Synthesis of chiral hydantoin derivatives by homogeneous Pd-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2016.10.006

5-Aryl substituted chiral hydantoin derivatives were synthesized via asymmetric hydrogenation of prochiral exocyclic alkenes using a Pd/BINAP catalyst. Moderate to good enantioselectivity were obtained (21–90% ee). A chiral Br?nsted acid additive was foun

Full text of DOI:10.1016/j.tetasy.2016.10.006

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of chiral hydantoin derivatives by homogeneous
Pd-catalyzed asymmetric hydrogenation
b
b
b
a
Bao-De Ma a,b, Sheng-Hua Du b, , Yu Wang , Xiao-Ming Ou , Ming-Zhi Huang , Li-Xin Wang ,
⇑
Xiao-Guang Wang b,
⇑
a State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
b National Engineering Research Centre for Agrochemicals, Hunan Haili Chemical Industry Co., Ltd, Changsha 410007, China
a r t i c l e i n f o
a b s t r a c t
Article history:
5-Aryl substituted chiral hydantoin derivatives were synthesized via asymmetric hydrogenation of
prochiral exocyclic alkenes using a Pd/BINAP catalyst. Moderate to good enantioselectivity were obtained
(21–90% ee). A chiral Brönsted acid additive was found to be a key factor to obtain high enantioselectivity.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 22 August 2016
Revised 26 September 2016
Accepted 4 October 2016
Available online xxxx
1. Introduction
were successfully hydrogenated with excellent enantiomeric
excess (up to 98% ee).8 In general, despite great success being made
Chiral hydantoin derivatives are widespread among natural
products and have shown great potential application in the area
of pharmaceuticals (Fig. 1).1 These compounds have been also used
as chiral catalysts and auxiliaries.2 Up to now, several methodolo-
gies have been developed to obtain these molecules, including
enzymatic synthesis, resolution and chiral pool approaches.3 These
methods, however, often suffer from low efficiency and poor econ-
omy. Thus developing a new catalytic asymmetric synthesis
method is important.
in the asymmetric hydrogenation of exocyclic alkenes, exploring a
new catalyst system and extending substrates ranges still remains
a great challenge.
Over the past fifteen years, Pd complexes have gradually been
demonstrated as effective catalysts in homogeneous asymmetric
hydrogenation,9 especially in the asymmetric hydrogenation of
imines, enamines and heteroarenes.10 Herein, we report the first
asymmetric hydrogenation of hydantoin derived exocyclic alkenes
using a Pd/BINAP catalyst (Fig. 2).
Asymmetric hydrogenation of hydantoin derived exocyclic
alkene is one of the most direct methods to obtain the target chiral
molecules. Although great success has been achieved in the metal
catalyzed homogeneous asymmetric hydrogenation of various
alkenes, imines, and ketones,4 the prochiral exocyclic alkene sub-
strates remains less studied.5 Before our research, there was no
report on the homogeneous asymmetric hydrogenation of hydan-
toin derived exocyclic alkenes. Compared with the acyclic and
endocyclic unsaturated substrates, exocyclic alkenes are difficult
to form catalyst–substrate complexes due to the ring hindrance,
which has been certified as a key factor to achieve high enantiose-
lectivity.6 Recently, Zhang et al. reported a new approach to syn-
thesise chiral succinimide derivatives with excellent yields and
ee values (up to 99% ee) by using Ir/BiphPHOX catalysts.7 Ding
et al. reported a highly effective method to obtain medium-sized
2. Results and discussion
The reaction conditions investigated are listed in Table 1. The
reaction took place in 2,2,2-trifluoroethanol (TFE) with only 5%
ee (entries 1–6).11 Both the conversion and enantioselectivity
could be improved by increasing the reaction temperature (entries
6–8). When the hydrogen gas pressure was increased, there is only
a subtle influence on the reaction conversion and selectivity
(entries 8–10).
