 2H), 1.48 (dt, J = 14.9, 7.4, 2H),
1
3
.96 (t, J = 7.4, 3H); C NMR (100 MHz, CDCl ) δ = 158.6, 152.9,
3
1
45.0, 144.2, 131.6, 130.4, 126.6, 125.8, 105.4, 55.7, 35.8, 31.2, 22.8, 13.9; HRMS Calculated for
+
C H N O [M+H] 261.1239, found 261.1235.
14
17
2
3
6
. Synthesis of Quinolin-3-amines 1
2
To a solution of 5 (0.60 mmol) in a mixed solvent of ethanol and H O with a ratio of 4/1 (5
mL) was added iron powder (134 mg, 2.40 mmol) followed by HCl (0.1 M, 0.3 mL, 0.03 mmol),
o
and the resulting mixture was vigorously stirred at 85 C for 0.5-1.5 h. When the reduction
reaction was complete (determined by TLC), saturated NaHCO (5 mL) was added and the
3
mixture was filtered through celite. The combined organic layers were dried (Na SO ). After
2
4
filtration, the solvent was removed under reduced pressure and the crude product was pure enough
for further reaction.
In a 25 mL round-bottom flask, the crude product and phthalic anhydride were combined in
o
AcOH (5 mL). The resulting mixture was vigorously stirred at 120 C for 18h. The solvent was
removed under reduced pressure, the residue was resolved in CH Cl (10 mL) and washed with
2
2
saturated NaHCO (15 mL). The organic layer was dried (Na SO ) and was taken to dryness under
3
2
4
reduced pressure, the residue was purified by flash chromatography on silica gel to yield the
product.
o
2
-(2-Butylquinolin-3-yl)isoindoline-1,3-dione (1a): 83% yield, white solid, mp 150-151 C,
1
R
f
= 0.45 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.12 (d, J = 8.5, 1H),
8
2
.05-7.95 (m, 3H), 7.88-7.71 (m, 4H), 7.53 (t, J = 7.4, 1H), 2.92-2.80 (m,
13
H), 1.84-1.71 (m, 2H), 1.42-1.26 (m, 2H), 0.84 (t, J = 7.3, 3H); C NMR
(
100 MHz, CDCl ) δ = 167.7, 160.8, 148.2, 136.8, 134.9, 132.0, 130.6,
3
1
29.1, 127.8, 127.0, 126.7, 124.9, 124.2, 34.6, 30.8, 22.8, 14.0; HRMS Calculated for C H N O
21 19 2 2
+
[
M+H] 331.1447, found 331.1441.
2
-(2-Methylquinolin-3-yl)isoindoline-1,3-dione (1b): 80% yield, white solid, mp 249-251
o
1
C, R
f
= 0.30 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.10 (d, J = 8.5, 1H),
8
7
1
.05 (s, 1H), 8.03-7.95 (m, 2H), 7.82 (d, J = 8.0, 3H), 7.76 (t, J = 7.7, 1H),
1
3
.54 (t, J = 7.4, 1H), 2.63 (s, 3H); C NMR (100 MHz, CDCl ) δ = 167.3,
3
57.1, 148.0, 136.5, 134.9, 132.1, 130.7, 128.9, 127.9, 127.1, 126.8, 125.1,
+
1
24.2, 22.2; HRMS Calculated for C H N O [M+H] 289.0977, found 289.0970.
18
13
2
2
o
2
-(2-Ethylquinolin-3-yl)isoindoline-1,3-dione (1c): 78% yield, white solid, mp 230-232 C,
1
R
f
= 0.30 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.13 (d, J = 8.5, 1H),
S8

8
.02 (s, 1H), 7.97 (td, J = 5.2, 2.1, 2H), 7.85-7.72 (m, 4H), 7.56-7.49 (m, 1H), 2.89 (q, J = 7.5,
13
2
1
2
H), 1.34 (t, J = 7.5, 3H); C NMR (100 MHz, CDCl ) δ = 167.7, 161.4,
3
48.2, 136.8, 134.8, 132.1, 130.6, 129.1, 127.9, 127.0, 126.7, 124.8, 124.2,
+
8.0, 12.8; HRMS Calculated for C H N O [M+H] 303.1134, found
19
15
2
2
3
03.1109.
