Asymmetric hydrogenation of heteroaromatic compounds mediated by iridium-(P-OP) complexes

Article abstract of DOI:10.1021/om100955t

A library of modular iridium complexes derived from P-OP ligands has been evaluated in iridium-mediated asymmetric hydrogenations of heteroaromatic compounds. The "lead" catalysts efficiently catalyzed the hydrogenation of several substituted quinolines and one quinoxaline (10 examples, up to 92% ee).

Full text of DOI:10.1021/om100955t

Organometallics 2010, 29, 6627–6631 6627
DOI: 10.1021/om100955t
Asymmetric Hydrogenation of Heteroaromatic Compounds Mediated
by Iridium-(P-OP) Complexes
†
†
†
Jos ꢀe L. N uꢀ n~ ez-Rico, H ꢀe ctor Fern ꢀa ndez-P ꢀe rez, J. Benet-Buchholz, and
Anton Vidal-Ferran*
,
†,‡
†
Institute of Chemical Research of Catalonia (ICIQ), Avgda. Paı¨sos Catalans 16, 43007 Tarragona, Spain,
and Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluı´s Companys 23,
‡
0
8010 Barcelona, Spain
Received October 1, 2010
8
phosphinites) for Pd-mediated allylic substitution and for
Rh-mediated asymmetric hydrogenation of functionalized
Summary: A library of modular iridium complexes derived from
P-OP ligands has been evaluated in iridium-mediated asymmetric
hydrogenations of heteroaromatic compounds. The “lead” cata-
lysts efficiently catalyzed the hydrogenation of several substi-
tuted quinolines and one quinoxaline (10 examples, up to 92% ee).
9
CdC bonds. Having found that literature precedent on the
use of P-OP ligands in the Ir-catalyzed hydrogenation of CdN
bonds was very limited, we felt that studying their applica-
tion in this transformation was the next logical step in as-
1
0
sessing their utility in asymmetric catalysis. We envisioned
that modular ligand design should enable catalyst optimiza-
tion via systematic variation of the catalytic system compo-
nents (R and G, Figure 1). Herein, we report synthesis of the
structurally diverse Ir-(P-OP) complexes 1 and subsequent
evaluation of them as catalysts for asymmetric hydrogena-
tion of CdN bonds.
Our initial set of precatalysts comprised Ir(I) complexes
with the general formula 1 that contain phosphine-phos-
phinite (2) or phosphine-phosphite (3) ligands, which we chose
in order to evaluate the effect of sterically and/or electronically
diverse phosphorus functionalities on the catalytic perfor-
mance of their corresponding iridium(I) complexes.
Before running any catalytic assays, we first evaluated the
ability of our bidentate P-OP ligands to form stable, well-
defined iridium(I) complexes, which could be used as pre-
catalysts in CdN hydrogenations. Complexation studies of
Chiral amines and N-containing compounds are key syn-
thetic intermediates for many biologically and physiologically
1
active products. Asymmetric hydrogenation of CdN-con-
2
3
taining functional groups (e.g., imines, CdN-X com-
4
5-7
pounds, and heteroaromatic compounds ) is one of the most
important methodologies for stereoselective formation of
C-N single bonds, enabling construction of diverse carbon
frameworks for both natural and non-natural products.
We recently reported the preparation of a library of highly
modular P-OP ligands (phosphine-phosphites and phosphine-
*To whom correspondence should be addressed. E-mail: avidal@
iciq.es.
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(
2
2
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2
(
3
j-l
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
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However, to the best of
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(
3) See, for example, ref 2 and: (a) Fache, F.; Schulz, E.; Tommasino,
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(
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Adv. Synth. Catal. 2003, 345, 103. (g) Tang, W.; Zhang, X. Chem. Rev.
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1
1
003, 103, 3029. (h) Di ꢀe guez, M.; P ꢁa mies, O.; Claver, C. Chem. Rev. 2004,
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(
(
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5
(
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r 2010 American Chemical Society
Published on Web 12/01/2010
pubs.acs.org/Organometallics

6
628 Organometallics, Vol. 29, No. 24, 2010
N uꢀ n~ ez-Rico et al.