In order to improve the catalytic activity and selectivity, we
screened a series of additives. It was reported by Zhou et al. that
a chiral Brönsted acid additive is crucial to achieve high enantios-
electivity in the Pd-catalyzed asymmetric hydrogenation of unpro-
tected indoles.12 Inspired by their work, we screened several chiral
Brönsted acids (Fig. 3).
cyclic carbonyl compounds bearing an a-stereogenic carbon center
by using Ir/SpinPhox catalysts. A broad range of exocyclic alkenes
We found that the reaction was obviously promoted by
Brönsted acid (entries 11–15). When two equivalents (compared
with catalyst) D-CSA acid were added, the conversion was 100%
⇑
Corresponding authors.
E-mail address: wangxg_hnhl@126.com (X.-G. Wang).
http://dx.doi.org/10.1016/j.tetasy.2016.10.006
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ma, B.-D.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.006

2
B.-D. Ma et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
HN
O
O
O
HO
NH
O
HN
O
HO
HN
NH2
N
HN
NH
NH
HO
(+)-hydantocidin
O
OH
O
HO
(R)-5-(4-hydroxybenzyl)-hydantoin
hydantoin alkaloids
insecticidal acitivity
antiprostrate cancer
herbicidal acitivity
Ph
O
O
HN
nBu
O
NH
N
N
F
O
Br
HN
O
N
O
N
O
N
Ar
H
O
F
mesantoin(Novartis)
anticonvulsant
minalrestal (Pfizer)
aldose reductase inhibitor
lead compounds(GlaxoSmithKline)
phosphodiesterase inhibitor
Figure 1. Chiral hydantoin derivatives with bioactivity.
iPr
iPr
+
[Pd]
H2
Aryl
O
Aryl
O
iPr
P(O)OH
iPr
O
O
*
HN
NH
HN
NH
TFE + additive
herein
O
O
10 examples
21%-90% ee
iPr
iPr
additive
Figure 2. Pd catalyzed asymmetric hydrogenation of exocyclic alkene.
and the enantioselectivity was raised to 33% ee. When the same
amount L-CSA was added, the ee value of the product decreased
to 9%. This phenomenon was probably due to the mismatch
between the chiral catalyst and the chiral additive. We also
screened several BINOL-derived phosphoric acid additives. It was
found that the starting material was completely converted into
the desired product and the ee value increased using this type
additive (entries 13–15). When (R)-BP3 was utilized, the ee value
was reached up to 45%. The absolute configuration was determined
as (S) by comparing the specific rotation with the literature sign. In
this case, the (R)-catalyst was matched with the (R)-additive. It is
worth mentioning that the enantioselectivity of the product
decreased when the additive exceeded or was less than two equiv-
alents (entries 15, 17 and 18).
We also screened several different chiral phosphine ligand cat-
alysts (entries 19–23). Except for (R,R)-DIOP-Pd catalyst, the other
catalysts all showed high catalytic activity. The enantioselectivity
was influenced by the different catalysts. For the (R,R)-DIOP-Pd
catalyst, only 30% ee was obtained. For the (R)-SegPhos-Pd catalyst,
44% ee was obtained, which was similar to the (R)-BINAP-Pd
catalyst.
Encouraged by these promising results obtained in the hydro-
genation of alkene 1a, a variety of other hydantoin derived exo-
cyclic alkenes were examined under the optimized conditions
(Table 2). The substituents on the aryl ring had a significant influ-
ence on the enantioselectivity. Substrates with an electron donat-
ing group showed much better enantioselectivity than those with
an electron withdrawing group (entries 1–4). For example, the
para-methoxy product was obtained with 63% ee while the para-
bromo product was only 21% ee (entries 2 and 3). When the same
substituent was attached to the meta- or ortho-position of the
phenyl ring, the enantioselectivity was clearly superior to the
para-substituted product (53% ee, 51% ee vs 26% ee, entries 4–6).
With these experimental results in hand, we speculated that the
electron donating group close to the double bond was probably
helpful with regards to the enantioselectivity. We synthesized sev-
eral substrates with electron donating group on the ortho position
of the phenyl ring. As expected, we found moderate to excellent ee
were obtained by using this type substrate. For the ortho-methyl
and ortho-methoxy substituted substrates, 90% ee and 88% ee were
obtained respectively (entries 7, 8). However, when the group
changed from methoxy to ethoxy or n-butoxy, much lower ee were
obtained (entries 9, 10).