2
-(2-Propylquinolin-3-yl)isoindoline-1,3-dione (1d): 75% yield, white solid, mp 120-122
o
1
C, R
f
= 0.50 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.12 (d, J = 8.5, 1H),
8
1
0
.02 (s, 1H), 8.00 (d, J = 3.0, 2H), 7.82 (dd, J = 12.4, 7.1, 3H), 7.78-7.72 (m,
H), 7.53 (t, J = 7.4, 1H), 2.92-2.75 (m, 2H), 1.83 (dd, J = 15.2, 7.5, 2H),
1
3
.93 (t, J = 7.3, 3H); C NMR (100 MHz, CDCl ) δ = 167.7, 160.5, 148.2,
3
1
36.7, 134.9, 132.0, 130.6, 129.1, 127.8, 127.0, 126.7, 124.9, 124.2, 36.9, 22.0, 14.4; HRMS
+
Calculated for C H N O [M+H] 317.1290, found 317.1284.
20
17
2
2
2
-(2-Isobutylquinolin-3-yl)isoindoline-1,3-dione (1e): 75% yield, white solid, mp 148-150
o
1
C, R
f
= 0.55 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.13 (d, J = 8.1, 1H),
8
6
.01 (d, J = 6.6, 3H), 7.82 (d, J = 18.2, 3H), 7.78-7.71 (m, 1H), 7.54 (t, J =
1
3
.9, 1H), 2.75 (d, J = 6.7, 2H), 2.37-2.18 (m, 1H), 0.88 (d, J = 6.0, 6H); C
NMR (100 MHz, CDCl ) δ = 167.6, 160.0, 148.1, 136.6, 134.9, 132.0, 130.6,
3
1
29.1, 127.8, 126.9, 126.7, 125.3, 124.2, 43.8, 28.5, 22.9; HRMS Calculated for C H N O
21 19 2 2
+
[
M+H] 331.1447, found 331.1441.
2
-(2-Isopentylquinolin-3-yl)isoindoline-1,3-dione (1f): 56% yield, white solid, mp 177-178
o
1
C, R
f
= 0.55 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.12 (d, J = 8.5, 1H),
7
2
=
.99 (dd, J = 8.6, 6.5, 3H), 7.71-7.87 (m, 4H), 7.52 (t, J = 7.4, 1H),
.93-2.80 (m, 2H), 1.72-1.61 (m, 2H), 1.56 (tt, J = 13.2, 6.6, 1H), 0.81 (d, J
13
6.5, 6H); C NMR (100 MHz, CDCl ) δ = 167.7, 161.0, 148.2, 136.9,
3
1
34.9, 132.0, 130.6, 129.1, 127.8, 127.0, 126.7, 124.9, 124.1, 37.8, 33.0, 28.2, 22.5; HRMS
+
Calculated for C H N O [M+H] 345.1603, found 345.1596.
22
21
2
2
o
2
-(2-Hexylquinolin-3-yl)isoindoline-1,3-dione (1g): 62% yield, white solid, mp 106-107 C,
1
R
f
= 0.55 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.12 (d, J = 8.4, 1H),
7
2
4
.99 (dd, J = 9.9, 6.8, 3H), 7.88-7.70 (m, 4H), 7.52 (t, J = 7.4, 1H),
.94-2.77 (m, 2H), 1.87-1.69 (m, 2H), 1.26-1.40 (m, 2H), 1.10-1.26 (m,
1
3
H), 0.77 (t, 3H); C NMR (100 MHz, CDCl ) δ = 167.6, 160.8, 148.2,
3
1
1
36.8, 134.8, 132.0, 130.6, 129.1, 127.8, 127.0, 126.7, 124.9, 124.2, 35.0, 31.7, 29.4, 28.7, 22.6,
4.2; HRMS Calculated for C H N O [M+H]+ 359.1760, found 359.1751.
