Asymmetric Hydrogenation of β-Secondary Amino Ketones Catalyzed by a Ruthenocenyl Phosphino-oxazoline-ruthenium Complex (RuPHOX-Ru): The Synthesis of γ-Secondary Amino Alcohols

Article abstract of DOI:10.1002/adsc.201500653

A ruthenocenyl phosphino-oxazoline-ruthenium complex (RuPHOX-Ru) was applied successfully to the asymmetric hydrogenation of β-secondary amino ketones, directly affording the corresponding chiral γ-secondary amino alcohols in up to 99% yield and with 99% ee. Reaction with β-(benzylamino)-1-phenylpropan-1-one could be performed on a gram-scale with a relatively low catalyst loading (up to 2000 S/C). The resulting hydrogenated product could be used for the synthesis of synthetically useful compounds.

Full text of DOI:10.1002/adsc.201500653

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DOI: 10.1002/adsc.201500653
Asymmetric Hydrogenation of b-Secondary Amino Ketones
Catalyzed by a Ruthenocenyl Phosphino-oxazoline-ruthenium
Complex (RuPHOX-Ru): the Synthesis of g-Secondary Amino
Alcohols
Jianxia Wang,a Yanzhao Wang,b Delong Liu,a,* and Wanbin Zhanga,b,*
a
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, Peopleꢀs Republic of China
E-mail: dlliu@sjtu.edu.cn
b
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
Peopleꢀs Republic of China
Fax: (+86)-21-5474-3265; phone: (+86)-21-5474-3265; e-mail: wanbin@sjtu.edu.cn
Received: July 7, 2015; Revised: July 28, 2015; Published online: October 14, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500653.
Abstract:
A
ruthenocenyl phosphino-oxazoline- (up to 2000 S/C). The resulting hydrogenated prod-
ruthenium complex (RuPHOX-Ru) was applied suc- uct could be used for the synthesis of synthetically
cessfully to the asymmetric hydrogenation of b-sec- useful compounds.
ondary amino ketones, directly affording the corre-
sponding chiral g-secondary amino alcohols in up to Keywords: asymmetric hydrogenation; RuPHOX-
99% yield and with 99% ee. Reaction with b-(benzyl- Ru; ruthenocenyl phosphino-oxazoline-ruthenium
amino)-1-phenylpropan-1-one could be performed complex; b-secondary amino ketones; g-secondary
on a gram-scale with a relatively low catalyst loading amino alcohols; synthesis
Introduction
access g-secondary amino alcohols from b-secondary
amino ketones directly are relatively rare, probably
In recent years, the preparation of chiral g-secondary due to the unstable nature of the starting materi-
amino alcohols has gained much attention due to als.[8–10] Achiwa disclosed the asymmetric hydrogena-
their potential use as drugs and bioactive com- tion of N-methyl b-secondary amino ketones using
pounds.[1–4] For example, they are important scaffolds
for norepinephrine reuptake inhibiting antidepres-
sants 1,[1] inhibitors of D2 and HT2 receptors 2a,[2] an-
ticancer agents 3,[3] and cyclic sulfamidates 4 which
possess multiple uses (Figure 1).[4] Additionally, chiral
g-secondary amino alcohols, in conjunction with metal
salt complexes, are useful for asymmetric catalytic re-
actions.[5]
Owing to the atom efficiency and minimal environ-
mental impact of asymmetric hydrogenation reactions,
one of the most promising methods for the synthesis
of chiral g-secondary amino alcohols is via the hydro-
genation of prochiral b-amino ketones.[6] However,
the majority of research has focused on the synthesis
of chiral g-tertiary amino alcohols via the asymmetric
hydrogenation of b-tertiary amino ketone precur-
sors.[7] A deprotection process is essential for the
preparation of the desired g-secondary amino alco-
hols. Useful methodologies which can be used to Figure 1. Potential drugs and bioactive compounds.
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Asymmetric Hydrogenation of b-Secondary Amino Ketones
a (2S,4S)-MCPPM-Rh complex, giving the corre- Results and Discussion
sponding chiral g-secondary amino alcohols in quanti-
tative yields but only 80% ee.[8] Zhang developed We first carried out the RuPHOX-Ru-catalyzed
a Rh-duanphos-catalyzed asymmetric hydrogenation asymmetric hydrogenation of b-(benzylamino)-1-phe-
of functionalized b-secondary amino ketones for the nylpropan-1-one (5a) under 50 bar H2 pressure in
preparation of N-methyl-substituted g-secondary a mixed solvent of toluene and water in the presence
amino alcohols in up to 92% yield and 99% ee.[9] of KOH at 258C – the optimal reaction conditions de-
Most recently, our group reported a Rh-bisphosphine scribed in our previous work.[13f] The hydrogenated
system-catalyzed asymmetric hydrogenation of b-sec- product 2a, which bears an N-benzyl substituent is
ondary amino ketones using ZnCl2 as a catalyst acti- often encountered in drug products and bioactive sub-
vator, providing the chiral g-secondary amino alcohols stances; it can be transformed to the g-primary amino
in 90–94% yields and with 90–99% enantioselectivi- alcohol via a simple deprotection process. However,
ties.[10] To the best of our knowledge, no chiral Ru cat- the above reaction conditions did not provide any of
alyst system has been applied to the asymmetric hy- the desired product 2a. Instead, a significant amount
drogenation of b-secondary amino ketones until now of by-product 6 was obtained. Unreacted starting ma-
(Scheme 1).[11]
terial 5a was also recovered [Scheme 2, Eq. (1), 5a/
6=54/46].
Scheme 1. Asymmetric hydrogenation catalyzed by chiral
Rh and Ru complexes.
The development of chiral catalysts via the fine-
tuning of steric, geometric and electronic properties
has greatly improved catalytic behavior in asymmetric
catalysis.[12] We have developed a ruthenocenyl phos-
phino-oxazoline-ruthenium complex (RuPHOX-Ru,
Scheme 1) which has shown promising catalytic activi-
ty in many asymmetric reactions due to its dual reac-
Scheme 2. Preliminary study under previous reaction condi-
tions.
This can be explained via competitive elimination
tion sites and large steric hindrance.[13] We have previ- of 5a to preferentially form conjugated enone 7 under
ously carried out asymmetric hydrogenations of b-ter- the action of KOH. The by-product 6 is then formed
tiary amino ketones and b-imide ketones with the bi- via a tandem reaction between 7 and another mole-
metallic RuPHOX-Ru complex to give both g-tertiary cule of 5a [Scheme 2, Eq. (2)]. However, a base is re-
and g-primary amino alcohols, respectively, in quanti- quired for the catalytic cycle. As shown in Scheme 2,
tative conversions and with up to 99.9% ee.[13f,h] RuPHOX-Ru can react with a molecule of H2 in the
Herein, we report that the RuPHOX-Ru catalytic presence of KOH to give Ru species 8. This complex
system could also be used for the asymmetric hydro- is proposed to be the active calaytic species for the
genation of b-secondary amino ketones for the direct hydrogenation of 5a to the product 2a [Scheme 2, Eq.
synthesis of g-secondary amino alcohols (Scheme 1).
(3)].[13f]
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Jianxia Wang et al.
Table 1. Screening of base.[a]
Table 2. Screening of solvent and H2 pressure.[a]
Entry
Base
2a/6[b]
ee [%][c]
Entry
H2 (bar)
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
KOH
90/10
89/11
80/20
85/15
77/23
70/30
94/6
94
69
92
87
90
92
95
96
1
2
3
4
5
6
7
8
50
50
50
50
50
60
40
20
MeOH
EtOH
i-PrOH
toluene
toluene/H2O
EtOH
97
99
93
trace
trace
98
98
98
96
98
97
-
NaOH
K2CO3
Na2CO3
KHCO3
NaHCO3
Et3N
-
96
97
96
EtOH
EtOH
DBU
99/1
[a]
Conditions: RuPHOX-Ru (0.5 mol%), base (10 mol%),
solvent (3 mL) and H2 (50 bar).
[a]
As in Table 1 using DBU as a base.
Isolated yields.
As in Table 1.
[b]
[c]
[b]
[c]
Determined by 1H NMR.