To elucidate the mechanism of the Pd-catalyzed asymmetric
hydrogenation of hydantoin derived exocyclic alkene in the pres-
ence of Brönsted acid, 1H NMR and isotopic labelling experiments
were carried out. Under the optimized conditions of the asymmet-
ric hydrogenation, only 4% equivalents (R)-BP3 compared with the
substrate was added. 1H NMR showed that there was no obvious
difference between the 1a with or without the (R)-BP3 except for
the NH proton. Even when 30% equivalent (R)-BP3 was added,
there was still no obvious difference. These results indicated that
the substrate could be protonated by (R)-BP3. However, tautomer-
ization between the enamine and imine was not observed. More-
over, 1a was hydrogenated in D2 with the (R)-BINAP-Pd catalyst
(Fig. 4). Deuterium at the 5-position of hydantoin ring was not
observed. However one deuterium was found in benzyl position.
These results confirmed that the carbon–carbon double bond was
asymmetrically hydrogenated rather than the carbon–nitrogen
double bond in our experiment.
To the best of our knowledge, this is the first example of a
homogeneous Pd-catalyzed highly enantioselective synthesis of
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B.-D. Ma et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
Optimizing the hydrogenation conditions of 1aa
O
O
(R)-BINAP + [Pd]
NH
NH
*
HN
HN
H2
O
O
1a
2a
Entry
Solvent
T (°C)
Additive
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
Methanol
DCM
Toluene
THF
Acetone
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
25
25
25
25
25
25
40
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
No
No
No
No
No
No
No
No
<5
<5
<5
<5
<5
20
25
60
58
N.d.
N.d.
N.d.
N.d.
N.d.
5
11
22
20
24
33
9
40
41
45
1
41
43
30
44
41
40
9d
10e
11
12
13
14
15
16f
17g
18h
19i
20j
22k
23l
No
No
63
(D)-CSA
(L)-CSA
(R)-BP1
(R)-BP2
(R)-BP3
(R)-BP3
(R)-BP3
(R)-BP3
(R)-BP3
(R)-BP3
(R)-BP3
(R)-BP3
>95
>95
>95
>95
>95
>95
>95
>95
61
TFE
TFE
TFE
TFE
>95
>95
>95
a
b
c
d
e
f
Reaction conditions: 0.05 mmol substrate in 2.0 mL solvent, 40 atm H2, substrate/catalyst = 50, 0.002 mmol additive, 24 h.
Based on 1H NMR analysis of the crude product.
Determined by HPLC with a chiral column.
10 atm H2.
60 atm H2.
(S)-BINAP-Pd catalyst.
0.001 mmol additive.
0.003 mmol additive.
g
h
i
(R,R)-DIOP-Pd catalyst.
j
(R)-SegPhos-Pd catalyst.
(R)-MeO-BIPHEP-Pd catalyst.
(R)-SynPhos-Pd catalyst.
k
l
iPr
iPr
O
O
iPr
P(O)OH
iPr
O
O
O
O
S
OH
O
O
O
S
O
O
P(O)OH
P(O)OH
HO
O
H
H
iPr
(R)-BP3
iPr
L
-CSA
D-CSA
(R)-BP1
(R)-BP2
O
O
Ph2P
PPh2
O
O
O
O
PPh2
PPh2
PPh2
PPh2
O
O
PPh2
PPh2
O
O
O
O
(R,R)-DIOP
(R)-SegPhos
(R)-MeO-BIPHEP
(R)-SynPhos
Figure 3. Chiral Brönsted acids additives and chiral ligands.
hydantoin derivatives by hydrogenation.
mechanism of this reaction and the asymmetric hydrogenation of
A
detailed reaction
5-alkyl substituted substrates are currently underway in our
laboratory.
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B.-D. Ma et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 2
4.2.1.1. (Z)-5-Benzylideneimidazolidine-2,4-dione 1a.
