Synthesis of a water-soluble cationic chiral diamine ligand bearing a diguanidinium and application in asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2011.08.012

A novel water-soluble cationic N-monosulfonated chiral diamine ligand diguanidinium 1c was easily prepared from (R,R)-DPEN and its rhodium complex and was successfully applied in the asymmetric transfer hydrogenation of prochiral ketones and imines in water by using sodium formate and formic acid as co-hydrogen donors. Various substrates were reduced with high yields and good to excellent enantioselectivities (up to >99% ee).

Full text of DOI:10.1016/j.tetasy.2011.08.012

Tetrahedron: Asymmetry 22 (2011) 1530–1535
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of a water-soluble cationic chiral diamine ligand bearing a
diguanidinium and application in asymmetric transfer hydrogenation
Yuanfu Tang b, Xuefeng Li c, Chunxia Lian b, Jin Zhu b, Jingen Deng a,b,
⇑
a Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
b Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
c College of Chemistry and Environment Protection Engineering, Southwest University for Nationalities, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel water-soluble cationic N-monosulfonated chiral diamine ligand diguanidinium 1c was easily pre-
pared from (R,R)-DPEN and its rhodium complex and was successfully applied in the asymmetric transfer
hydrogenation of prochiral ketones and imines in water by using sodium formate and formic acid as co-
hydrogen donors. Various substrates were reduced with high yields and good to excellent enantioselec-
tivities (up to >99% ee).
Received 13 July 2011
Accepted 17 August 2011
Available online 1 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
H2N
NH2
NaO3S
SO3Na
Water is an attractive solvent for organic reactions because it has
the potential of generatingless process waste, is safer to operate, and
is of low cost. As a result, great effort has been devoted to this field
and a great number of elegant and effective aqueous phase catalytic
reactions have been documented,1 especially for the asymmetric
transfer hydrogenation (ATH) of ketones and imines.2 Although a
disadvantage often associated with catalysis in water is the decrease
in catalytic activity and/or stereoselectivity on going from organic
solvents to an aqueous environment, the use of water-soluble li-
gands/catalysts can overcome these drawbacks, leading to high
selectivity and even better reactivity compared with those in organ-
ic media.2e–g,3,4 In our continuing effort regarding the aqueous-
phase ATH,5 two well-defined ligands derived from 1,2-diphenyle-
thylenediamine (DPEN) have been successively explored (Fig. 1, 1a
and 1b). Ligand 1a contains two hydrophilic sulfonate groups which
greatly improves the water-solubility of the ligand5a,b; compound
1b bears two amine groups which leads to a unique equilibrium of
hydrophilicity and hydrophobicity of the ligand.5c As a result, both
of them exhibit excellent catalytic performance in the case of the
enantioselective reduction of ketones and imines.
H2N
NHTs
H2N
NHTs
1a
1b
Figure 1. Structures of the water-soluble ligands 1a and 1b.
celle surface.6 Furthermore, Itsuno and Haraguchi also found that the
quaternary ammonium counterion of a sulfonated-polymer-sup-
ported ligand was crucial for increasing the reactivity and enantiose-
lectivity.7 Enlightened by these observations, we envisioned that the
direct involvement of cationic group in the ligand should be an
appealing modification. The guanidino group has been widely em-
ployed as an artificial host to anions in the molecular recognition8
and also a basic moiety embedded in natural arginine. It was prone
to be protonated over a wide pH range (pKa value is around 12–13)
and formed cationic guanidinium ions, which were identified as nat-
ural receptors for anionic carbonates through charge pairing and
hydrogen bonding.9 Inspired by the perfect character of the guanidi-
nium, we proposed that the combination of a guanidinium moiety
and DPEN in one chiral ligand (Fig. 2, 1c) should provide an excellent
opportunity for the development of a novel water-soluble ligand for
the ATH of ketones and imines. To the best of our knowledge, ligands
bearing a guanidinium have seldom been investigated as the chiral
ligand except for an example reported by Genêt.10
Onthe otherhand, we have investigatedthe effect of surfactantsin
case of the aqueous ATH of ketones and imines.5b,6 It is noteworthy
that superior result in terms of reactivity and enantioselectivity, were
observed in the presence of cationic surfactants compared with neu-
tral and anionic ones, which might be caused by the elevated concen-
tration of the hydrogen source around microreactors due to the
attraction between formate ions and the positive charge around a mi-
2. Result and discussion
As illustrated in Scheme 1, ligand 1c bearing a diguanidinium
was obtained by a six-step procedure originating from (R,R)-DPEN
⇑
Corresponding author.