23
23
2
2
2
-(2-Phenethylquinolin-3-yl)isoindoline-1,3-dione (1h): 86% yield, white solid, mp
o
1
1
43-144 C, R
f
= 0.45 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.18 (d, J =
8
4
.5, 1H), 8.06 (s, 1H), 7.98 (dd, J = 5.0, 3.0, 2H), 7.81 (dd, J = 16.7, 6.7,
1
3
H), 7.57 (t, J = 7.5, 1H), 7.25-7.10 (m, 5H), 3.28-3.13 (m, 4H); C NMR
(
100 MHz, CDCl ) δ = 167.5, 159.4, 148.1, 142.0, 136.8, 134.9, 132.0,
3
1
30.7, 129.2, 128.6, 128.6, 127.9, 127.1, 126.9, 126.1, 124.9, 124.2, 36.6, 34.4; HRMS Calculated
+
for C H N O [M+H] 379.1447, found 379.1439.
25
19
2
2
(
E)-2-(2-Styrylquinolin-3-yl)isoindoline-1,3-dione (1i): 72% yield, white solid, mp
o
1
2
44-246 C, R
f
= 0.40 (petroleum ether/CH
2
Cl
2
1:1). H NMR (400 MHz, CDCl
3
) δ = 8.18 (d, J =
S9

8
.5, 1H), 8.13–7.99 (m, 4H), 7.90–7.85 (m, 2H), 7.84-7.75 (m, 2H), 7.58-7.46 (m, 3H), 7.34-7.26
1
3
(
m, 3H), 7.08 (d, J = 15.6, 1H); C NMR (100 MHz, CDCl ) δ = 167.4,
3
1
1
52.9, 148.2, 136.9, 136.7, 136.6, 134.8, 131.9, 130.8, 129.4, 128.8, 128.6,
27.7, 127.6, 127.3, 126.8, 124.2, 124.2, 122.0; HRMS Calculated for
C H N O [M+H]+ 377.1290, found 377.1281.
25
17
2
2
2
-(2-Phenylquinolin-3-yl)isoindoline-1,3-dione (1j): 83% yield, white solid, mp 257-259
o
1
C, R
f
= 0.20 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.28-8.18 (m, 2H),
7
.89 (d, J = 8.1, 1H), 7.87-7.78 (m, 3H), 7.74 (dd, J = 5.3, 3.1, 2H), 7.61 (t, J
13
=
7.6, 1H), 7.59-7.53 (m, 2H), 7.31 (d, J = 6.2, 3H); C NMR (100 MHz,
CDCl ) δ = 167.4, 158.3, 148.2, 138.7, 137.6, 134.7, 131.8, 131.0, 129.9,
3
+
1
3
28.9, 128.7, 128.2, 127.9, 127.5, 124.3, 124.1; HRMS Calculated for C H N O [M+H]
23 15 2 2
51.1134, found 351.1126.
2
-(2-Butyl-6-methoxyquinolin-3-yl)isoindoline-1,3-dione (1k): 67% yield, white solid, mp
o
1
1
30-132 C, R
f
= 0.30 (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl
3
) δ = 8.00 (d, J =
.4, 3H), 7.90 (s, 1H), 7.82 (d, J = 2.8, 2H), 7.39 (d, J = 9.1, 1H),
.02 (s, 1H), 3.90 (s, 3H), 2.87-2.75 (m, 2H), 1.80-1.68 (m, 2H),
9
7
1
13
.40-1.25 (m, 2H), 0.83 (t, J = 7.3, 3H); C NMR (100 MHz, CDCl )
3
δ = 167.7, 158.0, 157.9, 144.4, 135.5, 134.8, 132.1, 130.5, 128.0, 125.2, 124.1, 123.4, 105.1, 55.7,
+
3
4.4, 30.9, 22.8, 14.0; HRMS Calculated for C H N O [M+H] 361.1552, found 361.1548.
22
21
2
3
7
. Asymmetric Hydrogenation of Quinolin-3-amines 1
In a nitrogen-filled glove box, a mixture of [Ir(COD)Cl] (1.3 mg, 0.002 mmol) and
2
(R)-DifluorPhos (3.0 mg, 0.0044 mmol) in PhMe/THF (3:1, 1.0 mL) was stirred at room
temperature for 10 min, then substrate 1 (0.10 mmol) and I (1.3 mg, 0.005 mmol) together with
2
the solvent (2.0 mL) were added to the reaction mixture. The hydrogenation was performed under
2
H (200 psi) in a stainless steel autoclave for 18 h. After carefully releasing the hydrogen, the
solvent was removed under reduced pressure. Purification was performed by a silica gel column
eluted with hexane/EtOAc to give desire product. The enantiomeric excesses were determined by
chiral HPLC.
