Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated Piperazin-2-ones

Article abstract of DOI:10.1002/adsc.201700175

Two different iridium catalyst systems, generated from the ruthenocene-based phosphine-oxazoline ligand tBu-mono-RuPHOX or the diphosphine ligand BINAP, were developed for the asymmetric hydrogenation of 5,6-dihydropyrazin-2(1H)-ones, affording chiral piperazin-2-ones in good yields and with moderate to good ees. Different catalytic behaviors for the hydrogenation of these types of substrate were observed with these two catalyst systems. Our tBu-mono-RuPHOX ligand, which bears a ruthenocene scaffold with planar chirality, was found to be the best ligand for the [Ir(L)(COD)]BArF catalyst system, affording the desired products with up to 94% ee. (Figure presented.).

Full text of DOI:10.1002/adsc.201700175

Title: Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated
Piperazin-2-ones
Authors: Yanzhao Wang, Yuanyuan Liu, Kun Li, Guoqiang Yang, and
Wanbin Zhang
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10.1002/adsc.201700175
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated
Piperazin-2-ones
Yanzhao Wang,a Yuanyuan Liu,a Kun Li,a Guoqiang Yang,a,* Wanbin Zhanga,*
a
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
200240, China
[Tel: +86-021-5474-3265; fax: +86-021-5474-3265; e-mail: gqyang@sjtu.edu.cn; wanbin@sjtu.edu.cn]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Two different iridium-catalyst systems, generated Our tBu-mono-RuPHOX ligand, which bears a ruthenocene
from the ruthenocene-based phosphine-oxazoline ligand tBu- scaffold with planar chirality, was found to be the best
mono-RuPHOX or diphosphine ligand BINAP, were ligand for the [Ir(L)(COD)]BArF catalyst system, affording
developed for the asymmetric hydrogenation of 5,6- the desired products with up to 94% ee.
dihydropyrazin-2(1H)-ones, affording chiral piperazin-2-
ones in good yields and with moderate to good ees. Different
catalytic behaviors for the hydrogenation of these types of
substrates were observed with these two catalyst systems.
Keywords: asymmetric hydrogenation; iridium; P,N-
ligand; cyclic imines; 3-substituted piperazin-2-ones
pharmaceutical compounds such as Vestipitant and
Mirtazapine.[3] Therefore, a reliable and efficient
synthetic pathway for the preparation of these chiral
skeletons is highly desired. However, most of the
present synthetic methodologies rely on the use of
chiral starting materials, large amounts of chiral
inducing reagents, or the resolution of diastereomeric
salts.[1,4]
Asymmetric catalysis is an efficient approach
towards the synthesis of chiral piperazin-2-ones, with
clear advantages with regards to structural diversity
and the ability to use smaller amounts of a chiral
source; however, such procedures have not been
widely reported. The Lattanzi group reported a one-
pot approach to enantioenriched 3-substituted
Introduction
Chiral piperazin-2-ones reside within
a
wide
assortment of potent drugs and bioactive natural
products (Figure 1).[1-2] Praziquantel is a drug of
tremendous importance for the treatment of
schistosomiasis and soil-transmitted helminthiasis.[2b]
Pseudotheonamides that possess serine inhibitory
activity were isolated from the marine sponge
Theonella swinhoei.[2d] In addition, analogous
piperazines are also important skeletons present in
piperazin-2-ones
employing
an
asymmetric
epoxidation of alkylidenemalononitriles as a key
step.[5] The Stoltz group has divulged a highly
enantioselective Pd-catalyzed allylic alkylation for
the preparation of chiral piperazin-2-ones.[6]
Asymmetric hydrogenation, one of the most efficient
and practical methods for the construction of chiral
skeletons, has attracted much attention over the past
several decades.[7] However, only several studies
concerning the preparation of chiral piperazines via
asymmetric hydrogenation have been reported.[8-11]
An elegant approach towards the synthesis of a
variety of chiral piperazines, including mono- and
disubstituted substrates, has been reported by the
Zhou group, and involves the use of an Ir-catalyzed
asymmetric hydrogenation and alkyl halide
activation.[11] Very recently, the Mashima group
reported a high yielding and enantioselective Ir-
Figure 1. Chiral Piperazin-2-ones and Piperazines
with Bioactivities.
1
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10.1002/adsc.201700175
Advanced Synthesis & Catalysis
catalyzed asymmetric hydrogenation of tosylamido-
substituted pyrazines for the preparation of chiral
tetrahydropyrazines bearing an amidine skeleton.
These products can be converted to chiral piperazines
and 5-substituted piperazin-2-ones via LiAlH4
reduction or hydrolysis, respectively.[12] Herein, we
report two independent Ir-catalyst systems for the
synthesis of chiral 3-substituted piperazin-2-ones via
the asymmetric hydrogenation of 5,6-dihydropyrazin-
2(1H)-ones (Scheme 1).
