Ruthenium(II)-catalyzed asymmetric transfer hydrogenation using unsymmetrical vicinal diamine-based ligands: Dramatic substituent effect on catalyst efficiency

Article abstract of DOI:10.1002/ejoc.201100299

The use of unsymmetrical vicinal diamines as ligands for Ru-catalyzed asymmetric transfer hydrogenation is described. With a SmI₂-mediated cross-coupling protocol, a series of enantiomerically pure unsymmetrical vicinal diamines were readily prepared and examined in the asymmetric transfer hydrogenation. It was found that an aromatic substituent on the carbon bearing the-NHTs group and a bulky alkyl substituent on the other side, are both very important for the effectiveness of the ligand, suggesting that the substituent has a dramatic effect on the catalyst efficiency. With ligand 8, excellent enantioselectivities that are comparable to N-tosyl-1,2-diphenylethane-1,2- diamine (TsDPEN) were achieved. The results provide some helpful information on the mechanism of Ru-catalyzed asymmetric transfer hydrogenation. A series of unsymmetrical vicinal diamines were prepared and examined as chiral ligands for Ru-catalyzed asymmetric transfer hydrogenation.

Full text of DOI:10.1002/ejoc.201100299

FULL PAPER
DOI: 10.1002/ejoc.201100299
Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation Using
Unsymmetrical Vicinal Diamine-Based Ligands: Dramatic Substituent Effect
on Catalyst Efficiency
Bo Zhang,[a] Hui Wang,[b] Guo-Qiang Lin,*[a] and Ming-Hua Xu*[a,b]
Keywords: Asymmetric catalysis / Hydride ligands / Hydrogenation / N ligands / Ruthenium / Substituent effects
The use of unsymmetrical vicinal diamines as ligands for Ru-
catalyzed asymmetric transfer hydrogenation is described.
With a SmI2-mediated cross-coupling protocol, a series of en-
antiomerically pure unsymmetrical vicinal diamines were
readily prepared and examined in the asymmetric transfer
hydrogenation. It was found that an aromatic substituent on
the carbon bearing the –NHTs group and a bulky alkyl sub-
stituent on the other side, are both very important for the
effectiveness of the ligand, suggesting that the substituent
has a dramatic effect on the catalyst efficiency. With ligand 8,
excellent enantioselectivities that are comparable to N-tosyl-
1,2-diphenylethane-1,2-diamine (TsDPEN) were achieved.
The results provide some helpful information on the mecha-
nism of Ru-catalyzed asymmetric transfer hydrogenation.
To understand the Ru-TsDPEN catalyzed hydrogen
transfer process, Noyori and co-workers proposed a con-
certed pathway for the reduction of ketones in 2-propanol
(Figure 2) that involved a concerted transfer of the protonic
hydrogen on the NH2 moiety and hydridic hydrogen on Ru-
H from 4 to the substrate in a cyclic six-membered transi-
tion state to give the alcohol product and 4b.[1a,4,5]
Introduction
Asymmetric transfer hydrogenation (ATH) of ketones, as
an excellent method for the synthesis of enantiomerically
pure alcohols, has attracted increasing attention in the last
decade due to its great potential for applications in the fine
chemicals, pharmaceuticals, and agrochemical industries
and in new materials.[1] Of the ATH catalysts reported
within the last decade, the most widely used ligands are
those based on 1,2-amino alcohols, such as cis-amino-
indanol 1,[2] and monosulfonylated vicinal diamines, such
as N-tosyl-1,2-diaminocyclohexane (TsDAC; 2),[3] and
N-tosyl-1,2-diphenylethane-1,2-diamine (TsDPEN; 3).[4]
In particular, TsDPEN-coordinated RuII complex (Ru-
TsDPEN), which was first reported by Noyori and Ikariya
in 1995,[4a] has become the catalyst of choice because of its
excellent catalytic activity and easy accessibility (Figure 1).
Figure 2. Proposed catalytic cycles.
Figure 1. The most widely used ligands in ATH.
This concerted mechanism was also supported by kinetic
isotope effect studies from Casey’s group,[6] which demon-
strated a reversible, concurrent hydride and proton transfer
from 2-propanol to the 16-electron species shown in Fig-
ure 1. The tosyl group at the diamine N-terminus was cru-
cial for the reactivity; complexes with the CF3SO2,
C6H5CO, and CH3CO groups were much less reactive.[1a]
In our earlier work,[7] we documented a successful asym-
metric synthesis of symmetrical and unsymmetrical vicinal
[a] Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax: +86-021-50807388
E-mail: lingq@mail.sioc.ac.cn
xumh@mail.shcnc.ac.cn
[b] Shanghai Institute of Materia Medica, Chinese Academy of
Sciences,
555 Zuchongzhi Road, Shanghai 201203, P. R. of China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100299.
Eur. J. Org. Chem. 2011, 4205–4211
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G.-Q. Lin, M.-H. Xu et al.
FULL PAPER
diamines using a samarium diiodide-induced coupling pro-
tocol. Excellent enantioselectivities as well as high dia-
stereoselectivities were achieved in both reactions. With
symmetrical
1,2-bis(3,5-di-tert-butylphenyl)ethylenedi-
amine, we recently discovered a new diamine ligand
TsDBuPEN for the asymmetric transfer hydrogenation of
2-acylarylcarboxylates[8] that enables efficient access to a
wide variety of 3-substituted phthalides in enantiomerically
pure form. In 2004, Wills and co-workers[9] synthesized
three derivatives of TsDPEN (5, 6, and 7) that contain,
respectively, a syn-orientation between the phenyl groups,
and a deleted phenyl group relative to TsDPEN 3. They
found that both disubstitution and the anti arrangement of
substituents on the ligands were very important. However,
the question of how the different kinds of substituent
groups, as well as the chiral environments of the vicinal di-
amine ligand, affect the catalyst reactivity and enantio-
selectivity remains unanswered.
