Hybrid NH2-benzimidazole ligands for efficient Ru-catalyzed asymmetric hydrogenation of aryl ketones

Article abstract of DOI:10.1021/ol802766u

Readily available hybrid NH₂/benzimidazole ligands (R-bimaH, 1) dramatically influence the outcome of established Ru-based catalysts during asymmetric hydrogenation of aryl ketones. The benzimidazole functionality results in reversal of the typically observed chiral induction and allows for hydrogenation to be uncharacteristically conducted in nonprotic solvents. The developed systems efficiently catalyzed the AH of a number of ketones in up to 99% ee.

Full text of DOI:10.1021/ol802766u

ORGANIC
LETTERS
2009
Vol. 11, No. 4
907-910
Hybrid NH2-Benzimidazole Ligands for
Efficient Ru-Catalyzed Asymmetric
Hydrogenation of Aryl Ketones†
Yuehui Li, Kuiling Ding, and Christian A. Sandoval*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
sandoVal@mail.sioc.ac.cn
Received December 12, 2008
ABSTRACT
Readily available hybrid NH2/benzimidazole ligands (R-bimaH, 1) dramatically influence the outcome of established Ru-based catalysts during
asymmetric hydrogenation of aryl ketones. The benzimidazole functionality results in reversal of the typically observed chiral induction and
allows for hydrogenation to be uncharacteristically conducted in nonprotic solvents. The developed systems efficiently catalyzed the AH of
a number of ketones in up to 99% ee.
The nonbiological generation of chiral alcohols by asym-
metric hydrogenation (AH) of ketones has been best achieved
using transition-metal-based catalysts comprised of well-
designed chiral ligand(s).1 For AH of simple aryl ketones,
the utilization of trans-RuCl2(diphosphane)(1,2-diamine)
catalysts have yielded the most efficient systems to date,2
where the unique reactivity stems from the coorperative
action of the Ru-H and NH2 components operating through
a metal-ligand bifunctional mechanism.3-5 More recently,
this concept has been furthered by development of several
unsymmetrical hybrid amino-ligands for AH.6,7 Of present
relevance is the NH2/pyridine combination,7,8 where the
functional and structural characteristics of the hybrid ligand
are believed responsible for the high catalytic performance.
In this connection, we considered that integration of the
structurally related imidazole moiety would further influence
the catalysis by virtue of its unique acid/base properties, best
exemplified by the various functions of histidine during
(3) (a) Sandoval, C. A.; Ohkuma, T.; Mun˜iz, K.; Noyori, R. J. Am. Chem.
Soc. 2003, 125, 13490–13503. (b) Noyori, R.; Sandoval, C. A.; Mun˜iz, K.;
Ohkuma, T. Phil. Trans. R. Soc. A 2005, 363, 901–912. (c) Sandoval, C. A.;
Ohkuma, T.; Yamaguchi, Y.; Kato, K.; Noyori, R. Magn. Reson. Chem.
2006, 44, 66–75. (d) Sandoval, C. A.; Li, Y.; Ding, K.; Noyori, R. Chem.
† This work is dedicated to Professor Ryoji Noyori in honor of his 70th
birthday.
(1) (a) Ohkuma, T.; Noyori, R. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Chapter 6.1. (b) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter
1. (c) Transition Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm,
C., Eds.; Wiley-VCH: Weinheim, 2004; pp 29-113. (d) The Handbook of
Homogeneous Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-
VCH: Weinheim, 2007; Vol. 1-3.
Asian. J. 2008, 3, 1801–1810
.
(4) (a) Abdur-Rashid, K.; Clapham, S. E.; Hadzovic, A.; Harvey, J. N.;
Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2002, 124, 15104–15118.