RuPHOX).[17] These ligands have shown excellent
performance in Pd-catalyzed asymmetric allylic
substitutions[18] and Ru-catalyzed asymmetric
(transfer) hydrogenations of ketones and unsaturated
carboxylic acids.[19] In this article, we report the
catalytic activity and enantioinducing ability of
mono-RuPHOX in
a
Ir-catalyzed asymmetric
hydrogenation of imines, for the first time. We have
also discovered an Ir/BINAP catalyst system that can
be used for the same hydrogenation reaction. A
comparison of the two catalyst systems is described.
Results and Discussion
3-Substituted 5,6-dihydropyrazin-2(1H)-ones could
be prepared via the condensation of ethylenediamine
with α-keto esters in one simple step [Eq. (1)].
Further protection of the amide with Bn, Ts and Me
was also conducted for 3-phenyl-5,6-dihydropyrazin-
2(1H)-one.
The screening of hydrogenation reaction conditions
was conducted as shown in Table 1. We began our
exploration with 1a as the model substrate. Firstly,
different catalysts with different chiral P,N-ligands
were screened under 50 bar of hydrogen in dioxane
(entries 1-8). It appeared that a more bulky tBu group
at the chiral center of the oxazoline is benefical for
both catalytic activity and enantioselectivity when
compared with the iPr group (entry 2 vs 1, entry 4 vs
3, entry 6 vs 5). Interestingly, compared to the results
of the reaction using an Ir-catalyst PHOX (L7) ligand,
planar chiral P,N ligands (L4 and L2) considerably
improved the enantioselectivity (entries 4 and 2 vs 7).
More importantly, our ruthenocene-based P,N-ligand
(mono-RuPHOX) showed a higher catalytic acivity
and enantioinducting ability than the ferrocene-based
P,N-ligand (entry 4 vs 2, entry 3 vs 1), and our
ruthenocene-based di-P,N-ligand (RuPHOX) showed
similar results to that of the ferrocene-based P,N-
ligand (entry 6 vs 2, entry 5 vs 1). BiphPHOX was
also tested as a ligand for this asymmetric
hydrogenation, however poor results were obtained
(L8, entry 8). Thus, 2a could be obtained in almost
quantitative conversion and with 72% ee when L4
was used as the chiral ligand (entry 4). The absolute
configuration of 2a was determined to (S) by X-ray
crystallographic analysis.[20] The effect of solvent on
this asymmetric hydrogenation reaction was
examined using L4 as the ligand. The result for the
hydrogenation in toluene was almost the same as that
in dioxane (entry 9). To our delight, haloalkane
solvents significantly enhanced enantioselectivity
(entries 10 and 11), with dicholoromethane (DCM)
giving the desired product with the best results (>
99% conversion, 94% ee). The enantioselectivity
decreased sharply when the solvent was changed to
Scheme 1. Synthesis of chiral piperazin-2-ones and
piperazines via asymmetric catalysis.
The application of chiral P,N-ligands for the Ir-
catalyzed asymmetric hydrogenation of imines was
first reported by Pfaltz and coworkers.[13] Following
this pioneering work, a number of different chiral
P,N-ligands have been developed for the Ir-catalyzed
asymmetric hydrogenation of various imines.[14] In
addition, chiral di- and monodentate P-ligands have
also shown excellent catalytic behavior for the Ir-
catalyzed asymmetric hydrogenation of imines.[15,16]
Previously, we designed a series of ruthenocene-
based PHOX-type ligands (mono-RuPHOX and
2
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10.1002/adsc.201700175
Advanced Synthesis & Catalysis
TBME, THF or MeOH (entries 12-14). A slightly
lower conversion and enantioselectivity was obtained
when the reaction was carried out under 30 bar H2
pressure (entry 15). Under 50 bar H2, and using DCM
as the solvent of choice, we explored the effects of
additives such as 4Å MS, TFA, NaHCO3 (entries 16-
18), and I2 (entry 19) on the reaction. Unfortunately,
use of these additives, especially I2, resulted in a
reduction in conversions and enantioselectivities. The
formation of the opposite enantiomer when I2 was
used cannot be easily explained. We propose that a
different catalyst is formed upon treatment with I2.[21]
Similar behavior was also observed when Ir-catalyst
was generated in situ from [Ir(COD)Cl]2 and L4
without weak-coordinating anion (entry 20).[21] When
the counterion was changed to BF4 or PF6 , the
enantioselectivity was significantly reduced, without
changing of the optical selection. (entries 20 and 21).
Therefore, the optimal reaction conditions were found
to be the following: using [Ir(L4)(COD)]BArF as a
catalyst in DCM under 50 bar H2 at room temperature.
18[g]
19[h]
20[i]
21[j]
DCM
DCM
DCM
DCM
DCM
L4
L4
L4
L4
L4
93
41
38
92
87
-40
-82
51
22[k]
>99
80
a)
Reaction conditions: ratio of substrate/catalyst (S/C) =
100, 1 mL solvent, H2 (50 bar). b) Determined by 1H NMR
c)
spectroscopy.