Scheme 1. Reagents and conditions: (a) SmI2, tBuOH, THF, –78 °C,
75%; (b) Zn, Cu(OAc)2, HOAc, 70 °C, 86%; (c) (1) HCl, MeOH;
(2) TsCl, TEA, CH2Cl2, 95% for two steps; (d) H2, Pd(OH)2/C,
82%; (e) (1) HCl, MeOH; (2) (Boc)2O, TEA, 82% for two steps;
(f) (1) H2, Pd(OH)2/C; (2) TsCl, TEA, CH2Cl2, 76% for two steps;
(g) CF3COOH, CH2Cl2, 91%.
Considering the ready availability of a range of enantio-
merically pure unsymmetrical vicinal diamines and their
utility in asymmetric catalysis, we therefore wished to inves-
tigate whether the differences in the substituent on the car-
bon bearing the –NH2/–NHTs group in the diamine was
critical to its effectiveness as a ligand in asymmetric transfer
hydrogenation. Towards this goal, we wanted to prepare
compounds 8 and 9, in which one phenyl group of TsDPEN
is replaced with an isopropyl group (Figure 3).
resulted in the formation of tosylate 16, which underwent
hydrolysis mediated by CF3COOH to give the expected li-
gand 9.
With ligands 8 and 9 in hand, we turned our attention
to their applications in the asymmetric transfer hydrogena-
tion of acetophenone. The reduction was carried out in 2-
propanol, formic acid–triethylamine (TEA) azeotrope, and
aqueous sodium formate (Table 1). As expected, both li-
gands 8 and 9 formed Ru-coordinated complexes that could
be used as catalysts for the asymmetric transfer hydrogena-
tion of acetophenone. When the two were compared, use of
the complex with ligand 8 led to higher reactivity and gave
Table 1. Ru-Catalyzed ATH of acetophenone using ligand 3, 8, or
9.[a]
Figure 3. TsDPEN derivatives.
Results and Discussion
Entry
L
Hydrogen
donors
T [°C]
t [h] Conv. [%][b] ee [%][c]
Following our reported procedure, the key intermediate
12 was easily prepared (Scheme 1). A solution of nitrone 10
and N-tert-butanesulfinyl imine 11 in tetrahydrofuran
(THF) at –78 °C was treated with 3 equiv. of SmI2 in the
presence of 2 equiv. of tert-butyl alcohol to give 12 as the
sole diastereomer in 75% yield.
Conversion of the cross-coupling product into the corre-
sponding free diamine could be accomplished in a three-
step reaction sequence. As shown in Scheme 1 (a), deoxy-
genation of the hydroxylamino function of the coupling
product 12 by Zn/Cu(OAc)2, followed by removal of the
sulfinyl group and subsequent tosylation, gave 14. Ligand
8 was finally obtained after removal of the benzyl group.
The approach that was designed for the synthesis of ligand
9 is outlined in Scheme 1 (b). The sulfinyl group of 13 was
removed to release the free amine, which was then protected
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3
3
3
8
8
8
8
8
8
8
9
9
9
9
iPrOH
HCOONa/H2O
HCOOH/TEA
iPrOH
HCOONa/H2O room temp.
HCOONa/H2O
HCOONa/H2O
28
40
28
40
10
2
20
40
12
6
98
Ͼ99
99
83
83
99
98
95
73
95
56
95
–
97
94
98
82
70
86
83
97
96
98
65
70
–
40
50
2
HCOOH/TEA room temp.
40
65
20
20
12
40
7 d
HCOOH/TEA
HCOOH/TEA
HCOONa/H2O
HCOONa/H2O
HCOOH/TEA room temp.
HCOOH/TEA 40
20
40
28
40
trace
–
[a] Substrate/catalyst ratio: 100:1; the reaction was conducted on a
1.0 mmol scale, [RuCl2(cymene)]2 (0.005 mmol) and ligand
(0.012 mmol) were added to the system. [b] Determined by 1H
NMR analysis. [c] Determined by HPLC on a Chiralcel OB-H col-
by a Boc group. Debenzylation of 15 followed by tosylation umn.
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Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation
better enantioselectivity in aqueous sodium formate able to generate a suitable single crystal of the Ru-9 com-
(Table 1, entries 6 vs. 12). The best result was obtained plex. Not surprisingly, the crystal data of Ru-8 was found
using 8 as ligand when the reaction was performed in for- to be similar to that of Ru-TsDPEN,[12] showing very sim-
mic acid–triethylamine (5:2) azeotrope at 40 °C (98% ee, ilar bond lengths and bond angles.[13]
Table 1, entry 10). In this case, the reactivity and enantio-
To gain more information on the effect of the substitu-
selectivity was comparable to that obtained using TsDPEN ent, we designed and synthesized several new ligands 19–22
as ligand (Table 1, entry 3). However, when 9 was employed (Figure 5), in which the steric and electronic properties were
under the same reaction conditions, only a trace amount of
product were observed, even when the reaction was allowed
to proceed for 7 days at 40 °C (Table 1, entry 14).
These results indicate that changing the substituent on
the carbon bearing the NH2/NHTs group in ligands 8 and
9 resulted in a significant difference in catalyst reactivity
and enantioselectivity. In comparison to TsDPEN, chang-
ing the substitution on the carbon bearing the –NH2 group
Figure 5. Ligands with modified substituents for ATH.
in ligand 8 did not cause much difference in enantio-
selectivity. In contrast, ligand 9 became less effective when
the substitution on the carbon bearing the –NHTs group
Table 2. Asymmetric transfer hydrogenation of aromatic ketones
catalyzed by Ru-8 complex.[a]
was changed to an aliphatic isopropyl group, suggesting the
importance of an aromatic substituent at this position.