Asymmetric hydrogenation of exocyclic alkene 1a
O
O
O
(R)-BINAP+[Pd]
NH
R
NH
*
HN
NH
R
HN
HN
1a
H2
O
O
O
1a-j
2a-j
Entry
R
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
4-H
4-MeO
4-Br
4-Cl
3-Cl
95
96
96
93
94
91
89
92
88
88
45 (S)
63
21
26
53
51
88
90
56
Yield: 85%; Colorless crystal, mp = 224.0–225.1 °C; 1H NMR
(300 MHz, d6-DMSO) d (ppm): 6.41 (s, 1H), 7.32–7.43 (m, 3H),
7.63 (t, J = 1.5 Hz, 2H), 10.52 (br s, 1H), 11.18 (br s, 1H); 13C NMR
(125 MHz, d6-DMSO) d (ppm): 166.0, 156.1, 133.4, 129.8, 129.2,
128.8, 128.4, 108.7.
2-Cl
2-MeO
2-Me
2-EtO
2-nBuO
4.2.1.2. (Z)-5-(4-Methoxybenzylidene)imidazolidine-2,4-dione
1b.
61
a
Reaction conditions: 0.05 mmol substrate in 2.0 mL TFE, substrate/catalyst = 50,
40 atm H2, 70 °C, 0.002 mmol additive, 24 h.
b
Isolated yield.
Determined by HPLC with a chiral column.
O
c
NH
HN
MeO
O
1b
H
O
H
O
D
H
(R)-BINAP + [Pd]
NH
NH
HN
HN
TFE, D2
Yield: 87%; Pale yellow crystal, mp >250.0 °C; 1H NMR (300 MHz,
d6-DMSO) d (ppm): 3.80 (s, 3H), 6.39 (s, 1H), 6.93–6.98 (m, 2H),
7.56–7.60 (m, 2H), 10.39 (br s, 1H), 11.12 (br s, 1H); 13C NMR
(125 MHz, d6-DMSO) d (ppm): 166.0, 159.9, 156.1, 131.5, 126.5,
125.9, 114.7, 109.1, 55.7.
O
O
Figure 4. Asymmetric hydrogenation of 1a with D2.
3. Conclusion
4.2.1.3. (Z)-5-(4-Bromobenzylidene)imidazolidine-2,4-dione 1c.
In conclusion, we have developed an efficient catalytic system
for the enantioselective synthesis of chiral hydantoin derivatives.
Moderate to good enantioselectivities were obtained (21–90%
ee). Chiral Brönsted acid additive was found to be a key figure to
achieve high enantioselectivity.
O
NH
HN
Br
4. Experimental
4.1. General
O
1c
Yield: 89%; Colorless crystal, mp >250.0 °C; 1H NMR (300 MHz,
d6-DMSO) d (ppm): 6.38 (s, 1H), 7.57 (s, 4H), 10.58 (br s, 1H),
11.25 (br s, 1H); 13C NMR (125 MHz, d6-DMSO) d (ppm): 165.9,
156.1, 132.7, 132.1, 131.7, 129.0, 121.9, 107.3.
Unless otherwise noted, all experiments were carried out under
an inert atmosphere of dry argon by using standard Schlenk-type
techniques. 1H and 13C NMR spectra were recorded on a Bruker
Model Avance DMX 400 Spectrometer (1H NMR 300 or 500 MHz
and 13C NMR 125 MHz) respectively. Chemical shifts (d) were given
in ppm and were referenced to residual solvent or TMS peaks. All
other chemicals were used as received from Aldrich or Acros with-
out further purification.
4.2.1.4. (Z)-5-(4-Chlorobenzylidene)imidazolidine-2,4-dione 1d.
O
4.2. General procedure for the synthesis of substrates
NH
HN
4.2.1. General procedure
Cl
A 250 mL flask was charged with hydantoin (10.0 g, 100 mmol),
aromatic aldehyde (100 mmol), ethanolamine (3.05 g, 50 mmol)
and 100 mL of solvent (ethnol/water = 1/1, v/v). The reaction mix-
ture was then heated and stirred at reflux for 24 h. After cooling to
room temperature, a large amount of crystals were formed. The
mixture was filtered and the filter cake was washed with 20 mL
of cold ethanol. The crystals were then collected and dried under
reduced pressure.