2
-((2R,3R)-2-Butyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2a): 94% yield,
2
0
9
3% ee, light yellow oil, [α] = +181.6 (c 0.64, CH
2
2 f
Cl ), R = 0.60 (petroleum ether/EtOAc 5:1).
D
1
3
H NMR (400 MHz, CDCl ) δ = 7.82 (dt, J = 7.0, 3.5, 2H), 7.76-7.66 (m,
2
4
H), 7.01 (dd, J = 14.8, 7.3, 2H), 6.72-6.64 (m, 1H), 6.57 (d, J = 7.8, 1H),
.78-4.87 (m, 1H), 4.06 (s, 1H), 3.93 (dd, J = 16.6, 9.6, 1H), 3.45 (d, J =
1
0
1
0.3, 1H), 3.04 (dd, J = 16.6, 6.2, 1H), 1.52-1.65 (m, 1H), 1.51-1.38 (m, 2H), 1.36-1.20 (m, 3H),
1
3
.85 (t, J = 7.1, 3H); C NMR (100 MHz, CDCl ) δ = 169.0, 143.4, 134.2, 132.0, 129.2, 127.2,
3
23.4, 120.0, 117.8, 114.6, 54.6, 50.6, 30.5, 28.8, 27.4, 22.9, 14.3; HRMS Calculated for
S10

+
o
C
21
H
23
N
2
O
2
[M+H] 335.1760, found 335.1753; HPLC: Chiracel OD-H column, 254 nm, 30 C,
n-hexane/i-propanol = 70/30, flow = 0.7 mL/min, retention time 12.1 min (major) and 14.5 min.
2
-((2R,3R)-2-Methyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2b): 97%
o
20
yield, 81% ee, light yellow solid, mp 167-169 C, [α]
2 2 f
= +170.2 (c 0.56, CH Cl ), R = 0.40
D
1
(
petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl ) δ = 7.87-7.78 (m,
3
2
7
H), 7.76-7.66 (m, 2H), 7.02 (t, J = 7.8, 2H), 6.70 (t, J = 7.4, 1H), 6.56 (d, J =
.9, 1H), 4.75-4.85 (m, 1H), 3.90 (dd, J = 16.6, 9.2, 2H), 3.68 (dt, J = 9.9, 4.9,
13
1
1
H), 3.07 (dd, J = 16.7, 6.2, 1H), 1.22 (dd, J = 6.5, 2.3, 3H); C NMR (100 MHz, CDCl ) δ =
3
69.0, 143.5, 134.2, 132.0, 129.0, 127.2, 123.4, 120.1, 118.0, 114.6, 50.5, 50.0, 27.0, 18.1; HRMS
+
Calculated for C H N O [M+H] 293.1290, found 293.1286; HPLC: Chiracel OD-H column,
1
8
17
2
2
o
2
54 nm, 30 C, n-hexane/i-propanol = 70/30, flow = 0.7 mL/min, retention time 21.3 min (major)
and 28.0 min.
2
-((2R,3R)-2-Ethyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2c): 97% yield,
o
20
9
0% ee, light yellow solid, mp 161-163 C, [α]
= +197.7 (c 0.60, CH Cl ), R = 0.45
D 2 2 f
1
(
petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl ) δ = 7.86-7.78 (m,
3
2
1
H), 7.74-7.66 (m, 2H), 7.02 (dd, J = 15.1, 7.5, 2H), 6.69 (dd, J = 10.7, 4.0,
H), 6.58 (d, J = 7.9, 1H), 4.81-4.89 (m, 1H), 4.11 (s, 1H), 3.95 (dd, J = 16.5,
9
3
.8, 1H), 3.36 (dt, J = 9.7, 3.6, 1H), 3.02 (dd, J = 16.6, 6.2, 1H), 1.68-1.45 (m, 2H), 0.97 (t, J = 7.4,
13
H); C NMR (100 MHz, CDCl ) δ = 169.1, 143.3, 134.2, 132.0, 129.2, 127.2, 123.4, 120.2,
3
+
117.8, 114.6, 56.2, 50.5, 27.2, 23.6, 10.9; HRMS Calculated for C H N O [M+H] 307.1447,
1
9
19
2
2
o
found 307.1443; HPLC: Chiracel OD-H column, 254 nm, 30 C, n-hexane/i-propanol = 70/30,
flow = 0.7 mL/min, retention time 14.0 min (major) and 21.2 min.