To further clarify the differences between ligand 8 and 9,
we then investigated the processes involved in coordination
of the two ligands. At first, a coordination control experi-
ment between TsDPEN and [RuCl2(cymene)]2 was carried
1
out and monitored by H NMR spectroscopy. The spectra
had almost no change from 10 min to 6 h, with the coordi-
nated complex and the free TsDPEN coexisting in a defined
proportion. Similar spectra were observed when ligand 8
was mixed with [RuCl2(cymene)]2. To our surprise, ligand 9
coordinated with ruthenium completely in less than
10 min.[10] According to the different catalytic performances
found in asymmetric transfer hydrogenations, we realized
that the ligand (e. g. TsDPEN or 8) did not react smoothly
with [RuCl2(cymene)]2 but displayed higher catalytic ac-
tivity and enantioselectivity in the reduction. Despite rapid
complexation of the less effective ligand 9, it is likely that
the resulting complex was either relatively inactive, or diffi-
cult to convert into a more active form that was more cap-
able of catalyzing the reaction. To better understand this
catalytic difference as well as the reaction mechanism, we
wished to compare the X-ray structures of ligands 8 and 9
as Ru complexes. After many trials, the Ru-8 complex was
obtained successfully (Figure 4),[11] however, we were un-
Entry
Substrate
t [h]
Conv. [%][b]
ee [%] of 18[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
17p
20
48
96
14
30
20
20
96
36
28
48
22
36
48
22
48
95
96
63
95
90
95
99
42
98
95
98
99
49
93
99
95
98
95
92
91
95
94
91
85
87
91
94
91
90
91
93
97
[a] Substrate/catalyst ratio: 100:1; the reaction was conducted on a
1.0 mmol scale, [RuCl2(cymene)]2 (0.005 mmol), Ligand
8
(0.012 mmol), HCOOH/Et3N (5:2, 1.5 mL) were added to the sys-
tem. [b] Determined by 1H NMR analysis. [c] Determined by
HPLC on a Chiralcel OD-H, OB-H, or OJ-H column.
Figure 4. X-ray structure of the Ru-8 complex.
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G.-Q. Lin, M.-H. Xu et al.
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charged with Sm metal powder (230 mg, 1.5 mmol), was added di-
iodomethane (0.081 mL, 1.0 mmol) in freshly distilled THF (5 mL)
at room temperature using a syringe. After approximately 5 min,
the solution turned deep-blue, indicating the formation of samar-
ium diiodide. The mixture was stirred at room temperature for 1 h
and then cooled to –78 °C. A mixture of tert-butyl alcohol
(1.0 mmol), nitrone (0.7 mmol), and chiral N-tert-butylsulfinyl im-
ine (0.5 mmol) in THF (6 mL) was then added dropwise. The reac-
tion was monitored by TLC and quenched by addition of saturated
aqueous Na2S2O3 (5 mL). Extraction with ethyl acetate and purifi-
considered. With these ligands, the catalytic transfer hydro-
genation of acetophenone was carried out with sodium for-
mate and TEA. As shown in Figure 5, ligand 20, which con-
tains a linear propyl group instead of a bulky isopropyl
group, was inefficient in the reaction, with very low conver-
sion being observed; the other ligands showed comparable
reactivities and enantioselectivities to that of ligand 8. As
can be seen, whereas the electronic properties of the aryl
substitution had nearly no influence on either the reactivity
or enantioselectivity, a bulky alkyl group on the carbon cation by flash column chromatography afforded the desired prod-
uct.
bearing –NH2 was important for the reaction. In general,
ligand 8 was thus a better choice for asymmetric transfer
hydrogenation of acetophenone.
Coupling Product 12: M.p. 122–124 °C. [α]2D0 = –142.6 (c = 1.05,
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.56 (d, J = 5.4 Hz, 3
1
H), 1.17 (m, 12 H), 2.30 (m, 1 H), 2.82 (dd, J = 10.2, 1.2 Hz, 1 H),
3.93 (d, J = 13.8 Hz, 1 H), 4.29 (d, J = 13.4 Hz, 1 H), 4.59 (d, J =
10.2 Hz, 1 H), 5.68 (s, 1 H), 6.64 (s, 1 H), 7.24–7.34 (m, 10 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 20.48, 22.14, 22.44, 26.01, 55.16,
57.06, 60.87, 72.25, 127.22, 127.67, 128.17, 128.31, 128.91, 129.12,
With the identification of the optimal reaction conditions
and ligand, the generality of the reaction was investigated
(Table 2). In most cases, the products were obtained in high
conversions and with good to excellent enantioselectivities.
The para- and meta-substituted acetophenones gave prod-
ucts with 91–95% ee (Table 2, entries 2–7 and 11–13), which
were comparable to results obtained by the group of
Noyori. For the challenging ortho-substituted ketones, a
slight decrease in the enantioselectivities were observed (85–
91% ee) (Table 2, entries 8–10). The reduction of 3,4-
methylenedioxyacetophenone, 1Ј-acetonaphthone, and α-
tetralone also afforded the chiral alcohol products in excel-
lent enantiomeric purities (91–97% ee) (Table 2, entries 14–
16).
138.23, 141.15 ppm. FTIR (KBr): ν = 3580, 3223, 3062, 3034, 2965,
˜
1475, 1031, 1010, 702 cm–1. MS (EI): m/z (%) = 331 (5.71) [M+
–
C4H9], 313 (0.59) [M+ – C4H9 – H2O], 179 (12.75), 178 (100.00),
162 (5.92), 106 (8.67), 92 (8.39), 91 (97.72), 57 (8.14). HRMS:
calcd. for C22H32N2O2S 389.2257; found 389.2295.