O
1d
Yield: 88%; Colorless crystal, mp >250.0 °C; 1H NMR (300 MHz,
d6-DMSO) d (ppm): 6.40 (s, 1H), 7.42–7.46 (m, 2H), 7.61–7.66 (m,
2H), 10.60 (br s, 1H), 11.21 (br s, 1H); 13C NMR (125 MHz, d6-DMSO)
d (ppm): 165.9, 156.1, 133.2, 132.4, 131.5, 129.2, 128.9, 107.2.
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B.-D. Ma et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
(m, 3H), 7.50–7.53 (m, 1H), 10.45 (br s, 1H), 11.17 (br s, 1H); 13C
NMR (125 MHz, d6-DMSO) d (ppm): 165.9, 156.1, 137.4, 132.2,
130.7, 129.3, 129.0, 128.8, 126.7, 106.2, 20.0.
4.2.1.5. (Z)-5-(3-Chlorobenzylidene)imidazolidine-2,4-dione 1e.
O
4.2.1.9. (Z)-5-(2-Ethoxybenzylidene)imidazolidine-2,4-dione 1i.
Cl
NH
HN
1e
O
OEt
O
NH
HN
Yield: 90%; Colorless crystal, mp = 243.2–244.0 °C; 1H NMR
(300 MHz, d6-DMSO) d (ppm): 6.56 (s, 1H), 7.32–7.41 (m, 2H),
7.51–7.54 (m, 1H), 7.70–7.73 (m, 1H), 10.65 (br s, 1H), 11.31 (br s,
1H); 13C NMR (125 MHz, d6-DMSO) d (ppm): 165.7, 156.1, 133.5,
131.3, 130.6, 130.5, 130.3, 130.1, 128.0, 103.3.
O
1i
Yield: 81%; Colorless crystal, mp = 219.4–220.7 °C; 1H NMR
(300 MHz, d6-DMSO) d (ppm): 1.37 (t, J = 6.9 Hz, 3H), 4.06–4.13
(m, 2H), 6.66 (s, 1H), 6.93–7.04 (m, 1H), 7.27–7.33 (m, 1H), 7.57–
7.60 (m, 1H), 7.58 (dd, J1 = 7.8 Hz, J2 = 1.5 Hz, 1H), 10.31 (br s, 1H),
11.15 (br s, 1H); 13C NMR (125 MHz, d6-DMSO) d (ppm): 166.0,
156.9, 155.9, 130.5, 129.8, 128.4, 122.0, 120.9, 112.4, 103.4, 64.1,
15.0.
4.2.1.6. (Z)-5-(2-Chlorobenzylidene)imidazolidine-2,4-dione 1f.
Cl
O
NH
4.2.1.10. (Z)-5-(2-Butoxybenzylidene)imidazolidine-2,4-dione 1j.
HN
O
1f
OnBu
O
Yield: 83%; Colorless crystal, mp >250.0 °C; 1H NMR (300 MHz, d6-
DMSO) d (ppm): 6.39 (s, 1H), 7.35–7.44 (m, 2H), 7.54–7.57 (m,
1H), 7.70 (s, 1H), 10.69 (br s, 1H), 11.27 (br s, 1H); 13C NMR
(125 MHz, d6-DMSO) d (ppm): 165.8, 156.2, 135.6, 134.1, 130.9,
129.5, 129.0, 128.5, 106.9.
NH
HN
O
1j
Yield: 79%; Colorless crystal, mp = 197.8–198.1 °C; 1H NMR
(300 MHz, d6-DMSO) d (ppm): 0.94 (t, J = 7.2 Hz, 3H), 1.40–1.52
(m, 2H), 1.69–1.79 (m, 2H), 4.04 (t, J = 6.6 Hz, 2H), 6.67 (s, 1H),
6.93–6.98 (m, 1H), 7.02–7.05 (m, 1H), 7.27–7.33 (m, 1H), 7.59 (dd,
J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 10.32 (br s, 1H), 11.15 (br s, 1H); 13C
NMR (125 MHz, d6-DMSO) d (ppm): 166.0, 157.0, 155.9, 130.4,
129.7, 128.4, 122.1, 120.9, 112.5, 103.2, 68.1, 31.2, 19.2, 14.1.