Determined by chiral HPLC analysis of the N-acyl deriv-
ative of 2a using a AD-H column.
ing: using DBU as a base in EtOH, under 50 bar H2
We envisaged that the reaction conditions could be pressure.
improved to increase the yield of the desired product Under the optimized reaction conditions, the sub-
2a and surpress the production of 6. As expected, re- strate scope (5a–t) was explored (Table 3). When sub-
placement of toluene/H2O with MeOH gave 2a in strates bearing electron-donating groups on the aro-
good yield and ee, with the accompanying by-product matic rings were examined, both excellent yields and
6 (Table 1, entry 1). Several other inorganic salts were enantioselectivies were obtained. Substrates bearing
then used as bases in MeOH. The reactions proceed- ortho-, meta- and para-Me groups were all successful-
ed smoothly with excellent enantioselectivities being ly reacted (entries 2–4). A substrate bearing a para-
obtained (entries 2–6). However, formation of signifi- MeO group afforded its corresponding product with
cant amounts of by-product 6 persisted. To our de- quantitative yield and 99% ee (entry 5). However,
light, the use of organic bases such as Et3N greatly only 93% ee was obtained for a substrate bearing
improved the ratio of 2a and provided excellent ee a phenyl group at the para-position of the phenyl ring
(entry 7). Thus, 2a can be obtained in almost quantita- (entry 6). Aromatic rings bearing multiple electron-
tive conversion and with 96% ee when DBU is used donating groups, such as di-Me and di-MeO substitu-
as a base (entry 8).
ents, all gave excellent results (entries 7 and 8). Sub-
The absolute configuration of 2a was determined strates bearing electron-withdrawing groups, such as
by comparing the sign of the optical rotation with re- a Cl atom, were also successfully reacted. However,
ported data.[14]
a sharp decrease in enantioselectivity was observed
The effect of solvent on this asymmetric hydrogena- for a substrate with a Cl atom at the ortho-position of
tion reaction was examined using DBU as a base the phenyl ring (entries 9–11). Substrates with F and
(Table 2). Several commonly used protic alcohol sol- Br groups at the para-position of the phenyl ring were
vents such as MeOH, EtOH and i-PrOH were examined and their corresponding products were ob-
screened. EtOH was found to be the best solvent ac- tained with both high yields and excellent enantiose-
cording to chemical yields and enantioselectivities lectivities (entries 12 and 13). The reaction conditions
(entries 1–3). For comparison, toluene and mixed tol- were also amenable for substrates bearing naphthyl
uene/H2O solvent systems were examined and only and furyl substituents (entries 14 and 15).
trace amounts of the desired product were obtained
The N-benzyl group could be replaced by N-aro-
(entries 4 and 5). H2 pressure has little effect on the matic substituents while retaining excellent catalytic
enantioselectivity. A slightly higher enantioselecitivity behavior. Excellent yields and enantioselectivities
was obtained when the reaction was carried out under were also obtained with regard to N-aromatic sub-
50 bar H2 pressure (entries 6–8). Therefore, the opti- strates possessing para-substituted Ar groups (en-
mal reaction conditions were found to be the follow- tries 16–20).
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Asymmetric Hydrogenation of b-Secondary Amino Ketones
Table 3. Scope screening.[a]
2a was obtained in 75% yield and with 93% ee
(Scheme 3). The g-secondary amino alcohol 2a can be
used directly as a drug candidate[2] or be transformed
to other bioactive compounds. For example, 2a could
be converted to a cyclic sulfamidate 9 in 71% yield
without any loss in enantioselectivity. And 9 can be
used for the construction of amine derivatives bearing
quaternary stereocenters, potential building blocks for
g-peptides and foldamer chemistry.[15] Alternatively,
the benzyl group of 2a can be removed with
Pd(OH)2/C (20%, m/m) to give g-primary amino alco-
hol 10 in almost quantitative yield. Alcohol 10 was
subsequently transformed to a chiral bicyclic iso-
thiourea 11, a new class of organic catalyst, in 37%
yield and with 85% ee over two steps.[16]
The hydrogenated product 2l is also a useful inter-
mediate for the synthesis of (À)-Paroxetine, a thera-
peutically important antidepressant.[4] Thus, 2l could
be transformed to cyclic sulfamidate 4 using a similar
method to that described for the synthesis of 9. (À)-
Paroxetine can then be obtained according to report-
ed procedures (Scheme 3).
Entry Ar
R
2
Yield [%][b] ee [%][c]
1
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
2a 98
2b 98
2c 94
2d 97
2e 99
2f 96
2g 98
2h 96
2i 93
2j 91
2k 97
2l 98
2m 95
2n 93
2o 97
2p 99
98
98
98
98
99
93
98
98
59
96
96
97
95
96
96
90
91
93
95
94
2
3
4
5
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
biphenyl
6
7
2,4-Me2C6H3
8
2,5-Me2OC6H3 Bn
9
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
naphthyl
furyl
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
10
11
12
13
14
15
16
17
18
19
20
Ph
Ph
4-BrC6H4 2q 97
Additionally, the catalytic system is also amenable
to the asymmetric hydrogenation of b-tertiary amino
ketones. As shown in Scheme 4, when 12 was applied
to the catalytic system, the corresponding product 13
could be obtained in quantitative yield and 97% ee.
The resulting product 14, a possible analgesic agent,
can be obtained easily by means of a reported
method.[17]
4-MeC6H4
4-MeOC6H4
4-Bu-tÀC6H4
Ph
Ph
Ph
2r 98
2s 97
2t 96
[a]
[b]
[c]
As in Table 2 using EtOH as solvent.
Isolated yields.
As in Table 1 using AD-H, IC-3 and OD-H columns;
The absolute configuration of products 2 were deter-
mined by comparing the sign of the optical rotations with
that of 2a.
Conclusions
To examine the efficiency of the catalyst system,
a gram-scale hydrogenation of 5a (1.44 g) was carried In summary, RuPHOX-Ru was successfully used for
out with a catalyst loading of 0.05 mol% (S/C=2,000) the asymmetric hydrogenation of a series of unstable
under a H2 pressure of 100 bar. The desired product b-secondary amino ketones, directly affording chiral
Scheme 3. Gram-scale synthesis and transformation.
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reaction began when the solution was transferred to an au-
toclave in the presence of H2 (50 bar). After 24 h, the reac-
tion mixture was concentrated under reduced pressure. The
residue was purified by flash chromatography using silica
gel (EtOAc/petrol ether=1/1) to afford the corresponding
products 2a–t and 13. To a solution of 2a–o (0.1 mmol) in
CH2Cl2 (2 mL) at 08C was added acetic anhydride
(0.1 mmol, 1.0 equiv.). The resulting mixture was stirred at
08C for 10 min. After removal of the solvent, the residue
was purified by flash chromatography using silica gel
(EtOAc/petrol ether=1/2 as an eluent) to give the desired
N-acyl derivatives 3a–o for HPLC analysis.
(R)-3-(Benzylamino)-1-phenylpropan-1-ol (2a): White
solid; yield: 47.4 mg (98%);[13f] mp 52–538C; [a]2D5: +29.5 (c
0.91, CH3OH); 1H NMR (400 MHz, CDCl3): d=7.40–7.20
(m, 10H), 5.81 (br s, 2H), 4.92 (dd, J=3.2, 8.8 Hz, 1H), 3.86
(s, 2H), 2.99–2.87 (m, 2H), 2.03–1.96 (m, 1H), 1.92–1.81 (m,
1H); 13C NMR (100 MHz, CDCl3): d=144.9, 138.2, 128.9,
128.8, 128.5, 127.9, 127.2, 125.8, 75.3, 53.7, 47.5, 37.1.
(R)-N-Benzyl-N-(3-hydroxy-3-phenylpropyl)acetamide
(3a): Colorless oil; yield: 25.2 mg (89%);[13f] 1H NMR
(400 MHz, CDCl3): d=7.39–7.16 (m, 10H), 4.61–4.38 (m,
3.3H), 4.10–4.00 (m, 0.7H), 3.36–3.29 (m, 0.5H), 3.18–3.12
(m, 0.7H), 2.12 (d, J=9.6 Hz, 2.5H), 1.94–1.72 (m, 2.3H);
13C NMR (100 MHz, CDCl3): d=172.9, 171.1, 144.3, 136.4,
129.3, 128.8, 128.8, 128.5, 128.4, 128.1, 128.0, 127.5, 127.3,
126.5, 125.8, 71.6, 70.3, 52.4, 48.3, 44.8, 43.1, 37.6, 37.5, 21.8,
21.6; HPLC (Daicel ChiralPak AD-H column, n-hexane/i-
PrOH=90/10, 1.0 mLminÀ1, UIV 220 nm): tR1 =19.2 min
(minor), tR2 =22.8 min (major), ee=98%.
Scheme 4. The synthesis of 13.
g-secondary amino alcohols in up to 99% yield and
with 99% ee. The products could be readily trans-
formed to g-primary amino alcohols, with the catalytic
system also being useful for the synthesis of chiral g-
tertiary amino alcohols. Gram-scale reaction could be
performed with a relatively low catalyst loading (up
to 2000 S/C), and the resulting g-secondary amino al-
cohols can be used for the synthesis of several useful
drugs and drug candidates.
Experimental Section
General
(R)-3-(Benzylamino)-1-ortho-tolylpropan-1-ol (2b): Color-
less oil; yield: 50.0 mg (98%); [a]2D5: +12.5 (c 0.46, CH3OH);
1H NMR (400 MHz, CDCl3): d=7.57–7.52 (m, 1H), 7.41–
7.26 (m, 5H), 7.23–7.10 (m, 3H), 5.14 (dd, J=2.8, 8.4 Hz,
1H), 4.86 (br s, 2H), 3.85 (ABq, J=15.8, 13.2 Hz, 2H),
3.04–2.98 (m, 1H), 2.95–2.88 (m, 1H), 2.30 (s, 3H), 1.94–
1.88 (m, 1H), 1.82–1.72 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=142.9, 138.4, 134.1, 130.4, 128.9, 128.8, 127.8,
127.0, 126.3, 125.7, 72.0, 53.7, 47.7, 35.5, 19.2; IR (KBr disc):
n=3028, 2923, 2853, 1669, 1661, 1608, 1555, 1496, 1434,
All hydrogenation reactions were performed in an autoclave
under an atmosphere of hydrogen, and the work-up was car-
ried out in air. Solvents were dried and degassed using stan-
dard procedures. Commercially available reagents were
used without further purification. Column chromatography
was performed using 100–200 mesh silica gel. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded
on a Varian MERCURY plus-400 spectrometer with TMS
as an internal standard. HR-MS was performed at the Anal-
ysis Center of Shanghai Jiao Tong University. Enantioselec-
tivity was measured by high performance liquid chromatog-
raphy (HPLC) using Daicel Chiralcel AD-H, IC-3 and OD-
H columns with n-hexane/i-PrOH as an eluent. Melting
points were measured with an SGW X-4 micro melting
point apparatus. IR was measured on a Perkin–Elmer Spec-
trum 100 FT-IR spectrometer.