General Procedure for the Preparation of Chiral Diamine Ligands 8
and 19–22: Under argon, to a 25 mL flask charged with AcOH
(1 mL) was added Cu(OAc)2 (9 mg, 0.05 mmol) and zinc powder
(162 mg, 2.5 mmol). The mixture was stirred for 15 min, followed
by the addition of a mixture of AcOH (1 mL) and distilled water
(0.35 mL) containing the obtained cross-coupling product
(0.5 mmol). The resulting mixture was heated to 70 °C and stirred
for 1 h. After cooling to room temperature, the reacting system was
mixed with EDTA-2Na (0.5 g) and stirred for 10 min. 3 n aqueous
KOH solution was then added until the mixture reached pH 10.
The resulting solution was extracted with ethyl acetate, and the
combined organic layer was successively washed with saturated
Conclusions
We have explored the use of unsymmetrical, vicinal di-
amine-based ligands in ruthenium-catalyzed asymmetric
transfer hydrogenation and realized that 8 could be a suit-
able ligand; the use of this ligand as a complex with ruthe- aqueous EDTA-2Na and brine. Purification by flash column
chromatography afforded the deoxygenation product 13 as a white
solid in quantitative yield.
nium leads to the desired alcohol products with good to
excellent enantioselectivities (85–98% ee). It was found that
the presence of an aromatic substituent on the carbon bear-
ing the –NHTs group, and a bulky alkyl substituent on the
other side, are both very important for the effectiveness of
the ligand, suggesting a dramatic effect of the substituent
on catalyst efficiency. These results might provide some
helpful information for future ligand design. Further stud-
ies to gain a better understanding on the role of ligand sub-
stituents in asymmetric transfer hydrogenation are under
investigation.
The obtained deoxygenation product 13 (1.0 mmol) was dissolved
in methanol (2.0 mL), to which was added 4 n HCl (2.0 mL) in 1,4-
dioxane (8.0 mmol). The mixture was stirred for 30 min at room
temperature and then concentrated. The residual acid was removed
by concentrating three times with further portions of methanol
(5 mL). The resulting solid and triethylamine (5.0 mmol) were dis-
solved in CH2Cl2 (20 mL), and TsCl (1.2 mmol) in CH2Cl2 (10 mL)
was added dropwise with magnetic stirring. The reaction was moni-
tored by TLC and purified by flash column chromatography to
give the monosulfonylated diamine 14 in 95% yield.
The monosulfonylated diamine 14 was dissolved in methanol
(5 mL) containing 10% Pd(OH)2/C. The mixture was reacted for
24 h under a H2 atmosphere (1 atm) then filtered through a pad of
Celite. Purification by flash column chromatography afforded the
corresponding ligand.
Experimental Section
General Remarks: All anaerobic and moisture-sensitive manipula-
tions were carried out with standard Schlenk techniques under pre-
dried nitrogen or argon. NMR spectra were recorded with a Varian
or Bruker spectrometer (300 or 400 MHz for 1H, and 75 or
100 MHz for 13C). Chemical shifts are reported in δ units (ppm)
referenced to internal SiMe4 for 1H NMR and CDCl3 (δ =
77.00 ppm) for 13C NMR spectroscopy. Optical rotations were
measured with a JASCO P1-030 polarimeter.
Ligand 8: Yield 82%; m.p. 115–116 °C. [α]2D0 = –61.1 (c 0.64,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.81 (d, J = 6.6 Hz, 3
H), 0.86 (d, J = 6.6 Hz, 3 H), 1.32 (br., 2 H), 1.48 (m, 1 H), 2.33
(s, 3 H), 2.60 (t, J = 6.0 Hz, 1 H), 4.27 (d, J = 6.3 Hz, 1 H), 7.02–
7.15 (m, 7 H), 7.45–7.48 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.66, 20.24, 21.33, 28.74, 59.51, 61.91, 126.99, 127.05,
General Procedure for the Cross-Coupling of Nitrones with N-tert-
Butylsulfinyl Imines:[7a] Under argon, to a 10 mL Schlenk flask
127.08, 128.16, 128.99, 137.93, 139.75, 142.54 ppm. FTIR (film): ν
= 3200, 2962, 2843, 1598, 1456, 1323, 1156, 1093, 1058, 970, 919,
˜
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Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation
882, 815, 755, 703, 648, 555, 535 cm–1. MS (ESI): m/z = 333.2 [M+
+ H]. HRMS: calcd. for C18H24N2O2SNa [M+ + Na] 355.1451;
found 355.1468.
(10 mL) was then added dropwise with magnetic stirring. DMAP
(5% mmol) was added as catalyst and the progress of the reaction
was monitored by TLC. Purification by flash column chromatog-
raphy gave 16 in 76% yield.
Ligand 19: Yield 62%; m.p. 86–88 °C. [α]2D1 = –55.2 (c 0.78, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.89–1.13 (m, 6 H), 1.62–1.70 Monosulfonylated diamine 16 (0.25 mmol) was dissolved in
(m, 5 H), 2.33 (s, 3 H), 2.61 (m, 1 H), 4.38 (d, J = 6.3 Hz, 1 H),
7.07–7.15 (m, 7 H), 7.49–7.53 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.38, 25.92, 25.98, 26.27, 27.88, 30.25, 38.73, 58.30,
61.45, 126.92, 127.03, 127.06, 128.24, 129.12, 138.11, 140.25,
CH2Cl2 (5 mL), and CF3COOH (2 mL) was added slowly at 0 °C.