Enantioselectivity was determined by
d)
e)
HPLC using a chiral column. H2 (30 bar). 4Å MS (50
f)
g)
mg) as an additive. TFA (0.1 equiv.) as an additive.
NaHCO3 (0.1 equiv.) as an additive. h) I2 (0.1 equiv.) as an
i)
additive.
Catalyst was in situ generated from
j)
-
[Ir(COD)Cl]2 (0.005 equiv.) and L4 (0.012 equiv.). BF4
anion instead of BArF. k) PF6 anion instead of BArF.
-
-
-
Table 2. Ligand Effect on Hydrogenation Using in situ
Generated Ir-Catalyst.[a]
Table 1. Condition Screening.[a]
Entry Ligand
Conv.[%][b]
>95
71
74
18
ee [%][c]
84
77
80
20
1
2
3
4
5
6
L9
L10
L11
L12
L13
L14
Entry
Solvent
Ligand
Conv.[%][b]
ee
31
NR
-64
--
[%][c]
45
63
49
72
44
64
49
--
a) Reaction conditions: ratio of substrate/catalyst (S/C) = 25,
1 mL solvent, H2 (70 bar), 72 h. b) Isolated yield. c) Ee was
determined by HPLC using a chiral column.
1
2
3
4
5
6
7
8
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DCM
DCE
THF
TBME
MeOH
DCM
54
87
75
>99
49
L1
L2
L3
L4
L5
L6
L7
L8
L4
L4
L4
L4
L4
L4
L4
L4
L4
During the screening of reaction conditions, we
also found that a catalyst generated in situ from
[Ir(COD)Cl]2 and the chiral bisphosphine ligand were
also capable of catalyzing this asymmetric
hydrogenation. After the screening of solvent,
hydrogen pressure, reaction time, and additives,
different chiral diphosphine ligands were tested using
[Ir(COD)Cl]2 as an Ir source and dioxane as the
solvent, under 70 bar of hydrogen pressure for 72 h
(Table 2). BINAP (L9) was found to be the best
ligand for this catalytic system (entry 1). Other chiral
biphenyl diphosphine ligands gave the desired
95
>99
trace
95
>99
87
>99
>99
>99
91
9
72
94
88
62
52
44
88
89
86
10
11
12
13
14
15[d]
16[e]
17[f]
DCM
DCM
88
93
3
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10.1002/adsc.201700175
Advanced Synthesis & Catalysis
product in lower yields and ees (entries 2-4). The P-
chiral QuinoxP* was also tested as a ligand, however
poor results were obtained (entry 5). No reaction
occurred when using our ferrocenyl diphosphine
ligand bearing only planar-chirality (entry 6). We
have also tried the hydrogenation of unsaturated 2-
oxopiperazinium chloride (1a•HCl). However, the
reaction did not proceed.
[Ir(L4)(COD)]BArF system (entries 11 and 13).
Similar substituent effects were observed in both
catalyst systems for substrates bearing meta-
substituents; the corresponding products were
obtained with lower ees compared to that of the
products obtained from substrates bearing a para-
substituent (entries 9/10 vs 4/6). For both catalyst
systems, substrates bearing electron-donating
substituents at the benzene ring showed better ees
than those bearing electron-withdrawing groups.
With the optimized reaction conditions in hand, the
asymmetric hydrogenation of 3-substituted 5,6-
dihydropyrazin-2(1H)-ones was conducted with the
preformed cationic catalyst ([Ir(L4)(COD)]BArF,
System A) and the “in situ” catalyst
([Ir(COD)Cl]2/BINAP, System B) (Table 3). The
influence of the electronic and steric effects of the
benzene ring at the 3-position of the 5,6-
dihydropyrazin-2(1H)-one groups on ee is different
for these two systems. Firstly, for the
[Ir(COD)Cl]2/BINAP system, the impact on ee is not
as dramatic as that of the [Ir(L4)(COD)]BArF system
(Table 3, entries 1-8). Secondly, an electron neutral
phenyl-substituted substrate gave the desired product
with the highest ee for the [Ir(L4)(COD)]BArF
system, while substrates bearing electron-donating
MeO or tBu groups showed the best ees in the para-
substituted ones for the [Ir(COD)Cl]2/BINAP system
(entry 1 of System A vs entries 3/4 of System B).
Finally, the ortho-methyl phenyl- and β-naphthyl-
substituted substrates can be hydrogenated using the
[Ir(COD)Cl]2/BINAP system to afford the
corresponding chiral piperazin-2-ones with better
results, presenting a striking contrast with the
(entries 2-8).
A
3,4-dimethyl-phenyl-substituted
compound gave its corresponding product in good
yields and ees (entry 12), with which the highest ee
was obtained using the [Ir(COD)Cl]2/BINAP system.