E-mail address: jgdeng@cioc.ac.cn (J. Deng).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.012

Y. Tang et al. / Tetrahedron: Asymmetry 22 (2011) 1530–1535
1531
(R,R)-1c with different metal complexes in degassed water at
40 °C for 1 h. As shown in Table 1, the combination of (R,R)-1c
and Rh(III) complex exhibited the best reactivity and enantioselec-
tivity compared with the Ir(III) and Ru(II) complexes (Table 1, en-
tries 1–3). These results are consistent with the amphiphilic ligand
1b5c and hydrophobic ligand TsDPEN,14b but contrary to the anio-
nic ligand 1a,5a,b with which a Ru(II) complex gave the best results
based on both reactivity and enantioselectivity. Chiral phenylethyl
alcohol 11a was obtained with 1c–Rh(III) complex as a catalyst in
53% conversion and with 95% ee within 1 h at 28 °C (entry 1).
Encouraged by these initial results, we further optimized the reac-
tion conditions to improve the catalytic efficiency. Early research
has demonstrated that the concentration of hydrogen source
exerted a positive effect on the reaction rate.14 Therefore, we
conducted the ATH of model substrate 10a with different concen-
trations of sodium formate. No significant improvement of reactiv-
ity was observed when the amount of sodium formate increased
from 7.5 to 15 equiv (entry 1 vs entry 4). However, the conversion
was enhanced remarkably from 53% to 67% and 84% while further
increasing the amount of hydrogen source to 23 and 30 equiv,
respectively (entries 5 and 6 vs entry 1). It is noteworthy that
the enantioselectivity required constant, despite variation of the
concentration of HCO2Na. It has been reported that the reactivity
and enantioselectivity of aqueous-phase asymmetric transfer
hydrogenation of aromatic ketones depended on the pH value of
the aqueous phase.14a,b,15 By controlling the pH value of the solu-
tion, much faster rates in conjunction with excellent ee values
could be obtained. Thus, this prompted us to investigate the corre-
lation of the pH value with the reactivity and enantioselectivity.
Because the ligand involves two cationic guanidinium functional
groups, which can exist as differently protonated forms under dif-
ferent pH values, it is necessary to keep the guanidinium groups
protonated for the purpose of water-solubility of the ligand. On
the other hand, strongly acid conditions should lead to enantiose-
lectivity erosion and inhibited reaction rates.14a Based on all of
H
N
H
N
H2N
H2N
NH2
NH2
H3N
NHTs
3CF3CO2
(R,R)-1c
Figure 2. Structure of the water-soluble cationic ligand 1c.
2. Nitration of 2 with concentrated nitric acid (65–69%) in concen-
trated sulfuric acid (98%) at 0 °C gave the crude nitrated product.
Although only one spot was detected by thin layer chromatogra-
phy (TLC) analysis with different elutes, the 1H NMR spectrum
clearly indicated that the resulting crude products were a mixture.
The meta-substituted, rather than the ortho-substituted product,
(R,R)-1,2-bis(3-nitrophenyl)ethylenediamine 3 was obtained after
recrystallization from ethyl acetate (EtOAc),11 which was con-
firmed by the 1H NMR, 13C NMR and NOESY spectrum and single
crystal X-ray diffraction analysis (Fig. 3).12 The mono-N-tosylated
derivative 4 was generated by treatment of 3 with p-toluenesulfo-
nyl chloride (TsCl) in the presence of N,N-diisopropylethylamine
(DIPEA) in dichloromethane (DCM). Further protection of the other
amine group of 4 was carried out with di-tert-butyl dicarbonate
[(Boc)2O)] and carbamate 5 was obtained. Hydrogenation of the
two nitro groups of 5 provided the primary aromatic amine 6.
Then, guanidylation of 6 with N,N0-bis-tert-butoxycarbonylthiou-
rea 7, using an analogue of Mukaiyama’s salt 8 as the desulfuriza-
tion reagent afforded Boc-protected diguanidino compound 9,13
which was converted into the diguanidinium (R,R)-1c after remov-
ing the protecting group with trifluoroacetic acid (TFA). The de-
sired ligand (R,R)-1c was obtained as a trifluoroacetic acid salt.