CH2Cl2 (20 mL) was added to dilute the system after 30 min, and
the pH was adjusted to pH 7 by addition of NH3·H2O. Extraction
with CH2Cl2 and purification by flash column chromatography af-
forded the desired ligand 9 in 91% yield.
142.62 ppm. FTIR (film): ν = 3129, 2928, 2852, 1599, 1495, 1455,
˜
1325, 1155, 1093, 1063, 706, 650, 545 cm–1. MS (ESI): m/z = 373
[M+ + H]. HRMS: calcd. for C21H29N2O2S [M+ + H] 373.1944;
found 373.1944.
Ligand 9: [α]2D1 = –23.7 (c = 0.59, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.73 (d, J = 6.9 Hz, 3 H), 0.81 (d, J = 6.6 Hz, 3 H),
1.67 (m, 1 H), 2.37 (s, 3 H), 3.30 (dd, J = 6.3, 5.1 Hz, 1 H), 3.92
(d, J = 6.0 Hz, 1 H), 7.11–7.26 (m, 7 H), 7.60–7.63 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 17.53, 19.86, 21.41, 30.44, 56.01,
65.10, 126.42, 126.80, 127.14, 128.56, 129.35, 138.60, 142.65,
Ligand 20: Yield 88%; m.p. 85–86 °C. [α]2D3 = –76.1 (c 0.83, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.80 (t, J = 6.8 Hz, 3 H), 1.10–
1.39 (m, 4 H), 2.34 (s, 3 H), 2.87–2.91 (m, 1 H), 4.15 (d, J = 4.8 Hz,
1 H), 7.06–7.11 (m, 4 H), 7.15–7.17 (m, 3 H), 7.53 (d, J = 8.4 Hz,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.83, 19.23, 21.35,
36.35, 56.04, 61.14, 126.80, 126.95, 127.06, 128.19, 129.08, 137.80,
143.60 ppm. FTIR (film): ν = 3296, 2964, 2930, 2876, 1599, 1454,
˜
1325, 1157, 1094, 1039, 914, 703, 667, 546 cm–1. MS (ESI): m/z =
333.1 [M+ + H]. HRMS: calcd. for C18H25N2O4S [M+ + H]
333.1631; found 333.1642.
139.93, 142.64 ppm. FTIR (film): ν = 3300, 2957, 1451, 1343, 1317,
˜
1151, 1093, 1058, 676, 547 cm–1. MS (ESI): m/z = 333.2 [M+ + H].
General Procedure for the Asymmetric Transfer Hydrogenation Cat-
alyzed by Ru-8 Complex: A 5 mL Schlenk tube was loaded with
[RuCl2(p-cymene)]2 (3 mg, 0.005 mmol) and diamine ligand 8
(4 mg, 0.012 mmol), and purged with argon. The vessel was
charged with distilled CH2Cl2 (2 mL) and then stirred at 40 °C.
After 30 min, the solvent was removed and HCOOH/Et3N (5:2,
1.5 mL) and substrate 1 (1.0 mmol) were added sequentially. The
reaction was continually stirred at 40 °C until full conversion of 1
was observed (determined by 1H NMR spectroscopy). The reaction
mixture was diluted with H2O (5 mL) and then extracted with di-
ethyl ether. The organic layer was dried with Na2SO4 and concen-
trated under reduced pressure. Purification of the residue by silica
gel column chromatography afforded the corresponding alcohols.
This procedure was based on a report by Xiao and co-workers,[4h]
similar results were obtained with Noyori’s procedure.[4b]
HRMS: calcd. for C18H25N2O2S[M+
333.1634.
+ H] 333.1631; found
Ligand 21: Yield 75%; m.p. 70–72 °C. [α]2D1 = –59.5 (c 0.54, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.78 (d, J = 6.6 Hz, 3 H), 0.85
(d, J = 6.6 Hz, 3 H), 1.48 (m, 1 H), 2.34 (s, 3 H), 2.58 (t, J =
6.0 Hz, 1 H), 3.74 (s, 3 H), 4.17 (d, J = 6.9 Hz, 1 H), 6.65 (d, J =
8.7 Hz, 2 H), 6.95 (d, J = 8.7 Hz, 2 H), 7.07 (d, J = 7.8 Hz, 2 H),
7.46 (d, J = 7.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
16.24, 20.36, 21.38, 28.51, 55.22, 59.23, 61.78, 113.64, 127.10,
128.26, 129.00, 131.62, 137.99, 142.49, 158.80 ppm. FTIR (film): ν
˜
= 3260, 2962, 1612, 1514, 1438, 1321, 1248, 1161, 1093, 1054, 1034,
812, 678, 560 cm–1. MS (ESI): m/z = 363.2 [M+ + H]. HRMS:
calcd. for C19H26N2O3SNa [M+ + Na] 385.1556; found 385.1576.
Ligand 22: Yield 63%; m.p. 70–72 °C. [α]2D1 = –59.5 (c 0.54, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.79 (d, J = 6.0 Hz, 3 H), 0.85
(d, J = 6.0 Hz, 3 H), 1.48 (m, 1 H), 2.35 (s, 3 H), 2.56 (m, 1 H),
4.22 (d, J = 6.3 Hz, 1 H), 6.81 (m, 2 H), 7.02 (m, 2 H), 7.08 (d, J
= 7.8 Hz, 2 H), 7.46 (d, J = 7.2 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.37, 20.31, 21.38, 28.60, 58.91, 61.84,
114.94, 115.16, 127.07, 128.75, 128.83, 129.08, 135.47, 135.51,
137.88, 142.82, 160.75, 163.20 ppm. 19F NMR (282 MHz, CDCl3):
Compound 18a: 1H NMR (300 MHz, CDCl3): δ = 1.48 (d, J =
6.6 Hz, 3 H), 2.41 (br., 1 H), 4.85 (q, J = 6.6 Hz, 1 H), 7.26–7.36
(m, 5 H) ppm. HPLC: Chiralcel OB-H; detected at 254 nm; hexane/
2-propanol = 90:10, flow rate = 0.7 mL/min, retention time: tminor
= 11.6 min, tmajor = 10.7 min.
