Tunable dendritic ligands of chiral 1,2-diamine and their application in asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2005.07.008

Tunable dendritic N-mono-sulfonyl ligands have been designed and synthesized via direct N-mono-sulfonylization of the chiral dendritic vicinal diamines and their ruthenium complexes demonstrated high catalytic and recyclable activities with comparable enantioselectivities to Noyori-Ikariya's TsDPEN-Ru in the asymmetric transfer hydrogenation of an extended range of substrates, such as ketones, keto esters, and olefins.

Full text of DOI:10.1016/j.tetasy.2005.07.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2525–2530
Tunable dendritic ligands of chiral 1,2-diamine and their
application in asymmetric transfer hydrogenation
Weiguo Liu,a Xin Cui,a Linfeng Cun,a,b Jin Zhua,b and Jingen Denga,b,
*
aKey Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric
Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
bGraduate School of the Chinese Academy of Sciences, Beijing, China
Received 18 May 2005; accepted 4 July 2005
Abstract—Tunable dendritic N-mono-sulfonyl ligands have been designed and synthesized via direct N-mono-sulfonylization of the
chiral dendritic vicinal diamines and their ruthenium complexes demonstrated high catalytic and recyclable activities with compa-
rable enantioselectivities to Noyori–IkariyaÕs TsDPEN-Ru in the asymmetric transfer hydrogenation of an extended range of
substrates, such as ketones, keto esters, and olefins.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
N-tosyl-1,2-diphenylethylenediamine (TsDPEN) is a
highly effective ligand for asymmetric transfer hydroge-
nation of simple ketones.8 Recently, a series of chiral
RSO2–DPEN ligands9–14 had been synthesized and
found to be much effective for the reduction of other sub-
strates, such as imines,9 keto esters10,11 and C@C double
bonds,12 as well as Michael addition.13 In our previous
work,5 amino-functionalized dendritic ligands of chiral
The search for an ideal catalyst that combines the
advantages of both homogeneous and heterogeneous
catalysis is the center of many investigations into green
chemistry. With this is mind, metallodendrimers are
emerging as a promising class of compounds in transi-
tion-metal catalysis as demonstrated in the pioneering
work by Knapen and Brunner in 1994.1,2 This interest
is due to the properties of dendrimers: high solubility,
high concentration of easily accessible active sites, and
´
1,2-diphenylethylenediamine (DPEN) with Frechet
polyether dendrons were synthesized and showed good
recyclable catalytic activity and enantioselectivity in the
transfer hydrogenation of aromatic ketone. However,
these dendritic ligands could not be further modified
on the amino groups or tuned,12b and are limited to the
transfer hydrogenation of simple ketones and imines.5b
In order to further research the application and influence
of dendritic ligands on the asymmetric reactions, a novel
series of dendritic ligands, 3a–d functionalized at the
benzene rings15 of chiral DPEN have been synthesized
from available enantiopure 1,2-para-methoxyphenyl eth-
ylenediamine 1,16 which can be modified on the amino
group NH2 and used as chiral ligands to generate highly
enantioselective catalysts for asymmetric transformation
of a variety of substrates.8–14 Herein, we report the syn-
thesis of a series of mono-sulfonyl dendritic ligands, 4a–g
based on the dendritic ligands 3a–d and the application
in the asymmetric transfer hydrogenation of ketones,
keto esters and C@C double bonds, as well as effects of
the dendrimer wedges on the asymmetric transfer
hydrogenation.17
easy separation by nanofiltration3 or precipitation4,5
6
´
under specific conditions. Frechet dendrimers have