1417, 1397, 1386, 1374, 1362, 1339, 785, 741, 699, 635 cmÀ1
;
HR-MS (ESI): m/z=256.1711, calcd. for C17H22NO [M+
H]+: 256.1701.
(R)-N-Benzyl-N-(3-hydroxy-3-ortho-tolylpropyl)acetam-
ide (3b): Colorless oil; yield: 24.7 mg (83%); 1H NMR
(400 MHz, CDCl3): d=7.64–7.09 (m, 9H), 4.93–4.38 (m,
3.7H), 4.17–4.10 (m, 0.8H), 3.40 (t, J=8.0 Hz, 0.6H), 3.12
(ddd, J=5.6, 3.6 Hz, 0.7H), 2.27 (s, 1.6H), 2.24 (s, 0.7H),
2.18 (s, 1.5H), 2.15 (s, 0.7H), 2.10–1.98 (m, 0.9H), 1.93–1.82
(m, 1.1H), 1.73–1.64 (m, 0.7H); 13C NMR (100 MHz,
CDCl3): d=172.8, 171.1, 142.3, 130.8, 130.4, 129.3, 128.8,
128.4, 128.1, 127.7, 127.5, 127.2, 126.7, 126.5, 125.4, 125.2,
68.1, 67.1, 52.3, 43.3, 36.3, 36.2, 21.8, 21.6, 19.3, 19.2; IR
(KBr disc): n=3384, 3030, 2931, 2837, 1621, 1513, 1452,
1363, 1247, 1176, 1113, 1076, 1034, 981, 947, 833, 733,
General Procedure for Asymmetric Hydrogenation
Products 5a–o: 5a–o·HCl (5 mmol) was dissolved in a mix-
ture of ethyl acetate and water. The mixture was cooled in
an ice-bath and aqueous saturated sodium carbonate was
added dropwise until the mixture was at pH 8. The two
phases were then separated and the aqueous layer was ex-
tracted with ethyl acetate (5 mL”3). The organic phases
were combined, dried with anhydrous Na2SO4 and evaporat-
ed under reduced pressure to afford compounds 5a–o.
Products 2a–t and 13: Amines 5a–t and 13 (0.2 mmol) and
RuPHOX-Ru (1.72 mg, 0.5 mol%) were dissolved in dis-
tilled and degassed ethanol (3 mL) under an N2 atmosphere.
DBU (3 mL) was added to the mixture in a glove-box. The
699 cmÀ1
;
HR-MS (ESI): m/z=298.1815, calcd. for
C19H24NO2 [M+H]+: 298.1807; HPLC (Daicel ChiralPak
AD-H column, n-hexane/i-PrOH=90/10, 1.0 mLminÀ1, UIV
220 nm): tR1 =17.8 min (minor), tR2 =20.1 min (major), ee=
98%.
(R)-3-(Benzylamino)-1-meta-tolylpropan-1-ol (2c): Color-
less oil; yield: 48.1 mg (94%); [a]2D5: +33.4 (c 0.33, CH3OH);
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Asymmetric Hydrogenation of b-Secondary Amino Ketones
1H NMR (400 MHz, CDCl3): d=7.38–7.26 (m, 5H), 7.22–
7.18 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.05 (d, J=7.6 Hz,
1H), 5.12 (br s, 2H), 4.91 (dd, J=3.2, 8.4 Hz, 1H), 3.85
(ABq, J=15.2, 13.2 Hz, 2H), 3.02–2.96 (m, 1H), 2.94–2.87
(m, 1H), 2.34 (s, 3H), 2.00–1.93 (m, 1H), 1.90–1.81 (m,
1H); 13C NMR (100 MHz, CDCl3): d=144.8, 138.1, 137.7,
128.9, 128.4, 128.0, 127.9, 126.5, 122.9, 75.0, 53.5, 47.3, 36.9,
21.7; IR (KBr disc): n=3305, 3063, 2924, 2853, 1647, 1521,
1516, 1489, 1418, 1397, 1386, 1362, 1339, 1120, 1073, 1028,
749, 699 cmÀ1; HR-MS (ESI): m/z=256.1711, calcd. for
C17H22NO [M+H]+: 256.1701.
832, 744, 698 cmÀ1; HR-MS (ESI): m/z=272.1656, calcd. for
C17H22NO2 [M+H]+: 272.1651.
(R)-N-Benzyl-N-[3-hydroxy-3-(4-methoxyphenyl)propyl]-
acetamide (3e): Colorless oil; yield: 27.6 mg (88%);
1H NMR (400 MHz, CDCl3): d=7.39–7.16 (m, 7H), 6.89–
6.83 (m, 2H), 4.60–4.42 (m, 3.7H), 4.10–4.00 (m, 0.8H), 3.78
(d, J=4.0 Hz, 2.4H), 3.32 (t, J=7.2 Hz, 0.5H), 3.16–3.10 (m,
0.7H), 2.14 (d, J=9.2 Hz, 2.6H), 1.90–1.73 (m, 2.3H);
13C NMR (100 MHz, CDCl3): d=172.7, 171.1, 159.5, 158.9,
138.0, 136.5, 129.3, 128.7, 128.3, 128.0, 127.5, 127.0, 126.5,
114.2, 113.9, 71.3, 70.0, 55.5, 52.5, 43.2, 37.5, 37.4, 21.8, 21.6;
IR (KBr): n=3367, 2925, 2855, 1622, 1489, 1454, 1418, 1362,
(R)-N-Benzyl-N-(3-hydroxy-3-meta-tolylpropyl)acetamide
(3c): Colorless oil; yield: 25.3 mg (85%); 1H NMR
(400 MHz, CDCl3): d=7.40–7.04 (m, 9H), 4.61–4.45 (m,
3.4H), 4.12–4.05 (m, 0.8H), 3.39–3.31 (m, 0.5H), 3.16–3.10
(m, 0.8H), 2.34 (s, 2.6H), 2.16 (s, 1.8H), 2.15 (s, 0.7H), 1.94–
1.72 (m, 2.4H); 13C NMR (100 MHz, CDCl3): d=172.8,
144.2, 138.1, 136.4, 129.3, 128.8, 128.8, 128.8, 128.4, 128.1,
128.0, 127.5, 126.5, 122.8, 71.8, 70.3, 52.5, 48.3, 44.8, 43.1,
37.6, 21.8, 21.7; IR (KBr disc): n=3382, 3029, 2923, 2858,
1625, 1485, 1451, 1363, 1244, 1166, 1076, 1029, 983, 788, 730,
1275, 1261, 750, 699, 600 cmÀ1
; HR-MS (ESI): m/z=
314.1764, calcd. for C19H24ClNO3 [M+H]+: 314.1756; HPLC
(Daicel ChiralPak AD-H column, n-hexane/i-PrOH=90/10,
1.0 mLminÀ1, UIV 220 nm): tR1 =30.0 min (minor), tR2
34.8 min (major), ee=99%.
=
(R)-3-(Benzylamino)-1-(biphenyl-4-yl)propan-1-ol
(2f):
Colorless oil; yield: 60.9 mg (96%); [a]2D5: +22.7 (c 0.33,
CH3OH); 1H NMR (400 MHz, CDCl3): d=7.61–7.55 (m,
4H), 7.45–7.42 (m, 4H), 7.38–7.28 (m, 6H), 5.02 (dd, J=8.6,
3.2 Hz, 1H), 3.84 (m, ABq, J=17.0, 12.8 Hz), 3.06–3.00 (m,
1H), 2.97–2.90 (m, 1H), 2.00–1.94 (m, 1H), 1.88–1.79 (m,
1H); 13C NMR (100 MHz, CDCl3): d=144.5, 141.6, 140.4,
139.3, 129.3, 129.1, 128.9, 128.0, 127.7, 127.6, 127.5, 126.6,
75.8, 54.3, 48.2, 37.6; IR (KBr disc): n=3291, 3027, 2924,
2854, 1507, 1487, 1456, 1418, 1376, 1339, 1075, 841, 764, 736,
701 cmÀ1
;
HR-MS (ESI): m/z=298.1811, calcd. for
C19H24NO2 [M+H]+: 298.1807; HPLC (Daicel ChiralPak
AD-H column, n-hexane/i-PrOH=90/10, 1.0 mLminÀ1, UIV
220 nm): tR1 =16.4 min (minor), tR2 =21.7 min (major), ee=
98%.