Compound 18b: 1H NMR (300 MHz, CDCl3): δ = 1.48 (d, J =
6.6 Hz, 3 H), 2.35 (s, 3 H), 4.86 (m, 1 H), 7.16 (d, J = 6.9 Hz, 2 H),
7.26 (d, J = 7.2 Hz, 2 H) ppm. HPLC: Chiralcel OD-H; detected at
254 nm; hexane/2-propanol = 99:1, flow rate = 0.7 mL/min, reten-
tion time: tminor = 14.7 min, tmajor = 17.4 min.
δ = –110.85 (m) ppm. FTIR (film): ν = 3344, 3293, 3084, 2965,
˜
1604, 1512, 1324, 1227, 1155, 1091, 1075, 973, 902, 832, 812, 666,
570, 540 cm–1. MS (ESI): m/z = 351.2 [M+ + H]. HRMS: calcd. for
C18H24N2O2SF [M+ + H] 351.1537; found 351.1553.
Compound 18c: 1H NMR (300 MHz, CDCl3): δ = 1.46 (d, J =
6.0 Hz, 3 H), 3.77 (s, 3 H), 4.84 (q, J = 6.3 Hz, 1 H), 6.85 (d, J =
8.4 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H) ppm. HPLC: Chiralcel OB;
detected at 254 nm; hexane/2-propanol = 95:5, flow rate = 1.0 mL/
min, retention time: tminor = 11.2 min, tmajor = 13.8 min.
General Procedure for the Preparation of Chiral Diamine Ligand 9:
The obtained diamine 13 (1.0 mmol) was dissolved in methanol
(2.0 mL), to which was added 4 n HCl (2.0 mL) in 1,4-dioxane
(8.0 mmol). The mixture was stirred for 30 min at room tempera-
ture and then concentrated. The residual acid was removed by con-
centrating three times with added methanol (5 mL). The resulting
solid and triethylamine (3.0 mmol) were dissolved in CH2Cl2
(20 mL) and (Boc)2O (1.5 mmol) was then added slowly with mag-
netic stirring. The reaction was monitored by TLC and purified by
flash column chromatography to give 15 in 82% yield.
Compound 18d: 1H NMR (300 MHz, CDCl3): δ = 1.45 (d, J =
6.6 Hz, 3 H), 4.91 (q, J = 6.3 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 2 H),
7.57 (d, J = 7.8 Hz, 2 H) ppm. HPLC: Chiralcel OB; detected at
254 nm; hexane/2-propanol = 95:5, flow rate = 0.7 mL/min, reten-
tion time: tminor = 10.8 min, tmajor = 11.7 min.
The Boc-protected diamine 15 was dissolved in methanol (10 mL)
containing 10% Pd(OH)2/C. The mixture was reacted for 24 h un-
der a H2 atmosphere (1 atm) and was filtered through a pad of
Celite. The resulting solid and triethylamine (2.4 mmol) were dis-
solved in CH2Cl2 (20 mL), and TsCl (0.97 mmol) in CH2Cl2
Compound 18e: 1H NMR (300 MHz, CDCl3): δ = 1.44 (d, J =
6.6 Hz, 3 H), 2.22 (br., 1 H), 4.83 (q, J = 6.6 Hz, 1 H), 7.26 (m, 4
H) ppm. HPLC: Chiralcel OB-H; detected at 254 nm; hexane/2-
propanol = 95:5, flow rate = 0.7 mL/min, retention time: tminor
13.5 min, tmajor = 14.4 min.
=
Eur. J. Org. Chem. 2011, 4205–4211
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4209

G.-Q. Lin, M.-H. Xu et al.
FULL PAPER
Compound 18f: 1H NMR (300 MHz, CDCl3): δ = 1.48 (dd, J = 1.2,
6.3 Hz, 3 H), 2.17 (br., 1 H), 4.89 (q, J = 6.2 Hz, 1 H), 7.03 (t, J
= 8.4 Hz, 2 H), 7.34 (t, J = 6.3 Hz, 2 H) ppm. HPLC: Chiralcel
OB-H; detected at 254 nm; hexane/2-propanol = 95:5, flow rate =
0.8 mL/min, retention time: tminor = 9.3 min, tmajor = 10.1 min.
Acknowledgments
This work was generously supported by the National Natural Sci-
ence Foundation of China (20672123, 21021063), the Chinese
Academy of Sciences, and the Major State Basic Research Devel-
opment Program.
Compound 18g: 1H NMR (300 MHz, CDCl3): δ = 1.47 (d, J =
6.3 Hz, 3 H), 2.32 (br., 1 H), 4.88 (q, J = 6.5 Hz, 1 H), 7.26 (d, J
= 6.9 Hz, 2 H), 7.47 (d, J = 7.8 Hz, 2 H) ppm. HPLC: Chiralcel
OB-H; detected at 254 nm; hexane/2-propanol = 95:5, flow rate =
0.8 mL/min, retention time: tminor = 9.0 min, tmajor = 10.1 min.
[1]
For reviews on asymmetric transfer hydrogenation, see: a) R.
Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97; b) M. J.
Palmer, M. Wills, Tetrahedron: Asymmetry 1999, 10, 2045; c)
M. Wills, M. Palmer, A. Smith, J. Kenny, T. Walsgrove, Mole-
cules 2000, 5, 4; d) C. Saluzzo, M. Lemaire, Adv. Synth. Catal.