been extensively applied to immobilize homogeneous
catalysts due to easy synthesis, characterization and
purification, as well as their different solubility in polar
solvent and nonpolar solvent, so they can be recovered
by solvent precipitation.4c–e,5 Moreover, many homo-
´
geneous catalysts based on Frechet dendrimers demon-
strated good catalytic activities and recyclable
application with comparable selectivities to the paren-
tally molecular catalysts.7
Chiral vicinal diamine and its derivatives have also
increased considerably, especially in the field of catalytic
asymmetric synthesis. Noyori et al. found that chiral
*
Corresponding author. Fax: +86 28 8522 3978; e-mail: jgdeng@
cioc.ac.cn
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.008

2526
W. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2525–2530
2. Results and discussion
TOF values are less than 12).5a However, when the third
generation catalyst, Ru[(R,R)-4d] was used, the reactiv-
ity had a notable drop in only 75% conversion (TOF
value is 4.3) along with a slight decrease of enantioselec-
tivity (entry 6) with the same reaction time. We pre-
sumed that the dendrons of Ru[(R,R)-4d] wrapped the
catalytic site so tight that substrates could not easily
access the active site of the catalyst.16,17 The second
generation catalyst, Ru[(R,R)-4c] can be recovered
by precipitation with an addition of methanol after
removed of DCM under reduced pressure20 and reused
four times with slightly higher enantioselectivities (en-
tries 7–10 vs entry 5). Lower activities in the successive
reactions in terms of the required reaction time and
conversion rate were evaluated by ICP analysis, which
showed that the catalyst had leached into the MeOH
solution (about 10 mol % for each reuse). Interestingly,
Ru[(R,R)-4c] was more active than the third generation
catalyst derived from amino-functionalized vicinal
diamine5a for the fifth use with 71.2% versus 52%
conversions. Although the enantioselectivities of the
second generation catalysts prepared from N-2,4,6-
triethylphenylsulfonyl-1,2-diamine ligand, (S,S)-4e,12
N-2,4,6-triisopropylphenylsulfony-1,2-diamine ligand,
(S,S)-4f,9b and [RuCl2(cymene)]2 decreased (entries 14
As shown in Scheme 1, the dendritic diamine ligands,
(R,R)-3a–d and (S,S)-3c were modified by mono-sulfon-
amidation to give the dendritic N-arylsulfony diamine
ligands, (R,R)-4a–d and (S,S)-4e–g in 65–85% yields.
However, the synthesis of the N-(N,N-dialkylamino)-
sulfamoyl diamine type ligands according to MoharÕs
procedure was unsuccessful.11b For comparison, a
monomeric ligand, (R,R)-2 was prepared by direct N-
sulfonylization of (R,R)-1 in 92% yield. All kinds of
nondendritic ligands, (R,R)-2 and dendritic ligands,
(R,R)-4a–d and (S,S)-4e–g were characterized by
NMR (1H and 13C), IR, and HRMS (ESI) or MAL-
DI-TOF.18,19
An asymmetric transfer hydrogenation was studied
using acetophenone 5 as the model substrate with the
results summarized in Table 1.20 Compared to the
complexes of monomeric ligand, (R,R)-2, as well as
TsDPEN, a slightly enhanced reactivity was observed
for the dendritic catalysts, Ru[(R,R)-4a–c] with similar
enantioselectivities (entries 3, 4, and 5 vs entries 1 and
2), which are more active than those dendritic catalysts
derived from amino-functionalized vicinal diamine (the
MeO
OMe
MeO
OMe
a
H2N
NH2
H2N
NHSO2C6H4-p-CH3
(R,R)-1
(R,R)-2 92%
O
O
O
O
O
O
O
n
n
R1HN
R2HN
NH2
*
*
*
a
* NH2
O
O
O
O
O
n
n
4 R1 = ArSO2; R2 = H
n = 0, 1, 2, 3
Ar = 4-CH3C6H4
(R,R)-4a, n = 0, 85%; (R,R)-4b, n = 1, 81%;
(R,R)-4c, n = 2, 83%; (R,R)-4d, n = 3, 65%.
(R,R)-3a, n = 0; (R,R)-3b, n = 1;
(R,R)-3c or (S,S)-3c, n = 2;
(R,R)-3d, n = 3.
Ar = 2, 4, 6-Et3-C6H2
Ar = 2, 4, 6-iPr3-C6H2
Ar = 1-naphthyl
(S,S)-4e, n = 2, 80%.