(b) Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem. ReV. 2004,
248, 2201–2237. (c) Hamilton, R. J.; Leong, C. G.; Bigam, G.; Miskolzie,
M.; Bergens, S. H. J. Am. Chem. Soc. 2005, 127, 4152–4153. (d) Hems,
W. P.; Groarke, M.; Zanotti-Gerosa, A.; Grasa, G. A. Acc. Chem. Res. 2007,
(2) (a) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa,
M.; Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem.,
Int. Ed. 1998, 37, 1703–1707. (b) Noyori, R.; Ohkuma, T. Angew. Chem.,
Int. Ed. 2001, 40, 40–73.
40, 1340–1347.
(5) See also: (a) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc.
2000, 122, 1466–1478. (b) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J.
Org. Chem. 2001, 66, 7931–7944
.
10.1021/ol802766u CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society

R-R-1H-benzimidazole-2-methanamine [R-bimaH, 1], for
Ru-based aryl ketone AH.
Scheme 1. Asymmetric Hydrogenation of Aryl Ketones
Both the (S)- and (R)-configuration of 1 were readily
obtained from simple condensation of 1,2-diaminobenzene
with the corresponding amino acid via established methods.10
Trials using in situ generated catalysts derived from 1-3
and RuCl2[(S)-binap](dmf)n [(S)-4]11 or trans-RuCl2[(R,S)-
Josiphos](pyridine)2 [(R,S)-5]12 for AH of acetophenone (6a)
revealed that systems based on 1 uncharacteristically per-
formed well in both protic and nonprotic solvents (toluene,
Et2O, THF), Table 1.13,14 Previous reactivity in nonprotic
Catalyzed by in Situ Generated Ru Complexes (4,5/1) or
RuCl2[(R,S)-Josiphos)][(S)-Me-bimaH)] [(RS,S)-8] Complex
(Idealized Configuration Shown)
Table 1. Asymmetric Hydrogenation of Acetophenone (6a)
Catalyzed by in Situ Generated Catalysts Comprised of
RuCl2(binap)(dmf)n (4) or trans-RuCl2[(R,S)-Josiphos](pyridine)2
[(R,S)-5] and Hybrid Ligands (1-3)a
catalyst
components
time yield eeb (%)
entry complex ligand
additive
solvent (h) (%) (config)
1
2
3
4
5
6
7
8
9
(S)-4
(S)-4
(S)-4
(R)-4
(S)-4
(S)-4
(S)-4
1a
1a
(S)-1b
(R)-1b
(S)-1b
(S)-1c
(S)-1d
toluene
i-PrOH
toluene
toluene
i-PrOH
toluene 12 100 87 (S)
toluene 10 100 91 (S)
toluene
toluene
toluene
toluene
toluene
i-PrOH
8
8
8
8
8
100 77 (S)
100 25 (S)
100 91 (S)
100 91 (R)
100 28 (S)
(R,S)-5 1a
(R,S)-5 (S)-1b
P(C6H5)3
9
9
9
9
9
9
100 82 (S)
95 91 (S)
100 96 (S)
100 96 (S)
50 93 (S)
100 30 (R)
92 95 (R)
100 78 (S)
100 93 (S)
100 89 (S)
100 92 (S)
10 (R,S)-5 (S)-1b P(C6H5)3
11 (R,S)-5 (S)-1c P(C6H5)3
12 (R,S)-5 (S)-1d P(C6H5)3
13 (R,S)-5 (S)-2
14c (R,S)-5 (S)-3
i-PrOH 10
15 (R,S)-5 (S)-1b P(C6H5)3
16 (R,S)-5 (S)-1b P(C6H5)3
17 (R,S)-5 (S)-1b P(C6H5)3
18 (R,S)-5 (S)-1b P(C6H5)3
19 (R,S)-5 (S)-1b P(4-ClC6H4)3
i-PrOH
t-BuOH
THF
9
8
9
9
Et2O
toluene 12 100 90 (S)
20 (R,S)-5 (S)-1b P[3,5-(C6H5)2C6H3]3 toluene 12 100 82 (S)
21 (R,S)-5 (S)-1b P(CH2CH2CH2CH3)3 toluene 18 52 98 (S)
enzymatic processes and catalyzes.9 Accordingly, we herein
report the application of NH2/benzimidazole hybrid ligands,
a Hydrogenation conditions: [6a] ) 0.33 M, [4 or 5] ) 0.33 mM, [1, 2,
or 3] ) 0.33 mM, P(H2) ) 8 atm, [KO-t-C4H9] ) 20 mM, [additive] ) 1.0
mM (3 equiv), T ) 25 °C. b Enantiomeric excess (ee) determined by GC
analysis; absolute configuration (config) determined from [R]D measurement.
c P(H2) ) 2 atm, [NaO-t-C4H9] ) 20 mM.