2
-((2R,3R)-2-Propyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2d): 94%
o
20
yield, 92% ee, light yellow solid, mp 157-159 C, [α]
2 2 f
= +204.3 (c 0.60, CH Cl ), R = 0.45
D
1
(
petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl ) δ = 7.86-7.78 (m,
3
2
1
H), 7.72 (td, J = 5.2, 2.0, 2H), 7.02 (dd, J = 14.3, 7.4, 2H), 6.68 (t, J = 7.4,
H), 6.57 (d, J = 7.9, 1H), 4.78-4.87 (m, 1H), 4.06 (s, 1H), 3.94 (dd, J = 16.6,
9
7
.6, 1H), 3.47 (dt, J = 10.2, 3.2, 1H), 3.04 (dd, J = 16.6, 6.2, 1H), 1.65-1.24 (m, 4H), 0.89 (t, J =
13
.1, 3H); C NMR (100 MHz, CDCl ) δ = 169.0, 143.4, 134.2, 132.0, 129.2, 127.2, 123.4, 120.2,
3
+
1
3
7
17.8, 114.6, 54.3, 50.6, 32.8, 27.3, 19.7, 14.2; HRMS Calculated for C H N O [M+H]
20 21 2 2
o
21.1603, found 321.1595; HPLC: Chiracel OD-H column, 254 nm, 30 C, n-hexane/i-propanol =
0/30, flow = 0.7 mL/min, retention time 12.8 min (major) and 17.1 min.
2
-((2R,3R)-2-Isobutyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2e): 99%
20
yield, 94% ee, light yellow oil, [α]
D
2 2 f
= +203.2 (c 0.66, CH Cl ), R = 0.65 (petroleum
1
ether/EtOAc 5:1). H NMR (400 MHz, CDCl ) δ = 7.83 (dd, J = 5.4, 3.0, 2H),
3
7
6
.71 (dd, J = 5.5, 2.9, 2H), 7.02 (dd, J = 14.2, 7.2, 2H), 6.69 (t, J = 7.4, 1H),
.57 (d, J = 7.9, 1H), 4.86-4.75 (m, 1H), 4.00 (s, 1H), 3.87 (dd, J = 16.7, 9.1,
1
1
1
H), 3.62-3.51 (m, 1H), 3.08 (dd, J = 16.7, 6.3, 1H), 1.81-1.65 (m, 1H), 1.64-1.50 (m, 1H),
13
.29-1.15 (m, 1H), 0.88 (dd, J = 21.4, 6.6, 6H); C NMR (100 MHz, CDCl ) δ = 169.0, 143.6,
3
34.2, 131.9, 129.1, 127.2, 123.5, 120.3, 117.9, 114.7, 52.2, 50.6, 39.7, 27.6, 24.7, 24.1, 21.6;
+
HRMS Calculated for C H N O [M+H] 335.1760, found 335.1755; HPLC: Chiracel OD-H
2
1
23
2
2
o
column, 254 nm, 30 C, n-hexane/i-propanol = 70/30, flow = 0.7 mL/min, retention time 10.2 min
major) and 17.9 min.