(R)-3-(Benzylamino)-1-para-tolylpropan-1-ol (2d): Color-
less oil; yield: 49.5 mg (97%); [a]2D5: +18.4 (c 0.28, CH3OH);
1H NMR (400 MHz, CDCl3): d=7.36–7.23 (m, 7H), 7.17–
7.12 (m, 2H), 4.92 (dd, J=8.6, 2.8 Hz, 1H), 3.80 (ABq, J=
18.8, 13.2 Hz, 2H), 3.01–2.96 (m, 1H), 2.91–2.85 (m, 1H),
2.33 (s, 3H), 1.93–1.86 (m, 1H), 1.82–1.73 (m, 1H);
13C NMR (100 MHz, CDCl3): d=142.2, 139.2, 136.7, 129.1,
128.8, 128.5, 127.6, 125.7, 75.6, 54.0, 48.0, 37.5, 21.3; IR (KBr
disc): n=3304, 3027, 2924, 2854, 1647, 1504, 1515, 1496,
1455, 1417, 1375, 1339, 1076, 818, 746, 699 cmÀ1; HR-MS
(ESI): m/z=256.1700, calcd. for C17H22NO [M+H]+:
256.1701.
697 cmÀ1
;
HR-MS (ESI): m/z=318.1864, calcd. for
C22H24NO [M+H]+: 318.1858.
(R)-N-Benzyl-N-[3-(biphenyl-4-yl)-3-hydroxypropyl]acet-
amide (3f): Colorless oil; yield: 28.4 mg (79%); 1H NMR
(400 MHz, CDCl3): d=7.60–7.19 (m, 14H), 4.68–4.46 (m,
3.6H), 4.15–4.06 (m, 0.8H), 3.43–3.34 (m, 0.5H), 3.20–3.15
(m, 0.7H), 2.17 (s, 2.2H), 2.00–1.89 (m, 1.4H), 1.85–1.77 (m,
0.8H); 13C NMR (100 MHz, CDCl3): d=172.8, 171.2, 143.4,
129.3, 129.1, 129.0, 128.8, 128.4, 128.1, 127.6, 127.5, 127.4,
127.3, 126.6, 126.3, 71.4, 70.1, 52.5, 48.4, 43.2, 37.6, 37.5, 21.8,
21.6; IR (KBr disc): n=3358, 3059, 3028, 2923, 2850, 1623,
1486, 1450, 1422, 1362, 1244, 1159, 1076, 1029, 1007, 981,
949, 839, 765, 733, 698, 621 cmÀ1; HR-MS (ESI): m/z=
360.1948, calcd. for C24H26NO2 [M+H]+: 360.1964; HPLC
(Daicel ChiralPak AD-H column, n-hexane/i-PrOH=90/10,
(R)-N-Benzyl-N-(3-hydroxy-3-para-tolylpropyl)acetamide
(3d): Colorless oil; yield: 26.8 mg (90%); 1H NMR
(400 MHz, CDCl3): d=7.40–7.11 (m, 9H), 4.60–4.44 (m,
3.5H), 4.08–4.01 (m, 0.8H), 3.35–3.31 (m, 0.5H), 3.17–3.11
(m, 0.7H), 2.34 (s, 0.8H), 2.32 (s, 1.7H), 2.15 (s, 1.8H), 2.13
(s, 0.7H), 1.96–1.73 (m, 2.5H); 13C NMR (100 MHz, CDCl3):
d=172.8, 171.2, 141.3, 136.9, 136.4, 129.5, 129.3, 129.2, 128.7,
128.4, 128.1, 127.5, 126.5, 125.8, 71.6, 70.2, 52.4, 48.3, 44.8,
43.1, 37.5, 21.8, 21.6, 21.3; IR (KBr disc): n=3384,3028,
2923, 1625, 1514, 1495, 1482, 1451, 1422, 1363, 1246, 1179,
1160, 1077, 1029, 983, 947, 819, 730, 699 cmÀ1; HR-MS
(ESI): m/z=298.1801, calcd. for C19H24NO2 [M+H]+:
298.1807; HPLC (Daicel ChiralPak AD-H column, n-
1.0 mLminÀ1, UIV 220 nm): tR1 =26.4 min (minor), tR2
36.5 min (major), ee=93%.
=
(R)-3-(Benzylamino)-1-(2,4-dimethylphenyl)propan-1-ol
(2g): Colorless oil; yield: 52.8 mg (98%); [a]2D5: +25.5 (c
1
0.29, CH3OH); H NMR (400 MHz, CDCl3): d=7.43 (d, J=
8.0 Hz, 1H), 7.40–7.26 (m, 5H), 7.04 (d, J=8.0 Hz, 1H),
6.95 (s, 1H), 5.12 (dd, J=8.6, 2.8 Hz, 1H), 4.42 (br s, 2H),
3.94 (ABq, J=17.2, 12.8 Hz, 2H), 3.04–2.98 (m, 1H), 2.94–
2.88 (m, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 1.91–1.86 (m, 1H),
1.78–1.74 (m, 1H); 13C NMR (100 MHz, CDCl3): d=140.1,
138.9, 136.4, 133.9, 131.2, 128.8, 128.7, 127.7, 127.0, 125.7,
72.1, 53.9, 48.0, 35.9, 21.2, 19.2; IR (KBr disc): n=3305,
3062, 3028, 2921, 2854, 1540, 1472, 1455, 1434, 1417, 1374,
1362, 1339, 1073, 826, 744, 699 cmÀ1; HR.MS (ESI): m/z=
270.1852, calcd. for C18H24NO [M+H]+: 270.1858.
(R)-N-Benzyl-N-[3-(2,4-dimethylphenyl)-3-hydroxyprop-
yl]acetamide (3g): Colorless oil; yield: 27.4 mg (88%);
1H NMR (400 MHz, CDCl3): d=7.40–7.18 (m, 6H), 7.02 (d,
J=8.0 Hz, 1H), 6.94 (d, J=6.4 Hz, 1H), 4.83–4.74 (m,
1.1H), 4.64 (dd, J=15.8, 5.6 Hz, 1.0H), 4.48 (t, J=13.6 Hz,
hexane/i-PrOH=90/10, 1.0 mLminÀ1, UIV 220 nm): tR1
20.4 min (minor), tR2 =23.8 min (major), ee=98%.
(R)-3-(Benzylamino)-1-(4-methoxyphenyl)propan-1-ol
=
(2e): Colorless oil; yield: 53.7 mg (99%); [a]2D5: +19.4 (c
0.33, CH3OH); 1H NMR (400 MHz, CDCl3): d=7.36–7.26
(m, 7H), 6.88–6.84 (m, 2H), 4.90 (dd, J=8.6, 3.2 Hz, 1H),
3.82–3.80 (m, 5H), 3.01–2.96 (m, 1H), 2.92–2.83 (m, 1H),
1.92–1.85 (m, 1H), 1.83–1.74 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=138.1, 137.1; 135.3, 128.9, 128.8, 127.8, 126.9,
113.9, 74.9, 55.5, 53.7, 47.5, 37.2; IR: n=3306, 2924, 2854,
1698, 1609, 1508, 1456, 1397, 1374, 1339, 1245, 1174, 1033,
Adv. Synth. Catal. 2015, 357, 3262 – 3272
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3267

FULL PAPERS
Jianxia Wang et al.
1.1H), 4.09 (m, 0.8H), 3.43–3.34 (m, 0.7H), 3.14 (ddd, J=
14.2, 5.8, 3.6 Hz, 0.8H), 2.30 (s, 0.9H), 2.29 (s, 1.8H), 2.24 (s,
1.8H), 2.22 (s, 0.9H), 2.18 (s, 1.8H), 2.15 (s, 0.9H), 1.90–1.79
(m, 1.6H), 1.75–1.66 (m, 0.8H); 13C NMR (100 MHz,
CDCl3): d=172.7, 171.1, 139.3, 126.4, 131.6, 131.2, 129.3,
128.8, 128.4,128.0, 127.5, 127.3, 127.1, 126.5, 125.4, 125.2,
68.0, 67.1, 52.4, 45.0, 43.4, 36.2, 21.8, 21.6, 21.2, 19.2, 19.1; IR
(KBr disc): n=3384, 3029, 2923, 1625, 1496, 1482, 1451,
1362, 1249, 1162, 1123, 1075, 1029, 982, 947, 823, 731,
0.8H), 2.21 (s, 1.9H), 2.17 (s, 0.5H), 2.13–2.01 (m, 1.4H),
1.85–1.75 (m, 0.4H), 1.56–1.48 (m, 0.8H); 13C NMR
(100 MHz, CDCl3): d=173.2, 141.8, 137.8, 136.1, 131.2,
129.7, 129.3, 128.9, 128.8, 128.4, 128.3, 128.1, 127.5, 127.2,
127.0, 126.5, 68.3, 66.9, 51.9, 48.1, 44.7, 42.4, 35.8, 35.7, 21.8,
21.6; IR (KBr disc): n=3390, 3064, 3030, 2925, 2850, 1681,
1622, 1574, 1507, 1495, 1472, 1440, 1362, 1339, 1312, 1263,
1204, 1078, 1049, 1032, 983, 756, 731, 700, 625, 601 cmÀ1
;
HR-MS (ESI): m/z=318.1263, calcd. for C18H21ClNO2 [M+
699 cmÀ1
;
HR-MS (ESI): m/z=312.1967, calcd. for
H]+: 318.1261; HPLC (Daicel ChiralPak AD-H column, n-
C20H26NO2 [M+H]+: 312.1964; HPLC (Daicel ChiralPak
IC-3 column, n-hexane/i-PrOH=90/10, 1.0 mLminÀ1, UIV
220 nm): tR1 =31.0 min (minor), tR2 =40.3 min (major), ee=
98%.
hexane/i-PrOH=90/10, 1.0 mLminÀ1, UIV 220 nm): tR1
14.5 min (minor), tR2 =15.8 min (major), ee=59%.