(6) (a) Genov, D. G.; Ager, D. J. Angew. Chem., Int. Ed. 2004, 43, 2816–
2819. (b) Abdur-Rashid, K.; Guo, R.; Lough, A. J.; Morris, R. H.; Songa,
D. AdV. Synth. Catal. 2005, 347, 571–579. (c) Chen, W.; Mbafor, W.;
Roberts, S. M.; Whittall, J. Tetrahedron: Asymmetry 2006, 17, 1161–1164.
(d) Ohkuma, T.; Utsumi, N.; Watanabe, M.; Tsutsumi, K.; Arai, N.; Murata,
K. Org. Lett. 2007, 9, 2565–2567. (e) Arai, N.; Ooka, H.; Azuma, K.;
Yabuuchi, T.; Kurono, N.; Inoue, T.; Ohkuma, T. Org. Lett. 2007, 9, 939–
941. (f) Saudan, L. A.; Saudan, C. M.; Debieux, C.; Wyss, P. Angew. Chem.,
Int. Ed. 2007, 46, 7473–7476. (g) Clarke, M. L.; Diaz-Valenzuela, M. B.;
Slawin, A. M. Z. Organometallics 2007, 26, 16–19. (h) Ito, M.; Sakaguchi,
A.; Kobayashi, C.; Ikariya, T. J. Am. Chem. Soc. 2007, 129, 290–291. (i)
Dahlenburg, L.; Ku¨hnlein, C. Inorg. Chim. Acta 2008, 361, 2785–2791. (j)
Arai, N.; Azuma, K.; Nii, N.; Ohkuma, T. Angew. Chem., Int. Ed. 2008,
47, 7457–7460.
solvents for related systems has been limited to reactive
Ru-hydride complexes representative of the active
catalyst.4a,7b,c,15,16 Better catalytic performance was obtained
for homochiral combinations, (S)-4/(S)-1 and (R,S)-5/(S)-1,
noting that the latter generally gave higher enantiomeric
excess (ee) values for 7a. Only a small influence on
enantioselectivity was exerted by the R group in 1. In
addition, for (R,S)-5/(S)-1b systems, the optical purity of
product alcohol was largely influenced by phosphine addi-
tives (regardless of the solvent media). Thus, the obtained
ee for (S)-7a varied from 82-98% depending on the
phosphine additive used. Despite of the structural similarities
(7) (a) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.;
Mun˜iz, K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288–8289. (b) Abdur-
Rashid, K.; Abbel, R.; Hadzovic, A.; Lough, A. J.; Morris, R. H. Inorg.
Chem. 2005, 44, 2483–2492. (c) Hadzovic, A.; Song, D.; MacLaughlin,
C. M.; Morris, R. H. Organometallics 2007, 26, 5987–5999. (d) Arai, N.;
Suzuki, K.; Sugizaki, S.; Sorimachi, H.; Ohkuma, T. Angew. Chem., Int.
Ed. 2008, 47, 1770–1773. (e) Baratta, W.; Ballico, M.; Chelucci, G.; Siega,
K.; Rigo, P. Angew. Chem., Int. Ed. 2008, 47, 4362–4365.
(8) Isolated homochiral 5/3 complex has previously been developed by
Baratta and co-workers for efficient catalytic asymmetric transfer hydro-
genation of aryl ketones; see: (a) Baratta, W.; Chelucci, G.; Herdtweck,
E.; Magnolia, S.; Siega, K.; Rigo, P. Angew. Chem., Int. Ed. 2007, 46,
7651–7654. (b) Baratta, W.; Rigo, P. Eur. J. Inorg. Chem. 2008, 4041–
4053.