4.2.1.7. (Z)-5-(2-Methoxybenzylidene)imidazolidine-2,4-dione 1g.
OMe
O
NH
HN
O
1g
4.3. General procedure for the asymmetric hydrogenation
4.3.1. General procedure for the preparation of the catalyst
At first, (R)-BINAP (68.4 mg, 0.11 mmol) and Pd(OCOCF3)2
(33.2 mg, 0.10 mmol) were placed in a dried Schlenk tube under
a nitrogen atmosphere, after which 5 mL of degassed anhydrous
acetone were added. The mixture was stirred at room temperature
for 1 h, then the solvent was removed under vacuum to give the
catalyst.
83%; Pale yellow crystal, mp = 224.3.2–225.0; 1H NMR (300 MHz,
d6-DMSO) d (ppm): 3.84 (s, 3H), 6.65 (s, 1H), 6.95–7.05 (m, 2H),
7.30–7.35 (m, 1H), 7.57–7.61 (m, 1H), 10.72 (br s, 2H); 13C NMR
(125 MHz, d6-DMSO) d (ppm): 166.0, 157.6, 156.0, 130.5, 129.7,
128.4, 121.9, 121.0, 111.6, 103.2, 56.1.
4.2.1.8. (Z)-5-(2-Methylbenzylidene)imidazolidine-2,4-dione 1h.
4.3.2. General procedure for the asymmetric hydrogenation
In a 10 mL glass-lined stainless steel reactor with a magnetic
stirring bar with substrate (0.05 mmol), the above prepared Pd-
catalyst (1 Â 10À3 mmol), additive (2 Â 10À3 mmol) and 2 mL of
TFE were added. The autoclave was closed and then pressurized
with H2 to 40 atm. The mixture was stirred at 70 °C for 24 h. After
carefully venting of the hydrogen, the reaction solvent was
removed under reduced pressure. The crude product was used to
determine the conversion and enantioselectivity.
O
NH
HN
O
1h
Yield: 87%; Colorless crystal, mp = 247.8–248.9 °C; 1H NMR
(300 MHz, d6-DMSO) d (ppm): 2.32 (s, 3H), 6.48 (s, 1H), 7.20–7.25
Please cite this article in press as: Ma, B.-D.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.006

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B.-D. Ma et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
(m, 2H), 4.42 (t, J = 5.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.43 (d,
4.3.2.1. (5-Benzylimidazolidine-2,4-dione 2a.
J = 8.5 Hz, 2H), 7.99 (br s, 1H), 10.55 (br s, 1H); 13C NMR
(125 MHz, d6-DMSO) d (ppm): 175.5, 157.6, 135.1, 132.0, 131.9,
131.5, 129.2, 128.5, 58.7, 36.2. HPLC: (OD-H, elute: Hex-
ane/iPrOH = 90/10, detector: 210 nm, flow rate: 1.0 mL/min),
t1 = 15.8 min, t2 = 17.7 min.
O
NH
HN
O
2a
4.3.2.5. (5-(3-Chlorobenzyl)imidazolidine-2,4-dione 2e.
O
Yield: 95%; White solid, mp = 183.9–184.0 °C; [
a
]
20 = À36.0 (c 0.1,
D
Cl
TFE) for 46% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 2.57–3.40
(m, 2H), 4.40 (t, J = 5.0 Hz, 1H), 7.25–7.37 (m, 5H), 7.98 (br s, 1H),
10.49 (br s, 1H); 13C NMR (125 MHz, d6-DMSO) d (ppm): 175.7,
157.7, 136.1, 130.3, 128.6, 127.2, 59.0, 37.0; HPLC: (OH-H, elute:
Hexane/iPrOH = 90/10, detector: 210 nm, flow rate: 1.0 mL/min),
t1 = 16.1 min, t2 = 19.2 min.