With the cationic diguanidinium ligand (R,R)-1c in hand, we
then examined its catalytic performance for the ATH of acetophe-
none 10a in neat water using sodium formate as a hydrogen
source. The precatalyst was prepared in situ by the treatment of
O2N
a
NO2
O2N
NO2
b
H2N
NH2
H2N
NH2
H2N
H2N
NHTs
4
2
3
O2N
NO2
NH2
c
d
e
BocHN
NHTs
BocHN
NHTs
5
6
S
+
N+
I-
Br
BocHN
NHBoc
CH3
7
8
NBoc
NHBoc
BocN
H
N
H
N
H
N
H
N
H2N
H2N
NH2
NH2
f
BocHN
BocHN
NHTs
H3N
(R,R)-1c
NHTs
3CF3CO2
9
Scheme 1. Synthesis of cationic diguanidinium ligand (R,R)-1c. Reagents and conditions: (a) Concd HNO3, concd H2SO4, then recrystallization from EtOAc; (b) TsCl, DIPEA,
CH2Cl2; (c) (Boc)2O, DIPEA, dioxane; (d) Pd/C, H2, MeOH; (e) TEA, CH2Cl2; (f) TFA, CH2Cl2.

1532
Y. Tang et al. / Tetrahedron: Asymmetry 22 (2011) 1530–1535
Figure 3. X-ray structure of 3 with thermal ellipsoids drawn at the 50% probability level (CCDC 831767).
Table 1
Asymmetric transfer hydrogenation of acetophenone 10a with (R,R)-1c as a chiral ligand in neat watera
O
OH
metal complex (1 mol%)
HCO2Na
H2O, 28 °C, 1 h
11a
10a
Entry
Metal complex
Acetophenone/HCO2Na/HCO2H
Starting pH value
Conv.b (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
[RhCl2Cp⁄]2
1/7.5/—
1/7.5/—
1/7.5/—
1/15/—
1/23/—
1/30/—
1/29.99/0.01
1/29.9/0.1
1/29/1
53 (65)c
22
8
54
95 (93)c
89
90
95
95
[IrCl2Cp⁄]2
[RuCl2(p-Cymene)]2
[RhCl2Cp⁄]2
[RhCl2Cp⁄]2
[RhCl2Cp⁄]2
[RhCl2Cp⁄]2
[RhCl2Cp⁄]2
[RhCl2Cp⁄]2
[RhCl2Cp⁄]2
67
84
85
95
7.46
6.98
6.61
5.66
5.23
95
95
95
96 (48)d
80
95 (95)d
94
1/28/2
a
Unless otherwise noted, the reaction was carried out in 1 mL of degassed water under an argon atmosphere at 28 °C for 1 h, using 0.4 mmol acetophenone 10a, S/C ratio of
100:1.
b
Determined by GC analysis.
c
The data in parentheses was obtained by adding 1 equiv of NaOH for the preparation of the precatalyst and the reaction was carried out at 28 °C for 4 h.
The data in parentheses was obtained at 0 °C for 3 h.
d
these considerations, we performed the following investigation
under weakly acidic conditions. The starting pH value was ad-
justed by adding HCO2Na and HCO2H at different ratios while
the total concentration of the formate remained constant. A sim-
ilar result was obtained when 0.01 equiv of formic acid was
added (entry 7). Further increasing the amount of formic acid
led to a remarkable improvement of reactivity (entries 8 and
9). When 1 equiv of formic acid was employed, the starting pH
value decreased to 5.66 and the reaction gave the highest con-
version (96%) and 95% ee (entry 9). When 2 equiv of formic acid
was added, the starting pH value was 5.23 and the conversion
dropped sharply from 96% to 80% with slightly decreased enanti-
oselectivity (94% ee, entry 10). These results showed that the
reaction was merely accelerated in the suitable pH value win-
dow (pH 5.66–6.61).
With the optimized conditions in hand, we subsequently exam-
ined the substrate scope and a wide range of ketones and imines
were reduced smoothly with good to excellent enantioselectivities
(Fig. 4). The reactivity and enantioselectivity were remarkably af-
fected by the electronic properties of the aromatic ring substituent.