=
(R)-3-(Benzylamino)-1-(3-chlorophenyl)propan-1-ol (2j):
Colorless oil; yield: 50.2 mg (91%); [a]2D5: +18.3 (c 0.07,
CH3OH); 1H NMR (400 MHz, CDCl3): d=7.36–7.18 (m,
9H), 5.10 (br s, 2H), 4.91 (dd, J=8.6, 3.2 Hz, 1H), 3.82
(ABq, J=15.8, 13.2 Hz, 2H), 3.00–2.86 (m, 2H), 1.96–1.89
(m, 1H), 1.82–1.72 (m, 1H); 13C NMR (100 MHz, CDCl3):
d=146.7, 135.7, 134.5, 129.8, 129.3, 129.1, 128.5, 127.4, 126.0,
123.9, 73.5, 52.9, 46.4, 36.0; IR (KBr disc): n=3310, 2924,
2854, 1647, 1555, 1521, 1496, 1418, 1374, 1362, 1339, 782,
745, 698 cmÀ1; HR-MS (ESI): m/z=276.1167, calcd. for
C16H19ClNO [M+H]+: 276.1155.
(R)-N-Benzyl-N-[3-(3-chlorophenyl)-3-hydroxypropyl]-
acetamide (3j): Colorless oil; 24.5 mg (77%); 1H NMR
(400 MHz, CDCl3): d=7.41–7.09 (m, 9H), 4.60–4.46 (m,
3.0H), 4.13–4.05 (m, 0.8H), 3.42–3.32 (m, 0.5H), 3.13–3.07
(m, 0.8H), 2.17–2.15 (d, J=9.6 Hz, 2.5H), 1.88–1.78 (m,
1.4H), 1.72–1.64 (m, 1.0H); 13C NMR (100 MHz, CDCl3):
d=173.0, 171.3, 146.4, 136.2, 129.8, 129.3, 128.8, 128.4, 128.2,
127.9, 127.6, 127.3, 126.6, 126.0, 123.9, 70.8, 69.6, 52.6, 48.5,
44.8, 43.0, 37.6, 21.8, 21.6; IR (KBr disc): n=3362, 3063,
3029, 2925, 2855, 1622, 1575, 1479, 1422, 1363, 1301, 1243,
1201, 1162, 1029, 928, 786, 729, 698 cmÀ1; HR-MS (ESI):
m/z=318.1263, calcd. for C18H21ClNO2 [M+H]+: 318.1261;
HPLC (Daicel ChiralPak AD-H column, n-hexane/i-
PrOH=90/10, 1.0 mLminÀ1, UIV 220 nm): tR1 =14.9 min
(minor), tR2 =18.7 min (major), ee=96%.
(R)-3-(Benzylamino)-1-(2,5-dimethoxyphenyl)propan-1-ol
(2h): Colorless oil; yield: 57.9 mg (96%); [a]2D5: +25.9 (c
0.27, CH3OH); 1H NMR (400 MHz, CDCl3): d=7.40–7.26
(m, 5H), 7.09 (d, J=2.4 Hz, 1H), 6.75–6.70 (m, 2H), 5.36
(br s, 2H), 5.16 (dd, J=8.2, 2.8 Hz, 1H), 3.89 (s, 2H), 3.74–
3.73 (m, 6H), 2.99–2.88 (m, 2H), 2.09–2.02 (m, 1H), 1.88–
1.79 (m, 1H); 13C NMR (100 MHz, CDCl3): d=154.0, 150.1,
136.3, 134.0, 129.9, 129.0, 128.2, 112.6, 112.6, 111.4, 69.3,
56.0, 52.8, 46.7, 34.4; IR (KBr disc): n=3305, 3062, 3028,
2997, 2929, 2833, 1496, 1463, 1456, 1434, 1418, 1386, 1362,
1273, 1215, 1178, 1156, 1076, 1047, 1027, 804, 737, 700 cmÀ1
;
HR-MS (ESI): m/z=302.1750, calcd. for C18H24NO3 [M+
H]+: 302.1756.
(R)-N-Benzyl-N-[3-(2,5-dimethoxyphenyl)-3-hydroxypro-
pyl]acetamide (3h): Colorless oil; yield: 30.6 mg (89%).
1H NMR (400 MHz, CDCl3): d=7.93–7.18 (m, 5H), 7.08 (d,
J=2.8 Hz, 1H), 6.85–6.72 (m, 2H), 4.86–4.79 (m, 1.0H),
4.67 (t, J=14.8 Hz, 1.2H), 4.54–4.42 (m, 1.3H), 4.10–4.02
(m, 0.8H), 3.79–3.76 (m, 4.9H), 3.41–3.36 (m, 0.7H), 3.16–
3.10 (m, 0.7H), 2.19 (s, 0.9H), 2.17 (s, 1.6H), 2.11–1.90 (m,
2.2H), 1.71–1.62 (m, 0.7H); 13C NMR (100 MHz, CDCl3):
d=172.7, 171.2, 136.5, 129.2, 128.7, 128.4, 127.9, 127.4, 126.5,
112.9, 112.9, 111.5, 67.9, 65.9, 56.1, 56.0, 52.0, 48.0, 43.0, 35.6,
35.4, 21.9, 21.7; IR (KBr disc): n=3381, 3063, 3029, 2997,
2937, 2834, 1743, 1621, 1495, 1452, 1363, 1275, 1216, 1178,
1158, 1128, 1093, 1076, 1047, 1026, 983, 947, 914, 880, 807,
733, 700, 621 cmÀ1; HR-MS (ESI): m/z=344.1871, calcd. for
C20H26NO4 [M+H]+: 344.1862; HPLC (Daicel ChiralPak
AD-H column, n-hexane/i-PrOH=90/10, 1.0 mLminÀ1, UIV
220 nm): tR1 =47.7 min (minor), tR2 =54.9 min (major), ee=
98%.
(R)-3-(Benzylamino)-1-(4-chlorophenyl)propan-1-ol (2k):
Colorless oil; yield: 53.5 mg (97%); [a]2D5: +29.5 (c 0.26,
CH3OH); 1H NMR (400 MHz, CDCl3): d=7.37–7.24 (m,
9H), 4.91 (dd, J=8.6, 2.4 Hz, 1H), 3.79 (ABq, J=17.0,
12.8 Hz, 2H), 2.98–2.92 (m, 1H), 2.90–2.84 (m, 1H), 1.90
-.84 (m, 1H), 1.78–1.68 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=143.6, 138.7, 132.7, 128.9, 128.6, 128.5, 127.7,
127.2, 75.1, 53.8, 47.7, 37.1; IR (KBr disc): n=3296, 3063,
3028, 2921, 2845, 1597, 1574, 1496, 1487, 1430, 1339, 1199,
(R)-3-(Benzylamino)-1-(2-chlorophenyl)propan-1-ol (2i):
Colorless oil; yield: 51.3 mg (93%); [a]2D5: +28.4 (c 0.25,
1
CH3OH); H NMR (400 MHz, CDCl3): d=7.60 (dd, J=7.6,
1102, 1074, 784, 746, 699 cmÀ1
; HR-MS (ESI): m/z=
1.6 Hz, 1H), 7.38–7.24 (m, 7H), 7.20–7.14 (m, 1H), 5.30 (dd,
J=8.4, 7.2 Hz, 1H), 3.84 (s, 2H), 3.00–2.91 (m, 2H), 2.10–
2.03 (m, 1H), 1.74–1.65 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=142.2, 137.8, 131.5, 129.4, 128.9, 128.6, 128.3,
128.0, 127.5, 127.2, 72.0, 53.4, 47.2, 34.5; IR: n=3447, 2924,
2854, 1669, 1622, 1540, 1507, 1488, 1456, 1374, 1362, 1128,
1032, 752, 698 cmÀ1; HR-MS (ESI): m/z=276.1160, calcd.
for C16H19ClNO [M+H]+: 276.1155.
(R)-N-Benzyl-N-[3-(2-chlorophenyl)-3-hydroxypropyl]-
acetamide (3i): Colorless oil; yield: 22.2 mg (70%); 1H NMR
(400 MHz, CDCl3): d=7.66–7.53 (m, 1H), 7.48–7.15 (m,
8H), 5.05 (dd, J=12.0, 3.2 Hz, 0.2H), 4.93 (dd, J=10.4,
2.0 Hz, 0.7H), 4.73–4.69 (m, 0.9H), 4.55–4.44 (m, 1.1H),
4.29–4.21 (m, 0.8H), 3.44–3.38 (m, 0.5H), 3.04–2.98 (m,
276.1168, calcd. for C16H19ClNO [M+H]+: 276.1155.