(S,S)-4f, n = 2, 77%.
(S,S)-4g, n = 2, 84%.
Scheme 1. Synthesis of the chiral monomer 2 and the chiral dendritic ligands 4. Reagents and conditions: (a) ArSO2Cl (1.05 equiv), DIPEA
(1.3 equiv), DCM, 0 °C to rt.

W. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2525–2530
2527
Table 1. Asymmetric transfer hydrogenation of acetophenone using the (R,R)-2–Ru(II) and (R,R) or (S,S)-4–Ru(II) complexesa
OH
O
2 or 4 + [RuCl2(cymene)]2
HCOOH / Et3N, DCM, 28 oC
5
6
Entry
Ligand
Time (h)
Conversionb (%)
TOFc (hꢀ1
)
eed (%)
1
2
3
4
5
(R,R)-TsDPEN
(R,R)-2
(R,R)-4a
(R,R)-4b
(R,R)-4c
5
20
20
20
20
51
>99
95
10.2
12.8
15.2
16.1
10.3
(13.2)e
4.3
nd
nd
nd
nd
nd
nd
nd
14.7
(8.9)e
10.4
(9.3)e
14.8
(15.9)e
96.5
96.3
96.8
>99
96.6
97.1
96.1
(90.4)e
75
(96.4)e
94.6
6
7
8
9
10
11g
12g
13h
14i
(R,R)-4d
20
21
25
31
40
13
36
96
20
(R,R)-4c (2nd use)f
(R,R)-4c (3rd use)f
(R,R)-4c (4th use)f
(R,R)-4c (5th use)f
(R,R)-4c
95.4
90.2
83.7
71.2
>99
97.5
97.2
97.5
97.0
90.1
91.1
95.0
(R,R)-4c (2nd use)f
(R,R)-4c
53
97
(S,S)-4e
93.0
(73.4)e
91.7
(90.6)e
>99
91.7
(89.5)e
92.8
15i
16i
(S,S)-4f
(S,S)-4g
20
20
(91.3)e
96.3
(89.0)e
(91.5)e
a (R)-Alcohol was obtained.
b Based on GC analysis.
c Average turn-over frequency calculated over the 5 h reaction time.
d Determined by GC on CP-Cyclodex B-236 M column.
e DMF as solvent, activation at 80 °C for 1 h.
f Recovered catalyst was used.
g Reaction at 40 °C.
h S/C = 500.
i (S)-Alcohol was obtained.
and 15), the second generation catalyst prepared from
N-1-naphthylsulfonyl-1,2-diamine ligand, (S,S)-4g9a
gave a high conversion with the same selectivity (entry
16). When DMF was used as solvent and the activated
temperature increased to 80 °C for preparation of the
second generation catalysts, a decrease in both conver-
sion and enantioselectivity was observed (entries 5, 14–16).