Substrates with different protecting groups at the
nitrogen amide could also be hydrogenated under our
catalyst system A, giving the corresponding products
with good results (entries 14-16). A substrate bearing
a Bn-protected amide was also subjected to the “in
situ” catalyst system ([Ir(COD)Cl]2/BINAP);
however, a poorer result was obtained compared to
when using the [Ir(L4)(COD)]BArF system (entry
14). We have also prepared a substrate bearing a
methyl R1 group and Bn protected amide. However,
this substrate is not stable and decomposes (or
rearranges) to a mixture of unidentified compounds at
room temperature or under the hydrogenation
conditions. It should be noted that 2k and 2o are key
intermediates for the preparation of Vestipitant and
Mirtazapine, respectively.
Table 3. Substrate Scope with [Ir(L4)(COD)]BArF Catalyst and [Ir(COD)Cl]2/BINAP Catalyst Systems.[a]
System A
System B
Yield [%][b]
Entry
R1
R2
2
Yield [%][b]
ee [%][c]
94(92)[e]
90
ee [%][c]
84
85
89
89
81
80
76
76
84
--
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
H
H
H
H
H
H
H
H
H
H
H
H
97(96)[e]
96
96
95
96
96
95
93
95
91
96
--
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
4-MeC6H4
4-tBuC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
3-OMeC6H4
3-ClC6H4
4-F-2-MeC6H3
3,4-Me2C6H3
β-naphthyl
Ph
96
96
95
94
93
92
91
88
84
84
75
75
93[f]
90[f]
72[g]
95
93
92
92
94
84[f]
72[f]
56[g]
90
~0
90
91
84
71
97
95
95
--
78
90
79
80
--
H
Bn
Me
Ts
Ph
Ph
--
--
a)
Catalyst System A: substrate (1.0 equiv), [Ir(L4)(COD)]BArF (0.01 equiv), 1 mL DCM, H2 (50 bar), room temperature
for 24 h. Catalyst System B: substrate (1.0 equiv), [Ir(COD)Cl]2 (0.02 equiv), (R)-BINAP (0.048 equiv), 1 mL 1,4-dioxane,
4
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10.1002/adsc.201700175
Advanced Synthesis & Catalysis
b)
c)
d)
H2 (70 bar), room temperature for 72 h. Isolated yield. Ee was determined by HPLC using a chiral column. The
absolute configuration of 2a was determined by X-ray crystallographic analysis.[20] The results in parentheses were
e)
obtained using 1 mmol of substrate 1a. f) Reaction time was 48 h. g) Reaction condition: H2 (70 bar), 72 h.
The intermediate α-ketoesters prepared by our
methodology[22] (20 mmol) was dissolved in dry toluene
(20 mL) under an inert atmosphere; ethylenediamine (1.6
mL) was added dropwise followed by Na2SO4 (3.7 g) and
the reaction mixture was heated at reflux for 2 hr. The
solids were removed by filtration and the crude product
obtained after evaporation of the solvent was purified by
flash chromatography (PE/EtOAc =2:1) affording the
substrates 1.
General Procedure for Synthesis of Ir Complexes
[Ir(L)(COD)]BArF
To a two-necked flask fitted with a condenser was added
ligand L4 (0.16 g, 0.3 mmol, 1.0 equiv.), [Ir(COD)Cl]2
Scheme 2. Synthesis of (S)-Mirtazapine
(0.10 g, 0.15 mmol, 0.5 equiv.), and dichloromethane (5.0
mL). The deep red mixture was heated under argon
atmosphere to reflux for 2 h, until TLC showed that the
coordination was completed. After the mixture was cooled
to room temperature, NaBArF (0.34 g, 0.36 mmol, 1.2
equiv.) was added followed by water (5.0 mL), and the
mixture was stirred vigorously for 1 h. The mixture was
extracted with dichloromethane (5 mL×3) and washed with
brine. The organic layer was dried over anhydrous Na2SO4
(S)-Mirtazapine shows potential for the treatment
of insomnia and climacteric symptoms. 1-Methyl-3-
phenylpiperazine 3 is an important intermediate for
the preparation of (S)-Mirtazapine.[3b] The reported
syntheses of 3 generally require 3−6 steps coupled
with chemical resolution. Starting from compound 1o,
3 was obtained in just two steps, significantly
shortening the synthetic route (Scheme 2).
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography on silica gel
eluting with EtOAc/petroleum ether = 1:1 to afford the Ir
complex.