(
S11

2
-((2R,3R)-2-Isopentyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2f): 97%
2
0
yield, 88% ee, yellow oil, [α]
= +176.8 (c 0.68, CH Cl ), R = 0.65 (petroleum ether/EtOAc
D 2 2 f
1
5
:1). H NMR (400 MHz, CDCl ) δ = 7.83 (dd, J = 4.7, 3.1, 2H), 7.76-7.62
3
(
m, 2H), 7.02 (dd, J = 15.5, 7.4, 2H), 6.69 (t, J = 7.1, 1H), 6.57 (d, J = 7.8,
H), 4.88-4.74 (m, 1H), 4.03 (s, 1H), 3.90 (dd, J = 16.5, 9.4, 1H), 3.47-3.34
m, 1H), 3.05 (dd, J = 16.6, 5.8, 1H), 1.58-1.41 (m, 3H), 1.29-1.38 (m, 1H),
1
(
1
3
1
1
.22-1.12 (m, 1H), 0.85-0.77 (m, 6H); C NMR (100 MHz, CDCl ) δ = 169.0, 143.5, 134.2,
3
32.0, 129.1, 127.2, 123.4, 120.2, 117.8, 114.6, 55.0, 50.5, 35.8, 28.7, 28.2, 27.6, 23.0, 22.6;
+
HRMS Calculated for C H N O [M+H] 349.1916, found 349.1910; HPLC: Chiracel OD-H
2
2
25
2
2
o
column, 254 nm, 30 C, n-hexane/i-propanol = 70/30, flow = 0.6 mL/min, retention time 13.4 min
(
major) and 15.3 min.
2
-((2R,3R)-2-Hexyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2g): 97% yield,
2
0
1
9
2% ee, yellow oil, [α]
D
2 2 f
= +180.4 (c 0.70, CH Cl ), R = 0.70 (petroleum ether/EtOAc 5:1). H
NMR (400 MHz, CDCl ) δ = 7.82 (dt, J = 6.9, 3.5, 2H), 7.75-7.67 (m,
NPhth
3
2
H), 7.01 (dd, J = 15.1, 7.4, 2H), 6.68 (t, J = 7.3, 1H), 6.57 (d, J = 7.9,
N
H
1H), 4.77-4.88 (m, 1H), 4.05 (s, 1H), 3.92 (dd, J = 16.6, 9.6, 1H), 3.45
(
(
d, J = 10.2, 1H), 3.04 (dd, J = 16.6, 6.2, 1H), 1.53-1.64 (m, 1H), 1.44 (t, J = 9.8, 2H), 1.31-1.18
1
3
m, 7H), 0.83 (t, J = 6.7, 3H); C NMR (100 MHz, CDCl ) δ = 168.8, 143.3, 134.0, 131.8, 129.0,
3
1
27.0, 123.2, 120.0, 117.6, 114.5, 54.4, 50.4, 31.8, 30.6, 29.3, 27.2, 26.5, 22.6, 14.0; HRMS
+
Calculated for C H N O [M+H] 363.2073, found 363.2066; HPLC: Chiracel OD-H column,
2
3
27
2
2
o
2
54 nm, 30 C, n-hexane/i-propanol = 70/30, flow = 0.7 mL/min, retention time 11.3 min (major)
and 12.8 min.
2
-((2R,3R)-2-Phenethyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2h): 99%
2
0
yield, 93% ee, yellow oil, [α]
= +156.0 (c 0.76, CH Cl ), R = 0.50 (petroleum ether/EtOAc
D 2 2 f
1
5
7
:1). H NMR (400 MHz, CDCl ) δ = 7.86-7.77 (m, 2H), 7.74-7.65 (m, 2H),
3
.20 (t, J = 7.2, 2H), 7.12 (t, J = 8.5, 3H), 7.01 (dd, J = 13.1, 7.0, 2H), 6.69
(
t, J = 7.0, 1H), 6.48 (d, J = 7.9, 1H), 4.77-4.85 (m, 1H), 3.94 (dd, J = 16.6,
9
1
1
.7, 2H), 3.49 (dt, J = 9.2, 3.5, 1H), 3.03 (dd, J = 16.6, 6.2, 1H), 2.74-2.95 (m, 1H), 2.71-2.58 (m,
13
H), 2.00-1.79 (m, 2H); C NMR (100 MHz, CDCl ) δ = 168.8, 143.0, 141.4, 134.0, 131.8, 123.0,
3
28.5, 128.4, 127.1, 126.0, 123.3, 120.0, 117.8, 114.7, 54.1, 50.4, 32.9, 32.0, 27.2; HRMS
+
Calculated for C H N O [M+H] 383.1760, found 383.1753; HPLC: Chiracel OD-H column,
2
5
23
2
2
o
2
54 nm, 30 C, n-hexane/i-propanol = 70/30, flow = 0.7 mL/min, retention time 20.2 min (major)
and 57.8 min.