(9) Selected representative examples: (a) Lodi, P. J.; Knowles, J. R.
Biochemistry 1991, 30, 6948–6956. (b) Brenner, C. Biochemistry 2002, 41,
9003–9014. (c) Ishida, T.; Kato, S. J. Am. Chem. Soc. 2003, 125, 12035–
12048. (d) Ishida, T. Biochemistry 2006, 45, 5413–5420. (e) Scheiner, S.
J. Phys. Chem. B 2008, 112, 6837–6846.
908
Org. Lett., Vol. 11, No. 4, 2009

between 1 and 3, the observed sense of chiral induction for
corresponding catalysts was opposite! While hydrogenation
in i-PrOH using the (S)-phosphine/(S)-3 combination gave
the expected (R)-7a in 46% and 95% ee for (S)-4 and (S)-
5,8 respectively,17 the analogous (S)-phosphine/(S)-1b sys-
tems gave the opposite (S)-7a as the major isomer in 28 and
78% ee. In toluene solvent, the latter similarly induced the
(S)-configured alcohol in significantly higher ee, 91% for
(S)-4 and 91/96% (no PPh3/added PPh3) for (S)-5, while poor
performance was observed for (S)-phosphine/(S)-3 combina-
tions.14 For systems comprised of the methylated bimaH-
analogue 2, the reactivity and sense of chiral induction
resembled the (S)-5/(S)-3 combination, although (R)-7a was
obtained in poor ee. Thus, although the reasons for the
dramatic change in prochiral face discrimination are not clear
at present, they are considered to originate from the added
functionality provided by the benzimidazole moiety in 1.
The air-stable isolated precatalyst (RS,S)-8 was readily
synthesized by simply mixing (S)-Me-bimaH (1b) and an
appropriate Ru-Josiphos precursor (e.g., 5) at elevated
temperature (100 °C).14 The 31P NMR spectrum in DMSO-
d6 indicated the presence of several isomers, predominantly
exhibiting two sets of resonances at δ 65.1 and 41.3 ppm
(2JP,P ) 41.0 Hz) and δ 72.3 and 41.0 ppm (2JP,P ) 44.0
Hz).14 The AH of 6a proceeded smoothly when catalyzed
by (RS,S)-8 (conditions: [8] ) 0.33 mM, [6a] ) 0.33 M,
P(H2) ) 8 atm, [KO-t-C4H9] ) 20 mM, [PPh3] ) 1.0 mM,
toluene solvent), giving (S)-7a in the same 96% ee (cf. Table
1, entry 10). Under analogous conditions, the hydrogenation
rate expectedly increased with increasing pressure giving 4,
51, 95, and 100% conversion after 1 h at 2, 4, 8, and 16
atm, respectively. Importantly, however, the chiral induction
was independent of pressure within this range, with (S)-7a
obtained in the same 96% ee (>80% conv). Hydrogenation
proceeded efficiently throughout the [K-O-t-C4H9] range of
15-50 mM (t ) 1 h, 95-96% ee, toluene solvent), while
reduced reactivity was found at lower (5 mM, <5% conv, t
) 1 h) or higher (100 mM, 57% conv, t ) 1 h, 87% ee)
base concentrations. Reaction in i-PrOH or t-BuOH pro-
ceeded considerably faster with complete conversion in under
1 h above 2 atm. For unknown reasons, reaction in methanol
and ethanol was inferior (<5% conv), although the system
was not sensitive to small amounts of water.14
Table 2. Asymmetric Hydrogenation of Simple Aryl Ketones (6,
9-11) Catalyzed by RuCl2[(R,S)-Josiphos)][(S)-Me-bimaH)]
[(RS,S)-8] Complexa
S/C
ratio
P/H2
(atm)
time
(h)
yieldb
(%)
eeb,c
(%)
entry
sub
1
6a
6a
6a
6b
6c
6d
6e
9
1000
10000
50000
5000
5000
5000
5000
5000
1000
1000
8
20
40
20
20
20
20
20
8
2
12
10
16
8
8
6
24
12
12
100
100
100
95
96 (S)
96 (S)
97 (S)
97 (S)
82 (S)
95 (S)
92 (S)
99 (R)
94 (S)
97 (S)
2
3d
4
5
6
90
100
100
95
92
100
7
8e
9
10
11
10
8
a Hydrogenation conditions: [6, 9-11] ) 0.3-1.9 M, [(RS,S)-8] )
0.04-0.3 mM, [KO-t-C4H9] ) 15-20 mM, [PPh3] ) 1.0-3.4 mM, T )
25 °C, solvent ) toluene/t-BuOH (9/1). b Determined by GC. c Determined
from [R]D. d Toluene/t-BuOH (7/3). e Yield determined by 1H NMR; ee
determined by HPLC.