þ
Scheme 1. Preparation of [Ir(cod)(P-OP)] Complexes Derived
from Phosphine-Phosphinites
phosphine-phosphinites 2a,b were prepared in good yields
by reacting stoichiometric amounts of phosphine-phosphinites
3
1
1
2
a,b with [{Ir(μ-Cl)(cod)} ] in DCM (Scheme 1). The P{ H}-
2
NMR spectrum of the reaction mixtures revealed that
complexation had been very clean, showing disappearance
of the P-OP signals and formation of one doublet for the
3
1
31
phosphinite group arising from P- P couplings (for ex-
ample, for the complex derived from ligand 2a: 92.0 ppm, J=
Figure 1. General structure of the Ir-(P-OP) complexes (top)
and initial set of P-OP ligands (bottom).
44.2 Hz) and another doublet for the phosphine moiety (for
example, for the complex derived from ligand 2a: 14.0 ppm, J=
1
1
44.2 Hz), as expected for a 1/1 Ir/ligand complex.
our knowledge, no examples of iridium complexes derived
from enantiomerically pure phosphine-phosphinites have
been reported to date. Neutral complexes derived from our
-
Iridium complexes containing BArF (BArF=[B((3,5-
-
(CF ) )C H ) ] ) have been reported as usually being more
3
2
6
3 4
stable toward moisture and catalyst deactivation during hydro-
1
2
genation than iridium complexes containing other ligands
(6) For asymmetric hydrogenations of isoquinolines, see, for example:
a) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int.
Ed. 2006, 45, 2260. For asymmetric hydrogenations of quinoxalines, see, for
example: (b) Murata, S.; Sugimoto, T.; Matsuura, S. Heterocycles 1987, 26,
-
-
-
(
(e.g., Cl ). Exchange of Cl by BArF was attempted by add-
ing stoichiometric amounts of NaBArF. Precipitation of NaCl
in the reaction media (DCM) indicated that the exchange had
occurred, and after filtration of the generated salts, followed by
chromatographic purification, cationic iridium complexes 4a,b
were obtained as highly pure red solids (Scheme 1).
7
63. (c) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M.
Organometallics 1998, 17, 3308. (d) Bianchini, C.; Barbaro, P.; Scapacci, G.
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Herzberg, D.; Peterson, J. A.; Wildsmith, A. J.; Cobley, C. J.; Casy, G. Adv.
Synth. Catal. 2003, 345, 300. (g) Mrsic, N.; Jerphagnon, T.; Minnaard, A. J.;
Feringa, B. L.; de Vries, J. G. Adv. Synth. Catal. 2009, 351, 2549.
The complexation of [{Ir(μ-Cl)(cod)} ] and phosphine-
2
phosphite 3 was similar to that for 2a,b and to that reported
3k
(
h) Cartigny, D.; Nagano, T.; Ayad, T.; Genet, J.-P.; Ohshima, T.; Mashima, K.;
by Pizzano et al. for other phosphine-phosphites. Stoichio-
metric amounts of the iridium precursor and 3 in THF gave a
Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2010, 352, 1886. For asymmetric
hydrogenations of quinolines, see, for example, ref 5a and: (i) Yang, P.-Y.; Zhou,
Y.-G. Tetrahedron: Asymmetry 2004, 15, 1145. (j) Lu, S.-M.; Han, X.-W.; Zhou,
Y.-G. Adv. Synth. Catal. 2004, 346, 909. (k) Xu, L.; Lam, K. H.; Ji, J.; Wu, J.;
Fan, Q.-H.; Lo, W.-H.; Chan, A. S. C. Chem. Commun. 2005, 1390. (l) Lam,
K. H.; Xu, L.; Feng, L.; Fan, Q.-H.; Lam, F. L.; Lo, W.-h.; Chan, A. S. C. Adv.
Synth. Catal. 2005, 347, 1755. (m) Qiu, L.; Kwong, F. Y.; Wu, J.; Lam, W. H.;
Chan, S.; Yu, W. Y.; Li, Y. M.; Guo, R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem.