Conclusion
In summary, we have developed two different Ir-
General Procedure for Ir-Catalyzed Asymmetric
Hydrogenation
catalyst systems for the asymmetric hydrogenation of
5,6-dihydropyrazin-2(1H)-ones, affording chiral
piperazin-2-ones in good yields and with moderate to
Procedure A: Under a nitrogen atomosphere, the catalyst
good ees. These two asymmetric catalyst systems
(1.7 mg, 0.001 mmol, 0.01 equiv.) and substrate 1 (0.1
mmol, 1.0 equiv.) were placed in a 5 mL tube equipped
show different catalytic behaviors for this
hydrogenation reaction. Protected and unprotected
with a magnetic stirrer bar. This tube was then put into an
amide substrates could be hydrogenated smoothly.
argon-filled autoclave. Solvent (1.0 mL) was added to the
mixture under a nitrogen atmosphere. The autoclave was
Our ruthenocene-based P-N ligand, tBu-mono-
RuPHOX, was found to be the best ligand for the
then closed, purged three times with hydrogen (less than
[Ir(L)(COD)]BArF catalyst system, affording the
the pressure needed), and finally pressurized to 50 bar. The
desired products with up to 94% ee.
reaction mixture was stirred at r.t. for 24 h. The hydrogen
gas was slowly released and the sovlent was removed by
vacumn epavoration. The residue was purified by
preparative TLC on silica gel to give the product 2. The ee
Experimental Section
was determined by chiral HPLC.
General Remarks
(S)-3-Phenylpiperazin-2-one (2a): white solid; 97%
yield; m. p. 144.2 – 145.0 oC; 1H NMR (400 MHz, CDCl3):
δ 7.45 – 7.42 (m, 2H), 7.39 – 7.29 (m, 3H), 4.59 (s, 1H),
3.60 – 3.54 (m, 1H), 3.43 – 3.37 (m, 1H), 3.21 – 3.16 (m,
1H), 3.12 – 3.06 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
171.1, 139.5, 128.7, 128.5, 128.1, 64.1, 43.4, 41.2; HRMS
(ESI): calcd for C10H13N2O [M+H]+: 177.1028, found
177.1036; HPLC [Enantiopak OD-H, hexane/i-PrOH =
85/15, 220 nm, 1.0 mL/min. tR1 = 23.7 min (S), tR2 = 28.1
min (R)]; ee = 94%; [α]D27 = 8.66 (c = 0.66, CHCl3).
(S)-3-(p-Tolyl)piperazin-2-one (2b): yellow solid; 96%
yield; m. p. 144.6 – 145.3 oC; 1H NMR (400 MHz, CDCl3):
δ 7.30 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 4.54 (s,
All reactions were carried out under an atmosphere of
nitrogen using standard Schlenk techniques, unless
otherwise noted. 1H NMR and 13C NMR spectra were
recorded at room temperature in CDCl3 on a 400 MHz
instrument with tetramethylsilane (TMS) as internal
standard. Enantiomeric excesses were determined by
HPLC analysis. Optical rotations were measured by a
polarimeter. Flash column chromatography was performed
on silica gel (200–300 mesh). All reactions were monitored
by TLC analysis.
General Procedure for Preparation of the Substrates 1
5
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10.1002/adsc.201700175
Advanced Synthesis & Catalysis
1H), 3.57 – 3.50 (m, 1H), 3.40 – 3.34 (m, 1H), 3.20 – 3.14
(m, 1H), 3.10 – 3.03 (m, 1H), 2.34 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 171.4, 137.6, 136.6, 129.3, 128.3, 63.6,
43.2, 41.1, 21.2; HRMS (ESI): calcd for C11H15N2O
[M+H]+: 191.1184, found 191.1192; HPLC [Enantiopak
min (S), tR2 = 44.6 min (R)]; ee = 75%; [α]D27 = 11.07 (c =
0.35, CHCl3).
(S)-3-(4-(Trifluoromethyl)phenyl)piperazin-2-one
o
1
(2h): yellow solid; 92% yield; m. p. 127.5 – 128.4 C; H
NMR (400 MHz, CDCl3): δ 7.65 – 7.58 (m, 4H), 4.63 (s,
1H), 3.58 – 3.52 (m, 1H), 3.39 – 3.35 (m, 1H), 3.19 – 3.07
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 170.2, 143.2,
130.3 (q, J = 32 Hz), 128.9, 125.6 (q, J = 4.0 Hz), 124.1 (q,
J = 262 Hz), 63.6, 43.4, 41.4; HRMS (ESI): calcd for
C11H12F3N2O [M+H]+: 245.0901, found 245.0905; HPLC
[Enantiopak OD-H, hexane/i-PrOH = 90/10, 220 nm, 1.0
mL/min. tR1 = 33.2 min (S), tR2 = 46.7 min (R)]; ee = 75%;
[α]D27 = 9.54 (c = 0.18, CHCl3).
OD-H, hexane/i-PrOH = 90/10, 220 nm, 1.0 mL/min. tR1
=
41.3 min (S), tR2 = 47.8 min (R)]; ee = 90%; [α]D27 = -8.55
(c = 0.50, CHCl3).