The ketones 10b–d bearing an electron-withdrawing nitro group
displayed higher reactivity and were completed within 1 h in high
yields. Reduction of m-(trifluoromethyl)acetophenone 10e and p-
fluoroacetophenone 10f required a longer reaction time due to
their poor solubility in water. Compared with the nitro compounds
10b–d (o-, 84% ee; m-, 82% ee; p-, 86% ee), 10e and 10f gave higher
enantioselectivities with 91% ee and 93% ee, respectively. As ex-
pected, m-methoxylacetophenone 10g bearing an electron-donat-
ing group took 5 h for full conversion and furnished the desired
product in 94% ee. The cyclic aromatic ketones, indanone 10h
and tetralone 10i, also proceeded smoothly with excellent enanti-
oselectivities (>99% ee) and high isolated yields. b-Acetonaphthone
10j was reduced in 99% yield and 94% ee. Heteroaromatic ketones
were tolerated and 2-acetylthiophene 10k was hydrogenated with
98% ee. The cyclic imines 10l and 10m were also favourable sub-
strates and gave rise to the corresponding optically active amines
with high yields and good to excellent enantioselectivities. The
asymmetric reduction of keto esters, 10n and 10o, proceeded
smoothly with high yields. b-Keto ester 10o furnished the desired
product with an excellent ee value (95%) in water.14b Interestingly,
when
a
,b-unsaturated ketone 10p was employed,16,17 the satu-
rated alcohol 11p (59%) was obtained as the major product with
31% allylic alcohol 11q in 37% and 58% ee, respectively
(Scheme 2).18
3. Conclusion
In summary, a novel water-soluble cationic chiral mono-N-
sulfonated 1,2-diamine ligand diguanidinium (R,R)-1c was easily
synthesized and its rhodium complex was successfully applied in
the asymmetric transfer hydrogenation of ketones and imines in
neat water. The concentration of sodium formate and the pH va-
lue of the reaction system exerted important effects on the reac-
tivities. Under optimized conditions, aryl alkyl ketones, cyclic
imines and keto esters were reduced in high yields with good
to excellent enantioselectivities (up to >99% ee). In addition, it

Y. Tang et al. / Tetrahedron: Asymmetry 22 (2011) 1530–1535
1533
O
O
O
4. Experimental
4.1. General methods
NO2
Melting points were determined using electrothermal capillary
apparatus and were uncorrected. TLC was performed on glass-
backed silica plates. Column chromatography was performed by
using silica gel (400 meshes) eluting with dichloromethane and
methanol or cyclohexane and ethyl acetate. NMR was recorded
on Bruker 300 MHz spectrometers and referenced to the solvent,
unless stated otherwise. The chemical shifts were reported in
ppm and the coupling constants (J) are given in Hertz (Hz). All
the reagents were used without purification as commercially
available.
NO2
10ca
10aa
10ba
96%, 84% ee
1 hour
96%,b 95% ee
1 hour
93%, 82% ee
1 hour
O
O
O
O2N
F
CF3
4.2. Synthesis of ligand
10da
94%, 86% ee
1 hour
10ea
10fa
95%, 93% ee
3 hours
96%, 91% ee
4 hours
4.2.1. (1R,2R)-1,2-Bis(3-nitrophenyl)ethylenediamine 3
A 100 mL round-bottomed flask was charged with 10 mL con-
centrated H2SO4 and stirred under an ice bath. Then (R,R)-DPEN
2 (2 g, 9.43 mmol) was added batchwise. Then a mixture of con-
centrated H2SO4 (6 mL) and concentrated HNO3 (4 mL) was added
dropwise to the resulting solution. The solution was stirred for an
additional 2 h then poured into 100 mL of ice-water. The pH value
of the solution was adjusted to 10 with 50% aqueous potassium
hydroxide then extracted with ethyl acetate (50 mL ꢀ 3). The com-
bined organic layer was rinsed with saturated brine (100 mL) and
dried over Na2SO4. After removal of the solvent in vacuo, the
resulting mixture was recrystallized from ethyl acetate to provide
O
O
O
OMe
10ga
96%, 94% ee
5 hours
10ha
10ia
97%, >99% ee
10 hours
95%, >99% ee
10 hours
1.11 g (39%) of 4 as brown crystal. Mp: 131–133 °C; ½a D25
¼ þ109:3
ꢁ
(c 1.0, CH3OH); 1H NMR (300 MHz, CDCl3), d 8.18 (s, 2H), 8.10 (d,
J = 8.1 Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 4.23
(s, 2H), 1.66 (br, 4H); 13C NMR (75 MHz, CDCl3), d 148.3, 145.0,
133.2, 129.3, 122.5, 121.9, 61.5; HRMS (ESI) calcd for
O
O
MeO
S
N
MeO
C14H15N4O4 + H: 303.1088, found: 303.1089.