NH
HN
2e
O
Yield: 94%; White solid, mp >250.0 °C; [
a
]
20 = +18.0 (c 0.1, TFE) for
D
53% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 2.97–3.06 (m, 2H),
4.44 (t, J = 4.5 Hz, 1H), 7.23 (d, J = 6.5 Hz, 3H), 7.336 (s, 1H), 7.38–
7.42 (m, 2H), 8.02 (br s, 1H), 10.54 (br s, 1H); 13C NMR (125 MHz,
d6-DMSO) d (ppm): 175.5, 157.6, 138.7, 133.1, 130.4, 130.0, 128.9,
127.2, 58.6, 36.5. HPLC: (OD-H, elute: Hexane/iPrOH = 90/10, detec-
tor: 210 nm, flow rate: 1.0 mL/min), t1 = 17.2 min, t2 = 19.7 min.
4.3.2.2. (5-(4-Methoxybenzyl)imidazolidine-2,4-dione 2b.
O
NH
HN
MeO
O
2b
4.3.2.6. (5-(2-Chlorobenzyl)imidazolidine-2,4-dione 2f.
20 = À27.0 (c 0.1,
Cl
O
Yield: 96%; White solid, mp = 180.0–182.3 °C; [a]
D
TFE) for 63% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 2.86 (d,
J = 5.0 Hz, 1H), 3.71 (s, 3H), 4.27 (t, J = 5.0 Hz, 1H), 6.83 (d,
J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.87 (br s, 1H), 10.38 (br s,
1H); 13C NMR (125 MHz, d6-DMSO) d (ppm): 175.7, 158.5, 157.6,
131.2, 127.8, 114.0, 59.0, 55.4, 35.9. HPLC: (OD-H, elute: Hex-
ane/iPrOH = 90/10, detector: 210 nm, flow rate: 1.0 mL/min),
t1 = 20.2 min, t2 = 23.3 min.
NH
HN
O
2f
Yield: 91%; White solid, mp = 201.5–202.0 °C; [
a
]
D
20 = À25.0 (c 0.1,
TFE) for 51% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 3.00–3.04
(m, 1H), 3.26–3.30 (m, 1H), 4.41 (t, J = 6.0 Hz, 1H), 7.36–7.38 (m,
2H), 7.43–7.44 (m, 1H), 7.51–7.53 (m, 1H), 7.98 (br s, 1H), 10.72
(br s, 1H); 13C NMR (125 MHz, d6-DMSO) d (ppm): 175.6, 157.8,
134.6, 133.9, 132.4, 129.7, 129.1, 127.6, 57.7, 35.5; HPLC: (OD-H,
elute: Hexane/iPrOH = 90/10, detector: 210 nm, flow rate: 1.0 mL/
min), t1 = 21.4 min, t2 = 24.9 min.
4.3.2.3. (5-(4-Bromobenzyl)imidazolidine-2,4-dione 2c.
O
NH
HN
Br
O
2c
4.3.2.7. (5-(2-Methoxybenzyl)imidazolidine-2,4-dione 2g.
Yield: 96%; Yellow solid, mp >250 °C; [
a
]
20 = À10.0 (c 0.1, TFE) for
D
21% ee; 1H NMR (500 MHz, d6-DMSO)
d
(ppm): 1H NMR
(500 MHz, d6-DMSO)
d (ppm): 2.86–2.94 (m, 2H), 4.33 (t,
OMe
O
J = 5.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.92
(br s, 1H), 10.46 (br s, 1H); 13C NMR (125 MHz, d6-DMSO) d
(ppm):175.5, 157.5, 135.5, 132.4, 131.4, 120.5, 58.6, 36.2. HPLC:
(OD-H, elute: Hexane/iPrOH = 90/10, detector: 210 nm, flow rate:
1.0 mL/min), t1 = 16.6 min, t2 = 19.1 min.
NH
HN
2g
O
20 = À105.0 (c 0.1,
4.3.2.4. (5-(4-Chlorobenzyl)imidazolidine-2,4-dione 2d.
Yield: 89%; White solid, mp = 189.1–190.2 °C; [
a
]
D
TFE) for 88% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 2.70–2.74
(m, 1H), 3.05–3.09 (m, 1H), 3.77 (s, 3H), 4.24 (t, J = 5.5 Hz 1H),
6.85–6.88 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 6.5 Hz, 1H),
7.22 (t, J = 7.0 Hz, 1H), 7.24 (br s, 1H), 10.53 (br s, 1H); 13C NMR
(125 MHz, d6-DMSO) d (ppm): 176.0, 157.9, 157.8, 131.4, 128.6,
124.9, 120.6, 111.1, 57.9, 55.8, 32.8. HPLC: (OD-H, elute: Hex-
ane/iPrOH = 90/10, detector: 210 nm, flow rate: 1.0 mL/min),
t1 = 17.8 min, t2 = 19.9 min.