(S)-3-(4-(tert-Butyl)phenyl)piperazin-2-one
(2c):
o
1
yellow solid; 96% yield; m. p. 161.5 – 162.2 C; H NMR
(400 MHz, CDCl3): δ 7.39 – 7.33 (m, 4H), 4.56 (s, 1H),
3.56 – 3.49 (m, 1H), 3.40 – 3.34 (m, 1H), 3.19 – 3.14 (m,
1H), 3.09 – 3.02 (m, 1H), 1.30 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 171.2, 150.8, 136.5, 128.1, 125.7, 63.7,
43.5, 41.3, 34.7, 31.5; HRMS (ESI): calcd for C14H21N2O
[M+H]+: 233.1654, found 233.1654; HPLC [Daicel
Chiralcel OD-H, hexane/i-PrOH = 92/8, 220 nm, 1.0
mL/min. tR1 = 34.3 min (S), tR2 = 51.1 min (R)]; ee = 91%;
[α]D27 = -15.98 (c = 0.39, CHCl3).
(S)-3-(3-Methoxyphenyl)piperazin-2-one (2i): yellow
o
1
solid; 93% yield; m. p. 142.1 – 142.9 C; H NMR (400
MHz, CDCl3): δ 7.28 (t, J = 8.0 Hz, 1H), 7.03 – 6.98 (m,
2H), 6.85 (ddd, J = 8.4, 2.4, 1.0 Hz, 1H), 4.55 (s, 1H), 3.81
(s, 3H), 3.56 – 3.50 (m, 1H), 3.40 – 3.34 (m, 1H), 3.20 –
3.14 (m, 1H), 3.10 – 3.03 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 170.8, 159.8, 140.9, 129.7, 120.8, 114.0, 113.7,
64.0, 55.4, 43.4, 41.2; HRMS (ESI): calcd for C11H15N2O2
[M+H]+: 207.1133, found 207.1127; HPLC [Enantiopak
(S)-3-(4-Methoxyphenyl)piperazin-2-one (2d): yellow
o
1
solid; 96% yield; m. p. 139.8 – 140.5 C; H NMR (400
MHz, CDCl3): δ 7.35 – 7.32 (m, 2H), 6.91 – 6.87 (m, 2H),
4.53 (s, 1H), 3.80 (s, 3H), 3.58 – 3.51 (m, 1H), 3.40 – 3.34
(m, 1H), 3.20 – 3.14 (m, 1H), 3.10 – 3.04 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 171.5, 159.2, 131.8, 129.5,
114.0, 63.4, 55.3, 43.2, 41.2; HRMS (ESI): calcd for
C11H15N2O2 [M+H]+: 207.1133, found 207.1137; HPLC
[Daicel Chiralcel OJ-H, hexane/i-PrOH = 90/10, 220 nm,
1.0 mL/min. tR1 = 43.1 min (R), tR2 = 46.6 min (S)]; ee =
88%; [α]D27 = -4.28 (c = 0.28, CHCl3).
OD-H, hexane/i-PrOH = 90/10, 220 nm, 1.0 mL/min. tR1
=
62.0 min (S), tR2 = 85.1 min (R)]; ee = 84%; [α]D27 = -22.83
(c = 0.14, CHCl3).
(S)-3-(3-Chlorophenyl)piperazin-2-one (2j): yellow
o
1
solid; 90% yield; m. p. 117.8 – 118.5 C; H NMR (400
MHz, CDCl3): δ 7.47 (s, 1H), 7.33 – 7.26 (m, 3H), 4.55 (s,
1H), 3.58 – 3.52 (m, 1H), 3.41 – 3.35 (m, 1H), 3.19 – 3.14
(m, 1H), 3.12 – 3.05 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 170.4, 141.4, 134.5, 129.8, 128.6, 128.2, 126.9,
63.4, 43.3, 41.2; HRMS (ESI): calcd for C10H12ClN2O
[M+H]+: 211.0638, found 211.0627; HPLC [Enantiopak
(S)-3-(4-Fluorophenyl)piperazin-2-one (2e): yellow
o
1
solid; 95% yield; m. p. 121.8 – 122.5 C; H NMR (400
MHz, CDCl3): δ 7.44 – 7.39 (m, 2H), 7.07 – 7.01 (m, 2H),
4.56 (s, 1H), 3.58 – 3.49 (m, 1H), 3.40 – 3.34 (m, 1H),
3.20 – 3.14 (m, 1H), 3.12 – 3.05 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 171.1, 162.5 (d, J = 245.0 Hz), 135.3 (d, J
= 2.0 Hz), 130.2 (d, J = 8.0 Hz), 115.4 (d, J = 21.0 Hz),
63.3, 43.2, 41.3; HRMS (ESI): calcd for C10H12FN2O
[M+H]+: 195.0933, found 195.0932; HPLC [Enantiopak
OD-H, hexane/i-PrOH = 90/10, 220 nm, 1.0 mL/min. tR1
=
38.6 min (S), tR2 = 48.0 min (R)]; ee = 72%; [α]D = 6.66
27
(c = 0.12, CHCl3).