10la
10ja
99%, 94% ee
11 hours
10ka
90%, 98% ee
4 hours
97%, 88% eec
5 hours
4.2.2. N-((1R,2R)-2-Amino-1,2-bis(3-nitrophenyl)ethyl)-4-
methylbenzenesulfonamide 4
To a stirring solution of 3 (906 mg, 3.0 mmol) and DIPEA
(0.57 mL, 3.3 mmol) in DCM (20 mL) was added dropwise a solu-
tion of p-toluenesulfonyl chloride (627 mg, 3.3 mmol) in DCM
(10 mL) at 0 °C. Once the addition was completed, the solution
was stirred overnight at room temperature. After being washed
with water, the organic layer was dried over Na2SO4. After removal
of the solvent under reduced pressure, the residue was purified by
flash chromatography (DCM/methanol) to afford 1.217 g (89%) of 4
O
O
O
Et
N
O
O
Et
O
N
H
10oa
10ma
96%, 94% eec
6 hours
10na,d
98%, 73% ee
0.5 hour
94%, 95% eec
10 hours
as a white solid. Mp: 190–192 °C; ½a D28
ꢁ
¼ þ32:9 (c 0.98, MeOH); 1H
NMR (300 MHz, 80% CDCl3 + 20% CD3OD), d 7.85–7.83 (m, 2H), 7.78
(d, J = 7.8 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H),
7.24–7.14 (m, 5H), 6.79 (d, J = 8.1 Hz, 2H), 4.38 (d, J = 6.7 Hz, 1H),
4.08 (d, J = 6.7 Hz, 1H), 2.09 (s, 3H); 13C NMR (75 MHz, 80%
CDCl3 + 20% CD3OD), d 147.8, 143.0, 142.7, 140.5, 136.9, 133.2,
133.0, 129.2, 129.1, 129.0, 126.2, 122.4, 122.1, 121.7, 121.6, 63.2,
59.6, 20.7; HRMS (ESI) calcd for C21H21N4O6S + H: 457.1176, found:
457.1164.
Figure 4. Asymmetric transfer hydrogenation of ketones and imines with Rh-(R,R)-
1c in water: aUnless otherwise noted, the reaction was carried out in 1 mL of
degassed water under an argon atmosphere at 28 °C for a certain time using
0.4 mmol substrate, 29 equiv of HCO2Na and 1 equiv of HCO2H as a co-hydrogen
donor, S/C = 100:1. The alcohols were obtained with the (R)-configuration; the
amines were provided with an (S)-configuration. All of the yields were isolated
yields and the ee values were determined by GC analysis. bThe conversion
determined by GC analysis. cEe value was determined by HPLC analysis. dProduct
was obtained with an (S)-configuration.
4.2.3. tert-Butyl-(1R,2R)-2-(4-methylphenylsulfonamido)-1,2-
bis(3-nitrophenyl)ethylcarbamate 5
To a stirring solution of 4 (1.14 g, 2.5 mmol) and DIPEA
(0.48 mL, 2.75 mmol) in dioxane (15 mL) was added dropwise a
solution of the di-tert-butyl dicarbonate (600 mg, 2.75 mmol) in
dioxane (10 mL) at 0 °C. The resulting solution was stirred over-
night at room temperature. After removal of the solvent under re-
duced pressure, the residue was dissolved in 50 mL DCM and then
washed with water. The organic layer was dried over Na2SO4. After
is noteworthy that meta-substituted product was obtained as the
major product in case of the nitration of DPEN. Further develop-
ment of the cationic ligand (such as using a quaternary ammo-
nium amphiphilic ligand) aiming at high catalytic reactivity
and the ability to reuse the catalyst is now being actively re-
searched in our laboratory.

1534
Y. Tang et al. / Tetrahedron: Asymmetry 22 (2011) 1530–1535
OH
O
Rh-(R,R)-1c (1mol%)
11p
HCO2Na (29equiv)
59%, 37% ee
HCO2H (1equiv)
+
OH
H2O, 28 °C, 5 h
10p
11q
31%, 58% ee
Scheme 2. Asymmetric transfer hydrogenation of benzylideneacetone 10p with Rh-(R,R)-1c in neat water. The yields were determined by 1H NMR.
removal of the solvent under reduced pressure, the residue was
purified by flash chromatography (DCM/methanol) to give 1.32 g
129.0, 128.4, 126.9, 124.5, 124.4, 121.8, 121.2, 121.1, 83.7, 83.6,
80.5, 79.7, 79.6, 63.3, 59.6, 28.3, 28.1, 28.0, 21.3; HRMS (ESI) calcd
for C48H69N8O12S + H: 981.4750, found: 981.4744.