Soc. 2006, 128, 5955. (n) Reetz, M. T.; Li, X. Chem. Commun. 2006, 2159.
31
1
very clean reaction, as indicated by P{ H} NMR, which showed
one sharp doublet for the phosphite group and another doublet
for the phosphine moiety, thus indicating the formation of a
1
1
1/1 Ir/ligand complex. Attempts to isolate these complexes
were unsuccessful. We hypothesized that the neutral complex 5
13
is the complexation product (Scheme 2). This compound
(
o) Tang, W.-J.; Zhu, S.-F.; Xu, L.-J.; Zhou, Q.-L.; Fan, Q.-H.; Zhou, H.-F.; Lam,
was subjected to ligand exchange (chloride to iodide) by re-
action with excess lithium iodide. The corresponding iodo
complex 6 was isolated in good yield (48% overall yield from
the phosphine-phosphite 3). Crystals of 6 suitable for X-ray
K.; Chan, A. S. C. Chem. Commun. 2007, 613. (p) Wang, Z.-J.; Deng, G.-J.; Li,
Y.; He, Y.-M.; Tang, W.-J.; Fan, Q.-H. Org. Lett. 2007, 9, 1243. (q) Chan, S. H.;
Lam, K. H.;Li, Y.-M.;Xu, L.;Tang, W.;Lam, F. L.;Lo, W. H.;Yu, W. Y.;Fan, Q.;
Chan, A. S. C. Tetrahedron: Asymmetry 2007, 18, 2625. (r) Deport, C.;
Buchotte, M.; Abecassis, K.; Tadaoka, H.; Ayad, T.; Ohshima, T.; Genet,
J.-P.; Mashima, K.; Ratovelomanana-Vidal, V. Synlett 2007, 2743. (s) Lu, S.-M.;
Han, X.-W.; Zhou, Y.-G. J. Organomet. Chem. 2007, 692, 3065. (t) Mrsic, N.;
Lefort, L.; Boogers, J. A. F.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Adv.
Synth. Catal. 2008, 350, 1081. (u) Lu, S.-M.; Bolm, C. Adv. Synth. Catal. 2008,
analysis could be grown in a DCM/Et O mixture; using this
2
technique, coordination of the iodo ligand to the iridium center
3
50, 1101. (v) Wang, X.-B.; Zhou, Y.-G. J. Org. Chem. 2008, 73, 5640.
(8) Panossian, A.; Fern ꢀa ndez-P ꢀe rez, H.; Popa, D.; Vidal-Ferran, A.
Tetrahedron: Asymmetry 2010, 21, 2281.
(7) For more examples on asymmetric hydrogenations of quinolines,
see, for example: (a) Zhou, H.; Li, Z.; Wang, Z.; Wang, T.; Xu, L.; He, Y.;
Fan, Q.-H.; Pan, J.;Gu, L.; Chan, A. S. C. Angew. Chem., Int. Ed. 2008, 47,
(9) (a) Fern ꢀa ndez-P ꢀe rez, H.; Peric ꢁa s, M. A.; Vidal-Ferran, A. Adv.
Synth. Catal. 2008, 350, 1984. (b) Donald, S. M. A.; Vidal-Ferran, A.;
Maseras, F. Can. J. Chem. 2009, 87, 1273. (c) Fern ꢀa ndez-P ꢀe rez, H.; Donald,
S. M. A.; Munslow, I. J.; Benet-Buchholz, J.; Maseras, F.; Vidal-Ferran, A.
Chem. Eur. J. 2010, 18, 6495. (d) Fern ꢀa ndez-P ꢀe rez, H.; Etayo, P.; N ꢀu ~n ez-
Rico, J. L.; Vidal-Ferran, A. Chim. Oggi 2010, 28, XXVI.
8
464. (b) Li, Z.-W.; Wang, T.-L.; He, Y.-M.; Wang, Z.-J.; Fan, Q.-H.; Pan, J.;
Xu, L.-J. Org. Lett. 2008, 10, 5265. (c) Wang, D.-W.; Wang, X.-B.; Wang, D.-
S.; Lu, S.-M.; Zhou, Y.-G.; Li, Y.-X. J. Org. Chem. 2009, 74, 2780.