2002, 344, 915; e) H. U. Blaser, C. Malan, B. Pugin, F. Spindler,
H. Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103; f) K.
Everaere, A. Mortreux, J. F. Carpentier, Adv. Synth. Catal.
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on Industrial Scale: Challenges, Approaches and Solutions (Eds.:
H. U. Blaser, E. Schmidt), Wiley, 2004, pp. 210 –216; h) S. E.
Clapham, A. Hadzovic, R. H. Morris, Coord. Chem. Rev. 2004,
248, 2201; i) E. Peris, R. H. Crabtree, Coord. Chem. Rev. 2004,
248, 2239; j) S. Gladiali, E. Alberico, Chem. Soc. Rev. 2006, 35,
226; k) T. Ikariya, K. Murata, R. Noyori, Org. Biomol. Chem.
2006, 4, 393; l) D. Mery, D. Astruc, Coord. Chem. Rev. 2006,
250, 1965; m) J. S. M. Samec, J. E. BMckvall, P. G. Andersson,
P. Brandt, Chem. Soc. Rev. 2006, 35, 237; n) X.-F. Wu, J.-L.
Xiao, Chem. Commun. 2007, 2449; o) P. Roszkowski, Z. Czar-
nocki, Mini-Rev. Org. Chem. 2007, 4, 190; p) S.-L. You, Chem.
Asian J. 2007, 2, 820; q) T. Ikariya, A.-J. Blacker, Acc. Chem.
Res. 2007, 40, 1300.
Compound 18h: 1H NMR (300 MHz, CDCl3): δ = 1.50 (d, J =
6.3 Hz, 3 H), 3.83 (s, 3 H), 5.12 (q, J = 6.3 Hz, 1 H), 6.85–7.36
(m, 4 H) ppm. HPLC: Chiralcel OB; detected at 254 nm; hexane/
2-propanol = 90:10, flow rate = 1.0 mL/min, retention time: tminor
= 15.3 min, tmajor = 27.2 min.
Compound 18i: 1H NMR (300 MHz, CDCl3): δ = 1.46 (d, J =
6.3 Hz, 3 H), 5.26 (q, J = 6.3 Hz, 1 H), 7.18–7.56 (m, 4 H) ppm.
HPLC: Chiralcel OB; detected at 254 nm; hexane/2-propanol =
95:5, flow rate = 1.0 mL/min, retention time: tminor = 10.0 min,
tmajor = 14.3 min.
Compound 18j: 1H NMR (300 MHz, CDCl3): δ = 1.50 (d, J =
6.6 Hz, 3 H), 2.26 (br., 1 H), 5.18 (q, J = 6.2 Hz, 1 H), 6.97–7.03
(m, 1 H), 7.11–7.16 (m, 1 H), 7.20–7.27 (m, 1 H), 7.45–7.50 (m, 1
H) ppm. HPLC: Chiralcel OB; detected at 254 nm; hexane/2-pro-
panol = 95:5, flow rate = 0.7 mL/min, retention time: tminor
7.7 min, tmajor = 10.1 min.
=
Compound 18k: 1H NMR (300 MHz, CDCl3): δ = 1.47 (d, J =
6.3 Hz, 3 H), 4.87 (q, J = 6.3 Hz, 1 H), 7.20–7.36 (m, 4 H) ppm.
HPLC: Chiralcel OB; detected at 254 nm; hexane/2-propanol =
95:5, flow rate = 1.0 mL/min, retention time: tminor = 8.0 min, tmajor
= 9.8 min.
[2]
For selected examples, see: a) J. Takehara, S. Hashiguchi, A.
Fujii, S. I. Inoue, T. Ikariya, R. Noyori, Chem. Commun. 1996,
233; b) M. Yamakawa, I. Yamada, R. Noyori, Angew. Chem.
Int. Ed. 2001, 40, 2818; c) M. J. Palmer, T. Walsgrove, M. Wills,
J. Org. Chem. 1997, 62, 5226; d) P. Brandt, P. Roth, P. G. An-
dersson, J. Org. Chem. 2004, 69, 4885; e) R. V. Wisman, J. G.
de Vriue, B.-J. Deelman, H. J. Heeres, Org. Process Res. Dev.
2006, 10, 423; f) J. W. Faller, A. R. Lavoie, Organometallics
2002, 21, 2010; g) D. A. Alonso, S. J. M. Nordin, P. Roth, T.
Tamai, P. G. Andersson, J. Org. Chem. 2000, 65, 3116.
Compound 18l: 1H NMR (300 MHz, CDCl3): δ = 1.48 (d, J =
6.6 Hz, 3 H), 2.35 (s, 3 H), 4.86 (m, 1 H), 7.07–7.26 (m, 4 H) ppm.
HPLC: Chiralcel OJ-H; detected at 254 nm; hexane/2-propanol =
95:5, flow rate = 0.7 mL/min, retention time: tminor = 12.7 min,
tmajor = 13.7 min.
[3]
[4]
For selected examples, see: a) K. Murata, T. Ikariya, R.
Noyori, J. Org. Chem. 1999, 64, 2186; b) B. Mohar, A. Valleix,
J.-R. Desmurs, M. Felemez, A. Wagner, C. Mioskowski, Chem.
Commun. 2001, 2572; c) S. Shirai, H. Nara, Y. Kayaki, T. Ika-
riya, Organometallics 2009, 28, 802; d) Z. M. Heiden, B. J. Go-
recki, T. B. Rauchfuss, Organometallics 2008, 27, 1572; e) X.-
F. Li, L.-C. Li, Y.-F. Tang, L. Zhang, L.-F. Cun, J. Zhu, J. Liao,
J.-G. Deng, J. Org. Chem. 2010, 75, 2981.