of (95%) 5 as a white solid. Mp: 174–176 °C; ½a D20
¼ þ22:4 (c
ꢁ
0.51, MeOH); 1H NMR (300 MHz, CD3OD), d 8.06–7.95 (m, 4H),
7.62–7.56 (m, 2H), 7.45–7.36 (m, 2H), 7.31 (d, J = 8.2 Hz, 2H),
6.97 (d, J = 8.1 Hz, 2H), 5.11 (d, J = 6.1 Hz, 1H), 4.94 (d, J = 6.3 Hz,
1H), 2.25 (s, 3H), 1.24 (s, 9H); 13C NMR (75 MHz, CD3OD), d
157.3, 149.5, 149.4, 144.4, 142.9, 142.1, 139.1, 135.0, 134.5,
130.6, 130.5, 130.4, 127.7, 123.4, 123.3, 123.2, 123.1, 81.1, 62.7,
4.2.6. N-(p-Toluenesulfonyl)-1,2-bis(3-guanidinophenyl)-
ethylenediamine trifluoroacetic acid salt 1c
To a stirring solution of 9 (700 mg, 0.71 mmol) in DCM (5 mL)
under an ice bath was added TFA (5 mL). The mixture was stirred
for 2 h. The solvent was removed in vacuo to yield 586 mg
59.8, 28.5, 21.2; HRMS (ESI) calcd for
574.1966, found: 574.1957.
C
26H32N5O8S + NH4:
(100%) of 1c as a white solid. Mp: 160 °C decomposed;
½
a 2D0
ꢁ
¼ þ19:8 (c 0.64, MeOH); 1H NMR (300 MHz, CD3OD), d 7.55
(d, J = 8.2 Hz, 2H), 7.40–7.36 (m, 1H), 7.28–7.22 (m, 3H), 7.15 (d,
J = 8.1 Hz, 2H), 7.10–7.05 (m, 1H), 6.99–6.97 (m, 1H), 6.83 (d,
J = 7.6 Hz, 1H), 6.70 (br s, 1H), 4.77, 4.72 (ABq, J = 10.5 Hz, 2H),
2.31 (s, 3H); 13C NMR (75 MHz, CD3OD), d 163.4 (q, J = 31.7 Hz),
157.8, 157.5, 145.1, 138.8, 138.7, 137.0, 136.8, 136.4, 131.9,
131.3, 130.5, 128.3, 128.1, 127.7, 127.0, 126.0, 125.3, 124.9, 118.2
(q, J = 289.9 Hz), 61.8, 59.8, 21.4; HRMS (ESI) calcd for
4.2.4. tert-Butyl (1R,2R)-1,2-bis(3-aminophenyl)-2-(4-methyl-
phenylsulfonamido)ethylcarbamate 6
At first, 110 mg of Pd/C (10%) was added to a solution of 5
(1.11 g, 2.0 mmol) in methanol (20 mL). The atmosphere was re-
placed with nitrogen gas before hydrogen gas was introduced into
the mixture. The mixture was stirred overnight at room tempera-
ture under hydrogen (balloon). Then the mixture was filtered
through Celite and subsequently washed with methanol. The sol-
vent was removed in vacuo to furnish 990 mg (100%) of 6 as a
C23H29N8O2S–3TFA + H: 481.2129, found: 481.2142.
4.3. Typical procedure for the asymmetric transfer
hydrogenation in water
slightly brown solid. Mp: 203–205 °C;
½
a 2D0
ꢁ
¼ þ47:1 (c 0.54,
MeOH); 1H NMR (300 MHz, CDCl3), d 7.48 (d, J = 8.2 Hz, 2H), 7.07
(d, J = 8.0 Hz, 2H), 6.94 (t, J = 7.8 Hz, 1H), 6.76 (t, J = 7.7 Hz, 1H),
6.48 (dd, J = 7.8 Hz, 1.5 Hz, 2H), 6.38–6.35 (m, 2H), 6.30 (s, 1H),
6.20 (d, J = 7.7 Hz, 1H), 6.15 (s, 1H), 6.07 (br s, 1H), 5.25 (d,
J = 8.1 Hz, 1H), 4.69 (t, J = 8.7 Hz, 1H), 4.45 (t, J = 8.4 Hz, 1H), 3.12
(br, 4H), 2.32 (s, 3H), 1.45 (s, 9H); 13C NMR (75 MHz, CD3OD), d
156.7, 146.5, 146.1, 142.6, 139.5, 139.1, 138.0, 129.3, 129.1,
128.8, 126.9, 118.0, 117.5, 114.6, 114.3, 114.2, 114.1, 80.3, 63.3,
59.7, 28.3, 21.3; HRMS (ESI) calcd for C26H33N4O4S + H: 497.2217,
found: 497.2219.
A mixture of (R,R)-1c (3.6 mg, 0.0044 mmol) and [RhCl2(Cp⁄)]2
(1.3 mg, 0.002 mmol) in a reaction tube was degassed three times.
Then 1 mL of degassed water was added and the mixture stirred at
40 °C for 1 h under argon. Substrates (0.4 mmol), HCO2Na (790 mg,
11.6 mmol) and HCO2H (15.1 lL, 0.4 mmol) were then introduced.