(d) Eggenstein, M.; Thomas, A.; Theuerkauf, J.; Franci, G.; Leitner, W. Adv.
Synth. Catal. 2009, 351, 725. (e) Tadaoka, H.; Cartigny, D.; Nagano, T.;
Gosavi, T.; Ayad, T.; Gen ^e t, J.-P.; Ohshima, T.; Ratovelomanana-Vidal, V.;
Mashima, K. Chem. Eur. J. 2009, 15, 9990. (f) Wang, Z.-J.; Zhou, H.-F.; Wang,
T.-L.; He, Y.-M.; Fan, Q.-H. Green Chem. 2009, 11, 767. (g) Tang, W.-J.; Tan,
J.; Xu, L.-J.; Lam, K.-H.; Fan, Q.-H.; Chan, A. S. C. Adv. Synth. Catal. 2010,
(10) For examples of asymmetric hydrogenation of imines involving
P-OP ligands, see refs 3j-3l; however, examples on the use of P-OP
ligands in the asymmetric hydrogenation of heteroaromatic compounds
are scarce (Rubio, M.; Pizzano, A. Molecules 2010, 15, 7732).
(11) See the Supporting Information for full details.
(12) See for example: (a) Lightfoot, A.; Schnider, P.; Pfaltz, A.
Angew. Chem., Int. Ed. 1998, 37, 2897. (b) Pfaltz, A.; Blankenstein, J.;
Hilgraf, R.; Hormann, E.; McIntyre, S.; Menges, F.; Schonleber, M.; Smidt,
S. P.; Wustenberg, B.; Zimmermann, N. Adv. Synth. Catal. 2003, 345, 33.
(13) This assumption was made on the basis of the coincidental NMR
data (see the Supporting Information for details) for 5 and for 6 (whose
structure was unequivocally elucidated by X-ray analysis).
352, 1055. (h) Wang, D.-S.; Zhou, J.; Wang, D.-W.; Guo, Y.-L.; Zhou, Y.-G.
Tetrahedron Lett. 2010, 51, 525. (i) Wang, D.-W.; Wang, D.-S.; Chen, Q.-A.;
Zhou, Y.-G. Chem. Eur. J. 2010, 16, 1133. (j) Tang, W.; Sun, Y.; Xu, L.; Wang, T.;
Fan, Q.; Lam, K.-H.; Chan, A. S. C. Org. Biomol. Chem. 2010, 8, 3464. (k)
Parekh, V.; Ramsden, J. A.; Wills, M. Tetrahedron: Asymmetry 2010, 21, 1549.
(l) Wang, D.-S.; Zhou, Y.-G. Tetrahedron Lett. 2010, 51, 3014. (m) Gou, F.-R.;
Wei, L.; Zhang, Z.; Liang, Y.-M. Adv. Synth. Catal. 2010, 352, 2441.

Communication
Organometallics, Vol. 29, No. 24, 2010 6629
Scheme 2. Preparation of Iridium Complexes Derived from Phosphine-Phosphites
Figure 3. P-OP Ligands with configurationally stable biaryl
moieties at the phosphite group.
Scheme 3. Asymmetric Hydrogenation of Two Model
Substrates: N-(1-Phenylethylidene)aniline (7) and
2
-Methylquinoline (9a)
˚
Figure 2. ORTEP view of 6. Selected bond lengths (A) and
angles (deg): Ir-P(1) = 2.3194(6), Ir-P(2) = 2.2283(7), Ir-
C(21) = 2.178(3), Ir-C(22) = 2.168(3), Ir-C(25) = 2.258(3),
Ir-C(26)=2.234(2), Ir-I=2.8132(3); P(2)-Ir-P(1)=86.99(2),
P(1)-Ir-C(21) = 94.51(7), P(1)-Ir-C(22) = 85.54(7), P(2)-
Ir-C(26)=100.62(8), P(2)-Ir-C(25)=87.08(8), P(1)-Ir-I=
0
.5 mol % of [{Ir(μ-Cl)(cod)} ] and 1.1 mol % of the P-OP
9
0.80(2), P(2)-Ir-I=98.57(2).