O
NH
HN
Cl
O
2d
Yield: 93%; White solid, mp = 202.7–203.0 °C; [
a]
20 = À50.0 (c 0.1,
D
TFE) for 26% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 2.97–3.04
Please cite this article in press as: Ma, B.-D.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.006

B.-D. Ma et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
ane/iPrOH = 90/10, detector: 210 nm, flow rate: 1.0 mL/min),
4.3.2.8. (5-(2-Methylbenzyl)imidazolidine-2,4-dione 2h.
t1 = 25.9 min, t2 = 34.3 min.
O
Acknowledgments
NH
HN
We thank the Natural Science Foundation of Hunan Province,
China (Grant No. 14JJ6051), China Postdoctoral Science Foundation
(2014M562108).
O
2h
A. Supplementary data
Yield: 92%; White solid, mp = 215.2–215.3 °C; [
a
]
20 = À125.0 (c 0.1,
D
TFE) for 88–90% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 2.36 (s,
3H), 2.92–2.96 (m, 1H), 3.07–3.11 (m, 1H), 4.37–4.40 (m, 1H), 7.18–
7.25 (m, 4H), 7.99 (br s, 1H), 10.62 (br s, 1H); 13C NMR (125 MHz,
d6-DMSO) d (ppm): 176.0, 157.8, 137.0, 135.2, 130.5, 130.4, 127.1,
126.1, 58.6, 19.9. HPLC: (AD-H, elute: Hexane/iPrOH = 90/10, detec-
tor: 210 nm, flow rate: 1.0 mL/min), t1 = 12.3 min, t2 = 13.4 min.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.10.
006.
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HN
O
2i
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Yield: 88%; White solid, mp >250 °C; [
a
]
20 = À27.0 (c 0.1, TFE) for
D
56% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 1.34 (t, J = 7.0 Hz,
3H), 2.70–2.72 (m, 1H), 3.04–3.08 (m, 1H), 4.00–4.04 (m, 2H),
4.25–4.27 (m, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.93–6.94 (m, 1H),
7.13–7.14 (m, 1H), 7.18–7.21 (m, 1H), 7.71 (br s, 1H), 10.53 (br s,
1H); 13C NMR (125 MHz, d6-DMSO) d (ppm): 176.0, 157.8, 157.1,
131.4, 128.5, 125.0, 120.5, 111.9, 63.6, 57.9, 32.9, 15.1; HPLC: (OJ-
H, elute: Hexane/iPrOH = 90/10, detector: 210 nm, flow rate:
1.0 mL/min), t1 = 16.3 min, t2 = 18.5 min.
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OnBu
O
NH
HN
O
2j
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Yield: 88%; Brown solid, mp >250 °C; [
a
]
20 = À30.0 (c 0.1, TFE) for
D
61% ee; 1H NMR (500 MHz, d6-DMSO) d (ppm): 0.94 (t, J = 7.5 Hz,
3H), 1.44–1.48 (m, 2H), 1.71–1.74 (m, 2H), 2.68–2.72 (m, 1H),
3.05–3.09 (m, 1H), 3.94–3.97 (m, 2H), 4.22–4.25 (m, 1H), 6.85 (t,
J = 7.5 Hz, 1H), 6.94 (d, J = 8.5, Hz 1H), 7.13–7.15 (m, 1H), 7.18–
7.21 (m, 1H), 7.73 (br s, 1H), 10.55 (br s, 1H); 13C NMR (125 MHz,
d6-DMSO) d (ppm): 176.0, 157.8, 157.2, 131.4, 128.5, 125.1, 120.5,
111.9, 67.6, 57.9, 33.1, 31.3, 19.3, 14.2. HPLC: (AS-H, elute: Hex-
Please cite this article in press as: Ma, B.-D.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.006