(R)-N-Benzyl-N-[3-(4-chlorophenyl)-3-hydroxypropyl]-
acetamide (3k): Colorless oil; yield: 25.4 mg (80%);
1H NMR (400 MHz, CDCl3): d=7.40–7.16 (m, 9H), 4.73 (d,
J=3.2 Hz, 0.6H), 4.61–4.46 (m, 2.7H), 4.16–4.09 (m, 0.8H),
3.42–3.31 (m, 0.5H), 3.09 (dt, J=4.4, 14.4 Hz, 0.8H), 2.19 (s,
1.9H), 2.17 (s, 0.4H), 1.90–1.78 (m, 1.2H), 1.72–1.65 (m,
1.1H); 13C NMR (100 MHz, CDCl3): d=173.0, 142.7, 138.0,
136.2, 132.8, 129.3, 129.0, 128.8, 128.6, 128.4, 128.2, 127.6,
126.6, 71.1, 69.5, 52.8, 48.4, 44.7, 43.0, 37.6, 21.8, 21.7; IR
(KBr disc): n=3363, 3087, 3064, 3030, 2927, 1625, 1489,
1451, 1363, 1289, 1243, 1203, 1161, 1090, 1029, 1014, 982,
949, 827, 730, 699, 630, 604 cmÀ1; HR-MS (ESI): m/z=
318.1261, calcd. for C18H21ClNO2 [M+H]+: 318.1261; HPLC
3268
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Adv. Synth. Catal. 2015, 357, 3262 – 3272

FULL PAPERS
Asymmetric Hydrogenation of b-Secondary Amino Ketones
(Daicel ChiralPak AD-H column, n-hexane/i-PrOH=90/10,
2924, 2852, 1669, 1661, 1622, 1602, 1555, 1496, 1434, 1417,
1397, 1386, 1374, 1362, 1339, 858, 820, 746, 698, 625 cmÀ1
;
1.0 mLminÀ1, UIV 220 nm): tR1 =17.5 min (minor), tR2
20.7 min (major), ee=96%.
=
HR-MS (ESI): m/z=292.1722, calcd. for C20H22NO [M+
(R)-3-(Benzylamino)-1-(4-fluorophenyl)propan-1-ol (2l):
H]+: 292.1701.
Colorless oil; yield: 50.8 mg (98%);[4] [a]D25: +41.2 (c 0.23,
(R)-N-Benzyl-N-[3-hydroxy-3-(naphthalen-2-yl)propyl]-
acetamide (3n): Colorless oil; yield: 24.3 mg (73%);
1H NMR (400 MHz, CDCl3): d=7.84–7.68 (m, 4H), 7.50–
7.19 (m, 8H), 4.78–4.75 (m, 1.0H), 4.63–4.47 (m, 2.0H),
4.19–4.11 (m, 0.8H), 3.43–3.37 (m, 0.7H), 3.20–3.14 (m,
0.8H), 2.18 (s, 1.9H), 2.17 (s, 0.7H), 2.02–1.92 (m, 1.3H),
1.88–1.81 (m, 0.8H); 13C NMR (100 MHz, CDCl3): d=173.0,
141.6, 136.3, 133.5, 129.3, 128.8, 128.4, 127.9, 127.8, 127.5,
126.6, 126.2, 125.8, 124.3, 71.8, 70.3, 52.5, 48.4, 43.1, 37.5,
37.4, 21.8, 21.6; IR (KBr disc): n=3335, 2924, 2855, 1657,
1646, 1622, 1507, 1489, 1455, 1434, 1418, 1374, 1260, 1028,
981, 859, 819, 749, 698 cmÀ1; HR-MS (ESI): m/z=334.1811,
calcd. for C22H24NO2 [M+H]+: 334.1807; HPLC (Daicel
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.37–7.26 (m, 7H),
7.00–6.94 (m, 2H), 4.92–4.89 (m, 3H), 3.84 (ABq, J=15.0,
13.2 Hz, 2H), 3.00–2.87 (m, 2H), 1.95–1.89 (m, 1H), 1.84–
1.76 (m, 1H); 13C NMR (100 MHz, CDCl3): d=139.4, 128.8,
128.5, 127.6, 127.4, 127.4, 115.3, 115.1, 75.2, 54.0, 47.9, 37.6.
(R)-N-Benzyl-N-[3-(4-fluorophenyl)-3-hydroxypropyl]-
acetamide (3l): Colorless oil; yield: 24.7 mg (82%);
1H NMR (400 MHz, CDCl3): d=7.40–7.17 (m, 7H), 7.02–
6.96 (m, 2H), 4.61–4.45 (m, 3.0H), 4.14–4.05 (m, 0.9H),
3.41–3.30 (m, 0.5H), 3.14–3.08 (m, 0.8H), 1.90 (s, 2.0H),
1.89 (s, 0.6H), 1.90–1.79 (m, 1.3H), 1.75–1.67 (m, 0.9H);
13C NMR (100 MHz, CDCl3): d=173.0, 163.3, 160.9, 136.3,
129.3, 128.8, 128.3, 128.1, 127.5, 127.4, 126.5, 115.8, 115.6,
115.3, 115.1, 71.0, 69.6, 52.5, 48.4, 44.8, 43.1, 37.6, 21.8, 21.6;
IR (KBr disc): n=3355, 3064, 3031, 2925, 2855, 1621, 1556,
1508, 1454, 1362, 1220, 1156, 1077, 1029, 1014, 982, 949, 837,
730, 698 cmÀ1; HR-MS (ESI): m/z=302.1561, calcd. for
C18H21FNO2 [M+H]+: 302.1556; HPLC (Daicel ChiralPak
AD-H column, n-hexane/i-PrOH=90/10, 1.0 mLminÀ1, UIV
220 nm): tR1 =16.1 min (minor), tR2 =19.1 min (major), ee=
97%.
(R)-3-(Benzylamino)-1-(4-bromophenyl)propan-1-ol (2m):
Colorless oil; yield: 60.8 mg (95%); [a]2D5: +15.0 (c 0.42,
CH3OH); 1H NMR (400 MHz, CDCl3): d=7.44–7.19 (m,
9H), 4.88 (dd, J=8.4, 2.8 Hz, 1H), 4.59 (br s, 2H), 3.79
(ABq, J=15.8, 13.2 Hz, 2H), 2.97–2.83 (m, 2H), 1.92–1.85
(m, 1H), 1.72–1.68 (m, 1H); 13C NMR (100 MHz, CDCl3):
d=144.2, 138.8, 131.5, 128.9, 128.6, 127.7, 127.6, 120.8, 75.0,
53.8, 47.7, 37.2; IR (KBr disc): n=3363, 3030, 2925, 1624,
1511, 1486, 1451, 1423, 1362, 1242, 1160, 1072, 1029, 1010,
982, 949, 823, 730, 698, 627 cmÀ1; HR-MS (ESI): m/z=
320.0657, calcd. for C16H19BrNO [M+H]+: 320.0650.
ChiralPak
AD-H
column,
n-hexane/i-PrOH=90/10,
1.0 mLminÀ1, UIV 220 nm): tR1 =38.4 min (minor), tR2
42.1 min (major), ee=96%.
=
(R)-3-(Benzylamino)-1-(furan-2-yl)propan-1-ol (2o): Col-
orless oil; yield: 44.9 mg (97%); [a]2D5: +13.6 (c 0.34,
CH3OH); 1H NMR (400 MHz, CDCl3): d=7.25–7.34 (m,
6H), 6.31 (dd, J=2.0, 3.2 Hz, 1H), 6.22 (dt, J=0.4, 3.2 Hz,
1H), 4.95 (t, J=5.6 Hz, 1H), 3.92 (br s, 2H), 3.79 (ABq, J=
25.0, 12.8 Hz, 2H), 3.01–2.85 (m, 2H), 2.00–1.94 (m, 2H);
13C NMR (100 MHz, CDCl3): d=157.3, 141.7, 139.2, 128.8,
128.5, 127.6, 110.3, 105.5, 69.7, 52.9, 47.6, 33.7; IR (KBr
disc): n=3306, 2924, 2853, 1681, 1647, 1555, 1516, 1496,
1417, 1397, 1386, 1362, 1339, 1146, 1070, 1008, 808, 732,
698 cmÀ1
;
HR-MS (ESI): m/z=232.1340, calcd. for
C14H18NO2 [M+H]+: 232.1338.
(R)-N-Benzyl-N-[3-(furan-2-yl)-3-hydroxypropyl]acetam-
ide (3o): Colorless oil; yield: 20.0 mg (73%); 1H NMR
(400 MHz, CDCl3): d=7.39–7.15 (m, 6H), 6.33–6.19 (m,
2H), 4.67–4.53 (m, 2.2H), 4.40 (d, J=17.2 Hz, 0.8H), 3.99–
3.92 (m, 0.9H), 3.36 (t, J=7.6 Hz, 0.4H), 3.24 (dt, J=14.4,
4.8 Hz, 0.8H), 2.17 (s, 0.5H), 2.11 (s, 2.2H), 2.08–1.95 (m,
2.2H); 13C NMR (100 MHz, CDCl3): d=173.1, 156.6, 141.9,
129.3, 128.3, 128.1, 126.4, 110.5, 110.4, 106.4, 105.7, 65.1,
64.5, 52.0, 48.2, 44.3, 42.0, 34.0, 33.2, 21.7, 21.6; IR (KBr
disc): n=3355, 3063, 3030, 2928, 1625, 1555, 1496, 1483,
1452, 1424, 1363, 1289, 1257, 1147, 1072, 1028, 1010, 946,
884, 811, 732, 699 cmÀ1; HR-MS (ESI): m/z=274.1423,
calcd. for C16H20NO3 [M+H]+: 274.1443; HPLC (Daicel
(R)-N-Benzyl-N-[3-(4-bromophenyl)-3-hydroxypropyl]-
acetamide (3m): Colorless oil; yield: 29.7 mg (82%);
1H NMR (400 MHz, CDCl3): d=7.45–6.99 (m, 9H), 4.77 (d,
J=4.0 Hz, 0.6H), 4.60–4.46 (m,2.7H), 4.14–4.06 (m, 0.8H),
3.43–3.28 (m, 0.5H), 3.12–3.06 (m, 0.8H), 2.18 (s, 1.9H),
2.15 (s, 0.5H), 1.88–1.77 (m, 1.4H), 1.71–1.63 (m, 0.8H);
13C NMR (100 MHz, CDCl3): d=173.0, 143.3, 137.9, 136.3,
131.9, 131.5, 129.3, 128.8, 128.4, 128.2, 127.6, 126.6, 120.9,
71.0, 69.5, 52.6, 48.4, 44.7, 43.0, 37.6, 21.8, 21.7; IR (KBr
disc): n=3362, 3030, 2925, 1624, 1511, 1486, 1451, 1423,
1362, 1242, 1160, 1072, 1029, 1010, 982, 949, 823, 730, 698,
ChiralPak
AD-H
column,
n-hexane/i-PrOH=90/10,
1.0 mLminÀ1, UIV 220 nm): tR1 =19.2 min (minor), tR2
21.0 min (major), ee=96%.