2
ligand (Scheme 3).
was determined. Figure 2 shows an ORTEP diagram of this
complex, along with selected bond distances and angles. The
complex 6 displays distorted-square-pyramidal coordination
geometry, with the iodo ligand located in the apical position.
Furthermore, this ligand forms two roughly right I-Ir-Pangles
with the phospino group and phosphite unit (90.8 and 98.6°,
respectively). The angles between the mutually cis ligands in
the base of the pyramid range from 85.5 to 100.6°. As previ-
The enantioselectivities obtained with the two substrates were
low (see Table 1 in the Supporting Information), regardless of
the ligand type (i.e., phosphine-phosphite or phosphine-
phosphinite), the nature of the iridium precursor (cationic
(4a) or neutral (5 and 6)), or the reaction conditions. How-
ever, the high conversions encouraged us to continue opti-
mizing the ligand and to consider the phosphine-phosphites
11a-d, which feature configurationally stable biaryl moi-
eties at the phosphite group and substituents of varying size
at the R-oxy position (Figure 3). The preparation of ligands
3
k
ously observed by other groups for related complexes, the
˚
Ir-P(phosphite) distance (2.228 A) is appreciably shorter
˚
9
than the Ir-P(phosphine) distance (2.319 A). The greater
11a,c has already been reported by us. Ligands 11b,d are
π-acceptor character of the phosphite is also reflected in the
Ir-C bond values of 6, with longer bonds for the olefinic car-
bons trans to phosphine (C(25) and C(26)) than for those
trans to the phosphite (C(21) and C(22); mean difference in
distance 0.07 A).
With a synthetic methodology for the preparation of [Ir-
reported for the first time here and were readily synthesized
using our standard route of epoxide ring opening followed by
O-phosphorylation (see the Supporting Information for
8
,9
details).
˚
Although all the iridium complexes gave good conversions
in the reduction of 7 and 9a (in MeOH and THF), the enan-
tioselectivities varied greatly (see Table 1). The iridium pre-
(cod)(P-OP)]Xor[Ir(X)(cod)(P-OP)] complexes, we began eval-
uating their activity and selectivity in iridium-mediated asym-
metric hydrogenations of CdN bonds. In the first set of
experiments, we examined their use in the reduction of
N-(1-phenylethylidene)aniline (7) and 2-methylquinoline (9a).
Hydrogenations were performed using either preformed
iridium precatalysts or in situ generated complexes from
catalysts that contain the phosphites derived from (S )- and
a
(R )-BINOL (11a,c, respectively) provided only moderate
a
selectivities in the reduction of 7 (entries 1 and 2 in Table 1).
However, these same iridium complexes and those featuring
the same phosphite moieties as well as a trityl group at the
R-oxy position (11b,d) gave high enantioselectivities in the

6
630 Organometallics, Vol. 29, No. 24, 2010
N uꢀ n~ ez-Rico et al.
a
Table 1. Asymmetric Hydrogenation of CdN Bonds Mediated by Iridium Complexes of Ligands 11a-d
b
c
ee (%) (confign)
d
entry
ligand
substrate
solvent
pressure (bar)
conversn (%)
e
1
2
3
4
5
6
7
8
9
11a
11c
7
7
MeOH
MeOH
THF
toluene
THF
toluene
THF
toluene
THF
toluene
50
50
80
80
80
80
80
80
80
80
>99
>99
69
19
75
44
87
53
64
39 (R)
29 (S)
62 (R)
68 (R)
70 (R)
76 (R)
83 (S)
86 (S)
79 (S)
90 (S)
e
11a
11a
11b
11b
11c
11c
11d
11d
9a
9a
9a
9a
9a
9a
9a
9a
10
16
a
All reactions were run with the iridium precatalyst generated in situ using a substrate/ligand/Ir precursor ratio of 100/1.1/0.5, at room temperature
for 20 h, unless otherwise cited. Conversion was determined by H NMR. Enantiomeric excess was determined by HPLC. The absolute configuration
b
1
c
d
e
was assigned by comparison with published data. A substrate/ligand/Ir precursor ratio of 100/2.2/1 was used.