(S)-3-(4-Fluoro-2-methylphenyl)piperazin-2-one (2k):
1
yellow liquid; 72% yield; H NMR (400 MHz, CDCl3): δ
7.26 (t, J = 7.2 Hz, 1H), 6.91 – 6.84 (m, 2H), 6.68 (s, 1H),
4.69 (s, 1H), 3.61 – 3.54 (m, 1H), 3.39 – 3.34 (m, 1H),
3.20 – 3.15 (m, 1H), 3.12 – 3.05 (m, 1H); 13C NMR (100
MHz, CDCl3):δ 171.3 , 162.3 (d, J = 244 Hz), 139.8 (d, J =
7.0 Hz), 133.6, 130.6 (d, J = 9.0 Hz), 117.7 (d, J = 21 Hz),
112.8 (d, J = 21 Hz), 61.7, 43.4, 41.9, 19.7; HRMS (ESI):
calcd for C11H14FN2O [M+H]+: 209.1090, found 209.1089;
HPLC [Daicel Chiralcel IC-3, hexane/i-PrOH = 80/20, 220
nm, 1.0 mL/min. tR1 = 31.8 min (S), tR2 = 41.7 min (R)]; ee
= 56%; [α]D27 = -18.99 (c = 0.61, CHCl3).
OD-H, hexane/i-PrOH = 90/10, 220 nm, 1.0 mL/min. tR1
=
41.4 min (S), tR2 = 47.1 min (R)]; ee = 84%; [α]D27 = 13.13
(c = 0.42, CHCl3).
(S)-3-(4-Chlorophenyl)piperazin-2-one (2f): yellow
o
1
solid; 94% yield; m. p. 122.7 – 123.5 C; H NMR (400
MHz, CDCl3): δ 7.41 – 7.39 (m, 2H), 7.34 – 7.32 (m, 2H),
4.56 (s, 1H), 3.59 – 3.53 (m, 1H), 3.41 – 3.36 (m, 1H),
3.20 – 3.15 (m, 1H), 3.13 – 3.07 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 170.6, 137.8, 133.9, 129.9, 128.8, 63.3,
43.3, 41.3; HRMS (ESI): calcd for C10H12ClN2O [M+H]+:
211.0638, found 211.0631; HPLC [Enantiopak OD-H,
hexane/i-PrOH = 90/10, 220 nm, 1.0 mL/min. tR1 = 42.1
(S)-3-(3,4-Dimethylphenyl)piperazin-2-one
(2l):
o
1
yellow solid; 95% yield; m. p. 156.0 – 157.0 C; H NMR
(400 MHz, CDCl3): δ 7.17 – 7.10 (m, 3H), 4.51 (s, 1H),
3.57 – 3.50 (m, 1H), 3.40 – 3.34 (m, 1H), 3.19 – 3.14 (m,
1H), 3.09 – 3.02 (m, 1H), 2.26 (s, 3H), 2.24 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 171.5, 137.0, 136.9, 136.4,
129.9, 129.6, 125.9, 63.9, 43.4, 41.3, 19.9, 19.6; HRMS
min (S), tR2 = 50.0 min (R)]; ee = 84%; [α]D = -7.05 (c =
27
0.17, CHCl3).
(S)-3-(4-Bromophenyl)piperazin-2-one (2g): yellow
o
1
solid; 93% yield; m. p. 150.4 – 151.2 C; H NMR (400
MHz, CDCl3): δ 7.48 (d, J = 8.4, 2H), 7.33 (d, J = 8.0, 2H), (ESI): calcd for C12H17N2O [M+H]+: 205.1341, found
4.53 (s, 1H), 3.56 – 3.50 (m, 1H), 3.39 – 3.33 (m, 1H),
3.18 – 3.13 (m, 1H), 3.11 – 3.05 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 170.3, 138.4, 131.7, 130.2, 122.1, 63.5,
43.4, 41.4; HRMS (ESI): calcd for C10H12BrN2O [M+H]+:
255.0133, found 255.0143; HPLC [Enantiopak OD-H,
hexane/i-PrOH = 90/10, 220 nm, 1.0 mL/min. tR1 = 38.0
205.1338; HPLC [Enantiopak OD-H, hexane/i-PrOH =
90/10, 220 nm, 1.0 mL/min. tR1 = 36.1 min (S), tR2 = 50.2
min (R)]; ee = 90%; [α]D27 = -7.66 (c = 0.24, CHCl3).
3-(Naphthalen-2-yl)piperazin-2-one (2m): yellow
solid; 93% yield; m. p. 196.5 – 197.4 C; H NMR (400
MHz, DMSO-d6): δ 7.89 – 7.78 (m, 4H, ArH), 7.55 – 7.46
o
1
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700175
Advanced Synthesis & Catalysis
Municipality (Nos. 14XD1402300 and 15JC1402200). We thank
the Instrumental Analysis Center of SJTU.