replacement of 1,3,5-trimethylbenzene with cymene
for the g-arene ligand may lead to higher enantioselec-
tivities (entry 12 vs 11). Although the dendritic ligands,
(S,S)-4e and 4g were found to reduce both reactivities
and enantioselectivities in the asymmetric transfer
hydrogenation of 7 and 8 (entries 4 and 5, 9 and 10),
they can dramatically enhance the enantioselectivities
to both 82% ee, from 64% ee for those N-tosyl-diamine
ligands (entries 18 and 20 vs entry 17) in the asymmet-
ric transfer hydrogenation of methyl benzoylformate
10. The highest enantioselectivity (92.0% ee) was
obtained by using (S,S)-4f as a ligand (entry 19). Those
that showed an increase of enantioselectivities in the
asymmetric reduction could be achieved by fine tuning
of the coordinating amino group NH2 of chiral 1,2-
diamines. The ACE inhibitor intermediate, ethyl 2-hy-
droxy-4-phenylbutanoate was obtained with 78.6% ee
by using (R,R)-4c as a ligand (entry 22). Good enanti-
oselectivity (84.5% ee) was obtained in the reduction of
ethyl 2-oxopropanoate 12 by using (R,R)-4c as a ligand
(entry 27). However, the prochiral b-dicyanoolefins, 13
and 14 could be reduced by using Ru–(S,S)-4e as cat-
alyst in high yields with 80% and 71% ee (entries 33
and 38), respectively, which can further form b-chiral
acids by hydrolyzing the products.12a
For further exploring the distinctive characteristic of
dendritic catalysts, several ketones, 7–9 were chosen
as substrates (Table 2), because their low enantioselec-
tivities were observed in the asymmetric transfer hydro-
genation before.8 In general, the conversions of 7 and 8
and the enantioselectivities of reduced products did not
obviously change when using dendritic (R,R)-4c as a
ligand compared to the monomeric ligand (R,R)-2
and TsDPEN (entries 1–10). Reduction of 9 with
(R,R)-2 and dendritic ligands, (R,R)-4c gave better
yields (>90%) than TsDPEN and much higher enantio-
selectivities (up to 95%) compared with that of the
literature (entries 11–14).8 We reasoned that the elec-
tronic effect of the electron-donating group at the
para-site of the benzene ring of the diamine ligands
in Ru(diamine) complexes can lead to a faster rate in
this asymmetric transfer hydrogenation while the

2528
W. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2525–2530
Table 2. Asymmetric transfer hydrogenation of ketones and olefins using the (R,R)-2–Ru(II) and (R,R) or (S,S)-4–Ru(II) complexesa
O
O
O
O
COOMe
CN
OMe
O2N
7
8
9
10
NC
NC
CN
O
O
CO2Et
CO2Et
11
12
13
14
Entry
Sub
Ligand
S/C
Time (h)
Yieldb (%)
eec (%) (Conf)d
1
2
3
4
5
7
7
7
7
7
TsDPEN
2
100
100
100
100
100
4.0
5.0
5.0
5.0
5.0
93
95
94
91
95
82.6 (R)
84.4 (R)
87.4 (R)
71.3 (S)
87.6 (S)
4c
4e
4g
6
7
8
9
8
8
8
8
8
TsDPEN
2
100
100
100
100
100
48
48
48
48
48
81
75
80
89.6 (R)
89.4 (R)
87.0 (R)
51.4 (S)
78.6 (S)
4c
4e
4g
5c
10
31
11
12
13
14
9
9
9
9
TsDPENe
TsDPEN
2
4c
100
100
100
100
28
28
28
28
88
80
95
90
81.7 (R)
95.1 (R)
95.0 (R)
94.9 (R)
15
16
17
18
19
20
10
10
10
10
10
10
TsDPEN
2
100
100
100
100
100
100
2.5
2.5
2.5
2.5
2.5
2.5
81
82
82
80
82
82
65.0 (S)
64.4 (S)
64.1 (S)
81.7 (R)
92.0 (R)
82.0 (R)
4c
4e
4f
4g
21
22
23
24
25
11
11
11
11
11
TsDPEN
40
40
40
40
40
24
24
24
24
24
96
94
96
94
95
79.7 (R)
78.6 (R)
60.0 (S)
69.0 (S)
64.5 (S)
4c
4e
4f
4g
26
27
28
29
30
12
12
12
12
12
TsDPEN
40
40
40
40
40
24
24
24
24
24
100
95
94
96
97
86 (R)11c
84.5 (R)
79.3 (S)
80.0 (S)
77.0 (S)
4c
4e
4f
4g
31
32
33
34
35
13
13
13
13
13
TsDPENf
100
100
100
100
100
4.5
4.5
4.5
4.5
4.5
98
96
97
97
94
60 (ꢀ)g,h
59 (ꢀ)g,h
80 (+)g,h
73 (+)g,h
76 (+)g,h
4cf
4ef
4ff
4gf
36
37
38
39
40
14
14
14
14
14
TsDPENf
100
100
100
100
100
2.5
2.5
2.5
2.5
2.5
95
82
87
83
91
51 (S)g
49 (S)g
71 (R)g
33 (R)g
66 (R)g
4cf
4ef
4ff
4gf
a Reaction condition showed in Ref. 20 (S/C = 100), unless otherwise noted.