The mixture was degassed three times and stirred at 28 °C for a
certain time under argon. The reaction mixture was extracted with
Et2O or DCM (5 mL ꢀ 3). The conversion was determined by GC
analysis and the enantioselectivity was determined by GC or HPLC
analysis. The isolated yield was obtained by flash chromatography.
4.2.5. N-(p-Toluenesulfonyl)-N-tert-butyloxycarbonyl-1,2-bis(3-
N,N0-di-tert-butyloxycarbonylguanidino-phenyl)ethylene-
diamine 9
Acknowledgments
A solution of 6 (685 mg, 1.38 mmol), N,N0-di-tert-butyloxycar-
bonyl thiourea 7 (916 mg, 3.32 mmol), N-methyl-2-bromopyridini-
um iodide 8 (994 mg, 3.32 mmol) and Et3N (0.85 mL, 6.08 mmol) in
DCM (10 mL) was stirred for 24 h at room temperature under an
argon atmosphere. After being rinsed with water, the solution
was dried over Na2SO4, concentrated in vacuo and purified by flash
chromatography (cyclohexane/ethyl acetate) to yield 808 mg (60%)
This work was financially supported by National Nature Science
Foundation of China (Grant No. 20972154), National Basic Re-
search Program of China (973 Program, No. 2010CB833300) and
Sichuan University.
References
of 9 as a white solid. Mp: 141 °C decomposed; ½a D20
¼ þ41:7 (c 0.7,
ꢁ
}
1. For selected reviews regarding organic reactions in water, see: (a) Lindstrom, U.
MeOH); 1H NMR (300 MHz, CDCl3), d 11.58 (s, H), 11.54 (s, 1H),
10.19 (s, 1H), 9.99 (s, 1H), 7.46–7.44 (m, 4H), 7.31 (s, 1H), 7.08–
7.00 (m, 4H), 6.89 (t, J = 7.9 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.54
(d, J = 7.7 Hz, 1H), 6.50 (br s, 1H), 5.33 (d, J = 7.9 Hz, 1H), 4.79 (t,
J = 8.8 Hz, 1H), 4.62 (t, J = 9.6 Hz, 1H), 2.27 (s, 3H), 1.54, 1.53,
1.48, 1.47, 1.45 (5 ꢀ s, 45H); 13C NMR (75 MHz, CDCl3), d 163.3,
156.7, 153.5, 153.2, 153.1, 142.4, 138.5, 138.1, 137.0, 136.6,
M. Chem. Rev. 2002, 102, 2751–2772; (b) Li, C. J.; Chen, L. Chem. Soc. Rev. 2006,
35, 68–82; (c) Shaughnessy, K. H. Chem. Rev. 2009, 109, 643–710.
2. For recent reviews regarding ATH, see: (a) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97–102; (b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999,
10, 2045–2061; (c) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226–236;
(d) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300–1308; (e) Wu, X. F.;
Xiao, J. L. Chem. Commun. 2007, 2449–2466; (f) Wang, C.; Wu, X. F.; Xiao, J. L.
Chem. Asian J. 2008, 3, 1750–1770; (g) Tang, Y. F.; Deng, J. G. Prog. Chem. 2010,
22, 1242–1253.

Y. Tang et al. / Tetrahedron: Asymmetry 22 (2011) 1530–1535
1535
3. For aqueous ATH employing water-soluble ligands/catalysts, see: (a) Bubert, C.;
Blacker, J.; Brown, S. M.; Crosby, J.; Fitzjohn, S.; Muxworthy, J. P.; Thorpea, T.;
Williams, J. M. J. Tetrahedron Lett. 2001, 42, 4037–4039; (b) Thorpe, T.; Blacker,
J.; Brown, S. M.; Bubert, C.; Crosby, J.; Fitzjohn, S.; Muxworthy, J. P.; Williams, J.
M. J. Tetrahedron Lett. 2001, 42, 4041–4043; (c) Li, B. Z.; Chen, J. S.; Dong, Z. R.;
Li, Y. Y.; Li, Q. B.; Gao, J. X. J. Mol. Catal. A: Chem. 2006, 258, 113–117; (d)
Canivet, J.; Süss-Fink, G. Green Chem. 2007, 9, 391–397; (e) Soltani, O.; Ariger,
M. A.; Carreira, E. M. Org. Lett. 2009, 11, 4196–4198.
11. In Refs. 5c and 16b, the same procedure was used and thus the diamino DPEN
must be 1,2-bis(3-aminophenyl)ethylenediamine.
12. Crystallographic data (excluding structure factors) for the structure of
3
reported in this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication No. CCDC
831767. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336 033; or e-
mail: deposit@ccdc.cam.ac.uk).