Table 2describes the AH of a number of aryl ketones
catalyzed by (RS,S)-8 using a toluene/t-BuOH (9/1) solvent
mixture. For the simple 6a, the hydrogenation proceeded
efficiently even at an S/C (substrate-to-catalyst) ratio of
50000 giving (S)-7a in 97% ee. Ring substitution influenced
the enantioselectivity. Most notably, alcohol (S)-7c was
obtained in only moderate ee (82%), with others ranging from
92-96%. Significantly, AH of biaryl ketone 9 (although less
reactive) proceeded with excellent enantioselectivity giving
alcohol product in 99% ee. Heteroaromatic 10 (94% ee) and
11 (97% ee) were considerably less reactive.
Reaction profiles for AH of 6a showed that addition of
PPh3 influences the general performance of (RS,S)-8 in terms
of both reactivity and selectivity, Figure 1. In toluene solvent,
(10) (a) Aminabhavi, T. M.; Biradar, N. S.; Patil, S. B. Inorg. Chim.
Acta 1986, 125, 125–128. (b) Balboni, G.; Guerrini, R.; Salvadori, S.;
Bianchi, C.; Rizzi, D.; Bryant, S. D.; Lazarus, L. H. J. Med. Chem. 2002,
45, 713–720.
(11) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth.
1993, 71, 1–13, BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.
(12) Akotsi, O. M.; Metera, K.; Reid, R. D.; McDonald, R.; Bergens,
S. H. Chirality 2000, 12, 514-522. JOSIPHOS ) 1-(diarylphosphano)-2-
[1-(dicyclohexylphosphano)ethyl]ferrocene.
(13) For use of histidine, see: Sui-Seng, C.; Hadzovic, A.; Lough, A. J.;
Morris, R. H. Dalton Trans. 2007, 2536–2541.
(14) See the Supporting Information for (additional) data/results.
(15) (a) Hamilton, R. J.; Leong, C. G.; Bigam, G.; Miskolzie, M.;
Bergens, S. H. J. Am. Chem. Soc. 2005, 127, 4152–4153. (b) Abbel, R.;
Abdur-Rashid, K.; Faatz, M.; Hadzovic, A.; Lough, A. J.; Morris, R. H.
J. Am. Chem. Soc. 2005, 127, 1870–1882. (c) Hamilton, R. J.; Bergens,
S. H. J. Am. Chem. Soc. 2006, 128, 13700–13701. (d) Hamilton, R. J.;
Bergens, S. H. J. Am. Chem. Soc. 2008, 130, 11979–11987.
(16) For AH of simple ketones in toluene, see: Naud, F.; Malan, C.;
Spindler, F.; Ru¨ggeberg, C.; Schmidt, A. T.; Blaser, H.-U. AdV. Synth. Catal.
2006, 348, 47–50.