b Isolated yields.
c Determined by GC on CP-Cyclodex B-236 M column.
d Determined by comparison with rotation sign in available references or the retention times of standard compounds on GC or HPLC analyses.
e 1,3,5-Trimethylbenzene was used as a ligand according to the literature.8
f After activated at 60 °C for 1 h, the reaction was conducted at 28 °C in THF.
g Determined by HPLC on chiral OD column.
h Rotation sign.

W. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2525–2530
2529
190; (d) Reek, J. N. H.; de Groot, D.; Oosterom, G. E.;
Kamer, P. C. J.; van Leeuwen, P. W. N. M. Rev. Mol.
Biotechnol. 2002, 90, 159–181; (e) Twyman, L. J.; King, A.
S. H.; Martin, I. K. Chem. Soc. Rev. 2002, 31, 69–82; (f)
van Heerbeek, R.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M.; Reek, J. N. H. Chem. Rev. 2002, 102, 3717–3756; (g)
Caminade, A.-M.; Maraval, V.; Laurent, R.; Majoral,
J.-P. Curr. Org. Chem. 2002, 6, 739–774; (h) Dahan, A.;
Portnoy, M. J. Polym. Sci. Part A: Polym. Chem. 2005, 43,
235–262.
3. Conclusion
In conclusion, a novel series of chiral dendritic N-mono-
sulfonyl 1,2-diamine ligands based on the phenyl-func-
tionalized 1,2-diamine have been designed and synthe-
sized in high yields with their ruthenium complexes
demonstrating higher reactivities when compared to
the monomeric catalyst with the same enantioselectivi-
ties. Moreover, better recyclable activities of the second
generation dendritic catalyst were observed when com-
pared with the polymer-supported catalysts,15b,d,e as
well as the dendritic catalysts derived from amino-func-
tionalized vicinal diamine5a by using the formic acid–tri-
ethylamine azeotrope as the hydrogen source in the
asymmetric transfer hydrogenation. It is notable that
the phenyl-functionalized dendritic 1,2-diamine ligands
can be selectively modified toward the development of
Ôfine-tunedÕ catalysts for the reduction of an extended
range of substrates, such as aromatic ketones, keto
esters, and olefins. A further interesting aspect of this
study is that such ligands can serve as a chiral
platform with which many types of reactions can be
carried out.
8. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–2522.
9. For reduction of imines, see: (a) Uematsu, N.; Fujii, A.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 4916–4917; (b) Meuzelaar, G. J.; van Vliet, M.
C. A.; Maat, L.; Sheldon, R. A. Eur. J. Org. Chem. 1999,
9, 2315–2321.
10. For dynamic kinetic resolution, see: Mohar, B.; Valleix,
A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.; Mioskow-
ski, C. Chem. Commun. 2001, 2572–2573.
11. For the reduction of keto esters, see: (a) Taran, F.;
Gauchet, C.; Mohar, B.; Meunier, S.; Valleix, A.; Renard,
´
P. Y.; Creminon, C.; Grassi, J.; Wagner, A.; Mioskowski,
ˇ
C. Angew. Chem., Int. Ed. 2002, 41, 124–127; (b) Sterk, D.;
Stephan, M. S.; Mohar, B. Tetrahedron: Asymmetry 2002,
ˇ
13, 2605–2608; (c) Sterk, D.; Stephan, M. S.; Mohar, B.
Tetrahedron Lett. 2004, 45, 535–537.
12. For reduction of C@C double bonds, see: (a) Chen, Y.-C.;
Xue, D.; Deng, J.-G.; Cui, X.; Zhu, J.; Jiang, Y.-Z.
Tetrahedron Lett. 2004, 45, 1555–1558; (b) Xue, D.; Chen,
Y. C.; Cui, X.; Wang, Q. W.; Zhu, J.; Deng, J. G. J. Org.
Chem. 2005, 70, 3584–3591.