=
627 cmÀ1
;
HR-MS (ESI): m/z=362.0757, calcd. for
(R)-1-Phenyl-3-(phenylamino)propan-1-ol (2p): Colorless
oil; yield: 45.0 mg (99%);[18] [a]D25: +14.7 (c 0.82, CH3OH);
1H NMR (400 MHz, CDCl3): d=7.40–7.26 (m, 5H), 7.20
(dd, J=7.6, 8.2 Hz, 2H), 6.75 (t, J=7.6 Hz, 1H), 6.64 (d, J=
7.6 Hz, 2H), 4.88 (dd, J=7.6, 5.2 Hz, 1H), 3.27 (t, J=
6.4 Hz, 2H), 2.10–1.98 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=148.5, 144.6, 129.5, 128.8, 127.9, 126.0, 118.1,
113.6, 73.9, 41.9, 38.4; HPLC (Daicel ChiralPak IC-3
column, n-hexane/i-PrOH=90/10, 0.5 mLminÀ1, UIV
210 nm): tR1 =18.3 min (minor), tR2 =25.5 min (major), ee=
90%.
C18H21BrNO2 [M+H]+: 362.0756; HPLC (Daicel ChiralPak
AD-H column, n-hexane/i-PrOH=90/10, 1.0 mLminÀ1, UIV
220 nm): tR1 =19.0 min (minor), tR2 =22.3 min (major), ee=
95%.
(R)-3-(Benzylamino)-1-(naphthalen-2-yl)propan-1-ol (2n):
Colorless oil; yield: 54.2 mg (93%); [a]2D5: +25.7 (c 0.27,
CH3OH); 1H NMR (400 MHz, CDCl3): d=7.85–7.79 (m,
4H), 7.49–7.43 (m, 3H), 7.3–7.29 (m, 5H), 5.12 (dd, J=8.6,
2.8 Hz, 1H), 4.73 (br s, 2H), 3.83 (ABq, J=16.4, 13.2 Hz,
2H), 3.02–2.90 (m, 2H), 2.06–1.99 (m, 1H), 1.93–1.84 (m,
1H); 13C NMR (100 MHz, CDCl3): d=142.5, 138.7, 133.6,
132.9, 128.9, 128.7, 128.2, 128.1, 127.9, 127.8, 126.2, 125.7,
124.4, 124.3, 75.6, 53.8, 47.7, 37.1; IR (KBr disc): n=3055,
(R)-3-(4-Bromophenylamino)-1-phenylpropan-1-ol (2q):
Colorless oil; yield: 59.4 mg (97%); [a]2D5: +6.4 (c 0.94,
CH3OH); 1H NMR (400 MHz, CDCl3): d=7.39–7.23 (m,
Adv. Synth. Catal. 2015, 357, 3262 – 3272
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FULL PAPERS
Jianxia Wang et al.
7H), 6.47–6.43 (m, 2H), 4.88 (dd, J=7.8, 4.8 Hz, 1H), 3.18
(t, J=6.8 Hz, 2H), 2.05, 1.94 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=147.8, 144.5, 132.2, 128.9, 128.0, 126.0, 115.0,
109.4, 73.7, 41.7, 38.1; IR (KBr disc) v/cmÀ1: 3270, 2923,
2853, 2303, 1669, 1595, 1456, 1377, 1157, 1074, 914, 812, 765,
700; HR-MS (ESI): m/z=306.0497, calcd. for C15H17BrNO
[M+H]+: 306.0494; HPLC (Daicel ChiralPak IC-3 column,
1583, 1455, 1377, 1243, 1182, 1138, 1091, 1031, 973, 955, 928,
868, 824, 801, 750, 702, 636, 608 cmÀ1; HR-MS (ESI): m/z=
327.2081, calcd. for C20H27N2O [M+H]+: 327.2073; HPLC
(Daicel ChiralPak AD-H column, n-hexane/i-PrOH=88/12,
1.0 mLminÀ1, UIV 200 nm): tR1 =13.3 min (minor), tR2
17.5 min (major), ee=97%.
=
n-hexane/i-PrOH=90/10, 0.5 mLminÀ1, UIV 210 nm): tR1
15.3 min (minor), tR2 =19.2 min (major), ee=91%.
=
Gram-Scale Synthesis of 2a
Compound 5a (1.44 g, 6 mmol) and RuPHOX-Ru (5.15 mg,
0.05 mol%) were dissolved in distilled and degassed ethanol
(7 mL) under an N2 atmosphere. DBU (13.4 mL, 0.15 mol%)
was added to the mixture in a glove-box under an N2 atmos-
phere. The reaction began when the solution was transferred
to an autoclave in the presence of H2 (100 bar). After 24 h,
the reaction mixture was concentrated under reduced pres-
sure. The residue was purified by flash chromatography
using silica gel (EtOAc/petrol ether=1/1) to afford 2a;
yield: 1.08 g (75%, 93% ee).
(R)-3-(Phenylamino)-1-para-tolylpropan-1-ol (2r): Color-
less oil; yield: 47.3 mg (98%); [a]2D5: +11.5 (c 0.78, CH3OH);
1H NMR (400 MHz, CDCl3): d=7.29–7.21 (m, 6H), 6.80 (t,
J=7.2 Hz, 1H), 6.66 (dd, J=8.4, 0.8 Hz, 2H), 4.82 (dd, J=
7.8, 5.2 Hz, 1H), 3.48 (br s, 2H), 3.25 (t, J=6.8 Hz, 2H),
2.42 (s, 3H), 2.11–1.98 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=148.6, 141.7, 137.6, 129.5, 129.5, 126.0, 118.0,
113.6, 73.6, 41.9, 38.4, 21.5; IR (KBr disc): n=3385, 3051,
3021, 2922, 2858, 1603, 1507, 1475, 1433, 1379, 1321, 1262,
1179, 1101, 1072, 1020, 992, 818, 750, 693 cmÀ1; HR-MS
(ESI): m/z=242.1542, calcd. for C16H20NO [M+H]+:
242.1545; HPLC (Daicel ChiralPak IC-3 column, n-hexane/ Synthesis of 9
i-PrOH=90/10, 0.5 mLminÀ1, UIV 210 nm): tR1 =21.6 min
(minor), tR2 =30.2 min (major), ee=93%.
SOCl2 (0.53 mmol) in anhydrous CH2Cl2 (2 mL) was added
dropwise to solution of 2a (0.50 mmol), imidazole
a
(R)-1-(4-Methoxyphenyl)-3-(phenylamino)propan-1-ol
(2s): Colorless oil; yield: 49.9 mg (97%); [a]2D5: +14.5 (c
0.63, CH3OH); 1H NMR (400 MHz, CDCl3): d=7.39–7.26
(m, 5H), 6.82–6.76 (m, 2H), 6.63–6.57 (m, 2H), 4.83 (dd, J=
7.0, 5.6 Hz, 1H), 3.75 (s, 3H), 3.64 (br s, 2H), 3.20 (t, J=
6.4 Hz, 2H), 2.05–1.97 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=152.8, 144.8, 142.5, 128.7, 127.8, 126.0, 115.4,
115.1, 73.9, 56.0, 43.3, 38.4; IR (KBr disc): n=3304, 3176,
3059, 2940, 2832, 1515, 1489, 1448, 1417, 1311, 1265, 1251,
1234, 1181, 1118, 1039, 819, 743, 697 cmÀ1; HR-MS (ESI):
m/z=258.1496, calcd. for C16H20NO2 [M+H]+: 258.1494;
HPLC (Daicel ChiralPak IC-3 column, n-hexane/i-PrOH=
90/10, 0.5 mLminÀ1, UIV 210 nm): tR1 =15.9 min (minor),
(1.9 mmol) and Et3N (1.1 mmol) in anhydrous CH2Cl2
(7 mL) at À208C. The solution was stirred for 15 min, and
then at 08C for 3 h. Water (6 mL) was added and the organ-
ic portion was isolated, washed with dilute HCl (1M, 6 mL),
brine (7 mL), dried over Na2SO4 and concentrated under
vacuum to afford a brown oil. The residue was filtered
through a pad of SiO2 (100 mesh, eluting with EtOAc) and
the eluent was concentrated under vacuum to afford a sulfa-
midite intermediate.