For selected examples, see: a) S. Hashiguchi, A. Fujii, J. Take-
hara, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995, 117, 7562;
b) A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori,
J. Am. Chem. Soc. 1996, 118, 2521; c) M. Watanabe, K. Mur-
ata, T. Ikariya, J. Org. Chem. 2002, 67, 1712; d) K. Murata, K.
Okano, M. Miyagi, H. Iwane, R. Noyori, T. Ikariya, Org. Lett.
1999, 1, 1119; e) K. J. Haack, S. Ashiguchi, A. Fujii, T. Ikariya,
R. Noyori, Angew. Chem. Int. Ed. Engl. 1997, 36, 285; f) K.
Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1997, 119, 8738; g) J. Cossrow, S. Rychnovsky, Org.
Lett. 2002, 4, 147; h) X. Wu, X. Li, W. Hems, F. King, J. Xiao,
Org. Biomol. Chem. 2004, 2, 1818; i) K. Maki, R. Motoki, K.
Fujii, M. Kanai, T. Kabayashi, M. Shibasaki, J. Am. Chem.
Soc. 2005, 127, 17111.
Compound 18m: 1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J =
7.2 Hz, 3 H), 1.75 (m, 2 H), 2.40 (br., 1 H), 4.56 (t, J = 7.5 Hz, 1
H), 5.92 (s, 2 H), 7.23–7.31 (m, 5 H) ppm. HPLC: Chiralcel OD;
detected at 254 nm; Hexane/i-propanol = 95:5, flow rate = 0.7 mL/
min, retention time: tmajor = 12.5 min, tminor = 13.9 min.
Compound 18n: 1H NMR (300 MHz, CDCl3): δ = 1.44 (d, J =
6.6 Hz, 3 H), 2.40 (br., 1 H), 4.77 (m, 1 H), 5.92 (s, 2 H), 6.72–6.89
(m, 3 H) ppm. HPLC: Chiralcel OD-H; detected at 254 nm; hex-
ane/2-propanol = 97.5:2.5, flow rate = 0.7 mL/min, retention time:
tmajor = 23.5 min, tminor = 25.3 min.
Compound 18o: 1H NMR (300 MHz, CDCl3): δ = 1.54 (d, J =
6.6 Hz, 3 H), 5.00 (m, 1 H), 4.75 (m, 1 H), 7.43–7.48 (m, 3 H),
7.75–7.81 (m, 4 H) ppm. HPLC: Chiralcel OD; detected at 254 nm;
hexane/2-propanol = 95:5, flow rate = 0.5 mL/min, retention time:
tmajor = 13.8 min, tminor = 15.2 min.
1
Compound 18p: H NMR (300 MHz, CDCl3): δ = 1.72–1.99 (m, 4
H), 2.72–2.85 (m, 2 H), 4.75 (m, 1 H), 7.06–7.42 (m, 4 H) ppm.
HPLC: Chiralcel OD; detected at 254 nm; hexane/2-propanol =
98:2, flow rate = 0.7 mL/min, retention time: tminor = 21.7 min,
tmajor = 24.1 min.
[5]
For related mechanistic studies on asymmetric transfer hydro-
genation, see: a) M. Yamakawa, H. Ito, R. Noyori, J. Am.
Chem. Soc. 2000, 122, 1466; b) R. Noyori, M. Yamakawa, S.
Hashiguchi, J. Org. Chem. 2001, 66, 7931; c) C. A. Sandoval,
T. Ohkuma, N. Utsumi, K. Tsutsumi, K. Murata, R. Noyori,
Chem. Asian J. 2006, 1–2, 102; d) D. A. Alonso, P. Brandt,
S. J. M. Nordin, P. G. Andersson, J. Am. Chem. Soc. 1999, 121,
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of the ligands and coordination study, and se-
lected X-ray data comparison.
4210
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4205–4211

Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation
9580; e) J.-W. Handgraaf, E. J. Meijer, J. Am. Chem. Soc. 2007,
129, 3099.
[6] C. P. Casey, J. B. Johnson, J. Org. Chem. 2003, 68, 1998.
[7] a) Y.-W. Zhong, K. Izumi, M.-H. Xu, G.-Q. Lin, Org. Lett.
2004, 6, 3953; b) Y.-W. Zhong, K. Izumi, M.-H. Xu, G.-Q. Lin,
Org. Lett. 2004, 6, 4747.
[8] B. Zhang, M.-H. Xu, G.-Q. Lin, Org. Lett. 2009, 11, 4712.
[9] A. Hayes, G. Clarkson, M. Wills, Tetrahedron: Asymmetry
2004, 15, 2079.
[10] For NMR spectra obtained in the coordination study, see the
Supporting Information.
17.124(2) Å, α = 90°, β = 90°, γ = 90°; V = 2865.3(6) Å3; Z =
4; ρcalc = 1.396 Mg/m3; F(000) = 1248; final R indices [I Ͼ 2σ
(I)]: R1 = 0.0409, wR2 = 0.0787; R indices (all data), R1 =
0.0586, wR2 = 0.0831; 16845 reflections measured, 6210 were
unique [R(int) = 0.1011]. CCDC-813453 contains the supple-
mentary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] For X-ray crystallographic data of the Ru-TsDPEN complex,
see ref.[4b]
[13] For selected X-ray data comparison, see the Supporting Infor-
mation.
[11] Crystallographic
X-ray
data
for
Ru-8
complex
(C28H37ClN2O2RuS): T = 293(2) K; wavelength: 0.71073 Å;
crystal system: orthorhombic; space group: P2(1)2(1)2(1); unit
cell dimensions: a = 12.7969(15) Å, b = 13.0758(15) Å, c =
Received: March 3, 2011
Published Online: June 1, 2011
Eur. J. Org. Chem. 2011, 4205–4211
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4211