Table 2. Effects of the Temperature, Solvent, Catalyst Loading, and Additive in the Asymmetric Hydrogenation of 9a Mediated by Iridium
Complexes Containing Ligands 11c,d
a
b
c
ee (%) (confign)
d
entry
reacn conditions
solvent
conversn (%)
1
2
3
4
5
6
7
8
9
ligand 11c, 1 mol % precatalyst, 10 mol % HCl, room temp, 20 h
ligand 11c, 1 mol % precatalyst, 10 mol % HCl, 0 °C, 20 h
ligand 11c, 0.2 mol % precatalyst, 10 mol % HCl, 40 °C, 20 h
ligand 11c, 1 mol % precatalyst, 10 mol % HCl, room temp, 20 h
ligand 11c, 1 mol % precatalyst, 10 mol % HCl, room temp, 65 h
ligand 11c, 0.5 mol % precatalyst, 10 mol % HCl, 40 °C, 20 h
ligand 11d, 1 mol % precatalyst, 10 mol % HCl, room temp, 20 h
ligand 11d, 1 mol % precatalyst, 10 mol % HCl, room temp, 20 h
ligand 11d, 1 mol % precatalyst, 10 mol % HCl, room temp, 65 h
THF
THF
THF
toluene
toluene
toluene
THF
>99
11
>99
63
>99
90
98
47
85
84 (S)
83 (S)
82 (S)
90 (S)
91 (S)
89 (S)
85 (S)
93 (S)
93 (S)
toluene
toluene
a
All reactions were run with the iridium precatalyst generated in situ using a substrate/ligand/Ir precursor ratio of 100/1.1/0.5 and under 80 bar of H
2
b
1
c
d
unless otherwise stated. Conversion was determined by H NMR. Enantiomeric excess was determined by HPLC. The absolute configuration was
assigned by comparison with published data.
reduction of heteroaromatic compound 9a in THF (62-83% ee;
entries 3, 5, 7, and 9 in Table 1). Furthermore, better enan-
tioselectivities were obtained for the same precatalysts in
toluene than in THF (compare entries 3, 5, 7, and 9 with 4, 6,
and 10a were obtained with (S )-BINOL-containing ligands
a
(11a,b) and (R )-BINOL-containing ligands (11c,d).
a
1
5
Several authors have reported that additives can im-
prove catalytic activity. Thus, we explored several additives
in the reduction of 9a catalyzed by an iridium complex of one
of our highest performing ligands (11c). We used 10 mol %
8
versions. Finally, we did not observe any clear relationship
, and 10 in Table 1), although at the expense of lower con-
1
4
15a
15b
15c
between enantioselectivity and the size of the R-oxy group.
In previous work on rhodium-mediated hydrogenations, we
(relative to 9a) of NBS, iodine, methanol, TFA, p-tol-
15c
15c
uenesulfonic acid, triflic acid or (þ)- or (-)-camphorsul-
9
15d
fonic acid. However, none of these provided any noticeable
improvement in conversion or in enantioselectivity. Remark-
observed that as the size of the ligand’s R group increased,
the enantioselectivity slightly decreased. In the iridium-
catalyzed hydrogenation of CdN bonds, the same trend is
observed in THF when switching from methyl to trityl in the
16
ably, addition of 10 mol % of anhydrous HCl afforded com-
plete conversion in the hydrogenation of 9a in THF with
iridium complexes derived from ligands that incorporate the
(
R )-BINOL-containing ligands 11c,d (enantioselectivity
a
dropped from 83% ee to 79% ee; entries 7 and 9 in Table 1,
respectively). In contrast, the enantioselectivity increased, in
THF or toluene as solvent, when changing from methyl to
(R )-BINOLfragment(forligand11c, compare entry 1 in Table 2
a
with entry 7 in Table 1; for ligand 11d, compare entry 7 in Table 2
with entry 9 in Table 1). Better conversions and enantio-
selectivities (entries 5 and 9 in Table 2) were achieved with
toluene, although this required longer reaction times (65 h).