The obtained sulfamidite intermediate was dissolved in
MeCN (6 mL) and the mixture was cooled to 08C.
RuCl3·xH2O (0.6 mg), NaIO4 (0.2 g) and H2O (6 mL) were
added and the solution was stirred vigorously for 2.5 h.
After Et2O (5 mL) was added, the layers were separated
and the aqueous layer was washed with Et2O (3”5 mL).
The combined organic phases were washed successively with
water until the green/black color was completely removed
from the organic phase. The solution was then dried with
Na2SO4 and concentrated under vacuum to afford a pale
brown oil. This residue was filtered through a pad of SiO2
(100 mesh, eluting with EtOAc) and the eluent was concen-
trated under vacuum to afford sulfamidate 9 as a white
solid; yield: 108 mg (71%); mp 87–888C; [a]2D5: À34.2 (c 0.8,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.43–7.34 (m,
10H), 5.80 (dd, J=12.4, 2.8 Hz, 1H), 4.47 (d, J=14.0 Hz,
1H), 4.37 (d, J=14.0 Hz, 1H), 3.77 (td, J=14.0, 2.8 Hz,
1H), 3.25 (ddd, J=14.0, 4.4, 2.0 Hz, 1H), 2.22–2.11 (m, 1H),
1.75 (ddd, J=14.8, 4.8, 2.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=137.5, 135.2, 129.5, 129.1, 129.0, 128.9, 128.5,
126.3, 86.4, 52.7, 46.8, 28.2; HPLC (Daicel ChiralPak AD-H
tR2 =21.1 min (major), ee=95%.
(R)-1-(4-tert-Butylphenyl)-3-(phenylamino)propan-1-ol
(2t): Colorless oil; yield: 54.4 mg (96%); [a]2D5: +8.1 (c 0.96,
CH3OH); 1H NMR (400 MHz, CDCl3): d=7.46 (d, J=
8.0 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.25 (t, J=7.6 Hz,
2H), 6.81 (td, J=7.2, 0.8 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H),
4.84 (dd, J=7.6, 4.8 Hz, 1H), 3.52 (br s, 2H), 3.29 (t, J=
6.4 Hz, 2H), 3.14–2.00 (m, 2H), 1.42 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=150.8, 148.6, 141.7, 129.5, 125.9,
125.8, 118.0, 113.6, 73.54, 41.9, 38.3, 34.9, 31.7; IR (KBr
disc): n=3385, 2961, 1680, 1602, 1506, 1434, 1362, 1319,
1180, 1154, 1109, 1073, 1017, 992, 932, 868, 834, 749, 692,
617 cmÀ1
;
HR-MS (ESI): m/z=284.2013, calcd. for
C19H26NO [M+H]+: 284.2014; HPLC (Daicel ChiralPak
IC-3 column, n-hexane/i-PrOH=90/10, 0.5 mLminÀ1, UIV
210 nm): tR1 =18.0 min (minor), tR2 =25.7 min (major), ee=
94%.
column,
n-hexane/i-PrOH=95/5,
0.5 mLminÀ1,
UIV
(R)-1-Phenyl-3-(4-para-tolylpiperazin-1-yl)propan-1-ol
(13): White solid ; yield: 64.6 mg (99%); mp 89–908C; [a]2D5:
254 nm): tR1 =19.8 min (minor), tR2 =20.8 min (major), ee=
92%.
1
+26.5 (c 0.52, CH3OH); H NMR (400 MHz, CDCl3): d=
7.40–7.33 (m, 4H), 7.28–7.23 (m, 1H), 6.93–6.89 (m, 2H),
6.87–6.83 (m, 2H), 4.98–4.95 (m, 1H), 3.77 (s, 3H), 3.14 (t,
J=4.8 Hz, 4H), 2.82–2.61 (m, 7H), 1.93–1.88 (m, 1H);
13C NMR (100 MHz, CDCl3): d=154.2, 145.6, 145.0, 128.5,
127.2, 125.8, 118.6, 114.7, 75.8, 75.8, 57.3, 57.3, 55.8, 53.6,
51.0, 33.9; IR (KBr disc): n=3227, 3061, 2946, 2826, 1603,
Synthesis of 4[9a]
Compound 4 was synthesized as a white solid, using a similar
method to that described for the synthesis of 9; yield:
127 mg (79%); 1H NMR (400 MHz, CDCl3): d=7.41–7.32
3270
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Adv. Synth. Catal. 2015, 357, 3262 – 3272

FULL PAPERS
Asymmetric Hydrogenation of b-Secondary Amino Ketones
(m, 7H), 7.11–7.06 (m, 2H), 5.77 (dd, J=12.4, 2.4 Hz, 1H), References
4.46 (d, J=14.0 Hz, 1H), 4.37 (d, J=14.0 Hz, 1H), 3.76 (td,
J=13.6, 2.8 Hz, 1H), 3.25 (ddd, J=14.4, 4.4, 2.0 Hz, 1H),
2.19–2.08 (m, 1H), 1.76–1.71 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=164.5, 162.0, 135.2, 133.5, 129.1, 129.0, 128.6,
128.4, 128.3, 116.1, 115.9, 85.6, 52.7, 46.8, 28.2; HPLC
(Daicel ChiralPak AD-H column, n-hexane/i-PrOH=85/15,
[1] For selected papers, see: a) K. Rickels, W. T. Smith, V.
Glaudin, J. B. Amsterdam, C. Weise, G. P. Settle, J.
Clin. Psychiatry 1985, 46, 38; b) M. P. Schneider, U.
Goergens, Tetrahedron: Asymmetry 1992, 3, 525;
c) T. M. Koenig, D. Mitchell, Tetrahedron Lett. 1994,
35, 1339; d) E. Romeo, A. Strçhle, G. Spalletta, F. di
Michele, B. Hermann, F. Holsboer, A. Pasini, R. Rup-
precht, Am. J. Psychiatry 1998, 155, 910; e) T. Ohkuma,
D. Ishii, H. Takeno, R. Noyori, J. Am. Chem. Soc. 2000,
122, 6510; f) J. A. Lowe III, S. E. Drozda, K. Fisher, C.
Strick, L. Lebel, C. Schmidt, D. Hiller, K. S. Zandi,
Bioorg. Med. Chem. Lett. 2003, 13, 1291; g) A. A. M.
Lapis, A. De Fatima, J. E. D. Martins, V. E. U. Costa,
R. A. Pilli, Tetrahedron Lett. 2005, 46, 495; h) A.
Mowla, M. Mosavinasab, A. Pani, J. Clin. Psychophar-
macol. 2007, 27, 67; i) F. D. Klingler, Acc. Chem. Res.
2007, 40, 1367; j) P. Dharmshaktu, V. Tayal, B. S. Kalra,
J. Clin. Pharmacol. 2012, 52, 6.
0.5 mLminÀ1, UIV 254 nm): tR1 =21.5 min (major), tR2
22.3 min (minor), ee=71%.
=
Synthesis of 11
To a solution of 2a (70 mg, 0.29 mmol) in MeOH (5 mL)
was added Pd(OH)2/C (20%, 60 mg) and the mixture was
vigorously stirred under an atmosphere of H2 (10 bar) over
24 h. The suspension was filtered through celite and the fil-
trate was concentrated under vacuum to afford (R)-3-
amino-1-phenylpropan-1-ol 10; yield: 43.5 mg (0.29 mmol).
A mixture of 10 (43.5 mg, 0.29 mmol), 2-chlorobenzothia-
zole (37 mL, 0.30 mmol) and (i-Pr)2NEt (75 mL, 0.43 mmol)
was heated to 1108C for 24 h. The mixture was directly puri-
fied by column chromatography using silica gel (MeOH/
CH2Cl2 =1/99) to yield an intermediate.
[2] A. Guarna, G. Menchi, G. Berti, N. Cini, A. Bottoncet-
ti, S. Raspanti, A. Politi, A. Pupi, Bioorg. Med. Chem.
2001, 9, 3197.
To a solution of the above obtained intermediate in THF
(3 mL) under an argon atmosphere at 08C was added Et3N
(0.1 mL, 0.84 mmol) and then MsCl (32 mL, 0.42 mmol). The
mixture was stirred for 1.5 h at the same temperature and
then at room temperature for 1.5 h. After excess MsCl was
quenched with MeOH (0.4 mL), Et3N (1.1 mL) was added
and the mixture was heated at reflux for another 24 h. After
cooling to room temperature, the reaction mixture was dilut-
ed with DCM (5 mL) and washed with water (2”5 mL) and
brine (5 mL). The organic layer was dried over anhydrous
MgSO4, filtered, evaporated and the crude material was pu-
rified by column chromatography using silica gel (MeOH/
CH2Cl2 =1/90) to afford 11 as a white solid; yield: 40.1 mg
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Acknowledgements
This work was partly supported by the National Nature Sci-
ence Foundation of China (No. 21172143, 21172145,
21232004 and 21372152), Nippon Chemical Industrial Co.
Ltd., Shanghai Jiao Tong University (SJTU) and the Instru-
mental Analysis Center of SJTU. We thank Prof. Tsuneo Im-
amoto and Dr. Masashi Sugiya of Nippon Chemical Industri-
al Co. Ltd. for helpful discussions.
Adv. Synth. Catal. 2015, 357, 3262 – 3272
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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