Figure 1. Reaction profiles for the asymmetric hydrogenation of
acetopheneone (6a) catalyzed by RuCl2[(R,S)-Josiphos)][(S)-Me-
bimaH)] [(RS,S)-8] complex. Conditions: [(RS,S)-8] ) 0.33 mM;
[6a] ) 0.33 M; P(H2) ) 4 atm; [KO-t-C4H9] ) 15.0 mM; [PPh3]
) 0 or 1.0 mM.
(17) Similarly, use of related (S)-4/(S)-1,2-diamine2b and (R,S)-5/(S)-
1,2-diamine ( Leong, C. G.; Akotsi, O. M.; Ferguson, M. J.; Bergens, S. H.
Chem. Commun. 2003, 750-751) catalysts give (R)-7a.
the presence of PPh3 resulted in overall enhanced reactivity
and a small (but consistent) increase in (S)-7a ee (91-96%).
Org. Lett., Vol. 11, No. 4, 2009
909

In t-BuOH, overall AH rates were similar but the increase
in ee for (S)-7a was more pronounced (73-93%). No further
improvements were observed for higher [PPh3].14 Accord-
ingly, we consider the predominantly active catalyst (solvent
independent) to be coordinatively saturated monohydride
species RuH[(R,S)-Josiphos)][(S)-Me-bima)](PPh3). In non-
protic solvent, AH most likely proceeds through intramo-
lecular H2 heterolytic cleavage,3-5,7b,15b-d,19 while in alco-
holic solvents the available protons allow for other more
kinetically favorable pathways.3,15c,d,20 The highly acidic
nature (particularly upon metal coordination) of 1 is critical,
assisting precatalyst activation in nonprotic solvents, and
providing an anionic-chelate during hydrogenation which
allows for (neutral) PPh3 coordination. Furthermore, the
enhanced basic strength of the amino moiety largely facili-
tates the intramolecular cleavage of H2.
developed. Resulting systems show unique enantioselection
properties giving product alcohol in up to 99% ee and high
reactivity in protic and nonprotic solvents (up to S/C )
50000) and display potential for further combinatorial
development. The origin of such significant features lies in
the added functionality provided by the benzimidazole moiety
in 1. Further work is now in progress to develop the practical
aspects of these systems and to further understand the nature
of the catalysis.
Acknowledgment. This work was supported by the
Chinese Academy of Sciences (No. O7210122R0) and the
National Natural Science Foundation (No. 20620140429).
Enantiotech Corporation Ltd. is acknowledged for financial
support.
Supporting Information Available: Synthetic and hy-
drogenation procedures; hydrogenation data and spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, efficient ketone asymmetric hydrogenation
catalysts based on Ru-complexes utilizing readily available
hybrid NH2/benzimidazole bimaH (1), and C1- (JOSIPHOS)
or C2-symmetric (BINAP) diphosphane ligands have been
OL802766U
(18) Similarly, 28% (no PPh3) and 78% ([PPh3] ) 1 mM) ee are obtained
in i-PrOH solvent.
(19) (a) Rautenstrauch, V.; Hong-Cong, X.; Churlaud, R.; Abdur-Rashid,
K.; Morris, R. H. Chem.sEur. J. 2003, 9, 4954–4967. (b) Di Tommaso,
D.; French, S. A.; Catlow, C. R. A. THEOCHEM 2007, 812, 39–49. (c)
Leyssens, T.; Peeters, D.; Harvey, J. N. Organometallics 2008, 27, 1514–
1523.
(20) (a) Ito, M.; Hirakawa, M.; Murata, K.; Ikariya, T. Organometallics
2001, 20, 379–381. (b) Hartmann, R.; Chen, P. Angew. Chem., Int. Ed.
2001, 40, 3581–3585. (c) Hartmann, R.; Chen, P. AdV. Synth. Catal. 2003,
345, 1353–1359. (d) Hedberg, C.; Ka¨llstro¨m, K.; Arvidsson, P. I.; Brandt,
P.; Andersson, P. G. J. Am. Chem. Soc. 2005, 127, 15083–15090.
910
Org. Lett., Vol. 11, No. 4, 2009