(m, 3H, ArH), 4.48 (s, 1H), 3.24 – 3.18 (m, 2H), 2.99 –
2.95 (m, 1H), 2.93 – 2.87 (m, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 169.5, 138.5, 132.7, 132.3, 127.7, 127.4,
127.2, 127.0, 126.0, 125.7, 63.4, 42.3, 41.0; HRMS (ESI):
calcd for C14H15N2O [M+H]+: 227.1184, found 227.1166;
HPLC [Daicel Chiralcel IC-3, hexane/i-PrOH = 80/20, 220
nm, 1.0 mL/min. tR1 = 25.5 min, tR2 = 34.1 min]; ee = 0%.
(S)-1-Benzyl-3-phenylpiperazin-2-one (2n): yellow
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1
liquid; 92% yield; H NMR (400 MHz, CDCl3): δ 7.44 –
[2] For selected papers, see: a) M. Iwatsuki, R. Uchida, H.
7.26 (m, 10H), 4.80 (s, 1H), 4.66 (s, 2H), 3.58 – 3.53 (m,
1H), 3.38 – 3.30 (m, 1H), 3.20 – 3.16 (m, 1H), 3.08 – 3.00
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 166.3, 136.4,
136.3, 129.1, 129.0, 128.9, 128.5, 128.0, 62.5, 50.5, 45.4,
40.3; HRMS (ESI): calcd for C17H19N2O [M+H]+:
267.1497, found 267.1495; HPLC [Enantiopak OD-H,
hexane/i-PrOH = 80/20, 220 nm, 1.0 mL/min. tR1 = 13.0
Yoshijima, H. Ui, K. Shiomi, Y.-P. Kim, T. Hirose, T.
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min (S), tR2 = 22.1 min (R)]; ee = 90%; [α]D = 9.15 (c =
27
0.24, CHCl3).
(S)-1-Methyl-3-phenylpiperazin-2-one (2o): yellow
1
liquid; 92% yield; H NMR (400 MHz, CDCl3): δ 7.40 –
[3] For selected papers, see: a) B. D. Dorsey, R. B. Levin,
S. L. McDaniel, J. P. Vacca, J. P. Guare, P. L. Darke, J.
A. Zugay, E. A. Emini, W. A. Schleif, J. C. Quintero, J.
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Pentassuglia, D. A. Pizzi, D. Donati, T. Rossi, G.
Guercio, M. Mattioli, Z. Cimarosti, C. Marchioro, S.
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7.26 (m, 5H), 4.56 (s, 1H), 3.55 – 3.49 (m, 1H), 3.33 –
3.28 (m, 1H), 3.19 – 3.14 (m, 1H), 3.10 – 3.02 (m, 1H),
3.01 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.8, 139.8,
128.5, 128.4, 127.8, 64.0, 50.3, 41.2, 34.9; HRMS (ESI):
calcd for C11H15N2O [M+H]+: 191.1184, found 191.1184;
HPLC [Enantiopak OD-H, hexane/i-PrOH = 90/10, 220
nm, 1.0 mL/min. tR1 = 40.8 min (S), tR2 = 66.0 min (R)]; ee
= 91%; [α]D27 = -28.46 (c = 1.16, CHCl3).
(S)-3-Phenyl-1-tosylpiperazin-2-one (2p): white solid;
o
1
94% yield; m. p. 108.2 – 108.9 C; H NMR (400 MHz,
CDCl3): δ 7.91 (d, J = 8.4 Hz, 2H), 7.31 – 7.21(m, 7H,
ArH), 4.51 (s, 1H), 4.12 – 4.05 (m, 1H), 3.98 – 3.91 (m,
1H), 3.33 – 3.27 (m, 1H), 3.16 – 3.09 (m, 1H), 2.42 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 168.9, 145.1, 138.0,
135.8, 129.5, 128.9, 128.7, 128.3, 128.2, 65.6, 47.9, 42.3,
21.8; HRMS (ESI): calcd for C17H19N2O3S [M+H]+:
331.1116, found 331.1117; HPLC [Enantiopak OD-H,
hexane/i-PrOH = 90/10, 220 nm, 0.5 mL/min. tR1 = 44.0
min (R), tR2 = 58.8 min (S)]; ee = 84%; [α]D27 = -31.54 (c =
0.38, CHCl3).
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Procedure B: Under nitrogen atomosphere, (R)-BIANP
(3.0 mg, 0.0048 mmol, 0.048 equiv.), [IrCODCl]2 (1.34
mg, 0.002 mmol, 0.02 equiv.) and solvent (1.0 mL) were
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hydrogen (less than the pressure needed), and finally
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21232004) and Science and Technology Commission of Shanghai
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This article is protected by copyright. All rights reserved.

10.1002/adsc.201700175
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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9
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Advanced Synthesis & Catalysis
FULL PAPER
Iridium-Catalyzed Asymmetric Hydrogenation of
Unsaturated Piperazin-2-ones
Adv. Synth. Catal. Year, Volume, Page – Page
Yanzhao Wang, Yuanyuan Liu, Kun Li, Guoqiang
Yang,* Wanbin Zhang*
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