13. For Michael addition, see: (a) Suzuki, T.; Torii, T.
Tetrahedron: Asymmetry 2001, 12, 1077–1081; (b) Watan-
abe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003,
125, 7508–7509; (c) Watanabe, M.; Ikagawa, A.; Wang,
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11148–11149.
Acknowledgements
This work was financially supported by the National
Natural Science Foundation of China (Nos. 20372061,
203900507 and 20025205).
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´
17. (a) Chow, H.-F.; Mak, C. C. J. Org. Chem. 1997, 62,
5116–5127; (b) Yi, B.; Fan, Q.-H.; Deng, G.-J.; Li, Y.-M.;
Qiu, L.-Q.; Chan, A. S. C. Org. Lett. 2004, 6, 1361–1364.
18. Full characterization of ligand (R,R)-4d as one represen-
6. Hawker, C. J.; Frechet, J. M. J. J. Am. Chem. Soc. 1990,
112, 7638–7647.
7. For the comprehensive reviews on dendritic catalysts, see:
(a) Oosterom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Angew. Chem., Int. Ed. 2001, 40,
1828–1849; (b) Astruc, D.; Chardac, F. Chem. Rev. 2001,
101, 2991–3024; (c) Crooks, R. M.; Zhao, M.; Sun, L.;
Chechik, V.; Yueng, L. K. Acc. Chem. Res. 2001, 34, 181–
22
tative: Mp 67–73 °C; ½aꢁD ¼ þ0.3 (c 2.24, CHCl3);
IR (KBr), mmax: 3492, 3449, 2871, 1596, 1450, 1157,
1
1050, 834, 737, 697 cmꢀ1; H NMR (300 MHz, CDCl3): d
7.41–7.30 (m, 82H), 7.00–6.94 (m, 6H), 6.74–6.57 (m,

2530
W. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 2525–2530
46H), 5.12–4.89 (m, 60H), 4.26 (br s, 1H), 4.00 (br s, 1H),
found 3576; (S,S)-4e calcd for C124H116N2NaO16S,
2.26 (s, 3H) ppm; partial 13C NMR (75 MHz, CDCl3): d
160.2, 160.1, 160.0, 159.9, 139.2, 136.8, 128.6, 128.5, 128.0,
127.9, 127.8, 127.6, 127.1, 106.4, 101.6, 70.1, 70.0,
28.5 ppm. Element Analysis for C231H202N2O32S Calcd:
C, 77.65; H, 5.80; N, 0.77; S, 0.88. Found: C, 77.35; H,
5.70; N, 0.92; S 1.00.
[M+Na]+ (MALDI-TOF): 1943.8, found 1943.4; (S,S)-4f
calcd for C127H122N2NaO16S, [M+Na]+ (MALDI-TOF):
1985.8,
122H106N2NaO16S, [M+Na]+ (MALDI-TOF): 1909.7,
found 1909.0.
found
1985.2;
(S,S)-4g
calcd
for
C
20. General procedure: The catalyst (1 mol %) was prepared
in situ by mixing 2 equiv of triethylamine, a dendritic
ligand and [RuCl2(cymene)]2 (1.1:0.5 M ratio) in a solu-
tion of DCM (2 M related to acetophenone) for 1 h under
argon at 28 °C. Then acetophenone and formic acid–
triethylamine azeotrope (0.5 mL per mmol of ketone) were
added and stirred at 28 °C.
19. MS data for the dendritic ligands: (R,R)-4a calcd for
C35H35N2O4S, [M+H]+: 579.2318, found 579.2312; (R,R)-
4b calcd for C63H58N2NaO8S, [M+Na]+: 1025.5267,
found 1025.3811; (R,R)-4c calcd for C119H107N2O16S,
[M+H]+: 1851.7341, found 1851.7369; (R,R)-4d calcd for
C
231H202N2NaO32S, [M+Na]+ (MALDI-TOF): 3570.4,