4. For aqueous ATH employing PEG-bound ligands/catalysts, see: (a) Li, X. G.; Wu,
X. F.; Chen, W. P.; Hancock, F. E.; King, F.; Xiao, J. L. Org. Lett. 2004, 6, 3321–
3324; (b) Liu, J.; Zhou, D.; Jia, X.; Huang, L.; Li, X.; Chan, A. S. C. Tetrahedron:
Asymmetry 2008, 19, 832–837; (c) Huang, L.; Liu, J.; Shan, W.; Liu, B.; Shi, A.; Li,
X. Chirality 2010, 22, 206–211.
5. (a) Ma, Y. P.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. G. Org. Lett. 2003, 5, 2103–
2106; (b) Wu, J. S.; Wang, F.; Ma, Y. P.; Cui, X.; Cun, L. F.; Zhu, J.; Deng, J. G.; Yu,
B. L. Chem. Commun. 2006, 1766–1768; (c) Li, L.; Wu, J. S.; Wang, F.; Liao, J.;
Zhang, H.; Lian, C. X.; Zhu, J.; Deng, J. G. Green Chem. 2007, 9, 23–25.
6. Wang, F.; Liu, H.; Cun, L. F.; Zhu, J.; Deng, J. G.; Jiang, Y. Z. J.Org. Chem. 2005, 70,
9424–9429.
7. (a) Arakawa, Y.; Haraguchi, N.; Itsuno, S. Tetrahedron Lett. 2006, 47, 3239–3243;
(b) Haraguchi, N.; Tsuru, K.; Arakawa, Y.; Itsuno, S. Org. Biomol. Chem. 2009, 7,
69–75; (c) Arakawa, Y.; Chiba, A.; Haraguchi, N.; Itsuno, S. Adv. Synth. Catal.
2008, 350, 2295–2304.
8. For selected reviews regarding guanidinium containing receptors for anions,
see: (a) Michael, D. B.; Suzanne, L. T.; Eric, V. A. Coord. Chem. Rev. 2003, 240, 3–
15; (b) Schug, K. A.; Lindner, W. Chem. Rev. 2005, 105, 67–113.
9. Christianson, D. W.; Lipscomb, W. N. Acc. Chem. Res. 1989, 22, 62–69.
10. Guerreiro, P.; Ratovelomanana-Vidal, V.; Genêt, J.-P.; Dellis, P. Tetrahedron Lett.
2001, 42, 3423–3426.
13. (a) Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem. Lett. 1977, 575–576; (b)
Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540–1542.
14. (a) Wu, X. F.; Li, X. G.; King, F.; Xiao, J. L. Angew. Chem., Int. Ed. 2005, 44, 3407–
3411; (b) Wu, X. F.; Li, X. H.; Gerosa, A. Z.; Pettman, A.; Liu, J. K.; Mills, A. J.;
Xiao, J. L. Chem. Eur. J. 2008, 14, 2209–2222; (c) Wu, X. F.; Li, J. K.; Tommaso, D.
D.; Iggo, J. A.; Catlow, C. R. A.; Bacsa, J.; Xiao, J. L. Chem. Eur. J. 2008, 14, 7699–
7715; (d) Wang, C.; Li, C. Q.; Wu, X. F.; Pettman, A.; Xiao, J. L. Angew. Chem., Int.
Ed. 2009, 48, 6524–6528.
15. (a) Ogo, S.; Abura, T.; Watanabe, Y. Organometallics 2002, 21, 2964–2969; also
see: (b) Himeda, Y.; Onozawa-Komatsuzaki, N.; Miyazawa, S.; Sugihara, H.;
Hirose, T.; Kasuga, K. Chem. Eur. J. 2008, 14, 11076–11081; (c) Mebi, C. A.; Nair,
R. P.; Frost, B. J. Organometallics 2007, 26, 429–438.
16. (a) Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.; Campbell, L.;
Walsgrove, T.; Wills, M. Tetrahedron 2006, 62, 1864–1876; (b) Xue, D.; Chen, Y.
C.; Cui, X.; Wang, Q. W.; Zhu, J.; Deng, J. G. J. Org. Chem. 2005, 70, 3584–3591;
(c) Muniz, K. Angew. Chem., Int. Ed. 2005, 44, 6622–6627.
17. Li, X. F.; Li, L. C.; Zhang, H.; Lian, C. X.; Zhong, L.; Zhu, J.; Deng, J. G. J. Org. Chem.
2010, 75, 2981–2988.
18. The absolute configuration of 11p and 11q were assigned according to GC
analysis, see: Mikhailine, A.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2009,
131, 1394–1395.