We sought to further increase the enantioselectivity by reducing
the temperature, but this strategy turned out to be ineffective, as
it led to dramatically lower conversion (entry 2 in Table 2). We
were able to use a lower catalyst loading with almost no loss in
catalytic activity: down to 0.2 mol % in THF (entry 3 in Table 2)
and to 0.5 mol % in toluene (entry 6 in Table 2).
trityl in the (S )-BINOL-containing ligands 11a,b (compare
a
entry 3 with 5 and entry 4 with 6 in Table 1). Interestingly, the
binaphthyl moiety strongly influences the stereochemical out-
come of the reaction: an opposite configuration of products 8
(14) The steric environment at this position has proven critical to
the catalytic activity of other chiral ligands derived from Sharpless
epoxy alcohols, in several asymmetric transformations. See, for example:
(
a) Vidal-Ferran, A.; Moyano, A.; Peric ꢁa s, M. A.; Riera, A. J. Org.
Chem. 1997, 62, 4970. (b) Vidal-Ferran, A.; Moyano, A.; Peric ꢁa s, M. A.;
Riera, A. Tetrahedron Lett. 1997, 38, 8773. (c) Vidal-Ferran, A.; Bampos,
N.; Moyano, A.; Peric ꢁa s, M. A.; Riera, A.; Sanders, J. K. M. J. Org. Chem.
(15) For a general reference on additive effects, see: Vogl, E. M.;
Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570. For
details on specific additives, see: (a) References 6u and 7c, for NBS.
(b) Reference 5a, for iodine. (c) Reference 7b, for TFA and p-toluenesulfonic
and triflic acids. (d) Reference 5t, for camphorsulfonic acids.
1
998, 63, 6309. (d) Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Peric ꢁa s,
M. A.; Riera, A. J. Org. Chem. 1999, 64, 7902. (e) Peric ꢁa s, M. A.; Puigjaner,
C.; Riera, A.; Vidal-Ferran, A.; G ꢀo mez, M.; Jim ꢀe nez, F.; Muller, G.;
Rocamora, M. Chem. Eur. J. 2002, 8, 4164. (f) Jimeno, C.; Vidal-Ferran,
A.; Pericas, M. A. Org. Lett. 2006, 8, 3895. (g) Popa, D.; Puigjaner, C.;
G ꢀo mez, M.; Benet-Buchholz, J.; Vidal-Ferran, A.; Peric ꢁa s, M. A. Adv.
Synth. Catal. 2007, 349, 2265. (h) Popa, D.; Marcos, R.; Sayalero, S.;
Vidal-Ferran, A.; Peric ꢁa s, M. A. Adv. Synth. Catal. 2009, 351, 1539.
(16) The use of ammonium or quinolinium chloride as additive has
6
t
7l
been reported by Feringa and Zhou. We chose adding anhydrousHCl
(10 mol %) to generate in situ the corresponding hydrochloride of each
substrate. Greater amounts of HCl (up to stoichiometric quantity) did
not provide any improvement.

Communication
Organometallics, Vol. 29, No. 24, 2010 6631
Table 3. Hydrogenations of a Structurally Diverse Array of Heteroaromatic Substrates Mediated by the Iridium Complex Containing
a
Ligand 11c
b
c
ee (%) (confign)
d
entry
substrate
substituents on the substrate
conversn (%)
1
R = H; R = Me; X = CH
2
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
>99
98
99
>99
92
74
38
23
>99
97
91 (S)
71 (S)
85 (S)
1
R = H; R = n-Pr; X = CH
2
1
2
R = H; R = n-Bu; X = CH
1
R = H; R = i-Bu; X = CH
2
e
88 (S)
1
R = F; R = Me; X = CH
2
88 (S)
92 (S)
89 (S)
1
R = Me; R = Me; X = CH
2
1
R = MeO; R = Me; X = CH
2
9g
9h
9i
1
R = MeO; R = Et; X = CH
2
e
87 (S)
84 (R)
70 (R)
1
2
R = H; R = Ph; X = CH
f
9j
1
R = H; R = Me; X = N
2
10
a
All reactions were run with the iridium precatalyst generated in situ using a substrate/additive/ligand/Ir precursor ratio of 100/10/1.1/0.5, at room
temperature for 65 h. Conversion was determined by H NMR. Enantiomeric excess was determined by HPLC. The absolute configuration was
b
1
c
d
e
assigned by comparison with published data. Configuration was tentatively assumed to be S by analogy. Iridium complex containing ligand 11a was
f
used as the precatalyst in this case.