2-((2R,3R)-2-Phenethyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione [2h, for the
asymmetric hydrogenation of (E)-2-(2-styrylquinolin-3-yl)isoindoline-1,3-dione (1i)]: 97% yield,
9
0% ee, yellow oil, R
f
= 0.50 (petroleum ether/EtOAc 5:1). HPLC: Chiracel
o
OD-H column, 254 nm, 30 C, n-hexane/i-propanol = 70/30, flow = 0.7
mL/min, retention time 20.3 min (major) and 58.5 min.
2
-((2R,3R)-2-Phenyl-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2j): 97%
o
20
yield, 40% ee, light yellow solid, mp 253-255 C, [α]
2 2 f
= +135.4 (c 0.70, CH Cl ), R = 0.40
D
1
NPhth (petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl ) δ = 7.77-7.63 (m,
3
4
H), 7.24-7.00 (m, 7H), 6.72 (t, J = 7.4, 1H), 6.62 (d, J = 7.9, 1H), 4.97 (dt, J
N
Ph
H
= 10.4, 5.1, 1H), 4.76 (d, J = 4.6, 1H), 4.31 (s, 1H), 3.95 (dd, J = 16.3, 10.6,
S12

1
3
1
1
3
H), 3.04 (dd, J = 16.3, 5.3, 1H); C NMR (100 MHz, CDCl ) δ = 168.3, 143.7, 141.3, 134.1,
31.7, 129.2, 128.5, 128.1, 127.6, 127.5, 123.3, 119.5, 117.7, 113.6, 57.9, 51.2, 26.7; HRMS
+
Calculated for C H N O [M+H] 355.1447, found 355.1439; HPLC: Chiracel OD-H column,
2
3
19
2
2
o
2
54 nm, 30 C, n-hexane/i-propanol = 70/30, flow = 0.7 mL/min, retention time 18.7 min (major)
and 33.0 min.
2
-((2R,3R)-2-Butyl-6-methoxy-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione (2k):
20
9
7% yield, 86% ee, yellow oil, [α]
D
= +146.3 (c 0.70, CH
2
Cl
2
), R
f
= 0.45 (petroleum
1
ether/EtOAc 5:1). H NMR (400 MHz, CDCl ) δ = 7.85-7.79 (m, 2H),
3
7
1
.71 (td, J = 5.2, 2.1, 2H), 6.66 (dd, J = 8.6, 2.8, 1H), 6.60 (d, J = 2.7,
H), 6.55 (d, J = 8.6, 1H), 4.77-4.85 (m, 1H), 3.78 (dd, J = 17.0, 8.3,
1
1
1
H), 3.74 (s, 3H), 3.38 (dt, J = 7.0, 3.2, 1H), 3.09 (dd, J=17.0, 6.8, 1H), 1.53-1.42 (m, 2H),
1
3
.36-1.23 (m, 4H), 0.85 (t, J = 7.1, 3H); C NMR (100 MHz, CDCl ) δ = 168.8, 152.3, 137.5,
3
34.0, 131.8, 123.2, 121.7, 115.9, 114.1, 113.1, 55.7, 55.0, 50.3, 30.2, 28.6, 28.0, 22.7, 14.1;
+
HRMS Calculated for C H N O [M+H] 365.1865, found 365.1861; HPLC: Chiracel OD-H
2
2
25
2
3
o
column, 254 nm, 30 C, n-hexane/i-propanol = 70/30, flow = 0.7 mL/min, retention time 12.8 min
major) and 24.2 min.
(
8. Removal of Phth Group and Determination of Absolute Configuration of 2a
[3]
Following a known literature report: A magnetically stirred suspension of 2a (26 mg, 0.08
mmol) in EtOH (3 mL) was treated with hydrazine monohydrate (0.10 mL) and the resulting
mixture stirred at 60 °C under N for 2 h. The cooled mixture was concentrated under reduced
2
2 2 2
pressure and the residue partitioned between CH Cl (10 mL) and H O (10 mL). The separated
aqueous phase was then extracted with CH Cl (10 mL×2), the combined organic fractions dried
2
2
(
MgSO ) and concentrated under reduced pressure. The ensuing residue was subjected to flash
4
chromatography to afford 3 as a colourless oil.