Scheme 4. Asymmetric Hydrogenation of Heteroaromatic
Compounds Mediated by the Iridium Complex Containing
Ligand 11c
substituted 1,2,3,4-tetrahydroquinoline 10e was obtained in
high conversion and enantioselectivity (entry 5 in Table 3),
and this compound is a key building block in the preparation
1
7
of the antibacterial agent flumequine. The iridium complex
derived from ligand 11a was preferably used for the hydro-
genation of substituted quinoxaline 9j (entry 10 in Table 3).
In conclusion, catalytic screening revealed that the iridium
complexes of chiral phosphine-phosphite ligands 11c,d are
excellent catalysts in the reduction of various aromatic
compounds that contain CdN bonds. In contrast, these
complexes failed to give high enantioselectivity in the reduc-
tion of imine 7 and quinoxaline 9j. The “lead” precatalyst of
the series (derived from ligand 11c) in combination with
catalytic amounts of anhydrous HCl exhibits excellent cata-
lytic properties in this transformation and tolerates a wide
range of substituents in the 2- and 6-positions of the quinoline
scaffold. Furthermore, we have validated our chiral catalyst
discovery strategy, which entails modifying the steric and
electronic properties of the molecular fragments or mod-
ules of a catalyst to generate higher performing analogues.
We are currently screening these ligands in new asymmetric
transformations and will report on this work in due course.
Iridium complexes derived from 11c,11d both enabled
efficient reduction of 2-methylquinoline: although slightly
higher enantioselectivities were obtained for ligand 11d in
toluene (93% ee vs 91% ee; entries 5 and 9, respectively, in
Table 2), ligand 11c gave the hydrogenated product in quan-
titative conversion. Thus, we chose 11c for studying the hydro-
genation of structurally diverse heteroaromatic substrates
(mostly quinolines; see Scheme 4). The results of these
hydrogenations are summarized in Table 3.
2
The chain length of the R group barely influenced the
catalytic activity, since enantioselectivities remained high for
2
R =Me, n-Bu, i-Bu (91%, 85%, and 88% ee, respectively;
2
entries 1, 3, and 4 in Table 3) and good for R =n-Pr (71% ee,
2
entry 2 in Table 3). Replacing the alkyl R group with a phenyl
Acknowledgment. We thank the MICINN (Grant CTQ-
2008-00950/BQU), DURSI (Grant 2009GR623), Consol-
ider Ingenio 2010 (Grant CSD2006-0003), and ICIQ
Foundation for financial support. H.F.-P. acknowledges
the “Programa Torres y Quevedo” for financial support.
substituent did not affect the catalytic activity, and the enan-
tioselectivity remained high (84% ee; entry 9 in Table 3).
1
Regardless of the electronic nature of the substituent R , sub-
strates were hydrogenated with high enantioselectivity (88-
9
2% ee; entries 5-7 in Table 3), although conversion decreased
1
dramatically in the case where R is an electron-donating
Supporting Information Available: Text, figures, tables, and a
CIF file giving experimental details, characterization data, NMR
spectra (for compounds 4-6 and 11b,d), crystallographic data
for 6, and details on catalytic experiments. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
1
group (9g,h, R =MeO; entries 7 and 8 in Table 3). Fluoro-
(17) Balint, J.; Egri, G.; Fogassy, E.; Bocskei, Z.; Simon, K.; Gajary,
A.; Friesz, A. Tetrahedron: Asymmetry 1999, 10, 1079.