In a 25 mL round-bottom flask, 3 and triethylamine (9.1 mg, 13 μL) were combined in
CH Cl (4.0 mL) under N . The flask was cooled in an ice bath, to which was slowly added the
2
2
2
solution of p-toluene sulfonyl chloride (TsCl) in CH Cl (4.0 mL). The ice bath was allowed to
2
2
warm to room temperature and the mixture was stirred for 2 h. The reaction mixture was washed
with HCl (1 M) and brine. The organic layer was dried (Na SO ) and was taken to dryness under
2
4
reduced pressure and the residue was purified by flash chromatography on silica gel to yield
product 4.
After recrystallization from solvent CH Cl /hexane, >99% ee was obtained. The absolute
2
2
configuration was determined to be cis-(R,R) based on single-crystal X-ray diffraction analysis of
[
3] M. Davoust, J. A. Kitching, M. J. Fleming, M. Lautens, Chem. Eur. J. 2010, 16, 50.
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4
. CCDC 962689 contains the supplementary crystallographic data. These can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.
(
2R,3R)-2-Butyl-1,2,3,4-tetrahydroquinolin-3-amine (3): 94% yield, 92% ee, light yellow
o
20
1
solid, mp 83-85 C, [α]
2 2 3
= +29.6 (c 0.22, CH Cl ). H NMR (400 MHz, CDCl ) δ = 6.97 (t, J =
D
8
3
1
.1, 2H), 6.63 (t, J = 7.3, 1H), 6.49 (d, J = 7.8, 1H), 3.23 (t, J = 6.7, 1H),
.17 (s, 1H), 3.07 (dd, J = 16.3, 4.5, 1H), 2.63 (dd, J = 16.3, 3.0, 1H),
.61-1.52 (m, 1H), 1.47 (dd, J = 14.3, 7.6, 1H), 1.38 (dd, J = 8.1, 5.1, 4H),
1
3
0
5
2
.94 (t, J = 7.0, 3H). C NMR (100 MHz, CDCl ) δ = 143.8, 130.6, 126.9, 118.7, 117.6, 113.8,
3
+
5.2, 46.2, 36.8, 31.9, 28.1, 22.8, 14.1; HRMS Calculated for C H N [M+H] 205.1705, found
13
21
2
05.1701; HPLC (corresponding N-4-toluenesulfonyl derivative): Chirapak AD-H column, 254
o
nm, 30 C, n-hexane/i-propanol = 80/20, flow = 0.9 mL/min, retention time 11.7 min (major) and
1
3.7 min.
4
-Methyl-N-((2S,3S)-2-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamide (4):
o
20
8
1% yield, >99% ee, white solid, mp 164-166 C, [α]
D
2 2 f
= -46.5 (c 0.20, CH Cl ), R = 0.60
1
(
petroleum ether/EtOAc 5:1). H NMR (400 MHz, CDCl ) δ = 7.72 (d, J =
3
7
6
.5, 2H), 7.27 (d, J = 8.3, 2H), 6.98 (t, J = 7.4, 1H), 6.77 (d, J = 7.3, 1H),
.63 (t, J = 7.1, 1H), 6.47 (d, J = 7.8, 1H), 4.92 (d, J = 9.0, 1H), 3.72 (d, J =
7
3
1
.6, 1H), 3.62 (s, 1H), 3.18 (d, J = 6.2, 1H), 2.86 (d, J = 16.5, 1H), 2.57 (d, J = 16.5, 1H), 2.42 (s,
1
3
H), 1.06-1.45 (m, 6H), 0.83 (t, J = 5.5, 3H); C NMR (100 MHz, CDCl ) δ = 143.7, 143.4, 138.9,
3
30.6, 129.8, 127.4, 127.2, 118.6, 118.0, 114.4, 55.0, 48.5, 34.5, 31.8, 27.8, 22.8, 21.7, 14.1;
+
HRMS Calculated for C H N O S [M+H] 359.1793, found 359.1790; Chirapak AD-H column,
20
27
2
2
o
2
54 nm, 30 C, n-hexane/i-propanol = 80/20, flow = 0.9 mL/min, retention time 11.7 min (major).
Figure 1. The Absolute Configuration of 4.
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9. Copy of NMR and HPLC for racemic and chiral compounds
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